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"abstract": "Life-threatening intracardiac and great vessels thrombi are rare in neonates. Recombinant tissue plasminogen activator (rTPA) is used in adults to stimulate fibrinolysis and facilitate thrombus resolution. Its use in neonates, along with heparin, remains controversial because of potential risk of serious bleeding. We aim to present our experience with the use of thrombolytic agents in seven neonates and young infants. In a retrospective study, over a period of 6 years, the medical records of neonates and young infants, who were diagnosed with intracardiac and great vessels thrombi, were reviewed. The following factors were collected: demographic data, primary diagnosis, thrombus site, risk factors, method of diagnosis, thrombolytic and/or anticoagulation agent, route, dose and duration of treatment, complications, and outcome. Six neonates and one 45-day-old infant were analyzed. Age ranged from 5 to 45 days (median age 12 days), and median weight was 2.9 kg (range 0.9-3.8 kg). The thrombi were diagnosed by echocardiography in five and by angiography in two cases. All patients had life-threatening thrombi; four were treated with rTPA (0.5 mg kg(-1) h(-1)) and heparin infusions with complete dissolution of the thrombi, within a median time of 60 h (6-72 h), and without complications. The remaining three patients (two who were premature, at 28 and 34 weeks of gestation, and the third who had a deranged coagulation profile) were treated with unfractionated heparin due to fear of bleeding. The thrombi dissolved in the premature babies (within 2 weeks and 3 months, respectively) but embolized and resulted in the death of the third infant after 2 weeks of treatment. The current case series confirmed the effectiveness and safety of intravenous rTPA infusion, at the dosages used, in neonates and young infants with life-threatening thrombi.",
"affiliations": "Department of Pediatric Cardiology, King Salman Heart Center, King Fahad Medical City, PO Box 59046, Riyadh, 11525, Kingdom of Saudi Arabia. milad.el-segaier@med.lu.se.;Department of Pediatric Cardiology, King Salman Heart Center, King Fahad Medical City, PO Box 59046, Riyadh, 11525, Kingdom of Saudi Arabia.;Department of Pediatric Hematology and Oncology, Comprehensive Cancer Center, King Fahad Medical City, Riyadh, Kingdom of Saudi Arabia.;Department of Pediatric Cardiology, King Salman Heart Center, King Fahad Medical City, PO Box 59046, Riyadh, 11525, Kingdom of Saudi Arabia.;Department of Pediatric Cardiology, King Salman Heart Center, King Fahad Medical City, PO Box 59046, Riyadh, 11525, Kingdom of Saudi Arabia.",
"authors": "El-Segaier|Milad|M|;Khan|Muhammad A|MA|;Khan|Zaheer Ullah|ZU|;Momenah|Tarek|T|;Galal|Mohammed Omar|MO|",
"chemical_list": "D005343:Fibrinolytic Agents; D011994:Recombinant Proteins; D006493:Heparin; D010959:Tissue Plasminogen Activator",
"country": "United States",
"delete": false,
"doi": "10.1007/s00246-015-1199-0",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0172-0643",
"issue": "36(8)",
"journal": "Pediatric cardiology",
"keywords": "Neonates; Thrombolysis; Thrombosis; Tissue plasminogen activator (rTPA)",
"medline_ta": "Pediatr Cardiol",
"mesh_terms": "D004452:Echocardiography; D005260:Female; D005343:Fibrinolytic Agents; D006331:Heart Diseases; D006470:Hemorrhage; D006493:Heparin; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007234:Infant, Premature; D008297:Male; D011994:Recombinant Proteins; D012189:Retrospective Studies; D013927:Thrombosis; D010959:Tissue Plasminogen Activator",
"nlm_unique_id": "8003849",
"other_id": null,
"pages": "1582-7",
"pmc": null,
"pmid": "25991571",
"pubdate": "2015-12",
"publication_types": "D016428:Journal Article",
"references": "19807732;25647465;9352973;1469167;10695499;17414572;22315277;8774496;12759624;1440499;11713447;26137799;21818649;15574174;1522647;12438051;7917699;11420316;3287158",
"title": "Recombinant Tissue Plasminogen Activator in the Treatment of Neonates with Intracardiac and Great Vessels Thrombosis.",
"title_normalized": "recombinant tissue plasminogen activator in the treatment of neonates with intracardiac and great vessels thrombosis"
} | [
{
"companynumb": "SA-FRESENIUS KABI-FK201600345",
"fulfillexpeditecriteria": "1",
"occurcountry": "SA",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "HEPARIN SODIUM"
},
"drugadditional": null... |
{
"abstract": "Zoledronic acid is recommended for patients with osteoporosis. To report a case of unilateral anterior uveitis after zoledronate infusion. An osteoporotic patient presented with pain, visual loss, hyperemia, photophobia, and watering from the left eye after zoledronate infusion. Circumcorneal injection, keratic precipitates, cells, and flare suggested anterior uveitis. Her symptoms resolved completely after 20 days of prednisolone acetate with atropine eye drops. Uveitis is a rare complication of zoledronic acid with an unclear mechanism. Proinflammatory cytokines may play a role in pathogenesis. Zoledronic acid may be associated with rare but serious inflammatory ocular adverse drug reactions.",
"affiliations": "Department of Ophthalmology, G.B. Pant Hospital, Andaman and Nicobar Islands Institute of Medical Sciences, Port Blair, Andaman and Nicobar, India.;Department of Ophthalmology, G.B. Pant Hospital, Andaman and Nicobar Islands Institute of Medical Sciences, Port Blair, Andaman and Nicobar, India.;Department of Pharmacology, G.B. Pant Hospital, Andaman and Nicobar Islands Institute of Medical Sciences, Port Blair, Andaman and Nicobar, India.",
"authors": "Gupta|Shipra|S|;Onkar|Abhishek|A|;Vashisht|Tushar|T|",
"chemical_list": "D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D007093:Imidazoles; D000077211:Zoledronic Acid",
"country": "India",
"delete": false,
"doi": "10.4103/ijo.IJO_1654_19",
"fulltext": "\n==== Front\nIndian J Ophthalmol\nIndian J Ophthalmol\nIJO\nIndian Journal of Ophthalmology\n0301-4738 1998-3689 Wolters Kluwer - Medknow India \n\n32823458\nIJO-68-2002\n10.4103/ijo.IJO_1654_19\nCase Reports\nZoledronic acid induced unilateral anterior uveitis\nGupta Shipra Onkar Abhishek Vashisht Tushar 1 Department of Ophthalmology, G.B. Pant Hospital, Andaman and Nicobar Islands Institute of Medical Sciences, Port Blair, Andaman and Nicobar, India\n1 Department of Pharmacology, G.B. Pant Hospital, Andaman and Nicobar Islands Institute of Medical Sciences, Port Blair, Andaman and Nicobar, India\n\nCorrespondence to: Dr. Abhishek Onkar, Department of Ophthalmology, Andaman and Nicobar Islands Institute of Medical Sciences, Room No. 31, G.B. Pant Hospital, Atlanta Point, Port Blair - 744 104, Andaman and Nicobar, India. E-mail: onkaratdmch@gmail.com\n9 2020 \n20 8 2020 \n68 9 2002 2003\n16 9 2019 12 12 2019 07 4 2020 Copyright: © 2020 Indian Journal of Ophthalmology2020This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.Zoledronic acid is recommended for patients with osteoporosis. To report a case of unilateral anterior uveitis after zoledronate infusion. An osteoporotic patient presented with pain, visual loss, hyperemia, photophobia, and watering from the left eye after zoledronate infusion. Circumcorneal injection, keratic precipitates, cells, and flare suggested anterior uveitis. Her symptoms resolved completely after 20 days of prednisolone acetate with atropine eye drops. Uveitis is a rare complication of zoledronic acid with an unclear mechanism. Proinflammatory cytokines may play a role in pathogenesis. Zoledronic acid may be associated with rare but serious inflammatory ocular adverse drug reactions.\n\nOsteoporosisuveitiszoledronic acid\n==== Body\nThe bisphosphonates exert multiple effects on bone mineral homeostasis, which make them useful for the treatment of hypercalcemia associated with malignancy, for Paget's disease, and for osteoporosis.[1] They owe at least part of their clinical usefulness and toxicity to their ability to retard the formation and dissolution of hydroxyapatite crystals within and outside the skeletal system. Some of the newer bisphosphonates appear to increase bone mineral density well beyond the 2-year period predicted for a drug whose effects are limited to slowing bone resorption. With the exception of the induction of a mineralization defect by higher than approved doses of etidronate and gastric and esophageal irritation by the oral bisphosphonates, these drugs have proved to be remarkably free of adverse effects when used at the doses recommended for the treatment of osteoporosis. Esophageal irritation can be minimized by taking the drug with a full glass of water and remaining upright for 30 minutes or by using the intravenous forms of these compounds. The initial infusion of zoledronate is commonly associated with several days of a flu-like syndrome that generally does not recur with subsequent infusions.[1] Zoledronic acid (Zoledronate) is the most potent bisphosphonate. It is generally well tolerated. Hypocalcemia is the most common side effect of zoledronic acid. The other frequently reported adverse events include bone pain, emesis, constipation, headache, fluctuations in serum electrolyte (magnesium, calcium, and phosphorus) levels, elevation in serum creatinine, osteonecrosis of the jaw (ONJ), and transient flu-like symptoms such as nausea, myalgia, arthralgia, and low-grade fever. In English literature, serious ocular side effects after the administration of zoledronic acid have been reported in only a few articles.[2] Here, we present a case of unilateral anterior uveitis associated with a single infusion of zoledronic acid.\n\nCase Report\nA 66-year-old woman with osteoporosis came for her first zoledronic acid infusion. Her past history was negative for any ocular disease and allergy. She had no history of any co-morbid disease. After 72 hours of the zoledronic acid injection, she developed her symptoms. She did not use any concomitant drug. She came to the eye outpatient department (OPD) 2 days post-development of her symptoms. On ocular examination, there was unilateral conjunctival suffusion. Her best-corrected visual acuity was 20/30 and 20/120 for right and left eye, respectively. Her intraocular pressure (IOP) was 12 and 7 mm Hg for right and left eye, respectively. There was circumciliary congestion in the left eye and pain during the movement of the left eyeball. Biomicroscopic anterior segment examination showed 3+ anterior segment cells with flare, the anterior chamber had fibrinous exudate, fresh keratic precipitates were observed in the whole of the cornea, but no vitreous inflammation was observed [Fig. 1]. The ocular examination of the right eye was normal. The dilated retinal examination was bilaterally normal. Laboratory evaluation including serum chemistries and complete blood count was unremarkable. A diagnosis of acute anterior uveitis secondary to zoledronic acid was made and she was treated with topical prednisolone e/d (1%) 8 times and atropine e/d 3 times after which there was a prompt resolution of all symptoms on her second follow-up visit after 7 days with only 1+ aqueous cells [Fig. 2]. She was continued on the same for five weeks on a tapering basis. She received no further doses of zoledronic acid. Her condition resolved completely in 20 days with best-corrected visual acuity of left eye recorded as 6/9.\n\nFigure 1 Day-1- OS 3+ cells on examination with circumciliary congestion\n\nFigure 2 Day-7- OS 1+ cells on examination\n\nDiscussion\nTill to date, a number of ocular side effects including conjunctivitis, ocular pain, scleritis, photophobia, episcleritis, blurred vision, and uveitis have been reported for different bisphosphonates including alendronate, pamidronate, etidronate, and risedronate.[23] Zoledronic acid is the most widely used bisphosphonate for metastatic bone disease and osteoporosis because of its relatively higher potency and short infusion time. It binds to the hydroxyapatite and accumulates in the bone, thus inhibiting osteoclast migration and maturation. Side effects of zoledronic acid are usually mild, which include a syndrome similar to flu; consisting of fever, chills, bone pain, and arthralgias. Ocular complications such as severe acute anterior uveitis, episcleritis, scleritis, and orbital inflammation requiring topical and at times even systemic steroid therapy, have been reported as a complication of pamidronate (another bisphosphonate), but only rarely with zoledronic acid.[45] Non-infectious uveitis is usually initiated by an inflammatory stimulus in which cytokines play a central role. Inflammatory ocular diseases including uveitis are thought to have an imbalance among proinflammatory cytokines such as tumor necrosis factor-a (TNF-a), interferon-c (IFN-c), interleukin-1 (IL-1), and interleukin-6 (IL-6), which regulate the immune system to maintain the inflammatory response.[5] Uveitis has also been characterized by a CD4(+) T-helper 1 cells-mediated inflammation with elevations in IL-2, IFN-a, and lymphotoxin, and has a distinctive cytokine pattern of IL-6, IL-8, IL-13, TNF-a, and IL-2 in aqueous humor.[5] Four cases of open unilateral and bilateral anterior uveitis post zoledronic acid infusion have been reported.[3678] It has been suggested that secretions of bisphosphonates into tears can cause conjunctivitis and other ocular inflammations. Bisphosphonates also secrete interleukins resulting in inflammatory responses in the eye.\n\nConclusion\nThe close relationship between zoledronic acid infusion and onset of ocular signs and symptoms in our case is in accordance with bisphosphonates-related ocular inflammation. On withdrawing the bisphosphonates and starting steroids therapy on time gave a positive result. This supports drug-related etiology for this ocular process. Patient receiving bisphosphonate infusion should be explained the need to visit ophthalmologists post infusion related any eye symptom. To the best of our knowledge, this is the first case report of zoledronate-induced unilateral uveitis being reported from the Andamans and India.\n\nDeclaration of patient consent\nThe authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.\n\nFinancial support and sponsorship\nNil.\n\nConflicts of interest\nThere are no conflicts of interest.\n==== Refs\n1 Lewiecki EM Bisphosphonates for the treatment of osteoporosis: Insights for clinicians Ther Adv Chronic Dis 2010 1 115 28 23251734 \n2 Fraunfelder FW Fraunfelder FT Bisphosphonates and ocular inflammation N Engl J Med 2003 348 1187 8 12646685 \n3 Kilickap S Ozdamar Y Altundag MK Dizdar O A case report: Zoledronic acid-induced anterior uveitis Med Oncol 2008 25 238 40 18488162 \n4 Ooi KG Galatowicz G Calder VL Lightman SL Cytokines and chemokines in uveitis: Is there a correlation with clinical phenotype? Clin Med Res 2006 4 294 309 17210978 \n5 Curnow SJ Murray PI Inflammatory mediators of uveitis: Cytokines and chemokines Curr Opin Ophthalmol 2006 17 532 7 17065921 \n6 Durnian JM Olujohungbe A Kyle G Bilateral acute uveitis and conjunctivitis after zoledronic acid therapy Eye 2005 19 221 2 15258605 \n7 El Saghir NS Otrock ZK Bleik JH Unilateral anterior uveitis complicating zoledronic acid therapy in breast cancer BMC Cancer 2005 5 156 16332258 \n8 Rathnam KK Sagar TG Cyriac S Acute uveitis following zoledronic acid infusion Oman J Ophthalmol 2009 2 102 3\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "0301-4738",
"issue": "68(9)",
"journal": "Indian journal of ophthalmology",
"keywords": "Osteoporosis; uveitis; zoledronic acid",
"medline_ta": "Indian J Ophthalmol",
"mesh_terms": "D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D005260:Female; D006801:Humans; D007093:Imidazoles; D014606:Uveitis, Anterior; D000077211:Zoledronic Acid",
"nlm_unique_id": "0405376",
"other_id": null,
"pages": "2002-2003",
"pmc": null,
"pmid": "32823458",
"pubdate": "2020-09",
"publication_types": "D002363:Case Reports",
"references": "15258605;17065921;16332258;23251734;17210978;20671842;18488162;12646685",
"title": "Zoledronic acid induced unilateral anterior uveitis.",
"title_normalized": "zoledronic acid induced unilateral anterior uveitis"
} | [
{
"companynumb": "IN-DRREDDYS-USA/IND/21/0136415",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ZOLEDRONIC ACID"
},
"drugadditional": "1... |
{
"abstract": "Cases reports and small series of patients with C3 glomerulopathy have reported variable efficacy of eculizumab.\n\n\n\nCase series of C3 glomerulopathy.\n\n\n\nPediatric and adult patients with C3 glomerulopathy treated with eculizumab between 2010 and 2016 were identified through the C3 glomerulopathy French registry database, and a questionnaire was sent to participating French pediatric and adult nephrology centers, as well as one pediatric referral center in Québec, Canada.\n\n\n\nGlobal or partial clinical renal response.\n\n\n\nEvolution of serum creatinine and proteinuria values.\n\n\n\n26 patients (13 children/adolescents) were included. 22 (85%) patients had received steroids, plasma exchange, or immunosuppressive therapy before eculizumab, and 3 of them had rapid progression of their kidney disease despite treatment. At the initiation of eculizumab therapy, 11 (42%) patients had chronic kidney disease, 7 (27%) had rapidly progressive disease, and 3 (12%) required dialysis. After eculizumab treatment (median duration, 14 months), 6 (23%) patients had a global clinical response; 6 (23%), a partial clinical response; and 14 (54%), no response. Compared with those who had a partial clinical or no response, patients who had a global clinical response had lower estimated glomerular filtration rates, a more rapidly progressive course, and more extracapillary proliferation on kidney biopsy. Age, extent of renal fibrosis, frequency of nephrotic syndrome, low serum C3 and C3 nephritic factor and elevated soluble C5b-9 concentrations, or complement gene variants did not differ between responders and nonresponders.\n\n\n\nRetrospective design without a control group, relatively small number of cases, inclusion of pediatric and adult cases.\n\n\n\nEculizumab appears to be a potential treatment for patients with crescentic rapidly progressive C3 glomerulopathy. Its benefit in patients with non-rapidly progressing forms seems to be limited.",
"affiliations": "Department of Nephrology, Centre Hospitalier Universitaire de Montpellier, Montpellier, France.;Division of Nephrology, Department of Pediatrics, Centre Hospitalier Universitaire Sainte Justine and University of Montreal, Montréal, Québec, Canada.;Department of Nephrology, Hôpital Huriez, Centre Hospitalier Universitaire de Lille, Lille.;Department of Pediatric Nephrology, Hospices Civils de Lyon, Bron.;Department of Nephrology, Centre Hospitalier Universitaire de Bordeaux, Bordeaux.;Department of Pediatric Nephrology, Centre Hospitalier Universitaire Robert Debré.;Department of Nephrology, Centre Hospitalier Universitaire Bichat, Paris.;Department of Pediatric Nephrology, Centre Hospitalier Universitaire de Toulouse, Toulouse.;Department of Nephrology, Hôpital Foch, Suresnes.;Department of Pediatric Nephrology, Centre Hospitalier Universitaire de la Timone, Marseille.;Department of Nephrology, Centre hospitalier William Morey, Chalon sur Saône.;Department of Nephrology, Centre Hospitalier Universitaire Necker, Paris.;Department of Nephrology, Hôpitaux du Léman, Léman.;Department of Nephrology, Centre Hospitalier Universitaire Henri Mondor, Créteil.;Department of Pediatric Nephrology, Centre Hospitalier Universitaire Robert Debré.;Department of Immunology, Centre Hospitalier Universitaire Hôpital Européen Georges Pompidou, Paris.;Department of Nephrology and Immunology, Centre Hospitalier Universitaire de Nantes, Nantes, France. Electronic address: fadi.fakhouri@univ-nantes.fr.",
"authors": "Le Quintrec|Moglie|M|;Lapeyraque|Anne-Laure|AL|;Lionet|Arnaud|A|;Sellier-Leclerc|Anne-Laure|AL|;Delmas|Yahsou|Y|;Baudouin|Véronique|V|;Daugas|Eric|E|;Decramer|Stéphane|S|;Tricot|Leila|L|;Cailliez|Mathilde|M|;Dubot|Philippe|P|;Servais|Aude|A|;Mourey-Epron|Catherine|C|;Pourcine|Franck|F|;Loirat|Chantal|C|;Frémeaux-Bacchi|Véronique|V|;Fakhouri|Fadi|F|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D003176:Complement C3; C481642:eculizumab",
"country": "United States",
"delete": false,
"doi": "10.1053/j.ajkd.2017.11.019",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0272-6386",
"issue": "72(1)",
"journal": "American journal of kidney diseases : the official journal of the National Kidney Foundation",
"keywords": "C3 glomerulopathy (C3G); C3 nephritic factor (C3Nef); anti-C5 monoclonal antibody; case series; clinical response; complement; eculizumab; kidney biopsy; membranoproliferative glomerulonephritis (MPGN); pediatric; proteinuria; rapidly progressive glomerulonephritis",
"medline_ta": "Am J Kidney Dis",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized; D002648:Child; D003176:Complement C3; D005260:Female; D005500:Follow-Up Studies; D015432:Glomerulonephritis, Membranoproliferative; D006801:Humans; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "8110075",
"other_id": null,
"pages": "84-92",
"pmc": null,
"pmid": "29429752",
"pubdate": "2018-07",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Patterns of Clinical Response to Eculizumab in Patients With C3 Glomerulopathy.",
"title_normalized": "patterns of clinical response to eculizumab in patients with c3 glomerulopathy"
} | [
{
"companynumb": "FR-ROCHE-2157569",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RITUXIMAB"
},
"drugadditional": "3",
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{
"abstract": "Daptomycin, a cyclic lipopeptide antibiotic, and 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) are commonly administered in the inpatient setting and are associated with creatine phosphokinase (CPK) elevations, myalgias, and muscle weakness. Safety data for coadministration of daptomycin with statins are limited. To determine the safety of coadministration of daptomycin with statin therapy, a multicenter, retrospective, observational study was performed at 13 institutions in the Southeastern United States. Forty-nine adult patients receiving statins concurrently with daptomycin were compared with 171 patients receiving daptomycin without statin therapy. Detailed information, including treatment indication and duration, infecting pathogen, baseline and subsequent CPK levels, and presence of myalgias or muscle complaints, was collected. Myalgias were noted in 3/49 (6.1%) patients receiving combination therapy compared with 5/171 (2.9%) of patients receiving daptomycin alone (P = 0.38). CPK elevations of >1,000 U/liter occurred in 5/49 (10.2%) patients receiving combination therapy compared to 9/171 (5.3%) patients receiving daptomycin alone (P = 0.32). Two of five patients experiencing CPK elevations of >1,000 U/liter in the combination group had symptoms of myopathy. Three patients (6.1%) discontinued therapy due to CPK elevations with concurrent myalgias in the combination group versus 6 patients (3.5%) in the daptomycin-alone group (P = 0.42). CPK levels and myalgias reversed upon discontinuation of daptomycin therapy. Overall musculoskeletal toxicity was numerically higher in the combination group but this result was not statistically significant. Further prospective study is warranted in a larger population.",
"affiliations": "Department of Clinical Pharmacy, Dwight D. Eisenhower Army Medical Center, Fort Gordon, Georgia, USA Department of Clinical Pharmacy & Outcomes Sciences, South Carolina College of Pharmacy at the University of South Carolina, Columbia, South Carolina, USA chris.bland@us.army.mil.;Department of Clinical Pharmacy & Outcomes Sciences, South Carolina College of Pharmacy at the University of South Carolina, Columbia, South Carolina, USA.;Department of Clinical Pharmacy & Outcomes Sciences, South Carolina College of Pharmacy at the University of South Carolina, Columbia, South Carolina, USA.;Department of Clinical Pharmacy & Outcomes Sciences, South Carolina College of Pharmacy at the University of South Carolina, Columbia, South Carolina, USA.;Department of Internal Medicine, Vidant Medical Center, Greenville, North Carolina, USA Campbell University School of Pharmacy, Buies Creek, North Carolina, USA.",
"authors": "Bland|Christopher M|CM|;Bookstaver|P Brandon|PB|;Lu|Z Kevin|ZK|;Dunn|Brianne L|BL|;Rumley|Kathey Fulton|KF|;|||",
"chemical_list": "D000900:Anti-Bacterial Agents; D004338:Drug Combinations; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D003402:Creatine Kinase; D017576:Daptomycin",
"country": "United States",
"delete": false,
"doi": "10.1128/AAC.02910-14",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0066-4804",
"issue": "58(10)",
"journal": "Antimicrobial agents and chemotherapy",
"keywords": null,
"medline_ta": "Antimicrob Agents Chemother",
"mesh_terms": "D000368:Aged; D000900:Anti-Bacterial Agents; D003402:Creatine Kinase; D017576:Daptomycin; D004338:Drug Combinations; D005260:Female; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008297:Male; D008875:Middle Aged; D009135:Muscular Diseases; D009141:Musculoskeletal System; D063806:Myalgia; D012189:Retrospective Studies",
"nlm_unique_id": "0315061",
"other_id": null,
"pages": "5726-31",
"pmc": null,
"pmid": "25022580",
"pubdate": "2014-10",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "15337732;21217178;16283159;19500039;24321853;17548489;22160888;23712701;15601805;11847951;16914701;15069169;16892458;21067805;21923436;11020247;19346518;21958456;19584384",
"title": "Musculoskeletal safety outcomes of patients receiving daptomycin with HMG-CoA reductase inhibitors.",
"title_normalized": "musculoskeletal safety outcomes of patients receiving daptomycin with hmg coa reductase inhibitors"
} | [
{
"companynumb": "US-DRREDDYS-USA/USA/14/0043943",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "DAPTOMYCIN"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nThe authors evaluated the ability of a fibrin sealant (TISSEEL™: Baxter Healthcare Corp, Deerfield, IL, USA) to reduce the incidence of post-operative seroma following abdominal wall hernia repair.\n\n\nMETHODS\nWe performed a 4-year retrospective review of patients undergoing abdominal wall hernia repair, with and without TISSEEL, by a single surgeon (FEE) at The Johns Hopkins Hospital. Demographics, surgical risk factors, operative data and 30-day outcomes, including wound complications and related interventions, were compared. The quantity and cost of Tisseel per case was reviewed.\n\n\nRESULTS\nA total of 250 patients were evaluated: 127 in the TISSEEL group and 123 in the non-TISSEEL control group. The average age for both groups was 56.6 years (P = 0.97). The majority of patients were female (TISSEEL 52.8%, non-TISSEEL 56.1%, P = 0.59) and ASA Class III (TISSEEL 56.7%, non-TISSEEL 58.5%, P = 0.40). There was no difference in the average defect size for both groups (TISSEEL 217 ± 187.6 cm(2), non-TISSEEL 161.3 ± 141.5 cm(2), P = 0.36). Surgical site occurrences occurred in 18.1% of the TISSEEL and 13% of the non-TISSEEL group (P = 0.27). There was a trend towards an increased incidence of seroma in the TISSEEL group (TISSEEL 11%, non-TISSEEL 4.9%, P = 0.07). A total of $124,472.50 was spent on TISSEEL, at an average cost of $995.78 per case.\n\n\nCONCLUSIONS\nIn the largest study to date, TISSEEL™ application offered no advantage for the reduction of post-operative seroma formation following complex abdominal hernia repair. Moreover, the use of this sealant was associated with significant costs.",
"affiliations": "Department of Surgery, The Johns Hopkins Hospital, Johns Hopkins University, School of Medicine, 600 N. Wolfe Street, Blalock 618, Baltimore, MD, 21287, USA. sazoury1@jhmi.edu.;Department of Plastic and Reconstructive Surgery, The Johns Hopkins Hospital, Baltimore, MD, USA.;Department of Surgery, The Johns Hopkins Hospital, Johns Hopkins University, School of Medicine, 600 N. Wolfe Street, Blalock 618, Baltimore, MD, 21287, USA.;Department of Surgery, The Johns Hopkins Hospital, Johns Hopkins University, School of Medicine, 600 N. Wolfe Street, Blalock 618, Baltimore, MD, 21287, USA.;Department of Surgery, The Johns Hopkins Hospital, Johns Hopkins University, School of Medicine, 600 N. Wolfe Street, Blalock 618, Baltimore, MD, 21287, USA.;Department of Surgery, The Johns Hopkins Hospital, Johns Hopkins University, School of Medicine, 600 N. Wolfe Street, Blalock 618, Baltimore, MD, 21287, USA.;School of Medicine, Johns Hopkins University, Baltimore, MD, USA.;Department of Plastic and Reconstructive Surgery, The Johns Hopkins Hospital, Baltimore, MD, USA.;Department of Surgery, The Johns Hopkins Hospital, Johns Hopkins University, School of Medicine, 600 N. Wolfe Street, Blalock 618, Baltimore, MD, 21287, USA.;Department of Surgery, The Johns Hopkins Hospital, Johns Hopkins University, School of Medicine, 600 N. Wolfe Street, Blalock 618, Baltimore, MD, 21287, USA.;Department of Surgery, The Johns Hopkins Hospital, Johns Hopkins University, School of Medicine, 600 N. Wolfe Street, Blalock 618, Baltimore, MD, 21287, USA. feckhau2@jhmi.edu.",
"authors": "Azoury|S C|SC|http://orcid.org/0000-0002-2263-4149;Rodriguez-Unda|N|N|;Soares|K C|KC|;Hicks|C W|CW|;Baltodano|P A|PA|;Poruk|K E|KE|;Hu|Q L|QL|;Cooney|C M|CM|;Cornell|P|P|;Burce|K|K|;Eckhauser|F E|FE|",
"chemical_list": "D015718:Fibrin Tissue Adhesive",
"country": "France",
"delete": false,
"doi": "10.1007/s10029-015-1403-4",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1248-9204",
"issue": "19(6)",
"journal": "Hernia : the journal of hernias and abdominal wall surgery",
"keywords": "Abdominal wall; Fibrin sealant; Hernia; Seroma; TISSEEL",
"medline_ta": "Hernia",
"mesh_terms": "D034861:Abdominal Wall; D000328:Adult; D000368:Aged; D003365:Costs and Cost Analysis; D005260:Female; D015718:Fibrin Tissue Adhesive; D006555:Hernia, Ventral; D059685:Herniorrhaphy; D006801:Humans; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D049291:Seroma; D014945:Wound Healing",
"nlm_unique_id": "9715168",
"other_id": null,
"pages": "935-42",
"pmc": null,
"pmid": "26152522",
"pubdate": "2015-12",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "17805151;9520825;22527929;24981370;1332552;21858593;11759799;12056469;17431557;23712288;23265118;11405092;7539943;18026789;25194761;23552769;21452012;23494512;24962857;23644773;19561486;16804848;22999328;21944353",
"title": "The effect of TISSEEL fibrin sealant on seroma formation following complex abdominal wall hernia repair: a single institutional review and derived cost analysis.",
"title_normalized": "the effect of tisseel fibrin sealant on seroma formation following complex abdominal wall hernia repair a single institutional review and derived cost analysis"
} | [
{
"companynumb": "US-BAXTER-2015BAX041600",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "FIBRINOGEN HUMAN\\THROMBIN HUMAN"
},
"drugaddi... |
{
"abstract": "Canagliflozin is a novel drug for diabetes mellitus with the mechanisms of inducing glucosuria through inhibition of the sodium-glucose cotransporter 2 in the kidney independent of insulin activity. We are reporting euglycemic ketoacidosis with severe life-threatening metabolic acidosis. The 2 patients described had type 2 diabetes mellitus and were in a state of relative starvation after abdominal surgery. The first patient had been given an oral diet but was restricted with regard to calorie and sugar intake. The second patient had been nil per os since the operation.",
"affiliations": "From the Department of Anesthesiology and Critical Care, University of Southern California, Los Angeles, California.",
"authors": "Darwish|Ahmed M|AM|",
"chemical_list": "D007004:Hypoglycemic Agents; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D000068896:Canagliflozin; D008687:Metformin",
"country": "United States",
"delete": false,
"doi": "10.1213/XAA.0000000000000888",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2575-3126",
"issue": "12(7)",
"journal": "A&A practice",
"keywords": null,
"medline_ta": "A A Pract",
"mesh_terms": "D000138:Acidosis; D000328:Adult; D000068896:Canagliflozin; D003924:Diabetes Mellitus, Type 2; D004359:Drug Therapy, Combination; D006801:Humans; D007004:Hypoglycemic Agents; D007662:Ketosis; D008297:Male; D008687:Metformin; D008875:Middle Aged; D011183:Postoperative Complications; D000077203:Sodium-Glucose Transporter 2 Inhibitors",
"nlm_unique_id": "101714112",
"other_id": null,
"pages": "221-222",
"pmc": null,
"pmid": "30234515",
"pubdate": "2019-04-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Metabolic Acidosis in Postsurgical Patient on Canagliflozin and Metformin: A Case Report.",
"title_normalized": "metabolic acidosis in postsurgical patient on canagliflozin and metformin a case report"
} | [
{
"companynumb": "US-JNJFOC-20190443088",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CANAGLIFLOZIN\\METFORMIN HYDROCHLORIDE"
},
"druga... |
{
"abstract": "The histopathologic presentation of varicella-zoster virus (VZV) infection of the central nervous system is varied and is not well understood. Here we report a case of VZV encephalomyelitis with prominent demyelinating pathology in a patient with a history of follicular lymphoma treated with allogeneic stem cell transplantation. The patient presented with waxing and waning bilateral limb weakness and mental status changes. MRI showed leptomeningeal, peripheral spinal cord and periventricular cerebral white matter lesions in the brain, and polymerase chain reaction on cerebrospinal fluid detected VZV DNA. The patient expired from developing atrial fibrillation that rapidly progressed to ventricular fibrillation 10 days after admission to our hospital. Autopsy revealed macrophage-rich areas of demyelination in the spinal cord and cerebrum with relative preservation of axons associated with inclusion bodies and positive immunostaining for VZV. This case represents a rare example of VZV encephalomyelitis presenting with a predominantly demyelinating, \"multiple sclerosis-like\" pathology. The clinical and histopathologic findings and relevant literature are presented and discussed.",
"affiliations": "Departments of Pathology.;Neurology.;Neurology.;Departments of Pathology.;Neurology.;Departments of Pathology.",
"authors": "Berth|Sarah|S|;Carbunar|Olimpia|O|;Yang|Ning Sarah|NS|;Fredericks|Brian|B|;Lipton|Howard L|HL|;Valyi-Nagy|Tibor|T|http://orcid.org/0000-0003-1212-584X",
"chemical_list": null,
"country": "Australia",
"delete": false,
"doi": "10.1111/neup.12224",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0919-6544",
"issue": "35(6)",
"journal": "Neuropathology : official journal of the Japanese Society of Neuropathology",
"keywords": "demyelination; encephalomyelitis; histopathology; varicella-zoster virus",
"medline_ta": "Neuropathology",
"mesh_terms": "D003711:Demyelinating Diseases; D020804:Encephalitis, Varicella Zoster; D017809:Fatal Outcome; D006801:Humans; D016867:Immunocompromised Host; D008224:Lymphoma, Follicular; D008297:Male; D008875:Middle Aged; D033581:Stem Cell Transplantation",
"nlm_unique_id": "9606526",
"other_id": null,
"pages": "587-91",
"pmc": null,
"pmid": "26114555",
"pubdate": "2015-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Varicella-zoster virus encephalomyelitis with a prominent demyelinating component.",
"title_normalized": "varicella zoster virus encephalomyelitis with a prominent demyelinating component"
} | [
{
"companynumb": "US-TEVA-629570USA",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ACYCLOVIR"
},
"drugadditional": null,
"drug... |
{
"abstract": "OBJECTIVE\nTo report the effects of twice-daily difluprednate in a child with pars planitis (PP).\n\n\nMETHODS\nCase report.\n\n\nRESULTS\nPP was controlled with topical difluprednate for 1 year. Then an atypical pattern of steroid response--delayed, relatively sudden onset of recalcitrant ocular hypertension (OHT)--and posterior subcapsular cataract (PSC) formation necessitated alternative treatment.\n\n\nCONCLUSIONS\nAlthough not a standard treatment, in select cases of PP topical difluprednate therapy could be a useful short-term treatment option while alternative treatments are considered or immunosuppressive agents build to therapeutic levels. Ophthalmologists must be aware of the potential for delayed onset of serious complications when using difluprednate.",
"affiliations": "Ohio State University, Havener Eye Institute, 915 Olentangy River Road, Columbus, OH 43212, USA. paul.kurz@osumc.edu",
"authors": "Kurz|Paul A|PA|;Chheda|Lena V|LV|;Kurz|Daryl E|DE|",
"chemical_list": "D004655:Emulsions; D005938:Glucocorticoids; D005477:Fluprednisolone; C015808:difluprednate; D011241:Prednisone",
"country": "England",
"delete": false,
"doi": "10.3109/09273948.2010.512993",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0927-3948",
"issue": "19(1)",
"journal": "Ocular immunology and inflammation",
"keywords": null,
"medline_ta": "Ocul Immunol Inflamm",
"mesh_terms": "D000287:Administration, Topical; D002386:Cataract; D002648:Child; D004655:Emulsions; D005477:Fluprednisolone; D005938:Glucocorticoids; D006801:Humans; D008297:Male; D009798:Ocular Hypertension; D015868:Pars Planitis; D011241:Prednisone; D007319:Sleep Initiation and Maintenance Disorders; D016896:Treatment Outcome; D014792:Visual Acuity; D015430:Weight Gain",
"nlm_unique_id": "9312169",
"other_id": null,
"pages": "84-5",
"pmc": null,
"pmid": "21034305",
"pubdate": "2011-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Effects of twice-daily topical difluprednate 0.05% emulsion in a child with pars planitis.",
"title_normalized": "effects of twice daily topical difluprednate 0 05 emulsion in a child with pars planitis"
} | [
{
"companynumb": "ALCN2010US004379",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "DIFLUPREDNATE"
},
"drugadditional": "1",
"dr... |
{
"abstract": "Fungal infections have a high incidence in patients receiving peritoneal dialysis. (1)
Peritoneal dialysis is often complicated by peritonitis which has only minimally mycotic etiology, but nonetheless it is associated with 15-45% mortality (8).
The opportunistic pathogens such as Candida can cause infection in immunocompromised conditions. Even the Acinetobacter tends to infect immunocompromised individuals and it has the same risk factors for infection as Candida: immunosuppression, malignancy, HIV positivity and all the other conditions of immunosuppression, central venous catheterization, mechanical ventilation and prolonged antibiotic therapy. The sepsis by Acinetobacter predicts a negative prognosis with the mortality rate between 20 to 60% (12), especially in cases of isolation of multi-resistant germs.
We present a case report of a CKD patient undergoing peritoneal dialysis therapy who was hospitalized for acute pancreatitis, later complicated by the development of pancreatic pseudocysts, C. albicans peritonitis with hematologic spread of the fungus, superimposed Acinetobacter baumannii sepsis and pneumonia. She has been subjected to percutaneous drainage of pseudocysts, to switch from peritoneal dialysis to hemodialysis, to various evacuative thoracentesis, and to polymicrobial therapy (meropenem, teicoplanina, tigeciclina, linezolid, colimicina, fluconazolo, etc.) that allowed the resolution of sepsis. The peculiarity of this case is represented by the numerous morbidity that the patient developed simultaneously, with the genesis of a complex clinical picture, by the combination of infections due to Candida albicans and Acinetobacter baumannii. Successful treatment strategies allowed to fight and cure a medical condition associated with a high mortality rate.",
"affiliations": null,
"authors": "Rapisarda|Francesco|F|;Aliotta|Roberta|R|;Pocorobba|Barbara|B|;Portale|Grazia|G|;Ferrario|Silvia|S|;Zanoli|Luca|L|;Fatuzzo|Pasquale|P|",
"chemical_list": null,
"country": "Italy",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0393-5590",
"issue": "32(6)",
"journal": "Giornale italiano di nefrologia : organo ufficiale della Societa italiana di nefrologia",
"keywords": null,
"medline_ta": "G Ital Nefrol",
"mesh_terms": "D000151:Acinetobacter Infections; D040981:Acinetobacter baumannii; D002177:Candidiasis; D005260:Female; D006801:Humans; D008875:Middle Aged; D010530:Peritoneal Dialysis; D010538:Peritonitis; D011379:Prognosis; D018805:Sepsis",
"nlm_unique_id": "9426434",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "26845211",
"pubdate": "2015",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Candida peritonitis and sepsis due to Acinetobacter baumannii in peritoneal dialysis: an association with prognosis not always unfavourable.",
"title_normalized": "candida peritonitis and sepsis due to acinetobacter baumannii in peritoneal dialysis an association with prognosis not always unfavourable"
} | [
{
"companynumb": "IT-STRIDES ARCOLAB LIMITED-2017SP002971",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional... |
{
"abstract": "BACKGROUND\nOpioid-induced respiratory depression (OIRD) is a life-threatening complication of opioid therapy in children. Naloxone administration triggered by OIRD has been used to monitor safety of opioid therapy in adults. We used this trigger as a quality measure of opioid safety in hospitalized children to identify risk predictors of OIRD.\n\n\nMETHODS\nWe retrospectively reviewed medical records of 38 patients identified from the hospital risk management database as requiring naloxone for critical respiratory events between January 2010 and June 2012 for demographics, comorbidities, surgery, naloxone event details, and outcomes. These data were compared with baseline prevalence in contemporary patients followed by pain service, who did not receive naloxone, to calculate unadjusted odds ratios. Thematic classification of preventable events was undertaken based on analysis of each event.\n\n\nRESULTS\nThe incidence of naloxone use among hospital inpatients, who received opioids at-least once, was 0.06% compared with 0.23% for patients on the pain service. A majority of naloxone events occurred in postoperative patients (n = 27/38, 71.1%) within the first 24 hours of surgery (n = 20/27, 75.1%) and in the critical care unit (50%). Patients undergoing airway surgeries had higher risk for OIRD (P = 0.01). Patient risk factors for naloxone use included age <1 year (P < 0.001), obstructive sleep apnea (P < 0.001), obesity (P = 0.019), being underweight (P < 0.0001), prematurity (P < 0.001), and developmental delay (P < 0.001). Majority of events (87%) were found to be preventable, which were classified into six main themes based on type of event.\n\n\nCONCLUSIONS\nOIRD is an important, albeit mostly preventable, complication of opioid therapy in children. Naloxone use can be used as a measure to track opioid safety in children, identify contributing factors, and formulate preventive strategies to reduce the risk for OIRD.",
"affiliations": "Department of Anesthesia and Pediatrics, University of Cincinnati, Cincinnati, Ohio, USA.",
"authors": "Chidambaran|Vidya|V|;Olbrecht|Vanessa|V|;Hossain|Monir|M|;Sadhasivam|Senthilkumar|S|;Rose|John|J|;Meyer|Mark J|MJ|",
"chemical_list": "D000701:Analgesics, Opioid; D009292:Narcotic Antagonists; D009270:Naloxone",
"country": "England",
"delete": false,
"doi": "10.1111/pme.12575",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1526-2375",
"issue": "15(12)",
"journal": "Pain medicine (Malden, Mass.)",
"keywords": "Naloxone; Opioid Safety; Opioid-Induced Respiratory Depression; Pediatric; Quality Measure; Risk Factors",
"medline_ta": "Pain Med",
"mesh_terms": "D000293:Adolescent; D000701:Analgesics, Opioid; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D009270:Naloxone; D009292:Narcotic Antagonists; D015995:Prevalence; D012131:Respiratory Insufficiency; D012189:Retrospective Studies; D012306:Risk",
"nlm_unique_id": "100894201",
"other_id": null,
"pages": "2139-49",
"pmc": null,
"pmid": "25319840",
"pubdate": "2014-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Risk predictors of opioid-induced critical respiratory events in children: naloxone use as a quality measure of opioid safety.",
"title_normalized": "risk predictors of opioid induced critical respiratory events in children naloxone use as a quality measure of opioid safety"
} | [
{
"companynumb": "US-MYLANLABS-2015M1004878",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHADONE HYDROCHLORIDE"
},
"drugadditional":... |
{
"abstract": "This case describes a patient with pericardial effusion as a phenomenon of the drug-induced lupus erythematosus (DILE) syndrome due to hydralazine. The relevance of this case report lies in the fact that although hydralazine has been a known causative agent of DILE, its presentation may involve a negative anti-nuclear antibody (ANA) study. Pericardial effusion is a documented adverse effect as a result of hydralazine use. It is typically common to screen for DILE with the serum ANA test prior to proceeding to more costly and specific tests (i.e., anti-histone antibody). As per our literature review, this is the second case of hydralazine causing DILE with a negative ANA. As in our case, although the screening serum ANA is the initial next best step for suspicion of DILE by hydralazine, it is important to consider the diagnosis without ANA positivity.",
"affiliations": "Department of Internal Medicine, Maricopa Integrated Health System, Phoenix, AZ, USA.;Department of Cardiology, Maricopa Integrated Health System, Phoenix, AZ, USA.",
"authors": "Zeitjian|Vicken|V|0000-0002-1125-5856;Mehdizadeh|Azar|A|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1155/2017/3521541",
"fulltext": "\n==== Front\nCase Rep MedCase Rep MedCRIMCase Reports in Medicine1687-96271687-9635Hindawi 10.1155/2017/3521541Case ReportANA-Negative Hydralazine-Induced Pericardial Effusion http://orcid.org/0000-0002-1125-5856Zeitjian Vicken vicken.zeitjian@mihs.org\n1\nMehdizadeh Azar \n2\n\n1Department of Internal Medicine, Maricopa Integrated Health System, Phoenix, AZ, USA\n2Department of Cardiology, Maricopa Integrated Health System, Phoenix, AZ, USAAcademic Editor: Walter Zidek\n\n2017 17 12 2017 2017 352154126 9 2017 19 11 2017 Copyright © 2017 Vicken Zeitjian and Azar Mehdizadeh.2017This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.This case describes a patient with pericardial effusion as a phenomenon of the drug-induced lupus erythematosus (DILE) syndrome due to hydralazine. The relevance of this case report lies in the fact that although hydralazine has been a known causative agent of DILE, its presentation may involve a negative anti-nuclear antibody (ANA) study. Pericardial effusion is a documented adverse effect as a result of hydralazine use. It is typically common to screen for DILE with the serum ANA test prior to proceeding to more costly and specific tests (i.e., anti-histone antibody). As per our literature review, this is the second case of hydralazine causing DILE with a negative ANA. As in our case, although the screening serum ANA is the initial next best step for suspicion of DILE by hydralazine, it is important to consider the diagnosis without ANA positivity.\n==== Body\n1. Introduction\nHydralazine is a medication known to cause DILE, and case reports have revealed this since its first use in the United States in 1953. The DILE syndrome caused by hydralazine occurs in 5–10% of patients and commonly includes arthralgia, myalgia, fever, and serositis [1]. One of its more infrequent presentations reported in medical literature is pericardial effusion reported at <5% [2]. As per our literature review, this is the second case of hydralazine causing DILE with a negative ANA [3].\n\n2. Case Report\nA 21-year-old man with a history of ESRD secondary to FSGS, placement of a temporary right subclavian catheter, and renovascular hypertension presented to the emergency department with fevers and myalgia. The patient had been taking several blood pressure medications including hydralazine at a dose of 50 mg TID. Hydralazine was initiated 2 months prior to presentation. Review of systems was positive for fevers, chills, night sweats, myalgia, and pleuritic chest pain. He denied chest pain at rest, shortness of breath, nausea, vomiting, and diarrhea.\n\nInitial vitals were remarkable for a temperature of 38.9°C, heart rate of 108, and blood pressure of 132/80. Physical exam was notable for a thin male with pleuritic chest pain on deep inspiration, slightly diminished heart sounds, no jugular venous distention, and a left brachiocephalic fistula with a palpable thrill.\n\nAn electrocardiogram (EKG) was done which showed low voltage and was otherwise insignificant. A chest X-ray (CXR) showed an enlarged cardiac silhouette. Initial labs indicated anemia of chronic disease and ESRD but were otherwise unremarkable. Blood cultures were negative. A noncontrast CT chest was done which showed a moderate-sized pericardial effusion (Figures 1 and 2). An echocardiogram was done which identified a moderate-sized pericardial effusion without tamponade, no intracardiac mass, and presence of pericardial thickening (Figures 3 and 4). The pericardial effusion was suspected to be related to ESRD; however, 3 sessions of dialysis did not resolve the effusion.\n\nCareful review of the medication list also brought forward the possibility of hydralazine-induced pericardial effusion as a presentation of DILE. ANA was ordered and found to be negative. Other etiologies of pericardial effusion were explored including pericarditis, autoimmune disease, malignancy, and myxedema; however, history and diagnostic and laboratory evaluations were not consistent with any of these disease processes.\n\nGiven the acuity of this disease process, there was still strong suspicion for drug-induced pericardial effusion. Anti-histone antibodies were ordered and were found to be positive. The diagnosis of DILE due to hydralazine causing pericardial effusion was made. The patient underwent pericardial drainage and pericardiectomy. Pericardial fluid cell count was significant for red blood cells of >700 k, as expected in this disease [2]. Pathologic analysis of the pericardium was consistent with fibrinous pericarditis. Cytology and pathology were negative for malignant cells. Infectious etiologies were ruled out, and prednisone 20 mg daily was started. Hydralazine was discontinued indefinitely, and patient's symptoms completely resolved.\n\n3. Discussion\nThis case illustrates the importance of clinical suspicion as opposed to serologic markers as an approach to diagnosis. Most cases describing a DILE syndrome by hydralazine entail a positive ANA, and while negative ANA has been reported, it is a rare manifestation. In our case, although the screening serum ANA is the initial next best step for suspicion of hydralazine-induced lupus, it is important to consider the diagnosis without ANA positivity. Tests such as anti-histone antibody should be considered in the presence of strong clinical suspicion. Anti-chromatin (histone DNA macromolecule) antibodies have also been reported to be positive in up to 100% of people with this syndrome, although reports of using this test are scarce [4]. ANA and AHA are present in >95% of cases of this syndrome; however, further studies would be needed to identify what percentage of DILE have a positive AHA and a negative ANA [5].\n\nTo this day, there are over 70 medications implicated as possible etiologic agents of DILE [6]. Other commonly used medications aside from hydralazine include sulfamethoxazole, isoniazid, procainamide, phenytoin, methyldopa, chlorpromazine, infliximab, etanercept, and ACE inhibitors [7]. The list of medications reported to have caused an AHA positive and ANA negative are much smaller. Thus far, medications reported aside from hydralazine include lisinopril, quinidine, and minocycline [7–9]. Over 140 cases of DILE due to hydralazine have been reported; however, this is the second reported case with a negative ANA and the first presented by Alarcon-Segovia et al. [10].\n\nFollowing the publication of the A-HeFT trial by Taylor et al. published in the NEJM in 2004, there has been an increase in the amount of hydralazine prescribed in patients with heart failure [2, 11]. For this reason, if pericardial effusion is suspected in patients with heart failure on combination hydralazine and isosorbide dinitrate, DILE should be in the differential. It was believed that DILE due to hydralazine was dose dependent; however, case reports now indicate that patients on lower doses of hydralazine (<100 mg) are not risk-free of this disease [5, 12].\n\nWith the increase of medications reported to cause DILE, it is important to keep in mind this potential side effect. In cases where suspicion is high, checking the AHA despite negative ANA may be indicated to identify the etiology of the disease. Anti-chromatin antibodies may also prove to be useful in diagnosis; however, given its limited medical literature, further studies would be needed to confirm its utility [4]. Steroids may be beneficial in the short term; however, discontinuing the offending agent is ultimately what will resolve this syndrome.\n\n4. Conclusion\nHydralazine is a known cause of pericardial effusion as part of the DILE syndrome; however, the diagnosis should not be precluded in the setting of negative ANA if suspicion is high. Although rare, positive anti-histone antibody with a negative ANA is a diagnostic possibility for DILE as shown by this case report.\n\nConsent\nInformed consent was obtained from the patient for publication of this case report and any accompanying images.\n\nDisclosure\nThere are no financial or nonfinancial interests in the publication of this paper for any of the authors. The paper is being published on the basis of educational investigation and medical research.\n\nConflicts of Interest\nThe authors declare that there are no conflicts of interest.\n\nFigure 1 CT chest coronal view (pericardial effusion denoted by ∗).\n\nFigure 2 CT chest transverse view (pericardial effusion denoted by ∗).\n\nFigure 3 Transthoracic echocardiogram parasternal long-axis view (pericardial effusion denoted by ∗).\n\nFigure 4 Transthoracic echocardiogram subcostal view (pericardial effusion denoted by ∗).\n==== Refs\n1 Aylward P. E. Tonkin A. M. Bune A. Cardiac tamponade in hydralazine-induced systemic lupus erythematosis Australian and New Zealand Journal of Medicine 1982 12 5 546 547 10.1111/j.1445-5994.1982.tb03845.x 2-s2.0-0020455564 6960881 \n2 Chamsi-Pasha M. A. R. Bassiouny M. Kim E. S. H. Hydralazine-induced lupus syndrome presenting with large pericardial effusion Quarterly Journal of Medicine 2014 107 4 305 307 10.1093/qjmed/hct223 2-s2.0-84897066588 \n3 Iyer P. Dirweesh A. Zijoo R. Hydralazine induced lupus syndrome presenting with recurrent pericardial effusion and negative antinuclear antibody Case Reports in Rheumatology 2017 2017 3 5245904 10.1155/2017/5245904 \n4 Burlingame R. Cervera R. Anti-chromatin (anti-nucleosome) autoantibodies Autoimmunity Reviews 2002 1 6 321 328 10.1016/s1568-9972(02)00083-6 2-s2.0-0041467346 12848987 \n5 Handler J. Hydralazine-induced lupus erythematosis Journal of Clinical Hypertension 2012 14 2 133 136 10.1111/j.1751-7176.2011.00573.x 2-s2.0-84856243132 22277146 \n6 Rich M. W. Drug-induced lupus: the list of culprits grow Postgraduate Medicine 1996 100 3 299 302 10.3810/pgm.1996.09.83 8795660 \n7 Carter J. Valeriano-Marcet J. Kanik K. Vasey F. Antinuclear antibody-negative, drug-induced lupus caused by lisinopril Southern Medical Journal 2001 94 11 1122 1123 10.1097/00007611-200111000-00017 11780682 \n8 Rubin R. L. Etiology and mechanisms of drug-induced lupus Current Opinion Rheumatology 1999 11 5 357 363 10.1097/00002281-199909000-00006 2-s2.0-0032705984 \n9 Borchers A. Keen C. Gershwin M. E. Drug-induced lupus Annals of the New York Academy of Sciences 2007 1108 1 166 182 10.1196/annals.1422.019 2-s2.0-34948858951 17893983 \n10 Alarcon-Segovia D. Drug-induced lupus syndromes Mayo Clinic Proceedings 1969 44 664 681 4898319 \n11 Taylor A. Ziesche S. Yancy C. Combination of isosorbide dinitrate and hydralazine in blacks with heart failure New England Journal of Medicine 2004 351 20 2049 2057 10.1056/nejmoa042934 2-s2.0-19644400578 15533851 \n12 Finks S. W. Finks A. L. Self T. H. Hydralazine-induced lupus: maintaining vigilance with increased use in patients with heart failure Southern Medical Journal 2006 99 1 18 22 10.1097/01.smj.0000197121.12352.19 2-s2.0-33644870797 16466117\n\n",
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"title": "ANA-Negative Hydralazine-Induced Pericardial Effusion.",
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"abstract": "We report a case of an adolescent with near fatal asthma (NFA). He presented with severe hypoxemia and lifethreatening acidemia, who failed to respond to conventional therapy. His hospital course was complicated by barotrauma and hemodynamic instability. Early introduction of extracorporeal membrane oxygenation (ECMO) led to dramatic improvement in gas exchange and lung mechanics. This case illustrates the important role of ECMO as salvage therapy in NFA.",
"affiliations": "Department of Critical Care, College of Medicine, King Saud University, Riyadh, Saudi Arabia.;Department of Critical Care, College of Medicine, King Saud University, Riyadh, Saudi Arabia.;Department of Critical Care, College of Medicine, King Saud University, Riyadh, Saudi Arabia.;Department of Critical Care, College of Medicine, King Saud University, Riyadh, Saudi Arabia.;King Fahad Cardiac Centre, King Khalid University Hospital, Riyadh, Saudi Arabia.",
"authors": "Alzeer|Abdulaziz H|AH|;Al Otair|Hadil A|HA|;Khurshid|Syed Moazzum|SM|;Badrawy|Sherif El|SE|;Bakir|Bakir M|BM|",
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"fulltext": "\n==== Front\nAnn Thorac MedAnn Thorac MedATMAnnals of Thoracic Medicine1817-17371998-3557Medknow Publications & Media Pvt Ltd India ATM-10-14310.4103/1817-1737.152461Case ReportA case of near fatal asthma: The role of ECMO as rescue therapy Alzeer Abdulaziz H. Al Otair Hadil A. Khurshid Syed Moazzum Badrawy Sherif El Bakir Bakir M. 1Department of Critical Care, College of Medicine, King Saud University, Riyadh, Saudi Arabia1 King Fahad Cardiac Centre, King Khalid University Hospital, Riyadh, Saudi ArabiaAddress for correspondence: Prof. Abdulaziz H. Alzeer, Department of Critical Care, College of Medicine-King Saud University, P. O. Box 18321, Riyadh-11415, Saudi Arabia. E-mail: alzeerahm@yahoo.comApr-Jun 2015 10 2 143 145 13 10 2014 05 12 2014 Copyright: © Annals of Thoracic Medicine2015This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.We report a case of an adolescent with near fatal asthma (NFA). He presented with severe hypoxemia and lifethreatening acidemia, who failed to respond to conventional therapy. His hospital course was complicated by barotrauma and hemodynamic instability. Early introduction of extracorporeal membrane oxygenation (ECMO) led to dramatic improvement in gas exchange and lung mechanics. This case illustrates the important role of ECMO as salvage therapy in NFA.\n\nECMOnear fatal asthmarescue therapy\n==== Body\nNear fatal asthma (NFA) is a serious medical condition that often results in profound hypoxemia, hypercapnia, and altered mental status.[1] Patient with NFA breathe at high lung volumes leading to increased mechanical load and elastic work of breathing.[2] Mechanical ventilation is often required to manage asthmatic patients who deteriorate despite aggressive management; however, it can have deleterious effects due to worsening dynamic hyperinflation and increase intrathoracic pressure. The reported mortality rate in patients who require ventilator assistance is 8%.[3] ECMO is an alternative method of cardio-pulmonary support in which oxygen is added and carbon dioxide (CO2) is removed through an extracorporeal membrane using arteriovenous or veno-venous cannulation.[4] The goal of this therapy is to minimize ventilator-induced lung injury and allow ample time for the lung inflammatory process to subside. Its use in severe asthma is limited to case reports or a case series.[56] In this case, we report a patient with NFA who had hypoxemia that was refractory to conventional therapeutic modalities and was managed by ECMO.\n\nCase Report\nA 15-year-old boy known to have asthma presented to the emergency room with one day history of cough and shortness of breath (SOB). On clinical examination, he was diaphoretic, tachypneic, and using his accessory muscles, blood pressure (BP) 120/70 mmHg, pulse 110/min, RR 42/min, temperature 37°C, and oxygen saturation was 92% on FiO2 of 6L/min. His initial arterial blood gas analysis (ABGs) was pH 7.35, PCO2 37 mmHg, PO2 64 mmHg, HCO3 25 mEq/L. Chest examination revealed decreased breath sounds and bilateral wheeze. Chest X-ray was normal. Complete blood count (CBC) and other blood tests were normal.\n\nHe was started on IV fluids; nebulizations with Salbutamol, Ipratropium Bromide, Budenoside, and Oxygen; intravenous (IV) Magnesium Sulphate, antibiotics, and high-dose IV steroids. He was also placed on Bi-Level Positive Airway Pressure to reduce the work of breathing (IPAP14 and EPAP 8, FiO2 of 70%). However, clinically unchanged, with repeat ABGs pH 7.20, pCO244 mmHg, pO270 mmHg, HCO318 mEq/L, and his serum lactate level was 3.1 mmol/L. Therefore, he was intubated and transferred to the intensive care unit (ICU).\n\nThe patient was started on assist control mode, with respiratory rate of 18, tidal volume 5ml/kg, FiO2100%, I:E ratio of 1:4, and positive end-expiratory pressure (PEEP) 5cmH2O. He was sedated with propofol, midazolam, fentanyl, IV muscle relaxant (cis-atracurium), norepinephrine 10 mcg/min, and salbutamol infusion at 5μg/min. Despite ventilator manipulations to decrease minute ventilation and allow permissive hypercapnia, his peak and plateau airway pressure were persistently high at 57 and 40 cmH2O, respectively. Sodium bicarbonate infusion was started due to severe concomitant metabolic acidosis. About 8 hours later, he developed surgical emphysema and bilateral chest tubes were placed prophylactically [Figure 1]. Bronchoscopy and bronchoalveolar lavage were performed to remove any mucus plugs; however, none were seen.\n\nFigure 1 Comparison of chest x-rays on admission before and after tube insertion\n\nDespite being on these measures, his respiratory status continued to deteriorate, so the decision was made to start him on ECMO, using the left femoral veno-venous route with heparin infusion and monitoring of activated clotting time (150-200 s). His ABGs improved over the next 2 hours [Table 1]. Ventilator settings were weaned to assist control mode, tidal volume 6 ml/kg, rate 14/min, FiO240%, and PEEP 5 cmH2O. ECMO was continued for 72 hours; meanwhile, the patient was kept sedated and ventilated; continued on antibiotics, nebulization, steroids, and IV salbutamol, along with heparin infusion, norepinephrine, and cis-atracurium. After 3 days, ECMO was discontinued with no consequences. On the fifth day, he was extubated and transferred to the ward and was discharged home on the sixteenth day after admission to be followed up in the pulmonary clinic.\n\nTable 1 Ventilator parameters and arterial blood gas analysis\n\nDiscussion\nThe severe derangement in gas exchange of this patient was managed beyond the current clinical practice guidelines. He had persistent extreme respiratory embarrassment and ventilatory failure despite being on maximum conventional therapy including mechanical ventilation. He also sustained both barotrauma and hemodynamic instability requiring vasopressors. The mechanism of hypoxemia and hypercapnia in acute asthmatic attack is mainly due to low ventilation perfusion, mismatch, shunting, and hypoventilation.[27] The application of ECMO in this case has provided a bypass where extra-corporeal blood flow through a membrane has achieved adequate oxygenation and CO2 removal. This was necessary to rest the lung, until the inflammation causing his bronchospasm has subsided.\n\nECMO has been used primarily to treat respiratory failure due to acute lung injury (ALI) that failed to respond to maximal medical therapy and its use in severe asthma is unusual.[578] In a recent report of acute respiratory failure due to influenza A (H1N1) epidemic in 2009, applying ECMO to these patient was associated with favorable results.[9]\n\nIn a retrospective cohort study, using life support organization (ELSO), Mikkelsen et al., found that among 1,257 patients treated with ECMO, 24 (1.9%) were asthmatics of whom 20 (83.3%) survived to hospital discharge, compared to 1,233 (50.8%) non-asthmatics.[10] The success of ECMO in asthma was likely due to the natural reversibility of the airflow obstruction in asthma. This is in contrast to the patient with diffuse alveolar damage due to ALI, where the recovery is usually slow.[10] Moreover, by virtue of its mechanism of action, applying ECMO allows reduction of both the tidal volume and minute ventilation, which subsequently decrease the dynamichyperinflation. These further reduce the development of barotraumas and hemodynamic instability particularly with persistent hypoxemia and acidemia, and who appear to have extremely severe disease.\n\nECMO complications can arise during catheter insertion or during patient's management. It is vital that operators are aware of these complications, to allow taking swift action to appropriately remedy the situation. The other common complication is bleeding, either due to fatal vascular perforation during cannulation or secondary to heparin infusion or platelets dysfunction.[48] Cerebral hemorrhage or infarction occurs in approximately 10-15% in patient with acute respiratory distress syndrome (ARDS). Systemic thromboembolism due to thrombus formation within the extracorporeal circuit is an infrequent but important complication.[4]\n\nConclusion\nSuccessful management of patient with NFA in ICU requires high level of expertise and intensive support. Aggressive therapy, including careful manipulation of mechanical ventilation, and possible use of ECMO in the proper setting can be life-saving.\n\nSource of Support: Nil\n\nConflict of Interest: None declared.\n==== Refs\nReferences\n1 Restrepo RD Peters J Near-fatal asthma: Recognition and management Curr Opin Pulm Med 2008 14 13 23 18043271 \n2 Papiris S Kotanidou A Malagari K Roussos C Clinical review: Severe asthma Crit Care 2002 6 30 44 11940264 \n3 Krishnan V Diette GB Rand CS Bilderback AL Merriman B Hansel NN Mortality in patients hospitalized for asthma exacerbations in the United States Am J Respire Crit Care Med 2006 174 633 8 \n4 Brogan TV Thiagarajan RR Rycus PT Bartlett RH Bratton SL Extracorporeal membrane oxygenation in adults with severe respiratory failure: A multi-center database Intensive Care Med 2009 35 2105 14 19768656 \n5 Chang CL Yates DH Use of early extra-corporeal membrane oxygenation (ECMO) for severe refractory status asthmaticus J Med Cases 2011 2 124 6 \n6 Mikkelsen ME Pugh ME Hansen-Flaschen JH Woo YJ Sager JS Emergency extracorporeal life support for asphyxic status asthmaticus Respir Care 2007 52 1525 9 17971256 \n7 Friedlander AL Fatal and near fatal asthma: Phenotypes, precipitating factors, and management Respir Rep 2007 3 22 33 \n8 Hirshberg E Miller RR 3rd Morris AH Extracorporeal membrane oxygenation in adults with acute respiratory distress syndrome Curr Opin Crit Care 2013 19 38 43 23222676 \n9 Davies A Jones D Bailey M Beca J Bellomo R Blackwell N Australia and New Zealand Extracorporeal Membrane Oxygenation (ANZ ECMO) Influenza Investigators. Extracorporeal membrane oxygenation for 2009 influenza a (H1N1) acute respiratory distress syndrome JAMA 2009 302 1888 95 19822628 \n10 Mikkelsen ME Woo YJ Sager JS Fuchs BD Christie JD Outcomes using extracorporeal life support or adult respiratory failure due to status asthmaticus ASAIO J 2009 55 47 52 19092662\n\n",
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"abstract": "The present case report describes a postmenopausal patient with hormone receptor (HR)+/human epidermal growth factor receptor 2 (HER2)+ metastatic breast cancer, who experienced progression of disease in bilateral lungs, lymph nodes and the liver under previous endocrine therapy and trastuzumab. Following the failure of two lines of endocrine-based treatment, the patient was administered the combined treatment of everolimus, trastuzumab and exemestane following surgical resection of the liver metastasis. A durable partial remission was achieved, which has continued for >27 months. This prominent clinical outcome in this patient demonstrates that the combined administration of endocrine therapy, trastuzumab and everolimus is clinically effective, and may induce long-term remission in patients with HR+/HER2+ metastatic breast cancer.",
"affiliations": "Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China.;Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China.;Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China.;Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China.;Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China.",
"authors": "Wang|Jian|J|;Sun|Chunxiao|C|;Huang|Xiang|X|;Qiu|Jinrong|J|;Yin|Yongmei|Y|",
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"title": "Long-term remission of hormone receptor-positive/HER2-positive metastatic breast cancer due to combined treatment with everolimus/trastuzumab/exemestane: A case report.",
"title_normalized": "long term remission of hormone receptor positive her2 positive metastatic breast cancer due to combined treatment with everolimus trastuzumab exemestane a case report"
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"abstract": "We report the case of a 32-year-old man who developed acute psychiatric disorders after repeated intravenous injections of methylphenidate. The behavioural disorders with extreme psychomotor restlessness and delirious syndrome have resolved within 24hours. The available data highlight the fact that the prescriptions of methylphenidate, an amphetamine-like substance, are constantly increasing in Europe and Northern America. The potential of abuse and addiction to this drug, which is growingly misused, is now clearly established. The medical professionals should be cautious and attentive to the risk of misuse of this drug.",
"affiliations": "EPSM de la Sarthe, unité d'accueil et d'orientation, 20, avenue du 19-Mars-1962, 72700 Allonnes, France. Electronic address: f.verite@epsm-sarthe.fr.;Service de pharmacologie, CEIP-addictovigilance PACA Corse, INT, institut des neurosciences Timone, Aix-Marseille université, CNRS, CHU Timone, AP-HM, 13385 Marseille, France.",
"authors": "Vérité|Fabrice|F|;Micallef|Joëlle|J|",
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"title": "Acute psychiatric symptoms during methylphenidate intravenous injections: A case report.",
"title_normalized": "acute psychiatric symptoms during methylphenidate intravenous injections a case report"
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"abstract": "Through a tracheostomy with a rigid esophagoscope in the esophagus, the authors simultaneously placed self-made magnetic twin stents in a critically ill patient with high tracheoesophageal fistula. The operation took 17 minutes. Oral nutrition was started immediately. The stents were checked and changed after the months 3, 7, and 14. At 18 months, a tracheal resection and esophageal reconstruction through a partial median sternotomy was completed successfully. The magnetic twin stent technique can temporize critically ill patients with an acquired nonmalignant tracheoesophageal fistula until they become operable.",
"affiliations": "Department of Surgery, Saint George University Teaching Hospital, Székesfehérvár, Hungary. Electronic address: altorjay@mail.fmkorhaz.hu.;Department of Oto-Rhino-Laryngology, Saint George University Teaching Hospital, Székesfehérvár, Hungary.;Department of Intensive Care, Saint George University Teaching Hospital, Székesfehérvár, Hungary.",
"authors": "Altorjay|Áron|Á|;Rüll|Miklós|M|;Sárkány|Ágnes|Á|",
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"title": "Magnetic Twin Stent for Short-Term Palliation of Acquired Nonmalignant Tracheoesophageal Fistula.",
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{
"abstract": "Literature regarding the effect of biologics on the course of mycosis fungoides (MF) is scarce. This multicentre study analysed retrospective data on 19 patients with MF, who were treated with biologics; 12 for inflammatory conditions coexisting with MF, and 7 for MF misdiagnosed as an inflammatory skin disease. Eight patients were treated with anti-tumour necrosis factor-α-monotherapy; 6 had early-stage MF, in 3 patients MF preceded and in 3 MF was diagnosed after initiation of biologics, with no stage-progression or with stable disease, respectively (median treatment time concurrent with MF 57 months). Two patients had advanced stage MF: IIB, treated for 15 months with no stage-progression, and IVA1, treated for 8 months, died of disease 10 months later. The other 11/19 patients received anti-interleukin-17A and/or anti-interleukin-12/23 or anti-interleukin-23 (with/without anti-tumour necrosis factor-α/anti-interleukin-4/13), with stage-progression in 8 patients after a median of 8 months' treatment. Although, in general, biologics should be avoided in patients with MF, these results indicate that anti-tumour necrosis factor-α-monotherapy might not aggravate the disease course in early-stage patients. Interleukin-17A, interleukin-12/23 and interleukin-23 pathway-blockers may prompt progression of MF.",
"affiliations": null,
"authors": "Amitay-Laish|Iris|I|;Guenova|Emmanuella|E|;Ortiz-Romero|Pablo L|PL|;Vico-Alonso|Cristina|C|;Rozati|Sima|S|;Geskin|Larisa J|LJ|;Nikolaou|Vasiliki|V|;Papadavid|Evangelia|E|;Barzilai|Aviv|A|;Pavlovsky|Lev|L|;Didkovsky|Elena|E|;Naveh|Hadas Prag|HP|;Akilov|Oleg E|OE|;Hodak|Emmilia|E|",
"chemical_list": "D016207:Cytokines; D007378:Interleukins",
"country": "Sweden",
"delete": false,
"doi": "10.2340/00015555-3642",
"fulltext": "\n==== Front\nActa Derm Venereol\nActa Derm Venereol\nActaDV\nActa Dermato-Venereologica\n0001-5555\n1651-2057\nSociety for Publication of Acta Dermato-Venereologica\n\n32965506\nActaDV-100-16-5890\n10.2340/00015555-3642\nClinical Report\nThe Course of Mycosis Fungoides under Cytokine Pathway Blockers: A Multicentre Analysis of Real-life Clinical Data*\nAMITAY-LAISH Iris 12\nGUENOVA Emmanuella 3\nORTIZ-ROMERO Pablo L. 4\nVICO-ALONSO Cristina 4\nROZATI Sima 5\nGESKIN Larisa J. 6\nNIKOLAOU Vasiliki 7\nPAPADAVID Evangelia 8\nBARZILAI Aviv 29\nPAVLOVSKY Lev 12\nDIDKOVSKY Elena 210\nNAVEH Hadas PRAG 1\nAKILOV Oleg E. 11#\nHODAK Emmilia 12#\n1 Division of Dermatology, Petach Tikva\n2 Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel\n3 Department of Dermatology, University Hospital Zürich & Lausanne University Hospital, University of Lausanne, Lausanne, Switzerland\n4 Department of Dermatology, 12 de Octubre Hospital, CIBERONC, Institute i+12, Medical School, University Complutense, Madrid, Spain\n5 Department of Dermatology, Johns Hopkins Medicine, Baltimore, MD, USA\n6 Department of Dermatology, Columbia University, New York, NY, USA\n7 Department of Dermatology, Andreas Sygros Hospital\n8 Department of Dermatology, Attikon General Hospital, University of Athens Medical School, Athens, Greece\n9 Department of Dermatology, Sheba Medical Center, Ramat-Gan, Israel\n10 Institute of Pathology, Rabin Medical Center – Beilinson Hospital, Petach Tikva\n11 Cutaneous Lymphoma Program, Department of Dermatology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA\n# These authors contributed equally to this work.\n\nCorr: Iris Amitay-Laish, Division of Dermatology, Rabin Medical Center – Beilinson Hospital, Petach Tikva 4941492, Israel. E mail: amitaylaishiris@gmail.com\n30 9 2020\n2020\n100 16 589018 9 2020\n© 2020 Acta Dermato-Venereologica\n2020\nhttps://creativecommons.org/licenses/by-nc/4.0/ This is an open access article under the CC BY-NC license\nLiterature regarding the effect of biologics on the course of mycosis fungoides (MF) is scarce. This multicentre study analysed retrospective data on 19 patients with MF, who were treated with biologics; 12 for inflammatory conditions coexisting with MF, and 7 for MF misdiagnosed as an inflammatory skin disease. Eight patients were treated with anti-tumour necrosis factor-α-monotherapy; 6 had early-stage MF, in 3 patients MF preceded and in 3 MF was diagnosed after initiation of biologics, with no stage-progression or with stable disease, respectively (median treatment time concurrent with MF 57 months). Two patients had advanced stage MF: IIB, treated for 15 months with no stage-progression, and IVA1, treated for 8 months, died of disease 10 months later. The other 11/19 patients received anti-interleukin-17A and/or antiinterleukin-12/23 or anti-interleukin-23 (with/without anti-tumour necrosis factor-α/anti-interleukin-4/13), with stageprogression in 8 patients after a median of 8 months’ treatment. Although, in general, biologics should be avoided in patients with MF, these results indicate that anti-tumour necrosis factor-α-monotherapy might not aggravate the disease course in early-stage patients. Interleukin-17A, interleukin-12/23 and interleukin-23 pathway-blockers may prompt progression of MF.\n\nKey words\n\ncutaneous T cell lymphoma\nmycosis fungoides\nbiologic treatment\nanti-TNFα\nanti-IL-12/23\nanti-IL23\nanti-IL17A\n==== Body\npmcThe introduction of anti-tumour necrosis factor-α (TNF-α), as well as newer biologics, including anti-interleukin (IL)-17, anti-IL-12/23 and anti-IL-23, has revolutionized the management of autoimmune and inflammatory diseases (1–3). Patients with psoriasis, one of the most common inflammatory dermatoses, affecting 2–4% of the population in Western countries, now receive biologic treatment sooner in the course of their disease, following treatment with fewer conventional agents (3).\n\nSIGNIFICANCE\n\nSince, almost as a rule, the treatment of patients with inflammatory conditions with biologics is terminated on diagnosis of mycosis fungoides, information on the course of mycosis fungoides under biologic treatment is scarce. Analysis of real-life data for 19 patients with mycosis fungoides being treated with biologics, revealed that anti-tumour necrosis factor-α-monotherapy may not always adversely affect early-stage disease. In contrast, in the vast majority of patients with mycosis fungoides, continuation of treatment with interleukin-17A, -12/23, and -23 pathway-blockers led to prompt progression of the disease. These observations may guide clinicians in considering the advantages and disadvantages in continuation of tumour necrosis factor-αblockers in the rare co-occurrence of early-stage mycosis fungoides and inflammatory conditions.\n\nThe risk of lymphoma under treatment with biologics, mainly anti-TNF-α, has been investigated and debated extensively (4–15). According to the US Food and Drug Administration (FDA) Adverse Event Reporting System, there was an increase in the risk of T-cell non-Hodgkin lymphomas, mainly mycosis fungoides (MF)/Sézary syndrome (SS), with anti-TNF-α combined with thiopurines or thiopurines alone, but not with anti-TNF-α alone (4).\n\nSpecific reviews of the literature yielded approximately 70 cases of MF and SS, in addition to 20 cases of other less common cutaneous T-cell lymphomas (CTCLs), under treatment with biologic agents, mostly anti-TNF-α and a few cases under treatment with anti-IL-12/23 or anti-IL-17 (11–25). The median interval from initiation of biologic treatment to diagnosis of CTCL was 5.5–32 months (11–13). Some patients, when information was provided, were also treated with thiopurines or cyclosporine (12, 16, 22, 23), which may also aggravate the course of lymphoma (4, 26).\n\nOverall, there are 2 settings in which MF/SS has been reported under biologic treatment, with approximately equal prevalence. In the first setting, patients were treated with biologics for a chronic inflammatory condition, such as inflammatory bowel disease (IBD) or rheumatoid arthritis (RA), and during the course of treatment, were diagnosed with MF/SS (12, 13, 20–22, 24, 25).\n\nIn the second setting, patients were treated with biologics for misdiagnosed psoriasis, atopic dermatitis, eczema, or idiopathic erythroderma, and were subsequently correctly diagnosed with MF while under treatment with biologics (11–16, 23, 24).\n\nIn almost all cases in both settings, biologic treatment was terminated on diagnosis of MF/SS. In a few patients, all with an inflammatory comorbidity, the treatment was continued despite the diagnosis of MF, after considering its advantages and disadvantages (11–25).\n\nTherefore, direct information is still lacking on the course of MF under biologic treatment.\n\nThe aim of the present study was to evaluate the effect of biologics on the course of MF.\n\nMETHODS\n\nSetting and patients\n\nData were retrospectively collected on all patients fulfilling the following inclusion criteria: patients who had MF while under treatment with any type of anti-TNF-α, and/or anti-IL-17, and/or anti-IL-12/23, and/or anti-IL-23 agent/s, for any time frame, and were managed at the following institutes: Cutaneous Lymphoma Clinics, Rabin Medical Center, Israel (from January 2009), University of Pittsburgh, USA (from January 2013), University Hospital Zürich, Switzerland (from November 2011), Hospital Universitario 12 de Octubre, Spain (from June 2003), Johns Hopkins Medicine, USA (from January 2016), and Andreas Sygros or Attikon General Hospital, Greece (from January 2011). The study endpoint, for all sites, was June 2019.\n\nThis cohort included 3 groups of patients. The first group comprised patients who, during treatment with systemic biologic/s for an inflammatory disease, including: IBD, RA, psoriasis, or ankylosing spondylitis (AS), developed MF. This group included patients only if biologic treatment was continued for any time-period. The second group comprised patients with MF diagnosed before biologic treatment, which was given for inflammatory comorbidities; (IBD, arthritis, etc.). The third group comprised patients with MF presenting prior to the biologic treatment, but misdiagnosed as other dermatoses, for which the biologic treatment was given.\n\nOf note, in the first 2 groups, treatment with biologics was continued due to significant inflammatory comorbidity, after careful consideration of the pros and the cons, while in the third group once misdiagnosis was recognized, biologic treatment was discontinued.\n\nPatients also treated with other immunosuppressive medication/s (azathioprine or cyclosporine) were excluded.\n\nMF was defined according to the World Health Organization – European Organization for Research and Treatment of Cancer (WHO–EORTC) classification of cutaneous lymphomas (27). Staging was determined using the tumour node metastasis (TNM) system (28), and stage progression was defined according to the International Society for Cutaneous Lymphomas (ISCL), the United States Cutaneous Lymphoma Consortium (USCLC), and the EORTC (29).\n\nDemographic, background, and disease-related parameters were recorded, as follows: sex, race, age at diagnosis of MF, inflammatory comorbidities, the indication for biologic treatment, type of biologic agent/s prescribed, duration of MF under biologic treatment since the index date (i.e. the date from which both conditions, including biologic treatment and MF occurrence, met); type of MF, TNMB staging at initiation of biologic treatment, most advanced stage and stage at last follow-up, treatment received for MF, and outcome. Follow-up data were assessed from the index date to the last follow-up. As some of the patients continued follow-up after cessation of the biologic treatment, the duration of biologic treatment concurrent with MF from the index date may have been shorter than the duration of follow-up from the index date to the last visit.\n\nThe study was approved by the local Institutional Review Committee of Rabin Medical Center.\n\nRESULTS\n\nTable I summarizes the clinical characteristics of the patients, types of biologics given, the course of MF on biologics, and duration of follow-up. Fig. 1 shows the status/stage of MF at initiation and during the course of biologic treatment, the type of biologic agent given, and the patients showing stage progression.\n\nTable I Demographic and clinical data for patients with mycosis fungoides (MF), treated with biologies\n\nStatus of MF at biologic treatment initiation\tPatient number sex/ race/age at MF diagnosis, years\tStage of diagnosed MF at biologic treatment initiation\tStage of MF at biologic treatment initiation in retrospectb\tInflammatory comorbidities\tType of biologic treatment/ indication\tDuration of biologic treatment concurrent with MF since index datec/F/U since index date to last visit, monthsd\tMaximal stage since index date, under biologic treatmentc, MF type\tCourse of MF on biologic treatment since index datec\tTreatments given for MF/ status at last F/U, stage (TNMB)\t\nMF diagnosed after the onset of biologic treatment\tMF patients treated only with anti-TNF-α\t\n1. F/African American/34\tNo diseasea\tNR\tIBD\tInfliximab/IBD\t16/21\tIA, (T1a, N0, M0, B0), hypopigmented\tStable\tTS/AWD, IA, (T1a,N0,M0,B0)\t\n2. M/Caucasian/74\tNo diseasea\tNR\tPsoriasis, PA\tAdalimumab, etanercept, golimumab/PA\t60/60\tIB, (T2a, N0, M0, B0), classic\tStable\tTS, NB UVB/AWD, IA, (T1a, N0, M0, B0)\t\n3. M/Caucasian/72\tNo diseasea\tNR\tRA\tEtanercept, adalimumab/RA\t80/117\tIB, (T2a, N0, M0, B0), classic\tStable\tBexarotene/Died of myelodysplastic-syndrome 2 years after it was diagnosed. MF was at stage IB, (T2a,N0,M0,B0)\t\nDiagnosed MF preceding biologic treatment\t4. M/Caucasian/64\tIB, (T2a, N0, M0, B0)\tNR\tIBD, AS\tAdalimumab/ IBD and AS\t36/45\tIB, (T2a, N0, M0, B0), classic\tNo stage progression\tTS, NM, NB UVB/AWD, IA, (T1a, N0, M0, B0)\t\n5. M/Caucasian/50\tIA, (T1a, N0, M0, B0)\tNR\tPsoriasis, AS\tEtanercept/AS\t110/110\tIA, (T1a, N0, M0, B0), classic\tNo stage progression\tTS, NM/AWD, IA, (T1a, N0, M0, B0)\t\n6. M/Caucasian/33\tIB, (T2a, N0, M0, B0)\tNR\tIBD\tAdalimumab/IBD\t54/60\tIB, (T2a, N0, M0, B0), classic with component of folliculotropic\tNo stage progression\tTS, NB UVB+ UVA/AWD, IA, (T1a, N0, M0, B0)\t\n7. M/Caucasian/70\tIVA1, (T4N0M0B2)\tNR\tRA\tAdalimumab/RA\t8/18\tIVA1, (T4, N0, M0, B2), classic\tNo stage progression\tMTX/DOD, IVA1, (T4, N0, M0, B0)\t\n8. F/Caucasian/64\tIIB, (T3, N0, M0, B0)\tNR\tPsoriasis\tAdalimumab/psoriasis (clinical and pathological diagnosis)\t15/62\tIIB, (T3, N0, M0, B0), classic\tNo stage progression\tIFN-α, bexaroten, skin directed radiotherapy/AWD, IIB, (T3,N0,M0, B0)\t\nMF patients treated with anti-IL-17A and/or anti-IL-12/23 or anti-IL-23 with or without other biologies\t\n9. M/Caucasian/47\tIA, (T1a, N0, M0, B0)\tNR\tPA\tEtanercept, secukinumab, ustekinumab, adalimumab/PA\t27 [etanercept-15 months, secukinumab-11 months, ustekinumab-1 month]/60\tIA, (T1a, N0, M0, B0), classic\tNo stage progression\tTS, PUVA, bexarotene/AWD, IA, (T1a, N0, M0, B0)\t\n10. M/Caucasian/62\tIB, (T2b, N0, M0, B0)\tNR\tPsoriasis\tIxekizumab/psoriasis (clinical and pathological diagnosis)\t1/7\tIIB, (T3, N0, M0, B0), and later stage IIIA, (T4, N1, M0, B0), psoriasiform\tStage progression (IB to IIB)\tPDX/DOD, IIIA, (T4, N1, M0, B0)\t\n11. F /Caucasian/36\tIB, (T2b, N0, M0, B0)\tNR\tPsoriasis, PA, IBD\tUstekinumab/psoriasis (clinical and pathological diagnosis), PA\t4/12\tIIIA, (T4, N0, M0, B0)\tStage progression (IB to IIIA)\tMTX, acitretin, bexaroten, PUVA, /DOD, IIIA, (T4, N0, M0, B0)\t\n12. M/Caucasian/64\tIB, (T2b, N0, M0, B0)\tNR\tPsoriasis\tUstekinumab/psoriasis (clinical and pathological diagnosis)\t4/10\tIIIA (T4, N0, M0, B0), and later stage IVA2, (T4, N3, M0, B2)\tStage progression (IB to IIIA)\tMTX, acitretin, bexarotene, IFN-α, PUVA, liposomal doxorubicin, brentuximab vedotin /DOD, IVA2, (T4, N3, M0, B2)\t\nMF pre-existing biologic treatment, but misdiagnosed as other dermatoses\t13. M/Caucasian/81\tNR\tIIIA, (T4, NI, M0, B0)\tNo\tSecukinumab/misdiagnosed as pityriasis rubra pilaris\t1.8/11\tIVA1, (T4, N1, M0, B2), erythrodermic\tStage progression (IIIA to IVA1)\tECP, subsequently patient declined treatment/ DOD, IVA1, (T4, N1, M0, B2)\t\n14. F/Caucasian/79\tNR\tIA, (T1b, N0, M0, B0)\tNo\tAdalimumab, ustekinumab/misdiagnosed as psoriasis\t10 [adalimumab-6 months, ustekinumab-4 months] /99\tIA, (T1b, N0, M0, B0), psoriasiform\tNo stage progressione\tMTX, acitretin, PUVA, NB UVB, bexarotene/AWD, IB, (T2b, N0, M0, B0)\t\n15. M/Caucasian/61\tNR\tIII A, (T4, N1, M0, B0)\tNo\tUstekinumab/misdiagnosed as psoriasis\t1/10\tIIIA, (T4, N1, M0, B0), erythrodermic with tumours\tStage progression (IIIA to IIIA with tumours)\tBrentuximab vedotin, PDX/ died of stroke, III, (T4,N1,M0,B0)\t\n16. F/Caucasian/42\tNR\tIB, (T2b, N0, M0, B0)\tNo\tSecukinumab, etanercept, ixekizumab/misdiagnosed as psoriasis\t10 [secukinumab-1 months, etanercept-8 months, ixekizumab-1 months]/25\tIIB, (T3, N0, M0, B0), psoriasiform\tStage progression (IB to IIB)\tPDX, PDX + romidepsin, TTI- 621 clinical trial, IFNα+TS/ AWD, IA, (T1a, N0, M0, B0)\t\n17. M/Caucasian/52\tNR\tIA, (T1a, N0, M0, B0)\tNo\tAdalimumab, secukinumab, dupilumab/misdiagnosed as psoriasis, and later as AD\t16 [adalimumab-7 months, secukinumab-6 months, dupilumab-3 months]/17\tIA, (T1b, N0, M0, B0, psoriasiform\tNo stage progressionf\tNM/AWD, IA, (T1b, N0, M0, B0)\t\n18. M/Caucasian/69\tNR\tIB, (T2b, N0, M0, B0)\tNo\tAdalimumab, secukinumab/ misdiagnosed as psoriasis\t8 [adalimumab-6 months, secukinumab-2 months]/13\tIIB, (T3, N0, M0, B0), psoriasiform\tStage progression (IB to IIB)\tNM and bexarotene/AWD, IA, (T1a, N0, M0, B0)\t\n19. F/Caucasian/72\tNR\tIII A, (T4, N0, M0, B0)\tNo\tDupilumab, adalimumab, guselkumab/ misdiagnosed as eczema, then psoriasis\t20 [Dupilumab-12 months, adalimumab-4 months, guselkumab-4 monthsj/30\tIVA1, (T4, N1, M0, B2)\tStage progression (IIIA to IVA1)\tECP/AWD, IVA1, (T4, N1, M0, B2)\t\na MF was diagnosed after biologic treatment initiation.\n\na In cases treated with biologics due to misdiagnosis of inflammatory skin disorders (cases 13–19), the stage of MF at biologic initiation was defined at retrospect.\n\nc Index date defined as the date from which both conditions including biologic treatment and MF occurrence are met.\n\nd Some patients were under follow-up after biologic treatment was stopped, and therefore the duration of biologic under MF since index date may be shorter compared with the time of follow-up since index date to last visit.\n\ne New lesions, but not stage progression, under ustekinumab.\n\nf Patches progressed to plaques.\n\nAD: atopic dermatitis; AWD: alive with disease; AS: ankylosing spondylitis; F/U: follow-up; DOD: died of disease; ECP: extracorporeal photopheresis; F: female; IBD: Inflammatory bowel disease; IFN: Interferon; M: male; MF: mycosis fungoides; MTX: methotrexate; NB UVB: narrow-band ultraviolet B; NM: nitrogen mustard; NR: not relevant; PA: psoriatic arthritis; PDX: pralatrexate; PUVA: psoralen + ultraviolet A; RA: rheumatoid arthritis; TS: topical steroids.\n\nFig. 1 Status and stage of mycosis fungoides (MF) at initiation and during the course of biologic therapy. *Some were also treated with other biologics. anti-TNF-α: anti-tumour necrosis factor-α; IL: interleukin; pts: patients; Dx: diagnosis.\n\nThe cohort included 19 patients (13 males, 6 females; 18 Caucasians and 1 African-American). Median age at diagnosis of MF was 64 years (range 33–81 years). In 12 patients (numbers 1–12), biologics were given for a true inflammatory comorbidity, including: biopsy proven psoriasis in 4 patients (also in 1 with psoriatic arthritis), and psoriatic arthritis, RA, IBD, and AS in 8 patients, as shown in Table I. In the other 7 patients (numbers 13–19), biologics were given for an initial misdiagnosis of another dermatosis.\n\nSixteen patients (numbers 4–19) had MF at initiation of biologic treatment, diagnosed either before treatment onset or in retrospect: 11 early-stage disease (IA/IB) and 5 advanced-stage disease (1-IIB, 3-IIIA, 1-IVA1). They were followed for a median of 10 months (range 1–110 months) from the index date, while being treated with biologic therapy. Eight patients (50%) had stage progression during follow-up (numbers 10–13, 15, 16, 18, 19). By the last follow-up (median 22 months, range 7–110), 5 had died of disease: 4 (numbers 10–13) after progression of MF under biologics, and 1 with stage IVA1 MF (number 7), diagnosed at this stage before biologic treatment was initiated.\n\nIn the other 3/19 patients (numbers 1–3), MF was diagnosed after the onset of biologic treatment. Administration of biologic agents with concurrent MF was continued for 16, 60 and 80 months. All 3 had early-stage MF and a stable disease course. By the last follow-up, one patient had died of myelodysplastic syndrome (number 3).\n\nSubanalysis of the course of mycosis fungoides by type of biologic treatment\n\nEight patients were treated only with anti-TNF-α, (numbers 1–8). Of these, 6 had early-stage MF: 3 before biologic treatment initiation and 3 were diagnosed as early-stage MF in the course of biologic treatment. All 6 patients received mostly skin-targeted therapies for the underlying disease (Table I) and responded well, as expected. The 3 patients with MF pre-existing biologic treatment (1-IA, 2-IB) did not progress to higher stages during continuation of anti-TNF-α, and all 3 patients with MF newly diagnosed after initiating anti-TNF-α (1-IA, 2-IB), had stable early-stage disease while continuing biologic treatment. The median duration of treatment of anti-TNF-α from the index date was 57 months (mean 59 months, range 16–110). At the last follow-up (median 60 months, range 21–117), 5 patients were alive with early-stage MF and 1 had died of myelodysplastic syndrome. The remaining 2/8 patients who received anti-TNF-α-monotherapy (numbers 7, 8) had advanced MF at treatment initiation. They were treated for 8 and 15 months, respectively. Patient 7, with stage IVA1 MF, died of disease 10 months after stopping treatment with anti-TNF-α and patient 8, with stage IIB, did not progress.\n\nEleven patients received anti-IL-17 and/or anti-IL-12/23, or anti-IL-23 agent/s, with/without anti-TNF-α and/or anti-IL4/13, for a median of 8 months (range 1–27) (numbers 9–19). Eight had early-stage MF at initiation of biologic therapy and 3 had advanced-stage MF. The indication for biologics was histologically confirmed psoriasis in 3 patients (numbers 10–12), in one also with psoriatic arthritis, and psoriatic arthritis in another (number 9). In the other 7 patients, biologic treatment was given for a presumed diagnosis of psoriasis, eczema, atopic dermatitis, or pityriasis rubra pilaris, and it was stopped when the diagnosis of MF was established. Stage progression was noted in 8/11 patients (Fig. 1, Table I): 3 patients with early-stage disease IB exhibited newly developed tumours (numbers 10, 16, 18; Figs 2 and 3), 2 patients with early-stage IB disease developed erythroderma (numbers 11, 12), and 3 with advanced-stage disease exhibited either blood involvement (stage B2; numbers 13, 19) or tumours in the context of erythroderma (number 15). Of note, in all 3 patients who were at stage IA MF at initiation of biologic treatments, stage progression according to the formal definition (29) was not recorded. However, in one patient (number 14) more lesions were recorded, and in another (number 17), some of the patches developed into plaques (Table I).\n\nFig. 2 Patient 10. Findings before and after treatment with ixekizumab. (A) Ill-defined erythemas on the cheek and nose beforebiologic treatment.(B) Appearance of a tumour on the ala nasi after biologic treatment.\n\nFig. 3 Patient 16. Findings before andaftertreatment withsecukinumab, etanercept,and ixekizumab.(A) Well-defined erythematous scaly plaques on the trunk, initially diagnosed as psoriasis, before biologic treatment. (B) Widespread plaques, some infiltrated, covered by yellowish thick scale-crusts on the trunk, after biologic treatment.\n\nThe median follow-up time for these patients was 13 months (range 7–99). At the last follow-up, 6/11 patients were alive with disease: 2 were down-staged to sustained stage IA, 2 remained at stage IA, one progressed from stage IA to IB, and one was at stage IVA1. The other 5 patients died, 4 of MF and one of stroke.\n\nOf note, 2 patients at some point during their management were treated with anti-IL4/13-dupilumab for a presumed diagnosis of atopic dermatitis (numbers 17, 19), but this proved ineffective and was discontinued after 3 and 12 months, respectively.\n\nDISCUSSION\n\nThis multicentre study adds considerably to the growing body of literature on the course of MF under biologics. Our experience suggests that the course of MF under treatment with biologic agents is not uniform. On the one hand, anti-TNF-α-monotherapy did not adversely affect the course of early-stage MF. On the other hand, rapid stage progression was noted in most of the patients treated with anti-IL-17 and/or anti-IL-12/23 agents.\n\nAmong the 6 patients with early-stage MF treated with anti-TNF-α for an inflammatory comorbidity, 3 had pre-existing MF and showed no stage progression during treatment. In the other 3 patients, early-stage MF was diagnosed after anti-TNF-α was started. Although we cannot rule out the possibility that, in these cases, MF was caused by the biologic treatment, continued treatment with anti-TNF-α did not result in further stage progression. Most of these patients received conventional skin-targeted agents for the early-stage MF and responded as expected (Table I).\n\nIn keeping with the findings of the current study, an earlier report, based on 2 French national registries, described 3 patients who had what was defined as limited MF while under biologic treatment, (infliximab; personal communication), for IBD or RA. All 3 achieved complete or partial remission after local treatment while continuing the biologics (13). Likewise, others reported that most patients diagnosed with MF while being treated with anti-TNF-α for an inflammatory systemic comorbidity were diagnosed at an early stage and had an indolent outcome (11–25). Tsimberidou et al. (30) described 2 patients with stage IB MF in whom partial remission or minor improvement were noted under treatment with etanercept.\n\nThe present study does not provide sufficient information on the course of advanced-stage MF under anti-TNF-α. Only 2 of our patients had advanced-stage MF, 1 of whom died of the disease. Interestingly, of the ˜60 patients previously reported in the context of MF/SS and anti-TNF-α, ˜35% were diagnosed at an advanced stage (11–25). Based on these patients, some of the authors concluded that the anti-TNF-α treatment may have aggravated the course of MF. However, most of these patients were given anti-TNF-α to treat inflammatory skin disorders, such that the possibility of an underdiagnosis of pre-existing advanced MF in at least some of them cannot be excluded.\n\nMost of the literature on MF and biologics focuses on anti-TNF-α, and data on the effect of anti-IL-17 and/ or anti-IL-12/23 on MF are very limited (11–14). In the present cohort, of the 11 patients treated with anti-IL17 and/or anti-IL-12/23, or anti-IL-23, 8 patients, all with at least stage IB, showed stage progression under treatment. They included 5 patients in whom MF was initially misdiagnosed as another dermatosis (Table I). Likewise, in all 6 previously reported cases of MF under treatment with anti-IL-17 and/or anti-IL-12/23, the biologic/s were given for a cutaneous indication, and most of the patients were subsequently diagnosed with advanced-stage MF (11, 12, 14). Yoo et al. (11) described 2 patients with a long history of diagnosed psoriasis who were subsequently diagnosed with stage IB and stage IIIA MF after 12 and 8 weeks’ treatment, respectively, with secukinumab (11). Others described patients with psoriasis/presumed psoriasis who were ultimately diagnosed with advanced-stage MF under treatment with etanercept and ixekizumab (n = 1) (14) or with stage IIB MF, SS, or primary cutaneous epidermotropic CTCL (n =1 each) under treatment with ustekinumab plus anti-TNF-α (12).\n\nThese cases, together with ours, suggest that anti-IL-17 and anti-IL-12/23 agents may aggravate MF. However, as most patients were initially misdiagnosed with other dermatoses, the stage of MF at initiation of biologic treatment is unclear.\n\nThe previously reported cases (11–25), together with our series, highlight the extreme caution that should be taken before initiating biologics for a presumed dermatosis, as MF is notorious for being a great imitator of cutaneous benign inflammatory diseases (31). Confirmatory skin biopsy prior to initiation of biologics is not a standard of care and is not performed routinely. The issue is particularly complicated in cases of psoriasis, as MF may mimic psoriasis both clinically and pathologically (12, 26, 31). The additional presence of alopecia, induration, erosions/ulcerative lesions should raise the suspicion of MF (31). Furthermore, some patients with MF may have concomitant psoriasis, as occurred in 6 patients in the present cohort. Longitudinal follow-up, repeated biopsies, and clone comparison may help to arrive at the correct diagnosis.\n\nThe pathomechanism underlying the seemingly differential effect of the various classes of biologics on the course of MF is unclear. The few studies of the TNF-α pathway in this context suggest that it plays a complex role in the pathophysiology of MF (30, 32–34). MF tumourigenesis was found to be associated with changes in the regulation of a combination of anti-apoptotic signalling through different TNF receptors (32). TNF has also been implicated in the development of CTCL by virtue of its ability to promote epidermotropism via induction of interferon-inducible protein. In addition, anti-TNF antibodies down-regulated NF-kB and inhibited CTCL growth in cell culture (33, 34). These findings may provide a theoretical explanation for the “nonharmful” effect of anti-TNF on the course of 6 patients with early-stage MF in the present cohort.\n\nStudies of the role of IL-17 in MF have yielded contradictory results (11, 35–38). Some have shown that IL-17 is highly expressed in a subset of patients with MF and is associated with progressive disease (35, 36), whereas others have reported low IL-17 levels in patients with MF (37, 38). Regarding the tumour-related immune response in general, there are several lines of evidence based on human and mouse tumours suggesting that TH17 cells can promote protective anti-tumour responses. TH-17 cells were found to be negatively correlated with the presence of TReg cells and positively correlated with effector immune cells, including IFNγ+ effector and cytotoxic CD8+ T cells, and natural killer cells, in the same tumour microenvironment (39).\n\nRegarding the IL-12 pathway, which was blocked in 5 of the patients in the current stduy treated with ustekinumab, IL-12 is a powerful inducer of IFN-γ production and was shown to augment natural killer cell cytotoxicity and cytotoxic T-cell proliferation and function, all of which may mitigate the Th2 skewing in advanced CTCL (40).\n\nTogether, these data suggest that TH-17 or IL-12 blockade may lead to disease progression.\n\nStudy limitations\n\nThe limitations of this study include the retrospective design, small cohort, and relatively limited long-term follow-up. In addition, further stage progression under biologics in patients initially misdiagnosed with advanced-stage MF, might be, to some extent, due to the fact that these advanced patients were untreated for MF, and not merely due to the biologic treatment.\n\nConclusion\n\nSeveral conclusions may be drawn from this study. First, before considering biologics for benign cutaneous inflammatory disorders, clinicians should re-think the indication, take a second look for clinical clues of MF, revise the histology or take another biopsy, and consider blood assessment, including flow cytometry. Secondly, although similar to other immunosuppressant treatments, biologics in general should be avoided in cases of MF. Nevertheless, based on our experience, together with the few cases reported in the literature, it seems that anti-TNF-α may not always adversely affect the course of unequivocal early-stage MF, and the pros and cons of anti-TNF-α-therapy should be considered on a case-by-case basis. Further studies are needed to search for a biomarker to assist in predicting the risk of MF aggravation under anti-TNF-α or other biologics. Thirdly, we found that anti-IL-17 and/or anti-IL-12/23 or anti-IL-23treatment/s were associated with rapid aggravation of diagnosed and undiagnosed MF in several patients, all with at least stage IB MF. Whether the course of unequivocal classic very early-stage MF-IA might also progress under these treatments is not known and requires further study. A large international observational study is needed to fully clarify the complex relationship between MF and biologic agents and to guide clinical decisions.\n\nThe authors have no conflicts of interest to declare.\n\n* Presented at the European Organisation for Research and Treatment of Cancer (EORTC), Cutaneous Lymphoma Task Force Meeting, Athens, in September 2019.\n==== Refs\nREFERENCES\n\n1 Paramsothy S, Rosenstein AK, Mehandru S, Colombel JF. The current state of the art for biological therapies and new small molecules in inflammatory bowel disease. Mucosal Immunol 2018; 11 : 1558–1570.29907872\n2 Aletaha D, Smolen JS. Diagnosis and management of rheumatoid arthritis: a review. JAMA 2018; 320 : 1360–1372.30285183\n3 van den Reek JMPA, Seyger MMB, van Lümig PPM, Driessen RJB, Schalkwijk CJM, Berends MAM, et al . The journey of adult psoriasis patients towards biologics: past and present – results from the BioCAPTURE registry. J Eur Acad Dermatol Venereol 2018; 32 : 615–623.29121430\n4 Deepak P, Sifuentes H, Sherid M, Stobaugh D, Sadozai Y, Ehrenpreis ED. T-cell non-Hodgkin’s lymphomas reported to the FDA AERS with tumor necrosis factor-alpha (TNF-a) inhibitors: results of the REFURBISH study. Am J Gastroenterol 2013; 108 : 99–105.23032984\n5 Fiorentino D, Ho V, Lebwohl MG, Leite L, Hopkins L, Galindo C, et al . Risk of malignancy with systemic psoriasis treatment in the Psoriasis Longitudinal Assessment Registry. 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Inflamm Bowel Dis 2015; 21 : 1847–1853.25993693\n10 Brown SL, Greene MH, Gershon SK, Edwards ET, Braun MM. Tumor necrosis factor antagonist therapy and lymphoma development: twenty-six cases reported to the Food and Drug Administration. Arthritis Rheum 2002; 46 : 3151–3158.12483718\n11 Yoo J, Shah F, Velangi S, Stewart G, Scarisbrick JS. Secukinumab for treatment of psoriasis: does secukinumab precipitate or promote the presentation of cutaneous T-cell lymphoma? Clin Exp Dermatol 2019; 44 : 414–417.30284290\n12 Martinez-Escala ME, Posligua AL, Wickless H, Rutherford A, Sable KA, Rubio-Gonzalez B, et al . Progression of undiagnosed cutaneous lymphoma after anti–tumor necrosis factor-alpha therapy. J Am Acad Dermatol 2018; 78 : 1068–1076.29307643\n13 Dequidt L, Franck N, Sanchez-Pena P, Dalle S, Adamski H, Boulinguez S, et al . Cutaneous lymphomas appearing under biologics: 44 cases from the French Study Group on Cutaneous Lymphomas and French Pharmacovigilance Database. Br J Dermatol 2019; 181 : 616–618.30835817\n14 Partarrieu-Mejías F, Díaz-Corpas T, Pérez-Ferriols A, Alegre-de Miquel V. Mycosis fungoides after treatment with tumor necrosis factor-alpha inhibitors for psoriasis: progression or onset? Int J Dermatol 2019; 8 : e103–e105.\n15 Espinosa ML, Nguyen MT, Aguirre AS, Martinez-Escala ME, Kim J, Walker CJ, et al . Progression of cutaneous T-cell lymphoma after dupilumab: case review of 7 patients. J Am Acad Dermatol 2020; 83 : 197–199.32229275\n16 Nikolaou V, Papadavid E, Economidi A, Marinos L, Moustou E, Karampidou K, et al . Mycosis fungoides in the era of anti-tumour necrosis factor-α treatments. Br J Dermatol 2015; 173 : 590–593.25639382\n17 Rohl R, Bax D, Schierer S, Bogner PN, Hernandez-Ilizaliturri F, Paragh G. A case for histologic verification of the diagnosis of atypical psoriasis before systemic therapy. JAAD Case Reports 2018; 4 : 465–467.29984284\n18 Dalle S, Balme B, Berger F, Hayette S, Thomas L. Mycosis fungoides-associated follicular mucinosis under adalimumab. Br J Dermatol 2005; 153 : 207–208.16029354\n19 Adams AE, Zwicker J, Curiel C, Kadin ME, Falchuk KR, Drews R, et al . Aggressive cutaneous T-cell lymphomas after TNF-alpha blockade. J Am Acad Dermatol 2004; 51 : 660–662.15389210\n20 Koens L, Senff NJ, Vermeer MH, Ronday HK, Willemze R, Jansen PM. Cutaneous gamma/delta T-cell lymphoma during treatment with etanercept for rheumatoid arthritis. Acta Derm Venereol 2009; 89 : 653–654.19997706\n21 Lourari S, Prey S, Livideanu C, Jamard B, Lamant L, Cantagrel A, et al . Cutaneous T-cell lymphoma following treatment of rheumatoid arthritis with tumour necrosis factor-α blocking agents: two cases. J Eur Acad Dermatol Venereol 2009; 23 : 967–968.19192017\n22 Mahe E, Descamps V, Grossin M, Fraitag S, Crickx B. CD30+ T-cell lymphoma in a patient with psoriasis treated with ciclosporin and infliximab. Br J Dermatol 2003; 149 : 170–173.12890213\n23 Suga H, Sugaya M, Toyama T, Sumida H, Fujita H, Kogure A, et al . A case of mycosis fungoides with large cell transformation associated with infliximab treatment. Acta Derm Venereol 2014; 94 : 233–234.23975254\n24 Berthelot C, Cather J, Jones D, Duvic M. Atypical CD8+ cutaneous T-cell lymphoma after immunomodulatory therapy. Clin Lymphoma Myeloma 2006; 6 : 329–332.16507211\n25 Dauendorffer JN, Rivet J, Allard A, Bachelez H. Sezary syndrome in a patient receiving infliximab for ankylosing spondylitis. Br J Dermatol 2007; 156 : 742–743.17263820\n26 Zackheim HS, Koo J, LeBoit PE, McCalmont TH, Bowman PH, Kashani-Sabet M, et al . Psoriasiform mycosis fungoides with fatal outcome after treatment with cyclosporine. J Am Acad Dermatol 2002; 47 : 155–157 12077599\n27 Willemze R, Jaffe ES, Burg G, Cerroni L, Berti E, Swerdlow SH, et al . WHO-EORTC classification for cutaneous lymphomas. Blood 2005; 105 : 3768–3785.15692063\n28 Olsen E, Vonderheid E, Pimpinelli N, Willemze R, Kim Y, Knobler R, et al . Revisions to the staging and classification of mycosis fungoides and Sezary syndrome: a proposal of the International Society for Cutaneous Lymphomas (ISCL) and the Cutaneous Lymphoma Task Torce of the European Organization of Research and Treatment of Cancer (EORT C). Blood 2007; 110 : 1713–1722.17540844\n29 Olsen E, Whittaker S, Kim YH, Duvic M, Prince HM, Lessin SR, et al . Clinical end points and response criteria in mycosis fungoides and Sézary syndrome: a consensus statement of the International Society for Cutaneous Lymphomas, the United States Cutaneous Lymphoma Consortium, and the Cutaneous Lymphoma Task Force of the European Organisation for Research and Treatment of Cancer. J Clin Oncol 2011; 29 : 2598–2607.21576639\n30 Tsimberidou AM, Giles FJ, Duvic M, Kurzrock R. Pilot study of etanercept in patients with relapsed cutaneous T-cell lymphomas. J Am Acad Dermatol 2004; 51 : 200–204.15280837\n31 Hodak E, Amitay-Laish I. Mycosis fungoides: a great imitator. Clin Dermatol 2019; 37 : 255–267.31178107\n32 Tracey L, Villuendas R, Dotor AM, Spiteri I, Ortiz P, Garcia JF, et al . Mycosis fungoides shows concurrent deregulation of multiple genes involved in the TNF signaling pathway: an expression profile study. Blood 2003; 102 : 1042–1050.12689942\n33 Daliani D, Ulmer RA, Jackow C, Pugh W, Gansbacher B, Cabanillas F, et al . Tumor necrosis factor-alpha and interferon gamma, but not HTLV-I tax, are likely factors in the epidermotropism of cutaneous T-cell lymphoma via induction of interferon-inducible protein-10. Leuk Lymphoma 1998; 29 : 315–328.9684929\n34 Giri DK, Aggarwal BB. Constitutive activation of NF-kappaB causes resistance to apoptosis in human cutaneous T cell lymphoma HuT-78 cells. Autocrine role of tumor necrosis factor and reactive oxygen intermediates. J Biol Chem 1998; 273 : 14008–14014.9593751\n35 Krejsgaard T, Litvinov IV, Wang Y, Xia L, Willerslev-Olsen A, Koralov SB, et al . Elucidating the role of interleukin-17F in cutaneous T-cell lymphoma. Blood 2013; 122 : 943–950.23801634\n36 Krejsgaard T, Ralfkiaer U, Clasen-Linde E, Eriksen KW, Kopp KL, Bonefeld CM, et al . Malignant cutaneous T-cell lymphoma cells express IL-17 utilizing the Jak3/Stat3 signaling pathway. J Invest Dermatol 2011; 131 : 1331–1338.21346774\n37 Wolk K, Mitsui H, Witte K, Gellrich S, Gulati N, Humme D, et al . Deficient cutaneous antibacterial competence in cutaneous T-cell lymphomas: Role of Th2-mediated biased Th17 function. Clin Cancer Res 2014; 20 ; 5507–5516.25212608\n38 Miyagaki T, Sugaya M, Suga H, Ohmatsu H, Fujita H, Asano Y, et al . IL-22, but Not IL-17, dominant environment in cutaneous T-cell lymphoma. Clin Cancer Res 2011; 17 ; 7529–7538.22048239\n39 Kryczek I, Banerjee M, Cheng P, Vatan L, Szeliga W, Wei S, et al . Phenotype, distribution, generation, and functional and clinical relevance of Th17 cells in the human tumor environments. Blood 2009; 114 : 1141–1149.19470694\n40 Rook AH, Wood GS, Yoo EK, Elenitsas R, Kao DM, Sherman ML, et al . Interleukin-12 therapy of cutaneous T-cell lymphoma induces lesion regression and cytotoxic T-cell responses. Blood 1999; 94 : 902–908.10419880\n\n",
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"issue": "100(16)",
"journal": "Acta dermato-venereologica",
"keywords": " anti-IL-12/23; anti-IL17A; anti-IL23; anti-TNFα; biologic treatment; mycosis fungoides; cutaneous T cell lymphoma",
"medline_ta": "Acta Derm Venereol",
"mesh_terms": "D016207:Cytokines; D006801:Humans; D007378:Interleukins; D009182:Mycosis Fungoides; D012189:Retrospective Studies; D012878:Skin Neoplasms",
"nlm_unique_id": "0370310",
"other_id": null,
"pages": "adv00277",
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"pmid": "32965506",
"pubdate": "2020-09-30",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "The Course of Mycosis Fungoides under Cytokine Pathway Blockers: A Multicentre Analysis of Real-life Clinical Data.",
"title_normalized": "the course of mycosis fungoides under cytokine pathway blockers a multicentre analysis of real life clinical data"
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"abstract": "Infusion fluids are often given to restore blood pressure (volume resuscitation), but may also be administered to replace ongoing losses, match insensible losses, correct electrolyte or acid-base disorders, or provide glucose. The development of new infusion fluids has provided clinicians with a wide range of products. Although the choice for a certain infusion fluid is often driven more by habit than by careful consideration, we believe it is useful to approach infusion fluids as drugs and consider their pharmacokinetic and pharmacodynamic characteristics. This approach not only explains why infusion fluids may cause electrolyte and acid-base disturbances, but also why they may compromise kidney function or coagulation. In this teaching case, we present a 19-year-old patient in whom severe hypernatremia developed as a result of normal saline solution infusion and explore the pharmacokinetic and pharmacodynamic effects of frequently used infusion fluids. We review clinical evidence to guide the selection of the optimal infusion fluid.",
"affiliations": "Department of Internal Medicine, Division of Nephrology & Transplantation, Erasmus Medical Center, Rotterdam, the Netherlands. Electronic address: d.severs@erasmusmc.nl.;Department of Nephrology & Hypertension, University Medical Center Utrecht, Utrecht, the Netherlands.;Department of Internal Medicine, Division of Nephrology & Transplantation, Erasmus Medical Center, Rotterdam, the Netherlands.",
"authors": "Severs|David|D|;Rookmaaker|Maarten B|MB|;Hoorn|Ewout J|EJ|",
"chemical_list": "D003102:Colloids; D000077324:Crystalloid Solutions; D007552:Isotonic Solutions; D010952:Plasma Substitutes; D012965:Sodium Chloride",
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"issue": "66(1)",
"journal": "American journal of kidney diseases : the official journal of the National Kidney Foundation",
"keywords": "Chloride; acute kidney injury (AKI); crystalloids; hypernatremia; hyponatremia; infusion fluid; intravenous solution; normal saline; solute diuresis; volume resuscitation",
"medline_ta": "Am J Kidney Dis",
"mesh_terms": "D000138:Acidosis; D058186:Acute Kidney Injury; D001810:Blood Volume; D002547:Cerebral Palsy; D002557:Cerebrospinal Fluid Shunts; D003102:Colloids; D003422:Critical Care; D000077324:Crystalloid Solutions; D004827:Epilepsy; D017809:Fatal Outcome; D005260:Female; D005440:Fluid Therapy; D016908:Gram-Positive Bacterial Infections; D006801:Humans; D006849:Hydrocephalus; D006955:Hypernatremia; D008607:Intellectual Disability; D007552:Isotonic Solutions; D007668:Kidney; D010952:Plasma Substitutes; D011183:Postoperative Complications; D016459:Prosthesis-Related Infections; D012151:Resuscitation; D012965:Sodium Chloride; D014883:Water-Electrolyte Imbalance; D055815:Young Adult",
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"references": null,
"title": "Intravenous solutions in the care of patients with volume depletion and electrolyte abnormalities.",
"title_normalized": "intravenous solutions in the care of patients with volume depletion and electrolyte abnormalities"
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"abstract": "Limited data exist on initial human immunodeficiency virus type 1 (HIV-1) treatment with dolutegravir plus lamivudine.\n\n\n\nA5353 is a phase 2, single-arm, pilot study of once-daily dolutegravir (50 mg) plus lamivudine (300 mg) in treatment-naive participants with HIV-1 RNA ≥1000 and <500000 copies/mL. Exclusion criteria included active hepatitis B or major protease, reverse transcriptase, or integrase resistance. The primary efficacy measure was the proportion with HIV-1 RNA <50 copies/mL (FDA [US Food and Drug Administration] Snapshot) at week 24. Virologic failure (VF) was confirmed HIV-1 RNA >400 copies/mL at week 16/20 or >200 copies/mL at or after week 24. Dolutegravir levels and drug resistance testing were performed at VF.\n\n\n\nOne hundred and twenty participants (87% male, median age 30 years, 37 (31%) HIV-1 RNA >100000 copies/mL) initiated study treatment. Median entry HIV-1 RNA and CD4 count were 4.61 log10 copies/mL and 387 cells/mm3. Virologic efficacy at week 24 was 108/120 (90%, confidence interval [83%, 95%]), with comparable results in the >100000 copies/mL and ≤100000 copies/mL strata, that is, 89% (75%, 97%) and 90% (82%, 96%), respectively. Three participants with VF, had undetected plasma dolutegravir at ≥1 time points; the M184V and R263R/K mutations developed in 1 participant. Two participants experienced grade 3 possible/probable treatment-related adverse events; none discontinued treatment due to adverse events.\n\n\n\nDolutegravir plus lamivudine demonstrated efficacy in individuals with pretreatment HIV-1 RNA up to 500000 copies/mL in this pilot trial, but a participant developed resistance mutations.\n\n\n\nNCT02582684.",
"affiliations": "Division of Infectious Diseases and Center for Global Health, Northwestern University, Chicago, Illinois.;Department of Biostatistics.;Statistical Data Management Center, Harvard T H Chan School of Public Health, Boston, Massachusetts.;Division of Infectious Diseases, Rutgers University, New Brunswick, New Jersey.;Division of Infectious Diseases and Center for Global Health, Northwestern University, Chicago, Illinois.;BARC South Africa and Lancet Laboratories, Johannesburg, South Africa.;Division of AIDS, National Institutes of Allergy and Infectious Diseases, Bethesda, Maryl.;Division of Infectious Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.;Department of Pharmacology and Toxicology, University of Alabama, Birmingham.;Department of Medicine, Vanderbilt University, Nashville, Tennessee.;ViiV Healthcare, Research Triangle Park, North Carolina.;Division of Infectious Diseases, Rush University, Chicago, Illinois.;Regional Center for Infectious Diseases, Cone Health, Greensboro, North Carolina.;Division of Infectious Diseases, Weill Cornell Medicine, New York, New York.",
"authors": "Taiwo|Babafemi O|BO|;Zheng|Lu|L|;Stefanescu|Andrei|A|;Nyaku|Amesika|A|;Bezins|Baiba|B|;Wallis|Carole L|CL|;Godfrey|Catherine|C|;Sax|Paul E|PE|;Acosta|Edward|E|;Haas|David|D|;Smith|Kimberly Y|KY|;Sha|Beverly|B|;Van Dam|Cornelius|C|;Gulick|Roy M|RM|",
"chemical_list": "D019380:Anti-HIV Agents; D006575:Heterocyclic Compounds, 3-Ring; D010078:Oxazines; D010879:Piperazines; D011728:Pyridones; D012367:RNA, Viral; D019259:Lamivudine; C562325:dolutegravir",
"country": "United States",
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"doi": "10.1093/cid/cix1083",
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"issn_linking": "1058-4838",
"issue": "66(11)",
"journal": "Clinical infectious diseases : an official publication of the Infectious Diseases Society of America",
"keywords": null,
"medline_ta": "Clin Infect Dis",
"mesh_terms": "D000328:Adult; D019380:Anti-HIV Agents; D018791:CD4 Lymphocyte Count; D004359:Drug Therapy, Combination; D005260:Female; D015658:HIV Infections; D015497:HIV-1; D006575:Heterocyclic Compounds, 3-Ring; D006801:Humans; D019259:Lamivudine; D008297:Male; D010078:Oxazines; D010865:Pilot Projects; D010879:Piperazines; D011728:Pyridones; D012367:RNA, Viral; D019562:Viral Load",
"nlm_unique_id": "9203213",
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"pages": "1689-1697",
"pmc": null,
"pmid": "29253097",
"pubdate": "2018-05-17",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural",
"references": "28537061;28375875;25101529;21716073;10928201;25394027;22197635;26188038;24329186;23830355;26658053;18480202;21807982;26854810;20124001;24698485;23306000;22205735;25103176;24195548;24783988;23432922",
"title": "ACTG A5353: A Pilot Study of Dolutegravir Plus Lamivudine for Initial Treatment of Human Immunodeficiency Virus-1 (HIV-1)-infected Participants With HIV-1 RNA <500000 Copies/mL.",
"title_normalized": "actg a5353 a pilot study of dolutegravir plus lamivudine for initial treatment of human immunodeficiency virus 1 hiv 1 infected participants with hiv 1 rna 500000 copies ml"
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"activesubstancename": "LAMIVUDINE"
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... |
{
"abstract": "BACKGROUND\nDyslipidemia is a well-known risk factor for the development of atherothrombosis; however, its involvement in venous thromboembolism (VTE) is still debated. Low levels of HDL cholesterol (HDL-C) have been found to be associated with VTE, which is a common complication of cancer and its treatment. VTE incidence is increased in cancer patients, especially those undergoing chemotherapy.\n\n\nOBJECTIVE\nWe sought to investigate the value of pretreatment HDL-C in the risk prediction of future VTE in a population of ambulatory cancer patients undergoing chemotherapy.\n\n\nMETHODS\nBlood lipid composition was retrospectively evaluated in 592 consecutive patients with primary (n = 373) or relapsing/recurrent (n = 219) solid cancers at the start of a new chemotherapy regimen (12% neoadjuvant, 31% adjuvant, 57% metastatic).\n\n\nRESULTS\nVTE occurred during chemotherapy in 38 patients (median time-to-event: 3 months). Mean HDL-C levels were lower in patients who developed VTE during chemotherapy (41 mg dL(-1) ; standard deviation [SD] 13 mg dL(-1) ) than in those who did not (48 mg dL(-1) ; SD 14 mg dL(-1) ). Cox proportional hazard survival analysis showed that HDL-C levels ≤ 43 mg dL(-1) were able to significantly predict a first VTE episode, with a hazard ratio of 2.87 (95% confidence interval 1.45-5.68). Moreover, patients with HDL-C levels ≤ 43 mg dL(-1) had worse 1-year VTE-free survival (86%) than those with HDL-C levels > 43 mg dL(-1) (96%; log rank test, 3.14).\n\n\nCONCLUSIONS\nPatients with low HDL-C levels have a three-fold higher risk of developing a first VTE episode during chemotherapy. Baseline analysis of HDL-C levels might be of clinical value in predicting VTE in cancer outpatients treated with anticancer drugs.",
"affiliations": "Biomarker Discovery and Advanced Biotechnology (BioDAT) Laboratory, IRCCS San Raffaele Pisana, Research Center, Rome, Italy.",
"authors": "Ferroni|P|P|;Roselli|M|M|;Riondino|S|S|;Guadagni|F|F|",
"chemical_list": "D000970:Antineoplastic Agents; D008076:Cholesterol, HDL",
"country": "England",
"delete": false,
"doi": "10.1111/jth.12737",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1538-7836",
"issue": "12(12)",
"journal": "Journal of thrombosis and haemostasis : JTH",
"keywords": "HDL cholesterol; cancer; chemotherapy; risk; venous thromboembolism",
"medline_ta": "J Thromb Haemost",
"mesh_terms": "D000368:Aged; D000970:Antineoplastic Agents; D008076:Cholesterol, HDL; D018572:Disease-Free Survival; D050171:Dyslipidemias; D005260:Female; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D009369:Neoplasms; D011237:Predictive Value of Tests; D016016:Proportional Hazards Models; D012189:Retrospective Studies; D012307:Risk Factors; D054556:Venous Thromboembolism",
"nlm_unique_id": "101170508",
"other_id": null,
"pages": "2049-53",
"pmc": null,
"pmid": "25256037",
"pubdate": "2014-12",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Predictive value of HDL cholesterol for cancer-associated venous thromboembolism during chemotherapy.",
"title_normalized": "predictive value of hdl cholesterol for cancer associated venous thromboembolism during chemotherapy"
} | [
{
"companynumb": "IT-ROCHE-1535290",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "GEMCITABINE\\GEMCITABINE HYDROCHLORIDE"
},
"drugadditi... |
{
"abstract": "Steroid eluting stents have proven to be a highly useful adjunctive therapy for chronic rhinosinusitis (CRS) and play an important role in the treatment of many inflammatory diseases of the sinuses. Few reports of adverse events were reported in clinical trials and are described in the literature. However, we describe the first known case of an immunocompetent patient developing non-invasive fungal tissue infection as a sequelae of stent-related tissue necrosis requiring surgical debridement.\nA 69-year-old immunocompetent male with CRS had Propel™ stents placed in the bilateral frontal sinus outflow tracts during revision endoscopic sinus surgery. He presented 2 weeks post-operatively with severe facial pain without vision changes, fevers, mental status changes, or evidence of cranial neuropathies. On rigid nasal endoscopy, necrotic tissue and gross fungal elements were visualized in the left frontal sinus outflow tract at the area of previous steroid stent position.\nThe patient was taken for urgent endoscopic sinus surgery and debridement given significant symptoms and concern for invasive fungal infection. A revision left maxillectomy, ethmoidectomy, and draf 2b frontal sinus drillout were performed, with healthy bleeding tissue encountered beneath necrotic tissue. Pathology revealed tissue necrosis, exudative lumenal debris, and extensive fungal elements with no evidence of tissue invasion, and cultures yielded growth of aspergillus niger. The patient's symptoms improved significantly on post-operative day 1, he had normal post-operative changes at 2 weeks following debridement, and had no recurrence of fungal infection with complete healing at 4 months.\nWhile likely rare, steroid-eluting stents may pose a risk of saprophytic tissue infection as a result of tissue necrosis and local immunosuppression. Caution should be taken in using these devices in immunocompromised patients.",
"affiliations": "Division of Otolaryngology, Department of Surgery, University of Utah School of Medicine, Salt Lake City, UT, USA.;Division of Otolaryngology, Department of Surgery, University of Utah School of Medicine, Salt Lake City, UT, USA.;Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT, USA.;Division of Otolaryngology, Department of Surgery, University of Utah School of Medicine, Salt Lake City, UT, USA.",
"authors": "Shipman|Paige|P|;Highland|Julie|J|https://orcid.org/0000-0002-7920-8749;Witt|Benjamin|B|;Alt|Jeremiah|J|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1177/00034894211036844",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0003-4894",
"issue": null,
"journal": "The Annals of otology, rhinology, and laryngology",
"keywords": "aspergillus niger; chronic rhinosinusitis; endoscopic sinus surgery; fungal sinusitis; saprophytic fungal sinusitis; steroid-eluting stent",
"medline_ta": "Ann Otol Rhinol Laryngol",
"mesh_terms": null,
"nlm_unique_id": "0407300",
"other_id": null,
"pages": "34894211036844",
"pmc": null,
"pmid": "34350789",
"pubdate": "2021-08-05",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Non-invasive Fungal Sinusitis as a Complication of a Steroid-Eluting Stent Following Endoscopic Sinus Surgery: A Case Report.",
"title_normalized": "non invasive fungal sinusitis as a complication of a steroid eluting stent following endoscopic sinus surgery a case report"
} | [
{
"companynumb": "US-MLMSERVICE-20220610-3611385-1",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "MOMETASONE FUROATE"
},
"drugadditional... |
{
"abstract": "We report a 48-day-old female infant, who developed cardiac conduction abnormalities and seizures secondary to supratherapeutic doses of oral flecainide. Flecainide was started in this infant for treatment of supraventricular tachycardia. The drug was withdrawn with successful normalization of the QRS complex and no further recurrence of seizures. The Naranjo probability score for adverse drug reaction was 8, making the causality \"probable.\" The case restates an important message that physicians should be aware of the side effects of the drugs that they prescribe, especially of those drugs which have a narrow therapeutic window.",
"affiliations": "Department of Pediatrics, Seth Gordhandas Sunderdas Medical College and King Edward Memorial Hospital, Mumbai, Maharashtra, India.;Department of Pediatrics, Seth Gordhandas Sunderdas Medical College and King Edward Memorial Hospital, Mumbai, Maharashtra, India.;Department of Pediatrics, Seth Gordhandas Sunderdas Medical College and King Edward Memorial Hospital, Mumbai, Maharashtra, India.;Department of Pediatrics, Seth Gordhandas Sunderdas Medical College and King Edward Memorial Hospital, Mumbai, Maharashtra, India.",
"authors": "Bajaj|S|S|;Tullu|M S|MS|;Khan|Zah|Z|;Agrawal|M|M|",
"chemical_list": "D000889:Anti-Arrhythmia Agents; D005424:Flecainide",
"country": "India",
"delete": false,
"doi": "10.4103/0022-3859.201422",
"fulltext": "\n==== Front\nJ Postgrad MedJ Postgrad MedJPGMJournal of Postgraduate Medicine0022-38590972-2823Medknow Publications & Media Pvt Ltd India 28272074JPGM-63-26510.4103/0022-3859.201422ADR ReportWhen potion becomes poison! A case report of flecainide toxicity Bajaj S Tullu MS Khan ZAH Agrawal M Department of Pediatrics, Seth Gordhandas Sunderdas Medical College and King Edward Memorial Hospital, Mumbai, Maharashtra, IndiaAddress for correspondence: Dr. Milind S Tullu, E-mail: milindtullu@yahoo.comOct-Dec 2017 63 4 265 267 19 6 2016 22 9 2016 03 1 2017 Copyright: © 2017 Journal of Postgraduate Medicine2017This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.We report a 48-day-old female infant, who developed cardiac conduction abnormalities and seizures secondary to supratherapeutic doses of oral flecainide. Flecainide was started in this infant for treatment of supraventricular tachycardia. The drug was withdrawn with successful normalization of the QRS complex and no further recurrence of seizures. The Naranjo probability score for adverse drug reaction was 8, making the causality “probable.” The case restates an important message that physicians should be aware of the side effects of the drugs that they prescribe, especially of those drugs which have a narrow therapeutic window.\n\nKEY WORDS\nArrhythmiascardiacdrug-related side effectsflecainideinfantseizures\n==== Body\nIntroduction\nFlecainide is a potent antiarrhythmic agent with a narrow window of safety.[1] Dosage errors leading to drug toxicity have been reported in the past.[234] Our case of flecainide toxicity manifested with cardiac conduction abnormalities and the rarer neurotoxicity, following a dose which was only 1.7 times the upper recommended dose.\n\nCase Report\nOur patient was a 48-day-old female infant, who presented with a history of convulsions 1 day before indoor admission. On eliciting a detailed history, it was suspected that the convulsions were probably secondary to drug toxicity. The case summary of the infant is presented in Table 1. The infant developed seizures following the 7th oral dose of flecainide at 1.7 times the recommended upper limit. On presentation to us, following the 9th supratherapeutic dose, the infant had prolonged QRS complexes too [Figure 1a]. The QRS complex normalized following the withdrawal of the drug within 3 days [Figure 1b], and there were no further seizures in the infant [Table 1]. There was no history of sudden stoppage of milk feeds before the onset of the seizures. The Naranjo probability score for adverse drug reaction was 8, making the causality “probable.”\n\nTable 1 Time-related events in the case history\n\nAge of the infant in days\tRelevant clinical and investigational details\t\n38\tIrritability, increased respiratory effort, poor feeding.\t\n\tWeight - 3.8 kg\t\n40\tProgressively increasing respiratory distress, altered sensorium, and shock\t\n\tChild intubated in a private hospital\t\n\tECG revealed SVT with AVRT with RBBB. Reverted with injectable adenosine in correct dosage\t\n\tFollowing reversion of the SVT, injectable metoprolol and injectable amiodarone were administered in appropriate dosage for 3 days\t\n44\tOral flecainide started at 10.2 mg/kg/day in two divided doses (1.7 times the recommended upper limit, i.e., 6 mg/kg/day)\t\n\tMother was instructed to divide each tablet of flecainide (50 mg) into two equal parts manually, crush the tablet manually and dissolve it in 2.5 ml of sterile water (10 mg/ml) and administer 2 ml of thec resultant solution to the baby (20 mg), twice a day\t\n\tDischarged the next day from the private hospital\t\n47\tAfter the seventh dose of oral flecainide, the infant developed generalized tonic seizures lasting for 5 min, resolved spontaneously, with postictal drowsiness\t\n\tAdmitted to a private hospital\t\n\tPreliminary investigations (complete blood counts, serum electrolytes, cerebrospinal fluid analysis) - normal\t\n\tUnsuspecting, no changes made in the existing prescription of ongoing high-dose flecainide\t\n48\tShifted to our center (ninth dose of flecainide administered)\t\n\tInfant stable hemodynamically, normal sensorium. Normal clinical examination.\t\n\tMRI brain - normal\t\n\tDetailed review of records alerted about the possibility of flecainide overdose\t\n\tECG - broad QRS complexes (0.20 s) [Figure 1a]\t\n\tFlecainide withdrawn completely\t\n\tDaily ECG - to monitor the QRS interval (flecainide effect on cardiac conduction)\t\n51\tComplete normalization of the ECG [Figure 1b]\t\n54\tAmiodarone started orally at 400 mg/1.73 m2/day in two divided doses after ensuring normal thyroid function on the 6th day after stopping oral flecainide\t\n\tFlecainide not reintroduced\t\n58\tInfant discharged from the hospital\t\n90\tAsymptomatic; thriving well\t\n\tNeurological examination normal\t\n\tGaining milestones normally\t\n\tCompliant with medications\t\nECG: Electrocardiography, SVT: Supraventricular tachycardia, AVRT: Atrioventricular reentrant tract, RBBB: Right bundle branch block, MRI: Magnetic resonance imaging\n\nFigure 1 (a) Lead V4; broad QRS complex (0.20 s) after 9 oral doses of flecainide at 1.7 times the recommended upper limit. (b) Lead V4; complete reversion of the electrocardiogram abnormalities. Normal electrocardiogram findings on the 3rd day after stopping flecainide completely\n\nDiscussion\nIn infants without an underlying structural heart disease, the first-line drugs for supraventricular tachycardia (SVT) include digoxin and propranolol.[5] Flecainide is a second-line agent for refractory SVT[5] though its use in children is considered to be off-label. A recent study done by Ferlini et al. documents the successful use of flecainide even as a first-line drug in newborns with SVT.[6]\n\nFlecainide is a drug with narrow therapeutic range,[1] the recommended starting dose in infants being 2 mg/kg/day in two to three divided doses,[6] with the maximum upper limit described at 6 mg/kg/day, administered orally.[2] Analogous to our case, at doses as precariously close as two times the upper limit, serious toxicities have been reported in infants.[2] Milk is known to interfere with the absorption of flecainide. Thus, sudden stoppage of milk feeds has been reported to be responsible for the precipitation of flecainide toxicity in the past;[7] an aspect absent in our case. The cardiac manifestations of flecainide toxicity (paradoxically) include proarrhythmic effects which are exaggerated in the presence of an underlying structural heart disease.[16] The neurotoxicity, though rarer than the hemodynamic toxicity, is manifested by seizures, myoclonus, hallucinations, diplopia, dizziness, and confusion.[3] Flecainide has a long plasma half-life of 12–27 h and takes 3–5 days for a steady state.[16] This increases the potential of side effects in the eventuality of an overdose. Although the literature records cases of flecainide toxicity in infancy, our infant is one of the youngest to be reported, with the exception of an 18-day-old neonate reported by Jang et al.[4]\n\nOral formulations for flecainide in India include tablets only, with the lowest available power being 50 mg/tablet. The correct administration of small doses in infants necessitates correct calculations, crushing and diluting the tablet, and dispensing it through the syringe or a precalibrated dispenser.[8] These steps are potential loopholes for serious dosage errors occurring during drug administration;[8] more so, when the mother herself has been instructed to crush, dilute, and administer the drug, as in our case. In countries like ours, where therapeutic drug monitoring for flecainide is not available, monitoring the QRS interval is a surrogate, and an inexpensive method to keep a check on the drug's efficacy and the cardiac conduction safety.[1] Widening of the QRS complex more than 25% above the baseline value is an indicator to reduce the dose of the drug.[1] In our patient, the QRS complex measured 0.20 seconds (for 98th percentile of 0.07 seconds, and a mean reference value of 0.05 seconds); a clear indicator of the cardiac toxicity. Although sodium bicarbonate has been advocated as an antidote in flecainide toxicity,[24] there are cases which have failed to show a significant effect of the drug in improving the QRS interval,[2] especially in asymptomatic cases with only mild to moderate QRS prolongation.[2] In the current case, since the infant was asymptomatic and hemodynamically stable when she presented, a conservative method of management was chosen; with success.\n\nIn the current case, the Naranjo probability score for adverse drug reaction was 8, making the causality “probable.” The drug was not readministered; neither placebo was given nor the drug level in the blood/body fluids was tested. Since this was the first case of the toxicity in the infant, we cannot comment on whether there were similar episodes in the past. These make an underscoring of the Naranjo scale in our case, highly possible. It may be noted that any score of 9 or above on the Naranjo scale indicates a “definite” association.[9]\n\nIn conclusion, our case is unique since it reports a very young infant with flecainide toxicity at a very small supratherapeutic dose. The case highlights the importance of being aware of the adverse drug effect of every prescribed drug, importance of correct dosage, availability of appropriate formulations, potential dangers of incorrect prescriptions, and high vigilance in case of drugs with a narrow therapeutic index.\n\nFinancial support and sponsorship\nNil.\n\nConflicts of interest\nThere are no conflicts of interest.\n==== Refs\n1 Tamargo J Le Heuzey JY Mabo P Narrow therapeutic index drugs: A clinical pharmacological consideration to flecainide Eur J Clin Pharmacol 2015 71 549 67 25870032 \n2 Close BR Banks CJ Pediatric flecainide toxicity from a double dose Am J Emerg Med 2012 30 2095.e1 2 \n3 Ghika J Goy JJ Naegeli C Regli F Acute reversible ataxo-myoclonic encephalopathy with flecainide therapy Schweiz Arch Neurol Psychiatr 1994 145 4 6 \n4 Jang DH Hoffman RS Nelson LS A case of near-fatal flecainide overdose in a neonate successfully treated with sodium bicarbonate J Emerg Med 2013 44 781 3 22981658 \n5 Kohli V Oral flecainide is effective in management of refractory tachycardia in infants Indian Heart J 2013 65 168 71 23647896 \n6 Ferlini M Colli AM Bonanomi C Salvini L Galli MA Salice P Flecainide as first-line treatment for supraventricular tachycardia in newborns J Cardiovasc Med (Hagerstown) 2009 10 372 5 19300276 \n7 Russell GA Martin RP Flecainide toxicity Arch Dis Child 1989 64 860 2 2505692 \n8 Chedoe I Molendijk HA Dittrich ST Jansman FG Harting JW Brouwers JR Incidence and nature of medication errors in neonatal intensive care with strategies to improve safety: A review of the current literature Drug Saf 2007 30 503 13 17536876 \n9 Naranjo CA Busto U Sellers EM Sandor P Ruiz I Roberts EA A method for estimating the probability of adverse drug reactions Clin Pharmacol Ther 1981 30 239 45 7249508\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "0022-3859",
"issue": "63(4)",
"journal": "Journal of postgraduate medicine",
"keywords": null,
"medline_ta": "J Postgrad Med",
"mesh_terms": "D000284:Administration, Oral; D000889:Anti-Arrhythmia Agents; D001145:Arrhythmias, Cardiac; D000075224:Cardiac Conduction System Disease; D064420:Drug-Related Side Effects and Adverse Reactions; D004562:Electrocardiography; D005260:Female; D005424:Flecainide; D006801:Humans; D007223:Infant; D012640:Seizures; D013617:Tachycardia, Supraventricular",
"nlm_unique_id": "2985196R",
"other_id": null,
"pages": "265-267",
"pmc": null,
"pmid": "28272074",
"pubdate": "2017",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "2505692;19300276;17536876;7526455;23647896;22386360;7249508;25870032;22981658",
"title": "When potion becomes poison! A case report of flecainide toxicity.",
"title_normalized": "when potion becomes poison a case report of flecainide toxicity"
} | [
{
"companynumb": "IN-ALVOGEN-2017-ALVOGEN-091761",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "FLECAINIDE"
},
"drugadditional": "1",
... |
{
"abstract": "BACKGROUND\nVentricular assist device is used in the patients with severe heart failure due to cardiotoxicity of anthracyclines, which are widely used chemotherapeutic agents for a wide range of malignant tumors. However, recovery of cardiac function is rare.\n\n\nMETHODS\nWe present the clinical course of a 43-year-old woman in remission from diffuse large B-cell lymphoma after the chemotherapy including anthracyclines, who presented in cardiogenic shock 8 months after the end of chemotherapy.\n\n\nRESULTS\nThe patient was initially treated with intra-aortic balloon pumping, followed by conversion to left ventricular assist device with an Abiomed AB5000 (Abiomed, Inc, Danvers, MA) and right ventricular assist device with a centrifugal pump and a membrane oxygenator, in addition to tricuspid annuloplasty, due to rapid deterioration to cardiogenic shock. With intensive medical treatments during biventricular support, her cardiac and respiratory functions gradually improved, although moderate mitral regurgitation persisted despite of left ventricular unloading. At 64 days of biventricular support, she underwent mitral valve annuloplasty to correct regurgitation under cardiopulmonary bypass. She was consequently weaned from biventricular assist successfully 8 days after mitral surgery (72 days of biventricular support). The patient discharged uneventfully from our hospital and survives at home 12 months after weaning from the ventricular assist devices.\n\n\nCONCLUSIONS\nOur case and the literature review highlight potential usefulness of aggressive mechanical biventricular support for cardiac recovery in patients with anthracycline-induced cardiomyopathy. Additional valve surgery and neurohormonal medications may be also promising in such patients with cancer, who are contraindicated for heart transplantation.",
"affiliations": "1 Department of Cardiovascular Surgery, Fujita Health University School of Medicine, Toyoake, Japan.;2 Department of Cardiology, Fujita Health University School of Medicine, Toyoake, Japan.;2 Department of Cardiology, Fujita Health University School of Medicine, Toyoake, Japan.;1 Department of Cardiovascular Surgery, Fujita Health University School of Medicine, Toyoake, Japan.;1 Department of Cardiovascular Surgery, Fujita Health University School of Medicine, Toyoake, Japan.;1 Department of Cardiovascular Surgery, Fujita Health University School of Medicine, Toyoake, Japan.;1 Department of Cardiovascular Surgery, Fujita Health University School of Medicine, Toyoake, Japan.;1 Department of Cardiovascular Surgery, Fujita Health University School of Medicine, Toyoake, Japan.;1 Department of Cardiovascular Surgery, Fujita Health University School of Medicine, Toyoake, Japan.;1 Department of Cardiovascular Surgery, Fujita Health University School of Medicine, Toyoake, Japan.;2 Department of Cardiology, Fujita Health University School of Medicine, Toyoake, Japan.",
"authors": "Takami|Yoshiyuki|Y|;Hoshino|Naoki|N|;Kato|Yasuchika|Y|;Sakurai|Yusuke|Y|;Amano|Kentaro|K|;Higuchi|Yoshiro|Y|;Tochii|Masato|M|;Ishida|Michiko|M|;Ishikawa|Hiroshi|H|;Takagi|Yasushi|Y|;Ozaki|Yukio|Y|",
"chemical_list": "D018943:Anthracyclines; D000970:Antineoplastic Agents",
"country": "United States",
"delete": false,
"doi": "10.1177/0391398818772497",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0391-3988",
"issue": "41(7)",
"journal": "The International journal of artificial organs",
"keywords": "Anthracycline; biventricular assist device; cardiomyopathy; recovery",
"medline_ta": "Int J Artif Organs",
"mesh_terms": "D000328:Adult; D018943:Anthracyclines; D000970:Antineoplastic Agents; D001021:Aortic Valve; D009202:Cardiomyopathies; D002315:Cardiopulmonary Bypass; D005260:Female; D016027:Heart Transplantation; D006352:Heart Ventricles; D006353:Heart-Assist Devices; D006801:Humans; D007423:Intra-Aortic Balloon Pumping; D016403:Lymphoma, Large B-Cell, Diffuse; D012770:Shock, Cardiogenic; D016896:Treatment Outcome",
"nlm_unique_id": "7802649",
"other_id": null,
"pages": "413-417",
"pmc": null,
"pmid": "29806528",
"pubdate": "2018-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Recovery from anthracycline-induced cardiomyopathy with biventricular assist and valve repairs: A case report and literature review.",
"title_normalized": "recovery from anthracycline induced cardiomyopathy with biventricular assist and valve repairs a case report and literature review"
} | [
{
"companynumb": "PHHY2017JP164947",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DOXORUBICIN"
},
"drugadditional": "3",
"drug... |
{
"abstract": "We have observed three patients on anticancer therapies presenting with asymmetric acral spared phenomenon and found six identical cases in the literature. All of them had common features, an alteration of the peripheral nerves affecting a limb unilaterally that was spared by a hand-foot syndrome or hand-foot skin reaction. A drug-induced neurotropic effect sounds logical for developing such alterations with specific chemotherapeutic agents (taxanes, cap-ecitabine), while we have not found good explanations concerning the multikinase inhibitor sorafenib nor the topo isomerase inhibitor adriamycin. Nevertheless, we know that clinical manifestations of many inflammatory diseases need intact neural components.",
"affiliations": "Nail Disease Center, Cannes, France.;Department of Oncology and Dermatology, Gustave Roussy Institute, Villejuif, France.;Department of Oncodermatology, Claudius Regaud Institute, Cancer University Institute, Toulouse Oncopole, Toulouse, France.",
"authors": "Baran|Robert|R|;Robert|Caroline|C|;Sibaud|Vincent|V|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000486021",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2296-9160",
"issue": "4(4)",
"journal": "Skin appendage disorders",
"keywords": "Anticancer therapies; Anticox 2; Hand-foot syndrome; Onycholysis; Reaction sparing a limb unilaterally; Taxanes; Unilateral acral changes",
"medline_ta": "Skin Appendage Disord",
"mesh_terms": null,
"nlm_unique_id": "101670617",
"other_id": null,
"pages": "315-319",
"pmc": null,
"pmid": "30410905",
"pubdate": "2018-10",
"publication_types": "D016428:Journal Article",
"references": "24471582;19379651;4574412;11289346;20298142;16176971;25846098;21764392;26521911;7684307;25132518;12164689;27550571",
"title": "Asymmetric Acral Spared Phenomenon Related to Systemic Anticancer Therapies.",
"title_normalized": "asymmetric acral spared phenomenon related to systemic anticancer therapies"
} | [
{
"companynumb": "GXKR2009ES06293",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LAPATINIB"
},
"drugadditional": "3",
"drugadm... |
{
"abstract": "Incorporation of liver transplant techniques in hepatopancreaticobiliary surgery has created an opportunity for the resection of locally advanced hepatic tumors formerly considered unresectable. A 73-year-old woman presented with cholangiocarcinoma involving inferior vena cava, all three hepatic veins, and right anterior portal pedicle, initially deemed nonoperative. This case demonstrates the first combined application of associating liver partition and portal vein ligation for staged hepatectomy and ex vivo resection to perform an R0. For diseases dependent upon resection, surgical advances and innovations expand the spectrum of interventions through interdisciplinary techniques.",
"affiliations": "Division of Hepatobiliary and Pancreatic Surgery, Atrium Health, Charlotte, North Carolina.;Division of Transplant Surgery, Atrium Health, Charlotte, North Carolina.;Division of Transplant Surgery, Atrium Health, Charlotte, North Carolina.;Division of Hepatobiliary and Pancreatic Surgery, Atrium Health, Charlotte, North Carolina.;Division of Hepatobiliary and Pancreatic Surgery, Atrium Health, Charlotte, North Carolina.;Division of Interventional Radiology, Atrium Health, Charlotte, North Carolina.;Division of Hepatobiliary and Pancreatic Surgery, Atrium Health, Charlotte, North Carolina.;Division of Hematology and Oncology, Levine Cancer Institute Carolinas Medical Center, Atrium Health, Charlotte, North Carolina.;Division of Hepatobiliary and Pancreatic Surgery, Atrium Health, Charlotte, North Carolina.;Division of Hepatobiliary and Pancreatic Surgery, Atrium Health, Charlotte, North Carolina.",
"authors": "Baimas-George|Maria R|MR|http://orcid.org/0000-0002-6649-4627;Levi|David M|DM|;Eskind|Lon B|LB|;Kirks|Russell C|RC|;Passeri|Michael|M|;Lessne|Mark|M|;Kardassis|Dimitrios|D|;Salmon|Stuart|S|;Iannitti|David A|DA|;Vrochides|Dionisios|D|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1002/jso.25375",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0022-4790",
"issue": "119(6)",
"journal": "Journal of surgical oncology",
"keywords": "cholangiocarcinoma; extracorporeal hepatectomy; hepatopancreaticobiliary surgery; locally advanced hepatic malignancy; venovenous bypass",
"medline_ta": "J Surg Oncol",
"mesh_terms": "D000368:Aged; D001807:Blood Vessel Prosthesis; D016461:Chemoembolization, Therapeutic; D018281:Cholangiocarcinoma; D005260:Female; D006498:Hepatectomy; D006503:Hepatic Veins; D006801:Humans; D008026:Ligation; D008113:Liver Neoplasms; D009361:Neoplasm Invasiveness; D011169:Portal Vein; D014682:Vena Cava, Inferior",
"nlm_unique_id": "0222643",
"other_id": null,
"pages": "771-776",
"pmc": null,
"pmid": "30644109",
"pubdate": "2019-05",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Ex vivo liver resection coupled with associated liver partition and portal vein ligation: Combining existing techniques to achieve surgical resectability.",
"title_normalized": "ex vivo liver resection coupled with associated liver partition and portal vein ligation combining existing techniques to achieve surgical resectability"
} | [
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"companynumb": "US-BAYER-2019-091302",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
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"drug": [
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"actiondrug": null,
"activesubstance": {
"activesubstancename": "ASPIRIN"
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"abstract": "Cryptococcosis following kidney transplantation (KT) is rare but is associated with considerably increased risk of mortality. At present, data on the association between cryptococcosis and KT in mainland China remain relatively limited.\nThis study aims to review our experience related to the management of cryptococcosis following KT at a Chinese tertiary hospital.\nAll patients with cryptococcosis following KT admitted to our hospital from January 2010 to December 2018 were reviewed.\nA total of 37 patients with cryptococcosis were enrolled (males: 62.2%). The mean age of the patients was 49.5 ± 9.38 (20-64) years. The average time to infection following KT was 7.0 ± 5.50 years (5 months to 21 years), and 30 patients (81.1%) had cryptococcosis onset >2 years following transplantation. The most common site of infection was the central nervous system, followed by the pulmonary system and skin. Most patients received fluconazole or voriconazole with or without flucytosine as their initial treatment regimen at our hospital. The 2-week mortality rate was 8.1% (3/37), and five patients (13.5%) died within 6 months of being diagnosed with cryptococcosis. Remarkably, all patients who received high-dose fluconazole (800 mg daily) or voriconazole ± flucytosine survived.\nCryptococcosis in kidney transplant recipients is typically a late-occurring infection, with most patients having cryptococcosis onset >2 years following KT at our hospital. The central nervous system, pulmonary system, and skin are the main sites of infection. Voriconazole or high-dose fluconazole can be used as an alternative therapy for post-KT cryptococcosis.",
"affiliations": "State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.;State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.;State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.;State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.;State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.",
"authors": "Yang|Meifang|M|;Zhang|Xuan|X|;Hu|Jianhua|J|;Zhao|Hong|H|;Li|Lanjuan|L|https://orcid.org/0000-0001-6945-0593",
"chemical_list": "D000935:Antifungal Agents; D000666:Amphotericin B; D015725:Fluconazole; D065819:Voriconazole",
"country": "United States",
"delete": false,
"doi": "10.1155/2019/7165160",
"fulltext": "\n==== Front\nBiomed Res IntBiomed Res IntBMRIBioMed Research International2314-61332314-6141Hindawi 10.1155/2019/7165160Research ArticleCryptococcosis in Patients following Kidney Transplantation: A 9-Year Retrospective Clinical Analysis at a Chinese Tertiary Hospital Yang Meifang \n1\n\n2\nZhang Xuan \n1\n\n2\nHu Jianhua \n1\n\n2\nZhao Hong \n1\n\n2\nhttps://orcid.org/0000-0001-6945-0593Li Lanjuan ljli@zju.edu.cn\n1\n\n2\n\n1State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China\n2Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, No. 79 Qingchun Road, Hangzhou 310003, ChinaAcademic Editor: Nobuo Kanazawa\n\n2019 11 11 2019 2019 71651609 5 2019 14 9 2019 24 10 2019 Copyright © 2019 Meifang Yang et al.2019This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Background\n Cryptococcosis following kidney transplantation (KT) is rare but is associated with considerably increased risk of mortality. At present, data on the association between cryptococcosis and KT in mainland China remain relatively limited. \n\nObjectives\n This study aims to review our experience related to the management of cryptococcosis following KT at a Chinese tertiary hospital. \n\nMethods\n All patients with cryptococcosis following KT admitted to our hospital from January 2010 to December 2018 were reviewed. \n\nResults\n A total of 37 patients with cryptococcosis were enrolled (males: 62.2%). The mean age of the patients was 49.5 ± 9.38 (20–64) years. The average time to infection following KT was 7.0 ± 5.50 years (5 months to 21 years), and 30 patients (81.1%) had cryptococcosis onset >2 years following transplantation. The most common site of infection was the central nervous system, followed by the pulmonary system and skin. Most patients received fluconazole or voriconazole with or without flucytosine as their initial treatment regimen at our hospital. The 2-week mortality rate was 8.1% (3/37), and five patients (13.5%) died within 6 months of being diagnosed with cryptococcosis. Remarkably, all patients who received high-dose fluconazole (800 mg daily) or voriconazole ± flucytosine survived. \n\nConclusions\n Cryptococcosis in kidney transplant recipients is typically a late-occurring infection, with most patients having cryptococcosis onset >2 years following KT at our hospital. The central nervous system, pulmonary system, and skin are the main sites of infection. Voriconazole or high-dose fluconazole can be used as an alternative therapy for post-KT cryptococcosis.\n\nZhejiang UniversityNational Science and Technology Major Project2017ZX102044010010022017ZX10204401002002Natural Science Foundation of Zhejiang ProvinceLQ19H190001\n==== Body\n1. Introduction\nCryptococcosis is an important opportunistic fungal infection responsible for significant mortality and morbidity among solid organ transplant (SOT) recipients, including kidney transplant recipients [1–3]. Several studies have demonstrated that cryptococcosis ranks the third most common cause of invasive fungal infection among SOT recipients [1, 4, 5]. With the improvements in transplantation practices and the wider use of antifungal prophylaxis, the incidence rates of invasive candidiasis and aspergillosis have substantially decreased in SOT recipients in the past decade [4, 6]. However, there has been no change in the incidence of cryptococcosis in SOT recipients [4]. China is one of the countries which perform a high number of kidney transplantations (KTs) worldwide; however, invasive fungal infection remains an important cause of death of KT recipients [7]. According to a previous review from China [8], the incidence of cryptococcosis in KT recipients was estimated to be 0.76% in China. However, few cases of cryptococcosis in patients who have undergone KT have been reported in China [9–11]. Therefore, the characteristics of cryptococcosis in KT recipients in China are not well defined.\n\nHere, we retrospectively reviewed a series of patients with post-KT cryptococcosis admitted to our hospital from 2010 to 2018 to evaluate the clinical characteristics, laboratory findings, diagnoses, treatments, and outcomes of cryptococcosis in this population.\n\n2. Patients and Methods\n2.1. Case Collection\nThis retrospective study was conducted at the First Affiliated Hospital of Zhejiang University, a 2,500-bed tertiary hospital located in Hangzhou, China, which is considered a top KT centre and centre for infectious diseases in China. We perform approximately 350–400 KTs per year. The medical records of all patients with cryptococcal infection following KT admitted to our hospital from January 1, 2010, to December 1, 2018, were collected. We reviewed patient records including demographic data, underlying diseases, clinical manifestations, laboratory findings, image findings, antifungal treatments, and outcomes.\n\nCases of cryptococcosis were defined as those in whom the identification of positive findings on Cryptococcus culture was obtained from any site or India ink staining in cerebrospinal fluid (CSF), histopathological findings showing the presence of 5–10 μm encapsulated yeasts within tissues or a positive result on cryptococcal antigen testing. Disseminated cryptococcosis is defined as the involvement of at least two organ systems or the presence of fungemia.\n\nThe present study was approved by the Ethics Committee of the First Affiliated Hospital of Zhejiang University and was performed in compliance with the Declaration of Helsinki.\n\n2.2. Treatment and Outcomes\nDetailed antifungal treatment information, including the details of induction and maintenance therapy, was available. Antifungal therapy was initiated upon the confirmation of diagnosis of cryptococcosis. The induction treatment included liposomal amphotericin B (liposomal-AMB) infusion, fluconazole (FLZ), and voriconazole (VRZ) or itraconazole alone or combined with 5-fluorocytosine (5-FC) for at least 14 days, followed by FLZ or VRZ as maintenance therapy for at least 6 months. The antifungal treatment regime was formulated by the attending physician and was mainly based on the Infectious Diseases Society of America (IDSA) guidelines from 2010 [12]. For the treatment group, we also considered the drug availability, disease severity, organ involvement, liver function, and renal function. The treatment duration was individualized according to a patient's response and the decision of the attending physician.\n\nFollowing discharge, all patients were followed up until death or for at least 6 months following the administration of the initial antifungal therapy. For patients who died during the follow-up, the date and cause of death were recorded. All-cause mortality at 2 weeks and 6 months following the initiation of antifungal therapy was analyzed.\n\n2.3. Statistical Analysis\nContinuous variables, including age and time from transplantation to cryptococcosis onset, were presented as mean ± standard deviation. Categorical variables, including sex, were presented as counts and proportions. T test, chi-squared test, Fisher's exact test, and Mann–Whitney U test were used to compare study variables between groups. All tests of statistical hypotheses were two-sided, and p ≤ 0.05 was considered statistically significant. All data were analyzed using SPSS 16.0 (SPSS Inc., Chicago, IL, USA).\n\n3. Results\n3.1. Demographic and Clinical Characteristics\nA total of 37 patients with post-KT cryptococcosis were enrolled during the 9-year study period. The demographic characteristics of all patients are summarized in Table 1. The average age at post-KT cryptococcosis onset was 49.5 ± 9.38 (20–64) years. Of these, 23 patients were male (62.2%), and the average time from transplantation to cryptococcosis onset was 7.0 ± 5.50 years (5 months to 21 years). Among the 37 patients, 30 (81.1%) had cryptococcosis onset >2 years following KT.\n\nThe most common underlying diseases in the study patients were hypertension (15/37, 40.5%), chronic viral hepatitis B (10/37, 27.0%; 1 patient had decompensated cirrhosis), type 2 diabetes (5/37, 13.5%), chronic viral hepatitis C (3/37, 8.1%), and systemic lupus erythematosus (1/37, 2.7%). None of the patients were positive for HIV.\n\nThe immunosuppressive regimens used are listed in Table 1. Three patients received intravenous methylprednisolone (500 mg d1, 320 mg d2, and 240 mg d3) for 3 days because of acute rejection-based biopsy within 2 years before cryptococcosis diagnosis. Graft loss prior to antifungal treatment occurred in 3 patients (8.1%). The average serum creatinine level prior to antifungal treatment was 202.90 ± 153.40 (55–693) μmol·L−1, and the baseline creatinine level was >176.8 μmol·L−1 in 14 patients (37.8%). Furthermore, the baseline creatinine level of the patients with disseminated cryptococcosis was significantly higher than that of the patients without disseminated cryptococcosis (234.47 ± 196.33 vs. 176.05 ± 102.24 μmol·L−1, p=0.022).\n\n3.2. Organ Involvement and Clinical Manifestations\nThe most commonly affected organs were central nervous system (CNS) (26 patients, 70.3%) and lungs (18 patients, 48.6%). Other involved sites included skin and soft tissue (2 patients, 5.4%) as part of disseminated infection. Disseminated cryptococcosis was identified among 17 patients (45.9%), 10 (27.0%) of which had cryptococcemia and 7 (18.9%) had at least two organ systems involved (4 cases involved CM and lung; 1 case involved CM, lung, and skin abscess; and 1 case involved CM and skin abscess). Furthermore, 7 (18.9%) patients had simple pulmonary infection.\n\nThe clinical manifestations in the patients with cryptococcal meningitis (CM) were as follows: fever (24/26, 92.3%), headache (25/26, 96.2%), vomiting (11/26, 42.3%), altered mental status (10/26, 38.5%), seizures (3/26, 11.5%), visual symptoms (2/26, 7.7%), and auditory symptoms (1/26, 3.8%). More patients with disseminated cryptococcosis presented fever than those without (15/17, 88.2% vs. 13/20, 65.0%), but the difference was nonsignificant (p=0.137). Cough and expectoration were the primary clinical manifestations in patients with pulmonary disease. Other manifestations included dyspnea and back pain. However, 12/18 patients with pulmonary involvement (66.7%) had no respiratory symptoms, and pulmonary lesions were revealed only by imaging. Among the 12 patients, 9 patients were diagnosed by routine lung CT scan because of symptoms such as fever and headache. Three patients with simple pulmonary infection and no other symptoms were found to have lung lesions on regular follow-up. The average time from the onset of symptoms or pulmonary lesions to diagnosis was 43.95 ± 12.78 (3–360) days.\n\n3.3. Laboratory Findings\nThe average white blood cell (WBC) count was 7,430 ± 3,050 (2,300–14,300) cells per mm3. The average C-reactive protein (CRP) level was 26.41 ± 28.00 (0.7–108) mg·L−1 (normal range, <8 mg·L−1), and the CRP level was elevated in 21 patients (56.8%). Patients with disseminated cryptococcosis had higher WBC counts and elevated CRP levels than those without, but the difference was nonsignificant. Blood culture was positive in 10 patients (27.0%). Other positive culture sites included lung tissue (2 patients), alveolar lavage fluid (1 patient), and soft tissue abscess (2 patients).\n\nLumbar punctures were performed at baseline in 26 patients with CM. Prior to the administration of antifungal treatment, the average CSF opening pressure was 281.91 ± 25.93 (50–450) mmH2O and 42.3% patients (11/26) had an elevated CSF pressure of >300 mmH2O. Furthermore, the average WBC count in CSF was 83.93 ± 16.93/mm3 (0–310/mm3). The average protein concentration in CSF was 0.97 ± 0.10 (0.01–2.27) g·L−1, and 92.3% of the patients (24/26) had an average protein concentration of >0.45 g·L−1. The average CSF glucose level was 2.25 ± 0.23 (0.10–5.0) mmol·L−1 (34.6% [9/26] < 2.0 mmol·L−1). CSF cultures were positive for Cryptococcus in 18/26 patients (69.2%), whereas India ink smears were positive in 19/26 patients (73.1%). Seven patients (26.9%) were smear negative but culture positive, and 6 patients (23.1%) were culture negative but smear positive. Histologic examinations revealed cryptococcosis in the lungs of 4 patients and the skin of 1 patient.\n\nOnly seven patients were tested for serum cryptococcal antigen. Among them, six patients were found to be positive, comprising 2 patients with disseminated cryptococcosis and 4 with cryptococcal pneumonia. The remaining patient tested negative for the antigen and was diagnosed with simple cryptococcal pneumonia by lung biopsy.\n\n3.4. Imaging Findings\nMR brain images were available for 24 patients with CM, and 16 patients (66.7%) had abnormal results. MRI detected hydrocephalus in 1 patient (4.2%) and local lesions in 16 (66.7%). Local lesions were characterized by a low signal on T1-weighted images and high signal on T2-weighted images and FLAIR in MRI with or without enhancement. The common sites involved included periventricular region (n = 9), centrum semiovale (n = 7), frontal lobe (n = 7), parietal lobe (n = 4), basal ganglion (n = 3), temporal lobe (n = 1), occipitallobe (n = 1), and corpus callosum (n = 1).\n\nChest CT images were available for 18 patients with pulmonary disease. The chest CT findings included nodules in 10 patients (55.6%), masses in 6 (33.3%), cavitations in 9 (50%), patchy shadows in 3 (16.7%), pleural effusion in 3 (16.7%), and miliary lesions in 1 with disseminated cryptococcosis (5.5%).\n\nThe typical abnormalities on cranial MRI and chest CT are shown in Figures 1 and 2.\n\n3.5. Treatment and Outcomes\nIn our study, the 2-week mortality rate was 8.1% (3/37), and 5/37 patients (13.5%) died within 6 months of being diagnosed with cryptococcosis. Three patients died within 2 weeks, two of which were diagnosed with CM and one was diagnosed with disseminated cryptococcosis. All deaths within 2 weeks were attributed to cryptococcosis. Among the five patients who died within 6 months, three were diagnosed with CM and two were diagnosed with disseminated cryptococcosis. One patient with disseminated cryptococcosis who received liposomal-AMB therapy died after 4 months of initial therapy because of severe septicemia. One patient with CM who received liposomal-AMB died after 7 months of initial therapy because of severe infective endocarditis. However, one patient who received 400 mg of FLZ daily for induction and maintenance therapy died of cryptococcemia 10 months after the initiation of antifungal treatment. All patients with simple pulmonary infections survived during follow-up.\n\nThe initial treatments were classified as follows: 7 patients, liposomal-AMB combined with 5-FC; 22, FLZ ± 5-FC; 7, VRZ ± 5-FC; and 1, itraconazole alone. 7 patients with CM and/or disseminated cryptococcosis in our study received domestic liposomal-AMB plus 5-FC for initial treatment. One patient who received 120 mg dosage of liposomal-AMB (about 2.0 mg/kg) daily for initial treatment had elevated serum creatinine three times higher than baseline after 7 days, and it returned to normal after we changed to FLZ 400 mg. The other 6 patients received liposomal-AMB 40 to 70 mg per day (about 0.8–1.0 mg/kg per day) for initial treatment. The average duration of liposomal-AMB treatment was 20.00 ± 4.57 (7–42) days in the 7 patients. As shown in Table 2, the all-cause 6-month mortality rate in patients with CM or disseminated cryptococcosis was 28.6% (2/7) in the liposomal-AMB combined with 5-FC group, 17.6% (3/17) in the FLZ ± 5-FC group, and 0% in the VRZ ± 5-FC and itraconazole groups. The mortality rate of patients with CM or disseminated cryptococcosis who received triazole (13.0%, 3/23) was lower than that of patients treated with liposomal-AMB (28.6%, 2/7). However, the difference was nonsignificant (p=0.565). Further analysis revealed that all patients in the high-dose FLZ (800 mg daily) and VRZ ± 5-FC groups survived. All patients received FLZ or VRZ for consolidation and maintenance therapy.\n\nGraft loss was observed in 3 patients prior to antifungal treatment, with 1 having received liposomal-AMB + 5-FC and 2 having received FLZ + 5-FC. Chronic rejection led to graft loss in these three patients. Five additional patients, who had preexisting renal dysfunction (including one treated with liposomal-AMB, two with FLZ, and two with VRZ for induction therapy), progressed to graft loss after starting antifungal treatment. No significant difference was found in terms of graft loss between patients who received liposomal-AMB and those who received triazole (16.7% vs. 14.3%, p=0.881).\n\n4. Discussion\nWe performed the first allograft KT in July 1977 at the First Affiliated Hospital of School of Medicine, Zhejiang University, which is the main transplantation centre in China. However, opportunistic infections, including invasive fungal or viral infections and tuberculosis, remain a concern in patients who have undergone KT in terms of successful long-term outcomes [1, 13]. Only a small number of cases of post-KT cryptococcosis have been reported in mainland China [9–11]. In the present study, 37 patients diagnosed with post-KT cryptococcosis and their characteristics were analyzed.\n\nOur findings showed that cryptococcosis in KT recipients is typically a late-occurring infection. Approximately 81.1% patients (30/37) had cryptococcosis onset after >2 years following KT. These findings are in agreement with those of previous reports [1, 5, 9, 14]. The results of a multicenter prospective surveillance from the United States [1] showed that the median time for cryptococcosis onset is 575 days following KT, and 75% of the cases occurred >3 years following KT. Another large retrospective cohort study from the United States showed the median time of cryptococcosis onset is 616 days following KT [14], similar to the findings of a recent overview of cryptococcosis following KT in China [9], which revealed that 93.1% of the infections occurred >1 year following transplantation and 79.3% occurred >3 years following transplantation. According to the literature, the majority of cryptococcosis onset in KT recipients is late and is generally considered to represent the reactivation of a latent infection [1, 14]; however, early-onset infections may reflect donor-derived infections [15, 16].\n\nPrevious studies [4, 9, 17, 18] have shown that the majority of cryptococcal infections in KT recipients involve the CNS, lungs, skin, and soft tissue. The present study also revealed that the most common site is the CNS, followed by the lungs, skin, and soft tissue. Similar to the findings of a previous study [9], fever, headache, vomiting, and altered mental status were found to be the most common clinical manifestations of post-KT CM.\n\nAccording to the IDSA guidelines from 2010 [12], induction therapy with the liposomal-AMB or AMB lipid complex combined with 5-FC is recognised as the preferred regimen for CM, disseminated cryptococcosis, and severe pulmonary cryptococcosis in SOT recipients. However, in the present study, apparent differences exist between the regime we adopted and those recommended in the guidelines. 7 simple cryptococcal pneumonia patients received triazole treatment. Among the 30 patients with CM or disseminated cryptococcosis, only 7 patient (23.3%, 7/30; 4 with CM and 3 with disseminated cryptococcosis) were treated with liposomal-AMB combined with 5-FC during the induction phase. A similarly low use of liposomal-AMB was reported in other Chinese centres [9] which we attribute to the fear of side effects. It is possible that the renal toxicity side effects associated with liposomal-AMB resulted in its decreased use in our population. In the present study, graft dysfunction was common in KT recipients with cryptococcosis prior to treatment initiation, and the baseline creatinine level was >176.8 μmol·L−1 in 37.8% of the patients. However, no significant difference in terms of graft loss was found between the patients who received liposomal-AMB and triazole (16.7% vs. 14.3%, p=0.88).\n\nIn the present study, the overall prognosis of cryptococcosis following KT was good. All cases of simple pulmonary infection survived following the administration of triazole treatment. Among patients with CM or disseminated cryptococcosis, the all-cause 6-month mortality rate in those who received triazole (13.0%, 3/23) was lower than that in patients who received liposomal-AMB (28.6%, 2/7); however, the difference was not statistically significant (p=0.565). The study also showed that all patients who received high-dose FLZ (800 mg daily) or VRZ ± 5-FC as the induction treatment survived.\n\nFLZ is widely used for the treatment of fungal diseases due to its effectiveness, low cost, and availability in oral and intravenous preparations. The IDSA guidelines recommend high-dose FLZ (≥800 mg daily), either alone or with other antifungal drugs, as an alternative anticryptococcal choice. It is also recommended for CM as consolidation and maintenance therapy and for mild-to-moderate pulmonary cryptococcosis [12]. VRZ is a triazole with a broad spectrum of antifungal activity but is not currently licensed for use for cryptococcosis. Case studies have demonstrated the successful treatment of CM with VRZ [19–22]. In vitro activities of VRZ [23, 24] show its better activity against Cryptococcus neoformans than itraconazole and FLZ, suggesting that VRZ is useful in the treatment of cryptococcosis.\n\nOur study suggested that high-dose FLZ or VRZ alone or with 5-FC may be used as an alternative therapy for post-KT cryptococcosis. However, further investigations on optimizing antifungal treatment and preventing the interaction of triazole with immunosuppressive agents among KT recipients in China should be carried out in the future.\n\nThe present study has several limitations. The study was designed as a retrospective study performed at a single tertiary hospital. Furthermore, it reflected a single-centre experience and the number of enrolled patients was relatively small, which may have led to several biases. Therefore, whether our findings are representative of the entire Chinese population is uncertain. Further large multicentre and prospective studies are required to obtain accurate data regarding cryptococcosis in KT recipients in the Chinese population.\n\nIn conclusion, most patients with post-KT cryptococcosis experienced cryptococcosis onset >2 years following KT at our hospital. The CNS, pulmonary system, and skin are the main sites of infection. Triazole can be used as an alternative therapy for post-KT cryptococcosis.\n\nAcknowledgments\nWe are thankful to the clinical and technical staff of the First Affiliated Hospital, College of Medicine, Zhejiang University, for their cooperation in this study. This work was supported by the National Science and Technology Major Project (2017ZX10204401001002 and 2017ZX10204401002002) and Zhejiang Provincial Natural Science Foundation of China (LQ19H190001).\n\nData Availability\nThe data used to support the findings of this study are included within the article.\n\nConflicts of Interest\nThe authors declare that there are no conflicts of interest.\n\nFigure 1 A 53-year-old woman with cryptococcal meningitis with a history of KT 12 years ago. Brain MRI shows local lesions in the right basal ganglion and frontal lobe. (a) Axial T2-weighted image showing a high signal. (b) Axial T1-weighted image showing a low signal.\n\nFigure 2 A 20-year-old woman with a history of KT 4 years ago. (a) Chest CT in the lung window shows subpleural multiple nodules, some with cavitations, located in bilateral lungs. (b) Follow-up chest CT (2 months after antifungal treatment) shows the resolution of the pulmonary lesions.\n\nTable 1 Demographic and clinical data of KT recipients with cryptococcosis (n = 37).\n\nVariable\t\nN (%)\t\nMale sex\t23 (62.3%)\t\n\n\n\t\nAge at diagnosis (years)\t49.5 ± 9.38\t\n\n\n\t\nUnderlying diseases\t \t\n Hypertension\t15 (40.5%)\t\n Chronic viral hepatitis B\t10 (27.0%)\t\n Type 2 diabetes\t5 (13.5%)\t\n Chronic viral hepatitis C\t3 (8.1%)\t\n Systemic lupus erythematosus\t1 (2.7%)\t\n\n\n\t\nImmunosuppressive regimen\t \t\n Prednisone\t37 (100%)\t\n Mycophenolate mofetil\t30 (80.1%)\t\n Mycophenolic acid\t1 (2.7%)\t\n Tacrolimus\t29 (78.4%)\t\n Cyclosporine A\t8 (21.6%)\t\n Azathioprine\t2 (5.4%)\t\n Leflunomide\t2 (5.4%)\t\n Rapamycin\t2 (5.4%)\t\n\n\n\t\nPosttransplantation time to diagnosis of cryptococcosis (years)\t7.0 ± 5.50\t\n <2 year\t7 (18.9%)\t\n >2 years\t30 (81.1%)\t\n\n\n\t\nOrgan involvement\t \t\n Central nervous system\t26 (70.3%)\t\n Lungs\t18 (48.6%)\t\n Skin\t2 (5.4%)\t\n\n\n\t\nDisseminated cryptococcosis\t17 (45.9%)\t\n\n\n\t\nCryptococcemia\t10 (27.0%)\t\n\n\n\t\nBaseline creatinine level (μmol·L−1)\t202.90 ± 153.40\t\nTable 2 Six-month outcome of cryptococcosis with different initial antifungal therapies.\n\nInitial therapy\tTotal\tCM or disseminated cryptococcosis\tLung disease only\t\nTotal\tEvaluated\tDeath\tMortality (%)\tEvaluated\tDeath\tMortality (%)\tEvaluated\tDeath\tMortality\t\nLiposomal-AMB + 5-FC\t7\t7\t2\t28.6\t7\t2\t28.6\t0\t0\t0\t\nFLZ ± 5-FC\t22\t22\t3\t13.6\t17\t3\t17.6\t5\t0\t0\t\n FLZ 400 mg daily ± 5-FC\t18\t18\t3\t16.7\t14\t3\t21.3\t4\t0\t0\t\n FLZ 800 mg daily ± 5-FC\t4\t4\t0\t0\t3\t0\t0\t1\t0\t0\t\nVRZ ± 5-FC\t7\t7\t0\t0\t5\t0\t0\t2\t0\t0\t\nItraconazole\t1\t1\t0\t0\t1\t0\t0\t0\t0\t0\n==== Refs\n1 Pappas P. G. Alexander B. D. Andes D. R. Invasive fungal infections among organ transplant recipients: results of the transplant-associated infection surveillance network (TRANSNET) Clinical Infectious Diseases 2010 50 8 1101 1111 10.1086/651262 2-s2.0-77950278696 20218876 \n2 Gassiep I. McDougall D. Douglas J. Francis R. Playford E. G. Cryptococcal infections in solid organ transplant recipients over a 15-year period at a state transplant center Transplant Infectious Disease 2017 19 1 e12639 10.1111/tid.12639 2-s2.0-85013655143 \n3 Chen M. Xu Y. Hong N. Epidemiology of fungal infections in China Frontiers of Medicine 2018 12 1 58 75 10.1007/s11684-017-0601-0 2-s2.0-85041119784 29380297 \n4 Sun H. Y. Wagener M. M. Singh N. Cryptococcosis in solid-organ, hematopoietic stem cell, and tissue transplant recipients: evidence-based evolving trends Clinical Infectious Diseases 2009 48 11 1566 1576 10.1086/598936 2-s2.0-66949141155 19402789 \n5 Neofytos D. Fishman J. A. Horn D. Epidemiology and outcome of invasive fungal infections in solid organ transplant recipients Transplant Infectious Disease 2010 12 3 220 229 10.1111/j.1399-3062.2010.00492.x 2-s2.0-77953215487 20113459 \n6 Singh N. Dromer F. Perfect J. R. Lortholary O. Immunocompromised hosts: cryptococcosis in solid organ transplant recipients: current state of the science Clinical Infectious Diseases 2008 47 10 1321 1327 10.1086/592690 2-s2.0-54249083471 18840080 \n7 Shi B. Y. L. Z. Kidney transplantation: from quality control to quality improvement plan Chinese Journal of Transplantation 2018 12 97 101 in Chinese \n8 Yuchong C. Fubin C. Jianghan C. Cryptococcosis in China (1985–2010): review of cases from Chinese database Mycopathologia 2012 173 329 335 10.1007/s11046-011-9471-1 2-s2.0-84860586453 21979866 \n9 Yang Y.-L. Chen M. Gu J.-L. Cryptococcosis in kidney transplant recipients in a Chinese university hospital and a review of published cases International Journal of Infectious Diseases 2014 26 154 161 10.1016/j.ijid.2014.05.028 2-s2.0-84907331302 25063020 \n10 Chen M. Wang X. Yu X. Pleural effusion as the initial clinical presentation in disseminated cryptococcosis and fungaemia: an unusual manifestation and a literature review BMC Infectious Diseases 2015 15 p. 385 10.1186/s12879-015-1132-4 2-s2.0-84944281188 \n11 Sang H. Zhou W. Q. Shi Q. L. Zhang X. H. Ni R. Z. Disseminated cryptococcosis with extensive subcutaneous nodules in a renal transplant recipient Chinese Medical Journal 2004 117 10 1595 1596 15498395 \n12 Perfect J. R. Dismukes W. E. Dromer F. Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the infectious diseases society of America Clinical Infectious Diseases 2010 50 3 291 322 10.1086/649858 2-s2.0-75749092958 20047480 \n13 Wu W. Yang M. Xu M. Diagnostic delay and mortality of active tuberculosis in patients after kidney transplantation in a tertiary care hospital in China PLoS One 2018 13 4 e0195695 10.1371/journal.pone.0195695 2-s2.0-85045510832 \n14 George I. Santos C. Olsen M. A. Powderly W. G. Epidemiology of cryptococcosis and cryptococcal meningitis in a large retrospective cohort of patients after solid organ transplantation Open Forum Infectious Diseases 2017 4 ofx004 \n15 Camargo J. F. Simkins J. Schain D. C. A cluster of donor-derived Cryptococcus neoformans infection affecting lung, liver, and kidney transplant recipients: case report and review of literature Transplant Infectious Disease 2018 20 e12836 10.1111/tid.12836 2-s2.0-85041837480 \n16 Baddley J. W. Schain D. C. Gupte A. A. Transmission of Cryptococcus neoformans by organ transplantation Clinical Infectious Diseases 2011 52 4 e94 e98 10.1093/cid/ciq216 2-s2.0-79951815654 21220771 \n17 Husain S. Wagener M. M. Singh N. \nCryptococcus neoformans infection in organ transplant recipients: variables influencing clinical characteristics and outcome Emerging Infectious Diseases 2001 7 3 375 381 10.3201/eid0703.010302 11384512 \n18 Ponzio V. Camargo L. F. Medina-Pestana J. Perfect J. R. Colombo A. L. Outcomes of cryptococcosis in renal transplant recipients in a less-resourced health care system Transplant Infectious Disease 2018 20 4 e12910 10.1111/tid.12910 2-s2.0-85047750492 \n19 Li S.-S. Tang X.-Y. Zhang S.-G. Ni S.-L. Yang N.-B. Lu M.-Q. Voriconazole combined with low-dose amphotericin B liposome for treatment of cryptococcal meningitis Infectious Diseases 2016 48 7 563 565 10.3109/23744235.2016.1157897 2-s2.0-84978760192 27044559 \n20 Yao Y. Zhang J.-T. Yan B. Voriconazole: a novel treatment option for cryptococcal meningitis Infectious Diseases 2015 47 10 694 700 10.3109/23744235.2015.1044260 2-s2.0-84962564054 26100526 \n21 Bandettini R. Castagnola E. Calvillo M. Voriconazole for cryptococcal meningitis in children with leukemia or receiving allogeneic hemopoietic stem cell transplant Journal of Chemotherapy 2009 21 1 108 109 10.1179/joc.2009.21.1.108 2-s2.0-63049099731 19297284 \n22 Sabbatani S. Manfredi R. Pavoni M. Consales A. Chiodo F. Voriconazole proves effective in long-term treatment of a cerebral cryptococcoma in a chronic nephropathic HIV-negative patient, after fluconazole failure Mycopathologia 2004 158 2 165 171 10.1023/b:myco.0000041904.71381.e3 2-s2.0-4544318239 15518344 \n23 Pfaller M. A. Zhang J. Messer S. A. In vitro activities of voriconazole, fluconazole, and itraconazole against 566 clinical isolates of Cryptococcus neoformans from the United States and Africa Antimicrobial Agents and Chemotherapy 1999 43 1 169 171 10.1128/aac.43.1.169 9869586 \n24 Xiao M. Chen S. C. A. Kong F. Five-year China Hospital Invasive Fungal Surveillance Net (CHIF-NET) study of invasive fungal infections caused by noncandidal yeasts: species distribution and azole susceptibility Infection and Drug Resistance 2018 11 1659 1667 10.2147/idr.s173805 2-s2.0-85057577090 30349323\n\n",
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"title": "Cryptococcosis in Patients following Kidney Transplantation: A 9-Year Retrospective Clinical Analysis at a Chinese Tertiary Hospital.",
"title_normalized": "cryptococcosis in patients following kidney transplantation a 9 year retrospective clinical analysis at a chinese tertiary hospital"
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"abstract": "Duodenal villous atrophy with olmesartan was described in 2012, 10 years following registration of olmesartan. Clinical features are severe watery diarrhoea, usually occurring in association with weight loss. Onset is delayed, with a mean duration of prior exposure to olmesartan of 3 years. Diagnosis may be delayed. Symptoms resolve over weeks following cessation of olmesartan. Epidemiological studies suggest increased risk with olmesartan, rather than a class effect of all angiotensin receptor blockers. Post-marketing surveillance for drug safety remains important.",
"affiliations": "Royal Adelaide Hospital, Central Adelaide Local Health Network, Adelaide, South Australia, Australia.;Drug Information Service, Pharmacy, Central Adelaide Local Health Network, Adelaide, South Australia, Australia.;Acute and Urgent Care, Royal Adelaide Hospital, Adelaide, South Australia, Australia.",
"authors": "Shukla|Nupur|N|;Moore|Kylies|K|;Gabb|Genevieve M|GM|0000-0002-2969-7900",
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"mesh_terms": "D047228:Angiotensin II Type 1 Receptor Blockers; D000959:Antihypertensive Agents; D001284:Atrophy; D006801:Humans; D006973:Hypertension; D007093:Imidazoles; D000068557:Olmesartan Medoxomil; D013777:Tetrazoles",
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"title": "Olmesartan-associated duodenal villous atrophy, an emerging clinical issue.",
"title_normalized": "olmesartan associated duodenal villous atrophy an emerging clinical issue"
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"abstract": "Invasive pulmonary aspergillosis is increasingly described in non-neutropenic patients, such as patients with COPD receiving corticosteroids and the critically ill. Here, we present a case of a lethal pulmonary Aspergillus niger infection in a COPD patient. Immunological tests showed an impaired innate and adaptive immune response to Aspergillus. A history of COPD, unresponsiveness to antibiotics and especially a suggestive CT-scan should trigger the clinician to consider diseases caused by Aspergillus.",
"affiliations": "Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.;Department of Pulmonology, Radboud University Medical Center, Nijmegen, The Netherlands.;Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.;Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.;Department of Intensive Care Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.;Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.;Department of Pulmonology, Radboud University Medical Center, Nijmegen, The Netherlands.;Department of Medical Microbiology, Radboud University Medical Center, Nijmegen, The Netherlands.",
"authors": "Workum|Jessica D|JD|;de Jong|Suzanne W|SW|;Gresnigt|Mark S|MS|;Becker|Katharina L|KL|;Pickkers|Peter|P|;van de Veerdonk|Frank L|FL|;Heijdra|Yvonne F|YF|;Kolwijck|Eva|E|",
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"fulltext": "\n==== Front\nMed Mycol Case RepMed Mycol Case RepMedical Mycology Case Reports2211-7539Elsevier S2211-7539(18)30020-410.1016/j.mmcr.2018.03.002Case ReportMicrobiological and immunological characteristics of a lethal pulmonary Aspergillus niger infection in a non-neutropenic patient Workum Jessica D. ab1de Jong Suzanne W. c1Gresnigt Mark S. aBecker Katharina L. aPickkers Peter bvan de Veerdonk Frank L. aHeijdra Yvonne F. cKolwijck Eva eva.kolwijck@radboudumc.nld⁎a Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlandsb Department of Intensive Care Medicine, Radboud University Medical Center, Nijmegen, The Netherlandsc Department of Pulmonology, Radboud University Medical Center, Nijmegen, The Netherlandsd Department of Medical Microbiology, Radboud University Medical Center, Nijmegen, The Netherlands⁎ Corresponding author. eva.kolwijck@radboudumc.nl1 Contributed equally.\n\n07 3 2018 9 2018 07 3 2018 21 4 7 29 12 2017 18 2 2018 1 3 2018 © 2018 The Authors2018This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Invasive pulmonary aspergillosis is increasingly described in non-neutropenic patients, such as patients with COPD receiving corticosteroids and the critically ill. Here, we present a case of a lethal pulmonary Aspergillus niger infection in a COPD patient. Immunological tests showed an impaired innate and adaptive immune response to Aspergillus. A history of COPD, unresponsiveness to antibiotics and especially a suggestive CT-scan should trigger the clinician to consider diseases caused by Aspergillus.\n\nKeywords\nInvasive pulmonary aspergillosisAspergillus nigerImmune systemIntensive care unitOxalate crystal\n==== Body\n1 Introduction\nInvasive pulmonary aspergillosis (IPA), defined as lung parenchyma invasion and necrosis due to Aspergillus, is known to be a life-threatening infection in severely immunocompromised patients with significant mortality of 25–50% [1], [2]. IPA has been increasingly reported in non-neutropenic patients, such as patients with COPD receiving corticosteroids, decompensated liver cirrhosis, and patients in the intensive care unit (ICU) [3], [4], [5]. The diagnosis of IPA in non-neutropenic patients is more challenging because signs and symptoms are often non-specific, risking delayed diagnosis. Here, we describe a case of lethal pulmonary aspergillosis due to Aspergillus niger complex in a COPD patient and studied the innate and adaptive immune response. Furthermore, we reviewed the microbiological characteristics of invasive pulmonary A. niger complex infections.\n\n2 Case\nA 55-year-old woman was admitted to a district hospital (day 0) with progressive cough and hemoptysis for four days. She had no relevant prior medical history other than COPD Gold II, recently diagnosed and yet untreated, and she was a heavy smoker. A chest X-ray performed on day 0 showed a cavitary lesion in the apex of the left lung, suggestive for tuberculosis. A broncho-alveolar lavage (BAL) was performed on day + 1. Ziehl-Neelsen staining for Mycobacteria was negative. Pending sputum and BAL cultures, the patient received amoxicillin/clavulanic acid and was discharged from the hospital. On day + 5, she presented to the emergency department of the same district hospital with fever, thoracic pain and severe dyspnea. Blood panel showed leukocytosis (26.5∙109/L (4.0–10.0∙109/L) with 89% polymorphonuclear cells (PMN)), C-reactive protein (CRP) of 436 mg/L (< 10 mg/L), a creatinin level of 282μmol/L (45–80μmol/L) and lactate of 2.7 mmol/L (0.5–1.6 mmol/L). The sputum and BAL cultures taken on day + 1 grew solely A. niger, which was considered contamination. The patient was admitted and treated with intravenous broad-spectrum antibiotics (flucloxacillin 1000 mg q8h and ciprofloxacin 400 mg q12h) as well as prednisone 50 mg q24h for exacerbation of COPD. On the same day, she was transferred to the ICU due to progressive respiratory failure and hemodynamic instability, requiring mechanical ventilation and hemodialysis. A thoracic computed tomography (CT) showed severe consolidations with cavities in the apex of the left lung and apical bullae in the right lung, parenchymal damage and pleural thickning (Fig. 1A). A CT-guided aspiration of one of the cavities revealed hyphae, suggestive for Aspergillus. The extensive cavitation, pleural thickening and parenchymal damage on the CT scan suggested either a previously undiagnosed chronic cavitary pulmonary aspergillosis (CCPA), presenting with an acute exacerbation, or a subacute invasive aspergillosis (SAIA).Fig. 1 A. Pulmonary CT-scan on day + 5 of admission showing dense alveolar consolidations in the apex of the left lung with multiple central and subpleural fluid filled cavities and apical bullae in the right lung. B. Calcium oxalate crystal deposition in bronchial debris obtained during broncho-suction. Magnification 400 × ; H&E stain. C. Innate and adaptive cytokine response to A. niger. IL-1β, TNFα, IL-6, IL-1Ra (top), IL-17, IL-22 and IFNγ (bottom) levels measured by ELISA in culture supernatants of PBMCs isolated from a healthy volunteer (black bars) and patient (grey bars) stimulated with live (top) or heat-inactivated (bottom) A. niger conidia for 24 h (top) or 7 days (bottom). D. Functional assessment of the antifungal host response. Top: IL-1β and TNFα measured by ELISA in culture supernatants of PBMCs isolated from a healthy volunteer (black bars) and patient (grey bars) stimulated for 24 h with LPS, Pam3Cys, β-glucan and β-glucan/Pam3Cys combination. Bottom left: Percentage of FITC-positive neutrophils measured by flowcytometry after 20 min exposure to FITC-labeled A. fumigatus conidia or C. albicans blastoconidia. Bottom right: Fungal killing capacity, measured by counted CFUs on sabouraud agar plated after exposure of live A. niger (1 × 105 conidia) to neutrophils (1 × 106 conidia) from a healthy volunteer (black dots) and patient (grey dots) for 24 h.\n\nFig. 1\n\nThat same day (day + 5), intravenous voriconazole 200 mg q12h was started. Blood cultures remained negative. On day + 7 she was transferred to our university medical center ICU due to progressive renal failure for which she needed continuous veno-venous hemofiltration (CVVH). At arrival, she required volume controlled mechanical ventilation, with FiO2 of 90% for 95% oxygen saturation, and had a respiratory acidosis with severe hypercapnia (pCO2 10.3 kPa (4.7–6.4kPa)). Since it was not possible to decrease FiO2, the patient was ventilated in prone position, initially with good response. A follow-up CT-scan on day + 9 showed increased destruction of the left lung. The antibiotic regimen was switched to piperacillin/tazobactam 4000/500 mg q12h intravenously and the corticosteroids were tapered down. During admission at our ICU, the patient produced excessive amounts of brown sputum, over 500 mL/day. Consecutive sputum cultures taken at our hospital all grew A. niger. The A. niger isolate cultured from the BAL on day + 1 and all following isolates tested resistant to voriconazole using epidemiological cut-off values of 2 mg/L according to EUCAST (A. niger minimum inhibitory concentration (MIC) 4 mg/L). On day + 10, based on the susceptibility testing results, antifungal treatment was switched to intravenous liposomal amphotericin B 3 mg/kg q24h (MIC 0.5 mg/L). As respiratory failure progressed, intravenous micafungin 100 mg q24h was added on day + 12.\n\nStandard immunological tests were performed on day + 8 to determine possible underlying immune deficiencies. Auto-antibody tests, HIV serology, white blood cell count (differential values and CD4 + ), complement system markers (CH50 and AP50), and immunoglobulins (IgA, IgM and IgG including subclasses) showed no abnormalities.\n\nOn day + 25, the patient became progressively hemodynamically unstable. Due to lack of respiratory improvement and poor prognosis, it was decided in accordance with the family to cease treatment. The patient was extubated and died soon thereafter. Autopsy was not allowed.\n\n3 Discussion\n3.1 Microbiological characteristics of Aspergillus niger\nAspergillus spores are amongst the dominant fungal components found during air sampling. The primary route of human infection is via inhalation of airborne conidia, which easily reach the pulmonary alveoli, due to their small size of 2–3 µm [6]. Aspergillus fumigatus is the most common species recovered from cases of invasive aspergillosis. It has more favorable characteristics (smaller size of conidia, more thermotolerant) than Aspergillus niger, Aspergillus flavus, and Aspergillus terreus, that are responsible for 8–9% of cases [7], [8]. Taxonomy of A. niger complex is challenging as black-spored aspergilla are difficult to distinguish morphologically. Using sequencing techniques, isolates can be further divided into 19 different taxa, grouped into 5 main clades of which A. awamori, A. tubingensis and A. niger are most often isolated from clinical samples [9]. Historically, A. niger complex has been primarily associated with otomycosis and cutaneous infections. However, an increasing incidence of invasive pulmonary infections with A. niger was reported recently [8].\n\nThe virulence of Aspergillus is multifactorial and depends on both the immune status of the patient and the biological characteristics of the fungus. A. niger produces oxalic acid (oxalate) as part of its fermentation process; a feature only rarely described in other Aspergillus species [10]. Pyruvate, the end product of glycolysis, is first transformed to oxaloacetate. Then, oxaloacetate acetylhydrolase, located in the cytoplasm of A. niger, catalyzes the hydrolysis of oxaloacetate to oxalate and acetate. In the human body, oxalate precipitates with calcium, forming calcium oxalate crystals. These depositions cause tissue damage and necrosis due to obstruction in blood vessels and direct cytotoxicity through oxidative stress [10]. Rapidly developing pulmonary necrosis due to the destructive nature of calcium oxalate produced by A. niger complex [11] as well as acute renal failure due to calcium oxalate crystal deposition [12] have been reported.\n\nIn our patient, tissue obtained during bronchoscopy was described as necrotic with excessive crystal-like structures (Fig. 1B). In addition, our patient produced excessive amounts of brown sputum, which has been reported in A. niger complex infections [11]. Our clinical chemistry department confirmed large amounts of calcium oxalate crystals present in the sputum, which unfortunately was not quantified. As calcium oxalate crystals are hypertonic, this provides a possible explanation for the excessive sputum production. The appearance of black or dark brown sputum with the presence of calcium oxalate crystals on pathological examination may thus be a key feature in the diagnosis of A. niger infection. As our patient was anuric, it was not possible to examine a urine sample for the presence of calcium oxalate crystals.\n\n3.2 Immunological defense mechanisms against Aspergillus niger invasion\nThe first defense against inhaled Aspergillus conidia begins with their removal by the ciliary action of the mucosal respiratory epithelium. Damage to pulmonary epithelial cells due to inflammation, chronic lung diseases, drugs, chemotherapy, or graft-versus-host disease result in a compromised physical barrier against inhaled fungi. It is now recognized that ICU patients are also prone to IPA. Apart from a critical illness-induced suppressed immunity, mechanical ventilation reduces first line defense of airway clearance and might allow free passage of fungi into the lower segments of the lung [4]. In COPD, impaired ciliary function and chronic inflammation reduce the capacity to clear fungal spores from the lungs and thus provide a natural environment that has a predilection for Aspergillus colonization and biofilm formation [13]. Still, it remains unclear why some COPD patients are benignly colonized with Aspergillus, whereas other patients develop subacute invasive aspergillosis (SAIA).\n\nTo investigate whether the severity of the infection in our patient could be attributed to an immune defect, we tested her A. niger innate and adaptive immune responses. First, peripheral blood mononuclear cells (PBMCs) were isolated and stimulated with A. niger CBS 101,706 live conidia and heat killed 1 × 107 conidia/mL. A slightly lower, but comparable innate cytokine response of our patient to live A. niger conidia was observed when compared to a healthy volunteer. (Fig. 1C).\n\nThe function of several pattern recognition receptors, known to be involved in the antifungal host defense to A. fumigatus\n[14], was investigated by stimulating PBMCs with specific ligands, including (lipopolysaccharide) LPS (TLR4), lipopeptide Pam3Cys (TLR2), β-glucan (dectin-1) and a combination of Pam3Cys/β-glucan. PBMCs of the patient demonstrated an adequate response to stimulation of TLR2 (Fig. 1D). It is known that TLR2 synergizes with dectin-1 [15] that can be observed by stimulating PBMCs with the combination of Pam3Cys and β-glucan (Fig. 1C). Although this synergistic effect was not observed in IL-1β production, it could be observed for TNFα. In contrast, stimulation with the TLR4 agonist LPS revealed much less cytokine induction indicating a possible impaired TLR4 function (Fig. 1D). In addition, we observed completely impaired T-helper cytokine production in response to A. niger, whereas the control produced significant concentration of T helper cytokines (Fig. 1C).\n\nImpaired neutrophil phagocytosis and killing, as seen in chronic granulomatous disease, might also play a role in the severity of the disease in our patient. PMNs were isolated from whole blood by hypotonic lysis. PMNs of the patient and a healthy volunteer were incubated with fluorescein isothiocyanate (FITC)-labeled A. fumigatus V05–27 (heat killed) and FITC-labeled heat-killed Candida albicans ATCC MYA-3573 (UC 820) at a final concentration of 2.5 × 107 /mL in a volume of 200 μL for 30 min at 37 °C and 5% CO2. The percentage of neutrophils that phagocytosed the fungi was quantified by a FC 500 flowcytometer. Fig. 1D shows 12% less FITC-positivity of the patient neutrophils compared to the healthy control when exposed to A. fumigatus, suggesting a slightly lower capacity to phagocytose A. fumigatus. Additionally, PMNs were co-cultured with live A. niger conidia (1 × 106) to investigate the killing capacity of the patient's neutrophils. After 24 h incubation at 37 °C and 5% CO2 higher numbers of colony forming units (CFUs) were counted in the patient's cells, indicating a decreased killing ability compared to healthy control. As corticosteroids are known to impair (monocyte) phagocytosis of Aspergillus spp. [16], it can therefore not be determined with certainty that our patient had a previously undiagnosed immune deficiency.\n\n4 Conclusion\nInvasive pulmonary aspergillosis is increasingly observed in non-neutropenic patients who appear only moderately immunocompromised. We presented a case of pulmonary aspergillosis, caused by Aspergillus niger complex, most likely either an acute exacerbation of CCPA or a SAIA, which could not be distinguished as our patient had no prior medical history apart from the very recent diagnosis of COPD. Immunological function tests showed impairment in both innate and adaptive immune system in our patient, which could either be an indication of a previously undiagnosed immune deficiency, or could be attributed to high dose of corticosteroid use. In view of the high mortality, a history of COPD, unresponsiveness to antibiotics and especially a suggestive CT-scan should trigger the clinician to consider diseases caused by opportunistic pathogens, such as Aspergillus species, to prevent treatment delays.\n\nConflict of interest\nThere are none.\n==== Refs\nReferences\n1 Bitar D. Lortholary O. Le Strat Y. Nicolau J. Coignard B. Tattevin P. Population-based analysis of invasive fungal infections, France, 2001–2010 Emerg. Infect. Dis. 20 7 2014 1149 1155 24960557 \n2 Nivoix Y. Velten M. Letscher-Bru V. Moghaddam A. Natarajan-Ame S. Fohrer C. Factors associated with overall and attributable mortality in invasive aspergillosis Clin. Infect. Dis. Off. Publ. Infect. Dis. Soc. Am. 47 9 2008 1176 1184 \n3 Bulpa P.A. Dive A.M. Garrino M.G. Delos M.A. Gonzalez M.R. Evrard P.A. Chronic obstructive pulmonary disease patients with invasive pulmonary aspergillosis: benefits of intensive care? Intensive care Med. 27 1 2001 59 67 11280674 \n4 Meersseman W. Lagrou K. Maertens J. Van Wijngaerden E. Invasive aspergillosis in the intensive care unit Clin. Infect. Dis. Off. Publ. Infect. Dis. Soc. Am. 45 2 2007 205 216 \n5 Wauters J. Baar I. Meersseman P. Meersseman W. Dams K. De Paep R. Invasive pulmonary aspergillosis is a frequent complication of critically ill H1N1 patients: a retrospective study Intensive care Med. 38 11 2012 1761 1768 22895826 \n6 Latge J.P. Aspergillus fumigatus and aspergillosis Clin. Microbiol. Rev. 12 2 1999 310 350 10194462 \n7 Dagenais T.R. Keller N.P. Pathogenesis of aspergillus fumigatus in invasive aspergillosis Clin. Microbiol. Rev. 22 3 2009 447 465 19597008 \n8 Vermeulen E. Maertens J. Meersseman P. Saegeman V. Dupont L. Lagrou K. Invasive aspergillus niger complex infections in a Belgian tertiary care hospital Clin. Microbiol. Infect. Off. Publ. Eur. Soc. Clin. Microbiol. Infect. Dis. 20 5 2014 O333 O335 \n9 Howard S.J. Harrison E. Bowyer P. Varga J. Denning D.W. Cryptic species and azole resistance in the aspergillus niger complex Antimicrob. Agents Chemother. 55 10 2011 4802 4809 21768508 \n10 Pabuccuoglu U. Aspects of oxalosis associated with aspergillosis in pathology specimens Pathol. Res. Pract. 201 5 2005 363 368 16047945 \n11 Kimmerling E.A. Fedrick J.A. Tenholder M.F. Invasive Aspergillus niger with fatal pulmonary oxalosis in chronic obstructive pulmonary disease Chest 101 3 1992 870 872 1541168 \n12 Vaideeswar P. Sakhdeo U.M. Pulmonary aspergilloma with renal oxalosis: fatal effect at a distance Mycoses 52 3 2009 272 275 18643917 \n13 Ramage G. Rajendran R. Gutierrez-Correa M. Jones B. Williams C. Aspergillus biofilms: clinical and industrial significance FEMS Microbiol. Lett. 324 2 2011 89 97 22092808 \n14 Chai L.Y. Vonk A.G. Kullberg B.J. Verweij P.E. Verschueren I. van der Meer J.W. Aspergillus fumigatus cell wall components differentially modulate host TLR2 and TLR4 responses Microbes Infect. Inst. Pasteur 13 2 2011 151 159 \n15 Ferwerda G. Meyer-Wentrup F. Kullberg B.J. Netea M.G. Adema G.J. Dectin-1 synergizes with TLR2 and TLR4 for cytokine production in human primary monocytes and macrophages Cell. Microbiol. 10 10 2008 2058 2066 18549457 \n16 Kyrmizi I. Gresnigt M.S. Akoumianaki T. Samonis G. Sidiropoulos P. Boumpas D. Corticosteroids block autophagy protein recruitment in aspergillus fumigatus phagosomes via targeting dectin-1/Syk kinase signaling J. Immunol. 191 3 2013 1287 1299 23817424\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2211-7539",
"issue": "21()",
"journal": "Medical mycology case reports",
"keywords": "Aspergillus niger; Immune system; Intensive care unit; Invasive pulmonary aspergillosis; Oxalate crystal",
"medline_ta": "Med Mycol Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101598259",
"other_id": null,
"pages": "4-7",
"pmc": null,
"pmid": "29984147",
"pubdate": "2018-09",
"publication_types": "D016428:Journal Article",
"references": "19597008;22092808;18643917;20971208;18808352;18549457;23817424;24102876;21768508;24960557;1541168;17578780;11280674;22895826;16047945;10194462",
"title": "Microbiological and immunological characteristics of a lethal pulmonary Aspergillus niger infection in a non-neutropenic patient.",
"title_normalized": "microbiological and immunological characteristics of a lethal pulmonary aspergillus niger infection in a non neutropenic patient"
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"abstract": "Long-acting muscarinic antagonist (LAMA) and long-acting β2-agonist (LABA) bronchodilators are key to the pharmacologic treatment of chronic obstructive pulmonary disease (COPD). This Phase IIb study investigated the safety and efficacy of four doses of the LAMA glycopyrronium (GP) delivered using co-suspension delivery technology via metered dose inhaler (MDI). The study was part of a wider clinical trial program performed to determine the optimal dose of GP MDI, the LABA formoterol fumarate dihydrate (FF) MDI, and glycopyrronium/formoterol fumarate dihydrate (GFF) MDI fixed-dose combination to be taken forward into Phase III studies.\n\n\n\nIn this randomized, double-blind, 7-day chronic-dosing, three-period incomplete block, cross-over study, patients with moderate-to-severe COPD received two of the four doses of GP MDI (28.8 μg, 14.4 μg, 7.2 μg, and 3.6 μg) twice daily (BID), and either placebo MDI BID or open-label ipratropium MDI 34 μg four times daily. The primary efficacy endpoint was forced expiratory volume in 1 s (FEV1) area under the curve from 0 to 12 h (AUC0-12) relative to baseline on Day 7. Secondary and exploratory efficacy endpoints were assessed on Days 1 and 7. Safety and tolerability were evaluated throughout the study.\n\n\n\nAll GP MDI treatments were superior to placebo MDI for the primary efficacy endpoint (all p < 0.0001). However, only GP MDI 28.8 μg and 14.4 μg demonstrated statistical superiority to placebo MDI for all secondary efficacy endpoints analyzed in this study, with the exception of GP MDI 14.4 μg versus placebo MDI for the proportion of patients achieving ≥12% improvement in FEV1. No nominally significant differences were observed between GP MDI 28.8 μg and GP MDI 14.4 μg for any of the endpoints. All doses of GP MDI were well tolerated, with no unexpected safety findings.\n\n\n\nThis study indicated that there was no advantage of GP MDI 28.8 μg compared with GP MDI 14.4 μg. It therefore added to the evidence from the Phase I/II clinical trial program, which identified GP MDI 14.4 μg as the most appropriate dose for use in the Phase III clinical studies.\n\n\n\nClinicalTrials.gov (NCT01350128). Registered May 09, 2011.",
"affiliations": "Clinical Research Institute of Southern Oregon, Medford, OR, USA. ekerwin@criresearch.com.;American Health Research, Charlotte, NC, USA.;Everest Clinical Research, Little Falls, NJ, USA.;Pearl - A member of the AstraZeneca Group, Morristown, NJ, USA.;Pearl - A member of the AstraZeneca Group, Morristown, NJ, USA.",
"authors": "Kerwin|Edward M|EM|;Spangenthal|Selwyn|S|;Kollar|Christine|C|;St Rose|Earl|E|;Reisner|Colin|C|",
"chemical_list": "D001993:Bronchodilator Agents; D018727:Muscarinic Antagonists; D006024:Glycopyrrolate",
"country": "England",
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"doi": "10.1186/s12931-018-0739-6",
"fulltext": "\n==== Front\nRespir ResRespir. ResRespiratory Research1465-99211465-993XBioMed Central London 73910.1186/s12931-018-0739-6ResearchA phase IIb randomized, chronic-dosing, incomplete block, cross-over study of glycopyrronium, delivered via metered dose inhaler, compared with a placebo and an active control in patients with moderate-to-severe COPD Kerwin Edward M. +1 541 858 1003ekerwin@criresearch.com 1Spangenthal Selwyn sspangenthal@charlottelung.com 2Kollar Christine ckollar@ecrscorp.com 3St Rose Earl estrose@pearltherapeutics.com 4Reisner Colin creisner@pearltherapeutics.com 451 Clinical Research Institute of Southern Oregon, Medford, OR USA 2 American Health Research, Charlotte, NC USA 3 Everest Clinical Research, Little Falls, NJ USA 4 Pearl – A member of the AstraZeneca Group, Morristown, NJ USA 5 grid.418152.bAstraZeneca, Gaithersburg, MD USA 5 3 2018 5 3 2018 2018 19 3819 12 2017 13 2 2018 © The Author(s). 2018Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nLong-acting muscarinic antagonist (LAMA) and long-acting β2-agonist (LABA) bronchodilators are key to the pharmacologic treatment of chronic obstructive pulmonary disease (COPD). This Phase IIb study investigated the safety and efficacy of four doses of the LAMA glycopyrronium (GP) delivered using co-suspension delivery technology via metered dose inhaler (MDI). The study was part of a wider clinical trial program performed to determine the optimal dose of GP MDI, the LABA formoterol fumarate dihydrate (FF) MDI, and glycopyrronium/formoterol fumarate dihydrate (GFF) MDI fixed-dose combination to be taken forward into Phase III studies.\n\nMethods\nIn this randomized, double-blind, 7-day chronic-dosing, three-period incomplete block, cross-over study, patients with moderate-to-severe COPD received two of the four doses of GP MDI (28.8 μg, 14.4 μg, 7.2 μg, and 3.6 μg) twice daily (BID), and either placebo MDI BID or open-label ipratropium MDI 34 μg four times daily. The primary efficacy endpoint was forced expiratory volume in 1 s (FEV1) area under the curve from 0 to 12 h (AUC0–12) relative to baseline on Day 7. Secondary and exploratory efficacy endpoints were assessed on Days 1 and 7. Safety and tolerability were evaluated throughout the study.\n\nResults\nAll GP MDI treatments were superior to placebo MDI for the primary efficacy endpoint (all p < 0.0001). However, only GP MDI 28.8 μg and 14.4 μg demonstrated statistical superiority to placebo MDI for all secondary efficacy endpoints analyzed in this study, with the exception of GP MDI 14.4 μg versus placebo MDI for the proportion of patients achieving ≥12% improvement in FEV1. No nominally significant differences were observed between GP MDI 28.8 μg and GP MDI 14.4 μg for any of the endpoints. All doses of GP MDI were well tolerated, with no unexpected safety findings.\n\nConclusions\nThis study indicated that there was no advantage of GP MDI 28.8 μg compared with GP MDI 14.4 μg. It therefore added to the evidence from the Phase I/II clinical trial program, which identified GP MDI 14.4 μg as the most appropriate dose for use in the Phase III clinical studies.\n\nTrial registration\nClinicalTrials.gov (NCT01350128). Registered May 09, 2011.\n\nKeywords\nBronchodilatorChronic obstructive pulmonary diseaseCo-suspension delivery technologyGlycopyrroniumLong-acting β2-agonistLong-acting muscarinic antagonistMetered dose inhalerPearl Therapeutics Inc., a member of the AstraZeneca Groupissue-copyright-statement© The Author(s) 2018\n==== Body\nBackground\nChronic obstructive pulmonary disease (COPD) is a commonly occurring disease characterized by persistent respiratory symptoms and airflow limitation [1]. The treatment of stable COPD aims to decrease both symptoms and the risk of exacerbations in patients, and mainly relies on the use of long-acting muscarinic antagonist (LAMA) and long-acting β2-agonist (LABA) bronchodilators [1].\n\nGlycopyrronium/formoterol fumarate dihydrate (GFF) metered dose inhaler (MDI) 14.4/10 μg (Bevespi Aerosphere®; equivalent to glycopyrrolate/formoterol fumarate 18/9.6 μg) is a dual LAMA/LABA fixed-dose combination (FDC) therapy formulated using innovative co-suspension delivery technology, which enables the uniform delivery of multiple treatments in a single inhaler [2–4]. GFF MDI is now approved in the USA for the long-term maintenance treatment of airflow obstruction in patients with COPD [5].\n\nThis study was part of a wider Phase I/II clinical trial program investigating the safety and efficacy of glycopyrronium (GP) MDI, formoterol fumarate dihydrate (FF) MDI, and GFF MDI, all formulated using the same innovative co-suspension delivery technology [6–11]. The overall aim of this program was to determine the optimal dose of GP MDI, FF MDI, and GFF MDI to be taken forward into the Phase III clinical trials, PINNACLE-1 and PINNACLE-2 [12], and the 28-week safety extension study, PINNACLE-3 [13].\n\nThe objective of this Phase IIb, randomized, placebo-controlled, double-blind, incomplete block, cross-over study was to assess the safety and efficacy of GP MDI across the dose range 3.6 μg to 28.8 μg twice daily (BID) after 7-day dosing, compared with placebo MDI BID and open-label ipratropium bromide MDI (Atrovent® hydrofluoroalkane [HFA]) four times daily (QID) in patients with moderate-to-severe COPD. The doses selected for evaluation in this study were based on the previous findings with GP MDI for doses from 14.4 μg to 115.2 μg [8, 9].\n\nMethods\nStudy population\nThe study population comprised male and female patients (40 to 80 years of age), who were current or former smokers with a history of at least 10 pack-years of cigarette smoking. Eligible patients were required to have a diagnosis of COPD as defined by the American Thoracic Society (ATS)/European Respiratory Society [14], with a severity defined as a pre- and post-bronchodilator forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) < 0.70 at screening, and a post-bronchodilator FEV1 ≥ 30% and < 80% of predicted normal and ≥750 mL at screening, and a pre-bronchodilator FEV1 < 80% of predicted normal at baseline. Laboratory tests and electrocardiogram (ECG) performed at screening, and chest X-ray or computerized tomography (CT) scan performed within 6 months prior to screening, had to be deemed acceptable by the investigator for inclusion in the study.\n\nPatients with not stable, exacerbating COPD, defined as acute worsening of COPD that required hospitalization in the 3 months prior to screening or the use of corticosteroids (parenteral or oral) or antibiotics in the 6 weeks prior to or during screening were excluded from participation in the study. Patients with a primary diagnosis of asthma, those who had alpha-1 antitrypsin deficiency, those who had undergone a lung resection, or those who had other respiratory disorders that may have impacted on the study were also excluded. Additionally, patients who had lower respiratory tract infections that required antibiotics within 6 weeks prior to screening, and patients who could not perform acceptable spirometry, were not eligible for inclusion in the study. Pregnant or lactating women, patients with a known or suspected history of substance abuse in the past 2 years, those with a history of hypersensitivity to short-acting or long-acting β2-agonists or muscarinic antagonists, or any component of the MDI, or patients who had clinically significant medical conditions (including, but not limited to, cardiovascular, neurological, psychiatric, hepatic [including liver function test abnormalities], gastrointestinal, immunological, glaucoma, symptomatic prostatic hypertrophy, endocrine [including uncontrolled diabetes or thyroid disease], hematological medical problems, urinary retention problems [including bladder-neck obstruction, i.e. difficulty passing urine, painful urination], uncontrolled hypertension, cancer not in complete remission for ≥5 years, creatinine clearance ≤50 mL/min, chest X-ray/CT scan abnormalities and ECG abnormalities) were also excluded. Patients taking prohibited medications, or those who were medically unable to withhold their short-acting bronchodilators for the 6-h period required prior to spirometry testing at each study visit, were also excluded from participation in this study. Furthermore, if patients were receiving long-term or nocturnal oxygen therapy for more than 12 h per day, if they had participated in the acute phase of a pulmonary rehabilitation program within 4 weeks prior to screening, or if they would enter the acute phase of a pulmonary rehabilitation program during the study, they were not eligible for inclusion. If patients required the use of a spacer to compensate for poor hand-to-breath coordination with an MDI, or if they had received treatment with an investigational study drug or had participated in another clinical study within the last 30 days or five half-lives prior to screening, they were also excluded.\n\nPatients were willing and able, in the opinion of the investigator, to change current COPD medication, were able to comply with study procedures and to remain at the study center as required, and had agreed to take acceptable contraceptive precautions during the study, where appropriate.\n\nStudy design\nThis was a 7-day, chronic-dosing, Phase IIb study with a randomized, double-blind, three-period, six-treatment, placebo-controlled, incomplete block, cross-over design, conducted in patients with moderate-to-severe COPD across nine sites in the USA between May 12, 2011 and October 04, 2011 (Fig. 1). Eligible participants were randomly assigned to one of 72 treatment sequences using a centralized interactive web response system. Each sequence included three of the six treatment groups (two doses of GP MDI and either placebo MDI or ipratropium MDI): GP MDI 28.8 μg, 14.4 μg, 7.2 μg, and 3.6 μg ex-actuator delivered as two actuations, BID; placebo MDI delivered as two actuations, BID; and open-label ipratropium bromide MDI 34 μg, as the active control, delivered as two actuations, QID.Fig. 1 Study design. PFT Pulmonary function test, Rx Treatment\n\n\n\nPatients underwent a washout period of 7 to 28 days before randomization. Patients reported to the clinic on Day 1 of each treatment period, and were discharged after all scheduled assessments had been completed. Patients reported to the clinic again on the last day of each treatment period (Day 7), and were discharged after all scheduled assessments had been completed. The treatment period lasted for 7 ± 2 days. Each treatment period was separated by a washout period of 7 to 21 days. Patients underwent a total of three treatment periods (Fig. 1). On the final clinic visit (7 to 14 days after the end of the third treatment period), patients underwent post-study assessments, including a final physical examination and safety assessments (Fig. 1).\n\nPatients were permitted to use albuterol sulfate 90 μg (Ventolin® HFA) for relief of COPD symptoms during each treatment period, if required. Patients were permitted to use albuterol MDI, ipratropium MDI, or albuterol/ipratropium combination MDI during each washout period, in accordance with recommendations from the investigator. Patients who received an inhaled corticosteroid (ICS) as part of an FDC therapy containing fluticasone and salmeterol, mometasone and formoterol, or formoterol and budesonide, and had been maintained on a stable dose for at least 4 weeks, were switched to the corresponding dose of fluticasone, mometasone, or budesonide, administered as a single agent with albuterol MDI, ipratropium MDI, or albuterol/ipratropium combination MDI at the investigator’s discretion. Patients who received ICS that was not administered as an FDC together with a LABA, and had been maintained on a stable dose for at least 4 weeks, were permitted to continue the ICS. Protocol-adjusted ICS therapy was continued and remained stable throughout the study. All COPD medications, including ICS, were withheld for at least 6 h prior to each clinic visit, or the visit was rescheduled as soon as was practical but within the specified visit windows.\n\nPatients were not allowed to consume grapefruit or grapefruit juice throughout the study and were not allowed xanthine-containing foods or beverages such as coffee, tea, chocolate, and cola (decaffeinated beverages were allowed) for at least 6 h prior to – and for the duration of – each clinic visit. Patients were required to refrain from smoking for at least 4 h prior to – and throughout the duration of – each clinic visit. Patients were permitted to use various nicotine-replacement treatments (such as chewing gum and patches) as needed, in accordance with recommendations from the investigator, during the entire clinic visit.\n\nThis study was conducted in accordance with Good Clinical Practice Guidelines including the International Conference on Harmonisation, the US Code of Federal Regulations, and the Declaration of Helsinki. An institutional review board (Independent Investigational Review Board, Inc., FL, USA; IRB00003563) approved the protocol and informed consent form, and written informed consent was obtained from patients prior to screening. The study was registered on the US National Institutes of Health’s ClinicalTrials.gov website (NCT01350128).\n\nEfficacy endpoints\nThe primary efficacy endpoint was FEV1 area under the curve from 0 to 12 h (AUC0–12) relative to baseline on Day 7. The secondary efficacy endpoints evaluated on Day 1 relative to baseline were: peak change in FEV1 (defined as highest value of FEV1 post-dose minus baseline); time to onset of action (≥10% improvement in mean FEV1); proportion of patients achieving ≥12% improvement in FEV1; and peak improvement in inspiratory capacity (IC; mean of 1- and 2- h post-dose values minus baseline). The secondary efficacy endpoints evaluated on Day 7 were: change from baseline in morning pre-dose FEV1 (defined as the average of the 60- and 30-min pre-dose values on Day 7 minus baseline); peak change from baseline in FEV1 (defined as highest value of FEV1 post-dose minus baseline); peak change from baseline in IC (mean of 1- and 2-h post-dose assessments minus baseline); and change from baseline at post-dose trough FEV1 (post-dose trough FEV1 defined as the mean of the FEV1 assessments taken at 11.5 and 12 h post-dose minus baseline). Exploratory efficacy endpoints on Day 7 included change from baseline in mean morning and evening pre- and post-dose daily peak flow readings taken by patients and recorded in patient diaries.\n\nEfficacy assessments\nPulmonary function tests including FEV1 and FVC, peak expiratory flow rate (PEFR), and slow vital capacity for IC were carried out using a spirometer that met or exceeded the minimum performance recommendations of the ATS, and were performed in accordance with ATS criteria [15]. All sites were provided with identical spirometry systems (KoKo® Spirometer, nSpire Health, Inc., Louisville, Colorado, USA) and all the study staff responsible for performing pulmonary function testing received standardized training.\n\nOn Day 1 of each treatment period, spirometry was performed at 1 h and at 30 min pre-dose, followed by 15 and 30 min, and 1 and 2 h post-dose. On Day 7 of each treatment period, spirometry was performed at 1 h and 30 min pre-dose, followed by 15 and 30 min, and 1, 2, 4, 5.5, 6.5, 8, 10, 11.5, and 12 h post-dose. The average of the two pre-dose assessments was used to establish Day 7 pre-dose FEV1 and FVC. On Day 1 of each treatment period, IC assessments were obtained at 1 h and at 30 min pre-dose, and at 1 and 2 h post-dose. On Day 7 of each treatment period, IC assessments were obtained at 1 h and at 30 min pre-dose, followed by 1, 2, 11.5, and 12 h post-dose. IC assessments preceded spirometry assessments. All patients were instructed on the performance of the IC maneuver. For the efficacy endpoints, baseline was defined as the mean of pre-dose values across Day 1 of each treatment period, where the pre-dose values for each visit day were averaged, and then all visit means were averaged. The baseline FEV1 on Day 1 of Treatment Periods 2 and 3 had to be within ±15% or 150 mL of the baseline FEV1 obtained on Day 1 of Treatment Period 1, or either the visit was rescheduled at the investigator's discretion or the patient was discontinued from the study.\n\nAt screening, patients were instructed on the use of a peak-flow meter to measure pre- and post-dose morning and evening peak flow rate at home. Peak flow rate was measured immediately before and 30 min after taking the study medication. Patients were required to complete diaries recording the actual time of dosing and home peak flow rate measurements. Diaries were provided at screening and on Day 1 of each Treatment Period, were completed daily by the patient, and were returned at the next visit. For the change from baseline in mean morning pre- and post-dose daily peak flow rate on Day 7, readings taken pre-dose on Day 1 of Treatment Period 1 were excluded.\n\nSafety evaluations\nThe safety profile of the study treatments was determined from physical examination findings, vital signs (including heart rate and blood pressure), clinical laboratory values (including hematology and chemistry) and 12-lead ECGs. These assessments were conducted at screening and final follow-up visit, and for up to 2 h post-dose on Day 1 and up to 12 h post-dose on Day 7 of each treatment period (physical examinations were conducted at screening and final follow-up only). Adverse events (AEs) were recorded at screening, on Day 1 and Day 7 of each treatment period and at final follow-up visit. AEs of interest were paradoxical bronchospasm and dry mouth.\n\nStatistical analyses\nThe safety population included all patients who were randomized, received at least one dose of any study medication, and had at least one post-dose safety assessment for that treatment. The intent-to-treat (ITT) population included all patients who were randomized, received at least one dose of a study medication, and had both baseline and post-baseline efficacy data for that study treatment. The modified intent-to-treat (mITT) population included all patients who completed at least two treatment periods, with at least one pre-dose assessment on Day 7 for each of these two treatment periods, and no protocol deviations that could have impacted efficacy results. The per-protocol (PP) population included all patients in the ITT population who completed all three treatment periods with at least 11.5 h of evaluable spirometry data on Day 7, and excluded any measurements that were excluded from the mITT population.\n\nThe primary efficacy analysis based on the primary efficacy endpoint (FEV1 AUC0–12 relative to baseline on Day 7), involved four a priori treatment comparisons for superiority of each of the four GP MDI treatments compared with placebo MDI. For the primary efficacy objective, strong control of the family-wise Type I error was achieved by hierarchical testing according to dose order, from the highest dose to the lowest dose [16]. The least squares mean (LSM), difference in LSM, and associated standard errors (SEs) and two-sided 95% confidence intervals (CIs) were based on a linear mixed-effect model with FEV1 AUC0–12 (dependent-variable) and the following factors: baseline FEV1 (covariate), patient (sequence) (a random factor), period, sequence, treatment, and prior treatment (carry-over). The mITT population was the primary analysis population for the efficacy endpoints. Sensitivity analyses on the primary efficacy endpoint were carried out in the ITT and PP populations.\n\nSecondary efficacy analysis of the primary efficacy endpoint involved comparisons of each treatment group to open-label ipratropium MDI, which assumed a non-inferiority margin of 0.1 L. These comparisons were performed using the same mixed model, algorithms, and hierarchical testing strategy as for the primary efficacy analysis. Non-inferiority for a comparison was supported only if the lower bound of the 95% CI for the difference of GP MDI minus ipratropium MDI was greater than − 0.1 L. Other secondary efficacy analyses involved primary efficacy comparisons (superiority of each treatment group to placebo MDI) and secondary efficacy comparisons (non-inferiority of each treatment group to ipratropium MDI) on secondary endpoints. The secondary and the exploratory efficacy objectives were analyzed using the same mixed model as used for the primary analysis, with baseline and prior treatment as a covariate where appropriate, with the exception of time to onset of action which was analyzed using Murray’s method for weighted Kaplan-Meier statistics for paired data [17], and proportion of patients achieving ≥12% improvement in FEV1 which was analyzed using McNemar’s test. Two-sided 95% CIs were tabulated for endpoints analyzed using the mixed model. Testing for first-order carry-over effects using a mixed model was performed for secondary and exploratory analyses.\n\nPower calculations were based on the primary efficacy endpoint, FEV1 AUC0–12 on Day 7 of each dosing period following administration of the study drug. A sample size of 100 randomized patients (84 completers) was planned to provide 90% power (assuming a significance test at the 5% level, with no multiplicity adjustment). For each efficacy comparison, between and within patient variance components were assumed to have standard deviations (SDs) of 0.13 L; the SE of each comparison was calculated using a generalized least squares analysis which assumed spherical errors with no carry-over effects. The non-centrality parameter of the t-test was calculated assuming the SE from the generalized least squares analysis and a difference of 0.1 L (the minimally clinically significant difference, which is defined as the change in pre-dose FEV1 that can be perceived by patients) [18].\n\nResults\nStudy population\nA total of 133 patients were screened and 103 were randomized to receive study treatment (Fig. 2). Of these, 89 (86.4%) completed the study. All 103 randomized patients were included in the ITT and safety populations, 91 patients (88.3%) were included in the mITT population and 68 patients (66.0%) were included in the PP population. There were no clinically relevant differences in demographic or clinical characteristics among the patients according to treatment received. The mean age of the overall study population was 61.2 years, and 55 (53.4%) patients were male. The majority of study participants (88.3%) were of Caucasian race (Table 1). Overall, 69 (67.0%) patients were current smokers. Patients had smoked for an average of 64.2 pack-years, and had a mean duration of COPD at baseline of 8.1 years (Table 1). In the mITT population, 69.2% of patients had moderate COPD (post-bronchodilator FEV1 of ≥50% and < 80% and FEV1/FVC < 0.70) and 30.8% of patients had severe COPD (post-bronchodilator FEV1 of ≥30% and < 50% and FEV1/FVC < 0.70).Fig. 2 Patient disposition. BID Twice daily, GP Glycopyrronium, MDI Metered dose inhaler, QID Four times daily\n\nTable 1 Patient demographics and characteristics (ITT/safety population)\n\nParameter\tGP MDI 28.8 μg BID, N = 49\tGP MDI 14.4 μg BID, N = 49\tGP MDI 7.2 μg BID, N = 49\tGP MDI 3.6 μg BID, N = 45\tPlacebo MDI BID, N = 48\tIpratropium MDI 34 μg QID, N = 48\tAll patients, N = 103\t\nMean age, years (SD)\t61.6 (7.9)\t63.3 (7.9)\t60.3 (8.2)\t60.6 (8.8)\t61.5 (7.8)\t61.3 (9.0)\t61.2 (8.2)\t\nGender, % male\t49.0\t55.1\t59.2\t48.9\t60.4\t43.8\t53.4\t\nRace, % Black or African/Caucasian/Other\t6.1/85.7/8.2\t8.2/87.8/4.1\t8.2/87.8/4.1\t6.7/88.9/4.4\t8.3/87.5/4.2\t6.3/87.5/6.3\t6.8/88.3/4.9\t\nMean BMI, kg/m2 (SD)\t30.1 (6.6)\t27.5 (7.2)\t29.0 (8.9)\t29.0 (8.1)\t28.2 (7.4)\t29.2 (8.1)\t28.8 (7.6)\t\nSmoking status, % current smokers\t63.3\t59.2\t67.3\t71.1\t64.6\t66.7\t67.0\t\nMean smoking history, pack-years (SD)\t63.4 (25.8)\t63.0 (28.2)\t61.8 (27.5)\t72.3 (28.0)\t67.8 (30.1)\t61.3 (25.9)\t64.2 (27.4)\t\nMean duration of COPD at baseline, years (SD)\t7.8 (4.8)\t8.6 (6.8)\t8.8 (5.5)\t7.8 (5.8)\t8.7 (6.5)\t7.8 (5.5)\t8.1 (5.9)\t\nFEV1 a, N\t45\t46\t44\t41\t46\t45\t91\t\n Mean screening FEV1 pre-bronchodilator, % predicted (SD)\t49.9 (13.6)\t47.0 (13.0)\t48.3 (12.6)\t47.4 (12.1)\t47.8 (13.2)\t48.6 (12.7)\t48.2 (12.9)\t\n Mean screening FEV1 pre-bronchodilator, L (SD)\t1.464 (0.546)\t1.379 (0.523)\t1.471 (0.572)\t1.407 (0.565)\t1.474 (0.553)\t1.406 (0.553)\t1.440 (0.551)\t\n Mean screening FEV1 post-bronchodilator, % predicted (SD)\t57.8 (12.7)\t55.0 (13.8)\t56.2 (12.6)\t56.1 (12.4)\t55.3 (12.9)\t57.3 (13.0)\t56.3 (12.9)\t\n Mean screening FEV1 post-bronchodilator, L (SD)\t1.692 (0.536)\t1.614 (0.584)\t1.708 (0.598)\t1.658 (0.613)\t1.696 (0.566)\t1.663 (0.611)\t1.680 (0.586)\t\n Mean baseline FEV1, % predicted (SD)\t47.1 (14.1)\t43.7 (13.3)\t46.5 (12.3)\t46.1 (12.4)\t45.4 (14.0)\t46.4 (12.3)\t45.9 (13.2)\t\n Mean baseline FEV1, L (SD)\t1.381 (0.548)\t1.285 (0.512)\t1.430 (0.570)\t1.372 (0.584)\t1.404 (0.584)\t1.346 (0.531)\t1.376 (0.556)\t\n Reversibilitya,b, N\t45\t46\t44\t41\t46\t45\t91\t\n Mean reversibility post-bronchodilator for FEV1, % (SD)\t18.3 (13.7)\t18.5 (13.2)\t18.1 (11.1)\t19.9 (13.3)\t17.4 (11.5)\t19.8 (14.1)\t18.6 (12.9)\t\n Reversible, n (%)\t28 (62.2)\t30 (65.2)\t28 (63.6)\t28 (68.3)\t31 (67.4)\t28 (62.2)\t59 (64.8)\t\namITT population\n\nbReversibility was defined as > 200 mL improvement in FEV1 post-bronchodilator administration compared to pre-bronchodilator value and/or > 12% and > 150 mL improvement in FEV1 post-bronchodilator administration compared to pre-bronchodilator value\n\nBID Twice daily, BMI Body mass index, COPD Chronic obstructive pulmonary disease, FEV1 Forced expiratory volume in 1 s, GP Glycopyrronium, ITT Intent-to-treat, mITT Modified intent-to-treat, MDI Metered dose inhaler, QID Four times daily, SD Standard deviation,\n\n\n\nPrimary efficacy endpoint: FEV1 AUC0–12 on day 7\nGP MDI treatments showed a similar profile for FEV1 improvement over time, demonstrating an early onset of action to peak treatment effect within 2 h post-dose, followed by a gradual elimination over the 12-h period (Fig. 3). All GP MDI treatments were superior to placebo MDI, as measured by FEV1 AUC0–12 on Day 7 relative to baseline in the mITT population (Fig. 4). The estimated LSM differences versus placebo MDI for each GP MDI treatment ranged from 0.121 to 0.191 L (all p < 0.0001; Fig. 4). No clear dose ordering in the LSM differences from placebo MDI for FEV1 AUC0–12 on Day 7 was observed among the GP MDI treatments (Fig. 4). All GP MDI treatments were shown to be non-inferior to ipratropium MDI. When the GP MDI doses were compared, only GP MDI 7.2 μg demonstrated a smaller treatment effect than GP MDI 3.6 μg (LSM difference: − 0.071 L; p = 0.0127). The results of the sensitivity analyses of the primary efficacy endpoint performed in the ITT and PP populations were consistent with the findings in the mITT population.Fig. 3 Mean change from baseline in FEV1 over time on Day 7 (mITT population). Error bars represent standard errors. BID Twice daily, FEV1 Forced expiratory volume in 1 s, GP Glycopyrronium, MDI Metered dose inhaler, mITT Modified intent-to-treat, QID Four times daily\n\nFig. 4 Adjusted difference from placebo in FEV1 AUC0–12 on Day 7 (mITT population). Error bars represent 95% confidence intervals. All p < 0.0001 versus placebo MDI. AUC0–12 Area under the curve from 0 to 12 h, BID Twice daily, FEV1 Forced expiratory volume in 1 s, GP Glycopyrronium, LSM Least squares mean, MDI Metered dose inhaler, mITT Modified intent-to-treat, QID Four times daily\n\n\n\nSecondary efficacy endpoints evaluated on day 1\nAll GP MDI doses demonstrated superiority to placebo MDI for peak change from baseline in FEV1 and IC, and a higher proportion of patients achieved ≥10% improvement from baseline in FEV1 within 30 min and 2 h for all GP MDI doses compared with placebo MDI (Table 2). The two highest doses of GP MDI, 28.8 μg and 14.4 μg, showed the largest benefits compared with placebo MDI for peak change in IC. All GP MDI doses had a faster onset of action than placebo (mean difference: − 0.37 to − 0.79 h, p ≤ 0.0045). A significantly higher proportion of patients achieved ≥12% improvement in FEV1 when receiving GP MDI 28.8 μg, 7.2 μg, and 3.6 μg compared with placebo MDI (Table 2). However, no clear dose ordering was observed among GP MDI doses for any of the secondary efficacy endpoints evaluated on Day 1 (Table 2). When the GP MDI doses were compared, peak change from baseline in FEV1 was greater with GP MDI 28.8 μg compared with GP MDI 7.2 μg (LSM difference: 0.064 L, p = 0.0335), and peak change from baseline in IC was greater with GP MDI 14.4 μg compared with GP MDI 7.2 μg (LSM difference: 0.091 L, p = 0.0427). Additionally, GP MDI 28.8 μg had a faster onset of action compared with GP MDI 7.2 μg and 3.6 μg (mean differences: − 0.42 and − 0.27 h, respectively, p ≤ 0.0362).Table 2 Secondary efficacy endpoints on Day 1 (mITT population)\n\n\tGP MDI 28.8 μg BID\tGP MDI 14.4 μg BID\tGP MDI 7.2 μg BID\tGP MDI 3.6 μg BID\tPlacebo MDI BID\tIpratropium MDI 34 μg QID\t\nPeak change from baseline in FEV1 a, L\t\n N\t45\t46\t44\t41\t46\t44\t\n LSM\t0.245†\t0.221†\t0.181***\t0.204†\t0.071\t0.250†\t\n 95% CI\t0.195–0.295\t0.172–0.270\t0.130–0.232\t0.153–0.255\t0.021–0.120\t0.198–0.301\t\nTime to onset of action (proportion of patients achieving ≥10% improvement from baseline in FEV1), %\t\n N\t44\t45\t43\t40\t45\t44\t\n Within 30 min\t63.6\t48.9\t25.6\t45.0\t15.6\t72.7\t\n Within 2 h\t70.5\t73.3\t62.8\t67.5\t33.3\t84.1\t\nPatients achieving ≥12% improvement in FEV1, %\t\n N\t45\t46\t44\t41\t46\t45\t\n Proportion of patients\t66.7**\t58.7\t52.3**\t61.0***\t17.4b\t77.8\t\nPeak change from baseline in ICc, L\t\n N\t45\t45\t44\t41\t46\t45\t\n LSM\t0.240†\t0.276†\t0.185**\t0.187**\t0.040\t0.252†\t\n 95% CI\t0.165–0.316\t0.201–0.351\t0.111–0.259\t0.111–0.262\t−0.036–0.117\t0.173–0.330\t\n95% CIs presented are for each individual treatment (not versus placebo MDI)\n\n**p ≤ 0.01, ***p ≤ 0.001, †p ≤ 0.0001 compared with placebo MDI\n\naHighest value of FEV1 post-dose on Day 1 minus baseline, where baseline = average of FEV1 pre-dose values across Day 1 of each treatment period\n\nbNo pairs\n\ncMean of 1 and 2 h post-dose on Day 1 minus baseline, where baseline = average of IC pre-dose values across Day 1 of each treatment period\n\nBID Twice daily, CI Confidence interval, FEV1 Forced expiratory volume in 1 s, GP Glycopyrronium, IC Inspiratory capacity, LSM Least squares mean, MDI Metered dose inhaler, mITT Modified intent-to-treat, QID Four times daily\n\n\n\nSecondary efficacy endpoints evaluated on day 7\nAll GP MDI doses demonstrated superiority to placebo MDI for peak change from baseline in FEV1 and IC (Table 3). Only GP MDI 28.8 μg and 14.4 μg demonstrated superiority to placebo MDI for change from baseline in morning pre-dose FEV1 and at 12-h post-dose trough FEV1 (Table 3). Based on the hierarchical testing strategy, no claim could be made for the superiority of GP MDI 3.6 μg to placebo MDI for these endpoints, because change from baseline in morning pre-dose FEV1 and at 12-h post-dose trough FEV1 for GP MDI 7.2 μg versus placebo MDI were not statistically significant. No clear dose ordering was observed among GP MDI doses for any of the secondary efficacy endpoints evaluated on Day 7 (Table 3). All GP MDI doses led to numerically greater changes from baseline in morning pre-dose FEV1 and 12-h post-dose trough FEV1 than ipratropium MDI. When GP MDI doses were compared, GP MDI 28.8 μg, 14.4 μg, and 3.6 μg had a greater mean change from baseline in morning pre-dose FEV1 than GP MDI 7.2 μg (LSM differences: 0.065 L to 0.078 L, p ≤ 0.0373).Table 3 Secondary and exploratory efficacy endpoints on Day 7 (mITT population)\n\n\tGP MDI 28.8 μg BID\tGP MDI 14.4 μg BID\tGP MDI 7.2 μg BID\tGP MDI 3.6 μg BID\tPlacebo MDI BID\tIpratropium MDI 34 μg QID\t\nChange from baseline in morning pre-dose FEV1 a, L\t\n N\t45\t45\t43\t41\t46\t43\t\n LSM\t0.088†\t0.075†\t0.010\t0.084†\t−0.043\t− 0.088\t\n 95% CI\t0.039–0.136\t0.027–0.124\t−0.039–0.059\t0.035–0.133\t−0.092–0.006\t−0.138 to −0.037\t\nPeak change from baseline in FEV1 b, L\t\n N\t45\t45\t43\t41\t44\t43\t\n LSM\t0.242†\t0.224†\t0.223†\t0.238†\t0.070\t0.225†\t\n 95% CI\t0.181–0.302\t0.164–0.284\t0.162–0.285\t0.176–0.300\t0.009–0.131\t0.164–0.287\t\nPeak change from baseline in ICc, L\t\n N\t45\t45\t43\t41\t44\t43\t\n LSM\t0.213†\t0.189†\t0.161†\t0.192†\t−0.029\t0.191†\t\n 95% CI\t0.130–0.295\t0.107–0.271\t0.077–0.245\t0.107–0.277\t−0.112–0.055\t0.106–0.275\t\nChange from baseline at 12-h post-dose trough FEV1 d, L\t\n N\t40\t41\t41\t39\t41\t42\t\n LSM\t0.018*\t0.079†\t0.004\t0.077†\t−0.054\t− 0.041\t\n 95% CI\t−0.045–0.080\t0.018–0.139\t−0.057–0.065\t0.016–0.139\t−0.117–0.009\t− 0.103–0.021\t\nChange from baseline in mean morning pre-dose daily PEFR, L/min\t\n N\t36\t34\t35\t29\t35\t14\t\n LSM\t10.826*\t14.230**\t13.574*\t2.582\t−7.877\t7.625\t\n 95% CI\t−2.749–24.402\t0.334–28.125\t−0.274–27.423\t−12.126–17.289\t−21.785–6.032\t−12.890–28.140\t\nChange from baseline in mean morning post-dose daily PEFR, L/min\t\n N\t32\t35\t31\t27\t32\t6\t\n LSM\t18.618***\t14.979**\t19.976***\t17.530**\t−13.040\t15.190\t\n 95% CI\t3.490–33.747\t0.987–28.970\t4.777–35.174\t1.929–33.131\t−27.150–1.069\t−16.092–46.472\t\nChange from baseline in mean evening pre-dose daily peak flow rate, L/min\t\n N\t35\t31\t33\t26\t32\t11\t\n LSM\t14.002**\t18.275**\t10.610*\t23.336***\t−3.928\t14.808\t\n 95% CI\t1.564–26.440\t5.220–31.330\t−2.155–23.374\t9.637–37.034\t−16.751–8.895\t−4.635–34.251\t\nChange from baseline in mean evening post-dose daily peak flow rate, L/min\t\n N\t19\t16\t20\t17\t20\t8\t\n LSM\t22.701*\t17.790\t24.585*\t36.885*\t− 12.269\t46.772*\t\n 95% CI\t− 0.329–45.732\t− 8.811–44.391\t−0.947–50.117\t9.152–64.619\t− 35.536–10.998\t7.415–86.130\t\n95% CIs presented are for each individual treatment (not versus placebo MDI)\n\n*p < 0.05, **p ≤ 0.01, ***p ≤ 0.001, †p ≤ 0.0001 compared with placebo MDI. Due to hierarchical testing, no claims were advanced for a GP MDI treatment vs. placebo MDI, unless all higher dose-levels of the GP MDI were superior to placebo MDI\n\naDefined as the average of the 60- and 30-min pre-dose values on Day 7 minus baseline (average across Day 1 of each treatment period)\n\nbDefined as highest value of FEV1 post-dose minus baseline on Day 7, where baseline = average of pre-dose values across Day 1 of each treatment period\n\ncMean of 1- and 2-h post-dose assessments on Day 7 minus baseline, where baseline = average of IC pre-dose values across Day 1 of each treatment period\n\ndMean of the FEV1 assessments taken at 11.5 and 12 h post-dose minus baseline, where baseline = average of FEV1 pre-dose values across Day 1 of each treatment period\n\nBID Twice daily, CI Confidence interval, FEV1 Forced expiratory volume in 1 s, GP Glycopyrronium, IC Inspiratory capacity, LSM Least squares mean, MDI Metered dose inhaler, mITT Modified intent-to-treat, QID Four times daily\n\n\n\nExploratory efficacy endpoints on day 7\nGP MDI 28.8 μg, 14.4 μg, and 7.2 μg demonstrated superiority to placebo MDI for change from baseline in mean morning pre-dose daily peak flow rate, whereas all GP MDI doses were superior to placebo MDI post-dose (Table 3). For change from baseline in mean evening daily peak flow rate, all GP MDI doses were superior to placebo MDI pre-dose, whereas only GP MDI 28.8 μg demonstrated superiority to placebo MDI post-dose (Table 3). Based on the hierarchical testing strategy, no claim could be made for superiority of GP MDI 7.2 μg and 3.6 μg to placebo MDI for this endpoint, because change from baseline in mean evening post-dose daily peak flow rate for GP MDI 14.4 μg versus placebo MDI was not statistically significant. There were no differences when comparisons were made between GP MDI doses.\n\nSafety\nOverall, 45 patients (43.7%) reported at least one treatment-emergent AE (TEAE) at any time during the study (GP MDI: 14.3–28.6%; placebo MDI, 14.6%; ipratropium MDI, 31.3%; Table 4). A total of 21 patients (20.4%) reported TEAEs related to the study treatment (GP MDI: 6.1–14.3%; placebo MDI, 6.3%; ipratropium MDI, 14.6%; Table 4). No TEAEs led to early withdrawal from the study and no deaths were reported.Table 4 Summary of TEAEs (safety population)\n\nParameter\tGP MDI 28.8 μg BID, N = 49\tGP MDI 14.4 μg BID, N = 49\tGP MDI 7.2 μg BID, N = 49\tGP MDI 3.6 μg BID, N = 45\tPlacebo MDI BID, N = 48\tIpratropium MDI 34 μg QID, N = 48\tAll patients, N = 103\t\nPatients with at least one TEAE, n (%)\t7 (14.3)\t11 (22.4)\t14 (28.6)\t10 (22.2)\t7 (14.6)\t15 (31.3)\t45 (43.7)\t\nPatients with TEAEs related to study treatment, n (%)\t3 (6.1)\t4 (8.2)\t7 (14.3)\t6 (13.3)\t3 (6.3)\t7 (14.6)\t21 (20.4)\t\nPatients with SAEs, n (%)\t0\t0\t0\t1 (2.2)\t0\t1 (2.1)\t2 (1.9)\t\nTEAEs reported in ≥2% of patients for any treatment arm, n (%) (preferred term)\t\n Dry mouth\t1 (2.0)\t2 (4.1)\t4 (8.2)\t4 (8.9)\t1 (2.1)\t3 (6.3)\t12 (11.7)\t\n Cough\t1 (2.0)\t2 (4.1)\t2 (4.1)\t0\t0\t3 (6.3)\t6 (5.8)\t\n Headache\t1 (2.0)\t1 (2.0)\t1 (2.0)\t2 (4.4)\t0\t0\t4 (3.9)\t\n Diarrhea\t1 (2.0)\t0\t1 (2.0)\t0\t0\t1 (2.1)\t3 (2.9)\t\n Dyspnea\t0\t1 (2.0)\t0\t0\t2 (4.2)\t0\t3 (2.9)\t\n Hypertension\t0\t0\t2 (4.1)\t1 (2.2)\t0\t0\t3 (2.9)\t\n Nasopharyngitis\t0\t1 (2.0)\t1 (2.0)\t0\t0\t1 (2.1)\t3 (2.9)\t\n Oropharyngeal pain\t0\t1 (2.0)\t0\t0\t0\t2 (4.2)\t3 (2.9)\t\n Pyrexia\t0\t0\t0\t0\t1 (2.1)\t2 (4.2)\t3 (2.9)\t\n Vomiting\t1 (2.0)\t0\t1 (2.0)\t1 (2.2)\t1 (2.1)\t1 (2.1)\t3 (2.9)\t\nBID Twice daily, GP Glycopyrronium, MDI Metered dose inhaler, QID Four times daily, SAE Serious adverse event, TEAE Treatment-emergent adverse event\n\n\n\nThe most commonly reported TEAEs were dry mouth (11.7%), cough (5.8%), and headache (3.9%). Other TEAEs reported in at least 2% of patients overall were diarrhea, vomiting, dyspnea, oropharyngeal pain, nasopharyngitis, pyrexia, and hypertension (2.9% each; Table 4). There were no clinically relevant differences in the occurrence of TEAEs across treatments. Furthermore, there was no dose relationship with these TEAEs, with dry mouth occurring most frequently in patients treated with GP MDI 7.2 μg and 3.6 μg (four patients each; 8.2% and 8.9%, respectively), followed by in patients in the ipratropium MDI treatment group (three patients; 6.3%). No cases of paradoxical bronchospasm were observed.\n\nTwo patients (1.9%) reported serious AEs (Table 4) of COPD exacerbation (GP MDI 3.6 μg) and left-lower-extremity deep vein thrombosis (ipratropium MDI), both of which were considered unrelated to study treatment. No important trends were observed among the treatments in changes from baseline in clinical laboratory results, vital signs, and ECGs.\n\nDiscussion\nThis Phase IIb, randomized, cross-over study assessed the efficacy and safety of GP MDI 28.8 μg, 14.4 μg, 7.2 μg, and 3.6 μg BID, in patients with moderate-to-severe COPD, compared with placebo MDI BID and open-label ipratropium MDI 34 μg QID.\n\nFor the primary efficacy endpoint, all doses of GP MDI demonstrated statistically significant and clinically relevant increases in FEV1 AUC0–12 compared with placebo MDI following 7 days of treatment, which is in agreement with findings for GP MDI 14.4 μg, 7.2 μg, and 3.6 μg following 14 days of treatment [6]. The short-acting muscarinic antagonist ipratropium is used as a standard comparator in early phase clinical studies with novel bronchodilators [19], and non-inferiority testing is commonly applied to compare the effects of bronchodilators with the active comparator. Non-inferiority to ipratropium MDI was observed for all doses of GP MDI for FEV1 AUC0–12 on Day 7. Additionally, for FEV1 improvement over time, the similarity of results between the first 5.5 h and the second 6.5 h with all GP MDI doses relative to ipratropium MDI provided further evidence supporting the appropriateness of BID dosing for GP MDI.\n\nGP MDI 28.8 μg and 14.4 μg demonstrated superiority to placebo MDI for all secondary efficacy endpoints statistically analyzed in this study, with the exception of the proportion of patients achieving ≥12% improvement in FEV1 on Day 1 for which GP MDI 14.4 μg did not show superiority to placebo MDI. These results are comparable with a 14-day study, where GP MDI 14.4 μg showed superiority to placebo MDI for all secondary efficacy endpoints, with the exception of change in morning pre-dose trough FEV1 on Day 7, although GP MDI 14.4 μg did show superiority to placebo MDI for the proportion of patients achieving ≥12% improvement in FEV1 on Day 1 in this study [6].\n\nNo clear dose ordering was observed among the GP MDI doses. All GP MDI doses showed superiority to placebo MDI for three of the secondary endpoints on Day 1, time to onset of action and peak change in FEV1 and in IC. In addition, for two of the secondary endpoints on Day 7, change from baseline in morning pre-dose FEV1 and at 12-h post-dose trough FEV1, superiority to placebo MDI was demonstrated for GP MDI 28.8 μg and 14.4 μg but, due to the results with 7.2 μg and the hierarchical testing strategy, superiority could not be declared for GP MDI 3.6 μg. The observations are largely consistent with previous findings, where a dose response was observed across GP MDI doses from 0.5 μg to 3.6 μg for the primary efficacy endpoint of FEV1 AUC0–12 relative to baseline at Day 14, with a relatively flat dose-response curve for the higher doses of 7.2 μg and 14.4 μg. Moreover, no clear dose-response was observed for many of the secondary efficacy endpoints for doses lower than 14.4 μg [6].\n\nThe exploratory peak flow rate endpoints also showed improvements following treatment with GP MDI compared with placebo MDI, without clear dose ordering for the GP MDI dose.\n\nAll doses of GP MDI were well tolerated, with no unexpected safety findings. There were no withdrawals from the study due to TEAEs. The most frequent TEAE was dry mouth, which is a well-established AE associated with LAMAs due to their anticholinergic activity [20, 21].\n\nLimitations of this study included the short 7-day treatment period, and the open-label nature of the ipratropium active control. Patient-reported outcomes, such as St George’s Respiratory Questionnaire and COPD assessment test scores, were not assessed due to the short timeframe. Additionally, patients eligible for inclusion in this study were not required to show reversibility to short-acting bronchodilators. An inclusion criteria of reversibility may have led to better dose-response ordering for GP MDI. However, as reversibility to short-acting bronchodilators does not influence treatment decisions in routine clinical practice, the absence of a requirement for reversibility may enhance the applicability of the findings of this study to real-world practice. A strength of this study was the cross-over design, although direct comparisons between ipratropium MDI and placebo MDI were not possible, as each patient received only one of these treatments.\n\nThe findings in this study did not demonstrate any advantage of GP MDI 28.8 μg compared with 14.4 μg in terms of lung function endpoints. Additionally, superiority to placebo MDI was demonstrated for GP MDI 3.6 μg for the primary efficacy endpoint and for some secondary efficacy endpoints, which indicated that this may not be the minimum effective dose. These results, therefore, supported further evaluation of GP MDI at doses below 3.6 μg and no higher than 14.4 μg BID, which were explored in a study that investigated the dose-response of GP MDI 14.4 μg, 7.2 μg, 3.6 μg, 1.9 μg, 1.0 μg, and 0.5 μg BID over 14 days and found that GP MDI 14.4 μg demonstrated the greatest efficacy versus placebo MDI, with no increase in the incidence of AEs [6]. The findings from these Phase IIb studies added to the evidence that resulted in GP MDI 14.4 μg BID being selected as the optimal dose for investigation in the Phase III studies PINNACLE-1, PINNACLE-2, and PINNACLE-3 [12, 13].\n\nConclusions\nThe findings of this study demonstrated the efficacy and safety of 7-day dosing with GP MDI 3.6 μg to 28.8 μg BID for patients with moderate-to severe COPD. All doses of GP MDI in this study were well tolerated, and the most frequent TEAE observed (dry mouth) was a well-established AE associated with LAMA therapy. No unexpected safety findings were observed. The results further supported GP MDI 14.4 μg for use in the Phase III clinical studies.\n\nAbbreviations\nAEAdverse event\n\nATSAmerican Thoracic Society\n\nAUC0–12Area under the curve from 0 to 12 h\n\nBIDTwice daily\n\nCIConfidence interval\n\nCOPDChronic obstructive pulmonary disease\n\nCTComputerized tomography\n\nECGElectrocardiogram\n\nFDCFixed-dose combination\n\nFEV1Forced expiratory volume in 1 s\n\nFFFormoterol fumarate dihydrate\n\nFVCForced vital capacity\n\nGFFGlycopyrronium/formoterol fumarate dihydrate\n\nGPGlycopyrronium\n\nHFAHydrofluoroalkane\n\nICInspiratory capacity\n\nICSInhaled corticosteroid\n\nITTIntent-to-treat\n\nLABALong-acting β2-agonist\n\nLAMALong-acting muscarinic antagonist\n\nLSMLeast squares mean\n\nMDImetered dose inhaler\n\nmITTModified intent-to-treat\n\nPEFRPeak expiratory flow rate\n\nPPPer-protocol\n\nQIDFour times daily\n\nSAESerious adverse event\n\nSDStandard deviation\n\nSEStandard error\n\nTEAETreatment-emergent adverse event\n\nAcknowledgements\nThe authors thank all the patients and their families, and the team of investigators, research nurses, and operations staff involved in this study. The authors would like to thank Chad Orevillo, Carlos Fernandez, and Joseph Covino for their valuable contributions. Medical writing support, under the direction of the authors, was provided by Pauline Craig, PhD, of CMC CONNECT, a division of Complete Medical Communications, Glasgow, UK, funded by AstraZeneca, Cambridge, UK in accordance with Good Publication Practice (GPP3) guidelines. [22].\n\nRole of funding source\nThe funder of the study was involved in study design, data collection, data analysis, data interpretation and writing of the report. All authors had full access to all the data in the study and the corresponding author had the final responsibility for the decision to submit for publication. No restrictions were placed on authors regarding the statements made in the manuscript.\n\nFunding\nThis work was supported by Pearl – A member of the AstraZeneca Group.\n\nAvailability of data and materials\nAll relevant data analyzed during this study are included in this published article.\n\nAuthors’ contributions\nESR and CR made substantial contributions to the conception or design of the work reported. EMK, SS and ESR participated in the acquisition of reported data. EMK, CK, ESR and CR participated in the analysis of reported data. EMK, ESR and CR participated in the interpretation of reported data. All authors contributed to the writing of the report and participated in the review and interpretation of the data. All authors read and approved the final report before submission.\n\nEthics approval and consent to participate\nThis study was conducted in accordance with Good Clinical Practice Guidelines including the International Conference on Harmonisation, the US Code of Federal Regulations, and the Declaration of Helsinki. An institutional review board (Independent Investigational Review Board, Inc., FL, USA; IRB00003563) approved the protocol and informed consent form, and written informed consent was obtained from patients prior to screening.\n\nConsent for publication\nNot applicable.\n\nCompeting interests\nEMK has served on advisory boards, speaker panels, or received travel reimbursement from Amphastar, AstraZeneca, Forest, Mylan, Novartis, Oriel, Sunovion, Teva, and Theravance. He has conducted multicenter clinical trials for ~ 40 pharmaceutical companies.\n\nSS serves on the speaker’s bureau for Boehringer Ingelheim, Mylan, Pearl – A member of the AstraZeneca Group, and Sunovion.\n\nCK has no potential conflicts of interest to disclose.\n\nESR is an employee of Pearl – A member of the AstraZeneca Group.\n\nCR is Chief Executive Officer of Pearl – A member of the AstraZeneca Group, and an employee of AstraZeneca.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. Global Initiative for Chronic Obstructive Lung Disease. Global Strategy for the Diagnosis, Management and Prevention of COPD. 2018. http://www.goldcopd.org. Accessed 23 Jan 2018.\n2. Lechuga-Ballesteros D Noga B Vehring R Cummings RH Dwivedi SK Novel cosuspension metered-dose inhalers for the combination therapy of chronic obstructive pulmonary disease and asthma Future Med Chem 2011 3 1703 1718 10.4155/fmc.11.133 21942257 \n3. Vehring R Lechuga-Ballesteros D Joshi V Noga B Dwivedi SK Cosuspensions of microcrystals and engineered microparticles for uniform and efficient delivery of respiratory therapeutics from pressurized metered dose inhalers Langmuir 2012 28 15015 15023 10.1021/la302281n 22985189 \n4. Doty A Schroeder J Vang K Sommerville M Taylor M Flynn B Drug delivery from an innovative LAMA/LABA co-suspension delivery technology fixed-dose combination MDI: evidence of consistency, robustness, and reliability AAPS PharmSciTech 2018 19 837 844 10.1208/s12249-017-0891-1 29019170 \n5. AstraZeneca Pharmaceuticals LP Bevespi aerosphere™ prescribing information 2017 \n6. Fabbri LM Kerwin EM Spangenthal S Ferguson GT Rodriguez-Roisin R Pearle J Dose-response to inhaled glycopyrrolate delivered with a novel co-suspension™ delivery technology metered dose inhaler (MDI) in patients with moderate-to-severe COPD Respir Res 2016 17 109 10.1186/s12931-016-0426-4 27586537 \n7. Quinn D Seale JP Reisner C Fischer T Golden M Fernandez C A randomized study of formoterol fumarate in a porous particle metered-dose inhaler in patients with moderate-to-severe COPD Respir Med 2014 108 1327 1335 10.1016/j.rmed.2014.06.009 25060541 \n8. Reisner C Fabbri LM Kerwin EM Fogarty C Spangenthal S Rabe KF A randomized, seven-day study to assess the efficacy and safety of a glycopyrrolate/formoterol fumarate fixed-dose combination metered dose inhaler using novel co-suspension™ delivery technology in patients with moderate-to-very severe chronic obstructive pulmonary disease Respir Res 2017 18 8 10.1186/s12931-016-0491-8 28061907 \n9. Rennard S Fogarty C Reisner C Fernandez C Fischer T Golden M Randomized study of the safety, pharmacokinetics, and bronchodilatory efficacy of a proprietary glycopyrronium metered-dose inhaler in study patients with chronic obstructive pulmonary disease BMC Pulm Med 2014 14 118 10.1186/1471-2466-14-118 25027304 \n10. Sethi S Fogarty C Hanania NA Martinez FJ Rennard S Orevillo C Efficacy of formoterol fumarate delivered by metered dose inhaler using co-suspension™ delivery technology versus Foradil® Aerolizer® in moderate-to-severe COPD: a randomized, dose-ranging study Chronic Obstr Pulm Dis 2017 4 21 33 \n11. Tashkin DP Martinez FJ Rodriguez-Roisin R Fogarty C Gotfried M Denenberg M A multicenter, randomized, double-blind dose-ranging study of glycopyrrolate/formoterol fumarate fixed-dose combination metered dose inhaler compared to the monocomponents and open-label tiotropium dry powder inhaler in patients with moderate-to-severe COPD Respir Med 2016 120 16 24 10.1016/j.rmed.2016.09.012 27817811 \n12. Martinez FJ Rabe KF Ferguson GT Fabbri LM Rennard S Feldman GJ Efficacy and safety of glycopyrrolate/formoterol metered dose inhaler formulated using co-suspension delivery technology in patients with COPD Chest 2017 151 340 357 10.1016/j.chest.2016.11.028 27916620 \n13. Hanania NA Tashkin DP Kerwin EM Donohue JF Denenberg M O'Donnell DE Long-term safety and efficacy of glycopyrrolate/formoterol metered dose inhaler using novel co-suspension™ delivery technology in patients with chronic obstructive pulmonary disease Respir Med 2017 126 105 115 10.1016/j.rmed.2017.03.015 28427541 \n14. Celli BR MacNee W committee members Standards for the diagnosis and treatment of patients with COPD: a summary of the ATS/ERS position paper Eur Respir J 2004 23 932 946 10.1183/09031936.04.00014304 15219010 \n15. Miller MR Hankinson J Brusasco V Burgos F Casaburi R Coates A Standardisation of spirometry Eur Respir J 2005 26 319 338 10.1183/09031936.05.00034805 16055882 \n16. Bauer P Röhmel J Maurer W Hothorn L Testing strategies in multi-dose experiments including active control Stat Med 1998 17 2133 2146 10.1002/(SICI)1097-0258(19980930)17:18<2133::AID-SIM901>3.0.CO;2-2 9789919 \n17. Murray S Using weighted Kaplan-Meier statistics in nonparametric comparisons of paired censored survival outcomes Biometrics 2001 57 361 368 10.1111/j.0006-341X.2001.00361.x 11414557 \n18. Donohue JF Minimal clinically important differences in COPD lung function COPD 2005 2 111 124 10.1081/COPD-200053377 17136971 \n19. Stockley RA Rennard SI Rabe K Celli B Stockley RA Rennard SI Rabe K Celli B Anticholinergics in COPD Chronic obstructive pulmonary disease: a practical guide to management 2007 Oxford, UK Blackwell Publishing Ltd 657 668 \n20. Alagha K Palot A Sofalvi T Pahus L Gouitaa M Tummino C Long-acting muscarinic receptor antagonists for the treatment of chronic airway diseases Ther Adv Chronic Dis 2014 5 85 98 10.1177/2040622313518227 24587893 \n21. Sharafkhaneh A Majid H Gross NJ Safety and tolerability of inhalational anticholinergics in COPD Drug Healthc Patient Saf 2013 5 49 55 10.2147/DHPS.S7771 23526112 \n22. Battisti WP Wager E Baltzer L Bridges D Cairns A Carswell CI Good publication practice for communicating company-sponsored medical research: GPP3 Ann Intern Med 2015 163 461 464 10.7326/M15-0288 26259067\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1465-9921",
"issue": "19(1)",
"journal": "Respiratory research",
"keywords": "Bronchodilator; Chronic obstructive pulmonary disease; Co-suspension delivery technology; Glycopyrronium; Long-acting muscarinic antagonist; Long-acting β2-agonist; Metered dose inhaler",
"medline_ta": "Respir Res",
"mesh_terms": "D000280:Administration, Inhalation; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001993:Bronchodilator Agents; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D016503:Drug Delivery Systems; D005260:Female; D006024:Glycopyrrolate; D006801:Humans; D008297:Male; D036501:Metered Dose Inhalers; D008875:Middle Aged; D018727:Muscarinic Antagonists; D015990:Placebo Effect; D029424:Pulmonary Disease, Chronic Obstructive; D012720:Severity of Illness Index",
"nlm_unique_id": "101090633",
"other_id": null,
"pages": "38",
"pmc": null,
"pmid": "29506504",
"pubdate": "2018-03-05",
"publication_types": "D017427:Clinical Trial, Phase II; D003160:Comparative Study; D016428:Journal Article; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": "28848908;9789919;21942257;23526112;24587893;17136971;27916620;27586537;15219010;11414557;26259067;28427541;16055882;29019170;25060541;22985189;25027304;28061907;27817811",
"title": "A phase IIb randomized, chronic-dosing, incomplete block, cross-over study of glycopyrronium, delivered via metered dose inhaler, compared with a placebo and an active control in patients with moderate-to-severe COPD.",
"title_normalized": "a phase iib randomized chronic dosing incomplete block cross over study of glycopyrronium delivered via metered dose inhaler compared with a placebo and an active control in patients with moderate to severe copd"
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"abstract": "BACKGROUND\nBullous serous retinal detachment (RD) with retinal pigment epithelial (RPE) tear is a rare and severe variant of chronic central serous chorioretinopathy (CSC). Due to its atypical presentation, it may raise diagnostic issues, leading to inappropriate therapeutic procedures. The optimum treatment for this CSC variant is still uncertain.\n\n\nMETHODS\nA 65-year-old male was referred for vitreo-retinal surgery with a provisional diagnosis of rhegmatogenous RD in his right eye. Dilated fundus examination showed an inferior bullous RD with no evidence of retinal breaks, while a large RPE tear was detected in the temporal quadrant. Ocular ultrasound showed no mass lesion. The axial length was 23.63 mm. Enhanced depth imaging optical coherence tomography (EDI-OCT) revealed a pachychoroid pattern in both eyes. The patient referred a history of CSC in the right eye and the recent use of intravenous corticosteroids for bronchitis. Laser therapy and photodynamic therapy were not applicable due to the extension and elevation of the RD. Two months after oral treatment with eplerenone, the subretinal fluid increased significantly. The patient underwent two 4 × 4 mm deep lamellar sclerectomies in the inferior quadrants. The surgical treatment resulted in complete RD resolution.\n\n\nCONCLUSIONS\nA correct diagnosis of bullous variant of chronic CSC with RPE tear is critical to avoid inappropriate procedures and to prevent severe visual loss as a result of neuroretinal damage. Scleral thinning surgery may be considered a valid option, resulting in rapid and long-lasting resolution of RD.",
"affiliations": "IRCCS Sacro Cuore Don Calabria Hospital, Via Don Sempreboni 5 - Negrar, 37024, Verona, Italy. emi_maggio@yahoo.it.;IRCCS Sacro Cuore Don Calabria Hospital, Via Don Sempreboni 5 - Negrar, 37024, Verona, Italy.;IRCCS Sacro Cuore Don Calabria Hospital, Via Don Sempreboni 5 - Negrar, 37024, Verona, Italy.;IRCCS Sacro Cuore Don Calabria Hospital, Via Don Sempreboni 5 - Negrar, 37024, Verona, Italy.",
"authors": "Maggio|Emilia|E|;Mete|Maurizio|M|;Maraone|Giorgia|G|;Arena|Fabrizio|F|;Pertile|Grazia|G|",
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"country": "England",
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"doi": "10.1186/s12886-020-01409-w",
"fulltext": "\n==== Front\nBMC Ophthalmol\nBMC Ophthalmol\nBMC Ophthalmology\n1471-2415 BioMed Central London \n\n1409\n10.1186/s12886-020-01409-w\nCase Report\nScleral thinning surgery for bullous retinal detachment with retinal pigment epithelial tear in central serous chorioretinopathy: a case report\nMaggio Emilia emi_maggio@yahoo.it Mete Maurizio Maraone Giorgia Arena Fabrizio Pertile Grazia grid.416422.70000 0004 1760 2489IRCCS Sacro Cuore Don Calabria Hospital, Via Don Sempreboni 5 - Negrar, 37024 Verona, Italy \n6 4 2020 \n6 4 2020 \n2020 \n20 13316 9 2019 27 3 2020 © The Author(s) 2020Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.Background\nBullous serous retinal detachment (RD) with retinal pigment epithelial (RPE) tear is a rare and severe variant of chronic central serous chorioretinopathy (CSC). Due to its atypical presentation, it may raise diagnostic issues, leading to inappropriate therapeutic procedures. The optimum treatment for this CSC variant is still uncertain.\n\nCase presentation\nA 65-year-old male was referred for vitreo-retinal surgery with a provisional diagnosis of rhegmatogenous RD in his right eye. Dilated fundus examination showed an inferior bullous RD with no evidence of retinal breaks, while a large RPE tear was detected in the temporal quadrant. Ocular ultrasound showed no mass lesion. The axial length was 23.63 mm. Enhanced depth imaging optical coherence tomography (EDI-OCT) revealed a pachychoroid pattern in both eyes. The patient referred a history of CSC in the right eye and the recent use of intravenous corticosteroids for bronchitis. Laser therapy and photodynamic therapy were not applicable due to the extension and elevation of the RD. Two months after oral treatment with eplerenone, the subretinal fluid increased significantly. The patient underwent two 4 × 4 mm deep lamellar sclerectomies in the inferior quadrants. The surgical treatment resulted in complete RD resolution.\n\nConclusion\nA correct diagnosis of bullous variant of chronic CSC with RPE tear is critical to avoid inappropriate procedures and to prevent severe visual loss as a result of neuroretinal damage. Scleral thinning surgery may be considered a valid option, resulting in rapid and long-lasting resolution of RD.\n\nKeywords\nBullous serous retinal detachmentChronic central serous chorioretinopathyPachychoroidRetinal pigment epithelialSclerectomiesScleral thinning surgeryissue-copyright-statement© The Author(s) 2020\n==== Body\nBackground\nBullous serous retinal detachment (RD) is a rare and severe manifestation of chronic central serous chorioretinopathy (CSC). It may present with a retinal pigment epithelial (RPE) tear, that, conversely, is not common in eyes with non-bullous CSC. Unlike neovascular age-related macular degeneration, RPE tear in CSC is thought to be the result of tractional forces generated by increased hydrostatic pressure from a fluid-filled pigment epithelial detachment (PED) [1].\n\nThe cause for this atypical presentation remains uncertain. It is thought to be an exaggerated form of CSC, resulting from a more pronounced breakdown in the permeability of the choroid and RPE [1–3]. It has not been frequently described as spontaneous; rather, it is mostly associated with a history of corticosteroid therapy, organ transplantation, haemodialysis, or during pregnancy [4–7]. Due to its atypical presentation, the disease may raise diagnostic issues, leading to inappropriate diagnoses of rhegmatogenous RD or serous RD due to other causes. Several previously reported cases [8–10] underwent scleral buckling, vitrectomy, cryopexy, or corticosteroid therapy as a result of misdiagnosis.\n\nHowever, the optimum treatment for this variant of CSC is still unclear. Effective therapeutic options are limited. Conventional treatments for CSC are often prevented by the extension and elevation of the exudative retinal detachment. Given the hypothesized pathogenetic mechanisms underlying the disease, a scleral thinning surgical treatment, aimed to improve the transscleral outflow, might be considered an effective option. Nevertheless, in the previous literature it has not been undertaken as a viable treatment for the bullous variant of CSC.\n\nHerein, we report the case of a patient affected by the bullous variant of chronic CSC with RPE tear, treated with scleral thinning surgery with a rapid and long-lasting resolution of the disease.\n\nCase presentation\nA 65-year-old white male was referred to our Vitreo-Retinal Surgery Service for a retinal detachment (RD) in his right eye. On examination, his best-corrected visual acuity (BCVA) was 20/63 in the right eye (RE) and 20/20 in the left eye (LE), with a small refractive error. Intraocular pressure was 15 mmHg OU. Slitlamp examination revealed quiet anterior chambers and slight nuclear sclerosis in both eyes. Dilated fundus examination of the right eye showed an inferior bullous RD involving the macula with no evidence of retinal breaks, while a large RPE tear was detected in the temporal quadrant (Fig. 1, A,B). There was no sign of uveitis or vitreitis. Fundus examination of the LE was unremarkable, except for slight RPE distrophic alterations at the posterior pole with RPE mottling. Enhanced depth imaging optical coherence tomography (EDI-OCT) revealed a pachychoroid pattern in both eyes (Fig. 2). Moreover, OCT scans of the right eye showed sub-retinal fluid (SRF) reaching the macular area from the inferior quadrants. No SRF was detected in the LE. Ocular ultrasound showed no mass lesion (Fig. 1, C,D). Upon questioning his medical history, the patient referred a history of central serous chorioretinopathy (CSC) in the RE and the recent use of intravenous corticosteroids for bronchitis. Fluorescein angiography (FA) and Indocyanine green angiography (ICGA) were performed, revealing hyperpermeable and dilated choroidal vessels and multifocal and diffuse leakage in the late angiograms of the RE (Fig. 3). No disc leak or vasculitis were detected. Swept-Source OCT angiography (SS-OCT-A) confirmed the pachychoroid pattern and clearly demonstrated the mid-pheripheral RPE tear in the inferotemporal quadrant (Fig. 2). Axial lengths were 23.63 mm (RE) and 23.35 mm (LE).\nFig. 1 Fundoscopic and ultrasound findings at presentation. a, b: Color fundus photographs of the right eye showing an inferior bullous retinal detachment involving the macula (a) with a large retinal pigment epithelial tear in the temporal quadrant (b). c, d: Ocular ultrasound showing exudative retinal detachment with no mass lesion\n\nFig. 2 Enhanced depth imaging optical coherence tomography (EDI-OCT) and Swept-Source OCT (SS-OCT-A) angiography findings. a, b. EDI-OCT revealing a pachychoroid pattern in both eyes (a) and sub-retinal fluid reaching the macular area from the inferior quadrants in the right eye (b). c, d. SS-OCT-A showing the mid-pheripheral RPE tear in the inferotemporal quadrant (c) and confirming the pachychoroid pattern\n\nFig. 3 Fluorescein angiography (FA) and Indocyanine green angiography (ICGA) at the presentation, revealing hyperpermeable and dilated choroidal vessels and multifocal and diffuse leakage. a, b. Early and late FA angiograms. d, e. Early and late ICGA angiograms. c, f. FA and ICGA angiograms at the site of the retinal pigment epithelial tear\n\n\n\nBased on the clinical features, a diagnosis of bullous variant of CSC with RPE tear was made. Oral therapy with eplerenone at a dose of 50 mg/day was initiated. However, no improvement was detected. In fact, two months later, the exudative RD increased with a worsening of the BCVA to 20/80 (Fig. 4), despite the continuing therapy with eplerenone. To prevent irreversible photoreceptor damage, management with observation or eplerenone treatment continuation were excluded, and alternative therapeutic procedures were discussed. Laser therapy was deemed inappropriate because the leakage was multifocal and diffuse, with multiple “ink blot” focal areas of leakage at the superior margin of the detached retina and other poorly defined leakage areas in the attached retina. Photodynamic therapy (PDT) was not applicable because of the extension and elevation of the RD. Therefore, the opportunity for surgical treatment was considered.\nFig. 4 OCT scans performed two months after oral treatment with eplerenone showing the increase in the exudative retinal detachment. a Horizontal scan. b Vertical scan\n\n\n\nWritten informed consent was given by the patient, after a comprehensive explanation of the procedures. Under general anesthesia, the patient’s eye was prepared with povidone-iodine and draped. After 180° inferior conjunctival peritomy, bridle suture was passed under the inferior, medial and lateral rectus muscles with 3–0 ticron, and the sclera was exposed. Two 4 × 4 mm almost full scleral thickness sclerectomies were done in the inferior quadrants, taking care to avoid the areas close to exit sites of the vortex veins. Finally, the conjunctiva was approximated with 8–0 Vicryl suture. The treatment resulted in complete RD resolution as of the first day after surgery. Upon follow-up six months after surgery- complete SRF resolution was confirmed and BCVA was stable at 20/80 (Fig. 5).\nFig. 5 Multimodal imaging performed six months after surgery. a Fluorescein angiography showing a sharply demarcated hyperfluorescence (window defect) at the site of the retinal pigment epithelial (RPE) tear and the resolution of the inferior retinal detachment. b Color fundus photograph showing the temporal RPE tear and RPE distrophic alterations at the posterior pole. C, D. OCT scans revealing the resolution of subretinal fluid\n\n\n\nDiscussion and conclusions\nBullous serous RD is a rare complication of chronic CSC. Since the original description by Gass in 1973 [11], there have been only a limited number of case series and case reports that have described the clinical features and management of this CSC variant [1, 12–14].\n\nWe report the case of a patient referred to our hospital for vitreo-retinal surgery with a provisional diagnosis of rhegmatogenous RD. However, upon examination, the clinical presentation was not consistent with rhegmatogenous RD, nor with inflammatory exudative RD. Causes of exudative RD include hypertension, VogtKoyanagi-Harada syndrome, metastasis or other intraocular tumors, posterior scleritis, uveal effusion syndrome (UES), and nanophthalmos. In our patient, blood pressure was normal and there was no evidence of intraocular inflammation or posterior scleritis. Mass lesions were excluded by ocular ultrasound. Nanophthalmos and UES were ruled out as the axial length was normal and there was no ciliochoroidal detachment. Bilateral increased choroidal thickness, recent use of intravenous corticosteroids, RPE tear, and RPE dystrophic changes led towards a diagnosis of bullous variant of CSC.\n\nCurrent treatment options for chronic CSC include laser therapy, PDT and oral mineralocorticoid receptor antagonists.\n\nIn patients with the bullous variant of CSC, previous authors have found no significant difference between laser treated and non-laser treated eyes with regards to SRF resolution and final visual outcome [3]. This suggests laser treatment is unable to change the natural course of this disease. Moreover, for our patient, the laser was deemed inappropriate because the leakage was multifocal and diffuse.\n\nPDT has been employed extensively for the treatment of chronic CSC. However, its efficacy for the bullous variant with retinal tears has not been established. Ng et al. [12] described SRF resolution after three months in a case of bullous RD secondary to chronic CSC treated with PDT with half-dose verteporfin. However, the detachment was much less pronounced when compared with our case, and no RPE tear was present. In our case, the elevation of the retina was greater, and the RD was even more extensive after two months of FU following the eprelenone treatment. Therefore, PDT was not applicable.\n\nOral mineralocorticoid receptor antagonists have been described to induce a decrease in or resolution of SRF in CSC cases that do not spontaneously resolve. Moreover, a previous report describes a case of a bullous CSC variant successfully treated with spironolactone [13]. However, in our case, treatment with oral eplerenone provided no benefit since SRF increased despite the treatment.\n\nPrevious authors have also described a case of bullous variant of chronic CSC in an eye with borderline-low axial length, successfully treated with partial thickness scleral resection with mitomycin C, suggesting the improved transscleral outflow as the mechanism underlying the procedure’s efficacy [14]. The authors hypothesized that in smaller eyes, there may be a component of reduced transscleral outflow similar to UES that, in the presence of other coexisting pathologies like chronic CSC, makes it unable to balance the marked exudative inflow. Therefore, they suggested scleral resection surgery for the bullous variant of chronic CSC in small axial length eyes.\n\nScleral resection surgery has been successfully employed to treat exudative retinal and ciliochoroidal detachment in UES. In those cases, the pathogenesis is thought to be related to scleral abnormalities with alterations of the transscleral diffusion of choroidal extravascular proteins and the accumulation of fluid in the choroid as a result of increased osmolarity [15, 16]. In eyes affected by UES, scleral thinning procedures have been shown to enhance transscleral protein diffusion, thus leading to the resolution of ciliochoroidal and serous retinal detachment [17].\n\nTo the best of our knowledge, no previous reports describe the management of the bullous variant of CSC in normal axial length eyes with scleral thinning surgery. Although the pathogenesis of the bullous variant of CSC is partially understood, evidence suggests that it is related to a more pronounced congestion and breakdown in the permeability of the choroidal vessels and RPE [1]. Therefore, it can be hypothesized that an improvement in transscleral outflow would be beneficial for these eyes, also in the presence of normal axial length. The rapid and long-lasting resolution of the bullous RD in our patient confirmed the efficacy of this treatment.\n\nIn previous literature, managing the bullous variant of CSC with alternative surgical procedures, such as scleral buckling, vitrectomy, cryopexy or internal drainage, has been described mostly as a result of misdiagnosis [8]. The scleral thinning surgery, when compared to vitrectomy with internal drainage, has the advantage of being a less invasive procedure with a reduced risk of complications, and producing a long-lasting improvement in transcleral outflow. Considering the chronicity of the disease, this might be additionally beneficial for long-term follow-up in these eyes.\n\nThe present case suggests that scleral thinning surgery may be considered a valid option for the treatment of bullous variant of chronic CSC with RPE tear, above all when alternative available therapeutic options, such as PDT and laser therapy, are not applicable.\n\nAbbreviations\nCSCCentral serous chorioretinopathy\n\nBCVABest-corrected visual acuity\n\nEDI-OCTEnhanced depth imaging optical coherence tomography\n\nFAFluorescein angiography\n\nFUFollow-up\n\nICGAIndocyanine green angiography\n\nLELeft eye\n\nPDTPhotodynamic therapy\n\nPEDPigment epithelial detachment\n\nRDRetinal detachment\n\nRERight eye\n\nRPERetinal pigment epithelial\n\nSRFsub-Retinal fluid\n\nSS-OCT-ASwept-Source OCT angiography\n\nUESUveal effusion syndrome\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nBrian Hawkins for his linguistic revision.\n\nAuthors’ contributions\nEM conceived and designed the study, participated in the acquisition, analysis and interpretation of data and wrote the manuscript. MM participated in the acquisition, analysis and interpretation of data and revised critically the manuscript. GM participated in the acquisition and analysis of data and critically revised the manuscript. FA participated in the acquisition and analysis of data and revised critically the manuscript. GP participated in the design and coordination of the study, gave contribution in the analysis and interpretation of data and critically revised the manuscript. All authors read and approved the final manuscript.\n\nFunding\nNo funding received.\n\nAvailability of data and materials\nAll data and material are included in the manuscript and the figures.\n\nEthics approval and consent to participate\nNot applicable.\n\nConsent for publication\nWritten informed consent was obtained from the patient for publication of this Case Report and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.\n\nCompeting interests\nAll the authors declare that they have no competing interests.\n==== Refs\nReferences\n1. Balaratnasingam C Freund KB Tan AM Mrejen S Hunyor AP Keegan DJ Bullous variant of central serous Chorioretinopathy: expansion of phenotypic features using multimethod imaging Ophthalmology. 2016 123 7 1541 1552 10.1016/j.ophtha.2016.03.017 27084564 \n2. Weiler W Foerster MH Wessing A Exudative retinal detachment, pigment epithelium tear and subretinal exudates in a case of CSR Klin Monatsbl Augenheilkd 1991 99 450 453 10.1055/s-2008-1046114 \n3. Sahu DK Namperumalsamy P Hilton GF de Sousa NF Bullous variant of idiopathic central serous chorioretinopathy Br J Ophthalmol 2000 84 5 485 492 10.1136/bjo.84.5.485 10781512 \n4. Gass JDM Bullous retinal detachment and multiple retinal pigment epithelium detachments in patients receiving haemodialysis Graefes Arch Clin Exp Ophthalmol 1992 230 454 458 10.1007/BF00175933 1521813 \n5. Dasatnik HR Gutman FA Bilateral exudative retinal detachment complicating systemic corticosteroid therapy in the presence of renal failure Am J Ophthalmol 1996 122 432 434 10.1016/S0002-9394(14)72075-6 8794721 \n6. Gass JDM Central serous chorioretinopathy and white subretinal exudation during pregnancy Arch Ophthalmol 1991 109 677 681 10.1001/archopht.1991.01080050091036 2025170 \n7. Gass JDM Little H Bilateral bullous exudative retinal detachment complicating idiopathic central serous chorioretinopathy during systemic corticosteroid therapy Ophthalmology 1995 102 737 747 10.1016/S0161-6420(95)30960-8 7777273 \n8. Chen HC Ho JD Chen SN Perfluorocarbon liquid-assisted external drainage in the management of central serous chorioretinopathy with bullous serous retinal detachment Chang Gung Med J 2003 26 10 777 781 14717214 \n9. Kang JE Kim HJ Boo HD Kim HK Lee JH Surgical management of bilateral exudative retinal detachment associated with central serous chorioretinopathy Korean J Ophthalmol 2006 20 2 131 138 10.3341/kjo.2006.20.2.131 16892652 \n10. Rueda-Rueda T Sánchez-Vicente JL Llerena-Manzorro L Medina-Tapia A González-García L Alfaro-Juárez A Bilateral exudative retinal detachment associated with central serous chorioretinopathy in a patient treated with corticosteroids Arch Soc Esp Oftalmol 2017 92 10 481 485 10.1016/j.oftal.2017.01.002 28242123 \n11. Gass JD Bullous retinal detachment. An unusual manifestation of idiopathic central serous choroidopathy Am J Ophthalmol 1973 75 5 810 821 10.1016/0002-9394(73)90887-8 4196284 \n12. Ng WW Wu ZH Lai TY Half-dose verteporfin photodynamic therapy for bullous variant of central serouschorioretinopathy: a case report J Med Case Rep 2011 5 208 10.1186/1752-1947-5-208 21615893 \n13. Yang D Eliott D Systemic mineralocorticoid antagonists in the treatment of central serous Chorioretinopathy Semin Ophthalmol 2017 32 1 36 42 10.1080/08820538.2016.1228418 27929707 \n14. Venkatesh P Chawla R Tripathy K Singh HI Bypareddy R Scleral resection in chronic central serous chorioretinopathy complicated by exudative retinal detachment Eye Vis (Lond) 2016 3 1 23 10.1186/s40662-016-0055-5 27617266 \n15. Ward RC Gragoudas ES Pon DM Albert DM Abnormal scleral findings in uveal effusion syndrome Am J Ophthalmol 1988 106 139 146 10.1016/0002-9394(88)90825-2 2969684 \n16. Jackson TL Hussain A Morley AM Sullivan PM Hodgetts A El-Osta A Scleral hydraulic conductivity and macromolecular diffusion in patients with uveal effusionsyndrome Invest Ophthalmol Vis Sci 2008 49 11 5033 5040 10.1167/iovs.08-1980 18552396 \n17. Maggio E Polito A Prigione G Pertile G Uveal effusion syndrome mimicking severe chronic posterior uveitis: a case series of seven eyes of four patients Graefes Arch Clin Exp Ophthalmol 2016 254 3 545 552 10.1007/s00417-015-3176-y 26376819\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1471-2415",
"issue": "20(1)",
"journal": "BMC ophthalmology",
"keywords": "Bullous serous retinal detachment; Chronic central serous chorioretinopathy; Pachychoroid; Retinal pigment epithelial; Scleral thinning surgery; Sclerectomies",
"medline_ta": "BMC Ophthalmol",
"mesh_terms": "D000368:Aged; D056833:Central Serous Chorioretinopathy; D005451:Fluorescein Angiography; D006801:Humans; D008297:Male; D033401:Microscopy, Acoustic; D012163:Retinal Detachment; D012167:Retinal Perforations; D055213:Retinal Pigment Epithelium; D012590:Sclera; D012599:Sclerostomy; D041623:Tomography, Optical Coherence",
"nlm_unique_id": "100967802",
"other_id": null,
"pages": "133",
"pmc": null,
"pmid": "32252699",
"pubdate": "2020-04-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "26376819;7777273;21615893;1791690;2025170;28242123;4196284;2969684;14717214;27617266;27929707;16892652;27084564;18552396;8794721;10781512;1521813",
"title": "Scleral thinning surgery for bullous retinal detachment with retinal pigment epithelial tear in central serous chorioretinopathy: a case report.",
"title_normalized": "scleral thinning surgery for bullous retinal detachment with retinal pigment epithelial tear in central serous chorioretinopathy a case report"
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"abstract": "BACKGROUND\nAn over-expression of CD19 has been shown in B cells of systemic sclerosis (SSc) and B cells are thought to contribute to the induction of skin fibrosis in the tight skin mouse model. The aim was to define the outcome on safety and the change in skin score after rituximab therapy in SSc patients and to correlate the clinical characteristics with the levels of interleukin (IL)-6 and with the immune cell infiltrate detected by immunohistochemistry.\n\n\nMETHODS\nNine patients with SSc with mean age 40.9 +/- 11.1 years were treated with anti-CD20, 1 g at time 0 and after 14 days. Skin biopsy was performed at baseline and during the follow-up. B-cell activating factor (BAFF) and IL-6 levels were also determined at the follow-up times.\n\n\nRESULTS\nAfter 6 months patients presented a median decrease of the skin score of 43.3% (range 21.1-64.0%), and a decrease in disease activity index and disease severity index. IL-6 levels decreased permanently during the follow up. After treatment, a complete depletion of peripheral blood B cells was observed in all but 2 patients. Only 3 patients presented CD20 positive cells in the biopsy of the involved skin at baseline.\n\n\nCONCLUSIONS\nAnti-CD20 treatment has been well tolerated and SSc patients experienced an improvement of the skin score and of clinical symptoms. The clear fall in IL-6 levels could contribute to the skin fibrosis improvement, while the presence of B cells in the skin seems to be irrelevant with respect to the outcome after B cell depletion.\n\n\nBACKGROUND\nISRCTN77554566.",
"affiliations": "Division of Rheumatology, Catholic University, Medical School, Via G, Moscati, 31 - Rome, 00168, Italy.",
"authors": "Bosello|Silvia|S|;De Santis|Maria|M|;Lama|Gina|G|;Spanò|Cristina|C|;Angelucci|Cristiana|C|;Tolusso|Barbara|B|;Sica|Gigliola|G|;Ferraccioli|Gianfranco|G|",
"chemical_list": "D000911:Antibodies, Monoclonal; D018951:Antigens, CD20; D053264:B-Cell Activating Factor; C508600:IL6 protein, human; D007155:Immunologic Factors; D015850:Interleukin-6; C505719:TNFSF13B protein, human",
"country": "England",
"delete": false,
"doi": "10.1186/ar2965",
"fulltext": "\n==== Front\nArthritis Res TherArthritis Research & Therapy1478-63541478-6362BioMed Central ar29652033804310.1186/ar2965Research articleB cell depletion in diffuse progressive systemic sclerosis: safety, skin score modification and IL-6 modulation in an up to thirty-six months follow-up open-label trial Bosello Silvia 1silvia.bosello@rm.unicatt.itDe Santis Maria 1maria.desantis@rm.unicatt.itLama Gina 2gina.lama@rm.unicatt.itSpanò Cristina 2crispan6@hotmail.comAngelucci Cristiana 2cristina.angelucci@rm.unicatt.itTolusso Barbara 1barbara.tolusso@rm.unicatt.itSica Gigliola 2gigliola@rm.unicatt.itFerraccioli Gianfranco 1gf.ferraccioli@rm.unicatt.it1 Division of Rheumatology, Catholic University, Medical School, Via G. Moscati, 31 - Rome, 00168, Italy2 Institute of Histology and Embryology, Catholic University, Medical School, L.go F.Vito, 1 - Rome, 00168, Italy2010 25 3 2010 12 2 R54 R54 5 5 2009 29 11 2009 25 3 2010 Copyright ©2010 Bosello et al.; licensee BioMed Central Ltd.2010Bosello et al.; licensee BioMed Central Ltd.This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Introduction\nAn over-expression of CD19 has been shown in B cells of systemic sclerosis (SSc) and B cells are thought to contribute to the induction of skin fibrosis in the tight skin mouse model. The aim was to define the outcome on safety and the change in skin score after rituximab therapy in SSc patients and to correlate the clinical characteristics with the levels of interleukin (IL)-6 and with the immune cell infiltrate detected by immunohistochemistry.\n\nMethods\nNine patients with SSc with mean age 40.9 ± 11.1 years were treated with anti-CD20, 1 g at time 0 and after 14 days. Skin biopsy was performed at baseline and during the follow-up. B-cell activating factor (BAFF) and IL-6 levels were also determined at the follow-up times.\n\nResults\nAfter 6 months patients presented a median decrease of the skin score of 43.3% (range 21.1-64.0%), and a decrease in disease activity index and disease severity index. IL-6 levels decreased permanently during the follow up. After treatment, a complete depletion of peripheral blood B cells was observed in all but 2 patients. Only 3 patients presented CD20 positive cells in the biopsy of the involved skin at baseline.\n\nConclusions\nAnti-CD20 treatment has been well tolerated and SSc patients experienced an improvement of the skin score and of clinical symptoms. The clear fall in IL-6 levels could contribute to the skin fibrosis improvement, while the presence of B cells in the skin seems to be irrelevant with respect to the outcome after B cell depletion.\n\nTrial registration\nISRCTN77554566.\n\nSee related editorial by van Laar, http://arthritis-research.com/content/12/2/112\n==== Body\nIntroduction\nAlthough the pathogenesis of systemic sclerosis (SSc) remains unknown, the B cell abnormalities characterized by autoantibody production [1], hyper-γ-globulinemia and polyclonal B cell hyperactivity [2] are thought to play an important role in the disease. It has been previously described that SSc patients have distinct abnormalities of blood homeostasis and B cell compartments, characterized by expanded naïve cells and activated, but diminished, memory B cells [3]. Furthermore, the expression of CD19, a critical signal transduction molecule of B cells that regulates autoantibody production, is significantly increased in memory and naïve B cells in SSc patients [3,4]. Analysis of DNA microarrays of cutaneous biopsies from diffuse SSc (dSSc) patients demonstrated a higher expression of clusters of genes of CD20-positive cells [5].\n\nIn the tight-skin mice, a genetic model of human SSc, the CD19 signaling pathway appeared to be constitutively activated [6,7] and the loss of CD19 expression significantly up-regulated surface IgM expression, completely abrogated hyper-γ-globulinemia and autoantibody production, and also inhibited IL-6 production [7]. Additionally, in this animal model, the down-regulation of B cell function led to a decrease in skin fibrosis during the disease onset [8]. Likewise, in a bleomycin-induced SSc mouse model, another animal model that shares many characteristics with human SSc, CD19 deficiency inhibited the development of skin and lung fibrosis, hyper-γ-globulinemia, and autoantibody production [9]. Thus, B cells could have a relevant impact on the development of fibrotic changes as reported in the mouse scleroderma models [6-9] and also in CCl4-induced liver injury, in an antibody- and T cell-independent manner [10].\n\nIn several studies focusing on the pathogenesis of SSc, the increased levels of IL-6 in the skin, serum, and bronchoalveolar lavage fluid of SSc patients suggest a role of this cytokine in promoting fibrosis by enhancing inflammation [11-13]. Furthermore, immunohistochemistry data demonstrated an over-expression of IL-6 on endothelium and fibroblasts of involved skin of scleroderma patients compared with normal skin [14]. SSc dermal fibroblasts constitutively produce about a four-fold increase in IL-6 levels with respect to healthy controls fibroblasts [15] and secretion of IL-6 from lung fibroblast is induced by SSc lung-derived B cells [16]. Recently, it has been reported that B-cell activating factor (BAFF), an essential component of B cell homeostasis and a potent B-cell survival factor associated with autoimmune disease in humans, is increased in SSc patients compared with healthy controls [17]. In the tight-skin mice, BAFF antagonist augmented anti-fibrogenic cytokines and inhibited the development of skin fibrosis. Finally, after BAFF stimulation, B-cells had a significantly enhanced ability to produce IL-6 [18].\n\nTwo recent open-label studies reported the safety of anti-CD20 treatment in SSc patients; despite both studies describing a decrease in myofibroblast score on serial skin biopsies after treatment, only one reported an improvement in skin score [19,20]. In these two studies, lung function remained stable during follow up, whereas a case report suggested a possible beneficial role of rituximab on lung involvement in scleroderma disease [21].\n\nThe primary aim of the current prospective study was to evaluate the changes in the skin score from baseline to at least 6 up to 36 months of follow up after anti-CD20 therapy. Secondary aims were to assess the potential efficacy of rituximab on lung function, to investigate the modification in IL-6 and BAFF serum levels as biological parameters of disease activity, and to correlate the clinical characteristics with the immune cell infiltrate detected by immunohistochemistry.\n\nMaterials and methods\nPatients and treatment\nNine patients with progressive cutaneous SSc involvement, who showed a worsening of skin score higher than 10% after the conventional cyclophosphamide therapy [22] (up to 6 g), were treated with rituximab, two infusions of 1000 mg, two weeks apart, together with 100 mg methylprednisolone at each infusion, after three months of wash-out. All patients fulfilled the American College of Rheumatology classification criteria for scleroderma [23] and gave their informed consent to enter the study, which was approved by our Ethics Institutional Committee. All patients accepted that their biographical and clinical information could be eventually published.\n\nInclusion criteria were: age older than 18 years, a worsening in skin score higher than 10% after the conventional cyclophosphamide therapy, and a diffuse disease with trunk involvement. Exclusion criteria were: rest dyspnoea or signs and symptoms of heart failure, serious and uncontrolled coexisting diseases, infection, immunodeficiency or a history of tuberculosis contact, or cancer. None of the patients was taking corticosteroids daily. Three patients were re-treated with rituximab 1 g × 2 (days 1 to 15): the first patient because after 18 months she presented with a reactivation of her arthritis, while the other two patients were re-treated after 12 months because they presented a precocious and quicker B cell-recovery at months 3 and 7 (CD19 >4.5%).\n\nThere were eight women and one man, with a mean (standard deviation (SD))age of 40.9 ± 11.1 years, and a median disease duration of 2.0 (range:1.0 to 12.0) years. Seven patients had an early disease, defined as a disease duration less than three years since the occurrence of Raynaud's phenomenon. All patients presented a diffuse skin disease (dSSc); moreover, six (66.7%) had antiScl70-Abs positivity and three (33.3%) only presented antinuclear antibodies (ANA) positivity (Table 1) [24]. All nine patients continued to receive iloprost (by an infusion of 0.5 to 2 ng/kg/minute for five days every two months), calcium-channel blockers (nifedipine 20 to 40 mg/day) and acetylsalicylic acid from the moment of medical diagnosis. One of the two patients with long disease also presented with a metacarpophalangeal and wrist arthritis and one patient had myositis with high creatine kinase levels. Both these patients received methotrexate 15 mg/week after cyclophosphamide, one for treatment of arthritis and the other for myositis therapy. Both patients experienced a worsening of their skin fibrosis despite this therapy.\n\nTable 1 Demographic and clinical characteristics of nine patients treated with rituximab\n\nAge (years) (mean (SD))\t40.9 (11.1)\t\n(median (range))\t41.5 (21.0-55.0)\t\nDisease duration (months) (mean (SD))\t49.0 (73.1)\t\n(median (range))\t24.0 (12-240)\t\n\t\nFemale (number,%)\t8 (88.9)\t\nMale (number,%)\t1 (11.1)\t\n\t\nANA positivity (number,%)\t9 (100)\t\nAnti-Scl70 positivity (number,%)\t6 (66.7)\t\n\t\nFollow-up (months)(mean (SD))\t16.7 (12.6)\t\n(median (range))\t12 (6-36)\t\nThe values are indicated as the mean (SD), median (range) or percentage. ANA, antinuclear antibodies; SD, standard deviation.\n\nThe extent of skin involvement was evaluated by the Rodnan skin score, performed by two observers and their results averaged [25]. Every three months, activity index [26] and severity index were assessed [27] and Global Health Status (GH) and Health Assessment Questionnaire (HAQ) were administered to patients to evaluate the influence of the disease on daily functions. At the same time intervals, blood samples were collected to determine IL-6 and BAFF levels and to count CD19-positive cells by flow cytometry.\n\nInternal organ involvement\nAll nine patients underwent pulmonary function tests to define forced vital capacity (FVC) and diffusing capacity for carbon monoxide (DLCO) before treatment and every six months. High-resolution computed tomography (HRCT) was performed before treatment and every 12 months. Renal involvement was defined as a scleroderma crisis or the presence of proteinuria or elevation in creatinine serum level. Creatinine levels and urine analysis were performed every three months. Cardiac involvement was defined as the presence of conduction disturbance, left ventricular ejection fraction (LVEF) less than 50%, pulmonary artery systolic pressure (PASP) more than 35 mmHg or presence of myocarditis; electrocardiography (ECG) and echocardiography were performed at the beginning of the treatment and every six months. Gastrointestinal involvement was defined as the presence of gastro-esophageal reflux symptoms or the evidence of gastrointestinal motility disturbance by barium swallow performed before treatment.\n\nBiological marker detection\nSerum levels of IL-6 and BAFF (R&D Systems, Minneapolis, MN, USA) were measured using an ELISA, as described by the manufacturer. Erythrocyte sedimentation rate, total immunoglobulin (Ig) G, IgM and IgA were part of the routine clinical care of each patient. ANA were determined by indirect immunofluorescence using Hep-2 cells as substrates and autoantibodies specificities were further assessed by ELISA (Shield, Dundee, UK). Peripheral blood CD19-positive cell count was obtained by flow cytometry every three months.\n\nSkin biopsies and immunohistochemical analysis\nSkin biopsies were performed in seven patients, who gave their informed consent, before treatment and in the five patients that achieved 12 months of follow up from the beginning of anti-CD20 therapy. Four healthy controls gave their informed consent to undergo forearm skin biopsy. In dSSc patients, cutaneous specimens were taken from the distal forearm for the clinically involved skin and from the buttock for clinically uninvolved skin. The biopsies were fixed into 10% formalin for two hours followed by paraffin inclusion for histological and immunohistochemical analysis.\n\nImmunohistochemistry was carried out on 5 μm thick sections on polylysine-coated slides. After routine deparaffinization and rehydration, antigen retrieval was performed. Slide-mounted sections were heated in a microwave oven at 700 watt twice for four minutes in 10 mmol/L sodium citrate buffer (pH 6.0). Tissue sections were allowed to cool at room temperature (RT). Quenching of endogenous peroxidase activity was performed with Tris-buffered saline (TBS; pH 7.6) containing 2% hydrogen peroxide for 10 minutes at RT. Blocking was performed with 20% normal goat serum in TBS for 60 minutes at RT.\n\nThe sections were incubated with anti-CD3 and anti-CD20 mouse monoclonal antibodies (mAbs, Clone PS1 and L26 respectively; IgG2a; Ylem, Rome, Italy) both 1:100 diluted in blocking solution (20% normal goat serum in TBS) for 60 minutes at RT. Then, the Super Picture Polymer detection kit (Zymed Laboratories, South San Francisco, CA, USA) was used for 30 minutes at RT. The chromogenic reaction was developed with 3,3'-diaminobenzidine tetrahydrochloride solution (Zymed Laboratories, South San Francisco, CA, USA). The nuclei were lightly counterstained with Mayer's hematoxylin. Negative controls without primary antibodies were performed for all reactions. As all mAbs were of IgG2a isotype, mouse mAb IgG2a served as an isotype-specific control. Human tonsil specimens were used as positive controls for both antibodies. All controls were run under the same conditions and the same IgG concentrations were used for the respective primary antibodies. Positive cells were counted by two independent observers in six randomly selected fields (total area: 7.38 mm2) for each section at × 400 magnification. Differences between observers about staining evaluation were resolved by consensus. The total number of positive cells was calculated.\n\nStatistical analysis\nAll analyses were carried out using SPSS 15.0 (Chicago, IL, USA). Categorical variables were expressed as numbers, and quantitative variables as mean ± SD if normally distributed, and as median plus range if not. Non-normally distributed data were compared using the Mann-Whitney's test, and the Wilcoxon's test for paired data. A value of P < 0.05 was considered statistically significant.\n\nResults\nSkin score, activity and severity indices\nAll nine SSc patients treated with rituximab experienced an improvement of the skin score, activity index, severity index, HAQ and GH during the follow up if compared to pre-treatment values (Table 2 and Figure 1). Neither infections nor infusion reactions were observed. The only serious adverse event was the development of an occult breast cancer, which was thought to be unrelated to the study medication. The mean follow up was 16.7 ± 12.6 months: all patients reached a six-month follow up, five patients reached a 12-month follow up, four patients reached an 18-month follow up, three patients reached a 24-month follow up and two patients reached a 36-month follow up.\n\nFigure 1 Clinical improvement during follow up in nine systemic sclerosis patients treated with anti-CD20. Clinical improvement in the nine patients treated with anti-CD20 during the follow-up times (3, 6, 12, 18, 24 and 36 months). Skin score, blood CD20 levels, severity index and activity index were assessed at baseline (0) and after 3, 6, 12, 18, 24 and 36 months. In the first graph precyclophosphamide (preCYP) skin score and skin score at time 0 (time of beginning of rituximab (RTX)) are reported. Each line represents the modification of different parameters in each patient during the follow up. Each symbol (on the left) represents one patient and corresponds to the number of the patient of Table 3.\n\nTable 2 Efficacy of rituximab on clinical and biologic parameters of nine SSc patients treated with anti-CD20 during the follow up\n\n\tBaseline\tAfter 3\nMonths\tAfter 6\nMonths\tAfter 12\nmonths*\tAfter 18\nmonths**\tAfter 24\nmonths***\tAfter 36\nmonths****\t\nRodnan skin score\t\t\t\t\t\t\t\t\n(mean (SD))\t21.1 (9.0)\t15.2 (6.0)\t12.0 (6.1)\t7.0 (4.0)\t7.0 (3.5)\t5.0 (2.0)\t4.0 (1.4)\t\n(median (range))\t19.0 (7-36)\t15.0 (5-27)\t10.0 (4-26)\t8.0 (3-14)\t7.5 (3-10)\t5.0 (3-7)\t4.0 (3-5)\t\nDisease activity index\t\t\t\t\t\t\t\t\n(mean (SD))\t4.8 (1.3)\t2.0 (1.2)\t1.2 (1.2)\t0.9 (1.0)\t1.0 (1.3)\t1.3 (1.4)\t1.7 (1.8)\t\n(median (range))\t4.5 (3.5-7.0)\t2.0 (0.5-3.5)\t0.5 (0.5-3.5)\t0.5 (0.5-3.0)\t0.5 (0.5-3.0)\t0.5 (0.5-3.0)\t1.7 (0.5-3.0)\t\n\t\t\t\t\t\t\t\t\nDisease severity index\t\t\t\t\t\t\t\t\n(mean (SD))\t10.5 (3.2)\t8.3 (2.9)\t7.2 (2.8)\t6.2 (2.8)\t6.7 (2.2)\t7.7 (1.5)\t8.5 (0.7)\t\n(median (range))\t11.0 (6-15)\t7.0 (4-13)\t6.0 (4-11)\t6.0 (3-9)\t7.0 (4-9)\t8.0 (6-9)\t8.5 (8-9)\t\nHAQ\t\t\t\t\t\t\t\t\n(mean (SD))\t0.9 (0.7)\t0.5 (0.5)\t0.4 (0.5)\t0.3 (0.7)\t0.3 (0.6)\t0.3 (0.6)\t0.6 (0.6)\t\n(median (range))\t0.8 (0.1-2.4)\t0.4 (0-1.6)\t0.2 (0-1.5)\t0 (0-1.5)\t0 (0-1.2)\t0 (0-1.1)\t0 (0-1.3)\t\n\t\t\t\t\t\t\t\t\nGH (mean (SD))\t59.4 (20.9)\t74.4 (16.5)\t82.8 (16.6)\t86.0 (10.8)\t82.5 (21.8)\t82.5 (17.7)\t82.5 (17.7)\t\n(median (range))\t60.0 (30-85)\t80.0 (50-95)\t90.0 (50-95)\t90.0 (70-95)\t92.5 (50-95)\t82.5 (70-95)\t82.5 (70-95)\t\n\t\t\t\t\t\t\t\t\nBlood CD20%\t\t\t\t\t\t\t\t\n(mean (SD))\t6.8 (3.9)\t0.7 (1.5)\t1.7 (2.4)\t3.0 (2.7)\t2.0 (1.6)\t1.0 (1.5)\t3.0 (3.3)\t\n(median (range))\t6.0 (2.5-14.7)\t0.1 (0.1-4.6)\t1.0 (0.1-7.0)\t4.0 (0.3-7.0)\t2.0 (0.2-3.0)\t1.0 (0.2-3.0)\t3.0 (0.3-5.0)\t\n\t\t\t\t\t\t\t\t\nIgG mg/ml\t\t\t\t\t\t\t\t\n(mean (SD))\t1055 (233)\t1001 (191)\t1021 (158)\t1028 (46.6)\t946.2 (178)\t944 (315)\t951 (69)\t\n(median (range))\t1140 (729-1340)\t932 (884-1440)\t1030 (802-1220)\t1005 (1000-1110)\t938 (738-1170)\t896 (656-1280)\t951 (902-1000)\t\n\t\t\t\t\t\t\t\t\nIgA mg/ml\t\t\t\t\t\t\t\t\n(mean (SD))\t184.0 (44.4)\t174.5 (39.2)\t177.8 (63.5)\t179.4 (69.8)\t152.5 (59.9)\t139.0 (67.5)\t100.0 (24.0)\t\n(median (range))\t183.5 (119-249)\t183.5 (119-262)\t200.0 (75-262)\t168.5 (93-281)\t154.0 (79-222)\t136.0 (73-208)\t100.0 (83-117)\t\n\t\t\t\t\t\t\t\t\nIgM mg/ml\t\t\t\t\t\t\t\t\n(mean (SD))\t133.7 (21.7)\t86.0 (12.8)\t90.9 (28.9)\t83.0 (18.7)\t61.5 (6.7)\t43.3 (10.6)\t71.0 (1.4)\t\n(median (range))\t132.5 (95-157)\t91.0 (56-136)\t96.0 (40-136)\t73.0 (64-105)\t61.5 (54-69)\t45.0 (32-53)\t71.0 (70-72)\t\n\t\t\t\t\t\t\t\t\nBAFF pg/ml\t\t\t\t\t\t\t\t\n(mean (SD))\t1233.5 (683.3)\t1719.4 (1264.3)\t3257.8 (1571.8)\t2057.0 (912.5)\t2988.0 (1804)\t3520.0 (1999)\t3608.0 (2824)\t\n(median (range))\t875.6 (683-2601)\t1008.6 (356-4038)\t3141.8 (723-6682)\t1580.6 (1321.6-3280)\t2406.2 (1534-5605)\t3224.8 (1684-5651)\t3608.0 (1610-5605)\t\n\t\t\t\t\t\t\t\t\nIL6 pg/ml\t\t\t\t\t\t\t\t\n(mean (SD))\t3.7 (5.3)\t1.0 (1.2)\t0.6 (0.9)\t0.4 (0.4)\t1.2 (2.0)\t0.1 (0.1)\t0.1 (0.1)\t\n(median (range))\t1.7 (0.1-16.9)\t0.1 (0.1-3.6)\t0.1 (0.1-2.8)\t0.4 (0.1-0.8)\t0.25 (0.1-4.2\t0.1 (0.1-0.1)\t0.1 (0.1-0.1)\t\nClinical and biological parameters of nine SSc patients treated with anti-CD20 at baseline, after 3, 6, 12, 18, 24 and 36 months. The values are indicated as the mean (SD) and median (range). All patients had trunk skin involvement.\n\n*Five SSc patients reached 12 months of follow up. **Four SSc patients reached 18 months of follow up. ***Three SSc patients reached 24 months of follow up. *****Two patients reached 36 months of follow up.\n\nBAFF, B-cell activating factor; GH, Global Health Status; HAQ, Health Assessment Questionnarie; Ig, immunoglobulin; SD, standard deviation; SSc, systemic sclerosis.\n\nInterestingly, in all nine patients treated with rituximab, the skin score improved gradually over time (Figure 1 and Table 2). After six months, the skin score improved in all the patients, decreasing from 21.1 ± 9.0 to 12.0 ± 6.1 (P = 0.001), with a median of improvement of 43.3% (range: 21.1 to 64.0%). Considering the last observation carried forward in each patient, the median skin improvement was 57.1% (range: 21.2 to 76.2).\n\nAfter six months, the activity index decreased from 4.8 ± 1.3 to 1.2 ± 1.2 (P = 0.01) and the severity index from 10.5 ± 3.2 to 7.2 ± 2.8 (P = 0.01; Figure 1 and Table 2). All patients reported an improvement of their conditions as supported by the decrease in HAQ from 0.9 ± 0.7 to 0.4 ± 0.5 (P = 0.01) and an increase in GH from 59.4 ± 20.9 to 82.8 ± 16.6 (P = 0.01; Table 2). The only patient who did not present an improvement of the activity and severity indices, HAQ and GH, had a long disease duration.\n\nOrgan involvement\nThe FVC and DLCO values showed no significant differences at follow up (96.8 ± 18.9% and 58.4 ± 14.2% of predicted value, respectively) compared with baseline (91.6 ± 20.7% and 58.0 ± 15.8% of the predicted value, respectively; P = ns for both comparison). Four (44.4%) patients presented an improvement higher than 10% of FVC, (median increase 14.9% (range: 11.8% to 29.5%)). None of the patients presented a reduction in FVC considered clinically significant (>10%), but one patient showed a decrease in FVC values suggesting a trend to a progression of her restrictive lung disease [28,29].\n\nTwo patients (22.2%) presented an isolated reduction of DLCO higher than 15%, both with an improvement in FVC values higher than 10% and with a stable echocardiography evaluation and no sign of pulmonary arterial hypertension. On the other hand, a clinical significant improvement in DLCO was reported in two patients (22.2%) [28,29] (Table 3).\n\nTable 3 Demographic and clinical chracteristics of the study population\n\nPatient\tE/L\tDisease duration (months)\tAuto-antibodies\tFollow-up duration (months)\tFVC at baseline\tFVC at the end of follow up\tDLCO at baseline\tDLCO at the end of follow up\tMusculoskeletal involvement\tUlcers\tRenal/cardiac/GI involvement\tConcomitant medications\t\n1\tE\t13\tANA\t36\t89%\t104%\t55%\t54%\tmyositis\tN\tN/Y/Y\tMTX\t\n2\tL\t240\tScl70\t36\t101%\t113%\t52%\t61%\tarthritis\tY\tN/N/Y\tMTX\t\n3\tE\t12\tANA\t12\t105%\t96%\t65%\t69%\tN\tN\tN/N/Y\t-\t\n4\tE\t24\tScl70\t24\t98%\t101%\t72%\t65%\tN\tY\tN/N/Y\t-\t\n5\tE\t12\tScl70\t18\t100%\t113%\t56%\t43%\tN\tY\tN/Y/Y\t-\t\n6\tE\t24\tScl70\t6\t95%\t94%\t86%\t85%\tN\tY\tN/N/Y\t-\t\n7\tE\t24\tANA\t6\t44%\t57%\t54%\t40%\tN\tY\tN/N/Y\t-\t\n8\tE\t32\tSCL70\t6\t77%\t78%\t28%\t47%\tN\tY\tN/Y/Y\t-\t\n9\tL\t60\tSCL70\t6\t115%\t115%\t54%\t62%\tN\tY\tN/N/Y\t-\t\nAll patients had a diffuse cutaneous disease.\n\nRenal involvement was defined as antecedent scleroderma crisis or the presence of proteinuria or elevation of creatinine serum level.\n\nCardiac involvement was defined as the presence of conduction disturbance, left ventricular ejection fraction less than 55%, pulmonary artery systolic pressure more than 35 mmHg or presence of myocarditis.\n\nGastro-intestinal involvement was defined as presence of gastro-oesophageal reflux symptoms or the evidence of gastrointestinal motility disturbance by barium swallow.\n\nConcomitant medications: treatment other than iloprost by an infusion of 0.5 to 2 ng/Kg/minute, lasting six hours, for five days every two months, calcium-channel blockers (nifedipine 20 to 40 mg/day) and acetylsalicylic acid.\n\nThe number, that identifies each patient, corresponds to the number of the patient in Figures 1 and 2.\n\nANA, antinuclear autoantibodies; DLCO, diffusing capacity for carbon monoxide; E, early disease (disease duration <3 years); FVC, forced vital capacity; GI, gastrointestinal; L, long disease (disease duration >3 years); MTX, methotrexate; N, no; Scl70, antitopoisomerasi I antibodies; Y, yes.\n\nNone of the patients showed signs of new or progressive cardiac disease, with stable ejection fractions and no modification on ECGs; none of the patients experienced renal crisis or symptoms suggesting progressive gastrointestinal disease.\n\nBiological markers\nAt baseline, patients presented high levels of IL-6 (3.7 ± 5.3 pg/ml), that permanently decreased after six months (0.6 ± 0.9 pg/ml, P = 0.02; Table 2 and Figure 2a). Three months after the rituximab infusion, circulating B cells evaluated by flow-cytometry were depleted (peripheral blood CD19 <0.1%) in all but one patient, and between 6 and 12 months they begun to repopulate. Upon B-cell depletion, BAFF levels increased relative to baseline (baseline: 1233.5 ± 683.3 pg/ml vs six months: 3257.8 ± 1571.8 pg/ml), while in one patient the BAFF levels did not increase until the time of repopulation (Figure 2b).\n\nFigure 2 (a) IL-6 and (b) BAFF levels at baseline and during follow up. IL-6 and B-cell activating factor (BAFF) levels evaluated in nine patients treated with anti-CD20 at baseline and during the follow up. (a and b) Each line represents the modification of IL-6 and BAFF parameters in each patient during the follow up. Each symbol (on the right) represents one patient and corresponds to the number of the patient of Table 3.\n\nThe autoantibody titers and IgG and IgA levels did not vary over the study period, while IgM levels decreased from 133.7 ± 21.7 mg/dl to 90.9 ± 28.9 mg/dl at six months follow up (P = 0.008), and to 83.0 ± 18.7 after 12 months of follow up (P = 0.04; Table 2).\n\nBefore rituximab treatment, one patient presented myositis with high creatine kinase levels, which decreased significantly after anti-CD20 treatment (data not shown). Creatine kinase levels remained within the normal range during the 36 months of follow up. The only patient with a long disease duration who did present the less significant clinical improvement, showed an important amelioration of her arthritis, with a change of disease activity score (DAS) from 4.3 to 2.0.\n\nThree (42.9%) out of the seven patients, who underwent skin biopsies before treatment, presented CD20-positive cells on biopsies of the clinically involved skin and uninvolved skin; only one patient of these three repeated the biopsy after 12 months and it showed a depletion of dermal B cells. The other two patients were treated only for six months and they did not agree to a repeat biopsy.\n\nCD3 lymphocytes were found, predominantly, in a perivascular location in the mid and deeper portion of the dermis in all the involved and uninvolved skin biopsies of patients before and after treatment with anti-CD20. Figure 3 illustrates the presence of B cells (a) and T cells (b) in forearm biopsy in patient number three before therapy. The mean number of CD3-positive cells in skin biopsies of four healthy subjects was 8.0 ± 2.0 and none presented B cells (data not shown). Before treatment, the mean number of CD3-positive cells was 54.7 ± 27.9 in involved skin and 65.6 ± 39.7 in uninvolved skin (P = ns; Figure 3). After treatment, a similar number of CD3-positive cells was found in involved skin (44.3 ± 24.0) and in uninvolved skin (62.7 ± 23.4) of the five patients who underwent skin biopsies after 12 months.\n\nFigure 3 B and T cell staining in systemic sclerosis biopsies. In a forearm biopsy, immunohistochemistry revealed an expression of the B-cell marker CD20 in a limited number of (a) lymphocytes while a prominent expression of the T-cell marker CD3 was detected in the (b) perivascular lymphocytic infiltrate. Original magnification × 400.\n\nDiscussion\nThe results of our study suggest that B cell depletion in patients with early and progressive dSSc, leads to a clinically relevant decrease in skin involvement and to a stabilization of organ function. The only patient who showed a less clear-cut response either in terms of severity and activity indexes was the one with a long-standing disease.\n\nIn our study, the safety of anti-CD20 treatment in SSc patients was also confirmed in up to 36 months of follow up. The observed skin score improvement is more than expected as the spontaneous improvement in patients with similar disease, and comparable with the study by Smith and colleagues [19]. Recently, two studies assessed the safety of anti-CD20 treatment in scleroderma patients. In the first open-label trial, eight SSc patients experienced a skin score improvement up to 43% after 24 weeks from the beginning of anti-CD20 treatment [19], while in the second, a cohort of 15 SSc patients, with a follow up of 12 months, showed no improvement in the skin score [20]. Only the first group used the corticosteroids premedication.\n\nIn these two studies, all SSc patients, as in our study, had an early diffuse disease and patients were similar for age, disease duration and clinical characteristics [19,20]. It is interesting to note that despite little changes reported in the skin score after rituximab treatment in the largest cohort, a decrease in myofibroblast score was observed in several patients [20]. As the myofibroblast score correlates with the skin thickness score [20,30], these data suggest that a decrease in myofibroblast score could be a preclinical indicator of improvement of scleroderma skin fibrosis. Furthermore, Lafyatis and colleagues reported the presence of B cells in all but one skin specimen at baseline and a complete or nearly complete depletion of dermal B cells six months after administration of rituximab [20]. This suggests a biological effect on the skin after drug administration that could with new courses of the drug lead to a clinical skin improvement. In fact, we treated patients with a progressive cutaneous disease after conventional cyclophosphamide therapy. Moreover, we decided to re-treat two of our patients, because they presented a slower improvement of the skin score in the first six months of follow up and an earlier repopulation of B cells, similar to the data reported by the Lafyatis and colleagues, in which the majority of patients presented a precocious recovery of B cells between 6 and 12 months [20].\n\nInterestingly, none of the SSc patients in the current study treated with anti-CD20 showed a progression of major end-organ involvement in a population with early diffuse disease that had a relatively high risk of organ complication. Parameters of internal organ involvement remained stable, but a further follow up in a more consistent group of patients is needed before drawing any conclusions.\n\nThe clear fall in IL-6 levels observed in our study is in agreement with findings obtained in a mouse model after B cell depletion [8]. This fall could be related, at least for the first stages, to the high dose of methylprednisolone used for the premedication in ours and the cohort of patients in the study by Smith and colleagues [19], but considering the follow times of evaluation (3 to 6 to 12 months) it has to be related to the rituximab treatment. This may suggest that IL-6 might contribute to the active phase of the disease. The decrease in IL-6 at the systemic levels could be the biological premise of the improvement in skin fibrosis. In fact, it has been previously reported that chronic IL-6 administration induces an increased synthesis of collagen in dermal fibroblasts [31] and in the liver [32]. Furthermore, IL-6 has been demonstrated to enhance resistance of lung fibroblasts to apoptosis, contributing to the fibrotic effect [33].\n\nImmunohistochemistry clearly demonstrated the presence of T cells either in uninvolved or in involved skin, but B cells were seen only in some patients, as previously reported [5,19]. These data suggest that the most relevant contribution of B cells comes from the systemic pool. In fact, it appears clear that the response of skin fibrosis to B cell depletion does not rely on the presence of B cells in the skin, because most of our treated patients had no B cells, but very likely depends upon the general contribution to the autoimmune derangement given by the B cell compartments in lymphoid organs. B cells, with their multiple mechanisms as antibody-producing cells, antigen-presenting cells and profibrotic and proinflammatory cytokines producing cells (IL-6, IL-4, transforming growth factor-β), seem to be of great impact in the development of fibrosis. Thus, their modulation could inhibit skin fibrosis, as reported in the scleroderma mouse model [8], but the data on BAFF levels need to be interpreted since, as observed in patients with Sjogren's syndrome [34] or rheumatoid arthritis [35], the levels went up after B cell depletion.\n\nConclusions\nOur data suggest that anti-CD20 treatment is well tolerated and that dSSc patients experience an improvement of the skin score and of clinical symptoms. The clear fall in IL-6 levels may contribute to the skin fibrosis improvement, while the presence of B cells in the skin seems to be irrelevant with respect to the outcome after B cell depletion. Although we cannot draw any conclusion due to the limited number of cases, the response in the early disease patients was striking suggesting that a trial is warranted to confirm these preliminary data.\n\nAbbreviations\nANA: antinuclear antibodies; BAFF: B-cell activating factor; DAS: disease activity score; DLCO: diffusing capacity for carbon monoxide; dSSc: diffuse systemic sclerosis; ECG: electrocardiogram; ELISA: enzyme-linked immunosorbent assay; FVC: forced vital capacity; GH: Global Health Status; HAQ: Health Assessment Questionnaire; HRCT: high-resolution computed tomography; Ig: immunoglobulin; IL-6: interleukin-6; LVEF: left ventricular ejection fraction; mAbs: monoclonal antibodies; PASP: pulmonary artery systolic pressure; RT: room temperature; SD: standard deviation; SSc: systemic sclerosis; TBS: Tris-buffered saline.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nAuthors' contributions\nBS conceived and designed the study, collected data, performed the statistical analysis, interpreted and analysed data, and drafted the manuscript. MDS conceived and designed the study, collected data, interpreted and analysed data, and drafted the manuscript. LG carried out the immunohistochemistry, interpreted and analysed data, and revised the manuscript. SC carried out the immunohistochemistry, collected data, interpreted and analysed data, and revised the manuscript. AC carried out the immunohistochemistry, and collected data. TB carried out immunoassay and collected data. SG participated in the design of the study, analysed data and revised the manuscript. GF conceived and designed the study, interpreted and analysed data and drafted the manuscript. All authors read and approved the final manuscript.\n\nAcknowledgements\nWritten consent for publication was obtained from all patients.\n==== Refs\nOkano Y Antinuclear antibody in systemic sclerosis (scleroderma) Rheum Dis Clin North Am 1996 22 709 735 10.1016/S0889-857X(05)70297-0 8923592 \nFamularo G Giacomelli R Alesse E Cifone MG Morrone S Boirivant M Danese C Perego MA Santoni A Tonietti G Polyclonal B lymphocyte activation in progressive systemic sclerosis J Clin Lab Immunol 1989 29 59 63 2632802 \nSato S Fujimoto M Hasegawa M Takehara K Altered blood B lymphocyte homeostasis in systemic sclerosis: expanded naive B cells and diminished but activated memory B cells Arthritis Rheum 2004 50 1918 1927 10.1002/art.20274 15188368 \nSato S Hasegawa M Fujimoto M Tedder TF Takehara K Quantitative genetic variation in CD19 expression correlates with autoimmunity J Immunol 2000 165 6635 6643 11086109 \nWhitfield ML Finlay DR Murray JI Troyanskaya OG Chi JT Pergamenschikov A McCalmont TH Brown PO Botstein D Connolly MK Systemic and cell type-specific gene expression patterns in scleroderma skin Proc Natl Acad Sci USA 2003 100 12319 12324 10.1073/pnas.1635114100 14530402 \nAsano N Fujimoto M Yazawa N Shirasawa S Hasegawa M Okochi H Tamaki K Tedder TF Sato S B lymphocyte signaling established by the CD19/CD22 loop regulates autoimmunity in the tight-skin mouse Am J Pathol 2004 165 641 650 15277237 \nSaito E Fujimoto M Hasegawa M Komura K Hamaguchi Y Kaburagi Y Nagaoka T Takehara K Tedder TF Sato S CD19-dependent B lymphocyte signaling thresholds influence skin fibrosis and autoimmunity in the tight-skin mouse J Clin Invest 2002 109 1453 1462 12045259 \nHasegawa M Hamaguchi Y Yanaba K Bouaziz JD Uchida J Fujimoto M Matsushita T Matsushita Y Horikawa M Komura K Takehara K Sato S Tedder TF B-lymphocyte depletion reduces skin fibrosis and autoimmunity in the tight-skin mouse model for systemic sclerosis Am J Pathol 2006 169 954 966 10.2353/ajpath.2006.060205 16936269 \nYoshizaki A Iwata Y Komura K Ogawa F Hara T Muroi E Takenaka M Shimizu K Hasegawa M Fujimoto M Tedder TF Sato S CD19 regulates skin and lung fibrosis via Toll-like receptor signaling in a model of bleomycin-induced scleroderma Am J Pathol 2008 172 1650 1663 10.2353/ajpath.2008.071049 18467694 \nNovobrantseva I Majeau GR Amatucci A Kogan S Brenner I Casola S Shlomchik MJ Koteliansky V Hochman PS Ibraghimov A Attenuated liver fibrosis in the absence of B cells J Clin Invest 2005 115 3072 3082 10.1172/JCI24798 16276416 \nScala E Pallotta S Frezzolini A Abeni D Barbieri C Sampogna F De Pità O Puddu P Paganelli R Russo G Cytokine and chemokine levels in systemic sclerosis: relationship with cutaneous and internal organ involvement Clin Exp Immunol 2004 138 540 546 10.1111/j.1365-2249.2004.02642.x 15544634 \nHasegawa M Sato S Fujimoto M Ihn H Kikuchi K Takehara K Serum levels of Interleukin 6 (IL-6), oncostatin M, soluble IL-6 receptor, and soluble gp130 in patients with systemic sclerosis J Rheumatol 1998 25 308 316 9489824 \nDe Santis M Bosello S La Torre G Capuano A Tolusso B Pagliari G Pistelli R Danza FM Zoli A Ferraccioli F Functional, radiological and biological markers of alveolitis and infections of the lower respiratory tract in patients with systemic sclerosis Respir Res 2005 6 96 106 10.1186/1465-9921-6-96 16107215 \nKoch AE Kronfeld-Harrington LB Szekanecz Z Cho MM Haines GK Harlow LA Strieter RM Kunkel SL Massa MC Barr WG Jimenez SA In situ expression of cytokines and cellular adhesion molecules in the skin of patients with systemic sclerosis. Their role in early and late disease Pathobiology 1993 61 239 246 10.1159/000163802 7507681 \nKadono T Kikuchi K Ihn H Takehara K Tamaki K Increased production of interleukin 6 and interleukin 8 in scleroderma fibroblasts J Rheumatol 1998 25 296 301 9489822 \nKondo K Okada T Matsui T Kato S Date K Yoshihara M Nagata Y Takagi H Yoneda M Sugie I Establishment and characterization of a human B cell line from the lung tissue of a patient with scleroderma; extraordinary high level of IL-6 secretion by stimulated fibroblasts Cytokine 2001 13 220 226 10.1006/cyto.2000.0822 11237429 \nMatsushita T Hasegawa M Yanaba K Kodera M Takehara K Sato S Elevated serum BAFF levels in patients with systemic sclerosis: enhanced BAFF signaling in systemic sclerosis B lymphocytes Arthritis Rheum 2006 54 192 201 10.1002/art.21526 16385515 \nMatsushita T Fujimoto M Hasegawa M Matsushita Y Komura K Ogawa F Watanabe R Takehara K Sato S BAFF antagonist attenuates the development of skin fibrosis in tight-skin mice J Invest Dermatol 2007 127 2772 2780 17581616 \nSmith V Van Praet JT Vandooren B Van der Cruyssen B Naeyaert JM Decuman S Elewaut D De Keyser F Rituximab in diffuse cutaneous systemic sclerosis: an open-label clinical and histopathological study Ann Rheum Dis 2010 69 193 197 10.1136/ard.2008.095463 19103636 \nLafyatis R Kissin E York M Farina G Viger K Fritzler MJ Merkel PA Simms RW B cell depletion with Rituximab in patients with diffuse cutaneous systemic sclerosis Arthritis Rheum 2009 60 578 583 10.1002/art.24249 19180481 \nMcGonagle D Tan AL Madden J Rawstron AC Rehman A Emery P Thomas S Successful treatment of resistant scleroderma-associated interstitial lung disease with rituximab Rheumatology 2008 47 552 553 10.1093/rheumatology/kem357 18281368 \nCalguneri M Apras S Ozbalkan Z Ertenli I Kiraz S Ozturk MA Celik I The efficacy of oral cyclophosphamide plus prednisolone in early diffuse systemic sclerosis Clin Rheumatol 2003 22 289 294 10.1007/s10067-003-0733-2 14579158 \nSubcommittee for Scleroderma Criteria of the American Rheumatism Association Diagnostic and Therapeutic Criteria Committee Preliminary criteria for the classification of systemic sclerosis (scleroderma) Arthritis Rheum 1980 23 581 590 10.1002/art.1780230510 7378088 \nLeRoy EC Black C Fleischmajer R Jablonska S Krieg T Medsger TA JrRowell N Wollheim F Scleroderma (systemic sclerosis): classification, subset and pathogenesis J Rheumatol 1988 15 202 205 3361530 \nValentini G D'Angelo S Della Rossa A Bencivelli W Bombardieri S European Scleroderma Study Group to define disease activity criteria for systemic sclerosis. IV: Assessment of skin thickening by modified Rodnan skin score Ann Rheum Dis 2003 62 904 905 10.1136/ard.62.9.904 12922969 \nValentini G Silman AJ Veale D Assessment of disease activity Clin Exp Rheumatol 2003 21 Suppl 29 S39 S41 12889221 \nMedsger TA JrBombardieri S Czirjak L Scorza R Della Rossa A Bencivelli W Assessment of disease severity and prognosis Clin Exp Rheumatol 2003 21 Suppl 29 S42 S46 12889222 \nEgan JJ Martinez FJ Wells AU Williams T Lung function estimates in idiopathic pulmonary fibrosis: the potential for a simple classification Thorax 2005 60 270 273 10.1136/thx.2004.035436 15790978 \nBehr J Furst DE Pulmonary function tests Rheumatol 2008 47 Suppl 5 v65 v67 10.1093/rheumatology/ken313 18784151 \nKissin EY Merkel PA Lafyatis R Myofibroblasts and hyalinized collagen as markers of skin disease in systemic sclerosis Arthritis Rheum 2006 54 3655 3660 10.1002/art.22186 17075814 \nDuncan MR Berman B Stimulation of collagen and glycosaminoglycan production in cultured human adult dermal fibroblasts by recombinant human interleukin 6 J Invest Dermatol 1991 97 686 692 10.1111/1523-1747.ep12483971 1940439 \nChoi I Kang HS Yang Y Pyun KH IL-6 induces hepatic inflammation and collagen synthesis in vivo Clin Exp Immunol 1994 95 530 535 8137551 \nMoodley YP Misso NL Scaffidi AK Fogel-Petrovic M McAnulty RJ Laurent GJ Thompson PJ Knight DA Inverse effects of interleukin-6 on apoptosis of fibroblasts from pulmonary fibrosis and normal lungs Am J Respir Cell Mol Biol 2003 29 490 498 10.1165/rcmb.2002-0262OC 12714376 \nPers JO Devauchelle V Daridon C Bendaoud B Le Berre R Bordron A Hutin P Renaudineau Y Dueymes M Loisel S Berthou C Saraux A Youinou P BAFF-modulated repopulation of B lymphocytes in the blood and salivary glands of rituximab-treated patients with Sjögren syndrome Arthritis Rheum 2007 56 1464 1477 10.1002/art.22603 17469105 \nLavie F Miceli-Richard C Ittah M Sellam J Gottenberg JE Mariette X Increase of B cell-activating factor of the TNF family (BAFF) after Rituximab treatment: insights into a new regulating system of BAFF production Ann Rheum Dis 2007 66 700 703 10.1136/ard.2006.060772 17040963\n\n",
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"mesh_terms": "D000328:Adult; D000911:Antibodies, Monoclonal; D000920:Antibody-Dependent Cell Cytotoxicity; D018951:Antigens, CD20; D053264:B-Cell Activating Factor; D001402:B-Lymphocytes; D005260:Female; D006304:Health Status; D006801:Humans; D007155:Immunologic Factors; D015850:Interleukin-6; D008212:Lymphocyte Depletion; D008297:Male; D008875:Middle Aged; D012595:Scleroderma, Systemic; D012720:Severity of Illness Index; D012867:Skin; D055815:Young Adult",
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"title": "B cell depletion in diffuse progressive systemic sclerosis: safety, skin score modification and IL-6 modulation in an up to thirty-six months follow-up open-label trial.",
"title_normalized": "b cell depletion in diffuse progressive systemic sclerosis safety skin score modification and il 6 modulation in an up to thirty six months follow up open label trial"
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"abstract": "To describe a unique presentation of Central Nervous System Burkitt Lymphoma.\nA 59-year-old male presented with new onset binocular horizontal diplopia five days after initial presentation with abdominal distension, weight loss, and night sweats. He was diagnosed with Burkitt Lymphoma with base of skull metastasis that was initially visible only on PET scan and subsequently resolved with chemotherapy.\nBurkitt Lymphoma (BL) is an aggressive type of B-cell, non-Hodgkin, lymphoma that arises due to a translocation of the MYC proto-oncogene. Although central nervous system (CNS) involvement has been described previously with BL, isolated sixth nerve palsy as the initial sign of CNS metastasis is rare. Suspicion should remain high for metastatic disease in patients presenting with acute-onset neurologic complaints even when initial imaging is negative as timely treatment can prevent poor outcomes.",
"affiliations": "School of Medicine (SY), (Department of Ophthalmology (AGL), Baylor College of Medicine, 1 Baylor Plaza, Houston, TX, 77030, USA.;Department of Ophthalmology, Blanton Eye Institute, Houston Methodist Hospital, 6550 Fannin St, Houston, TX, 77030, USA.;Department of Ophthalmology, Blanton Eye Institute, Houston Methodist Hospital, 6550 Fannin St, Houston, TX, 77030, USA.;School of Medicine (SY), (Department of Ophthalmology (AGL), Baylor College of Medicine, 1 Baylor Plaza, Houston, TX, 77030, USA.",
"authors": "Yennam|Sowmya|S|;Kini|Ashwini T|AT|;Al Othman|Bayan|B|;Lee|Andrew G|AG|",
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"fulltext": "\n==== Front\nAm J Ophthalmol Case RepAm J Ophthalmol Case RepAmerican Journal of Ophthalmology Case Reports2451-9936Elsevier S2451-9936(19)30157-410.1016/j.ajoc.2019.100565100565Case ReportSixth nerve palsy in sporadic Burkitt Lymphoma Yennam Sowmya aKini Ashwini T. ashkini1@gmail.combAl Othman Bayan bLee Andrew G. aglee@houstonmethodist.orgabcdefg∗a School of Medicine (SY), (Department of Ophthalmology (AGL), Baylor College of Medicine, 1 Baylor Plaza, Houston, TX, 77030, USAb Department of Ophthalmology, Blanton Eye Institute, Houston Methodist Hospital, 6550 Fannin St, Houston, TX, 77030, USAc Departments of Ophthalmology, Neurology, and Neurosurgery, Weill Cornell Medicine, 1305 York Ave, New York, NY, 10021, USAd Department of Ophthalmology, University of Texas Medical Branch, 700 University Blvd, Galveston, TX, 77555, USAe University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX, 77030, USAf Texas A and M College of Medicine, 8447 Bryan Rd, Bryan, TX, 77807, USAg Department of Ophthalmology, The University of Iowa Hospitals and Clinics, 200 Hawkins Drive, Iowa City, IA, 52242, USA∗ Corresponding author. Blanton Eye Institute, Houston Methodist Hospital, 6560 Fannin Street Suite 450, Houston, TX, 77030, USA. aglee@houstonmethodist.org31 10 2019 12 2019 31 10 2019 16 1005659 4 2019 27 10 2019 © 2019 The Authors2019This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Purpose\nTo describe a unique presentation of Central Nervous System Burkitt Lymphoma.\n\nObservations\nA 59-year-old male presented with new onset binocular horizontal diplopia five days after initial presentation with abdominal distension, weight loss, and night sweats. He was diagnosed with Burkitt Lymphoma with base of skull metastasis that was initially visible only on PET scan and subsequently resolved with chemotherapy.\n\nConclusions and Importance\nBurkitt Lymphoma (BL) is an aggressive type of B-cell, non-Hodgkin, lymphoma that arises due to a translocation of the MYC proto-oncogene. Although central nervous system (CNS) involvement has been described previously with BL, isolated sixth nerve palsy as the initial sign of CNS metastasis is rare. Suspicion should remain high for metastatic disease in patients presenting with acute-onset neurologic complaints even when initial imaging is negative as timely treatment can prevent poor outcomes.\n\nKeywords\nCavernous sinus syndromeSixth nerve palsyHorizontal diplopiaMetastatic burkitt lymphoma\n==== Body\n1 Introduction\nBurkitt Lymphoma (BL) is an aggressive type of B-cell, non-Hodgkin, lymphoma that typically arises due to a translocation of the MYC proto-oncogene.1 There are three known subtypes of BL: endemic, sporadic, and immunodeficiency-related. The sporadic variant of BL accounts for only 1–2% of Non-Hodgkin Lymphoma in adults and typically presents as an abdominal tumor.1 Although central nervous system (CNS) involvement has been described previously, isolated sixth nerve palsy is rare.2 We report binocular, horizontal diplopia due to isolated CN VI palsy as the presenting sign for CNS BL. To our knowledge, this is the first such case to be reported in the English language ophthalmic literature.\n\n2 Case report\nA 59-year-old male presented with new onset binocular horizontal diplopia. Past medical, surgical, social, and family history were non-contributory. The patient presented with abdominal distension, three weeks of weight loss, and night sweats. Computed tomography of the abdomen showed a terminal ileal and ileocecal valve mass extending to the cecum with mesenteric metastatic implants, adenopathy and ascites. A biopsy of the terminal ileum and two small nodules in the sigmoid colon showed Burkitt lymphoma, with the neoplastic cells expressing CD20, CD10, BCL-6, MYC, and FOXP1.\n\nFive days after initial presentation, the patient developed diplopia. Neuro-ophthalmic exam showed visual acuity of 20/30 in the right eye (OD) and 20/20 in the left eye (OS). Intraocular pressure measured 23 mm Hg OD and 22 mm Hg OS. Both pupils measured 4mm in the dark and 2mm in the light, with no relative afferent pupillary defect (RAPD). Motility examination showed a 14 prism diopter incomitant esotropia in primary gaze with an abduction deficit of −3, consistent with a 6th nerve palsy OS (Fig. 1). No motility deficits were present OD. Slit lamp and fundus examinations were unremarkable bilaterally.Fig. 1 Patient demonstrates a left incomitant esotropia and an abduction deficit consistent with a 6th cranial nerve palsy OS.\n\nFig. 1\n\nInitial cranial magnetic resonance imaging (MRI) was negative, but positron emission tomography (PET) scan showed multiple areas of osseous involvement, including increased uptake in the skull base, specifically near the left cavernous sinus (Fig. 2). Repeat cranial MRI then showed abnormal tissue in the left cavernous sinus (Fig. 3). The body PET scan showed diffuse uptake in abdomen consistent with lymphomatosis, hepatic involvement, left internal mammary chain of nodes and multiple areas of osseous uptake. CSF analysis was negative for any malignant cells confirmed by flow cytometry.Fig. 2 PET scan showing increased base of skull uptake.\n\nFig. 2Fig. 3 MRI showing heterogenous signal intensity with decreased enhancement of the lesion in the left cavernous sinus compared with normal enhancement on the right side.\n\nFig. 3\n\nThe patient was treated with intrathecal methotrexate and cytarabine and four cycles of chemotherapy with C3D226 R-CODOX-M (Rituximab-cyclophosphamide, doxorubicin, vincristine-methotrexate). This regimen has been shown to markedly improve rates of remission, progression-free survival and overall survival in BL.3, 4, 5 Intrathecal methotrexate is used as a prophylactic or treatment agent for CNS spread in BL.6 Although previous intrathecal regimens for CNS BL (including methotrexate and cytosine arabinoside) had some initial success, CSF relapse occurred in up to 60–100% of these patients.6 In contrast, intensive R-CODOX with methotrexate has achieved about an 88% remission rates with 71–75% progression free survival and 77–80% overall survival at 5 years.4,5 Post-treatment cranial MRI showed an interval decrease in abnormal tissue in the left cavernous sinus (Fig. 4).Fig. 4 MRI sequences showing left cavernous sinus tissue before and after treatment of Burkitt lymphoma with R-CODOX-M Rituximab. (Image credits to Dr. Kuang-Chun Hsieh, Department of Neuroradiology, Houston Methodist).\n\nFig. 4\n\nAt a 3 month follow up visit (Fig. 5), the abduction deficit had improved and the residual small angle esotropia was treated with prism. His clinical course while on chemotherapy was complicated by E. coli bacteremia, tumor lysis syndrome, lactic acidosis, neutropenic fever, thrombocytopenia and anemia. He was adequately managed for his systemic complications and was in complete remission after his last cycle of chemotherapy in February 2019. His last PET scan showed resolution of all the previously noted hypermetabolic lesions and nodes including the skull base involvement.Fig. 5 In primary gaze, a small esotropia continues to persist after chemotherapy. Left gaze shows improvement in abduction of the left eye consistent with resolving 6th cranial nerve palsy.\n\nFig. 5\n\n3 Discussion\nBurkitt lymphoma (BL) is an aggressive, B-cell, non-Hodgkin lymphoma. Endemic BL is one of the most common childhood cancers in tropical Africa and as classically described by Burkitt, involves the jaw.7 The immunodeficiency-related type of BL occurs frequently in patients with human immunodeficiency virus (HIV) and often presents with abdominal symptoms and extranodal disease. Similarly, the sporadic variant of BL (as in our patient) commonly presents in adults with bulky abdominal tumor, B symptoms, and evidence of tumor lysis.8 CNS involvement by BL is seen in up to 38% of cases.9\n\nCNS BL can be diagnosed via cerebrospinal fluid (CSF) analysis or neuromaging.10 However, CSF cytology and initial cranial CT/MRI scans may be normal in CNS BL and a high clinical suspicion should be maintained in these cases. In our patient, the CSF and initial cranial MRI were negative. PET scan however showed skull base hypermetabolic activity that was confirmed by repeat cranial MRI demonstrating the lesion in the left cavernous sinus corresponding to the left sixth nerve palsy.\n\nSkull base tumors comprise a vast array of masses arising from neurovascular structures or meninges, the cranial base itself, or subcranial structures.11 The most common skull base tumors, particularly in the anterior and middle fossas, are meningiomas.12 Metastases to the skull base arise most commonly from breast, lung, and prostate cancer.13 Although lymphomas comprise approximately 5% of skull base metastases, to our knowledge there have been only eight previously reported cases of cavernous sinus syndrome from sporadic BL (Table 1). Most cases involved multiple cranial nerves or CN III. To our knowledge, this is the first case of an isolated sixth nerve palsy as the presenting sign of CNS sporadic BL in the English language ophthalmic literature.Table 1 Burkitt lymphoma involving the cavernous sinus.\n\nTable 1\tPatient\tNeuro-Ophthalmologic Presentation\tImaging (MRI)\t\nLiang Y et al.14\t29yo male\tCN III palsy\tNo corresponding lesion was seen – MRI only showed diffuse abnormal signals in bones\t\nRasper M, Kesari S15\t33yo female\tDiplopia (CN unspecified), blurred vision, retro-orbital headache\tBilateral enlargement and enhancement in the pituitary gland, cavernous sinus, and optic nerves\t\nKalina P et al.16\t4yo female\tLeft CN III and IV palsy, headache\tMass in cavernous sinus and sphenoid sinus\t\nSeixas DV et al.17\t11yo male\tRight cranial nerve III palsy\tEnlarged right cavernous sinus\t\nMoghaddasi M et al.18\t47yo female\tLeft CN III, IV, V1, V2, VI palsy, headache, nausea\tBilateral enlargement of the cavernous sinus\t\nTanaka Y et al.19\t62yo female\tCN III, IV, and IV palsy, ptosis, frontal headache\tSwelling of the optic nerves, and external ocular muscles, exophthalmos and bilateral tumors in the cavernous sinus\t\nHuisman TA et al.20\t12yo male\tCranial nerve III palsy, exophthalmos, headache\tHomogenously enhancing mass in right cavernous sinus (treatment with NHL-BFM-1995 protocol was ineffective: patient died of progressive liver failure within 3 months of diagnosis)\t\nLee AG et al.21\t9yo male\tVertical diplopia, CN III palsy and CN VI palsy OS.\tBilateral cavernous sinus lesions\t\n\n\nPatient consent\nThe patient consented to publication of the case orally. This report does not contain any personal information that could lead to identification of the patient.\n\nFunding\nNo funding or grant support.\n\nAuthorship\nAll authors attest that they meet the current ICMJE criteria for Authorship.\n\nDeclaration of competing interest\nThe following authors have no financial disclosures: SY, AK, BAL, AGL.\n\nAcknowledgements\nNone.\n==== Refs\nReferences\n1 Gastwirt J.P. Roschewski M. Management of adults with Burkitt lymphoma Clin Adv Hematol Oncol 16 12 2018 Dec \n2 Ziegler J.L. Bluming A.Z. Morrow R.H. Fass L. Carbone P.P. Central nervous system involvement in Burkitt's lymphoma Blood 36 6 1970 Dec 718 728 5536703 \n3 Barnes J.A. Evaluation of the addition of rituximab to CODOX-M/IVAC for Burkitt's lymphoma: a retrospective analysis Ann Oncol 22 8 2011 Aug 1859 1864 21339382 \n4 Zhu K.Y. Excellent real-world outcomes of adults with Burkitt lymphoma treated with CODOX-M/IVAC plus or minus rituximab Br J Haematol 181 6 2018 Jun 782 790 29741758 \n5 Hoelzer D. Serve H. Gokbuget N. Improved outcome of adult Burkitt lymphoma/leukemia with rituximab and chemotherapy: report of a large prospective multicenter trial Blood 124 26 2014 Dec 18 3870 3879 25359988 \n6 Ziegler J.L. Bluming A.Z. Intrathecal chemotherapy in Burkitt's lymphoma Br Med J 3 5773 1971 508 512 5109411 \n7 Morton L.M. Wang S.S. Devesa S.S. Hartge P. Weisenburger D.D. Linet M.S. Lymphoma incidence patterns by WHO subtype in the United States Blood 107 1 1992-2001 265 276 \n8 Perkins A.S. Friedberg J.W. Burkitt lymphoma in adults Hematol Am Soc Hematol Educ Progr 2008 2008 341 348 \n9 Blum K.A. Lozanski G. Byrd J.C. Adult Burkitt leukemia and lymphoma Blood 104 10 2004 Nov 15 3009 3020 15265787 \n10 Pui C.H. Thiel E. Central nervous system disease in hematologic malignancies: historical perspective and practical applications Semin Oncol 36 4 Suppl 2 2009 S2 S16 19660680 \n11 Chernov M. DeMonte F. Skull Base Tumors. Intracranial Extra-axial Primary Tumors 2002 Feb 300 319 \n12 Shih R.Y. Smirniotopoulos J.G. Posterior fossa tumors in adult patients Neuroimaging Clin N Am 26 4 2016 Nov 493 510 27712791 \n13 Greenberg H.S. Deck M.D. Vikram B. Metastasis to the base of the skull: clinical findings in 43 patients Neurology 31 1981 530 537 6972014 \n14 Liang Y. Ding L. Li X. Wang W. Zhang X. Oculomotor nerve palsy as a preceding symptom of adult sporadic Burkitt lymphoma: a case report and review of the literature Oncol Lett 13 3 2017 March 1315 1318 28454254 \n15 Rasper M. Kesari S. Burkitt lymphoma presenting as a rapidly evolving cavernous sinus syndrome Arch Neurol 65 12 2008 1668 19064758 \n16 Kalina P. Black K. Woldenberg R. Pediatr Radiol 26 1996 416 8657480 \n17 Seixas D.V. Burkitt leukemia with numb chin syndrome and cavernous sinus involvement Eur J Paediatr Neurol 10 3 2006 May 145 147 16621630 \n18 Moghaddasi M. Nabovvati M. Razmeh S. Bilateral cavernous sinus thrombosis as first manifestation of primary Burkitt lymphoma of the thyroid gland Neurol Int 9 2 2017 Jun 7133 28713532 \n19 Tanaka Y. Takagi Y. Kasahara S. Burkitt lymphoma presenting rapid progression from unilateral to bilateral cavernous sinus syndrome as the initial symptom Neurol Clin Neurosci 2 2014 204 206 \n20 Huisman T.A. Tschirch F. Schneider J.F. Niggli F. Martin-Fiori E. Willi U.V. Burkitt's lymphoma with bilateral cavernous sinus and mediastinal involvement in a child Pediatr Radiol 33 10 2003 Oct 719 721 12879319 \n21 Lee A.G. Quick S.J. Liu G.T. A childhood cavernous conundrum Surv Ophthalmol 49 2004 231 236 14998694\n\n",
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"issue": "16()",
"journal": "American journal of ophthalmology case reports",
"keywords": "Cavernous sinus syndrome; Horizontal diplopia; Metastatic burkitt lymphoma; Sixth nerve palsy",
"medline_ta": "Am J Ophthalmol Case Rep",
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"title": "Sixth nerve palsy in sporadic Burkitt Lymphoma.",
"title_normalized": "sixth nerve palsy in sporadic burkitt lymphoma"
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"abstract": "We report the case of a 50-year-old woman with a triple-negative Ki67 80% breast cancer with liver metastases, who obtained a radiological long-lasting complete response after treatment with eribulin. The patient initially experienced progressive disease after a standard anthracycline/taxane-based adjuvant chemotherapy, a first-line treatment for metastatic disease with paclitaxel-bevacizumab, and a second-line maintenance treatment with bevacizumab and capecitabine. Eribulin was administered according to a 1.23 mg/m2 scheme on days 1 and 8 every 3 weeks, and the treatment was always well tolerated. After 45 cycles of therapy, we still detected radiological evidence of complete response on liver sites of disease. This case report underlines the great efficacy of eribulin as third-line treatment for metastatic disease in a very aggressive form of breast cancer.",
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"authors": "Dottorini|Lorenzo|L|;Catena|Laura|L|;Sarno|Italo|I|;Di Menna|Giandomenico|G|;Marte|Annamaria|A|;Bajetta|Emilio|E|",
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"pubdate": "2018",
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"title": "Long-Lasting Exceptional Radiological Complete Response after Treatment with Eribulin in a Patient with Triple-Negative Breast Cancer with Liver Involvement.",
"title_normalized": "long lasting exceptional radiological complete response after treatment with eribulin in a patient with triple negative breast cancer with liver involvement"
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"abstract": "We report a case of acute focal bacterial nephritis(AFBN)as a complication of chemotherapy in esophageal cancer patient. A 54-year-old woman underwent thoracoscopic esophagectomy for thoracic esophageal cancer. The final pathological diagnosis was a squamous cell carcinoma, pT1b, N2(No. 110), M0, pStage II . She received adjuvant chemotherapy with docetaxel, CDDP and 5-FU(mDCF)in our hospital from February, 2016. There was no complication in first course. She visited our hospital with complaints of a fever and right flank pain on the 22 nd day after second course of chemotherapy. There was a severe inflammation reaction in the laboratory test. An enhanced CT revealed swelling and partial low density area in the right kidney. Therefore, we diagnosed AFBN, and administrated antibiotic levofloxacin for 16 days. Her symptom improved immediately, and renal function was normal when followed up 10 months later.",
"affiliations": "Dept. of Surgery, Kagoshima Kouseiren Hospital.",
"authors": "Tsuruda|Yusuke|Y|;Okumura|Hiroshi|H|;Setoyama|Tetsuro|T|;Hiwatashi|Kiyokazu|K|;Minami|Koji|K|;Maenohara|Shigeho|S|;Uchikado|Yasuto|Y|;Omoto|Itaru|I|;Sasaki|Ken|K|;Natsugoe|Shoji|S|",
"chemical_list": "D043823:Taxoids; D000077143:Docetaxel; D002945:Cisplatin; D005472:Fluorouracil",
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"issue": "44(12)",
"journal": "Gan to kagaku ryoho. Cancer & chemotherapy",
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"medline_ta": "Gan To Kagaku Ryoho",
"mesh_terms": "D000208:Acute Disease; D000971:Antineoplastic Combined Chemotherapy Protocols; D017024:Chemotherapy, Adjuvant; D002945:Cisplatin; D000077143:Docetaxel; D004938:Esophageal Neoplasms; D016629:Esophagectomy; D005260:Female; D005472:Fluorouracil; D006801:Humans; D008875:Middle Aged; D009393:Nephritis; D043823:Taxoids",
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"publication_types": "D002363:Case Reports; D016428:Journal Article",
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"title": "Case Report of an Acute Focal Bacterial Nephritis Associated with Adjuvant Chemotherapy in Esophageal Cancer Patient.",
"title_normalized": "case report of an acute focal bacterial nephritis associated with adjuvant chemotherapy in esophageal cancer patient"
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"abstract": "Coronavirus disease 2019 has presented itself with a variety of clinical signs and symptoms. One of these has been the accordance of spontaneous pneumothorax which in instances has caused rapid deterioration of patients. Furthermore pneumothorax may happen secondary to intubation and the resulting complications. Not enough is discussed regarding cases with COVID-19 related pneumothorax and proper management of these patients. The present article reports an elderly patient with spontaneous pneumothorax secondary to COVID-19 and reviews the existing literature.",
"affiliations": "Department of Radiology, Urmia University of Medical Sciences, Urmia, Iran.;Department of Internal Medicine, Urmia University of Medical Sciences, Urmia, Iran.;Students' Scientific Research Center, Tehran University of Medical Sciences, Tehran, Iran.;Medical Radiation Sciences Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.",
"authors": "Mohammadi|Afshin|A|https://orcid.org/0000-0001-6763-2430;Boroofeh|Behdad|B|;Mohebbi|Alisa|A|;Mirza-Aghazadeh-Attari|Mohammad|M|https://orcid.org/0000-0001-7927-6912",
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"doi": "10.34172/jcvtr.2021.16",
"fulltext": "\n==== Front\nJ Cardiovasc Thorac Res\nJ Cardiovasc Thorac Res\nJ Cardiovasc Thorac Res\nJCVTR\nTBZMED\nJournal of Cardiovascular and Thoracic Research\n2008-5117\n2008-6830\n2008-5117\nTabriz University of Medical Sciences\n\n10.34172/jcvtr.2021.16\nCase Report\nExpanding spontaneous pneumothorax in COVID-19 pneumonia: Case report and review of literature\nhttps://orcid.org/0000-0001-6763-2430\nMohammadi Afshin 1\nBoroofeh Behdad 2\nMohebbi Alisa 3\nhttps://orcid.org/0000-0001-7927-6912\nMirza-Aghazadeh-Attari Mohammad 4 *\n1Department of Radiology, Urmia University of Medical Sciences, Urmia, Iran\n2Department of Internal Medicine, Urmia University of Medical Sciences, Urmia, Iran\n3Students’ Scientific Research Center, Tehran University of Medical Sciences, Tehran, Iran\n4Medical Radiation Sciences Research Center, Tabriz University of Medical Sciences, Tabriz, Iran\n* Corresponding Author: Mohammad Mirza-Aghazadeh-Attari, Email: m.aghazadeh75@yahoo.com\n2021\n07 2 2021\n13 3 258262\n28 6 2020\n06 11 2020\n© 2021 The Author(s)\n2021\nhttps://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.\nhttp://jcvtr.tbzmed.ac.ir\nCoronavirus disease 2019 has presented itself with a variety of clinical signs and symptoms. One of these has been the accordance of spontaneous pneumothorax which in instances has caused rapid deterioration of patients. Furthermore pneumothorax may happen secondary to intubation and the resulting complications. Not enough is discussed regarding cases with COVID-19 related pneumothorax and proper management of these patients. The present article reports an elderly patient with spontaneous pneumothorax secondary to COVID-19 and reviews the existing literature.\n\nCT\nChest\nPneumothorax\nCOVID-19\n==== Body\npmcIntroduction\n\nThe severe acute respiratory syndrome – coronavirus-2 (SARS-CoV-2) causes various clinical signs and symptoms but usually presents itself as a mild form of viral pneumonitis. Epidemiologic studies have shown that although most cases of those infected with the virus do not show severe signs or symptoms.1 However, pediatric and the elderly, and individuals with pre-existing conditions are at increased risk of respiratory distress syndrome, inappropriate immune responses, and other un-common manifestations of the disease.2 Studies focusing on those mentioned above demographic have suggested that they manifest specific radiologic signs and clinical scenarios, which can make diagnostic workup and clinical decision making complicated.\n\nChest CT has been one of the most prominent diagnostic tools available for clinicians, yielding a higher sensitivity than other diagnostic methods, such as molecular assays. The collective findings in chest CT of infected individuals consist of multi-focal ground-glass opacities, airspace consolidation, and air-Bronchogram. Nevertheless, other unusual imaging signs are also reported, such as nodular lesions, cavities, tree-in-bud appearances, halo and reverse halo signs, and more.3\n\nOne of the rarely mentioned radiologic findings has been visible visceral pleural edges and non-existent lung markings on the periphery of the lungs, which is suggestive of pneumothorax.4 In the present case report, we discuss an elderly male patient who developed spontaneous pneumothorax secondary to COVID-19.\n\nCase Presentaion\n\nAn 82-year-old male, with a history of coronary artery disease, presented to our emergency ward with low-grade fever, dyspnea and cough. The patient had a respiratory rate of 21, pulse rate of 90 and blood pressure of 135/80 on admission. Pulse oximetry revealed a blood O2 saturation of 87%. The patient did not smoke, did not have any pre-existing respiratory disease and had an active lifestyle.\n\nThe patient was then visited by an internal medicine specialist and underwent diagnostic workup for COVID-19. Lab results were otherwise typical except a mild lymphopenia (1100 /mm3)\n\nThe initial CT scan obtained on the first day of admission (Figure 1) showed a uni-focal peripheral ground-glass opacity in the middle segments of the right lung. A small linear line of non-existent lung texture was visible on the left lung periphery. Based on institutional guidelines, the patient was admitted, and conservative management was chosen for the pneumothorax, and the initial estimation of its size was 7% of the hemi-thoracic cavity. The results of the molecular assay obtained on the first day of admission came back positive on the third day. The patient was put on hydroxychloroquine 200 twice daily, ceftriaxone 500 mg daily and Tamiflu 75 mg twice daily. He was also given steroids (prednisolone, 40 mg, IV). The patient had a stable clinical course until the fifth day of hospitalization when the patient reported an aggregation of dyspnea and emergence of dull chest pain, localized in the periphery of the left hemithorax. The patient had an ECG took, which was normal, Troponin-I was negative, Vital signs were stable, and emergency consultation with a cardiologist did not yield any further results. Physical examination yielded no positive findings other than a mildly reduced respiration sounds on the left hemithorax.\n\nFigure 1 First Chest CT of the patient showing posterior-peripheral ground-glass opacities, with a thin radiolucent line presenting a small pneumothorax. The patient had minimal involvement in the apex of the lungs, and involvement was mostly observed in the bases\n\nThe patient had a chest X-ray performed which showed signs of pneumothorax, with a barely visible reduced lung marking in the periphery of the left lung. The patient had a second CT imaging done (Figure 2), which showed a radiolucent peripheral space, a grossly visible visceral pleural edge and absent lung markings in the periphery. The diagnosis of an expanding pneumothorax was established, and utilizing the Colling’s method, the percentage of the pneumothorax was estimated to be 25.3%. The patient had an urgent consultation done with the pulmonology department, which recommended that a chest tube be inserted. The patient was stable after insertion of the chest tube, and had a complete absorption of the pneumothorax, and was discharged six days after the insertion of the chest tube.\n\nFigure 2 Second CT of the patient taken after a rapid deterioration in clinical signs and symptoms. The pneumothorax had extended beyond its original boundaries and occupied over one-fifth of the thoracic cavity, which warranted insertion of a chest tube. Ground-glass-opacities also increased in size and frequency over the time between the two chest CTs\n\nDiscussion\n\nEarly studies being reported from china showed that most patients infected with the novel coronavirus had conventional signs of viral pneumonia. However, as the virus spread, more scholars pointed out the rare complication of the infection, such as neurovascular and dermatologic involvement, and significant involvement of the respiratory tract. Probably the two most important of these complications have been pulmonary thromboembolism and pneumothorax. These phenomena can complicate a patient with pre-existing respiratory compromise, and as they may mimic clinical signs of the coronavirus, timely diagnosis may prove to be a challenge.\n\nUntil the day this manuscript is being written, a limited number of pneumothoraxes have been reported in the setting of COVID-19. Based on aetiology, pneumothorax can be classified into two main groups, spontaneous and Iatrogenic/traumatic. The first group can be further classified to primary and secondary spontaneous. Primary spontaneous pneumothorax happens in individuals with no pre-disposing lung condition, and secondary spontaneous pneumothorax is defined as having a pneumothorax secondary to specific pathologies of the respiratory system, such as the existence of bullae, emphysema, etc. scholars suggest that COVID-19 can cause pneumothorax in several ways. It can cause excessive coughing, which can cause pneumothorax, and also can directly invade the alveoli, induce inflammation and damage the delicate respiratory epithelium. COVID-19 can form cystic lesions, increasing the risk of pneumothorax.5\n\nA review of the literature revealed 18 discrete cases of pneumothorax in the setting of COVID-19 (Table 1). Most of the patients were elderly male with pre-existing conditions, with left-sided or bilateral pneumothorax. Older women were less involved. Importantly, a substantial number of young adults existed among the patients. Most of the authors declared that they treated their patients with chest tube insertion. This could have resulted from delayed diagnosis, as the clinical picture may be blurred by COVID-19. We also report an elderly patient infected with COVID-19 who had a pneumothorax and possibly misdiagnosed in the early stages. Any rapid deterioration of COVID-19 infected individuals should prompt a diagnostic workup towards pulmonary thromboembolism and pneumothorax. Clinical studies show that detecting pneumothorax in the elderly may be a challenge, as it is less symptomatic, may not be associated with pleuritic chest pain. Furthermore, a pneumothorax may have deleterious effects in the elderly compared to younger patients.20\n\nTable 1 List of previous case reports of COVID-19 complicated with pneumothorax\n\nReference\tPost Intubation\tHistory of trauma\tGender\tAge\tPre-existing conditions\tInitial presentation on admission\tSide\tTreatment\tOther Radiologic signs\t\n5\tNo\tNo\tMale\t24\tNone\tYes\tLeft\ttube thoracostomy\tGGO\t\n6\tNo\tYes (falling on right side)\tMale\t55\tNone\tNo\tBilateral\tChest tube insertion\tGGO, Consolidation\t\n7\tNo\tNo\tMale\t62\tNone\tNo\tRight\tConservative\tGGO, pneumomediastinum,\t\n3\tNo\tNo\tMale\t38\tbinaural hearing loss and tinnitus\tNo\tLeft\tConservative\tGGO, consolidation, mediastinal emphysema, giant bulla,\t\n8\tNo\tNo\tMale\t36\t10 p/y smoking, childhood asthma\tYes\tLeft\temergency needle decompression and then chest tube insertion\tGGO\t\n4\tNo\tNo\tMale\t26\tNone\tYes\tRight\tChest tube insertion\tCollapse\t\n9\tNo\tNo\tMale\t38\tHeavy smoker, excess alcohol consumption\tNo\tLeft\tConservative\tGGO, consolidation\t\n10\tYes\tNo\tMale\t70\tN/A\tNo\tLeft\tChest tube insertion,,Video-assisted thoracoscopic surgery)\tGGO\t\n10\tYes\tNo\tMale\t56\tHeavy smoker,\tNo\tLeft\tVideo-assisted thoracoscopic surgery following a failed chest tube\tGGO\t\n11\tNo\tNo\tFemale\t82\tNo\tYes\tLeft\tChest tube insertion\tpneumomediastinum, left-sided massive pneumothorax and subcutaneous emphysema\t\n12\tNo\tNo\tMale\t87\tCOPD\tYes\tLeft\tChest tube insertion\tCollapse, GGO, consolidation\t\n13\tNo\tNo\tMale\t67\tN/A\tYes\tBilateral\tChest tube insertion\tGGO, pneumomediastinum\t\n13\tNo\tNo\tFemale\t84\tprosthetic valve replacement, renal failure, Heart failure, hypertension, hypercholesterolemia\tNo\tBilateral\tN/A\tGGO, pneumomediastinum\t\n14\tYes\tNo\tMale\t59\tdecompensated cirrhosis, liver transplantation\tNo\tN/A\tChest tube insertion\tGGO\t\n15\tYes\tNo\tFemale\t59\tMorbid obesity\tNo\tRight\tSurgical intervention\tGGO, pneumomediastinum\t\n16\tYes\tNo\tMale\t67\tcoronary artery bypass, tuberculosis, chronic bronchitis, and emphysema\tNo\tBilateral\tChest tube insertion\tSubcutaneous emphysema, mediastinal emphysema, GGO\t\n17\tYes\tNo\tMale\t31\tsmoker\tNo\tN/A\tN/A\tGGO\t\n18\tyes\tNo\tFemale\t70\tnone\tNo\tN/A\tN/A\tGGO\t\n19\tNo\tNo\tMale\t41\tNone\tYes\tLeft\tChest tube insertion\tGGO, pneumomediastinum. subcutaneous emphysema\t\n\nOf interest, pneumothorax has been seen in the setting of COVID-19 in neonates delivered from infected mothers. Although the relationship is not defined, and the occurrence of pneumothorax could be related to prenatal complications.21\n\nCurrently, contradicting evidence exists regarding the proper management of a symptom-free pneumothorax, but some studies do show conservative management to be non-inferior to invasive interventions.22 The limited evidence existent in regards to COVID-19 associated pneumonia favor the early utilization of more invasive methods.\n\nConclusion\n\nCOVID-19 associated spontaneous pneumothorax may have an inclination to progress and cause severe deterioration. Prompt management with chest tube insertion seems to be superior to conservative management, especially in high-risk demographic groups such as the elderly.\n\nCompeting interests\n\nThe authors declare no conflict of interest.\n\nEthical approval\n\nThis study was approved by the local ethics committee of Urmia University of Medical Sciences. The patient had signed a written informed consent note.\n==== Refs\nReferences\n\n1 Zhou F Yu T Du R Fan G Liu Y Liu Z Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study Lancet 2020 395 10229 1054 1062 10.1016/s0140-6736(20)30566-3 32171076\n2 Mohammadi A Mohebbi I Khademvatani K Pirnejad H Mirza-Aghazadeh J Gharebaghi N Clinical and radiological characteristics of pediatric patients with COVID-19: focus on imaging findings Jpn J Radiol 2020 38 10 987 992 10.1007/s11604-020-01003-6 32535725\n3 Sun R Liu H Wang X Mediastinal emphysema, giant bulla, and pneumothorax developed during the course of COVID-19 pneumonia Korean J Radiol 2020 21 5 541 544 10.3348/kjr.2020.0180 32207255\n4 Rohailla S Ahmed N Gough K SARS-CoV-2 infection associated with spontaneous pneumothorax CMAJ 2020 192 19 E510 10.1503/cmaj.200609 32317275\n5 Aydın S Öz G Dumanlı A Balcı A Gencer A A case of spontaneous pneumothorax in COVID-19 pneumonia J Surg Res 2020 3 2 96 101 10.26502/jsr.10020060\n6 Pinotti E Montuori M Carissimi F Baronio G Ongaro D Mauri G Massive bilateral pneumothorax associated with COVID-19 pneumonia Open J Clin Med Case Rep 2020 6 7 1648\n7 Wang W Gao R Zheng Y Jiang L COVID-19 with spontaneous pneumothorax, pneumomediastinum and subcutaneous emphysema J Travel Med 2020 27 5 taaa062 10.1093/jtm/taaa062 32330274\n8 Flower L Carter JL Rosales Lopez J Henry AM Tension pneumothorax in a patient with COVID-19 BMJ Case Rep 2020 13 5 e235861 10.1136/bcr-2020-235861\n9 Lyu R Li X Diagnosis and treatment of severe COVID-19 complicated with spontaneous pneumothorax: a case report Advanced Ultrasound in Diagnosis and Therapy 2020 4 2 142 146 10.37015/audt.2020.200019\n10 Aiolfi A Biraghi T Montisci A Bonitta G Micheletto G Donatelli F Management of persistent pneumothorax with thoracoscopy and bleb resection in COVID-19 patients Ann Thorac Surg 2020 110 5 e413 e415 10.1016/j.athoracsur.2020.04.011 32353441\n11 Ucpinar BA Sahin C Yanc U Spontaneous pneumothorax and subcutaneous emphysema in COVID-19 patient: case report J Infect Public Health 2020 13 6 887 889 10.1016/j.jiph.2020.05.012 32475804\n12 Poggiali E Vercelli A Iannicelli T Tinelli V Celoni L Magnacavallo A COVID-19, chronic obstructive pulmonary disease and pneumothorax: a frightening triad Eur J Case Rep Intern Med 2020 7 7 001742 10.12890/2020_001742 32665932\n13 López Vega JM Parra Gordo ML Diez Tascón A Ossaba Vélez S Pneumomediastinum and spontaneous pneumothorax as an extrapulmonary complication of COVID-19 disease Emerg Radiol 2020 27 6 727 730 10.1007/s10140-020-01806-0 32524296\n14 Huang JF Zheng KI George J Gao HN Wei RN Yan HD Fatal outcome in a liver transplant recipient with COVID-19 Am J Transplant 2020 20 7 1907 1910 10.1111/ajt.15909 32277591\n15 Abou-Arab O Huette P Berna P Mahjoub Y Tracheal trauma after difficult airway management in morbidly obese patients with COVID-19 Br J Anaesth 2020 125 1 e168 e170 10.1016/j.bja.2020.04.004 32334809\n16 Xiang C Wu G SARS-CoV-2 pneumonia with subcutaneous emphysema, mediastinal emphysema, and pneumothorax: a case report Medicine (Baltimore) 2020 99 20 e20208 10.1097/md.0000000000020208 32443345\n17 Bloemen H Hagmolen Of Ten Have W Clappers-Gielen GAL [Chest pain and dyspnea during the recovery period of COVID-19 pneumonia] Ned Tijdschr Geneeskd 2020 164 D5095 32395965\n18 Sher Y Rabkin B Maldonado JR Mohabir P COVID-19-associated hyperactive intensive care unit delirium with proposed pathophysiology and treatment: a case report Psychosomatics 2020 61 5 544 550 10.1016/j.psym.2020.05.007 32591212\n19 Brogna B Bignardi E Salvatore P Alberigo M Brogna C Megliola A Unusual presentations of COVID-19 pneumonia on CT scans with spontaneous pneumomediastinum and loculated pneumothorax: a report of two cases and a review of the literature Heart Lung 2020 49 6 864 868 10.1016/j.hrtlng.2020.06.005 32693960\n20 Liston R McLoughlin R Clinch D Acute pneumothorax: a comparison of elderly with younger patients Age Ageing 1994 23 5 393 395 10.1093/ageing/23.5.393 7825485\n21 Schwartz DA An analysis of 38 pregnant women with COVID-19, their newborn infants, and maternal-fetal transmission of SARS-CoV-2: maternal coronavirus infections and pregnancy outcomes Arch Pathol Lab Med 2020 10.5858/arpa.2020-0901-SA\n22 Brown SGA Ball EL Perrin K Asha SE Braithwaite I Egerton-Warburton D Conservative versus interventional treatment for spontaneous pneumothorax N Engl J Med 2020 382 5 405 415 10.1056/NEJMoa1910775 31995686\n\n",
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"issue": "13(3)",
"journal": "Journal of cardiovascular and thoracic research",
"keywords": "COVID-19; CT; Chest; Pneumothorax",
"medline_ta": "J Cardiovasc Thorac Res",
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"pages": "258-262",
"pmc": null,
"pmid": "34630976",
"pubdate": "2021",
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"title": "Expanding spontaneous pneumothorax in COVID-19 pneumonia: Case report and review of literature.",
"title_normalized": "expanding spontaneous pneumothorax in covid 19 pneumonia case report and review of literature"
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"abstract": "We present a case of glatiramer acetate-associated refractory immune thrombocytopenic purpura (ITP) in a female patient with multiple sclerosis. A search of MEDLINE/PubMed did not find any connection between glatiramer acetate and thrombocytopenia, specifically ITP. The autoimmune reaction was resistant to conservative ITP treatment, and was eventually managed only by splenectomy. To the best of our knowledge, this is the first report of glatiramer acetate-associated ITP. Physicians should be aware of this condition, and consider performing routine blood counts at the beginning of glatiramer acetate treatment.\nWe present a unique case of glatiramer acetate-associated refractory immune thrombocytopenic purpura (ITP) in a female patient with multiple sclerosis, which was eventually managed only by splenectomy.Although glatiramer acetate is known for its immunomodulatory effect, a literature search did not reveal any reports of an association with ITP.Physicians should be aware of this condition, and consider performing routine blood counts at the beginning of and during glatiramer acetate treatment.",
"affiliations": "Department of Medicine F, Soroka University Medical Center, Beer-Sheva, Israel.;Department of Medicine F, Soroka University Medical Center, Beer-Sheva, Israel.;Faculty of Health Sciences, Ben-Gurion University, Beer-Sheva, Israel.;Department of Medicine F, Soroka University Medical Center, Beer-Sheva, Israel.;Faculty of Health Sciences, Ben-Gurion University, Beer-Sheva, Israel.;Department of Medicine F, Soroka University Medical Center, Beer-Sheva, Israel.",
"authors": "Sagy|Iftach|I|;Shalev|Leah|L|;Levi|Itai|I|;Shleyfer|Elena|E|;Valdman|Svetlana|S|;Barski|Leonid|L|",
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"fulltext": "\n==== Front\nEur J Case Rep Intern MedEur J Case Rep Intern MedEuropean Journal of Case Reports in Internal Medicine2284-2594SMC Media Srl 10.12890/2016_000399399-1-2668-1-10-20160311ArticlesGlatiramer Acetate-associated Refractory Immune Thrombocytopenic Purpura Sagy Iftach 12Shalev Leah 12Levi Itai 23Shleyfer Elena 12Valdman Svetlana 23Barski Leonid 12\n1 Department of Medicine F, Soroka University Medical Center, Beer-Sheva, Israel\n2 Faculty of Health Sciences, Ben-Gurion University, Beer-Sheva, Israel\n3 Department of Hematology, a University Medical Center, Beer-Sheva, Israel\n4 Department of Neurology, Soroka University Medical Center, Beer-Sheva, Israel2016 27 1 2016 3 3 00039914 3 2016 31 1 2016 © EFIM 20162016This article is licensed under a Commons Attribution Non-Commercial 4.0 LicenseWe present a case of glatiramer acetate-associated refractory immune thrombocytopenic purpura (ITP) in a female patient with multiple sclerosis. A search of MEDLINE/PubMed did not find any connection between glatiramer acetate and thrombocytopenia, specifically ITP. The autoimmune reaction was resistant to conservative ITP treatment, and was eventually managed only by splenectomy. To the best of our knowledge, this is the first report of glatiramer acetate-associated ITP. Physicians should be aware of this condition, and consider performing routine blood counts at the beginning of glatiramer acetate treatment.\n\nLEARNING POINTS\nWe present a unique case of glatiramer acetate-associated refractory immune thrombocytopenic purpura (ITP) in a female patient with multiple sclerosis, which was eventually managed only by splenectomy.\n\nAlthough glatiramer acetate is known for its immunomodulatory effect, a literature search did not reveal any reports of an association with ITP.\n\nPhysicians should be aware of this condition, and consider performing routine blood counts at the beginning of and during glatiramer acetate treatment.\n\nGlatiramer acetatedrug associated immune thrombocytopenic purpurathrombocytopenia\n==== Body\nINTRODUCTION\nGlatiramer acetate (Copaxone) is an immunomodulatory agent approved by the FDA for the treatment of relapsing-remitting multiple sclerosis (MS). It has been proposed that the mechanism of action of glatiramer acetate is by activation of T-lymphocyte suppressor cells and interference with pathological antigen presenting on the myelin sheath. The adverse effects of glatiramer acetate consist mostly of local site injection reactions along with transient systemic reactions. These reactions usually begin 30 sec to 30 min after agent injection, and consist of flushing, chest discomfort, palpitations, dyspnoea and anxiety. They are considered sporadic and self-limiting[1]. In a multi-centric double blind placebo controlled trial comparing glatiramer acetate to placebo, additional adverse events (apart from local and transient systemic reactions) occurred approximately equally in both groups. No routine ECG, laboratory blood counts or chemical tests are recommended for patient monitoring[2].\n\nImmune thrombocytopenia purpura (ITP) is an autoimmune disorder characterized by immunological destruction of otherwise normal platelets, leading to platelet counts of less than 100×109/L. ITP may occur in isolation (primary) or in association with other disorders (secondary) due to viral infections [such as hepatitis C (HCV), cytomegalovirus (CMV) or human immunodeficiency virus (HIV), systemic lupus erythematosus (SLE), lymph proliferative disorders and certain drugs[3]. We present a case of glatiramer acetate-associated refractory ITP in a female patient with multiple sclerosis.\n\nCASE REPORT\nA 40-year-old woman was admitted to hospital with a chief complaint of new onset rash. A day before her admission the patient had noticed an unusual transient bleeding while brushing her teeth. Her past medical history included multiple sclerosis diagnosed at the age of 27 and treated with interferon beta from the time of diagnosis. The patient was hospitalized a year before her current admission due to relapsing disease, which was treated with prednisone that was later tapered down. Two months before her latest admission the interferon beta was switched to glatiramer acetate by her neurologist because of postural tremor. This was the only medication she was prescribed during that period.\n\nUpon arrival the patient was alert and without respiratory distress. Her temperature was 37.9°C, heart rate was 95/min, blood pressure was 147/90 mmHg and oxygen saturation was 98% in room air. The physical examination was unremarkable except for petechial rash on her legs and shoulders and the previously diagnosed tremor associated with her primary disease.\n\nHaemoglobin level was 12.1 g/dL, leukocyte count was 4,870/mm3 and platelet count was 1,000/mm3. In a routine outpatient blood count 2 months before her admission, the platelet count had been 263,000/mm3. A clotting test as well as serum electrolytes, AST, ALT, lipase, amylase and alkaline phosphatase were all within normal limits. LDH was 515 U/L. Antinuclear antibodies, rheumatoid factor, anticardiolipin, HCV, HIV, CMV IgM and EBV IgM were all negative. Bone marrow aspiration demonstrated normocellular marrow with multi-lobate forms of megakaryocytes, without evidence of tumour.\n\nGlatiramer acetate was discontinued on admission. During her hospital stay, the patient had transient episodes of vaginal, oral, dermal and gastrointestinal bleeding. She remained haemodynamically stable, with a mild normocytic anaemia. All the bleeding episodes resolved conservatively under treatment with Hexakapron (tranexamic acid). The patient received prednisone 1 mg/kg from the time of her admission, together with a 4-day trial of dexamethasone 40 mg daily. The patient was also treated with Rh0 (D) immune globulin 75 μg/kg and with a preceding trial of intravenous gamma globulins (IV IgG) 2 g/kg without any change in platelet count.\n\nDue to the therapeutic failure of all regimens mentioned above, the decision to perform a splenectomy was made because of the consequences of refractory symptomatic severe ITP. The patient was administered three courses of romiplostim for 3 weeks as a bridging therapy before the procedure, with lack of success in increasing platelet counts. After being vaccinated against pneumococcus, meningococcus and haemophilus influenza, the patient underwent splenectomy on the 37th day of hospitalization without complications. The platelet count started to increase immediately after the procedure. On discharge the platelet count was 328/mm3. The patient’s neurologist has informed the manufacturer about the hospitalization and the suspected association with glatiramer acetate. Two years of haematological follow-up in the hospital outpatient clinic has revealed normal blood counts, without additional thrombocytopenia events or the need for further medical treatment for thrombocytopenia.\n\nDISCUSSION\nHerein we present the case of a patient who was admitted to hospital due to refractory symptomatic ITP, which was successfully managed only by splenectomy. Treatment for multiple sclerosis with glatiramer acetate had been initiated 2 months before her admission. This was the only treatment she was prescribed before the onset of the thrombocytopenia. Other causes of thrombocytopenia (such as viral infections, haematological and autoimmune conditions) were excluded. Thus, we can refer to this patient as having secondary drug-associated ITP.\n\nDistinguishing between drug-associated ITP and other thrombocytopenia aetiologies may be very challenging for the clinician. The incidence of this phenomenon is 10 cases per 1,000,000 persons per year and there are several possible mechanisms for this condition:\n\nhapten-dependent antibodies – in the case of penicillins or cephalosporins, the beta-lactam (hapten) binds to the autologous target site (cell membrane protein of the thrombocyte) to create an allergen;\n\ndrug-induced platelet-reactive auto-antibodies – certain drugs generate antibodies against platelets without the presence of the drug (for instance, gold and procainamide);\n\ndrug-dependent antibodies – the forming antibodies destroy the platelets only when the drug, such as ranitidine, is present[4].\n\nA systemic review of 247 case reports of drug-associated thrombocytopenia identified 98 different potential drugs. The most common drugs associated with thrombocytopenia were quinidine, gold and trimethoprim-sulfamethoxazole. Sporadic reports also mentioned penicillins, cephalosporins, NSAIDs, acetaminophen, digoxin, amiodarone and lithium. Of the 247 patients involved, 9% had a major bleed (defined as intracranial or retroperitoneal haemorrhage) and 0.8% died of bleeding[5].\n\nThe clinical presentation of drug-associated ITP is mucocutaneous bleeding that begins 1–2 weeks, sometimes longer, after the patient has taken the sensitizing agent. Severe bleeding such as melena, haematuria and intracranial or retroperitoneal haemorrhage, is unusual and indicates severe thrombocytopenia of less than 20/mm3. The most important differential diagnosis is drug-associated thrombocytopenia (DIT). DIT is characterized by the same clinical features as ITP, starts after exposure to the sensitizing agent for at least a week and can be sometimes accompanied by neutropenia and haemolytic anaemia together with thrombocytopenia. After the suspected agent has been discontinued, the platelet count tends to return to normal within a week.\n\nFrom the neurological aspect, it is worth mentioning that the association between MS and auto-immune diseases (e.g. diabetes, inflammatory bowel disease, rheumatoid arthritis, etc.) is well established. ITP was found to be 25 times more prevalent among MS patients compared with the general population. In addition, recently there have been reports that ITP can be linked to Interferon beta therapy in MS patients, along with more common haematological adverse effects such as a transient decrease in white blood cell counts. In this instance, the immunomodulatory effect of glatiramer acetate may be associated with the refractory thrombocytopenia in our patient. Unfortunately, since a routine laboratory kit to test for glatiramer acetate-associated antibodies is not available, we cannot establish the definitive diagnosis of immune thrombocytopenia purpura. The fact that cessation of the drug did not result in an instant increase in the platelet count, is another factor against a causal association between glatiramer acetate and thrombocytopenia. Nonetheless, in the absence of any other reasonable aetiology, the clinical suspicion for drug associated ITP still remains very high.\n\nConflicts of Interests: The authors declare that there are no competing interests.\n==== Refs\nREFERENCES\n1 Galetta SL Markowitz C US FDA-approved disease-modifying treatments for multiple sclerosis CNS Drugs 2005 19 239 252 15740178 \n2 Johnson K Brooks B Cohen J Copolymer 1 reduces relapse rate and improves disability in relapsing-remitting multiple sclerosis: results of a phase III multicenter, double-blind, placebo-controlled trial Neurology 1995 45 1268 1276 7617181 \n3 Neunert C Lim W Crowther M Cohen A Solberg L Jr Crowther MA The American Society of Hematology 2011 evidence-based practice guideline for immune thrombocytopenia Blood 2011 117 4190 4207 21325604 \n4 van den Bemt PMLA Meyboom RH Egberts AC Drug-induced immune thrombocytopenia Drug Safety 2004 27 1243 1252 15588119 \n5 George JN Raskob GE Shah SR Drug-induced thrombocytopenia: a systematic review of published case reports Ann Intern Med 1998 129 886 890 9867731\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2284-2594",
"issue": "3(3)",
"journal": "European journal of case reports in internal medicine",
"keywords": "Glatiramer acetate; drug associated immune thrombocytopenic purpura; thrombocytopenia",
"medline_ta": "Eur J Case Rep Intern Med",
"mesh_terms": null,
"nlm_unique_id": "101648453",
"other_id": null,
"pages": "000399",
"pmc": null,
"pmid": "30755869",
"pubdate": "2016",
"publication_types": "D016428:Journal Article",
"references": "15588119;15740178;21325604;7617181;9867731",
"title": "Glatiramer Acetate-associated Refractory Immune Thrombocytopenic Purpura.",
"title_normalized": "glatiramer acetate associated refractory immune thrombocytopenic purpura"
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"activesubstancename": "GLATIRAMER ACETATE"
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"abstract": "OBJECTIVE\nThrombocytopenia is an independent adverse prognostic factor in patients with Myelodysplastic syndromes (MDS). Azacitidine, first-line treatment for the majority of patients with higher-risk MDS, is associated with aggravated thrombocytopenia during the first cycles. Eltrombopag is a novel thrombopoietin receptor agonist, which also has been shown to inhibit proliferation of leukaemia cell lines in vitro. This phase I clinical trial was designed to explore the safety and tolerability of combining eltrombopag with azacitidine in patients with MDS. In addition, we assessed the potential effects of eltrombopag on hematopoietic stem and progenitor cells (HSPCs) from included patients.\n\n\nMETHODS\nPreviously untreated patients with MDS eligible for treatment with azacitidine and with a platelet count <75 × 10(9) /L were included. Patients received eltrombopag in dose escalation cohorts during three cycles of azacitidine.\n\n\nRESULTS\nTwelve patients, with a median age of 74 yr, were included. Severe adverse events included infectious complications, deep vein thrombosis and transient ischaemic attack. The maximal tolerated eltrombopag dose was 200 mg qd. Complete remission or bone marrow remission was achieved in 4 of 12 patients. Platelet counts improved or remained stable in 9 of 12 patients despite azacitidine treatment. No increase in blast count, disease progression, or bone marrow fibrosis related to study medication was reported. Eltrombopag did not induce cycling of HSPCs.\n\n\nCONCLUSIONS\nThe combination of eltrombopag with azacitidine in high-risk MDS patients is feasible and well tolerated. Improvements in platelet counts and the potential antileukaemic effect of eltrombopag should be explored in a randomised study.",
"affiliations": "Department of Medical Sciences, Section of Hematology, Uppsala University Hospital, Uppsala, Sweden.",
"authors": "Svensson|Tobias|T|;Chowdhury|Onima|O|;Garelius|Hege|H|;Lorenz|Fryderyk|F|;Saft|Leonie|L|;Jacobsen|Sten-Eirik|SE|;Hellström-Lindberg|Eva|E|;Cherif|Honar|H|",
"chemical_list": "D000970:Antineoplastic Agents; D001565:Benzoates; D006834:Hydrazines; D011720:Pyrazoles; D053628:Receptors, Thrombopoietin; D001374:Azacitidine; C520809:eltrombopag",
"country": "England",
"delete": false,
"doi": "10.1111/ejh.12383",
"fulltext": null,
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"issn_linking": "0902-4441",
"issue": "93(5)",
"journal": "European journal of haematology",
"keywords": "Myelodysplastic syndrome; azacitidine; eltrombopag; thrombocytopenia; thrombopoietin-receptor",
"medline_ta": "Eur J Haematol",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents; D001374:Azacitidine; D001565:Benzoates; D001792:Blood Platelets; D002453:Cell Cycle; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005260:Female; D006412:Hematopoietic Stem Cells; D006801:Humans; D006834:Hydrazines; D002546:Ischemic Attack, Transient; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes; D010865:Pilot Projects; D010976:Platelet Count; D011720:Pyrazoles; D053628:Receptors, Thrombopoietin; D012074:Remission Induction; D013921:Thrombocytopenia; D016896:Treatment Outcome; D020246:Venous Thrombosis",
"nlm_unique_id": "8703985",
"other_id": null,
"pages": "439-45",
"pmc": null,
"pmid": "24853277",
"pubdate": "2014-11",
"publication_types": "D017426:Clinical Trial, Phase I; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "A pilot phase I dose finding safety study of the thrombopoietin-receptor agonist, eltrombopag, in patients with myelodysplastic syndrome treated with azacitidine.",
"title_normalized": "a pilot phase i dose finding safety study of the thrombopoietin receptor agonist eltrombopag in patients with myelodysplastic syndrome treated with azacitidine"
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"abstract": "We report a case of a 19-year-old female with a history of hyperoxaluria type 1 and renal failure. The patient presented for a second renal transplantation 17 years after her first combined liver and kidney transplantation. Postoperative shock was highly resistant to fluids and required massive pharmacologic hemodynamic support. Vasoplegic shock was the presumed diagnosis, and methylene blue was utilized as a rescue therapy, with a rapid hemodynamic response and no apparent side effects.",
"affiliations": "Department of Pediatric Intensive Care, Ruth Rappaport Children's Hospital at Rambam Health Care Campus, Haifa, Israel.;Department of Pediatric Intensive Care, Ruth Rappaport Children's Hospital at Rambam Health Care Campus, Haifa, Israel.;Department of Pediatric Intensive Care, Ruth Rappaport Children's Hospital at Rambam Health Care Campus, Haifa, Israel.;Department of Pediatric Intensive Care, Ruth Rappaport Children's Hospital at Rambam Health Care Campus, Haifa, Israel.",
"authors": "Hershman|Eli|E|;Hadash|Amir|A|;Attias|Ori|O|;Ben-Ari|Josef|J|",
"chemical_list": "D008751:Methylene Blue",
"country": "France",
"delete": false,
"doi": "10.1111/pan.12742",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1155-5645",
"issue": "25(11)",
"journal": "Paediatric anaesthesia",
"keywords": "intensive care units; kidney transplantation; methylene blue; pediatric; postoperative care; shock; vasoplegia",
"medline_ta": "Paediatr Anaesth",
"mesh_terms": "D000328:Adult; D005260:Female; D006801:Humans; D016030:Kidney Transplantation; D008751:Methylene Blue; D011183:Postoperative Complications; D012769:Shock; D056987:Vasoplegia; D055815:Young Adult",
"nlm_unique_id": "9206575",
"other_id": null,
"pages": "1168-9",
"pmc": null,
"pmid": "26428738",
"pubdate": "2015-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Methylene blue treatment for resistant shock following renal transplantation.",
"title_normalized": "methylene blue treatment for resistant shock following renal transplantation"
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"activesubstancename": "MYCOPHENOLATE MOFETIL"
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"abstract": "To report the case of a patient with refractory chronic eosinophilic pneumonia who developed rheumatoid arthritis during anti-interleukin (IL)-5 therapy.\nThe case of a 66-year-old male ex-smoker with allergic rhinitis who had dyspnea and chronic cough for 6 months and who was ultimately diagnosed with chronic eosinophilic pneumonia is reported. Long-term corticosteroid therapy was necessary due to recurrence of the chronic eosinophilic pneumonia during tapering of the corticosteroid. As a steroid sparing strategy, mepolizumab was initiated, and the steroid was tapered gradually. When the dose of prednisolone was 2 mg/day, he developed polyarthralgia. Mepolizumab was changed to benralizumab considering the possibility that arthralgia was a side effect of mepolizumab; however, the arthralgia continued and he was ultimately diagnosed with rheumatoid arthritis. Methotrexate was initiated and his arthritis improved. Thereafter, benralizumab was discontinued after 5 injections, and he subsequently required neither systemic corticosteroids nor biologics.\nThe present case may suggest that suppression of IL-5 induces rheumatoid arthritis in certain patients; however, it is also possible that initial steroid therapy improved subclinical RA and made it remain undiagnosed, and the parallel OCS tapering during IL-5 therapy could have contributed to unveil the underlying RA. Further studies are required to establish guidelines on the optimum use of anti-IL-5 therapy and to understand the interactions between chronic eosinophilic pneumonia, anti-IL-5 therapy, tapering of corticosteroid and development of rheumatoid arthritis.",
"affiliations": "Department of Respiratory Medicine, University of Occupational and Environmental Health, Kitakyushu, Fukuoka, 807-8555, Japan.;Department of Clinical Nursing, University of Occupational and Environmental Health, Kitakyushu, Fukuoka, 807-8555, Japan.;Department of Respiratory Medicine, University of Occupational and Environmental Health, Kitakyushu, Fukuoka, 807-8555, Japan.",
"authors": "Kawabata|Hiroki|H|;Satoh|Minoru|M|;Yatera|Kazuhiro|K|",
"chemical_list": null,
"country": "New Zealand",
"delete": false,
"doi": "10.2147/JAA.S342993",
"fulltext": "\n==== Front\nJ Asthma Allergy\nJ Asthma Allergy\njaa\nJournal of Asthma and Allergy\n1178-6965\nDove\n\n342993\n10.2147/JAA.S342993\nCase Report\nDevelopment of Rheumatoid Arthritis During Anti-Interleukin-5 Therapy in a Patient with Refractory Chronic Eosinophilic Pneumonia\nKawabata et al\nKawabata et al\nKawabata Hiroki 1\nSatoh Minoru 2\nYatera Kazuhiro 1\n1 Department of Respiratory Medicine, University of Occupational and Environmental Health, Kitakyushu, Fukuoka, 807-8555, Japan\n2 Department of Clinical Nursing, University of Occupational and Environmental Health, Kitakyushu, Fukuoka, 807-8555, Japan\nCorrespondence: Hiroki Kawabata Department of Respiratory Medicine, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahata-nishiku, Kitakyushu, Fukuoka, 807-8555, Japan Tel +81-93-691-7453 Fax +81-93-602-9373 Email hirokik@med.uoeh-u.ac.jp\n26 11 2021\n2021\n14 14251430\n06 10 2021\n16 11 2021\n© 2021 Kawabata et al.\n2021\nKawabata et al.\nhttps://creativecommons.org/licenses/by-nc/3.0/ This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php).\nPurpose\n\nTo report the case of a patient with refractory chronic eosinophilic pneumonia who developed rheumatoid arthritis during anti-interleukin (IL)-5 therapy.\n\nCase Report\n\nThe case of a 66-year-old male ex-smoker with allergic rhinitis who had dyspnea and chronic cough for 6 months and who was ultimately diagnosed with chronic eosinophilic pneumonia is reported. Long-term corticosteroid therapy was necessary due to recurrence of the chronic eosinophilic pneumonia during tapering of the corticosteroid. As a steroid sparing strategy, mepolizumab was initiated, and the steroid was tapered gradually. When the dose of prednisolone was 2 mg/day, he developed polyarthralgia. Mepolizumab was changed to benralizumab considering the possibility that arthralgia was a side effect of mepolizumab; however, the arthralgia continued and he was ultimately diagnosed with rheumatoid arthritis. Methotrexate was initiated and his arthritis improved. Thereafter, benralizumab was discontinued after 5 injections, and he subsequently required neither systemic corticosteroids nor biologics.\n\nConclusion\n\nThe present case may suggest that suppression of IL-5 induces rheumatoid arthritis in certain patients; however, it is also possible that initial steroid therapy improved subclinical RA and made it remain undiagnosed, and the parallel OCS tapering during IL-5 therapy could have contributed to unveil the underlying RA. Further studies are required to establish guidelines on the optimum use of anti-IL-5 therapy and to understand the interactions between chronic eosinophilic pneumonia, anti-IL-5 therapy, tapering of corticosteroid and development of rheumatoid arthritis.\n\nKeywords\n\nasthma\nchronic eosinophilic pneumonia\nrheumatoid arthritis\nmepolizumab\nbenralizumab\nJSPS KAKENHI This research was partly supported by a grant from JSPS KAKENHI grant number JP19K17689 (H.K.).\n==== Body\npmcIntroduction\n\nHumanized monoclonal antibody to interleukin-5 (IL-5; mepolizumab) or the α-chain of the IL-5 receptor (benralizumab) is effective treatment for eosinophilic asthma, chronic eosinophilic pneumonia (CEP), and other eosinophilic diseases.1 However, development of arthritis is a potential concern given that the consequent suppression of allergic Th2 cytokines would shift the cytokine balance toward Th1- and Th17-associated responses, which can lead to various inflammatory diseases, including rheumatoid arthritis (RA).2 Here, we describe the case of a patient with CEP who was treated with long-term oral glucocorticoid and developed RA during anti-IL-5 therapy and tapering of the glucocorticoid. Initial corticosteroid treatment might have suppressed RA symptom to make it remained undiagnosed and tapering of corticosteroid might help unmasking RA. Further investigation is needed to understand the role of anti-IL-5 therapy in the development of RA.\n\nCase Presentation\n\nA 66-year-old man with a history of smoking and allergic rhinitis for the last 14 years presented at our clinic in May 2012 due to dyspnea and productive cough lasted for 6 months in spite of treatment with inhaled fluticasone (1000 µg/day)/salmeterol (50 µg/day). His chest X-ray in October 2012 showed multiple infiltrative shadows (Figure 1A). A chest computed tomography revealed patchy infiltrations with ground glass attenuations predominantly around the pleura with air bronchograms inside in the left upper lobe (Figure 1B). A physical exam revealed wheezing in all lung fields. He had neither nasal polyposis nor signs for atopic dermatitis or peripheral neuropathy. His white blood cell count was 14,600/µL with eosinophil count of 5,563/µL (38.1%). Serum immunoglobulin E (IgE) was 2,356 IU/mL (normal value <175) and Candida albicans specific IgE was positive (1.06 UA/mL, normal value < 0.34) but all other specific IgE antibodies were negative. His serum showed no evidence of parasitic infection, and was negative for antinuclear antibodies, myeloperoxidase-specific antineutrophil cytoplasmic antibodies, and anti-cyclic citrullinated peptide antibodies (< 0.5 U/m, normal value <5), while positive for rheumatoid factor (RF, 26.2 IU/mL, normal value <15). Bronchoalveolar lavage fluid (BALF) from the left upper lobe was predominantly eosinophilic (69.3%) without significant pathogens. A transbronchial lung biopsy from the left upper lobe revealed eosinophilic inflammation without evidence of vasculitis or granuloma. Bone marrow aspiration was performed and was negative for malignancy and the FIP1L1-PDGFR fusion gene.Figure 1 (A, B) Chest X-ray and chest CT scan in October 2012. Patchy infiltrations predominantly around the pleura with air bronchograms in the left upper lobe are seen. (C, D) Chest X-ray and chest CT scan in February 2013. Dramatic improvement is seen. (E, F) Chest X-ray and chest CT scan in April 2013. Relapse of CEP showing infiltration in right upper lobe is shown. (G) Chest X-ray in August 2015. Infiltrative shadow in left lower lung field is seen.\n\nAbbreviation: CT, computed tomography.\n\nAfter ruling out other known causes of eosinophilic pneumonias, a diagnosis of CEP was made based on the duration of clinical symptoms (>2 weeks), abnormal chest radiographic findings, eosinophilia, and evident eosinophilic infiltration in the lung.3 His respiratory symptoms quickly resolved with prednisolone (PSL) therapy but relapsed in April 2013. BALF from the right upper lobe was eosinophilic (16.9%) despite oral prednisolone therapy. Continuous prednisolone therapy was necessary because of 2 flares including abovementioned flare that occurred during the tapering (Figure 2). In September 2017, subcutaneous injection of mepolizumab (100 mg every 4 weeks) was initiated to control CEP and to reduce the corticosteroid dose; PSL was tapered by 1 to 2 mg per 4 weeks without worsening of respiratory symptom; however, in January 2018, after 5 injections with mepolizumab and during PSL tapering at the dose of 2 mg/day, he developed polyarthralgia and joint stiffness. In May 2018, PSL was tapered off without worsening of respiratory symptom. His arthralgia in bilateral proximal interphalangeal joints continued but he was not treated as RA because signs of active synovitis were absent and his hand X-ray did not show bone erosion. However, his arthritis gradually exacerbated and the number of affected joints increased. Finally in July 2018, a diagnosis of RA was made based on the criteria of American College of Rheumatology/European League Against Rheumatism; namely, arthritis in 8 small joints, positive rheumatoid factor (22.6 IU/mL), and articular symptoms lasting longer than 6 weeks. Methotrexate was started at 8mg/week and increased to 12mg/week. In August 2018, his treatment was switched from mepolizumab (total of 10 injections) to benralizumab (initial 2 doses, 30 mg every 4 weeks; subsequently, 30 mg every 8 weeks) because it was difficult to completely rule out the possibility that his arthritis was an adverse reaction related to mepolizumab. Meanwhile, his arthritis gradually resolved with methotrexate. In May 2019, benralizumab was discontinued after 5 injections because no respiratory symptoms were noted during benralizumab therapy. Although his eosinophil count increased from 0% to ~10% at 3 months after the last benralizumab injection, no respiratory symptoms appeared for more than a year.Figure 2 Clinical course of the patient. Oral prednisolone to control CEP was tapered off during mepolizumab therapy. Methotrexate was initiated for rheumatoid arthritis and mepolizumab was replaced by benralizumab. No exacerbations were noted after the discontinuation of benralizumab. The degree of respiratory symptom (*green) and arthritis (**blue) are indicated.\n\nAbbreviations: CEP, chronic eosinophilic pneumonia; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; FVC, forced vital capacity.\n\nDiscussion\n\nThe clinical course of this patient suggests a potential interaction between CEP, anti-IL-5 therapy, tapering of corticosteroids and RA because the development of arthritis and a diagnosis of RA occurred during anti-IL-5 therapy and tapering of corticosteroid therapy. IL-5 is a classic Th2 cytokine associated with various allergic diseases and eosinophilic inflammation. It also is responsible for the maturation and release of eosinophils from the bone marrow, their activation, and elongation of their life span. Thus, anti-IL-5 therapy not only shifts the cytokine balance from allergic Th2 responses to inflammatory Th1 and Th17 responses, but it also significantly reduces eosinophils. All of these are in favor of development of RA. Additionally, emerging evidence indicated that eosinophils actively participate in the resolution of inflammation seen in RA.2 Data from animal models demonstrated the anti-inflammatory effects of eosinophils in alleviating arthritis.4,5 Thus, suppression of IL-5 or eosinophils by mepolizumab or benralizumab therapy can lead to arthritis or arthralgia. A few small-scale retrospective studies on mepolizumab indeed reported arthralgia as one of the most common adverse events along with headache (20%–30%). However, double-blinded clinical trials showed a low incidence of arthralgia, with no differences between the treatment and placebo groups.6 A meta-analysis found no association between benralizumab and an increased prevalence of arthralgia.7 Nevertheless, development of RA with mepolizumab therapy was reported in a patient with hypereosinophilic syndrome.8 Benralizumab therapy exacerbated arthritis in another patient with severe eosinophilic asthma complicated by refractory RA.9 Although the asthma was well controlled in the latter patient, asthma and RA could be successfully managed by a combination of benralizumab and golimumab.9 Furthermore, one study that evaluated the impact of mepolizumab in patients with concomitant eosinophilic asthma and RA who had low disease activity for at least 6 months reported that 6 out of 8 patients with RA developed flares of arthritis after mepolizumab therapy.5 In the present case, the patient developed RA during mepolizumab therapy. The half-life of mepolizumab is approximately 20–36 days.10 Mepolizumab was injected 5 times every 4 weeks before the development of arthralgia, therefore, mepolizumab concentration probably reached the steady state and might cause side effects via cytokine imbalance in the present case. Another factor that might affect the development of arthritis is administration and tapering of oral prednisolone. When he was first diagnosed with CEP, he was positive for RF. Although RF is positive in ~5% of healthy individual and only a fraction of RF positive individual develops RA, RF is known to precede the development of arthritis and RA.11 Thus, he might be predisposed to development of RA prior to treatment for CEP and the initiation of corticosteroid treatment might suppress the development of RA for a while, then anti-IL-5 therapy and the tapering of glucocorticoid might help uncover the natural course of development of arthritis.\n\nDiscontinuing biologics in asthma is usually challenging due to persistent eosinophilic inflammation; however, the interaction between anti-IL-5 therapy and RA in our patient could have resolved the eosinophilic inflammation, which then permitted discontinuation of both biologics and steroids. Nevertheless, anti-IL-5 therapy could have promoted the development of RA while suppressing eosinophilic inflammation, and the possibility that the steroid tapering helped unmasking an underlying RA cannot be completely ruled out. Once RA is established, its pathogenic Th1- and Th17-mediated inflammation, in combination with anti-IL-5 therapy, might suppress Th2 cytokine- and eosinophil-mediated inflammation. However, it is also possible that methotrexate, which is sometimes used to treat eosinophilic inflammatory diseases including EGPA, hypereosinophilic syndrome, and eosinophilic fasciitis,12 also facilitated discontinuation of benralizumab though the efficacy of MTX for CEP has not been reported before. The optimal treatment duration and criteria for discontinuing biologics in asthma are not yet known and warrant further investigation.\n\nConclusion\n\nAnti-IL-5 therapy has various biological effects that could favor a development of arthritis or its flare. The present case may suggest that IL-5 suppression can induce or help unmasking RA in certain patients; however, it is also possible that initial steroid therapy improved subclinical RA and made it remain undiagnosed and the parallel OCS tapering during IL-5 therapy could have contributed to unveil the underlying RA. Regardless, earlier signs of arthritis/morning stiffness should be taken into consideration during anti-IL-5 therapy. Both anti-IL-5 therapy and corticosteroids were discontinued in our patient; however, majority of patients is prescribed prolonged anti-IL-5 therapy because the optimal duration of this therapy is not yet known. Further studies are required to establish guidelines on the optimal use of anti-IL-5 therapy and to understand the possible interactions between CEP, anti-IL-5 therapy, tapering of corticosteroid therapy and development of RA.\n\nEthics Approval and Informed Consent\n\nThe authors certify that they have obtained written informed consent documents. In the document, the patient agreed with the use of the images and clinical information to be reported in the journal. The patient understood that his name and initials would not be published, and all due efforts would be made to maintain his dignity. This study was approved by the research ethics committee of University of Occupational and Environmental Health, Japan (IRB No. H27-238).\n\nConsent for Publication\n\nThe patient gave written consent to publish this material.\n\nAuthor Contributions\n\nAll authors significantly contributed to the reported study, whether in the conception, study design, execution, data acquisition, analysis, or interpretation. All authors participated in the drafting, revising, and critical review of the article, gave their final approval for the version to be published, agreed on the journal to which the article was to be submitted, and agreed to be responsible for all aspects of the work.\n\nDisclosure\n\nKY received a research grant from GlaxoSmithKline (GSK) and lecture fees from AstraZeneca and GSK. The other authors have no conflicts of interest for this work.\n==== Refs\nReferences\n\n1. Harish A, Schwartz SA. Targeted anti-IL-5 therapies and future therapeutics for hypereosinophilic syndrome and rare eosinophilic conditions. Clin Rev Allergy Immunol. 2020;59 (2 ):231–247. doi:10.1007/s12016-019-08775-4 31919743\n2. Chen Z, Bozec A, Ramming A, Schett G. Anti-inflammatory and immune-regulatory cytokines in rheumatoid arthritis. Nat Rev Rheumatol. 2019;15 (1 ):9–17. doi:10.1038/s41584-018-0109-2 30341437\n3. Suzuki Y, Suda T. Eosinophilic pneumonia: a review of the previous literature, causes, diagnosis, and management. Allergol Int. 2019;68 (4 ):413–419. doi:10.1016/j.alit.2019.05.006 31253537\n4. Chen Z, Andreev D, Oeser K, et al. Th2 and eosinophil responses suppress inflammatory arthritis. Nat Commun. 2016;7 (1 ):11596. doi:10.1038/ncomms11596 27273006\n5. Andreev D, Liu M, Kachler K, et al. Regulatory eosinophils induce the resolution of experimental arthritis and appear in remission state of human rheumatoid arthritis. Ann Rheum Dis. 2020;80 (4 ):451–468. doi:10.1136/annrheumdis-2020-218902\n6. Khatri S, Moore W, Gibson PG, et al. Assessment of the long-term safety of mepolizumab and durability of clinical response in patients with severe eosinophilic asthma. J Allergy Clin Immunol. 2019;143 (5 ):1742–1751. doi:10.1016/j.jaci.2018.09.033 30359681\n7. Liu W, Ma X, Zhou W. Adverse events of benralizumab in moderate to severe eosinophilic asthma: a meta-analysis. Medicine. 2019;98 (22 ):e15868. doi:10.1097/MD.0000000000015868 31145343\n8. Roufosse FE, Kahn JE, Gleich GJ, et al. Long-term safety of mepolizumab for the treatment of hypereosinophilic syndromes. J Allergy Clin Immunol. 2013;131 (2 ):461–467. doi:10.1016/j.jaci.2012.07.055 23040887\n9. Yamada H, Hida N, Kurashima Y, et al. A case of severe eosinophilic asthma and refractory rheumatoid arthritis well controlled by combination of IL-5Ralpha antibody and TNFalpha inhibitor. Allergol Int. 2019;68 (4 ):536–538. doi:10.1016/j.alit.2019.04.003 31027977\n10. Tsukamoto N, Takahashi N, Itoh H, et al. Pharmacokinetics and pharmacodynamics of mepolizumab, an anti-Interleukin 5 monoclonal antibody, in healthy Japanese male subjects. Clin Pharmacol Drug Dev. 2018;5 (2 ):102–108. doi:10.1002/cpdd.205\n11. Quirke AM, Perry E, Cartwright A, et al. Bronchiectasis is a model for chronic bacterial infection inducing autoimmunity in rheumatoid arthritis. Arthritis Rheumatol. 2015;67 (9 ):2335–2342. doi:10.1002/art.39226 26017630\n12. Groh M, Pagnoux C, Baldini C, et al. Eosinophilic granulomatosis with polyangiitis (Churg-Strauss) (EGPA) Consensus Task Force recommendations for evaluation and management. Eur J Intern Med. 2015;26 (7 ):545–553. doi:10.1016/j.ejim.2015.04.022 25971154\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1178-6965",
"issue": "14()",
"journal": "Journal of asthma and allergy",
"keywords": "asthma; benralizumab; chronic eosinophilic pneumonia; mepolizumab; rheumatoid arthritis",
"medline_ta": "J Asthma Allergy",
"mesh_terms": null,
"nlm_unique_id": "101543450",
"other_id": null,
"pages": "1425-1430",
"pmc": null,
"pmid": "34858033",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": "27273006;23040887;31027977;27138023;25971154;31253537;31919743;33148700;26017630;30341437;30359681;31145343",
"title": "Development of Rheumatoid Arthritis During Anti-Interleukin-5 Therapy in a Patient with Refractory Chronic Eosinophilic Pneumonia.",
"title_normalized": "development of rheumatoid arthritis during anti interleukin 5 therapy in a patient with refractory chronic eosinophilic pneumonia"
} | [
{
"companynumb": "JP-GLAXOSMITHKLINE-JP2021GSK267026",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "MEPOLIZUMAB"
},
"drugadditional": "1... |
{
"abstract": "Trichosporon asahii is a yeast-like fungus that is emerging as an important cause of invasive infections in tertiary medical centres. A 58-year-old Chinese man with no known medical illnesses presented with liver lacerations and multiple fractures following an alleged 12-foot fall at a construction site. The gravity of his injuries and poor haemodynamic status necessitated an intensive care unit (ICU) admission, during which several febrile episodes were detected and multiple antibiotics were administered. After being in the ICU for at least two weeks, a urease-positive yeast was isolated from the patient's blood. The yeast formed dry, fuzzy and wrinkled white colonies on Sabouraud dextrose agar following prolonged incubation, and produced blastoconidia, true hyphae, pseudohyphae and arthroconidia on slide culture. It was identified biochemically by the ID 32 C kit as T. asahii. The yeast had elevated minimal inhibitory concentration (MIC) values to fluconazole, amphotericin B, flucytosine and all echinocandins tested. In view of this, the patient was treated with voriconazole and was successfully transferred to the general medical ward.",
"affiliations": "Universiti Kebangsaan Malaysia Medical Centre, Faculty of Medicine, Department of Medical Microbiology and Immunology, kuala Lumpur, Malaysia. dingch@ppukm.ukm.edu.my.",
"authors": "Ding|C H|CH|;Khaithir|T M N|TMN|;Wahab|A A|AA|;Faiz|M A|MA|;Saarah|W R|WR|",
"chemical_list": "D000900:Anti-Bacterial Agents; D000935:Antifungal Agents; D000666:Amphotericin B; D065819:Voriconazole",
"country": "Malaysia",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0126-8635",
"issue": "42(2)",
"journal": "The Malaysian journal of pathology",
"keywords": null,
"medline_ta": "Malays J Pathol",
"mesh_terms": "D000666:Amphotericin B; D000900:Anti-Bacterial Agents; D000935:Antifungal Agents; D001487:Basidiomycota; D026141:Drug Resistance, Multiple, Fungal; D016469:Fungemia; D006801:Humans; D008297:Male; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D009104:Multiple Trauma; D060586:Trichosporonosis; D065819:Voriconazole",
"nlm_unique_id": "8101177",
"other_id": null,
"pages": "293-296",
"pmc": null,
"pmid": "32860385",
"pubdate": "2020-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Trichosporon Asahii fungaemia in an immunocompetent polytrauma patient who received multiple antibiotics.",
"title_normalized": "trichosporon asahii fungaemia in an immunocompetent polytrauma patient who received multiple antibiotics"
} | [
{
"companynumb": "MY-MYLANLABS-2020M1081138",
"fulfillexpeditecriteria": "1",
"occurcountry": "MY",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PIPERACILLIN SODIUM\\TAZOBACTAM SODIUM"
},
"d... |
{
"abstract": "BACKGROUND\nAcetaminophen (paracetamol) overdose (AOD) has recently emerged as the leading cause of acute liver failure (ALF) in the United States, with an incidence approaching that seen in the United Kingdom. We describe a new way to treat AOD ALF patients fulfilling King's College criteria for \"super-urgent\" liver transplantation.\n\n\nMETHODS\nBeginning in June 1998, we have been piloting a clinical program of subtotal hepatectomy and auxiliary orthotopic liver transplantation (ALT) for AOD ALF. Our technique is based on the following principles: (1) subtotal hepatectomy; (2) auxiliary transplantation of a whole liver graft; (3) gradual withdrawal of immunosuppression after recovery. Results were compared with patients who had undergone an orthotopic liver transplantation (OLT) for AOD ALF in the same period. Quality of life comparisons were made using the SF36 questionnaire.\n\n\nRESULTS\nThirteen patients underwent this procedure between June 1998 and March 2005. Median survival is 68 months (range, 0-102 m). Actual survival data show that 9 of 13 patients are alive (69%) compared with 7 of 13 OLT patients (54%). One ALT patient required a retransplantation with an OLT due to hepatic vein thrombosis, and immunosuppression is therefore maintained. The other 8 surviving ALT patients are off immunosuppression. These 8 ALT patients have normal liver function and have a better quality of life compared with the 7 surviving OLT patients.\n\n\nCONCLUSIONS\nOur results with this new technique are encouraging: 69% actual survival, no long-term immunosuppression requirement, and improved quality of life in the 62% successful cases.",
"affiliations": "HPB and Transplant Unit, St James's University Hospital, Leeds, United Kingdom. peterlodge@aol.com",
"authors": "Lodge|J Peter A|JP|;Dasgupta|Dowmitra|D|;Prasad|K Rajendra|KR|;Attia|Magdy|M|;Toogood|Giles J|GJ|;Davies|Mervyn|M|;Millson|Charles|C|;Breslin|Niall|N|;Wyatt|Judith|J|;Robinson|Philip J|PJ|;Bellamy|Mark C|MC|;Snook|Nicola|N|;Pollard|Stephen G|SG|",
"chemical_list": "D018712:Analgesics, Non-Narcotic; D000082:Acetaminophen",
"country": "United States",
"delete": false,
"doi": "10.1097/SLA.0b013e31816401ec",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0003-4932",
"issue": "247(2)",
"journal": "Annals of surgery",
"keywords": null,
"medline_ta": "Ann Surg",
"mesh_terms": "D000082:Acetaminophen; D000293:Adolescent; D000328:Adult; D018712:Analgesics, Non-Narcotic; D005260:Female; D005500:Follow-Up Studies; D006498:Hepatectomy; D006801:Humans; D017114:Liver Failure, Acute; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged; D010865:Pilot Projects; D011788:Quality of Life; D012189:Retrospective Studies; D015996:Survival Rate; D013997:Time Factors; D016896:Treatment Outcome",
"nlm_unique_id": "0372354",
"other_id": null,
"pages": "238-49",
"pmc": null,
"pmid": "18216528",
"pubdate": "2008-02",
"publication_types": "D003160:Comparative Study; D016428:Journal Article",
"references": null,
"title": "Emergency subtotal hepatectomy: a new concept for acetaminophen-induced acute liver failure: temporary hepatic support by auxiliary orthotopic liver transplantation enables long-term success.",
"title_normalized": "emergency subtotal hepatectomy a new concept for acetaminophen induced acute liver failure temporary hepatic support by auxiliary orthotopic liver transplantation enables long term success"
} | [
{
"companynumb": "PHHY2019GB035632",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ACETAMINOPHEN"
},
"drugadditional": "3",
"dr... |
{
"abstract": "OBJECTIVE\nThe objective of this study is to determine whether an initial methotrexate (MTX) dosage is associated with an increased risk of liver toxicity in patients with rheumatoid arthritis (RA).\n\n\nMETHODS\nThis retrospective study included 730 RA patients who started MTX treatment between 2004 and 2019 at the rheumatology clinic at Seoul National University Hospital. The patients were divided into three groups according to the initial dosage of MTX they received: low (MTX ≤ 7.5 mg/week), intermediate (MTX 10-12.5 mg/week), and high (MTX ≥ 15 mg/week) dosage groups. Hepatotoxicity, defined as elevations in aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) levels more than twofold above the upper limit of normal (2 × ULN), was examined during 90 days of MTX treatment. Predictors of hepatotoxicity were identified using logistic regression analyses.\n\n\nRESULTS\nOf the 730 patients, 10 (1.4%) patients developed hepatotoxicity. The rate of hepatotoxicity was not different between the three MTX dosage groups. Univariate logistic regression analyses showed that the risk of hepatotoxicity was not higher in the intermediate MTX dosage group (odds ratio (OR): 0.89, 95% confidential interval (CI): 0.20-4.00, p = 0.877) or in the high MTX dosage group (OR: 1.23, 95% CI: 0.24-6.14, p = 0.804) than in the low MTX dosage group. Multivariate logistic regression analyses showed that elevated baseline AST and/or ALT levels above ULN and concomitant leflunomide use were associated with MTX hepatotoxicity.\n\n\nCONCLUSIONS\nThe initial MTX dosage is not associated with increased hepatotoxicity in RA patients.\n\n\nCONCLUSIONS\n• An initial methotrexate (MTX) dosage is not associated with liver toxicity in patients with rheumatoid arthritis (RA). • RA patients with a baseline liver function test (LFT) abnormality or receiving concomitant leflunomide treatment should be monitored closely for LFT abnormalities during the early phase of MTX treatment.",
"affiliations": "Division of Rheumatology, Department of Internal Medicine, Seoul National University Hospital and Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Korea.;Division of Rheumatology, Department of Internal Medicine, Seoul National University Hospital and Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Korea.;Division of Rheumatology, Department of Internal Medicine, Seoul National University Hospital and Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Korea.;Division of Rheumatology, Department of Internal Medicine, Seoul National University Hospital and Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Korea. jinkyunpark@gmail.com.",
"authors": "Choi|Se Rim|SR|;Park|Jun Won|JW|;Lee|Eun Bong|EB|;Park|Jin Kyun|JK|http://orcid.org/0000-0003-2167-9393",
"chemical_list": "D018501:Antirheumatic Agents; D008727:Methotrexate",
"country": "Germany",
"delete": false,
"doi": "10.1007/s10067-021-05811-7",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0770-3198",
"issue": "40(11)",
"journal": "Clinical rheumatology",
"keywords": "East Asia; Liver toxicity; Methotrexate; Rheumatoid arthritis",
"medline_ta": "Clin Rheumatol",
"mesh_terms": "D018501:Antirheumatic Agents; D001172:Arthritis, Rheumatoid; D056486:Chemical and Drug Induced Liver Injury; D006801:Humans; D008727:Methotrexate; D012189:Retrospective Studies",
"nlm_unique_id": "8211469",
"other_id": null,
"pages": "4493-4500",
"pmc": null,
"pmid": "34115231",
"pubdate": "2021-11",
"publication_types": "D016428:Journal Article",
"references": "20149325;15338491;26690890;12684695;16758511",
"title": "Initial methotrexate dosage is not associated with an increased risk of liver toxicity in patients with rheumatoid arthritis.",
"title_normalized": "initial methotrexate dosage is not associated with an increased risk of liver toxicity in patients with rheumatoid arthritis"
} | [
{
"companynumb": "KR-SA-2021SA204380",
"fulfillexpeditecriteria": "1",
"occurcountry": "KR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "METHOTREXATE"
},
"drugadditional": null,
"... |
{
"abstract": "Treatment options for platinum-refractory metastatic urothelial cancer (mUC) are limited, and outcomes remain poor. Nab-paclitaxel is an albumin-bound formulation of paclitaxel showing promising activity and tolerability in a prior single-arm trial.\nTo evaluate the efficacy and safety of nab-paclitaxel vs paclitaxel in platinum-refractory mUC.\nIn this investigator-initiated, open-label, phase 2 randomized clinical trial conducted across Canada and Australia from January 2014 to April 2017, eligible patients had histologically confirmed, radiologically evident mUC of the urinary tract. Mixed histologic findings, except small cell, were permitted provided UC was the predominant histologic finding. All patients had received platinum-based chemotherapy either in the metastatic setting or were within 12 months of perioperative chemotherapy. Patients with prior taxane chemotherapy were not included. Patients had an Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0 to 2 and adequate organ function.\nPatients were randomized to nab-paclitaxel, 260 mg/m2, or paclitaxel, 175 mg/m2, every 3 weeks.\nThe primary end point was progression-free survival (PFS).\nAmong 199 patients, median age was 67 (range, 24-88) years; 144 (72%) were men; 167 (84%) were ECOG PS 0-1; 59 (30%) had liver metastases; and 110 (55%) were within 6 months of prior platinum-based chemotherapy. At a median follow-up of 16.4 months, there was no significant difference between nab-paclitaxel vs paclitaxel for median PFS (3.4 months vs 3.0 months; hazard ratio [HR], 0.92; 90% CI, 0.68-1.23; 1-sided P = .31). Median overall survival was 7.5 months for nab-paclitaxel vs 8.8 months for paclitaxel (HR, 0.95; 90% CI, 0.70-1.30; 1-sided P = .40); and objective response rate (ORR) was 22% for nab-paclitaxel vs 25% for paclitaxel (P = .97). Grade 3/4 adverse events were more frequent with nab-paclitaxel (64/97 [66%]) compared with paclitaxel (45/97 [46%]), P = .009; but peripheral sensory neuropathy was similar (all grades, 72/97 [74%] vs 64/97 [66%]; grade 3/4, 7/97 [7%] vs 3/97 [3%]; P = .27). There were no apparent differences in scores for health-related quality of life.\nIn this open-label, phase 2 randomized clinical trial of patients with platinum-refractory mUC, nab-paclitaxel had similar efficacy to paclitaxel; but worse toxic effects. The ORR with either taxane, however, was higher than previously reported and similar to those reported for the immune checkpoint inhibitors, suggesting that the taxanes remain a reasonable option in this setting.\nClinicalTrials.gov Identifier: NCT02033993.",
"affiliations": "Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.;Centre Hospitalier de l'Université de Montréal, Montréal, Quebec, Canada.;Peter MacCallum Cancer Centre, Victoria, Australia.;Ottawa Hospital Cancer Centre, Ottawa, Ontario, Canada.;Cross Cancer Institute, Edmonton, Alberta, Canada.;NHMRC Clinical Trials Centre, Sydney, Australia.;British Columbia Cancer Agency Vancouver, British Columbia, Canada.;Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.;Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.;Tom Baker Cancer Centre, Calgary, Alberta, Canada.;Juravinski Cancer Centre, Hamilton, Ontario, Canada.;Stronach Regional Cancer Centre, Newmarket, Ontario, Canada.;London Health Sciences Centre, London, Ontario, Canada.;Department of Oncology, Queen's University, Kingston, Ontario, Canada.;Hopital Charles-LeMoyne, Montreal, Quebec, Canada.;Frankston Hospital/Cabrini/Monash University, Parkdale, Australia.;Tom Baker Cancer Centre, Calgary, Alberta, Canada.;Canadian Cancer Trials Group (CCTG), Queen's University, Kingston, Ontario, Canada.;Canadian Cancer Trials Group (CCTG), Queen's University, Kingston, Ontario, Canada.;Canadian Cancer Trials Group (CCTG), Queen's University, Kingston, Ontario, Canada.",
"authors": "Sridhar|Srikala S|SS|;Blais|Normand|N|;Tran|Ben|B|;Reaume|M Neil|MN|;North|Scott A|SA|;Stockler|Martin R|MR|;Chi|Kim N|KN|;Fleshner|Neil E|NE|;Liu|Geoffrey|G|;Robinson|John W|JW|;Mukherjee|Som D|SD|;Rahim|Yasmin|Y|;Winquist|Eric|E|;Booth|Christopher M|CM|;Nguyen|Nghia Trung|NT|;Beardsley|Emma K|EK|;Alimohamed|Nimira S|NS|;McDonald|Gail T|GT|;Ding|Keyue|K|;Parulekar|Wendy R|WR|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1001/jamaoncol.2020.3927",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2374-2437",
"issue": "6(11)",
"journal": "JAMA oncology",
"keywords": null,
"medline_ta": "JAMA Oncol",
"mesh_terms": null,
"nlm_unique_id": "101652861",
"other_id": null,
"pages": "1751-1758",
"pmc": null,
"pmid": "32940628",
"pubdate": "2020-11-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Efficacy and Safety of nab-Paclitaxel vs Paclitaxel on Survival in Patients With Platinum-Refractory Metastatic Urothelial Cancer: The Canadian Cancer Trials Group BL.12 Randomized Clinical Trial.",
"title_normalized": "efficacy and safety of nab paclitaxel vs paclitaxel on survival in patients with platinum refractory metastatic urothelial cancer the canadian cancer trials group bl 12 randomized clinical trial"
} | [
{
"companynumb": "CA-PFIZER INC-2020380561",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "PACLITAXEL"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nAfter a successful trabeculectomy, a sudden intraocular pressure decrease may alter the intracranial to intraocular pressure ratio and cause decompression retinopathy. Frequent Valsalva maneuvers may also play a role in its pathogenesis. This condition may manifest as multiple retinal hemorrhages, edema of the optic disc, macular edema, or a sudden decrease in visual acuity postoperatively. Outcomes for patients are usually good, with spontaneous resolution occurring within a matter of weeks. It has been rarely reported in the literature as a bilateral condition.\n\n\nMETHODS\nWe present a case of consecutive bilateral decompression retinopathy in a 54-year-old severely obese Caucasian woman (body mass index 37 kg/m(2)) with open angle glaucoma and a poor history of medical therapeutic compliance, who chose surgical treatment based on her inability to consistently use ocular drops. Our patient underwent a trabeculectomy with mitomycin C in both eyes, with surgeries taking place 3 months apart. After the first surgery, 2 weeks postoperatively, she complained of decreased visual acuity. Examination of her right eye fundus revealed multiple retinal hemorrhages and disc edema. There was a similar pattern in her left eye, this time including maculopathy. Her visual acuity and fundoscopic changes resolved spontaneously over a period of a month in both cases. Currently, our patient has well-controlled bilateral intraocular pressure, ranging between 14 and 16 mmHg, without hypotensive medication.\n\n\nCONCLUSIONS\nDecompression retinopathy is a potential complication after glaucoma surgery, but has rarely been described as a bilateral consecutive condition. A comprehensive approach could help to anticipate its occurrence and manage it.",
"affiliations": "Ophthalmology Department - Centro Hospital do Porto, EPE - Hospital de Santo António, Largo Professor Abel Salazar, 4099-001, Porto, Portugal. anamarcosfigueiredo@gmail.com.;Ophthalmology Department - Centro Hospital do Porto, EPE - Hospital de Santo António, Largo Professor Abel Salazar, 4099-001, Porto, Portugal.;Ophthalmology Department - Centro Hospital do Porto, EPE - Hospital de Santo António, Largo Professor Abel Salazar, 4099-001, Porto, Portugal.;Wills Eye Hospital, Jefferson Medical College, 840 Walnut Street, Philadelphia, PA, 19107, USA.",
"authors": "Figueiredo|Ana Raquel Marcos|ARM|;Sampaio|Isabel Coutinho|IC|;Menéres|Maria João Fernandes Dos Santos|MJFDS|;Spaeth|George L|GL|",
"chemical_list": "D003432:Cross-Linking Reagents; D016685:Mitomycin",
"country": "England",
"delete": false,
"doi": "10.1186/s13256-016-0814-x",
"fulltext": "\n==== Front\nJ Med Case RepJ Med Case RepJournal of Medical Case Reports1752-1947BioMed Central London 81410.1186/s13256-016-0814-xCase ReportConsecutive bilateral decompression retinopathy after mitomycin C trabeculectomy: a case report Figueiredo Ana Raquel Marcos anamarcosfigueiredo@gmail.com Sampaio Isabel Coutinho isabel_sampaio@netcabo.pt Menéres Maria João Fernandes dos Santos mariajoaomeneres@gmail.com Spaeth George L. gspaeth@willseye.org Ophthalmology Department - Centro Hospital do Porto, EPE – Hospital de Santo António, Largo Professor Abel Salazar, 4099-001 Porto, Portugal Wills Eye Hospital, Jefferson Medical College, 840 Walnut Street, Philadelphia, PA 19107 USA 4 2 2016 4 2 2016 2016 10 327 5 2015 14 1 2016 © Figueiredo et al. 2016\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nAfter a successful trabeculectomy, a sudden intraocular pressure decrease may alter the intracranial to intraocular pressure ratio and cause decompression retinopathy. Frequent Valsalva maneuvers may also play a role in its pathogenesis. This condition may manifest as multiple retinal hemorrhages, edema of the optic disc, macular edema, or a sudden decrease in visual acuity postoperatively. Outcomes for patients are usually good, with spontaneous resolution occurring within a matter of weeks. It has been rarely reported in the literature as a bilateral condition.\n\nCase presentation\nWe present a case of consecutive bilateral decompression retinopathy in a 54-year-old severely obese Caucasian woman (body mass index 37 kg/m2) with open angle glaucoma and a poor history of medical therapeutic compliance, who chose surgical treatment based on her inability to consistently use ocular drops. Our patient underwent a trabeculectomy with mitomycin C in both eyes, with surgeries taking place 3 months apart. After the first surgery, 2 weeks postoperatively, she complained of decreased visual acuity. Examination of her right eye fundus revealed multiple retinal hemorrhages and disc edema. There was a similar pattern in her left eye, this time including maculopathy. Her visual acuity and fundoscopic changes resolved spontaneously over a period of a month in both cases. Currently, our patient has well-controlled bilateral intraocular pressure, ranging between 14 and 16 mmHg, without hypotensive medication.\n\nConclusions\nDecompression retinopathy is a potential complication after glaucoma surgery, but has rarely been described as a bilateral consecutive condition. A comprehensive approach could help to anticipate its occurrence and manage it.\n\nKeywords\nDecompression retinopathyMacular edemaOpen angle glaucomaRetinal hemorrhagesTrabeculectomyissue-copyright-statement© The Author(s) 2016\n==== Body\nBackground\nOcular decompression retinopathy was first described by Fechtner et al. in 1992 [1] as a complication of the abrupt iatrogenic lowering of intraocular pressure (IOP) after glaucoma filtering surgery. During intraocular surgery, entry into the eye allows the IOP to fall and equalize with the atmospheric pressure. If this change is sudden and large, it can induce hemodynamic changes that may result in bilateral decompression retinopathy. Immediately following surgery, the clinical situation is characterized by the appearance of diffuse retinal hemorrhages and edema of the optic disc in association with decreased visual acuity [2]. The most common optic nerve findings described are peripapillary and optic nerve head hemorrhages. Retinal manifestations mainly comprise intraretinal hemorrhages (92 % of retinal hemorrhages) and, less commonly, macular edema (3 %) or serous macular detachment (5 %) [13].\n\nOutcomes are generally good for affected patients, with spontaneous resolution occurring within a few weeks. Over the years, the word “ocular” has been dropped, and “ocular decompression retinopathy” is now described in the literature as “decompression retinopathy” (DR). Besides a large drop in IOP after surgery, many of the cases presented in the literature have demonstrated a significant increase in IOP over a relatively short period of time pre-surgery, or large variations in IOP with spikes followed by significant drops in pressure [3]. These and other factors are believed to be related to the etiopathogenesis of DR [4]. Even the use of mitomycin C has been questioned as a potential adjuvant, and other hypotheses remain open [5].\n\nThere are few published cases of DR. Although Fechtner et al. described it as a complication following trabeculectomy (which represents half of total cases described), cases have been reported in other situations, such as neodymium: yttrium–aluminum–garnet iridotomies [6], anterior chamber paracentesis [7], pars plana vitrectomies [8], orbital decompression, and drainage implant insertions [9, 10]. In 2006, Bui et al. [11] were the first to describe maculopathy as an additional characteristic of DR. Our presented case concerns an extremely rare entity in ophthalmology, particularly with respect to our patient’s post trabeculectomy status, and represents an event rarely before described in the literature with this course and much less with a bilateral consecutive presentation.\n\nCase presentation\nA 54-year-old Caucasian woman with open angle glaucoma and a history of suboptimal medical therapeutic compliance owing to an intolerance to drops was referred to our Ophthalmology Department. She was severely obese (body mass index 37 kg/m2) and had type 2 diabetes but was using insulin with good metabolic control. Her best corrected visual acuity (BCVA) in both eyes was 1.0. Her IOP was 35 mmHg without the use of medication, though she achieved values of 18 mmHg in her right eye and 16 mmHg in her left eye with the use of tafluprost once daily. No changes were identified in an examination of her anterior segment. The papillary cup was 0.3 in her right eye with a temporal notch and her left eye had a normal appearance.\n\nOur patient’s compliance to medical therapy continued to be poor, because she blamed her drops for coughing and dyspnea attacks. Without the use of drops, her IOP values remained consistently in the 30s. After continuous non-compliance with several other ocular medications, surgery was discussed as an alternative treatment option. The risks and potential complications of surgery were explained to our patient. No signs of cornea or ocular media opacity, retinal hemorrhage, macular or peripheral detachments, or other contraindications were observed in either eye. Our patient decided to opt for surgery. Her right eye was operated on first with an uneventful mitomycin C trabeculectomy (0.3 mg/ml, 3 minutes).\n\nOn the first postoperative day, our patient presented with a diffuse, functioning, and non-leaking filtration bleb, associated with a well-formed anterior chamber, and an IOP of 8 mmHg, with a normal appearance on fundoscopy. Two weeks postoperatively she complained of decreased visual acuity; her BCVA was 20/32 and her IOP was 10 mmHg without medication. Fundoscopy exhibited multiple superficial, flame-shaped retinal hemorrhages located centrifugally from the optic disc associated with optic disc edema (Fig. 1a). There was no evidence of choroidal effusion. A fundus examination of her left eye was unremarkable.Fig. 1 Right eye retinography, angiography, and optical coherence tomography 2 weeks after surgery. a Right eye fundus photograph showing multiple superficial, flame-shaped retinal hemorrhages located centrifugally from the optic disc associated with optic disc edema. b Fluorescein angiography exhibited macular microaneurysms associated with fluoroscein diffusion, peripapillary hemorrhages, and late optic disc leakage. c Optical coherence tomography image revealing folding of the macular retina and a small detachment of the neurosensory retina\n\n\n\nOptical coherence tomography (OCT) revealed folding of the macular retina associated with a small detachment of the neurosensory retina (Fig. 1c). The angiographic pattern showed macular microaneurysms associated with fluorescein diffusion, peripapillary hemorrhages, and late optic disc leakage, without ischemic areas or neovascularization (Fig. 1b). One month later the overall fundoscopic changes resolved spontaneously (Fig. 2a–d). Given this situation, a suspected diagnosis of DR was proposed. Other possible diagnoses were retinal venous occlusion or Valsalva retinopathy, but these were considered unlikely given the diagnostic results pattern. Subsequent follow-up visits were satisfactory, with our patient maintaining a steady IOP of 8–14 mmHg without medication. The peripapillary hemorrhages and optic disc edema spontaneously recovered during the second postoperative month, and our patient’s BCVA reached 20/25.Fig. 2 Right eye images 1 and 7 months after surgery. a, b Right eye fundus photograph and optical coherence tomography image 1 month after surgery. c, d Fundus photograph and optical coherence tomography image in the last follow-up visit (7 months after surgery). The peripapillary hemorrhages and optic disc edema spontaneously recovered\n\n\n\nThree months later, she underwent an uncomplicated left eye trabeculectomy with mitomycin C (0.3 mg/ml, 3 minutes). No postoperative hypotony was registered. On the first postoperative day, the anterior chamber was formed, the bleb was diffuse, her IOP was 8 mmHg, and results from fundoscopy were normal, without choroidals. The pattern of clinical evolution of this eye was similar, with decreased vision complaints 10 days after surgery (her BCVA was 20/32). Her IOP was 9 mmHg, with no medication. A fundus examination revealed identifiable multiple peripapillary retinal hemorrhages, optic disc swelling, and macular edema (Fig. 3a). OCT revealed macular folding and neurosensory retinal detachment (Fig. 3b). Choroidal striation, optic disc leakage, and signs of macular microangiopathy and epitheliopathy were visible on angiography (Fig. 3c). The localized hemorrhages and sectorial optic disc edema reduced progressively and her macular edema recovered spontaneously during the first postoperative month (Fig. 4). Her left eye IOP on the last follow-up visit was 16 mmHg without hypotensive medication and her BCVA was 20/25.Fig. 3 Left eye retinography, optical coherence tomography (OCT), and angiography 10 days after surgery. a Fundus photograph showing multiple peripapillary retinal hemorrhages, optic disc swelling, and macular edema. b Optical coherence tomography revealed macular edema with neurosensory retinal detachment. c Angiography demonstrated choroidal striation, optic disc leakage, and signs of macular microangiopathy and epitheliopathy\n\nFig. 4 Left eye fundus photographs and optical coherence tomography image 2 and 4 months after surgery. a, c Gradual reduction of the localized hemorrhages and sectorial optic edema in the second postoperative month b, d Optical coherence tomography revealed progressive spontaneous macular edema recovery in the second postoperative month. e, f Images from the last visit (4 months after surgery)\n\n\n\nGiven the occurrence of the same pattern in the contralateral eye, our patient’s complete medical history was reviewed again, with inquiries about possible hypertensive peaks, usual medication, and frequent Valsalva maneuvers. A summary infectious test was performed to rule out any possible systemic causes of bilateral papillitis. Results for the infectious study were negative.\n\nDiscussion\nOcular DR presents as retinal hemorrhages and other fundoscopic changes following an acute lowering of IOP that cannot be explained by other processes [4]. The mean drop of IOP reported in the literature is 33.2 ± 15.8 mmHg (range, 4–57 mmHg) [12].\n\nOur patient had all the described characteristics of DR, including retinal hemorrhages, optic disc edema, macular edema, and decreased visual acuity. Previous reports have described a subset of these characteristics in other cases. An article review revealed that DR resolves between 2 and 72 weeks (mean ± standard deviation of 13 ± 12.4 weeks), which is in agreement with what happened in our case [12]. Visual outcomes are generally good, with baseline vision returning in 85 % of cases. Previous studies have reported a mean drop in visual acuity from 20/50 to 20/100, though for most patients no intervention is required [12]. In our patient, her BCVA dropped from 20/20 to 20/25, which does not represent a significant decrease and can be considered a favorable outcome.\n\nIn previously reported cases, fluorescein angiography demonstrated normal retinal and choroidal vascular filling [12], which could help distinguish DR from other conditions associated with intraretinal hemorrhages. One such case was reported by Bui et al., where OCT scans exhibited macular edema and neurosensory macular detachment in the context of DR after trabeculectomy; however, this is not a common event in this context [11, 16, 17].\n\nAll of these findings alert us to the importance of a complete fundoscopic examination immediately after surgery in patients undergoing trabeculectomy or other hypotensive techniques involving low pressure, especially when pre-surgical pressure is high.\n\nThe main differential diagnosis for DR involves retinopathy associated with Valsalva maneuver or venous occlusion. Our patient’s clinical characteristics (that is, her physical constitution) could suggest the first diagnosis; however, typical ocular findings are classically described as pre-retinal hemorrhages with predilection for the macula and possible vitreous hemorrhages. Additionally, this condition is usually simultaneously bilateral. Venous occlusion was ruled out because there was no angiographic evidence of venous dilatation, delayed venous filling, or occlusive phenomena as is expected in acute central retinal vein occlusion. Furthermore, DR appears in patients who are typically younger, asymptomatic, and whose fundus examinations show a full return to pre-event state. A benign idiopathic intracranial hypertension pattern was also considered, given that our patient was severely obese. This possibility was rejected, by the absence of not only typical clinical findings (headache, nausea, and vomiting) but also optic disc edema on preoperative fundus examination. Additionally, her intracranial pressure was in the high-normal range, which matched her biotype [18]. Although carotid doppler ultrasonography was not performed, the lack of venous dilatation, ocular pain, peripheral retinal hemorrhages, and retina and optic disc neovessels, as well as her good visual recovery, make the diagnosis of ocular ischemic syndrome less likely. The diagnosis of DR was based on her typical history, retinal findings, and the exclusion of the other possible causes mentioned above.\n\nCurrently, there is no consensus about the etiologic mechanisms of DR, though mechanical and vascular origins are likely. One of the possible mechanical explanations is that the decrease in IOP into the low-normal range after trabeculectomy may alter the intracranial pressure/IOP ratio at the lamina cribrosa, resulting in its anterior shift and expansion [1, 19]. This forward movement might block axonal transport, leading to compression of the central retinal vein and producing optic disc hemorrhages and edema. This may explain why DR shares similar clinical findings with central retinal vein occlusion [1, 6, 12, 14, 20].\n\nA likely vascular mechanism of DR is the loss of autoregulation of the retinal vessels due to longstanding glaucoma, which overwhelms their capacity to respond to changes in IOP (that is, reduced retinal arterial resistance causing an increased flow and leakage through fragile capillaries), resulting in retinal hemorrhage [1, 3, 7, 21]. Indeed, young individuals without hypertension or vasculopathy tolerate hemodynamic changes in choroidal vasculature very well. However, in patients in whom retinal vasculature autoregulation capacity might be impaired, DR can certainly occur.\n\nInterestingly, the fact that DR presented bilaterally probably denotes individual susceptibility, as it is based on vascular instability and pressure fluctuations.\n\nTo the best of our knowledge, this is the first case of consecutive bilateral DR after mitomycin C trabeculectomies in the context of open-angle glaucoma. This discussion on the mechanisms behind its appearance may help predict the occurrence of DR and thus suggest other surgical modalities for patients with glaucoma who are potentially at risk.\n\nConclusion\nDR is an exclusion diagnosis. Impaired autoregulation of the retinal vasculature, in which acute lowering of the IOP increases blood flow through the retinal capillary bed, leads to multiple focal leaks presenting as blot hemorrhages. Valsalva maneuver, transitory hypotony, and mechanical factors may play a role, either in combination or individually, in the pathogenesis of DR.\n\nFundoscopy reveals a multifocal hemorrhagic retinopathy possibly associated with optic disc or macular changes. Generally, the overall fundoscopic changes gradually fade without sequelae.\n\nAlthough DR infrequently results in significant ocular morbidity, a gradual reduction in IOP might prevent this complication [12]. Nevertheless, if a rapid reduction in IOP is critical to preserving vision, this goal should be pursued because DR tends to have a benign course with visual acuity returning to preoperative levels without any treatment.\n\nAlthough DR is a potential complication after glaucoma surgery, we are unaware of other published and individually discussed clinical case reports of a consecutive bilateral presentation.\n\nConsent\nWritten informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nAbbreviations\nBCVABest corrected visual acuity\n\nDRDecompression retinopathy\n\nIOPIntraocular pressure\n\nOCTOptical coherence tomography\n\nCompeting interests\n\nThe authors declare that they have no competing interests.\n\nAuthors’ contributions\n\nAF operated both eyes of the patient , wrote the original article as well as selected and organized the most important images of the case. IS followed the patient and proposed surgery. MJM analyzed and interpreted all the patient data. GS was a major contributor in writing the manuscript. All authors read and approved the final manuscript.\n\nAcknowledgements\nFernando Emanuel Dias Correia, Neurology Department, Centro Hospital do Porto, Hospital Santo de António, Porto, Portugal FC, performed the lumbar puncture. Maria João Furtado, Ophtalmology Department, Centro Hospitalar do Porto, Hospital de Santo António, performed angiograms and was very helpful in assisting the interpretation of angiographic images.\n==== Refs\nReferences\n1. Fechtner RD Minckler D Weinreb RN Frangei G Jampol LM Complications of glaucoma surgery. Ocular decompression retinopathy Arch Ophthalmol 1992 110 965 8 10.1001/archopht.1992.01080190071032 1637282 \n2. Juberías JR Maquet JA Ussa F Decompression retinopathy with maculopathy after trabeculectomy with mitomycin C Arch Soc Esp Oftalmol 2008 83 6 373 6 10.4321/S0365-66912008000600007 18521770 \n3. Bansal A Ramanathan US Ocular decompression retinopathy after trabeculectomy with mitomycin-C for angle recession glaucoma Indian J Ophthalmol 2009 57 2 153 4 10.4103/0301-4738.45510 19237794 \n4. Saricaoglu MS Kalayci D Guven D Karakurt A Hasiripi H Decompression retinopathy and possible risk factors Acta Ophthalmol 2009 87 1 94 5 10.1111/j.1600-0420.2007.01083.x 19053962 \n5. Kozobolis VP Kalogianni E Katsanos A Dardabounis D Koukoula S Labiris G Ocular decompression retinopathy after deep sclerectomy with mitomycin C in an eye with exfoliation glaucoma Eur J Ophthalmol 2011 21 3 324 7 10.5301/EJO.2010.5731 20872360 \n6. Landers J Craig J Decompression retinopathy and corneal oedema following Nd:YAG laser peripheral iridotomy Clin Exp Ophthalmol. 2006 34 182e4 \n7. Gupta R Browning AC Amoaku WM Multiple retinal haemorrhages (decompression retinopathy) following paracentesis for macular branch artery occlusion Eye. 2005 19 592 3 10.1038/sj.eye.6701530 15319789 \n8. Rezende F Regis LG Kicknger M Alcantara S Decompression retinopathy after 25- gauge transconjuntival sutureless vitrectomy: report of 2 cases Arch Ophthalmol. 2007 15 699 700 10.1001/archopht.125.5.699 17502513 \n9. Yalvac IS Kocaoglan H Eksioglu U Demir N Duman S Decompression retinopathy after Ahmed glaucoma valve implantation in a patient with congenital aniridia and pseudophakia J Cataract Refract Surg. 2004 30 1582e5 15210243 \n10. Samra KA Sieminski SF Sarup V Decompression retinopathy after ExPRESS shunt implantation for steroid-induced ocular hypertension: a case report Case Rep Ophthalmol Med. 2011 21 303287 22611508 \n11. Bui CM Recchia FM Recchia CC Kammer JA Optical coherence tomography findings in ocular decompression retinopathy Ophthalmic Surg Lasers Imaging. 2006 37 333 5 16898399 \n12. Mukkamala SK Patel A Dorairaj S McGlynn R Sidoti PA Weinreb RN Ocular decompression retinopathy: a review Surv Ophthalmol 2013 58 6 505 12 10.1016/j.survophthal.2012.11.001 24160727 \n13. Nonoyama S Tanito M Katsube T Matsuoka Y Ohira A Decompression retinopathy and serous retinal detachment after trabeculotomy in a patient with systemic amyloidosis Jpn J Ophthalmol 2009 53 1 73 5 10.1007/s10384-008-0606-y 19184321 \n14. Lai JS Lee VY Leung DY Cheung TC Decompression retinopathy following laser peripheral iridoplasty for acute primary angle closure Eye. 2005 19 1345e7 15618976 \n15. Wakita M Kawaji T Ando E Koga T Inatani M Tanihara H Ocular decompression retinopathy following trabeculectomy with mitomycin C associated with familial amyloidotic polyneuropathy Br J Ophthalmol. 2006 90 515 6 10.1136/bjo.2005.082735 16547341 \n16. Tyagi P Hashim A Ocular decompression retinopathy following post-trabeculectomy suture lysis and management with triamcinolone acetonide Int Ophthalmol. 2011 31 425 8 10.1007/s10792-011-9472-6 22057789 \n17. Danias J Rosenbaum J Podos SM Diffuse retinal hemorrhages (ocular decompression syndrome) after trabeculectomy with mitomycin C for neovascular glaucoma Acta Ophthalmol Scand 2000 78 4 468 9 10.1034/j.1600-0420.2000.078004468.x 10990054 \n18. Kawasaki A Purvin V Unilateral optic disc edema following trabeculectomy J Neuroophthalmol 1998 18 2 121 3 10.1097/00041327-199806000-00010 9621269 \n19. Lee EJ Kim TW Weinreb RN Reversal of lamina cribrosa displacement and thickness after trabeculectomy in glaucoma Ophthalmology 2012 119 7 1359e66 10.1016/j.ophtha.2012.01.034 22464141 \n20. Grieshaber MC Mozaffarieh M Flammer J What is the link between vascular dysregulation and glaucoma? Surv Ophthalmol 2007 52 Suppl 2 S144e54 17998040 \n21. Grunwald JE Riva CE Stone RA Keates EU Petrig BL Retinal autoregulation in open-angle glaucoma Ophthalmology. 1984 91 1690e4 6521997\n\n",
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"mesh_terms": "D003432:Cross-Linking Reagents; D003664:Decompression; D005260:Female; D005902:Glaucoma, Open-Angle; D006801:Humans; D008875:Middle Aged; D016685:Mitomycin; D010211:Papilledema; D012164:Retinal Diseases; D012166:Retinal Hemorrhage; D014130:Trabeculectomy",
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"title": "Consecutive bilateral decompression retinopathy after mitomycin C trabeculectomy: a case report.",
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"abstract": "Hydralazine, an arterial vasodilator, is a widely used medication for the management of hypertension and heart failure, especially for patients who cannot tolerate the use of ACEIs or ARBs. It is generally well-tolerated and has a safe profile in pregnancy. However, hydralazine can induce immune-mediated side effects, such as hydralazine-induced lupus and less commonly hydralazine- induced ANCA vasculitis. The latter most commonly affects the kidneys with or without other organ involvement. There are several cases reported in the literature of hydralazine-induced ANCA associated vasculitis (AAV) that have pulmonary manifestations, also known as hydralazine- induced pulmonary-renal syndrome (PRS), a condition with a high risk of mortality. We are reporting a case of Hydralazine-induced ANCA associated glomerulonephritis with severe diffuse alveolar hemorrhage (DAH). In addition, we will review the current literature and discuss the importance of prompt diagnosis and early management to decrease mortality and morbidity associated with this serious condition.",
"affiliations": "University of Texas Health Science Center at Houston, Houston, TX 77030, United States.;University of Massachusetts Medical School-Baystate, Springfield, MA 01655, United States.;University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, United States.;University of Texas Health Science Center at Houston, Houston, TX 77030, United States.;Overland Park Regional Medical Center-HCA Midwest Health, Overland Park, KS 66211, United States.;Department of Medicine, State University of New York, Downstate Medical Center, Brooklyn, NY 11203, United States.;Department of Medicine, State University of New York, Downstate Medical Center, Brooklyn, NY 11203, United States.",
"authors": "Doughem|Karim|K|;Battisha|Ayman|A|;Sheikh|Omar|O|;Konduru|Lakshmi|L|;Madoukh|Bader|B|;Al-Sadawi|Mohammed|M|;Shaikh|Shakil|S|",
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"fulltext": "\n==== Front\nCurr Cardiol Rev\nCurr Cardiol Rev\nCCR\nCurrent Cardiology Reviews\n1573-403X\n1875-6557\nBentham Science Publishers\n\n32418528\nCCR-17-182\n10.2174/1573403X16666200518092814\nArticle\nHydralazine-Induced ANCA Associated Vasculitis (AAV) Presenting with Pulmonary-Renal Syndrome (PRS): A Case Report with Literature Review\nDoughem Karim 1*\nBattisha Ayman 2\nSheikh Omar 3\nKonduru Lakshmi 1\nMadoukh Bader 4\nAl-Sadawi Mohammed 5\nShaikh Shakil 5\n1 University of Texas Health Science Center at Houston, Houston, TX77030, United States; 2University of Massachusetts Medical School-Baystate, Springfield, MA01655, USA; 3University of Texas Health Science Center at San Antonio, San Antonio, TX78229, USA; 4Overland Park Regional Medical Center-HCA Midwest Health, Overland Park, KS66211, USA; 5Department of Medicine, State University of New York, Downstate Medical Center, Brooklyn, NY11203, USA\n* Address correspondence to this author at University of Texas Health Science Center at Houston, Houston, TX 77030, United States; E-mail: Karim.Doughem@uth.tmc.edu\n3 2021\n3 2021\n17 2 182187\n16 12 2019\n29 2 2020\n23 3 2020\n© 2021 Bentham Science Publishers\n2021\nhttps://creativecommons.org/licenses/by-nc/4.0/ This is an open access article licensed under the terms of the Creative Commons Attribution-Non-Commercial 4.0 International Public License (CC BY-NC 4.0) (https://creativecommons.org/licenses/by-nc/4.0/legalcode), which permits unrestricted, non-commercial use, distribution and reproduction in any medium, provided the work is properly cited.\nHydralazine, an arterial vasodilator, is a widely used medication for the management of hypertension and heart failure, especially for patients who cannot tolerate the use of ACEIs or ARBs. It is generally well-tolerated and has a safe profile in pregnancy. However, hydralazine can induce immune-mediated side effects, such as hydralazine-induced lupus and less commonly hydralazine-induced ANCA vasculitis. The latter most commonly affects the kidneys with or without other organ involvement. There are several cases reported in the literature of hydralazine-induced ANCA associated vasculitis (AAV) that have pulmonary manifestations, also known as hydralazine-induced pulmonary-renal syndrome (PRS), a condition with a high risk of mortality. We are reporting a case of Hydralazine-induced ANCA associated glomerulonephritis with severe diffuse alveolar hemorrhage (DAH). In addition, we will review the current literature and discuss the importance of prompt diagnosis and early management to decrease mortality and morbidity associated with this serious condition.\n\nKeywords:\n\nHydralazine\nvasculitis\npulmonary hemorrhage\nhypertension\nheart failure\npulmonary-renal syndrome\n==== Body\n1. Introduction\n\nHydralazine is commonly used as an antihypertensive agent as well as an afterload reducer in patients with heart failure. The management of chronic heart failure has significantly improved after hydralazine gained mainstream use, especially when combined with nitrates [1]. However, the use of hydralazine can be associated with the development of autoimmune diseases, such as lupus-like syndrome, and less commonly, AAV. When such an association is found, hydralazine should be discontinued, and appropriate immunosuppressive treatment can be considered [2, 3]. A high index of suspicion and early identification of hydralazine-associated vasculitis is essential to prevent irreversible damage [3].\n\n2. Case Presentation\n\nA 75-year-old female with a past medical history significant for hypertension, hyperlipidemia, biopsy-proven Membranoproliferative Glomerulonephritis (MPGN), CKD Stage III, pulmonary hypertension, aortic stenosis and paroxysmal\n\natrial fibrillation initially presented to the hospital with acute kidney injury, generalized volume overload, and acute hypoxemic respiratory failure requiring intubation and mechanical ventilation. Chest X-Ray (Fig. 1) was remarkable for diffuse patchy bilateral airspace opacities and interstitial prominence concerning either atypical pulmonary edema or diffuse hemorrhage. CT scan (Fig. 2) showed consolidative opacities corresponding to the X-ray related opacities. Transthoracic echocardiogram revealed normal systolic function, mild diastolic dysfunction with preserved ejection fraction. Bronchoscopy with bronchoalveolar lavage confirmed the existence of diffuse pulmonary hemorrhage. Lung involvement was so severe that the patient required several bronchoscopies to aid suctioning of blood from the airways.\n\nRenal biopsy was performed in the setting of deteriorating renal function. While the patient had prior biopsy-proven membranoproliferative glomerulonephritis with immune-complex deposition on immunofluorescence, the new renal biopsy revealed pauci-immune focal crescentic glomerulonephritis. Immune workup showed highly elevated ANA titer (1:1280), positive anti-Histone and anti-MPO antibodies, low complements (C3 and C4), with normal serum immunofixation. Anti-ds-DNA, anti-Ro (SS-A) and anti-La (SS-B) antibodies were negative.\n\nOf note, the patient was using hydralazine among other medicines in the setting of difficult control of her hypertension secondary to her baseline kidney disease. She used 100 mg of hydralazine TID for 4 years. Hydralazine was discontinued, and the patient was started on pulse steroids, without significant clinical response. The patient was started on hemodialysis due to anuria. She was subsequently started on plasmapheresis and Rituximab for hydralazine-induced ANCA vasculitis treatment. The patient’s condition improved and was discharged to a skilled nursing facility to wean off supplemental oxygen requirements. Subsequent chest X-Ray showed improving airspace opacities. The patient survived, however, remained on outpatient scheduled dialysis without recovery of renal function, and was declared end-stage renal disease (ESRD) after 3 months.\n\n3. Discussion\n\nHydralazine was first introduced in the market in 1951. Despite its general tolerability, it was known to be associated with immune-mediated syndromes, especially Drug-Induced Lupus Erythematosus (DILE), which classically spares the kidneys, and lacks antibodies to ds-DNA [3]. The first case of hydralazine-induced lupus was reported in 1953 [4]. This was followed by the first reports of hydralazine-induced cutaneous vasculitis [5], and renal vasculitis [6] in 1980 and 1981, respectively. The first case report of hydralazine-induced glomerulonephritis was reported in 1983 [7]. Since then, hydralazine-related renal vasculitis has been well-described in the literature and was known to be associated with extra-renal manifestations [8]. Pulmonary involvement, however, had the strongest association with mortality [9]. The association of pulmonary symptoms with hydralazine-induced glomerulonephritis was first described in 1992 in a study by Almroth et al., which investigated seventeen patients with hydralazine-associated nephritis, out of which four patients were reported to have pulmonary symptoms including hemoptysis. In that study, all patients except one had positive anti-nuclear antibody (ANA) and twelve (out of fourteen tested) were positive for anti-myeloperoxidase (Anti-MPO). Anti-ds-DNA was negative in all of them [10]. Subsequent studies by Short [11], Choi [12], and Dobre [13] also reported associated pulmonary symptoms with hydralazine-induced glomerulonephritis; however, the term “pulmonary-renal syndrome” secondary to hydralazine use was first described by Yokogawa et al. in 2009 [8]. They identified 68 patients with hydralazine-induced nephritis and reported the first case of hydralazine-induced PRS with cutaneous involvement and gangrene. Idiopathic or autoimmune pulmonary-renal syndrome has been well-known in the literature and was associated with primary vasculitides, including, but not limited to Granulomatosis with Polyangiitis (GPA), Microscopic Polyangiitis (MPA), and Eosinophilic Granulomatosis with Polyangiitis (EGPA) [14]. Drug-induced pulmonary-renal syndrome was first reported in 1982 and was related to propylthiouracil use [15]. A review of all reported cases (to the best of our knowledge) of hydralazine-induced ANCA associated Pulmonary-Renal Syndrome is summarized in Table 1.\n\nThe risks for developing hydralazine-induced ANCA vasculitis include female gender, thyroid disease [16] and human leucocyte antigen (HLA)-DR4 genotype, slow hepatic acetylation, and null gene for C4 [17]. While the risk for hydralazine-induced ANCA vasculitis seems to be dose-dependent, PRS seems to be dose-independent. Based on our review of reported cases of hydralazine-induced PRS, hydralazine dosing ranging from 50 to 300 mg per day and the duration of therapy ranged from a few weeks to more than a decade. Some reported cases developed PRS within weeks [8] or years [18] after the hydralazine dose was increased. The majority of cases of hydralazine-induced PRS underwent kidney biopsy, which classically reveals pauci-immune crescentic glomerulonephritis (although other findings exist). None of the cases we reviewed had lung biopsy performed, however.\n\nAnti-MPO (p-ANCA) has been implicated in almost all cases of hydralazine-induced PRS to date. Anti-histone antibodies in hydralazine-induced PRS were first reported by Dobre in 2009 [13]. Weakly positive anti-PR3 was reported. The first case of hydralazine-induced PRS with predominant anti-PR3 (c-ANCA) and low titers of anti-MPO (p-ANCA) was first reported in 2014 [23].\n\nIn 2016, a study by Kumar et al. identified 323 patients diagnosed with ANCA-associated vasculitis from the beginning of 2001 till the end of 2016. Twelve patients were known to use hydralazine, out of which seven patients had bilateral pulmonary infiltrates. On our review of the supplementary material for this article, six patients had acute kidney injury at presentation (based on creatinine change from baseline), out of which three underwent kidney biopsy consistent with pauci-immune necrotizing glomerulonephritis with crescent formation (absent immune complexes). ANA and p-ANCA (anti-MPO) were positive in all seven patients, with only one patient with positive c-ANCA (anti-PR3). Anti-histone antibody was positive in six patients. Surprisingly, six patients were positive for anti-dsDNA, the youngest of which was 46 years old at the time of diagnosis. None of these seven patients had prior diagnosis of systemic lupus erythematosus or any other auto-immune condition. Anti-Smith antibody was either negative or not tested in all seven patients [30]. None of these patients was on other medications implicated in drug-induced ANCA vasculitis like propylthiouracil, minocycline, etc.\n\nThe pathophysiologic mechanism by which hydralazine induces an immune response is still not completely understood. The hypothesis most agreed upon is that hydralazine accumulates in cytoplasmic granules of neutrophils, with subsequent binding to myeloperoxidase, which leads to the release of cytotoxic products and cell death. This eventually exposes normally sequestered antigens to antigen-presenting cells (APCs) with subsequent production of anti-neutrophil cytoplasmic antibodies (ANCA) and anti-nuclear antibodies (ANA) [33]. This hypothesis might be supported by the fact that ANCA antibodies are usually specific to single ANCA antigen in idiopathic ANCA vasculitis, but are usually multispecific in drug-induced ANCA vasculitis, with other antibodies present like anti-elastase and anti-lactoferrin [2]. The cross-reactivity to elastase and lactoferrin, however, was often weak, and no cross-inhibition studies were performed, making it difficult to interpret these associations. In addition, it must be noted that circulating ANCA antibodies can exist in the absence of vasculitis in drug-induced lupus.\n\nThe hallmark of treatment of drug-induced ANCA vasculitis is the discontinuation of the culprit drug (e.g. hydralazine). Since no guidelines exist for management of hydralazine-induced vasculitis, further management is mainly stemmed from the available guidelines for the management of idiopathic ANCA vasculitis, which comprises immunosuppression with corticosteroids and biologics as well as plasmapheresis in severe cases. Cyclophosphamide has been widely used in most initial cases reported of hydralazine-induced AAV with PRS (Table 1). The first successful treatment of hydralazine-induced PRS with Rituximab was reported in a severely sick patient who required dialysis and ECMO [18]. According to the 2016 European League against Rheumatism/European Renal Association-European Dialysis Transplant Association (EULAR/ERA-EDTA) guidelines for the management of idiopathic ANCA-associated vasculitis, glucocorticoids plus Cyclophosphamide or Rituximab are recommended for remission-induction in life or organ threatening AAV. This includes pulmonary hemorrhage of any severity, cardiac involvement, meningeal involvement, and acute onset mononeuritis multiplex. In non-organ threatening situations, glucocorticoids plus Methotrexate or Mycophenolate Mofetil are recommended [34]. Plasmapheresis is generally recommended in life or organ-threatening situations, creatinine greater than 5.7 mg/dL, and severe diffuse alveolar hemorrhage. Based on (Plasma Exchange and Glucocorticoids for Treatment of Anti-Neutrophil Cytoplasm Antibody (ANCA) - Associated Vasculitis) or PEXIVAS trial in 2019, it was shown that plasma exchange did not reduce the risk of end-stage renal disease or mortality in patients with ANCA-associated vasculitis [35]. It also showed that reduced-dose glucocorticoids resulted in fewer serious infections and did not substantially increase the risk for end-stage renal disease or death compared to standard-dose glucocorticoids [36]. Ultrasound-guided percutaneous renal biopsy is recommended to support the diagnosis and management of AAV and has been shown to have a low risk of complications, such as hemorrhage [37]. Increased bleeding risk has been known to be associated with patients who received plasma exchange [38].\n\nConclusion\n\nPatients presenting with acute kidney injury of non-identifiable cause should raise clinical suspicion for prompt early initiation of immune workup and renal biopsy. A review of medication history is key to identifying the possible culprit drug (e.g. hydralazine) and discontinuing it. Additional treatment includes the use of immunosuppressant agents with or without plasmapheresis. Hydralazine-induced ANCA vasculitis and pulmonary–renal syndrome can be rapidly progressive and fatal. Although AAV is considered a rare condition, its actual incidence is questionable given an unknown number of unreported, missed, or undiagnosed cases in the setting of rapid progression and high mortality associated with this condition. Hydralazine has been well-implicated in AAV development as well as its life-threatening complications. Prompt diagnosis and treatment can be organ as well as life-saving.\n\nAcknowledgements\n\nDeclared none.\n\nConsent for Publication\n\nVerbal consent was obtained.\n\nFunding\n\nNone.\n\nConflict of Interest\n\nThe authors declare no conflict of interest, financial or otherwise.\n\nFig. (1) Initial Chest X-Ray showing bilateral airspace and interstitial opacities concerning atypical pulmonary edema of alveolar hemorrhage. (A higher resolution / colour version of this figure is available in the electronic copy of the article).\n\nFig. (2) CT scan of the chest without contrast showing consolidative opacity in the lateral basal left lower lobe, as well as small portion of the lingula. (A higher resolution / colour version of this figure is available in the electronic copy of the article).\n\nTable 1 Reported cases of Pulmonary-Renal Syndrome (PRS) secondary to Hydralazine-Induced ANCA Associated Vasculitis (AAV).\n\nYear\tAuthor(s)\tn\tHA Daily Dose (mg)\tHA Duration\tANA\tAnti-MPO\tAnti-PR3\tAHA\tAnti-DS-DNA\tAnti-GBM\tLow C3, C4\tTreatment*\tSurvived**\t\n1992\tAlmroth et al. [10]\t4\t50-200\t6 m -10 y\t4\t4\tN/A\tN/A\t0\tN/A\tN/A\tS(4), Cy (2), Az (1), P(1)\t3\t\n1995\tShort et al. [11]\t2\t75\t4-5 y\t2\t2\tN/A\tN/A\t0\tN/A\tN/A\tS(2), Cy(1)\tN/A\t\n2000\tChoi et al. [2]\t5\t100-200\t1-10 y\t4 or 5\t5\t0\tN/A\t0\tN/A\tN/A\tS(5), Cy(5)\t4\t\n2009\tDobre et al. [13]\t1\t225\t3 y\t1\t1\t1 (low)\t1\t1\tN/A\t0\tS, Cy\t1\t\n2009\tYokogawa et al. [8]\t1\t300\t16 m\t1\t1\tN/A\t1\t0\t0\t1\tS, Cy\t1\t\n2011\tMarina et al. [19]\t1\t150\t4 y\t1\t1\tN/A\t1\t0\t0\t0\tS, Cy\t0\t\n2012\tKalra et al. [20]\t1\t225\t2 y\t1\t1\tN/A\t1\t1\tN/A\t0\tS, Cy, MMF\t0\t\n2013\tKassa Y et al. [21]\t1\tN/A\tN/A\t1\tN/A\tN/A\tN/A\t1\tN/A\t0\tS, P, R\t0\t\n2014\tNamas et al. [22]\t1\t150\t3 y\t1\t1\t1 (low)\t1\t0\tN/A\t0\tS, Cy, P\t1\t\n2014\tAgarwal et al. [23]\t1\t300\t4.5 y\t1\t1\t1 (high)\t1\t0\t0\t1(slight)\tS, Cy\t1\t\n2016\tRasla et al. [24]\t1\t50\t6 y\tN/A\t1\tN/A\t1\tN/A\t0\t1\tS, Cy, P\t1\t\n2016\tBabar*** et al. [25]\t1\t50\tN/A\tN/A\t1\t0\t1\tN/A\tN/A\t0\tS, Cy, P\t0\t\n2016\tGoehler et al. [26]\t1\tN/A\tN/A\t0\t1\tN/A\tN/A\tN/A\tN/A\tN/A\tS, Cy, R\t1\t\n2016\tAl Ahwel et al. [27]\t1\tN/A\tN/A\t1\t1\tN/A\t1\tN/A\tN/A\t0\tS, P, R\t1\t\n2017\tPatel et al. [28]\t1\tN/A\t2 y\t1\t1\tN/A\t1\t0\t0\t0\tN/A\t0\t\n2017\tZuckerman et al. [29]\t2\t100-300\t6 w – 5 y\t1\t1\t1 (high)\t2\t1\t0\t1\tS(2), R(2), P(1)\t1\t\n2018\tKumar et al.**** [30]\t7\t100-300\t1-4 y\t7\t7\t1\t6\t6\t0/4\t3\tS(6), Cy(4), MMF(2)*****\t7\t\n2018\tAeddula et al. [31]\t1\tN/A\tN/A\t0\t1\t0\tN/A\tN/A\t0\t1(slight)\tS, R, P\t1\t\n2019\tNguyen et al. [32]\t1\tN/A\tN/A\t1\t1\t1\t1\t1\tN/A\tN/A\tS, R\t1\t\n2019\tPaley et al.[18]\t1\t300\t4 y\t1\t1\t0\t1\t1\t0\t1\tS, R\t1\t\nAbbreviations: HA: Hydralazine; ANA: antinuclear antibody; MPO: myeloperoxidase; PR3: proteinase 3; AHA: anti-histone antibody; Cy: Cyclophosphamide; R: Rituximab; S: Corticosteroids; P: plasmapheresis; Az: Azathioprine; MMF: mycophenolate mofetil; N/A: not available or not reported, n = number of cases per report or study.\n\n* Number in brackets represents the number of patients per study who received that treatment. No brackets if only one patient per report.\n\n** Survived acute setting and discharged (not to hospice) but might have died within months from other complications.\n\n*** Babar’s case did not clearly state pulmonary involvement but reported respiratory symptoms and multi-organ failure, which might have involved the lungs.\n\n**** Kumar’s study reported 8 cases with pulmonary involvement. We excluded one case as it had pleural effusion, but no pulmonary infiltrate.\n\n***** One of the two patients on MMF was already on baseline immunosuppression with MMF due to renal transplant.\n==== Refs\nReferences\n\n1 Farag M. Mabote T. Shoaib A. Hydralazine and nitrates alone or combined for the management of chronic heart failure: A systematic review. Int. J. Cardiol. 2015 196 61 69 10.1016/j.ijcard.2015.05.160 26073215\n2 Timlin H. Liebowitz J.E. Jaggi K. Geetha D. Outcomes of hydralazine induced renal vasculitis. Eur. J. Rheumatol. 2018 5 1 5 8 10.5152/eurjrheum.2017.17075 29657868\n3 Ihle B.U. Whitworth J.A. Dowling J.P. Kincaid-Smith P. Hydralazine and lupus nephritis. Clin. Nephrol. 1984 22 5 230 238 6240359\n4 Morrow J.D. Schroeder H.A. Perry H.M. Jr Studies on the control of hypertension by hyphex. II. Toxic reactions and side effects. Circulation 1953 8 6 829 839 10.1161/01.CIR.8.6.829 13106903\n5 Bernstein R.M. Egerton-Vernon J. Webster J. Hydralazine-induced cutaneous vasculitis. BMJ 1980 280 6208 156 157 10.1136/bmj.280.6208.156-a\n6 Ludmerer K. Renal failure, dyspnea and anemia in a 57 year old woman. Clinicopathologic conference. Am. J. Med. 1981 71 5 876 886 10.1016/0002-9343(81)90385-5 6458208\n7 Björck S. Westberg G. Svalander C. Mulec H. Rapidly progressive glomerulonephritis after hydralazine. Lancet 1983 2 8340 42 10.1016/S0140-6736(83)90021-1\n8 Yokogawa N. Vivino F.B. Hydralazine-induced autoimmune disease: Comparison to idiopathic lupus and ANCA-positive vasculitis. Mod. Rheumatol. 2009 19 3 338 347 10.3109/s10165-009-0168-y 19424772\n9 Hogan S.L. Nachman P.H. Wilkman A.S. Jennette J.C. Falk R.J. Prognostic markers in patients with antineutrophil cytoplasmic autoantibody-associated microscopic polyangiitis and glomerulonephritis. J. Am. Soc. Nephrol. 1996 7 1 23 32 8808106\n10 Almroth G. Eneström S. Hed J. Samuelsson I. Sjöström P. Autoantibodies to leucocyte antigens in hydralazine-associated nephritis. J. Intern. Med. 1992 231 1 37 42 10.1111/j.1365-2796.1992.tb00496.x 1310098\n11 Short A.K. Lockwood C.M. Antigen specificity in hydralazine associated ANCA positive systemic vasculitis. QJM 1995 88 11 775 783 8542262\n12 Choi H.K. Merkel P.A. Walker A.M. Niles J.L. Drug-associated antineutrophil cytoplasmic antibody-positive vasculitis: Prevalence among patients with high titers of antimyeloperoxidase antibodies. Arthritis Rheum. 2000 43 2 405 413 10.1002/1529-0131(200002)43:2<405:AID-ANR22>3.0.CO;2-5 10693882\n13 Dobre M. Wish J. Negrea L. Hydralazine-induced ANCA-positive pauci-immune glomerulonephritis: A case report and literature review. Ren. Fail. 2009 31 8 745 748 10.3109/08860220903118590 19814644\n14 Chung S.A. Seo P. Microscopic polyangiitis. Rheum. Dis. Clin. North Am. 2010 36 3 545 558 10.1016/j.rdc.2010.04.003 20688249\n15 Reidy T.J. Upshaw J.D. Jr Chesney T.M. Propylthiouracil-induced vasculitis: A fatal case. South. Med. J. 1982 75 10 1297 1298 10.1097/00007611-198210000-00044 7123315\n16 Herman L.L. Tivakaran V.S. Hydralazine. StatPearls Publishing 2020\n17 Lionaki S. Hogan S.L. Falk R.J. Association between thyroid disease and its treatment with ANCA small-vessel vasculitis: A case-control study. Nephrol. Dial. Transplant. 2007 22 12 3508 3515 10.1093/ndt/gfm493 17686815\n18 McKinnon R.A. Nebert D.W. Possible role of cytochromes P450 in lupus erythematosus and related disorders. Lupus 1994 3 6 473 478 10.1177/096120339400300608 7704004\n19 Paley M.A. Edrees F. Kudose S. Gaut J.P. Ranganathan P. Vijayan A. Successful use of rituximab for hydralazine-induced anti-neutrophil cytoplasmic antibodies-associated vasculitis. Saudi J. Kidney Dis. Transpl. 2019 30 1 226 230 10.4103/1319-2442.252915 30804286\n20 Marina V.P. Malhotra D. Kaw D. Hydralazine-induced ANCA vasculitis with pulmonary renal syndrome: a rare clinical presentation. Int. Urol. Nephrol. 2012 44 6 1907 1909 10.1007/s11255-011-9989-7 21590349\n21 Kalra A. Yokogawa N. Raja H. Hydralazine-associated vasculitis: Overlapping features of drug-induced lupus and vasculitis. Semin. Arthritis Rheum. 2012 48 2 283 287\n22 Kassa Y. Hydralazine (HY) induced antineutrophile cytoplasmic (ANCA) and antinuclear (ANA) positive pulmonary-renal syndrome (PRS). Am. J. Kidney Dis. 2013 61 4 B52\n23 Namas R. Rubin B. Adwar W. Meysami A. A challenging twist in pulmonary renal syndrome. Case Rep. Rheumatol. 2014 2014 516362 10.1155/2014/516362 25525550\n24 Agarwal G. Sultan G. Werner S.L. Hura C. Hydralazine induces myeloperoxidase and proteinase 3 anti-neutrophil cytoplasmic antibody vasculitis and leads to pulmonary renal syndrome. Case Rep. Nephrol. 2014 2014 868590 10.1155/2014/868590 25210633\n25 Rasla S El Meligy A Cucu DF 2016\n26 Babar F. Posner J.N. Obah E.A. Hydralazine-induced pauci-immune glomerulonephritis: Intriguing case series with misleading diagnoses. J. Community Hosp. Intern. Med. Perspect. 2016 6 2 30632 10.3402/jchimp.v6.30632 27124161\n27 Manne-Goehler J. Berwick J. Case of hydralazine-induced anca vasculitis. 2016\n28 Al Ahwel Y.A. Ali A. Kubbara A. Hydralazine induced hemoptysis. Am. J. Respir. Crit. Care Med. 2016 193 A1656\n29 Patel N.R. Castelino P.M. Ramasra E. Al-Khalisy H. Shingala H. Fatal autoimmune complication of hydralazine. Am. J. Respir. Crit. Care Med. 2017 195 A1468\n30 Zuckerman R. Patel M. Costanzo E.J. Hydralazine-associated adverse events: A report of two cases of hydralazine-induced ANCA vasculitis. J. Bras. Nefrol. 2018 40 2 193 197 10.1590/2175-8239-jbn-3858 29738027\n31 Kumar B. Strouse J. Swee M. Lenert P. Suneja M. Hydralazine-associated vasculitis: Overlapping features of drug-induced lupus and vasculitis. Semin. Arthritis Rheum. 2018 48 2 283 287 10.1016/j.semarthrit.2018.01.005 29519741\n32 Aeddula NR Pathireddy S Ansari A Juran PJ Hydralazine-associated antineutrophil cytoplasmic antibody vasculitis with pulmonary-renal syndrome. 2018\n33 Tsai-Nguyen G. Modrykamien A.M. Bredeweg A. Hereditary afibrinogenemia and pulmonary-renal hydralazine-induced vasculitis. Proc. Bayl. Univ. Med. Cent. 2019 32 3 397 398 10.1080/08998280.2019.1619397 31384199\n34 Hogan J.J. Markowitz G.S. Radhakrishnan J. Drug-induced glomerular disease: Immune-mediated injury. Clin. J. Am. Soc. Nephrol. 2015 10 7 1300 1310 10.2215/CJN.01910215 26092827\n35 Yates M. Watts R.A. Bajema I.M. EULAR/ERA-EDTA recommendations for the management of ANCA-associated vasculitis. Ann. Rheum. Dis. 2016 75 9 1583 1594 10.1136/annrheumdis-2016-209133 27338776\n36 Derebail V K Falk R J ANCA-Associated Vasculitis-Refining Therapy with Plasma Exchange and Glucocorticoids 2020\n37 Prasad N. Kumar S. Manjunath R. Real-time ultrasound-guided percutaneous renal biopsy with needle guide by nephrologists decreases post-biopsy complications. Clin. Kidney J. 2015 8 2 151 156 10.1093/ckj/sfv012 25815170\n38 Basic-Jukic N. Kes P. Glavas-Boras S. Brunetta B. Bubic-Filipi L. Puretic Z. Complications of therapeutic plasma exchange: Experience with 4857 treatments. Ther. Apher. Dial. 2005 9 5 391 395 10.1111/j.1744-9987.2005.00319.x 16202013\n\n",
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"issue": "17(2)",
"journal": "Current cardiology reviews",
"keywords": "Hydralazine; heart failure; hypertension; pulmonary hemorrhage; pulmonary-renal syndrome.; vasculitis",
"medline_ta": "Curr Cardiol Rev",
"mesh_terms": "D000368:Aged; D056648:Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; D005260:Female; D005921:Glomerulonephritis; D006333:Heart Failure; D006470:Hemorrhage; D006801:Humans; D006830:Hydralazine; D006973:Hypertension; D008168:Lung; D008171:Lung Diseases; D014665:Vasodilator Agents",
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"title": "Hydralazine-Induced ANCA Associated Vasculitis (AAV) Presenting with Pulmonary-Renal Syndrome (PRS): A Case Report with Literature Review.",
"title_normalized": "hydralazine induced anca associated vasculitis aav presenting with pulmonary renal syndrome prs a case report with literature review"
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"abstract": "The objective of this trial was to compare effectiveness of certolizumab pegol added to conventional synthetic DMARDs (csDMARDs) in RA patients, followed by continuing vs discontinuing background csDMARDs after treatment response.\n\n\n\nPatients with active RA who had certolizumab pegol added to their existing csDMARD regimen due to inadequate response were eligible. At 3 or 6 months, patients who achieved a change (Δ) in DAS28 of ⩾1.2 were randomized to continue combination therapy (COMBO) or withdraw csDMARD therapy (MONO) (unblinded). The primary outcome was non-inferiority of stopping vs continuing csDMARD(s) in terms of maintaining ΔDAS28 ⩾ 1.2 or achieving DAS28 low disease activity at 18 months (non-inferiority margin: 15 percentile units).\n\n\n\nA total of 125 patients were enrolled, 88 randomized to COMBO (n = 43) or MONO (n = 45). No significant differences were observed between groups in baseline age, gender, race, RF status or prior biologics (16% vs 11%). Although the rate of ΔDAS28 ⩾ 1.2 and/or DAS28 low disease activity achievement at 18 months was clinically comparable between the two groups (72% vs 69%), non-inferiority assumptions were not met [absolute risk difference (upper limit of 90% CI): 2.6% (19.1%)]. Similar baseline-adjusted improvements were seen in DAS28 (COMBO vs MONO: -2.3 vs -2.1; P = 0.49) and all endpoints were not statistically different including 59% vs 56% achieved DAS28 low disease activity, 69% vs 59% ΔDAS28 ⩾ 1.2, and 41% each remission.\n\n\n\nAmong RA patients achieving a therapeutic response on combination therapy with certolizumab pegol and csDMARDs, withdrawing csDMARDs was not non-inferior to maintaining csDMARDs but improvements were sustained in both groups at 18 months.",
"affiliations": "Department of Medicine, University of Western Ontario, ON.;Medical Affairs, JSS Medical Research, Montréal, QC.;Medical Affairs, JSS Medical Research, Montréal, QC.;Department of Medicine, Laval University, Québec, QC.;Department of Medicine, Dalhousie University, Saint John, NB.;Institut de Rhumatologie de Montréal, Montréal, QC.;Medical Affairs, JSS Medical Research, Montréal, QC.",
"authors": "Pope|Janet|J|;Rampakakis|Emmanouil|E|;Vaillancourt|Julie|J|;Bessette|Louis|L|;Lazovskis|Juris|J|;Haraoui|Boulos|B|;Sampalis|John S|JS|",
"chemical_list": "D018501:Antirheumatic Agents; D000079424:Tumor Necrosis Factor Inhibitors; D012460:Sulfasalazine; D006886:Hydroxychloroquine; D000077339:Leflunomide; D000068582:Certolizumab Pegol; D008727:Methotrexate",
"country": "England",
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"doi": "10.1093/rheumatology/kez470",
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"issue": "59(7)",
"journal": "Rheumatology (Oxford, England)",
"keywords": "DMARD; TNF; biologics; certolizumab pegol; observational; real-world; rheumatoid arthritis",
"medline_ta": "Rheumatology (Oxford)",
"mesh_terms": "D000328:Adult; D000368:Aged; D018501:Antirheumatic Agents; D001172:Arthritis, Rheumatoid; D000068582:Certolizumab Pegol; D000069340:Deprescriptions; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D006886:Hydroxychloroquine; D000077339:Leflunomide; D008297:Male; D008727:Methotrexate; D008875:Middle Aged; D012460:Sulfasalazine; D000079424:Tumor Necrosis Factor Inhibitors",
"nlm_unique_id": "100883501",
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"pubdate": "2020-07-01",
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"references": null,
"title": "An open-label randomized controlled trial of DMARD withdrawal in RA patients achieving therapeutic response with certolizumab pegol combined with DMARDs.",
"title_normalized": "an open label randomized controlled trial of dmard withdrawal in ra patients achieving therapeutic response with certolizumab pegol combined with dmards"
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"abstract": "OBJECTIVE\nThis paper reports a case of chorioamnionitis due to Morganella morganii in a mother who presented with ruptured membranes at 24 weeks' gestation and was treated with dexamethasone and prophylactic ampicillin. Her premature infant developed severe early onset infection due to the same organism and expired.\n\n\nMETHODS\nA clinical case report of M. morganii infection complicating preterm rupture of membranes is presented. Possible risk factors for maternal and neonatal infection with this organism as well as the therapy of neonatal M. morganii infection are discussed.\n\n\nRESULTS\nRisk factors in the mother included having a cervical cerclage in place and treatment with dexamethasone and prophylactic ampicillin. The major risk factors in the infant were maternal chorioamnionitis and extreme prematurity. The mother responded to treatment with ampicillin, metronidazole, and gentamicin following delivery and had an uncomplicated recovery. Her infant developed severe early onset M. morganii infection complicated by neutropenia, thrombocytopenia, and severe acidosis and expired. Postmortem cultures of pleural fluid, peritoneal fluid, and blood were positive despite treatment with gentamicin, an antibiotic to which the organism was sensitive.\n\n\nCONCLUSIONS\nM. morganii may cause serious infection in pregnancy and in the neonatal period. The use of dexamethasone and prophylactic ampicillin may have increased the risk of infection with this ampicillin-resistant organism. The failure of gentamicin to sterilize the infant's blood and body fluids emphasizes the necessity of treating such infections with a combination of an aminoglycoside and a third-generation cephalosporin, such as cefotaxime.",
"affiliations": "Department of Pediatrics, State University of New York, Health Science Center at Brooklyn, USA.",
"authors": "Ranu|S S|SS|;Valencia|G B|GB|;Piecuch|S|S|",
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"issue": "19(7)",
"journal": "Journal of perinatology : official journal of the California Perinatal Association",
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"mesh_terms": "D000328:Adult; D000667:Ampicillin; D000893:Anti-Inflammatory Agents; D002821:Chorioamnionitis; D003907:Dexamethasone; D004756:Enterobacteriaceae Infections; D017809:Fatal Outcome; D005260:Female; D005322:Fetal Membranes, Premature Rupture; D006801:Humans; D007230:Infant, Low Birth Weight; D007231:Infant, Newborn; D018445:Infectious Disease Transmission, Vertical; D020613:Morganella morganii; D010403:Penicillin Resistance; D010406:Penicillins; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious",
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"title": "Fatal early onset infection in an extremely low birth weight infant due to Morganella morganii.",
"title_normalized": "fatal early onset infection in an extremely low birth weight infant due to morganella morganii"
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"abstract": "Carcinoid crisis is a life-threatening manifestation of carcinoid syndrome characterized by profound autonomic instability in the setting of catecholamine release from stress, tumor manipulation, or anesthesia. Here, we present an unusual case of carcinoid crisis leading to acute systolic heart failure requiring mechanical circulatory support. (Level of Difficulty: Intermediate.).",
"affiliations": "Department of Medicine, University of California, San Francisco, San Francisco, California.;Department of Anesthesia and Perioperative Care, University of California-San Francisco, San Francisco, California.;Department of Medicine, Division of Cardiology, University of California-San Francisco, San Francisco, California.;Department of Medicine, University of California, San Francisco, San Francisco, California.;Department of Medicine, Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, University of California-San Francisco, San Francisco, California.;Department of Anesthesia and Perioperative Care, University of California-San Francisco, San Francisco, California.;Department of Medicine, Division of Hematology and Medical Oncology, University of California-San Francisco, San Francisco, California.;Department of Radiology and Biomedical Imaging, University of California-San Francisco, San Francisco, California.;Department of Medicine, Division of Cardiology, University of California-San Francisco, San Francisco, California.",
"authors": "Maddali|Manoj V|MV|;Chiu|Catherine|C|;Cedarbaum|Emily R|ER|;Yogeswaran|Vidhushei|V|;Seedahmed|Mohamed|M|;Smith|Wendy|W|;Bergsland|Emily|E|;Fidelman|Nicholas|N|;Kennedy|Jamie L W|JLW|",
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"doi": "10.1016/j.jaccas.2020.08.026",
"fulltext": "\n==== Front\nJACC Case Rep\nJACC Case Rep\nJACC Case Reports\n2666-0849\nElsevier\n\nS2666-0849(20)31102-5\n10.1016/j.jaccas.2020.08.026\nMini-Focus Issue: Cardiomyopathies and Myocarditis\nCase Report: Clinical Case\nCarcinoid Crisis–Induced Acute Systolic Heart Failure\nMaddali Manoj V. MD manoj.maddali@ucsf.edu\na∗\nChiu Catherine MD b\nCedarbaum Emily R. MD c\nYogeswaran Vidhushei MD a\nSeedahmed Mohamed MD d\nSmith Wendy MD b\nBergsland Emily MD e\nFidelman Nicholas MD f\nKennedy Jamie L.W. MD c\na Department of Medicine, University of California, San Francisco, San Francisco, California\nb Department of Anesthesia and Perioperative Care, University of California-San Francisco, San Francisco, California\nc Department of Medicine, Division of Cardiology, University of California-San Francisco, San Francisco, California\nd Department of Medicine, Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, University of California-San Francisco, San Francisco, California\ne Department of Medicine, Division of Hematology and Medical Oncology, University of California-San Francisco, San Francisco, California\nf Department of Radiology and Biomedical Imaging, University of California-San Francisco, San Francisco, California\n∗ Address for correspondence: Dr. Manoj V. Maddali, University of California-San Francisco, 505 Parnassus Avenue, Room M-1480, Box 0119, San Francisco, California 94143. manoj.maddali@ucsf.edu\n28 10 2020\n11 2020\n28 10 2020\n2 13 20682071\n1 7 2020\n7 8 2020\n17 8 2020\n© 2020 The Authors\n2020\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).\nCarcinoid crisis is a life-threatening manifestation of carcinoid syndrome characterized by profound autonomic instability in the setting of catecholamine release from stress, tumor manipulation, or anesthesia. Here, we present an unusual case of carcinoid crisis leading to acute systolic heart failure requiring mechanical circulatory support. (Level of Difficulty: Intermediate.)\n\nGraphical abstract\n\nKey Words\n\nacute heart failure\ncardiac assist devices\ninotropes\nAbbreviations and Acronyms\n\nCI, cardiac index\nSVR, systemic vascular resistance\nTACE, transcatheter arterial chemoembolization\n==== Body\nHistory of Present Illness\n\nA 59-year-old woman with a stage IV, World Health Organization grade 2 ileal neuroendocrine tumor was referred for transcatheter arterial chemoembolization (TACE) of extensive bilobar hepatic metastases (Figure 1A). Two years prior, she underwent ileocolectomy and began octreotide depot injections (escalated to 60 mg/month) to manage diarrhea and flushing from carcinoid syndrome. Transthoracic echocardiography performed 1 month prior to TACE revealed normal biventricular size and function.Learning Objectives\n\n• To review and be aware of the perioperative management of carcinoid crisis.\n\n• To discuss the management of acute systolic heart failure in the setting of carcinoid crisis.\n\n• To recognize how high-dose octreotide could exacerbate cardiogenic shock.\n\nFigure 1 Contrast-Enhanced Computed Tomography of the Abdomen\n\n(A) Before transcatheter arterial chemoembolization (TACE), with nearly 70% of liver parenchyma replaced by hepatic metastases. (B) Two weeks post-TACE, with extensive hepatic necrosis of both embolized and untreated lesions.\n\nThe patient’s admission vital signs were normal. Pre-operative findings were unremarkable aside from mildly abnormal liver function test results. Pre-procedurally, she received an octreotide infusion at 150 μg/h as well as H1- and H2-blockers for carcinoid syndrome prophylaxis. During the TACE procedure, performed under general anesthesia, an emulsion of doxorubicin and mitomycin followed by embolization was administered to the largest lesions in hepatic segments 2 and 4. Her intraoperative course was notable for tachycardia and hypertension managed with beta-blockade. Given concern for carcinoid crisis secondary to TACE, the patient’s octreotide infusion was increased to 300 μg/h. The procedure was completed uneventfully, and she was admitted to the hospital for a planned 24-h course of continuous octreotide at 150 μg/h followed by subcutaneous injections of octreotide 150 μg 3 times daily until discharge. Within 12 h of hospital admission, the patient developed progressive shock and respiratory failure requiring high-flow nasal cannula. Physical examination disclosed bilateral rales, cool extremities, and tachycardia without murmurs or jugular venous distension.\n\nMedical History\n\nThe patient additionally had a history of hypertension, hyperlipidemia, and depression.\n\nDifferential Diagnosis\n\nDifferential diagnosis included cardiogenic shock from acute coronary syndrome, acute systolic heart failure, and carcinoid crisis.\n\nInvestigations\n\nLactate was 4.8 mmol/l (normal range: 0.5 to 2.2 mmol/l), troponin 6.5 μg/l (normal range <0.05 μg/l), and B-type natriuretic peptide 475 pg/ml (normal range <82 pg/ml). Chest radiography revealed new diffuse interstitial opacities consistent with pulmonary edema. Electrocardiography showed sinus tachycardia with new ST-segment elevation and T-wave inversions in leads V1 and V2. Transthoracic echocardiography disclosed severely depressed left ventricular function (ejection fraction <20%) with akinesis of apical segments and preserved contraction of basal segments (Videos 1A and 1B).\n\nManagement\n\nDobutamine and vasopressin were administered for cardiogenic shock. The patient was emergently taken to the cardiac catherization laboratory for coronary angiography, which revealed diffuse coronary vasospasm without significant atherosclerotic plaques (Figure 2, Videos 2A and 2B). On inopressors, her cardiac index (CI) by thermodilution was 1.15 l/min/m2, left ventricular end-diastolic pressure 40 mm Hg, and systemic vascular resistance (SVR) 5,213 dyn·s·cm−5. Because of concern for catecholamine excess, the dobutamine and vasopressin infusions were discontinued in favor of milrinone and nitroprusside. The patient’s CI improved to 1.44 l/min/m2 during the peak nitroprusside challenge. The octreotide infusion was increased to 500 μg/h, and intermittent octreotide boluses of 500 μg were administered to widen her narrow pulse pressure from presumed catecholamine-driven vasoconstriction.Figure 2 Coronary Angiogram With Femoral Arterial Access\n\n(A) Right coronary artery angiography showing diffuse vasospasm. (B) Left coronary artery angiography showing diffuse vasospasm throughout the left main coronary artery, left anterior descending coronary artery, and left circumflex coronary artery.\n\nDespite these interventions, cardiogenic shock persisted (CI 1.3 to 1.5 l/min/m2), resulting in anuric renal failure necessitating continuous renal replacement therapy. The troponin level rose above the laboratory’s upper limit of detection (>81 μg/l). The patient thus returned to the cardiac catherization laboratory several hours later for placement of a percutaneous axillary ventricular assist device (Impella CP, Abiomed, Danvers, Massachusetts) under general anesthesia. Despite Impella flow rates of 3.5 l/min with mean arterial pressure of 60 to 70 mm Hg, her cardiac output as measured by thermodilution remained <2.0 l/min, with SVR of 3,700 dyn·s·cm−5. This discrepancy was believed to be due to severe systemic vasoconstriction exacerbated by high doses of octreotide. As a result, the octreotide infusion was slowly weaned to 50 μg/h. With unchanged Impella settings, cardiac output measured by thermodilution improved to 3.3 l/min, and SVR decreased to 1,500 dyn·s·cm−5.\n\nOver the following week, the patient’s cardiac function completely recovered, permitting discontinuation of milrinone and removal of the Impella device (Video 1C). She was extubated to ambient air. She required hemodialysis for 5 weeks. Chromogranin A level decreased from 10,000 ng/ml (normal range 0 to 160 ng/ml) prior to TACE to 3,000 ng/ml on post-operative day 21. Contrast-enhanced computed tomography performed 2 weeks following TACE showed extensive necrosis of both untreated and embolized liver lesions (Figure 1B). The patient’s hospital course was complicated by delirium, critical illness myopathy, upper gastrointestinal bleeding, and small bowel obstruction, all of which were managed conservatively.\n\nDiscussion\n\nAcute systolic heart failure due to carcinoid crisis has been rarely described, with catecholamine excess postulated as a potential etiology (1). Our patient’s markedly elevated troponin levels suggested widespread cardiac ischemia resulting in apical akinesis and severe global hypokinesis. This was likely driven by diffuse coronary vasospasm from carcinoid crisis–induced serotonin and catecholamine surge. We thus opted for noncatecholamine inopressors, afterload reduction, and temporary mechanical circulatory support to minimize iatrogenic catecholamine toxicity. We simultaneously treated carcinoid crisis with high-dose octreotide infusion.\n\nOctreotide has been used for both carcinoid crisis prophylaxis and treatment. Pre-operative prophylaxis with subcutaneous octreotide (150 to 500 μg) is often administered either immediately pre-operatively or up to 2 weeks pre-procedurally (2). Prophylactic octreotide infusion of 50 to 100 μg/h and treatment infusion of up to 300 μg/h have both been described (3). Notably, tachyphylaxis to octreotide can occur. Our patient required progressively higher doses of octreotide than have been previously described (4).\n\nAlthough important for the management of carcinoid crises, the physiological effects of octreotide carry some risk. Increased systemic and pulmonary pressures and decreased cardiac output can occur within 30 min of intravenous octreotide administration (5). As our patient’s carcinoid crisis resolved, the high-dose octreotide infusion likely contributed to markedly elevated SVR. Like all mechanical circulatory support devices, the ability of the Impella CP device to provide forward flow (up to 4.0 l/min) is sensitive to systemic afterload, with higher left ventricular–aortic pressure gradients resulting in lower pump flow (6). In this case, severe systemic vasoconstriction contributed to persistently low cardiac output despite mechanical circulatory support. While on high-dose octreotide, our patient’s cardiac output measured by thermodilution (1.8 l/min) was consistently lower than the flow reported on the Impella monitor (3.5 l/min). This mismatch resolved once the octreotide infusion was weaned and SVR improved.\n\nFinally, our patient’s cardiogenic shock likely contributed to worsened carcinoid crisis through positive feedback mechanisms. The extent of hepatic tumor necrosis seen on subsequent imaging was more pronounced than expected after focal TACE. This suggests that severe hepatic hypoperfusion from cardiogenic shock triggered diffuse necrosis of liver metastases supplied exclusively by the hepatic artery (Figure 1B). This extensive tumor necrosis markedly increased the severity and duration of the carcinoid crisis, which in turn increased the severity of cardiac failure.\n\nFollow-Up\n\nThe patient was discharged to a rehabilitation facility after a 7-week hospitalization. Four months following TACE, the patient reported no symptoms of the carcinoid syndrome. Her cardiac and renal function have recovered, and she continues to rehabilitate from her critical illness myopathy.\n\nConclusions\n\nThis case offers several insights into the diagnosis and management of circulatory failure from carcinoid crisis. We are among the first to describe acute systolic heart failure from carcinoid crisis due to both catecholamine excess and diffuse coronary vasospasm. We postulate that noncatecholamine inopressors and mechanical circulatory support can mitigate iatrogenic catecholamine excess. Our experience indicates that high-dose octreotide administration can result in increased systemic afterload that worsens circulatory shock and limits the efficacy of mechanical circulatory support devices. Clinicians should maintain a high index of suspicion for iatrogenic systemic vasoconstriction when administering high-dose octreotide for carcinoid crisis.\n\nAuthor Disclosures\n\nPublication was made possible in part by support from the University of California-San Francisco Open Access Publishing Fund. Dr. Bergsland has received royalties from UpToDate; and has received research funding from Novartis and Lexicon. Dr. Fidelman has received research funding from Merck, BTG, and Sirtex Medical. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.\n\nAppendix\n\nVideo 1A\n\nTransthoracic Echocardiography, Apical 4-Chamber View, During Acute Heart Failure Phase\n\nVideo 1B\n\nTransthoracic Echocardiography, Apical 4-Chamber View, During Acute Heart Failure Phase, With Color Doppler Showing Mild Mitral Regurgitation\n\nVideo 1C\n\nTransthoracic Echocardiography, Apical 4-Chamber View, During Recovery Phase\n\nVideo 2A\n\nSelective Coronary Angiography of the Right Coronary Artery\n\nVideo 2B\n\nSelective Coronary Angiography of the Left Main Coronary Artery, Left Anterior Descending Coronary Artery, and Left Circumflex Coronary Artery\n\nThe authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the JACC: Case Reportsauthor instructions page.\n\nAppendix\n\nFor supplemental videos, please see the online version of this paper.\n==== Refs\nReferences\n\n1 Mehta N.K. Aurigemma G. Rafeq Z. Starobin O. Reverse takotsubo cardiomyopathy: after an episode of serotonin syndrome Tex Heart Inst J 38 2011 568 572 22163138\n2 Kaltsas G. Caplin M. Davies P. ENETS consensus guidelines for the standards of care in neuroendocrine tumors: pre- and perioperative therapy in patients with neuroendocrine tumors Neuroendocrinology 105 2017 245 254 28253514\n3 Castillo J. Silvay G. Weiner M. Anesthetic management of patients with carcinoid syndrome and carcinoid heart disease: the Mount Sinai algorithm J Cardiothorac Vasc Anesth 32 2018 1023 1031 29273478\n4 Seymour N. Sawh S.C. Mega-dose intravenous octreotide for the treatment of carcinoid crisis: a systematic review Can J Anaesth 60 2013 492 499 23328959\n5 McCormick P.A. Chin J. Greenslade L. Cardiovascular effects of octreotide in patients with hepatic cirrhosis Hepatology 21 1995 1255 1260 7737631\n6 Lawson W.E. Koo M. Percutaneous ventricular assist devices and ECMO in the management of acute decompensated heart failure Clin Med Insights Cardiol 9 2015 41 48 25983563\n\n",
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"title": "Carcinoid Crisis-Induced Acute Systolic Heart Failure.",
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"abstract": "Takotsubo or stress cardiomyopathy is a non ischemic disease affecting the myocardium, which presents with typical features of myocardial ischemia. Although the presentation with acute central chest pain and shortness of breath mimics acute myocardial ischemia, there is an absence of actual disruption of cardiac blood supply via the coronaries due to acute plaque rupture or vascular spasm. The underlying pathophysiology of this clinical entity remains largely unclear, but a definite association with physical or emotional stress has been well established, hence the term \"stress cardiomyopathy.\" The list of potential triggers continues to grow as the disorder is increasingly detected by clinicians and cardiologists, with better clinical insight and improved availability of cardiac investigations. We report a patient with Takotsubo cardiomyopathy associated with severe hyponatremia.",
"affiliations": "Colombo North Teaching Hospital, Ragama, Sri Lanka.;Colombo North Teaching Hospital, Ragama, Sri Lanka.;Colombo North Teaching Hospital, Ragama, Sri Lanka.",
"authors": "Perera|Irushna|I|https://orcid.org/0000-0003-1051-9570;Rajapakse|Sanjeewa|S|;De Silva|Shamila T|ST|",
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"fulltext": "\n==== Front\nCase Rep Cardiol\nCase Rep Cardiol\nCRIC\nCase Reports in Cardiology\n2090-6404 2090-6412 Hindawi \n\n10.1155/2020/2961856\nCase Report\nSevere Hyponatremia-Induced Stress Cardiomyopathy: A Case Report and Review of Literature\nhttps://orcid.org/0000-0003-1051-9570Perera Irushna irushna.p@gmail.com\n1\n Rajapakse Sanjeewa \n1\n De Silva Shamila T. \n1\n\n2\n \n1Colombo North Teaching Hospital, Ragama, Sri Lanka\n\n2Faculty of Medicine, University of Kelaniya, Sri Lanka\nAcademic Editor: Kathleen Ngu\n\n\n2020 \n31 3 2020 \n2020 296185622 11 2019 23 1 2020 21 3 2020 Copyright © 2020 Irushna Perera et al.2020This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Takotsubo or stress cardiomyopathy is a non ischemic disease affecting the myocardium, which presents with typical features of myocardial ischemia. Although the presentation with acute central chest pain and shortness of breath mimics acute myocardial ischemia, there is an absence of actual disruption of cardiac blood supply via the coronaries due to acute plaque rupture or vascular spasm. The underlying pathophysiology of this clinical entity remains largely unclear, but a definite association with physical or emotional stress has been well established, hence the term “stress cardiomyopathy.” The list of potential triggers continues to grow as the disorder is increasingly detected by clinicians and cardiologists, with better clinical insight and improved availability of cardiac investigations. We report a patient with Takotsubo cardiomyopathy associated with severe hyponatremia.\n==== Body\n1. Introduction\nTakotsubo cardiomyopathy is a potentially reversible disorder affecting the myocardium. It is characterized by transient apical ballooning of the left ventricle, evident on transthoracic echocardiography. Typically, the disease is seen in postmenopausal women, who present with central tightening chest pain and shortness of breath, with electrocardiographic changes which mimic coronary artery disease and a mild elevation of cardiac enzymes [1]. The condition is usually benign and has a self-limiting course, with recovery within days to weeks following removal of the emotional or physical trigger. Rarely, the syndrome may be complicated by lethal ventricular arrhythmias or ventricular rupture [2].\n\n2. Case Report\nA 73-year-old woman was admitted to the Emergency Department with vomiting, diarrhea, and confusion for two days. She had been generally unwell during the preceding two weeks, with poor oral intake. She had also developed a few presyncopal episodes during this time, but she had not lost consciousness. She denied chest pain or fever. She was on treatment for hypertension with verapamil, losartan, and spironolactone, along with atorvastatin for elevated lipids.\n\nOn admission, she was unwell, with a heart rate of 100 beats/minute, blood pressure of 140/90 mmHg, peripheral oxygen saturation of 97% breathing ambient air, and respiratory rate of 25 breaths/minute. She did not appear dehydrated. Electrocardiogram revealed ST segment elevations in leads I, II, aVF, and V3 to V6. A cardiac biomarker assay revealed a Troponin I of 0.343 ng/ml (upper limit of reference 0.04 ng/ml). She was initiated on treatment for an acute coronary event, with loading doses of oral aspirin, clopidogrel, atorvastatin, and subcutaneous low molecular weight heparin. Echocardiography revealed apical ballooning of the left ventricle (Figure 1) with mild left ventricular systolic dysfunction, suggestive of stress cardiomyopathy. However, treatment of a presumed acute coronary event was continued.\n\nShe was severely hyponatremic, with serum sodium of 104 mmol/L. Serum potassium was 3.7 mmol/L, and serum chloride was 72 mmol/L. As the patient was symptomatic, serum sodium was corrected slowly, with 3% saline infusions over a few days. Concurrently, all medications liable to cause sodium depletion were withheld.\n\nThe day after admission, the patient developed a transient drop in blood pressure, which was managed with inotrope support for 18 hours, following which her hemodynamic status remained stable.\n\nWith the slow correction of serum sodium and treatment of a presumed acute coronary event, the patient's general condition improved, but she continued to have a residual amount of confusion. A psychiatry consultation was requested, and a diagnosis of a mixed anxiety, and depressive disorder was made. However, no drug treatment was given for her psychiatric illness, since the consulting psychiatrist felt counseling alone would be sufficient treatment.\n\nA coronary angiogram was performed which failed to reveal any obstruction to the coronary blood flow (Figure 2), and a subsequent echocardiogram revealed a completely recovered myocardium with a left ventricular ejection fraction of 60% (Figure 3). These finding make stress cardiomyopathy the most likely diagnosis, possibly triggered by severe hyponatremia.\n\nInvestigations to identify the cause of hyponatremia revealed a serum osmolality of 234 mOsm/L, a urinary osmolality of 597 mOsm/L, and a urinary sodium excretion of 145 mmol/L. There was no evidence of renal or hepatic derangement, and thyroid functions were normal, making the syndrome of inappropriate ADH secretion (SIADH) a possible cause for hyponatremia. However, as the patient was on long-term angiotensin converting enzyme inhibitors and spironolactone for hypertension, a complex interplay of mechanisms could possibly have resulted in severe hyponatremia. Over the next six months at follow-up visits, the patient remained well, with normal serum sodium levels.\n\n3. Discussion\nTakotsubo cardiomyopathy is a syndrome characterized by transient, regional, systolic dysfunction of the left ventricle, mimicking regional wall motion abnormalities seen in coronary artery disease, but with absence of angiographic evidence of coronary artery obstruction [3]. The entity is also known as the apical ballooning syndrome due to its characteristic appearance on echocardiography and left ventriculography. Takotsubo in Japanese means “a fishing pot for trapping octopus,” similar in shape to the left ventricle in patients with this condition [4]. Usually, the regional wall motion abnormality extends beyond the territory perfused by a single coronary artery [5].\n\nThe pathophysiology of Takotsubo cardiomyopathy remains poorly understood, even though numerous theories on its pathogenesis have been proposed. One of the postulated mechanisms is a surge of catecholamines in the circulation resulting in a stunned myocardium, microvascular dysfunction, and spasm of coronary arteries [1]. The proposed role of a catecholamine surge in the development of Takotsubo cardiomyopathy has been observed where cardiomyopathy has developed with infusions of noradrenaline and dopamine, initiated for causes other than cardiogenic shock [6, 7]. Limited data is available on possible triggers, even though the list keeps growing with increasing recognition of the disorder. Commonly, the onset follows intense emotional or physical stress. However, a few cases of Takotsubo cardiomyopathy associated with endocrine abnormalities and electrolyte disturbances have been described, where hyponatremia-associated Takotsubo cardiomyopathy has been reported [8–10].\n\nHyponatremia is a common electrolyte disorder, encountered especially among elderly patients, in whom finding the etiology of hyponatremia remains challenging as most often it tends to be multifactorial [7]. However, prescription drugs for various comorbidities, especially in the elderly, is the usual culprit, as was observed in our patient as well. The drugs with established potential to cause hyponatremia are diuretics, antidepressants, antipsychotics, and anticonvulsants, resulting in a significant number of Takotsubo cardiomyopathy cases being detected in patients on treatment for hypertension or heart failure and among those in psychiatry wards [8]. Development of Takotsubo cardiomyopathy, secondary to hyponatremia resulting from prescribed drugs, is well recognized. As with the well-known sequelae of hyponatremia, the rapidity with which the electrolyte disturbance develops is likely to be a deciding factor in the occurrence of Takotsubo cardiomyopathy, as chronic, persistent hyponatremia is a less likely trigger [9]. The mechanism of transient cardiac dysfunction in the setting of hyponatremia, whatever the etiology may be, remains unclear, but this association has been previously observed [10–13]. The possible mechanisms proposed are central nervous system dysfunction secondary to hyponatremia, which results in myocardial injury due to raised catecholamine levels, interference of myocardial contractility by low sodium concentration due to disruption of myocyte sodium and calcium exchange, and swelling of cardiac myocytes due to the resultant hypotonicity [9].\n\nThe case presented demonstrates the possible association of hyponatremia with stress cardiomyopathy, where the patient made a complete recovery from the cardiac disorder with correction of the electrolyte disturbance. As the detection rate of Takotsubo cardiomyopathy increases with increasing availability of sophisticated cardiac investigations, its possible triggers need to be kept in mind to guide clinicians towards an early and accurate diagnosis.\n\nAcknowledgments\nWe gratefully acknowledge the assistance given to us to collect clinical data by Drs. T N K Gamage and U. Illangasekera.\n\nEthical Approval\nSince this is not a research project involving people or animals, the requirement in our local setting is to obtain informed written consent for publication.\n\nConsent\nWritten informed consent was obtained from the patient for publication of this case report.\n\nConflicts of Interest\nThe authors declare no conflict of interests.\n\nFigure 1 Echocardiogram long axis view revealed apical ballooning of the LV.\n\nFigure 2 Coronary angiogram revealed normal coronary arteries.\n\nFigure 3 Subsequent echocardiogram revealing a completely recovered myocardium.\n==== Refs\n1 Akashi Y. J. Goldstein D. S. Barbaro G. Ueyama T. Takotsubo Cardiomyopathy Circulation 2008 118 25 2754 2762 10.1161/CIRCULATIONAHA.108.767012 2-s2.0-58249141565 19106400 \n2 Lampropoulos K. M. Kotsas D. Iliopoulos T. A. Apical ballooning syndrome: a case report BMC Research Notes 2012 5 1 10.1186/1756-0500-5-698 2-s2.0-84871572671 \n3 Bybee K. A. Kara T. Prasad A. Systematic review: transient left ventricular apical ballooning: a syndrome that mimics ST-segment elevation myocardial infarction Annals of Internal Medicine 2004 141 11 858 865 10.7326/0003-4819-141-11-200412070-00010 2-s2.0-10044225734 15583228 \n4 Virani S. S. Khan A. N. Mendoza C. E. Ferreira A. C. de Marchena E. Takotsubo cardiomyopathy, or broken-heart syndrome Texas Heart Institute Journal 2007 34 1 76 79 17420797 \n5 Y-Hassan S. Tornvall P. Epidemiology, pathogenesis, and management of takotsubo syndrome Clinical Autonomic Research 2018 28 1 53 65 10.1007/s10286-017-0465-z 2-s2.0-85029481520 28917022 \n6 Vieira A. Batista B. Tribolet de Abreu T. Iatrogenic Takotsubo cardiomyopathy secondary to norepinephrine by continuous infusion for shock European Journal of Case Reports in Internal Medicine 2018 5 7 p. 1 10.12890/2018_000894 \n7 Hajsadeghi S. Dobutamine-induced takotsubo cardiomyopathy: a systematic review of the literature and case report The Anatolian Journal of Cardiology 2018 19 6 412 416 29848925 \n8 Nakamura M. Nagamine T. Severe lamotrigine-induced hyponatremia associated with Takotsubo cardiomyopathy Innov Clin Neurosci 2019 16 7-08 32 34 31832263 \n9 Şimşek E. Ç. Unusual combined cause of Takotsubo cardiomiyopathy: hyponatremia and seizure Northern Clinics of Istanbul 2018 6 3 304 307 10.14744/nci.2018.65148 31650120 \n10 Gupta S. Goyal P. Idrees S. Aggarwal S. Bajaj D. Mattana J. Association of endocrine conditions with Takotsubo cardiomyopathy: a comprehensive review Journal of the American Heart Association 2018 7 19, article e009003 10.1161/JAHA.118.009003 30371307 \n11 Elikowski W. Małek-Elikowska M. Greberska W. Słomczyński M. Marchlewska J. Korol L. Takotsubo syndrome in a patient with adrenal insufficiency, severe hyponatremia and coexistent coronary artery disease Pol Merkur Lekarski 2019 46 274 182 186 31099766 \n12 Andreozzi F. Cominetti G. Karmali R. Kamgang P. Electrolyte disorders as triggers for Takotsubo cardiomyopathy European Journal of Case Reports in Internal Medicine 2018 5 LATEST ONLINE p. 1 eCollection 2018 10.12890/2018_000760 \n13 Schrier R. W. Bansal S. Diagnosis and management of hyponatremia in acute illness Current Opinion in Critical Care 2008 14 6 627 634 10.1097/MCC.0b013e32830e45e3 2-s2.0-57149083284 19005303\n\n",
"fulltext_license": "CC BY",
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"journal": "Case reports in cardiology",
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"title": "Severe Hyponatremia-Induced Stress Cardiomyopathy: A Case Report and Review of Literature.",
"title_normalized": "severe hyponatremia induced stress cardiomyopathy a case report and review of literature"
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"abstract": "To highlight the occurrence of cardiac arrest due to hyperkalemia in diabetic ketoacidosis (DKA).\nDiabetic ketoacidosis is a commonly encountered condition. These patients can have normal or mildly elevated levels of potassium. Our patient had severe hyperkalemia due to DKA resulting in cardiac arrest. Her high potassium diet and use of angiotensin receptor blocker along with acute kidney injury (AKI) would have also contributed to hyperkalemia.\nA 58-year-old female, known case of diabetes mellitus on insulin therapy and hypertension on telmisartan, presented with nausea, vomiting, and abdominal pain. She was diagnosed to have DKA with AKI precipitated by missed insulin and urinary tract infection. She was also on high potassium diet. Her electrocardiogram showed sinus bradycardia with prolonged QRS interval. Her potassium levels were elevated. She soon went into asystole and cardiac arrest and was resuscitated. Diabetic ketoacidosis protocols were followed along with antibiotics, and the patient improved.\nSevere hyperkalemia in DKA is uncommon, and this hyperkalemia resulting in cardiac arrest is an unreported scenario. Potassium correction along with DKA management protocol forms the mainstay of treatment.\nMild to moderate elevation in serum potassium occurs frequently in DKA. However, severe hyperkalemia is uncommon and is likely to be the result of insulin deficiency, acidosis, hyperosmolality, severe dehydration, and renal potassium retention. Such elevated level of potassium requires urgent correction in order to prevent cardiac arrest.\nManappallil RG, Nambiar J. Hyperkalemic Cardiac Arrest in a Patient with Diabetic Ketoacidosis. Indian J Crit Care Med 2020;24(8):737-738.",
"affiliations": "Department of Internal Medicine, Baby Memorial Hospital, Calicut, Kerala, India.;Department of Cardiology, Baby Memorial Hospital, Calicut, Kerala, India.",
"authors": "Manappallil|Robin G|RG|;Nambiar|Jayasree|J|",
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"fulltext": "\n==== Front\nIndian J Crit Care Med\nIndian J Crit Care Med\nIJCCM\nIndian Journal of Critical Care Medicine : Peer-reviewed, Official Publication of Indian Society of Critical Care Medicine\n0972-5229 1998-359X Jaypee Brothers Medical Publishers \n\n10.5005/jp-journals-10071-23526\nLetter to the Editor\nHyperkalemic Cardiac Arrest in a Patient with Diabetic Ketoacidosis\nManappallil Robin G 1 Nambiar Jayasree 2 1 Department of Internal Medicine, Baby Memorial Hospital, Calicut, Kerala, India\n2 Department of Cardiology, Baby Memorial Hospital, Calicut, Kerala, India\nRobin G Manappallil, Department of Internal Medicine, Baby Memorial Hospital, Calicut, Kerala, India, Phone: +91 8547753396, e-mail: drrobingeorgempl@gmail.com\n8 2020 \n24 8 737 738\nCopyright © 2020; Jaypee Brothers Medical Publishers (P) Ltd.2020© The Author(s). 2020 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by-nc/4.0/), which permits unrestricted use, distribution, and non-commercial reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Abstract\nAim\nTo highlight the occurrence of cardiac arrest due to hyperkalemia in diabetic ketoacidosis (DKA).\n\nBackground\nDiabetic ketoacidosis is a commonly encountered condition. These patients can have normal or mildly elevated levels of potassium. Our patient had severe hyperkalemia due to DKA resulting in cardiac arrest. Her high potassium diet and use of angiotensin receptor blocker along with acute kidney injury (AKI) would have also contributed to hyperkalemia.\n\nCase description\nA 58-year-old female, known case of diabetes mellitus on insulin therapy and hypertension on telmisartan, presented with nausea, vomiting, and abdominal pain. She was diagnosed to have DKA with AKI precipitated by missed insulin and urinary tract infection. She was also on high potassium diet. Her electrocardiogram showed sinus bradycardia with prolonged QRS interval. Her potassium levels were elevated. She soon went into asystole and cardiac arrest and was resuscitated. Diabetic ketoacidosis protocols were followed along with antibiotics, and the patient improved.\n\nConclusion\nSevere hyperkalemia in DKA is uncommon, and this hyperkalemia resulting in cardiac arrest is an unreported scenario. Potassium correction along with DKA management protocol forms the mainstay of treatment.\n\nClinical significance\nMild to moderate elevation in serum potassium occurs frequently in DKA. However, severe hyperkalemia is uncommon and is likely to be the result of insulin deficiency, acidosis, hyperosmolality, severe dehydration, and renal potassium retention. Such elevated level of potassium requires urgent correction in order to prevent cardiac arrest.\n\nHow to cite this article\nManappallil RG, Nambiar J. Hyperkalemic Cardiac Arrest in a Patient with Diabetic Ketoacidosis. Indian J Crit Care Med 2020;24(8):737–738.\n\nKeywords\nCardiac arrestDiabetesDiabetic ketoacidosisHyperkalemiaInsulinUrinary tract infection\n==== Body\nDear Sir,\n\nA 58-year-old female was brought at night to the emergency department with complaints of recurrent vomiting, nausea, and diffuse abdominal pain since morning. She was a diabetic on insulin therapy and hypertensive on telmisartan (40 mg once daily) for the past 10 years. She had changed her diet plan to only fruits (pomegranate, bananas, apple, orange, and watermelon), salad (cucumber, carrots, lettuce, and olives), tender coconut water, and soup (chicken, mushroom, tomato) for the past 5 days. During this period she stopped insulin but continued telmisartan.\n\nOn presentation, she was conscious, oriented, and dehydrated. Her pulse was 60 minute and blood pressure 100/60 mm Hg. She had Kussmaul breathing with respiratory rate of 32 minute (saturation 94% room air). She had diffuse abdominal pain with mild guarding (no rigidity). Other systemic examinations were normal.\n\nHer blood glucose level was 412 mg/dL, and arterial blood gas (ABG) report revealed pH 7.04, pCO2 15 mm Hg, HCO3 10 mEq/L, and anion gap of 19 mEq/L. Sinus bradycardia with prolonged QRS interval was seen on her electrocardiogram (ECG). Her blood investigations showed hemoconcentration (hemoglobin 17.2 g/dL and hematocrit 51%), leukocytosis (WBC 12,400 cells/mm3 with neutrophils 80% and lymphocytes 20%), mildly elevated renal parameters (urea 74 mg/dL and creatinine 1.85 mg/dL), mild hyponatremia (129 mEq/L), and hyperkalemia (8.5 mEq/L). Her liver functions, calcium, magnesium, and ammonia were normal. Serum amylase was mildly elevated (100 U/L), but lipase was normal. Her ECG (on cardiac monitor) suddenly showed asystole, and patient went into cardiac arrest. Cardiopulmonary resuscitation was carried out, and the patient was put on mechanical ventilation. A single dose of intravenous sodium bicarbonate (50 mEq) was given along with multiple doses of intravenous 10% calcium gluconate (10 mL every 30 minutes for 2 hours) and salbutamol nebulization (10 mg every 2 hours for 4 hours). Urine ketones were positive (4+), with pus cells (20–25 HPF) and no hematuria. Serum β-hydroxybutyrate was elevated (4 mg/dL). Intravenous ceftriaxone was started. Insulin infusion and fluid management was carried out according to diabetic ketoacidosis (DKA) protocol. Echocardiography, ultrasound abdomen, and chest X-ray were normal. Her repeat electrolytes (after 4 hours) showed sodium 131 mEq/L, potassium 6.7 mEq/L, and bicarbonate 16 mEq/L. Her repeat ECG (after 2 hours) was normal. After about 8 hours, the patient became conscious and was obeying commands, with stable vitals and ECG. Her blood glucose levels were 200 mg/dL, sodium 134 mEq/L, potassium 4.2 mEq/L, bicarbonate 23 mEq/L, and pH of 7.37 on ABG. Serum β-hydroxybutyrate reduced to 2 mg/dL. She was extubated, and oral diet was started. Insulin infusion was stopped and changed to subcutaneous insulin (basal bolus regimen). Her urine culture grew Escherichia coli, and intravenous ceftriaxone was continued (as per antibiotic sensitivity report). Her coronary angiogram was normal. She was discharged on day 5 of admission and educated not to skip insulin and avoid high-potassium diet. Telmisartan was stopped and changed to oral amlodipine (5 mg once daily). On review after 1 week, her vitals were stable, with normal electrolytes, renal functions, and blood glucose levels.\n\nDiabetic ketoacidosis is an acute life-threatening condition precipitated by inadequate insulin, infection, and infarction. The diagnosis requires hyperglycemia (blood glucose 250–600 mg/dL), ketosis (elevated plasma ketones), and metabolic acidosis (pH 6.8–7.3, bicarbonate <15 mEq/L, high anion gap).1\n\nIn DKA, the potassium levels may be normal or mildly elevated. However, severe hyperkalemia is rare. In DKA, the lack of insulin produces hyperglycemia and also causes the shift of potassium from the intracellular to extracellular space by reducing Na+ K+ ATPase activity. Since there is no proper metabolism of glucose, ketones get produced and the pH decreases with increase in H+. The body tries to compensate by exchanging the intracellular K+ for extracellular H+, thereby increasing serum potassium levels. Moreover, due to acute kidney injury, there will be reduced renal excretion of potassium.2 Telmisartan, an angiotensin receptor blocker, can cause hyperkalemia by inhibition of renin-angiotensin-aldosterone axis leading to decreased potassium excretion.3\n\nOur patient was a diabetic on insulin therapy, which she stopped for few days. She also had urinary tract infection (UTI). Due to missed insulin and UTI, she developed DKA. She was found to have hyperkalemia as a part of DKA, which was aggravated by her potassium rich diet, acute kidney injury and use of telmisartan. The aftermath was hyperkalemia-induced cardiac arrest. With less than a handful of cases of severe hyperkalemia in DKA being observed, this scenario is uncommon.4–8 And the occurrence of cardiac arrest, to the best of our knowledge, has not been reported yet. Patients should be well educated regarding consequences of skipping their antidiabetic medications. Also, they should consult their doctor before starting a diet plan.\n\nSource of support: Nil\n\nConflict of interest: None\n==== Refs\nReferences\n1. Powers AC. Diabetes mellitus: management and therapies. Kasper F Hauser L Jameson L Harrison's principles of internal medicine. 19th ed., McGraw Hill education 2417 2420 \n2. Adrogue HJ Lederer ED Suki WN Eknoyan G. Determinants of plasma potassium levels in diabetic ketoacidosis. Medicine 1986 65 3 163 172 DOI: 10.1097/00005792-198605000-00004 3084904 \n3. Mount DB. Fluid and electrolyte disturbances. Kasper F Hauser L Jameson L Harrison's Principles of Internal Medicine. 19th ed., McGraw Hill education 308 312 \n4. Yamada H Funazaki S Kakei M Hara K Ishikawa SE. Diabetic ketoacidosis producing extreme hyperkalemia in a patient with type I diabetes on hemodialysis. Endocrinol Diabetes Metab Case Rep 2017 2017 17-0068. DOI: 10.1530/EDM-17-0068 \n5. Carrizales-Sepúlveda EF Del Cueto-Aguilera ÁN Jiménez-Castillo RA et al. pseudomyocardial infarction in a patient with severe diabetic ketoacidosis and mild hyperkalemia. Case Rep Cardiol 2019 2019 4063670. DOI: 10.1155/2019/4063670 31049229 \n6. Bellazzini MA Meyer T. Pseudo-myocardial infarction in diabetic ketoacidosis with hyperkalemia. J Emerg Med 2010 39 4 139 141 DOI: 10.1016/j.jemermed.2007.04.024 \n7. Ziakas A Basagiannis C Stiliadis I. Pseudoinfarction pattern in a patient with hyperkalemia, diabetic ketoacidosis and normal coronary vessels: a case report. J Med Case Rep 2010 4 115 DOI: 10.1186/1752-1947-4-115 20420664 \n8. Wray J Yoo MJ Bridwell RE Tannenbaum L Henderson J. ST-segment elevation in the setting of diabetic ketoacidosis: is it acute coronary syndrome? Cureus 2020 12 3 e7409 DOI: 10.7759/cureus.7409 32337133\n\n",
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"keywords": "Cardiac arrest; Diabetes; Diabetic ketoacidosis; Hyperkalemia; Insulin; Urinary tract infection",
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"abstract": "Narcolepsy is a life-long neurological disorder characterized by excessive daytime sleepiness (EDS) and cataplexy. At present, Sodium oxybate, modafinil, methylphenidate and other stimulants are recommended first-line therapies for narcolepsy but are difficult to obtain in China. One hundred forty-eight patients with narcolepsy were treated with antidepressants and administered the Epworth Sleepiness Scale (ESS) and the Maintenance of Wakefulness Test (MWT) before and after treatment from August 2012 to August 2017. The subjects were followed for 1-6 years after treatment. Improvement in sleepiness, cataplexy, cataplexy-like episodes, and antidepressant side effects were assessed. There were significant differences in the mean sleep latency (MSL) and sleep onset rapid eye movement periods (SOREMPs) in MWT and ESS scores, cataplexy and cataplexy-like episodes before and after treatment (p < 0.01). Venlafaxine demonstrated significantly greater improvements in MSL in the MWT (p < 0.01). Early awakenings and dry mouth were the most common adverse effects.",
"affiliations": "Department of Neurology, Xijing Hospital, The Fourth Military Medical University, Xi'an, China.;Department of Neurology, XiAn XD Group Hospital, Xi'an, China.;Department of Neurology, Xijing Hospital, The Fourth Military Medical University, Xi'an, China.;Department of Neurology, Xijing Hospital, The Fourth Military Medical University, Xi'an, China.;Department of Neurology, Xijing Hospital, The Fourth Military Medical University, Xi'an, China.;Department of Neurology, Xijing Hospital, The Fourth Military Medical University, Xi'an, China. Electronic address: liuyhong@fmmu.edu.cn.",
"authors": "Jin|Lang|L|;Shi|Liang|L|;Zhang|Ying|Y|;Chen|Bei-Bei|BB|;Wang|Xiao-Li|XL|;Liu|Yong-Hong|YH|",
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"mesh_terms": "D000328:Adult; D000928:Antidepressive Agents; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D000077408:Modafinil; D009290:Narcolepsy; D011446:Prospective Studies; D000069470:Venlafaxine Hydrochloride",
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"abstract": "Most of the 19 mitochondrial aminoacyl-tRNA synthetases (mt-aaRSs) involved in mitochondrial protein synthesis are already linked to specific entities, one of the exceptions being PARS2 mutations for which pathogenic significance is not finally validated. The aim of the study was to characterize the PARS2- related phenotype.Three siblings with biallelic PARS2 mutations presented from birth with infantile spasms, secondary microcephaly, and similar facial dysmorphy. Mental development was deeply impaired with speech absence and no eye contact. A dilated cardiomyopathy and multiorgan failure developed in childhood at the terminal stage, together with mitochondrial dysfunction triggered by valproate administration.Brain MRI showed progressive volume loss of the frontal lobes, both cortical and subcortical, with widening of the cortical sulci and frontal horns of the lateral ventricles. Hypoplasia of the corpus callosum and progressive demyelination were additional findings. Similar brain features were seen in three already reported PARS2 patients and seemed specific for this defect when compared with other mt-aaRSs defects (DARS2, EARS2, IARS2, and RARS2).Striking resemblance of the phenotype and Alpers-like brain MRI changes with predominance of frontal cerebral volume loss (FCVL-AS) in six patients from three families of different ethnicity with PARS2 mutations, justifies to distinguish the condition as a new disease entity.",
"affiliations": "Department of Medical Genetics, The Children's Memorial Health Institute, Warsaw, Poland. E.CIARA@IPCZD.PL.;Department of Pediatrics Nutrition and Metabolic Diseases, The Children's Memorial Health Institute, Warsaw, Poland. D.ROKICKI@IPCZD.PL.;Centre of New Technologies, University of Warsaw, Banacha 2c Street, 02-071, Warsaw, Poland.;Department of Child Neurology, Institute of Mother and Child, Warsaw, Poland.;Department of Diagnostic Imaging, The Children's Memorial Health Institute, Warsaw, Poland.;Department of Diagnostic Imaging, Institute of Mother and Child, Warsaw, Poland.;Department of Medical Genetics, The Children's Memorial Health Institute, Warsaw, Poland.;Department of Audiology and Phoniatrics, Children's Memorial Health Institute, Warsaw, Poland.;Department of Pediatrics Nutrition and Metabolic Diseases, The Children's Memorial Health Institute, Warsaw, Poland.;Department of Medical Genetics, Medical University of Warsaw, Warsaw, Poland.;Department of Medical Genetics, Medical University of Warsaw, Warsaw, Poland.;Department of Medical Genetics, Medical University of Warsaw, Warsaw, Poland.;Department of Pathology, The Children's Memorial Health Institute, Warsaw, Poland.;Centre of New Technologies, University of Warsaw, Banacha 2c Street, 02-071, Warsaw, Poland.;Department of Medical Genetics, Medical University of Warsaw, Warsaw, Poland.;Department of Medical Genetics, The Children's Memorial Health Institute, Warsaw, Poland.",
"authors": "Ciara|Elżbieta|E|http://orcid.org/0000-0002-1065-7968;Rokicki|Dariusz|D|;Lazniewski|Michal|M|;Mierzewska|Hanna|H|;Jurkiewicz|Elżbieta|E|;Bekiesińska-Figatowska|Monika|M|;Piekutowska-Abramczuk|Dorota|D|;Iwanicka-Pronicka|Katarzyna|K|;Szymańska|Edyta|E|;Stawiński|Piotr|P|;Kosińska|Joanna|J|;Pollak|Agnieszka|A|;Pronicki|Maciej|M|;Plewczyński|Dariusz|D|;Płoski|Rafał|R|;Pronicka|Ewa|E|",
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"title": "Clinical and molecular characteristics of newly reported mitochondrial disease entity caused by biallelic PARS2 mutations.",
"title_normalized": "clinical and molecular characteristics of newly reported mitochondrial disease entity caused by biallelic pars2 mutations"
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"abstract": "Umbilical cord blood (UCB) is the preferred donor cell source for children with Hurler syndrome undergoing transplant, and its use has been associated with improved \"engrafted survival\" rates. However, as in other pediatric recipients of UCB transplants for nonmalignant disease, immune-mediated cytopenia (IMC) is a significant complication. This article describes 8 episodes of IMC in 36 patients with Hurler syndrome undergoing UCB transplant. The incidence of IMC was increased in those with a higher preconditioning absolute lymphocyte count and in those conditioned with fludarabine-containing regimens rather than cyclophosphamide, and it included red cell alloantibodies directed at cord blood group antigens that are novel to the recipient. In several cases, IMC was a precursor to immune-mediated complete graft rejection. We describe IMC as part of a spectrum of graft rejection by a residual competent host immune system and a forme fruste of complete graft rejection.",
"affiliations": "Department of Blood and Marrow Transplant, Royal Manchester Children's Hospital, Manchester, United Kingdom.;Department of Blood and Marrow Transplant, Royal Manchester Children's Hospital, Manchester, United Kingdom.;Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, United Kingdom.;Transplantation Laboratory, Manchester Royal Infirmary, Manchester, United Kingdom.;Transplantation Laboratory, Manchester Royal Infirmary, Manchester, United Kingdom.;Department of Inherited Metabolic Disease, Royal Manchester Children's Hospital, Manchester, United Kingdom; and.;Department of Haematology, John Radcliffe Hospital, Oxford, United Kingdom.;Department of Blood and Marrow Transplant, Royal Manchester Children's Hospital, Manchester, United Kingdom.;Department of Blood and Marrow Transplant, Royal Manchester Children's Hospital, Manchester, United Kingdom.;Department of Blood and Marrow Transplant, Royal Manchester Children's Hospital, Manchester, United Kingdom.",
"authors": "Deambrosis|David|D|;Lum|Su Han|SH|;Hum|Ryan M|RM|;Poulton|Kay|K|;Ogden|Wendy|W|;Jones|Simon|S|;Stanworth|Simon|S|;Bonney|Denise|D|;Hiwarkar|Prashant|P|;Wynn|Robert F|RF|",
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"doi": "10.1182/bloodadvances.2018026963",
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"issn_linking": "2473-9529",
"issue": "3(4)",
"journal": "Blood advances",
"keywords": null,
"medline_ta": "Blood Adv",
"mesh_terms": "D005312:Fetal Blood; D006084:Graft Rejection; D006801:Humans; D018655:Lymphocyte Count; D008231:Lymphopenia; D008059:Mucopolysaccharidosis I; D019172:Transplantation Conditioning",
"nlm_unique_id": "101698425",
"other_id": null,
"pages": "570-574",
"pmc": null,
"pmid": "30787020",
"pubdate": "2019-02-26",
"publication_types": "D016428:Journal Article",
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"title": "Immune cytopenia post-cord transplant in Hurler syndrome is a forme fruste of graft rejection.",
"title_normalized": "immune cytopenia post cord transplant in hurler syndrome is a forme fruste of graft rejection"
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"abstract": "This study describes 12 cases of drivers stopped for impaired driving, where a designer benzodiazepine was detected, specifically etizolam or flubromazolam. Etizolam was detected in three cases, with blood concentrations ranging from 40 to 330 ng/mL. Two of these cases had low concentrations of methamphetamine and/or amphetamine, and in the third case tetrahydrocannabinol (THC) was detected. Flubromazolam was detected in nine cases; in all cases, at least one other drug was detected, with THC being the most prevalent. The mean blood concentration of flubromazolam was 16.3 ng/mL and had a median concentration of 17.0 ng/mL, ranging from 7.0 to 31 ng/mL. The low concentrations of designer benzodiazepines that produce pharmacological effects may allow many of these drugs to go undetected using routine testing in laboratories; therefore, it is necessary to include these novel compounds within validated analytical methods to reduce the chance of reporting false negative results. The prevalence in which laboratories are detecting the presence of novel benzodiazepines in impaired drivers illustrates the increased threat to public safety. These case studies demonstrate the importance of investigating agencies and forensic laboratories to be vigilant in monitoring the emerging novel psychoactive substances in their region.",
"affiliations": "Sedgwick County Regional Forensic Science Center, 1109 N. Minneapolis, Wichita, KS 67214, USA.;Sedgwick County Regional Forensic Science Center, 1109 N. Minneapolis, Wichita, KS 67214, USA.;Sedgwick County Regional Forensic Science Center, 1109 N. Minneapolis, Wichita, KS 67214, USA.;Sedgwick County Regional Forensic Science Center, 1109 N. Minneapolis, Wichita, KS 67214, USA.",
"authors": "Rohrig|Timothy P|TP|;Osawa|Kei A|KA|;Baird|Tyson R|TR|;Youso|Kimberly B|KB|",
"chemical_list": "D014149:Tranquilizing Agents; D001569:Benzodiazepines; C000628386:flubromazolam; C044610:etizolam; D003975:Diazepam",
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"mesh_terms": "D001334:Automobile Driving; D001569:Benzodiazepines; D003975:Diazepam; D000066448:Driving Under the Influence; D006801:Humans; D015813:Substance Abuse Detection; D014149:Tranquilizing Agents",
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"title": "Driving Impairment Cases Involving Etizolam and Flubromazolam.",
"title_normalized": "driving impairment cases involving etizolam and flubromazolam"
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"abstract": "A single dose of pegfilgrastim or the daily administration of colony-stimulating factors can be used to prevent febrile neutropenia. This may delay the detection of rapidly progressive infections among cancer patients undergoing chemotherapy. We report a case of Pseudomonas aeruginosa bacteremic pneumonia that occurred in a patient receiving pegfilgrastim.",
"affiliations": "Department of General Medicine, Juntendo University Faculty of Medicine, Japan.;Department of General Medicine, Juntendo University Faculty of Medicine, Japan.;Department of General Medicine, Juntendo University Faculty of Medicine, Japan.;Department of General Medicine, Juntendo University Faculty of Medicine, Japan.;Department of General Medicine, Juntendo University Faculty of Medicine, Japan.;Department of Gastroenterological Medicine, Juntendo University Faculty of Medicine, Japan.;Department of Gastroenterological Medicine, Juntendo University Faculty of Medicine, Japan.;Department of General Medicine, Juntendo University Faculty of Medicine, Japan.",
"authors": "Morita|Fujiko|F|;Hirai|Yuji|Y|;Suzuki|Kiyozumi|K|;Uehara|Yuki|Y|;Mitsuhashi|Kazunori|K|;Takahashi|Masahito|M|;Watanabe|Sumio|S|;Naito|Toshio|T|",
"chemical_list": "D000900:Anti-Bacterial Agents; D000970:Antineoplastic Agents; D011994:Recombinant Proteins; C455861:pegfilgrastim; D011092:Polyethylene Glycols; D000069585:Filgrastim",
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"fulltext": "\n==== Front\nIntern MedIntern. MedInternal Medicine0918-29181349-7235The Japanese Society of Internal Medicine 2876897710.2169/internalmedicine.56.8245Case ReportThe First Case of Pseudomonas aeruginosa Bacteremic Pneumonia in a Cancer Patient Receiving Pegfilgrastim Morita Fujiko 1Hirai Yuji 1Suzuki Kiyozumi 1Uehara Yuki 1Mitsuhashi Kazunori 1Takahashi Masahito 2Watanabe Sumio 2Naito Toshio 1\n1 Department of General Medicine, Juntendo University Faculty of Medicine, Japan\n2 Department of Gastroenterological Medicine, Juntendo University Faculty of Medicine, JapanCorrespondence to Dr. Yuji Hirai, y-hirai@juntendo.ac.jp\n\n1 8 2017 56 15 2039 2042 10 9 2016 8 12 2016 Copyright © 2017 by The Japanese Society of Internal Medicine2017The Internal Medicine is an Open Access article distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view the details of this license, please visit (https://creativecommons.org/licenses/by-nc-nd/4.0/).A single dose of pegfilgrastim or the daily administration of colony-stimulating factors can be used to prevent febrile neutropenia. This may delay the detection of rapidly progressive infections among cancer patients undergoing chemotherapy. We report a case of Pseudomonas aeruginosa bacteremic pneumonia that occurred in a patient receiving pegfilgrastim. \n\npegfilgrastimPseudomonas aeruginosabacteremic pneumoniasolid cancerGram stain\n==== Body\nIntroduction\nWith the spread of outpatient chemotherapy, pegfilgrastim has been used for the prevention of febrile neutropenia (FN) because its prolonged half-life permits single-dose administration. However, cancer patients receiving chemotherapy are always at risk of invasive infections regardless of the presence of neutropenia.\n\nPseudomonas aeruginosa bacteremic pneumonia (PABP) is an infection that is usually fatal, which generally occurs in neutropenic patients undergoing chemotherapy. This is the first report of a case of PABP in a solid cancer patient without neutropenia following outpatient chemotherapy and pegfilgrastim treatment.\n\nCase Report\nA 69-year-old man presented with high fever and general fatigue. He had been diagnosed with stage IV pancreatic cancer with multiple lung metastases two and a half years previously. He had been treated with gemcitabine (GEM) for two years and then TS-1 for 1 month. He developed FN after his first course of third-line chemotherapy with navelbine plus GEM due to progressive disease. Thereafter, he received outpatient chemotherapy along with pegfilgrastim. Fourteen days after the fifth course of third-line chemotherapy, he visited the hospital on the date of his scheduled outpatient appointment. He had a high fever (39°C) and general fatigue and was admitted to hospital with a suspected lung abscess.\n\nOn admission, the patient had no cough, sputum, dyspnea, chest pain, headache, or vomiting. He had no known contact with sick individuals. A physical examination revealed a body temperature of 39.0°C, a pulse rate of 66 beats/min, a respiratory rate of 18 breaths/min, and blood pressure of 90/56 mmHg. Lungs auscultation was clear, with the exception of decreased breath sounds in the right lung. No heart murmur was audible. There was mild pitting edema in his lower legs. Chest radiography on arrival showed consolidation in the upper field of the right lung (Fig. 1). Computed tomography (CT) disclosed a cavitary lesion, measuring 45×43 mm, with surrounding inflammation in the right upper lobe (Fig. 2). The laboratory data showed that he did not have neutropenia (white blood cell [WBC] count, 44,700/μL [neutrophils, 93%]). The other values were as follows: hemoglobin, 8.7 g/dL; platelets, 239,000/μL; aspirate aminotransferase, 24 U/L; alanine aminotransferase, 15 U/L; lactic dehydrogenase, 272 U/L; total protein, 5.3 g/dL; albumin, 2.1 g/dL; creatinine, 0.87 mg/dL; serum urea nitrogen, 26 mg/dL; and C-reactive protein, 7.9 mg/dL.\n\nFigure 1. A chest radiograph taken on admission.\n\nFigure 2. Computed tomography images taken on admission (top), 3 days after admission (middle), and 7 weeks after admission (bottom).\n\nHe was initially treated with intravenous ampicillin/sulbactam (12 g/day) as a pulmonary abscess was suspected after blood and sputum culturing. Sputum Gram staining (Miller and Jones sputum classification: P1) revealed abundant Gram-negative bacilli and few WBCs (Fig. 3). Respiratory symptoms, such as purulent and bloody sputum, cough, dyspnea, and chest pain, appeared on the day after admission and supplemental oxygen was required. His fever persisted and the cavitary lesion rapidly grew within only a few days (Fig. 2). Two sets of blood and sputum cultures were positive for P. aeruginosa after 3 days of incubation. The pathogen was susceptible to all of the anti-pseudomonal tested antibiotics. The patient was diagnosed with PABP based on these clinical and microbiological findings. Thus, ampicillin/sulbactam was immediately changed to piperacillin/tazobactam (18 g/day). Blood culturing, which was performed 6 days later, revealed no organisms in two sets of blood cultures. At 4 weeks after the treatment, the patient's respiratory symptoms gradually improved and the cavitary lesion became smaller. He was discharged at 12 weeks after admission.\n\nFigure 3. Sputum Gram staining.\n\nDiscussion\nGranulocyte colony-stimulating factors (G-CSFs) reduce the duration and severity of neutropenia and the risk of FN and may improve survival. According to the American Society of Clinical Oncology, pegfilgrastim and filgrastim (conventional G-CSFs that are administered daily) are equally recommended for the prevention of FN (1). Some systematic reviews have suggested that pegfilgrastim is similar or more effective than filgrastim in reducing the risk of FN (2, 3).\n\nPseudomonas aeruginosa is one of the most frequent pathogens implicated in nosocomial infection and causes a variety of infections that are associated with considerable morbidity and mortality in immunocompromised hosts (4). The mortality rate of cancer patients with P. aeruginosa bacteremia is 18-25% regardless of the presence of neutropenia (5-7). PABP is frequently fatal, with a mortality rate of 51-57% (7-9). The classical clinical features of PABP include the initial absence of respiratory symptoms—with the exception of fever—followed by the rapid progression of pneumonia and abscess formation at 48 hours after the disease onset (10, 11). The presence of pulmonary cavities, which are rare in neutropenic patients, are a poor prognostic sign (5, 12). In this case, the patient developed fever without neutropenia and abscess formation, which suggests that a few days had passed since the onset of PABP. We presume that patients receiving pegfilgrastim undergo fewer medical examinations because they have fewer hospital visits in comparison to patients who receive conventional filgrastim. Thus, the administration of pegfilgrastim may cause physicians to overlook the early symptoms and delay the diagnosis and initial treatment of infectious diseases such as PABP, the clinical presentation of which is initially non-typical. A review study showed lower incidences of FN and FN-related hospitalization among patients who received pegfilgrastim in comparison to those who received filgrastim (2); however, proper attention is necessary to detect invasive infections in patients without neutropenia. Clinicians should advise patients to visit the hospital immediately if they feel unwell.\n\nConsistent with some reports that have shown that PABP can occur in patients with solid organ cancer—irrespective of the presence of neutropenia (5, 6, 11)—our case suggests that disseminated P. aeruginosa infection may occur in cancer patients recovering from myelosuppression after chemotherapy. G-CSFs are known to enhance the production and maturation of neutrophils. In this case, the numbers of WBCs and neutrophils in the peripheral blood were markedly elevated on admission. However, we believe that neutrophil dysfunction might have been present because neutrophil dysfunction has been reported to occur in association with hyper-activation in association with the use of G-CSFs (13). Neutrophils stimulated by G-CSFs showed cytoskeletal rearrangement related to F-actin polymerization. These modifications in the neutrophils are probably related to a reduction in chemotaxis (13, 14). In addition, malignancy and malnutrition cause functional defects in chemotaxis and microbicidal activity (15). In the present case, sputum Gram staining revealed abundant gram-negative bacilli, but we did not detect phagocytosis by neutrophils. This phenomenon may be associated with neutrophil dysfunction due to the use of G-CSFs.\n\nIt is not clear whether empirical treatment with anti-pseudomonas is necessary for febrile patients without neutropenia after chemotherapy. Furthermore, the prediction of the risk of pneumonia caused by multidrug-resistant (MDR) pathogens, including P. aeruginosa is essential for determining the empirical therapy. According to the 2005 American Thoracic Society/Infectious Diseases Society of America (ATS/IDSA) guidelines, treatment with extended-spectrum antibiotics is recommended for patients with hospital-acquired pneumonia, ventilator-associated pneumonia, or healthcare-associated pneumonia (HCAP) in patients with at least one of the risk factors for MDR pathogens (16). The predictive risk factors for pneumonia may be insufficient for patients with MDR pathogens. Several studies have proposed various predictive risk factors and prediction scores for MDR pathogens (17-21). In a previous study, in which clinical prediction scores were derived and validated, the drug resistance in pneumonia (DRIP) score was a better predictor of the risk of pneumonia due to MDR pathogens than the HCAP criteria (the ATS/IDSA guidelines) (DRIP vs. the HCAP criteria: area under the receiver operator curve [AUROC], 0.88 [95% confidence interval (CI): 0.82-0.93] vs. 0.72 [95% CI: 0.64-0.79]) (17). The patient in the present case was diagnosed with HCAP, had no risk factors for MDR pathogens (according to the ATS/IDSA guidelines), and his DRIP score indicated that he did not have a high risk of infection with MDR pathogens. Thus, initial treatment with extended-spectrum antibiotics was not recommended. However, pneumonia due to MDR pathogens was suspected based on the results of sputum Gram staining. In this case, sputum Gram staining prior to antimicrobial treatment showed abundant Gram-negative bacilli, suggesting that P. aeruginosa was present in the upper airway. A prospective observational study in Japan reported that the sensitivity and specificity of sputum Gram staining in patients with HCAP due to P. aeruginosa were 22.2% and 99.8%, respectively (22). Sputum Gram staining may be useful in the early diagnosis of PABP regardless of a patient's respiratory symptoms. Empirical treatment with anti-pseudomonas agents should be considered for febrile patients undergoing cancer chemotherapy regardless of the presence of neutropenia. To the best of our knowledge, this is the first report of a case of PABP in a patient receiving pegfilgrastim. Further studies are necessary to investigate the epidemiology of infections in patients receiving outpatient chemotherapy plus pegfilgrastim.\n\nIn conclusion, the administration of pegfilgrastim may lead to a delay in the detection of the early symptoms of rapidly progressive infections, such as PABP, and physicians must pay close attention to detect invasive infections in patients without neutropenia. Empirical treatment with anti-pseudomona agents should be considered for febrile cancer patients, particularly those in whom sputum Gram staining reveals Gram-negative bacilli, which can be presumed to represent P. aeruginosa infection.\n\n\nThe authors state that they have no Conflict of Interest (COI).\n\nAcknowledgement\nThis case was presented at a poster session (Presentation number 803) for the American Thoracic Society (ATS) 2016, San Francisco, May 13 to 18, 2016.\n==== Refs\n1. \nSmith TJ , Bohlke K , Lyman GH , et al \nRecommendations for the use of WBC growth factors: American Society of Clinical Oncology clinical practice guideline update . J Clin Oncol \n33 : 3199 -3212 , 2015 .26169616 \n2. \nPfeil AM , Allcott K , Pettengell R , von Minckwitz G , Schwenkglenks M , Szabo Z \nEfficacy, effectiveness and safety of long-acting granulocyte colony-stimulating factors for prophylaxis of chemotherapy-induced neutropenia in patients with cancer: a systematic review . Support Care Cancer \n23 : 525 -545 , 2015 .25284721 \n3. \nMitchell S , Li X , Woods M , et al \nComparative effectiveness of granulocyte colony-stimulating factors to prevent febrile neutropenia and related complications in cancer patients in clinical practice: A systematic review . J Oncol Pharm Pract \n2016 (Epub ahead of print) .\n4. \nBennett JE , Dolin R , Blaser MJ In: Mandell, Douglas, and Bennett's principles and practice of infections diseases . 8th ed \nElsevier , Philadelphia, PA , 2015 : 2518 -2531 .\n5. \nChatzinikolaou I , Abi-Said D , Bodey GP , Rolston KV , Tarrand JJ , Samonis G \nRecent experience with Pseudomonas aeruginosa bacteremia in patients with cancer: Retrospective analysis of 245 episodes . Arch Intern Med \n160 : 501 -509 , 2000 .10695690 \n6. \nJoo EJ , Kang CI , Ha YE , et al \nClinical predictors of Pseudomonas aeruginosa bacteremia among Gram-negative bacterial infections in non-neutropenic patients with solid tumor . J Infect \n63 : 207 -214 , 2011 .21777616 \n7. \nTodeschini G , Franchini M , Tecchio C , et al \nImproved prognosis of Pseudomonas aeruginosa bacteremia in 127 consecutive neutropenic patients with hematologic malignancies . Int J Infect Dis \n3 : 99 -104 , 1998-1999 .\n8. \nPark SY , Park HJ , Moon SM , et al \nImpact of adequate empirical combination therapy on mortality from bacteremic Pseudomonas aeruginosa pneumonia . BMC Infect Dis \n12 : 308 , 2012 .23157735 \n9. \nCarratalà J , Rosón B , Fernández-Sevilla A , Alcaide F , Gudiol F \nBacteremic pneumonia in neutropenic patients with cancer: causes, empirical antibiotic therapy, and outcome . Arch Intern Med \n158 : 868 -872 , 1998 .9570172 \n10. \nIannini PB , Claffey T , Quintiliani R \nBacteremic Pseudomonas pneumonia . JAMA \n230 : 558 -561 , 1974 .4212965 \n11. \nFujita T , Gu Y , Kishida N , Okinaka K , Ohmagari N \nTwo cases of bacteremic pneumonia caused by Pseudomonas aeruginosa in solid-organ cancer patients . Kansenshogaku Zasshi \n84 : 588 -591 , 2010 (in Japanese, Abstract in English).20960938 \n12. In: Infections in Hematology . Maschmeyer G , Rolston KV , Eds. Springer , New York , 2015 : 3 -15 .\n13. \nFazzi R , Orciuolo E , Trombi L , et al \nPEG-Filgrastim activity on granulocyte functions . Leuk Res \n31 : 1453 -1455 , 2007 .17197023 \n14. \nInvernizzi R , Grasso D , Travaglino E , et al \nBiological effects of pegfilgrastim on circulating neutrophils in breast cancer patients undergoing dose-dense chemotherapy . Oncology \n75 : 237 -244 , 2008 .18854646 \n15. \nKasper DL , Fauci AS , Hauser SL , et al In: Harrison's principle of internal medicine . 19th ed \nMcGraw-Hill Education , New York, NY , 2015 : 413 -421 .\n16. \nAmerican Thoracic Society; Infectious Diseases Society of America \nGuidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia . Am J Respir Crit Care Med \n171 : 388 -416 , 2005 .15699079 \n17. \nWebb BJ , Dascomb K , Stenehjem E , et al \nDerivation and multicenter validation of the drug resistance in pneumonia clinical prediction score . Antimicrob Agents Chemother \n60 : 2652 -2663 , 2016 .26856838 \n18. \nShindo Y , Ito R , Kobayashi D , et al \nRisk factors for drug-resistant pathogens in community-acquired and healthcare-associated pneumonia . Am J Respir Crit Care Med \n188 : 985 -995 , 2013 .23855620 \n19. \nAliberti S , Di Pasquale M , Zanaboni AM , et al \nStratifying risk factors for multidrug-resistant pathogens in hospitalized patients coming from the community with pneumonia . Clin Infect Dis \n54 : 470 -478 , 2012 .22109954 \n20. \nShorr AF , Zilberberg MD , Micek ST , Kollef MH \nPrediction of infection due to antibiotic-resistant bacteria by select risk factors for health care-associated pneumonia . Arch Intern Med \n168 : 2205 -2210 , 2008 .19001196 \n21. \nPrina E , Ranzani OT , Polverino E , et al \nRisk factors associated with potentially antibiotic-resistant pathogens in community-acquired pneumonia . Ann Am Thorac Soc \n12 : 153 -160 , 2015 .25521229 \n22. \nFukuyama H , Yamashiro S , Kinjo K , Tamaki H , Kishaba T \nValidation of sputum Gram stain for treatment of community-acquired pneumonia and healthcare-associated pneumonia: a prospective observational study . BMC Infect Dis \n14 : 534 , 2014 .25326650\n\n",
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"issue": "56(15)",
"journal": "Internal medicine (Tokyo, Japan)",
"keywords": "Gram stain; Pseudomonas aeruginosa; bacteremic pneumonia; pegfilgrastim; solid cancer",
"medline_ta": "Intern Med",
"mesh_terms": "D000368:Aged; D000900:Anti-Bacterial Agents; D000970:Antineoplastic Agents; D016470:Bacteremia; D000069585:Filgrastim; D006801:Humans; D016867:Immunocompromised Host; D008297:Male; D009503:Neutropenia; D010190:Pancreatic Neoplasms; D018410:Pneumonia, Bacterial; D011092:Polyethylene Glycols; D011552:Pseudomonas Infections; D011859:Radiography; D011994:Recombinant Proteins; D014057:Tomography, X-Ray Computed",
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"title": "The First Case of Pseudomonas aeruginosa Bacteremic Pneumonia in a Cancer Patient Receiving Pegfilgrastim.",
"title_normalized": "the first case of pseudomonas aeruginosa bacteremic pneumonia in a cancer patient receiving pegfilgrastim"
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"abstract": "Described are the findings in a 57-year-old man who developed a large carcinoma 2 years after heart transplantation. Mental anxiety or depression may have contributed to a delay in seeking medical care. The result was amputation of the right arm below the elbow.",
"affiliations": "Center for Advanced Heart and Lung Disease, Baylor University Medical Center, Dallas, Texas. Electronic address: sandra.carey@bswhealth.org.;Baylor Medical Psychology Consultants, Dallas, Texas.;Department of Pathology, Baylor University Medical Center, Dallas, Texas.;Department of Pathology, Baylor University Medical Center, Dallas, Texas.;Center for Advanced Heart and Lung Disease, Baylor University Medical Center, Dallas, Texas.",
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"title": "Development of a Squamous Cell Carcinoma of the Hand and Wrist After Cardiac Transplantation.",
"title_normalized": "development of a squamous cell carcinoma of the hand and wrist after cardiac transplantation"
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"abstract": "OBJECTIVE\nTo describe a case of cytomegalovirus retinitis in a patient after treatment with lenalidomide, a novel therapy in the treatment of multiple myeloma.\n\n\nMETHODS\nDescriptive case report of a 67-year-old man on Lenalidomide maintenance therapy for multiple myeloma, who presented with unilateral painless blurring of vision because of retinitis.\n\n\nRESULTS\nPolymerase chain reaction of the vitreous sampling confirmed cytomegalovirus retinitis, although the patient's serum polymerase chain reaction was negative for cytomegalovirus. The patient was treated with ganciclovir with good effect.\n\n\nCONCLUSIONS\nCytomegalovirus retinitis is rare in immunocompetent patients and not commonly reported in myeloma patients. Given the increasing use of novel therapies such as Lenalidomide, unusual infections such as cytomegalovirus retinitis should be considered in patients with visual symptoms, even if they are considered to be immune competent at presentation.",
"affiliations": "*Department of Ophthalmology, Royal Melbourne Hospital, Parkville, Victoria, Australia †Centre for Eye Research Australia, University of Melbourne, East Melbourne, Victoria, Australia.",
"authors": "Lim|Hui Y|HY|;Francis|David|D|;Yeoh|Jonathan|J|;Lim|Lyndell L|LL|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1097/ICB.0b013e31827aee62",
"fulltext": null,
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"issn_linking": "1935-1089",
"issue": "7(2)",
"journal": "Retinal cases & brief reports",
"keywords": null,
"medline_ta": "Retin Cases Brief Rep",
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"nlm_unique_id": "101298744",
"other_id": null,
"pages": "172-5",
"pmc": null,
"pmid": "25390816",
"pubdate": "2013",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Cytomegalovirus retinitis after treatment with lenalidomide for multiple myeloma.",
"title_normalized": "cytomegalovirus retinitis after treatment with lenalidomide for multiple myeloma"
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"abstract": "Chronic granulomatous disease (CGD) is a heterogeneous condition due to defects in NADPH oxidase characterized by granuloma formation and increased susceptibility to invasive infections, in particular moulds. The use of broad-spectrum, mould-active antifungal prophylaxis has improved mortality. However rare resistant moulds have emerged as important pathogens. Diagnosis of these rare fungi requires molecular techniques, and treatment data are limited. Herein, we present a case of with disseminated Rasamsonia infection involving the heart.",
"affiliations": "Department of Medicine, Division of Infectious Diseases, University of Pittsburgh Medical Center, Pittsburgh, PA, 15213, PA, USA.;Department of Medicine, Division of Infectious Diseases, University of Pittsburgh Medical Center, Pittsburgh, PA, 15213, PA, USA.;Fungus Testing Laboratory & Molecular Diagnostics Laboratory, Department of Pathology and Laboratory Medicine, University of Texas Health at San Antonio, San Antonio, TX, 78229, USA.;Fungus Testing Laboratory & Molecular Diagnostics Laboratory, Department of Pathology and Laboratory Medicine, University of Texas Health at San Antonio, San Antonio, TX, 78229, USA.;Fungus Testing Laboratory & Molecular Diagnostics Laboratory, Department of Pathology and Laboratory Medicine, University of Texas Health at San Antonio, San Antonio, TX, 78229, USA.;Fungus Testing Laboratory & Molecular Diagnostics Laboratory, Department of Pathology and Laboratory Medicine, University of Texas Health at San Antonio, San Antonio, TX, 78229, USA.;Fungus Testing Laboratory & Molecular Diagnostics Laboratory, Department of Pathology and Laboratory Medicine, University of Texas Health at San Antonio, San Antonio, TX, 78229, USA.;Department of Medicine, Division of Infectious Diseases, University of Pittsburgh Medical Center, Pittsburgh, PA, 15213, PA, USA.;Department of Medicine, Division of Infectious Diseases, University of Pittsburgh Medical Center, Pittsburgh, PA, 15213, PA, USA.;Department of Medicine, Division of Infectious Diseases, University of Pittsburgh Medical Center, Pittsburgh, PA, 15213, PA, USA.",
"authors": "Babiker|Ahmed|A|;Gupta|Nupur|N|;Gibas|Connie F C|CFC|;Wiederhold|Nathan P|NP|;Sanders|Carmita|C|;Mele|James|J|;Fan|Hongxin|H|;Iovleva|Alina|A|;Haidar|Ghady|G|;Fernandes|Carolyn|C|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.mmcr.2019.04.002",
"fulltext": "\n==== Front\nMed Mycol Case RepMed Mycol Case RepMedical Mycology Case Reports2211-7539Elsevier S2211-7539(19)30014-410.1016/j.mmcr.2019.04.002Case ReportRasamsonia sp: An emerging infection amongst chronic granulomatous disease patients. A case of disseminated infection by a putatively novel Rasamsonia argillacea species complex involving the heart Babiker Ahmed babikera@upmc.eduaGupta Nupur aGibas Connie F.C. bWiederhold Nathan P. bSanders Carmita bMele James bFan Hongxin bIovleva Alina aHaidar Ghady aFernandes Carolyn fernandescr@upmc.edua∗a Department of Medicine, Division of Infectious Diseases, University of Pittsburgh Medical Center, Pittsburgh, PA, 15213, PA, USAb Fungus Testing Laboratory & Molecular Diagnostics Laboratory, Department of Pathology and Laboratory Medicine, University of Texas Health at San Antonio, San Antonio, TX, 78229, USA∗ Corresponding author. fernandescr@upmc.edu16 4 2019 6 2019 16 4 2019 24 54 57 1 2 2019 31 3 2019 11 4 2019 © 2019 The Authors2019This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Chronic granulomatous disease (CGD) is a heterogeneous condition due to defects in NADPH oxidase characterized by granuloma formation and increased susceptibility to invasive infections, in particular moulds. The use of broad-spectrum, mould-active antifungal prophylaxis has improved mortality. However rare resistant moulds have emerged as important pathogens. Diagnosis of these rare fungi requires molecular techniques, and treatment data are limited. Herein, we present a case of with disseminated Rasamsonia infection involving the heart.\n\nKeywords\nChronic granulomatous diseaseFilamentous fungiInvasive fungal infections\n==== Body\n1 Introduction\nChronic granulomatous disease (CGD) is a heterogeneous condition due to defects in NADPH oxidase characterized by granuloma formation and increased susceptibility to invasive infections. The defect in NADPH oxidase and the subsequent inability to generate microbicidal reactive oxidants predispose CGD patients to a wide array of infections. Most common pathogens which cause disease include, Staphylococcus aureus, Serratia marcescens, Burkholderia cepacia complex, Nocardia and Aspergillus spp [1]. Among fungi, filamentous species, especially Aspergillus spp., have emerged as a major cause of mortality and morbidity amongst CGD patients. This has led to the routine use of anti-mould prophylaxis which has improved mortality [2]. However rare moulds with reduced antifungal susceptibility profiles have emerged as important pathogens. Diagnosis of these rare fungi requires molecular techniques, and treatment data are limited. The use of DNA sequence analysis and the increasing number of fungal sequences available in databases have permitted improved identification. Herein, we present a case of with disseminated Rasamsonia infection involving the heart.\n\n2 Case\nA 35-year-old male with CGD and ulcerative colitis presented with persistent fevers, night sweats, weight loss, fatigue, and cough. His symptoms had been ongoing for a period of several months after being off prophylactic antimicrobials for several years (day 0). Initial imaging at that time had shown pulmonary nodules. Repeat imaging at time of presentation showed increase in the size of the pulmonary nodules, and new chest and abdominal lymphadenopathy, splenomegaly, as well as a lytic lesion in the left acetabulum (day +165). Attempts to establish a diagnosis by a sampling of the left acetabular lesion were unsuccessful. Pathology of the acetabular lesion revealed non-specific micro-abscesses and non-necrotizing granulomas. However, staining and cultures for bacteria, fungal, and mycobacteria were negative (day +179). He was resumed on trimethoprim-sulfamethoxazole, voriconazole prophylaxis, and interferon-gamma, which resulted in a resolution of his symptoms (day +284). Serial imaging over the next 1.5 years showed decreasing size of the lymphadenopathy and nodules. Two years after the resolution of symptoms, he was started on azathioprine due to worsening ulcerative colitis (day + 797). However, he developed similar symptoms soon after (day +879). Computed tomography (CT) scan showed an increase in the size of pulmonary nodules and a new infiltrating right ventricular mass extending to the pericardial space that measured 4.4 × 3.6 cm (Fig. 1) (day + 902). He underwent a sternotomy and debridement of the cardiac mass and wedge resection of a lung nodule (day +919). Operative cultures of both the lung nodule and the cardiac mass grew mould (Fig. 2, Fig. 3). Operative pathology revealed septate hyphae (Fig. 4).Fig. 1 CT chest with contrast demonstrating lung nodule.\n\nFig. 1Fig. 2 Macroscopic morphology of Rasamsonia sp. UTHSCSA DI19-1 on Sabouraud dextrose agar.\n\nFig. 2Fig. 3 Microscopic morphology of Rasamsonia sp. UTHSCSA DI19-1 showing asymmetric biverticillate penicillus and cylindrical to ovoid shaped conidia on SDA.\n\nFig. 3Fig. 4 Grocott methenamine staining of cardiac mass pathology showing septate hyphae fungi.\n\nFig. 4\n\nInitially, his operative cultures were thought to be either Penicillium or Paecilomyces species based on the morphological examination. He was placed on intravenous (IV) liposomal amphotericin B (5 mg/kg/day), IV caspofungin (150 mg/day), and high dose oral posaconazole extended release tablets (500 mg/day for target levels of 3–5 μg/mL) with improvement in symptoms (day + 928).\n\nThe isolate was sent to the Fungus Testing Lab at the University of Texas Health at San Antonio, Texas for species identification and was accessioned as UTHSCSA DI19-1. Macroscopic and microscopic examination of the culture, showed phenotypic features salient to Rasamsonia species i.e. cream to tan colonies on potato flakes agar (PFA, prepared inhouse) and sabouraud dextrose agar (SDA, Bio-Rad), growth at 37C, roughened conidiophores and phialides, smooth, hyaline, cylindrical conidia in chains (Fig. 3). Isolate UTHSCSA DI19-1 was identified as a Rasamsonia species based on these characteristics [3]. The ITS region and partial beta tubulin gene (TUB) gene were chosen for sequencing to compare with sequences of the same loci in previous studies [3]. DNA extraction was done as previously described [4]. PCR and sequencing were carried out using primer pairs ITS1F and ITS4R for ITS and BT2a and Bt2b for partial TUB [5,6]. The generated sequences, GenBank accessions MK630678 (ITS), MK636872 (TUB) were used to perform BLASTn searches in GenBank [7]. BLASTn search results were considered significant with an E-value of 0.0, at 97–100% identity and from 90% query coverage. Phylogenetic analyses were conducted independently with each locus and combined to assess the relationship of isolate UTHSCSA DI19-1 to species in the R. argillacea species complex. The maximum likelihood method was used based on the Tamura 3-parameter evolutionary model with a Gamma distribution (TN92+G) for ITS and the Kimura 2-parameter with Gamma distribution for TUB [8,9]. The evolutionary models were determined by the Finding Model program as implemented in Molecular Evolutionary Genetics Analysis ver. 7 software (MEGA 7) [10]. (Kumar 2016). BLASTn search results for ITS and TUB showed UTHSCSA DI19-1 closest to species in the Rasamsonia argillacea species complex. The ITS BLAST search showed 98% identity with R. argillacea CBS 101.69T (NR_ 103623), 98% with R. eburnea CBS 100538T (NR_119934), 99% with R. piperina CBS 408.73T (NR_120176) and 99% with R. aegroticola IHEM 22641T (NR_111447) and in the TUB BLASTn search, 98% identity with R. argillacea CBS 101.69T (JF417456), 98% with R. eburnea CBS 100538T (JF417462), 97% with R. piperina CBS 408.73T (JX273000) and 97% with R. aegroticola DTO 137C3 (JX273007). Independent phylogenetic analysis of the ITS and TUB showed the isolate placed within the R. argillacea complex but not grouping with any of the 4 species clades in the complex (data not shown). The maximum likelihood tree of combined ITS and TUB also showed that our isolate is phylogenetically distant from the other species in the complex (Fig. 5) and could represent a new species (day 948). Additional genes would need to be included in the phylogenetic analysis and other phenotypic features need to be investigated to confirm that UTHSCSA DI19-1 is a novel species within the R. argillacea species complex. Minimum inhibitory concentrations (MICs) against amphotericin B, posaconazole, and voriconazole were measured by broth microdilution according to the methods in the CLSI M38-A2 standard, and were 1.0, 1.0, and >16.0 μg/mL, respectively. The minimum effective concentration (MEC) of caspofungin was determined to be 0.03 μg/mL.Fig. 5 Maximum likelihood tree based on combined datasets of ITS and partial β-tubulin sequences showing isolate UTHSCSA DI19-1 embedded within the Rasamsonia argillacea species complex. The numbers to the left of the species names are GenBank accession numbers of ITS and partial β-tubulin sequences respectively. Bootstrap values ≥ 70% are shown above the branches. Talaromyces stollii CBS 408.93 was used as an outgroup.\n\nFig. 5\n\nOver the following four to eight weeks, the patient had radiographic resolution of his cardiac mass and pulmonary nodules. After six months of combination therapy with IV liposomal amphotericin B, IV caspofungin, and oral posaconazole, he was transitioned to lifelong monotherapy with high dose oral posaconazole (day + 1150) and is currently doing well (day +1468).\n\n3 Discussion\nAmong fungi, filamentous species, especially Aspergillus spp., have emerged as a major cause of mortality and morbidity amongst patients with CGD. This has led to the routine use of mould-active azole prophylaxis, which has improved mortality, though breakthrough infections with atypical moulds have been known to occur [2,11].\n\nRasamsonia argillacea is a thermotolerant fungus, previously classified as Geosmithia argillacea [12]. Routine identification using phenotypic methods can be challenging because of its similarity to Paecilomyces and Penicillium spp. as was the case with our patient [[12], [13], [14]]. A restrospective study of isolates from cystic fibrosis patients in 2013 showed that Rasamsonia argillacea is a complex comprising four species: R. argillacea, R. aegroticola, R. eburnea and R. piperina [15].\n\nWith improvement in diagnostic techniques, particularly DNA sequencing, species within the Rasamsonia argillacea species complex have been reported with increasing frequency as a cause of invasive disease amongst vulnerable populations. The first case of invasive disease was reported in 2009 [16]. Since then, two case series consisting of a total of nine patients with CGD and disseminated Rasamsonia spp. infections have been published [14,17]. In both case series, patients developed disseminated disease with pneumonitis, pulmonary nodules, and mediastinal and cerebral abscesses, with a mortality rate of approximately 50%, despite treatment with combination therapy and surgical resection. Additionally, in a case report of a patient with cystic fibrosis who developed disseminated fungal disease post-lung transplant, it was suggested that colonization by Rasamsonia spp. of the patient's inherent respiratory system led to serious clinical implications post-transplant [18].\n\nTreatment data are limited, though combination therapy with azoles, echinocandins and in a few instances, amphotericin B, in conjunction with surgical resection are the preferred therapy of choice. While no interpretive criteria for antifungal sensitivities exist, susceptibility testing of isolates demonstrates good in vitro activity against echinocandins and terbinafine, followed by amphotericin B and posaconazole. Isolates are invariably resistant to voriconazole and itraconazole [15]. The majority of patients have required surgical resection or drainage of the lesions in addition to combination antifungal therapy, but despite these measures, mortality rates remain high [17].\n\nIn conclusion, emerging mould infections should be considered in patients with CGD who develop invasive infections while on mould-active prophylaxis [11,14]. Amongst these, Rasamsonia spp. are important pathogens in CGD patients as they can cause disseminated disease. Thus, recognition and identification with biopsy and DNA sequence analysis is recommended. Therapy with combination therapy including an echinocandin should be considered along with surgical intervention.\n\nConflict of interest\n‘There are none.’\n\nAcknowledgements\nThe authors would like to acknowledge Dr. William Pasculle Sc.D. and Mr. Richard Cumbie at the University of Pittsburgh Medical Center’s mycology lab for their assistance, as well as Dr. Christa Zerbe M.D. at the National Institutes of Health for her correspondence during the patient's treatment course.\n==== Refs\nReferences\n1 Holland S.M. Chronic granulomatous disease Clin. Rev. Allergy Immunol. 38 1 2010 3 10 19504359 \n2 Blumental S. Mouy R. Mahlaoui N. Bougnoux M.E. Debre M. Beaute J. Invasive mold infections in chronic granulomatous disease: a 25-year retrospective survey Clin. Infect. Dis. 53 12 2011 e159 e169 22080130 \n3 Doyon J.B. Sutton D.A. Theodore P. Dhillon G. Jones K.D. Thompson E.H. Rasamsonia argillacea pulmonary and aortic graft infection in an immune-competent patient J. Clin. Microbiol. 51 2 2013 719 722 23241382 \n4 Rainwater K.L. Wiederhold N.P. Sutton D.A. Garner M.M. Maguire C. Sanders C. Novel Paranannizziopsis species in a Wagler's viper (Tropidolaemus wagleri), tentacled snakes (Erpeton tentaculatum), and a rhinoceros snake (Rhynchophis boulengeri) in a zoological collection Med. Mycol. 2018 10.1093/mmy/myy134 \n5 Glass N.L. Donaldson G.C. Development of primer sets designed for use with the PCR to amplify conserved genes from filamentous ascomycetes Appl. Environ. Microbiol. 61 4 1995 1323 1330 7747954 \n6 White T. Bruns T. Lee S. Taylor J. Amplification and direct sequencing of fungal ribosomal RNA genes for phylogenetics Innis M. Gelfand D. Sninsky J. White T. PCR Protocols: A Guide to Methods and Applications 1990 Academic Press Inc New York 315 322 \n7 Zhang Z. Schwartz S. Wagner L. Miller W. A greedy algorithm for aligning DNA sequences J. Comput. Biol. J. Comput. Mol. Cell Biol. 7 1–2 2000 203 214 \n8 Nei M. Kumar S. Molecular Evolution and Phylogenetics 2000 Oxford University Press New York \n9 Tamura K. Estimation of the number of nucleotide substitutions when there are strong transition-transversion and G+C-content biases Mol. Biol. Evol. 9 4 1992 678 687 1630306 \n10 Kumar S. Stecher G. Tamura K. MEGA7: molecular evolutionary Genetics analysis version 7.0 for bigger datasets Mol. Biol. Evol. 33 7 2016 1870 1874 27004904 \n11 Haidar G. Zerbe C.S. Cheng M. Zelazny A.M. Holland S.M. Sheridan K.R. Phellinus species: an emerging cause of refractory fungal infections in patients with X-linked chronic granulomatous disease Mycoses 60 3 2017 155 160 27781311 \n12 Houbraken J. Spierenburg H. Frisvad J.C. Rasamsonia, a new genus comprising thermotolerant and thermophilic Talaromyces and Geosmithia species Antonie Van Leeuwenhoek 101 2 2012 403 421 21965082 \n13 Houbraken J. Verweij P.E. Rijs A.J. Borman A.M. Samson R.A. Identification of Paecilomyces variotii in clinical samples and settings J. Clin. Microbiol. 48 8 2010 2754 2761 20519470 \n14 Machouart M. Garcia-Hermoso D. Rivier A. Hassouni N. Catherinot E. Salmon A. Emergence of disseminated infections due to Geosmithia argillacea in patients with chronic granulomatous disease receiving long-term azole antifungal prophylaxis J. Clin. Microbiol. 49 4 2011 1681 1683 21270214 \n15 Houbraken J. Giraud S. Meijer M. Bertout S. Frisvad J.C. Meis J.F. Taxonomy and antifungal susceptibility of clinically important Rasamsonia species J. Clin. Microbiol. 51 1 2013 22 30 23077129 \n16 Romanelli A.M.W.B. Disseminated Geosmithia argillacea infection in a German shepherd dog Med. Mycol. 47 2009 221 226 19169949 \n17 De Ravin S.S. Challipalli M. Anderson V. Shea Y.R. Marciano B. Hilligoss D. Geosmithia argillacea: an emerging cause of invasive mycosis in human chronic granulomatous disease Clin. Infect. Dis. 52 6 2011 e136 e143 21367720 \n18 Hong G. White M. Lechtzin N. West N.E. Avery R. Miller H. Fatal disseminated Rasamsonia infection in cystic fibrosis post-lung transplantation J. Cyst. Fibros. Off. J. Eur. Cyst. Fibros. Soc. 16 2 2017 e3 e7\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2211-7539",
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"journal": "Medical mycology case reports",
"keywords": "Chronic granulomatous disease; Filamentous fungi; Invasive fungal infections",
"medline_ta": "Med Mycol Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101598259",
"other_id": null,
"pages": "54-57",
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"pubdate": "2019-06",
"publication_types": "D002363:Case Reports",
"references": "10890397;1630306;19169949;19504359;20519470;21270214;21367720;21965082;22080130;23077129;23241382;27004904;27781311;28185887;30520962;7747954",
"title": "Rasamsonia sp: An emerging infection amongst chronic granulomatous disease patients. A case of disseminated infection by a putatively novel Rasamsonia argillacea species complex involving the heart.",
"title_normalized": "rasamsonia sp an emerging infection amongst chronic granulomatous disease patients a case of disseminated infection by a putatively novel rasamsonia argillacea species complex involving the heart"
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"abstract": "We present a case of fatal intoxication by the application of a transdermal fentanyl patch upon a superficial bleeding abrasion of a 2-year-old girl. The grandmother discovered the body of the child in bed at approximately 7 a.m. External examination revealed a properly developed, nourished, and hydrated child, with some vomit in the nostrils and inside the mouth. There was no evidence of trauma besides small contusions and abrasions on the knees, with a patch placed over the largest abrasion. Closer inspection revealed that this was transdermal fentanyl patch. Internal examination and microscopic analysis revealed regurgitation of stomach content, cerebral and pulmonary edema, and liver congestion. Toxicology analysis revealed trace levels of fentanyl in the blood just above the limit of detection (2 ng/mL), while concentrations in the urine, liver, and kidney were approximately 102, 28, and 10 ng/mL, respectively. Investigation discovered that the child injured her knee while playing the evening before. The grandmother applied the patch to cover the injury, unaware that she had used a fentanyl transdermal patch instead of simple band-aid. Although fatal intoxications are uncommon among young children in high-income countries, it is of major interest to raise awareness of such events especially since a great majority of these are preventable. The presented case points at the need for more thorough education of users and more strict rules in prescribing and handling of this potent medicine. As well, we find this case to be a useful contribution to the evaluation of postmortem fentanyl concentrations in fatal intoxication in a small child.",
"affiliations": "Institute of Forensic Medicine and Criminalistics, School of Medicine, University of Zagreb, Šalata 11, 10 000, Zagreb, Croatia.;Institute of Forensic Medicine and Criminalistics, School of Medicine, University of Zagreb, Šalata 11, 10 000, Zagreb, Croatia.;Institute of Forensic Medicine and Criminalistics, School of Medicine, University of Zagreb, Šalata 11, 10 000, Zagreb, Croatia. dmayer@mef.hr.",
"authors": "Bakovic|Marija|M|;Nestic|Marina|M|;Mayer|Davor|D|",
"chemical_list": "D000701:Analgesics, Opioid; D005283:Fentanyl",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00414-015-1209-z",
"fulltext": null,
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"issn_linking": "0937-9827",
"issue": "129(6)",
"journal": "International journal of legal medicine",
"keywords": "Child fatality; Fatal intoxication; Postmortem; Skin abrasion; Transdermal fentanyl patch",
"medline_ta": "Int J Legal Med",
"mesh_terms": "D000061:Accidents, Home; D000701:Analgesics, Opioid; D001458:Bandages; D002675:Child, Preschool; D005260:Female; D005283:Fentanyl; D006801:Humans; D007668:Kidney; D008099:Liver; D012867:Skin; D057968:Transdermal Patch",
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"references": "14523881;22561319;21920539;21926884;23272763;16015396;22417834;17115172;1517627;22165864;17132259;9305315;9952166;7389247;14607006;10668859;1978306",
"title": "Death by band-aid: fatal misuse of transdermal fentanyl patch.",
"title_normalized": "death by band aid fatal misuse of transdermal fentanyl patch"
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"companynumb": "HR-TEVA-685044ISR",
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"abstract": "BACKGROUND\nRituximab (RTX) is approved for induction therapy of granulomatosis with polyangiitis and microscopic polyangiitis. In eosinophilic granulomatosis with polyangiitis (EGPA), organ-threatening manifestations are mainly treated with cyclophosphamide (CYC). RTX as treatment in EGPA has been described in small case series; however long-term data and the efficacy of RTX in EGPA refractory to CYC have not been reported yet.\n\n\nOBJECTIVE\nTo investigate the efficacy and safety of RTX and conventional immunosuppressive therapy with CYC in EGPA as induction therapy and during long-term follow-up.\n\n\nMETHODS\nRetrospective analysis of 28 patients with EGPA was done. Treatment response and disease activity were determined by Birmingham Vasculitis Activity Score, C-reactive protein, eosinophils, antineutrophil cytoplasmic antibody, and peripheral CD19+ B cells.\n\n\nRESULTS\nFourteen patients with EGPA treated with RTX were compared with 14 age- and sex-matched patients with EGPA treated with CYC for remission induction; 64% of the RTX-treated patients with EGPA had previously failed CYC treatment. Disease duration was longer and the number of previous immunosuppressants higher in RTX-treated patients. Five RTX-treated patients (36%) and 4 CYC-treated patients (29%) achieved complete remission. All other patients were in partial remission. There was no difference between both groups in respect to treatment response and partial and complete remission. In both treatment groups, eosinophils, C-reactive protein, and IgE levels dropped. Relapse-free survival within an observation period of 36 months was comparable between RTX- and CYC-treated patients. RTX was well tolerated, but resulted in a decline in serum immunoglobulin levels.\n\n\nCONCLUSIONS\nRTX was effective in inducing remission and during long-term follow-up in patients with EGPA, even when previously refractory to standard immunosuppressive therapy including CYC. RTX-treated patients should be monitored for hypogammaglobulinemia.",
"affiliations": "Department of Rheumatology and Clinical Immunology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.;Department of Rheumatology and Clinical Immunology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.;Department of Rheumatology and Clinical Immunology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.;Department of Rheumatology and Clinical Immunology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.;Department of Rheumatology and Clinical Immunology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.;Department of Rheumatology and Clinical Immunology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.;Department of Rheumatology and Clinical Immunology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.;Department of Rheumatology and Clinical Immunology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.;Department of Rheumatology and Clinical Immunology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.;Department of Rheumatology and Clinical Immunology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany. Electronic address: nils.venhoff@uniklinik-freiburg.de.",
"authors": "Thiel|Jens|J|;Troilo|Arianna|A|;Salzer|Ulrich|U|;Schleyer|Theresa|T|;Halmschlag|Kirsten|K|;Rizzi|Marta|M|;Frede|Natalie|N|;Venhoff|Ana|A|;Voll|Reinhard E|RE|;Venhoff|Nils|N|",
"chemical_list": "D019268:Antibodies, Antineutrophil Cytoplasmic; D007166:Immunosuppressive Agents; D000069283:Rituximab; D003520:Cyclophosphamide; D002097:C-Reactive Protein",
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"issue": "5(6)",
"journal": "The journal of allergy and clinical immunology. In practice",
"keywords": "ANCA-associated vasculitis; B-cell depletion; B-cell repopulation; Churg-Strauss syndrome; Cyclophosphamide; EGPA; Eosinophilic granulomatosis with polyangiitis; Hypogammaglobulinemia; Rituximab",
"medline_ta": "J Allergy Clin Immunol Pract",
"mesh_terms": "D000328:Adult; D019268:Antibodies, Antineutrophil Cytoplasmic; D001402:B-Lymphocytes; D002097:C-Reactive Protein; D015267:Churg-Strauss Syndrome; D003520:Cyclophosphamide; D004359:Drug Therapy, Combination; D004804:Eosinophils; D005260:Female; D005500:Follow-Up Studies; D014890:Granulomatosis with Polyangiitis; D006801:Humans; D007166:Immunosuppressive Agents; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D000069283:Rituximab; D016896:Treatment Outcome",
"nlm_unique_id": "101597220",
"other_id": null,
"pages": "1556-1563",
"pmc": null,
"pmid": "28916432",
"pubdate": "2017",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Rituximab as Induction Therapy in Eosinophilic Granulomatosis with Polyangiitis Refractory to Conventional Immunosuppressive Treatment: A 36-Month Follow-Up Analysis.",
"title_normalized": "rituximab as induction therapy in eosinophilic granulomatosis with polyangiitis refractory to conventional immunosuppressive treatment a 36 month follow up analysis"
} | [
{
"companynumb": "DE-ROCHE-2055565",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RITUXIMAB"
},
"drugadditional": "3",
"drugad... |
{
"abstract": "The aim of this case report was to present the management of the aesthetic consequences of the treatment for granuloma removal in the zygomatic region, with concentrated growth factors (CGF) activated by medical ozone. A 54-year-old woman presented with bilateral lesion in the zygomatic region, caused by treatment with hyaluronidase and laser for removal of a granuloma, developed after infiltration with hyaluronate. The lesion was treated by local application of platelet-rich plasma obtained with CGF centrifuge, and containing CD34+ cells, mixed and activated by ozone in a 1:1 proportion, at a concentration of 40 mg/ml for 30 sec, in a syringe. Five consecutive bilateral infiltrations were made at 3-week intervals. Lesion volume was measured, and patient's quality of life was assessed with PGWBI (Psychological General Well Being Index) questionnaire. After the third infiltration of CGF-ozone, a consistent reduction of the lesion was observed, until disappearance at the end of the treatment. The result was maintained after 4-year follow-up. Considerable improvement of patient's well-being was reported. This case report showed that CGF-ozone combined therapy may promote dermal regeneration, achieving excellent facial esthetics outcomes. This result needs to be confirmed by further studies with a larger sample size.",
"affiliations": "Private practice, Mirandola, (MO), Italy.;Research Laboratory in Regenerative Medicine and Tissue Engineering, Saint Camillus International University of Health Sciences, Rome, Italy.;Department of Biomedical, Surgical and Dental Sciences, University of Milan, Milan, Italy.;Research Laboratory in Regenerative Medicine and Tissue Engineering, Saint Camillus International University of Health Sciences, Rome, Italy.",
"authors": "Pederzoli|P|P|;Greco Lucchina|A|A|;Del Fabbro|M|M|;Mortellaro|C|C|",
"chemical_list": "D036341:Intercellular Signaling Peptides and Proteins; D010126:Ozone",
"country": "Italy",
"delete": false,
"doi": "10.23812/21-2supp1-34",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0393-974X",
"issue": "35(2 Suppl. 1)",
"journal": "Journal of biological regulators and homeostatic agents",
"keywords": "concentrated growth factors; facial esthetics; ozone; platelet-rich plasma; zygomatic dermal lesion",
"medline_ta": "J Biol Regul Homeost Agents",
"mesh_terms": "D004954:Esthetics; D005260:Female; D006099:Granuloma; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D008875:Middle Aged; D010126:Ozone; D011788:Quality of Life",
"nlm_unique_id": "8809253",
"other_id": null,
"pages": "345-350",
"pmc": null,
"pmid": "34281331",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Concentrated growth factors gel activated with ozone for facial aesthetics purpose after granuloma removal: a case report.",
"title_normalized": "concentrated growth factors gel activated with ozone for facial aesthetics purpose after granuloma removal a case report"
} | [
{
"companynumb": "IT-BAUSCH-BL-2021-028394",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "HYALURONIDASE"
},
"drugadditional": "4",
... |
{
"abstract": "BACKGROUND\nPembrolizumab is a humanised monoclonal antibody targeting the receptor programmed cell death protein-1 (PD-1), with anti-tumour activity demonstrated for many malignancies. Such immune checkpoint inhibitors are associated with many immune-related adverse events including rash, colitis, hepatitis, pneumonitis, endocrinopathy and, rarely, haematological adverse events, including immune-related thrombocytopenia.\n\n\nMETHODS\nWe report a 60-year-old female with metastatic non-small cell lung cancer treated with pembrolizumab every three weeks. Following her fifth cycle, she presented to our hospital with community-acquired pneumonia. Thrombocytopenia developed the next day and, after detailed investigations, thrombotic thrombocytopenic purpura was diagnosed.\nPembrolizumab was immediately ceased and plasma exchange commenced along with IV methylprednisolone 250 mg daily for three days followed by oral prednisolone. After five days of plasma exchange, platelet counts normalised and haemolytic anaemia resolved.\n\n\nCONCLUSIONS\nAcquired thrombotic thrombocytopenic purpura is an autoimmune disorder caused by an inhibitory autoantibody against ADAMTS-13. While most cases of acquired thrombotic thrombocytopenic purpura are idiopathic, certain conditions (e.g. bacterial infection, autoimmune disorders, malignancies) and medications are associated with thrombotic thrombocytopenic purpura. Other potential causes were eliminated in our patient. As acquired thrombotic thrombocytopenic purpura is an autoimmune disorder, pembrolizumab, given its unique mechanism of action and association with immune-related adverse events, is believed to be implicated in the development of thrombotic thrombocytopenic purpura. This case is one of only two linking anti-PD-1 therapy to thrombotic thrombocytopenic purpura development (the other occurring in a patient on nivolumab plus ipilimumab). Thrombotic thrombocytopenic purpura is life-threatening and clinicians are advised to be aware of its possible occurrence in immune checkpoint inhibitor-treated patients.",
"affiliations": "Cancer Care Services, Toowoomba Hospital, Toowoomba, Australia.;Cancer Care Services, Toowoomba Hospital, Toowoomba, Australia.;Cancer Care Services, Toowoomba Hospital, Toowoomba, Australia.;Cancer Care Services, Toowoomba Hospital, Toowoomba, Australia.;Cancer Care Services, Toowoomba Hospital, Toowoomba, Australia.;Cancer Care Services, Toowoomba Hospital, Toowoomba, Australia.;Cancer Care Services, Toowoomba Hospital, Toowoomba, Australia.",
"authors": "Dickey|Marcus Sr|MS|;Raina|Anant J|AJ|;Gilbar|Peter J|PJ|https://orcid.org/0000-0001-7748-1891;Wisniowski|Brendan L|BL|;Collins|Joel T|JT|;Karki|Bhaskar|B|;Nguyen|Andrew Dk|AD|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D000074322:Antineoplastic Agents, Immunological; C582435:pembrolizumab",
"country": "England",
"delete": false,
"doi": "10.1177/1078155219887212",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1078-1552",
"issue": "26(5)",
"journal": "Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners",
"keywords": "Pembrolizumab; immunotherapy; thrombotic thrombocytopenic purpura",
"medline_ta": "J Oncol Pharm Pract",
"mesh_terms": "D061067:Antibodies, Monoclonal, Humanized; D000074322:Antineoplastic Agents, Immunological; D002289:Carcinoma, Non-Small-Cell Lung; D005260:Female; D006801:Humans; D008175:Lung Neoplasms; D008875:Middle Aged; D010951:Plasma Exchange; D011697:Purpura, Thrombotic Thrombocytopenic",
"nlm_unique_id": "9511372",
"other_id": null,
"pages": "1237-1240",
"pmc": null,
"pmid": "31718453",
"pubdate": "2020-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Pembrolizumab-induced thrombotic thrombocytopenic purpura.",
"title_normalized": "pembrolizumab induced thrombotic thrombocytopenic purpura"
} | [
{
"companynumb": "AU-009507513-1911AUS012218",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PEMBROLIZUMAB"
},
"drugadditional": "1",
... |
{
"abstract": "The reports for secondary esophageal cancer treated by radiotherapy or chemoradiotherapy is few, however they potentially yield a cure for esophageal cancer. We report a case of definitive radiotherapy for a patient with secondary locally advanced unresectable esophageal cancer after hematopoietic stem cell transplantation for acute myeloid leukemia. Definitive radiotherapy for the current patient was completed with acceptable toxicity despite the poor general condition with long-term chronic graft-versus-host disease. Radiotherapy may be the definitive treatment for this population unfit for concurrent chemotherapy or surgery.",
"affiliations": "Department of Radiation Oncology and Image-Applied Therapy, Graduate School of Medicine, Kyoto University, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto, 606-8507 Japan.;Department of Radiation Oncology and Image-Applied Therapy, Graduate School of Medicine, Kyoto University, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto, 606-8507 Japan.;Department of Radiation Oncology and Image-Applied Therapy, Graduate School of Medicine, Kyoto University, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto, 606-8507 Japan.;Department of Radiation Oncology and Image-Applied Therapy, Graduate School of Medicine, Kyoto University, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto, 606-8507 Japan.;Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto, 606-8507 Japan.;Department of Radiation Oncology and Image-Applied Therapy, Graduate School of Medicine, Kyoto University, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto, 606-8507 Japan.",
"authors": "Ino|Aki|A|;Sakanaka|Katsuyuki|K|0000-0002-1590-0250;Inoo|Hiroyuki|H|;Ishida|Yuichi|Y|;Kanda|Junya|J|;Mizowaki|Takashi|T|",
"chemical_list": null,
"country": "Singapore",
"delete": false,
"doi": "10.1007/s13691-021-00479-x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2192-3183",
"issue": "10(3)",
"journal": "International cancer conference journal",
"keywords": "Esophageal cancer; Hematopoietic stem cell transplantation; Radiotherapy; Secondary malignancy",
"medline_ta": "Int Cancer Conf J",
"mesh_terms": null,
"nlm_unique_id": "101734231",
"other_id": null,
"pages": "201-206",
"pmc": null,
"pmid": "34221832",
"pubdate": "2021-07",
"publication_types": "D002363:Case Reports",
"references": "32513403;24319403;15908969;20410055;24399081;6158354;27821503;31549271;7625377;33387042;17236971;18506734;12860946;30087108;1584260;15687239;29423555;27537591;10235156;27475126;20926773;20065176;23225908;30127467",
"title": "Definitive radiotherapy for secondary esophageal cancer after allogeneic hematopoietic stem cell transplantation.",
"title_normalized": "definitive radiotherapy for secondary esophageal cancer after allogeneic hematopoietic stem cell transplantation"
} | [
{
"companynumb": "JP-TEVA-2021-JP-1940034",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nHeparin dosing of patients anticoagulated with direct oral anticoagulants (DOACs) undergoing atrial fibrillation (AF) ablation can be challenging as they require more heparin than those on warfarin therapy. We sought to compare periprocedural activated clotting times (ACTs) of patients on warfarin vs. DOAC and determine an optimal weight-based heparin dosage strategy.\n\n\nMETHODS\nPatients who underwent AF ablation over 28 months were reviewed for type of anticoagulation, intraprocedural heparin dosing, ACTs, and adverse outcomes. A heparin dosing strategy was then tested in a prospective validation cohort.\n\n\nRESULTS\nThere were 89 patients in the DOAC group and 43 in the warfarin group. Demographics, comorbidities, and complication rates were similar. Mean ACT and percentage of therapeutic ACTs were lower in the DOAC group, most significantly in those with a weight > 90 kg. In DOAC patients, a higher initial heparin bolus ≥ 150 units/kg yielded a higher percentage of therapeutic intraprocedural ACTs (49% ± 10 vs. 29% ± 7, p = 0.0008). In a prospective validation cohort of 25 patients administered an initial heparin bolus ≥ 150 units/kg, the mean ACT was 295 ± 33 and 49% of the ACTs collected were therapeutic, similar to findings of our high-dose retrospective subgroup.\n\n\nCONCLUSIONS\nPatients on DOACs require more heparin during AF ablation to achieve therapeutic ACT. We suggest an initial heparin dose of at least 150 units/kg in this subset of patients, particularly in those with a weight > 90 kg.",
"affiliations": "Division of Cardiology/Electrophysiology, Medical University of South Carolina, 114 Doughty Street- MSC 592, Charleston, SC, 29425, USA.;Division of Cardiology/Electrophysiology, Medical University of South Carolina, 114 Doughty Street- MSC 592, Charleston, SC, 29425, USA.;Division Department of Internal Medicine, University of Missouri, One Hospital Drive, MA432, Columbia, MO, 65212, USA.;Division of Cardiovascular Medicine, University of Missouri, One Hospital Drive, CE 306, Columbia, MO, 65212, USA.;Division of Cardiovascular Medicine, University of Missouri, One Hospital Drive, CE 306, Columbia, MO, 65212, USA.;Division of Cardiovascular Medicine, University of Missouri, One Hospital Drive, CE 306, Columbia, MO, 65212, USA. gautamsa@health.missouri.edu.",
"authors": "Payne|Joshua E|JE|http://orcid.org/0000-0002-4547-1549;Koerber|Scott M|SM|;Bickel|Trent|T|;Ghadban|Rugheed|R|;Flaker|Greg|G|;Gautam|Sandeep|S|",
"chemical_list": "D000925:Anticoagulants; D006493:Heparin",
"country": "Netherlands",
"delete": false,
"doi": "10.1007/s10840-019-00579-y",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1383-875X",
"issue": "58(2)",
"journal": "Journal of interventional cardiac electrophysiology : an international journal of arrhythmias and pacing",
"keywords": "Atrial fibrillation ablation; Heparin dosing; Intraprocedural anticoagulation",
"medline_ta": "J Interv Card Electrophysiol",
"mesh_terms": "D000925:Anticoagulants; D001281:Atrial Fibrillation; D017115:Catheter Ablation; D006493:Heparin; D006801:Humans; D012189:Retrospective Studies",
"nlm_unique_id": "9708966",
"other_id": null,
"pages": "185-191",
"pmc": null,
"pmid": "31230179",
"pubdate": "2020-08",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Higher initial weight-based heparin dosing is required with direct oral anticoagulants during catheter ablation for atrial fibrillation.",
"title_normalized": "higher initial weight based heparin dosing is required with direct oral anticoagulants during catheter ablation for atrial fibrillation"
} | [
{
"companynumb": "US-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2020-BI-041813",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "DABIGATRAN ETEXILATE MESYLATE"
... |
{
"abstract": "BACKGROUND\nPortugal is one of the countries with the highest tuberculosis (TB) burden in the European Union. Patients who are receiving antitumor necrosis factor (TNF) treatment should be screened and treated for latent tuberculosis infection (LTBI). This study aimed to evaluate the prevalence of LTBI and the number of active TB cases in patients with inflammatory bowel disease (IBD) treated with anti-TNF agents.\n\n\nMETHODS\nThis was a retrospective study from a Portuguese center that included patients with IBD who started anti-TNF treatment between 2013 and 2017. LTBI screening was considered positive in case of positive tuberculin skin test, positive/indeterminate interferon gamma release test, or history of exposure to TB irrespective of the results of the screening.\n\n\nRESULTS\nOne hundred and seventeen patients were included, 56% female, mean age 40 years; 91% had Crohn's disease; infliximab was initiated in 79%, adalimumab in 21%, and golimumab in 1%. Of these, 37 (32%) presented LTBI - tuberculin skin test was positive in 18 (49%) patients; interferon gamma release test was positive in 14 (38%) patients and undetermined in seven (19%); and there was a history of exposure in 12 (32%) patients. All patients screened with LTBI were on isoniazid for 9 months. During follow-up (mean 21.6 months), one patient under infliximab developed pleural TB 5 years after receiving treatment with isoniazid. None of the patients with negative LTBI screening developed active TB.\n\n\nCONCLUSIONS\nIn this sample of patients with IBD, the prevalence of LTBI before starting anti-TNF treatment was significant (32%), but only one patient had active TB after LTBI treatment.",
"affiliations": "Departments of Gastroenterology.;Pneumology, Centro Hospitalar de Vila Nova de Gaia e Espinho, Rua Conceição Fernandes, s/n, Vila Nova de Gaia, Portugal.;Departments of Gastroenterology.;Departments of Gastroenterology.;Departments of Gastroenterology.;Departments of Gastroenterology.;Departments of Gastroenterology.;Departments of Gastroenterology.;Departments of Gastroenterology.;Departments of Gastroenterology.",
"authors": "Sousa|Mafalda|M|;Ladeira|Inês|I|;Ponte|Ana|A|;Fernandes|Carlos|C|;Rodrigues|Adélia|A|;Silva|Ana P|AP|;Silva|João|J|;Gomes|Catarina|C|;Afeto|Edgar|E|;Carvalho|João|J|",
"chemical_list": "D000911:Antibodies, Monoclonal; D005765:Gastrointestinal Agents; D014409:Tumor Necrosis Factor-alpha; C529000:golimumab; D000069285:Infliximab; D000068879:Adalimumab",
"country": "England",
"delete": false,
"doi": "10.1097/MEG.0000000000001469",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0954-691X",
"issue": "31(9)",
"journal": "European journal of gastroenterology & hepatology",
"keywords": null,
"medline_ta": "Eur J Gastroenterol Hepatol",
"mesh_terms": "D000068879:Adalimumab; D000328:Adult; D000911:Antibodies, Monoclonal; D005260:Female; D005765:Gastrointestinal Agents; D006801:Humans; D015212:Inflammatory Bowel Diseases; D000069285:Infliximab; D055985:Latent Tuberculosis; D008297:Male; D011174:Portugal; D015995:Prevalence; D012189:Retrospective Studies; D014409:Tumor Necrosis Factor-alpha",
"nlm_unique_id": "9000874",
"other_id": null,
"pages": "1099-1102",
"pmc": null,
"pmid": "31206406",
"pubdate": "2019-09",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Screening for latent tuberculosis in patients with inflammatory bowel disease under antitumor necrosis factor: data from a Portuguese center.",
"title_normalized": "screening for latent tuberculosis in patients with inflammatory bowel disease under antitumor necrosis factor data from a portuguese center"
} | [
{
"companynumb": "PT-JNJFOC-20190716698",
"fulfillexpeditecriteria": "1",
"occurcountry": "PT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "INFLIXIMAB"
},
"drugadditional": "3",
"... |
{
"abstract": "Intranasal corticosteroid use during pregnancy has increased over the past decade.\n\n\n\nWe aim to estimate the safety of intranasal triamcinolone use during pregnancy, which was introduced for over-the-counter use in October 2013.\n\n\n\nWe designed a population-based prospective cohort study. From a cohort of 289,723 pregnancies in Montreal, Quebec, Canada, from 1998-2008, intranasal triamcinolone-exposed, other intranasal corticosteroid-exposed, and nonexposed women during the first trimester were studied for major congenital malformations (overall and organ specific) and spontaneous abortions and during the second/third trimesters for small-for-gestational age (SGA) newborns. The first trimester is the time window of interest for malformations and spontaneous abortion (organogenesis), and the second/third trimesters are the time windows of interest for SGA (fetal growth). Logistic regression model-based generalized estimating equations were used.\n\n\n\nAdjusting for potential confounders, use of intranasal triamcinolone during the first trimester of pregnancy was not significantly associated with the risk of overall congenital malformations (odds ratio [OR], 0.88; 95% CI, 0.60-1.28; 31 exposed cases) compared with nonexposure; however, it was associated with the risk of respiratory defects (OR, 2.71; 95% CI, 1.11-6.64; 5 exposed cases). Pregnancy exposure to intranasal triamcinolone was not significantly associated with the risk of spontaneous abortion (OR, 1.04; 95% CI, 0.76-1.43; 50 exposed cases). No association was found between second- or third-trimester exposure to intranasal triamcinolone and the risk of SGA (OR, 1.06; 95% CI, 0.79-1.43; 50 exposed cases).\n\n\n\nMaternal exposure to intranasal triamcinolone during pregnancy was not associated with the risk of SGA/spontaneous abortions/overall malformations. However, it has been shown to increase the risk of respiratory system defects. Chance finding cannot be ruled out.",
"affiliations": "Research Center, CHU Ste-Justine, Montreal, Quebec, Canada; Faculty of Pharmacy, University of Montreal, Montreal, Quebec, Canada. Electronic address: anick.berard@umontreal.ca.;Faculty of Pharmacy, University of Montreal, Montreal, Quebec, Canada.;Sanofi, R&D, Global Pharmacovigilance and Epidemiology, Paris, France.;Sanofi, R&D, Global Pharmacovigilance and Epidemiology, Bridgewater, NJ.",
"authors": "Bérard|Anick|A|;Sheehy|Odile|O|;Kurzinger|Marie-Laure|ML|;Juhaeri|Juhaeri|J|",
"chemical_list": "D000893:Anti-Inflammatory Agents; D005938:Glucocorticoids; D014221:Triamcinolone",
"country": "United States",
"delete": false,
"doi": "10.1016/j.jaci.2016.01.021",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0091-6749",
"issue": "138(1)",
"journal": "The Journal of allergy and clinical immunology",
"keywords": "Triamcinolone; major congenital malformations; pregnancy; rhinitis; small for gestational age; spontaneous abortions",
"medline_ta": "J Allergy Clin Immunol",
"mesh_terms": "D000022:Abortion, Spontaneous; D000281:Administration, Intranasal; D000328:Adult; D000893:Anti-Inflammatory Agents; D002170:Canada; D015897:Comorbidity; D000013:Congenital Abnormalities; D005260:Female; D005938:Glucocorticoids; D006801:Humans; D007236:Infant, Small for Gestational Age; D008137:Longitudinal Studies; D018811:Maternal Exposure; D016017:Odds Ratio; D011247:Pregnancy; D011256:Pregnancy Outcome; D062486:Public Health Surveillance; D012307:Risk Factors; D014221:Triamcinolone; D055815:Young Adult",
"nlm_unique_id": "1275002",
"other_id": null,
"pages": "97-104.e7",
"pmc": null,
"pmid": "27045580",
"pubdate": "2016-07",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Intranasal triamcinolone use during pregnancy and the risk of adverse pregnancy outcomes.",
"title_normalized": "intranasal triamcinolone use during pregnancy and the risk of adverse pregnancy outcomes"
} | [
{
"companynumb": "CA-PFIZER INC-2016497927",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drugadditional": "3",
... |
{
"abstract": "OBJECTIVE\nWe investigated the incidence of stroke and stroke subtypes in a population-based cohort of patients in France treated with growth hormone (GH) for short stature in childhood.\n\n\nMETHODS\nAdult morbidity data were obtained in 2008-2010 for 6,874 children with idiopathic isolated GH deficiency or short stature who started GH treatment between 1985 and 1996. Cerebrovascular events were validated using medical reports and imaging data and classified according to standard definitions of subarachnoid hemorrhage, intracerebral hemorrhage, and ischemic stroke. Case ascertainment completeness was estimated with capture-recapture methods. The incidence of stroke and of stroke subtypes was calculated and compared with population values extracted from registries in Dijon and Oxford, between 2000 and 2012.\n\n\nRESULTS\nUsing both Dijon and Oxford population-based registries as references, there was a significantly higher risk of stroke among patients treated with GH in childhood. The excess risk of stroke was mainly attributable to a very substantially and significantly higher risk of hemorrhagic stroke (standardized incidence ratio from 3.5 to 7.0 according to the registry rates considered, and accounting or not accounting for missed cases), and particularly subarachnoid hemorrhage (standardized incidence ratio from 5.7 to 9.3).\n\n\nCONCLUSIONS\nWe report a strong relationship between hemorrhagic stroke and GH treatment in childhood for isolated growth hormone deficiency or childhood short stature. Patients treated with GH worldwide should be advised about this association and further studies should evaluate the potentially causal role of GH treatment in these findings.",
"affiliations": "From the Biostatistics and Epidemiology Unit (A.P., E.E., J.C.), and APEMAC Equipe d'Accueil 4360, Hôtel Dieu, Assistance Publique-Hôpitaux de Paris, Université de Lorraine and University Paris Descartes, Paris; University Paris Diderot (A.P., F.L., J.-C.C.), Sorbonne Paris Cité; Service d'Endocrinologie Diabétologie Pédiatrique et Centre de Référence des Maladies Endocriniennes Rares de la Croissance (A.P., F.L., J.-C.C.), Hôpital Robert Debré, Assistance Publique-Hôpitaux de Paris; Institut National de la Santé et de la Recherche Médicale Unité CIE-5 (A.P., F.L., J.-C.C.), Paris; Université Caen Basse Normandie (E.T.), Inserm U919, CHU Côte de Nacre, Caen; Dijon Stroke Registry (Y.B., M.G.), EA4184, University Hospital, Medical School of Dijon, University of Burgundy, Dijon, France; and Stroke Prevention Research Unit (P.M.R.), Nuffield Department of Clinical Neuroscience, University of Oxford, UK.;From the Biostatistics and Epidemiology Unit (A.P., E.E., J.C.), and APEMAC Equipe d'Accueil 4360, Hôtel Dieu, Assistance Publique-Hôpitaux de Paris, Université de Lorraine and University Paris Descartes, Paris; University Paris Diderot (A.P., F.L., J.-C.C.), Sorbonne Paris Cité; Service d'Endocrinologie Diabétologie Pédiatrique et Centre de Référence des Maladies Endocriniennes Rares de la Croissance (A.P., F.L., J.-C.C.), Hôpital Robert Debré, Assistance Publique-Hôpitaux de Paris; Institut National de la Santé et de la Recherche Médicale Unité CIE-5 (A.P., F.L., J.-C.C.), Paris; Université Caen Basse Normandie (E.T.), Inserm U919, CHU Côte de Nacre, Caen; Dijon Stroke Registry (Y.B., M.G.), EA4184, University Hospital, Medical School of Dijon, University of Burgundy, Dijon, France; and Stroke Prevention Research Unit (P.M.R.), Nuffield Department of Clinical Neuroscience, University of Oxford, UK.;From the Biostatistics and Epidemiology Unit (A.P., E.E., J.C.), and APEMAC Equipe d'Accueil 4360, Hôtel Dieu, Assistance Publique-Hôpitaux de Paris, Université de Lorraine and University Paris Descartes, Paris; University Paris Diderot (A.P., F.L., J.-C.C.), Sorbonne Paris Cité; Service d'Endocrinologie Diabétologie Pédiatrique et Centre de Référence des Maladies Endocriniennes Rares de la Croissance (A.P., F.L., J.-C.C.), Hôpital Robert Debré, Assistance Publique-Hôpitaux de Paris; Institut National de la Santé et de la Recherche Médicale Unité CIE-5 (A.P., F.L., J.-C.C.), Paris; Université Caen Basse Normandie (E.T.), Inserm U919, CHU Côte de Nacre, Caen; Dijon Stroke Registry (Y.B., M.G.), EA4184, University Hospital, Medical School of Dijon, University of Burgundy, Dijon, France; and Stroke Prevention Research Unit (P.M.R.), Nuffield Department of Clinical Neuroscience, University of Oxford, UK.;From the Biostatistics and Epidemiology Unit (A.P., E.E., J.C.), and APEMAC Equipe d'Accueil 4360, Hôtel Dieu, Assistance Publique-Hôpitaux de Paris, Université de Lorraine and University Paris Descartes, Paris; University Paris Diderot (A.P., F.L., J.-C.C.), Sorbonne Paris Cité; Service d'Endocrinologie Diabétologie Pédiatrique et Centre de Référence des Maladies Endocriniennes Rares de la Croissance (A.P., F.L., J.-C.C.), Hôpital Robert Debré, Assistance Publique-Hôpitaux de Paris; Institut National de la Santé et de la Recherche Médicale Unité CIE-5 (A.P., F.L., J.-C.C.), Paris; Université Caen Basse Normandie (E.T.), Inserm U919, CHU Côte de Nacre, Caen; Dijon Stroke Registry (Y.B., M.G.), EA4184, University Hospital, Medical School of Dijon, University of Burgundy, Dijon, France; and Stroke Prevention Research Unit (P.M.R.), Nuffield Department of Clinical Neuroscience, University of Oxford, UK.;From the Biostatistics and Epidemiology Unit (A.P., E.E., J.C.), and APEMAC Equipe d'Accueil 4360, Hôtel Dieu, Assistance Publique-Hôpitaux de Paris, Université de Lorraine and University Paris Descartes, Paris; University Paris Diderot (A.P., F.L., J.-C.C.), Sorbonne Paris Cité; Service d'Endocrinologie Diabétologie Pédiatrique et Centre de Référence des Maladies Endocriniennes Rares de la Croissance (A.P., F.L., J.-C.C.), Hôpital Robert Debré, Assistance Publique-Hôpitaux de Paris; Institut National de la Santé et de la Recherche Médicale Unité CIE-5 (A.P., F.L., J.-C.C.), Paris; Université Caen Basse Normandie (E.T.), Inserm U919, CHU Côte de Nacre, Caen; Dijon Stroke Registry (Y.B., M.G.), EA4184, University Hospital, Medical School of Dijon, University of Burgundy, Dijon, France; and Stroke Prevention Research Unit (P.M.R.), Nuffield Department of Clinical Neuroscience, University of Oxford, UK.;From the Biostatistics and Epidemiology Unit (A.P., E.E., J.C.), and APEMAC Equipe d'Accueil 4360, Hôtel Dieu, Assistance Publique-Hôpitaux de Paris, Université de Lorraine and University Paris Descartes, Paris; University Paris Diderot (A.P., F.L., J.-C.C.), Sorbonne Paris Cité; Service d'Endocrinologie Diabétologie Pédiatrique et Centre de Référence des Maladies Endocriniennes Rares de la Croissance (A.P., F.L., J.-C.C.), Hôpital Robert Debré, Assistance Publique-Hôpitaux de Paris; Institut National de la Santé et de la Recherche Médicale Unité CIE-5 (A.P., F.L., J.-C.C.), Paris; Université Caen Basse Normandie (E.T.), Inserm U919, CHU Côte de Nacre, Caen; Dijon Stroke Registry (Y.B., M.G.), EA4184, University Hospital, Medical School of Dijon, University of Burgundy, Dijon, France; and Stroke Prevention Research Unit (P.M.R.), Nuffield Department of Clinical Neuroscience, University of Oxford, UK.;From the Biostatistics and Epidemiology Unit (A.P., E.E., J.C.), and APEMAC Equipe d'Accueil 4360, Hôtel Dieu, Assistance Publique-Hôpitaux de Paris, Université de Lorraine and University Paris Descartes, Paris; University Paris Diderot (A.P., F.L., J.-C.C.), Sorbonne Paris Cité; Service d'Endocrinologie Diabétologie Pédiatrique et Centre de Référence des Maladies Endocriniennes Rares de la Croissance (A.P., F.L., J.-C.C.), Hôpital Robert Debré, Assistance Publique-Hôpitaux de Paris; Institut National de la Santé et de la Recherche Médicale Unité CIE-5 (A.P., F.L., J.-C.C.), Paris; Université Caen Basse Normandie (E.T.), Inserm U919, CHU Côte de Nacre, Caen; Dijon Stroke Registry (Y.B., M.G.), EA4184, University Hospital, Medical School of Dijon, University of Burgundy, Dijon, France; and Stroke Prevention Research Unit (P.M.R.), Nuffield Department of Clinical Neuroscience, University of Oxford, UK.;From the Biostatistics and Epidemiology Unit (A.P., E.E., J.C.), and APEMAC Equipe d'Accueil 4360, Hôtel Dieu, Assistance Publique-Hôpitaux de Paris, Université de Lorraine and University Paris Descartes, Paris; University Paris Diderot (A.P., F.L., J.-C.C.), Sorbonne Paris Cité; Service d'Endocrinologie Diabétologie Pédiatrique et Centre de Référence des Maladies Endocriniennes Rares de la Croissance (A.P., F.L., J.-C.C.), Hôpital Robert Debré, Assistance Publique-Hôpitaux de Paris; Institut National de la Santé et de la Recherche Médicale Unité CIE-5 (A.P., F.L., J.-C.C.), Paris; Université Caen Basse Normandie (E.T.), Inserm U919, CHU Côte de Nacre, Caen; Dijon Stroke Registry (Y.B., M.G.), EA4184, University Hospital, Medical School of Dijon, University of Burgundy, Dijon, France; and Stroke Prevention Research Unit (P.M.R.), Nuffield Department of Clinical Neuroscience, University of Oxford, UK.;From the Biostatistics and Epidemiology Unit (A.P., E.E., J.C.), and APEMAC Equipe d'Accueil 4360, Hôtel Dieu, Assistance Publique-Hôpitaux de Paris, Université de Lorraine and University Paris Descartes, Paris; University Paris Diderot (A.P., F.L., J.-C.C.), Sorbonne Paris Cité; Service d'Endocrinologie Diabétologie Pédiatrique et Centre de Référence des Maladies Endocriniennes Rares de la Croissance (A.P., F.L., J.-C.C.), Hôpital Robert Debré, Assistance Publique-Hôpitaux de Paris; Institut National de la Santé et de la Recherche Médicale Unité CIE-5 (A.P., F.L., J.-C.C.), Paris; Université Caen Basse Normandie (E.T.), Inserm U919, CHU Côte de Nacre, Caen; Dijon Stroke Registry (Y.B., M.G.), EA4184, University Hospital, Medical School of Dijon, University of Burgundy, Dijon, France; and Stroke Prevention Research Unit (P.M.R.), Nuffield Department of Clinical Neuroscience, University of Oxford, UK. joel.coste@htd.aphp.fr.",
"authors": "Poidvin|Amélie|A|;Touzé|Emmanuel|E|;Ecosse|Emmanuel|E|;Landier|Fabienne|F|;Béjot|Yannick|Y|;Giroud|Maurice|M|;Rothwell|Peter M|PM|;Carel|Jean-Claude|JC|;Coste|Joël|J|",
"chemical_list": "D019382:Human Growth Hormone",
"country": "United States",
"delete": false,
"doi": "10.1212/WNL.0000000000000737",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0028-3878",
"issue": "83(9)",
"journal": "Neurology",
"keywords": null,
"medline_ta": "Neurology",
"mesh_terms": "D000328:Adult; D001827:Body Height; D002648:Child; D005602:France; D006130:Growth Disorders; D019382:Human Growth Hormone; D006801:Humans; D015994:Incidence; D012307:Risk Factors; D020521:Stroke",
"nlm_unique_id": "0401060",
"other_id": null,
"pages": "780-6",
"pmc": null,
"pmid": "25122206",
"pubdate": "2014-08-26",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Growth hormone treatment for childhood short stature and risk of stroke in early adulthood.",
"title_normalized": "growth hormone treatment for childhood short stature and risk of stroke in early adulthood"
} | [
{
"companynumb": "FR-ROCHE-1521754",
"fulfillexpeditecriteria": "1",
"occurcountry": null,
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "SOMATROPIN"
},
"drugadditional": "4",
"druga... |
{
"abstract": "The global pandemic of Corona Virus Disease 2019 (COVID-19) has led to the re-purposing of medications, such as hydroxychloroquine and lopinavir-ritonavir in the treatment of the earlier phase of COVID-19 before the recognized benefit of steroids and antiviral. We aim to explore the corrected QT (QTc) interval and 'torsadogenic' potential of hydroxychloroquine and lopinavir-ritonavir utilising a combination of smartphone electrocardiogram and 12-lead electrocardiogram monitoring.\n\n\n\nBetween 16-April-2020 to 30-April- 2020, patients with suspected or confirmed for COVID-19 indicated for in-patient treatment with hydroxychloroquine with or without lopinavir-ritonavir to the Sarawak General Hospital were monitored with KardiaMobile smartphone electrocardiogram (AliveCor®, Mountain View, CA) or standard 12-lead electrocardiogram. The baseline and serial QTc intervals were monitored till the last dose of medications or until the normalization of the QTc interval.\n\n\n\nThirty patients were treated with hydroxychloroquine, and 20 (66.7%) patients received a combination of hydroxychloroquine and lopinavir-ritonavir therapy. The maximum QTc interval was significantly prolonged compared to baseline (434.6±28.2msec vs. 458.6±47.1msec, p=0.001). The maximum QTc interval (456.1±45.7msec vs. 464.6±45.2msec, p=0.635) and the delta QTc (32.6±38.5msec vs. 26.3±35.8msec, p=0.658) were not significantly different between patients on hydroxychloroquine or a combination of hydroxychloroquine and lopinavir-ritonavir. Five (16.7%) patients had QTc of 500msec or more. Four (13.3%) patients required discontinuation of hydroxychloroquine and 3 (10.0%) patients required discontinuation of lopinavirritonavir due to QTc prolongation. However, no torsade de pointes was observed.\n\n\n\nQTc monitoring using smartphone electrocardiogram was feasible in COVID-19 patients treated with hydroxychloroquine with or without lopinavir-ritonavir. The usage of hydroxychloroquine and lopinavir-ritonavir resulted in QTc prolongation, but no torsade de pointes or arrhythmogenic death was observed.",
"affiliations": "Sarawak General Hospital, Department of Medicine, Kuching, Sarawak, Malaysia. andyko1989@gmail.com.;Sarawak Heart Centre, Department of Cardiology, Sarawak, Malaysia.;Sarawak Heart Centre, Department of Cardiology, Sarawak, Malaysia.;Sarawak Heart Centre, Department of Cardiology, Sarawak, Malaysia.;Sarawak General Hospital, Department of Medicine, Kuching, Sarawak, Malaysia.;Sarawak General Hospital, Department of Medicine, Kuching, Sarawak, Malaysia.;Sarawak Heart Centre, Department of Cardiology, Sarawak, Malaysia.",
"authors": "Andy Ko|T Y|TY|;Chen|L S|LS|;Pang|I X|IX|;Ling|H S|HS|;Wong|T C|TC|;Sia Tonnii|L L|LL|;Koh|K T|KT|",
"chemical_list": "D000998:Antiviral Agents; D004338:Drug Combinations; D004791:Enzyme Inhibitors; C558899:lopinavir-ritonavir drug combination; D061466:Lopinavir; D006886:Hydroxychloroquine; D019438:Ritonavir",
"country": "Malaysia",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0300-5283",
"issue": "76(2)",
"journal": "The Medical journal of Malaysia",
"keywords": null,
"medline_ta": "Med J Malaysia",
"mesh_terms": "D000328:Adult; D000368:Aged; D000998:Antiviral Agents; D000086382:COVID-19; D004338:Drug Combinations; D004562:Electrocardiography; D004791:Enzyme Inhibitors; D005260:Female; D006801:Humans; D006886:Hydroxychloroquine; D008133:Long QT Syndrome; D061466:Lopinavir; D008297:Male; D008875:Middle Aged; D063731:Mobile Applications; D019438:Ritonavir; D000068997:Smartphone",
"nlm_unique_id": "0361547",
"other_id": null,
"pages": "125-130",
"pmc": null,
"pmid": "33742617",
"pubdate": "2021-03",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Smartphone electrocardiogram for QT interval monitoring in Coronavirus Disease 2019 (COVID-19) patients treated with Hydroxychloroquine.",
"title_normalized": "smartphone electrocardiogram for qt interval monitoring in coronavirus disease 2019 covid 19 patients treated with hydroxychloroquine"
} | [
{
"companynumb": "NVSC2021MY106601",
"fulfillexpeditecriteria": "1",
"occurcountry": "MY",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "HYDROXYCHLOROQUINE SULFATE"
},
"drugadditional": null,... |
{
"abstract": "BACKGROUND\nARIEL (Darunavir in treatment-experienced pediatric population) was a phase II, open-label study assessing safety and antiviral activity of darunavir/ritonavir twice daily with an optimized background regimen (OBR) in treatment-experienced, HIV-1-infected pediatric patients (3 to <6 years, weighing 10 to <20 kg).\n\n\nMETHODS\nThe study consisted of an initial 4-week screening period, 48 weeks of treatment and a 4-week follow-up period. Patients initially received darunavir/ritonavir 20/3 mg/kg twice-daily for 2 weeks. Following review of pharmacokinetic, safety and antiviral data, the doses of darunavir/ritonavir were adjusted to 25/3 mg/kg twice-daily for patients <15 kg, and 375/50 mg twice-daily for patients 15 to <20 kg.\n\n\nRESULTS\nOf the 34 patients screened, 21 were treated (median treatment duration 48.6 weeks). Darunavir plus an OBR was well tolerated over 48 weeks, with no new safety concerns, and a comparable safety profile to that seen in older children and adults. All treatment-emergent lipid-related and glucose-related laboratory abnormalities were grade 1 or 2. At week 48, 17 of 21 patients (81.0%) had a confirmed virologic response (intent-to-treat, time-to-loss of virologic response). Improvements in height and weight were seen during the study.\n\n\nCONCLUSIONS\nNo new safety concerns were observed over a 48 week period. These results led to lowering the age to 3 years at which darunavir/ritonavir is indicated for use in treatment-experienced pediatric patients. This study also established doses of darunavir to use in treatment-experienced, HIV-1-infected patients aged 3 to <6 years. A high virologic response was observed with this dose. No development of resistance was observed in patients who experienced virologic failure.",
"affiliations": "From the *Perinatal HIV Research Unit, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa; †Helios Salud, Buenos Aires, Argentina; ‡Gaitonade Center for AIDS Research and Education (YRG CARE), VHS, Chennai, India; §Department of Infectious Diseases, Hospital Geral De Nova Iguacu & Laboratório de AIDS e Imunologia Molecular, Fiocruz/IOC, Rio De Janeiro, Brazil; ¶Janssen Infectious Diseases BVBA, Beerse, Belgium; and ‖Janssen Research & Development LLC, Titusville, New Jersey.",
"authors": "Violari|Avy|A|;Bologna|Rosa|R|;Kumarasamy|Nagalingeswaran|N|;Pilotto|Jose Henrique|JH|;Hendrickx|Annemie|A|;Kakuda|Thomas N|TN|;Lathouwers|Erkki|E|;Opsomer|Magda|M|;Van de Casteele|Tom|T|;Tomaka|Frank L|FL|",
"chemical_list": "D019380:Anti-HIV Agents; D019438:Ritonavir; D000069454:Darunavir",
"country": "United States",
"delete": false,
"doi": "10.1097/INF.0000000000000644",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0891-3668",
"issue": "34(5)",
"journal": "The Pediatric infectious disease journal",
"keywords": null,
"medline_ta": "Pediatr Infect Dis J",
"mesh_terms": "D019380:Anti-HIV Agents; D002648:Child; D002675:Child, Preschool; D000069454:Darunavir; D024882:Drug Resistance, Viral; D005260:Female; D015658:HIV Infections; D015497:HIV-1; D006801:Humans; D008297:Male; D055118:Medication Adherence; D019438:Ritonavir",
"nlm_unique_id": "8701858",
"other_id": null,
"pages": "e132-7",
"pmc": null,
"pmid": "25719453",
"pubdate": "2015-05",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Safety and efficacy of darunavir/ritonavir in treatment-experienced pediatric patients: week 48 results of the ARIEL trial.",
"title_normalized": "safety and efficacy of darunavir ritonavir in treatment experienced pediatric patients week 48 results of the ariel trial"
} | [
{
"companynumb": "ZA-CIPLA LTD.-2015ZA08198",
"fulfillexpeditecriteria": "1",
"occurcountry": "ZA",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LOPINAVIR\\RITONAVIR"
},
"drugadditional": nu... |
{
"abstract": "We describe two Malawian adults on successful antiretroviral therapy who experienced frequent malaria episodes after stopping cotrimoxazole prophylaxis. We argue that, in addition to stopping cotrimoxazole, diminished malaria immunity and drug interactions between efavirenz and artemether-lumefantrine may have played a causative role in the recurrent malaria our patients experienced.",
"affiliations": "Dignitas International, Zomba, Malawi.;Dignitas International, Zomba, Malawi.;Blantyre Malaria Project, College of Medicine, University of Malawi, Blantyre, Malawi.;Blantyre Malaria Project, College of Medicine, University of Malawi, Blantyre, Malawi.;Blantyre Malaria Project, College of Medicine, University of Malawi, Blantyre, Malawi.;Blantyre Malaria Project, College of Medicine, University of Malawi, Blantyre, Malawi.;Division of Malaria Research, Institute for Global Health, University of Maryland School of Medicine, Baltimore, Maryland, USA.;Department of Medicine, College of Medicine, University of Malawi, Blantyre, Malawi.;Blantyre Malaria Project, College of Medicine, University of Malawi, Blantyre, Malawi.;Division of Malaria Research, Institute for Global Health, University of Maryland School of Medicine, Baltimore, Maryland, USA.;Division of Malaria Research, Institute for Global Health, University of Maryland School of Medicine, Baltimore, Maryland, USA.;Dignitas International, Zomba, Malawi.",
"authors": "Nyangulu|Wongani Js|WJ|;Mwinjiwa|Edson|E|;Divala|Titus H|TH|;Mungwira|Randy G|RG|;Nyirenda|Osward|O|;Kanjala|Maxwell|M|;Mbambo|Gillian|G|;Mallewa|Jane|J|;Taylor|Terrie E|TE|;Laurens|Matthew B|MB|;Laufer|Miriam K|MK|;van Oosterhout|Joep J|JJ|",
"chemical_list": "D019380:Anti-HIV Agents; D000962:Antimalarials; D015662:Trimethoprim, Sulfamethoxazole Drug Combination",
"country": "Malawi",
"delete": false,
"doi": "10.4314/mmj.v29i1.12",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1995-7262",
"issue": "29(1)",
"journal": "Malawi medical journal : the journal of Medical Association of Malawi",
"keywords": null,
"medline_ta": "Malawi Med J",
"mesh_terms": "D000328:Adult; D019380:Anti-HIV Agents; D000962:Antimalarials; D023241:Antiretroviral Therapy, Highly Active; D004347:Drug Interactions; D005260:Female; D015658:HIV Infections; D006801:Humans; D008288:Malaria; D008875:Middle Aged; D015662:Trimethoprim, Sulfamethoxazole Drug Combination",
"nlm_unique_id": "9500170",
"other_id": null,
"pages": "57-60",
"pmc": null,
"pmid": "28567199",
"pubdate": "2017-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "18978480;17918086;24885714;17885296;12377597;24729586;17720665;25391641;27332904;25656623;24505451;16631881;25807475;22423133;20347483;19136431;27431995;25906774;25297720",
"title": "Frequent malaria illness episodes in two Malawian patients on antiretroviral therapy soon after stopping cotrimoxazole preventive therapy.",
"title_normalized": "frequent malaria illness episodes in two malawian patients on antiretroviral therapy soon after stopping cotrimoxazole preventive therapy"
} | [
{
"companynumb": "MW-SUN PHARMACEUTICAL INDUSTRIES LTD-2017R1-148962",
"fulfillexpeditecriteria": "1",
"occurcountry": "MW",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TENOFOVIR"
},
"druga... |
{
"abstract": "Pure red cell aplasia is a relatively rare disease characterized by selective suppression of erythroid precursors in the bone marrow. This disease can also develop secondary to several other diseases and as a side effect of certain drugs. Tacrolimus, a potent immunosuppressant, is widely used in organ transplant. Several cases of pure red cell aplasia due to tacrolimus administration in organ transplant recipients have been reported.Here, we report a case of reversible pure red cell aplasia that developed during tacrolimus therapy following living-donor liver transplant. The patient, a 1-year-old girl diagnosed with progressive familial intrahepatic cholestasis type II, underwent living-donor liver transplant when she was 10 months old. She was started on 3 immunosuppressants posttransplant: tacrolimus (0.1 mg/kg/day twice daily), mycophenolate mofetil, and prednisolone (0.2 mg/kg/day). One year after transplant, she developed severe progressive anemia. Her hemoglobin concentration was extremely low (5.4 g/dL). A bone marrow biopsy revealed severe hypoplasia of the erythroblasts with no abnormality of other myelocytes. These findings were suggestive of pure red cell aplasia; we suspected that tacrolimus had caused this based on similar previous cases of tacrolimus-associated pure red cell aplasia. Accordingly, tacrolimus was switched to cyclosporine after this diagnosis. One week after this switch, the patient's red blood cell counts, reticulocytes, and hemoglobin concentration increased. Although tacrolimus is considered to have no significant potential for myelosuppression, cases of tacrolimus-related pure red cell aplasia have occurred. In patients who develop pure red cell aplasia during tacrolimus treatment following living-donor liver transplant, clinicians should consider switching from tacrolimus to another immunosuppressant.",
"affiliations": "From the Department of Pediatrics, Kumamoto University, Kumamoto, Japan.",
"authors": "Watanabe|Suguru|S|;Sakamoto|Rieko|R|;Yamamoto|Hidekazu|H|;Imaya|Masayuki|M|;Yamashita|Takahiro|T|;Anann|Tadashi|T|;Nakamura|Kimitoshi|K|",
"chemical_list": "D007166:Immunosuppressive Agents; D016572:Cyclosporine; D016559:Tacrolimus",
"country": "Turkey",
"delete": false,
"doi": "10.6002/ect.2019.0075",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1304-0855",
"issue": "18(7)",
"journal": "Experimental and clinical transplantation : official journal of the Middle East Society for Organ Transplantation",
"keywords": null,
"medline_ta": "Exp Clin Transplant",
"mesh_terms": "D002780:Cholestasis, Intrahepatic; D016572:Cyclosporine; D057915:Drug Substitution; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents; D007223:Infant; D016031:Liver Transplantation; D019520:Living Donors; D012010:Red-Cell Aplasia, Pure; D016559:Tacrolimus; D016896:Treatment Outcome",
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"title": "Pediatric Pure Red Cell Aplasia Caused by Tacrolimus After Living-Donor Liver Transplant.",
"title_normalized": "pediatric pure red cell aplasia caused by tacrolimus after living donor liver transplant"
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"abstract": "OBJECTIVE\nTo analyze the drug adherence rates and overall survival for in patients treated with arbiraterone acetate (AA) for castration-resistant prostate cancer (CRPC).\n\n\nMETHODS\nThe database of the largest insurance company in Austria (Wiener Gebietskrankenkasse) was analyzed. Data on all CRPC patients with at least one prescription of AA between November 2011 and December 2014 in the postchemotherapy setting were collated and compared to the Austrian death and hospital admission statistics. Drug adherence was estimated by the medication possession ratio (MPR).\n\n\nRESULTS\nData of 270 patients (mean age 73.5 ± 8.9 years) were analyzed. The mean duration of AA treatment was 9.8 months (range 1-38 months). The duration of AA treatment was as follows: 0-2 months 53 patients (19.6 %), 3-5 months 73 patients (28.1 %), 6-10 months 67 patients (24.8 %) and >10 months 97 patients (35.9 %). The median MPR was 100 % and in 241 (89.2 %) the MPR exceeded ≥80 %. The median overall survival (OS) was 11 months. Based on Kaplan-Meier analysis, the 6 month OS was 61 %, 12 month OS 43 %, 18 month OS 35 % and >24 month OS 24 %. The OS was strongly correlated to patient age and the duration of AA treatment. Of all 270 patients, only 19 (7 %) were not hospitalized during their remaining life span and 71 (26.2 %) spent more than 50% of their remaining life span in hospital care.\n\n\nCONCLUSIONS\nThe OS was shorter than in phase III trials and strongly correlated to patient age and the duration of AA treatment. The high mortality rate within the first 6 months of AA treatment in this real-life setting suggests a less stringent patient selection than in a phase III trial.",
"affiliations": "Department of Urology and Andrology, Kaiser-Franz-Josef Spital, Kundratstrasse 3, 1100, Vienna, Austria.;Department of Urology, Medical University of Vienna, Vienna, Austria.;Department of Urology and Andrology, Kaiser-Franz-Josef Spital, Kundratstrasse 3, 1100, Vienna, Austria. stephan.madersbacher@wienkav.at.;Department of Urology, Landesklinikum Wiener Neustadt, Wiener Neustadt, Austria.",
"authors": "Mohamad Al-Ali|Badereddin|B|;Kramer|Gero|G|;Madersbacher|Stephan|S|;Berger|Ingrid|I|",
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"fulltext": "\n==== Front\nWien Klin WochenschrWien. Klin. WochenschrWiener Klinische Wochenschrift0043-53251613-7671Springer Vienna Vienna 27596230106710.1007/s00508-016-1067-9Original ArticleAbiraterone for castration-resistant prostate cancer: adherence, survival and hospitalization Analysis of a medical claims databaseMohamad Al-Ali Badereddin 14Kramer Gero 2Madersbacher Stephan MD, FEBU+43-1-601914808+43-1-601914809stephan.madersbacher@wienkav.at 1Berger Ingrid 31 grid.414836.cDepartment of Urology and Andrology, Kaiser-Franz-Josef Spital, Kundratstrasse 3, 1100 Vienna, Austria 2 0000 0000 9259 8492grid.22937.3dDepartment of Urology, Medical University of Vienna, Vienna, Austria 3 Department of Urology, Landesklinikum Wiener Neustadt, Wiener Neustadt, Austria 4 0000 0000 8988 2476grid.11598.34Department of Urology, Medical University of Graz, Graz, Austria 5 9 2016 5 9 2016 2017 129 11 380 384 12 1 2016 29 7 2016 © The Author(s) 2016\nOpen Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.Summary\nObjective\nTo analyze the drug adherence rates and overall survival for in patients treated with arbiraterone acetate (AA) for castration-resistant prostate cancer (CRPC).\n\nMethods\nThe database of the largest insurance company in Austria (Wiener Gebietskrankenkasse) was analyzed. Data on all CRPC patients with at least one prescription of AA between November 2011 and December 2014 in the postchemotherapy setting were collated and compared to the Austrian death and hospital admission statistics. Drug adherence was estimated by the medication possession ratio (MPR).\n\nResults\nData of 270 patients (mean age 73.5 ± 8.9 years) were analyzed. The mean duration of AA treatment was 9.8 months (range 1–38 months). The duration of AA treatment was as follows: 0–2 months 53 patients (19.6 %), 3–5 months 73 patients (28.1 %), 6–10 months 67 patients (24.8 %) and >10 months 97 patients (35.9 %). The median MPR was 100 % and in 241 (89.2 %) the MPR exceeded ≥80 %. The median overall survival (OS) was 11 months. Based on Kaplan-Meier analysis, the 6 month OS was 61 %, 12 month OS 43 %, 18 month OS 35 % and >24 month OS 24 %. The OS was strongly correlated to patient age and the duration of AA treatment. Of all 270 patients, only 19 (7 %) were not hospitalized during their remaining life span and 71 (26.2 %) spent more than 50% of their remaining life span in hospital care.\n\nConclusion\nThe OS was shorter than in phase III trials and strongly correlated to patient age and the duration of AA treatment. The high mortality rate within the first 6 months of AA treatment in this real-life setting suggests a less stringent patient selection than in a phase III trial.\n\nKeywords\nMedication adherenceProstate cancerAbiraterone acetateCastration-resistant prostate cancerSurvivalno fundingissue-copyright-statement© Springer-Verlag GmbH Austria 2017\n==== Body\nIntroduction\nIn the past 15 years oral anticancer medications have become more widely available for the treatment of a variety of cancers and have increasingly been used as an alternative to intravenous (iv) therapy. This trend is also demonstrable in the management of advanced prostate cancer (PC). The introduction of the oral drugs abiraterone acetate (AA) and enzalutamide [1] has revolutionized the management of castration resistant prostate cancer (CRPC). The availability of oral anticancer drugs aligns with the preferences of cancer patients and may help to improve patient quality of life and reduce the time spent in healthcare settings; however, the availability of oral drugs induces the issue of drug compliance or adherence [2, 3]. Both terms define the extent to which patients take medications as prescribed by their healthcare providers. Without adequate adherence, the efficacy of oral drugs might fall below of those administered intravenously. The second threat of an oral drug, particularly if well tolerated such as AA and enzalutamide, is that these drugs might be prescribed too liberally.\n\nPrompted by the paucity of data of both aspects we investigated these issues by analyzing the database of the largest public health insurance in Austria (Wiener Gebietskrankenkasse, WGKK). This database was compared to the Austria death statistics and hospital admission registry. For decades Austria has had a public healthcare system with compulsory state insurance. The high prevalence of CRPC as well as the cost of these drugs further emphasize the economic impact of drug adherence and prescription pattern.\n\nThe aim of this study was to evaluate (i) adherence patterns for AA and concomitant prednisone in patients with CRPC in Austria, (ii) the overall survival of CRPC receiving AA in a real-life setting and (iii) hospital admission rates in this cohort by using a large administrative healthcare database.\n\nMaterial and methods\nAfter receiving institutional board approval from our hospital the prescription database of the largest public insurance company in Austria the WGKK was reviewed. Data from all patients with at least one prescription of AA from November 2011 to December 2014 were extracted, where AA [1] is typically prescribed at 1000 mg daily taken orally with 10 mg oral prednisone. The following data were extracted from this database: age, data of the first AA prescription, number of AA prescriptions, number of hospital admissions and duration of hospital admissions. This database was matched to the Austria death and hospital admission statistics.\n\nAdherence [2, 3] was calculated using the medication possession ratio (MPR), which is the sum of all days of AA supplied within a given period, divided by the total number of days in that period. There is no consensus standard for what constitutes adequate adherence. Some trials consider rates of greater than 80 % to be acceptable [4, 5].\n\nStatistical analyses\nThe SPSS 17.0 package for Windows (SPSS, Chicago, IL) was used for statistical analysis and all the values were expressed in terms of means ± SD for the efficacy analysis. Survival time was calculated from the initiation of AA and the date of death. Patients alive were censored at the last known follow-up date. Overall survival (OS) rates were estimated using the Kaplan-Meier method.\n\nResults\nPatient characteristics and AA prescription pattern\nData of 270 patients with CRPC with at least 1 prescription of AA were analyzed. The mean patient age was 73.5 ± 8.3 years (median 74 years). The age distribution was as follows: ≤60 years 19 patients (7.0 %), 61–70 years 82 patients (30.4 %), 71–80 years 105 patients (38.9 %) and >80 years 66 patients (24.4 %). The mean duration of AA treatment in all patients was 9.5 months (range 1–38 months). The duration of AA treatment was as follows: 0–2 months 53 (19.6 %), 3–5 months 73 (28.1 %), 6–10 months 67 (24.8 %) and >10 months 97 (35.9 %).\n\nDrug adherence\nThe mean MPR was 94.8 ± 11.9 with a median value of 100 %. The mean MPR ranged from 40–100 %. The MPR was not dependent on patient age (Table 1). In the age group ≤70 years the mean MPR was 95.7 ± 12.1 as compared to 95 ± 10.7 in those older than 70 years. In 241 (89.3 %) patients the MPR was ≥80 % and the MPR was below the critical value of 80 % only in 29 (10.7 %) patients.Table 1 Medication possession ratio\n\n\tMedication possession ratio\t\nMean\tMedian\t\nTotal patients (n = 270)\t94.8 ± 11.9\t100\t\nAge 46–60 (years, n = 19)\t94.9 ± 12.2\t100\t\nAge 61–70 (years, n = 80)\t95.7 ± 12.1\t100\t\nAge 71–80 (years, n = 105)\t95 ± 10.7\t100\t\nAge 81–92 (years, n = 66)\t93.5 ± 13.6\t100\t\n\n\n\nSurvival\nThe mean OS was 15.7 ± 1.1 months (median 11 months) with a range of 1–38 months (Fig. 1a). According to Kaplan-Meier analysis, the 6 month OS was 61 %, the 12 month OS 43 %, the 18 month OS 35 % and the 24 month OS 24 %. One quarter of patients survived longer than 2 years (Fig. 1a). Patient age had a profound impact on OS (Fig. 2). At 18 month follow-up, 42 % of the younger age cohort (median age 69.5 years) were still alive as compared to only 19 % in the elderly cohort (median age 83 years) (Fig. 2). It is worth noting that 35 % of all patients in the younger cohort experienced a survival of longer than 2 years. The median OS in the younger cohort was 17 months (mean 19.1 ± 1.4 months) as compared to only 5 months (mean 8.8 ± 1.0 months) in the elderly cohort. Fig. 3 presents the OS depending on the length of AA treatment and OS was also strongly dependent on the duration of AA treatment (Fig. 3).Fig. 1 \na Overall survival of the total study cohort (n = 270). b Frequency distribution of the remaining life span spent in hospital care\n\n\nFig. 2 Overall survival stratified by patient age\n\n\nFig. 3 Overall survival stratified by duration of AA treatment\n\n\n\n\nHospital admissions\nIn Austria the vast majority of chemotherapies for CRPC are given on an outpatient basis in urological or oncological institutions. For reimbursement reasons, these patients are admitted on a day case basis and are included to the hospital admission statistics; therefore, we have deleted all admissions for 24 h or less from further analyses.\n\nThe mean length of hospital stay was 4.5 ± 4.8 days (median 2 days). The duration of the hospital admissions was as follows: 1–2 days 55.8 %, 3–4 days 13.4 %, 5–6 days 6.9 %, 6–8 days 7.3 %, 8–10 days 5.5 % and >10 days 11.1 %. The patients in this series spent a considerable time of their remaining life in hospital care. Of all 270 patients only 19 (7 %) were not hospitalized during their remaining life span. On the other end of the spectrum 71 (26.2 %) spent more than 50 % of their remaining life span in hospital care (Fig. 1b).\n\nDiscussion\nThe principal findings of this Austrian prescription database analysis were (i) high adherence to AA, (ii) high mortality within the first months of AA prescription, (iii) 24 % long-term survivors under AA and (iv) high rate of hospitalization in patients under AA.\n\nPrior to discussion, several pros and cons of our approach need to be discussed. Strengths are: (i) the population-based character of this database. The WGKK is the biggest insurance company in Austria (8.4 million insured persons) and it has 1.2 million members in all socioeconomic classes, (ii) for decades Austria has had a public and equal access healthcare system with compulsory state health insurance company and (iii) long follow-up and complete survival data due to matching with the Austrian death statistics. The main limitation is the lack of any clinical information (e.g. indications, previous chemotherapy, staging and reason for drug discontinuation). Finally, the data on hospital admissions have to be interpreted in the context of the Austrian healthcare system.\n\nCancer treatment is evolving. Chronic oral administration transfers responsibility from the practitioner to the patient, making adherence an important parameter in reducing the risk of treatment failure. Adherence to medical treatment is a complex and multifaceted issue that can substantially alter the outcome of therapy [6–10].\n\nOutside randomized controlled trials (RCT) few studies have reported on the adherence to AA. Smith et al. [4] analyzed pharmacy claims of the Canadian Saskatchewan Cancer Agency. All patients with at least one AA prescription were eligible and a total of 86 patients were followed for a minimum of 6 months. Optimal drug adherence was achieved in 82.6 % of patients with 79.1 % reaching a MPR of at least 90 %. At 6 months the mean MPR was 89.6 % (median 100 %) and after 12 months 86.6 % (median 99.5 %). Lafeuille et al. [5] studied this issue by analyzing two large-scale US administrative healthcare claims databases. The mean age of the patients was 72.2 years and the mean MPR was 93 % (median 98 %). The mean MPR in our series was 94.8 ± 11.9 (median 100 %) with no relevant impact of patient age in contrary to the study by Grundmark et al. [6]. Taken together, these two studies with a substantial number of analyzed patients indicate that the adherence to AA in a real-life setting is satisfactory with median values exceeding 95 %.\n\nIn contrast to the prescription database studies described previously, this current one is unique with respect to the availability of survival data. There is a major concern that survival data generated by RCT or registries do not reflect the real life setting [11–16]. It has been previously shown that eligibility to a chemotherapy protocol represents per se a good prognostic factor [17]. In the pivotal phase III trial of AA in the postchemotherapy setting de Bono et al. [18] reported on a median survival of 14.8 months as compared to 11 months in our series. The median age of our patients, however, was 6 years older compared to the de Bono et al. [18] trial. The maximum follow-up in our study was considerable longer (38 months) as compared to the pivotal phase III trial with 20 months. There are a considerable number of long-term survivors. In our series, 24 % of patients survived longer than 20 months and 37 % in the phase III trial. The early mortality rate, however, was substantially higher in our series. Within the first 6 months of AA treatment 39 % of our patients died as compared to only 15 % in the de Bono et al. phase III trial [18]. These data suggest that patient selection in real life is substantially less stringent than in a phase III trial. In our series, patient age had a relevant impact on overall survival. In patients aged 46–76 years the median survival was 17 months and thus longer than in the pivotal RCT as compared to only 5 months in those older than 76 years. Houede et al. [19] reported on the long-term outcome of the AA temporary authorization for use program in France: 306 patients with a median age of 63 years were analyzed. The overall survival in this cohort after initiation of AA was 14.6 months, almost identical to the RCT and longer than in our series. As expected, OS was correlated to the duration of AA treatment, a similar phenomenon was observed in our series (see Fig. 3).\n\nThe third aspect of this study was the analysis of hospital admissions and length of hospitalization after initiation of AA. In our series, these patients spent a considerable time of their remaining life in hospital care. Only 7 % were not hospitalized and one quarter of patients (26.2 %) spent more than 50 % of their remaining life span in hospital care. These data have to be interpreted in the context of the Austrian healthcare system, where admission to hospital care is liberal and free of charge to the patient; furthermore, there is no incentive to discharge patients as early as possible. We could not identify a comparable analysis with CRPC patients under chemotherapy and second-line endocrine therapy in the literature.\n\nAccording to Svensson et al. [20] patients were on average 2 years older than those in the RCT, which is partly in agreement with our study population, OS in Swedish patients was the same like de Bono et al. [18] (COU-AA-301 trial), in contrary to our results, and the researchers concluded that the treated population and treatment patterns, organization of healthcare, as well as country setting could contribute to differences in outcomes between the clinical trial and the real world treatment, which could be an explanation for our OS results in comparison to the randomized controlled trials.\n\nOutcomes of treatment in clinical practice can differ from outcomes in RCT with regard to the estimated effectiveness and the estimated resource utilization. Discrepancies in patient and physician behavior between the trial and the real world may have an impact on outcome and treatment cost.\n\nIn clinical trials patients continued treatment until documented progression while the real world evidence study\ncollected information on progression. There is much interest in confirming whether the efficacy of AA demonstrated within\nthe trial setting is reproducible in routine clinical practice in a non-trial setting and many differences should be\ntaken in consideration between both, such as the selection of patients and ethnic differences.\n\nThe OS in the study of Poon et al. [21] of\nchemotherapy-naive patients was 18.1 months and much shorter than that reported in the COU-AA-302 study (of 34.7 months)\nRyan [16] and a higher proportion of elderly patients, which is in agreement with our study.\n\nLimitations\nThe main limitation is the lack of any clinical information (e.g. indications, previous chemotherapy, staging and reason for drug discontinuation). Finally, the data on hospital admissions have to be interpreted in the context of the Austrian healthcare system where admission to hospital care is voluntary and free of charge to the patient; furthermore, there is no incentive to discharge patients as early as possible.\n\nConclusion\nThis Austrian prescription database allows some relevant insights into the outcome of patients treated with AA for CRPC in a real life setting. Drug adherence was satisfactory and OS was shorter as compared to the pivotal phase III trial. The high early mortality rate in our series suggests poor patient selection in real life. One quarter of patients experience long-term survival. The hospitalization rate within this cohort was substantial.\n\nAcknowledgements\nSabine Wiener PhD and Bernd Laimich PhD provided the dataset of the Wiener Gebietskrankenkasse.\n\nFunding\nNone\n\nOpen access funding provided by Medical University of Graz.\n\nCompliance with ethical guidelines\nConflict of interest\nB. Mohamad Al-Ali, G. Kramer, S. Madersbacher, and I. Berger declare that they have no competing interests.\n\nEthical standards\nAll studies on humans described in the present manuscript were carried out with the approval of the responsible ethics committee and in accordance with national law and the Helsinki Declaration of 1975 (in its current, revised form). Informed consent was obtained from all patients included in studies. Institutional Board review was obtained, data and names of patients were blinded, informed consent was not needed.\n==== Refs\nReferences\n1. Heidenreich A Bastian PJ Bellmunt J EAU guidelines on prostate cancer. Part II: treatment of advanced, relapsing, and castration-resistant prostate cancer Eur Urol 2014 65 467 479 10.1016/j.eururo.2013.11.002 24321502 \n2. http://www.who.int/chp/knowledge/publications/adherence_Section1.pdf. Accessed 1 Dec 2011.\n3. Sabaté E Adherence to long-term therapies: evidence for action 2003 Geneva World Health Organization \n4. Smith AD Olson C Lyons B Adherence to abiraterone among the first 86 recipients after release in Saskatchewan Curr Oncol 2015 22 64 67 10.3747/co.22.2219 25684990 \n5. Lafeuille MH Grittner AM Lefebvre P Adherence patterns for abiraterone acetate and concomitant prednisone use in patients with prostate cancer J Manag Care Spec Pharm 2014 20 477 484 10.18553/jmcp.2014.20.5.477 24761819 \n6. Grundmark B Garmo H Zethelius B Anti-androgen prescribing patterns, patient treatment adherence and influencing factors; results from the nationwide PCBaSe Sweden Eur J Clin Pharmacol 2012 68 1619 1630 10.1007/s00228-012-1290-x 22562608 \n7. Partridge AH LaFountain A Mayer E Adherence to initial adjuvant anastrozole therapy among women with early-stage breast cancer J Clin Oncol 2008 26 556 562 10.1200/JCO.2007.11.5451 18180462 \n8. Owusu C Buist DS Field TS Predictors of tamoxifen discontinuation among older women with estrogen receptor-positive breast cancer J Clin Oncol 2008 26 549 555 10.1200/JCO.2006.10.1022 18071188 \n9. Balkrishnan R Predictors of medication adherence in the elderly Clin Ther 1998 20 764 771 10.1016/S0149-2918(98)80139-2 9737835 \n10. Smith MR Rathkopf DE Mulders PF Efficacy and safety of abiraterone acetate in elderly (75 years or older) chemotherapy naive patients with metastatic castration resistant prostate cancer J Urol 2015 194 1277 1284 26151676 \n11. Leibowitz-Amit R Templeton AJ Omlin A Clinical variables associated with PSA response to abiraterone acetate in patients with metastatic castration-resistant prostate cancer Ann Oncol 2014 25 657 662 10.1093/annonc/mdt581 24458472 \n12. Kluetz PG Ning YM Maher VE Abiraterone acetate in combination with prednisone for the treatment of patients with metastatic castration-resistant prostate cancer: U.S. Food and Drug Administration drug approval summary Clin Cancer Res 2013 19 6650 6656 10.1158/1078-0432.CCR-13-2134 24150234 \n13. Gupta E Guthrie T Tan W Changing paradigms in management of metastatic Castration Resistant Prostate Cancer (mCRPC) BMC Urol 2014 14 55 62 10.1186/1471-2490-14-55 25062956 \n14. Goodman OB Jr. Flaig TW Molina A Exploratory analysis of the visceral disease subgroup in a phase III study of abiraterone acetate in metastatic castration-resistant prostate cancer Prostate Cancer Prostatic Dis. 2014 17 34 39 10.1038/pcan.2013.41 24080993 \n15. Matsubara N Uemura H Satoh T A phase 2 trial of abiraterone acetate in Japanese men with metastatic castration-resistant prostate cancer and without prior chemotherapy (JPN-201 study) Jpn J Clin Oncol 2014 44 1216 1226 10.1093/jjco/hyu149 25320340 \n16. Ryan CJ Smith MR de Bono J Abiraterone in metastatic prostate cancer without previous chemotherapy N Engl J Med 2013 368 138 148 10.1056/NEJMoa1209096 23228172 \n17. Madersbacher S Thalmann GN Fritsch JC Is eligibility for a chemotherapy protocol a good prognostic factor for invasive bladder cancer after radical cystectomy? J Clin Oncol 2004 22 4103 4108 10.1200/JCO.2004.04.127 15483019 \n18. de Bono JS Logothetis CJ Molina A Abiraterone and increased survival in metastatic prostate cancer N Engl J Med 2011 364 1995 2005 10.1056/NEJMoa1014618 21612468 \n19. Houede N Beuzeboc P Gourgou S Abiraterone acetate in patients with metastatic castration-resistant prostate cancer: long term outcome of the temporary authorization for use programme in France BMC Cancer 2015 15 222 230 10.1186/s12885-015-1257-2 25884302 \n20. Svensson J Andersson E Persson U Value of treatment in clinical trials versus the real world: the case of abiraterone acetate (Zytiga) for postchemotherapy metastatic castration-resistant prostate cancer patients in Sweden Scand J Urol 2016 50 286 291 27109827 \n21. Poon DM Chan K Lee SH Abiraterone acetate in metastatic castration-resistant prostate cancer-the unanticipated real-world clinical experience BMC Urol 2016 16 12 10.1186/s12894-016-0132-z 27001043\n\n",
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"issue": "129(11-12)",
"journal": "Wiener klinische Wochenschrift",
"keywords": "Abiraterone acetate; Castration-resistant prostate cancer; Medication adherence; Prostate cancer; Survival",
"medline_ta": "Wien Klin Wochenschr",
"mesh_terms": "D000284:Administration, Oral; D000368:Aged; D000369:Aged, 80 and over; D000736:Androstenes; D000970:Antineoplastic Agents; D001317:Austria; D017052:Hospital Mortality; D006760:Hospitalization; D006801:Humans; D007345:Insurance Claim Review; D008297:Male; D055118:Medication Adherence; D008875:Middle Aged; D015995:Prevalence; D064129:Prostatic Neoplasms, Castration-Resistant; D012307:Risk Factors; D015996:Survival Rate; D016896:Treatment Outcome",
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"pages": "380-384",
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"pubdate": "2017-06",
"publication_types": "D016428:Journal Article",
"references": "22562608;24080993;25062956;25320340;25884302;27001043;24321502;21612468;18180462;27109827;24150234;23228172;18071188;24761819;15483019;26151676;24458472;9737835;25684990",
"title": "Abiraterone for castration-resistant prostate cancer: adherence, survival and hospitalization : Analysis of a medical claims database.",
"title_normalized": "abiraterone for castration resistant prostate cancer adherence survival and hospitalization analysis of a medical claims database"
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"abstract": "While aromatase inhibitors (AIs) have been known to cause minor elevations in liver enzymes, severe hepatotoxicity is rare. To the best of our knowledge, this is the first reported case of Letrozole-induced hepatitis with autoimmune features. A 70-year-old female with estrogen positive, invasive ductal carcinoma of the breast, presented with jaundice 3 months after starting letrozole. Hepatic transaminases were markedly elevated and her ANA and anti-smooth muscle antibody was positive. Liver biopsy featured drug-induced hepatitis. After stopping letrozole, liver tests trended back to normal within 3 weeks. She scored 9 for Roussel-Uclaf Causality Assessment Method (RUCAM). Over the last 10 years, there have been reported cases of drug-induced hepatitis secondary to AIs. We anticipate that there will be more widespread use of AIs based on recommendations from the TEXT, SOFT and extended AI trials. Therefore, physicians must be aware of this rare but life-threatening complication.",
"affiliations": "Department of Haematology and Oncology, University of Florida College of Medicine Jacksonville, FL, USA.;Department of Internal Medicine, University of Florida College of Medicine Jacksonville, FL, USA.;Department of Internal Medicine, University of Florida College of Medicine Jacksonville, FL, USA.;Department of Pathology, University of Florida College of Medicine Jacksonville, FL, USA.;Department of Gastroenterology, University of Florida College of Medicine Jacksonville, FL, USA.;Department of Haematology and Oncology, University of Florida College of Medicine Jacksonville, FL, USA.",
"authors": "Gharia|Bharatsinh|B|;Seegobin|Karan|K|;Maharaj|Satish|S|;Marji|Noor|N|;Deutch|Amie|A|;Zuberi|Lara|L|",
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"fulltext": "\n==== Front\nOxf Med Case ReportsOxf Med Case ReportsomcrOxford Medical Case Reports2053-8855Oxford University Press 10.1093/omcr/omx074omx074Case ReportLetrozole-induced hepatitis with autoimmune features: a rare adverse drug reaction with review of the relevant literature Gharia Bharatsinh 1Seegobin Karan 2Maharaj Satish 2Marji Noor 3Deutch Amie 4Zuberi Lara 1\n1 Department of Haematology and Oncology, University of Florida College of Medicine Jacksonville, FL, USA\n2 Department of Internal Medicine, University of Florida College of Medicine Jacksonville, FL, USA\n3 Department of Pathology, University of Florida College of Medicine Jacksonville, FL, USA\n4 Department of Gastroenterology, University of Florida College of Medicine Jacksonville, FL, USA* Correspondence address. Internal Medicine Unit, University of Florida College of Medicine, Jacksonville, 655 West 8th Street, Jacksonville, FL 32209, USA. Tel: +90-42260044; E-mail: karanseegobin@hotmail.com11 2017 13 11 2017 13 11 2017 2017 11 omx07422 7 2017 16 9 2017 23 9 2017 © The Author 2017. Published by Oxford University Press.2017This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.comAbstract\nWhile aromatase inhibitors (AIs) have been known to cause minor elevations in liver enzymes, severe hepatotoxicity is rare. To the best of our knowledge, this is the first reported case of Letrozole-induced hepatitis with autoimmune features. A 70-year-old female with estrogen positive, invasive ductal carcinoma of the breast, presented with jaundice 3 months after starting letrozole. Hepatic transaminases were markedly elevated and her ANA and anti-smooth muscle antibody was positive. Liver biopsy featured drug-induced hepatitis. After stopping letrozole, liver tests trended back to normal within 3 weeks. She scored 9 for Roussel-Uclaf Causality Assessment Method (RUCAM). Over the last 10 years, there have been reported cases of drug-induced hepatitis secondary to AIs. We anticipate that there will be more widespread use of AIs based on recommendations from the TEXT, SOFT and extended AI trials. Therefore, physicians must be aware of this rare but life-threatening complication.\n==== Body\nINTRODUCTION\nPrior to 2007, more than 30 000 patients with breast cancer have been treated with aromatase inhibitors (AIs) with good liver safety [1]. Approximately, 185 000 new cases of invasive breast cancer are diagnosed yearly, and at least half are eligible for therapy with AI [2]. AI are used as first-line adjuvant hormonal therapy in postmenopausal women with hormone-receptor positive breast cancer [3]. Over the past 10 years, there have been reported cases of hepatitis and autoimmune diseases resulting from AI use [4, 5]. We report a rare case of letrozole-induced hepatitis with autoimmune features. Health professionals ought to be aware of the hepatotoxic effect of this agent, because there is likely to be extended use of AI in postmenopausal women [6], and increased use in premenopausal women with breast cancer [7].\n\nCASE\nA 70-year-old female with estrogen receptor positive, invasive ductal carcinoma of the breast (T1aN0M0), was initially managed with lumpectomy and radiation, and subsequently started on Letrozole. Her other comorbidities included hypertension which was managed on atenolol 50 mg once daily, and chronic urinary tract infections (UTIs), for which she was on Macrobid since more than a year. She had no history of alcohol or illicit drug use. After starting letrozole, she was seen in clinic at 2 weeks and then at 3 months. At her 3-month visit, her exam was unremarkable other than icterus. Laboratory evaluation showed AST 2030 (14–33 IU/l); ALT 2323 (10–42IU/l); albumin 2.9 (3.8–4.9 g/dl); direct bilirubin 7.3 (0–0.2 mg/dl); indirect bilirubin 2.6 mg/dl; total bilirubin 10.3 (0.2–1.0 mg/dl); alkaline phosphatase 298 (35–104 IU/l); PT 14.5; INR 1.1; aPTT 33. Further workup revealed a negative Hepatitis profile, but positive autoimmune workup. ANA was positive with 1:160 speckled pattern, alpha 1 antitrypsin 231 (90–200 mg/dl), antimitochondrial antibody 22.5 (0–20 units), anti-smooth muscle antibody 36 (0–19 units).\n\nShe was hospitalized to expedite workup in view of severe hepatic impairment. Liver biopsy showed hepatocellular injury with portal tract and lobular inflammation with cholestasis consistent with drug-induced hepatitis (Figs 1 and 2). After withdrawal of the drug, she clinically improved over the following three weeks and her liver tests trending back to normal. Thereafter, she was monitored in the outpatient clinic every 4 weeks for 2 months, and remained asymptomatic with normal liver tests. Her subsequent follow-up intervals were gradually extended.\n\n\nFigure 1: Liver tissue with apoptotic bodies, lobular mixed inflammation and clusters of ceroid cells.\n\nFigure 2: Portal triads show mild bile ductular proliferation with mixed inflammation predominantly neutrophils, in addition to lymphocytes, eosinophils and fewer plasma cells.\n\nDISCUSSION\nApproximately, 185 000 new cases of invasive breast cancer are diagnosed yearly, and at least half of these women are both postmenopausal and eligible for adjuvant therapy with AI [2]. Letrozole is a nonsteroidal inhibitor of aromatase, which effectively blocks estrogen synthesis in postmenopausal women [8]. It is used as therapy for estrogen receptor positive breast cancer, usually after resection and after failure of tamoxifen [8]. It was approved for use in postmenopausal women with estrogen receptor positive breast cancer in the USA in 1997 [8].\n\nWhile AI have been reported to cause minor elevation in liver enzymes, severe hepatotoxicity is rarely reported [3]. Liver injury is believed to be due to metabolic and immune-mediated damage, superimposed on individual susceptibility [4]. From this class of medication anastrozole and exemestane have been reported to cause drug-induced hepatitis [1, 3]. Anastrozole has been specifically reported in cases of drug- induced autoimmune hepatitis [4].\n\nLetrozole on the other hand, have been reported to cause elevated liver enzymes in up to 1% of women. These elevations are usually mild, asymptomatic, self-limited and rarely require dose modification [8]. It is metabolized in the liver by the cytochrome P450 system and is a strong inhibitor of CYP 2A6 and to a lesser extent CYP 2C19 [8]. Thus, liver injury from letrozole might arise as a result of a toxic or immunogenic metabolite [8]. There have been no published instances of clinically apparent liver injury associated with long term letrozole therapy as of 2017 according to the US National Library of Medicine [2]. Furthermore, there have been no cases of severe jaundice, acute liver failure, chronic hepatitis or vanishing bile duct syndrome attributed to letrozole use [8]. To the best of our knowledge, this is the first case of drug- induced autoimmune hepatitis secondary to letrozole.\n\nThe risk of recurrence of hormone-receptor–positive breast cancer continues indefinitely [6]. Reduction in that risk of recurrence has been achieved with tamoxifen, AIs or a combination of the two. In the postmenopausal group, AI therapy was previously recommended up to five years, however it is now recommended up to 10 years based on the extended AI trial [6]. The TEXT and SOFT trials showed that exemestane, is significantly more effective than tamoxifen, in premenopausal women [7]. We expect there to be more widespread use of AI.\n\nReview of the English literature reports four cases of AI induced hepatitis (Table 1). All patients were admitted to hospital. Three of the four patients were exposed to anastrozole. All patients’ onset of hepatitis occurred within 6 months, however hepatitis occurred within 3 weeks for two of the four patients. All had improvement in liver tests after withdrawal of the drug, however, one patient required a tapered course of steroids due to features of autoimmune hepatitis. One patient was treated with tamoxifen after resolution of her hepatitis which she tolerated well.\nTable 1: Literature review of characteristics of patients with hepatitis due to AIs\n\nReference\tAge\tInterval between onset of hepatitis and drug use\tDrug\tDose\tInpatient admission\tAntibodies positive\tOutcome\t\nde la Cruz et al. [1]\t58\t3 weeks\tanastrozole\t1 mg/day\tYes\t\tImproved liver tests after 1 month however patient died from another cause\t\nInno et al [10]\t70\t4 months\tanastrozole\t1 mg/day\tYes\tANA\tNormal liver tests after one month, then switched to tamoxifen which was well tolerated.\t\nBao et al. [3]\t47\t3 weeks\texemestane\t25 mg/day\tYes\t\tLiver tests normalized after 4 months\t\nIslam et al. [10]\t66\t6 months\tanastrozole\t\tYes\tANA, anti-smooth muscle antibody\tInitial improvement after 3 months, 12 months later treated with tapered steroids for asymptomatic acute liver derangement with elevated IgG\t\n\n\nDiagnosis of autoimmune hepatitis is confirmed by liver biopsy [4]. Overall, the time lapse between drug exposure and the onset of hepatitis, the age of the patient, exclusion of other non-drug-related causes, improvement achieved after drug withdrawal and letrozole being reported as a potential cause of drug-induced liver disease in the product label, allow our case to achieve a score of 9 according the Roussel-Uclaf Causality Assessment Method (RUCAM) [9].\n\nThe goal of treatment is withdrawal of the drug. Patients generally do well with improvement in liver function.\n\nCONCLUSION\nAI is an extremely rare cause of hepatitis. It can present in association with autoimmune features. In the modern era, where breast cancer management is rapidly evolving, and AI use is becoming more widespread, with many patients expected to be on these medications for up to 10 years, physicians must be aware of this rare but life-threatening complication. After starting AI therapy, it may be important to monitor these patients closely during the first 6 months when drug-induced hepatitis is most common, followed by the minimum requirement of six month follow-up.\n\nCONFLICT OF INTEREST STATEMENT\nThe authors have no areas of conflict to declare.\n\nFUNDING\nThe authors have not received funding.\n\nPATIENT CONSENT\nWritten informed consent was obtained from the patient for publication of this case report and the accompanying images. A copy of the written consent is available for review by the editorial board of this journal.\n\nAUTHORS' CONTRIBUTION\nThe idea for reporting this case was that of B.G., K.S. and L.Z. Further intellectual content and editing was done by all authors. All authors saw, edited and approved the final contents. K.S. assumes responsibility for the integrity of the contents.\n==== Refs\nREFERENCES\n1 \nDe la Cruz L , Romero-Vazquez J , Jiménez-Sáenz M , Padron JR , Herrerias-Gutierrez JM \nSevere acute hepatitis in a patient treated with anastrozole . Lancet 2007 ;369 :23 –4 .17208628 \n2 \nFabian CJ \nThe what, why and how of aromatase inhibitors: hormonal agents for treatment and prevention of breast cancer . Int J Clin Pract 2007 ;61 :2051 –63 .17892469 \n3 \nBao T , Fetting J , Mumford L , Zorzi J , Shahverdi K , Jeter S , et al \nSevere prolonged cholestatic hepatitis caused by exemestane . Breast Cancer Res Treat 2010 ;121 :789 –91 .19834799 \n4 \nIslam MS , Wright G , Tanner P , Lucas R \nA case of anastrazole-related drug-induced autoimmune hepatitis . Clin J Gastroenterol 2014 ;7 :414 –7 .26184021 \n5 \nZarkavelis G , Kollas A , Kampletsas E , Vasiliou V , Kaltsonoudis E , Drosos A , et al \nAromatase inhibitors induced autoimmune disorders in patients with breast cancer: a review . J Adv Res 2016 ;7 :719 –26 .28275510 \n6 \nGoss PE , Ingle JN , Pritchard KI , Robert NJ , Muss H , Gralow J , et al \nExtending aromatase-inhibitor adjuvant therapy to 10 years . N Engl J Med 2016 ;375 :209 –19 . doi:10.1056/NEJMoa1604700 .27264120 \n7 \nFrancis PA , Regan MM , Fleming GF , Láng I , Ciruelos E , Bellet M , et al \nAdjuvant ovarian suppression in premenopausal breast cancer . N Engl J Med 2015 ;372 :436 –46 . doi:10.1056/NEJMoa1412379 .25495490 \n8 \nhttps://livertox.nih.gov/Letrozole.htm. Accessed 25 June 2017.\n9 \nDanan G , Teschke R \nRUCAM in drug and herb induced liver injury: the update . Int J Mol Sci 2016 ;17 :14 .\n10 \nInno A , Basso M , Vecchio FM , Marsico VA , Cerchiaro E , D’Argento E , et al \nAnastrozole-related acute hepatitis with autoimmune features: a case report . BMC Gastroenterol 2011 ;11 :32 .21453541\n\n",
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"abstract": "Despite optimal pharmacotherapy and cognitive-behavioral treatments, a proportion of patients with obsessive-compulsive disorder (OCD) remain refractory to treatment. Neurosurgical ablative or nondestructive stimulation procedures to treat these refractory patients have been investigated. However, despite the potential benefits of these surgical procedures, patients show significant surgery-related complications. This preliminary study investigated the use of bilateral thermal capsulotomy for patients with treatment-refractory OCD using magnetic resonance-guided focused ultrasound (MRgFUS) as a novel, minimally invasive, non-cranium-opening surgical technique. Between February and May 2013, four patients with medically refractory OCD were treated with MRgFUS to ablate the anterior limb of the internal capsule. Patients underwent comprehensive neuropsychological evaluations and imaging at baseline, 1 week, 1 month and 6 months following treatment. Outcomes were measured with the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS), the Hamilton Rating Scale for Depression (HAM-D) and the Hamilton Rating Scale for Anxiety (HAM-A), and treatment-related adverse events were evaluated. The results showed gradual improvements in Y-BOCS scores (a mean improvement of 33%) over the 6-month follow-up period, and all patients showed almost immediate and sustained improvements in depression (a mean reduction of 61.1%) and anxiety (a mean reduction of 69.4%). No patients demonstrated any side effects (physical or neuropsychological) in relation to the procedure. In addition, there were no significant differences found in the comprehensive neuropsychological test scores between the baseline and 6-month time points. This study demonstrates that bilateral thermal capsulotomy with MRgFUS can be used without inducing side effects to treat patients with medically refractory OCD. If larger trials validate the safety, effectiveness and long-term durability of this new approach, this procedure could considerably change the clinical management of treatment-refractory OCD.",
"affiliations": "Department of Neurosurgery, Brain Research Institute, Yonsei University College of Medicine, Seoul, Korea.;Department of Psychiatry, Institute of Behavioral Science in Medicine, Yonsei University College of Medicine, Seoul, Korea.;Department of Psychiatry, Chunchon Sacred Heart Hospital, Hallym University College of Medicine, Chunchon, Korea.;Department of Psychiatry, Institute of Behavioral Science in Medicine, Yonsei University College of Medicine, Seoul, Korea.;Department of Neurosurgery, Brain Research Institute, Yonsei University College of Medicine, Seoul, Korea.;Department of Neurosurgery, Brain Research Institute, Yonsei University College of Medicine, Seoul, Korea.;Department of Psychiatry, Institute of Behavioral Science in Medicine, Yonsei University College of Medicine, Seoul, Korea.;Department of Neurosurgery, Brain Research Institute, Yonsei University College of Medicine, Seoul, Korea.",
"authors": "Jung|H H|HH|;Kim|S J|SJ|;Roh|D|D|;Chang|J G|JG|;Chang|W S|WS|;Kweon|E J|EJ|;Kim|C-H|CH|;Chang|J W|JW|",
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"mesh_terms": "D000328:Adult; D005260:Female; D006801:Humans; D020772:Internal Capsule; D053783:Magnetic Resonance Imaging, Interventional; D008297:Male; D009483:Neuropsychological Tests; D019635:Neurosurgical Procedures; D009771:Obsessive-Compulsive Disorder; D059708:Ultrasonic Surgical Procedures; D018084:Ultrasonography, Interventional",
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"title": "Bilateral thermal capsulotomy with MR-guided focused ultrasound for patients with treatment-refractory obsessive-compulsive disorder: a proof-of-concept study.",
"title_normalized": "bilateral thermal capsulotomy with mr guided focused ultrasound for patients with treatment refractory obsessive compulsive disorder a proof of concept study"
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"abstract": "Factors associated with olaparib toxicity remain unknown in ovarian cancer patients. The large inter-individual variability in olaparib pharmacokinetics could contribute to the onset of early significant adverse events (SAE). We aimed to retrospectively analyze the pharmacokinetic/pharmacodynamic relationship for toxicity in ovarian cancer patients from \"real life\" data. The clinical endpoint was the onset of SAE (grade III/IV toxicity or dose reduction/discontinuation). Plasma olaparib concentration was assayed using liquid chromatography at any time over the dosing interval. Trough concentrations (CminPred) were estimated using a population pharmacokinetic model. The association between toxicity and clinical characteristics or CminPred was assessed by logistic regression and non-parametric statistical tests. Twenty-seven patients were included, among whom 13 (48%) experienced SAE during the first six months of treatment. Olaparib CminPred was the only covariate significantly associated with increased risk of SAE onset (odds ratio = 1.31, 95%CI = [1.10; 1.57], for each additional 1000 ng/mL). The ROC curve identified a threshold of CminPred = 2500 ng/mL for prediction of SAE onset (sensitivity/specificity 0.62 and 1.00, respectively). This study highlights a significant association between olaparib plasma exposure and SAE onset and identified the threshold of 2500 ng/mL trough concentration as potentially useful to guide dose adjustment in ovarian cancer patients.",
"affiliations": "Department of Medical Oncology, Cochin University Hospital, Assistance Publique-Hôpitaux de Paris, 75014 Paris, France.;Department of Pharmacokinetics and Pharmacochemistry, Cochin University Hospital, Assistance Publique-Hôpitaux de Paris, 75014 Paris, France.;Department of Pharmacokinetics and Pharmacochemistry, Cochin University Hospital, Assistance Publique-Hôpitaux de Paris, 75014 Paris, France.;Department of Medical Oncology, Cochin University Hospital, Assistance Publique-Hôpitaux de Paris, 75014 Paris, France.;Department of Medical Oncology, Georges Pompidou European Hospital, Assistance Publique-Hôpitaux de Paris, 75015 Paris, France.;Department of Medical Oncology, Georges Pompidou European Hospital, Assistance Publique-Hôpitaux de Paris, 75015 Paris, France.;Department of Medical Oncology, Georges Pompidou European Hospital, Assistance Publique-Hôpitaux de Paris, 75015 Paris, France.;Department of Pharmacokinetics and Pharmacochemistry, Cochin University Hospital, Assistance Publique-Hôpitaux de Paris, 75014 Paris, France.;Department of Pharmacokinetics and Pharmacochemistry, Cochin University Hospital, Assistance Publique-Hôpitaux de Paris, 75014 Paris, France.;Gustave Roussy Cancer Center, Department of Medical Oncology, Université Paris-Saclay, 94805 Villejuif, France.;Gustave Roussy Cancer Center, Department of Medical Oncology, Université Paris-Saclay, 94805 Villejuif, France.;Department of Medical Oncology, Cochin University Hospital, Assistance Publique-Hôpitaux de Paris, 75014 Paris, France.;Department of Medical Oncology, Cochin University Hospital, Assistance Publique-Hôpitaux de Paris, 75014 Paris, France.;Department of Medical Oncology, Cochin University Hospital, Assistance Publique-Hôpitaux de Paris, 75014 Paris, France.;Department of Medical Oncology, Cochin University Hospital, Assistance Publique-Hôpitaux de Paris, 75014 Paris, France.;Department of Medical Oncology, Cochin University Hospital, Assistance Publique-Hôpitaux de Paris, 75014 Paris, France.",
"authors": "Velev|Maud|M|0000-0002-3617-7698;Puszkiel|Alicja|A|;Blanchet|Benoit|B|;de Percin|Sixtine|S|;Delanoy|Nicolas|N|;Medioni|Jacques|J|;Gervais|Claire|C|;Balakirouchenane|David|D|;Khoudour|Nihel|N|0000-0002-8269-9817;Pautier|Patricia|P|;Leary|Alexandra|A|;Ajgal|Zahra|Z|0000-0002-2322-9612;Hirsch|Laure|L|;Goldwasser|François|F|;Alexandre|Jerome|J|;Beinse|Guillaume|G|",
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"fulltext": "\n==== Front\nPharmaceuticals (Basel)\nPharmaceuticals (Basel)\npharmaceuticals\nPharmaceuticals\n1424-8247\nMDPI\n\n10.3390/ph14080804\npharmaceuticals-14-00804\nArticle\nAssociation between Olaparib Exposure and Early Toxicity in BRCA-Mutated Ovarian Cancer Patients: Results from a Retrospective Multicenter Study\nhttps://orcid.org/0000-0002-3617-7698\nVelev Maud 1†\nPuszkiel Alicja 23†\nBlanchet Benoit 24\nde Percin Sixtine 1\nDelanoy Nicolas 5\nMedioni Jacques 5\nGervais Claire 5\nBalakirouchenane David 2\nhttps://orcid.org/0000-0002-8269-9817\nKhoudour Nihel 2\nPautier Patricia 6\nLeary Alexandra 6\nhttps://orcid.org/0000-0002-2322-9612\nAjgal Zahra 1\nHirsch Laure 1\nGoldwasser François 1\nAlexandre Jerome 17*†\nBeinse Guillaume 17†\nOmri Abdelwahab Academic Editor\n1 Department of Medical Oncology, Cochin University Hospital, Assistance Publique-Hôpitaux de Paris, 75014 Paris, France; Maud.velev@etu.upmc.fr (M.V.); sixtine.depercin@aphp.fr (S.d.P.); zahra.ajgal@hotmail.fr (Z.A.); laure.hirsch@aphp.fr (L.H.); François.goldwasser@aphp.fr (F.G.); guillaume.beinse@aphp.fr (G.B.)\n2 Department of Pharmacokinetics and Pharmacochemistry, Cochin University Hospital, Assistance Publique-Hôpitaux de Paris, 75014 Paris, France; alicja.puszkiel@aphp.fr (A.P.); benoit.blanchet@aphp.fr (B.B.); David.Balakirouchenane@aphp.fr (D.B.); Nihel.Khoudour@aphp.fr (N.K.)\n3 INSERM UMR-S1144, Faculté de Pharmacie, Université de Paris, 75006 Paris, France\n4 UMR8038 CNRS, U1268 INSERM, Faculté de Pharmacie, Université de Paris, PRES Sorbonne Paris Cité, CARPEM, 75006 Paris, France\n5 Department of Medical Oncology, Georges Pompidou European Hospital, Assistance Publique-Hôpitaux de Paris, 75015 Paris, France; Nicolas.Delanoy@aphp.fr (N.D.); Jacques.Medioni@aphp.fr (J.M.); Claire.Gervais@aphp.fr (C.G.)\n6 Gustave Roussy Cancer Center, Department of Medical Oncology, Université Paris-Saclay, 94805 Villejuif, France; Patricia.PAUTIER@gustaveroussy.fr (P.P.); Alexandra.LEARY@gustaveroussy.fr (A.L.)\n7 Centre de Recherche des Cordeliers, Université de Paris, Sorbonne Université, Inserm, Team Personalized Medicine, Pharmacogenomics and Therapeutic Optimization (MEPPOT), 75006 Paris, France\n* Correspondence: jerome.alexandre@aphp.fr; Tel.: +33-01-(58)-414141\n† Equal contribution.\n\n16 8 2021\n8 2021\n14 8 80408 7 2021\n12 8 2021\n© 2021 by the authors.\n2021\nhttps://creativecommons.org/licenses/by/4.0/ Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).\nFactors associated with olaparib toxicity remain unknown in ovarian cancer patients. The large inter-individual variability in olaparib pharmacokinetics could contribute to the onset of early significant adverse events (SAE). We aimed to retrospectively analyze the pharmacokinetic/pharmacodynamic relationship for toxicity in ovarian cancer patients from “real life” data. The clinical endpoint was the onset of SAE (grade III/IV toxicity or dose reduction/discontinuation). Plasma olaparib concentration was assayed using liquid chromatography at any time over the dosing interval. Trough concentrations (CminPred) were estimated using a population pharmacokinetic model. The association between toxicity and clinical characteristics or CminPred was assessed by logistic regression and non-parametric statistical tests. Twenty-seven patients were included, among whom 13 (48%) experienced SAE during the first six months of treatment. Olaparib CminPred was the only covariate significantly associated with increased risk of SAE onset (odds ratio = 1.31, 95% CI = [1.10; 1.57], for each additional 1000 ng/mL). The ROC curve identified a threshold of CminPred = 2500 ng/mL for prediction of SAE onset (sensitivity/specificity 0.62 and 1.00, respectively). This study highlights a significant association between olaparib plasma exposure and SAE onset and identified the threshold of 2500 ng/mL trough concentration as potentially useful to guide dose adjustment in ovarian cancer patients.\n\nolaparib\npopulation pharmacokinetics\nPK-toxicity relationship\novarian cancer\ntherapeutic drug monitoring\n==== Body\n1. Introduction\n\nOlaparib is an oral poly(ADP-ribose) polymerase (PARP) inhibitor [1]. By inhibiting PARP1 and PARP2, enzymes involved in DNA single-strand breaks (SSB) repair, olaparib leads to accumulation of SSB and subsequent deleterious double-strand breaks (DSB). While a cell with an intact homologous recombination (HR) pathway can repair these DSB effectively, olaparib causes synthetic lethality in HR deficient tumor cells, such as in BRCA1/2-mutated cancers [2]. Olaparib was therefore initially developed for the treatment of HR-deficient cancers in patients carrying BRCA1/2 mutation [3]. Beyond BRCA1/2 mutations, a number of studies showed a survival benefit in patients affected by HR-deficient ovarian, breast, prostate or pancreatic cancers [4,5,6,7,8,9,10].\n\nClinical studies reported incidences of serious adverse events and dose reduction/discontinuation of 21% and 30%, respectively, in maintenance therapy for newly diagnosed patients [8], and of 35% and 28%, respectively, in platinum-sensitive ovarian cancer relapse [10]. The most common toxicities were digestive (nausea, vomiting), hematological (anemia) and asthenia. In a meta-analysis of olaparib safety from four randomized clinical trials data, Ricci et al. reported an overall incidence of grade III-IV adverse events of 41% [11]. However, despite this high frequency of significant adverse events, factors associated with olaparib toxicity remain largely unknown, supporting the need for reports from “real-life” patients [12,13].\n\nBecause of a wide inter-patient pharmacokinetic (PK) variability observed in the last decade with oral antineoplastic agents, therapeutic drug monitoring (TDM) emerged as an important tool [14,15]. Many factors have been shown to significantly influence olaparib exposure. Food has been shown to delay olaparib absorption resulting in a significant decrease in peak plasma concentrations (Cmax) but the impact on area under the concentration–time curve (AUC) is only marginal [16]. In vitro studies suggested that large variations of serum albumin concentrations may impact the unbound fraction of olaparib and subsequently increase the toxicity. Olaparib is mainly metabolized via CYP3A4/5 isoenzymes and co-administration of a potent CYP3A4/5 inhibitor or inducer could also influence olaparib exposure [17]. Finally, impaired renal function has been associated with increased exposure to olaparib [18]. Of note, a new potential source of variability emerged with the approval of a new formulation (capsule and tablets, capsule being now withdrawn from the market) [19].\n\nThe PK of olaparib has been assessed by nonlinear mixed-effects modeling using clinical trials’ data [19]. However, the inter-individual variability in olaparib plasma exposure in non-selected real-life ovarian cancer patients has never been assessed [17,19] and little is known about its pharmacokinetic/pharmacodynamic (PK/PD) relationship for toxicity.\n\nIn the present retrospective multicenter study, we aimed to investigate the association between olaparib toxicity and potential explanatory factors, such as patient characteristics and olaparib plasma exposure, in patients treated for ovarian cancer in a real-life setting.\n\n2. Results\n\n2.1. Patient Characteristics\n\nAmong 31 patients for whom at least one olaparib plasma concentration was available between November 2016 and August 2020, 4 were excluded (age < 18 years old: N = 1; breast cancer: N = 2; out-of-label use: N = 1). Overall, 27 patients were included in the statistical analysis (Figure 1). These patients were followed in three University Hospitals: Cochin Hospital (Paris, N = 16), Georges Pompidou European Hospital (Paris, N = 6), and Gustave Roussy Cancer Campus (Villejuif, N = 5). Table 1 presents patient and cancer characteristics. The median age at diagnosis was 63 years. Six patients (22%) had an ECOG-PS = 2 at olaparib initiation. None had residual biological toxicities beyond grade I from previous treatments. Ten patients (62%) had renal insufficiency (Cockcroft clearance < 60 mL/min) at baseline, including 2 patients with Cockcroft–Gault clearance of 30–50 mL/min who were treated at full dose. Except for one 85-year-old patient who received an initial dose of 200 mg tablet bid, all patients received the initial recommended dose of 400 mg bid for capsules (N = 16) or 300 mg bid for tablets (N = 10).\n\n2.2. Pharmacokinetic Analysis\n\nOverall, 66 plasma concentrations were analyzed in 27 patients. Among these, three samples were excluded (N = 3 patients) because of unavailable data on delay between olaparib intake and sampling, and two (N = 2 patients) because of a delay of more than 24 h. Finally, 61 plasma concentrations were included in the PK analysis (N = 22 patients). The median number of concentrations per patient was 2 (range: 1–7) with a median sampling time of 10 h post-dose (range: 0.75–24).\n\nA two-compartment population PK model was applied for the analysis of the concentration–time data. The median prediction error (PE) was −11.9% [interquartile range, IQR = −15.9; −4.9] showing good accuracy and precision of the model predictions. Figure 2A,B present observed vs. predicted concentrations and PE vs. observed concentrations. The prediction-corrected visual predictive check (pcVPC) plot showed good agreement between simulated and observed olaparib plasma concentrations (Figure 2C). Although a slight underestimation of the observed concentrations was observed, the number of concentrations with absolute PE < 20% and <30% was 53 (86.9%) and 60 (98.4%), respectively, showing that the observed concentrations were satisfactorily well predicted.\n\nThe median [IQR] predicted trough concentration (CminPred) was 1241 ng/mL [881–2412 ng/mL] in the entire study population. In patients treated with the recommended dose, the median [IQR] CminPred was 997 ng/mL [737–1985 ng/mL] and 2503 ng/mL [1688–3213 ng/mL], for those receiving 400 mg bid capsule (N = 39 concentrations) and 300 mg bid tablets (N = 9 concentrations), respectively (Figure 3A). CminPred were not significantly different according to ECOG-PS (Figure 3B). The inter-individual variability in CminPred (coefficient of variation, CV%) was 64% and 53% for capsule and tablet formulation, respectively (when considering 1st plasma concentration for patients treated with the recommended dose, N = 22).\n\nIntra-patient variability was evaluated by the deviation from each Cminpred to mean CminPred within each patient (N = 11 patients with more than one olaparib exposure assessment and treated at standard dose). Median [IQR] absolute intra-individual variability was 19.7% [11.6–32.7%]. (Figure A1).\n\n2.3. Association between Patients’ Baseline Characteristics and Onset of Clinically Significant Adverse Events (SAE)\n\nDuring the first six months of treatment, 13 patients (48%) experienced a SAE: (i) seven patients experienced a grade III–IV adverse event (anemia N = 5; asthenia N = 1; skin rash N = 1); (ii) six patients experienced an adverse event resulting in dose reduction or discontinuation (digestive: N = 3; asthenia: N = 2; anemia: N = 1). The median time to SAE onset was 2 months [0.9–2.1]. Patients’ baseline characteristics and galenic formulation were not associated with the onset of SAE in the univariate analysis (Table 2).\n\n2.4. Association between Olaparib Exposure and Toxicity\n\nAmong 22 patients from the PK analysis, 19 were included in the PK-toxicity analysis. Three patients were excluded because the delay between SAE and measurement of olaparib plasma concentration was more than 6 months. Among these 19 patients, 8 experienced SAE over the treatment course (including two patients with SAE beyond 6 months after olaparib initiation: anemia at 12 months and digestive toxicity at 26 months) and 11 patients did not experience SAE. The delay between the SAE occurrence and the measurement of olaparib plasma concentrations was 2 to 4 months (Figure 4C).\n\nPatients who experienced SAE had higher median plasma olaparib CminPred than other patients (2862 ng/mL vs. 1195 ng/mL, respectively; p = 0.026) (Figure 4A). Increased CminPred was associated with a higher risk of SAE, with an odds ratio of 1.31 (95% CI = 1.10–1.57) for each additional 1000 ng/mL. CminPred was found predictive of SAE onset in the ROC analysis with an AUC of 0.81 (95% CI = 0.57–1.00) (Figure 4B). Based on the distribution of CminPred in the studied population and sensitivity/specificity in the ROC analysis, a threshold of 2500 ng/mL was selected as the lowest (i.e., most sensitive) threshold at specificity = 100% (Figure 4B). At this threshold, only one of 11 patients without SAE had a CminPred above 2500 ng/mL, vs. 5 of 8 patients who experienced an olaparib-related SAE (Figure 4C,D) (9.1 vs. 62.5%, respectively; Chi2 test, p = 0.01).\n\nAmong the three patients who experienced an SAE and exhibited CminPred below 2500 ng/mL, two of them had a dose reduction in the first month of olaparib treatment for grade II asthenia while being ECOG-PS = 2 at baseline (patient #10: 73 years old patient with albuminemia 46 g/L; patient #12: 85 years old patient with 39 g/L albuminemia). Patient #20 experienced a grade II anemia resulting in dose reduction, controlled thereafter with a CminPred at 1241 ng/mL with a grade I anemia.\n\n2.5. Pharmacokinetic Drug–Drug Interactions\n\nAmong 27 patients, 4 (15%) had a potential drug interaction (PDI) which could result in olaparib over-exposure. Three patients were concomitantly treated with CYP3A4/5 inhibitors at baseline: amiodarone (N = 2), aprepitant (N = 1). These three patients experienced toxicity within three months. According to DDI predictor, the mean predicted increase in plasma olaparib exposure (AUC) is 1.39 (95% CI = 0.99–1.97) and 2.07 (95% CI = 1.30–3.29]) for amiodarone 1200 mg/day and aprepitant 80 mg/day, respectively.\n\nPatient #8 (Figure 4C) treated with amiodarone 200 mg daily for severe amyloidosis cardiomyopathy had several available PK samples: (i) CminPred of 3964 ng/mL at SAE onset, 1 month after olaparib treatment start (tablet 300 mg bid), was associated with an episode of asthenia grade II, leading to a dose reduction to 150 mg bid; (ii) one month after olaparib dose reduction, CminPred was 1649 ng/mL, and (iii) four months later, at another acute event occurrence (acute pyelonephritis with bacteriemia), olaparib CminPred was 2732 ng/mL. Olaparib was held during the acute event, and reintroduced after resolution at the same dose. No further olaparib plasma concentration assessment was performed for this patient.\n\nPatient #2 (Figure 4C) was treated for atrial fibrillation cardioversion with a high intravenous dose of amiodarone after 26 months of olaparib treatment (capsule 400 mg bid). She experienced a grade II digestive toxicity two months after amiodarone introduction. Olaparib CminPred at SAE onset was 3919 ng/mL. After 5 months of amiodarone discontinuation, olaparib CminPred was still increased (2876 ng/mL) without any modification of olaparib dose. The long terminal half-life of amiodarone (9–77 days [20]) could explain this slow decrease in olaparib CminPred. In this context, olaparib dose was finally reduced to 100 mg bid. CminPred was 1133 ng/mL after 20 days of dose reduction.\n\n3. Discussion\n\nOur study is the first to comprehensively analyze factors potentially leading to olaparib SAE. We observed a significant relationship between plasma olaparib exposure and SAE onset, leading us to propose a threshold of plasma trough concentration > 2500 ng/mL as significantly associated with an increased risk of SAE onset.\n\nIn our study, blood samples for plasma drug monitoring were collected at any time after dose intake. Thereby, we used a previously published population PK model for olaparib to estimate trough concentrations [17] to avoid bias in the PK-toxicity analysis related to the variability in the sampling time. The predictive performance of the model when applied to real-life data was evaluated by calculation of PE and simulation-based pcVPC. The median PE was −11.9% [IQR = −15.9; −4.9] showing that the observed and predicted concentrations were in good agreement although a slight underestimation of the concentrations was observed. The pcVPC showed good predictive performance of the model when applied to our data. However, the median of the observed concentrations was slightly higher than the prediction interval at 10 h post-dose. This might be due to the low number of patients and sparse PK data in our study and potential enrichment in concentrations in patients presenting a toxic event. Thus, olaparib plasma concentrations in our cohort might be higher than those observed in clinical trials used to develop the PK model by Zhou et al. Nevertheless, when considering absolute PE values, 86.9% and 98.4% of concentrations had an absolute PE <20% and <30%, respectively. In addition, the median PE was lower than the median intra-individual variability in CminPred. Taken together with all these arguments, CminPred can be considered as a reasonable estimation of the trough exposure in our study. Furthermore, the median CminPred for 400 mg bid capsules and 300 mg bid tablets (997 ng/mL and 2503 ng/mL, respectively) were in accordance with values previously reported from clinical trials data (mean steady-state Cmin of 1290 ng/mL (CV = 133%) and 1840 ng/mL (CV = 67%) for capsule 400 mg bid and tablet 300 mg bid, respectively) [21]. However, a slightly higher CminPred was observed in patients treated with 300 mg tablets compared to the literature data. This could be explained by enrichment in olaparib concentration assessment at SAE onset. Overall, our external validation of the PK model allowed using it for the prediction of trough concentrations, which also suggests that this model could be used in daily clinical practice. Despite the selection bias due to the exclusive consideration of patients for whom an olaparib exposure assessment was performed, the rate of clinically significant adverse events in our population (48%) was consistent with the rate of 41% of grade III-IV adverse events previously reported [11].\n\nTo date, factors associated with a higher risk of SAE have not been clearly identified in ovarian cancer patients from the “real world”. Additionally, the olaparib PK/PD relationship in this population has not yet been evaluated. In the present study, increased olaparib CminPred was the only factor significantly associated with a higher risk of SAE occurrence (OR = 1.31, 95% CI = 1.10–1.57). As far as we know, no such relation was previously reported in patients from clinical trials. In this study, we focused on a non-selected real-life population which is likely more fragile than that included in clinical trials. This results in both greater sensitivity to the induced-olaparib toxic effects and in a larger inter-individual variability in the olaparib PK. These two elements could contribute in part to explaining the discrepancy of our results with those reported in the literature. In order to help physicians in their therapeutic decision, we decided to determine CminPred threshold predicting the occurrence of SAE with a specificity of 100%. In this context, a threshold of 2500 ng/mL was selected with a sensitivity of 68%. This threshold value seems to be clinically meaningful since 9% of patients without SAE had a CminPred above 2500 ng/mL, vs. 62.5% for patients who experienced SAE.\n\nDrug–drug interactions are a major concern in the management of cancer patients [22] since they often receive multiple drugs to maximize the therapeutic effect, counter the adverse events of chemotherapy, or treat comorbidities. Additionally, they can concomitantly consume herbs, food and dietary supplements that can interact significantly on the PK of anticancer drugs [23]. PDI may result in severe adverse events related to plasma overexposure or decreased efficacy in the case of subtherapeutic concentration. CYP3A4-based drug–drug interactions are often observed in daily clinical practice [22]. Olaparib is a candidate for PDI because it is mainly metabolized through the CYP3A4 pathway. In the present study, the two illustrative cases of PDI with amiodarone highlight the three stages of PDI: CYP3A4 inhibition resulting in plasma drug overexposure and in consequence, the occurrence of an SAE. Overall, these results suggest that a multidisciplinary approach including oncologists, pharmacists and pharmacologists should be conducted to prevent clinically significant drug–drug interactions before the start and during olaparib treatment.\n\nThe large inter-individual variability in olaparib plasma exposure observed in our study (CV = 64% and 53% for capsules and tablets, respectively), as well as the PK-toxicity relationship, supports the use of therapeutic drug monitoring strategies in a context of personalized drug management. Our study shows that the application of model-informed therapeutic drug monitoring for olaparib could be considered in routine practice to guide dose adaptations. Indeed, a blood sample for olaparib quantification can be collected at any time after dose intake and a corresponding trough concentration can be estimated using the previously published PK model. However, since this approach is not yet used in all the hospital laboratories, olaparib trough concentration can be obtained by sampling blood at 10 to 14 h after dose intake (considering terminal half-life of 15 h [21]. The proposed threshold of 2500 ng/mL could help to guide dose adaptation in order to prevent the onset of SAE and/or to confirm whether a clinical event is due to olaparib plasma overexposure. Other PK endpoints such as area under the concentration–time curve (AUC) or maximum concentration (Cmax) were not evaluated in this study since we aimed to find a PK target that could be easily obtained in routine care.\n\nFew limitations should be taken into consideration. This threshold value could be under- or overestimated due to the possible biased inclusion of patients for whom plasma drug monitoring was performed because of apparent frailty. In addition, our PK-toxicity analysis was based on CminPred estimated using sparse PK data in real-life patients and a population PK model from the literature. The model was developed based on data from clinical trials and therefore might not represent the unselected patients seen in routine practice. Therefore, the threshold of 2500 ng/mL associated with SAE should be interpreted cautiously and can now be used when the estimation of CminPred is performed with the PK model by Zhou et al. Further validation should confirm this threshold on measured trough concentrations in a larger prospective cohort with standard TDM practice.\n\nFurthermore, the covariates included in the PK model were formulation (capsule or tablet), tablet strength and ECOG-PS (0 vs. 1–2). Although a reduced initial dose of olaparib is currently recommended in patients with renal impairment [24], in two population PK analyses, creatinine clearance (CLCR) did not have a statistically significant impact on olaparib elimination (CL/F) [19,25]. Therefore, renal impairment was not included in our estimations. However, other factors such as concomitant intake of CYP3A inhibitors or inducers or inflammation might impact the PK of olaparib [26,27]. The use of a physiologically-based PK (PBPK) model could be more accurate to predict CminPred in such patients. A PBPK model for olaparib has been previously proposed and allows predicting changes in olaparib exposure in various scenarios such as intake of CYP3A modulators and might be more suitable to use in routine practice [17]. In addition, a PBPK model could be used to predict concentrations at the site of action (tumor tissue) for a better description of the PK–efficacy relationship. Future investigations should consider the use of PBPK models for the estimation of olaparib individual exposure.\n\nFinally, recent olaparib approvals in first-line treatment in ovarian and breast cancer [4,28], together with development in combination with other drugs [29,30,31] prompt to anticipate a wide use of this drug in a heterogeneous population. In this context, the development of a pharmacokinetic-guided dosing strategy appears relevant to encompass expected heterogeneous clinical and toxicity profiles. Beyond olaparib, our results suggest that these approaches should be developed also in other PARP inhibitors.\n\n4. Materials and Methods\n\n4.1. Patients\n\nAll consecutive patients who were referred to Cochin University Hospital for olaparib plasma exposure assessment as per routine practice between January 2016 and September 2020 were considered for inclusion in this retrospective cohort. Patients were treated and followed in Paris urban area University Hospitals (Cochin University Hospital, Georges Pompidou European Hospital, Gustave-Roussy Cancer Campus). We included only patients who received olaparib in maintenance for high-grade serous or endometrioid ovarian cancer, primary peritoneal cancer, or fallopian tube cancer, with a BRCA1/2 mutation, and who had a complete or partial clinical response after platinum-based chemotherapy, regardless of the line of treatment. Exclusion criteria were: minor patients, patients receiving olaparib for other cancers, and patients referred for a second medical opinion and for whom follow-up data were not available. Patient and olaparib therapeutic management was performed according to routine practice.\n\n4.2. Data Collection\n\nPatient electronic medical records were retrospectively searched for patients (age, comorbidity), cancer characteristics (International Federation of Gynecology and Obstetrics classification (FIGO), histological type, BRCA1/2 mutation), and therapeutic management (surgery, previous chemotherapy) at diagnosis. Clinical and biological characteristics were collected at olaparib initiation: body weight, size, functional status (as per Eastern Cooperative Oncology Group Performance Status (ECOG-PS)), hemoglobin, platelets, white blood cells count, kidney function (estimated Glomerular Filtration Rate (eGFR)), and serum albumin concentration. Olaparib dose, galenic formulation (tablet or capsule) and concomitant treatments were also notified. Potential PK drug–drug interactions (PDI) with olaparib were assessed using both the Cancer Drug Interaction website (Radboud UMC and University of Liverpool [32] and DDI Predictor [33]. They were classified in five degrees of interaction, increasing in significance: no clear data, no interaction expected, potential weak interaction, potential interaction, do not co-administer.\n\nOlaparib-induced adverse events were graded using the National Cancer Institute Common Toxicity Criteria (CTCAE), version 5.0.\n\n4.3. Pharmacokinetic Analysis\n\nMonitoring of plasma olaparib concentrations was performed as per routine practice at the practitioner’s discretion. Blood samples were collected in heparinized tubes (5 mL) at any time during the dosing interval, then centrifuged at 4000 RPM for 10 min within 2 h after collection. Plasma was collected, then stored at −20 °C until analysis. Quantification of olaparib plasma concentrations was performed using a validated high-performance liquid chromatography (HPLC)-UV method. Briefly, 200 µL of plasma sample (calibration standard, internal quality control (IQC) or patients’ sample) were firstly spiked with 400 µL of erlotinib (250 ng/mL) used as internal standard (IS), then with 400 µL of acetonitrile including 0.1% trifluoroacetic acid (TFA). Samples were vortexed for 10 min, centrifuged (13,000 RPM, 5 min) and the organic layer was evaporated under nitrogen stream at 40 °C. Dry residue was reconstituted with 100 µL of mobile phase (ammonium acetate 20 mM acidified to pH 4.5 with TFA and acetonitrile 0.1% TFA (75:25, v/v)). The vials were vortexed, then ultracentrifuged (13,000 RPM, 5 min). Finally, 50 µL of supernatant was injected into the chromatographic system. This latter consisted of Dionex Ultimate 300 equipped with a gradient pump with degas option and gradient mixer, a UV-visible detector, an autosampler, and a Chromeleon® chromatography workstation (Dionex Corporation, Sunnyvale, CA, USA). The separation of analytes was performed using a NUCLEOSHELL Bluebird RP 18 (2.7 µm, 150 × 4.6 mm) column (Macherey-Nagel, Düren, Germany) associated with a guard column packed with the same bonded phase. The column temperature was maintained at 40 °C and the auto-sampler at 4 °C. The mobile phase consisted of a mixture of ammonium acetate 20 mM acidified to pH 4.5 with TFA (reagent A) and of acetonitrile 0.1% TFA (reagent B). The mobile phase was delivered using isocratic elution (75% A; 25% B, v/v) at a flow rate of 1 mL/min. UV detection was performed at 210 nm and 323 for olaparib and erlotinib (IS), respectively. The calibration curve was linear in the range 100–10,000 ng/mL Within-day imprecision and accuracy were for three levels of IQC: 3.0% and −1.1% for 200 ng/mL, 5.6% and −1.8% for 700 ng/mL and 2.7% and 4.7% for 4000 ng/mL, respectively. Between-day imprecision and accuracy were 9.6% and 4.7% for 200 ng/mL, 6.8% and 2.5% for 700 ng/mL and 6.5% and 6.7% for 4000 ng/mL, respectively. The lower limit of quantification (LLOQ) was 100 ng/mL with between-day imprecision and accuracy of 7.4% and −1.2%, respectively.\n\nSince PK sampling was performed at any time during the dosing interval, a previously published population PK model for olaparib was used to predict trough concentrations (i.e., 12 h post-dose, CminPred) [19]. Briefly, the model consisted of two compartments for olaparib distribution, sequential zero- and first-order absorption and first-order elimination for both capsules and tablets formulation. To account for the differences in plasma exposure between capsules and tablets formulations, the relative bioavailability (Frel) of the capsule and tablets formulation was included in the PK model, with capsule < 100 mg dose as the reference (i.e., Frel = 1). The residual error was coded according to the proportional model and the inter-individual variability was included according to the exponential model. The covariates included in the published PK model and used in the current analysis were: olaparib formulation (capsule or tablet), tablet strength and ECOG-PS (0 vs. 1–2). The PK analysis was performed in NONMEM software version 7.5.0 (ICON Development Solutions, Ellicott City, Maryland). The first-order conditional estimation with interaction (FOCE-I) method was used with MAXEVAL = 0 option with the parameter values fixed to the values estimated in [19]. The PK model parameters are summarized in Table A1.\n\nPredictive performance of the PK model was evaluated by calculating the prediction error (PE) as the difference between the observed and predicted plasma olaparib concentrations according to the following equation: PEij = (Cpred,ij − Cobs,ij)/Cobs,ij × 100 where Cpred,ij is the jth predicted concentration for individual i and Cobs,ij is the jth observed concentrations for individual i. The accuracy was estimated using the median PE while the precision was measured by the interquartile range (IQR) of the PE. The absolute value of PE was computed and the number of concentrations with absolute PE <20% and <30% was reported. In addition, a prediction-corrected visual predictive check (pcVPC) was performed to evaluate the accordance between the concentrations simulated with mean population parameter values (fixed and random effects) issued from the published model and the observed olaparib concentrations in our study population.\n\nThe PK model was used to compute 12-h post-dose plasma olaparib concentrations (trough concentration, CminPred) considering each individual concentration separately, which allowed accounting for potential intra-patient variability.\n\n4.4. Pharmacodynamic Analysis\n\n4.4.1. Olaparib Toxicity\n\nThe primary endpoint of the study was the occurrence of clinically significant adverse events (SAE) considered as olaparib-related (as stated in medical records). No secondary interpretation nor adjudication of causality between olaparib and adverse events was performed. SAEs were defined as: (i) grade III-IV adverse events, or (ii) adverse events resulting in dose reduction or treatment discontinuation.\n\n4.4.2. Statistical Analyses\n\nPatient characteristics were described as number (percentage) for binary/categorical variables and median [interquartile range, IQR] or range (min–max) for continuous variables. Associations between continuous and binary variables were assessed using the non-parametric unpaired Wilcoxon test. Associations between binary/categorical variables were assessed by Fisher or Chi2 test, as appropriate.\n\nThe association between patient baseline characteristics and SAE occurring within the first six months of treatment was assessed by logistic regression. The PK-toxicity relationship was assessed based on SAE events for which olaparib plasma concentration (CminPred) close to the onset (+/− 6 months) was available. In patients who experienced an SAE, CminPred closest to SAE was considered for statistical analysis. In patients who did not present any SAE, the mean plasma exposure was calculated by averaging all available CminPred for each patient. The association between CminPred and SAE onset was assessed by logistic regression. Performances of CminPred as a predictor of SAE onset were evaluated by area under the ROC curve (AUC) analyses. We aimed to identify a CminPred threshold with high specificity (high predictive positive value for olaparib toxicity), to suggest dose reduction only in patients with high confidence of over-exposure. All tests were two-sided. Variables reaching p < 0.1 in univariable logistic regression analyses were considered eligible for multivariable analysis. Statistical significance was defined by p < 0.05. Statistical analyses were performed using R software (v4).\n\n5. Conclusions\n\nOur study shows an association between olaparib plasma exposure and toxicity in patients treated for BRCA1/2 mutated ovarian cancer. Although further validations are warranted to confirm or refine the threshold of CminPred identified as indicative of SAE, our results suggest that personalized olaparib drug monitoring is feasible in this setting, and should be considered to guide therapeutic decisions of dose adjustment.\n\nAcknowledgments\n\nGB received institutional funding from ITMO Cancer AVIESAN (French National Cancer Institute) during the conduct of the study. GB and JA belong to a research team supported by the Ligue Nationale Contre le Cancer (LNCC, Program “Equipe labelisée LIGUE”; no. EL2016.LNCC). Institutions were not directly involved in the conduct of the study.\n\nAuthor Contributions\n\nConceptualization, J.A., G.B.; methodology, M.V., A.P., B.B., J.A., G.B.; software, A.P., G.B.; validation, M.V., A.P., J.A., G.B.; formal analysis, M.V., A.P., G.B.; investigation, M.V., A.P., B.B., G.B., J.A.; resources, B.B., F.G., J.A.; data curation, M.V., A.P., G.B.; writing—original draft preparation, M.V., A.P., G.B.; writing—review and editing, all authors; visualization, M.V., A.P., G.B.; supervision, B.B., J.A., G.B.; project administration, G.B. All authors have read and agreed to the published version of the manuscript.\n\nFunding\n\nThis research received no external funding.\n\nInstitutional Review Board Statement\n\nThe study fulfilled MR004 ethical guidelines as per French regulatory standards for retrospective non-interventional data analysis studies and obtained institutional approval for patient inclusion based on patient non-opposition (Approval number 20210420140656).\n\nInformed Consent Statement\n\nPatient inclusion was based on written informed non-opposition, as per French MR004 ethical guidelines for retrospective non-interventional data analysis. No patient can be identified based on published results.\n\nData Availability Statement\n\nData is contained within the article.\n\nConflicts of Interest\n\nNicolas Delanoy discloses: Board/consulting: MSD, Astra Zeneca, GSK, Clovis oncology, outside the submitted work. Patricia Pautier discloses: Board/consulting: Astra Zeneca, GSK, Clovis oncology, outside the submitted work. Alexandra Leary discloses: grants, personal fees and non-financial support from AZ, grants, personal fees and non-financial support from Tesaro, grants, personal fees and non-financial support from clovis, grants and personal fees from MSD, personal fees from biocad, grants and personal fees from ability, other from merck serono, personal fees from seattle genetics, grants, non-financial support and other from GSK, personal fees from Zentalis, outside the submitted work. Jerome Alexandre discloses: research funding from MSD; advisory board: GSK, MSD, AstraZeneca, Eisaï, outside the submitted work. The other authors declare no potential conflicts of interest.\n\nAppendix A\n\npharmaceuticals-14-00804-t0A1_Table A1 Table A1 Parameters used in the PK analysis obtained from Zhou et al. [19].\n\nParameter\tDescription\tValue Used in the Predictions (Mean Estimate from Zhou et al.)\t\nCL (L h−1)\tSteady-state clearance\t3.60\t\nθECOG-PS on CL\tEffect of ECOG-PS on clearance for ECOG-PS ≥ 1 a\t−0.240\t\nVc (L)\tVolume of distribution of the central compartment\t2.57\t\nVp (L)\tVolume of distribution of the peripheral compartment\t19.7\t\nQ (L h−1)\tIntercompartmental clearance\t1.11\t\nFrel capsule b\tRelative bioavailability for capsule > 100 mg dose\t0.282\t\nFrel tablet c\tRelative bioavailability for tablet formulation\t0.627\t\nka (h−1) capsule\tFirst-order absorption rate constant for capsules\t0.247\t\nka (h−1) tablet\nstrength 100 mg\tFirst-order absorption rate constant for tablets strength 100 mg\t0.374\t\nka (h−1) tablet\nstrength 150 mg\tFirst-order absorption rate constant for tablets strength 150 mg\t0.267\t\nD1 (h) capsule\tDuration of zero-order absorption for capsules\t0.901\t\nD1 (h) tablet\tDuration of zero-order absorption for tablets\t0.467\t\nω CL (CV%)\tInter-individual variability in CL\t0.340 (58.3)\t\nω Vc (CV%)\tInter-individual variability in Vc\t0.448 (66.9)\t\nω Vp (CV%)\tInter-individual variability in Vp\t1.44 (120)\t\nω Q (CV%)\tInter-individual variability in Q\t0.560 (77.2)\t\nω D1 (CV%)\tInter-individual variability in D1\t0.534 (73.1)\t\nω ka (CV%)\tInter-individual variability in ka\t0.063 (25.1)\t\nProportional residual error\tResidual unexplained variability\t0.354\t\nCV, coefficient of variation; ECOG-PS, Eastern Cooperative Oncology Group Performance Status. a reference: ECOG-PS = 0, coded as TVCL = θCL × (1 + θECOG-PS). Of note, in the published model, ECOG-PS was coded as 0 (reference), 1 and 2. In our analysis, ECOG-PS = 1 and 2 were gathered into one category because of the limited number of patients and the clinical variability in terms of functional status assessment depending on clinicians. b relative to capsule < 100 mg dose (i.e., Frel = 1), coded as TVF1 = 1−θFrel,capsule × LOG10(DOSE). c relative to capsule < 100 mg dose (i.e., Frel = 1).\n\nFigure A1 Intra-individual variability in olaparib CminPred calculated as % deviation of each individual CminPred from the mean concentration over the treatment period for the same individual (N = 11 patients with more than one olaparib exposure assessment and treated at standard dose).\n\nFigure A2 Goodness-of-fit plots. (A) Observed vs. population predicted concentrations; (B) Conditional weighted residuals vs. population predicted concentrations; (C) Conditional weighted residuals vs. time since treatment start. The blue line is the local regression.\n\nFigure 1 Flow chart. * Olaparib-related iatrogenic adverse events were considered as any clinically significant adverse event (SAE) defined by: (i) grade III–IV adverse events, or (ii) adverse events resulting in dose reduction or treatment discontinuation.\n\nFigure 2 Evaluation of the predictive performance of the population PK model. (A) Observed vs. individual predicted olaparib concentrations. Solid line represents the identity line (y = x) (B) Prediction error (PE) vs. observed concentrations. (C) Prediction-corrected visual predictive check (pcVPC) for olaparib. pcVPC obtained by N = 1000 simulations of the original dataset with the mean parameters (fixed and random effects). The shaded areas represent the 95% confidence intervals around the 5th, 50th (median) and 95th percentile of the simulated concentrations, the lines represent the 5th, 50th (median) and 95th percentile of the observed concentrations and the circles represent the observed concentrations.\n\nFigure 3 Olaparib steady-state predicted trough concentrations (CminPred) according to olaparib formulation and ECOG-PS. (A) CminPred according to olaparib dose and formulation. (B) CminPred according to ECOG-PS. ECOG-PS: Eastern Cooperative Oncology Group Performance Status. Patients included in this analysis are patients treated with the recommended dose.\n\nFigure 4 Association between olaparib predicted trough concentration (CminPred) and onset of olaparib-related clinically significant adverse events (SAE). The black dashed line indicates the threshold identified by ROC curve analysis (2500 ng/mL). (A) Olaparib CminPred in patients with or without olaparib-related SAE. Toxic event refers to SAE onset. (B) Performances of olaparib CminPred for prediction of olaparib-related SAE (ROC curve). Se: sensitivity. Sp: specificity. AUC: area under curve. The 95% confidence intervals were computed by 2000 stratified bootstrap replicates. (C) Olaparib CminPred in patients who experienced a SAE. Patients included in this analysis are patients who experienced a SAE, with an olaparib exposure assessment at SAE onset (+/− 6 months around SAE). (D) Olaparib predicted trough concentration (CminPred) in patients without olaparib-related adverse event. Patients included in this analysis are patients with at least one plasma concentration available, and no adverse event within the six months around.\n\npharmaceuticals-14-00804-t001_Table 1 Table 1 Patient and cancer characteristics.\n\nVariable\tValue\t\nPatients and cancer characteristics at diagnostic\t\nAge, median [Q1–Q3] (years), (27 ‡)\t59 [53–66]\t\nHistological subtypes, N (%), (27 ‡)\t\t\nHigh grade ovarian serous carcinoma\t25 (93%)\t\nOthers\t2 (7%)\t\nFIGO stage at diagnosis, N (%), (27 ‡)\t\t\nI\t2 (8%)\t\nIII\t22 (81%)\t\nIVB\t3 (11%)\t\nBRCA mutations §, N (%), (27 ‡)\t\t\nBRCA1\t19 (70%)\t\nBRCA2\t8 (30%)\t\nInitial therapeutic management, N (%), (27 ‡)\t\t\nInduction/neoadjuvant platinum-based chemotherapy\t14 (52%)\t\nCytoreductive surgery\t25 (93%)\t\nComplete resection achieved\t23 (85%)\t\nAdjuvant platinum-based chemotherapy\t25 (93%)\t\nPatient characteristics at olaparib initiation\t\nAge, median [Q1–Q3] (years), (27 ‡)\t63 [57–72]\t\nECOG-PS, N (%), (27 ‡)\t\t\n0\t5 (19%)\t\n1\t16 (59%)\t\n2\t6 (22%)\t\nBody mass index (kg/m2), median [Q1–Q3], (25 ‡)\t23 [20–26]\t\nHemoglobin (g/dL), median [Q1–Q3], (26 ‡)\t11.8 [11.1–12.4]\t\nWhite blood cells count (G/L), median [Q1–Q3], (25 ‡)\t5.1 [3.6–6.2]\t\nPlatelet count (G/L), median [Q1–Q3], (26 ‡)\t233 [187–288]\t\nSerum albumin (g/L), median [Q1–Q3], (20 ‡)\t42 [39–44]\t\nEstimated creatinine clearance (Cockcroft–Gault formula), median [Q1–Q3] (mL/min) (26 ‡)\t78 [54–97]\t\nCancer characteristics at olaparib initiation\t\nOlaparib introduction setting, N (%), (27 ‡)\t\t\nMaintenance after adjuvant chemotherapy\t7 (26%)\t\nFirst relapse\t12 (44%)\t\nBeyond first relapse\t8 (30%)\t\nNumber of metastatic sites, N (%), (27 ‡)\t\t\nComplete remission at olaparib initiation\t10 (37%)\t\n1\t11 (40%)\t\n2\t5 (19%)\t\n3\t1 (4%)\t\nMetastatic sites, N (%), (27 ‡)\t\t\nPeritoneal metastases\t15 (55%)\t\nNode metastases\t4 (15%)\t\nVisceral abdominal metastases\t3 (11%)\t\nExtra abdominal metastases\t2 (7%)\t\nOlaparib formulation and dosing, N (%), (27 ‡)\t\t\nCapsule 400 mg bid\t16 (59%)\t\nCapsule 200 mg bid\t1 (4%)\t\nTablet 300 mg bid\t10 (37%)\t\nTotal\t27 (100%)\t\n‡ Number of patients with available data. FIGO: International Federation of Gynecology and Obstetrics (FIGO) classification (2014). § the somatic or germline status was not determined for all patients. ECOG-PS: Eastern Cooperative oncology Group Performance status.\n\npharmaceuticals-14-00804-t002_Table 2 Table 2 Association between baseline patient characteristics and risk of olaparib toxicity.\n\nCategories\tSAE within 6 Months *\nOdds Ratio † [95% CI]\tp-Value †\t\nAge at olaparib initiation (years), (27 ‡), for each additional year\t1.01 [0.99; 1.03]\t0.13\t\nECOG-PS > 1, (27 ‡)\t2.66 [0.42; 22.5]\t0.31\t\nBody mass index (kg/m2), (25 ‡), for each additional unit\t1.03 [0.99; 1.07]\t0.10\t\nSerum albumin (g/L), (20 ‡), for each additional unit\t0.95 [0.91; 1.00]\t0.10\t\nRenal insufficiency, (27 ‡), Cockcroft–Gault estimated clearance < 60 mL/min\t0.77 [0.15; 3.85]\t0.75\t\nHemoglobin (g/dL), (26 ‡), for each additional unit\t0.93 [0.72; 1.18]\t0.57\t\nOlaparib formulation (27 ‡), capsule (reference) vs. tablet\t2.14 [0.44; 11.3]\t0.34\t\nOlaparib introduction setting (27 ‡), maintenance (reference) vs. first relapse and beyond\t0.26 [0.03; 1.57]\t0.16\t\n* SAE: significant olaparib-related adverse event defined by (i) grade III–IV adverse events, or (ii) adverse events resulting in dose reduction or treatment discontinuation. † p-value and odds-ratio computed using univariable logistic regression analysis. ‡ Number of patients with available data included in the logistic regression analysis. ECOG-PS: Eastern Cooperative oncology Group Performance status.\n\nPublisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. Evers B. Drost R. Schut E. de Bruin M. van der Burg E. Derksen P.W.B. Holstege H. Liu X. van Drunen E. Beverloo H.B. Selective Inhibition of BRCA2-Deficient Mammary Tumor Cell Growth by AZD2281 and Cisplatin Clin. Cancer Res. 2008 14 3916 3925 10.1158/1078-0432.CCR-07-4953 18559613\n2. Lord C.J. Ashworth A. PARP Inhibitors: Synthetic Lethality in the Clinic Science 2017 355 1152 1158 10.1126/science.aam7344 28302823\n3. Fong P.C. Boss D.S. Yap T.A. Tutt A. Wu P. Mergui-Roelvink M. Mortimer P. Swaisland H. Lau A. O’Connor M.J. Inhibition of Poly(ADP-Ribose) Polymerase in Tumors from BRCA Mutation Carriers N. Engl. J. Med. 2009 361 123 134 10.1056/NEJMoa0900212 19553641\n4. Eikesdal H.P. Yndestad S. Elzawahry A. Llop-Guevara A. Gilje B. Blix E.S. Espelid H. Lundgren S. Geisler J. Vagstad G. Olaparib Monotherapy as Primary Treatment in Unselected Triple Negative Breast Cancer Ann. Oncol. 2021 32 240 249 10.1016/j.annonc.2020.11.009 33242536\n5. Hussain M. Mateo J. Fizazi K. Saad F. Shore N. Sandhu S. Chi K.N. Sartor O. Agarwal N. Olmos D. Survival with Olaparib in Metastatic Castration-Resistant Prostate Cancer N. Engl. J. Med. 2020 383 2345 2357 10.1056/NEJMoa2022485 32955174\n6. De Bono J. Mateo J. Fizazi K. Saad F. Shore N. Sandhu S. Chi K.N. Sartor O. Agarwal N. Olmos D. Olaparib for Metastatic Castration-Resistant Prostate Cancer N. Engl. J. Med. 2020 382 2091 2102 10.1056/NEJMoa1911440 32343890\n7. Golan T. Hammel P. Reni M. Van Cutsem E. Macarulla T. Hall M.J. Park J.-O. Hochhauser D. Arnold D. Oh D.-Y. Maintenance Olaparib for Germline BRCA-Mutated Metastatic Pancreatic Cancer N. Engl. J. Med. 2019 381 317 327 10.1056/NEJMoa1903387 31157963\n8. Moore K. Colombo N. Scambia G. Kim B.-G. Oaknin A. Friedlander M. Lisyanskaya A. Floquet A. Leary A. Sonke G.S. Maintenance Olaparib in Patients with Newly Diagnosed Advanced Ovarian Cancer N. Engl. J. Med. 2018 379 2495 2505 10.1056/NEJMoa1810858 30345884\n9. Robson M. Im S.-A. Senkus E. Xu B. Domchek S.M. Masuda N. Delaloge S. Li W. Tung N. Armstrong A. Olaparib for Metastatic Breast Cancer in Patients with a Germline BRCA Mutation N. Engl. J. Med. 2017 377 523 533 10.1056/NEJMoa1706450 28578601\n10. Ledermann J. Harter P. Gourley C. Friedlander M. Vergote I. Rustin G. Scott C. Meier W. Shapira-Frommer R. Safra T. Olaparib Maintenance Therapy in Platinum-Sensitive Relapsed Ovarian Cancer N. Engl. J. Med. 2012 366 1382 1392 10.1056/NEJMoa1105535 22452356\n11. Ricci A.D. Rizzo A. Novelli M. Tavolari S. Palloni A. Tober N. Abbati F. Mollica V. DE Lorenzo S. Turchetti D. Specific Toxicity of Maintenance Olaparib Versus Placebo in Advanced Malignancies: A Systematic Review and Meta-Analysis Anticancer Res. 2020 40 597 608 10.21873/anticanres.13989 32014900\n12. Liposits G. Wulff C.N. Otland A. Fokdal L.U. Olaparib Treatment in Older Patients with Ovarian Cancer: Need for “real-World” Data beyond Clinical Trials Ecancermedicalscience 2020 14 1104 10.3332/ecancer.2020.1104 33082854\n13. Lorusso D. Bologna A. Cecere S.C. De Matteis E. Scandurra G. Zamagni C. Arcangeli V. Artioli F. Bella M. Blanco G. Sharing Real-World Experiences to Optimize the Management of Olaparib Toxicities: A Practical Guidance from an Italian Expert Panel Support. Care Cancer 2020 28 2435 2442 10.1007/s00520-020-05320-4 32048043\n14. Yu H. Steeghs N. Nijenhuis C.M. Schellens J.H.M. Beijnen J.H. Huitema A.D.R. Practical Guidelines for Therapeutic Drug Monitoring of Anticancer Tyrosine Kinase Inhibitors: Focus on the Pharmacokinetic Targets Clin. Pharm. 2014 53 305 325 10.1007/s40262-014-0137-2\n15. Verheijen R.B. Yu H. Schellens J.H.M. Beijnen J.H. Steeghs N. Huitema A.D.R. Practical Recommendations for Therapeutic Drug Monitoring of Kinase Inhibitors in Oncology Clin. Pharmacol. Ther 2017 102 765 776 10.1002/cpt.787 28699160\n16. Plummer R. Swaisland H. Leunen K. van Herpen C.M.L. Jerusalem G. De Grève J. Lolkema M.P. Soetekouw P. Mau-Sørensen M. Nielsen D. Olaparib Tablet Formulation: Effect of Food on the Pharmacokinetics after Oral Dosing in Patients with Advanced Solid Tumours Cancer Chemother. Pharmacol 2015 76 723 729 10.1007/s00280-015-2836-2 26242220\n17. Pilla Reddy V. Bui K. Scarfe G. Zhou D. Learoyd M. Physiologically Based Pharmacokinetic Modeling for Olaparib Dosing Recommendations: Bridging Formulations, Drug Interactions, and Patient Populations Clin. Pharmacol. Ther. 2019 105 229 241 10.1002/cpt.1103 29717476\n18. Rolfo C. de Vos-Geelen J. Isambert N. Molife L.R. Schellens J.H.M. De Grève J. Dirix L. Grundtvig-Sørensen P. Jerusalem G. Leunen K. Pharmacokinetics and Safety of Olaparib in Patients with Advanced Solid Tumours and Renal Impairment Clin. Pharm. 2019 58 1165 1174 10.1007/s40262-019-00754-4\n19. Zhou D. Li J. Bui K. Learoyd M. Berges A. Milenkova T. Al-Huniti N. Tomkinson H. Xu H. Bridging Olaparib Capsule and Tablet Formulations Using Population Pharmacokinetic Meta-Analysis in Oncology Patients Clin. Pharm. 2019 58 615 625 10.1007/s40262-018-0714-x 30357650\n20. Freedman M.D. Somberg J.C. Pharmacology and Pharmacokinetics of Amiodarone J. Clin. Pharmacol. 1991 31 1061 1069 10.1002/j.1552-4604.1991.tb03673.x 1753010\n21. NDA/BLA Multi-Disciplinary Review and Evaluation NDA 208558 LynparzaTM (Olaparib) Available online: https://www.google.com/url?sa=t&rct=j&q=&esrc=s&source=web&cd=&ved=2ahUKEwiO3u64zLXwAhUMsxQKHc3MCbsQFjAAegQIAxAD&url=https%3A%2F%2Fwww.accessdata.fda.gov%2Fdrugsatfda_docs%2Fnda%2F2017%2F208558Orig1s000MultidisciplineR.pdf&usg=AOvVaw0sCeqI6xDGleC3aRwY5l3v (accessed on 12 August 2021)\n22. Ismail M. Khan S. Khan F. Noor S. Sajid H. Yar S. Rasheed I. Prevalence and Significance of Potential Drug-Drug Interactions among Cancer Patients Receiving Chemotherapy BMC Cancer 2020 20 335 10.1186/s12885-020-06855-9 32307008\n23. Fabre E. Thomas-Schoemann A. Blanchet B. Letter to the Editor Regarding the Paper by Loquai C et al. “Use of Complementary and Alternative Medicine: A Multicenter Cross-Sectional Study in 1089 Melanoma Patients” Eur. J. Cancer 2017 85 158 159 10.1016/j.ejca.2017.07.035 28877854\n24. Lynparza—Summary of Product Characteristics Available online: https://www.google.com/url?sa=t&rct=j&q=&esrc=s&source=web&cd=&ved=2ahUKEwj1z7u_9fDwAhX76OAKHZyJDTMQFnoECAUQAA&url=https%3A%2F%2Fwww.ema.europa.eu%2Fen%2Fdocuments%2Fproduct-information%2Flynparza-epar-product-information_en.pdf&usg=AOvVaw3CrQwyaKRC8QKpzVqArXFi (accessed on 12 August 2021)\n25. Peer C.J. Lee J.-M. Roth J. Rodgers L. Nguyen J. Annunziata C.M. Minasian L. Kohn E.C. Figg W.D. Population Pharmacokinetic Analyses of the Effect of Carboplatin Pretreatment on Olaparib in Recurrent or Refractory Women’s Cancers Cancer Chemother. Pharmacol. 2017 80 165 175 10.1007/s00280-017-3346-1 28577239\n26. Dirix L. Swaisland H. Verheul H.M.W. Rottey S. Leunen K. Jerusalem G. Rolfo C. Nielsen D. Molife L.R. Kristeleit R. Effect of Itraconazole and Rifampin on the Pharmacokinetics of Olaparib in Patients With Advanced Solid Tumors: Results of Two Phase I Open-Label Studies Clin. Ther. 2016 38 2286 2299 10.1016/j.clinthera.2016.08.010 27745744\n27. Simon F. Gautier-Veyret E. Truffot A. Chenel M. Payen L. Stanke-Labesque F. Tod M. Modeling Approach to Predict the Impact of Inflammation on the Pharmacokinetics of CYP2C19 and CYP3A4 Substrates Pharm. Res. 2021 38 415 428 10.1007/s11095-021-03019-7 33686560\n28. Banerjee S. Gonzalez-Martin A. Harter P. Lorusso D. Moore K.N. Oaknin A. Ray-Coquard I. First-Line PARP Inhibitors in Ovarian Cancer: Summary of an ESMO Open—Cancer Horizons Round-Table Discussion ESMO Open 2020 5 e001110 10.1136/esmoopen-2020-001110 33310779\n29. Lee Y.J. Lim M.C. Kim B.G. Ngoi N.Y. Choi C.H. Park S.Y. Tan D.S. Go Y. Lee J.Y. A Single-Arm Phase II Study of Olaparib Maintenance with Pembrolizumab and Bevacizumab in BRCA Non-Mutated Patients with Platinum-Sensitive Recurrent Ovarian Cancer (OPEB-01) J. Gynecol. Oncol. 2021 e31 10.3802/jgo.2021.32.e31 33559413\n30. Ali R. Alblihy A. Toss M.S. Algethami M. Al Sunni R. Green A.R. Rakha E.A. Madhusudan S. XRCC1 Deficient Triple Negative Breast Cancers Are Sensitive to ATR, ATM and Wee1 Inhibitor Either Alone or in Combination with Olaparib Ther. Adv. Med. Oncol. 2020 12 10.1177/1758835920974201\n31. Mansouri A. McGregor N. Dunn R. Dobbie S. Holmes J. Collins L. Nicum S. Randomised Phase II Trial of Olaparib, Chemotherapy or Olaparib and Cediranib in Patients with Platinum-Resistant Ovarian Cancer (OCTOVA): A Study Protocol BMJ Open 2021 11 10.1136/bmjopen-2020-041463\n32. Available online: https://cancer-druginteractions.org (accessed on 12 August 2021)\n33. Available online: https://www.ddi-predictor.org/ (accessed on 12 August 2021)\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1424-8247",
"issue": "14(8)",
"journal": "Pharmaceuticals (Basel, Switzerland)",
"keywords": "PK-toxicity relationship; olaparib; ovarian cancer; population pharmacokinetics; therapeutic drug monitoring",
"medline_ta": "Pharmaceuticals (Basel)",
"mesh_terms": null,
"nlm_unique_id": "101238453",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34451901",
"pubdate": "2021-08-16",
"publication_types": "D016428:Journal Article",
"references": "24566736;32955174;28302823;18559613;29717476;28577239;28699160;31157963;1753010;30877569;19553641;33082854;33686560;33242536;33559413;22452356;28877854;30357650;33425022;30345884;33452192;28578601;32048043;33310779;27745744;32307008;32343890;32014900;26242220",
"title": "Association between Olaparib Exposure and Early Toxicity in BRCA-Mutated Ovarian Cancer Patients: Results from a Retrospective Multicenter Study.",
"title_normalized": "association between olaparib exposure and early toxicity in brca mutated ovarian cancer patients results from a retrospective multicenter study"
} | [
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"companynumb": "FR-009507513-2203FRA001566",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
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{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "APREPITANT"
},
"drugadditional": "3",
... |
{
"abstract": "OBJECTIVE\nTo report a case of microsporidia (Encephalitozoon hellem) keratoconjunctivitis acquired through avian transmission in an immunocompetent adult, diagnosed by metagenomic deep sequencing (MDS), and confirmed by polymerase chain reaction.\n\n\nMETHODS\nA case report.\n\n\nRESULTS\nAn 18-year-old woman was referred with unilateral keratoconjunctivitis unresponsive to topical and systemic therapy after exposure to birdcage debris. Slit-lamp examination of the left eye revealed a follicular papillary reaction of the palpebral conjunctiva and multiple corneal punctate epithelial opacities that stained minimally with fluorescein. In vivo confocal microscopy revealed bright double-walled structures and smaller bright round structures in the superficial epithelial debris and epithelium. Molecular diagnosis with MDS of E. hellem was confirmed by polymerase chain reaction. Clinical resolution and normalization of in vivo confocal microscopy was observed after a 6-week course of topical azithromycin. The patient elected a 3-week course of topical voriconazole 1% for definitive antimicrosporidial treatment, with no evidence of persistent infection 1 month later.\n\n\nCONCLUSIONS\nMicrosporidial (E. hellem) keratoconjunctivitis can occur through avian transmission in immunocompetent hosts. Topical azithromycin may be effective against this pathogen. MDS has utility in the diagnosis of atypical keratoconjunctivitis.",
"affiliations": "Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA.;Department of Ophthalmology, University of California, San Francisco, CA; and.;Department of Ophthalmology, University of California, San Francisco, CA; and.;Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA.;Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA.",
"authors": "Ma|Kevin K|KK|;Kinde|Benyam|B|;Doan|Thuy|T|;Jacobs|Deborah S|DS|;Ong Tone|Stephan|S|",
"chemical_list": "D000900:Anti-Bacterial Agents; D000935:Antifungal Agents; D017963:Azithromycin; D065819:Voriconazole",
"country": "United States",
"delete": false,
"doi": "10.1097/ICO.0000000000002466",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0277-3740",
"issue": "40(2)",
"journal": "Cornea",
"keywords": null,
"medline_ta": "Cornea",
"mesh_terms": "D000293:Adolescent; D000900:Anti-Bacterial Agents; D000935:Antifungal Agents; D017963:Azithromycin; D004359:Drug Therapy, Combination; D016819:Encephalitozoon; D015821:Eye Infections, Fungal; D005260:Female; D006801:Humans; D007121:Immunocompetence; D007637:Keratoconjunctivitis; D056186:Metagenomics; D018613:Microscopy, Confocal; D016881:Microsporidiosis; D016133:Polymerase Chain Reaction; D065819:Voriconazole",
"nlm_unique_id": "8216186",
"other_id": null,
"pages": "242-244",
"pmc": null,
"pmid": "32826651",
"pubdate": "2021-02-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Dual Molecular Diagnosis of Microsporidia (Encephalitozoon hellem) Keratoconjunctivitis in an Immunocompetent Adult.",
"title_normalized": "dual molecular diagnosis of microsporidia encephalitozoon hellem keratoconjunctivitis in an immunocompetent adult"
} | [
{
"companynumb": "US-TEVA-2020-US-1837568",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
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{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "AZITHROMYCIN ANHYDROUS"
},
"drugadditional": nu... |
{
"abstract": "OBJECTIVE\nTo report a case of toxic epidermal necrolysis (TEN) possibly induced by captopril.\n\n\nMETHODS\nAn 11-week-old boy was referred to our hospital for tetrology of fallot surgical repair, performed on admission day 2. On day 3, the patient developed third-degree heart block, necessitating pacemaker connection and oral theophylline 3 mg/kg 3 times daily. Captopril 1 mg orally twice daily, intravenous furosemide 7 mg every 12 hours, and oral aldactone 7 mg twice daily were started. On day 5, the patient developed scaling erythematous skin lesions. On day 7, his temperature spiked to 37.8 degrees C, and pus discharge from the pacing wire site was noticed. Intravenous vancomycin 80 mg 3 times daily and intravenous ceftazidime 200 mg 3 times daily were initiated. On the same day, captopril was discontinued because we suspected that it had induced the skin reaction. On day 15, the infant's skin problem progressed. The dermatologist diagnosed partial TEN. On that day, theophylline and furosemide were also discontinued. On day 16, the patient still had some blisters, but the skin started to show signs of healing, until complete healing occurred on day 22. The infant was discharged on oral medications: furosemide 7 mg twice daily, aldactone 7 mg twice daily, and enalapril 0.1 mg twice daily. Three weeks later, he was followed up. No recurrences were observed.\n\n\nCONCLUSIONS\nThis case suggests captopril induces TEN when combined with other sulfonamide medications. An objective causality assessment revealed that the adverse drug event was possible. Although it is a rare complication, healthcare providers should be familiar with its potential to occur and take appropriate treatment and prevention measures.",
"affiliations": "King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.",
"authors": "Alkurtass|Delal A|DA|;Al-Jazairi|Abdulrazaq S|AS|",
"chemical_list": "D000806:Angiotensin-Converting Enzyme Inhibitors; D003879:Dermatologic Agents; D002216:Captopril; D015034:Zinc Oxide; D012837:Silver Sulfadiazine",
"country": "United States",
"delete": false,
"doi": "10.1345/aph.1C284",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1060-0280",
"issue": "37(3)",
"journal": "The Annals of pharmacotherapy",
"keywords": null,
"medline_ta": "Ann Pharmacother",
"mesh_terms": "D000806:Angiotensin-Converting Enzyme Inhibitors; D002216:Captopril; D003879:Dermatologic Agents; D006801:Humans; D007223:Infant; D008297:Male; D012837:Silver Sulfadiazine; D013262:Stevens-Johnson Syndrome; D015034:Zinc Oxide",
"nlm_unique_id": "9203131",
"other_id": null,
"pages": "380-3",
"pmc": null,
"pmid": "12639167",
"pubdate": "2003-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Possible captopril-induced toxic epidermal necrolysis.",
"title_normalized": "possible captopril induced toxic epidermal necrolysis"
} | [
{
"companynumb": "SA-TEVA-03-06-0780",
"fulfillexpeditecriteria": "1",
"occurcountry": "SA",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "THEOPHYLLINE ANHYDROUS"
},
"drugadditional": null,
... |
{
"abstract": "Choroid plexus carcinomas (CPCs) are rare epithelial central nervous system tumors. CPC occurs mainly in infants and young children, comprising ≈ 1 to 4% of all pediatric brain neoplasms. There is very limited information available regarding tumor biology and CPC treatment due to its rarity. There have been various case reports and meta-analyses of reported cases with CPC. Surgical resection is often challenging but remains a well-established treatment option. Chemotherapy is often reserved for recurrent or refractory cases, but the goal of treatment is usually palliative. We present a case of recurrent, adult CPC with disseminated leptomeningeal involvement treated with salvage chemotherapy including high-dose ifosfamide, carboplatin, and etoposide; once a remission was achieved, this response was consolidated with a syngeneic stem cell (bone marrow) transplant after a preparative regimen of high-dose chemotherapy with carboplatin, etoposide, and thiotepa. Although the patient tolerated the transplant well and remained disease-free for 12 months, she subsequently succumbed to relapsed disease 18 months posttransplant. We believe that this is the first report of using syngeneic stem cell transplant in CPC to consolidate a remission achieved by salvage chemotherapy.",
"affiliations": "Department of Medicine, Hematology/Oncology, Georgia Health Sciences University, Augusta, Georgia, United States.;Department of Medicine, Georgia Health Sciences University, Augusta, Georgia, United States.;Department of Pathology, Georgia Health Sciences University, Augusta, Georgia, United States.;Department of Neurosurgery, Georgia Health Sciences University, Augusta, Georgia, United States.;Department of Medicine, Georgia Health Sciences University, Augusta, Georgia, United States.;Department of Medicine, Georgia Health Sciences University, Augusta, Georgia, United States.;Department of Medicine, Georgia Health Sciences University, Augusta, Georgia, United States.;Department of Medicine, Georgia Health Sciences University, Augusta, Georgia, United States.",
"authors": "Samuel|Thomas A|TA|;Parikh|Jigarkumar|J|;Sharma|Suash|S|;Giller|Cole A|CA|;Sterling|Kristen|K|;Kapoor|Suraj|S|;Pirkle|Christen|C|;Jillella|Anand|A|",
"chemical_list": "D000970:Antineoplastic Agents",
"country": "Germany",
"delete": false,
"doi": "10.1055/s-0032-1333419",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2193-6315",
"issue": "74 Suppl 1()",
"journal": "Journal of neurological surgery. Part A, Central European neurosurgery",
"keywords": null,
"medline_ta": "J Neurol Surg A Cent Eur Neurosurg",
"mesh_terms": "D000970:Antineoplastic Agents; D016026:Bone Marrow Transplantation; D002277:Carcinoma; D002528:Cerebellar Neoplasms; D002530:Cerebellopontine Angle; D059248:Chemoradiotherapy; D016545:Choroid Plexus Neoplasms; D018572:Disease-Free Survival; D017809:Fatal Outcome; D005260:Female; D034381:Hearing Loss; D006801:Humans; D008279:Magnetic Resonance Imaging; D009464:Neuroma, Acoustic; D010166:Palliative Care; D012640:Seizures; D033581:Stem Cell Transplantation; D014185:Transplantation, Isogeneic; D014427:Twins; D055815:Young Adult",
"nlm_unique_id": "101580767",
"other_id": null,
"pages": "e149-54",
"pmc": null,
"pmid": "23427033",
"pubdate": "2013-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Recurrent adult choroid plexus carcinoma treated with high-dose chemotherapy and syngeneic stem cell (bone marrow) transplant.",
"title_normalized": "recurrent adult choroid plexus carcinoma treated with high dose chemotherapy and syngeneic stem cell bone marrow transplant"
} | [
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"companynumb": "PHHY2015US031655",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
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"actiondrug": null,
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"activesubstancename": "CARBOPLATIN"
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{
"abstract": "Background: Torsades de pointes (TdP) is a life-threatening ventricular tachycardia occurring in long QT-syndrome patients. It usually develops when multiple QT-prolonging factors are concomitantly present, more frequently drugs and electrolyte imbalances. Since proton-pump inhibitors (PPIs)-associated hypomagnesemia is an increasingly recognized adverse event, PPIs were recently included in the list of drugs with conditional risk of TdP, despite only few cases of TdP in PPI users have been reported so far. Objectives: Aim of the present study is to evaluate whether PPI-induced hypomagnesemia actually has a significant clinical impact on the risk of TdP in the general population. Methods: Forty-eight unselected patients who experienced TdP were consecutively enrolled (2008-2017). Shortly after the first TdP episode, in those patients who did not receive magnesium sulfate and/or potassium or calcium replacement therapy, serum electrolytes were measured and their relationship with PPI usage analyzed. Results: Many patients (28/48, 58%) were under current PPI treatment when TdP occurred. Among TdP patients in whom serum electrolyte determinations were obtained before replacement therapy (27/48), those taking PPIs had significantly lower serum magnesium levels than those who did not. Hypomagnesemia occurred in ~40% of patients receiving PPIs (6/14), in all cases after an extended treatment (>2 weeks). In patients taking PPIs the mean QT-prolonging risk factor number was significantly higher than in those who did not, a difference which was mainly driven by lower magnesium levels. Conclusions: In unselected TdP patients, PPI-induced hypomagnesemia was common and significantly contributed to their cumulative arrhythmic risk. By providing clinical support to current recommendations, our data confirm that more awareness is needed when a PPI is prescribed, specifically as regards the risk of life-threatening arrhythmias.",
"affiliations": "Department of Medical Sciences, Surgery and Neurosciences, University of Siena, Siena, Italy.;Cardiology Intensive Therapy Unit, Department of Internal Medicine, Hospital of Carrara, Carrara, Italy.;Department of Medical Sciences, Surgery and Neurosciences, University of Siena, Siena, Italy.;Stroke Unit, University Hospital of Siena, Siena, Italy.;Department of Medical Sciences, Surgery and Neurosciences, University of Siena, Siena, Italy.;Department of Medical Sciences, Surgery and Neurosciences, University of Siena, Siena, Italy.;Department of Molecular and Developmental Medicine, University of Siena, Siena, Italy.;Department of Molecular and Developmental Medicine, University of Siena, Siena, Italy.;Department of Medical Sciences, Surgery and Neurosciences, University of Siena, Siena, Italy.;Department of Medical Sciences, Surgery and Neurosciences, University of Siena, Siena, Italy.;Department of Medical Sciences, Surgery and Neurosciences, University of Siena, Siena, Italy.;Department of Medical Sciences, Surgery and Neurosciences, University of Siena, Siena, Italy.;Department of Medical Biotechnologies, University of Siena, Siena, Italy.;Department of Medical Sciences, Surgery and Neurosciences, University of Siena, Siena, Italy.;Department of Medical Sciences, Surgery and Neurosciences, University of Siena, Siena, Italy.",
"authors": "Lazzerini|Pietro E|PE|;Bertolozzi|Iacopo|I|;Finizola|Francesco|F|;Acampa|Maurizio|M|;Natale|Mariarita|M|;Vanni|Francesca|F|;Fulceri|Rosella|R|;Gamberucci|Alessandra|A|;Rossi|Marco|M|;Giabbani|Beatrice|B|;Caselli|Michele|M|;Lamberti|Ilaria|I|;Cevenini|Gabriele|G|;Laghi-Pasini|Franco|F|;Capecchi|Pier L|PL|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3389/fphar.2018.00363",
"fulltext": "\n==== Front\nFront PharmacolFront PharmacolFront. Pharmacol.Frontiers in Pharmacology1663-9812Frontiers Media S.A. 10.3389/fphar.2018.00363PharmacologyOriginal ResearchProton Pump Inhibitors and Serum Magnesium Levels in Patients With Torsades de Pointes Lazzerini Pietro E. 1*Bertolozzi Iacopo 2Finizola Francesco 1Acampa Maurizio 3Natale Mariarita 1Vanni Francesca 1Fulceri Rosella 4Gamberucci Alessandra 4Rossi Marco 15Giabbani Beatrice 1Caselli Michele 1Lamberti Ilaria 1Cevenini Gabriele 6Laghi-Pasini Franco 1†Capecchi Pier L. 1†1Department of Medical Sciences, Surgery and Neurosciences, University of Siena, Siena, Italy2Cardiology Intensive Therapy Unit, Department of Internal Medicine, Hospital of Carrara, Carrara, Italy3Stroke Unit, University Hospital of Siena, Siena, Italy4Department of Molecular and Developmental Medicine, University of Siena, Siena, Italy5Centre of Pharmacovigilance, University Hospital of Siena, Siena, Italy6Department of Medical Biotechnologies, University of Siena, Siena, ItalyEdited by: Esther Pueyo, University of Zaragoza, Spain\n\nReviewed by: Øyvind Bruserud, University of Bergen, Norway; Domenico Criscuolo, Genovax S.r.l., Italy; Stefano Giovagnoli, University of Perugia, Italy\n\n*Correspondence: Pietro E. Lazzerini lazzerini7@unisi.itThis article was submitted to Pharmaceutical Medicine and Outcomes Research, a section of the journal Frontiers in Pharmacology\n\n†These authors have contributed equally to this work.\n\n20 4 2018 2018 9 36308 10 2017 28 3 2018 Copyright © 2018 Lazzerini, Bertolozzi, Finizola, Acampa, Natale, Vanni, Fulceri, Gamberucci, Rossi, Giabbani, Caselli, Lamberti, Cevenini, Laghi-Pasini and Capecchi.2018Lazzerini, Bertolozzi, Finizola, Acampa, Natale, Vanni, Fulceri, Gamberucci, Rossi, Giabbani, Caselli, Lamberti, Cevenini, Laghi-Pasini and CapecchiThis is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.Background: Torsades de pointes (TdP) is a life-threatening ventricular tachycardia occurring in long QT-syndrome patients. It usually develops when multiple QT-prolonging factors are concomitantly present, more frequently drugs and electrolyte imbalances. Since proton–pump inhibitors (PPIs)-associated hypomagnesemia is an increasingly recognized adverse event, PPIs were recently included in the list of drugs with conditional risk of TdP, despite only few cases of TdP in PPI users have been reported so far.\n\nObjectives: Aim of the present study is to evaluate whether PPI-induced hypomagnesemia actually has a significant clinical impact on the risk of TdP in the general population.\n\nMethods: Forty-eight unselected patients who experienced TdP were consecutively enrolled (2008-2017). Shortly after the first TdP episode, in those patients who did not receive magnesium sulfate and/or potassium or calcium replacement therapy, serum electrolytes were measured and their relationship with PPI usage analyzed.\n\nResults: Many patients (28/48, 58%) were under current PPI treatment when TdP occurred. Among TdP patients in whom serum electrolyte determinations were obtained before replacement therapy (27/48), those taking PPIs had significantly lower serum magnesium levels than those who did not. Hypomagnesemia occurred in ~40% of patients receiving PPIs (6/14), in all cases after an extended treatment (>2 weeks). In patients taking PPIs the mean QT-prolonging risk factor number was significantly higher than in those who did not, a difference which was mainly driven by lower magnesium levels.\n\nConclusions: In unselected TdP patients, PPI-induced hypomagnesemia was common and significantly contributed to their cumulative arrhythmic risk. By providing clinical support to current recommendations, our data confirm that more awareness is needed when a PPI is prescribed, specifically as regards the risk of life-threatening arrhythmias.\n\nproton-pump inhibitorsTorsades de pointesserum magnesium levelslong-QT syndromesudden cardiac death\n==== Body\nIntroduction\nTorsades de pointes (TdP) is a life-threatening polymorphic ventricular tachycardia that can degenerate into ventricular fibrillation (VF) and cause sudden cardiac death (SCD) (Drew et al., 2010). It is characterized by a pattern of twisting points and occurs in patients with long QT syndrome (LQTS), both acquired and congenital. Indeed, in congenital-LQTS the more the heart rate-corrected QT interval (QTc) prolongs, the greater the TdP risk exponentially increases (i.e., 5–7% risk increase each 10 ms prolongation in QTc) until being significant for QTc>500 ms; such a value associated with a 2–3-fold higher risk for TdP (Drew et al., 2010).\n\nSince a marked QTc prolongation is usually required for TdP development, in most cases the simultaneous presence of multiple QTc-prolonging factors synergistically operating in impairing ion channels responsible for the ventricular repolarization process is necessary. Congenital factors are included, mainly resulting from mutations affecting genes encoding for potassium or sodium channels, as well as acquired risk factors (Viskin, 1999; El-Sherif and Turitto, 2003; Drew et al., 2010; Itoh et al., 2016). Among the latter factors, electrolyte imbalances (i.e., hypokaliemia, hypocalcemia, hypomagnesemia) and QT-prolonging drugs blocking the hERG potassium channel are those most frequently implicated in TdP development. Other established causes of acquired LQTS and TdP include structural heart diseases, bradyarrhythmias, endocrine disorders, liver diseases, nervous system injuries, HIV infection, starvation, hypothermia and toxins (El-Sherif and Turitto, 2003; Drew et al., 2010). In addition, autoimmunity (Lazzerini et al., 2017d) (particularly anti-Ro/SSA antibodies) (Yue et al., 2015; Lazzerini et al., 2016) and systemic inflammation (Lazzerini et al., 2015, 2017a,b) in the recent years are being increasingly recognized as novel acquired QT-prolonging risk factors significantly impacting TdP risk in the general population.\n\nProton–pump inhibitors (PPIs) are the most effective therapeutic agents for acid related disorders (ARD), including peptic ulcer disease and gastroesophageal reflux disease (Strand et al., 2017). Moreover, such drugs are also used for the prevention of non-steroidal anti-inflammatory drug-induced gastric injury and as a part of Helicobacter pylori eradication regimens (Strand et al., 2017). As a result, PPIs currently represent the fifth best-selling drug in the market with millions of chronic users worldwide (Patterson Burdsall et al., 2013). During the last years, concern has been raised because of PPIs long-term overutilization. In fact, in the clinical practice PPIs are often prescribed in patients without a specific ARD, and such a habit is leading to significant cost expenditure and possible adverse events (Moayyedi and Leontiadis, 2012).\n\nHypomagnesemia is a potentially serious side effect of PPIs, that could account for ~1% of all adverse events reported by drug users (Famularo et al., 2013; Luk et al., 2013). Although several data suggest an interference on intestinal magnesium absorption, the exact underlying mechanism is poorly understood (Famularo et al., 2013). In 2011 the US FDA warned that long-term use of PPI has the potential to reduce circulating magnesium levels, particularly in patients concomitantly receiving other drugs capable to cause magnesium depletion such as diuretics (2011)1. Accordingly, in 2016 the Arizona Center for Education and research on Therapeutics (AZCERT) included the PPIs omeprazole, esomeprazole, lansoprazole and pantoprazole in the list of drugs with conditional risk of TdP and to be avoided in patients with congenital LQTS (AZCERT, 2016), despite only few cases of QTc prolongation and TdP have been reported in patients with severe PPI-induced hypomagnesemia and/or taking a PPI concomitantly with drugs known to directly prolong QTc (Asajima et al., 2012; Bibawy et al., 2013; Hansen and Bruserud, 2016). As a result, it is now recommended that in patients taking a PPI for an extended period of time (>2 weeks) serum magnesium levels be monitored periodically, particularly if extended PPI therapy is used in association with drugs carrying a known risk of TdP (Asajima et al., 2012; 2016). Notably, a very recent longitudinal observational study performed in a large primary cohort of new users of acid suppression therapy followed for a median of 5.7 years, found a significant association between PPI use and risk of all-cause mortality. The risk was increased among those with no documented medical indications for PPI use and prolonged duration of use (Xie et al., 2017).\n\nRegardless of official recommendations, available real-life information on this subject is relatively poor so far. The present study is specifically aimed at evaluating whether PPI-induced hypomagnesemia has a significant clinical impact on the risk of TdP in the general population. Thus, the actual usage of PPIs and its relationship with serum magnesium levels were analyzed in a cohort of TdP patients, prospectively and consecutively enrolled independent of ongoing therapies and concomitant diseases.\n\nPatients and methods\nStudy populations\nLocal Ethical Committee approved the study, and patients gave their oral and written informed consent in accordance with the Principles of the Declaration of Helsinki.\n\nWe prospectively enrolled (from January 2008 to May 2017) 48 consecutive hospitalized patients who presented with TdP, independent of ongoing therapies and concomitant diseases. Since the only inclusion criteria was the occurrence of TdP, all patients who came to our attention in that period of time were enrolled. No patients were excluded. Demographic, clinical and laboratory characteristics of study patients, as well as ongoing treatment with QTc-prolonging medications are provided in Table 1. In these patients, PPI usage was assessed, and a cut-off time of 2 weeks was used to define treatment duration as extended (>2 weeks) or not, according to current AZCERT recommendations to minimize the risk of TdP in patients treated with PPI (AZCERT, 2016).\n\nTable 1 Demographic, clinical and laboratory characteristics of patients with Torsades de pointes.\n\nPatients, n\t48\t\nAge, median years (interquartile range)\t81(73–85)\t\nFemales, n\t31/48(65%)\t\nMean QTc, ms(range)\t596.0 ± 80.7(490–910)\t\nElectrolyte imbalances, n\t37/47(79%)\t\nHypokaliemia\t28/45(62%)\t\nHypocalcemia\t22/37(59%)\t\nHypomagnesemia\t7/27(26%)\t\nConcomitant diseases*, n\t45/48(94%)\t\nCardiac diseases\t40/48(83%)\t\nLeft ventricular hypertrophy\t19/48(40%)\t\nDilated cardiomyopathy/heart failure\t13/48(27%)\t\nII-III degree atrioventricular block\t10/48(21%)\t\nAcute coronary syndrome\t9/48(19%)\t\nChronic coronary artery disease\t7/48(15%)\t\nSinus bradycardia\t6/48(13%)\t\nExtra-cardiac diseases\t20/48(42%)\t\nDiabetes mellitus type II\t13/48(27%)\t\nChronic kidney disease\t8/48(17%)\t\nHypothyroidism\t2/48(4%)\t\nSubarachnoid hemorrhage\t1/48(2%)\t\nCirrhosis\t1/48(2%)\t\nAnorexia nervosa\t1/48(2%)\t\nHIV infection\t1/48(2%)\t\nQTc prolonging-medications, n\t34/48(71%)\t\nAmiodarone\t14/48(29%)\t\nCitalopram\t5/48(10%)\t\nSertraline\t4/48(8%)\t\nFluconazole\t3/48(6%)\t\nTrazodone\t3/48(6%)\t\nLevofloxacin\t2/48(4%)\t\nClarithromycin\t2/48(4%)\t\nPromazine\t2/48(4%)\t\nQuetiapine\t2/48(4%)\t\nMean medication number per patient\t1.1 ± 1.0\t\nAnti-Ro/SSA positivity, n\t18/32(56%)\t\nSystemic inflammation, n†\t38/48(79%)\t\nC-reactive protein, mg/dl(range)\t2.66(0.1–29.65)\t\nDefinite inflammatory diseases\t22/48(46%)\t\nAcute infections\t15/48(31%)\t\nImmuno-mediated diseases\t5/48(10%)\t\nOthers\t2/48(4%)\t\nMean QTc-prolonging risk factor number per patient§\t5.3 ± 1.5\t\nExcept where indicated otherwise, data are expressed as mean ± standard deviation or median (range).\n\nAppropriate serum potassium, calcium or magnesium measurements available in 45, 37, and 27 out of 48 patients, respectively; anti-Ro/SSA antibodies tested in 32 out of 48 patients.\n\n* Diseases recognized to be a risk factor for QTc prolongation (Viskin, 1999; El-Sherif and Turitto, 2003; Drew et al., 2010).\n\n† Increased C-reactive protein level (>0.5 mg/dl) with or without a definite inflammatory disease.\n\n§ Including electrolyte imbalances, diseases, QTc-prolonging medications, anti-Ro/SSA positivity, and systemic inflammation (Viskin, 1999; El-Sherif and Turitto, 2003; Drew et al., 2010; Yue et al., 2015; Lazzerini et al., 2016, 2017b).\n\nECG recordings\nDiagnosis of TdP was based on the presence of at least one episode of polymorphic ventricular arrhythmia at a rate ranging from 160 to 240 beats/min, associated with QTc prolongation (Drew et al., 2010; Figure 1). The QT interval was manually measured on a standard 12-lead ECG, from the onset of the Q wave or the onset of the QRS complex to the end of the T wave, defined as the return to the T-P baseline. When present, prominent U waves (>1 mm) merging into T waves were included in QT measurement (Gupta et al., 2007). QTc, determined as the longest hand-measured QTc in any lead (Rautaharju et al., 2009) was corrected for heart rate by the Bazett formula (dividing the QT by the square root of the preceding R-R interval of each beat: QT/√RR) to yield the QTc value. QTc was measured from 3 non-consecutive beats (mean value) by a single investigator.\n\nFigure 1 Electrocardiographic findings of a patient with TdP and PPI-associated hypomagnesemia. ECG strip in sinus rhythm (A) and during TdP (B) from a patient who was under current and extended treatment with oral lansoprazole (15 mg/day), and had low magnesium levels (1.46 mg/dl) and a QTc of 670 ms. Red vertical lines and arrow in lead II show QT interval.\n\nLaboratory analysis\nShortly after the first TdP episode [no later than 24 h (median 6 h, range 1–22 h)], patients underwent a venous withdrawal to determine serum electrolyte levels, including potassium, sodium, calcium, and magnesium. Potassium and sodium were determined by indirect potentiometry (COBAS-6000 platform); values were expressed as mEq/L (reference values: potassium 3.5–5.5; sodium 132–148). Calcium and magnesium were assayed by a colorimetric method (COBAS-6000 platform); values were expressed as mg/dl (reference values: calcium 8.0-11.0; magnesium 1.5–2.5).\n\nOnly determinations obtained before the administration of intravenous magnesium sulfate and/or replacement therapy with potassium or calcium were considered appropriate to be included in the study. As a result, serum potassium, calcium or magnesium measurements were available in 45, 37, and 27 out of 48 patients, respectively.\n\nOther laboratory parameters included circulating levels of anti-Ro/SSA antibodies (see\nSupplementary Methods for more details) and C-reactive protein (CRP), as well as pH, bicarbonates and serum glucose.\n\nStatistical analysis\nTo compare TdP patients subgroups, the following parametric or non-parametric statistical analyses were respectively carried out: the two-tail Student's unpaired t-test, or the two-tail Mann-Whitney test to evaluate differences in quantitative variables; the Pearson or Spearman rank correlation-test to verify possible statistical association between quantitative variables; the two-sided Fisher's exact test to evaluate statistical correlation between categorical variables. p < 0.05 were considered as significant. All statistical analyses were performed using GraphPad-InStat, version 3.06 for Windows 2000.\n\nResults\nTdP patients characteristics\nAs detailed in Table 1, demographic, clinical and laboratory characteristics of our cohort were fully consistent with those expected in TdP patients based on established epidemiological data. In fact, the large majority of subjects were females (31/48, 65%) and older than 65 years (median age: ~80 years). Moreover, many recognized QTc-prolonging risk factors of acquired origin were identifiable, particularly an underlying cardiac disease (45/48, 83%, more frequently ventricular hypertrophy, dilated cardiomyopathy/heart failure and atrio-ventricular blocks), electrolyte imbalances (37/47, 79%) and QTc-prolonging medications (34/48, 71%). Hypokalemia occurred in 62% of patients (28/45), thereby representing the most common specific risk factor. Anti-Ro/SSA-52 kD antibodies were detected in 56% of the tested cases (18/32), although a history of autoimmune disease was present in two patients only (1 rheumatoid arthritis, 1 celiac disease). The majority of TdP patients (38/48, 79%) showed signs of systemic inflammation, as indicated by the increase in CRP levels (>0.5 mg/dl; median value 2.66 mg/dl). A definite inflammatory disease was present in 22/48 patients (46%), most commonly an acute infection (n = 15, particularly sepsis and pneumonia), but also chronic immune-mediated diseases (n = 5, including 3 chronic inflammatory arthritis), or acute aseptic inflammatory processes (n = 2). Among drugs, amiodarone was the most frequently administered (14/48, 29%). Notably, in almost all cases more than one known QTc-prolonging factor was simultaneously identifiable; on average ~5. In addition, a significant proportion of patients (25/48, 52%) experienced an adverse short-term arrhythmic outcome, i.e., VF/cardiac arrest (CA), and/or underwent electric shock (TdP rapidly degenerated to VF/CA; out-of-hospital VF/CA followed with DC-shock, only later revealing a manifestation of TdP episodes; sustained TdP not responsive to medical therapy).\n\nProton-pump inhibitors usage in TdP patients\nIn our cohort, a significant percentage of patients were under active treatment with PPI when TdP occurred (28/48, 58%). Many subjects (16/25, 64%) were taking a PPI for an extended period of time, i.e., >2 weeks. The most frequently administered PPI was pantoprazole, followed by lansoprazole, together accounting for ~85% of the cases (24/28). Remaining patients (n = 4), were administered with omeprazole (n = 3), or esomeprazole (n = 1). In three patients under extended home PPI therapy, the molecule was changed during hospitalization, before TdP development (from oral lansoprazole or pantoprazole to intravenous pantoprazole in two cases; from oral omeprazole to oral pantoprazole in the other one). The commonest route of administration was the oral one, but in 6/28 cases (21%) where the PPI was being given intravenously at the time of TdP occurrence (Table 2). Notably, none of the intravenously-treated patients showed hypomagnesemia.\n\nTable 2 Proton-pump inhibitors use in patients with Torsades de Pointes.\n\nPatients under active treatment with PPIs, n\t28/48(58%)\t\nSpecific PPI used, n\t\t\nPantoprazole\t18/28(64%)\t\nLansoprazole\t6/28(21%)\t\nOmeprazole\t3/28(11%)\t\nEsomeprazole\t1/28(4%)\t\nTreatment duration*\t\t\nExtended therapy (>2 weeks), n\t16/25(64%)\t\nNot extended therapy (<2 weeks), n\t9/25(36%)\t\nDaily dose, mg†\t\t\nPantoprazole\t33.3 ± 9.7\t\nLansoprazole\t27.5 ± 6.1\t\nOmeprazole\t26.7 ± 11.5\t\nEsomeprazole\t20\t\nRoute of administration, n†\t\t\nOral\t22/28(79%)\t\nIntravenous\t6/28(21%)\t\nExcept where indicated otherwise, values are expressed as mean ± standard deviation.\n\n* Data missing in 3 out of 28 patients.\n\n† At the moment of TdP occurrence.\n\nSerum electrolytes levels and other TdP risk factors in patients taking or not taking proton-pump inhibitors\nConsistently with the findings obtained in the whole TdP population, a high prevalence of electrolyte imbalances (collectively ~80%) was found in both patients taking (PPI+) or not taking PPI (PPI−). However, while the prevalence of hypokaliemia and hypocalcemia as well as serum potassium, calcium (and sodium) levels in the two groups were overalapping, circulating magnesium levels were significantly lower in PPI+ than in PPI− subjects (1.60 ± 0.21 vs. 1.84 ± 0.33 mg/dl, Δ = −0.24 mg/dl; p = 0.03) (Figures 2, 3). Hypomagnesemia (< 1.5 mg/dl) occurred 5-times more frequently in the PPI+ vs. PPI- group (6/14, 43% vs. 1/13, 8%), although this difference did not reach statistical significance (p = 0.07) (Table 3). Notably, hypomagnesemia was found almost exclusively (6 out of 7 cases, 85%) in patients receiving PPI therapy; all cases of PPI-associated hypomagnesemia (n = 6) were observed in patients under extended PPI therapy (>2 weeks), involving all the 4 different PPIs used in the cohort (pantoprazole, n = 3; lansoprazole, n = 1; omeprazole, n = 1; esomeprazole, n = 1). Diuretics usage, which was not different in the PPI+ vs. PPI− group (Table 3), was not per se associated with significant magnesium changes in our cohort. In fact, by comparing patients taking (n = 16) and not taking diuretics (n = 11), neither serum magnesium levels (1.67 ± 0.31 vs. 1.78 ± 0.26 mg/dl; p = 0.32, two-tail unpaired t-test) nor the prevalence of hypomagnesemia (6/16, 37% vs. 1/11, 9%; p = 0.18, two-sided Fisher's exact test) were significantly different. Although these findings suggest that diuretics alone, differently to PPIs alone, were not sufficient to cause magnesium depletion, nevertheless diuretics may exacerbate PPI-associated magnesium reduction when administered in association. Indeed, in patients concomitantly receiving PPIs and diuretics (n = 9, vs. others n = 18) serum magnesium levels further decreased slightly (1.55 ± 0.21 vs. 1.80 ± 0.30 mg/dl, Δ = −0,25 mg/dl; p = 0.02, two-tail Mann-Whitney test), and the prevalence of hypomagnesemia increased, reaching statistical significance (5/9, 56% vs. 2/18, 11%; p = 0.02, two-sided Fisher's exact test). Despite a specific investigation, no any significant impact of other common causes of hypomagnesemia was found in our cohort of patients (see Supplementary Results for more details). Moreover, no significant correlation was present between magnesium levels and other continuous variables, particularly calcium (r = 0.33, p = 0.10; Pearson correlation-test) potassium (r = 0.10, p = 0.57; Pearson correlation-test), sodium (r = 0.11, p = 0.58; Spearman rank correlation-test) or CRP levels (r = −0.14, p = 0.46; Spearman rank correlation-test), or QTc duration (r = −0.19, p = 0.32; Pearson correlation-test).\n\nFigure 2 Serum magnesium levels in TdP patients taking or not taking PPIs. Patients taking PPIs (PPI+), n = 14; patients not taking PPIs (PPI−), n = 13. Two-tail Student's unpaired t-test, *p < 0.05. Horizontal dotted line indicates the lower limit of reference values for serum magnesium levels, i.e., 1.5 mg/dl.\n\nFigure 3 Serum levels of calcium, potassium and sodium in TdP patients taking or not taking PPIs. (A) Serum calcium levels. Patients taking PPIs (PPI+), n = 20; patients not taking PPIs (PPI−), n = 17. Two-tail Student's unpaired t-test (p > 0.05). Horizontal dotted line indicates the lower limit of reference values for calcium levels, i.e., 8.0 mg/dl. (B) Serum potassium levels. PPI+, n = 27; PPI−, n = 18. Two-tail Student's unpaired t-test (p > 0.05). Horizontal dotted line indicates the lower limit of reference values for potassium levels, i.e., 3.5 mEq/L. (C) Serum sodium levels. PPI+, n = 28; PPI−, n = 20. Two-tail Student's unpaired t-test (p > 0.05). Horizontal dotted line indicates the lower limit of reference values for sodium levels, i.e., 132 mEq/L.\n\nTable 3 Demographic, clinical and laboratory characteristics in proton pump inhibitor users (PPI+) vs. non-proton pump inhibitor users (PPI−).\n\n\tPPI+\tPPI−\tp\t\nPatients, n\t28\t20\t\t\nAge, median years (interquartile range)\t80.5(73–85)\t81.5(75–87.5)\t0.40\t\nFemales, n\t18/28(64%)\t15/20(75%)\t0.53\t\nMean QTc, ms\t591.9 ± 88.8\t601.5 ± 70.1\t0.69\t\nFV/CA/EcS\t15/28(54%)\t10/20(50%)\t1\t\nElectrolyte imbalances, n\t22/28(79%)\t15/19(79%)\t1\t\nHypokaliemia\t17/27(63%)\t11/18(61%)\t1\t\nHypocalcemia\t12/20(60%)\t10/17(59%)\t1\t\nHypomagnesemia\t6/14(43%)\t1/13(8%)\t0.07\t\nPotassium, mEq/L (r.v.3.5–5.5)\t3.25 ± 0.61\t3.41 ± 0.74\t0.47\t\nCalcium, mg/dl (r.v.8.0–11.0)\t7.71 ± 0.67\t7.85 ± 0.65\t0.44\t\nMagnesium, mg/dl (r.v.1.5–2.5)\t1.60 ± 0.21\t1.84 ± 0.33\t0.03\t\nSodium, mEq/L (r.v.132–148)\t139.1 ± 10.0\t136.1 ± 2.9\t0.23\t\nDiuretics use, n\t19/28(68%)\t10/20(50%)\t0.24\t\nFurosemide median daily dose, mg (range)\t25(10–100)\t72.5(20–500)\t0.58\t\nGlucose, mg/dl\t171.2 ± 78.8\t172.8 ± 80.4\t0.96\t\npH\t7.46 ± 0.11\t7.50 ± 0.12\t0.53\t\nBicarbonates, mmol/L\t25.4 ± 1.8\t25.3 ± 2.2\t0.97\t\nConcomitant diseases*, n\t26/28(93%)\t19/20(95%)\t1\t\nCardiac diseases\t23/28(82%)\t17/20(85%)\t1\t\nExtra-cardiac diseases\t14/28(50%)\t6/20(30%)\t0.23\t\nQTc prolonging-medications, n\t21/28(75%)\t13/20(65%)\t0.52\t\nAmiodarone\t8/28(29%)\t6/20(30%)\t1\t\nMean medication number per patient\t1.3 ± 1.1\t1.0 ± 0.9\t0.17\t\nAnti-Ro/SSA positivity, n\t8/18(44%)\t10/14(71%)\t0.16\t\nSystemic inflammation, n\t23/28(82%)\t13/20(80%)\t1\t\nMean QTc-prolonging risk factor number per patient\t\t\t\t\nPer patient†\t5.8 ± 1.6\t4.9 ± 1.\t0.04\t\nMean QTc-prolonging risk factor number\t\t\t\t\nPer patient† excluding hypomagnesemia\t5.6 ± 1.5\t4.9 ± 1.4\t0.07\t\nWherever not specified, data are expressed as mean±standard deviation. Appropriate serum potassium, calcium or magnesium measurements available in 45, 37, and 27 out of 48 patients, respectively; anti-Ro/SSA antibodies tested in 32 out of 48 patients.\n\nVF, ventricular fibrillation; CA, cardiac arrest; EcS, electric shock.\n\n* Diseases recognized to be a risk factor for QTc prolongation (Viskin, 1999; El-Sherif and Turitto, 2003; Drew et al., 2010).\n\n† Including electrolyte imbalances, diseases, QTc-prolonging medications, anti-Ro/SSA positivity, and systemic inflammation (Viskin, 1999; El-Sherif and Turitto, 2003; Drew et al., 2010; Yue et al., 2015; Lazzerini et al., 2016, 2017b).\n\nDifferences were evaluated by the two-tailed unpaired t-test, or the two-tailed Mann-Whitney test. Difference in categorical variables were evaluated by the two-sided Fisher's exact test.\n\nStatistically significant p values are reported in bold.\n\nAs regards the other QTc-prolonging risk factors of acquired origin, individually considered, no significant differences in terms of concomitant diseases, both cardiac and extra.-cardiac, QTc prolonging medications use, anti-Ro/SSA positivity or presence of systemic inflammation were observed by comparing PPI+ vs. PPI− patients (Table 3). Nevertheless, when all these factors were considered together, also including electrolyte imbalances, the mean QTc-prolonging risk factor number per patient was significantly higher in the PPI+ than the PPI- group (5.8 ± 1.6 vs. 4.9 ± 1.4, Δ: 0.9; p = 0.04). Notably, statistical significance of this difference was lost if hypomagnesemia, i.e., the only individual TdP risk factor discriminating the two groups, was selectively excluded by the total count (5.6 ± 1.5 vs. 4.9 ± 1.4, Δ: 0.7; p = 0.07; Table 3). It is important to underline that for a number of patients, some data on QT-prolonging risk factors were missing, particularly serum levels of potassium (available in 26/28 of PPI+ 19/20 of PPI− patients, respectively), calcium (27/28 of PPI+ and 18/20 of PPI− patients, respectively), magnesium (14/28 of PPI+ and 13/20 of PPI− patients, respectively), and anti-Ro/SSA positivity (18/28 of PPI+ and 14/20 of PPI− patients, respectively). Nevertheless, when we restricted the analysis to patients with full data only, i.e., 8 PPI+ and 10 PPI−, differences (Δ) in mean QTc-prolonging risk factor number per patient remained completely unchanged, both when all risk factors were considered (6.1 ± 1.7 vs. 5.2 ± 1.3, Δ: 0.9) and when hypomagnesemia was excluded (5.8 ± 1.4 vs. 5.1 ± 1.3, Δ: 0.7), thus indicating that the results were not influenced by missing data.\n\nConversely, PPI treatment did not seem to affect the short-term outcome in our cohort of patients. In fact, the percentage of subjects experiencing VF/CA, and/or that underwent electric shock was not significantly different by comparing PPI+ vs. PPI− patients (15/28, 54% vs. 10/20, 50%) (Table 3).\n\nFinally, in order to specifically address the question of whether magnesium levels are different between PPI+ patients who developed TdP vs. PPI+ patients who did not, 21 hospitalized patients matched for age, gender and concomitant diseases (Supplementary Table 1), but without QTc prolongation or history of TdP were prospectively enrolled as a control group (C). Similarly to that observed in TdP subjects, more than a half of control patients were under current treatment with PPIs (12/21, 57%), in most cases for an extended period of time (10/12, 83%) (Supplementary Table 2). Among these patients, hypomagnesemia was found in 2 patients (2/21, 9%), one treated and one untreated with PPIs. As shown in Figure 4A, circulating magnesium levels were significantly lower in TdP vs. controls (1.72 ± 0.30 vs. 1.91 ± 0.40 mg/dl; p = 0.0094). Such a difference significantly increased when the comparison was restricted to PPI-treated patients from the two groups (TdP/PPI+: 1.60 ± 0.21 vs. C/PPI+: 1.93 ± 0.48 mg/dl; p = 0.0007; Figure 4B), while serum magnesium levels were not different in PPI-untreated TdP vs. control patients (TdP/PPI−: 1.84 ± 0.33 vs. C/PPI−: 1.88 ± 0.30 mg/dl; p = 0.78, two-tail Student's unpaired t-test).\n\nFigure 4 Comparison of serum magnesium levels in TdP patients and controls. (A) Serum magnesium levels in all TdP patients (n = 27) vs. controls (C, n = 21), regardless of PPI therapy. Two-tail Mann-Whitney test, **p < 0.01. (B) Serum magnesium levels in TdP patients under PPI therapy (TdP/PPI+) (n = 14) vs. controls under PPI therapy (C/PPI+, n = 12). Two-tail Student's unpaired t-test, ***p < 0.001. Horizontal dotted line indicates the lower limit of reference values for magnesium levels, i.e., 1.5 mg/dl.\n\nAs a confirmation of the results on subgroups, we also evaluated the interaction between magnesemia and PPI treatment (PPI+/PPI−), by combining (multiplying) the two variables in the whole population (TdP vs. C). We found that sample differences between TdP and C in such interaction-corrected levels of magnesium were not longer statistically significant (p = 0.09, two-tail Mann-Whitney test).\n\nDiscussion\nThe key findings of the present study are the following: a large proportion of patients (>50%) who developed TdP were under current treatment with a PPI; TdP patients taking PPIs had significantly lower serum magnesium levels with respect to TdP patients not taking PPIs; hypomagnesemia frequently occurred in patients receiving PPIs (~40%, 6/14), in all cases after an extended period of time (>2 weeks) of administration; in subjects taking PPIs the mean QTc-prolonging risk factor number per patient was significantly higher than it was in those not taking PPIs, a difference which was mainly driven by lower magnesium levels.\n\nMagnesium, representing the most abundant intracellular divalent cation, plays a key role in regulating potassium and calcium channels in the heart (Gupta et al., 2007). Experimental studies demonstrated that cytosolic magnesium promotes repolarization of myocardial cells via modulating effects on several potassium currents, including the rapid component of the delayed rectifier potassium current (IKr) and transient outward current (Ito) (Kelepouris et al., 1993; El-Sherif and Turitto, 2011). Moreover, magnesium markedly inhibits the L(long-lasting)-type calcium current (ICaL), possibly as a result of a direct block of the L-type-calcium channel pore by external magnesium or via modification of the activity of protein kinases or phosphoprotein phosphatases (Zhao et al., 2015). ICaL determines the plateau phase thereby critically contributing to action potential duration (APD) (Viskin, 1999; El-Sherif and Turitto, 2003). Moreover, ICaL is the main depolarizing current that generates early after depolarizations (EADs), in turn representing the primary electrophysiological mechanism underlying TdP development (Viskin, 1999; El-Sherif and Turitto, 2003). This supports the fact that hypomagnesemia is a recognized risk factor for QTc prolongation and TdP (Viskin, 1999; El-Sherif and Turitto, 2003, 2011), as well as the clinical evidence that magnesium sulfate is very effective for the treatment of TdP thus being considered the standard of care for this arrhythmia (Drew et al., 2010).\n\nPPI-induced hypomagnesemia, for the first time described in 2006, has been increasingly recognized in the last years as a potentially life-threatening adverse event whose actual incidence is probably largely underestimated (Famularo et al., 2013). Two recent systematic reviews and meta-analysis, each one including nine studies and over 100,000 patients, consistently found that PPI users have a ~40–80% higher risk of developing hypomagnesemia when compared to non-users (Park et al., 2014; Cheungpasitporn et al., 2015).\n\nPPI-associated hypomagnesemia occurs after extended treatments (>2 weeks, but in most cases > 1 year), is not clearly dose-related, and was reported with different PPIs, thus suggesting a class effect. Until PPI interruption, hypomagnesemia is refractory to oral or parenteral magnesium replacement irrespective of high-dose supplementation; when the PPI is stopped, serum magnesium levels returned to normal in less than 2 weeks (2011; Famularo et al., 2013). However, hypomagnesemia may recur after re-challenge with the same or a different PPI. In these patients, when prolonged antiacid treatment is needed, prescription of a H2 histamine receptor-blocker (H2-blocker) may be an appropriate therapeutic alternative (Famularo et al., 2013). In fact, although mechanisms of PPI-induced hypomagnesemia are not clear, hypochlorhydria does not seem to be involved. Pathogenesis possibly includes both gastrointestinal and renal losses, via dysfunction of the Transient Receptor Potential Melastatin 6/7 (TRPM6/7) located in the intestine as well as in the distal convoluted tubule (Famularo et al., 2013). Accordingly, recent data suggest that carriers of TRPM6 polymorphisms are at increased risk (Hess et al., 2017).\n\nTo date only three reports of patients who developed TdP while they were taking a PPI (i.e., omeprazole, pantoprazole, or lansoprazole, respectively) (Asajima et al., 2012; Bibawy et al., 2013; Hansen and Bruserud, 2016) have been described in the literature, in two cases associated with hypomagnesemia (Bibawy et al., 2013; Hansen and Bruserud, 2016). The results of the present study suggest that the phenomenon is significantly more common than reported, being probably underestimated because in the clinical practice PPIs do not currently receive the due attention as a factor potentially contributing to QTc prolongation and TdP. Consistently with literature data (Famularo et al., 2013), PPI-associated hypomagnesemia seems to be a class effect which requires extended drug administration to occur. In fact, although in our TdP patients most subjects used pantoprazole, hypomagnesemia was found to be associated with all 4 PPIs included in the AZCERT list (AZCERT, 2016) (i.e., pantoprazole, omeprazole, esomeprazole, lansoprazole), in all cases administered for an extended period of time (>2 weeks). Our data seem also to confirm that the risk of PPI-induced hypomagnesemia further increases when PPIs are co-administered with diuretics, probably as a result of an enhancement of the renal loss of magnesium. Conversely, although in PPI users hypomagnesemia has been reported to be often accompanied by hypocalcemia and hypokalaemia (Famularo et al., 2013), the prevalence of these electrolyte imbalances as well as serum calcium, potassium and sodium levels were similar in PPI+ vs. PPI− TdP patients, thus indicating a rather selective effect of this class of drugs on magnesium levels.\n\nAnother important suggestion arising from the present study is that PPI-associated changes in magnesium levels have a relevant clinical impact by increasing the risk of developing TdP in these patients. In fact, PPI users showed a significantly higher mean total number of QTc-prolonging risk factors per patient when compared to non-users. Nevertheless, despite a comprehensive evaluation also taking into account recently recognized “non-classical” QT-prolonging factors, such as anti-Ro/SSA antibodies (Yue et al., 2015; Lazzerini et al., 2016, 2017d) and systemic inflammatory activation (Lazzerini et al., 2015, 2017a,b), serum magnesium levels represented the only specific TdP risk factor which was significantly different between the two groups. Accordingly, when hypomagnesemia was excluded from the total risk factor count, this difference was no longer statistically significant.\n\nNotably, we also found that magnesium levels in TdP/PPI+ patients were significantly lower when compared to C/PPI+ matched for age, gender and concomitant diseases. It suggests that TdP may act as a “clustering factor” for those patients, among the general population, who are more susceptible to the magnesium-lowering effect of PPIs, possibly as a result of a genetic predisposition (Hess et al., 2017). This view, further supporting the role of PPI-induced hypomagnesemia as a risk factor for TdP, warrants specific investigation.\n\nAlthough our data point to the conclusion that PPIs can increase the risk of TdP by inducing hypomagnesemia, the involvement of additional, possibly molecule-related mechanisms could not be ruled out. In particular, this may be the case of lansoprazole which has been recently associated to an increased risk of QTc prolongation and TdP when used in combination with ceftriaxone, via direct blocking effects of the drug association on the hERG potassium channel (Lorberbaum et al., 2016; Lazzerini et al., 2017c). Indeed, 2 patients in our cohort were under current treatment with lansoprazole + ceftriaxone when TdP occurred, in 1 case in the absence of hypomagnesemia. Notably, it has been demonstrated that also lansoprazole alone significantly inhibits hERG potassium channel and related current IKr (−14%), although to a lesser extent when compared to the drug combination (−58%) (Lorberbaum et al., 2016). This may help explain why serum magnesium level was normal in one out of three case reports of PPI-associated TdP, in which lansoprazole administration precipitated arrhythmia development in a patients under long-term treatment with a drug known to directly prolong QTc (disopyramide) (Asajima et al., 2012). Thus, it cannot be ruled out that also in our patients, particularly those without hypomagnesemia, lansoprazole (and possibly also the other PPIs involved, since to date no specific patch-clamp studies are available) could have contributed to promote TdP occurrence also via a direct electrophysiological interference.\n\nOur data suggest a number of important recommendations to translate in the clinical practice. In particular, patients may experience TdP in the presence of hypomagnesemia while they were under active treatment with a PPI. Such patients may be required to stop PPI treatment as it could have significantly contributed to development and maintenance of the electrolyte imbalance. Since it is expected that PPI-induced hypomagnesemia is refractory to magnesium oral or parenteral supplementation despite high doses (Famularo et al., 2013), drug discontinuation is a key action to normalize serum magnesium levels and thereby reduce the associated risk of TdP recurrence. This measure may be of particular importance in patients concomitantly requiring diuretic therapy, given the role of this class of drugs in exacerbating magnesium depletion. Moreover, based on the evidence that PPI-induced hypomagnesemia may rapidly recur after re-challenge with the same or a different PPI (median time ~2 weeks; Famularo et al., 2013), the alternative use of a H2-blocker may be appropriate in the case the patient needs prolonged antiacid treatment. Finally, since some data suggest that PPIs may also directly contribute to QTc prolongation via electrophysiological effects on the cardiomyocyte, it cannot be excluded that PPI discontinuation could be a useful therapeutic measure even in TdP patients without evidence of hypomagnesemia, particularly when the PPI involved is lansporazole and other known QT-prolonging drugs are concomitantly administered.\n\nIn conclusion, the present study demonstrates that PPI-induced hypomagnesemia is a more than expected common finding in unselected patients with TdP, significantly contributing to increase the cumulative risk of developing this life-threatening arrhythmia. Our real-life data provide important clinical evidence in support to AZCERT recommendations which cautiously already had warned about the potential role of PPI-induced hypomagnesemia in promoting TdP, despite only few cases were reported. Nevertheless, considering the relative small sample size as well as the main focus on magnesium levels, we did not perform any multivariate analysis on our population. Since this may represent a limitation of the study, larger sample studies are warranted to confirm our results. They should include non-TdP patients and/or younger populations, and could clarify whether PPIs significantly influence the QTc also regardless of hypomagnesemia.\n\nIn practice, more awareness is needed by the clinician when a PPI is prescribed since the safety profile of this class of drugs is probably not so neutral as commonly believed, specifically as regards the risk of life-threatening arrhythmias and SCD.\n\nAuthor contributions\nPL: Conception and design of the work; PL, IB, FF, MA, MN, FV, BG, MC, and IL: Substantial contributions to the acquisition of data for the work; PL, RF, AG, MR, GC, FL-P, and PC: Substantial contributions to the analysis of data for the work; PL, RF, AG, MR, GC, FL-P, and PC: Substantial contributions to the interpretation of data for the work; PL and PC: Drafting the work; PL, RF, AG, MR, FL-P, and PC: Revising the draft of the work critically for important intellectual content; PL, IB, FF, MA, MN, FV, RF, AG, MR, BG, MC, IL, GC, FL-P, and PC: Final approval of the version to be published; PL, IB, FF, MA, MN, FV, RF, AG, MR, BG, MC, IL, GC, FL-P, and PC: Agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.\n\nConflict of interest statement\nThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n\nThis work has received funding from FAS-Salute ToRSADE project (FAS Salute 2014, Regione Toscana).\n\n1FDA Drug Safety Communication: Low magnesium levels can be associated with long-term use of proton pump inhibitor drugs (PPIs). Available at www.fda.gov/Drugs/DrugSafety/ucm245011.htm Accessed May 26 (2017).\n\nSupplementary material\nThe Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fphar.2018.00363/full#supplementary-material\n\nClick here for additional data file.\n\n Click here for additional data file.\n\n Click here for additional data file.\n==== Refs\nReferences\n(2011 ). In brief: PPI's and hypomagnesemia . Med. Lett. Drugs Ther. \n53 :25 .\n(2016 ). In brief: PPIs and Torsades de Pointes . Med. Lett. Drugs Ther. \n58 :153 .\nAsajima H. Saito N. Ohmura Y. Ohmura K. (2012 ). Lansoprazole precipitated QT prolongation and torsade de pointes associated with disopyramide . Eur. J. Clin. Pharmacol. \n68 :331 . 10.1007/s00228-011-1119-z 21898101 \nAZCERT (2016 ). New Drugs Added to CredibleMeds Drugs Lists . Available online at: www.crediblemeds.org/blog/news-drugs-added-qtdrugs-lists (Accessed May 26, 2017).\nBibawy J. N. Parikh V. Wahba J. 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Systemic inflammation and arrhythmic risk: lessons from rheumatoid arthritis . Eur. Heart J. \n38 , 1717 –1727 . 10.1093/eurheartj/ehw208 27252448 \nLazzerini P. E. Capecchi P. L. Laghi-Pasini F. Boutjdir M. (2017d ). Autoimmune channelopathies as a novel mechanism in cardiac arrhythmias . Nat. Rev. Cardiol. \n14 , 521 –535 . 10.1038/nrcardio.2017.61 28470179 \nLazzerini P. E. Laghi-Pasini F. Bertolozzi I. Morozzi G. Lorenzini S. Simpatico A. . (2017a ). Systemic inflammation as a novel QT-prolonging risk factor in patients with torsades de pointes . Heart \n103 , 1821 –1829 . 10.1136/heartjnl-2016-311079 28490617 \nLazzerini P. E. Yue Y. Srivastava U. Fabris F. Capecchi P. L. Bertolozzi I. . (2016 ). Arrhythmogenicity of anti-Ro/SSA antibodies in patients with torsades de pointes . Circ. Arrhythm. Electrophysiol. \n9 :e003419 . 10.1161/CIRCEP.115.003419 27030700 \nLorberbaum T. Sampson K. J. Chang J. B. Iyer V. Woosley R. L. Kass R. S. . (2016 ). Coupling data mining and laboratory experiments to discover drug interactions causing QT prolongation . J. Am. Coll. Cardiol. \n68 , 1756 –1764 . 10.1016/j.jacc.2016.07.761 27737742 \nLuk C. P. Parsons R. Lee Y. P. Hughes J. D. (2013 ). Proton pump inhibitor-associated hypomagnesemia: what do FDA data tell us? \nAnn. Pharmacother. \n47 , 773 –780 . 10.1345/aph.1R556 23632281 \nMoayyedi P. Leontiadis G. I. (2012 ). The risks of PPI therapy . Nat. Rev. Gastroenterol. Hepatol. \n9 , 132 –139 . 10.1038/nrgastro.2011.272 22330810 \nPark C. H. Kim E. H. Roh Y. H. Kim H. Y. Lee S. K. (2014 ). The association between the use of proton pump inhibitors and the risk of hypomagnesemia: a systematic review and meta-analysis . PLoS ONE \n9 :e112558 . 10.1371/journal.pone.0112558 25394217 \nPatterson Burdsall D. Flores H. C. Krueger J. Garretson S. Gorbien M. J. Iacch A. . (2013 ). Use of proton pump inhibitors with lack of diagnostic indications in 22 Midwestern US skilled nursing facilities . J. Am. Med. Dir. Assoc. \n14 , 429 –432 . 10.1016/j.jamda.2013.01.021 23583000 \nRautaharju P. M. Surawicz B. Gettes L. S. Bailey J. J. Childers R. Deal B. J. . (2009 ). AHA/ACCF/HRS recommendations for the standardization and interpretation of the electrocardiogram: part IV: the ST segment, T and U waves, and the QT interval: a scientific statement from the American Heart Association Electrocardiography and Arrhythmias Committee, Council on Clinical Cardiology; the American College of Cardiology Foundation; and the Heart Rhythm Society. Endorsed by the International Society for Computerized Electrocardiology . J. Am. Coll. Cardiol. \n53 , 982 –991 . 10.1016/j.jacc.2008.12.014 19281931 \nStrand D. S. Kim D. Peura D. A. (2017 ). 25 Years of proton pump inhibitors: a comprehensive review . Gut Liver \n11 , 27 –37 . 10.5009/gnl15502 27840364 \nViskin S. (1999 ). Long QT syndromes and torsade de pointes . Lancet \n354 , 1625 –1633 . 10.1016/S0140-6736(99)02107-8 10560690 \nXie Y. Bowe B. Li T. Xian H. Yan Y. Al-Aly Z. (2017 ). Risk of death among users of Proton Pump Inhibitors: a longitudinal observational cohort study of United States veterans . BMJ Open \n7 :e015735 \n10.1136/bmjopen-2016-015735 \nYue Y. Castrichini M. Srivastava U. Fabris F. Shah K. Li Z. . (2015 ). Pathogenesis of the novel autoimmune-associated long QT syndrome . Circulation \n132 , 230 –240 . 10.1161/CIRCULATIONAHA.115.009800 25995318 \nZhao M. Feng R. Shao D. Liu S. Lei M. Wang H. . (2015 ). Mg(2+)-dependent facilitation and inactivation of L-type Ca(2+) channels in guinea pig ventricular myocytes . J. Pharmacol. Sci. \n129 , 143 –149 . 10.1016/j.jphs.2015.08.001 26422671\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1663-9812",
"issue": "9()",
"journal": "Frontiers in pharmacology",
"keywords": "Torsades de pointes; long-QT syndrome; proton-pump inhibitors; serum magnesium levels; sudden cardiac death",
"medline_ta": "Front Pharmacol",
"mesh_terms": null,
"nlm_unique_id": "101548923",
"other_id": null,
"pages": "363",
"pmc": null,
"pmid": "29731714",
"pubdate": "2018",
"publication_types": "D016428:Journal Article",
"references": "23592872;27926584;19281931;26798623;22330810;20142454;26108134;23808631;27737742;23632281;26422671;25995318;12496496;26715165;25394217;21660912;10560690;27471598;21898101;21464802;23583000;28676480;28385319;17540188;27840364;28490617;28470179;8264514;27252448;27030700;27906148",
"title": "Proton Pump Inhibitors and Serum Magnesium Levels in Patients With Torsades de Pointes.",
"title_normalized": "proton pump inhibitors and serum magnesium levels in patients with torsades de pointes"
} | [
{
"companynumb": "IT-GLAXOSMITHKLINE-IT2018078435",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LANSOPRAZOLE"
},
"drugadditional": "3",... |
{
"abstract": "Biologic disease-modifying anti-rheumatic drugs (bDMARD) have transformed the treatment paradigm of chronic autoimmune rheumatic diseases (ARDs), but they are often associated with adverse drug reactions. The present study evaluated the frequency, characteristics and type of infections, other than tuberculosis (TB), in ARD patients receiving bDMARDs. The multicentre, cross-sectional, retrospective, observational study was conducted across 12 centers in Karnataka, India, between January to August 2016. The study included patients receiving bDMARD therapy for various ARDs. Outcome variables considered were any infection, minor infections and major infections, other than TB. Clinical variables were compared between infection and no infection group, and the increase in the likelihood of infection with respect to various clinical variables was assessed. The study involved 209 subjects with a median (range) age of 41 (16-84) years and male to female ratio of 0.97:1. A total of 29 (13.88%) subjects developed infection following bDMARD therapy, out of whom a majority had minor infection (n = 26). The likelihood of developing any infection was noted to be more in subjects receiving anti-TNF (golimumab, P = 0.03) and those on three or more conventional synthetic (cs) DMARDs (P < 0.01). Infection risk was higher in patients with systemic lupus erythematosus (P = 0.04), other connective tissue disease (P < 0.01) and in patients with comorbidities (P = 0.13). The risk of infection was associated with the use of anti-TNF therapy and more than three csDMARDs, co morbidities and Adds such as systemic lupus erythematosus and connective tissue disease.",
"affiliations": "ChanRe Rheumatology and Immunology Center and Research, No. 65 (414), 20th Main, West of Chord Road, 1st Block, Rajajinagar, Bangalore-10, India. chandrashekara_s@yahoo.com.;St. John's Medical College Hospital, Bangalore, India.;Manipal Hospital, Bangalore, India.;St. John's Medical College Hospital, Bangalore, India.;Fortis Hospital, Bangalore, India.;SAKRA Hospital, Bangalore, India.;Columbia Asia Hospital, Bangalore, India.;Apollo Hospital, Bangalore, India.;Aster CMI Hospital, Bangalore, India.;Samarpan Health Centre, Bangalore, India.;Vikram Hospital and Heart Care, Mysore, India.;Narayana Health City, Bangalore, India.;Manipal Hospital, Bangalore, India.;Apollo Hospital, Bangalore, India.;SPARSH Hospital, Bangalore, India.;ChanRe Rheumatology and Immunology Center and Research, No. 65 (414), 20th Main, West of Chord Road, 1st Block, Rajajinagar, Bangalore-10, India.",
"authors": "Chandrashekara|S|S|0000-0003-2661-9840;Shobha|Vineeta|V|;Rao|Vijay|V|;Desai|Anu|A|0000-0002-9525-3435;Jois|Ramesh|R|;Dharmanand|B G|BG|;Kumar|Sharath|S|;Kumar|Pradeep|P|;Dharmapalaiah|Chethana|C|;Mahendranath|Kurugodu Mathada|KM|;Prasad|Shiva|S|;Daware|Manisha Ashwin|MA|;Singh|Yogesh|Y|;Karjigi|Uma|U|;Nagaraj|S|S|;Anupama|K R|KR|",
"chemical_list": "D018501:Antirheumatic Agents; D001685:Biological Factors; D000079424:Tumor Necrosis Factor Inhibitors",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00296-019-04245-4",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0172-8172",
"issue": "39(3)",
"journal": "Rheumatology international",
"keywords": "ARDs; Comorbidities; Infection; bDMARDs; csDMARDS",
"medline_ta": "Rheumatol Int",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018501:Antirheumatic Agents; D015535:Arthritis, Psoriatic; D001172:Arthritis, Rheumatoid; D001327:Autoimmune Diseases; D001685:Biological Factors; D003430:Cross-Sectional Studies; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D015994:Incidence; D007194:India; D007239:Infections; D008180:Lupus Erythematosus, Systemic; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D012216:Rheumatic Diseases; D025242:Spondylarthropathies; D000079424:Tumor Necrosis Factor Inhibitors; D055815:Young Adult",
"nlm_unique_id": "8206885",
"other_id": null,
"pages": "497-507",
"pmc": null,
"pmid": "30684040",
"pubdate": "2019-03",
"publication_types": "D016428:Journal Article; D064888:Observational Study; D013485:Research Support, Non-U.S. Gov't",
"references": "25970800;25112605;22553077;21109520;16871531;27613285;18260176;25183244;20699241;30295095;30581616;16868999;12355475;1930310;24657513;26768759;27682255;14872478;16867042;26315675;25975452;29740441;21745378",
"title": "Incidence of infection other than tuberculosis in patients with autoimmune rheumatic diseases treated with bDMARDs: a real-time clinical experience from India.",
"title_normalized": "incidence of infection other than tuberculosis in patients with autoimmune rheumatic diseases treated with bdmards a real time clinical experience from india"
} | [
{
"companynumb": "IN-JNJFOC-20190305350",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "GOLIMUMAB"
},
"drugadditional": "3",
"d... |
{
"abstract": "We report on a challenging case of a 34-year-old male patient with giant cell myocarditis (GCM) and fulminant relapse after discontinuing immunomodulatory therapy 2 years after the initial event. Specific combined immunosuppressive therapy with antithymocyte globulin (ATG), cyclosporine and high-dose glucocorticoids combined with guideline-based heart failure medication led to the recovery of GCM, improvement of systolic left ventricular function and clinical remission. This case report emphasises the importance of an immunosuppressive therapy for the prognosis and outcome and the risk of discontinuation. Most importantly, ATG seems to be one new possible potential treatment option for patients with acute GCM.",
"affiliations": "Department of General and Interventional Cardiology, University Heart Center, Hamburg Eppendorf, Hamburg, Germany.;Department of Cardiology and Pneumology, Charité Berlin, Campus Benjamin Franklin (CBF), Berlin, Germany.;Department of General and Interventional Cardiology, University Heart Center, Hamburg Eppendorf, Hamburg, Germany.;Department of General and Interventional Cardiology, University Heart Center, Hamburg Eppendorf, Hamburg, Germany.",
"authors": "Fluschnik|Nina|N|;Escher|Felicitas|F|;Blankenberg|Stefan|S|;Westermann|Dirk|D|",
"chemical_list": "D007166:Immunosuppressive Agents",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2014()",
"journal": "BMJ case reports",
"keywords": null,
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000328:Adult; D015726:Giant Cells; D006801:Humans; D007166:Immunosuppressive Agents; D008297:Male; D009205:Myocarditis; D009206:Myocardium; D012008:Recurrence",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "25246472",
"pubdate": "2014-09-22",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "23735345;23149495;8061036;7484795;9197214;22265922;1122272;17959655;10593350;19026310",
"title": "Fatal recurrence of fulminant giant cell myocarditis and recovery after initialisation of an alternative immunosuppressive regime.",
"title_normalized": "fatal recurrence of fulminant giant cell myocarditis and recovery after initialisation of an alternative immunosuppressive regime"
} | [
{
"companynumb": "PHHY2014DE151694",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CYCLOSPORINE"
},
"drugadditional": null,
"dr... |
{
"abstract": "BACKGROUND\nThere is no consensus on the use of thrombus aspiration (TA) in primary percutaneous coronary intervention (PPCI), and few studies have focused on the performance of tirofiban via TA catheter after PPCI. Our study investigated the clinical outcome of tirofiban injection through TA in acute ST-segment elevation myocardial infarction (STEMI) patients with large thrombus burden undergoing PPCI treatment.\n\n\nMETHODS\nThe study comprised 122 STEMI patients who underwent TA during PPCI. Participants were randomly divided into two groups. Group A received intravenous tirofiban injection and tirofiban injection via a TA catheter to the infarcted coronary artery after aspiration (n = 61). Group B received intravenous tirofiban injection only (n = 61). Baseline clinical information and follow-up data were collected for both groups. Coronary angiography, electrocardiography, and echocardiography findings as well as major adverse cardiovascular events (MACE) were recorded.\n\n\nRESULTS\nThere were significant differences in postprocedural Thrombolysis in Myocardial Infarction (TIMI) grade 2 and 3 flow between the two groups (p = 0.021, p = 0.006, respectively). The incidence of slow-flow in group A was significantly lower than that of group B (p = 0.011). An increased incidence of no ST-segment resolution was observed in group B (p = 0.011). There were fewer major adverse cardiovascular events in group A than in group B, but the difference was not statistically significant.\n\n\nCONCLUSIONS\nSelective tirofiban injection via TA catheter during PPCI may improve myocardial reperfusion in STEMI patients with large thrombus burden.",
"affiliations": "Department of Cardiology, Panyu Central Hospital (Cardiovascular Institute of Panyu District), 511400, Guangzhou, China.;Department of Cardiology, Ganzhou City People's Hospital, 341000, Ganzhou, China.;Department of Cardiology, Panyu Central Hospital (Cardiovascular Institute of Panyu District), 511400, Guangzhou, China.;Department of Cardiology, Panyu Central Hospital (Cardiovascular Institute of Panyu District), 511400, Guangzhou, China.;Department of Cardiology, Panyu Central Hospital (Cardiovascular Institute of Panyu District), 511400, Guangzhou, China.;Department of Cardiology, Panyu Central Hospital (Cardiovascular Institute of Panyu District), 511400, Guangzhou, China.;Department of Ultrasound, Guangdong Women and Children Hospital, No. 521 Xingnan Avenue, 511400, Guangzhou, China. Dr_zhangyl@163.com.",
"authors": "Zhang|Z|Z|;Li|W|W|;Wu|W|W|;Xie|Q|Q|;Li|J|J|;Zhang|W|W|;Zhang|Y|Y|",
"chemical_list": "D005343:Fibrinolytic Agents; D000077466:Tirofiban",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00059-018-4716-0",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0340-9937",
"issue": "45(3)",
"journal": "Herz",
"keywords": "Angioplasty; Anticoagulants; Myocardial infarction; Percutaneous coronary intervention; Thrombectomy",
"medline_ta": "Herz",
"mesh_terms": "D015906:Angioplasty, Balloon, Coronary; D005343:Fibrinolytic Agents; D006801:Humans; D015425:Myocardial Reperfusion; D062645:Percutaneous Coronary Intervention; D000072657:ST Elevation Myocardial Infarction; D013927:Thrombosis; D000077466:Tirofiban; D016896:Treatment Outcome",
"nlm_unique_id": "7801231",
"other_id": null,
"pages": "280-287",
"pmc": null,
"pmid": "29947833",
"pubdate": "2020-05",
"publication_types": "D016428:Journal Article; D016449:Randomized Controlled Trial",
"references": null,
"title": "Myocardial reperfusion with tirofiban injection via aspiration catheter : Efficacy and safety in STEMI patients with large thrombus burden.",
"title_normalized": "myocardial reperfusion with tirofiban injection via aspiration catheter efficacy and safety in stemi patients with large thrombus burden"
} | [
{
"companynumb": "CN-AGG-06-2018-1944",
"fulfillexpeditecriteria": "2",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CLOPIDOGREL BISULFATE"
},
"drugadditional": null,
... |
{
"abstract": "Post-transplant lymphoproliferative disorders (PTLD) are lymphoid proliferations associated with post-transplant immunosuppression. Most originate from B cells and are associated with Epstein-Barr virus (EBV) infection. Although extranodal involvement is common, cutaneous presentation is rare.\n\n\n\nTo report and characterize cutaneous manifestations of PTLD from clinical, histopathologic, and immunohistochemistry standpoints.\n\n\n\nPatients' information was obtained retrospectively by reviewing medical records. Skin biopsies were submitted to histological and immunohistochemistry analysis, and EBV detection was performed by in situ hybridization and polymerase chain reaction (PCR) analysis. Staging examinations were included. A literature review of reported cutaneous PTLD cases was performed.\n\n\n\nWe describe two cases of primary cutaneous and 2 cases of systemic PTLD with secondary cutaneous manifestations. All had late onset disease, which presented at least 6 years after transplantation. Histopathologic findings were compatible with monomorphic PTLD in three cases and plasmacytic hyperplasia in one case. EBV was detected in two patients. Both patients with systemic disease had fatal outcome, and those with primary cutaneous involvement responded to treatment.\n\n\n\nDue to the rare incidence of cutaneous manifestation of PTLD, the analysis of a large number of cases was not possible.\n\n\n\nAlthough rare, PTLD should be considered in the differential diagnosis of late onset cutaneous complications post-renal transplant.",
"affiliations": "Department of Dermatology, Federal University of São Paulo, São Paulo, Brazil.;Department of Dermatology, Federal University of São Paulo, São Paulo, Brazil.;Department of Dermatology, Federal University of São Paulo, São Paulo, Brazil.;Department of Dermatology, Federal University of São Paulo, São Paulo, Brazil.;Department of Dermatology, Federal University of São Paulo, São Paulo, Brazil.;Department of Dermatology, Federal University of São Paulo, São Paulo, Brazil.",
"authors": "Ferreira|Maria Carolina Corsi|MCC|0000-0003-0217-6643;Arai Seque|Camila|C|;Enokihara|Mílvia Maria Simões E Silva|MMSES|;Batista|Mariana Dias|MD|;Tomimori|Jane|J|;Porro|Adriana Maria|AM|",
"chemical_list": null,
"country": "Denmark",
"delete": false,
"doi": "10.1111/ctr.14162",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0902-0063",
"issue": "35(2)",
"journal": "Clinical transplantation",
"keywords": "kidney transplantation; lymphoma; lymphoproliferative disorders; skin",
"medline_ta": "Clin Transplant",
"mesh_terms": "D020031:Epstein-Barr Virus Infections; D004854:Herpesvirus 4, Human; D006801:Humans; D016030:Kidney Transplantation; D008232:Lymphoproliferative Disorders; D012189:Retrospective Studies",
"nlm_unique_id": "8710240",
"other_id": null,
"pages": "e14162",
"pmc": null,
"pmid": "33217057",
"pubdate": "2021-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Post-transplant lymphoproliferative disorder with cutaneous involvement: A series of four cases.",
"title_normalized": "post transplant lymphoproliferative disorder with cutaneous involvement a series of four cases"
} | [
{
"companynumb": "BR-ALKEM LABORATORIES LIMITED-BR-ALKEM-2021-04332",
"fulfillexpeditecriteria": "1",
"occurcountry": "BR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "AZATHIOPRINE"
},
"dru... |
{
"abstract": "Landau-Kleffner syndrome (LKS) has been demonstrated in the past to respond to immunotherapy. Recently, some cases of LKS have been shown to be secondary to glutamate receptor (GRIN2A) mutations. Whether such cases respond to immunotherapy is not known. Here, we present the case of a 3-year-old boy with LKS found to have a GRIN2A heterozygous missense mutation, whose clinical symptoms and EEG responded to a course of combination oral steroids and monthly infusions of intravenous immunoglobulin. He then relapsed after discontinuation of this therapy, and responded again after a second course of intravenous immunoglobulin. We conclude that immunotherapy should be considered as a therapeutic option in patients with LKS who are also found to harbour GRIN2A mutations.",
"affiliations": "Duke University Medical Center, Durham.;Carolinas Healthcare System, Charlotte, NC, USA.;Duke University Medical Center, Durham.;Duke University Medical Center, Durham.",
"authors": "Fainberg|Nina|N|;Harper|Amy|A|;Tchapyjnikov|Dmitry|D|;Mikati|Mohamad A|MA|",
"chemical_list": "D016194:Receptors, N-Methyl-D-Aspartate; C440500:N-methyl D-aspartate receptor subtype 2A",
"country": "France",
"delete": false,
"doi": "10.1684/epd.2016.0791",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1294-9361",
"issue": "18(1)",
"journal": "Epileptic disorders : international epilepsy journal with videotape",
"keywords": "NMDA 2A receptor; electrical status epilepticus in sleep (ESES); epilepsy; speech regression",
"medline_ta": "Epileptic Disord",
"mesh_terms": "D001921:Brain; D002675:Child, Preschool; D004569:Electroencephalography; D006801:Humans; D007167:Immunotherapy; D018887:Landau-Kleffner Syndrome; D008297:Male; D009154:Mutation; D016194:Receptors, N-Methyl-D-Aspartate; D012890:Sleep; D013226:Status Epilepticus",
"nlm_unique_id": "100891853",
"other_id": null,
"pages": "97-100",
"pmc": null,
"pmid": "26806548",
"pubdate": "2016-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Response to immunotherapy in a patient with Landau-Kleffner syndrome and GRIN2A mutation.",
"title_normalized": "response to immunotherapy in a patient with landau kleffner syndrome and grin2a mutation"
} | [
{
"companynumb": "US-UCBSA-2016017278",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LEVETIRACETAM"
},
"drugadditional": "3",
... |
{
"abstract": "Primary hyperparathyroidism is rarely produced by parathyroid carcinoma. We present the case of a 63-yr-old man who was admitted due to recent onset of constipation, weakness and progressive lethargy. At physical examination, a left cervical mass was palpated. Marked hypercalcemia (serum calcium 25 mg/dl) (6.22 mmol/l) complicated by renal insuficiency (serum creatinine 4.4 mg/dl) (388 micromol/l) was found, but both were unresponsive to conventional therapy and hemofiltration. Autopsy examination showed a carcinoma of the upper left parathyroid gland, multiple foci of metastatic calficications in the vessel walls and parenchyma of both lungs and kidneys, and the myocardium, which contributed to multi-organ failure and death. In addition to describing the clinical presentation, we review the mechanism of metastatic calcifications as well as the role of renal function and hyperphosphatemia, and the basis for therapy of hypercalcemic crisis.",
"affiliations": "Department of Internal Medicine, Universidad de Málaga, Málaga, Spain. valdivielso@uma.es",
"authors": "Valdivielso|P|P|;López-Sánchez|J|J|;Garrido|A|A|;Sánchez-Carrillo|J J|JJ|",
"chemical_list": null,
"country": "Italy",
"delete": false,
"doi": "10.1007/BF03344164",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0391-4097",
"issue": "29(7)",
"journal": "Journal of endocrinological investigation",
"keywords": null,
"medline_ta": "J Endocrinol Invest",
"mesh_terms": "D001344:Autopsy; D002114:Calcinosis; D017809:Fatal Outcome; D006338:Heart Neoplasms; D006801:Humans; D006934:Hypercalcemia; D007680:Kidney Neoplasms; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged; D010282:Parathyroid Neoplasms",
"nlm_unique_id": "7806594",
"other_id": null,
"pages": "641-4",
"pmc": null,
"pmid": "16957413",
"pubdate": "2006",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "11351191;15719375;3686357;9565811;9451731;4689443;3712056;11251025;849084;7353514;3096464;2225672;4693587;8989242;8797054;15956079;11113666;9505219;12960210;3404653;15531515;14585940;9543122;8772648;2247829;11124857",
"title": "Metastatic calcifications and severe hypercalcemia in a patient with parathyroid carcinoma.",
"title_normalized": "metastatic calcifications and severe hypercalcemia in a patient with parathyroid carcinoma"
} | [
{
"companynumb": "ES-PFIZER INC-2021022066",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE SODIUM SUCCINATE"
},
"druga... |
{
"abstract": "This article is a case-report series showing the effectiveness of a three-month exposure to a synthetic analogue of Human Appeasing Pheromone as add-on strategy to psychopharmacological treatment on behavioral and residual symptoms of three patients suffering from severe psychiatric disorders with complex clinical pictures.",
"affiliations": "Dipartimento di Medicina Clinica e Sperimentale - Section of Psychiatry University of Pisa Via Roma 67 Pisa 56126 Italy.;Dipartimento di Medicina Clinica e Sperimentale - Section of Psychiatry University of Pisa Via Roma 67 Pisa 56126 Italy.;Dipartimento di Medicina Clinica e Sperimentale - Section of Psychiatry University of Pisa Via Roma 67 Pisa 56126 Italy.;Dipartimento di Medicina Clinica e Sperimentale - Section of Psychiatry University of Pisa Via Roma 67 Pisa 56126 Italy.;Fondazione BRF Onlus - Institute for Research in Psychiatry and Neuroscience Via Vecchia III 51 Lucca 55100 Italy.;Fondazione BRF Onlus - Institute for Research in Psychiatry and Neuroscience Via Vecchia III 51 Lucca 55100 Italy.",
"authors": "Piccinni|Armando|A|;Veltri|Antonello|A|;Marazziti|Donatella|D|;Mucci|Federico|F|0000-0002-9746-8237;Cozzi|Alessandro|A|;Pageat|Patrick|P|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1002/ccr3.1348",
"fulltext": "\n==== Front\nClin Case RepClin Case Rep10.1002/(ISSN)2050-0904CCR3Clinical Case Reports2050-0904John Wiley and Sons Inc. Hoboken 10.1002/ccr3.1348CCR31348Case ReportCase ReportsHuman Appeasing Pheromone (HAP) influence on behavior and psychopathological residual symptoms of patients with complex psychiatric disorders A. Piccinni et al.Piccinni Armando armando.piccinni@gmail.com \n1\n\n2\nVeltri Antonello \n1\n\n2\nMarazziti Donatella \n1\n\n2\nMucci Federico http://orcid.org/0000-0002-9746-8237\n1\nCozzi Alessandro \n2\n\n3\nPageat Patrick \n2\n\n3\n\n1 \nDipartimento di Medicina Clinica e Sperimentale – Section of Psychiatry\nUniversity of Pisa\nVia Roma 67\nPisa\n56126\nItaly\n\n2 \nFondazione BRF Onlus – Institute for Research in Psychiatry and Neuroscience\nVia Vecchia III 51\nLucca\n55100\nItaly\n\n3 \nIRSEA ‐ Research Institute in Semiochemistry and Applied Ethology\nQuartier Salignan\nApt\n84400\nFrance\n* Correspondence\n\nArmando Piccinni, Dipartimento di Medicina Clinica e Sperimentale, Psychiatric Unit, University of Pisa, Via Roma 67, 56126 Pisa, Italy. Tel: +39050992642; Fax: +390502219787; E‐mail: armando.piccinni@gmail.com\n23 2 2018 4 2018 6 4 10.1002/ccr3.2018.6.issue-4664 668 25 5 2017 21 11 2017 05 12 2017 © 2018 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.Key Clinical Message\nThis article is a case‐report series showing the effectiveness of a three‐month exposure to a synthetic analogue of Human Appeasing Pheromone as add‐on strategy to psychopharmacological treatment on behavioral and residual symptoms of three patients suffering from severe psychiatric disorders with complex clinical pictures.\n\nAutism spectrum disordersbipolar disordersHuman Appeasing Pheromoneobsessive‐compulsive symptomspheromonespsychiatric disordersseparation anxietysocial anxiety source-schema-version-number2.0component-idccr31348cover-dateApril 2018details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:version=5.3.4 mode:remove_FC converted:06.04.2018\n\nClinical Case Reports \n2018 ; 6 (4 ): 664 –668\n==== Body\nIntroduction\nPheromones are volatile compounds released into the environment through body secretions and perceived by members of the same species, in which they trigger a behavioral or hormonal response, or modulate endocrine states and development 1. Initially described in insects, subsequently they have been detected and investigated in mammals 2. A specialized region of the olfactory system, the so‐called vomeronasal organ (VNO) or Jacobson's organ, is considered to be responsible for pheromones detection.\n\nAlthough anatomical evidence for a specialized pheromone system in humans is still matter of debate, a VNO is present in our species 3, and a putative pheromone receptor gene is expressed directly in the human olfactory mucosa 4. It is generally agreed that apocrine glands in the axillae and pubic region represent the main sources of human pheromones 5: the main ones are 4,16‐androstadien‐3‐one (AND) and estra‐1,3,5 (10),16‐tetraen‐3‐ol (EST) which structurally resemble sexual hormones 6. The first experimental evidence supporting the involvement of pheromones in some human behaviors was that reporting the synchronization of the menstrual cycle amongst women living together 7, and the one showing that odorless compounds from women's armpits of women could influence menstrual cycle duration 8. In the next decades, accumulating data suggested the possible role of androstadienone in emotions 3, giving the demonstration that accessory olfactory bulb sends its terminals to hypothalamus and related brain areas 2, 9.\n\nMore recently, increasing attention has been directed toward potential therapeutic applications in psychiatric symptoms/disorders of a different class of pheromones, the so‐called appeasing pheromones (APs), which are secreted in the breast region shortly after delivery 10 and characterized by almost the same chemical structure in all mammals including humans 11, 12. A core of three methyl esters of C16 and C8 unsaturated acids (oleic acid, palmitic acid, and linoleic acid) is associated with a group of two to three compounds varying from one species to another. Because of their reassuring and appeasing effects on both young and adult animals, the synthetic analogues of these pheromones currently are largely used in animals for the treatment of behavioral disorders 13.\n\nThe AP products are available under the forms of sprays, collars, and electric diffusers (the same technology used for antimosquito products) that gained a great success in the treatment of behavioral and anxiety‐related problems in dogs and cats, with no side or adverse effects 14, 15. A human AP (HAP) has been isolated by from the Montgomery glands' secretions of maternal breast region after delivery 11.\n\nThis article summarizes a series of case reports showing the potentiality of HAP as add‐on strategy to standard psychopharmacological treatments on behavioral and residual symptoms of three patients suffering from complex psychiatric disorders. The patients, who all signed an informed written consent, received a synthetic analogue of the native secretion of HAP for 3 months by means of an electric diffuser located in their houses and covering an area of 50–70 m2. Each diffuser refill lasted about 4 weeks. Each chemical compound identified in the native secretion was obtained from industrial chemistry procedures and then used to form the AP synthetic analogue. All the methyl esters used to prepare the product were obtained from plant oils or semisynthesis: No animal derivates were used in this product. All the compounds of the pheromone are methyl esters of fatty acids that are well known as compounds of several food products and well identified as nontoxic products.\n\nCase #1\nPatient #1 is a 40‐year‐old, unemployed single woman who lives with her parents. She has been suffering from bipolar disorder of type I (BDI), according to DSM‐IV‐TR criteria, since her adolescence, when she had suffered from a mixed episode with psychotic features (persecution and reference delusions, auditory hallucinations), psychomotor agitation, aggressiveness, and sleeplessness. Subsequently, she alternated mixed episodes with depressive phases (depressed mood, diminished interest and pleasure, loss of energy, feelings of worthlessness, indecisiveness, and crying), with just short symptom‐free periods and with a consequent severe impairment in work and social functioning. She had been treated with mood stabilizers, typical and atypical antipsychotics, tricyclic (TCA) or selective serotonin reuptake inhibitor (SSRI) antidepressants, and benzodiazepines that had led to a significant global improvement consisting in mood stabilization, absence of psychotic symptoms, no aggressiveness, and no sleep disturbances. In any case, as residual and invalidating symptoms, in particular marked separation anxiety toward her parents, insecurity, social anxiety and performance/social avoidance, and hoarding behavior, were still present, HAP was proposed to her as an add‐on treatment. Her coadministered pharmacological drugs were the following: lithium 900 mg/die, clozapine 50 mg/die, paliperidone 6 mg/die, paroxetine 20 mg/die, and imipramine 50 mg/die. After her informed written consent was obtained, she was exposed to synthetic HAP analogue for 3 months and maintained on the same drugs for at least 1 month before and throughout the entire HAP exposure period. At baseline (T0) and at the end of each month (T1, T2, T3), she underwent a psychiatric examination and assessed by means of rating scales specific for her residual symptoms. In particular, she was asked to fill in the following scales: Adult Separation Anxiety Self‐report Checklist (ASA‐27; 16), Liebowitz Social Phobia Scale (LSPS; 17), and Obsessive‐Compulsive Inventory – Revised (OCI‐R; 18). Moreover, in order to objectively evaluate her overall functioning, her caregivers (parents and sister) were asked to fill the questionnaire Life Skills Profile (LSP). After just 1 month of HPA exposure (T1), a significant improvement in residual symptoms was observed and described by the patient herself, with no adverse effects. Even her parents, who carefully reported their opinion on clinical changes at T1 in a written form, testified the overall clinical opinion.\n\nThe clinical improvement was confirmed by the LSPS score that decreased of about 29% from T0 to T3 (T0: 48, T1: 29, T2: 28, T3: 34), while the LSP score increased of about 47% from T0 to T2 and of about 28% from T0 to T3 (T0: 96, T1: 110, T2: 141, T3: 123). On the contrary, no substantial changes were recorded for ASA‐27 (T0: 54, T1: 57, T2: 59, T3: 57) and OCI‐R (T0: 56, T1: 51, T2: 54, T3: 57).\n\nCase #2\nPatient # 2 is a 20‐year‐old man living with his parents, who has been suffering from an autism spectrum disorder (ASD) and marked intellectual disability with pervasive deficits in cognitive, motor, and communicative functioning. He is unable to complete even the most rudimentary aspects of self‐care such as eating and toileting, firstly referred for psychiatric evaluation because of severe self‐injurious behavior. When we met him and his mother for the first time, his hands were covered by hyperkeratotic lesions and bleeding wounds as a result of bites, his face and ears were full of scratches and lacerations due to blows and slaps, he could not remain alone in a room or without physical contact with his mother, and during the visit, he continued to cry, scream, and slap himself in the face. He was treated for about 1 year with a combination of anticonvulsants (carbamazepine up to 1200 mg/die), antipsychotics (haloperidol up to 6 mg/die and chlorpromazine up to 300 mg/die), and benzodiazepines (clonazepam up to 4 mg/die), while obtaining only poor and transient results. A trial with clozapine was not tolerated because of blood dyscrasias. Therefore, after informing his parents and obtaining their informed written consent, the patient was exposed to synthetic HAP analogue for 3 months, while maintaining the same psychopharmacological regimen during the entire HAP exposure period. At baseline (T0) and at the end of each month (T1, T2, T3), he underwent a psychiatric examination and his mother was asked to complete the LSP questionnaire 19. After 1 month, the HAP exposure provoked a significant reduction in self‐injuring (no more bleeding wounds), although he continued to slap himself only occasionally, in separation anxiety (he was able to stay alone in his room with no need of physical contact), and in screaming and crying during medical evaluation. LSP score increased of about 55% from T0 to T1 and of about 49% from T0 to T3 (T0: 73, T1: 113, T2: 111, T3: 109). No adverse effects were reported.\n\nCase #3\nPatient #3 is a 34‐year‐old, unemployed single woman living with her parents and one sister. She has been suffering from BDI, according to DSM‐IV‐TR criteria, since she was 18. The index episode was a mixed one with psychotic features (persecution and reference delusions), feelings of sadness, indecisiveness, crying, diminished interest and pleasure, racing thoughts, psychomotor agitation, and severe insomnia. Then, she experienced multiple recurrences with a similar clinical picture. Treatment with anticonvulsants and lithium resulted to be ineffective and poorly tolerated. During the last 3 years, she was successfully treated with clozapine (up to 50 mg/die) and citalopram (20 mg/die), and gradually obtained mood stabilization, with no psychotic symptoms or sleep disturbances. Unfortunately, she was still suffering from some residual symptoms, such as marked interpersonal sensitivity, suspiciousness and mistrust, obsessive ruminations, separation anxiety toward her relatives, avolition, and social withdrawal. The patient was informed of the possibility to be exposed to synthetic a HAP analogue for 3 months and provided her informed written consent to this strategy. At baseline (T0) and at the end of each month (T1, T2, T3), she underwent a psychiatric visit and filled in the following scales: ASA‐27, LSPS, and OCI‐R. The OCI‐R score decreased of about 69% from T0 to T3 (T0: 13, T1: 9, T2: 6, T3: 4) and that of ASA‐27 of about 33% from T0 to T3 (T0: 21, T1: 25, T2: 20, T3: 14), with no side effect. No substantial changes were observed for LSPS one (T0: 91, T1: 91, T2: 81, T3: 81).\n\nDiscussion\nThe case‐report series reported herein provides preliminary observations on the potential effectiveness as add‐on treatment of a three‐month exposure to a HAP synthetic analogue in some psychiatric patients, two suffering from BDI and one of autism and self‐injurious behavior. HPA exposure seemed to provoke a significant improvement of some residual psychopathological symptoms/dimensions such as social anxiety, obsessive‐compulsive symptoms, separation anxiety, and behavioral disturbances. These symptoms were persistent despite psychopharmacological treatment had led to an overall improvement of the clinical picture. To minimize the confounding effect due to changes in drug regimens, the patients were maintained on the same treatment for at least 1 month before and during the entire HAP exposure period. The clinical improvement was recorded during the monthly psychiatric examinations, shown by changes in the rating scale scores, and even reported from patients and caregivers.\n\nOur observations are in line with the results of other studies exploring the potential pheromones effects on psychiatric symptoms. A placebo‐controlled study on 30 patients suffering from major depressive disorder demonstrated that an intranasally administered pherin (PH10), a neurosteroid that specifically engages peripheral chemoreceptors in the nasal passages, elicited a rapid antidepressant effect. In particular, it caused a significant Hamilton Rating Scale for Depression (HRSD; 20) score reduction and a Self‐rated Quality of Life Enjoyment and Satisfaction Questionnaire (QLESQ; 21) score increase already from the first week of administration 22. A very recent phase‐two, multicenter, double‐blind, placebo‐controlled, single‐dose study on 91 women with generalized social anxiety disorder showed that another pherin (PH94B – 3β‐androsta‐4,16‐dien‐3‐ol) significantly decreased anxiety during both a public‐speaking and social interaction challenges 23. Such studies suggest that some pherins could represent novel, effective, and well‐tolerated treatment options for a specific mood and anxiety disorders.\n\nAs far APs are concerned, in the last 20 years they were proven to be effective in animals in the control and prevention of acute and chronic stress, aggression, but also in the treatment of anxiety disorders such as separation anxiety, various sound phobias (fireworks and thunderstorms), neophobia in puppies, transport‐related problems, and social stress 13, 14, 24, 25, 26. On the contrary, no human study on HAP effects on psychopathological symptoms is available. Extracts of the Montgomery glands' secretions were tested on 22 infants: No evidence of adverse effects was reported, while the smell of breast areolar secretions increased inspiratory activity and sucking reflex of infants, significantly more than other tested odorous stimuli 10. Moreover, a HAP synthetic analogue was tested in a placebo‐controlled study on a sample of 100 children aged between 18 and 36 months: During pediatric visits, the children treated with HAP showed a significant reduction of anxiety, less increase in heart rate, and less behavioral signs of discomfort compared to those treated with placebo 27. Consequently, the present case‐report series is the first clinical experience on HAP effects on psychiatric patients. In all our patients, HAP exposure with a concomitant psychopharmacological regimen was rapidly effective on social and separation anxiety, obsessive‐compulsive symptoms, and self‐injurious behavioral disturbances.\n\nThese preliminary observations would suggest that pheromones, and in particular HAP, may possibly represent putative, novel, and “natural” therapeutic opportunities to fulfill some unmet needs in the treatment of complex psychiatric disorders, given also the evidence that HAP exerts a local action without systemic absorption, appears to have rapid effects and an excellent safety profile.\n\nTherefore, further studies are extremely needed to explore its preclinical activities on different CNS parameters, as well as large randomized placebo‐controlled studies to clarify its potential therapeutic effectiveness on different psychiatric disorders and/or specific symptom clusters or psychopathological dimensions.\n\nConflict of Interest\nNone declared.\n\nAuthorship\nAP, PP, DM, AV, and AC: planned the study. FM, AV, and AC: selected and assessed the patients. AP, AV, DM, FM, AC, and PP: analyzed the ensuing findings, wrote and revised together the manuscript.\n==== Refs\nReferences\n1 \n\nKarlson , P. \n, and \nM. \nLuscher \n. 1959 \n‘Pheromones’: a new term for a new class of biologically active substances . Nature \n183 :155 –156 .\n2 \n\nBrennan , P. A. \n, and \nE. B. \nKeverne \n. 2004 \nSomething in the air? New insights into mammalian pheromones . Curr. Biol. \n14 :R81 –R89 .14738757 \n3 \n\nMonti‐Bloch , L. \n, \nC. \nJennings‐White \n, and \nD. L. \nBerliner \n. 1998 \nThe human vomeronasal system. A review . Ann. N. Y. Acad. Sci. \n855 :373 –389 .9929629 \n4 \n\nRodriguez , I. \n, \nC. A. \nGreer \n, \nM. Y. \nMok \n, and \nP. \nMombaerts \n. 2000 \nA putative pheromone receptor gene expressed in human olfactory mucosa . Nat. Genet. \n26 :18 –19 .10973240 \n5 \n\nGrammer , K. \n, \nB. \nFink \n, and \nN. \nNeave \n. 2005 \nHuman pheromones and sexual attraction . Eur. J. 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Sci. \n101 :144 –153 .\n25 \n\nGaultier , E. \n, \nD. \nVienet‐Legué \n, \nC. \nFalewee \n, \nL. \nBonnafous \n, \nL. \nBougrat \n, \nC. \nLafont \n, et al. 2008 \nEfficacy of Dog Appeasing Pheromone in reducing stress related behaviours in newly adopted puppies (Canis familiaris) . Vet. Rec. \n163 :73 –80 .18641375 \n26 \n\nGaultier , E. \n, \nD. \nVienet‐Legué \n, \nC. \nFalewee \n, \nL. \nBonnafous \n, \nL. \nBougrat \n, \nC. \nLafont \n, et al. 2009 \nEfficacy of Dog Appeasing Pheromone in preventing fear‐related behaviours in puppies (Canis familiaris) facing unfamiliar people and new surroundings . Vet. Rec. \n164 :708 –714 .19502626 \n27 \n\nPageat , P. \n, \nC. \nLecuelle \n, and \nA. \nAlameda \n. A maternal semiochemical controls fear reactions in children (18 to 36 months‐old) experiencing routine examination in a pediatric hospital . 1st World Congress on Olfaction and Issues, Paris Maison de la Recherche, 4‐5 November 2010.\n\n",
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"issn_linking": "2050-0904",
"issue": "6(4)",
"journal": "Clinical case reports",
"keywords": "Autism spectrum disorders; Human Appeasing Pheromone; bipolar disorders; obsessive‐compulsive symptoms; pheromones; psychiatric disorders; separation anxiety; social anxiety",
"medline_ta": "Clin Case Rep",
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"nlm_unique_id": "101620385",
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"pages": "664-668",
"pmc": null,
"pmid": "29636936",
"pubdate": "2018-04",
"publication_types": "D002363:Case Reports",
"references": "9929629;2885745;15016474;15653193;8290681;15849342;19851461;10973240;18641375;1892788;14738757;12701508;12501574;9515961;24700254;2017913;13622694;19502626;11548956;14399272;4994256;12658624",
"title": "Human Appeasing Pheromone (HAP) influence on behavior and psychopathological residual symptoms of patients with complex psychiatric disorders.",
"title_normalized": "human appeasing pheromone hap influence on behavior and psychopathological residual symptoms of patients with complex psychiatric disorders"
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"abstract": "Lymphocyte transformation test (LTT) has been widely used to evaluate non-immediate drug hypersensitivity reactions (NIDHRs). However, the lack of standardization and the low sensitivity have limited its routine diagnostic use. The drug presentation by dendritic cells (DCs) and the assessment of proliferation on effector cells have shown promising results. Flow-cytometry-based methods can help apply these improvements. We aimed to assess the added value of using drug-primed-DCs and the determination of the proliferative response of different lymphocyte subpopulations in NIDHRs.\n\n\n\nPatients with confirmed NIDHR were evaluated by both conventional (C-LTT) and with drug-primed-DCs LTT (dDC-LTT)analysing the proliferative response in T cells and other effector cell subpopulations by using the fluorescent molecule, carboxyfluorescein diacetate succinimidyl ester (CFSE).\n\n\n\nThe C-LTT showed a significantly lower sensitivity (29.4%) compared with dDC-LTT (61.8%), which was confirmed analysing each particular clinical entity: SJS-TEN (62.5% vs 87.5%), MPE (15% vs 47.4%) and AGEP (33% vs 80%). When including the effector cell subpopulations involved in each clinical entity, CD3+ +CD4+ Th 1 or CD3+ +NK cells in SJS-TEN, CD3+ +CD4+ Th 1+NK cells in MPE and CD3+ +NK cells in AGEP, we could significantly increase the sensitivity of the in vitro test to 100%, 68.4% and 100%, respectively, with an overall sensitivity of 87% and 85% of specificity in NIDHR.\n\n\n\nThe use of a flow-cytometry-based test, DCs as drug presenting cells, and focusing on effector cell subpopulations for each clinical entity significantly improved the drug-specific proliferative response in NIDHRs with a unique cellular in vitro test.",
"affiliations": "Allergy Research Group, Instituto de Investigación Biomédica de Málaga-IBIMA, Málaga, Spain.;Allergy Unit, Hospital Regional Universitario de Málaga-HRUM, Málaga, Spain.;Allergy Research Group, Instituto de Investigación Biomédica de Málaga-IBIMA, Málaga, Spain.;Allergy Unit, Hospital Regional Universitario de Málaga-HRUM, Málaga, Spain.;Allergy Research Group, Instituto de Investigación Biomédica de Málaga-IBIMA, Málaga, Spain.;Allergy Research Group, Instituto de Investigación Biomédica de Málaga-IBIMA, Málaga, Spain.;Allergy Unit, Hospital 12 de Octubre, Madrid, Spain.;Allergy Unit, Hospital Regional Universitario de Málaga-HRUM, Málaga, Spain.;Allergy Research Group, Instituto de Investigación Biomédica de Málaga-IBIMA, Málaga, Spain.;Allergy Research Group, Instituto de Investigación Biomédica de Málaga-IBIMA, Málaga, Spain.",
"authors": "Fernandez-Santamaria|Ruben|R|0000-0002-0255-4280;Bogas|Gador|G|;Palomares|Francisca|F|0000-0001-5591-7877;Salas|Maria|M|0000-0002-0583-9492;Fernandez|Tahia D|TD|0000-0003-0625-2156;Jimenez|Isabel|I|;Barrionuevo|Esther|E|;Doña|Inmaculada|I|0000-0002-5309-4878;Torres|Maria Jose|MJ|0000-0001-5228-471X;Mayorga|Cristobalina|C|0000-0001-8852-8077",
"chemical_list": null,
"country": "Denmark",
"delete": false,
"doi": "10.1111/all.14755",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0105-4538",
"issue": "76(7)",
"journal": "Allergy",
"keywords": "drug hypersensitivity reactions; in vitro tests; lymphocytes; non-immediate reactions; proliferation",
"medline_ta": "Allergy",
"mesh_terms": "D049109:Cell Proliferation; D003713:Dendritic Cells; D004342:Drug Hypersensitivity; D006801:Humans; D006969:Hypersensitivity, Immediate; D008213:Lymphocyte Activation",
"nlm_unique_id": "7804028",
"other_id": null,
"pages": "2123-2134",
"pmc": null,
"pmid": "33523478",
"pubdate": "2021-07",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Dendritic cells inclusion and cell-subset assessment improve flow-cytometry-based proliferation test in non-immediate drug hypersensitivity reactions.",
"title_normalized": "dendritic cells inclusion and cell subset assessment improve flow cytometry based proliferation test in non immediate drug hypersensitivity reactions"
} | [
{
"companynumb": "ES-FAESFV-2022-7135",
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{
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"activesubstance": {
"activesubstancename": "ALLOPURINOL"
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{
"abstract": "Isoniazid is the mainstay of anti-tubercular therapy. Used in isolation or in combination with other anti-tubercular drugs, it is generally well-tolerated. While hepatotoxicity and neurotoxicity are reported, significant neurotoxicity remains uncommon. In this report, we present a case of rare neurological complication secondary to anti-tubercular therapy in a patient with stage 5 chronic kidney disease.",
"affiliations": "Department of Nephrology and Renal Transplantation, Medanta, The Medicity, Gurgaon, Haryana, India.;Department of Nephrology and Renal Transplantation, Medanta, The Medicity, Gurgaon, Haryana, India.;Department of Radiology, Medanta, The Medicity, Gurgaon, Haryana, India.;Department of Nephrology and Renal Transplantation, Medanta, The Medicity, Gurgaon, Haryana, India.",
"authors": "Pathania|D|D|;Phanish|M K|MK|;Vishal|J|J|;Kher|V|V|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.4103/0971-4065.157803",
"fulltext": "\n==== Front\nIndian J NephrolIndian J NephrolIJNIndian Journal of Nephrology0971-40651998-3662Medknow Publications & Media Pvt Ltd India IJN-26-5210.4103/0971-4065.157803Case ReportAtaxia in a chronic kidney disease patient on anti-tubercular therapy Pathania D. Phanish M. K. Vishal J. 1Kher V. Department of Nephrology and Renal Transplantation, Medanta, The Medicity, Gurgaon, Haryana, India1 Department of Radiology, Medanta, The Medicity, Gurgaon, Haryana, IndiaAddress for correspondence: Dr. M. K. Phanish, Department of Nephrology and Renal Transplantation, Medanta, The Medicity, Gurgaon, Haryana, India. E-mail: phanishmk@gmail.comJan-Feb 2016 26 1 52 54 Copyright: © 2016 Indian Journal of Nephrology2016This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.Isoniazid is the mainstay of anti-tubercular therapy. Used in isolation or in combination with other anti-tubercular drugs, it is generally well-tolerated. While hepatotoxicity and neurotoxicity are reported, significant neurotoxicity remains uncommon. In this report, we present a case of rare neurological complication secondary to anti-tubercular therapy in a patient with stage 5 chronic kidney disease.\n\nKey words\nAtaxiacerebellumchronic kidney diseasedentate nucleiisoniazid toxicity\n==== Body\nIntroduction\nIsoniazid is widely used for the treatment of tuberculosis. Neurotoxicity due to Isoniazid generally manifests as peripheral neuropathy. In this report we present a patient with stage5 CKD who developed rare central nervous system toxicity due to Isoniazid.\n\nCase Report\nA 29-year-old woman, a known case of chronic kidney disease (CKD) presented with history of fever from last 4 months. Her basic renal disease was unknown as she had presented with bilateral small kidneys. Fever was high grade, intermittent and was associated with poor appetite. She had no dysuria, cough or abdominal complaints. The examination was unremarkable except for left-sided axillary lymphadenopathy. There was no hepatosplenomegaly and breast examination was normal. Neurological examination was unremarkable. Her creatinine on admission was 6.9 mg/dl with an estimated glomerular filtration rate (eGFR) of 7 ml/min/1.73 m2.\n\nShe was evaluated for fever. Serological tests for malaria, dengue, and enteric fever were negative; urine cultures were sterile. Her hemoglobin, total leukocyte count and platelet counts were 8.5 g/dl, 5880/µl, and 1.5 lakhs/µl, respectively. The kidney function tests revealed serum urea of 223 mg/dl and serum creatinine of 6.90 mg/dl. The serum sodium and potassium levels were 136 mmol/l and 4.8 mmol/l, respectively. The liver function tests and thyroid function tests were normal. Blood cultures were sterile.\n\nUltrasound abdomen showed hepatosplenomegaly with irregular, shrunken kidneys. There was no hydroureteronephrosis. Computed tomography of chest and abdomen showed splenomegaly, retroperitoneal and axillary lymphadenopathy with no mediastinal lymphadenopathy. There was no consolidation, collapse or cavitating lesion.\n\nFine needle aspiration from the axillary lymph node was inconclusive. Endoscopic ultrasound-guided fine needle aspiration cytology of the retroperitoneal nodes showed reactive lymphoid cells with few histiocytes. Her tuberculosis gold quantiferon test was positive. In view of persistent fever, lymphadenopathy, hepatosplenomegaly and positive quantiferon gold test, she was empirically initiated on antitubercular therapy with four drugs (isoniazid [INH], rifampicin, pyrazinamide and ethambutol) with appropriate dose adjustments for her kidney function. She was also commenced on pyridoxine 40 mg once daily. Hemodialysis (HD) was initiated through left radiocephalic fistula. One-week after initiation of antitubercular therapy, she developed slurring of speech with unstable gait. On examination, she had pulse 100 beats/min, blood pressure was 150/90 mmHg with no postural drop. The oxygen saturations were 100% on room air, blood glucose levels, serum sodium, and calcium levels were normal. Central nervous system examination showed dysarthria with impaired finger-nose test on left side with past pointing. Her gait was ataxic with swaying on left side. She was unable to perform rapid alternating movements on left side. Motor examination done showed decreased tone with normal power and reflexes on left side. There were no neurological findings on the right side. Sensory examination was normal with negative Romberg's sign.\n\nMagnetic resonance imaging (MRI) brain showed diffusion restriction in bilateral dentate nuclei with T2 fluid-attenuated inversion recovery hyperintensity with no evidence of hemorrhage [Figure 1]. There were no features suggestive of tuberculoma or abscess. As there was no other obvious explanation of the sudden development of cerebellar ataxia, a diagnosis of INH induced toxic encephalopathy was considered and INH was withdrawn. Two days after withdrawal of INH, patient's condition started to improve and had complete neurological recovery within a week. She was commenced on HD via a left radio-cephalic arteriovenous fistula. She was discharged on modified antitubercular therapy that included rifampicin at dose of 450 mg/day, pyrazinamide at dose of 500 mg twice daily and levofloxacin at dose of 250 mg/day. On follow-up after 3 weeks, she has remained afebrile with no neurodeficit.\n\nFigure 1 Diffusion-weighted image, (a) diffusion restriction in bilateral dentate (arrow) nucleus in cerebellum showing corresponding low apparent diffusion coefficient (ADC) value on ADC images (b), hyperintensity noted on T2 fluid-attenuated inversion recovery images (c). There are no signal changes seen on T2 weighted images (d)\n\nDiscussion\nIsoniazid is a bactericidal antitubercular drug that interferes with pyridoxine metabolism leading to deficiency of this vitamin. Adverse effects occur in about 5% of patients on INH, who are also on adequate doses of pyridoxine (10–50 mg/day). Common neurotoxicity of INH is that of peripheral neuropathy that is usually mild and reversible. Due to its hepatic clearance, no dose modification is generally required in patients with kidney disease. INH is used extensively in patients with CKD, on dialysis and following a renal transplant.[1] It is usually well-tolerated in this population and when toxicity occurs, it generally manifests with hepatotoxicity.\n\nCentral nervous system toxicity due to INH presenting with altered consciousness level secondary to encephalopathy has been described, but cerebellar ataxia is very rare.[2] Severe neurotoxicity presenting with encephalopathy and seizures has been described with INH overdose in children which requires treatment with intravenous pyridoxine.[3] Our patient was given with 40 mg/day of pyridoxine along with INH 300 mg once a day. She was not treated with higher doses of pyridoxine as the neurological features were not severe, and they responded to withdrawal of the drug. Cerebellar ataxia due to INH has been described in the past in children[4] but to our knowledge, it has not been described before in a patient with stage 5 CKD with MRI scan demonstrating hyperintense lesions in the dentate nuclei. However, it is worthwhile noting that cerebellar lesions with similar involvement of dentate nuclei have been described before in a patient on metronidazole therapy.[5] Our patient was not taking metronidazole. We did not measure INH levels in our patient and therefore we are unable to comment if the toxicity was related to drug levels.\n\nIn summary, we describe a patient with stage 5 CKD developing cerebellar ataxia and MRI findings of B/L dentate nuclei lesions after the commencement of INH. The neurological features completely resolved after withdrawal of INH. Clinicians should be aware of this rare complication of INH therapy.\n\nSource of Support: Nil\n\nConflict of Interest: None declared.\n==== Refs\n1 Vikrant S Agarwal SK Gupta S Bhowmik D Tiwari SC Dash SC Prospective randomized control trial of isoniazid chemoprophylaxis during renal replacement therapy Transpl Infect Dis 2005 7 99 108 16390397 \n2 Wang HY Chien CC Chen YM Huang CC Encephalopathy caused by isoniazid in a patient with end stage renal disease with extrapulmonary tuberculosis Ren Fail 2003 25 135 8 12617341 \n3 Shah BR Santucci K Sinert R Steiner P Acute isoniazid neurotoxicity in an urban hospital Pediatrics 1995 95 700 4 7724306 \n4 Lewin PK McGreal D Isoniazid toxicity with cerebellar ataxia in a child CMAJ 1993 148 49 50 8439890 \n5 Deenadayalu VP Orinion EJ Chalasani NP Yoo HY Abnormal enhancing lesion of dentate nuclei causing neurologic symptoms induced by metronidazole toxicity Clin Gastroenterol Hepatol 2005 3 xxix 15765436\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "0971-4065",
"issue": "26(1)",
"journal": "Indian journal of nephrology",
"keywords": "Ataxia; cerebellum; chronic kidney disease; dentate nuclei; isoniazid toxicity",
"medline_ta": "Indian J Nephrol",
"mesh_terms": null,
"nlm_unique_id": "8914356",
"other_id": null,
"pages": "52-4",
"pmc": null,
"pmid": "26937081",
"pubdate": "2016",
"publication_types": "D002363:Case Reports",
"references": "7724306;8439890;12617341;15765436;16390397",
"title": "Ataxia in a chronic kidney disease patient on anti-tubercular therapy.",
"title_normalized": "ataxia in a chronic kidney disease patient on anti tubercular therapy"
} | [
{
"companynumb": "IN-CMP PHARMA-2016CMP00015",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
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{
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"activesubstance": {
"activesubstancename": "ETHAMBUTOL HYDROCHLORIDE"
},
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{
"abstract": "The primary objective of this phase II study was to evaluate the efficacy of rituximab in the management of adult patients with physician-diagnosed presumed thrombotic thrombocytopenic purpura (TTP); relapsed or refractory. We conducted a multicentre study in four Canadian hospital-based apheresis units. Forty patients with presumed TTP (20 refractory and 20 relapsing) were sequentially enrolled and all received rituximab in a standardized manner. A complete response was documented in 14 of 19 refractory patients by week 8 and 15/16 were alive and in remission at 52 weeks (one patient was lost to follow-up, one was a non-responder, and three died). Among relapsing patients, 16/18 had a complete response at week 8 and 18/18 at week 52 (one patient lost to follow-up and one withdrew). At 1 year, all relapsing and 85% of refractory patients survived. Of 38/40 patients who had ADMATS13 testing at study entry, 13/19 refractory and 10/19 relapsing patients had ADAMTS13 < 10% (typical TTP); whereas 6/19 refractory and 9/19 relapsing cases had ADAMTS13 > 10% (other thrombotic microangiopathy; TMA). Refractory-typical TTP in contrast to refractory-other TMA and all relapsing patients treated with plasma exchange and rituximab, were less likely to be responsive and more likely to die or relapse.",
"affiliations": "Division of Nephrology, Department of Medicine, Western University, London, ON, Canada.;Department of Pathology, University of Ottawa, Ottawa, ON, Canada.;Department of Medicine, University of Toronto, Toronto, ON, Canada.;Division of Hematology and Thromboembolism, Department of Medicine, McMaster University, Hamilton, ON, Canada.;Division of Hematology and Thromboembolism, Department of Medicine and Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada.;Division of Hematology, Department of Medicine, Vancouver General Hospital, Vancouver, BC, Canada.;Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada.;Division of Nephrology, Department of Medicine, Western University, London, ON, Canada.;Division of Clinical Pathology, Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada.",
"authors": "Clark|William F|WF|;Rock|Gail|G|;Barth|David|D|;Arnold|Donald M|DM|;Webert|Kathyrn E|KE|;Yenson|Paul R|PR|;Kelton|John G|JG|;Li|Lihua|L|;Foley|Steven R|SR|;|||",
"chemical_list": "D058846:Antibodies, Monoclonal, Murine-Derived; D007155:Immunologic Factors; D000069283:Rituximab",
"country": "England",
"delete": false,
"doi": "10.1111/bjh.13408",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0007-1048",
"issue": "170(2)",
"journal": "British journal of haematology",
"keywords": "ADAMTS13; plasma exchange; rituximab; thrombotic microangiopathy; thrombotic thrombocytopenic purpura",
"medline_ta": "Br J Haematol",
"mesh_terms": "D000328:Adult; D058846:Antibodies, Monoclonal, Murine-Derived; D005260:Female; D006801:Humans; D007155:Immunologic Factors; D008297:Male; D008875:Middle Aged; D010951:Plasma Exchange; D011697:Purpura, Thrombotic Thrombocytopenic; D012008:Recurrence; D000069283:Rituximab; D013997:Time Factors; D016896:Treatment Outcome",
"nlm_unique_id": "0372544",
"other_id": null,
"pages": "208-17",
"pmc": null,
"pmid": "25855259",
"pubdate": "2015-07",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "A phase-II sequential case-series study of all patients presenting to four plasma exchange centres with presumed relapsed/refractory thrombotic thrombocytopenic purpura treated with rituximab.",
"title_normalized": "a phase ii sequential case series study of all patients presenting to four plasma exchange centres with presumed relapsed refractory thrombotic thrombocytopenic purpura treated with rituximab"
} | [
{
"companynumb": "CA-ROCHE-1567150",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "RITUXIMAB"
},
"drugadditional": null,
"druga... |
{
"abstract": "Warfarin is the most widely used oral anticoagulant and is indicated for many clinical conditions. Levofloxacin, a fluoroquinolone, is one of the most commonly prescribed antibiotics in clinical practice and is effective against Gram-positive, Gram-negative, and atypical bacteria. While small prospective studies have not revealed any significant drug-drug interaction between warfarin and levofloxacin, several case reports have indicated that levofloxacin may significantly potentiate the anticoagulation effect of warfarin. We report 3 cases of serious bleeding complications that appear to be the result of the interaction between warfarin and levofloxacin. Physicians should be aware of this potential interaction and use caution when prescribing levofloxacin to patients taking warfarin.",
"affiliations": "Department of Internal Medicine, Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614-0622, USA. ismail@etsu.edu",
"authors": "Vadlamudi|Raja S|RS|;Smalligan|Roger D|RD|;Ismail|Hassan M|HM|",
"chemical_list": "D000900:Anti-Bacterial Agents; D000925:Anticoagulants; D014859:Warfarin; D064704:Levofloxacin; D015242:Ofloxacin",
"country": "United States",
"delete": false,
"doi": "10.1097/SMJ.0b013e318073c7ee",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0038-4348",
"issue": "100(7)",
"journal": "Southern medical journal",
"keywords": null,
"medline_ta": "South Med J",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents; D000925:Anticoagulants; D004347:Drug Interactions; D005260:Female; D006470:Hemorrhage; D006801:Humans; D064704:Levofloxacin; D008297:Male; D015242:Ofloxacin; D010490:Pericardial Effusion; D012187:Retroperitoneal Space; D014859:Warfarin",
"nlm_unique_id": "0404522",
"other_id": null,
"pages": "720-4",
"pmc": null,
"pmid": "17639754",
"pubdate": "2007-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Interaction between warfarin and levofloxacin: case series.",
"title_normalized": "interaction between warfarin and levofloxacin case series"
} | [
{
"companynumb": "US-Glenmark Generics Europe Ltd.-GGEL20110800767",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "LEVOFLOXACIN"
},
"dru... |
{
"abstract": "BACKGROUND\nDrugs teratogenicity has been studied for many years, especially teratogenic effects of antiepileptic drugs, because of the important impact that epilepsy has always had for young women, but data from literature are often conflicting.\n\n\nMETHODS\nWe have carried out a critical review of all human studies about the antiepileptic drugs teratogenicity. A systematic search was performed in Medline and PubMed up to May 1, 2015. The use of older antiepileptic drugs in pregnancy is associated with an increased risk of fetus malformations; in particular, Valproate can determine neural-tube-like defects; in Phenytoin and Phenobarbital-exposed pregnancies, orofacial clefts, cardiac and genitourinary malformations are the major anomalies described. Spina bifida is the only specific major congenital malformation significantly associated with exposure to Carbamazepine monotherapy Despite the small number of studies on the teratogenic effects of new antiepileptic drugs, the analysis of the literature shows that exposure of the fetus to the new antiepileptic drugs is associated with a lower risk of major congenital malformations compared to the use of older drugs.\n\n\nCONCLUSIONS\nWhere possible, Valproate should be avoided in women of childbearing potential. Results about the safety of newer antiepileptic drugs require validation and further investigation.",
"affiliations": "a 1 University of Perugia, Department of Pediatrics , S. Andrea delle Fratte, Perugia, Italy , +39 07 55 78 44 15 ; alberto.verrottidipianella@unipg.it.;a 1 University of Perugia, Department of Pediatrics , S. Andrea delle Fratte, Perugia, Italy , +39 07 55 78 44 15 ; alberto.verrottidipianella@unipg.it.;a 1 University of Perugia, Department of Pediatrics , S. Andrea delle Fratte, Perugia, Italy , +39 07 55 78 44 15 ; alberto.verrottidipianella@unipg.it.;b 2 Unit of Neurology, Florence Health Authority, Department of Medicine , Florence, Italy.",
"authors": "Verrotti|Alberto|A|;Mencaroni|Elisabetta|E|;Castagnino|Miriam|M|;Zaccara|Gaetano|G|",
"chemical_list": "D000927:Anticonvulsants; D013723:Teratogens",
"country": "England",
"delete": false,
"doi": "10.1517/14740338.2015.1084288",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1474-0338",
"issue": "14(10)",
"journal": "Expert opinion on drug safety",
"keywords": "antiepileptic drugs; foetal malformations; neurodevelopmental disorders; teratogenicity",
"medline_ta": "Expert Opin Drug Saf",
"mesh_terms": "D000014:Abnormalities, Drug-Induced; D000818:Animals; D000927:Anticonvulsants; D004827:Epilepsy; D005260:Female; D006801:Humans; D011247:Pregnancy; D011248:Pregnancy Complications; D011297:Prenatal Exposure Delayed Effects; D013723:Teratogens",
"nlm_unique_id": "101163027",
"other_id": null,
"pages": "1563-71",
"pmc": null,
"pmid": "26329145",
"pubdate": "2015-10",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": null,
"title": "Foetal safety of old and new antiepileptic drugs.",
"title_normalized": "foetal safety of old and new antiepileptic drugs"
} | [
{
"companynumb": "IT-ALEMBIC PHARMACUETICALS LIMITED-2015SCAL000736",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "LAMOTRIGINE"
},
"dru... |
{
"abstract": "We describe a case of paediatric stroke secondary to atrial myxoma, diagnosed in the Emergency Department by Point-of-Care echocardiography. A previously fit and healthy teenage male presented to our paediatric emergency department following a collapse with loss of consciousness. He had suffered a stroke, and had facial paralysis and hemiplegia. His cardiac examination revealed a 3/6 ejection systolic murmur. Whilst his CT was being reported, he had a Point-of-Care echocardiogram in the resuscitation room which showed a very large mass arising from the left atrium and occupying >50% of the chamber. A piece of the myxoma had detached and caused the stroke. The patient was rapidly transferred to a cardiac intensive care unit and underwent emergency surgery the same day. His tumour was successfully completely resected, and he has only a mild residual hemiplegia. Cardiac myxoma should be considered in any child who presents with unexplained acute stroke and a cardiac murmur. Point-of-Care Ultrasound echocardiography in the Paediatric Emergency Department can be used to make a life-saving diagnosis, enabling early surgical management and preventing lifelong complications in children.",
"affiliations": "Department of Paediatric Emergency Medicine Children's Health Ireland at Temple Street Dublin Ireland.;Department of Paediatric Emergency Medicine Children's Health Ireland at Temple Street Dublin Ireland.;Department of Cardiology Children's Health Ireland at Crumlin Dublin Ireland.;Department of Cardiothoracic Surgery Children's Health Ireland at Crumlin Dublin Ireland.",
"authors": "Quinn|Nuala|N|https://orcid.org/0000-0002-7725-7678;Kalichuran|Rohan|R|;Prenderville|Terence|T|;McGuinness|Jonathan|J|",
"chemical_list": null,
"country": "Australia",
"delete": false,
"doi": "10.1002/ajum.12201",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1836-6864",
"issue": "23(1)",
"journal": "Australasian journal of ultrasound in medicine",
"keywords": "Point‐of‐Care Ultrasound; echocardiography; myxoma; paediatric stroke",
"medline_ta": "Australas J Ultrasound Med",
"mesh_terms": null,
"nlm_unique_id": "101583539",
"other_id": null,
"pages": "80-83",
"pmc": null,
"pmid": "34760587",
"pubdate": "2020-02",
"publication_types": "D002363:Case Reports",
"references": "24976098;15846157;8409267;25825532;25870340;30045317;24502581",
"title": "Point-of-Care Ultrasound echocardiography diagnosis of an atrial myxoma in a child presenting with stroke.",
"title_normalized": "point of care ultrasound echocardiography diagnosis of an atrial myxoma in a child presenting with stroke"
} | [
{
"companynumb": "IE-VALIDUS PHARMACEUTICALS LLC-IE-2020VAL000189",
"fulfillexpeditecriteria": "1",
"occurcountry": "IE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FUROSEMIDE"
},
"drugadd... |
{
"abstract": "Azathioprine is a commonly prescribed therapy for connective tissue disease-associated interstitial lung disease (CTD-ILD). Combination therapy that included azathioprine was recently shown to increase the risk of death and hospitalization in patients with idiopathic pulmonary fibrosis. Whether azathioprine increases the risk of adverse outcomes in patients with fibrotic CTD-ILD, including those with CTD-associated usual interstitial pneumonia (UIP), remains unknown.\n\n\n\nA retrospective cohort analysis was performed to determine the combined incidence rate of death, transplant and respiratory hospitalization associated with azathioprine exposure. A fibrotic CTD-ILD cohort treated with mycophenolate mofetil served as a comparator group. Incidence rates were compared with an incidence rate ratio (IRR) generated by negative binomial regression. Longitudinal pulmonary function response was then assessed using mixed effects linear regression models.\n\n\n\nFifty-four patients were treated with azathioprine and forty-three with mycophenolate. Medication discontinuation due to non-respiratory side effects occurred in 27% and 5% of the azathioprine and mycophenolate cohorts, respectively. The combined incidence rate of adverse outcomes was 0.015 and 0.013 for azathioprine and mycophenolate, respectively (IRR 1.23; 95% CI 0.49-3.12; p = 0.66). Similar incidence rates were observed among those with CTD-UIP (IRR 0.83; 95% CI 0.21-3.31; p = 0.79). Both groups demonstrated pulmonary function stability over time, with the azathioprine group demonstrating a marginal improvement.\n\n\n\nA significant minority of patients could not tolerate azathioprine due to non-respiratory side effects. Of those who did tolerate azathioprine, a similar incidence of adverse outcomes was observed as those treated with mycophenolate. Both therapies were associated with stability in pulmonary function.",
"affiliations": "Department of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, The University of California at Davis, United States. Electronic address: joldham@ucdavis.edu.;Department of Medicine, The University of Chicago, United States.;Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, The University of Pittsburgh, United States.;Department of Medicine, Section of Pulmonary and Critical Care Medicine, The University of Chicago, United States.;Department of Medicine, Section of Pulmonary and Critical Care Medicine, The University of Chicago, United States.;Department of Medicine, Section of Pulmonary and Critical Care Medicine, The University of Chicago, United States.;Department of Medicine, Section of Pulmonary and Critical Care Medicine, The University of Chicago, United States.;Department of Radiology, The University of Chicago, United States.;Department of Radiology, The University of Chicago, United States.;Department of Medicine, Section of Pulmonary and Critical Care Medicine, The University of Chicago, United States.;Department of Medicine, Section of Pulmonary and Critical Care Medicine, The University of Chicago, United States.;Department of Medicine, Section of Pulmonary and Critical Care Medicine, The University of Chicago, United States.",
"authors": "Oldham|Justin M|JM|;Lee|Cathryn|C|;Valenzi|Eleanor|E|;Witt|Leah J|LJ|;Adegunsoye|Ayodeji|A|;Hsu|Scully|S|;Chen|Lena|L|;Montner|Steven|S|;Chung|Jonathan H|JH|;Noth|Imre|I|;Vij|Rekha|R|;Strek|Mary E|ME|",
"chemical_list": "D007166:Immunosuppressive Agents; D009173:Mycophenolic Acid; D001379:Azathioprine",
"country": "England",
"delete": false,
"doi": "10.1016/j.rmed.2016.11.007",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0954-6111",
"issue": "121()",
"journal": "Respiratory medicine",
"keywords": "Connective tissue disease; Idiopathic pulmonary fibrosis; Interstitial lung disease; Mycophenolate mofetil; Rheumatology; Usual interstitial pneumonia",
"medline_ta": "Respir Med",
"mesh_terms": "D000328:Adult; D000368:Aged; D001379:Azathioprine; D003240:Connective Tissue Diseases; D018592:Cross-Over Studies; D005260:Female; D006760:Hospitalization; D006801:Humans; D007166:Immunosuppressive Agents; D017563:Lung Diseases, Interstitial; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid; D011653:Pulmonary Diffusing Capacity; D012042:Registries; D012189:Retrospective Studies; D014797:Vital Capacity",
"nlm_unique_id": "8908438",
"other_id": null,
"pages": "117-122",
"pmc": null,
"pmid": "27888985",
"pubdate": "2016-12",
"publication_types": "D016428:Journal Article",
"references": "18464307;16840379;23457378;11177318;8810621;19996193;15803924;22655194;12697731;25474431;21915609;17218621;20735863;22607134;24700149;24836309;17888219;22901890;15186274;21924888;16082627",
"title": "Azathioprine response in patients with fibrotic connective tissue disease-associated interstitial lung disease.",
"title_normalized": "azathioprine response in patients with fibrotic connective tissue disease associated interstitial lung disease"
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"abstract": "To show a surgical video in which an isolated hemidiaphragmatic tumor nodule was resected laparoscopically in a patient with isolated recurrence of endometrial cancer.\n\n\n\nCase report (Canadian Task Force Classification study design III).\n\n\n\nTertiary referral center in New Haven, CT.\n\n\n\nThis is a step-by-step illustration of tumor nodule resection from the right hemidiaphragm. The patient was a 55-year-old white woman who was diagnosed with stage IIIA endometrioid endometrial adenocarcinoma in June 2011 after surgical debulking. She received adjuvant carboplatin and paclitaxel and vaginal brachytherapy. She was disease free until March 2015 when she presented with right upper abdominal pain. A computed tomographic scan showed a 1-cm implant on the right hepatic dome. The implant was noted to be enlarged to 1.8 cm on a subsequent computed tomographic scan in August 2015. The patient was taken to the operating room for exploratory laparoscopy and resection of the hepatic dome/hemidiaphragmatic tumor nodule. The tumor nodule was noted to involve the full thickness of the right hemidiaphragm. The resection of the entire nodule required perforation of the diaphragm, which was reapproximated after the excision.\n\n\n\nThe procedure was performed without any complications. The patient had an uneventful postoperative course and was discharged home on postoperative day 1. Pathology revealed metastatic endometrioid endometrial adenocarcinoma with negative resection margins.\n\n\n\nLaparoscopic resection of the diaphragmatic tumor nodule and the reapproximation of the diaphragm were successfully performed in this patient with isolated disease recurrence. The laparoscopic approach should be considered for management of isolated recurrences in gynecologic cancers by experienced laparoscopic surgeons because it might otherwise be associated with significant morbidity and mortality [1-3].",
"affiliations": "Department of Obstetrics, Gynecology, and Reproductive Sciences, Section of Gynecologic Oncology, Yale University School of Medicine, New Haven, Connecticut. Electronic address: guldenmenderes@gmail.com.;Department of Obstetrics, Gynecology, and Reproductive Sciences, Section of Gynecologic Oncology, Yale University School of Medicine, New Haven, Connecticut.;Department of Obstetrics, Gynecology, and Reproductive Sciences, Section of Gynecologic Oncology, Yale University School of Medicine, New Haven, Connecticut.;Department of Obstetrics, Gynecology, and Reproductive Sciences, Section of Gynecologic Oncology, Yale University School of Medicine, New Haven, Connecticut.",
"authors": "Menderes|Gulden|G|;Schwab|Carlton|C|;Black|Jonathan|J|;Silasi|Dan-Arin|DA|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": null,
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"fulltext_license": null,
"issn_linking": "1553-4650",
"issue": "23(4)",
"journal": "Journal of minimally invasive gynecology",
"keywords": null,
"medline_ta": "J Minim Invasive Gynecol",
"mesh_terms": "D000230:Adenocarcinoma; D003964:Diaphragm; D016889:Endometrial Neoplasms; D005260:Female; D006801:Humans; D010535:Laparoscopy; D008875:Middle Aged; D019042:Muscle Neoplasms; D009364:Neoplasm Recurrence, Local; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "101235322",
"other_id": null,
"pages": "473-4",
"pmc": null,
"pmid": "26776674",
"pubdate": "2016",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D059040:Video-Audio Media",
"references": null,
"title": "Laparoscopic Resection of the Diaphragmatic Tumor Nodule for Management of Recurrent Endometrial Cancer.",
"title_normalized": "laparoscopic resection of the diaphragmatic tumor nodule for management of recurrent endometrial cancer"
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"abstract": "Background: Hypothermia is a potentially fatal adverse effect of antipsychotic drug (APD) use. With only 69 cases described in the literature, the condition is considered rare. Methods: We describe five new cases, in which we estimated the role of clozapine, haloperidol, olanzapine, penfluridol, risperidone, and zuclopentixol with the aid of two structured assessment tools. Results: In addition to APD use, all five patients described by us had been exposed to one or more additional predisposing factors for hypothermia. Therefore, with the aid of the assessment tools, the causal role of APDs was considered \"possible\" in four cases of moderate hypothermia and \"doubtful\" in the remaining one of mild hypothermia. Conclusion: Although the best way to detect APD-related hypothermia is measuring the body temperature for a duration of at least 7-10 days after the start (or a dose increase) of APDs, the use of assessment tools to identify additional predisposing factors for hypothermia and to thus establish their causal relationship with APD use would seem to be valuable for clinical decision-making (i.e., whether or not to discontinue APD use). Further research is needed to obtain reliable prevalence figures for APD-related hypothermia and its consequences, preferably in relation with physiological changes in body temperature.",
"affiliations": "Parnassia Academy, Parnassia Psychiatric Institute, The Hague, Netherlands.;Parnassia Academy, Parnassia Psychiatric Institute, The Hague, Netherlands.;Parnassia Academy, Parnassia Psychiatric Institute, The Hague, Netherlands.;Parnassia Academy, Parnassia Psychiatric Institute, The Hague, Netherlands.",
"authors": "Zonnenberg|Cherryl|C|;Bueno-de-Mesquita|Jolien M|JM|;Ramlal|Dharmindredew|D|;Blom|Jan Dirk|JD|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3389/fpsyt.2019.00543",
"fulltext": "\n==== Front\nFront PsychiatryFront PsychiatryFront. PsychiatryFrontiers in Psychiatry1664-0640Frontiers Media S.A. 10.3389/fpsyt.2019.00543PsychiatryCase ReportAntipsychotic-Related Hypothermia: Five New Cases Zonnenberg Cherryl \n1\nBueno-de-Mesquita Jolien M. \n1\nRamlal Dharmindredew \n1\nBlom Jan Dirk \n1\n\n2\n\n3\n\n*\n\n1Parnassia Academy, Parnassia Psychiatric Institute, The Hague, Netherlands\n2Faculty of Social Sciences, Leiden University, Leiden, Netherlands\n3Department of Psychiatry, University of Groningen, Groningen, NetherlandsEdited by: Paul Moser, Independent Researcher, Toulouse, France\n\nReviewed by: Anna Maria Szota, Nicolaus Copernicus University in Toruń, Poland; Yogaratnam Jegan, Consultant, Colombo, Sri Lanka\n\n*Correspondence: Jan Dirk Blom, jd.blom@parnassia.nl\nThis article was submitted to Psychopathology, a section of the journal Frontiers in Psychiatry\n\n29 7 2019 2019 10 54301 4 2019 12 7 2019 Copyright © 2019 Zonnenberg, Bueno-de-Mesquita, Ramlal and Blom2019Zonnenberg, Bueno-de-Mesquita, Ramlal and BlomThis is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.\nBackground: Hypothermia is a potentially fatal adverse effect of antipsychotic drug (APD) use. With only 69 cases described in the literature, the condition is considered rare.\n\n\nMethods: We describe five new cases, in which we estimated the role of clozapine, haloperidol, olanzapine, penfluridol, risperidone, and zuclopentixol with the aid of two structured assessment tools.\n\n\nResults: In addition to APD use, all five patients described by us had been exposed to one or more additional predisposing factors for hypothermia. Therefore, with the aid of the assessment tools, the causal role of APDs was considered “possible” in four cases of moderate hypothermia and “doubtful” in the remaining one of mild hypothermia.\n\n\nConclusion: Although the best way to detect APD-related hypothermia is measuring the body temperature for a duration of at least 7–10 days after the start (or a dose increase) of APDs, the use of assessment tools to identify additional predisposing factors for hypothermia and to thus establish their causal relationship with APD use would seem to be valuable for clinical decision-making (i.e., whether or not to discontinue APD use). Further research is needed to obtain reliable prevalence figures for APD-related hypothermia and its consequences, preferably in relation with physiological changes in body temperature.\n\nbody temperatureneurolepticpharmacotherapypsychosisschizophreniaside effectthermoregulation\n==== Body\nIntroduction\nFour homeless people died of exposure to cold in Portland, Oregon, during the first 10 days of 2017, after temperatures had unexpectedly dropped to −7°C (1). One of the victims was a 52-year-old woman diagnosed with schizophrenia who had lost her home a few months beforehand. She was found in a parking garage, mumbling and confused, and in the act of paradoxically undressing herself, a well-known symptom of lethal hypothermia (2). Paramedics were called to the scene, but nonetheless, the woman died within half an hour. Her fate resonated with the local community and drew attention to the need for care for the homeless. Although various obvious predisposing factors for hypothermia had been present (i.e., outdoor exposure to cold and inadequate clothing), an additional factor may well have been the use of antipsychotic drugs (APDs).\n\nAPD-related hypothermia was first described by Loughnane (3). Although its underlying pathophysiological mechanism is not entirely clear, peripheral vasodilatation and a failure of central thermoregulation seem to play a role (4). In spite of its potentially fatal consequences, APD-related hypothermia has received substantially less attention than its clinical counterpart, APD-related hyperthermia, which has been described extensively in the context of malignant antipsychotic syndrome (5). For the purpose of a prior systematic review, we found no more than 57 original case descriptions of APD-related hypothermia, published over a time span of 50 years (i.e., 1.1 cases per year; 6). From these cases, we inferred that the risk of APD-related hypothermia is highest during the week following the initiation—or a dose increase—of APDs, notably in combination with old age, exposure to cold, the adjuvant use of benzodiazepines, and/or (subclinical) hypothyroidism. On the basis of data from drug-monitoring agencies, we moreover inferred that the prevalence of APD-related hypothermia may well be 10 times higher than that suggested by the literature (6). The publication of seven additional papers over the past 2 years, collectively describing 12 new cases, indicates that awareness of this clinically relevant condition may finally be growing (7–13). To add to the burgeoning body of literature, we here describe five cases from our own clinical practice and highlight implications for clinical practice.\n\nMethods\nAll five patients presented here were under our treatment at Parnassia Psychiatric Institute (The Hague). Patients B and D provided written permission for publication of their cases. On behalf of patients A, C, and E, written permission was obtained from their respective family members, in accordance with Dutch national guidelines. In conformity with Sund-Levander et al. (14), we defined a normal body temperature for men (measured rectally) as 36.7–37.5°C and for women as 36.8–37.1°C. Following Khasawneh et al. (15), we defined hypothermia as a core body temperature of <35.0°C, mild hypothermia as 33–35°C, moderate hypothermia as 28–33°C, and severe hypothermia as <28°C (measured rectally). In all cases, a regular digital thermometer was used. To assess and quantify the causal role of APDs in the mediation of hypothermia, we used the Adverse Drug Reaction (ADR) Probability Scale (16). For calculating the mean number of predisposing factors for hypothermia, we used the methodology developed by Brevik and Farver (17).\n\nResults\nPresentation of Cases\nPatient A\nPatient A was a 74-year-old, unmarried Dutch man, who resided in the nursing home that is part of our psychiatric hospital. He had been diagnosed years ago with schizophrenia. His medication consisted of a zuclopentixol depot of 200 mg/week, vitamin D, acetylsalicylic acid, pantoprazole, and simvastatin. By the time we saw him, he was also using doxycycline because he was feeling ill and had slightly elevated infection parameters. The sedimentation rate was 48 mm/h (N 2–20 mm/h), and the C-reactive protein was 19 mg/l (N 0–8 mg/l). Nonetheless, a focus for the infection could not be found. Patient A presented with a body temperature of 32.5°C (measured rectally) at our outpatient department after his depot had been administered earlier that day. At the time of administration, it had been 36.8°C (measured aurically). The physical examination showed a bradycardia of 58 BPM but no other abnormalities. Patient A was diagnosed with moderate hypothermia, possibly due to the use of zuclopentixol. He was gradually rewarmed with warm blankets. His vital signs, which were being monitored, remained stable. After several hours, his body temperature normalized to 37.3°C. Although his hypothermia did not recur, the zuclopentixol depot was postponed and administered a week later. This time, the body temperature remained normal. However, during the subsequent 2 years, our patient had three more episodes of hypothermia (with temperatures of 34.6°C, measured aurically, and 33.4°C and 32.4°C, measured rectally, respectively, once while using zuclopentixol, once while using haloperidol). On all occasions, he recovered after gradual rewarming.\n\nPatient B\nPatient B was a 27-year-old, unmarried, homeless French man, who experienced psychotic symptoms, probably in the context of schizophrenia. His antipsychotic medication consisted of a weekly penfluridol depot of 20 mg. Although he did not use any additional medication, he did use heroin and cannabis. He was referred to our psychiatric hospital with a body temperature of 32.0°C (measured rectally) after the police had found him wandering the streets. He had made a confused impression and had told the police officers that he had been sleeping outdoors the night before. The outside temperature that day had ranged from 11.3 to 18.4°C (mean, 15.1°C). The physical examination revealed a bradycardia of 47 BPM. The ECG showed pointed T-tops (which were probably idiopathic or due to hypokalemia) and signs of possible left-ventricle hypertrophy. His urine tested positive for heroin and cannabis. Patient B was diagnosed with moderate hypothermia, probably due to outdoor exposure to cold and the use of penfluridol (as well as heroin and cannabis). He was gradually rewarmed, and his vital signs were being monitored. Within a few hours, his body temperature normalized to 35.6°C. The penfluridol was discontinued. Since patient B refused to use APDs any longer, a period of 18 months elapsed before he could be persuaded to switch to haloperidol 3 mg/day. After that, he experienced no more episodes of hypothermia.\n\nPatient C\nPatient C was a 77-year-old, unmarried Dutch woman, who lived in the same nursing home as patient A. She had been diagnosed with a schizoaffective disorder and was treated with haloperidol 0.5 mg twice a day and lorazepam 8.5 mg/day. She had a history of transient ischemic attacks, cerebrovascular accidents, immobility, and subclinical hypothyroidism. She presented with a body temperature of 33.4°C (measured rectally). Her behavior was unaltered, there were no signs of illness, and her intake of food and drinks was normal. On that summer’s day, the weather had been warm, sunny, and dry but chilly at night (with a mean night temperature of 16.3°C). The physical examination revealed no additional abnormalities. Blood tests showed only signs of her subclinical hypothyroidism. Patient C was diagnosed with mild hypothermia, possibly due to the use of haloperidol. She was put to bed with warm blankets. However, the following morning, her temperature dropped even further to 32.8°C. She was once again rewarmed with the aid of warm blankets. Her vital signs were monitored, and this time her body temperature stabilized within a few hours. The haloperidol was continued, and, from then onwards, her body temperature was monitored closely. Four months later, while still on haloperidol, she developed a moderate hypothermia of 32.3°C (measured rectally). After gradual rewarming, her body temperature normalized to 36.7°C. One month later, patient C died, probably due to circulatory insufficiency in the context of dehydration, developed during a state of lethal catatonia.\n\nPatient D\nPatient D was a 65-year-old, divorced Hindustani-Surinamese man, who had been admitted to our psychiatric hospital for 9 months because of a psychotic relapse. He had previously been diagnosed with schizophrenia and was being treated with a haloperidol depot. Owing to severe extrapyramidal side effects, the haloperidol was switched to clozapine 50 mg/day. As his psychotic symptoms remained unaltered and the clozapine plasma level was 0.33 mg/l (N 0.35–0.80 mg/l), the dose was increased to 62.5 mg/day. Five days later, he presented with a Glasgow Coma Score of 6 (N 15) and a body temperature of 33.2°C (measured rectally). The physical examination showed a dry, flaky skin, and reduced skin turgor; there were no other abnormalities. Patient D had suffered from hypothyroidism in the past, but his hormone levels had been adequately restored with the aid of levothyroxine 0.025 mg/day. He was diagnosed with mild hypothermia, possibly due to the use of clozapine, and referred to a somatic hospital. There, a clozapine intoxication was excluded, and he was gradually rewarmed until his body temperature and consciousness had normalized. The clozapine was discontinued. With his psychotic symptoms untreated, patient D was unable to return to his home. As a consequence, he was referred to the nursing home of our psychiatric hospital. Four months later, he was diagnosed with active neurolues (i.e., neurosyphilis or tertiary syphilis), for which he was treated with benzathine benzylpenicillin. Because his psychotic symptoms did not subside, olanzapine 2.5 mg/day was added. The hypothermia did not recur.\n\nPatient E\nPatient E was a 59-year-old, married Dutch woman, who had resided for several years in the long-stay department of our psychiatric hospital. She had been diagnosed with a schizoaffective disorder. Owing to prior therapy resistance, she was treated with a combination of clozapine, risperidone, and olanzapine. The dosage of the risperidone was 9 mg/day (the other dosages are unknown). In addition, she also used lorazepam 7.5 mg/day. Because of a manic-psychotic relapse, the dose of risperidone was increased to 12 mg/day. Ten days later, she presented with a body temperature of 34.0°C (measured rectally). Her behavior was uncontrollable, and she was continually undressing. Although her intake of food and drinks had been adequate, she also suffered from mild renal failure, with a serum creatinine of 166 μmol/l (N 50–95 μmol/l) and a renal clearance of 27 ml/min (N > 52 ml/min). Despite a thrombocyte count of 24 × 109/l (N 150–400 × 109/l), there were no clinical signs of coagulopathy. Patient E was diagnosed with mild hypothermia, probably due to her unusual combination of APDs (especially the recent dose increase in risperidon) and her recurring state of undress. She was gradually rewarmed with the aid of warm blankets and warm drinks, under strict monitoring of her vital signs. The following day, clozapine and olanzapine were discontinued. Because the hypothermia persisted, 4 days later, the dosage of the risperidone was lowered to 6 mg/day. Additionally, amoxicillin/clavulanic acid was started in a dosage of 625 mg twice a day because of increased infection parameters [leukocyte count 11.4 × 109/l (N 4.0–10.0 × 109/l), neutrophil count 10.49 × 109/l (N 1.5–7.5 × 109/l), C-reactive protein 130 mg/l (N 0–8 mg/l)] in the absence of any clinical signs of infection. On day 6, her temperature normalized to 36.4°C, and the thrombocyte count also normalized. The antipsychotic treatment was continued with a combination of olanzapine 10 mg and aripiprazole 10 mg/day. Although hypothermia did not recur, patient E died three and a half years later, due to renal insufficiency.\n\nSummary and Analysis of the Case Series\nAll five patients described by us had been exposed to APDs, as well as to one or more additional predisposing factors for hypothermia (\nTable 1\n). With the aid of the methodology developed by Brevik and Farver (17), we calculated that the mean number of these factors was 2.6 (range, 2–4). The most prevalent factors were advanced age (60%) and (subclinical) hypothyroidism (40%). As quantified in accordance with the Adverse Drug Reaction (ADR) Probability Scale (16), in one case, there was a doubtful, and in four cases, a possible adverse drug-related event (\nTable 2\n).\n\nTable 1 Degrees of hypothermia and analysis of predisposing factors.\n\nPatient\tMinimum body temperature (degree of hypothermia)\tType of antipsychotic\tNumber of additional predisposing factors (characterization)*\t\nA\t32.5°C (moderate)\tZuclopentixol\t2 (PAH, MD)\t\nB\t32.0°C (moderate)\tPenfluridol\t2 (PAH, M)\t\nC\t32.3°C (moderate)\tHaloperidol\t4 (PAH, CNS, MD, M)\t\nD\t33.2°C (moderate)\tClozapine\t2 (PAH, MD)\t\nE\t33.5°C (mild)\tRisperidone\nClozapine\nOlanzapine\t3 (PAH, M, O)\t\n\t\t\tMean: 2.6 (range 2–4)\t\n*PAH, Primary Accidental Hypothermia; CNS, Central Nervous System; MD, Metabolic Disorder; M, Medication; O, other.\n\nTable 2 Patient scores on the Naranjo Adverse Drug Reaction Probability Scale.\n\nPatient (sex, age)\tScore per episode of hypothermia*\tMedication\t\nA (M, 74 years)\t4\tZuclopentixol\t\nB (M, 27 years)\t0\tPenfluridol\t\nC (F, 77 years)\t4\tHaloperidol\t\nD (M, 65 years)\t3\tClozapine\t\nE (F, 59 years)\t3\n0\n0\tRisperidone\nClozapine\nOlanzapine\t\n*Scoring legend:\n\n>9 = definitive adverse drug reaction.\n\n5 to 8 = probable adverse drug reaction.\n\n1 to 4 = possible adverse drug reaction.\n\n0 = doubtful adverse drug reaction.\n\nDiscussion\nContrary to the woman in Portland, none of our five patients died—at least not during a phase of hypothermia. This may well be due to the fact that none of them had been exposed to freezing, but perhaps also to the fact that they had all been under regular care, and that even patient B, the homeless man who had slept outside, had been detected in time by the police and referred to our hospital. Since systematic studies are lacking, the actual prevalence of APD-related hypothermia is unknown, as is the proportion of fatal outcomes. With APD use ranging worldwide from 3.2/1,000 in Colombia to 78.2/1,000 in Taiwan (18), the impact of ensuing hypothermia on global health must be substantial. In the present case series, we describe hypothermia in the context of clozapine, haloperidol, olanzapine, penfluridol, risperidone, and zuclopentixol use. A recent review by our group showed that APD-related hypothermia had been described before in the context of haloperidol (13 cases), clozapine (3 cases), risperidone (10 cases), and olanzapine (13 cases) use (6). As far as we know, there are no earlier publications of this type on penfluridol and zuclopentixol. Given the fact that undertreatment of psychosis has its own adverse effects on mental and physical health, quality of life, and mortality (19), the solution would not seem to lie in withholding psychotic patients from treatment with APDs, but rather in proper monitoring of the body temperature. This should be done for a duration of at least 7–10 days after starting with an APD or a dose increase (6), although some authors argue that several weeks would be even better, since hypothermia has also been described after two or more weeks (20, 21). That said, our case series indicates that even in the absence of any dose alterations, APD use may be a risk factor for hypothermia. This finding is all the more pressing, since individuals with psychosis are at risk for hypothermia anyway due to a lower mean baseline temperature and—if present—poverty and/or homelessness, which have also been established as risk factors (22–25). Although treatment of hypothermia is relatively easy and cheap (26), prevention would seem to be the solution worth striving for. If it has already set in, the goal must be early detection and treatment, preferably aided by an assessment of the causal role of APDs.\n\nThe body temperature should preferably be measured with the aid of a hypothermia thermometer. When frequent monitoring is not feasible, the method developed by Brevik and Farver (17) may be helpful to identify patients with an elevated risk of APD-related hypothermia. This method allows for a quick inventory of predisposing factors and a global impression of the severity of the ensuing risk. Still, the decision whether to continue or discontinue an APD may prove difficult. In clinical practice, this needs to be assessed in the light of the severity of the psychotic symptoms that might recur. Usually, cases of APD-related hypothermia tend to resolve—after proper monitoring and treatment—within 24–48 h. After that, only few patients tend to experience another episode of hypothermia, even after continuing the original APD or switching to another type (6). To facilitate the decision-making process, a structured assessment tool such as the ADR Probability Scale (16) may be of use, which gives an estimate of the causal role of APDs in the presence of other predisposing factors for hypothermia. If APD use was the only predisposing factor, and the causal role “possible,” “probable,” or “definitive” (\nTable 2\n), we recommend to stop or lower the dose during rewarming. If this is not possible, we advise to continue the APD under strict monitoring of the temperature and other vital functions. Finally, we recommend to review the APD treatment regimen an sich (e.g., proper dosage and—if possible—monotherapy). As may have been the case with our patient E, polypharmacy may add to the risk of APD-related hypothermia. After normalization of the temperature, there would seem to be no strict contraindications for reintroducing the same APD, even in its initial dose, as long as proper attention for additional predisposing factors for hypothermia is guaranteed (6).\n\nConclusions\nWith the five new cases of APD-related hypothermia here described, we add to the burgeoning literature on this underreported and still poorly understood side effect. Moreover, as far as we know, this is the first description of hypothermia in the context of penfluridol and zuclopentixol. To prevent severe APD-related hypothermia and detect it at an early stage, we recommend to measure the body temperature for a duration of 7–10 days after starting—or increasing the dose of—APDs. When this is not possible, we recommend to estimate the risk of hypothermia while also considering the role of additional predisposing factors. In cases of established hypothermia, we recommend to estimate the causal role of APDs with the aid of a structured assessment tool, such as the Naranjo Adverse Drug Reaction Probability Scale, and use the outcome to guide clinical decision-making (i.e., whether to continue or discontinue this specific APD).\n\nLimitations\nOur knowledge of APD-related hypothermia is still limited, as is our knowledge of the prevalence of idiopathic hypothermia in the general population. As a consequence, a reliable estimation of the relative risk of hypothermia due to APD use is hard to make.\n\nData Availability\nAll datasets generated for this study are included in the manuscript and the supplementary files.\n\nEthics Statement\nThe study was exempt from testing by a medical ethical committee. All five patients presented here were under our treatment at Parnassia Psychiatric Institute (The Hague). Patients B and D provided written permission for publication of their cases. On behalf of patients A, C, and E, written permission was obtained from their respective family members.\n\nAuthor contributions\nCZ contributed to the conception and design of the work, and to the acquisition, analysis, and interpretation of data for the work, drafted and revised the work, gave final approval for the final version to be published, and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. JB-d-M contributed to the conception and design of the work, and to the acquisition, analysis, and interpretation of data for the work, revised the work, gave final approval for the final version to be published, and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. DR contributed to the interpretation of data for the work, revised the work, gave final approval for the final version to be published, and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. JDB contributed to the conception and design of the work, and to the analysis, and interpretation of data for the work, drafted and revised the work, gave final approval for the final version to be published, and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.\n\nConflict of Interest Statement\nThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n\n\nAcknowledgments\nThe authors thank Dr. Sandra van Staveren and Dr. Henk Kruithof for bringing to their attention one of the cases described above.\n==== Refs\nReferences\n1 \nWilson J \nThe death of Karen Batts: the homelessness case that shocked Portland. The Guardian (2017 ). https://www.theguardian.com/society/2017/feb/17/karen-batts-homelessness-death-portland-oregon Retrieved on January 20, 2019 .\n2 \nRothschild MA \nLethal hypothermia: paradoxical undressing and hide-and-die syndrome can produce obscure death scene . Forensic Pathol Rev (2004 ) 1 :263–72. 10.1007/978-1-59259-786-4_11 \n\n3 \nLoughnane T \nHypothermia in a young adult . Lancet (1968 ) 292 :455–56. 10.1016/S0140-6736(68)90491-1 \n\n4 Bueno de Mesquita J Balk FJE \nOlanzapine, hypothermie en winterse vrieskou . Psyfar (2013 ) 2 :27 –31 .\n5 \nTse L Barr AM Scarapicchia V Vila-Rodrigues F \nNeuroleptic malignant syndrome: a review from a clinically oriented perspective . Curr Neuropharmacol (2015 ) 13 :395 –406 . 10.2174/1570159X13999150424113345 \n26411967 \n6 \nZonnenberg C Bueno de Mesquita JM Ramlal D Blom JD \nHypothermia due to antipsychotic medication: a systematic review . Front Psychiatry (2017 ) 8 :165 . 10.3389/fpsyt.2017.00165 \n28936184 \n7 \nAjayi OO Holroyd S \nSevere recurrent hypothermia in an elderly patient with refractory mania associated with atypical antipsychotic, valproic acid and oxcarbazepine therapy . BMJ Case Rep (2017 ) bcr2017222462. 10.1136/bcr-2017-222462 \n\n8 \nChen TR Chen YC Ouyang WC \nZotepine-associated hypothermia in a schizophrenic patient . J Clin Psychopharmacol (2017 ) 37 :367–8. 10.1097/JCP.0000000000000686 \n\n9 \nDekkers BGJ Eck RJ Maaten JC Touw DJ \nAn acute oral intoxication with haloperidol decanoate . Am J Emerg Med (2017 ) 35 :1387 e1–1387.e2. 10.1016/j.ajem.2017.07.013 \n\n10 \nKäräjämäki A Lauri T Ebeling T \nAntipsychotic drug-induced hypoglycemia and hypothermia . Duodecim (2017 ) 133 :301–4.\n11 \nScherl TA Langguth B Kreuzer PM \nHypothermia associated with antipsychotic medication: a clinical surveillance study . J Clin Psychopharmacol (2017 ) 37 :751–3. 10.1097/JCP.0000000000000795 \n\n12 \nSzota AM Araszkiewicz AS \nThe risk factors, frequency and diagnosis of atypical drug-induced hypothermia: practical advice for doctors . Int Clin Psychopharmacol (2019 ) 34 :1 –8 . 10.1097/YIC.0000000000000244 \n30398998 \n13 \nKozian R Schmid G Demian S \nHypothermie unter der Gabe von Aripiprazol . Psychiatr Prax (2019 ) 46 :49 –51 . 10.1055/a-0671-6803 \n30149396 \n14 \nSund-Levander M Forsberg C Wahren LK \nNormal oral, rectal, tympanic and axillary body temperature in adult men and women: a systematic literature review . Scand J Caring Sci (2002 ) 16 :122–8. 10.1046/j.1471-6712.2002.00069.x \n\n15 \nKhasawneh FA Thomas A Thomas S \nAccidental hypothermia . Hospital Physician (2016 ) 12 :16 –21 .\n16 \nNaranjo CA Busto U Sellers EM Sandor P Ruiz I Roberts EA \nA method for estimating the probability of adverse drug reactions . Clin Pharmacol Ther (1981 ) 30 :239–45. 10.1038/clpt.1981.154 \n\n17 \nBrevik A Farver D \nAtypical antipsychotic induced mild hypothermia . S D J Med (2003 ) 56 :67 –70 .12621956 \n18 \nHálfdánarson Ó Zoëga H Aagaard L Bernardo M Brandt L Fusté AC \nInternational trends in antipsychotic use: a study in 16 countries, 2005–2014 . Eur Neuropsychopharmacol (2017 ) 27 :1064–76. 10.1016/j.euroneuro.2017.07.001 \n\n19 \nSharifi V Eaton WW Wu LT Roth KB Burchett BM Mojtabai R \nPsychotic experiences and risk of death in the general population: 24–27 year follow-up of the Epidemiologic Catchment Area Study . Br J Psychiatry (2015 ) 207 :30–6. 10.1192/bjp.bp.113.143198 \n\n20 \nBrandon Bookstaver P Miller AD \nPossible long-acting risperidone-induced hypothermia precipitating phenytoin toxicity in an elderly patient . J Clin Pharm Ther (2011 ) 36 :426–42. 10.1111/j.1365-2710.2010.01189.x \n\n21 \nKreuzer P Landgrebe M Wittmann M Schecklmann M Poppl TB Hajak G \nHypothermia associated with antipsychotic drug use: a clinical case series and review of current literature . J Clin Psychopharmacol (2011 ) 52 :1090–7. 10.1177/0091270011409233 \n\n22 \nIrvine RE \nHypothermia in old age . Practitioner (1974 ) 213 :795 –800 .4156586 \n23 \nShiloh R Hermesh H Weizer N Dorfman-Etrog P Weizman A Munitz H \nAcute antipsychotic drug administration lowers body temperature in drug-free male schizophrenic patients . Eur Neuropsychopharmacol (2000 ) 10 :443–5. 10.1016/S0924-977X(00)00106-1 \n\n24 \nChong TWH Castle DJ \nLayer upon layer: thermoregulation in schizophrenia . Schizophr Res (2004 ) 69 :149–57. 10.1016/S0920-9964(03)00222-6 \n\n25 \nKudoh A Takase H Takazawa T \nChronic treatment with antipsychotics enhances intraoperative core hypothermia . Anesth Analg (2004 ) 98 :111–5. 10.1213/01.ANE.0000093313.16711.5E \n\n26 \nAslam AF Aslam AK Vasavada BC Khan IA \nHypothermia: evaluation, electrocardiographic manifestations, and management . Am J Med (2006 ) 119 :297 –301 . 10.1016/j.amjmed.2005.09.062 \n16564768\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1664-0640",
"issue": "10()",
"journal": "Frontiers in psychiatry",
"keywords": "body temperature; neuroleptic; pharmacotherapy; psychosis; schizophrenia; side effect; thermoregulation",
"medline_ta": "Front Psychiatry",
"mesh_terms": null,
"nlm_unique_id": "101545006",
"other_id": null,
"pages": "543",
"pmc": null,
"pmid": "31417438",
"pubdate": "2019",
"publication_types": "D002363:Case Reports",
"references": "11115733;12000664;12621956;14693598;15469188;16564768;21545623;21956608;25953893;26411967;28277401;28705742;28755801;28936184;29045305;29197846;30149396;30398998;4156586;4174175;7249508",
"title": "Antipsychotic-Related Hypothermia: Five New Cases.",
"title_normalized": "antipsychotic related hypothermia five new cases"
} | [
{
"companynumb": "NL-ACCORD-153050",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CLOZAPINE"
},
"drugadditional": "1",
"drugad... |
{
"abstract": "An 18-year-old woman had an etonogestrel implant inserted into her left upper arm 2 years earlier for menorrhagia. Her symptoms were not well controlled and she requested the implant to be removed. However, clinicians were unable to locate the implant on her left arm. Computed tomography showed that the implant had migrated to a sub-lobar branch of the left lower lobe pulmonary artery. The long-term effect of leaving an etonogestrel implant in the pulmonary arterial system is unknown. This report adds to the small body of evidence on intravascular migration of a subdermally placed contraceptive implant.",
"affiliations": "1 Department of Cardiothoracic Surgery, Queen Elizabeth Hospital, Birmingham, UK.;2 Department of Thoracic Surgery, Birmingham Heartlands Hospital, Birmingham, UK.;3 Department of Radiology, Birmingham Heartlands Hospital, Birmingham, UK.;2 Department of Thoracic Surgery, Birmingham Heartlands Hospital, Birmingham, UK.",
"authors": "Kew|Ee Phui|EP|;Senanayake|Eshan|E|;Djearaman|Madava|M|;Bishay|Ehab|E|",
"chemical_list": "D003271:Contraceptive Agents, Female; D004343:Drug Implants; C044815:etonogestrel; D017135:Desogestrel",
"country": "England",
"delete": false,
"doi": "10.1177/0218492317716589",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0218-4923",
"issue": "25(7-8)",
"journal": "Asian cardiovascular & thoracic annals",
"keywords": "Contraceptive agents; Drug implants; Etonogestrel; Foreign-body migration; Pulmonary artery; Pulmonary embolism; female",
"medline_ta": "Asian Cardiovasc Thorac Ann",
"mesh_terms": "D000293:Adolescent; D000072226:Computed Tomography Angiography; D003271:Contraceptive Agents, Female; D017135:Desogestrel; D004343:Drug Implants; D005548:Foreign-Body Migration; D006801:Humans; D008297:Male; D011651:Pulmonary Artery; D034941:Upper Extremity; D057832:Watchful Waiting",
"nlm_unique_id": "9503417",
"other_id": null,
"pages": "537-539",
"pmc": null,
"pmid": "28605952",
"pubdate": "2017",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Migration of contraceptive implant into the left pulmonary arterial system.",
"title_normalized": "migration of contraceptive implant into the left pulmonary arterial system"
} | [
{
"companynumb": "GB-009507513-1711GBR004367",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "ETONOGESTREL"
},
"drugadditional": null,
... |
{
"abstract": "There are few reports about the rapid appearance of anti-adalimumab antibodies in patients with Crohn's disease positive for anti-infliximab antibodies. We report the case of a 29-year-old female patient with a diagnosis of Crohn's disease who revealed a loss of response to infliximab due to high levels of antibodies to infliximab, and did not respond to the subsequent therapy by adalimumab, with a rapid appearance of antibodies to adalimumab. As one of the possible mechanisms of non-response to adalimumab, immunologic reactivity of infliximab to adalimumab was suspected, since the patient's IgG that was obtained just before the induction of adalimumab reacted with infliximab and adalimumab. We should pay attention to the easy appearance of anti-adalimumab antibodies in association with reactivity of anti-infliximab antibodies to adalimumab in patients with high levels of anti-infliximab antibodies.",
"affiliations": "Department of Medicine, Shiga University of Medical Science, Seta Tsukinowa, Otsu, 520-2192, Japan.",
"authors": "Takahashi|Kenichiro|K|;Fujimoto|Takehide|T|;Shioya|Makoto|M|;Nishida|Atsushi|A|;Bamba|Shigeki|S|;Inatomi|Osamu|O|;Imaeda|Hirotsugu|H|;Kitoh|Katsuyuki|K|;Andoh|Akira|A|",
"chemical_list": "D005765:Gastrointestinal Agents; D007074:Immunoglobulin G; D000069285:Infliximab; D000068879:Adalimumab",
"country": "Japan",
"delete": false,
"doi": "10.1007/s12328-015-0558-y",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1865-7265",
"issue": "8(2)",
"journal": "Clinical journal of gastroenterology",
"keywords": null,
"medline_ta": "Clin J Gastroenterol",
"mesh_terms": "D000068879:Adalimumab; D000328:Adult; D003424:Crohn Disease; D005260:Female; D005765:Gastrointestinal Agents; D006801:Humans; D007074:Immunoglobulin G; D000069285:Infliximab",
"nlm_unique_id": "101477246",
"other_id": null,
"pages": "88-91",
"pmc": null,
"pmid": "25795267",
"pubdate": "2015-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": "22443153;17301106;25069030;21486979;17229796;23575576;19235918;18691349;19581278;22261535;23666424;17470824;15224278;22062358;21427713;21953314;19664627;24913041",
"title": "A case of Crohn's disease that developed anti-infliximab and anti-adalimumab antibodies.",
"title_normalized": "a case of crohn s disease that developed anti infliximab and anti adalimumab antibodies"
} | [
{
"companynumb": "JP-JNJFOC-20150516913",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "BACILLUS SUBTILIS\\LACTOBACILLUS ACIDOPHILUS\\STREPTOCOCCUS FAECAIS"... |
{
"abstract": "Sleep-related eating disorder (SRED) is classified as an NREM-related parasomnia characterized by recurrent episodes of dysfunctional eating that occur after an arousal from the main sleep period with partial or complete amnesia for the event, resulting in weight gain from eating high calorie foods and causing various injuries due to consumption of inedible or toxic items. SRED can be idiopathic or commonly associated with other primary sleep disorders such as sleepwalking, restless legs syndrome (RLS), obstructive sleep apnea syndrome (OSAS), other clinical conditions, or use of sedative-hypnotic medications. First-line treatment of idiopathic SRED includes selective serotonin reuptake inhibitors (SSRIs) at mean dosages of 20 to 30 mg/day. Topiramate at 100-300 mg/day and clonazepam at 0.5-2.0 mg/day can be valid alternative options. SRED related to other parasomnias or sleep disturbances that cause sleep fragmentation benefit most from treatment of the associated sleep disorder. In particular, RLS-related SRED is best treated with dopamine agonists such as pramipexole, while sleepwalking-related SRED benefits from low-dose benzodiazepines such as clonazepam. Different kinds of drug associations have been proposed in a limited number of cases, especially in the past. We strongly recommend that all patients suffering from SRED should undergo consistent and regular follow-up about 2-3 times per year or otherwise according to the physician's judgment, in order to assess the evolution of symptom severity and frequency and re-evaluate treatment efficacy and any side effects that may arise.",
"affiliations": "Department of Biomedical and Neuromotor Sciences, University of Bologna, Bellaria Hospital, Via Altura, 3, 40139, Bologna, Italy, giacomo.chiaro@studio.unibo.it.",
"authors": "Chiaro|Giacomo|G|;Caletti|Maria Turchese|MT|;Provini|Federica|F|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1007/s11940-015-0361-6",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1092-8480",
"issue": "17(8)",
"journal": "Current treatment options in neurology",
"keywords": null,
"medline_ta": "Curr Treat Options Neurol",
"mesh_terms": null,
"nlm_unique_id": "9815940",
"other_id": null,
"pages": "361",
"pmc": null,
"pmid": "26037737",
"pubdate": "2015-08",
"publication_types": "D016428:Journal Article",
"references": "25495278;15885046;22481958;23436890;17876738;15746509;23205019;16895263;10947025;8032349;7973318;15955122;12702899;24424097;21056212;14388031;18819825;17196052;22841035;25110909;12143918;25203463;21677903;8104356;15003084;24394729;19199358;20877520;1759095;19744399;14592329;20492858;19961034;15536205;9491060;19378289",
"title": "Treatment of sleep-related eating disorder.",
"title_normalized": "treatment of sleep related eating disorder"
} | [
{
"companynumb": "CL-CIPLA LTD.-2015CL06689",
"fulfillexpeditecriteria": "1",
"occurcountry": "CL",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TOPIRAMATE"
},
"drugadditional": null,
... |
{
"abstract": "We evaluated the acute complications that occurred during the treatment of childhood acute lymphoblastic leukemia (ALL) and documented the survival rates of children with ALL.\n\n\n\nWe retrospectively evaluated 110 children with a diagnosis of ALL treated with the Children's Oncology Group protocol from 1999 to 2014. The demographic, clinical, and laboratory data of 110 patients and acute complications of eligible and evaluable 105 patients were recorded.\n\n\n\nOf the 110 patients, 65 were male and 45 were female. The mean age at admission was 8.3 ± 5.2 years. Ninety-seven patients (88.2%) had been diagnosed with pre-B-cell ALL, 11 (10%) with T-cell ALL, 1 (0.9%) with mixed phenotype acute leukemia, and 1 (0.9%) with mature B-cell acute leukemia. Of the 110 patients, 40 (36.3%) were in the standard-risk group and 70 (63.7%) were in high-risk group. Of the 110 patients, 105 had been followed up regularly and evaluated for acute complications. Infection was the most common complication (n = 93; 88.5%), followed by gastrointestinal (n = 29; 27.6%), neurologic (n = 28; 26.6%), metabolic/endocrine (n = 16; 15.2%), drug-related hypersensitivity (n = 16; 15.2%), avascular necrosis (n = 13; 12.3%), thrombotic (n = 11; 10.4%), severe psychiatric (n = 2; 1.9%), and various other (n = 12; 11.4%) complications. Of the 110 patients, 98 were assessed in terms of survival analysis. The 5- and 10-year overall survival rates were both 85.9% (standard error [SE], 3.6%). The relapse-free survival rates at 1, 3, and 5 years were 97.9% (SE, 1.5%), 91.3% (SE, 3%), and 86.3% (SE, 3.7%), respectively.\n\n\n\nChildhood ALL, although categorized as curable malignancy owing to the improvements in treatment strategies in recent years, can cause acute complications affecting various systems. Thus, patients should be treated and followed up by multidisciplinary medical teams with high expertise.",
"affiliations": "Department of Pediatrics, Istanbul University, Cerrahpasa Faculty of Medicine, Istanbul, Turkey. Electronic address: pozturk@hotmail.com.;Department of Pediatric Hematology-Oncology, Istanbul University Oncology Institute, Istanbul, Turkey.;Department of Pediatric Hematology-Oncology, Istanbul University Oncology Institute, Istanbul, Turkey.",
"authors": "Öztürk|Ayşe Pınar|AP|;Koç|Başak|B|;Zülfikar|Bülent|B|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.clml.2020.08.025",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2152-2669",
"issue": "21(1)",
"journal": "Clinical lymphoma, myeloma & leukemia",
"keywords": "Acute leukemia; Childhood; Complications; Relapse; Survival",
"medline_ta": "Clin Lymphoma Myeloma Leuk",
"mesh_terms": null,
"nlm_unique_id": "101525386",
"other_id": null,
"pages": "e39-e47",
"pmc": null,
"pmid": "33046422",
"pubdate": "2021-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Acute Complications and Survival Analysis of Childhood Acute Lymphoblastic Leukemia: A 15-year Experience.",
"title_normalized": "acute complications and survival analysis of childhood acute lymphoblastic leukemia a 15 year experience"
} | [
{
"companynumb": "TR-PFIZER INC-2021415405",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CYTARABINE"
},
"drugadditional": null,
... |
{
"abstract": "A 75-year old man with long-term arterial hypertension was diagnosed in 1998 with stage 3 chronic kidney disease due to hypertensive nephropathy. Since May 2004 the patient has been treated with intermittent hemodialysis. Since 1998 he has been hospitalized several times because of palpitations in the course of paroxysmal tachycardia with narrow QRS complexes. Initially, class I antiarrhythmic agents were administered; afterwards therapy with beta-adrenolytics was introduced. Because of the ineffectiveness of monotherapy, beta-adrenolytic therapy was combined with amiodarone; however, side effects of this treatment in a form of drug-induced bradycardia appeared. During an invasive electrophysiological investigation, a typical recurrent atrioventricular nodal reentrant tachycardia (AVNRT) was repeatedly released. Subsequently performed percutaneous ablation resulted in effective modification of the slow pathway. During 25 months of follow up after the procedure, recurrence of AVNRT was not observed. Effectiveness of ablation and low risk of adverse effects in non-dialyzed patients encourage us to recommend this method of AVNRT treatment also in patients undergoing intermittent hemodialysis.",
"affiliations": "International Dialysis Center, Rawicz, Poland.",
"authors": "Ratajewska|Aniela M|AM|;Banachowicz|Wojciech W|WW|;Grzegorzewska|Alicja E|AE|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1007/s11255-007-9302-y",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0301-1623",
"issue": "41(1)",
"journal": "International urology and nephrology",
"keywords": null,
"medline_ta": "Int Urol Nephrol",
"mesh_terms": "D000368:Aged; D017115:Catheter Ablation; D006801:Humans; D008297:Male; D012008:Recurrence; D006435:Renal Dialysis; D013611:Tachycardia, Atrioventricular Nodal Reentry",
"nlm_unique_id": "0262521",
"other_id": null,
"pages": "225-30",
"pmc": null,
"pmid": "18196470",
"pubdate": "2009",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "1721982;9679723;7697935;8269323;11025889;9445172;8222125;1378134;10437369;9474665;10695459",
"title": "Recurrent atrioventricular nodal re-entrant tachycardia treated with percutaneous ablation in a 75-year old patient undergoing intermittent hemodialysis.",
"title_normalized": "recurrent atrioventricular nodal re entrant tachycardia treated with percutaneous ablation in a 75 year old patient undergoing intermittent hemodialysis"
} | [
{
"companynumb": "PL-PFIZER INC-2017516721",
"fulfillexpeditecriteria": "1",
"occurcountry": "PL",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ERYTHROPOIETIN"
},
"drugadditional": null,
... |
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