article dict | reports listlengths 1 3.97k |
|---|---|
{
"abstract": "The effectiveness and safety of dabigatran for stroke prevention in atrial fibrillation (SPAF) demonstrated in RE-LY needs to be confirmed in daily care. To evaluate treatment persistence, effectiveness and safety of dabigatran therapy in SPAF patients in daily care, we used data from an ongoing, prospective, non-interventional registry of more than 2,500 patients on novel oral anticoagulants in daily care. Between October 1, 2011 and February 28, 2013, a total of 341 SPAF patients receiving dabigatran were enrolled. The combined endpoint of stroke/transient ischaemic attack/systemic embolism occurred at a rate of 2.93/100 patient-years in the intention-to-treat analysis (95%-CI 1.6-4.9) and at 1.9/100 patient-years in the on treatment analysis (events within three days after last intake). On-treatment rates were higher in patients selected for 110 mg dabigatran (n=183) BID compared to the 158 patients selected for 150 mg BID (2.88 [95% CI 1.16- 5.93] vs 0.86/100 patient-years [95% CI 0.10, 3.12]). On treatment, major bleeding occurred at a rate of 2.3/100 patient-years and numerically more often in patients receiving the 110 mg BID dose compared to the 150 mg BID dose (2.9 vs 1.7/100 patient-years). Dabigatran treatment discontinuation occurred in a total of 124 patients during follow-up (25.8 per 100 patient-years in Kaplan Meier analysis). Main reasons for treatment discontinuation were non-bleeding side effects. Our data contribute to the confirmation of effectiveness and relative safety of dabigatran in unselected patients in daily care. However, discontinuation rates are not lower than those reported for patients treated with vitamin K antagonists.",
"affiliations": "Jan Beyer-Westendorf, MD, Center for Vascular Medicine, University Hospital \"Carl Gustav Carus\", Technical University Dresden, Fetscherstrasse 74; 01307 Dresden, Germany, Tel.: +49 351 4583659; Fax +49 531 4584359, E-mail: jan.beyer@uniklinikum-dresden.de.",
"authors": "Beyer-Westendorf|Jan|J|;Ebertz|Franziska|F|;Förster|Kait|K|;Gelbricht|Vera|V|;Michalski|Franziska|F|;Köhler|Christina|C|;Werth|Sebastian|S|;Endig|Heike|H|;Pannach|Sven|S|;Tittl|Luise|L|;Sahin|Kurtulus|K|;Daschkow|Katharina|K|;Weiss|Norbert|N|",
"chemical_list": "D000991:Antithrombins; D000069604:Dabigatran",
"country": "Germany",
"delete": false,
"doi": "10.1160/TH14-11-0954",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0340-6245",
"issue": "113(6)",
"journal": "Thrombosis and haemostasis",
"keywords": "Anticoagulation; atrial fibrillation; bleeding; dabigatran",
"medline_ta": "Thromb Haemost",
"mesh_terms": "D000284:Administration, Oral; D000368:Aged; D000369:Aged, 80 and over; D000991:Antithrombins; D001281:Atrial Fibrillation; D000069604:Dabigatran; D004334:Drug Administration Schedule; D004617:Embolism; D005260:Female; D005858:Germany; D006470:Hemorrhage; D006801:Humans; D057194:Intention to Treat Analysis; D002546:Ischemic Attack, Transient; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D012042:Registries; D018570:Risk Assessment; D012307:Risk Factors; D020521:Stroke; D013997:Time Factors; D016896:Treatment Outcome",
"nlm_unique_id": "7608063",
"other_id": null,
"pages": "1247-57",
"pmc": null,
"pmid": "25739533",
"pubdate": "2015-06",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Effectiveness and safety of dabigatran therapy in daily-care patients with atrial fibrillation. Results from the Dresden NOAC Registry.",
"title_normalized": "effectiveness and safety of dabigatran therapy in daily care patients with atrial fibrillation results from the dresden noac registry"
} | [
{
"companynumb": "DE-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2015-BI-13934GD",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "DABIGATRAN ETEXILATE MESYLATE"
... |
{
"abstract": "BACKGROUND\nWe describe the feasibility and safety of an oral administration schedule of hydration, alkalinization and leucovorin rescue with an ambulatory high-dose methotrexate regimen.\n\n\nMETHODS\nSingle-centre prospective observational study conducted within a tertiary hospital where all patients have received systemic high-dose methotrexate (3.5 g/m2). Patients were instructed to keep an adequate ambulatory oral hydration and alkalinization to monitor urine pH and to adjust bicarbonate according to our institution's treatment protocol. High-dose methotrexate was infused over 4 h. Urine pH was checked before high-dose methotrexate administration, and for any value less than 7 a sodium bicarbonate bolus was given. Leucovorin at a standard dose was begun 24 h after high-dose methotrexate. methotrexate serum concentrations were monitored daily from 24 h after administration until clearance (level ≤ 0.1 µmol/L).\n\n\nRESULTS\nFrom January 2016 to June 2018, 49 ambulatory high-dose methotrexate courses were given to 18 patients. No dose reduction was required afterwards. All patients completed succesfully the planned three doses in an outpatient basis, except four patients, one of them due to pneumonitis. Previous to methotrexate infusion, urinary pH > 7 was achieved in 35 (79.5%) cycles. Methotrexate clearance was achieved by 72 h in 35 courses (71.4%), and by 96 h in 100%. Neutropenia/trombocytopenia grades III/IV were observed in four cycles (8.16%) and two (4.08%) cycles, respectively. Around 20.40% were associated with stomatitis, 14.20% vomiting, 10.20% asthenia, 8.16% diarrhea and 6.12% with renal toxicity.\n\n\nCONCLUSIONS\nAmbulatory administration of high-dose methotrexate as CNS prophylaxis is safe and feasible following the described approach, allowing us to optimize healthcare resources.",
"affiliations": "Hospital de Cabuenes, Asturias, Spain.;Hospital de Cabuenes, Asturias, Spain.;Hospital de Cabuenes, Asturias, Spain.;Hospital de Cabuenes, Asturias, Spain.;Hospital de Cabuenes, Asturias, Spain.;Hospital de Cabuenes, Asturias, Spain.",
"authors": "Pampín|Rubén|R|https://orcid.org/0000-0002-2516-391X;Labeaga|Yoar|Y|;Rodríguez|Belén|B|;Fernández|Beatriz|B|;Fernández|Rubén|R|;Carbajales|Mónica|M|",
"chemical_list": "D017693:Sodium Bicarbonate; D002955:Leucovorin; D008727:Methotrexate",
"country": "England",
"delete": false,
"doi": "10.1177/1078155219852412",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1078-1552",
"issue": "26(3)",
"journal": "Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners",
"keywords": "Methotrexate; folinic acid; non-Hodgkin lymphoma and ambulatory care; sodium bicarbonate",
"medline_ta": "J Oncol Pharm Pract",
"mesh_terms": "D000328:Adult; D000368:Aged; D000554:Ambulatory Care Facilities; D003967:Diarrhea; D005260:Female; D006801:Humans; D002955:Leucovorin; D008228:Lymphoma, Non-Hodgkin; D008297:Male; D008727:Methotrexate; D008875:Middle Aged; D009503:Neutropenia; D011446:Prospective Studies; D017693:Sodium Bicarbonate; D014839:Vomiting; D055815:Young Adult",
"nlm_unique_id": "9511372",
"other_id": null,
"pages": "549-555",
"pmc": null,
"pmid": "31156052",
"pubdate": "2020-04",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": null,
"title": "Experience with ambulatory high-dose methotrexate administration as CNS prophylaxis in patients with non-Hodgkin lymphoma.",
"title_normalized": "experience with ambulatory high dose methotrexate administration as cns prophylaxis in patients with non hodgkin lymphoma"
} | [
{
"companynumb": "NVSC2020ES249495",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LEUCOVORIN"
},
"drugadditional": "3",
"druga... |
{
"abstract": "Pregnancy is an insulin resistant state. Hyperglycaemia and gestational diabetes mellitus are well-recognised complications even in women without existing metabolic syndrome or obesity. Pregnant women also appear to be more vulnerable to ketoacidosis, particularly after short periods of reduced oral intake in the third trimester, and may present with very severe starvation ketoacidosis, prompting emergent delivery. We present a case of a woman with a background of depression and psychotic episodes. Olanzapine had been commenced after a psychotic episode at 20 weeks' gestation. Gestational diabetes mellitus was diagnosed at 28 weeks, and she was then admitted at 31 weeks with severe euglycaemic ketoacidosis following a short period of vomiting. She underwent caesarean section when the metabolic disturbances did not resolve with medical treatment. We believe atypical antipsychotic therapy contributed to the profound insulin resistance seen here, and that obstetricians, physicians and psychiatrists must be aware of the risks conferred by these agents in pregnancy.",
"affiliations": "John Radcliffe Hospital, Oxford University Hospitals NHS Foundation Trust, UK.;John Radcliffe Hospital, Oxford University Hospitals NHS Foundation Trust, UK.;John Radcliffe Hospital, Oxford University Hospitals NHS Foundation Trust, UK.;John Radcliffe Hospital, Oxford University Hospitals NHS Foundation Trust, UK.",
"authors": "Frise|Charlotte|C|;Attwood|Ben|B|;Watkinson|Peter|P|;Mackillop|Lucy|L|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1177/1753495X15621153",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1753-495X",
"issue": "9(1)",
"journal": "Obstetric medicine",
"keywords": "Olanzapine; high anion gap metabolic acidosis; hyperglycaemia; starvation ketoacidosis",
"medline_ta": "Obstet Med",
"mesh_terms": null,
"nlm_unique_id": "101464191",
"other_id": null,
"pages": "46-9",
"pmc": null,
"pmid": "27512491",
"pubdate": "2016-03",
"publication_types": "D002363:Case Reports",
"references": "8960616;20520598;23131345;15337666;18162037;6103486;25061324;20238348;1547179;23278567;12046641;21563902;17035934;6808166;21982116;23231880;18370761;19906788",
"title": "Life-threatening ketoacidosis in a pregnant woman with psychotic disorder.",
"title_normalized": "life threatening ketoacidosis in a pregnant woman with psychotic disorder"
} | [
{
"companynumb": "PHHY2016GB041320",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "SODIUM BICARBONATE"
},
"drugadditional": null,
... |
{
"abstract": "A 60 -year-old man complained of dysphagia and was admitted to our hospital for adjuvant chemotherapy under a diagnosis of esophageal carcinoma(squamous cell carcinoma[SCC], Stage II ). He was treated with cisplatin(CDDP)and 5- fluorouracil(5-FU). On the fifth day after administration, he experienced mild disorientation, and early morning on the sixth day, he showed impaired consciousness. Laboratory studies revealed a serum sodium level of 111mEq/L and a serum chloride level of 73mEq/L. The findings of computed tomography and magnetic resonance imaging of the head were unremarkable. Other laboratory studies revealed a plasma vasopressin level of 19.2 pg/mL, a plasma osmolality of 219mOsm/kg, a serum creatinine level of 0.61mg/dL, a serum cortisol level of 27.1 mg/dL, a urine osmolality of 665mOsm/kg, and a urine sodium level of 157.1mEq/L. There were no signs of dehydration, and so the patient was diagnosed with syndrome of inappropriate antidiuretic hormone secretion(SIADH). We discontinued chemotherapy and initiated fluid restriction and sodium supplementation. After this treatment, the patient's consciousness progressively improved. On the fifth day of treatment, laboratory studies revealed a serum sodium level of 138mEq/L and a serum chloride level of 98mEq/L, indicating recovery from hyponatremia.",
"affiliations": "Dept. of Gastroenterological Surgery, Hirosaki University, Graduate School of Medicine.",
"authors": "Sawano|Takeyuki|T|;Kawasaki|Hitoshi|H|;Wajima|Naoki|N|;Miyamoto|Keiichi|K|;Ishizawa|Yoshiya|Y|;Nakai|Makoto|M|;Hakamada|Kenichi|K|",
"chemical_list": "D002945:Cisplatin; D005472:Fluorouracil",
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0385-0684",
"issue": "41(8)",
"journal": "Gan to kagaku ryoho. Cancer & chemotherapy",
"keywords": null,
"medline_ta": "Gan To Kagaku Ryoho",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D002945:Cisplatin; D004938:Esophageal Neoplasms; D005472:Fluorouracil; D006801:Humans; D007177:Inappropriate ADH Syndrome; D008297:Male; D020360:Neoadjuvant Therapy; D009367:Neoplasm Staging",
"nlm_unique_id": "7810034",
"other_id": null,
"pages": "999-1003",
"pmc": null,
"pmid": "25132033",
"pubdate": "2014-08",
"publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article; D016454:Review",
"references": null,
"title": "A case of syndrome of inappropriate antidiuretic hormone secretion in a patient with esophageal carcinoma possibly induced by cisplatin in neoadjuvant chemotherapy.",
"title_normalized": "a case of syndrome of inappropriate antidiuretic hormone secretion in a patient with esophageal carcinoma possibly induced by cisplatin in neoadjuvant chemotherapy"
} | [
{
"companynumb": "JP-TEVA-513993ISR",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CISPLATIN"
},
"drugadditional": null,
"drug... |
{
"abstract": "We experienced a case of retroperitoneal hematoma secondary to spontaneous lumbar artery rupture in a kidney transplant patient. A 48-year-old woman underwent kidney transplantation for end-stage renal disease. Fifteen days after transplantation, the patient presented with strong abdominal and back pain on the right side, and blood examination showed severe anemia. Contrast-enhanced computed tomography and emergent angiography was performed, which showed extravasation from the lumbar artery. Selective angiographic embolization of the lumbar artery was performed, and the patient received a transfusion of red blood cells, following which, hemoglobin increased to 7.6 g/dl. Renal function then stabilized, and anemia improved.",
"affiliations": "Department of Urology, Faculty of Medicine, Kagawa University, Kagawa, Japan.;Department of Urology, Faculty of Medicine, Kagawa University, Kagawa, Japan.;Department of Urology, Faculty of Medicine, Kagawa University, Kagawa, Japan.",
"authors": "Ueda|Nobufumi|N|;Naito|Hirohito|H|;Sugimoto|Mikio|M|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.eucr.2019.101092",
"fulltext": "\n==== Front\nUrol Case RepUrol Case RepUrology Case Reports2214-4420Elsevier S2214-4420(19)30428-010.1016/j.eucr.2019.101092101092Trauma and ReconstructionSpontaneous lumbar artery rupture in a kidney transplant patient: A case report Ueda Nobufumi nob@med.kagawa-u.ac.jp∗Naito Hirohito Sugimoto Mikio Department of Urology, Faculty of Medicine, Kagawa University, Kagawa, Japan∗ Corresponding author. Department of Urology, Faculty of Medicine, Kagawa University, Kagawa, 1750-1 Ikenobe Miki-cho Kida-gun Kagawa, Japan. nob@med.kagawa-u.ac.jp11 12 2019 3 2020 11 12 2019 29 1010929 10 2019 10 12 2019 © 2019 Published by Elsevier Inc.2019This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).We experienced a case of retroperitoneal hematoma secondary to spontaneous lumbar artery rupture in a kidney transplant patient. A 48-year-old woman underwent kidney transplantation for end-stage renal disease. Fifteen days after transplantation, the patient presented with strong abdominal and back pain on the right side, and blood examination showed severe anemia. Contrast-enhanced computed tomography and emergent angiography was performed, which showed extravasation from the lumbar artery. Selective angiographic embolization of the lumbar artery was performed, and the patient received a transfusion of red blood cells, following which, hemoglobin increased to 7.6 g/dl. Renal function then stabilized, and anemia improved.\n\nKeywords\nKidney transplantLumbar artery raptureEmbolizationAbbreviations\nCT, computed tomographyRBC, red blood cells\n==== Body\nIntroduction\nWe experienced a case of retroperitoneal hematoma due to spontaneous lumbar artery rapture in kidney transplant patient. The lumbar artery bleeding was successfully controlled by intravascular embolization.\n\nCase report\nA 48-year-old woman underwent kidney transplant for end stage renal disease due to IgA nephropathy. She was hospitalizes 2 weeks before transplantation and performed immunosuppressive therapy. For ABO-incompatible transplantation, induction therapy consisted of basiliximab, rituximab, plasma exchange (PE) and double-filtration plasmapheresis (DFPP) followed by maintenance immunosuppression with tacrolimus, mycophenolate mofetil, and methylprednisolone. Because of delayed renal function, hemodialysis restart was needed in five days after transplantation. On the eighth day after transplant, spike wave form was recognized with Doppler echo in renal allograft. As a result of renal biopsy, we diagnosed acute antibody mediated rejection, and steroid pulse, intravenous immunoglobulin, PE, and rituximab injection was performed. Fifteen days later after transplant, she presented strong abdominal and back pain in the right side and hemoglobin dropped to 4.1 g/dl from 7.5 g/dl. Two hours later, hemoglobin further dropped to 3.7 g/dl and her systolic blood pressure decreased to 90/43 mmHg, we took a computerized tomography (CT) of the abdomen with rapid blood transfusion. A contrast-enhanced CT showed a large retroperitoneal hematoma and leakage of contrast medium (Fig. 1). Angiography was performed, which showed extravasation from the lumbar artery (Fig. 2). Selective angiographic embolization of the lumbar artery was performed and patient received 4 units of RBC, hemoglobin increased to 7.6 g/dl. Then her renal function began to improve gradually, it was able to stop dialysis after this day. Six days later after embolization, the hemoglobin level decreased from 7.6 g/dl to 6.9 g/dl and abdominal CT revealed pseudo aneurysm of the lumbar artery, it was performed embolization again. She was discharged on the 41st postoperative day without progression of anemia.Fig. 1 The abdominal CT image shows retroperitoneal hematoma with contrast leakage (white arrows).\n\nFig. 1Fig. 2 The angiography shows contrast extravasation from the right forth lumbar arteries (white arrows).\n\nFig. 2\n\nDiscussion\nSpontaneous retroperitoneal hematoma mostly results from traumatic vascular injury, iatrogenic complication, aortic aneurysm, retroperitoneal neoplasm, and coagulopathy. Old age, renal dysfunction, hemodialysis, and anticoagulation therapy are regarded as risk factors of spontaneous lumbar artery rapture.1 In our case, retroperitoneal hematoma occurred during hemodialysis using heparin for delayed graft function. Furthermore, steroid pulses and plasmapheresis performed as a treatment for rejection might affect lumbar artery rapture. Common symptoms and signs are progressive abdominal pain accompanying hypotension and subsequent development of abdominal mass.2 The spontaneous lumbar artery rapture is rare, however, it is potentially lethal complications of anticoagulation therapy or hemodialysis.1,3 For diagnosis, CT is useful for the initial evaluation of spontaneous lumbar artery rapture. Retroperitoneal masses are homogeneous and images showing relatively high concentrations in contrast CT indicate that blood is contained. Abdominal angiography is also useful for detecting active bleeding of the lumbar artery and further treatment. Treatment of retroperitoneal hemorrhage is usually conservative when abdominal compartment syndrome is not developing. Abdominal angiography and intravascular embolization are well documented and commonly done. The surgical management is difficult for both identification and management of bleeding sites.3 With a large series of abdominal trauma patients and/or retroperitoneal hemorrhage, the success rate of embolization is 91–97%.4,5 Early diagnosis and appropriate intervention are necessary to reduce the risk of morbidity and mortality; we should be kept in mind lumbar artery rupture in patients treated for anticoagulation therapy or hemodialysis with progressive abdominal pain accompanying hypotension and rapid onset of anemia.\n\nAuthor contributions\nNobufumi Ueda carried drafted the manuscript. Hirohito Naito participated in the design of the manuscript. Mikio Sugimoto participated in its design and coordination and helped to draft the manuscript. All authors read and approved the final manuscript.\n\nDeclaration of competing interest\nNone declared.\n==== Refs\nReferences\n1 Hwang Na K. Rhee H. Kim Y. Three cases of spontaneous lumbar artery rupture in hemodialysis patients Hemodial Int 21 2017 e18 e21 27670146 \n2 Quartey B. Nelson J. Massive spontaneous retroperitoneal hemorrhage induced by enoxaparin and subsequent abdominal compartment syndrome requiring surgical decompression: a case report and literature review Int J Case Rep Images 2 2011 14 18 \n3 Isokangas J.M. Perälä J.M. Endovascular embolization of spontaneous retroperitoneal hemorrhage secondary to anticoagulant treatment Cardiovasc Interv Radiol 27 2004 607 611 \n4 Jander H.P. Russinovich N.A. Transcatheter Gelfoam embolization in abdominal, retroperitoneal, and pelvic hemorrhage Radiology 136 1980 337 344 6967615 \n5 Velmahos G.C. Chahwan S. Hanks S.E. Angiographic embolization of bilateral internal iliac arteries to control life-threatening hemorrhage after blunt trauma to the pelvis Am Surg 66 2000 858 862 10993617\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2214-4420",
"issue": "29()",
"journal": "Urology case reports",
"keywords": "CT, computed tomography; Embolization; Kidney transplant; Lumbar artery rapture; RBC, red blood cells",
"medline_ta": "Urol Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101626357",
"other_id": null,
"pages": "101092",
"pmc": null,
"pmid": "31908959",
"pubdate": "2020-03",
"publication_types": "D002363:Case Reports",
"references": "10993617;15578136;27670146;6967615",
"title": "Spontaneous lumbar artery rupture in a kidney transplant patient: A case report.",
"title_normalized": "spontaneous lumbar artery rupture in a kidney transplant patient a case report"
} | [
{
"companynumb": "NVSC2020JP001487",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE"
},
"drugadditional": "3",
... |
{
"abstract": "OBJECTIVE\nThis article reviews important complications of targeted drug therapies for solid malignancies that can be identified on diagnostic imaging. Wherever possible, known or proposed mechanistic explanations for drug complications are emphasized.\n\n\nCONCLUSIONS\nFamiliarity with the toxicity profiles of different targeted cancer therapies is important for identifying drug-related complications and for differentiating drug effects from disease progression. A mechanistic understanding may be useful for associating individual drugs with their complications and for predicting the complications of emerging agents.",
"affiliations": "Department of Radiology and Radiological Science, Vanderbilt University School of Medicine, 1161 21st Ave S, CCC-1121 MCN, Nashville, TN 37232-2675, USA. richard.abramson@vanderbilt.edu",
"authors": "Abramson|Richard G|RG|;Abramson|Vandana G|VG|;Chan|Emily|E|;Horn|Leora|L|;Keedy|Vicki L|VL|;Pao|William|W|;Sosman|Jeffrey A|JA|",
"chemical_list": "D000970:Antineoplastic Agents",
"country": "United States",
"delete": false,
"doi": "10.2214/AJR.12.9049",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0361-803X",
"issue": "200(3)",
"journal": "AJR. American journal of roentgenology",
"keywords": null,
"medline_ta": "AJR Am J Roentgenol",
"mesh_terms": "D000970:Antineoplastic Agents; D064420:Drug-Related Side Effects and Adverse Reactions; D006801:Humans; D058990:Molecular Targeted Therapy; D009369:Neoplasms",
"nlm_unique_id": "7708173",
"other_id": null,
"pages": "475-83",
"pmc": null,
"pmid": "23436834",
"pubdate": "2013-03",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D016454:Review",
"references": "17519900;19224857;17577204;18160686;21639808;15696205;15196739;17215529;19198837;22256804;17890216;19212145;15114088;19482548;17625975;19688063;16549611;18849018;11306470;20442535;19474123;18037875;22109345;18165622;16574271;16493605;16735708;17686822;16257339;19934295;16510760;21785048;17307580;18337594;18024865;17461715;16806903;17008686;21183492;20979469;19451442;12941834;19213671;22733894;19926757",
"title": "Complications of targeted drug therapies for solid malignancies: manifestations and mechanisms.",
"title_normalized": "complications of targeted drug therapies for solid malignancies manifestations and mechanisms"
} | [
{
"companynumb": "US-ROCHE-1317069",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BEVACIZUMAB"
},
"drugadditional": "3",
"drug... |
{
"abstract": "The objective of this randomized placebo-controlled study was to investigate the efficacy and safety of clarithromycin in combination with bortezomib-cyclophosphamide-dexamethasone (VCD) in patients with newly diagnosed multiple myeloma eligible for high-dose therapy.\nPatients were randomized to receive tablet clarithromycin 500 mg or matching placebo tablet twice daily during the first 3 cycles of VCD induction therapy. Primary endpoint was to compare the rate of very good partial response (VGPR) or better response after three cycles of VCD combined with clarithromycin or placebo.\nThe study was prematurely stopped for safety reasons after the inclusion of 58 patients (36% of the planned study population). The patients were randomly assigned to clarithromycin (n = 27) or placebo (n = 31). VGPR or better response after the VCD induction therapy was obtained in 12 patients (44.4%, 95% CI 25.5-64.7) and in 16 patients (51.6%, 33.1-69.8) (p = 0.59) in the clarithromycin group and the placebo group, respectively. Seven patients (25.9%) in the clarithromycin group developed severe gastrointestinal complications (≥ grade 3) comprising pain, neutropenic enterocolitis, paralytic ileus or peptic ulcer. These complications occurred in only one patient in the placebo group. Septicemia with Gram negative bacteria was observed in 5 patients in the clarithromycin group in contrast to one case of pneumococcal septicemia in the placebo group. Patient-reported QoL were negatively affected in the clarithromycin group compared to the placebo group.\nThe study was prematurely stopped due to serious adverse events, in particular serious gastrointestinal complications and septicemia. The response data do not suggest any effect of clarithromycin when added to the VCD regimen. The combination of clarithromycin and bortezomib containing regimens is toxic and do not seem to offer extra anti-myeloma efficacy.Trial registration EudraCT (no. 2014-002187-32, registered 7 October 2014, https://www.clinicaltrialsregister.eu/ctr-search/trial/2014-002187-32/DK) and ClinicalTrials.gov (no NCT02573935, retrospectively registered 12 October 2015, https://www.clinicaltrials.gov/ct2/show/NCT02573935?term=Gregersen&cntry=DK&rank=9).",
"affiliations": "1Department of Hematology, Aalborg University Hospital, Mølleparkvej 4, 9000 Aalborg, Denmark.;2Department of Hematology, Herlev Hospital, 2730 Herlev, Denmark.;3Department of Hematology, Vejle Hospital, 7100 Vejle, Denmark.;4Department of Hematology, Zealand University Hospital, 4000 Roskilde, Denmark.;5Department of Hematology, Aarhus University Hospital, 8000 Aarhus, Denmark.;6Quality of Life Research Center OUH, Odense University Hospital, 5000 Odense C, Denmark.;4Department of Hematology, Zealand University Hospital, 4000 Roskilde, Denmark.;2Department of Hematology, Herlev Hospital, 2730 Herlev, Denmark.;7Department of Hematology, Rigshospitalet, 2100 Copenhagen, Denmark.;8Department of Hematology, Odense University Hospital, 5000 Odense C, Denmark.",
"authors": "Gregersen|Henrik|H|0000-0001-6632-5308;Do|Trung|T|;Kristensen|Ida Bruun|IB|;Frølund|Ulf Christian|UC|;Andersen|Niels Frost|NF|;Nielsen|Lene Kongsgaard|LK|;Andersen|Christen Lykkegaard|CL|;Klausen|Tobias Wirenfeldt|TW|;Vangsted|Annette Juul|AJ|;Abildgaard|Niels|N|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1186/s40164-018-0110-0",
"fulltext": "\n==== Front\nExp Hematol OncolExp Hematol OncolExperimental Hematology & Oncology2162-3619BioMed Central London 11010.1186/s40164-018-0110-0ResearchA randomized placebo-controlled phase II study of clarithromycin or placebo combined with VCD induction therapy prior to high-dose melphalan with stem cell support in patients with newly diagnosed multiple myeloma http://orcid.org/0000-0001-6632-5308Gregersen Henrik (+45) 97 66 38 48henrik.gregersen@rn.dk 1Do Trung trung.hieu.do@regionh.dk 2Kristensen Ida Bruun idabk@dadlnet.dk 3Frølund Ulf Christian ucf@regionsjaelland.dk 4Andersen Niels Frost nielande@rm.dk 5Nielsen Lene Kongsgaard Lene.Kongsgaard.Nielsen@rsyd.dk 6Andersen Christen Lykkegaard christenla@gmail.com 4Klausen Tobias Wirenfeldt Tobias.Wirenfeldt.Klausen@regionh.dk 2Vangsted Annette Juul annette.juul.vangsted@regionh.dk 7Abildgaard Niels Niels.Abildgaard@rsyd.dk 81 0000 0004 0646 7349grid.27530.33Department of Hematology, Aalborg University Hospital, Mølleparkvej 4, 9000 Aalborg, Denmark 2 0000 0004 0646 8325grid.411900.dDepartment of Hematology, Herlev Hospital, 2730 Herlev, Denmark 3 0000 0004 0512 5814grid.417271.6Department of Hematology, Vejle Hospital, 7100 Vejle, Denmark 4 grid.476266.7Department of Hematology, Zealand University Hospital, 4000 Roskilde, Denmark 5 0000 0004 0512 597Xgrid.154185.cDepartment of Hematology, Aarhus University Hospital, 8000 Aarhus, Denmark 6 0000 0004 0512 5013grid.7143.1Quality of Life Research Center OUH, Odense University Hospital, 5000 Odense C, Denmark 7 grid.475435.4Department of Hematology, Rigshospitalet, 2100 Copenhagen, Denmark 8 0000 0004 0512 5013grid.7143.1Department of Hematology, Odense University Hospital, 5000 Odense C, Denmark 13 8 2018 13 8 2018 2018 7 189 6 2018 6 8 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\nThe objective of this randomized placebo-controlled study was to investigate the efficacy and safety of clarithromycin in combination with bortezomib–cyclophosphamide–dexamethasone (VCD) in patients with newly diagnosed multiple myeloma eligible for high-dose therapy.\n\nMethods\nPatients were randomized to receive tablet clarithromycin 500 mg or matching placebo tablet twice daily during the first 3 cycles of VCD induction therapy. Primary endpoint was to compare the rate of very good partial response (VGPR) or better response after three cycles of VCD combined with clarithromycin or placebo.\n\nResults\nThe study was prematurely stopped for safety reasons after the inclusion of 58 patients (36% of the planned study population). The patients were randomly assigned to clarithromycin (n = 27) or placebo (n = 31). VGPR or better response after the VCD induction therapy was obtained in 12 patients (44.4%, 95% CI 25.5–64.7) and in 16 patients (51.6%, 33.1–69.8) (p = 0.59) in the clarithromycin group and the placebo group, respectively. Seven patients (25.9%) in the clarithromycin group developed severe gastrointestinal complications (≥ grade 3) comprising pain, neutropenic enterocolitis, paralytic ileus or peptic ulcer. These complications occurred in only one patient in the placebo group. Septicemia with Gram negative bacteria was observed in 5 patients in the clarithromycin group in contrast to one case of pneumococcal septicemia in the placebo group. Patient-reported QoL were negatively affected in the clarithromycin group compared to the placebo group.\n\nConclusion\nThe study was prematurely stopped due to serious adverse events, in particular serious gastrointestinal complications and septicemia. The response data do not suggest any effect of clarithromycin when added to the VCD regimen. The combination of clarithromycin and bortezomib containing regimens is toxic and do not seem to offer extra anti-myeloma efficacy.\n\nTrial registration EudraCT (no. 2014-002187-32, registered 7 October 2014, https://www.clinicaltrialsregister.eu/ctr-search/trial/2014-002187-32/DK) and ClinicalTrials.gov (no NCT02573935, retrospectively registered 12 October 2015, https://www.clinicaltrials.gov/ct2/show/NCT02573935?term=Gregersen&cntry=DK&rank=9)\n\nKeywords\nMultiple myelomaClarithromycinBortezomibAdverse drug eventInduction chemotherapyDouble blind studyThe Obel Family FoundationThe Karen Elise Jensen FoundationDanish Myeloma Study Groupissue-copyright-statement© The Author(s) 2018\n==== Body\nBackground\nClarithromycin has been proposed as a potentially good candidate for addition to multiple myeloma therapy in pursuit of synergistic effects [1]. This concept is based on the favorable toxicity profile of clarithromycin when used in the treatment of infections, the very low cost and response data from combination with immunomodulatory drugs (IMiDs) in phase II trials and in one case-matched study [2–5]. In a study by Niesvizky et al. the combination of clarithromycin, 500 mg twice daily with lenalidomide and dexamethasone led to partial response or better in 90% of treatment-naive patients with symptomatic multiple myeloma [4]. Gay et al. conducted a case-matched analysis based on the Niesvizky study and compared 72 patients treated with clarithromycin, lenalidomide and dexamethasone with an equal number of patients seen at the Mayo Clinic only treated with lenalidomide and dexamethasone [5]. The study indicated a very favorable effect of clarithromycin with a higher frequency of complete response (CR), and very good partial response (VGPR) or better in the clarithromycin group. In addition, time-to-progression and progression-free survival were longer in the clarithromycin group. However, there are so far no data from randomized controlled studies to support an effect of clarithromycin in multiple myeloma.\n\nCellular studies have shown that clarithromycin attenuates autophagy in myeloma cells at clinically relevant concentrations (6–50 μg/mL) [6]. The combination of clarithromycin and bortezomib results in increased cytotoxicity compared to bortezomib alone in myeloma cell lines [7]. A possible mechanism underlying this synergistic effect might be simultaneous inhibition of the ubiquitin–proteasome system by bortezomib and the autophagy-lysosome system by clarithromycin resulting in over-loading endoplasmic reticulum-stress in myeloma cells [7]. However, it is unknown whether this observation could be translated into clinical efficacy in treatment of multiple myeloma patients.\n\nThe Danish Myeloma Study Group (DMSG) therefore initiated a randomized, double-blind, placebo-controlled phase 2 study to evaluate the efficacy and safety of adding clarithromycin to the bortezomib-containing triplet induction regimen bortezomib–cyclophosphamide–dexamethasone (VCD) in multiple myeloma patients eligible for high-dose melphalan with stem cell support (HDT).\n\nMethods\nTrial design\nThis randomized, double-blind, placebo-controlled phase II study was designed and conducted by the Danish Myeloma Study Group (DMSG). It included multiple myeloma patients from six Danish sites and was planned to include a total of 160 patients. The study was approved Danish Health and Medicines Authority (No. 2014061645) and Danish Data Protection Agency (No. 2008-58-0028). EudraCT and ClinicalTrials.gov Numbers are 2014-002187-32 and NCT02573935, respectively. Independent monitors from the Danish Good Clinical Practice units in Copenhagen, Aarhus and Odense carried out the monitoring.\n\nPatients\nThe study included patients with newly diagnosed multiple myeloma with treatment demanding disease according to the International Myeloma Working Group (IMWG) criteria [8]. Only patients eligible for high-dose melphalan with stem cell support were included. The key exclusion criteria were any given anti-myeloma treatment prior to inclusion, except radiotherapy, bisphosphonates/denosumab or corticosteroids for symptom control, prolonged QT corrected (QTc) interval (> 500 ms on screening ECG), uncontrolled or severe cardiovascular disease, severe renal dysfunction (estimated creatinine clearance < 10 mL/min) and concurrent treatment with certain potentially interacting medications, e.g. fluconazole, verapamil and simvastatin.\n\nTrial treatment\nPatients were randomized (1:1 ratio) to receive oral clarithromycin 500 mg or a matching placebo tablet twice daily during the first 3 cycles of VCD induction therapy. The randomization was stratified according to International Staging System stage (1, 2 or 3). The VCD consisted of 21-day cycles of subcutaneous bortezomib 1.3 mg/sqm days 1, 4, 8, 11, intravenous cyclophosphamide 500 mg/sqm on days 1 and 8, and oral dexamethasone 40 mg days 1, 2, 4, 5, 8, 9, 11, 12. The number of VCD series was changed from three to four in the national Danish guidelines for treatment of multiple myeloma during conduct of the study. Consequently, after a protocol amendment the induction therapy was changed to four series of VCD but the treatment duration of clarithromycin or placebo was unchanged. After the induction therapy the patients proceeded to cyclophosphamide priming (2000 mg/sqm), peripheral blood stem cell harvest by leukapheresis and high-dose melphalan (200 mg/sqm) with stem cell support.\n\nEnd-points and assessments\nThe primary end-point of the study was to compare the rate of very good partial response or better response (≥ VGPR) after three courses of VCD combined with clarithromycin or placebo. The response was assessed according to the International Myeloma Working Group criteria for response in multiple myeloma [9]. An important secondary end-point was to compare the rate of ≥ VGPR 2 months after high-dose melphalan with stem cell support. Other secondary end-points included the frequency of infections and the number of stem cells harvested in patients in the two treatment groups. Patient-reported quality of life (QoL) and neurotoxicity were secondary end-points, and assessed at inclusion and after 2 and 6 months. Two European Organisation for Research and Treatment of Cancer QoL (EORTC) questionnaires were used; EORTC QLQ-C30 and the Multiple Myeloma module EORTC QLQ-MY20 [10, 11]. Neurotoxicity was assessed by the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT/GOG-Ntx) subscale questionnaire [12]. Analyses were by intention-to-treat.\n\nSafety assessment\nAdverse events were graded according to National Cancer Institute Common Toxicity Criteria (NCI CTC) Version 4.0.\n\nUnblinding\nUnblinding of study drug status of the individual patient was performed after final study evaluation 2 months after HDT provided that all CRFs had been completed and approved by the study office. This approach was used to allow for participation in other myeloma studies or the use of tandem transplantation in selected patients.\n\nStatistical analysis\nComparisons of binary variables were conducted by Fisher’s exact test, mid-P approach as appropriate. Differences in primary endpoints between treatment arms were presented using absolute risk difference with 95% confidence intervals (95% CI). Continuous variables were presented using medians with range or interquartile range. Continuous and ordinal variables were compared using Mann–Whitney test except for patient related outcomes. For analyzing time to exclusion the Kaplan–Meier method was used and differences between treatment arms were compared using the Log-rank test. Differences of patient related outcomes between groups were adjusted for baseline measures and analyzed using a constrained longitudinal data analysis (cLDA) estimated by a mixed model using unstructured covariance [13]. All confidence intervals are 95% and all confidence intervals and p-values are two-sided. Data analyses were performed using R version 3.3.3 (R Foundation for Statistical Computing, Vienna, Austria) except for mixed models which were performed using SAS version 9.4 (SAS institute, Cary, SC, USA).\n\nResults\nThe study was prematurely stopped by the study safety board for safety reasons after inclusion of 58 patients (36% of the planned study population). The median age of included patients was 63 years (interquartile range 55–66 years). Twenty-seven patients were assigned to clarithromycin treatment and 31 to placebo. The clinical characteristics at baseline are described in Table 1.Table 1 Baseline characteristics of patients\n\n\t\tClarithromycin group (N = 27)\tPlacebo group (N = 31)\t\nVariable\t\n Age (years)\tMedian (IQR)\t63 (55.0–66.5)\t63 (55.5–66.0)\t\n Male sex\tNo. (%)\t20 (74.1%)\t20 (64.5%)\t\n Type of myeloma\tNo. (%)\t\t\t\n IgA\t\t3 (11.1%)\t9 (29.0%)\t\n IgG\t\t20 (74.1%)\t17 (54.8%)\t\n Light chain\t\t4 (14.8%)\t5 (16.1%)\t\n International staging system\tNo. (%)\t\t\t\n I\t\t7 (%) (25.9%)\t9 (29.0%)\t\n II\t\t10 (%) (37.0%)\t17 (54.8%)\t\n III\t\t9 (33.1%)\t4 (12.9%)\t\n Missing\t\t1 (3.8%)\t1 (3.2%)\t\n Cytogenetic features\tNo. (%)\t\t\t\n Standard risk\t\t18 (66.7%)\t18 (58.1%)\t\n High riska\t\t6 (22.2%)\t8 (25.8%)\t\n Data not available\t\t3 (11.1%)\t5 (16.1%)\t\n WHO performance status\tNo. (%)\t\t\t\n 0\t\t14 (51.9%)\t17 (54.8%)\t\n ≥ 1\t\t13 (48.1%)\t14 (45.2%)\t\n Serum creatinine ≥ 130 µmol/L\tNo. (%)\t5 (18.5%)\t2 (6.5%)\t\n Serum LDH ≥ 260 U/L\tNo. (%)\t1 (3.7%)\t4 (12.9%)\t\n Serum C-reactive protein ≥ 8 mg/L\tNo. (%)\t9 (33.3%)\t9 (29.0%)\t\nIQR interquartile range, LDH lactate dehydrogenase\n\nat(4;14), t(14;16), t(14;20) or del(17p)\n\n\n\n\nEfficacy\nThe primary end-point VGPR or better response after the VCD induction therapy was obtained in 12 patients (44.4%, 95% CI 25.5–64.7%) and in 16 patients (51.6%, 33.1–69.8%) (p = 0.59) in the clarithromycin group and the placebo group, respectively. There were no differences between the two groups for any of the secondary endpoints VGPR or better response 2 months after high-dose melphalan with stem cell support, yield of harvested stem cells and number of infections (Table 2).Table 2 Clinical outcomes\n\n\t\tClarithromycin group (N = 27)\tPlacebo group (N = 31)\tPclarithromycin − Pcontrol\t\nClinical outcomes\t\n VGPR or better response after VCD induction\tNo. (%, 95% CI)\t12 (44.4%, 25.5–64.7%)\t16 (51.6%, 33.1–69.8%)a\t− 7.2% (− 30.7–17.6%)c\t\n VGPR or better response after HDT\tNo. (%, 95% CI)\t16 (59.3%, 38.8–77.6%)\t23 (74.2%, 55.4–88.1%)a\t− 14.9% (− 37.1–8.9%)c\t\n Leukapheresis\t106/kg (range)\t8 (2–20)\t8.5 (2–18)b\t–\t\n Any infection\tNo. (%, 95% CI)\t16 (59.3%, 38.8–77.6%)\t18 (58.1%, 39.1–75.5%)a\t1.2% (− 23.0–24.9%)c\t\nVGPR very good partial response, HDT high-dose melphalan with hematopoietic stem cell support\n\naNot significant (Fisher’s exact test)\n\nbNot significant (Mann–Whitney test)\n\ncPclarithromycin − Pcontrol For response negative numbers indicate lower response in clarithromycin group. For infection positive number indicates higher risk of infection in clarithromycin group\n\n\n\n\nSafety\nMost patients in the clarithromycin group and the placebo group had at least one adverse event during the VCD induction therapy (96.3% and 90.3%, respectively) (Table 3). The most common adverse events of any grade are summarized in Table 4. Frequent adverse events in the clarithromycin group were thrombocytopenia, septicemia, oral candidiasis, peripheral sensory neuropathy (p = 0.03), dizziness, peripheral edema, hypotension and various psychiatric symptoms. By contrast, the occurrence of respiratory tract infection was low in the clarithromycin group.Table 3 Overall safety profile and drug doses in the clarithromycin group and placebo group\n\n\tClarithromycin group, No = 27\tPlacebo group, No = 31\t\n120/180 days follow-up—%\t77.8% (63.6%; 95.2%)\t90.3% (80.5%; 100%)\t\nTreatment cycles—no. (%)\t\n 1\t1 (3.7%)\t2 (6.4%)\t\n 2\t3 (11.1%)\t1 (3.2%)\t\n 3\t16 (59.3%)\t19 (61.2%)\t\n 4\t7 (25.9%)\t9 (29.0%)\t\nAny adverse event—no. (%)\t26 (96.3%)\t28 (90.3%)\t\nAny ≥ 3 adverse event—no. (%)\t16 (59.3%)\t12 (38.7%)\t\nAny serious adverse event—no. (%)\t16 (59.3%)\t10 (32.3%)\t\nAdverse event resulting in dose reduction of study drug—no. (%)\t9 (33.3%)\t3 (9.7%)a\t\nAdverse event resulting in dose reduction of bortezomib—no. (%)\t9 (33.3%)\t4 (12.9%)b\t\nAdverse event resulting in dose reduction of dexamethasone—no. (%)\t9 (33.3%)\t3 (9.7%)a\t\nAdverse event resulting in dose reduction of cyclophosphamide—no. (%)\t4 (14.8%)\t1 (3.2%)b\t\nap = 0.049 (Fisher’s exact test)\n\nbNot significant (Fisher’s exact test)\n\n\nTable 4 Most common adverse events in the clarithromycin and placebo group\n\n\tClarithromycin group, No = 27\tPlacebo group, No = 31\t\nAny grade\tGrade 3 or 4\tAny grade\tGrade 3 or 4\t\nHematologic events\t\n Thrombocytopenia\t11 (40.7%)\t2 (7.4%)\t7 (22.6%)\t0\t\n Anemia\t12 (44.4%)\t2 (7.4%)\t11 (35.5%)\t0\t\n Neutropenia\t11 (40.7%)\t1 (3.7%)\t13 (41.9%)\t0\t\nGastrointestinal events\t\n Typhlitis and perforation of colon\t2 (7.4%)\t2 (7.4%)\t1 (3.2%)\t1 (3.2%)\t\n Paralytic ileus\t2 (7.4%)\t2 (7.4%)\t0\t0\t\n Constipation\t6 (22.2%)\t1 (3.7%)\t5 (16.1%)\t0\t\n Diarrhea\t4 (14.8%)\t3 (11.1%)\t5 (16.1%)\t1 (3.2%)\t\n Dyspepsia\t3 (11.1%)\t0\t1 (3.2%)\t0\t\n Nausea\t5 (18.5%)\t0\t6 (19.4%)\t0\t\nInfections\t\n Respiratory tract infection\t5 (18.5%)\t2 (7.4%)\t8 (25.8%)\t5 (16.1%)\t\n Urinary tract infection\t3 (11.1%)\t1 (3.7%)\t5 (16.1%)\t1 (3.2%)\t\n Septicemia\t5 (18.5%)\t5 (18.5%)\t1 (3.2%)\t1 (3.2%)\t\n Other infections\t6 (22.2%)\t4 (14.8%)\t9 (29.0%)\t5 (16.1)\t\n Oral candidiasis\t7 (25.9%)\t1 (3.7%)\t1 (3.2%)\t0\t\nNervous system disorders\t\n Peripheral sensory neuropathy\t15 (55.6%)\t0\t8 (25.8%)\t0\t\n Dizziness\t4 (14.8%)\t1 (3.7%)\t3 (9.7%)\t0\t\nOther conditions\t\n Peripheral edema\t11 (40.7%)\t1 (3.7%)\t7 (22.6%)\t1 (3.2%)\t\n Hypotension\t4 (14.8%)\t2 (7.4%)\t1 (3.2%)\t0\t\n Fatigue\t4 (14.8%)\t1 (3.7%)\t3 (9.7%)\t0\t\n Rash\t2 (7.4%)\t0\t4 (12.9%)\t0\t\n Insomnia\t2 (7.4%)\t0\t6 (19.4%)\t0\t\n Weight loss\t3 (11.1%)\t0\t1 (3.2%)\t0\t\n Mucositis\t2 (7.4%)\t0\t4 (12.9%)\t0\t\n Psychiatric symptomsa\t5 (18.5%)\t1 (3.7%)\t2 (6.5%)\t1 (3.2%)\t\nThe table included adverse event of any grade that occurred in more than 10% in any of the treatment groups or adverse events grade 3 or more that occurred in more than 5% in any of the treatment groups\n\naThe group psychiatric symptoms encompass anxiety, agitation, depression and psychosis\n\n\n\n\nA total of 26 serious adverse events (SAEs) were reported in 16 (59.3%) patients in the clarithromycin group and 16 SAEs in 10 (32.3%) patients in the placebo group. A large fraction of the SAEs was constituted by gastrointestinal complaints with associated serious complications which were seen in 7 (25.9%) patients in the clarithromycin group and in 1 patient (3.2%) in the placebo group. A common complication in patients with gastrointestinal complaints in the clarithromycin group was septicemia which was detected in 5 cases and constituted well-known gastrointestinal bacteria. By contrast, the only case of septicemia detected in the placebo group was pneumococcal sepsis associated with pneumonia. There was one death in the clarithromycin group (duodenal ulcer) and one death in the control group (perforated diverticulitis). As a consequence of the imbalance in gastrointestinal symptoms and septicemia the study safety board decided to terminate inclusion of new patients and administration of the study drug ceased on 16 September 2016. The VCD treatment and follow-up in the study continued.\n\nTreatment\nThe fraction of patients who either had a reduced dose of study drug or discontinued study drug due to adverse events was higher in the clarithromycin group compared with the placebo group (33.3% and 9.7%, respectively). In addition, there was a trend towards more frequent reduction of VCD drug doses in the clarithromycin group compared with the placebo group, e.g. for bortezomib 33.3% and 12.9%, respectively (Table 3).\n\nPatient-reported outcomes\nPatients in the clarithromycin group reported more and clinical relevant neurotoxicity on the FACT/GOG-Ntx subscale and clinical relevant reduced global Qol on the EORTC QLQ C30 than patients in the placebo group after three VCD series. Two month after HDT there was still a mean score difference between the two treatment groups, but the differences were not clinical relevant anymore (Fig. 1).Fig. 1 Patient reported neurotoxicity and global quality of life in the clarithromycin and the placebo group. In the FACT/GOG-Ntx score positive values indicate worsening of neurotoxicity and negative values indicate improvement of neurotoxicity. In the Global Quality of Life Scale (GQOL) positive values indicate improvement in quality of life and negative values indicate worsening of quality of life\n\n\n\nDiscussion\nTo our knowledge, this study is the first randomized placebo-controlled trial examining the effect of adding clarithromycin to conventional myeloma therapy. The study was prematurely stopped for safety reasons, which affect the interpretation of the results, but our data do not suggest any anti-myeloma effect of clarithromycin when added to the VCD regimen.\n\nThe case-matched retrospective analysis by Gay et al. found a very pronounced effect of adding clarithromycin to treatment with lenalidomide and dexamethasone, e.g. tripling of the CR rate [5]. The lack of efficacy of clarithromycin in combination with CVD in our study does not rule out a significant and clinical meaningful effect of clarithromycin in combination with other myeloma drugs, e.g. the immunomodulatory agents (IMiDs). The potential effect of the combination of clarithromycin and lenalidomide is to our knowledge currently being assessed in two active recruiting randomized controlled trials.\n\nAt the planning of our study a major concern was potential serious cardiac side effects since clarithromycin may increase the QT interval, and the drug has been associated with risk of cardiovascular events and increased mortality in patients with stable coronary heart disease and in patients without heart disease [14, 15]. The exclusion criteria in our study were therefore strict in regard to previous cardiovascular disease and concomitant use of drugs that might increase the QT interval. Maybe due to this, we did not encounter any serious cardiovascular morbidity during conduct of the study.\n\nSurprisingly, we observed an increased occurrence of several types of adverse events in patients who received clarithromycin in combination with VCD and several mechanisms may underlie this finding. First, bortezomib is metabolized by the cytochrome P450 (CYP) enzymes, and in particular the CYP3A4 is the major contributor to bortezomib metabolism [16]. Secondly, clarithromycin inhibits CYP3A4 and probably the observed adverse events in our study were merely an effect of increased biological bortezomib exposure due to reduced metabolism [17]. Peripheral neuropathy is a common adverse event during treatment with bortezomib and we found a clear difference between the two treatment groups in our study [18]. In accordance with this observation an increased occurrence of peripheral neuropathy and also thrombocytopenia has been observed in patients who received concomitantly bortezomib and itraconazole, another potent CYP3A4 inhibitor [19]. Possibly, this mechanism might explain some of the observed gastrointestinal symptoms, e.g. increased occurrence of constipation and paralytic ileus in our study. In addition, other factors might have contributed, e.g. clarithromycin increases the pharmacologic effect of steroids and cases of pseudomembranous colitis have been observed in patients treated with clarithromycin as part of eradication therapy for Helicobacter pylori infection [4, 20–22]. In accordance with our findings an increased rate of grade 3–4 adverse events was also observed in the clarithromycin group in the case-matched study by Gay et al. [5], and noteworthy three cases of perforated colon occurred in the clarithromycin group in contrast to none in the control group. However, the occurrence of septicemia was the same in the groups in the study by Gay et al. which is in contrast to our results [5]. Although most of the measures of safety in our study did not reach statistical significance our data consistently suggest an unfavorable pattern of clarithromycin combined with VCD on the number and degree of adverse events, on feasibility of the regimen and on the two patient-reported outcomes quality of life and neurotoxicity. Such a pattern is not acceptable in an era of novel potent anti-myeloma drugs with favorable safety profiles where in particular the monoclonal antibodies daratumumab and elotuzumab are likely to constitute important elements of bortezomib-containing regimens [23, 24].\n\nIn conclusion, although we were only able to analyze response data in 58 included patients, our data do not indicate any additional effect of clarithromycin when added to the VCD regimen, and due to treatment toxicity our trial does not encourage further clinical studies on the combination of clarithromycin and bortezomib. In patients treated with combined clarithromycin and VCD we observed an increased frequency of serious adverse events, in particular serious gastrointestinal complications and septicemia. This emphasizes the need for controlled studies on the efficacy of clarithromycin, both in assessment of potential anti-myeloma effects as well as for assessment of safety measures.\n\nAuthors’ contributions\nAll authors contributed to conception and design of the study. HG, TD, IBK, UCK, NFA, AJV and NA contributed to acquisition of data. TWK and HG performed analysis of data. HG drafted the manuscript. All authors contributed to interpretation of the results and revised the manuscript. All authors read and approved the final manuscript.\n\nAcknowledgements\nThe authors would like to thank Sanne Kjær, Susanne Christiansen, Ulla Kjær and Louise Vistisen at the Clinical Trial Unit, Aalborg University Hospital.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nAvailability of data and materials\nAll data generated or analysed during this study are included in this published article.\n\nConsent for publication\nNot applicable.\n\nEthics approval and consent to participate\nThe study was approved by North Denmark Region Committee on Health Research Ethics (N-20140037). Patients provided written informed consent, and the trial was conducted in accordance with the principles of the Declaration of Helsinki.\n\nFunding\nThe study received financial support from the Obel Family Foundation, the Karen Elise Jensen Foundation and Danish Myeloma Study Group (DMSG).\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. Van Nuffel AM Sukhatme V Pantziarka P Meheus L Sukhatme VP Bouche G Repurposing drugs in oncology (ReDO)-clarithromycin as an anti-cancer agent Ecancermedicalscience 2015 9 513 25729426 \n2. Morris TC Kettle PJ Drake M Clarithromycin with low dose dexamethasone and thalidomide is effective therapy in relapsed/refractory myeloma Br J Haematol 2008 143 3 349 354 10.1111/j.1365-2141.2008.07360.x 18759764 \n3. Coleman M Leonard J Lyons L BLT-D (clarithromycin [Biaxin], low-dose thalidomide, and dexamethasone) for the treatment of myeloma and Waldenstrom’s macroglobulinemia Leuk Lymphoma 2002 43 9 1777 1782 10.1080/1042819021000006303 12685831 \n4. Niesvizky R Jayabalan DS Christos PJ BiRD (Biaxin [clarithromycin]/Revlimid [lenalidomide]/dexamethasone) combination therapy results in high complete- and overall-response rates in treatment-naive symptomatic multiple myeloma Blood 2008 111 3 1101 1109 10.1182/blood-2007-05-090258 17989313 \n5. Gay F Rajkumar SV Coleman M Clarithromycin (Biaxin)-lenalidomide-low-dose dexamethasone (BiRd) versus lenalidomide-low-dose dexamethasone (Rd) for newly diagnosed myeloma Am J Hematol 2010 85 9 664 669 10.1002/ajh.21777 20645430 \n6. Nakamura M Kikukawa Y Takeya M Mitsuya H Hata H Clarithromycin attenuates autophagy in myeloma cells Int J Oncol 2010 37 4 815 820 10.3892/ijo_00000737 20811702 \n7. Moriya S Che XF Komatsu S Macrolide antibiotics block autophagy flux and sensitize to bortezomib via endoplasmic reticulum stress-mediated CHOP induction in myeloma cells Int J Oncol 2013 42 5 1541 1550 10.3892/ijo.2013.1870 23546223 \n8. International Myeloma Working Group Criteria for the classification of monoclonal gammopathies, multiple myeloma and related disorders: a report of the International Myeloma Working Group Br J Haematol 2003 121 5 749 757 10.1046/j.1365-2141.2003.04355.x 12780789 \n9. Rajkumar SV Harousseau JL Durie B Consensus recommendations for the uniform reporting of clinical trials: report of the International Myeloma Workshop Consensus Panel Blood 2011 117 18 4691 4695 10.1182/blood-2010-10-299487 21292775 \n10. Cocks K Cohen D Wisloff F An international field study of the reliability and validity of a disease-specific questionnaire module (the QLQ-MY20) in assessing the quality of life of patients with multiple myeloma Eur J Cancer 2007 43 11 1670 1678 10.1016/j.ejca.2007.04.022 17574838 \n11. Aaronson NK Ahmedzai S Bergman B The European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology J Natl Cancer Inst 1993 85 5 365 376 10.1093/jnci/85.5.365 8433390 \n12. Huang HQ Brady MF Cella D Fleming G Validation and reduction of FACT/GOG-Ntx subscale for platinum/paclitaxel-induced neurologic symptoms: a gynecologic oncology group study Int J Gynecol Cancer 2007 17 2 387 393 10.1111/j.1525-1438.2007.00794.x 17362317 \n13. Coffman CJ Edelman D Woolson RF To condition or not condition? Analysing ‘change’ in longitudinal randomised controlled trials BMJ Open 2016 6 12 e013096 10.1136/bmjopen-2016-013096 28039292 \n14. Schembri S Williamson PA Short PM Cardiovascular events after clarithromycin use in lower respiratory tract infections: analysis of two prospective cohort studies BMJ 2013 346 f1235 10.1136/bmj.f1235 23525864 \n15. Winkel P Hilden J Hansen JF Clarithromycin for stable coronary heart disease increases all-cause and cardiovascular mortality and cerebrovascular morbidity over 10 years in the CLARICOR randomised, blinded clinical trial Int J Cardiol 2015 182 459 465 10.1016/j.ijcard.2015.01.020 25602299 \n16. Uttamsingh V Lu C Miwa G Gan LS Relative contributions of the five major human cytochromes P450, 1A2, 2C9, 2C19, 2D6, and 3A4, to the hepatic metabolism of the proteasome inhibitor bortezomib Drug Metab Dispos 2005 33 11 1723 1728 10.1124/dmd.105.005710 16103134 \n17. Rodrigues AD Roberts EM Mulford DJ Yao Y Ouellet D Oxidative metabolism of clarithromycin in the presence of human liver microsomes. Major role for the cytochrome P4503A (CYP3A) subfamily Drug Metab Dispos 1997 25 5 623 630 9152603 \n18. Richardson PG Briemberg H Jagannath S Frequency, characteristics, and reversibility of peripheral neuropathy during treatment of advanced multiple myeloma with bortezomib J Clin Oncol 2006 24 19 3113 3120 10.1200/JCO.2005.04.7779 16754936 \n19. Hashimoto N Yokoyama K Sadahira K Ueda T Tsukada Y Okamoto S Itraconazole may increase the risk of early-onset bortezomib-induced peripheral neuropathy Int J Hematol 2012 96 6 758 763 10.1007/s12185-012-1224-5 23179905 \n20. Spahn JD Fost DA Covar R Clarithromycin potentiates glucocorticoid responsiveness in patients with asthma: results of a pilot study Ann Allergy Asthma Immunol 2001 87 6 501 505 10.1016/S1081-1206(10)62264-8 11770698 \n21. Trifan A Girleanu I Cojocariu C Pseudomembranous colitis associated with a triple therapy for Helicobacter pylori eradication World J Gastroenterol 2013 19 42 7476 7479 10.3748/wjg.v19.i42.7476 24259981 \n22. Teare JP Booth JC Brown JL Martin J Thomas HC Pseudomembranous colitis following clarithromycin therapy Eur J Gastroenterol Hepatol 1995 7 3 275 277 7743311 \n23. Wang Y Sanchez L Siegel DS Wang ML Elotuzumab for the treatment of multiple myeloma J Hematol Oncol 2016 9 1 55 10.1186/s13045-016-0284-z 27417553 \n24. Sanchez L Wang Y Siegel DS Wang ML Daratumumab: a first-in-class CD38 monoclonal antibody for the treatment of multiple myeloma J Hematol Oncol 2016 9 1 51 10.1186/s13045-016-0283-0 27363983\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2162-3619",
"issue": "7()",
"journal": "Experimental hematology & oncology",
"keywords": "Adverse drug event; Bortezomib; Clarithromycin; Double blind study; Induction chemotherapy; Multiple myeloma",
"medline_ta": "Exp Hematol Oncol",
"mesh_terms": null,
"nlm_unique_id": "101590676",
"other_id": null,
"pages": "18",
"pmc": null,
"pmid": "30123673",
"pubdate": "2018",
"publication_types": "D016428:Journal Article",
"references": "17989313;9152603;12780789;11770698;27417553;12685831;20645430;21292775;7743311;23525864;16754936;8433390;27363983;28039292;23179905;24259981;16103134;20811702;17574838;25602299;17362317;18759764;23546223;25729426",
"title": "A randomized placebo-controlled phase II study of clarithromycin or placebo combined with VCD induction therapy prior to high-dose melphalan with stem cell support in patients with newly diagnosed multiple myeloma.",
"title_normalized": "a randomized placebo controlled phase ii study of clarithromycin or placebo combined with vcd induction therapy prior to high dose melphalan with stem cell support in patients with newly diagnosed multiple myeloma"
} | [
{
"companynumb": "DK-TAKEDA-2018MPI011465",
"fulfillexpeditecriteria": "1",
"occurcountry": "DK",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CYCLOPHOSPHAMIDE"
},
"drugadditional": null,
... |
{
"abstract": "Better understanding of the dynamics of HIV reservoirs under ART is a critical step to achieve a functional HIV cure. Our objective was to assess the genetic diversity of archived HIV-1 DNA over 48 weeks in blood cells of individuals starting treatment with a dolutegravir-based regimen.\n\n\n\nEighty blood samples were prospectively and longitudinally collected from 20 individuals (NCT02557997) including: acutely (n = 5) and chronically (n = 5) infected treatment-naive individuals, as well as treatment-experienced individuals who switched to a dolutegravir-based regimen and were either virologically suppressed (n = 5) or had experienced treatment failure (n = 5). The integrase and V3 loop regions of HIV-1 DNA isolated from PBMCs were analysed by pyrosequencing at baseline and weeks 4, 24 and 48. HIV-1 genetic diversity was calculated using Shannon entropy.\n\n\n\nAll individuals achieved or maintained viral suppression throughout the study. A low and stable genetic diversity of archived HIV quasispecies was observed in individuals starting treatment during acute infection. A dramatic reduction of the genetic diversity was observed at week 4 of treatment in the other individuals. In these patients and despite virological suppression, a recovery of the genetic diversity of the reservoirs was observed up to 48 weeks. Viral variants bearing dolutegravir resistance-associated substitutions at integrase position 50, 124, 230 or 263 were detected in five individuals (n = 5/20, 25%) from all groups except those who were ART-failing at baseline. None of these substitutions led to virological failure.\n\n\n\nThese data demonstrate that the genetic diversity of the HIV-1 reservoir is reshaped following the initiation of a dolutegravir-based regimen and strongly suggest that HIV-1 can continue to replicate despite successful treatment.",
"affiliations": "Virology Laboratory, Strasbourg University Hospitals, Strasbourg, France.;The Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA.;Le Trait d'Union, HIV-infection care center, CHU de Strasbourg, Strasbourg, France.;McGill University AIDS Centre, Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Quebec, Canada.;Le Trait d'Union, HIV-infection care center, CHU de Strasbourg, Strasbourg, France.;Le Trait d'Union, HIV-infection care center, CHU de Strasbourg, Strasbourg, France.;Internal Medicine Department, HIV-infection care center, GHR Mulhouse Sud Alsace, Mulhouse, France.;Department of Infectious Diseases, Hôpital Nord Franche Comté, Belfort, France.;Internal Medicine and Rheumatology Department, Hôpital Civil de Colmar, Colmar, France.;Internal Medicine and Rheumatology Department, Hôpital Civil de Colmar, Colmar, France.;McGill University AIDS Centre, Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Quebec, Canada.;Virology Laboratory, Strasbourg University Hospitals, Strasbourg, France.",
"authors": "Gantner|Pierre|P|;Lee|Guinevere Q|GQ|;Rey|David|D|;Mesplede|Thibault|T|;Partisani|Marialuisa|M|;Cheneau|Christine|C|;Beck-Wirth|Geneviève|G|;Faller|Jean-Pierre|JP|;Mohseni-Zadeh|Mahsa|M|;Martinot|Martin|M|;Wainberg|Mark A|MA|;Fafi-Kremer|Samira|S|",
"chemical_list": "D004279:DNA, Viral; D015699:HIV Envelope Protein gp120; D019428:HIV Integrase Inhibitors; D006575:Heterocyclic Compounds, 3-Ring; D010078:Oxazines; D010879:Piperazines; D011728:Pyridones; C514793:gp120 protein, Human immunodeficiency virus 1; C562325:dolutegravir; D019427:HIV Integrase",
"country": "England",
"delete": false,
"doi": "10.1093/jac/dkx475",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0305-7453",
"issue": "73(4)",
"journal": "The Journal of antimicrobial chemotherapy",
"keywords": null,
"medline_ta": "J Antimicrob Chemother",
"mesh_terms": "D000328:Adult; D000368:Aged; D004279:DNA, Viral; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D015699:HIV Envelope Protein gp120; D015658:HIV Infections; D019427:HIV Integrase; D019428:HIV Integrase Inhibitors; D015497:HIV-1; D006575:Heterocyclic Compounds, 3-Ring; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D010078:Oxazines; D010879:Piperazines; D011446:Prospective Studies; D011728:Pyridones; D017422:Sequence Analysis, DNA; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "7513617",
"other_id": null,
"pages": "1045-1053",
"pmc": null,
"pmid": "29244129",
"pubdate": "2018-04-01",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Dolutegravir reshapes the genetic diversity of HIV-1 reservoirs.",
"title_normalized": "dolutegravir reshapes the genetic diversity of hiv 1 reservoirs"
} | [
{
"companynumb": "FR-VIIV HEALTHCARE LIMITED-FR2018065332",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TENOFOVIR DISOPROXIL FUMARATE"
},
... |
{
"abstract": "As many as 30% of individuals with a schizophrenia spectrum disorder experience obsessive-compulsive symptoms (OCS). Clozapine has demonstrated superior efficacy for the treatment of medication-resistant schizophrenia but it is also associated with an increased risk for OCS. Because pharmacologic management of clozapine-related OCS can be particularly challenging, cognitive behavioral therapy (CBT) should be considered. Nevertheless, there are few detailed accounts of CBT for OCS and schizophrenia.\n\n\n\nThe authors describe the interdisciplinary outpatient care of a client who had a 25-year history of schizoaffective disorder, bipolar type, and OCS. The case formulation was used to guide interventions to target core schemas of being dangerous and defective. The case study describes the cognitive behavioral formulation, treatment targets, treatment course, and functional and symptom response.\n\n\n\nThe client received 21 sessions of a formulation-based CBT for psychosis protocol, which included a 6-session course of exposure with response prevention, consisting of imaginal and in vivo exposure to multiple salient harm stimuli. Reduced ratings of distress and a 50% reduction in OCS suggest that habituation and inhibitory learning occurred. The treatment of OCS resulted in the complete resolution of thought broadcasting. Subsequently, the client was more successful in his efforts to adhere to an action schedule.\n\n\n\nThe use of both the treatment approach described in this clinical case report and contemporaneous medication management preclude comment on the mechanism(s) of the therapeutic change observed in this case.\n\n\n\nThis report presents a means of conceptualizing the interplay between thought broadcasting and harm obsessions and discusses considerations in identifying and treating individuals with similar comorbid conditions, particularly in the context of clozapine treatment for medication-resistant psychosis.",
"affiliations": null,
"authors": "Kopelovich|Sarah L|SL|;Wood|Keith|K|;Cotes|Robert O|RO|;Goldsmith|David R|DR|",
"chemical_list": "D014150:Antipsychotic Agents; D003024:Clozapine",
"country": "United States",
"delete": false,
"doi": "10.1097/PRA.0000000000000470",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1527-4160",
"issue": "26(4)",
"journal": "Journal of psychiatric practice",
"keywords": null,
"medline_ta": "J Psychiatr Pract",
"mesh_terms": "D000369:Aged, 80 and over; D014150:Antipsychotic Agents; D000068105:Bipolar and Related Disorders; D003024:Clozapine; D003071:Cognition; D003210:Concept Formation; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009770:Obsessive Behavior; D009771:Obsessive-Compulsive Disorder; D011618:Psychotic Disorders; D012559:Schizophrenia; D055815:Young Adult",
"nlm_unique_id": "100901141",
"other_id": null,
"pages": "329-336",
"pmc": null,
"pmid": "32692132",
"pubdate": "2020-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Integration of Clozapine-associated Harm Obsessions into Cognitive Behavioral Conceptualization and Treatment Planning for Thought Broadcasting: A Case Study.",
"title_normalized": "integration of clozapine associated harm obsessions into cognitive behavioral conceptualization and treatment planning for thought broadcasting a case study"
} | [
{
"companynumb": "US-MYLANLABS-2020M1074058",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "CLOZAPINE"
},
"drugadditional": "1",
... |
{
"abstract": "BACKGROUND\nThe off-label use of high-dose baclofen (HDB) for alcohol-dependence has recently spread. However, HDB has been associated with numerous reports of adverse events (AEs). Pharmacovigilance reporting is supposed to differentiate AEs from adverse drug reactions (ADRs), for which the causality of the drug is determined using validated methods.\n\n\nMETHODS\nSince 2010, we found 20 publications on baclofen-related AEs in alcohol dependence, in Medline-referenced journals or national pharmacovigilance reports. We focused on whether these reports used causality algorithms, and provided essential elements for determining baclofen causality and excluding the involvement of alcohol and other psychoactive substances or psychotropic drugs. In half of the cases, no causality algorithm was used. Detailed information on baclofen dosing was found in 17 out of 20 (85%) articles, whereas alcohol doses were given only in 10 (50%) publications. Other psychoactive substances and psychotropic drugs were broached in 14 (70%) publications.\n\n\nCONCLUSIONS\nfuture publications reporting suspected HDB-induced ADRs should use validated causality algorithms and provide sufficient amount of contextual information for excluding other potential causes. For HDB, the psychiatric history, and the longitudinal description of alcohol consumptions and associated doses of psychoactive substances or psychotropic medications should be detailed for every reported case.",
"affiliations": "a Service d'Addictologie, CHU Lille , Lille , France.;c Centre Régional de Pharmacovigilance , INSERM U1171, CHU Lille , Lille , France.;d Service d'Addictologie, CHU Toulouse , France.",
"authors": "Rolland|Benjamin|B|;Auffret|Marine|M|;Franchitto|Nicolas|N|",
"chemical_list": "D058786:GABA-B Receptor Agonists; D001418:Baclofen",
"country": "England",
"delete": false,
"doi": "10.1517/14740338.2016.1168397",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1474-0338",
"issue": "15(6)",
"journal": "Expert opinion on drug safety",
"keywords": "Pharmacovigilance; alcohol dependence; baclofen; causality; drug safety",
"medline_ta": "Expert Opin Drug Saf",
"mesh_terms": "D000428:Alcohol Drinking; D000437:Alcoholism; D000465:Algorithms; D001418:Baclofen; D004305:Dose-Response Relationship, Drug; D058786:GABA-B Receptor Agonists; D006801:Humans; D056687:Off-Label Use; D060735:Pharmacovigilance",
"nlm_unique_id": "101163027",
"other_id": null,
"pages": "747-51",
"pmc": null,
"pmid": "26987987",
"pubdate": "2016-06",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": null,
"title": "Safety reports on the off-label use of baclofen for alcohol-dependence: recommendations to improve causality assessment.",
"title_normalized": "safety reports on the off label use of baclofen for alcohol dependence recommendations to improve causality assessment"
} | [
{
"companynumb": "FR-IMPAX LABORATORIES, INC-2016-IPXL-00809",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "BACLOFEN"
},
"drugadditional... |
{
"abstract": "Omadacycline is an aminomethylcycline antimicrobial approved by the US Food and Drug Administration in 2018 for community-acquired bacterial pneumonia and acute bacterial skin and skin structure infections. It has in vitro activity against nontuberculous mycobacteria, including Mycobacterium abscessus complex, but clinical data for this indication are lacking.\nOmadacycline use was reviewed at an 804-bed academic medical center. Patients were included if they received omadacycline for culture-proven M abscessus disease in 2019.\nFour patients received omadacycline for the treatment of culture-positive M abscessus disease in 2019. Two patients had cutaneous disease, 1 had pulmonary disease, and 1 had osteomyelitis and bacteremia. The patients received omadacycline for a median duration of 166 days (range, 104-227) along with a combination of other antimicrobial agents. Omadacycline-containing regimens were associated with a clinical cure in 3 of 4 patients, with 1 patient improving on ongoing treatment. Omadacycline's tolerability was acceptable for patients with M abscessus disease, with 1 patient discontinuing therapy in month 6 due to nausea.\nOmadacycline is a novel oral option for the treatment of M abscessus disease, for which safe and effective options are needed. Although this case series is promising, further data are required to determine omadacycline's definitive role in the treatment of M abscessus disease.",
"affiliations": "Department of Pharmacy, Brigham and Women's Hospital, Boston, Massachusetts, USA.;Department of Pharmacy, Brigham and Women's Hospital, Boston, Massachusetts, USA.;Division of Infectious Diseases, Brigham and Women's Hospital, Boston, Massachusetts, USA.;Division of Infectious Diseases, Brigham and Women's Hospital, Boston, Massachusetts, USA.;Division of Infectious Diseases, Brigham and Women's Hospital, Boston, Massachusetts, USA.;Division of Infectious Diseases, Brigham and Women's Hospital, Boston, Massachusetts, USA.;Division of Infectious Diseases, Brigham and Women's Hospital, Boston, Massachusetts, USA.;Division of Infectious Diseases, Brigham and Women's Hospital, Boston, Massachusetts, USA.;Division of Infectious Diseases, Brigham and Women's Hospital, Boston, Massachusetts, USA.",
"authors": "Pearson|Jeffrey C|JC|0000-0002-5276-1050;Dionne|Brandon|B|;Richterman|Aaron|A|0000-0001-7920-7191;Vidal|Samuel J|SJ|;Weiss|Zoe|Z|;Velásquez|Gustavo E|GE|;Marty|Francisco M|FM|0000-0002-3708-8734;Sax|Paul E|PE|;Yawetz|Sigal|S|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1093/ofid/ofaa415",
"fulltext": "\n==== Front\nOpen Forum Infect Dis\nOpen Forum Infect Dis\nofid\nOpen Forum Infectious Diseases\n2328-8957 Oxford University Press US \n\n10.1093/ofid/ofaa415\nofaa415\nMajor Articles\nAcademicSubjects/MED00290\nOmadacycline for the Treatment of Mycobacterium abscessus Disease: A Case Series\nhttp://orcid.org/0000-0002-5276-1050Pearson Jeffrey C 12 Dionne Brandon 13 http://orcid.org/0000-0001-7920-7191Richterman Aaron 2 Vidal Samuel J 2 Weiss Zoe 2 Velásquez Gustavo E 256 http://orcid.org/0000-0002-3708-8734Marty Francisco M 247 Sax Paul E 24 Yawetz Sigal 24 1 \nDepartment of Pharmacy, Brigham and Women’s Hospital, Boston, Massachusetts, USA\n2 \nDivision of Infectious Diseases, Brigham and Women’s Hospital, Boston, Massachusetts, USA\n3 \nSchool of Pharmacy, Northeastern University, Boston, Massachusetts, USA\n4 \nHarvard Medical School, Boston, Massachusetts, USA\n5 \nDivision of Global Health Equity, Brigham and Women’s Hospital, Boston, Massachusetts, USA\n6 \nDepartment of Global Health and Social Medicine, Harvard Medical School, Boston, Massachusetts, USA\n7 \nDivision of Infectious Diseases, Dana Farber Cancer Institute, Boston, Massachusetts, USA\nCorrespondence: Jeffrey C. Pearson, PharmD, 181 Longwood Avenue, Boston, MA 02115 (jcpearson@bwh.harvard.edu).\n10 2020 \n09 9 2020 \n09 9 2020 \n7 10 ofaa41507 8 2020 01 9 2020 03 9 2020 15 10 2020 © The Author(s) 2020. Published by Oxford University Press on behalf of Infectious Diseases Society of America.2020This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.comAbstract\nBackground\nOmadacycline is an aminomethylcycline antimicrobial approved by the US Food and Drug Administration in 2018 for community-acquired bacterial pneumonia and acute bacterial skin and skin structure infections. It has in vitro activity against nontuberculous mycobacteria, including Mycobacterium abscessus complex, but clinical data for this indication are lacking.\n\nMethods\nOmadacycline use was reviewed at an 804-bed academic medical center. Patients were included if they received omadacycline for culture-proven M abscessus disease in 2019.\n\nResults\nFour patients received omadacycline for the treatment of culture-positive M abscessus disease in 2019. Two patients had cutaneous disease, 1 had pulmonary disease, and 1 had osteomyelitis and bacteremia. The patients received omadacycline for a median duration of 166 days (range, 104–227) along with a combination of other antimicrobial agents. Omadacycline-containing regimens were associated with a clinical cure in 3 of 4 patients, with 1 patient improving on ongoing treatment. Omadacycline’s tolerability was acceptable for patients with M abscessus disease, with 1 patient discontinuing therapy in month 6 due to nausea.\n\nConclusions\nOmadacycline is a novel oral option for the treatment of M abscessus disease, for which safe and effective options are needed. Although this case series is promising, further data are required to determine omadacycline’s definitive role in the treatment of M abscessus disease.\n\nWe describe longer-term use of omadacycline as part of a treatment regimen for 4 patients with Mycobacterium abscessus disease and summarize the evidence to-date for the use of omadacycline in mycobacterial diseases.\n\nmycobacterial infectionsMycobacterium abscessusnontuberculous mycobacteriaomadacyclineNational Institute of Allergy and Infectious Diseases10.13039/100000060K08 AI141740L30 AI120170P30 AI060354National Institutes of Health10.13039/100000002T32 AI007387\n==== Body\nMycobacterium abscessus complex, consisting of subspecies M abscessus, Mycobacterium massiliense, and Mycobacterium bolletii, most frequently causes pulmonary or skin and soft tissue diseases [1]. The American Thoracic Society/Infectious Diseases Society of America nontuberculous mycobacterial (NTM) diseases guidelines recommend a combination of a macrolide with amikacin and either high-dose cefoxitin or imipenem for the initial treatment of serious skin, soft tissue, and bone diseases caused by M abscessus [2]. Pulmonary disease-specific NTM guidelines recommend a combination including a macrolide and at least 3 active antimicrobials for the initial treatment phase [3]. However, resistance to multiple antibacterial classes is common for M abscessus, making management particularly challenging [4]. For example, although a macrolide is considered one of the cornerstones of therapy, M abscessus subsp abscessus often has a functional erythromycin ribosomal methylase gene 41 (erm41), which confers inducible resistance to macrolides [5]. Treatment is prolonged and includes multiple active antimicrobials, several available only in intravenous formulations and/or limited by tolerability [2].\n\nOmadacycline is a novel aminomethylcycline antimicrobial related to tigecycline available in both intravenous and oral formulations. It was approved by the US Food and Drug Administration in 2018 for the treatment of community-acquired bacterial pneumonia and acute bacterial skin and skin structure infections. It shows in vitro activity against both Gram-positive and Gram-negative organisms [6]. Since its approval, multiple studies have shown that omadacycline has favorable in vitro minimum inhibitory concentrations (MICs) against NTM, most notably M abscessus [7–9]. We report our clinical experience with the use of omadacycline as part of combination therapy for M abscessus disease.\n\nMETHODS\nWe reviewed omadacycline use at our 804-bed academic medical center and included patients who received omadacycline for culture-proven M abscessus disease in 2019. Follow-up data were collected up until June 24, 2020. The University of Texas Health Science Center at Tyler performed mycobacterial susceptibility testing for 3 of the 4 isolates (cases 2–4), whereas the Laboratory Corporation of America provided susceptibility for case 1. Both laboratories were able to evaluate for inducible macrolide resistance, and both followed Clinical and Laboratory Standards Institute (CLSI) M24 performance standards for susceptibility testing [10]. Meropenem/vaborbactam testing for case 4 was done at a research laboratory at Harvard Medical School using an alamarBlue cell proliferation assay.\n\nPatient Consent Statement\nAll patients provided verbal consent for this case series to be published. The case series received exempt status from the Partners HealthCare Institutional Review Board (protocol 2019P003244). Health Insurance Portability and Accountability Act (HIPAA) privacy rules have been followed.\n\nRESULTS\nFour patients received omadacycline for the treatment of M abscessus in the 12-month study period.\n\nCase 1\nA 45-year-old female underwent elective silicone breast implantation, liposuction, and liposculpting of both arms, chest wall, upper lateral buttocks, back, and brachioplasty in the southern United States. Four weeks later, she developed persistent breast and back wound drainage and dehiscence requiring multiple debridements and implant replacements. After M abscessus subsp bolletii was cultured from the breast and back, empiric treatment with clarithromycin and trimethoprim-sulfamethoxazole was initiated. Three months into treatment, her implants were removed, and her regimen was changed to clarithromycin and linezolid due to poor response. Shortly thereafter, she experienced worsening of her skin abscesses and was hospitalized to initiate amikacin, clarithromycin, and tigecycline. Her treatment was changed to azithromycin, linezolid, and tigecycline once susceptibilities resulted (Table 1). Because her organism’s tigecycline MIC was 0.25 mcg/mL, it was inferred that omadacycline may be active against the isolate. She was changed to oral omadacycline 450 mg daily for 2 doses as a loading dose, followed by 300 mg daily, and she was ultimately discharged with an all-oral regimen of azithromycin, linezolid, and omadacycline.\n\nTable 1. Minimum Inhibitory Concentration Resultsa\n\nAntimicrobial\tIsolate 1\t\tIsolate 2\t\tIsolate 3\t\tIsolate 4\t\t\nAmikacin\t32\tI\t8\tS\t8\tS\t16\tS\t\nCefoxitin\t128\tR\t32\tI\t32\tI\t64\tI\t\nCiprofloxacin\t>4\tR\t>4\tR\t>4\tR\t>4\tR\t\nClarithromycin\t2\tS\t>16\tR\tR\tR\tR\tR\t\nDoxycycline\t>16\tR\t>16\tR\t16\tR\t>16\tR\t\nImipenem\t32\tR\t8\tI\t16\tI\t8\tI\t\nLinezolid\t16\tI\t16\tI\t16\tI\t8\tS\t\nMinocycline\t>8\tR\t>8\tR\t>8\tR\t>8\tR\t\nMoxifloxacin\t>8\tR\t8\tR\t>8\tR\t>8\tR\t\nTrimethoprim/sulfamethoxazole\t>8/152\tR\t4/76\tR\t8/152\tR\t8/152\tR\t\nTigecycline\t0.25\t\t0.12\t\t0.25\t\t0.25\t\t\nClofazimine\t\t\t0.5\t\t0.5\t\t0.5\t\t\nBedaquiline\t\t\t\t\t0.12\t\t0.12\t\t\nMeropenem/vaborbactam\t\t\t\t\t>8/8\t\t4/8b\t\t\nOmadacycline\t\t\t\t\t0.25\t\t\t\t\n\naAll susceptibility testing was performed at The University of Texas Health Science Center at Tyler (cases 2–4) or the Laboratory Corporation of America (case 1) following Clinical and Laboratory Standards Institute (CLSI) M24 performance standards for susceptibility testing.\n\n\nbMeropenem/vaborbactam susceptibility testing for isolate 4 was performed at a research laboratory at Harvard Medical School using an alamarBlue cell proliferation assay.\n\nDuring treatment, she required 3 additional drainage procedures in her lower back. She experienced cytopenias and paresthesias in her hands and feet, attributed to linezolid, which improved with a change to tedizolid. She now has minimal residual nodules and noticeable healing in areas of prior surgical drainage. She completed 6 months of omadacycline therapy in combination with azithromycin and an oxazolidinone, tolerating omadacycline without adverse events and to date has no evidence of disease recurrence 8 months after antibiotic completion.\n\nCase 2\nA 72-year-old male developed head and neck cancer for which he underwent surgery and radiation therapy resulting in chronic aspiration events. He later developed a rheumatological disease characterized by weight loss, elevated inflammatory markers, and fluorodeoxyglucose (FDG)-avid thoracic and abdominal lesions consisting of dense lymphoplasmacytic infiltrates that were negative by mycobacterial culture. This disease remained undifferentiated despite extensive multidisciplinary evaluation. He was ultimately treated with 1 year of glucocorticoids with resolution of his symptoms and biochemical and radiographic abnormalities. Near the end of his glucocorticoid course, he developed fatigue, night sweats, and dyspnea, and a computed tomography (CT) scan of the chest revealed a large right middle lobe consolidation. Endobronchial biopsy demonstrated granulomatous changes with abundant acid-fast bacilli and culture identified M abscessus subsp abscessus.\n\nHis corticosteroid dose was tapered, and he completed a 2-month induction course of amikacin, imipenem, clofazimine, and oral omadacycline dosed at 450 mg daily for 2 days, then 300 mg daily. He developed significant hearing loss and renal dysfunction on this regimen due to amikacin. After the 2-month induction phase, his treatment was changed to omadacycline, clofazimine, and tedizolid for an all-oral regimen. Shortly after tedizolid initiation, he developed increased fatigue and dizziness, and tedizolid was therefore discontinued within days of initiation. Clofazimine and omadacycline were continued.\n\nDespite medical management, he continued to experience fatigue and weight loss, and his chest CT showed a persistent right middle lobe consolidation. There was concern for ongoing infection, and he therefore underwent thoracoscopic right middle lobe resection 5 months into omadacycline therapy. During his hospitalization, he was unable to tolerate oral therapy for 1 week, so his clofazimine and omadacycline were briefly substituted with imipenem and eravacycline. After surgery, he continued clofazimine and omadacycline, and there was gradual improvement in his fatigue and weight loss. Pathology from the lobectomy revealed granulomas, scarring, and interstitial chronic inflammation. There were no acid-fast bacilli on standard and modified stains, and immunohistochemistry showed degenerated and fragmented mycobacterial forms. With negative lobectomy and bronchoalveolar lavage cultures, his antimicrobial therapy was discontinued 3 months postoperatively. Overall, he tolerated omadacycline for over 7 months and has had no evidence of disease recurrence in 4 months since discontinuation.\n\nCase 3\nA 35-year-old female underwent abdominoplasty and back and buttocks liposuction in the Dominican Republic. One month later, she developed a postoperative wound infection treated empirically with moxifloxacin and clindamycin. Her infection worsened, and she subsequently transferred to our hospital with sepsis, wound dehiscence, and a clinical concern for a necrotizing skin and soft tissue infection. She had extensive deep tissue involvement in the flanks, abdominal wall, and thighs. She underwent multiple abdominal wall washouts, and intraoperative cultures resulted in mixed bacteria, including M abscessus subsp abscessus. At the time of discharge, she was treated with azithromycin, amikacin, imipenem, and linezolid. Susceptibility testing ultimately demonstrated resistance to linezolid and macrolides, and linezolid was discontinued (Table 1). Imipenem was discontinued after she complained of knee and ankle pain and chills suggestive of a serum sickness reaction. At that point, 19 days into her treatment course, oral omadacycline 300 mg daily was added to azithromycin and amikacin. She experienced mild nausea upon omadacycline initiation, which resolved after several days without medical management. Shortly thereafter, the patient reported tinnitus, so amikacin was discontinued and clofazimine was initiated for an all-oral regimen of omadacycline, clofazimine, and azithromycin.\n\nHer initial debridement procedures in the hospital had left her with open wounds in both flanks, abdominal wall, and thighs. These wounds demonstrated slow improvement, but during the first 2 months of therapy, she required several additional debridements in areas that continued to demonstrate poor healing. Her infection has slowly improved without recent flares but has not fully resolved. Her most recent operative cultures are negative for M abscessus. In month 6 of omadacycline therapy, she developed nausea and vomiting for which she discontinued omadacycline. Since then, she has continued on clofazimine and azithromycin with no additional adverse events noted.\n\nCase 4\nA 41-year-old male with Guillain-Barré syndrome (GBS), chronic inflammatory demyelinating polyneuropathy, erythromelalgia, and prior lengthy antibiotic therapy for Lyme disease underwent a below-the-knee amputation for noninfectious complications of neuropathy. He had a chronic indwelling intravenous catheter for ongoing intravenous lidocaine for pain control and plasmapheresis for GBS. One month after his surgery, he developed a fever and progressive back pain. He ultimately presented to our hospital where M abscessus subsp abscessus was cultured from the blood. A lumbar spine magnetic resonance image (MRI) revealed findings compatible with vertebral discitis and osteomyelitis.\n\nHis indwelling catheter was removed, and subsequent blood cultures were negative. Diagnostic aspiration cultured M abscessus from the disc and vertebral bone. He began treatment with cefoxitin, amikacin, and tigecycline and underwent epidural abscess evacuation and vertebral debridement without placement of hardware. Tissue cultures were positive for M abscessus. Cefoxitin was changed to imipenem due to worsening transaminitis, and clofazimine was added to his regimen. Amikacin was changed to bedaquiline when he developed vestibular toxicity and a mild creatinine elevation. Due to ongoing back discomfort, MRIs were obtained 2 months and again 5 months into therapy, which revealed ongoing discitis and a small fluid collection, but a repeat aspiration was culture-negative at 60 days. Clofazimine was discontinued due to QT prolongation, and imipenem, tigecycline, and bedaquiline were continued. Shortly thereafter, imipenem was changed to meropenem/vaborbactam based on a lower MIC (Table 1), and tigecycline was discontinued due to continued transaminitis.\n\nHe continued to have mild intermittent drug-induced transaminitis and thrombocytopenia. A switch to an all-oral regimen was planned; he did not tolerate a trial of linezolid due to finger and toe paresthesias, so omadacycline was added to his bedaquiline to complete a 2-year total course of therapy. Oral omadacycline was initiated at 300 mg daily without a loading dose. Since omadacycline initiation, his transaminases have improved. He recently completed 24 months of therapy, 3 and a half months of which were with omadacycline, with no evidence of disease recurrence since treatment discontinuation 6 months ago.\n\nSummary\nFour patients received omadacycline for the treatment of culture-positive M abscessus disease in 2019 at our institution. Two patients had cutaneous disease, 1 had pulmonary disease, and 1 had osteomyelitis and bacteremia. Overall, omadacycline was well tolerated for over 7 months of treatment (median, 166 days; range, 104–227) and was associated with clinical cure in 3 of the 4 patients, with the other patient improving with ongoing treatment off omadacycline.\n\nDISCUSSION\nIntrinsic and acquired resistance to multiple antimicrobials make M abscessus disease challenging to treat, leading one review to describe it as an “antibiotic nightmare” [1]. Due to the prevalence of resistance, susceptibility testing and prolonged combination therapy are recommended for all clinically significant M abscessus diseases. However, in vitro susceptibility testing may not necessarily correlate with patient outcomes, particularly in pulmonary disease [2, 3, 11]. In a 2011 study, Jarand et al [12] found that only 48% of patients with M abscessus pulmonary disease converted to negative cultures without recurrence after treatment, despite ≥85% susceptibility to azithromycin and amikacin—2 of the treatment mainstays, and the only agents considered to have adequate correlation between in vitro activity and microbiological response [3].\n\nParenteral therapy is used in the majority of M abscessus diseases, posing a significant challenge because patients are on therapy for at least 4 months, and often ≥12 months [2, 3, 13]. The introduction of novel oral antibiotics with in vitro activity against mycobacteria offers the opportunity to complete an extended treatment duration with an all-oral regimen. Oral antimicrobials with in vitro activity against rapidly growing mycobacteria include macrolides, fluoroquinolones, oxazolidinones, rifamycins, clofazimine, bedaquiline, and, most recently, omadacycline [7, 13]. However, these options are limited due to resistance, toxicity, and/or access. For example, inducible resistance against macrolides is common [5]. Oxazolidinones may cause myelosuppression, peripheral neuropathy, and optic neuritis [14], and clofazimine and bedaquiline may cause QTc prolongation [15, 16]. Clofazimine also requires an investigational new drug submission for use in the United States, and bedaquiline has only been approved for treatment of multidrug-resistant tuberculosis [17, 18]. Although in vitro data support these options, clinical data with combinations of these oral antimicrobials are lacking.\n\nIn our case series, all 4 M abscessus isolates were identified to the subspecies level, which is not always performed routinely in clinical practice despite expert recommendation [19]. Three of the 4 patients had M abscessus subsp abscessus, which has lower response rates compared with M abscessus subsp massiliense [20]. The most active antimicrobials using CLSI M62 breakpoints were amikacin, linezolid, imipenem, and cefoxitin (Table 1). All but 1 patient had a macrolide-resistant isolate, with the M abscessus isolates for cases 2–4 all returning positive for the inducible erm41 gene. The MIC of tigecycline ranged from 0.12 to 0.25 mcg/mL. There are currently no clinically defined breakpoints to help interpret these values for tigecycline, but a susceptibility breakpoint of ≤0.5 mcg/mL has been proposed [21]. Omadacycline susceptibility testing was performed on one isolate, resulting in the same MIC as tigecycline (0.25 mcg/mL).\n\nGiven the variability in susceptibility profiles of the mycobacterial isolates and adverse events experienced, several treatment regimens were used. This mirrors the lack of standard treatment options described by Novosad et al [4] in 2016, where a total of 21 different combinations were used in a cohort of 65 patients with M abscessus disease. The most commonly used antimicrobials in our case series besides omadacycline were amikacin (4 cases), imipenem (3 cases), and clofazimine (3 cases). All 4 patients had at least 1 antimicrobial regimen adjustment, primarily due to potential drug toxicities.\n\nAll 4 patients developed antimicrobial-related toxicities during their extended treatment courses (Table 2). In phase 3 clinical trials, the most common adverse events seen with intravenous omadacycline were nausea (14.9%), vomiting (8.3%), and increased transaminases (5.4%) [22]. Compared with the variety of toxicities seen in patients from our study, omadacycline was relatively well tolerated. One patient experienced nausea for several days after initiation, and then the patient ended up discontinuing omadacycline in month 6 of treatment due to recurrent nausea. It is notable that the patient did not receive an omadacycline loading dose. In the phase 3 randomized controlled trial that investigated oral omadacycline with a loading dose for acute bacterial skin and skin structure infections, 30% of patients experienced nausea [23], more than double the rate seen with omadacycline use in the other phase 3 trials [24, 25]. Based on a pharmacokinetic analysis, a dose of 300 mg daily would reach similar concentrations without a loading dose by day 5, which may be adequate in the treatment of NTM infections given their slow growth kinetics compared with typical bacteria [26]. Loading doses may be beneficial when the inoculum is high; this strategy was used in 2 patients who initiated omadacycline before source control without adverse events.\n\nTable 2. Case Summaries\n\nCase No.\tOrganism Isolated\t\nMycobacterium abscessus Infection Location\tOmadacycline Loading Dose\tOmadacycline Maintenance Dose\tAntimicrobials Before Omadacycline\tConcurrent Antimicrobials\tSurgical Management\tTreatment Duration (Days)\tResolution\tPossible Treatment-Related Adverse Events\t\n1\t\nM abscessus subsp bolletii\tSkin (back, breast)\t450 mg daily ×2 doses\t300 mg daily\t• clarithromycin, TMP-SMX\n• clarithromycin, linezolid\n• amikacin, clarithromycin, tigecycline\n• azithromycin, linezolid, tigecycline\t• azithromycin, linezolid\n• azithromycin, tedizolid\tYes: implant removal, multiple debridements, and drainages\tTotal: 264\nOmada: 227\tCure\tLinezolid: cytopenias, paresthesias\t\n2\t\nM abscessus subps abscessus\tPulmonary\t450 mg daily ×2 doses\t300 mg daily\tN/A\t• amikacin, imipenem, clofazimine\tYes: wedge resection, lobectomy\tTotal: 227\nOmada: 227\tCure\tAmikacin: hearing loss, renal impairment\nTedizolid: fatigue and dizziness\t\n\t\t\t\t\t\t• clofazimine, tedizolid\n• clofazimine\n• imipenem and eravacyclinea\t\t\t\t\t\n3\t\nM abscessus subsp abscessus\tSkin (abdominal wall)\tN/A\t300 mg daily\t• azithromycin, linezolid, amikacin, imipenem\t• azithromycin, amikacin\n• azithromycin, clofazimine\tYes: multiple abdominal wall washouts and debridements\tTotal: >332\nOmada: 159\tOngoing, but improving\tImipenem: serum sickness\nAmikacin: tinnitus\nOmadacycline: nausea and vomiting\t\n4\t\nM abscessus subsp abscessus\tBlood, Vertebrae\tN/A\t300 mg daily\t• amikacin, cefoxitin, tigecycline\n• imipenem, tigecycline, clofazimine, bedaquiline\n• meropenem-vaborbactam, bedaquiline, tigecycline\n• meropenem-vaborbactam, bedaquiline\t• bedaquiline\tYes: epidural abscess evacuation and vertebral debridement\tTotal: 731\nOmada: 104\tCure\tCefoxitin, tigecycline, bedaquiline: transaminitis\nClofazimine: QTc elevation\nAmikacin: vestibular symptoms and mild creatinine elevation\nBedaquiline: thrombocytopenia\nLinezolid: numbness of extremities\t\nAbbreviations: N/A, not applicable; NPO, nothing by mouth; TMP-SMX, trimethoprim-sulfamethoxazole.\n\n\naDuring case 2’s omadacycline course, there was a brief switch to imipenem and eravacycline when the patient was NPO for 7 days.\n\n\nMycobacterium abscessus isolates have been tested against omadacycline in 4 recent in vitro studies [7–9, 27]. In one study, the activity of omadacycline for M abscessus treatment was directly compared with the activity of tigecycline using 1 mycobacterial strain [7]. The MIC for both medications was 4 mcg/mL, but the mycobacterial killing concentration for omadacycline was ≥16 mcg/mL, whereas tigecycline showed mycobacterial killing at lower concentrations of ≥4 mcg/mL. This in vitro difference may not be clinically relevant, however, because omadacycline’s total drug exposure in vivo is approximately 3-fold higher than that of tigecycline in plasma, epithelial lining fluid, and alveolar cells [28]. Because of this, the authors concluded that omadacycline and tigecycline may have similar clinical activity against M abscessus.\n\nAnother recent study tested tigecycline, omadacycline, and eravacycline against 28 M abscessus isolates [8]. The MIC50/MIC90 of tigecycline, omadacycline, and eravacycline were 1/2 mcg/mL, 1/2 mcg/mL, and 0.5/1 mcg/mL, respectively. Given the difference in total drug exposure clinically, both omadacycline and eravacycline had more favorable pharmacokinetic-pharmacodynamic profiles than tigecycline. We have used omadacycline in our patients over eravacycline due to the convenience of outpatient oral administration because eravacycline is only available in an intravenous formulation. However, in admitted patients with M abscessus infection, eravacycline may be another promising agent, which we used briefly in case 2.\n\nA third published study tested omadacycline, tigecycline, and doxycycline against 24 M abscessus isolates [9]. The MIC50/MIC90 of omadacycline and doxycycline were 1/2 mcg/mL and >64/>64 mcg/mL, respectively. Tigecycline was tested against 14 of these isolates and showed similar MICs to omadacycline (MIC50/MIC90 1/2 mcg/mL). The tigecycline MICs recorded in our 4 patients were all ≤0.25 mcg/mL, lower than the MIC data presented in this paper.\n\nThe final published study obtained MICs of omadacycline, minocycline, and 11 other antimicrobials against 20 M abscessus isolates [27]. The MIC50/MIC90 of omadacycline and minocycline were 16/128 mcg/mL and 256/>256 mcg/mL, respectively. The omadacycline MICs in this study differed from the previous in vitro studies. Of note, this was the only study to use Middlebrook 7H9 supplemented with 10% oleic acid dextrose citrate as a growth medium, whereas the other studies used cation-adjusted Mueller-Hinton broth. The authors point out that omadacycline may potentially degrade during incubation over time, which could explain the higher-than-expected MICs. Degradation was addressed in only one of the previous in vitro studies [7].\n\nIn the first 3 studies discussed above, omadacycline MICs correlated well with tigecycline MICs. Despite the growing literature of favorable in vitro data for M abscessus, there has been only 1 report of omadacycline clinical use in this situation [29]. This case series provides the most clinical data published on the use of omadacycline for M abscessus disease to date. This is also the largest data set describing the long-term use of omadacycline in humans. Omadacycline was well tolerated for up to 13 weeks in toxicity studies in rats and monkeys [30]. Here, we show tolerability for over 7 months of omadacycline therapy, with all 4 patients receiving at least 3 months of omadacycline and only 1 patient experiencing an adverse event in month 6 of treatment.\n\nAs a small single-center retrospective case series, no definitive conclusions can be made from our use of omadacycline in M abscessus disease. With a diverse group of patients and no control group, conclusions about efficacy cannot be drawn. All patients received combination therapy with multiple antimicrobial agents, and 2 of the 4 patients received omadacycline for less than half of their total treatment durations. Surgical source control is also likely just as important as medical management in M abscessus disease, and all 4 of our patients underwent surgical management [31].\n\nCONCLUSIONS\nIn 4 patients who received omadacycline for M abscessus disease at our institution, omadacycline was relatively well tolerated in long-term treatment. This case series and the published in vitro data make omadacycline a promising alternative agent in the management of NTM infections, especially as part of an all-oral regimen. Further data are required to determine omadacycline’s definitive role in the treatment of M abscessus disease.\n\nAcknowledgments\n\nDisclaimer. The contents of this manuscript are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health or the institutions with which the authors are affiliated. The funding source had no role in the following: study design; collection, analysis, or interpretation of data; writing of the report; or the decision to submit the report for publication.\n\n\nFinancial support. S. J. V. received funding from the Multidisciplinary AIDS Training Program supported by the National Institute of Allergy and Infectious Diseases (NIAID) at the National Institutes of Health (Grant Number T32 AI007387). G. E. V. received funding from the NIAID (Grant Numbers K08 AI141740, L30 AI120170, and P30 AI060354), the Dr. Lynne Reid/Drs. Eleanor and Miles Shore Fellowship at Harvard Medical School, the Burke Global Health Fellowship at the Harvard Global Health Institute, and the Harvard University Center for AIDS Research.\n\n\nPotential conflicts of interest. All authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest.\n==== Refs\nReferences\n1. \nNessar R , Cambau E , Reyrat JM , et al. Mycobacterium abscessus: a new antibiotic nightmare\n. J Antimicrob Chemother 2012 ; 67 :810 –8\n.22290346 \n2. \nGriffith DE , Aksamit T , Brown-Elliott BA , et al. ; ATS Mycobacterial Diseases Subcommittee ; American Thoracic Society ; Infectious Disease Society of America . An official ATS/IDSA statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases\n. Am J Respir Crit Care Med 2007 ; 175 :367 –416\n.17277290 \n3. \nDaley CL , Iaccarino JM , Lange C , et al. Treatment of nontuberculous mycobacterial pulmonary disease: an official ATS/ERS/ESCMID/IDSA clinical practice guideline: executive summary\n. Clin Infect Dis 2020 ; 71 :e1 –36\n.32628747 \n4. \nNovosad SA , Beekmann SE , Polgreen PM , et al. ; M. abscessus Study Team \nTreatment of Mycobacterium abscessus infection\n. Emerg Infect Dis 2016 ; 22 :511 –4\n.26890211 \n5. \nNash KA , Brown-Elliott BA , Wallace RJ Jr \nA novel gene, erm(41), confers inducible macrolide resistance to clinical isolates of Mycobacterium abscessus but is absent from Mycobacterium chelonae\n. Antimicrob Agents Chemother 2009 ; 53 :1367 –76\n.19171799 \n6. \nWatkins RR , Deresinski S \nOmadacycline: a novel tetracycline derivative with oral and intravenous formulations\n. Clin Infect Dis 2019 ; 69 :890 –6\n.30893428 \n7. \nBax HI , de Vogel CP , Mouton JW , de Steenwinkel JEM \nOmadacycline as a promising new agent for the treatment of infections with Mycobacterium abscessus\n. J Antimicrob Chemother 2019 ; 74 :2930 –3\n.31236595 \n8. \nKaushik A , Ammerman NC , Martins O , et al. In vitro activity of new tetracycline analogs omadacycline and eravacycline against drug-resistant clinical isolates of Mycobacterium abscessus\n. Antimicrob Agents Chemother 2019 ; 63 :e00470-19 .30962331 \n9. \nShoen C , Benaroch D , Sklaney M , Cynamon M \nIn vitro activities of omadacycline against rapidly growing mycobacteria\n. Antimicrob Agents Chemother 2019 ; 63 :e02522-18 .30858221 \n10. \nCLSI . Performance Standards for Susceptibility Testing of Mycobacteria, Nocardia spp., and Other Aerobic Actinomycetes. 1 st ed. CLSI supplement M62\n. Wayne, PA ; Clinical and Laboratory Standards Institute ; 2018 .\n11. \nvan Ingen J , Boeree MJ , van Soolingen D , Mouton JW \nResistance mechanisms and drug susceptibility testing of nontuberculous mycobacteria\n. Drug Resist Updat 2012 ; 15 :149 –61\n.22525524 \n12. \nJarand J , Levin A , Zhang L , et al. Clinical and microbiologic outcomes in patients receiving treatment for Mycobacterium abscessus pulmonary disease\n. Clin Infect Dis 2011 ; 52 :565 –71\n.21292659 \n13. \nNathavitharana RR , Strnad L , Lederer PA , et al. Top questions in the diagnosis and treatment of pulmonary M. abscessus disease\n. Open Forum Infect Dis 2019 ; 6 :ofz221 .31289727 \n14. \nNuermberger E \nEvolving strategies for dose optimization of linezolid for treatment of tuberculosis\n. Int J Tuberc Lung Dis 2016 ; 20 :48 –51\n.28240573 \n15. \nDiacon AH , Dawson R , von Groote-Bidlingmaier F , et al. Bactericidal activity of pyrazinamide and clofazimine alone and in combinations with pretomanid and bedaquiline\n. Am J Respir Crit Care Med 2015 ; 191 :943 –53\n.25622149 \n16. \nDiacon AH , Pym A , Grobusch MP , et al. ; TMC207-C208 Study Group \nMultidrug-resistant tuberculosis and culture conversion with bedaquiline\n. N Engl J Med 2014 ; 371 :723 –32\n.25140958 \n17. \nMadariaga MG \nOmadacycline in the treatment of Mycobacterium abscessus infection\n. Clin Infect Dis 2020 ; 71 :1124 .\n18. \nMase S , Chorba T , Lobue P , Castro K \nProvisional CDC guidelines for the use and \n safety monitoring of bedaquiline fumarate (Sirturo) for the treatment of multidrug-resistant tuberculosis. Available at: https://www.cdc.gov/mmwr/preview/mmwrhtml/rr6209a1.htm. Accessed 20 June 2020 .\n19. \nGriffith DE , Brown-Elliott BA , Benwill JL , Wallace RJ Jr \nMycobacterium abscessus. “Pleased to meet you, hope you guess my name.”\n Ann Am Thorac Soc 2015 ; 12 :436 –9\n.25643064 \n20. \nPasipanodya JG , Ogbonna D , Ferro BE , et al. Systematic review and meta-analyses of the effect of chemotherapy on pulmonary Mycobacterium abscessus outcomes and disease recurrence\n. Antimicrob Agents Chemother 2017 ; 61 :e01206-17 .28807911 \n21. \nFerro BE , Srivastava S , Deshpande D , et al. Tigecycline is highly efficacious against Mycobacterium abscessus pulmonary disease\n. Antimicrob Agents Chemother 2016 ; 60 :2895 –900\n.26926649 \n22. \nOpal S , File TM , van der Poll T , et al. An integrated safety summary of omadacycline, a novel aminomethylcycline antibiotic\n. Clin Infect Dis 2019 ; 69 :40 –7\n.\n23. \nO’Riordan W , Cardenas C , Shin E , et al. ; OASIS-2 Investigators \nOnce-daily oral omadacycline versus twice-daily oral linezolid for acute bacterial skin and skin structure infections (OASIS-2): a phase 3, double-blind, multicentre, randomised, controlled, non-inferiority trial\n. Lancet Infect Dis 2019 ; 19 :1080 –90\n.31474458 \n24. \nO’Riordan W , Green S , Overcash JS , et al. Omadacycline for acute bacterial skin and skin-structure infections\n. N Engl J Med 2019 ; 380 :528 –38\n.30726689 \n25. \nStets R , Popescu M , Gonong JR , et al. Omadacycline for community-acquired bacterial pneumonia\n. N Engl J Med 2019 ; 380 :517 –27\n.30726692 \n26. \nBundrant LA , Tzanis E , Garrity-Ryan L , et al. Safety and pharmacokinetics of the aminomethylcycline antibiotic omadacycline administered to healthy subjects in oral multiple-dose regimens\n. Antimicrob Agents Chemother 2017 ; 62 :e01487-17 .\n27. \nGumbo T , Cirrincione K , Srivastava S \nRepurposing drugs for treatment of Mycobacterium abscessus: a view to a kill\n. J Antimicrob Chemother 2020 ; 75 :1212 –7\n.32016429 \n28. \nGotfried MH , Horn K , Garrity-Ryan L , et al. Comparison of omadacycline and tigecycline pharmacokinetics in the plasma, epithelial lining fluid, and alveolar cells of healthy adult subjects\n. Antimicrob Agents Chemother 2017 ; 61 :e01135-17 .28696233 \n29. \nMinhas R , Sharma S , Kundu S \nUtilizing the promise of omadacycline in a resistant, non-tubercular mycobacterial pulmonary infection\n. Cureus 2019 ; 11 :e5112 .31523543 \n30. \nAntimicrobial Drugs Advisory Committee (AMDAC) briefing book : omadacycline p-toluenesulfonate tablets and injection for the treatment of acute bacterial skin and skin structure infections (ABSSSI) and community-acquired bacterial pneumonia (CABP). Available at: https://www.fda.gov/media/115100/download. Accessed 17 December 2019 .\n31. \nGriffith DE , Girard WM , Wallace RJ Jr \nClinical features of pulmonary disease caused by rapidly growing mycobacteria. An analysis of 154 patients\n. Am Rev Respir Dis 1993 ; 147 :1271 –8\n.8484642\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2328-8957",
"issue": "7(10)",
"journal": "Open forum infectious diseases",
"keywords": "Mycobacterium abscessus; mycobacterial infections; nontuberculous mycobacteria; omadacycline",
"medline_ta": "Open Forum Infect Dis",
"mesh_terms": null,
"nlm_unique_id": "101637045",
"other_id": null,
"pages": "ofaa415",
"pmc": null,
"pmid": "33094118",
"pubdate": "2020-10",
"publication_types": "D016428:Journal Article",
"references": "26890211;25643064;30893428;31289727;22290346;17277290;31474458;25140958;30726692;21292659;24157696;30962331;31236595;32628747;19171799;25622149;22525524;28240573;29180524;32016429;26926649;31523543;28696233;8484642;30726689;31367740;28807911;31612905;30858221",
"title": "Omadacycline for the Treatment of Mycobacterium abscessus Disease: A Case Series.",
"title_normalized": "omadacycline for the treatment of mycobacterium abscessus disease a case series"
} | [
{
"companynumb": "US-009507513-2101USA004003",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CILASTATIN SODIUM\\IMIPENEM"
},
"drugadditio... |
{
"abstract": "This case report describes a 56-year-old woman receiving regular hemodialysis for three years who presented with an unsteady gait for one month, dysarthria, and frequent choking on liquids for two weeks. Brain MRI revealed a characteristic \"lentiform fork sign\" with hyperintense T2W/FLAIR signal in the bilateral lentiform nuclei and restricted diffusion in bilateral globus pallidus. She was inadvertently prescribed metformin 1,000 mg per day one month ago by a physician who was unaware of her end-stage kidney disease. After intensive hemodialysis therapy with eight hemodialysis sessions within 12 days, her neurological deficits fully resolved. Clinicians should be aware of metformin-induced encephalopathy, presenting with relevant medication history, neurological symptoms, and the lentiform fork sign.",
"affiliations": "Division of Nephrology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.;Division of Nephrology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.;Division of Nephrology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.",
"authors": "Chang|Yen-An|YA|;Tarng|Der-Cherng|DC|;Yang|Chih-Yu|CY|https://orcid.org/0000-0001-9899-3159",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1080/15563650.2021.1953519",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1556-3650",
"issue": null,
"journal": "Clinical toxicology (Philadelphia, Pa.)",
"keywords": "End-stage kidney disease; encephalopathy; lentiform nucleus; metabolic acidosis; metformin",
"medline_ta": "Clin Toxicol (Phila)",
"mesh_terms": null,
"nlm_unique_id": "101241654",
"other_id": null,
"pages": "1-2",
"pmc": null,
"pmid": "34256673",
"pubdate": "2021-07-14",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Lentiform fork sign in a uremic patient after inadvertent exposure to metformin.",
"title_normalized": "lentiform fork sign in a uremic patient after inadvertent exposure to metformin"
} | [
{
"companynumb": "TW-INVENTIA-000509",
"fulfillexpeditecriteria": "1",
"occurcountry": "TW",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CARVEDILOL HYDROCHLORIDE"
},
"drugadditional": null... |
{
"abstract": "Stevens-Johnson syndrome (SJS) is a life-threating mucocutaneous reaction predominantly induced by drugs. Targeted cancer therapies such as pembrolizumab, which has been approved for the treatment of metastatic malignancy, can cause severe skin toxicities, including SJS. They are rare and inconsistently reported. In this article, we report the case of a 80-year-old woman with metastatic non-small cell lung cancer who had a SJS-like eruption involving oral mucosa after 15 weeks of exposure of pembrolizumab (6 doses) and 7 days after 1 dose of recombinant zoster vaccine. SJS is a rare blistering disorder with high mortality rate and significant morbidity. Causes include drugs, herpes viruses, and immunization. The timing of the eruption soon after the receipt of recombinant zoster vaccine suggests a role of vaccination in our patient, yet patients receiving cancer immunotherapy may develop late-onset skin toxicity. Therefore, we recommend long-term monitoring for mucocutaneous reactions after initiation of pembrolizumab. Further research is needed to characterize the immunological pathogenesis and improve timely recognition and treatment strategies.",
"affiliations": "MetroWest Medical Center, Framingham, MA, USA.;MetroWest Medical Center, Framingham, MA, USA.;MetroWest Medical Center, Framingham, MA, USA.",
"authors": "Riano|Ivy|I|0000-0002-3312-286X;Cristancho|Cagney|C|;Treadwell|Thomas|T|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D053061:Herpes Zoster Vaccine; C582435:pembrolizumab",
"country": "United States",
"delete": false,
"doi": "10.1177/2324709620914796",
"fulltext": "\n==== Front\nJ Investig Med High Impact Case Rep\nJ Investig Med High Impact Case Rep\nHIC\nsphic\nJournal of Investigative Medicine High Impact Case Reports\n2324-7096 SAGE Publications Sage CA: Los Angeles, CA \n\n10.1177/2324709620914796\n10.1177_2324709620914796\nCase Report\nStevens-Johnson Syndrome–Like Reaction After Exposure to\nPembrolizumab and Recombinant Zoster Vaccine in a Patient With Metastatic Lung\nCancer\nhttps://orcid.org/0000-0002-3312-286XRiano Ivy MD1 Cristancho Cagney MD1 Treadwell Thomas MD12 1 MetroWest Medical Center, Framingham,\nMA, USA\n2 Boston University, Boston, MA, USA\nIvy Riano, MD, Department of Internal\nMedicine, MetroWest Medical Center, 115 Lincoln Street, Framingham, MA 01702,\nUSA. Email: ivy.rianomonsalve@mwmc.com\n24 3 2020 \nJan-Dec 2020 \n8 23247096209147965 2 2020 13 2 2020 17 2 2020 © 2020 American Federation for Medical\nResearch2020American Federation for Medical\nResearchThis article is distributed under the terms of the Creative Commons\nAttribution 4.0 License (https://creativecommons.org/licenses/by/4.0/) which permits\nany use, reproduction and distribution of the work without further\npermission provided the original work is attributed as specified on the SAGE\nand Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).Stevens-Johnson syndrome (SJS) is a life-threating mucocutaneous reaction\npredominantly induced by drugs. Targeted cancer therapies such as pembrolizumab,\nwhich has been approved for the treatment of metastatic malignancy, can cause\nsevere skin toxicities, including SJS. They are rare and inconsistently\nreported. In this article, we report the case of a 80-year-old woman with\nmetastatic non–small cell lung cancer who had a SJS-like eruption involving oral\nmucosa after 15 weeks of exposure of pembrolizumab (6 doses) and 7 days after 1\ndose of recombinant zoster vaccine. SJS is a rare blistering disorder with high\nmortality rate and significant morbidity. Causes include drugs, herpes viruses,\nand immunization. The timing of the eruption soon after the receipt of\nrecombinant zoster vaccine suggests a role of vaccination in our patient, yet\npatients receiving cancer immunotherapy may develop late-onset skin toxicity.\nTherefore, we recommend long-term monitoring for mucocutaneous reactions after\ninitiation of pembrolizumab. Further research is needed to characterize the\nimmunological pathogenesis and improve timely recognition and treatment\nstrategies.\n\nStevens-Johnson syndromepembrolizumabrecombinant zoster vaccineskin reactionsskin cytotoxicitymucocutaneous adverse drug reactionscover-dateJanuary-December 2020typesetterts1\n==== Body\nIntroduction\nStevens-Johnson syndrome (SJS) is a severe mucocutaneous reaction usually caused by drugs.1 Pembrolizumab, an anti-programmed death-1 (anti-PD-1) antibody, is approved\nas therapy for several metastatic cancers. SJS has become a rare serious\ncomplication associated with immunotherapy for cancer.2 Very few cases of SJS associated with pembrolizumab have been reported in the literature.3 Recombinant zoster vaccine (RZV), an alternative to the live-attenuated\nherpes simplex vaccine, was recently approved for prevention of herpes zoster. There\nis no report of RZV as a cause of SJS. In this article, we present the case of a\npatient with metastatic non–small cell lung cancer who had a SJS-like eruption\ninvolving oral mucosa after 6 doses of therapy with pembrolizumab and 1 dose of RZV.\nThe patient’s lesions improved after prednisone treatment and cessation of\npembrolizumab.\n\nCase Presentation\nAn 80-year-old Caucasian woman had a 13-year history of lung adenocarcinoma. She was\ntreated with lobectomy. Despite several surgeries and chemotherapy, progression to\nadvanced lung adenocarcinoma with invasion of the visceral pleura occurred. Based on\nbiomarker testing (PD-L1 positive, EGFR/ALK negative), the patient received\nimmunotherapy with a single-agent pembrolizumab that resulted in improvement of\ndisease progression. During this treatment period, she received RZV. The patient\npresented with a 2-day history of multiple small oral ulcers. She had last taken\npembrolizumab 2 days prior and the first dose of RZV 7 days before presentation. She\nreceived a total of 6 doses of pembrolizumab before presentation. Associated\nsymptoms included fatigue. There were no other new medications recorded either\nprevious experience with other immunotherapy agents or corticosteroids. The oral\nmucositis was considered nonspecific; thus, an antiseptic solution was prescribed.\nAfter 2 days, she developed new ulcers in the tongue associated with difficulty\nswallowing solids. She received treatment with acyclovir without improvement.\nSubsequently, the patient exhibited worsening of ulcers over the lips and a\nnonpruritic and nontender rash in the upper back and upper extremities.\n\nThe physical examination revealed hemorrhagic crust more prominent in the lower lip,\nshowing cracking and fissuring with blood encrustation (Figure 1A). Oral mucosa examination showed\nextensive vesicles with erythematous borders scattered in hard palate, mucosa, and\ngums (Figure 1B). The tongue\nwas denuded, with prominent taste buds and a rough surface appearance. Some scabs\nwere noticed in the upper extremities and upper back without any surrounding\nerythema.\n\nFigure 1. Clinical features. (A) Hemorrhagic crust more prominent in the lower lip. (B)\nBuccal mucosa with extensive vesicular lesions with erythematous\nborders.\n\nA buccal mucosa biopsy revealed focally ulcerated mildly parakeratotic stratified\nsquamous epithelium overlying fibrovascular connective tissue. The ulcer bed was\ncovered by a fibrin clot composed of enmeshed erythrocytes, neutrophils, and\nlymphocytes (Figure 2A).\nNumerous ectatic endothelial-lined vascular channels were noticed throughout the\nsubjacent connective tissue stroma, which exhibits a diffuse acute and chronic\ninflammatory cell infiltrate (Figure 2B). No immunoreactants (C3, immunoglobulin [Ig] G, IgA, IgM)\nwere detected.\n\nFigure 2. Histopathologic findings. (A) Ulcer bed composed of granulation tissue and\ncovered by a fibrin clot. A diffuse acute and chronic inflammatory cell\ninfiltrate is appreciated throughout the subjacent connective tissue stroma\n(hematoxylin and eosin [H&E]; 100×). (B) Mildly parakeratotic stratified\nsquamous epithelium overlying fibrous connective tissue. A patchy\npredominately chronic inflammatory cell infiltrate is noticed, focally\naligned along the epithelial-connective tissue interface (H&E;\n100×).\n\nThe viral culture and polymerase chain reaction did not detect herpes simplex virus.\nAlthough the histopathologic findings were nonspecific, when correlated with the\nclinical presentation and onset of new medications, the findings were compatible\nwith the diagnosis of SJS-like eruption. The patient received prednisone, which\nslowed the progression of her lesions. She had not been maintained on steroid\ntherapy prior. The patient did not receive the second dose of RZV and pembrolizumab\nwas discontinued. At a 1-month follow-up appointment, her initial eruptions\nimproved. Unfortunately, the patient subsequently presented to our hospital with\nsevere sepsis from a perforated duodenal ulcer. It is possible that the\ncorticosteroids given for her SJS-like syndrome contributed to her death.\n\nDiscussion\nStevens-Johnson syndrome is recognized as a severe delayed-type hypersensitivity\nreaction that is almost always caused by drugs. SJS is a blistering disorder that\ninvolves mucosa and cutaneous tissue. It is characterized by <10% of total body\nsurface area of epidermal detachment; when more than 30% of skin is involved the\ndisorder is called toxic epidermal necrolysis.4 Clinically, SJS presents with a prodromal period of flu-like symptoms (fever,\nmalaise, anorexia) followed by erythematous dusky-red macules that can involve neck,\ntrunk, and extremities as well as inflammation and pain of oral, ocular, and genital mucosa.1 Although SJS is rare, the mortality rate approaches 30% with significant\nshort- and long-term morbidities.1 The most common drugs associated with SJS are sulfonamide antibiotics,\nanticonvulsants, nonsteroidal anti-inflammatory drugs, and corticosteroids. Other\netiologies, such as viruses (ie, herpes simplex virus) and vaccinations, have been\nimplicated as a cause of SJS.1,5\nSome predisposing factors, namely, drug-specific T-cell-mediated cytotoxicity, and\ngenetic susceptibility of the patient (human leukocyte antigen [HLA] and non-HLA\ngenes) may play a role in its pathogenesis.1,6 The immune response in SJS is\nmediated by T-cell activation by drug-related haptens.7 In recent years, a new concept has been elucidated describing a direct and\nreversible interaction of the drug between T-cell receptors and major\nhistocompatibility complex molecules to stimulate cytokine secretion and cytotoxicity.7\n\nOur patient developed SJS-like eruptions in oral mucosa after 15 weeks of exposure of\npembrolizumab (6 doses) and 7 days after 1 dose of RZV. SJS only rarely occurs 8\nweeks following suspected drug exposure, but late onset in patients receiving\nimmunotherapy has been reported.6,8 The association of some\nanticancer drugs with rare life-threatening serious adverse events such as SJS has\nbeen anecdotally reported, but has not been systematically examined.9\n\nPembrolizumab is usually a well-tolerated therapy for metastatic cancers. The most\ncommon immune-related skin lesions reported are lichenoid reaction, eczema, and vitiligo.10 Pembrolizumab rarely causes skin reactions, but severe responses such as SJS\ncan occur. The latent period between pembrolizumab exposure and onset of symptoms in\nSJS varies from 7 to 140 days.8 In histologic analyses of adverse cutaneous induced by anti-PD-1 therapy,\nthere is evidence of accumulation of CD8+ T-cell at the dermoepidermal junction and\nCD8+ T-cell exocytosis into the epidermis with apoptotic keratinocytes.2 These features are also observed in SJS.2 In addition, gene expression profiles from skin lesions caused by anti-PD-1\ntherapy and SJS has similarities.2,8 These findings suggests that\nanti-PD-1 antibody can induce SJS-like adverse reactions.2\n\nFurthermore, cases of SJS following herpes zoster vaccination are exceedingly rare.\nIn a recent systematic review, there were 2 postmarketing surveillance studies\nimplicating live-attenuated varicella vaccine with SJS. A total of 8 patients\nbetween 1 and 29 years old were reported with a latency period of 3 to 5 days.11 The immunologic theory behind vaccine-induced cutaneous hypersensitivity\nstates that antigens in the vaccine are expressed on the surface of keratinocytes,\ngenerating a CD8+ T lymphocyte immune response against epidermal cells. This leads\nto apoptosis of keratinocytes and detachment of the dermal-epidermal junction.11 Our patient received the new vaccine RZV that promotes strong CD4+ T-cell and\nhumoral immune response against recombinant proteins. SJS induced by RZV has not\nbeen reported.12\n\nWhat caused our patient’s SJS-like reaction? It is difficult to ignore the appearance\nof her severe mucocutaneous eruption shortly after she received zoster vaccine,\nsuggesting that herpes virus antigens, perhaps in combination with her\nimmunotherapy, may have induced the cytotoxic skin reaction. However,\nimmunotherapies require time to induce immune responses, and skin immune–mediated\nadverse effect may take longer to appear compared with cytotoxic therapies.\n\nTimely diagnosis can facilitate cessation of a suspected drug, leading to decreased\nmorbidity from associated drug reactions. We recommend long-term monitoring for\nmucocutaneous adverse drug reactions after initiation of pembrolizumab. More\ninvestigations of severe skin toxicity associated with immunotherapy are warranted\nto elucidate the immunological pathogenesis as well as improve early recognition and\ntreatment strategies.\n\nThe authors gratefully thank the patient’s family for their kind support.\n\nAuthor Contributions: Ivy Riano and Thomas Treadwell wrote the original draft of the paper. Cagney\nCristancho participated in gathering the data for the case. All authors read and\napproved the final manuscript.\n\nDeclaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the\nresearch, authorship, and/or publication of this article.\n\nFunding: The author(s) received no financial support for the research, authorship, and/or\npublication of this article.\n\nEthics Approval: Our institution does not require ethical approval for reporting individual cases\nor case series.\n\nInformed Consent: Verbal informed consent was obtained from the patient’s legal guardian for her\nanonymized information to be published in this article.\n\nORCID iD: Ivy Riano \nhttps://orcid.org/0000-0002-3312-286X\n==== Refs\nReferences\n1 \nDodiuk-Gad RP Chung WH Valeyrie-Allanore L Shear NH. \nStevens-Johnson syndrome and toxic epidermal necrolysis: an\nupdate\n. Am J Clin Dermatol .\n2015 ;16 :475 -493\n.26481651 \n2 \nGoldinger SM Stieger P Meier B , et al\nCytotoxic cutaneous adverse\ndrug reactions during anti-PD-1 therapy\n. Clin Cancer\nRes .\n2016 ;15 ;22 :4023 -4029\n.\n3 \nSaw S Lee HY Ng QS. \nPembrolizumab-induced Stevens-Johnson syndrome in non-melanoma\npatients\n. Eur J Cancer .\n2017 ;81 :237 -239\n.28438440 \n4 \nBastuji-Garin S Rzany B Stern RS Shear NH Naldi L Roujeau JC. \nClinical classification of cases of toxic epidermal necrolysis,\nStevens-Johnson syndrome, and erythema multiforme\n.\nArch Dermatol .\n1993 ;129 :92 -96\n.8420497 \n5 \nCheriyan S Patterson R. \nRecurrent Stevens-Johnson syndrome secondary to herpes simplex: a\nfollow up on a successful management program\n.\nAllergy Asthma Proc .\n1996 ;17 :71 -73\n.8934796 \n6 \nLerch M Mainetti C Terziroli Beretta-Piccoli B Harr T. \nCurrent perspectives on Stevens-Johnson syndrome and toxic\nepidermal necrolysis\n. Clin Rev Allergy\nImmunol .\n2018 ;54 :147 -176\n.29188475 \n7 \nWerner J. \nThe p-i concept: pharmacological interaction of drugs with immune\nreceptors\n. World Allergy Organ J .\n2008 ;1 :96 -102\n.23282405 \n8 \nChen CB Wu MY Ng CY , et al\nSevere cutaneous adverse\nreactions induced by targeted anticancer therapies and\nimmunotherapies\n. Cancer Manag Res .\n2018 ;10 :1259 -1273\n.29844705 \n9 \nRosen AC Balagula Y Raisch DW , et al\nLife-threatening\ndermatologic adverse events in oncology\n. Anticancer\nDrugs .\n2014 ;25 :225 -234\n.24108082 \n10 \nHwang SJ Carlos G Wakade D , et al\nCutaneous adverse events\n(AEs) of anti-programmed cell death (PD)-1 therapy in patients with\nmetastatic melanoma: a single-institution cohort\n. J\nAm Acad Dermatol .\n2016 ;74 :455 -461.e1\n.26793994 \n11 \nChahal D Aleshin M Turegano M Chiu M Worswick S. \nVaccine-induced toxic epidermal necrolysis: a case and systematic\nreview\n. Dermatol Online J .\n2018 ;24 :13030/qt7qn5268s.\n12 \nLal H Cunningham AL Godeaux O , et al\nEfficacy of an adjuvanted\nherpes zoster subunit vaccine in older adults\n. N\nEngl J Med .\n2015 ;372 :2087 -2096\n.25916341\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2324-7096",
"issue": "8()",
"journal": "Journal of investigative medicine high impact case reports",
"keywords": "Stevens-Johnson syndrome; mucocutaneous adverse drug reactions; pembrolizumab; recombinant zoster vaccine; skin cytotoxicity; skin reactions",
"medline_ta": "J Investig Med High Impact Case Rep",
"mesh_terms": "D000369:Aged, 80 and over; D061067:Antibodies, Monoclonal, Humanized; D002289:Carcinoma, Non-Small-Cell Lung; D005076:Exanthema; D017809:Fatal Outcome; D005260:Female; D053061:Herpes Zoster Vaccine; D006801:Humans; D008175:Lung Neoplasms; D013262:Stevens-Johnson Syndrome",
"nlm_unique_id": "101624758",
"other_id": null,
"pages": "2324709620914796",
"pmc": null,
"pmid": "32207346",
"pubdate": "2020",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "28438440;8934796;24108082;26957557;8420497;23282405;29844705;26793994;25916341;26481651;29188475;29469759",
"title": "Stevens-Johnson Syndrome-Like Reaction After Exposure to Pembrolizumab and Recombinant Zoster Vaccine in a Patient With Metastatic Lung Cancer.",
"title_normalized": "stevens johnson syndrome like reaction after exposure to pembrolizumab and recombinant zoster vaccine in a patient with metastatic lung cancer"
} | [
{
"companynumb": "NVSC2020US208026",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drugadditional": null,
"drug... |
{
"abstract": "OBJECTIVE\nAutoimmune hepatitis (AIH) is a chronic inflammatory liver disease that requires long-term immunosuppressive therapy. Although most patients have an excellent response to standard therapy (azathioprine in combination with corticosteroids), approximately 10%-15% have intolerance or an insufficient response to azathioprine treatment. We investigated whether 6-mercaptopurine (6-MP) is an effective second-line therapy for patients with AIH.\n\n\nMETHODS\nWe performed a retrospective study of 22 patients with AIH who were switched to 6-MP therapy after treatment with the combination of azathioprine and prednisolone at 2 tertiary care institutions in Europe (Germany and the United Kingdom) before November 15, 2014. We performed statistical analyses of data on clinical and biochemical responses collected 4 weeks after 6-MP treatment and then at regular physician visits.\n\n\nRESULTS\nA total of 15 of 20 patients with prior azathioprine intolerance (75%) responded to 6-MP treatment; 8 of these patients had a complete response and 7 had partial remission, based on biochemical features. In these 15 patients, 6-MP was well tolerated, whereas the 5 remaining patients had to be switched to different immunosuppressive regimes because of 6-MP intolerance. The 2 patients with insufficient response to azathioprine treatment also showed no response to 6-MP.\n\n\nCONCLUSIONS\nIn patients with AIH and azathioprine intolerance, 6-MP seems to be an effective and well-tolerated second-line treatment. 6-MP might be ineffective in patients with insufficient response to azathioprine.",
"affiliations": "Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.;Centre for Liver Research, University of Birmingham Liver Unit, Birmingham, United Kingdom.;Centre for Liver Research, University of Birmingham Liver Unit, Birmingham, United Kingdom.;Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.;Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.;Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.;Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. Electronic address: cschramm@uke.de.",
"authors": "Hübener|Sina|S|;Oo|Ye Htun|YH|;Than|Nwe Ni|NN|;Hübener|Peter|P|;Weiler-Normann|Christina|C|;Lohse|Ansgar W|AW|;Schramm|Christoph|C|",
"chemical_list": "D007166:Immunosuppressive Agents; D015122:Mercaptopurine",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1542-3565",
"issue": "14(3)",
"journal": "Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association",
"keywords": "6-Mercaptopurine; Autoimmune Hepatitis; Azathioprine Intolerance; Second-Line Therapy",
"medline_ta": "Clin Gastroenterol Hepatol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D005858:Germany; D019693:Hepatitis, Autoimmune; D006801:Humans; D007166:Immunosuppressive Agents; D008297:Male; D015122:Mercaptopurine; D008875:Middle Aged; D012189:Retrospective Studies; D062606:Tertiary Care Centers; D016896:Treatment Outcome; D006113:United Kingdom; D055815:Young Adult",
"nlm_unique_id": "101160775",
"other_id": null,
"pages": "445-53",
"pmc": null,
"pmid": "26492846",
"pubdate": "2016-03",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Efficacy of 6-Mercaptopurine as Second-Line Treatment for Patients With Autoimmune Hepatitis and Azathioprine Intolerance.",
"title_normalized": "efficacy of 6 mercaptopurine as second line treatment for patients with autoimmune hepatitis and azathioprine intolerance"
} | [
{
"companynumb": "DE-MYLANLABS-2016M1015796",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "MERCAPTOPURINE"
},
"drugadditional": null,
... |
{
"abstract": "Vertebroplasty (VP) and balloon kyphoplasty (KP) are minimally invasive stabilization procedures for pathologic vertebral compression fractures (VCF). Concurrent administration of photodynamic therapy (PDT) as a tumor-ablative modality has yet to be studied in humans as a potential complement to improved mechanical stability that is afforded by vertebral cement augmentation (VCA).\n\n\n\nThis first-in-human trial used a single 6 mg/m2 dose of the clinical photosensitizer Visudyne with escalating laser light doses. Following a cohort of light-only controls (n = 6), the drug and light treatment groups (n = 6 each) were 50, 100, 150, and 200 J/cm. VCA was performed within 15 minutes following PDT. Patients were clinically reviewed at 1 and 6 weeks. The primary outcome measure was safety from a neurologic perspective.\n\n\n\nThirty patients comprising a variety of primary tumors were treated with PDT and either KP or VP. Vertebral PDT was technically feasible and delivered in all study patients. No dose groups showed significant increases in pain as defined by the generic SF-36 as well as disease-specific EORTC-QLQ-BM22 and EORTC-QLQ-C15-PAL questionnaires. The 50 and 100 J/cm groups showed the most significant pain reduction (P < 0.05). Twelve (40%) patients experienced complications during the study including 3 patients with further vertebral fracture progression by 6 weeks despite VCA. No complications were directly attributed to PDT.\n\n\n\nUsing the parameters described, vertebral PDT as an adjunct to VCA is safe from a pharmaceutical and neurologic perspective. The results of this trial motivate scale-up study evaluating potential PDT efficacy in vertebral metastatic treatment.",
"affiliations": "Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.;Royal College of Surgeons in Ireland, Dublin, Ireland.;Department of Radiation Oncology, Sunnybrook Health Sciences Centre, Odette Cancer Centre, Toronto, Ontario, Canada.;Department of Radiation Oncology, Sunnybrook Health Sciences Centre, Odette Cancer Centre, Toronto, Ontario, Canada.;Department of Medical Imaging, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada.;Holland Bone and Joint Program, Division of Orthopaedic Surgery, Sunnybrook Health Sciences; Orthopaedic Biomechanics Laboratory, Physical Sciences Platform, Sunnybrook Research Institute; and Department of Surgery, University of Toronto, Toronto, Ontario, Canada.;Techna Institute, University Health Network, Toronto, Ontario, Canada.;Department of Radiation Oncology, Sunnybrook Health Sciences Centre, Odette Cancer Centre, Toronto, Ontario, Canada.;Holland Bone and Joint Program, Division of Orthopaedic Surgery, Sunnybrook Health Sciences; Orthopaedic Biomechanics Laboratory, Physical Sciences Platform, Sunnybrook Research Institute; and Department of Surgery, University of Toronto, Toronto, Ontario, Canada.;Department of Orthopaedic Surgery, University of California, San Francisco, San Francisco, California.;Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.;Holland Bone and Joint Program, Division of Orthopaedic Surgery, Sunnybrook Health Sciences; Orthopaedic Biomechanics Laboratory, Physical Sciences Platform, Sunnybrook Research Institute; and Department of Surgery, University of Toronto, Toronto, Ontario, Canada. albert.yee@sunnybrook.ca.",
"authors": "Fisher|Carl|C|;Ali|Zakariya|Z|;Detsky|Jay|J|;Sahgal|Arjun|A|0000-0001-7991-8970;David|Elizabeth|E|;Kunz|Monica|M|;Akens|Margarete|M|0000-0003-3523-2381;Chow|Edward|E|;Whyne|Cari|C|;Burch|Shane|S|;Wilson|Brian C|BC|;Yee|Albert|A|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1158/1078-0432.CCR-19-0673",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1078-0432",
"issue": "25(19)",
"journal": "Clinical cancer research : an official journal of the American Association for Cancer Research",
"keywords": null,
"medline_ta": "Clin Cancer Res",
"mesh_terms": "D000328:Adult; D000368:Aged; D001859:Bone Neoplasms; D005260:Female; D006801:Humans; D058498:Kyphoplasty; D008297:Male; D008875:Middle Aged; D009369:Neoplasms; D010778:Photochemotherapy; D013125:Spinal Neoplasms; D013131:Spine; D016896:Treatment Outcome; D054854:Vertebroplasty",
"nlm_unique_id": "9502500",
"other_id": null,
"pages": "5766-5776",
"pmc": null,
"pmid": "31266832",
"pubdate": "2019-10-01",
"publication_types": "D017426:Clinical Trial, Phase I; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Photodynamic Therapy for the Treatment of Vertebral Metastases: A Phase I Clinical Trial.",
"title_normalized": "photodynamic therapy for the treatment of vertebral metastases a phase i clinical trial"
} | [
{
"companynumb": "CA-BAUSCH-BL-2020-012851",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "VERTEPORFIN"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nLinezolid is an oxazolidinone antibiotic that is increasingly used to treat drug-resistant, gram-positive pathogens. The mechanism of action is inhibition of bacterial protein synthesis. Optic and/or peripheral neuropathy and lactic acidosis are reported side effects, but the underlying pathophysiological mechanism has not been unravelled.\n\n\nMETHODS\nWe studied mitochondrial ultrastructure, mitochondrial respiratory chain enzyme activity, and mitochondrial DNA (mtDNA) in muscle, liver, and kidney samples obtained from a patient who developed optic neuropathy, encephalopathy, skeletal myopathy, lactic acidosis, and renal failure after prolonged use of linezolid. In addition, we evaluated mtDNA, respiratory chain enzyme activity, and protein amount in muscle and liver samples obtained from experimental animals that received linezolid or placebo.\n\n\nRESULTS\nIn the patient, mitochondrial respiratory chain enzyme activity was decreased in affected tissues, without ultrastructural mitochondrial abnormalities and without mutations or depletion of mtDNA. In the experimental animals, linezolid induced a dose- and time-dependent decrease of the activity of respiratory chain complexes containing mtDNA-encoded subunits and a decreased amount of protein of these complexes, whereas the amount of mtDNA was normal.\n\n\nCONCLUSIONS\nThese results provide direct evidence that linezolid inhibits mitochondrial protein synthesis with potentially severe clinical consequences. Prolonged courses of linezolid should be avoided if alternative treatment options are available.",
"affiliations": "Department of Internal Medicine, AZ Sint-Jan AV, Bruges, Belgium. an.devriese@azbrugge.be",
"authors": "De Vriese|An S|AS|;Coster|Rudy Van|RV|;Smet|Joel|J|;Seneca|Sara|S|;Lovering|Andrew|A|;Van Haute|Lindsey L|LL|;Vanopdenbosch|Ludo J|LJ|;Martin|Jean-Jacques|JJ|;Groote|Chantal Ceuterick-de|CC|;Vandecasteele|Stefaan|S|;Boelaert|Johan R|JR|",
"chemical_list": "D000081:Acetamides; D000890:Anti-Infective Agents; D004272:DNA, Mitochondrial; D023303:Oxazolidinones; D011500:Protein Synthesis Inhibitors; D000069349:Linezolid; D012293:Rifampin",
"country": "United States",
"delete": false,
"doi": "10.1086/501356",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1058-4838",
"issue": "42(8)",
"journal": "Clinical infectious diseases : an official publication of the Infectious Diseases Society of America",
"keywords": null,
"medline_ta": "Clin Infect Dis",
"mesh_terms": "D000081:Acetamides; D000818:Animals; D000890:Anti-Infective Agents; D004272:DNA, Mitochondrial; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007668:Kidney; D000069349:Linezolid; D008297:Male; D008875:Middle Aged; D008928:Mitochondria; D008930:Mitochondria, Liver; D008931:Mitochondria, Muscle; D023303:Oxazolidinones; D011500:Protein Synthesis Inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley; D012293:Rifampin; D013203:Staphylococcal Infections",
"nlm_unique_id": "9203213",
"other_id": null,
"pages": "1111-7",
"pmc": null,
"pmid": "16575728",
"pubdate": "2006-04-15",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Linezolid-induced inhibition of mitochondrial protein synthesis.",
"title_normalized": "linezolid induced inhibition of mitochondrial protein synthesis"
} | [
{
"companynumb": "BE-PFIZER INC-2003172860BE",
"fulfillexpeditecriteria": "1",
"occurcountry": "BE",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "LINEZOLID"
},
"drugadditional": "1",
... |
{
"abstract": "We present the case of a 43-year-old man with a clinical diagnosis of acute generalised exanthematous pustulosis in the setting of a recent 9-day holiday to Bali, Indonesia, to visit a female partner whom he had visited five times this year for unprotected sexual intercourse and from whom he had contracted a sexually transmitted infection. He also reports having taken some Indonesian cold and flu medications and ibuprofen.",
"affiliations": "Department of Dermatology, Royal Brisbane and Women's Hospital, Brisbane, Qld., Australia.;Department of Dermatology, Royal Brisbane and Women's Hospital, Brisbane, Qld., Australia.",
"authors": "Blake|Tristan|T|;Scuderi|Salvatore|S|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000358868",
"fulltext": "\n==== Front\nCase Rep DermatolCase Rep DermatolCDECase Reports in Dermatology1662-6567S. Karger AG Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH–4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, karger@karger.ch 10.1159/000358868cde-0006-0029Published online: February, 2014A Case of Acute Generalised Exanthematous Pustulosis after Unprotected Sexual Intercourse on Holidays in Bali Blake Tristan *Scuderi Salvatore Department of Dermatology, Royal Brisbane and Women's Hospital, Brisbane, Qld., Australia*Dr. Tristan Blake, Department of Dermatology, Royal Brisbane and Women's Hospital, Butterfield Street, Brisbane, QLD 4006 (Australia), E-Mail blake.tristan@gmail.comJan-Apr 2014 8 2 2014 8 2 2014 6 1 29 33 Copyright © 2014 by S. Karger AG, Basel2014This is an Open Access article licensed under the terms of the Creative Commons Attribution-NonCommercial 3.0 Unported license (CC BY-NC) (www.karger.com/OA-license), applicable to the online version of the article only. Users may download, print and share this work on the Internet for noncommercial purposes only, provided the original work is properly cited, and a link to the original work on http://www.karger.com and the terms of this license are included in any shared versions.We present the case of a 43-year-old man with a clinical diagnosis of acute generalised exanthematous pustulosis in the setting of a recent 9-day holiday to Bali, Indonesia, to visit a female partner whom he had visited five times this year for unprotected sexual intercourse and from whom he had contracted a sexually transmitted infection. He also reports having taken some Indonesian cold and flu medications and ibuprofen.\n\nKey Words\nAcute generalised exanthematous pustulosisIbuprofen\n==== Body\nIntroduction\nAcute generalised exanthematous pustulosis (AGEP) is a significant adverse cutaneous reaction, most often provoked by drugs and acute infections [1, 2]. The clinical hallmark is the presence of multiple disseminated sterile non-follicular pustules on an erythematous background, predominantly in the folds and/or the face. It is associated with fever, neutrophilia and sometimes eosinophilia. The disease is characterised by an acute onset and typically a spontaneous resolution within 2 weeks [2].\n\nCase Report\nA 43-year-old man presented to a rural hospital in Australia for lethargy, fever, arthralgia, chills, peri-orbital oedema and an erythematous pustular rash increasing in size over his hands, back, chest and face for approximately 48 h. He was a fly-in fly-out worker in the catchment area of the hospital. He mentioned holidaying in Bali, Indonesia, for 9 days to visit a female partner with whom he had unprotected sexual intercourse. The symptoms started promptly upon his return. All in all, he had visited his partner five times this calendar year. He reported to have contracted genital herpes from this partner on his first visit and had sought treatment with antivirals (acyclovir) upon his return to Australia and had remained on them ever since. He also mentioned that both he and his partner had been monogamous since the day they met each other. Furthermore, he described some recent coryzal symptoms towards the end of his holiday, for which he bought some local cold and flu medication, the name and ingredients of which being unknown but being somewhat ‘like Sudafed®’. He also took some Nurofen® tablets (ibuprofen) in Bali and upon returning to Australia. Apart from cystic acne 25 years ago and intermittently taking ibuprofen, the patient reported no significant past medical history.\n\nAt this rural hospital, he continued to decline systemically (fever >39.5°C, heart rate >125 bpm) over 36 h and was flown to a tertiary referral hospital in Brisbane. On arrival, he had widespread pustules on his face, neck, back, chest, upper and lower limbs (fig. 1, fig. 2, fig. 3). It was noted that he was also erythematous and had an oedematous face. He described only a mild itch and denied any genitourinary symptoms. Some inguinal and cervical lymphadenopathy and minimal oral involvement were observed. He had a raised white blood cell count (13.2), neutrophilia (12.17), a mild lymphocytosis (0.56), a raised C-reactive protein level (273), and was started immediately on intravenous piperacillin/tazobactam three times daily, intravenous vancomycin twice daily and intravenous acyclovir three times daily with a suspected but yet unknown infection.\n\nHe had negative serologies over the initial week for the following infections: streptococcus, syphilis, Ross River virus, Barmah Forest virus, alphavirus, Rickettsia rickettsii, measles, mumps, leptospirosis, parvovirus B19, enterovirus, varicella and HIV.\n\nHistological examination of biopsies revealed conflicting features. A biopsy of the hand showed evidence of spongiotic dermatitis with eosinophilic dermal infiltrates and occasional intra-epidermal vesicles harbouring Langerhans cells. A second specimen of the abdomen revealed acute neutrophilic suppurative folliculitis. Direct immunofluorescence of the abdomen biopsy was negative. These results were considered inconsistent with the clinical impression of AGEP held at that time. Further biopsies were then taken from his chest and left thigh, which showed spongiform subcorneal pustules accompanied by dermal inflammatory infiltrates and perivascular infiltrates with occasional eosinophils reported as ‘acute neutrophilic folliculitis’. Acanthosis and papillomatosis were not observed. A biopsy of the right foot favoured a spongiotic hypersensitivity reaction with a vasculitic component.\n\nClinically, his symptoms appeared to indicate AGEP at this stage, and given that serologies up until this point were negative, he was started on oral prednisone 0.5 mg/kg and topical betamethasone dipropionate 0.05% ointment twice daily, with a very good effect over the proceeding 5 days. It was only on day 6 of this treatment that, with the help of the infectious diseases team, a positive scrub typhus (Orientia tsutsugamushi) Igtotal serology was confirmed, with a titre of 1:128. This was not considered a primary infection, and paired tests 1 and 4 weeks later showed that the titre was stable and that this was likely an old rickettsial infection or a cross-reaction. This was also paired with scrub typhus and spotted fever PCR testing, which was also negative. Prednisone was weaned down to half the dose over the following 5 days, and he was discharged home on day 13 of admission (significantly improved on emollients and weaning dose of prednisone). Post-pustular desquamation was observed around this time. An outpatient review 12 days following discharge revealed a slight flare-up again at home after taking ibuprofen tablets for 48 h for aches and pain. However, this resolved promptly with the cessation of the non-steroidal anti-inflammatory drug.\n\nDiscussion\nThis case represents a challenging diagnostic case with a variety of potential precipitants. Clinically, this patient had all the hallmark symptoms of AGEP as described in the literature [1, 2, 3] but was confused initially with having an acute infectious disease given his preceding history. A wide variety of other cutaneous diseases or reactions can cause pustular eruptions, and most of them can be easily differentiated from AGEP [1]. The primary clinical differential diagnosis of AGEP remains pustular psoriasis (von Zumbusch type), and often presents with a positive history of psoriasis, more generalised rash distribution, longer durations of pustules and fever, lack of a history of drug reactions or recent drug administration, more arthritis, and papillomatosis plus acanthosis on histology [1].\n\nSidoroff et al. [1] developed a sophisticated AGEP validation scoring system based on the EuroSCAR study group. We noted that our patient scored 10 out of a possible 12 on this scale, which they have denoted as ‘definitely AGEP’. His cutaneous symptoms included an acute-onset rash on the face and flexures, and oedematous erythema, which then developed into a widespread rash consisting of hundreds of small (<5 mm) non-follicular sterile pustules. This was accompanied by the classic symptoms of fever >38°C, leucocytosis mostly due to neutrophilia >7 × 109/l and lymphadenopathy.\n\nWhilst his recent sexual history remains a red flag, we acknowledge that 90% of cases are attributable to drugs [3], although the causative agent in this case is not confirmed. The patient's cold and flu medication in Bali remains unknown but likely contained a sympathomimetic agent such as pseudoephedrine and anti-pyretic/analgesic agent such as paracetamol, both of which have been known to cause AGEP [4]. However, we assume that this presentation could more likely be caused by the use of ibuprofen premorbidly, and his flare-up after his discharge, when he consumed more ibuprofen, somewhat confirms this.\n\nThe patient's initial histopathology was not conclusive and did not fit with the clinical impression of the treating team, which may relate to either the disease process evolving, sampling error, or the lack of specific guidance to look for AGEP features by the pathologist. However, the second set of biopsies did show the typical features of AGEP including: spongiform subcorneal and/or intra-epidermal pustules, an often marked oedema of the papillary dermis, and perivascular infiltrates with neutrophils and exocytosis of some eosinophils [5]. Vasculitis and/or some single-cell necroses of keratinocytes may be present [6] (acute vasculitis demonstrated in foot biopsy). Psoriatic changes like acanthosis and papillomatosis are usually absent [6].\n\nConclusion\nWe presented this case to demonstrate that the combination of a diffuse pustular rash in combination with high fever and leucocytosis is often misinterpreted as an acute infectious disease. It is important to diagnose AGEP early to avoid unnecessary and/or expensive investigations and treatments. It also demonstrates that AGEP is largely a clinical diagnosis and clinicians may wish to use the AGEP validation score [1] to assist in their diagnosis.\n\nFig. 1 Facial erythema, oedema and numerous pustules with crusting around the nose and mouth.\n\nFig. 2 Close-up of the back: non-follicular pustules on an erythematous base.\n\nFig. 3 Chest: pustules on an erythematous base.\n==== Refs\nReferences\n1 Sidoroff A Halevy S Bavinck JN Vaillant L Roujeau JC Acute generalized exanthematous pustulosis (AGEP): a clinical reaction pattern J Cutan Pathol 2001 28 113 11168761 \n2 Speeckaert MM Speeckaert R Lambert J Brochez L Acute generalized exanthematous pustulosis: an overview of the clinical, immunological and diagnostic concepts Eur J Dermatol 2010 20 425 433 20542841 \n3 Roujeau JC Bioulac-Sage P Bourseau C Acute generalized exanthematous pustulosis. Analysis of 63 cases Arch Dermatol 1991 127 1333 1338 1832534 \n4 Saissi EH Beau-Salinas F Jonville-Béra AP Lorette G Autret-Leca E Drugs associated with acute generalized exanthematic pustulosis Ann Dermatol Venereol 2003 130 612 618 13679697 \n5 Burrows NP Russell Jones RR Pustular drug eruptions: a histopathological spectrum Histopathology 1993 22 569 8354488 \n6 Beylot C Doutre MS Beylot-Barry M Acute generalized exanthematous pustulosis Semin Cutan Med Surg 1996 15 244 9069592\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1662-6567",
"issue": "6(1)",
"journal": "Case reports in dermatology",
"keywords": "Acute generalised exanthematous pustulosis; Ibuprofen",
"medline_ta": "Case Rep Dermatol",
"mesh_terms": null,
"nlm_unique_id": "101517685",
"other_id": null,
"pages": "29-33",
"pmc": null,
"pmid": "24707246",
"pubdate": "2014-01",
"publication_types": "D002363:Case Reports",
"references": "8354488;1832534;20542841;9069592;13679697;11168761",
"title": "A case of acute generalised exanthematous pustulosis after unprotected sexual intercourse on holidays in bali.",
"title_normalized": "a case of acute generalised exanthematous pustulosis after unprotected sexual intercourse on holidays in bali"
} | [
{
"companynumb": "AU-PFIZER INC-2018158222",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "IBUPROFEN"
},
"drugadditional": "1",
... |
{
"abstract": "The scapula is a flat, triangular bone overlying the posterior chest wall and forming the posterior aspect of the shoulder girdle. To the best of our knowledge, there is no previous description of a notch of the medial aspect of the superior border of the scapula in the literature. The imaging findings of a supero-medial scapula border notch mimicking a bone tumour are presented in this case report.",
"affiliations": "Khoo Teck Puat Hospital, Department of Diagnostic Radiology, Singapore. puayjoo@hotmail.com.;Khoo Teck Puat Hospital, Department of Diagnostic Radiology, Singapore.",
"authors": "Kuan|Y C|YC|;Tan|F|F|",
"chemical_list": null,
"country": "Malaysia",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0300-5283",
"issue": "69(6)",
"journal": "The Medical journal of Malaysia",
"keywords": null,
"medline_ta": "Med J Malaysia",
"mesh_terms": null,
"nlm_unique_id": "0361547",
"other_id": null,
"pages": "231-3",
"pmc": null,
"pmid": "25934952",
"pubdate": "2014-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Hypercalcemic crisis - a fatal case of primary hyperparathyroidism.",
"title_normalized": "hypercalcemic crisis a fatal case of primary hyperparathyroidism"
} | [
{
"companynumb": "PHHY2015MY060153",
"fulfillexpeditecriteria": "1",
"occurcountry": "MY",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "SODIUM CHLORIDE"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nHIV-1 integration can be efficiently inhibited by strand-transfer inhibitors such as raltegravir, elvitegravir or dolutegravir. Three pathways conferring raltegravir/elvitegravir cross-resistance (involving integrase residues Q148, N155 and Y143) were identified. Dolutegravir, belonging to the second generation of strand-transfer compounds, inhibits the Y143 and N155 pathways, but is less efficient at inhibiting the Q148 pathway. The aim of this study was to characterize the combination of two pathways involved in raltegravir resistance described in one patient failing a dolutegravir regimen for their propensity to confer dolutegravir resistance.\n\n\nMETHODS\nIn this study, a patient first failing a regimen including raltegravir was treated with dolutegravir and showed an increase in viruses carrying a combination of two pathways (N155 and Q148). Impacts of these mutations on integrase activity and resistance to strand-transfer inhibitors were characterized using both in vitro and virological assays.\n\n\nRESULTS\nOur data showed that the combination of N155H, G140S and Q148H mutations led to strong resistance to dolutegravir.\n\n\nCONCLUSIONS\nCombination of N155H, G140S and Q148H mutations originating from two distinct resistance pathways to raltegravir or elvitegravir led to a high level of dolutegravir resistance. Due to its high genetic barrier of resistance, it would be reasonable to use dolutegravir in first-line therapy before emergence of raltegravir or elvitegravir resistance.",
"affiliations": "Laboratoire de Virologie, AP-HP, Groupe Hospitalier Pitié-Salpêtrière, UPMC Université Pierre et Marie Curie, INSERM UMR-S 1136, Paris 75014, France.;Laboratoire de Biologie et Pharmacologie Appliquée, Centre National de la Recherche Scientifique UMR8113, ENS-Cachan, Cachan 94235, France.;Laboratoire de Virologie, AP-HP, Groupe Hospitalier Pitié-Salpêtrière, UPMC Université Pierre et Marie Curie, INSERM UMR-S 1136, Paris 75014, France.;Laboratoire de Biologie et Pharmacologie Appliquée, Centre National de la Recherche Scientifique UMR8113, ENS-Cachan, Cachan 94235, France.;Laboratoire de Biologie et Pharmacologie Appliquée, Centre National de la Recherche Scientifique UMR8113, ENS-Cachan, Cachan 94235, France.;Laboratoire de Virologie, AP-HP, Groupe Hospitalier Pitié-Salpêtrière, UPMC Université Pierre et Marie Curie, INSERM UMR-S 1136, Paris 75014, France.;Laboratoire de Biologie et Pharmacologie Appliquée, Centre National de la Recherche Scientifique UMR8113, ENS-Cachan, Cachan 94235, France.;Laboratoire de Virologie, AP-HP, Groupe Hospitalier Pitié-Salpêtrière, UPMC Université Pierre et Marie Curie, INSERM UMR-S 1136, Paris 75014, France.;Laboratoire de Virologie, AP-HP, Groupe Hospitalier Pitié-Salpêtrière, UPMC Université Pierre et Marie Curie, INSERM UMR-S 1136, Paris 75014, France.;Laboratoire de Biologie et Pharmacologie Appliquée, Centre National de la Recherche Scientifique UMR8113, ENS-Cachan, Cachan 94235, France delelis@lbpa.ens-cachan.fr.",
"authors": "Malet|Isabelle|I|;Thierry|Eloise|E|;Wirden|Marc|M|;Lebourgeois|Samuel|S|;Subra|Frédéric|F|;Katlama|Christine|C|;Deprez|Eric|E|;Calvez|Vincent|V|;Marcelin|Anne-Geneviève|AG|;Delelis|Olivier|O|",
"chemical_list": "D004279:DNA, Viral; D019428:HIV Integrase Inhibitors; D006575:Heterocyclic Compounds, 3-Ring; D010078:Oxazines; D010879:Piperazines; D011728:Pyridones; D000068898:Raltegravir Potassium; C562325:dolutegravir; D019427:HIV Integrase",
"country": "England",
"delete": false,
"doi": "10.1093/jac/dkv197",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0305-7453",
"issue": "70(10)",
"journal": "The Journal of antimicrobial chemotherapy",
"keywords": null,
"medline_ta": "J Antimicrob Chemother",
"mesh_terms": "D023241:Antiretroviral Therapy, Highly Active; D002460:Cell Line; D004279:DNA, Viral; D024882:Drug Resistance, Viral; D015658:HIV Infections; D019427:HIV Integrase; D019428:HIV Integrase Inhibitors; D015497:HIV-1; D006575:Heterocyclic Compounds, 3-Ring; D006801:Humans; D009154:Mutation; D010078:Oxazines; D010879:Piperazines; D011533:Proviruses; D011728:Pyridones; D000068898:Raltegravir Potassium; D017422:Sequence Analysis, DNA; D017211:Treatment Failure; D019562:Viral Load; D014779:Virus Replication",
"nlm_unique_id": "7513617",
"other_id": null,
"pages": "2870-80",
"pmc": null,
"pmid": "26205139",
"pubdate": "2015-10",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Combination of two pathways involved in raltegravir resistance confers dolutegravir resistance.",
"title_normalized": "combination of two pathways involved in raltegravir resistance confers dolutegravir resistance"
} | [
{
"companynumb": "FR-VIIV HEALTHCARE LIMITED-FR2015GSK183206",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "RALTEGRAVIR"
},
"drugadditio... |
{
"abstract": "Reduction in bone mineral density (BMD) measured by dual-energy X-ray absorptiometry (DXA) occurs in secondary hyperparathyroidism associated with chronic kidney disease. BMD generally increases following parathyroidectomy, however longitudinal changes to other DXA-derived parameters, the trabecular bone score (TBS) and hip structural analysis (HSA), have not been described. Postoperative calcium requirements and positive calcium balance raise concerns for an increased risk of vascular calcification. This case illustrates the dramatic increase in BMD that can follow parathyroidectomy in a patient on dialysis, and for the first time demonstrates improvements to HSA parameters and to the TBS.\n\n\n\nA 30-year old woman on haemodialysis underwent subtotal parathyroidectomy for secondary hyperparathyroidism. She developed a post-operative 'hungry bone syndrome' requiring substantial calcium and calcitriol supplementation. Six months post-parathyroidectomy, BMD increased by 42% at the lumbar spine, 30% at the femoral neck and 25% at the total proximal femur, with increases sustained over the following 18 months. The TBS increased by 8%. HSA showed a 63% increase in femoral neck cortical thickness and 38% reduction in the buckling ratio, consistent with increased femoral neck stability. The abdominal aortic vascular calcification score (0-24) increased from zero 8-years pre-parathyroidectomy to 2/24 at 18-months post-parathyroidectomy.\n\n\n\nBMD losses incurred by secondary hyperparathyroidism recover rapidly after parathyroidectomy, particularly at sites of trabecular bone. Bone architectural parameters, measured as the TBS and by HSA, also improve. Greater BMD gains may be associated with higher post-operative calcium requirements. While bone is the major reservoir for post-parathyroidectomy calcium supplementation, positive calcium balance may contribute to vascular calcification risk.",
"affiliations": "Department of Renal Medicine, Westmead Hospital, Westmead, NSW, 2145, Australia.;Department of Renal Medicine, Westmead Hospital, Westmead, NSW, 2145, Australia.;Department of Renal Medicine, Westmead Hospital, Westmead, NSW, 2145, Australia. g.elder@garvan.org.au.",
"authors": "Lin|Raymond|R|;Vucak-Dzumhur|Mirna|M|;Elder|Grahame J|GJ|0000-0001-5685-4636",
"chemical_list": "D000077264:Calcium-Regulating Hormones and Agents; D002117:Calcitriol; D002118:Calcium",
"country": "England",
"delete": false,
"doi": "10.1186/s12882-020-02168-y",
"fulltext": "\n==== Front\nBMC Nephrol\nBMC Nephrol\nBMC Nephrology\n1471-2369 BioMed Central London \n\n2168\n10.1186/s12882-020-02168-y\nCase Report\nChanges to bone mineral density, the trabecular bone score and hip structural analysis following parathyroidectomy: a case report\nLin Raymond 1 Vucak-Dzumhur Mirna 123 http://orcid.org/0000-0001-5685-4636Elder Grahame J. g.elder@garvan.org.au 124 1 grid.413252.30000 0001 0180 6477Department of Renal Medicine, Westmead Hospital, Westmead, NSW 2145 Australia \n2 University of Notre Dame Medical School, Darlinghurst, NSW Australia \n3 grid.1029.a0000 0000 9939 5719Western Sydney University, Campbelltown Campus, Campbelltown, NSW Australia \n4 grid.415306.50000 0000 9983 6924Garvan Institute of Medical Research, Osteoporosis and Bone Biology Division, Darlinghurst, NSW Australia \n26 11 2020 \n26 11 2020 \n2020 \n21 51311 8 2020 15 11 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\nReduction in bone mineral density (BMD) measured by dual-energy X-ray absorptiometry (DXA) occurs in secondary hyperparathyroidism associated with chronic kidney disease. BMD generally increases following parathyroidectomy, however longitudinal changes to other DXA-derived parameters, the trabecular bone score (TBS) and hip structural analysis (HSA), have not been described. Postoperative calcium requirements and positive calcium balance raise concerns for an increased risk of vascular calcification. This case illustrates the dramatic increase in BMD that can follow parathyroidectomy in a patient on dialysis, and for the first time demonstrates improvements to HSA parameters and to the TBS.\n\nCase presentation\nA 30-year old woman on haemodialysis underwent subtotal parathyroidectomy for secondary hyperparathyroidism. She developed a post-operative ‘hungry bone syndrome’ requiring substantial calcium and calcitriol supplementation. Six months post-parathyroidectomy, BMD increased by 42% at the lumbar spine, 30% at the femoral neck and 25% at the total proximal femur, with increases sustained over the following 18 months. The TBS increased by 8%. HSA showed a 63% increase in femoral neck cortical thickness and 38% reduction in the buckling ratio, consistent with increased femoral neck stability. The abdominal aortic vascular calcification score (0–24) increased from zero 8-years pre-parathyroidectomy to 2/24 at 18-months post-parathyroidectomy.\n\nConclusion\nBMD losses incurred by secondary hyperparathyroidism recover rapidly after parathyroidectomy, particularly at sites of trabecular bone. Bone architectural parameters, measured as the TBS and by HSA, also improve. Greater BMD gains may be associated with higher post-operative calcium requirements. While bone is the major reservoir for post-parathyroidectomy calcium supplementation, positive calcium balance may contribute to vascular calcification risk.\n\nKeywords\nHyperparathyroidismParathyroidectomyBone mineral densityHip structural analysisissue-copyright-statement© The Author(s) 2020\n==== Body\nBackground\nMany patients with end-stage kidney disease (ESKD) and secondary hyperparathyroidism have reduced bone mineral density (BMD), particularly in regions consisting primarily of cortical bone, and with relative sparing of trabecular bone. Following parathyroidectomy, BMD generally increases, but longitudinal changes to the trabecular bone score, and to parameters measured by hip structural analysis have not been described. In addition, post-operative positive calcium balance caused by requirements for massive supplementation with calcium and calcitriol or its analogues, raises concern for the risk of vascular calcification.\n\nCase presentation\nA 30-year old woman underwent subtotal parathyroidectomy in September 2018, with removal of three parathyroid glands and auto-transplantation of half an excised gland to the sternocleidomastoid. Her background included ESKD secondary to atypical haemolytic uraemic syndrome, with haemodialysis from 2009 until a living-related kidney transplant in 2010 at the age of 22. However, disease recurrence resulted in graft failure, nephrectomy and recommencement of home haemodialysis in 2014.\n\nIn 2015, 1 year after recommencing dialysis, her serum parathyroid hormone (PTH) was 111.3 pmol/L (normal range 1.6–7.5 pmol/L), rising to 273 pmol/L in 2017. Hand X-rays showed subperiosteal resorption consistent with hyperparathyroidism (Fig. 1a). In September 2018 her medications included calcitriol 0.25 μg alternating with 0.5 μg daily, sevelamer 2400 mg three-times daily and risedronate 35 mg weekly, which was discontinued 3 weeks prior to her parathyroidectomy in September 2018. Despite pre-operative loading with calcitriol 2.25 μg daily for 3 days, she developed a postoperative ‘hungry bone syndrome’ requiring intermittent intravenous calcium for up to 17 days, and daily doses of 8 μg calcitriol and 9600 mg calcium carbonate at discharge. She was also dialysed against an ionised calcium dialysate of 1.7 mmol/L for 6 months. Three months post-parathyroidectomy her daily dose of calcitriol had reduced to 1.5 μg and calcium carbonate 600 mg, which was maintained until a second kidney transplant in February 2020. Values of serum calcium, phosphate, ALP, PTH and bone turnover markers are shown in Table 1.\nFig. 1 a Hand X-ray demonstrating cortical erosion of the radial aspect of the right middle phalanges (X) and loss of distal tuft of the right index finger (Y). b Rugger-Jersey spine with an alternating sclerotic-lucent appearance is characteristic of hyperparathyroidism. Sclerosis occurs towards the vertebral endplates, which are a bilayer of porous, fused trabecular bone, which allows for nutrient transport to the intervertebral disc, and cartilage with horizontally oriented collagen fibres. Linear calcification is visible in the abdominal aorta opposite the L4 vertebra, together with a fleck opposite L3\n\nTable 1 Laboratory values before and after parathyroidectomy in September 2018, and kidney transplantation in February 2020. Patient was on haemodialysis from 2014 to February 2020\n\n\tNov 2017\tJune 2018\n3 months Pre-PTx\tDec. 2018\n3 months Post-PTx\tFeb. 2020\nPre-Tx\tMay 2020\n3 months Post-Tx\t\nCorrected Calcium (2.15–2.55 mmol/L)\t2.23\t2.29\t2.37\t2.47\t2.32\t\nPhosphate (0.75–1.50 mmol/L)\t1.93\t1.75\t0.92\t1.50\t0.96\t\nParathyroid Hormone (1.6–7.5 pmol/L)\t273.3\t267.9\t18.0\t2.8\t9.8\t\nAlkaline Phosphatase (30–110 U/L)\t353\t503\t41\t43\t38\t\nCTX (100–700 ng/L)\t–\t–\t–\t879\t472\t\nP1NP (15–90 μg/L)\t–\t–\t–\t127\t48\t\nPTx Parathyroidectomy, Tx Kidney transplantation, CTX C-Terminal Collagen Type 1 Telopeptide Crosslinks, P1NP Procollagen Type 1 N-Terminal Propeptide\n\n\n\nHer BMD was measured by dual-energy X-ray absorptiometry (DXA) at her first transplant in 2010, 8 months prior to parathyroidectomy in January 2018, 6 months after parathyroidectomy in March 2019 and at her 2nd transplant in March 2020 (Table 2). The trabecular bone score (TBS) and hip structural analysis (HSA) were also measured from DXA pre- and post-parathyroidectomy (Table 2). TBS is an indirect measure of cancellous bone microarchitectural integrity, and HSA provides information on cortical thickness at sites around the hip, and the buckling ratio (BR), calculated as the femoral neck radius divided by the femoral neck cortical thickness. Higher BR values are consistent with increased femoral neck instability.\nTable 2 Bone mineral densities (BMD), trabecular bone score (TBS) and hip structural analysis parameters over time. Due to her age, T and Z-scores are identical\n\n\tAugust 2010 a\tJanuary 2018 b\n8 months Pre-PTx\tMarch 2019 b\n6 months Post-PTx\tMarch 2020 b\n18 months Post-PTx\t\nBone Mineral Density\t\n LS BMD (g/cm2)\t1.06\t1.02\t1.44\t1.38\t\n LS T-score\t−0.3\t−1.4\t+ 1.8\t+ 1.3\t\n % Change\t\tBaseline\t+ 42%\t+ 38%\t\n TPF BMD (g/cm2)\t0.94\t0.84\t1.05\t1.16\t\n TPF T-score\t−0.2\t−1.6\t0\t+ 0.8\t\n % Change\t\tBaseline\t+ 25%\t+ 36%\t\n FN BMD (g/cm2)\t0.94\t0.81\t1.05\t1.16\t\n FN T-score\t0.0\t−1.6\t+ 0.2\t+ 1.1\t\n %Change\t\tBaseline\t+ 30%\t+ 43%\t\n UD-R BMD (g/cm2)\t0.28c\t0.27\t0.31\t0.34\t\n UD-R T-score\t−0.9c\t−4.3\t−3.4\t−2.8\t\n % Change\t\tBaseline\t+ 13%\t+ 23%\t\n 1/3-R BMD (g/cm2)\t0.76c\t0.62\t0.59\t0.63\t\n 1/3-R T-score\t\t−2.9\t−3.3\t−2.9\t\n % Change\t\tBaseline\t−4.8%\t+ 1.6%\t\n TBS\t\t1.56\t1.68\t1.56\t\n TBS T-score\t\t+ 0.8\t+ 2.0\t+ 0.8\t\n % Change\t\tBaseline\t+ 8%\t0%\t\nHip Geometry and Hip Structural Analysis\t\n Femoral neck cortical width (mm) (% Change)\t\t4.6\t7.5 (+ 63%)\t6.9 (+ 50%)\t\n Femoral calcar width (mm) (% Change)\t\t3.5\t4.1 (+ 17%)\t4.2 (+ 20%)\t\n Femoral shaft width (mm) (% Change)\t\t5.5\t5.6 (+ 1.8%)\t6.5(+ 18%)\t\n Buckling Ratio (% Change)\t\t3.4\t2.1 (−38%)\t2.2 (−35%)\t\n Body Mass Index (kg/m2)\t\t26.71\t26.80\t25.64\t\naScan performed on Norland XR800\n\nbScan performed on Lunar iDXA\n\ncNorland measures combined ultradistal radius and ulnar BMD. 1/3 radius T-score was unavailable\n\n\n\nBy 6 months post-parathyroidectomy, BMD at the lumbar spine increased by 42% and at the hip by 25–30%. The TBS T-score increased from + 0.8 to 2. Using HSA, the femoral neck cortical thickness increased by 63% and the buckling ratio fell by 38%. Her BMI remained stable throughout. The abdominal aorta calcification score (AACS) (0–24) was measured by the Kauppila semiquantitative scoring method from a lateral spine X-ray that included the abdominal aorta [1]. The score was zero in 2011 and 2/24 in March 2020 (Fig. 1b). Radiological changes of Rugger-Jersey spine were present in 2011 and were more prominent in 2020 (Fig. 1b).\n\nDiscussion and conclusions\nThis patient’s BMD declined between 2010 and January 2018, with the likely nadir immediately pre-parathyroidectomy. Although moderately elevated circadian PTH values are anabolic to bone, persistently high values increase osteoblast expression of RANK ligand and reduce levels of osteoprotegerin, the decoy receptor for RANK ligand, which increases osteoclastogenesis and osteoclast activity. In addition, high PTH levels cause proliferation of pre-osteoblasts, which do not mature due to a lack of bone morphogenic protein 7, a growth factor primarily of renal origin [1]. The effects of hyperparathyroidism differ by site [2], with exclusively cortical sites such as the metacarpals and 1/3 distal radius often showing greatest BMD loss. However, using peripheral quantitative computed tomography, deterioration of trabecular bone has also been demonstrated in dialysis patients with hyperparathyroidism and patients with primary hyperparathyroidism [3, 4]. In this patient, predominantly cortical forearm sites were most severely affected prior to parathyroidectomy, with the 1/3 radius T-score − 2.9 and ultradistal radius T-score − 4.3, while the hip and vertebrae showed lesser BMD reductions.\n\nWithin 6 months of parathyroidectomy, BMD gains up to 42% occurred at the spine and hip, with a smaller but significant improvement at the ultradistal radius and no significant change at the 1/3 radius, a site of cortical bone. After parathyroidectomy, the high surface area of trabecular bone facilitates mineralisation of former resorption sites, and secondary mineralisation due to reduced bone remodelling, whereas in cortical bone, the reduced cortical thickness and increased porosity are less readily repaired. In the lumbar spine, the TBS was high normal (TBS T-score + 0.8) prior to parathyroidectomy, suggesting that the trabecular network had not been severely compromised in this patient. The TBS showed an increase following parathyroidectomy, which returned to the baseline value over the subsequent year on dialysis.\n\nPatients with primary and secondary hyperparathyroidism are recognised to have gains in BMD of 10–15% following parathyroidectomy [5, 6], and patients on haemodialysis have recorded gains of 7–23% [7]. The ‘hungry bone syndrome’ has also been associated with impressive BMD gains. In a case series of Indian patients with primary hyperparathyroidism, 46 of 51 patients developed post-operative hypocalcaemia, with BMD increases at 12 months of 106% (IQR 67–178%) at the spine and 133% (IQR 54–176%) at the hip [8]. The current case demonstrates that large increases in BMD may also occur in a patient on dialysis with severe secondary hyperparathyroidism and the ‘hungry bone syndrome’.\n\nHSA uses two-dimensional hip DXA images to estimate bone geometry and bone strength. HSA has been shown to enhance hip fracture risk stratification and is comparable to CT-based HSA measurements [9, 10]. A recent study showed that HSA parameters are markedly abnormal in patients on dialysis [11], but longitudinal changes to HSA parameters have not been reported. This patient showed marked improvements in all hip parameters including femoral neck, calcar and shaft width, and a reduction in the buckling ratio after parathyroidectomy, indicative of improved femoral neck stability and possibly lower fracture risk.\n\nThe necessity for high dose calcium and vitamin D following parathyroidectomy and treatment of the ‘hungry bone syndrome’ raises concern for the development of vascular calcification due to a positive calcium balance [12]. This patient required ongoing high dose oral calcium and calcitriol and was dialysed against a high dialysate calcium for 6 months from the time of parathyroidectomy. The 2017 Kidney Disease Improving Global Outcomes (KDIGO) guidelines for Mineral and Bone Disorders suggest that patients identified with vascular calcification on a lateral abdominal radiograph be considered at highest cardiovascular risk [13] and recent data indicates that the AACS (0–24) also predicts cardiovascular risk and mortality after transplantation [14]. Over the period from 2011 to 2020, this patient’s AACS (0–24) increased from zero to 2/24. This small, but possibly significant rise may reflect her longer time on dialysis, increasing age, or hyperparathyroidism and markedly elevated ALP, which hydrolyses pyrophosphate, an endogenous inhibitor of calcification in blood vessels and bone. However, we cannot exclude a contribution from the positive calcium balance that occurred during treatment of her post-parathyroidectomy hypocalcaemia. For a patient with hypocalcaemia, even relatively low (1.25 mmol/L) calcium dialysate may result in positive calcium mass transfer from dialysate to blood [13] .\n\nThis patient’s clinical progress demonstrates that BMD losses associated with secondary hyperparathyroidism recover after parathyroidectomy, particularly at sites of trabecular bone. There may also be improvement in bone architectural parameters, because TBS and HSA parameters improved. Longitudinal changes to these parameters have not been previously reported in patients on dialysis following parathyroidectomy. BMD gains may be greater in patients who develop a ‘hungry bone syndrome’. Although bone is the major reservoir for calcium following parathyroidectomy, we cannot exclude the possibility of positive calcium balance potentiating risks for progression of vascular calcification.\n\nAbbreviations\nAACS (0–24)Abdominal Aorta Calcification Score (0–24)\n\nALPAlkaline Phosphatase\n\nBMDBone Mineral Density\n\nBRBuckling Ratio\n\nDXADual-Energy X-ray Absorptiometry\n\nESKDEnd-Stage Kidney Disease\n\nHSAHip Structural Analysis\n\nKDIGOKidney Disease Improving Global Outcomes\n\nPTHParathyroid Hormone\n\nTBSTrabecular Bone Score\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAcknowledgements\nNone.\n\nAuthors’ contributions\nRL, MVD and GE were major contributors in writing the manuscript. All authors read and approved the final manuscript.\n\nFunding\nNone.\n\nAvailability of data and materials\nNot applicable.\n\nEthics approval and consent to participate\nNot applicable.\n\nConsent for publication\nWritten consent for publication was obtained from the patient discussed in this report.\n\nCompeting interests\nNone.\n==== Refs\nReferences\n1. Chaudhary LR Hofmeister AM Hruska KA Differential growth factor control of bone formation through osteoprogenitor differentiation Bone. 2004 34 3 402 411 10.1016/j.bone.2003.11.014 15003788 \n2. Nickolas TL Stein EM Dworakowski E Nishiyama KK Komandah-Kosseh M Zhang CA Rapid cortical bone loss in patients with chronic kidney disease J Bone Miner Res 2013 28 8 1811 1820 10.1002/jbmr.1916 23456850 \n3. Stein EM Silva BC Boutroy S Zhou B Wang J Udesky J Primary hyperparathyroidism is associated with abnormal cortical and trabecular microstructure and reduced bone stiffness in postmenopausal women J Bone Miner Res 2013 28 5 1029 1040 10.1002/jbmr.1841 23225022 \n4. Brancaccio D Di Leo C Bestetti A Carpani P Tagliabue L Cozzolino M Severe cortical and trabecular osteopenia in secondary hyperparathyroidism Hemodial Int 2003 7 2 122 129 10.1046/j.1492-7535.2003.00021.x 19379351 \n5. Silverberg SJ Gartenberg F Jacobs TP Shane E Siris E Staron RB Increased bone mineral density after parathyroidectomy in primary hyperparathyroidism J Clin Endocrinol Metab 1995 80 3 729 734 7883824 \n6. Chou F-F Chen J-B Lee C-H Chen S-H Sheen-Chen S-M Parathyroidectomy can improve bone mineral density in patients with symptomatic secondary hyperparathyroidism Arch Surg 2001 136 9 1064 1068 10.1001/archsurg.136.9.1064 11529832 \n7. Abdelhadi M Nordenström J Bone mineral recovery after parathyroidectomy in patients with primary and renal hyperparathyroidism J Clin Endocrinol Metab 1998 83 11 3845 3851 10.1210/jcem.83.11.5249 9814456 \n8. Agarwal G Mishra SK Kar DK Singh AK Arya V Gupta SK Recovery pattern of patients with osteitis fibrosa cystica in primary hyperparathyroidism after successful parathyroidectomy Surgery. 2002 132 6 1075 1083 10.1067/msy.2002.128484 12490858 \n9. Ohnaru K Sone T Tanaka K Akagi K Ju Y-I Choi H-J Hip structural analysis: a comparison of DXA with CT in postmenopausal Japanese women Springerplus 2013 2 331 10.1186/2193-1801-2-331 23961402 \n10. Yang L Peel N Clowes JA McCloskey EV Eastell R Use of DXA-based structural engineering models of the proximal femur to discriminate hip fracture J Bone Mineral Res 2009 24 1 33 42 10.1359/jbmr.080906 \n11. Aleksova J, Milat F, Kotowicz MA, Pasco JA, Schultz C, Wong P, et al. Patients with end-stage kidney disease have markedly abnormal cortical hip parameters by dual-energy X-ray absorptiometry. Nephrol Dial Transplant. 2019;gfz195. 10.1093/ndt/gfz195. Online ahead of print.\n12. Hill KM Martin BR Wastney ME McCabe GP Moe SM Weaver CM Oral calcium carbonate affects calcium but not phosphorus balance in stage 3-4 chronic kidney disease Kidney Int 2013 83 5 959 966 10.1038/ki.2012.403 23254903 \n13. KDIGO 2017 clinical practice guideline update for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease 2013; mineral and bone disorder (CKD-MBD) Kidney Int Suppl 2017 7 1 1 59 10.1016/j.kisu.2017.04.001 \n14. Lewis JR Wong G Taverniti A Vucak-Dzumhur M Elder GJ Association between aortic calcification, cardiovascular events, and mortality in kidney and pancreas-kidney transplant recipients Am J Nephrol 2019 50 3 177 186 10.1159/000502328 31394536\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1471-2369",
"issue": "21(1)",
"journal": "BMC nephrology",
"keywords": "Bone mineral density; Hip structural analysis; Hyperparathyroidism; Parathyroidectomy",
"medline_ta": "BMC Nephrol",
"mesh_terms": "D015502:Absorptiometry, Photon; D000328:Adult; D015519:Bone Density; D002117:Calcitriol; D002118:Calcium; D000077264:Calcium-Regulating Hormones and Agents; D000071556:Cancellous Bone; D005260:Female; D006801:Humans; D006962:Hyperparathyroidism, Secondary; D007676:Kidney Failure, Chronic; D010024:Osteoporosis; D016105:Parathyroidectomy; D010384:Pelvic Bones; D011183:Postoperative Complications; D006435:Renal Dialysis",
"nlm_unique_id": "100967793",
"other_id": null,
"pages": "513",
"pmc": null,
"pmid": "33243169",
"pubdate": "2020-11-26",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "31697355;15003788;18767924;23254903;9814456;19379351;23961402;30681074;7883824;11529832;31394536;23456850;23225022;12490858",
"title": "Changes to bone mineral density, the trabecular bone score and hip structural analysis following parathyroidectomy: a case report.",
"title_normalized": "changes to bone mineral density the trabecular bone score and hip structural analysis following parathyroidectomy a case report"
} | [
{
"companynumb": "AU-LUPIN PHARMACEUTICALS INC.-2021-25352",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CALCIUM"
},
"drugadditional": ... |
{
"abstract": "BACKGROUND\nRamsay Hunt syndrome (RHS) is a rare manifestation of varicella-zoster virus (VZV) reactivation in geniculate ganglion. It usually manifests with a characteristic triad of symptoms including ipsilateral ear pain, vesicles in the external auditory canal, and facial nerve palsy.\n\n\nMETHODS\nWe present a case report showing RHS additionally manifested by meningitis and involvement of VIII cranial nerve. Clinical course was complicated by acute kidney injury induced by acyclovir therapy.\n\n\nRESULTS\nDespite the involvement of the geniculate ganglion and vestibulocochlear nerve in the course of herpes zoster, and the occurrence of acute kidney injury, the patient fully recovered.\n\n\nCONCLUSIONS\nA complete recovery of cranial nerves VII and VIII in the course of RHS can be achieved.",
"affiliations": "Student's Scientific Group at Department of Children's Infectious Diseases, Medical University of Warsaw, Poland.;Student's Scientific Group at Department of Children's Infectious Diseases, Medical University of Warsaw, Poland.;Department of Children's Infectious Diseases, Medical University of Warsaw, Poland.;Department of Children's Infectious Diseases, Medical University of Warsaw, Poland.;Department of Neurology, Medical University of Warsaw, Poland.;Department of Children's Infectious Diseases, Medical University of Warsaw, Poland.",
"authors": "Bienkowski|Carlo|C|;Kowalczyk|Monika|M|;Talarek|Ewa|E|;Pokorska-Spiewak|Maria|M|;Kierdaszuk|Biruta|B|;Marczynska|Magdalena|M|",
"chemical_list": null,
"country": "Sweden",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0172-780X",
"issue": "40(3)",
"journal": "Neuro endocrinology letters",
"keywords": null,
"medline_ta": "Neuro Endocrinol Lett",
"mesh_terms": "D058186:Acute Kidney Injury; D000293:Adolescent; D005158:Facial Paralysis; D005260:Female; D016697:Herpes Zoster Oticus; D014645:Herpesvirus 3, Human; D006801:Humans; D008587:Meningitis, Viral; D000160:Vestibulocochlear Nerve Diseases",
"nlm_unique_id": "8008373",
"other_id": null,
"pages": "149-151",
"pmc": null,
"pmid": "31816219",
"pubdate": "2019-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Meningitis and Ramsay-Hunt syndrome in a 17-year old girl.",
"title_normalized": "meningitis and ramsay hunt syndrome in a 17 year old girl"
} | [
{
"companynumb": "PL-BAUSCH-BL-2019-066833",
"fulfillexpeditecriteria": "1",
"occurcountry": "PL",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ACYCLOVIR SODIUM"
},
"drugadditional": "1",
... |
{
"abstract": "Only a few studies have been conducted regarding the palliative radiation therapy(RT)for gastric cancer(GC)bleeding. Data of 9 patients with gastric cancer requiring blood transfusions due to gastric bleeding who were treated with RT were reviewed. All patients were men with a median age of 83(range, 70-91)years. The clinical stage was ⅡB in 2 patients, Ⅲin 1, ⅣA in 1, and ⅣB in 5. Performing gastrectomy was difficult in 4 patients with distant metastasis or tumor invasion to adjacent organ, 3 with poor performance status, and 2 with advanced age. The median hemoglobin levels before RT was 6.0 (range, 3.3-7.7)g/dL, and all patients received blood transfusions before RT. Seven patients received 30 Gy RT and 2 patients received 50 Gy. Two patients received concurrent chemotherapy. A total of 2 hematological and 4 non-hematological treatment-related adverse events occurred. All patients improved conservatively. Hemorrhage occurred in 8 patients, except for 1. Of the 8 patients who responded to RT, 1 had rebleeding on day 81. The median rebleeding-free survival time from the beginning of RT was 125(range, 21-421)days. Palliative radiation therapy was useful for bleeding control in nonresectable gastric cancer.",
"affiliations": "Dept. of Surgery, Yokohama Minami Kyousai Hospital.",
"authors": "Tsuchida|Kazuhito|K|;Saeki|Hiroyuki|H|;Yasukawa|Mio|M|;Toda|Soji|S|;Kamioka|Yuto|Y|;Suematsu|Hideaki|H|;Numata|Koji|K|;Higuchi|Akio|A|;Matsukawa|Hiroshi|H|;Oka|Hiroyuki|H|;Okazaki|Hiroshi|H|;Tayama|Yoshifumi|Y|;Rino|Yasushi|Y|;Masuda|Munetaka|M|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0385-0684",
"issue": "46(13)",
"journal": "Gan to kagaku ryoho. Cancer & chemotherapy",
"keywords": null,
"medline_ta": "Gan To Kagaku Ryoho",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D006471:Gastrointestinal Hemorrhage; D006801:Humans; D008297:Male; D010166:Palliative Care; D011879:Radiotherapy Dosage; D012189:Retrospective Studies; D013274:Stomach Neoplasms; D016896:Treatment Outcome",
"nlm_unique_id": "7810034",
"other_id": null,
"pages": "2500-2502",
"pmc": null,
"pmid": "32156978",
"pubdate": "2019-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Clinical Outcomes of Palliative Radiation Therapy for Gastric Cancer Bleeding.",
"title_normalized": "clinical outcomes of palliative radiation therapy for gastric cancer bleeding"
} | [
{
"companynumb": "NVSC2020JP146471",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LEUCOVORIN CALCIUM"
},
"drugadditional": "3",
... |
{
"abstract": "This study describes an incision-free minimally invasive conjunctival surgical (MICS) technique to repair late-onset leaking blebs after trabeculectomy.\n\n\n\nA surgical technique to repair leaking blebs without incision or excision of conjunctiva is described. This is followed by retrospective review of all patients treated at the Glaucoma Unit at St. Michael's Hospital for bleb leaks repaired with MICS from 2012 to 2017. With Research Ethics Board approval, clinical data obtained from the charts included demographic information, vision, intraocular pressure (IOP) data before and after surgery, need for additional medication, and complications. Resolution of the bleb leak without the need for additional therapy or intervention for glaucoma control was considered a success.\n\n\n\nThe MICS approach was applied to 14 eyes of 13 consecutive patients with a leaking bleb. Mean age of presentation was 70.2 ± 14.8 years, and all patients had a history of mitomycin use at the time of glaucoma surgery. The onset of bleb leak following trabeculectomy ranged from 7 months to 16.3 years. Mean pre-operative IOP was 4.5 ± 2.8 mm Hg; IOP measured 12.3 ± 3.0 mm Hg immediately after the procedure. Complete resolution of the bleb leak was observed following surgery in all cases. The follow-up period ranged from 2 weeks to 61 months (10.2 ± 18.1). Recurrent bleb leak was reported in 1 patient 2 years following initial surgery. In all cases, the initially repaired filtering blebs remained functional at last follow-up, and no additional medications were required.\n\n\n\nThe MICS procedure is an effective option for treating late-onset leaking blebs without cutting or excising conjunctival tissue. The minimal requirements of this method make it additionally accessible to low-resource settings. NOTE: Publication of this article is sponsored by the American Ophthalmological Society.",
"affiliations": "Departments of Ophthalmology and Vision Sciences and Laboratory Medicine and Pathobiology, University of Toronto, and Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada; and Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Unity Health Toronto, Canada. Electronic address: guptan@smh.ca.",
"authors": "Gupta|Neeru|N|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.ajo.2019.04.031",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0002-9394",
"issue": "207()",
"journal": "American journal of ophthalmology",
"keywords": null,
"medline_ta": "Am J Ophthalmol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D003228:Conjunctiva; D005260:Female; D005500:Follow-Up Studies; D005902:Glaucoma, Open-Angle; D006801:Humans; D007429:Intraocular Pressure; D008297:Male; D008875:Middle Aged; D019060:Minimally Invasive Surgical Procedures; D012086:Reoperation; D012189:Retrospective Studies; D013529:Surgical Wound Dehiscence; D014065:Tonometry, Ocular; D014130:Trabeculectomy",
"nlm_unique_id": "0370500",
"other_id": null,
"pages": "333-342",
"pmc": null,
"pmid": "31095952",
"pubdate": "2019-11",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Incision-Free Minimally Invasive Conjunctival Surgery (MICS) for Late-Onset Bleb Leaks After Trabeculectomy (An American Ophthalmological Society Thesis).",
"title_normalized": "incision free minimally invasive conjunctival surgery mics for late onset bleb leaks after trabeculectomy an american ophthalmological society thesis"
} | [
{
"companynumb": "CA-ACCORD-130300",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FLUOROURACIL"
},
"drugadditional": "3",
"dru... |
{
"abstract": "Acute interstitial nephritis is an immune-related adverse event that can occur in patients receiving immune checkpoint inhibitor therapy. Differentiating checkpoint inhibitor-associated acute interstitial nephritis from other causes of acute kidney injury in patients with cancer is challenging and can lead to diagnostic delays and/or unwarranted immunosuppression. In this case report, we assess the use of 18F-flourodeoxyglucose positron-emission tomography imaging as an alternative diagnostic modality in the evaluation of potential acute interstitial nephritis.\n\n\n\nA 55-year-old woman with metastatic vulvar melanoma underwent treatment with two cycles of ipilimumab plus nivolumab, followed by seven cycles of nivolumab combined with radiation therapy. During her treatment, she developed non-oliguric acute kidney injury to a creatinine of 4.5 mg/dL from a baseline of 0.5 mg/dL. A clinical diagnosis of acute interstitial nephritis was made, and steroids were initiated, with rapid improvement of her acute kidney injury. Retrospectively, four positron-emission tomography scans obtained for cancer staging purposes were reviewed. We found a markedly increased 18F-flourodeoxyglucose uptake in the renal cortex at the time acute interstitial nephritis was diagnosed compared to baseline. In three cases of acute kidney injury due to alternative causes there was no increase in 18F-flourodeoxyglucose uptake from baseline.\n\n\n\nTo our knowledge, this is the first report describing increased 18F-flourodeoxyglucose uptake in the renal cortex in a patient with checkpoint inhibitor-associated acute interstitial nephritis. Our findings suggest that 18F-flourodeoxyglucose positron-emission tomography may be a valuable test for diagnosing immune-mediated nephritis, particularly in patients where timely kidney biopsy is not feasible.",
"affiliations": "Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.;Division of Nephrology, Department of Medicine, Harvard Medical School, Massachusetts General Hospital, 165 Cambridge Street Suite 302, Boston, MA, 02114, USA.;Harvard Medical School, Boston, MA, USA.;Department of Radiology, Massachusetts General Hospital, Boston, MA, USA.;Department of Radiology, Massachusetts General Hospital, Boston, MA, USA.;Division of Nephrology, Department of Medicine, Harvard Medical School, Massachusetts General Hospital, 165 Cambridge Street Suite 302, Boston, MA, 02114, USA.;Division of Oncology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.;Division of Oncology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.;Division of Nephrology, Department of Medicine, Harvard Medical School, Massachusetts General Hospital, 165 Cambridge Street Suite 302, Boston, MA, 02114, USA. msise@partners.org.",
"authors": "Qualls|David|D|;Seethapathy|Harish|H|;Bates|Halla|H|;Tajmir|Shahein|S|;Heidari|Pedram|P|;Endres|Paul|P|;Reynolds|Kerry|K|;Lawrence|Donald|D|;Sise|Meghan|M|",
"chemical_list": "D000074322:Antineoplastic Agents, Immunological; D019788:Fluorodeoxyglucose F18",
"country": "England",
"delete": false,
"doi": "10.1186/s40425-019-0820-9",
"fulltext": "\n==== Front\nJ Immunother CancerJ Immunother CancerJournal for Immunotherapy of Cancer2051-1426BioMed Central London 82010.1186/s40425-019-0820-9Case ReportPositron emission tomography as an adjuvant diagnostic test in the evaluation of checkpoint inhibitor-associated acute interstitial nephritis Qualls David 1Seethapathy Harish 2Bates Halla 3Tajmir Shahein 4Heidari Pedram 4Endres Paul 2Reynolds Kerry 5Lawrence Donald 5Sise Meghan msise@partners.org 21 0000 0004 0386 9924grid.32224.35Department of Medicine, Massachusetts General Hospital, Boston, MA USA 2 Division of Nephrology, Department of Medicine, Harvard Medical School, Massachusetts General Hospital, 165 Cambridge Street Suite 302, Boston, MA 02114 USA 3 000000041936754Xgrid.38142.3cHarvard Medical School, Boston, MA USA 4 0000 0004 0386 9924grid.32224.35Department of Radiology, Massachusetts General Hospital, Boston, MA USA 5 0000 0004 0386 9924grid.32224.35Division of Oncology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA USA 21 12 2019 21 12 2019 2019 7 35617 7 2019 13 11 2019 © The Author(s). 2019Open 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\nAcute interstitial nephritis is an immune-related adverse event that can occur in patients receiving immune checkpoint inhibitor therapy. Differentiating checkpoint inhibitor-associated acute interstitial nephritis from other causes of acute kidney injury in patients with cancer is challenging and can lead to diagnostic delays and/or unwarranted immunosuppression. In this case report, we assess the use of 18F-flourodeoxyglucose positron-emission tomography imaging as an alternative diagnostic modality in the evaluation of potential acute interstitial nephritis.\n\nCase presentation\nA 55-year-old woman with metastatic vulvar melanoma underwent treatment with two cycles of ipilimumab plus nivolumab, followed by seven cycles of nivolumab combined with radiation therapy. During her treatment, she developed non-oliguric acute kidney injury to a creatinine of 4.5 mg/dL from a baseline of 0.5 mg/dL. A clinical diagnosis of acute interstitial nephritis was made, and steroids were initiated, with rapid improvement of her acute kidney injury. Retrospectively, four positron-emission tomography scans obtained for cancer staging purposes were reviewed. We found a markedly increased 18F-flourodeoxyglucose uptake in the renal cortex at the time acute interstitial nephritis was diagnosed compared to baseline. In three cases of acute kidney injury due to alternative causes there was no increase in 18F-flourodeoxyglucose uptake from baseline.\n\nConclusions\nTo our knowledge, this is the first report describing increased 18F-flourodeoxyglucose uptake in the renal cortex in a patient with checkpoint inhibitor-associated acute interstitial nephritis. Our findings suggest that 18F-flourodeoxyglucose positron-emission tomography may be a valuable test for diagnosing immune-mediated nephritis, particularly in patients where timely kidney biopsy is not feasible.\n\nissue-copyright-statement© The Author(s) 2019\n==== Body\nBackground\nAcute interstitial nephritis (AIN) is increasingly being recognized as an immune-related adverse event (irAE) in patients receiving immune checkpoint inhibitor (ICPI) therapy [1]. A recent meta-analysis of 11 clinical trials demonstrated an overall incidence of kidney irAEs of 2.2%, with incidence rising to 4.9% with combination immunotherapy targeting cytotoxic T lymphocyte antigen-4 (CTLA-4) and programmed cell death protein-1 (PD-1) [1]. While relatively uncommon, AIN is an important consideration when evaluating acute kidney injury (AKI) in patients receiving immunotherapy, as early recognition and treatment with steroids can lead to recovery of kidney function; on the other hand, delays in identification and treatment may lead to permanent damage to the kidneys [1]. However, AKI is common in patients with cancer, with a broad differential diagnosis including sepsis, dehydration, nephrotoxin exposure, and metastatic disease leading to urinary tract obstruction [2]. Diagnosing AIN remains a challenge, as clinical features, laboratory testing, and conventional imaging do not reliably distinguish AIN from other common causes of AKI [3–6]. Biopsy remains the gold standard, but is invasive and carries risks of bleeding, and is often delayed by the use of aspirin and anticoagulants in these patients [7–9]. At the same time, empiric management of AIN with corticosteroids without a definitive diagnosis may lead to inappropriate interruption or discontinuation of cancer immunotherapy, and may compromise the efficacy of cancer treatment in these patients [10].\n\nWith the rapidly expanding FDA approval of these agents, establishing reliable noninvasive diagnostic testing strategies for the evaluation of AKI in patients on immunotherapy is of paramount importance. One consideration is the use of 18F-flourodeoxyglucose positron emission tomography-computed tomography scan (FDG PET-CT). While most commonly utilized for the staging of malignancies, FDG PET-CT has also been used to identify other inflammatory conditions including large-vessel vasculitis, sarcoidosis, and various infections [11]. A recent case series described PET scans in two cases of AIN, noting elevated 18F-flourodeoxyglucose (FDG) uptake in the renal cortex for both patients, providing some precedent that FDG PET-CT may be a useful adjuvant diagnostic test in the evaluation of AIN [12]. Anecdotal evidence supporting these findings in 3 other biopsy-proven AIN cases has been reported [6].\n\nIn this case report, we discuss a patient with metastatic vulvar melanoma on immunotherapy who developed ICPI-related AIN. Using serial images, we present the evolution of her AIN as seen through FDG uptake in the renal cortices. In patients for whom there is diagnostic uncertainty and a kidney biopsy is not clinically tenable, FDG PET-CT may represent an additional tool for the evaluation of AIN.\n\nCase presentation\nClinical course\nA 56-year-old woman was diagnosed with vulvar melanoma and pulmonary, hepatic and pelvic nodal metastases (Fig. 1). She initially underwent two cycles of combination ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1) with staging CT scans one month later showing progression of metastatic disease. This prompted a transition to nivolumab monotherapy combined with palliative radiation; ipilimumab was discontinued due to its toxicity with concurrent radiation. She underwent 7 additional cycles of nivolumab, 24 Gy to the vulvar mass and pelvic adenopathy, and 72 Gy total to tibial, T-spine and sacral lesions without apparent complication. Her 8th cycle of nivolumab was delayed for two weeks due to subclinical elevations in liver transaminases. When she re-presented to resume immunotherapy, the patient reported one week of fatigue, nausea and vomiting, along with cough and congestion. Laboratory studies performed at the time were notable for an AKI with a serum creatinine of 4.5 mg/dL, up from a baseline of 0.5 mg/dL. She was admitted to Massachusetts General Hospital for further evaluation and management.\nFig. 1 Clinical course of immune checkpoint inhibitor-related acute interstitial nephritis, response to therapy, and timing of PET-CT scans. The patient tolerated 2 cycles of combined ipilimumab and nivolumab followed by 7 cycles of nivolumab monotherapy with stable renal function. After the seventh cycle of nivolumab, an AKI rapidly developed reaching a peak of 4.84 mg/dL. After failing to improve with IV hydration, she was treated with methylprednisolone 500 mg IV daily for 3 days (arrows) followed by a prednisone taper, with rapid improvement in creatinine. Due to progression of disease and AIN, immunotherapy was discontinued indefinitely, and she began therapy with carboplatin and paclitaxel. Notably throughout the course, 4 PET-CT scans were performed, including two prior to the patient’s AKI, one during the AKI, and one following recovery of renal function. Abbreviations: PET-CT Positron emission tomography – computed tomography, AKI acute kidney injury, AIN acute interstitial nephritis\n\n\n\nOn admission she was given two liters of normal saline for possible dehydration, and despite this, her creatinine rose to 4.8 mg/dL. She was noted to be non-oliguric with a urine output of over 2 liters on the first day of hospitalization. Her other medications included omeprazole 40 mg daily and aspirin 325 mg daily, along with oxycontin and oxycodone for cancer pain. She denied use of any over-the-counter medications, specifically use of any nonsteroidal anti-inflammatory drugs (NSAIDs) or herbal medications.\n\nInitial laboratory testing is shown in Table 1. Urinalysis showed only 1+ blood and 1+ leukocyte esterase, and was otherwise unremarkable; sediment was bland without erythrocytes, nucleated cells, or cellular casts. Urine protein-creatinine ratio was mildly elevated at 331 mg/g and microalbumin/creatinine ratio was also mildly elevated at 72 mg/g. Serologic workup for other etiologies of AKI was negative (Table 1). Ultrasound of her kidneys performed on admission was notable for increased echogenicity of the kidney parenchyma bilaterally, but with no evidence of hydronephrosis or obstruction. Her right kidney measured 11.8 cm and left kidney measured 12 cm. Because she was taking aspirin 325mg daily until the day of admission, kidney biopsy could not be safely performed on presentation.\nTable 1 Laboratory data obtained during admission for acute kidney injury\n\nLab\tReference Range\tResult\t\nSodium (mmol/L)\t135–145\t126\t\nPotassium (mmol/L)\t3.4–5.0\t3.6\t\nChloride (mmol/L)\t98–108\t87\t\nCarbon Dioxide (mmol/L)\t23–32\t24\t\nBUN (mg/dL)\t8–25\t43\t\nCreatinine (mg/dL)\t0.60–1.50\t4.5\t\nGlucose (mg/dL)\t70–110\t158\t\nCalcium (mg/dL)\t8.5–10.5\t7\t\nAlbumin (g/dL)\t3.3–5.0\t3.4\t\nTotal Protein (g/dL)\t6.0–8.3\t7.3\t\nAlkaline Phosphatase (U/L)\t30–100\t124\t\nBilirubin (Total) (mg/dL)\t0.0–1.0\t0.2\t\nAST (SGOT) (U/L)\t9–32\t15\t\nALT (SGPT) (U/L)\t7–33\t6\t\nTSH (uIU/mL)\t0.40–5.00\t4.2\t\nESR (mm/hr)\t0–20\t104 mm/hr.\t\nCRP (mg/L)\t< 8.0\t102.1 mg/L\t\nTotal Complement (U/ml)\t42–95\t71.3\t\nC3 (mg/dL)\t81–157\t124\t\nC4 (mg/dL)\t12–39\t36\t\nANA\tNegative\tPositive at 1:40, negative at 1:80\t\ndsDNA Antibody\tNegative\tNegative at 1:10\t\nANCA\tNegative\tNegative\t\nAbbreviations:BUN Blood urea nitrogen, AST Aspartate aminotransferase, ALT Alanine aminotransferase, TSH Thyroid-stimulating hormone, ESR Erythrocyte sedimentation rate, CRP C-reactive protein, ANA Antinuclear antibody; dsDNA Double-stranded DNA, ANCA Antineutrophil cytoplasmic antibody.\n\n\n\nGiven the high probability of ICPI-related AIN and inability to perform kidney biopsy in a timely manner, she was started on pulse dose intravenous methylprednisolone 500 mg daily for 3 days, followed by a prednisone taper starting at 40 mg daily. Her home omeprazole was changed to an H2 blocker, given its known association with AIN [13]. Her creatinine quickly improved from a peak of 4.8 mg/dL on the day steroids were initiated, to 2.7 mg/dL on the fourth day of steroid treatment (Fig. 1). One month after steroid initiation, her creatinine had stabilized at a new baseline of 1.1–1.2 mg/dL. Given the lack of clinical response of her metastatic disease to ICPI-therapy, she was not re-challenged, and was instead treated with paclitaxel and carboplatin.\n\nEvaluation of FDG PET-CT scan data\nWe noted that 10 days prior to the diagnosis of the patient’s AKI, she had an FDG PET-CT performed for routine cancer staging. At the time of the scan, the contrast-enhanced CT portion of the exam demonstrated multifocal patchy bilateral heterogeneous enhancement in her kidneys, without mass lesions or evidence of obstruction; however, at the time, elevated FDG uptake in the renal cortex was not specifically interpreted. Retrospectively, the FDG PET-CT scans were re-evaluated by a nuclear radiologist (PH) in light of the clinical suspicion for ICPI-AIN. The scans demonstrated increased FDG uptake in the renal cortices bilaterally with a maximum standardized uptake value (SUVmax) of 4 at the time of AKI (Fig. 2). These findings were compared to the FDG uptake in PET-CT scans performed on the same patient on three other occasions: prior to initiation of checkpoint inhibitor therapy, after ICPI initiation but before onset of AKI (2 months before AKI), and after recovery from the AKI (3 months after AKI diagnosis). Fig. 1 shows the relationship of FDG PET-CT scans to clinical course of AKI. Compared to baseline and follow-up, the FDG uptake in the renal cortices on the PET-CT scan just before AKI diagnosis had the highest SUVmax (Table 2).\nFig. 2 PET-CT scans obtained before and during patient’s treatment course. The initial scan (a) was obtained prior to immunotherapy treatment, and the subsequent scan (b) was performed after initiation of immunotherapy. Both (b) and (b) were performed at baseline renal function, and results of the scans show normal renal parenchymal FDG uptake and expected excretion of FDG into the renal pelvises. The third scan (c) was obtained during the patient’s AKI, and demonstrates markedly increased FDG uptake within the renal parenchyma compared to (a) and (b). Following steroid treatment and recovery of renal function, a fourth scan (d) was obtained, showing a return to baseline renal parenchymal FDG uptake, consistent with resolution of interstitial inflammation. Abbreviations: PET-CT positron emission tomography–computed tomography, FDG fluorodeoxyglucose\n\n\nTable 2 Cortical SUVMax over time in patient with checkpoint inhibitor-related AIN\n\nTime\tClinical Context\tSUVMax\t\n0 months\tBaseline (prior to ICPI)\t2.3\t\n4 months\tPost-ICPI initiation, renal function stable\t3.4\t\n6 months\tDuring AKI, prior to steroids\t4.0\t\n8 months\tAfter steroid treatment and AKI recovery\t2.6\t\nAbbreviations: SUV Standardized uptake value, ICPI Immune checkpoint inhibitor\n\n\n\nEvaluation of FDG PET-CT in non-inflammatory AKI\nIn order to further evaluate whether enhanced FDG uptake could differentiate AIN from other causes of AKI in patients taking ICPIs, we evaluated 3 patients who had FDG PET-CT performed within 2 weeks of AKI diagnosis and in whom a non-inflammatory etiology of their AKI could clearly be established. Each patient also had a separate PET-CT performed prior to AKI which served as a baseline image. We assessed control and AKI images for SUVMax, with the results demonstrated in Table 3. For all 3 patients with non-AIN AKI, including pre-renal azotemia or cardiorenal syndrome, SUVMax at the time of AKI was stable or slightly decreased as compared to baseline FDG PET-CT.\nTable 3 PET-CT scan findings in patients with hemodynamic (non-inflammatory) AKI\n\nPatient\tEtiology of AKI\tBaseline SUVMax\tSUVMax at time of AKI\tChange in SUVMax\t\n1\tCardiorenal AKI from decompensated cirrhosis, atrial mass requiring resection\t4\t3.8\t−0.2\t\n2\tPrerenal AKI due to small bowel obstruction\t2.8\t2.8\t0\t\n3\tPrerenal AKI due to intraabdominal sepsis\t3.1\t2.9\t−0.2\t\nComparison of cortical SUVMax before and during AKI for 3 patients undergoing checkpoint inhibitor therapy who had PET performed at the time of AKI. All patients had AKI attributed to clear hemodynamic causes and the AKI resolved without the need for corticosteroids. Patients had PET scans within 0–12 days of AKI\n\nAbbreviations: AKI Acute kidney injury, SUV Standardized uptake value, AIN Acute interstitial nephritis\n\n\n\nDiscussion and conclusion\nIn this case report we describe a patient with a clinical diagnosis of ICPI-AIN, with PET-CT showing increased FDG uptake in the renal cortex at the time of ICPI-AIN. Checkpoint inhibitor-related AIN is characterized by a lymphocyte-predominant infiltrate with varying degrees of plasma cells and eosinophils [1]. Such metabolically active infiltrates readily take up FDG and can be appreciated on FDG PET-CT scan [14]. The described case supports the hypothesis that the inflammatory infiltrate in AIN drives FDG uptake, as our patient with ICPI-AIN had increasing cortical FDG uptake, in contrast to the 3 patients with non-AIN AKI had no change or a decrease in FDG uptake during PET-CT scans obtained at the time of AKI.\n\nOnly one other case series by Katagiri et al. has reported on the use of PET-CT scan for evaluating AIN [12]. In this report two patients with drug-induced AIN resulting in oliguric kidney failure were found to have increased kidney parenchymal FDG uptake on PET-CT. A third patient with pauci-immune crescentic glomerulonephritis had PET-CT which showed no parenchymal FDG uptake, suggesting that the enhanced uptake seen in the AIN cases was driven by metabolically active inflammatory cells invading the tubulointerstitial space.\n\nThere are key differences between the cases reported by Katagiri et al. and the above report. This is the first reported case of FDG PET-CT detecting changes in checkpoint-associated AIN, as opposed to drug-induced AIN. In the cases reported by Katagiri et al., all patients were oliguric, and scans showed parenchymal FDG uptake without excretion into the renal pelvis. There was concern that in non-oliguric patients, excretion of FDG into the renal pelvis may interfere with the interpretation of renal cortical FDG update. However, our case demonstrates that in a non-oliguric AKI with ongoing active excretion of FDG into the renal pelvis, a pathologically elevated SUVmax within the renal cortex could still be appreciated on PET-CT.\n\nNon-invasive diagnosis of AIN is challenging. The classic clinical criteria, including fevers, arthralgias, and rash, are found in the minority of patients with drug-induced or ICPI-related AIN [1, 3]. Diagnostics including urine chemistries and sediment analysis are unreliable markers for differentiating AIN from other causes of AKI [4–6]. Urine eosinophils are frequently obtained in the evaluation of AIN, but its performance has been unreliable in a number of smaller studies, with the largest study to date finding a sensitivity of 30% and specificity of 68% [4, 6]. A recent study showed that leukocyturia occurs in only half of the patients with checkpoint-related AIN [15]. Moledina and colleagues evaluated if specific T-cell cytokine levels could serve as biomarkers to distinguish AIN from other causes of AKI and found higher levels of urinary tumor necrosis factor-alpha and interleukin-9 in the urine of patients with biopsy proven AIN compared to other kidney diseases [16]. Studies that evaluate these cytokines in patients taking ICPIs are needed. Other imaging modalities, such as gallium scans, have been proposed as an alternative diagnostic strategy in AIN. 67Gallium binds to lactoferrin, which is released by infiltrating leukocytes and expressed on the surface of lymphocytes found in the tubular interstitium in AIN, and early studies had suggested that gallium scans were highly sensitive for AIN [17]. However, subsequent studies have found lower sensitivities ranging from 58 to 69% and low specificities of 50–60%, limiting their utility [6].\n\nThe only reliable method for diagnosing AIN remains a kidney biopsy, which is often not feasible in patients with advanced malignancies. As in this case, patients are often on aspirin, NSAIDs, or anticoagulation. In such cases, a wash-out period of 7–10 days is recommended to minimize the risk of clinically significant bleeding related to a biopsy [7]. Even in the absence of blood thinners, there is still a ≥ 1% risk of clinically significant bleeding requiring transfusions [8]. Additionally, many patients have absolute or relative contraindications to kidney biopsy, such as having a solitary functioning kidney, morbid obesity, or an inability to hold anti-platelet agents or anticoagulants [9].\n\nGiven the risks and potential delays associated with kidney biopsy, clinicians are often left with the dilemma of whether to empirically treat for AIN without a definitive diagnosis. However, a misdiagnosis of AIN and empiric treatment are not without risk, and may compromise treatment of the underlying cancer. While some studies suggest the treatment of irAEs with high-dose steroids do not adversely affect outcomes, their harm has not been definitively ruled out, and one study has shown increased mortality with the use of higher doses of steroids in patients with immune-related hypophysitis [10, 18]. As such, establishing the etiology of AKI in these patients to the greatest extent of certainty possible is vital, and FDG PET-CT may represent an additional tool in determining the etiology.\n\nFDG-PET CT has also been investigated in checkpoint inhibitor-associated gastrointestinal toxicities. Lang et al. prospectively evaluated 100 patients treated with ipilimumab for melanoma, and had PET-CT performed prior to ipilimumab and after 2 and 4 cycles of ipilimumab [19]. They noted a statistically significant correlation between increased FDG uptake throughout the colon and clinical symptoms of colitis; 29 patients developed clinical signs of colitis, and 21 of these patients had increased colonic uptake on PET-CT. The remaining 8 patients with colitis symptoms and negative PET-CT did not have diarrhea at the time PET-CTs were performed. Two separate case reports describe instances of gastroduodenitis and esophagitis/gastritis in patients receiving ICPIs, where FDG PET-CT detected enhanced FDG uptake within the affected organs [20, 21].\n\nAs a single case report, significant research is still required to investigate whether FDG PET-CT would be a reliable diagnostic tool for ICPI-AIN. There are other limitations to the utility of FDG PET-CT in general, including its expense and lack of availability at all institutions [22], though PET-CTs are widely available in centers which have an immunotherapy program and patients on ICPIs. Limitations in the resolution of PET-CT may also limit its ability to detect changes in parenchymal FDG uptake; the average renal cortex thickness is approximately 6 mm, and the resolutions of PET scanners can range from < 5 mm for newer models utilizing time-of-flight technology to 10 mm in older models [23]. Variability in PET acquisition protocols, reconstruction algorithms, and the timing and dose of FDG injection may also affect the interpretation of SUVmax, particularly if scans are obtained at separate facilities [24]. We found the comparison with a baseline scan to be extremely helpful, with increasing FDG-avidity from baseline in our patient with checkpoint nephritis, compared to those with other causes of AKI where there was no increase in FDG uptake at the time of AKI.\n\nOther confounders, including kidney neoplasms, metastases, or alternative causes of immune kidney disease, may also interfere with the interpretation of results. As such, FDG PET-CT will need to be used and interpreted in the context of the patient’s renal disease as well as that of the patient’s underlying cancer.\n\nFinally, our case is limited by the fact that the diagnosis of ICPI-AIN was made without kidney biopsy; however, given the clinical features of this case, including enlarged, echogenic kidneys on ultrasound, lack of improvement despite intravenous hydration with normal saline, and the rapid improvement in creatinine after initiating corticosteroids, the treating nephrologist and oncologist were confident in the diagnosis of ICPI-AIN.\n\nDespite these limitations, FDG PET-CT represents a unique opportunity for diagnostic insight in a disease where noninvasive testing is extremely limited. PET-CT has the advantage of being a non-invasive and non-nephrotoxic study if performed without iodinated contrast. In cancer patients specifically, there may be pre-treatment FDG PET-CT scans available for direct comparison, which may assist in diagnostic clarity. As the indications for ICPI therapy expand, the number of cases of AKI with immune-related kidney injury will continue to rise. FDG PET-CT could potentially help differentiate AIN from other causes of AKI, thereby facilitating more accurate and timely diagnosis, and proper treatment. Further evaluation of PET-CT scans performed in patients with AKI on ICPI therapy may yield greater insight into the frequency and pathophysiology of ICPI-associated AIN.\n\nAbbreviations\nAINAcute interstitial nephritis\n\nAKIAcute kidney injury\n\nCTLA-4Cytotoxic T lymphocyte antigen-4\n\nFDG18F-flourodeoxyglucose\n\nICPIImmune checkpoint inhibitor\n\nirAEImmune-related adverse event\n\nNSAIDNonsteroidal anti-inflammatory drug\n\nPD-1Programmed cell death protein-1\n\nPET-CTPositron emission tomography-computed tomography scan\n\nSUVmaxMaximum standardized uptake value\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nNot applicable.\n\nAuthors’ contributions\nDQ analyzed and interpreted the patient’s clinical data and drafted the manuscript. HS reviewed the patient’s clinical data and edited the manuscript. HB reviewed and interpreted patient data, edited the manuscript and generated Fig. 1. ST and PH reviewed and interpreted the FDG PET-CT images, and contributed to the manuscript. PE obtained the patient’s imaging for radiologist review. KR reviewed and edited the manuscript. DL was the primary provider for the patient, and contributed to the manuscript. MS obtained the primary clinical data, and supervised the investigation and manuscript production. All authors read and approved the final manuscript.\n\nFunding\nNone.\n\nAvailability of data and materials\nNot applicable.\n\nEthics approval and consent to participate\nNeed for approval was waived.\n\nConsent for publication\nAll patient information was de-identified and patient consent was not required.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n==== Refs\nReferences\n1. Cortazar FB Marrone KA Troxell ML Ralto KM Hoenig MP Brahmer JR Clinicopathological features of acute kidney injury associated with immune checkpoint inhibitors Kidney Int 2016 90 3 638 647 27282937 \n2. Rosner MH Perazella MA Acute kidney injury in patients with Cancer N Engl J Med 2017 376 18 1770 1781 28467867 \n3. Perazella MA Clinical approach to diagnosing acute and chronic Tubulointerstitial disease Adv Chronic Kidney Dis 2017 24 2 57 63 28284380 \n4. Muriithi AK Nasr SH Leung N Utility of urine eosinophils in the diagnosis of acute interstitial nephritis Clin J Am Soc Nephrol 2013 8 11 1857 1862 24052222 \n5. Fogazzi GB Ferrari B Garigali G Simonini P Consonni D Urinary sediment findings in acute interstitial nephritis Am J Kidney Dis 2012 60 2 330 332 22677261 \n6. Perazella MA Diagnosing drug-induced AIN in the hospitalized patient: a challenge for the clinician Clin Nephrol 2014 81 06 381 388 24691017 \n7. Douketis JD Spyropoulos AC Spencer FA Mayr M Jaffer AK Eckman MH Perioperative Management of Antithrombotic Therapy Chest. 2012 141 e326S e350S 22315266 \n8. Corapi KM Chen JLT Balk EM Gordon CE Bleeding complications of native kidney biopsy: a systematic review and meta-analysis Am J Kidney Dis 2012 60 1 62 73 22537423 \n9. Hogan JJ Mocanu M Berns JS The native kidney biopsy: update and evidence for best practice Clin J Am Soc Nephrol 2016 11 2 354 362 26339068 \n10. Faje AT, Lawrence D, Flaherty K, Freedman C, Fadden R, Rubin K, et al. High-dose glucocorticoids for the treatment of ipilimumab-induced hypophysitis is associated with reduced survival in patients with melanoma. Cancer. 2018124(18):3706-3714;\n11. Hess S Hansson SH Pedersen KT Basu S Høilund-Carlsen PF FDG-PET/CT in infectious and inflammatory diseases PET Clin 2014 9 4 497 519 26050949 \n12. Katagiri D Masumoto S Katsuma A Minami E Hoshino T Inoue T Positron emission tomography combined with computed tomography (PET-CT) as a new diagnostic tool for acute tubulointerstitial nephritis (AIN) in oliguric or haemodialysed patients NDT Plus 2010 3 2 155 159 \n13. Nochaiwong S Ruengorn C Awiphan R Koyratkoson K Chaisai C Noppakun K The association between proton pump inhibitor use and the risk of adverse kidney outcomes: a systematic review and meta-analysis Nephrol Dial Transplant 2018 33 2 331 342 28339835 \n14. Kubota R Yamada S Kubota K Ishiwata K Tamahashi N Ido T Intratumoral distribution of fluorine-18-fluorodeoxyglucose in vivo: high accumulation in macrophages and granulation tissues studied by microautoradiography J Nucl Med 1992 33 11 1972 1980 1432158 \n15. Seethapathy H, Zhao S, Chute D, et al. The incidence, causes, and risk factors of acute kidney injury in patients receiving immune checkpoint inhibitors. J Am Soc Nephrol. 2019. [Epublicationahead of print]\n16. Moledina DG Wilson FP Pober JS Perazella MA Singh N Luciano RL Urine TNF-α and IL-9 for clinical diagnosis of acute interstitial nephritis JCI Insight 2019 4 10 1 14 \n17. Joaquim AI Mendes GEF Ribeiro PFF Baptista MAF Burdmann EA Ga-67 scintigraphy in the differential diagnosis between acute interstitial nephritis and acute tubular necrosis: an experimental study Nephrol Dial Transplant 2010 25 10 3277 3282 20348147 \n18. Horvat TZ, Adel NG, Dang TO, Momtaz P, Postow MA, Callahan MK, et al. Immune-related adverse events, need for systemic immunosuppression, and effects on survival and time to treatment failure in patients with melanoma treated with ipilimumab at memorial Sloan Kettering cancer center. J Clin Oncol. 2015;33(28):3193–8.\n19. Lang N Dick J Slynko A Schulz C Dimitrakopoulou-Strauss A Sachpekidis C Clinical significance of signs of autoimmune colitis in 18 F-fluorodeoxyglucose positron emission tomography-computed tomography of 100 stage-IV melanoma patients Immunotherapy. 2019 11 8 667 676 31088239 \n20. Cǎlugǎreanu A Rompteaux P Bohelay G Goldfarb L Barrau V Cucherousset N Late onset of nivolumab-induced severe gastroduodenitis and cholangitis in a patient with stage IV melanoma Immunotherapy. 2019 11 12 1005 1013 31304833 \n21. Boike J Dejulio T Severe esophagitis and gastritis from Nivolumab therapy ACG Case Reports J 2017 4 1 e57 \n22. Saif MW Tzannou I Makrilia N Syrigos K Role and cost effectiveness of PET/CT in management of patients with cancer Yale J Biol Med 2010 83 2 53 65 20589185 \n23. Akamatsu G Ishikawa K Mitsumoto K Taniguchi T Ohya N Baba S Improvement in PET/CT image quality with a combination of point-spread function and time-of-flight in relation to reconstruction parameters J Nucl Med 2012 53 11 1716 1722 22952340 \n24. Adams MC Turkington TG Wilson JM Wong TZ A systematic review of the factors affecting accuracy of SUV measurements Am J Roentgenol 2010 195 2 310 320 20651185\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2051-1426",
"issue": "7(1)",
"journal": "Journal for immunotherapy of cancer",
"keywords": null,
"medline_ta": "J Immunother Cancer",
"mesh_terms": "D000208:Acute Disease; D000074322:Antineoplastic Agents, Immunological; D000971:Antineoplastic Combined Chemotherapy Protocols; D005260:Female; D019788:Fluorodeoxyglucose F18; D006801:Humans; D008875:Middle Aged; D009369:Neoplasms; D009395:Nephritis, Interstitial; D000072078:Positron Emission Tomography Computed Tomography; D049268:Positron-Emission Tomography",
"nlm_unique_id": "101620585",
"other_id": null,
"pages": "356",
"pmc": null,
"pmid": "31864416",
"pubdate": "2019-12-21",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural",
"references": "20589185;31092735;26282644;20651185;28467867;22537423;31672794;26050949;24691017;22315266;31304833;26339068;29975414;1432158;22952340;28459081;24052222;22677261;28284380;27282937;31088239;28339835;20348147",
"title": "Positron emission tomography as an adjuvant diagnostic test in the evaluation of checkpoint inhibitor-associated acute interstitial nephritis.",
"title_normalized": "positron emission tomography as an adjuvant diagnostic test in the evaluation of checkpoint inhibitor associated acute interstitial nephritis"
} | [
{
"companynumb": "US-BRISTOL-MYERS SQUIBB COMPANY-BMS-2020-004914",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "OMEPRAZOLE"
},
"drugadd... |
{
"abstract": "Blue rubber bleb nevus syndrome (BRBNS) is a rare disorder that is characterized by multiple dome-shaped cutaneous venous malformations on the skin and visceral organs. Typical extra-cutaneous lesions have the appearance of blueish nipple-shaped nodules that can easily compress and refill. We described a rare case of a 23-year-old female with BRBNS and tuberous sclerosis complex (TSC) that presented with central nervous system (CNS) involvement including unprovoked focal impaired awareness seizure. Her BRBNS presents with hemangiomas involving multiple organs in the body including the brain, gastrointestinal (GI) system, and skin. This case highlights the importance of studying and understanding the association between BRBNS and TSC as it may lead to improved understanding.",
"affiliations": "From the Department of Neuroscience, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.;From the Department of Neuroscience, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.",
"authors": "Alreefi|Hajar|H|;AlKhateeb|Mashael|M|",
"chemical_list": null,
"country": "Saudi Arabia",
"delete": false,
"doi": "10.17712/nsj.2021.2.20200111",
"fulltext": "\n==== Front\nNeurosciences (Riyadh)\nnsj\nnsj\nNeurosciences\nNeurosciences\n1319-6138\n1319-6138\nRiyadh : Armed Forces Hospital\n\n33814375\nNeurosciences-26-2-207\n10.17712/nsj.2021.2.20200111\nCase Reports\nBlue rubber bleb nevus syndrome associated with tuberous sclerosis complex and CNS involvement\nAlreefi Hajar MBBS\nAlKhateeb Mashael MD\nFrom the Department of Neuroscience, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia\nAddress correspondence and reprint request to: Dr. Hajar Alreefi, Alfaisal University, College of Medicine, Riyadh, Saudi Arabia. E-mail: halreefi@alfaisal.eduORCID ID: https://orcid.org/0000-0002-3268-043X\n4 2021\n26 2 207211\n03 8 2020\n03 10 2020\nCopyright: © Neurosciences\n2021\nhttps://creativecommons.org/licenses/by-nc/3.0/ Neurosciences is an Open Access journal and articles published are distributed under the terms of the Creative Commons Attribution-NonCommercial License (CC BY-NC). Readers may copy, distribute, and display the work for non-commercial purposes with the proper citation of the original work.\nABSTRACT\n\nBlue rubber bleb nevus syndrome (BRBNS) is a rare disorder that is characterized by multiple dome-shaped cutaneous venous malformations on the skin and visceral organs. Typical extra-cutaneous lesions have the appearance of blueish nipple-shaped nodules that can easily compress and refill. We described a rare case of a 23-year-old female with BRBNS and tuberous sclerosis complex (TSC) that presented with central nervous system (CNS) involvement including unprovoked focal impaired awareness seizure. Her BRBNS presents with hemangiomas involving multiple organs in the body including the brain, gastrointestinal (GI) system, and skin. This case highlights the importance of studying and understanding the association between BRBNS and TSC as it may lead to improved understanding\n==== Body\nFirst described in 1860, blue rubber bleb nevus syndrome (BRBNS) is a disorder characterized by multiple dome-shaped cutaneous venous malformations on the skin and visceral organs.1 The BRBNS is an extremely rare disorder with only approximately 200 cases being reported since the term was coined.1 Typical extra-cutaneous lesions have the appearance of blueish nipple-shaped nodules that can easily compress and refill.2 These lesions frequently affect the gastrointestinal (GI) system and cause hemorrhage, iron-deficiency anemia, intussusception, and volvulus.3 In addition to GI involvement, these lesions have been shown to affect the central nervous system and may cause fatal hemorrhage.2 Herein, we report a case of BRBNS in a patient with TSC and CNS involvement that resulted in focal impaired awareness seizures.\n\nCase Report\n\nPatient information and clinical findings\n\nA 23-year-old female presented to the clinic with a history of focal impaired awareness seizure. She is a known case of tuberous sclerosis (confirmed by genetic testing and evident on MRI brain) and BRBNS, which the patient was diagnosed with early in childhood. Her BRBNS presents with hemangiomas involving multiple organs in the body including the brain, GI system, and skin.\n\nDiagnostic assessment and therapeutic intervention\n\nEarlier in her diagnosis, she was managed with various modalities, such as chemotherapy and interventional radiology, which failed to control her disease and specifically her active GI bleeding. To treat her subsequent iron-deficiency anemia, she was transfused on a weekly basis. Owing to her progressive uncontrolled disease, she traveled to seek further treatment at medical centers in the United States, where her disease was controlled by surgical resection and interventional sclerotherapy. The patient returned to Saudi Arabia and was later commenced on sirolimus, which she showed some response to. In 2016, the patient started developing multiple new lesions on her neck and trunk. Later, she started presenting complaints that are consistent with focal aware seizures. These attacks are characterized by loss of memory over a couple of minutes that is slowly regained in the proceeding 30 min. The patient reports feeling fear that lasts seconds to minutes preceding the seizure. It has been reported that her first attack happened when she was 2 years old. It occurred daily at any time during the day or night. After 9 years of age, it became less frequent and occurred once per week in the form of staring and behavioral arrest with mouth automatism lasting less than 10 seconds. At that time, she had been started initially on ethosuximide and valproic acid. After her 20th birthday, the semiology changed to focal impaired awareness seizure presenting in the form of palpitations and fear followed by behavioral arrest lasting less than 30 seconds. Carbamazepine was effective at that time in controlling her seizures as a mono-therapy. Alas, at the age of 23 years, the seizure recurred. At that time, the immunosuppressant for her dermatological case, sirolimus, was commenced and had interacted with the carbamazepine she was on. Therefore, levetiracetam (LEV) was added and was later reported to have aggravated her anxiety symptoms. Our patient was then shifted to lamotrigine (LTG) due to the psychiatric side effects she developed from LEV including anxiety and depression, which has successfully kept her seizure free during her 6-months follow up.\n\nFollow-Up and outcomes\n\nUpon examining the patient, she had small, dark blue, round or ellipsoid, soft compressible nevi (20-mm diameter) on her face, abdomen, and back. Her physical exam and vital signs were otherwise within normal limits. Upon further investigation, a 30-min EEG study performed was found to be normal with rhythmic mid-temporal theta bursts of drowsiness (RMTD), a benign variant also known as the psychomotor variant. Video-EEG or continuous EEG to ensure the absence of seizures is yet to be performed. Multisequential multiplanar nonenhanced and enhanced MRIs of the head and neck were performed showing extensive scalp, neck, chest wall as well as para-spinal soft tissue mass lesions involving also deep regions like the deep neck and chest, posterior deep cervical, oral, around the thyroid and para-tracheal regions. Additionally, the radiological findings showed a similar soft tissue lesion in the right oropharynx causing narrowing. The overall appearance was described as suggestive of extensive multiple vascular malformations in keeping with the known diagnosis of Blue Rubber Bleb Nevus Syndrome. Other MRI findings have shown to be consistent with Tuberous Sclerosis of multiple bilateral cortical/subcortical tubers involving bilateral frontal, parietal as well as left temporal lobes with ill-defined gray-white matter junction and cortical thickening.\n\nFigure 1 - Magnetic resonance imaging (MRI) T1 of head and neck sagittal section showing extensive vascular hemangioma of the posterior neck.\n\nFigure 2 - Magnetic resonance imaging (MRI) T1 of head and neck transverse section showing extensive para-spinal soft tissue mass lesions.\n\nFigure 3 - Post-contrast coronal MR of the head and neck shows extensive scalp, neck, upper chest and posterior para-spinal lobulated T2 hyper-intense soft tissue mass lesions suggestive of soft tissue venous malformation.\n\nFigure 4 - Axial FLAIR of the brain demonstrates multiple bilateral cortical/subcortical tubers involving bilateral frontal parietal as well as left temporal lobes with ill-defined gray-white matter junction and cortical thickening.\n\nDiscussion\n\nThe BRBNS with CNS involvement is rare and has been seldom reported. Some of the diagnoses in the reported cases were not clear. To date, 6 cases have been described including the case that has been thoroughly documented by Waybright et al.2 In 1978, Waybright et al. have described a BRBNS patient who presented with focal seizures and lateralized neurologic signs. The possible neurologic outcomes of BRBNS can present in multiple ways depending on the size and location of the cerebral angiomas.5 Owing to the heterogeneity of CNS manifestations and the risk of developing angioma thrombosis, it is typically challenging to evaluate the prognosis of the disease. Thus, it is essential for patients to undergo strict monitoring and thorough neurologic evaluation.5 However, to date, there have been no documented cases of BRBNS associated with TSC and subsequent CNS involvement. The patient in this study had multiple cutaneous venous malformations, bilateral cortical/ subcortical tubers, slight prominence of the ventricular system without evidence of acute hydrocephalus, and multiple hemangiomas in the brain, scalp, oropharynx, and chest. The diagnosis was confirmed on the basis of typical skin lesions and other clinical findings. For GI lesions, angiography, endoscopy, and MRI are favorable for diagnosis. In cases of CNS involvement, further imaging studies (e.g., CT and MRI) have been described as useful noninvasive tools. In addition, MRI has been described as a useful tool for screening asymptomatic patients.2 Typically, the treatment is symptom- and patient-based. This includes modalities to manage the bleeding and transfusion therapy. A combined laser-steroid therapy for GI hemangiomas has been reported by some investigators. The BRBNS cases are mostly sporadic in nature; familial cases have been recently associated with somatic mutations in TEK, the gene encoding TIE2, the endothelial cell tyrosine kinase receptor for the angiopoietins. These cases appear to be inherited in an autosomal dominant pattern. The TIE/angiopoietin family are closely implicated in and responsible for processes driving angiogenesis, be it in the physiological or in the pathological setting. The TIE2 activation integrates several intracellular signaling pathways, including the phosphati-dylinositol-3-kinase (PI3K)/AKT pathway promoting endothelial cell survival. PI3K in turn stimulates downstream regulation of mTOR.3 Similarly, TSC1/2 complex, the tumor suppressor genes responsible for Tuberous Sclerosis Complex, stimulates upstream activation signals from growth factor receptors via the pathway of (PI3K)/AKT. The mechanisms by which the TSC1/2 complex is regulated and in turn controls mTOR activity are merely beginning to be unraveled.4 Tuberous sclerosis complex is an autosomal genetic disorder characterized by the development of several benign tumors in the body. Vascular malformations or abnormalities in the setting of TSC are well-described in scientific literature. Angiomyolipomas are most commonly described, followed by arterial malformations, which are considerably less common. According to previous publications, most patients with TSC develop epilepsy, and most develop multiple seizure types. It has been reported that the most frequent seizure types in TSC are focal seizures and focal spasms.7 In the current case, our patient first presented with seizures at the age of 2 years. Her most recent seizures presented as focal impaired awareness seizures described as loss of memory over a couple of minutes that is preceded by feeling of fear lasting between seconds to minutes. Typically, seizure onset occurs in the first year of life, yet adults remain at risk. Because TSC-associated epilepsy usually presents early in life, seizure semiology often reflects the locations of cortical tubers and can potentially affect functional maturation.3 Focal seizures or infantile spasms frequently present in TSC patients with early onset epilepsy.7 In regards to the fact that drug-resistant epilepsy in TSC is common, many patients achieve full seizure control despite the presence of lesions in the brain.6 Studies conducted show that focal rhythmic slow wave activity, predominant on the temporal region without diffusion, was the typical reported pattern in TSC patients presenting with focal epilepsy.7 In the contrary, our patient presented with a normal 30-minute EEG study displaying rhythmic mid-temporal theta bursts of drowsiness (RMTD). RMTDs are generally considered benign variants with uncertain significance; however, concerns have been raised for their ictal potential.8 They were later confirmed to be the least epileptogenic of temporal discharges.8 However, generalized spike and wave discharges may be completely absent during wakefulness in some patients, making routine EEG studies yield a low sensitivity for identifying interictal epileptiform discharges (IEDs). It is safe to say that long-term video-EEG monitoring is the gold standard to confirm the diagnosis, classification and localization of epileptic seizures.9 A study by X. Liu et al10 concluded that the first-hour sleep EEG is able to reliably predict the occurrence of IEDs during long-term video-EEG recording and can be utilized as a time-efficient method to identify patients with IEDs, mitigating the burden in the adult epilepsy monitoring unit. Guidelines suggest that antiepileptic drugs (AEDs) are indicated as the first treatment option and shall follow those of other epilepsies.4 The presence of BRBNS in the setting of TSC has never been documented before. Moreover, it is unclear whether the patient’s epileptiform activity is a result of her BRBNS manifesting with cerebral hemangiomas or TSC cortical tubers, yet it has been evident that compliance with the selected mono-therapeutic antiepileptic medication has been beneficial in seizure control. Nevertheless, our study is limited by a number of factors including its retrospective and single case nature, the atypical presentation of TSC and the absence of a long-term video-EEG recording. Additional genetic mutations or complex pathways may be involved and require further characterization. Despite the limitations, the present case highlights the importance of studying the associations between BRBNS and TSC as it may lead to improved understanding of combined pathways and the further development of preferable management plans for patients.\n\nFigure 5 - 30-Minute EEG results showing rhythmic midtemporal theta bursts of drowsiness.\n\nFigure 6 - Case report timeline.\n\nIn conclusion, our patient diagnosed with BRBNS and TSC in her childhood demonstrated a rare presentation of focal impaired awareness seizure. Her BRBNS presents with hemangiomas involving multiple organs in the body including the brain, GI system and skin. We report this case to illustrate the importance of studying and understanding the association between these two diseases as it may lead to improved understanding of combined pathways.\n\nPatient’s perspective\n\nThe patient reports that she feels relieved to have her seizures in control. Moreover, she is glad that the previous psychiatric side effects including anxiety and depression have remitted after the drug switch to lamotrigine. She reports noticing major improvement in her quality of daily life.\n\nAcknowledgment\n\nWe would like to sincerely thank Dr. Khalid Omar Alahmadi, for his review of the radiology images. We would also like to thank Falcon Scientific Editing [http://www. https://falconediting.com/] for editing and reviewing this manuscript for English language.\n\nDisclosure. The authors declare no conflicting interests, support or funding from any drug company.\n==== Refs\nReferences\n\n1. Nahm WK, Moise S, Eichenfield LF, Paller AS, Nathanson L, Malicki DM, Friedlander SF. Venous malformations in blue rubber bleb nevus syndrome: variable onset of presentation. J Am Acad Dermatol 2004; 50 : S101–S106.15097941\n2. Kim SJ. Blue rubber bleb nevus syndrome with central nervous system involvement. Pediatr Neurol 2000; 22 : 410–412.10913737\n3. Wong XL, Phan K, Rodriguez Bandera AI, Sebaratnam DF. Sirolimus in blue rubber bleb naevus syndrome: A systematic review. J Paediatr Child Health 2019; 55 : 152–155. doi: 10.1111/jpc.14345.30565378\n4. Chu-Shore CJ, Major P, Camposano S, Muzykewicz D, Thiele EA. The natural history of epilepsy in tuberous sclerosis complex. Epilepsia 2010; 51 : 1236–1241.20041940\n5. Eirís-Puñal J, Picón-Cotos M, Viso-Lorenzo A, Castro-Gago M. Epileptic disorder as the first neurologic manifestation of blue rubber bleb nevus syndrome. J Child Neurol 2002; 17 : 219–222.12026239\n6. Song J, Swallow E, Said Q, Peeples M, Meiselbach M, Signorovitch J, et al. Epilepsy treatment patterns among patients with tuberous sclerosis complex. J Neurol Sci 2018; 391 : 104–108.30103955\n7. Savini MN, Mingarelli A, Vignoli A, Briola FL, Chiesa V, Peron A, et al. Ictal signs in tuberous sclerosis complex: Clinical and video-EEG features in a large series of recorded seizures. Epilepsy Behav 2018; 85 : 14–20.29906696\n8. Kang JY, Krauss GL. Normal Variants Are Commonly Overread as Interictal Epileptiform Abnormalities. J Clin Neurophysiol 2019; 36 : 257–263.31274688\n9. Shih JJ, Fountain NB, Herman ST, Bagic A, Lado F, Arnold S, et al. Indications and methodology for video-electroencephalographic studies in the epilepsy monitoring unit. Epilepsia 2018; 59 : 27–36.29124760\n10. Liu X, Issa NP, Rose S, Wu S, Sun T, Towle LV, et al. The first-hour-of-the-day sleep EEG reliably identifies interictal epileptiform discharges during long-term video-EEG monitoring. Seizure 2018; 63 : 48–51.30399461\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1319-6138",
"issue": "26(2)",
"journal": "Neurosciences (Riyadh, Saudi Arabia)",
"keywords": null,
"medline_ta": "Neurosciences (Riyadh)",
"mesh_terms": "D001921:Brain; D005260:Female; D005770:Gastrointestinal Neoplasms; D006801:Humans; D008279:Magnetic Resonance Imaging; D018329:Nevus, Blue; D012878:Skin Neoplasms; D014402:Tuberous Sclerosis; D055815:Young Adult",
"nlm_unique_id": "101252453",
"other_id": null,
"pages": "207-211",
"pmc": null,
"pmid": "33814375",
"pubdate": "2021-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "10913737;30399461;30565378;31274688;20041940;12026239;15097941;29124760;29906696;30103955",
"title": "Blue rubber bleb nevus syndrome associated with tuberous sclerosis complex and CNS involvement.",
"title_normalized": "blue rubber bleb nevus syndrome associated with tuberous sclerosis complex and cns involvement"
} | [
{
"companynumb": "SA-MLMSERVICE-20211221-3279557-1",
"fulfillexpeditecriteria": "1",
"occurcountry": "SA",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "SIROLIMUS"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nThe combination of fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) is more toxic than gemcitabine, but it is a safe regimen with manageable toxicities.\n\n\nMETHODS\nWe report a case with steatohepatitis mimicking liver metastasis as toxicity that was not seen in study patient population.Management and outcome: In the adjuvant statement with FOLFIRINOX due to biopsy, we give the same regimen by excluding metastasis.\n\n\nCONCLUSIONS\nThe adverse events of drugs are important predictive factor for treatment management, as important as efficacy. Especially the new lesion and metastasis is the most important factor for changing treatment. The clinicians must be careful about adverse events of regimens.\n\n\nCONCLUSIONS\nFOLFIRINOX regimen is the most important combination in pancreas cancer adjuvant setting. This case shows us the different presentation of usual adverse event.",
"affiliations": "Department of Medical Oncology, 448249University of Health Sciences, Adana City Education and Research Hospital, Adana, Turkey.;Department of Medical Oncology, 448249University of Health Sciences, Adana City Education and Research Hospital, Adana, Turkey.",
"authors": "Bozkurt Duman|Berna|B|https://orcid.org/0000-0003-0295-6295;Çil|Timuçin|T|",
"chemical_list": "C000627770:folfirinox; D000077150:Oxaliplatin; D000077146:Irinotecan; D002955:Leucovorin; D005472:Fluorouracil",
"country": "England",
"delete": false,
"doi": "10.1177/1078155220904422",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1078-1552",
"issue": "26(7)",
"journal": "Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners",
"keywords": "FOLFIRINOX; pancreas cancer; steatohepatitis",
"medline_ta": "J Oncol Pharm Pract",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D005234:Fatty Liver; D005260:Female; D005472:Fluorouracil; D006801:Humans; D000077146:Irinotecan; D002955:Leucovorin; D008113:Liver Neoplasms; D008875:Middle Aged; D000077150:Oxaliplatin; D010190:Pancreatic Neoplasms",
"nlm_unique_id": "9511372",
"other_id": null,
"pages": "1738-1742",
"pmc": null,
"pmid": "32070199",
"pubdate": "2020-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Steatohepatitis due to FOLFIRINOX regimen in adjuvant pancreas cancer treatment mimicking liver metastasis.",
"title_normalized": "steatohepatitis due to folfirinox regimen in adjuvant pancreas cancer treatment mimicking liver metastasis"
} | [
{
"companynumb": "TR-PFIZER INC-2020129772",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "OXALIPLATIN"
},
"drugadditional": "3",
... |
{
"abstract": "Kaposi sarcoma (KS) is an angioproliferative disease that is caused by human herpesvirus 8. The epidemic form of KS is associated with acquired immunodeficiency syndrome (AIDS) and is common in HIV-positive patients with CD4 counts less than 200 cells/mm. We present the case of a 63-year-old man with well-controlled HIV and normal CD4 count developing atypical nasal KS associated with intranasal steroid use.",
"affiliations": "12255Tulane University School of Medicine, New Orleans, LA, USA.;Department of Dermatology, 8785University of California, San Francisco, San Francisco, CA, USA.;Sutter West Bay Medical Group, San Francisco, CA, USA.;Department of Head and Neck Surgery, 7154Kaiser Permanente, San Francisco, CA, USA.;Department of Pathology, 7154Kaiser Permanente, San Francisco, CA, USA.;Department of Dermatology, 8785University of California, San Francisco, San Francisco, CA, USA.",
"authors": "Htet|Kyaw Zin|KZ|0000-0002-4376-8031;Waul|Michael|M|;Edelstein|Howard|H|;Mui|Stanley|S|;Cherny|Sarah|S|;Leslie|Kieron|K|",
"chemical_list": "D013256:Steroids",
"country": "England",
"delete": false,
"doi": "10.1177/0956462420980644",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0956-4624",
"issue": "32(6)",
"journal": "International journal of STD & AIDS",
"keywords": "HIV dermatology; Kaposi sarcoma; human herpesvirus 8; immunosuppressive therapy",
"medline_ta": "Int J STD AIDS",
"mesh_terms": "D000163:Acquired Immunodeficiency Syndrome; D018791:CD4 Lymphocyte Count; D019288:Herpesvirus 8, Human; D006801:Humans; D008297:Male; D008875:Middle Aged; D012514:Sarcoma, Kaposi; D013256:Steroids",
"nlm_unique_id": "9007917",
"other_id": null,
"pages": "582-584",
"pmc": null,
"pmid": "33533293",
"pubdate": "2021-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Primary nasal Kaposi Sarcoma in well-controlled HIV-positive patient with normal CD4 count associated with long-term nasal steroid use.",
"title_normalized": "primary nasal kaposi sarcoma in well controlled hiv positive patient with normal cd4 count associated with long term nasal steroid use"
} | [
{
"companynumb": "US-APOTEX-2021AP020612",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "NEVIRAPINE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nThe standard treatment of patients with metastatic germ-cell tumor (GCT) relapsing after first-line chemotherapy is based on a cisplatin and ifosfamide-containing three-drug regimen, which usually yields a complete response (CR) rate <50%. As gemcitabine consistently displayed activity in patients with advanced GCT and as synergy with cisplatin was reported, we integrated this drug into the salvage triplet regimen and assessed its activity in this phase II study.\n\n\nMETHODS\nThe GIP regimen consisted in gemcitabine 1000 mg/m(2) day 1 and 5, ifosfamide 1200 mg/m(2)/day day 1-5, cisplatin 20 mg/m(2)/day day 1-5, and granulocyte colony-stimulating factor 263 μg/day day 7-15, repeated every 3 weeks for four cycles. Eligibility criteria were that patients had favorable prognostic factors to conventional-dose salvage chemotherapy including a testis primary tumor and a previous CR to first-line chemotherapy for metastatic disease. The primary end point was the CR rate and a two-stage Simon design was used.\n\n\nRESULTS\nThirty-seven patients were accrued and 29 (78%) achieved a favorable response, including a CR in 20 (54%) and a partial response with normalization of tumor markers (PRm-) in 9 (24%). With a median follow-up of 53 months (13-81), the 2-year overall survival rate is 73% (57%-84%) and the continuous progression-free survival rate is 51% (35%-66%). Myelosuppression was the main toxicity including febrile neutropenia in 8 (22%) patients and 18 (50%) cases required platelet infusion. No grade 3 and 4 peripheral neurotoxicity or renal toxicity occurred. Two patients died of treatment-related toxicity, one of them with cancer progression.\n\n\nCONCLUSIONS\nIn a multicenter context, four cycles of the GIP regimen achieved a high CR rate in patients with relapsed testicular GCT. The GIP regimen avoided severe neurotoxicity and yielded a high survival rate.\n\n\nBACKGROUND\nNCT00127049.",
"affiliations": "Department of Cancer Medicine, Institut Gustave Roussy, Villejuif.",
"authors": "Fizazi|K|K|;Gravis|G|G|;Flechon|A|A|;Geoffrois|L|L|;Chevreau|C|C|;Laguerre|B|B|;Delva|R|R|;Eymard|J C|JC|;Rolland|F|F|;Houede|N|N|;Laplanche|A|A|;Burcoveanu|D|D|;Culine|S|S|",
"chemical_list": "D003841:Deoxycytidine; C056507:gemcitabine; D002945:Cisplatin; D007069:Ifosfamide",
"country": "England",
"delete": false,
"doi": "10.1093/annonc/mdu099",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0923-7534",
"issue": "25(5)",
"journal": "Annals of oncology : official journal of the European Society for Medical Oncology",
"keywords": "chemotherapy; gemcitabine; germ-cell tumor; salvage",
"medline_ta": "Ann Oncol",
"mesh_terms": "D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D002945:Cisplatin; D003841:Deoxycytidine; D004334:Drug Administration Schedule; D006801:Humans; D007069:Ifosfamide; D053208:Kaplan-Meier Estimate; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D009373:Neoplasms, Germ Cell and Embryonal; D011446:Prospective Studies; D016879:Salvage Therapy; D013736:Testicular Neoplasms; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "9007735",
"other_id": null,
"pages": "987-91",
"pmc": null,
"pmid": "24595454",
"pubdate": "2014-05",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Combining gemcitabine, cisplatin, and ifosfamide (GIP) is active in patients with relapsed metastatic germ-cell tumors (GCT): a prospective multicenter GETUG phase II trial.",
"title_normalized": "combining gemcitabine cisplatin and ifosfamide gip is active in patients with relapsed metastatic germ cell tumors gct a prospective multicenter getug phase ii trial"
} | [
{
"companynumb": "FR-PFIZER INC-2020489349",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CISPLATIN"
},
"drugadditional": "3",
... |
{
"abstract": "Cerebral venous sinus thrombosis (CVT) is rare but sometimes develops in association with malignant neoplasm. We report two cases of CVT that occurred during cisplatin-based chemotherapy for testicular cancer. A 46-year-old man with stage IIA non-seminomatous germ cell tumour was treated with conventional doses of etoposide and cisplatin (EP). On day 11 of the third treatment course, he developed a systemic seizure. Brain computed tomography (CT) and magnetic resonance (MR) imaging could not detect the cause. Enhanced chest-pelvic CT revealed pelvic thrombosis. Administration of phenytoin for epilepsy of unknown cause and heparin for thrombosis was started. He had completed 4 courses of EP therapy without seizure recurrence. After re-evaluating the brain CT images retrospectively, we found high density of superior sagittal sinus (SSS) and strongly suspected CVT. Another patient was a 47-year-old man with stage IIIB seminomatous germ cell tumour treated with bleomycin, etoposide, and cisplatin (BEP) therapy. On day 11 of the second treatment course, he developed a systemic seizure. Brain CT revealed subarachnoid haemorrhage localised in the right parietal lobe. CT venography revealed a filling defect in the superior sagittal sinus (SSS). MR venography revealed a SSS stenosis. We diagnosed the cause of the seizure as CVT and started administration of anticoagulant therapy. After the thrombus had diminished, chemotherapy was restarted and another 2 courses of BEP therapy was completed.",
"affiliations": "Department of Urology, Yamagata University Faculty of Medicine.;Department of Urology, Yamagata University Faculty of Medicine.;Department of Urology, Yamagata University Faculty of Medicine.;Department of Urology, Yamagata University Faculty of Medicine.;Department of Urology, Yamagata University Faculty of Medicine.;Department of Urology, Yamagata University Faculty of Medicine.;Department of Urology, Yamagata University Faculty of Medicine.;Department of Urology, Yamagata University Faculty of Medicine.;Department of Urology, Yamagata University Faculty of Medicine.;Department of Urology, Yamagata University Faculty of Medicine.;Department of Urology, Yamagata University Faculty of Medicine.;Department of Urology, Yamagata University Faculty of Medicine.;Department of Urology, Yamagata University Faculty of Medicine.;Department of Urology, Yamagata University Faculty of Medicine.;Department of Urology, Yamagata University Faculty of Medicine.;Department of Urology, Yamagata University Faculty of Medicine.;Department of Urology, Yamagata University Faculty of Medicine.;Department of Diagnositic Radiology, Yamagata University Faculty of Medicine.",
"authors": "Kuboki|Yuya|Y|;Yamagishi|Atsushi|A|;Kurokawa|Masayuki|M|;Kikuta|Masato|M|;Takai|Satoshi|S|;Takai|Yuki|Y|;Ushijima|Masaki|M|;Kurota|Yuta|Y|;Yagi|Mayu|M|;Sakurai|Toshihiko|T|;Nishida|Hayato|H|;Shibasaki|Tomohiro|T|;Kawazoe|Hisashi|H|;Ichiyanagi|Osamu|O|;Kato|Tomoyuki|T|;Nagaoka|Akira|A|;Tsuchiya|Norihiko|N|;Konno|Yoshihiro|Y|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": "10.5980/jpnjurol.108.225",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0021-5287",
"issue": "108(4)",
"journal": "Nihon Hinyokika Gakkai zasshi. The japanese journal of urology",
"keywords": "cerebral venous sinus thrombosis; chemotherapy; testicular cancer",
"medline_ta": "Nihon Hinyokika Gakkai Zasshi",
"mesh_terms": null,
"nlm_unique_id": "2984841R",
"other_id": null,
"pages": "225-228",
"pmc": null,
"pmid": "30333447",
"pubdate": "2017",
"publication_types": "D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "CEREBRAL VENOUS SINUS THROMBOSIS IN PATIENTS WITH METASTATIC TESTICULAR CANCER DURING CHEMOTHERAPY: REPORTS OF TWO CASES.",
"title_normalized": "cerebral venous sinus thrombosis in patients with metastatic testicular cancer during chemotherapy reports of two cases"
} | [
{
"companynumb": "JP-ACCORD-218958",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ETOPOSIDE"
},
"drugadditional": "1",
"drugad... |
{
"abstract": "Medication-related problems are a leading cause of morbidity and mortality. Patients requiring dialysis are at heightened risk for adverse drug reactions because of the prevalence of polypharmacy, multiple chronic conditions, and altered (but not well understood) medication pharmacokinetics and pharmacodynamics inherent to kidney failure. To minimize preventable medication-related problems, health care providers need to prioritize medication safety for this population. The cornerstone of medication safety is medication reconciliation. We present a case highlighting adverse outcomes when medication reconciliation is insufficient at care transitions. We review available literature on the prevalence of medication discrepancies worldwide. We also explain effective medication reconciliation and the practical considerations for implementation of effective medication reconciliation in dialysis units. In light of the addition of medication reconciliation requirements to the Centers for Medicare & Medicaid Services End-Stage Renal Disease Quality Incentive Program, this review also provides guidance to dialysis unit leadership for improving current medication reconciliation practices. Prioritization of medication reconciliation has the potential to positively affect rates of medication-related problems, as well as medication adherence, health care costs, and quality of life.",
"affiliations": "Dialysis Clinic, Inc, Nashville, TN.;Duke University School of Medicine, Durham, NC.;Dialysis Clinic, Inc, Nashville, TN. Electronic address: harold.manley@dciinc.org.",
"authors": "Frament|Jill|J|;Hall|Rasheeda K|RK|;Manley|Harold J|HJ|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1053/j.ajkd.2020.07.021",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0272-6386",
"issue": "76(6)",
"journal": "American journal of kidney diseases : the official journal of the National Kidney Foundation",
"keywords": "Patient safety; adverse drug events; best practices; dialysis unit; drug dosing; drug safety; end-stage renal disease (ESRD); medication discrepancy; medication reconciliation; polypharmacy; quality improvement; renal failure; review",
"medline_ta": "Am J Kidney Dis",
"mesh_terms": "D000369:Aged, 80 and over; D006801:Humans; D007676:Kidney Failure, Chronic; D008297:Male; D008508:Medication Errors; D059065:Medication Reconciliation; D006435:Renal Dialysis",
"nlm_unique_id": "8110075",
"other_id": null,
"pages": "868-876",
"pmc": null,
"pmid": "32920154",
"pubdate": "2020-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't; D016454:Review",
"references": "18436732;29299004;30637032;17853014;22819386;12596688;32173107;27185210;25703922;20727511;22217691;30530657;19175192;16492794;20674113;29719884;16615703;21395973;25864928;19423571;19947803;23990162;22478921;31156957;18464351;20595717;32426840;23089295;24357869;26113460;27785165;25695529;28223862",
"title": "Medication Reconciliation: The Foundation of Medication Safety for Patients Requiring Dialysis.",
"title_normalized": "medication reconciliation the foundation of medication safety for patients requiring dialysis"
} | [
{
"companynumb": "US-STRIDES ARCOLAB LIMITED-2021SP001277",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "GABAPENTIN"
},
"drugadditional"... |
{
"abstract": "OBJECTIVE\nCarboplatin is a key drug for gynecologic cancers. However, hypersensitivity reactions (HSR) are major adverse effects that might necessitate carboplatin discontinuation. Desensitization is an effective method in patients who developed initial HSR and further required carboplatin treatment. Here, we aimed to evaluate our experience with the use of the carboplatin desensitization protocol in five patients at the University of Tokyo Hospital.\n\n\nMETHODS\nWe established a four-step, 5-h desensitization protocol for our hospital. Observational and retrospective analyses were performed. Additionally, we have shared the patients' clinical information with the emergency department to ensure the safety of this protocol.\n\n\nRESULTS\nFive patients with recurrent gynecological cancer were treated using this protocol. Four of the five patients were treated effectively and 28 of 29 desensitization protocols were completed successfully. In one patient, we switched to olaparib successfully after two courses of our protocol. One patient who developed grade 4 HSR during initial carboplatin administration developed grade 2 HSR and we discontinued the protocol.\n\n\nCONCLUSIONS\nThe carboplatin desensitization protocol is very efficient. The outcome of our protocol was on a par with other protocols. To the best of our knowledge, this is the first study to indicate that switching to olaparib can be considered a suitable option in patients who develop HSR to carboplatin.",
"affiliations": "Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Tokyo, Japan.;Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Tokyo, Japan.;Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Tokyo, Japan.;Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Tokyo, Japan.;Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Tokyo, Japan.;Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Tokyo, Japan.;Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Tokyo, Japan.;Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Tokyo, Japan.;Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Tokyo, Japan.;Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Tokyo, Japan.;Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Tokyo, Japan.;Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Tokyo, Japan.",
"authors": "Toyohara|Yusuke|Y|;Sone|Kenbun|K|;Nishida|Haruka|H|;Taguchi|Ayumi|A|;Miyamoto|Yuichiro|Y|;Tanikawa|Michihiro|M|;Mori|Mayuyo|M|;Tsuruga|Tetsushi|T|;Matsumoto|Yoko|Y|;Oda|Katsutoshi|K|;Osuga|Yutaka|Y|;Fujii|Tomoyuki|T|",
"chemical_list": "D000970:Antineoplastic Agents; D016190:Carboplatin",
"country": "Australia",
"delete": false,
"doi": "10.1111/jog.14443",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1341-8076",
"issue": "46(11)",
"journal": "The journal of obstetrics and gynaecology research",
"keywords": "carboplatin; desensitization; hospital emergency service; hypersensitivity; retrospective study",
"medline_ta": "J Obstet Gynaecol Res",
"mesh_terms": "D000970:Antineoplastic Agents; D016190:Carboplatin; D003888:Desensitization, Immunologic; D004342:Drug Hypersensitivity; D005260:Female; D006801:Humans; D009364:Neoplasm Recurrence, Local; D012189:Retrospective Studies",
"nlm_unique_id": "9612761",
"other_id": null,
"pages": "2298-2304",
"pmc": null,
"pmid": "32830407",
"pubdate": "2020-11",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Desensitization strategy for hypersensitivity reactions to carboplatin in five patients with gynecological cancer.",
"title_normalized": "desensitization strategy for hypersensitivity reactions to carboplatin in five patients with gynecological cancer"
} | [
{
"companynumb": "JP-TEVA-2020-JP-1832949",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "CARBOPLATIN"
},
"drugadditional": null,
... |
{
"abstract": "Relapsing polychondritis (RP) is a rare autoimmune disorder, characterized by the inflammation of cartilaginous structures and proteoglycan-rich tissues. Due to its rarity and the notoriously variable presentations, the diagnosis of RP could be challenging. We report an unusual case of RP with isolated tracheal involvement and very non-specific symptoms of exertional dyspnoea and dry cough. The initial chest radiograph showed long-segment narrowing of the trachea, and the computed tomography of the chest revealed thickened cartilaginous walls of the trachea, while the posterior membranous portion was spared. The tracheal narrowing was readily observed under bronchoscopy. The patient was treated with oral prednisolone. Although the subsequent course was transiently complicated by an episode of severe Pneumocystis jirovecii pneumonia with acute respiratory distress syndrome, the patient overall responded well to systemic corticosteroid therapy. No new symptoms developed during a two-year follow-up.",
"affiliations": "Division of Chest Medicine, Department of Internal Medicine National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University Tainan Taiwan.;Division of Rheumatology and Immunology, Department of Internal Medicine National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University Tainan Taiwan.;Department of Diagnostic Radiology National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University Tainan Taiwan.;Division of Chest Medicine, Department of Internal Medicine National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University Tainan Taiwan.",
"authors": "Wang|Sheng-Yuan|SY|;Weng|Chia-Tse|CT|;Cheng|Lili|L|;Huang|Tang-Hsiu|TH|https://orcid.org/0000-0002-7675-9561",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1002/rcr2.651",
"fulltext": "\n==== Front\nRespirol Case Rep\nRespirol Case Rep\n10.1002/(ISSN)2051-3380\nRCR2\nRespirology Case Reports\n2051-3380 John Wiley & Sons, Ltd Chichester, UK \n\n10.1002/rcr2.651\nRCR2651\nCase Report\nCase Reports\nRelapsing polychondritis with isolated tracheal involvement and airway‐only symptoms\nAirway‐only relapsing polychondritisS.‐Y. Wang et al.Wang Sheng‐Yuan \n1\n Weng Chia‐Tse \n2\n Cheng Lili \n3\n Huang Tang‐Hsiu https://orcid.org/0000-0002-7675-9561\n1\ntangomycin0713@gmail.com \n1 \nDivision of Chest Medicine, Department of Internal Medicine\nNational Cheng Kung University Hospital, College of Medicine, National Cheng Kung University\nTainan\nTaiwan\n\n\n2 \nDivision of Rheumatology and Immunology, Department of Internal Medicine\nNational Cheng Kung University Hospital, College of Medicine, National Cheng Kung University\nTainan\nTaiwan\n\n\n3 \nDepartment of Diagnostic Radiology\nNational Cheng Kung University Hospital, College of Medicine, National Cheng Kung University\nTainan\nTaiwan\n\n* Correspondence\n\nTang‐Hsiu Huang, Division of Chest Medicine, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, No 138, Sheng‐Li Road, Tainan 704, Taiwan. E‐mail: tangomycin0713@gmail.com\n\n31 8 2020 \n10 2020 \n8 7 10.1002/rcr2.v8.7e0065116 7 2020 08 8 2020 10 8 2020 © 2020 The Authors. Respirology Case Reports published by John Wiley & Sons Australia, Ltd on behalf of The Asian Pacific Society of Respirology.This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.Abstract\nRelapsing polychondritis (RP) is a rare autoimmune disorder, characterized by the inflammation of cartilaginous structures and proteoglycan‐rich tissues. Due to its rarity and the notoriously variable presentations, the diagnosis of RP could be challenging. We report an unusual case of RP with isolated tracheal involvement and very non‐specific symptoms of exertional dyspnoea and dry cough. The initial chest radiograph showed long‐segment narrowing of the trachea, and the computed tomography of the chest revealed thickened cartilaginous walls of the trachea, while the posterior membranous portion was spared. The tracheal narrowing was readily observed under bronchoscopy. The patient was treated with oral prednisolone. Although the subsequent course was transiently complicated by an episode of severe Pneumocystis jirovecii pneumonia with acute respiratory distress syndrome, the patient overall responded well to systemic corticosteroid therapy. No new symptoms developed during a two‐year follow‐up.\n\nWe describe an atypical case of relapsing polychondritis that involved solely the tracheal cartilages and presented clinically as non‐specific airway symptoms. Timely diagnosis and treatment through a multidisciplinary approach is crucial to prevent subsequent serious complications.\n\n\nBronchoscopycentral airway obstructiontracheal stenosis source-schema-version-number2.0cover-dateOctober 2020details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:5.8.8 mode:remove_FC converted:31.08.2020\n\n\nWang , S‐Y \n, \nWeng , C‐T \n, \nCheng , L \n, \nHuang , T‐H \n. (2020 ) Relapsing polychondritis with isolated tracheal involvement and airway‐only symptoms\n. Respirology Case Reports , 8 (7 ), e00651\n10.1002/rcr2.651 \n\n\n\n\nAssociate Editor: Arata Azuma\n==== Body\nIntroduction\nRelapsing polychondritis (RP) is a rare multi‐system autoimmune disease. Chondritis (especially auricular and nasal) and polyarthritis are the most common presentations, but the eyes, heart valves, skin, and blood vessels can also be affected [1]. Because of such clinical variations, RP has been associated with a diagnostic delay. Laryngo‐tracheo‐bronchial involvement eventually occurs in 50% of RP patients, leading to significant morbidity and mortality, but it is uncommon as the initial presentation [2, 3]. In this report, we describe an unusual case of RP that had tracheal chondritis as the initial and main manifestation.\n\nCase Report\nThe patient was a 47‐year‐old man, who initially presented to a cardiologist with exertional dyspnoea and dry cough for several months. There was no fever, no neck or chest pain, no haemoptysis, no joint pain or skin eruption, and no visual, nasal, or auditory complaints. He did not have abdominal discomfort, chronic diarrhoea, or haematochezia. His childhood growth and past medical history were unremarkable. He was an ex‐smoker and worked as an operator of forklift at a warehouse. Initial workups including the electrocardiogram, the echocardiography, a treadmill stress test, and a thallium‐201 myocardial scan were normal. He was treated with aspirin and beta‐blocker, but the symptoms persisted. Upon the combined examination by a pulmonologist and a rheumatologist six months later, neither stridor nor wheeze was auscultated. Ophthalmologic, auricular, and nasopharyngeal examinations were unremarkable; his hearing test was normal. However, the initial chest radiograph showed evident narrowing of both the extra‐ and intra‐thoracic trachea (Fig. 1A). The pulmonary spirometry also detected an obstructive ventilatory deficit (Table 1), wherein a “flattening curve” was observed in both the inspiratory and expiratory phases (Fig. 1B), suggesting a fixed central airway obstruction. Computed tomography (CT) of the chest revealed diffuse thickening of the cartilaginous portion of his trachea that spared the posterior membranous portion (Fig. 2A); there was not enlarged lymph node in the cervical, clavicular, or mediastinal regions. Although an elevated erythrocyte sedimentation rate (ESR: 50, normal range: 0–15, mm/h) was found, other pertinent blood workups (including the haemogram, renal and hepatic parameters, the albumin‐to‐globulin ratio, and levels of C‐reactive protein, creatinine kinase, rheumatoid factor, immunoglobulins, and selected autoantibodies; Table 2) reported normal values. A gallium‐67 inflammation scan also revealed no definite inflammatory focus. Under fibreoptic bronchoscopy, significant narrowing of the mid‐to‐lower portion of the trachea was readily observed, but without excessive invagination or outpouching of the posterior wall. The narrowed lumen was neither crescent‐shaped nor sabre‐sheath‐like in the transverse view, and the mucosal surface was smooth without nodularity (Fig. 1C, Video S1, Supporting Information). A subsequent magnetic resonance imaging (MRI) showed hyperintensity and post‐gadolinium enhancement typically involving the periphery of the cartilaginous portions of the trachea (Fig. 2B, C). The diagnosis of RP was established following multidisciplinary evaluation and discussion, and treatment with high‐dose oral prednisolone (1 mg/kg/day) plus methotrexate (15 mg/week) was initiated. Just three weeks into treatment, the patient had an episode of severe Pneumocystis jirovecii pneumonia (PJP), which was diagnosed based on the typical radiographic findings of bilateral ground‐glass opacity and the detection of P. jirovecii in the deep tracheal aspirate (using an automated quantitative real‐time polymerase chain reaction (PCR) platform from Becton Dickinson in the central laboratory). The disease led to acute respiratory distress syndrome (ARDS) within three days. Methotrexate was discontinued immediately, but systemic steroid was maintained (and adjusted) as part of the treatment for PJP. After 13 days of invasive mechanical ventilation, the patient was successfully extubated and recovered well afterwards. No other pathogen (including mycobacteria) was isolated from his lower airway specimens. Over the next five months, corticosteroid therapy was carefully tapered to 2.5–5 mg daily of oral prednisolone, with a prophylaxis against PJP. His exertional dyspnoea and cough gradually improved, and he was able to return to work. CT of the chest five months later revealed decreased thickness of the tracheal cartilages, which remained stable at 10 months (Fig. 2D, E). The follow‐up pulmonary function test showed a significant improvement in his obstructive deficit (Table 1), and serial ESR levels were within normal ranges (Table 2). Two years had passed since the first onset of his symptoms, and the patient still receives active surveillance and has not developed new symptoms.\n\nFigure 1 (A) The initial chest radiograph showed evident narrowing of both the extra‐ and intra‐thoracic portions of the trachea. (B) The flow–volume revealed a flattened curve in both the inspiratory and expiratory phases, suggesting a fixed central airway obstruction. (C) Bronchoscopic examination showed severe narrowing and loss of integrity of the cartilaginous rings throughout the mid‐to‐lower portion of the trachea (the asterisk marks the posterior membranous surface of the trachea).\n\nTable 1 Serial measurements of pulmonary spirometry of the patient.\n\n\tFEV1/FVC, %\tPre‐BD FEV1, L (% prediction)\tPost‐BD FEV1, L (% prediction)\tFVC, L (% prediction)\tNotes\t\nOctober 2018\t66\t2.77 (80)\t2.79 (80)\t4.17 (107)\tThe initial spirometry before treatment\t\nAugust 2019\t81\t3.11 (90)\t3.06 (88)\t3.86 (99)\tPost‐treatment spirometries (corticosteroid treatment started in May 2019)\t\nFebruary 2020\t83\t3.18 (93)\tNA\t3.85 (99)\t\t\n\nBD, bronchodilator; FEV1, forced expiratory volume in 1 sec; FVC, forced vital capacity; NA, not available.\n\n\nFigure 2 (A) Computed tomography (CT) of the chest revealed diffuse thickening of the cartilaginous portion of the trachea, with the posterior membrane spared. (B) Magnetic resonance imaging (MRI) of the chest showed that the periphery of the tracheal cartilaginous C‐ring exhibited hyperintensity on the T2‐weighted image and (C) enhancement on the post‐gadolinium T1‐weighted image. (D) Five months into treatment, follow‐up CT showed decreased thickness of the cartilaginous wall of the trachea, which remained stable at 10 months as shown in (E).\n\nTable 2 Data on the baseline blood tests of the patient.\n\nHaemogram\tReference range\t\nTotal WBC count\t3.5\t3.2–9.2 x 103/μL\t\nTotal RBC count\t3.48\t3.72–4.93 x 106/μL\t\nTotal platelet count\t198\t151–366 x 103/μL\t\nHb\t11.4\t11.6–14.8 g/dL\t\nHct\t33.8\t33.8–43.4%\t\nBlood biochemistry\t\t\nCreatinine\t0.50\t0.5–0.9 mg/dL\t\nAST\t33\t10–35 U/L\t\nALT\t23\t10–35 U/L\t\nAlbumin\t4.0\t3.5–5.0 g/dL\t\nTotal protein\t7.4\t6.4–8.3 g/dL\t\nCK\t124\t37–308 U/L\t\nInflammation‐associated markers\t\t\nLDH\t185\t135–225 U/L\t\nESR\t\t0–15 mm/h\t\n20 June 2018\t50\t\n24 June 2019\t10\t\n6 March 2020\t6\t\nCRP\t<7\t0.0–8.0 mg/L\t\nIg\t\t\nIgG\t1120\t750–1690 mg/dL\t\nIgA\t415\t82–463 mg/dL\t\nIgM\t64.5\t46–304 mg/dL\t\nIgE\t10.3\t0–100 U/mL\t\nAuto‐antibodies\t\t\nANA\t1:40\t≤1:40\t\nRF\t<20\t<20 U/mL\t\nAnti‐CCP Ab\t0.6\t<7 U/mL\t\nAnti‐cardiolipin IgG\t0.7\t<10 U/mL\t\nAnti‐cardiolipin IgM\t2.0\t<10 U/mL\t\nAnti‐SmDP Ab\t0.7\t<7 U/mL\t\nAnti‐RNP Ab\t0.5\t<5 U/mL\t\nAnti‐SSA (Ro) Ab\t0.3\t<7 U/mL\t\nAnti‐SSB (La) Ab\t0.2\t<7 U/mL\t\nAnt‐MPO Ab\t0.1\t<3.5 U/mL\t\nAnti‐PR3 Ab\t0.1\t<2 U/mL\t\n\nAb, antibody; ALT, alanine transaminase; ANA, anti‐nuclear antibody; AST, aspartate transaminase; CCP, cyclic citrullinated peptide; CK, creatinine kinase; CRP, C‐reactive protein; ESR, erythrocyte sedimentation rate; Hb, haemoglobin; Hct, haematocrit; Ig, immunoglobulin; LDH, lactic dehydrogenase; MPO, myeloperoxidase; PR3, proteinase 3; RBC, red blood cell; RF, rheumatoid factor; RNP, ribonucleoprotein; SmDP, Smith protein D; SSA, Sjogren's‐syndrome‐related antigen A; SSB, Sjogren's‐syndrome‐related antigen B; WBC, white blood cell.\n\n\nDiscussion\nRP is a rare autoimmune disease, with reported prevalence rates ranging from 4.5 to 9 cases per million persons [1, 4, 5, 6]. RP is difficult to diagnose due to the rarity, the episodic nature, and its diverse clinical presentation. Significant delays in diagnosis have been described [4, 7, 8, 9]. Currently, these are still no standardized guidelines for the diagnosis of RP. Several sets of diagnostic criteria, which are mainly based on the presence of symptoms suggesting chondritis or arthritis at multiple sites, have been proposed previously [9, 10, 11, 12, 13]. These sets of criteria, however, have limitations in terms of sensitivity and accuracy, as was demonstrated by recent retrospective case analyses [9, 10]. Histologic confirmation has been included into the criteria proposed by Demiani and Levine [12], but the histologic findings are not specific, and the site of inflammation is not always safe for biopsy. Moreover, although chondritis of the airway eventually develop in up to 50% of patients, only 10% of patients have symptoms or signs suggesting airway involvement at presentation [3, 7]. A recent large case series reported that only 4% and 3.5% of patients had cough and dyspnoea, respectively, as their initial symptoms [14]. Hazra et al. reported that respiratory symptoms were associated with the longest delay in diagnosis, with a median delay time of 10.4 years, while leaving 64% of patients pending diagnosis for more than two years [5]. The presence of respiratory symptoms in a patient known to have RP raises the clinical suspicion of airway involvement [15], but it would be challenging to establish the diagnosis of RP in someone presenting only with cough and dyspnoea. Considering the non‐specific and airway‐only manifestation of our patient, it was not helpful to diagnose his RP by applying those aforementioned sets of criteria. Besides, central airway biopsy was withheld for safety concerns, as the patient had already exhibited significant tracheal narrowing and respiratory deficit at the time of the bronchoscopy. Nevertheless, with a multidisciplinary approach integrating his past histories, symptoms, and serologico‐biochemical, bronchoscopic, radiographic, and spirometric findings, other diseases with similar clinico‐radiological presentations (such as tuberculous tracheitis, anti‐neutrophilic cytoplasmic autoantibodies (ANCA)‐associated vasculitis, sarcoidosis, amyloid deposition, tracheomalacia, excessive dynamic airway collapse, tracheal involvement in inflammatory bowel disease, rhinoscleroma, or tracheobronchopathia osteochondroplastica) were ruled out. Our patient received the correct diagnosis within 12 months after the onset of his symptoms, which might be considered a relatively short delay.\n\nThere is likely heterogeneity among patients with RP [1, 3, 14, 16]. Using cluster analysis, Dion et al. discovered that patients with RP could be categorized into three clinically relevant phenotypes, namely haematological, respiratory, and mild phenotypes [14]. The haematological phenotype and the mild phenotype represent the two extremes of the spectrum, with the former being associated with older ages of onset and high risks of concurrent myelodysplastic syndrome and mortality, and the latter, the best prognosis and the highest likelihood of long‐term remission. Patients with the respiratory phenotype appeared to have intermediate prognosis. They were reported to be younger and had predominantly airway involvement but less involvement of the heart and ears. Interestingly, they were also most likely to have received immunosuppressive agents and had high rates of infectious complications (35%) and intensive care admission (27%) [14]. Considering the overall clinical manifestations and disease course, our patient can be reasonably classified as having the respiratory phenotype.\n\nLong‐term airway complications of RP, such as tracheomalacia or tracheobrochial stenosis, have been well documented. Around 35–40% of patients with known airway involvement eventually required some form of interventions, such as tracheostomy, balloon dilatation, stenting, or a combination [2, 3, 10]. Moreover, for patients with long‐standing RP, life‐threatening airway collapse could be the first manifestation to unveil occult airway involvement [15]. The treatment of RP is largely based on experiences from previous case reports and small series, and there are still no evidence‐based guidelines [1, 3, 17]. Corticosteroids and non‐steroidal anti‐inflammatory drugs (NSAIDs) were administered most frequently, particularly for those milder cases, while conventional disease‐modifying antirheumatic drugs (DMARDs) and newer biologics are usually used as steroid‐sparing agents or in severe scenarios [1, 17, 18]. Despite the infectious complication, our patient has overall responded well to the treatment with systemic corticosteroid, which has been gradually tapered to his current low‐maintenance dose (2.5–5 mg of prednisolone daily).\n\nIn conclusion, through this case report, we would like to emphasize that, although uncommon, RP could have an airway‐only manifestation, thereby leading to great diagnostic difficulties. The treatment should be tailored according to individual patient's organ involvement and complications, although no guidelines exist to date. RP patients with airway involvement have higher infection risks and high rates of long‐term airway complications, so it is pivotal to recognize and manage these airway morbidities in a timely fashion to prevent fatal consequences.\n\nDisclosure Statement\nAppropriate written informed consent was obtained for publication of this case report and accompanying images.\n\nSupporting information\n\nVideo S1. Bronchoscopic examination of the patient before the initiation of corticosteroid treatment. This video, recorded during the bronchoscopic examination of the patient before the initiation of corticosteroid treatment, began at the lower trachea close to the main carina, and then moved slowly and proximally towards the vocal cords. The video displayed the persistent narrowing of the mid‐to‐lower trachea of the patient.\n\n\nClick here for additional data file.\n\n Acknowledgment\nWe are thankful to the patient for his kind permission to report the clinical presentations and the laboratory and radiographic data relating to his illness.\n==== Refs\nReferences\n1 \n\nMathian \nA \n, \nMiyara \nM \n, \nCohen‐Aubart \nF \n, et al. 2016 \nRelapsing polychondritis: a 2016 update on clinical features, diagnostic tools, treatment and biological drug use\n. Best Pract. Res. Clin. Rheumatol. \n30 (2 ):316 –333\n.27886803 \n2 \n\nErnst \nA \n, \nRafeq \nS \n, \nBoiselle \nP \n, et al. 2009 \nRelapsing polychondritis and airway involvement\n. Chest \n135 (4 ):1024 –1030\n.19017885 \n3 \n\nde Montmollin \nN \n, \nDusser \nD \n, \nLorut \nC \n, et al. 2019 \nTracheobronchial involvement of relapsing polychondritis\n. Autoimmun. Rev. \n18 :102353.31323366 \n4 \n\nKent \nPD \n, \nMichet \nCJ \nJr\n, and \nLuthra \nHS \n. 2004 \nRelapsing polychondritis\n. Curr. Opin. Rheumatol. \n16 (1 ):56 –61\n.14673390 \n5 \n\nHazra \nN \n, \nDregan \nA \n, \nCharlton \nJ \n, et al. 2015 \nIncidence and mortality of relapsing polychondritis in the UK: a population‐based cohort study\n. Rheumatology (Oxford) \n54 (12 ):2181 –2187\n.26187053 \n6 \n\nHorváth \nA \n, \nPáll \nN \n, \nMolnár \nK \n, et al. 2016 \nA nationwide study of the epidemiology of relapsing polychondritis\n. Clin. Epidemiol. \n8 :211 –230\n.27418855 \n7 \n\nMathew \nSD \n, \nBattafarano \nDF \n, and \nMorris \nMJ \n. 2012 \nRelapsing polychondritis in the Department of Defense population and review of the literature\n. Semin. Arthritis Rheum. \n42 (1 ):70 –83\n.22417894 \n8 \n\nTrentham \nDE \n, and \nLe \nCH \n. 1998 \nRelapsing polychondritis\n. Ann. Intern. Med. \n129 :114 –122\n.9669970 \n9 \n\nMaciążek‐Chyra \nB \n, \nSzmyrka \nM \n, \nSkoczyńska \nM \n, et al. 2019 \nRelapsing polychondritis – analysis of symptoms and criteria\n. Reumatologia \n57 (1 ):8 –18\n.30858626 \n10 \n\nRose \nT \n, \nSchneider \nU \n, \nBertolo \nM \n, et al. 2018 \nObservational study and brief analysis of diagnostic criteria in relapsing polychondritis\n. Rheumatol. Int. \n38 (11 ):2095 –2101\n.30084004 \n11 \n\nMcAdam \nLP \n, \nO'Hanlan \nMA \n, \nBluestone \nR \n, et al. 1976 \nRelapsing polychondritis: prospective study of 23 patients and a review of the literature\n. Medicine (Baltimore). \n55 (3 ):193 –215\n.775252 \n12 \n\nDamiani \nJM \n, and \nLevine \nHL \n. 1979 \nRelapsing polychondritis—report of ten cases\n. Laryngoscope \n89 :929 –946\n.449538 \n13 \n\nMichet \nCJ \n, \nMcKenna \nCH \n, \nLuthra \nHS \n, et al. 1986 \nRelapsing polychondritis: survival and predictive role of early disease manifestations\n. Ann. Intern. Med. \n104 :74 –78\n.3484422 \n14 \n\nDion \nJ \n, \nCostedoat‐Chalumeau \nN \n, \nSène \nD \n, et al. 2016 \nRelapsing polychondritis can be characterized by three different clinical phenotypes: analysis of a recent series of 142 patients\n. Arthritis Rheumatol. \n68 (12 ):2992 –3001\n.27331771 \n15 \n\nYu \nC \n, and \nJoosten \nSA \n. 2019 \nRelapsing polychondritis with large airway involvement\n. Respirol. Case Rep. \n8 (1 ):e00501.31741739 \n16 \n\nShimizu \nJ \n, \nYamano \nY \n, \nYudoh \nK \n, et al. 2018 \nOrgan involvement pattern suggests subgroups within relapsing polychondritis: comment on the article by Dion et al\n. Arthritis Rheumatol. \n70 :148 –149\n.28941194 \n17 \n\nPuéchal \nX \n, \nTerrier \nB \n, \nMouthon \nL \n, et al. 2014 \nRelapsing polychondritis\n. Joint Bone Spine \n81 (2 ):118 –124\n.24556284 \n18 \n\nOka \nH \n, \nYamano \nY \n, \nShimizu \nJ \n, et al. 2014 \nA large‐scale survey of patients with relapsing polychondritis in Japan\n. Inflamm. Regen. \n34 :149 –156\n.\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2051-3380",
"issue": "8(7)",
"journal": "Respirology case reports",
"keywords": "Bronchoscopy; central airway obstruction; tracheal stenosis",
"medline_ta": "Respirol Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101631052",
"other_id": null,
"pages": "e00651",
"pmc": null,
"pmid": "32884814",
"pubdate": "2020-10",
"publication_types": "D002363:Case Reports",
"references": "775252;22417894;30084004;28941194;14673390;27331771;19017885;449538;31323366;24556284;3484422;27418855;27886803;30858626;31741739;26187053;9669970",
"title": "Relapsing polychondritis with isolated tracheal involvement and airway-only symptoms.",
"title_normalized": "relapsing polychondritis with isolated tracheal involvement and airway only symptoms"
} | [
{
"companynumb": "TW-ACCORD-204402",
"fulfillexpeditecriteria": "1",
"occurcountry": "TW",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"drugadditional": null,
"dr... |
{
"abstract": "OBJECTIVE\nData regarding the comparative effectiveness and safety of sofosbuvir (SOF) in combination with ribavirin (RBV), daclatasvir (DCV), or ledipasvir (LDV) for hepatitis C virus genotype 2 (HCV-2) patients were limited. We aimed to evaluate the performance of these regimens in Taiwan.\n\n\nMETHODS\nOne hundred eighty-seven HCV-2 patients with compensated liver diseases receiving SOF in combination with RBV (n = 82), DCV (n = 66), or LDV (n = 39) for 12 weeks were retrospectively enrolled. The effectiveness was determined by sustained virologic response 12 weeks off therapy (SVR12 ). The patient characteristics potentially related to SVR12 were compared. The safety profiles and laboratory abnormalities were assessed.\n\n\nRESULTS\nThe SVR12 rates were 93.9% (95% confidence interval [CI]: 86.5-97.4%), 98.5% (95% CI: 91.9-99.7%), and 100% (95% CI: 91.0-100%) in patients receiving SOF combined with RBV, DCV, and LDV, respectively. All patients tolerated treatment well. The stratified SVR12 rates were comparable regardless of baseline characteristics or week 4 viral decline among these regimens. Six (3.2%) patients had serious adverse events which were not related to treatment. The rates of fatigue, pruritus, and anemia tended to be higher in patients receiving RBV (22.0%, 19.5%, and 8.5%) combination than those receiving DCV (10.6%, 6.1%, and 1.5%) or LDV (10.3%, 5.1%, and 0%) combination.\n\n\nCONCLUSIONS\nSofosbuvir in combination with RBV, DCV, or LDV for 12 weeks is effective and well-tolerated for HCV-2 patients. Compared with DCV or LDV combination, the risks of fatigue, pruritus, and anemia are higher in patients receiving RBV combination.",
"affiliations": "Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.;Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.;Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.;Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.;Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.;Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.;Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.;Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.;Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.",
"authors": "Liu|Chen-Hua|CH|;Su|Tung-Hung|TH|;Liu|Chun-Jen|CJ|;Hong|Chun-Ming|CM|;Yang|Hung-Chih|HC|;Tseng|Tai-Chung|TC|;Chen|Pei-Jer|PJ|;Chen|Ding-Shinn|DS|;Kao|Jia-Horng|JH|",
"chemical_list": "D000998:Antiviral Agents; D001562:Benzimidazoles; D002219:Carbamates; D005449:Fluorenes; D007093:Imidazoles; D011759:Pyrrolidines; C000595958:ledipasvir, sofosbuvir drug combination; D012254:Ribavirin; D014542:Uridine Monophosphate; D014633:Valine; C549273:daclatasvir; D000069474:Sofosbuvir",
"country": "Australia",
"delete": false,
"doi": "10.1111/jgh.14615",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0815-9319",
"issue": "34(9)",
"journal": "Journal of gastroenterology and hepatology",
"keywords": "direct acting antiviral agent; genotype 2; hepatitis C virus; sofosbuvir; sustained virologic response",
"medline_ta": "J Gastroenterol Hepatol",
"mesh_terms": "D000368:Aged; D000998:Antiviral Agents; D001562:Benzimidazoles; D002219:Carbamates; D057186:Comparative Effectiveness Research; D005260:Female; D005449:Fluorenes; D005838:Genotype; D016174:Hepacivirus; D019698:Hepatitis C, Chronic; D006801:Humans; D007093:Imidazoles; D008297:Male; D008875:Middle Aged; D011759:Pyrrolidines; D012189:Retrospective Studies; D012254:Ribavirin; D000069474:Sofosbuvir; D000072230:Sustained Virologic Response; D013624:Taiwan; D013997:Time Factors; D016896:Treatment Outcome; D014542:Uridine Monophosphate; D014633:Valine",
"nlm_unique_id": "8607909",
"other_id": null,
"pages": "1620-1625",
"pmc": null,
"pmid": "30693965",
"pubdate": "2019-09",
"publication_types": "D003160:Comparative Study; D016428:Journal Article",
"references": null,
"title": "Sofosbuvir-based direct acting antiviral therapies for patients with hepatitis C virus genotype 2 infection.",
"title_normalized": "sofosbuvir based direct acting antiviral therapies for patients with hepatitis c virus genotype 2 infection"
} | [
{
"companynumb": "TW-GILEAD-2019-0389975",
"fulfillexpeditecriteria": "1",
"occurcountry": "TW",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "LEDIPASVIR\\SOFOSBUVIR"
},
"drugadditional": nul... |
{
"abstract": "A 75-year-old woman was referred for advice regarding surface electrocardiographic modifications after the initiation of rivastigmine. In our patient, the baseline ECGs appeared perfectly normal. However, the initiation of a cholinesterase inhibitor unmasked a left lateral accessory pathway that had never been diagnosed before. Although cholinesterase inhibitors are known to increase vagal tone, the PR interval was shortened after rivastigmine administration, thus excluding this hypothesis to explain the appearance of the accessory pathway. Therefore, we hypothesized that cholinesterase inhibitors may have increased conduction velocity in the accessory pathway or in the atria.",
"affiliations": "Cardiology Department, University Hospital, Dijon, France; LPPCM, INSERM UMR 866, Univ. Bourgogne Franche-Comté, Dijon, France. Electronic address: charles.guenancia@gmail.com.;Cardiology Department, University Hospital, Dijon, France.;Cardiology Department, University Hospital, Dijon, France.;Cardiology Department, University Hospital, Dijon, France.;Cardiology Department, University Hospital, Dijon, France.",
"authors": "Guenancia|Charles|C|;Fichot|Marie|M|;Garnier|Fabien|F|;Montoy|Mathieu|M|;Laurent|Gabriel|G|",
"chemical_list": "D000068836:Rivastigmine",
"country": "United States",
"delete": false,
"doi": "10.1016/j.jelectrocard.2017.01.008",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0022-0736",
"issue": "50(3)",
"journal": "Journal of electrocardiology",
"keywords": "Accessory pathway; Cholinesterase inhibitors; Electrocardiogram",
"medline_ta": "J Electrocardiol",
"mesh_terms": "D058606:Accessory Atrioventricular Bundle; D000368:Aged; D003937:Diagnosis, Differential; D004562:Electrocardiography; D005260:Female; D006329:Heart Conduction System; D006801:Humans; D015203:Reproducibility of Results; D000068836:Rivastigmine; D012680:Sensitivity and Specificity",
"nlm_unique_id": "0153605",
"other_id": null,
"pages": "368-371",
"pmc": null,
"pmid": "28129887",
"pubdate": "2017",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A left lateral accessory pathway unmasked by rivastigmine.",
"title_normalized": "a left lateral accessory pathway unmasked by rivastigmine"
} | [
{
"companynumb": "FR-ALVOGEN-2017-ALVOGEN-091406",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PROPRANOLOL HYDROCHLORIDE"
},
"drugaddit... |
{
"abstract": "A 64-year-old man with type 2 diabetes mellitus and plaque psoriasis presented to the emergency room with 3 days of progressive right eye pain and decreased vision. After extensive workup and multidisciplinary team effort, the patient was diagnosed with and treated for unilateral endogenous methicillin-sensitive Staphylococcus aureus endophthalmitis, bacteraemia and osteomyelitis of the foot. The patient had been started on the interleukin 17 (IL-17) inhibitor secukinumab for his treatment-resistant plaque psoriasis 4 weeks prior to presentation. After treatment, his final vision was light perception and the foot infection resolved without sequelae. To our knowledge, this is the first reported case of both endogenous endophthalmitis and osteomyelitis associated with an IL-17 inhibitor.",
"affiliations": "Havener Eye Institute, Department of Ophthalmology and Visual Science, Ohio State University Wexner Medical Center, Columbus, Ohio, USA.;Havener Eye Institute, Department of Ophthalmology and Visual Science, Ohio State University Wexner Medical Center, Columbus, Ohio, USA.;Havener Eye Institute, Department of Ophthalmology and Visual Science, Ohio State University Wexner Medical Center, Columbus, Ohio, USA.;Havener Eye Institute, Department of Ophthalmology and Visual Science, Ohio State University Wexner Medical Center, Columbus, Ohio, USA.",
"authors": "Martinez|Christine E|CE|;Allen|John B|JB|;Davidorf|Frederick H|FH|;Cebulla|Colleen M|CM|",
"chemical_list": "D000900:Anti-Bacterial Agents; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D007155:Immunologic Factors; D020381:Interleukin-17; C555450:secukinumab",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2017-219296",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2017()",
"journal": "BMJ case reports",
"keywords": "Bone And Joint Infections; Dermatology; Ophthalmology; Safety; Skin",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000900:Anti-Bacterial Agents; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D016470:Bacteremia; D048909:Diabetes Complications; D003924:Diabetes Mellitus, Type 2; D009877:Endophthalmitis; D005123:Eye; D015818:Eye Infections, Bacterial; D006801:Humans; D007155:Immunologic Factors; D020381:Interleukin-17; D008297:Male; D055624:Methicillin-Resistant Staphylococcus aureus; D008875:Middle Aged; D010019:Osteomyelitis; D010146:Pain; D011565:Psoriasis; D013203:Staphylococcal Infections; D015354:Vision, Low",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "28667056",
"pubdate": "2017-06-29",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "21343874;22512341;23118134;24702755;25113611;25802752;25995495;25998834;26092291;26449198;26559476;27180926;27545070;27785085",
"title": "Endogenous endophthalmitis and osteomyelitis associated with interleukin 17 inhibitor treatment for psoriasis in a patient with diabetes.",
"title_normalized": "endogenous endophthalmitis and osteomyelitis associated with interleukin 17 inhibitor treatment for psoriasis in a patient with diabetes"
} | [
{
"companynumb": "PHHY2017US105106",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "SECUKINUMAB"
},
"drugadditional": "3",
"drug... |
{
"abstract": "In 2014 a 66-year-old woman presented with anemia and an IgAk monoclonal spike. Bone marrow (BM) biopsy showed 80% lymphocytes and lymphoplasmacytoid cells. Computed Tomography (CT) scan documented neither adenopathy nor splenomegaly. Diagnosis of IgA lymphoplasmacytic lymphoma was made. After three lines of treatment, progressive disease with adenopathies, splenomegaly, and ascites were documented on a CT scan. Our patient developed thrombocytopenia, transfusion-dependent anemia, and clinical deterioration. We performed genetic studies of peripheral blood lymphocytes with the NGS approach. Given the identification of MYD88 L265P mutation, in February 2018 our patient started ibrutinib off-label. Hb and PLT improved from day +35. In July 2018 no ascites and 50% reduction of adenopathies and spleen were shown on a CT scan. In April 2019 the patient was still on ibrutinib with transfusion independence and good performance status.",
"affiliations": "Stem Cell Research Laboratory, Section of Hematology, Department of Medicine, University of Verona, Verona, Italy.;Hematology Section, Department of Medical Sciences, Azienda Ospedaliero-Universitaria, Arcispedale S.Anna, University of Ferrara, Ferrara, Italy.;Hematology Section, Department of Medical Sciences, Azienda Ospedaliero-Universitaria, Arcispedale S.Anna, University of Ferrara, Ferrara, Italy.;Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy.;Hematology Section, Department of Medical Sciences, Azienda Ospedaliero-Universitaria, Arcispedale S.Anna, University of Ferrara, Ferrara, Italy.;Hematology Section, Department of Medical Sciences, Azienda Ospedaliero-Universitaria, Arcispedale S.Anna, University of Ferrara, Ferrara, Italy.;Hematology Section, Department of Medical Sciences, Azienda Ospedaliero-Universitaria, Arcispedale S.Anna, University of Ferrara, Ferrara, Italy.;Hematology Section, Department of Medical Sciences, Azienda Ospedaliero-Universitaria, Arcispedale S.Anna, University of Ferrara, Ferrara, Italy.;Hematology Section, Department of Medical Sciences, Azienda Ospedaliero-Universitaria, Arcispedale S.Anna, University of Ferrara, Ferrara, Italy.;Hematology Section, Department of Medical Sciences, Azienda Ospedaliero-Universitaria, Arcispedale S.Anna, University of Ferrara, Ferrara, Italy.",
"authors": "Quaglia|Francesca Maria|FM|;Rigolin|Gian Matteo|GM|;Saccenti|Elena|E|;Negrini|Massimo|M|;Volta|Eleonora|E|;Dabusti|Melissa|M|;Ciccone|Maria|M|;Urso|Antonio|A|;Laudisi|Michele|M|;Cuneo|Antonio|A|",
"chemical_list": null,
"country": "Italy",
"delete": false,
"doi": "10.4084/MJHID.2019.057",
"fulltext": "\n==== Front\nMediterr J Hematol Infect DisMediterr J Hematol Infect DisMediterranean Journal of Hematology and Infectious DiseasesMediterranean Journal of Hematology and Infectious Diseases2035-3006Università Cattolica del Sacro Cuore 10.4084/MJHID.2019.057mjhid-11-1-e2019057Case ReportResponse to Ibrutinib of a Refractory IgA Lymphoplasmacytic Lymphoma Carrying the MYD88 L265P Gene Mutation Quaglia Francesca Maria 12Rigolin Gian Matteo 2Saccenti Elena 2Negrini Massimo 3Volta Eleonora 2Dabusti Melissa 2Ciccone Maria 2Urso Antonio 2Laudisi Michele 2Cuneo Antonio 2\n1 Stem Cell Research Laboratory, Section of Hematology, Department of Medicine, University of Verona, Verona, Italy\n2 Hematology Section, Department of Medical Sciences, Azienda Ospedaliero-Universitaria, Arcispedale S.Anna, University of Ferrara, Ferrara, Italy\n3 Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, ItalyCorrespondence to: Gian Matteo Rigolin. Hematology Section, Department of Medical Sciences, Azienda Ospedaliero-Universitaria, Arcispedale S.Anna, University of Ferrara, Via Aldo Moro, 8, 44124, Cona, Ferrara, Italy. Tel. +39 0532 239674, Fax +39 0532 236049. E-mail: rglgmt@unife.it2019 01 9 2019 11 1 e201905719 6 2019 16 8 2019 2019This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by-nc/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.In 2014 a 66-year-old woman presented with anemia and an IgAk monoclonal spike. Bone marrow (BM) biopsy showed 80% lymphocytes and lymphoplasmacytoid cells. Computed Tomography (CT) scan documented neither adenopathy nor splenomegaly. Diagnosis of IgA lymphoplasmacytic lymphoma was made. After three lines of treatment, progressive disease with adenopathies, splenomegaly, and ascites were documented on a CT scan. Our patient developed thrombocytopenia, transfusion-dependent anemia, and clinical deterioration. We performed genetic studies of peripheral blood lymphocytes with the NGS approach. Given the identification of MYD88 L265P mutation, in February 2018 our patient started ibrutinib off-label. Hb and PLT improved from day +35. In July 2018 no ascites and 50% reduction of adenopathies and spleen were shown on a CT scan. In April 2019 the patient was still on ibrutinib with transfusion independence and good performance status.\n\nIgA-secreting lymphoplasmacytic lymphomaIbrutinibMYD88\n==== Body\nIntroduction\nLymphoplasmacytic lymphoma (LPL) is a rare chronic lymphoproliferative neoplasm characterized by the proliferation of B lymphocytes with varying degrees of plasmacytic differentiation involving bone marrow (BM), lymph nodes, or spleen.1 Waldenstrom macroglobulinemia (WM) is a subset of LPL that has a detectable level of monoclonal IgM gammopathy, with BM involvement by LPL.2,3 Indeed in over 95% of LPL cases, the malignant clone produces an IgM paraprotein consistent with WM.4 However, the remaining LPL cases do not fulfill the diagnostic criteria of WM. These conditions are mainly represented by rare cases of primary nonsecretory lymph node-based presentations of LPL or by lymphoplasmacytic B-cell proliferation in the BM associated with IgA or IgG gammopathies.1,5 Accurate diagnosis of LPL can be difficult because of the absence of morphologic, immunophenotypic, or chromosomal markers, especially in non-WM cases where there is no IgM gammopathy to support the diagnosis.1 The identification of the MYD88 L265P gene mutation represented a major advance in the diagnosis of LPL3,5 although the real incidence of this mutation in LPL patients is unknown and a small number of WM patients with unmutated MYD88 exist. Indeed in a study by Treon et al.6 about 90% of WM or LPL have MYD88 L265P mutation and a small subgroup of patients with marginal zone lymphoma (MZL) were shown to carry this genetic lesion.6 In contrast, MYD88 L265P mutation was absent in tissue samples from patients with myeloma, including samples from patients with IgM secreting myeloma.6\nMYD88 L265P mutation may, therefore, be useful in distinguishing LPL from B-cell disorders showing partially overlapping clinicopathological features.6 Few cases of non-IgM LPL have been reported demonstrating the presence of MYD88 L265P.5,7–11\n\nMYD88 L265P triggers survival signaling through BTK and HCK, and MYD88 L265P expressing cell lines undergo apoptosis in response to ibrutinib, which targets both of these kinases.4 Moreover, Ibrutinib has demonstrated significant activity in patients with relapsed/refractory B-Cell malignancies.12,13 In 2015, the FDA and the EMA approved ibrutinib for the treatment of symptomatic WM but not for LPL, based on a clinical trial in previously treated patients. The patients with LPL not fulfilling the diagnostic criteria of WM were excluded from WM trials and should be treated as the other indolent lymphoproliferative neoplasms, while recent guidelines14–17 included recommendations on the usage of ibrutinib specifically for WM. For these reasons, the use of ibrutinib in non-IgM LPL has not yet been reported. We present here the first report of a patient with MYD88-mutated IgA LPL who underwent salvage therapy with ibrutinib.\n\nCase Report\nIn September 2014 a 66-year-old woman presented with symptomatic anemia (Hemoglobin, Hb: 9 g/dl), with IgA/k monoclonal spike (1.6 g/dl) (Figure 1) and an otherwise unremarkable serum chemistry profile. A Computed Tomography (CT) scan documented neither adenopathy nor splenomegaly. BM biopsy showed an 80% infiltrate by lymphocytes and lymphoplasmacytoid cells with admixed atypical plasma cells (25%). Flow cytometry showed a kappa-restricted B-cell population (strong sIg kappa positivity) that expressed CD20, CD19, CD22, CD38, CD138, FMC7, and was negative for CD5, CD3, CD10, CD56, CD79a, CD23. The malignant plasma cells showed IgA+ kappa-restriction. The karyotype on BM cells was normal and so, no t(4,14), t(14,16), t(11,14), or del(17p) aberrations were detected by fluorescence in situ hybridization (FISH) using a probe-panel for multiple myeloma (MM); a deletion of 13q14 DLEU was detected by FISH using a 5 probe-panel for CLL (13q14, chromosome-12 centromere, 11q22, 17p13, 6q21). A diagnosis of IgA-secreting LPL was made.\n\nThe patient was treated with rituximab-cyclophosphamide-dexamethasone (RCD regimen) with Partial Response (PR)18 (Figure 1). Eighteen months later the patient, who presented with progressive disease (PD) (Hb 8 g/dl, lymphocytes 3.56 × 109/L with 80% lymphoplamacytic cells, IgAk monoclonal spike 1.9 g/dl), was treated with bendamustine. In January 2017, after five cycles, the BM aspirate showed 90% lymphoid cells and adenopathies, splenomegaly and ascites were noted on a CT scan. Thus, cyclophosphamide-doxorubicin-vincristine-prednisone (CHOP) was started and, after three cycles, the patient developed thrombocytopenia (Platelets, PLT: 30 × 10^9/L), transfusion-dependent anemia (Hb 7.7 g/dl), persistent lymphocytosis (Lymphocytes: 7.15 × 109/L) in the peripheral blood (PB) and clinical deterioration (Figure 1). We performed genetic studies of PB lymphocytes (after separation over a Ficoll gradient, yielding >80% clonal B lymphocytes) with a targeted NGS approach detecting mutations in 20 genes frequently mutated in CLL (ATM, BIRC3, BRAF, CDKN2A, PTEN, CDH2, DDX3X, FBXW7, KIT, KLHL6, KRAS, MYD88, NOTCH1, NRAS, PIK3CA, POT1, SF3B1, TP53, XPO1, ZMYM3). The MYD88 L265P mutation was identified in 65.7% of the reads. Given the identification of MYD88 L265P in the peripheral blood, ibrutinib appeared a reasonable option. In February 2018, our patient started ibrutinib off-label, 420 mg once daily (Figure 1). Hb and PLT improved from day +35 (Hb 10–12 g/dl, PLT > 100 × 10^9/L). In July 2018 no ascites and 50% reduction of adenopathies and spleen were shown on a CT scan. In April 2019, the patient was still on full dose ibrutinib with transfusion independence and good performance status.\n\nThis patient is unique in that it represents - to the best of our knowledge - the first reported case of response to ibrutinib in symptomatic aggressive IgA secreting LPL with MYD88 mutation refractory to multiple lines of treatment. Guidelines for treatment of WM pose indication for ibrutinib in relapsed or untreated patients who are not candidates for chemoimmunotherapy.14–17 Our case clearly indicates that ibrutinib may represent a valuable therapeutic option for chemorefractory LPL not fulfilling the diagnostic criteria of WM. Our patient had previously been exposed to alkylators, immunomodulators, anti-CD20 monoclonal antibodies and steroids. Her therapeutic options at the time of her most recent relapse were limited and given the identification of the MYD88 L265P mutation in the peripheral blood, ibrutinib appeared as a reasonable option. In our patient, ibrutinib produced a response within 4–6 weeks, that is a typical time-frame during which a response is usually observed. The partial response has been sustained for approximately 15 months at the time of this report. The kynetics of response in different disease compartments (blood, nodal, extranodal, spleen) were similar to those observed in WM patients15,19 and CLL patients on single-agent ibrutinib20 with few treatment emergent adverse events consisting in grade 1 bruising, arthralgias and diarrhea, which improved and resolved with continued treatment.\n\nIn conclusion, we present the case of a heavily pretreated patient with MYD88-mutated IgA LPL, who has obtained a partial response to ibrutinib that is ongoing after more than one year of therapy. This observation suggests that ibrutinib appears to be potentially effective in this difficult-to-treat-condition.\n\nCompeting interests: AC speaker bureau and advisory board (ABBVIE, GILEAD, JANSSEN, ROCHE); GMR: speaker bureau (ABBVIE, GILEAD) and research support (GILEAD).\n\nFigure 1 The diagram illustrates modifications in hemoglobin (Hb) and IgAk monoclonal spike (left Y axis), platelets (PLT) and symptoms (right Y axis) by treatment in our patient. Symptom Scale: 0–100-point scale, based on patient’s reported symptoms. Higher scores indicate more severe symptoms. RCD: Rituximab-Cyclophosphamide-Dexamethasone; CHOP: Cyclophosphamide-Doxorubicin-Vincristine-Prednisone. Red arrow: initiation of ibrutinib.\n==== Refs\nReferences\n1 Naderi N Yang DT Lymphoplasmacytic Lymphoma and Waldenstrom Macroglobulinemia Arch Pathol Lab Med 2013 137 580 585 10.5858/arpa.2012-0034-RS 23544948 \n2 Mazzucchelli M Frustaci AM Deodato M Cairoli R Tedeschi A Waldenstrom’s macroglobulinemia: an update Mediterr J Hematol Infect Dis 2018 10 1 e2018004 10.4084/mjhid.2018.004 29326801 \n3 Swerdlow SH Campo E Pileri SA Harris NL Stein H Siebert R Advani R Ghielmini M Salles GA Zelenetz AD Jaffe ES The 2016 revision of the World Health Organization classification of lymphoid neoplasms Blood 2016 9 127 20 2375 2390 10.1182/blood-2016-01-643569 Epub 2016 Mar 15. 10.1182/blood-2016-01-643569 26980727 \n4 Castillo JJ Ghobrial IM Treon SP Response to ibrutinib in a patient with IgG lymphoplasmacytic lymphoma carrying the MYD88 L265P gene mutation Leuk Lymphoma 2016 57 11 2699 2701 10.3109/10428194.2016.1157875 10.3109/10428194.2016.1157875 26980069 \n5 Martino G Marra A Ascani S Sportoletti P Uncommon lymphoplasmacytic lymphoma with IgA paraproteinemia: a challenging clinical diagnosis solved by MYD88 mutation analysis Ann Hematol 2018 10.1007/s00277-018-3545-9 30426157 \n6 Treon SP Xu L Yang G Zhou Y Liu X Cao Y Sheehy P Manning RJ Patterson CJ Tripsas C Arcaini L Pinkus GS Rodig SJ Sohani AR Harris NL Laramie JM Skifter DA Lincoln SE Hunter ZR MYD88 L265P Somatic Mutation in Waldenström’s Macroglobulinemia N engl j med 2012 367 9 826 833 10.1056/NEJMoa1200710 22931316 \n7 Mori N Ohwashi M Yoshinaga K Mitsuhashi K Tanaka N Teramura M Okada M Shiseki M Tanaka J Motoji T L265P mutation of the MYD88 gene is frequent in Waldenstrom’s macroglobulinemia and its absence in myeloma PloS One 2013 8 11 e80088 10.1371/journal.pone.0080088 24224040 \n8 Swerdlow SH Kuzu I Dogan A Dirnhofer S Chan JKC Sander B Ott G Xerri L Quintanilla-Martinez L Campo E The many faces of small B cell lymphomas with plasmacytic differentiation and the contribution of MYD88 testing VirchowsArch 2016 468 3 259 275 10.1007/s00428-015-1858-9 26454445 \n9 Cao X Medeiros LJ Xia Y Wang X Thomas SK Loghavi S Li X Shah JJ Gustafson SA Weber DM Miranda RN Xu-Monette ZY Orlowski RZ Young KH Clinicopathologic features and outcomes of lymphoplasmacytic lymphoma patients with monoclonal IgG or IgA paraprotein expression Leuk Lymphoma 2016 57 5 1104 13 10.3109/10428194.2015.1096357 26421453 \n10 Jiménez C Sebastián E Chillón MC Giraldo P Mariano Hernández J Escalante F González-López TJ Aguilera C de Coca AG Murillo I Alcoceba M Balanzategui A Sarasquete ME Corral R Marín LA Paiva B Ocio EM Gutiérrez NC González M San Miguel JF García-Sanz R MYD88 L265P is a marker highly characteristic of, but not restricted to, Waldenstrom’s macroglobulinemia Leukemia 2013 27 1722 1728 10.1038/leu.2013.62 23446312 \n11 King RL Gonsalves WI Ansell SM Greipp PT Frederick LA Viswanatha DS He R Kyle RA Gertz MA Kapoor P Morice WG Howard MT Lymphoplasmacytic Lymphoma With a Non-IgM Paraprotein Shows Clinical and Pathologic Heterogeneity and May Harbor MYD88 L265P Mutations Am J Clin Pathol 2016 145 6 843 851 10.1093/ajcp/aqw072 27329639 \n12 Advani RH Buggy JJ Sharman JP Smith SM Boyd TE Grant B Kolibaba KS Furman RR Rodriguez S Chang BY Sukbuntherng J Izumi R Hamdy A Hedrick E Fowler NH Bruton Tyrosine Kinase Inhibitor Ibrutinib (PCI-32765) Has Significant Activity in Patients With Relapsed/Refractory B-Cell Malignancies J Clin Oncol 2013 31 1 88 94 10.1200/JCO.2012.42.7906 23045577 \n13 Noy A de Vos S Thieblemont C Martin P Flowers CR Morschhauser F Collins GP Ma S Coleman M Peles S Smith S Barrientos JC Smith A Munneke B Dimery I Beaupre DM14 Chen R15 Targeting Bruton tyrosine kinase with ibrutinib in relapsed/refractory marginal zone lymphoma Blood 2017 129 16 2224 2232 10.1182/blood-2016-10-747345 28167659 \n14 Leblond V Kastritis E Advani R Ansell SM Buske C Castillo JJ García-Sanz R Gertz M Kimby E Kyriakou C Merlini G Minnema MC Morel P Morra E Rummel M Wechalekar A Patterson CJ Treon SP Dimopoulos MA Treatment recommendations from the Eighth International Workshop on Waldenström’s Macroglobulinemia Blood 2016 128 1321 8 10.1182/blood-2016-04-711234 27432877 \n15 Treon SP Tripsas CK Meid K Warren D Varma G Green R Argyropoulos KV Yang G Cao Y Xu L Patterson CJ Rodig S Zehnder JL Aster JC Harris NL Kanan S Ghobrial I Castillo JJ Laubach JP Hunter ZR Salman Z Li J Cheng M Clow F Graef T Palomba ML Advani RH Ibrutinib in Previously Treated Waldenström’s Macroglobulinemia N engl J Med 2015 372 15 1430 1440 10.1056/NEJMoa1501548 25853747 \n16 Castillo JJ Palomba ML Advani R Treon SP Ibrutinib in Waldenström macroglobulinemia: latest evidence and clinical experience Ther Adv Hematol 2016 7 4 179 186 10.1177/2040620716654102 27493708 \n17 Kastritis E Leblond V Dimopoulos MA Kimby E Staber P Kersten MJ Tedeschi A Buske C ESMO Guidelines Committee Waldenstrom’s macroglobulinaemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up Ann Oncol 2018 29 Supplement 4 iv41 iv50 10.1093/annonc/mdy146 29982402 \n18 Cheson BD Fisher RI Barrington SF Cavalli F Schwartz LH Zucca E Lister TA Alliance, Australasian Leukaemia and Lymphoma Group; Eastern Cooperative Oncology Group; European Mantle Cell Lymphoma Consortium; Italian Lymphoma Foundation; European Organisation for Research; Treatment of Cancer/Dutch Hemato-Oncology Group; Grupo Español de Médula Ósea; German High-Grade Lymphoma Study Group; German Hodgkin’s Study Group; Japanese Lymphorra Study Group; Lymphoma Study Association; NCIC Clinical Trials Group; Nordic Lymphoma Study Group; Southwest Oncology Group; United Kingdom National Cancer Research Institute Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification J Clin Oncol 2014 9 20 32 27 3059 68 10.1200/JCO.2013.54.8800 25113753 \n19 Dimopoulos MA Trotman J Tedeschi A Matous JV Macdonald D Tam C Tournilhac O Ma S Oriol A Heffner LT Shustik C García-Sanz R Cornell RF de Larrea CF Castillo JJ Granell M Kyrtsonis MC Leblond V Symeonidis A Kastritis E Singh P Li J Graef T Bilotti E Treon S Buske C iNNOVATE Study Group and the European Consortium for Waldenström’s Macroglobulinemia Ibrutinib for patients with rituximab-refractory Waldenström’s macroglobulinaemia (iNNOVATE): an open-label substudy of an international, multicentre, phase 3 trial Lancet Oncol 2017 2 18 2 241 250 10.1016/S1470-2045(16)30632-5 27956157 \n20 Ahn IE Farooqui MZH Tian X Valdez J Sun C Soto S Lotter J Housel S Stetler-Stevenson M Yuan CM Maric I Calvo KR Nierman P Hughes TE Saba NS Marti GE Pittaluga S Herman SEM Niemann CU Pedersen LB Geisler CH Childs R Aue G Wiestner A Depth and durability of response to ibrutinib in CLL: 5-year follow-up of a phase 2 study Blood 2018 131 21 2357 2366 10.1182/blood-2017-12-820910 29483101\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2035-3006",
"issue": "11(1)",
"journal": "Mediterranean journal of hematology and infectious diseases",
"keywords": "Ibrutinib; IgA-secreting lymphoplasmacytic lymphoma; MYD88",
"medline_ta": "Mediterr J Hematol Infect Dis",
"mesh_terms": null,
"nlm_unique_id": "101530512",
"other_id": null,
"pages": "e2019057",
"pmc": null,
"pmid": "31528323",
"pubdate": "2019",
"publication_types": "D002363:Case Reports",
"references": "22931316;23045577;23446312;23544948;24224040;25113753;25853747;26421453;26454445;26980069;26980727;27329639;27432877;27493708;27956157;28167659;29326801;29483101;29982402;30426157",
"title": "Response to Ibrutinib of a Refractory IgA Lymphoplasmacytic Lymphoma Carrying the MYD88 L265P Gene Mutation.",
"title_normalized": "response to ibrutinib of a refractory iga lymphoplasmacytic lymphoma carrying the myd88 l265p gene mutation"
} | [
{
"companynumb": "IT-BAXTER-2019BAX020461",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "SPIRONOLACTONE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND Spinal hematomas can be post-traumatic, iatrogenic, or spontaneous. A spontaneous spinal hematoma is a rare finding, but one with very serious clinical implications. There are some risk factors linked to its occurrence, e.g. arteriovenous malformations, lumbar puncture, coagulopathy, neoplasms, or therapeutic anticoagulation. At present, only a few cases of spontaneous spinal hematoma (SSH) associated with new oral anticoagulants (NOACs) have been described, three of which were linked with rivaroxaban. CASE REPORT We report the case of an 82-year-old Caucasian woman with persistent atrial fibrillation treated with rivaroxaban, who presented to the Urology Department with acute-onset back pain which was thought to be due to urolithiasis. No kidney stones were found, but her creatinine serum level was elevated, so she was transferred to our clinic for further treatment. During hospitalization she quickly developed paraplegia with urine and stool retention. MRI was performed, and demonstrated an acute epidural hemorrhage in her thoracic and lumbar spine. The neurosurgeons disqualified this patient from surgical intervention due to the extent of the hematoma and its location. The patient was referred to the Neurology Department for treatment and rehabilitation, but, to the best of our knowledge, she did not recover her motor function. CONCLUSIONS Although rivaroxaban has been shown to be more effective than warfarin in stroke prevention in patients with atrial fibrillation, physicians must remember that its use also carries the risk of major bleeding. SSH occurrence should be taken into account in a patient taking NOACs who develops paraplegia, even if there is no history of trauma prior to admission.",
"affiliations": "Department of Nephrology, Transplantology and Internal Medicine, Independent Public Clinical Hospital No. 2, Szczecin, Poland.;Department of Nephrology, Transplantology and Internal Medicine, Independent Public Clinical Hospital No. 2, Szczecin, Poland.;Department of Nephrology, Transplantology and Internal Medicine, Independent Public Clinical Hospital No. 2, Szczecin, Poland.",
"authors": "Feret|Wiktoria B|WB|;Kwiatkowska|Ewa|E|;Domański|Leszek|L|",
"chemical_list": "D000925:Anticoagulants; D000069552:Rivaroxaban",
"country": "United States",
"delete": false,
"doi": "10.12659/AJCR.923607",
"fulltext": "\n==== Front\nAm J Case Rep\nAm J Case Rep\namjcaserep\nThe American Journal of Case Reports\n1941-5923 International Scientific Literature, Inc. \n\n32636352\n10.12659/AJCR.923607\n923607\nArticles\nParaplegia Caused by Spontaneous Spinal Hemorrhage in a Patient Undergoing Rivaroxaban Therapy\nFeret Wiktoria B. ABEF Kwiatkowska Ewa AE Domański Leszek AG Department of Nephrology, Transplantology and Internal Medicine, Independent Public Clinical Hospital No. 2, Szczecin, Poland\nCorresponding Author: Wiktoria B. Feret, e-mail: feretwiktoria@gmail.comAuthors’ Contribution:\n\nA Study Design\n\nB Data Collection\n\nC Statistical Analysis\n\nD Data Interpretation\n\nE Manuscript Preparation\n\nF Literature Search\n\nG Funds Collection\n\nConflict of interest: None declared\n\n\n2020 \n07 7 2020 \n21 e923607-1 e923607-5\n18 2 2020 13 4 2020 29 5 2020 © Am J Case Rep, 20202020This work is licensed under Creative Common Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)Patient: Female, 82-year-old\n\nFinal Diagnosis: Spinal hemorrhage\n\nSymptoms: Back pain • paraplegia • stool retention\n\nMedication: —\n\nClinical Procedure: —\n\nSpecialty: General and Internal Medicine\n\nObjective:\nUnusual clinical course\n\nBackground:\nSpinal hematomas can be post-traumatic, iatrogenic, or spontaneous. A spontaneous spinal hematoma is a rare finding, but one with very serious clinical implications. There are some risk factors linked to its occurrence, e.g. arteriovenous malformations, lumbar puncture, coagulopathy, neoplasms, or therapeutic anticoagulation. At present, only a few cases of spontaneous spinal hematoma (SSH) associated with new oral anticoagulants (NOACs) have been described, three of which were linked with rivaroxaban.\n\nCase Report:\nWe report the case of an 82-year-old Caucasian woman with persistent atrial fibrillation treated with rivaroxaban, who presented to the Urology Department with acute-onset back pain which was thought to be due to urolithiasis. No kidney stones were found, but her creatinine serum level was elevated, so she was transferred to our clinic for further treatment. During hospitalization she quickly developed paraplegia with urine and stool retention. MRI was performed, and demonstrated an acute epidural hemorrhage in her thoracic and lumbar spine. The neurosurgeons disqualified this patient from surgical intervention due to the extent of the hematoma and its location. The patient was referred to the Neurology Department for treatment and rehabilitation, but, to the best of our knowledge, she did not recover her motor function.\n\nConclusions:\nAlthough rivaroxaban has been shown to be more effective than warfarin in stroke prevention in patients with atrial fibrillation, physicians must remember that its use also carries the risk of major bleeding. SSH occurrence should be taken into account in a patient taking NOACs who develops paraplegia, even if there is no history of trauma prior to admission.\n\nMeSH Keywords:\nAnticoagulantsHematoma, Subdural, SpinalParaplegia\n==== Body\nBackground\nSpinal hematomas are quite an uncommon finding. In most cases, they are associated with trauma or medical intervention such as lumbar puncture [1]. Sometimes, however, no identifiable reason for occurrence of a hematoma can be seen, and that is when we classify it as spontaneous. Certain risk factors may contribute to developing a spinal hematoma, such as: coagulopathies, vascular malformations, therapeutic anticoagulation, or neoplasms [2]. Spontaneous spinal bleeding may occur in the subarachnoid, epidural, or subdural space, or in the spinal cord itself. Spontaneous spinal epidural hematoma (SSEH) occurs with an incidence of 0.1/100 000/year, which is still estimated to be four times more common than spontaneous spinal subdural hematoma (SSSH) [2,3]. To the best of our knowledge, there have been about 150 cases of SSSH described in the literature, most of them linked to warfarin use. Our case seems to be the fourth SSSH linked to rivaroxaban, a direct factor Xa inhibitor, since its initial approval for stroke prevention in patients with atrial fibrillation in November 2011 [3–5].\n\nCase Report\nAn 82-year-old Polish woman was redirected to our department from the urology admission room, where she primarily presented with acute-onset back pain that was thought to be due to urolithiasis. No obstruction in the urinary tract was found in the abdominal ultrasonography performed there, but the laboratory tests showed elevated creatinine serum level [2.33 mg/dl with a glomerular filtration rate (GFR) of 19 ml/min], so she was admitted to our department, the Department of Nephrology. She had a history of diabetes mellitus type 2, stage 4 chronic kidney disease according to KDIGO guidelines, persistent atrial fibrillation, ischemic stroke, and myocardial infarction followed by coronary artery bypass graft. Her daily medication included i.a. rivaroxaban in a dose of 20 mg for stroke prevention. No other anticoagulant was in use, as her other medications were: nebivolol 5 mg 1-0-1/2, digoxin 100 mg 1×1 Monday-Friday, furosemide 40 mg 1×1, and insulin (Humalog Mix50/50) with a total daily dose of 18 units. She denied taking any other medications that are not listed above, including NSAIDs or over-the-counter supplements.\n\nOn admission, her main complaint was the back pain. Her other complaints were transient left lower extremity paresthesia, abdominal discomfort, and an episode of vomiting a few hours before admission. We decided to repeat the abdominal ultrasonography in our unit. It showed some small gallstones in the gallbladder and a 7-mm cyst in the right kidney cortex. The liver, spleen, pancreas, left kidney, and urinary bladder were normal. As no clinically important deviations were found by abdominal ultrasonography, we decided to perform a lumbar spine X-ray even though she denied trauma history. It showed advanced osteoarthritis of the spine, but there was no sign of injury. A chest X-ray also showed no abnormalities, besides osteoarthritis and changes secondary to coronary artery bypass graft surgery.\n\nThe physical examination at admission showed features of moderate dehydration and completely irregular heart rate. There were no obvious neurological deficits.\n\nAmong the laboratory tests conducted on admission, only elevated plasma creatinine and urea levels (2.33 mg/dl and 152.3 mg/dl, respectively) were notable. Other laboratory parameters were: WBC=6.73 g/l, RBC=3.43 T/l, HGB=6.6 mmol/l, HCT=0.328, MCV=95.6 fl, PLT=187 g/l, CRP=1.23 mg/dl, APTT=38.3 s, PT=21.6 s, INR=1.92, ALT=32 U/l, AST=40 U/l. The patient was admitted to the hospital with a diagnosis of exacerbation of chronic kidney disease (CKD), most likely caused by dehydration. The patient was given tramadol as a painkiller and i.v. fluids for proper hydration, as well as her regular daily medication as stated above.\n\nOn the second day of hospitalization, the patient reported muscle weakness in both lower limbs. The physical examination at that time found muscular strength of the right lower limb to be 0/5 and left lower limb 1/5; there was no reaction in the indicator muscles. Sensitivity to the touch was preserved, with mild hyperalgesia (the patient felt the touch as a burning pain stimulus). In laboratory tests, a transient increase in CRP to 45 mg/dL appeared. After a neurological consultation, an MRI of the thoracolumbar spine (C5–S3) was performed, which showed multilevel hemorrhage. At the Th9 level, the spinal canal had narrowed to 8 mm (Figure 1A–1C). At the L5–S2 level, an intraspinal pathological mass measuring 49×12×9 mm was seen (Figure 2A–2C). MRI of the thoracic and lumbosacral region was performed with a GE SIGNA 1.5T device. T1-dependent, T2-dependent, and STIR images were obtained, as well as FSE T1-dependent images after 14 ml of Clariscan™ administration. The differential diagnosis the neurologist took into account before the MRI was Guillain-Barre Syndrome, but, with the MRI result described above, there was no need for further assessment with electromyography. The patient was brought to our neurosurgeons for urgent consultation. Unfortunately, she was disqualified from surgical drainage, as the size and abdominal location of the hemorrhagic lesions made their safe removal unlikely. There was a concern that surgical intervention would not bring the expected improvement, and could only aggravate neurological deficits. The patient was referred for further treatment and rehabilitation to the neurology department of the local hospital. Following the information acquired from the family, no improvement in the patient’s motor function has been achieved so far.\n\nDiscussion\nAccording to all available literature, the most common manifestation of spinal hemorrhage is sudden, severe back pain and progressive muscle weakness. SSSH mostly occurs in the thoracic spine. Other locations are the lumbar and, rarely, cervical spine [6]. In the presented case, the occurrence of severe, stabbing pain in the lumbar region was initially taken as a sign of urolithiasis, and this delayed the implementation of further treatment.\n\nThere are two treatment options for SSH. The first is laminectomy and hematoma drainage, and the second is conservative management, which may be successful in patients with minor neurological deficits. Based on the available literature, the success of interventional treatment largely depends on the time elapsed from the onset of neurological symptoms to neuro-surgical intervention, clinical manifestation at admission, and excess of bleeding [7,8].\n\nNew oral anticoagulants (NOACs), unlike warfarin, do not have as many interactions with food and other medications and do not require routine monitoring of international normalized ratio (INR). Their mechanism of action is centered on inhibition of specific points in the coagulation cascade, for example factor Xa, of which rivaroxaban is a direct inhibitor. Factor Xa is a catalyst for the conversion of prothrombin into thrombin. Thrombin, in turn, converts water-soluble fibrinogen into insoluble fibrin, which leads to the formation of a clot.\n\nRivaroxaban is eliminated as follows: 2/3 is metabolized by the liver and 1/3 is excreted in its active, unchanged form by the kidneys [9]. It is important to note that patients with severe renal dysfunction (with eGFR lower than 30 ml/min) were excluded from all phase III clinical trials of rivaroxaban. Our patient presented with an eGFR of 20 ml/min. We suggest that, in patients with renal insufficiency, rivaroxaban should be used with high caution due to delayed drug elimination [10]. Our patient also had an INR of 1.92, but it is worth noting that INR is not useful in patients taking NOACs, as this ratio is only standardized for coumarins. Clinicians should only expect longer prothrombin time (PT) and activated partial thromboplastin time (APTT), as these are both dose-dependent. Although we did not determine factor Xa activity in this case, it could be presumed that the reason for spontaneous bleeding into the meninges was exacerbation of kidney disease, and thus an increase in blood anticoagulant levels. According to rivaroxaban’s Summary of Product Characteristics for Xarelto, no interactions between rivaroxaban and any of the drugs taken by the patient (listed above) are known. Also, none of the patient’s chronic diseases are known to affect coagulation. The drugs that are known to interfere with rivaroxaban metabolism, thus affecting hemostasis, are azole antifungals and HIV-protease inhibitors. Other drugs, like NSAIDs or antiplatelet agents, should be used with caution and avoided when possible.\n\nAlthough there is no clear contraindication for using rivaroxaban in older patients, most of the available literature assessing its safety profile, including final clinical trials of the drug, includes patients up to 76 years of age. The drug’s half-life can be up to 50% longer in elderly subjects than in younger subjects [9,10]. Our patient was 82, and this factor might also alter the pharmacodynamics. As no other clear reason for hematoma occurrence can be seen in this case – no history of trauma or lumbar puncture, no drug interactions, no neoplasms, no liver insufficiency – we concluded that the case was directly linked to rivaroxaban use. Each patient should be assessed for the risk of ischemic complications using the CHA2DS2-VASc scale and the results should be correlated with the sum of points obtained on the HAS-BLED scale, assessing the risk of serious bleeding in patients with non-valvular atrial fibrillation [11]. Our patient’s score of 7 points on the CHA2D2S2-VASc scale (age >75 years, diabetes, history of stroke, history of myocar-dial infarction, female sex) is associated with a bleeding risk of about 9.6% per year. On the HAS-BLED scale, her score was 3 points (episode of stroke, chronic kidney disease with creatinine level above 2.2 mg/dL and age >65 years), which is associated with a high risk of bleeding (about 5.6% per year). In this case, statistically, the benefit of anticoagulant treatment outweighs the risk associated with it. However, the use of the maximum possible dose of 20 mg (the recommended dose for stroke prevention in patients with persistent atrial fibrillation) in a patient over age 80 with stage 4 chronic kidney disease raises doubts about the real safety of this scheme. In such patients, it seems reasonable to use lower doses of rivaroxaban, in light of how easily glomerular filtration rate deteriorates as a result of dehydration. In the elderly, the activity of the thirst center in the brain decreases, which leads to intravascular volume decrease and impaired renal flow. With deteriorating renal function, rivaroxaban clearance slows, and the AUC can be over 1.6-fold higher in subjects with eGFR of less than 30 ml/min. [9]\n\nConclusions\nClinicians should be aware of the possibility of SSH occurrence in patients treated with NOACs [12,13], despite widespread opinions about their safety. In this group of patients, if sudden, severe pain and paraplegia appears, major spinal bleeding should be urgently ruled out, as outcome depends on the patient’s neurological status and time from onset of symptoms to surgical intervention. In addition, the increased risk of major bleeding in older patients with severely impaired renal function should be borne in mind. In our opinion, practitioners should consider lowering rivaroxaban dose for preventing stroke in non-valvular atrial fibrillation from 20 mg to 15 mg in patients with severe renal impairment, when possible [9].\n\nConflict of interest\n\nNone.\n\nFigure 1. (A–C) Features of acute bleeding in the thoracic spine, visible at the Th7-Th11 level. The changes were the most widespread at the Th9 level, where they narrow the spinal canal to 8 mm, which corresponds to absolute narrowing of the spinal canal. (A) T1-dependent sagittal image; arrow denotes weakly textured pathological masses in the ventral part of the spinal canal, probably intrathecal. Their signal and lack of contrast suggest acute hemorrhagic changes. (B) T1-dependent transverse image, at level Th8. Notice the lighter color in the ventral spinal canal, indicating the presence of blood (arrow). (C) STIR sagittal image showing dark signal intensity indicating hemorrhage (arrow).\n\nFigure 2. (A–C) Notice features of acute bleeding in the lumbosacral spine at the L5–S2 segment. (A) T2-dependent sagittal image; arrow denotes an intrathecal pathological mass measuring 49×12×9 mm (hypointense in the image). (B) T2-dependent transverse image, at level L5/S1. Notice the hyperintense signal of blood (arrow). (C) STIR sagittal image showing an intrathecal pathological mass at the L5–S2 segment of the spinal cord (arrow).\n==== Refs\nReferences:\n1. Park J Ahn R Son D Acute spinal subdural hematoma with hemiplegia after acupuncture: A case report and review of the literature Spine J 2013 13 10 59 63 \n2. De Beer MH Eysink Smeets MM Koppen H Spontaneous spinal subdural hematoma Neurologist 2017 22 1 34 39 28009771 \n3. Goldfine C Glazer C Ratzan R Spontaneous spinal epidural hematoma from Rivaroxaban Clin Pract Cases Emerg Med 2018 2 2 151 54 29849242 \n4. Jaeger M Jeanneret B Schaeren S Spontaneous spinal epidural haematoma during Factor Xa inhibitor treatment (Rivaroxaban) Eur Spine J 2012 21 4 433 35 \n5. Castillo JM Afanador HF Manjarrez E Morales XA Non-traumatic spontaneous spinal subdural hematoma in a patient with non-valvular atrial fibrillation during treatment with rivaroxaban Am J Case Rep 2015 16 377 81 26090890 \n6. Joubert C Gazzola S Sellier A Dagain A Acute idiopathic spinal subdural hematoma: What to do in an emergency? Neurochirurgie 2019 65 2–3 93 97 30744959 \n7. Ismail R Zaghrini E Hitti E Spontaneous spinal epidural hematoma in a patient on Rivaroxaban: Case report and literature review J Emerg Med 2017 53 4 536 39 29079069 \n8. Rettenmaier LA Holland MT Abel TJ Acute, nontraumatic spontaneous spinal subdural hematoma: A case report and systematic review of the literature Case Rep Neurol Med 2017 2017 2431041 29441210 \n9. Kreutz R Pharmacokinetics and pharmacodynamics of Rivaroxaban – an oral, direct Factor Xa inhibitor Curr Clin Pharmacol 2014 9 1 75 83 24218999 \n10. Fox KA Piccini JP Wojdyla D Prevention of stroke and systemic embolism with rivaroxaban compared with warfarin in patients with non-valvular atrial fibrillation and moderate renal impairment Eur Heart J 2011 32 19 2387 94 21873708 \n11. Yao X Gersh BJ Sangaralingham LR Comparison of the CHA2DS2-VASc, CHADS2, HAS-BLED, ORBIT, and ATRIA risk scores in predicting nonvitamin K antagonist oral anticoagulants-associated bleeding in patients with atrial fibrillation Am J Cardiol 2017 120 9 1549 56 28844514 \n12. Ardebol J Cahueque M Lopez W Azmitia E Spontaneous thoracic spinal subdural hematoma associated with apixaban therapy J Surg Case Rep 2019 4 rjz115 \n13. McHaourab A Evans GYHR Austin R Spontaneous spinal subdural haematoma in a patient on apixaban BMJ Case Rep 2019 12 1 e227311\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "1941-5923",
"issue": "21()",
"journal": "The American journal of case reports",
"keywords": null,
"medline_ta": "Am J Case Rep",
"mesh_terms": "D000369:Aged, 80 and over; D000925:Anticoagulants; D001281:Atrial Fibrillation; D005260:Female; D046748:Hematoma, Epidural, Spinal; D006801:Humans; D008159:Lumbar Vertebrae; D008279:Magnetic Resonance Imaging; D010264:Paraplegia; D000069552:Rivaroxaban; D013904:Thoracic Vertebrae",
"nlm_unique_id": "101489566",
"other_id": null,
"pages": "e923607",
"pmc": null,
"pmid": "32636352",
"pubdate": "2020-07-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "28009771;24218999;30674492;24094991;28844514;21874549;31044059;30744959;29849242;29441210;29079069;21873708;26090890",
"title": "Paraplegia Caused by Spontaneous Spinal Hemorrhage in a Patient Undergoing Rivaroxaban Therapy.",
"title_normalized": "paraplegia caused by spontaneous spinal hemorrhage in a patient undergoing rivaroxaban therapy"
} | [
{
"companynumb": "PL-JNJFOC-20200830918",
"fulfillexpeditecriteria": "1",
"occurcountry": "PL",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "RIVAROXABAN"
},
"drugadditional": "2",
... |
{
"abstract": "antipsychotic drugs (APs) have been associated with falls and fractures in elderly individuals but limited knowledge on specific drugs exist.\n\n\n\nto investigate the association between individual APs and fractures in elderly persons.\n\n\n\nnationwide register-based cohort study.\n\n\n\nall Danish individuals aged ≥65 who had not been in treatment with any AP in the year before inclusion.\n\n\n\nincidence rate ratios (IRRs) of fractures of hip, pelvis or upper extremities during treatment with commonly used APs were assessed in multivariable Poisson models. Exposure was divided into time periods from initiation of treatment: 0-30 days, 31-365 days or >365 days.\n\n\n\none year prior to inclusion, 1,540,915 individuals ≥65 years had not received APs and of these 93,298 initiated treatment with APs. Mean follow-up was 9.6 years. During follow-up, 246,057 (16%) experienced a fracture. Associations were for all APs highest in the initial treatment period (0-30 days) with IRRs for risperidone 1.97 (95% CI: 1.70-2.28), olanzapine 2.31 (95% CI: 1.96-2.73), quetiapine 2.09 (95% CI: 1.73-2.52), zuclopenthixol 2.19 (95% CI: 1.82-2.63), chlorprothixen 1.62 (95% CI: 1.18-2.24), flupenthixol 1.43 (95% CI: 1.06-1.93), levomepromazine 1.19 (95% CI 0.86-1.66), haloperidol 2.98 (95% CI 2.57-3.45), compared with the background population.\n\n\n\nuse of APs is associated with fractures in elderly persons especially in the initial treatment period. If AP use in an elderly person is deemed necessary, individual falls prophylaxis should be considered.",
"affiliations": "Department of Internal Medicine, Nykøbing Falster Hospital, Nykøbing Falster, Denmark.;Department of Internal Medicine, Nykøbing Falster Hospital, Nykøbing Falster, Denmark.;Department of Cardiology, University Hospital Gentofte, Gentofte, Denmark.;Department of Health, Science and Technology, Aalborg University and Department of Cardiology and Clinical Epidemiology Aalborg University Hospital, Denmark.;Department of Cardiology, University Hospital Gentofte, Gentofte, Denmark.;Department of Internal Medicine, Nykøbing Falster Hospital, Nykøbing Falster, Denmark.",
"authors": "Torstensson|Maia|M|;Leth-Møller|Katja|K|;Andersson|Charlotte|C|;Torp-Pedersen|Christian|C|;Gislason|Gunnar Hilmar|GH|;Holm|Ellen Astrid|EA|",
"chemical_list": "D014150:Antipsychotic Agents",
"country": "England",
"delete": false,
"doi": "10.1093/ageing/afw209",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0002-0729",
"issue": "46(2)",
"journal": "Age and ageing",
"keywords": "antipsychotics; falls; fractures; older people; pharmacoepidemiology",
"medline_ta": "Age Ageing",
"mesh_terms": "D000058:Accidental Falls; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D014150:Antipsychotic Agents; D003718:Denmark; D005260:Female; D050723:Fractures, Bone; D006801:Humans; D015994:Incidence; D008297:Male; D012042:Registries; D012307:Risk Factors; D013997:Time Factors",
"nlm_unique_id": "0375655",
"other_id": null,
"pages": "258-264",
"pmc": null,
"pmid": "27932365",
"pubdate": "2017-03-01",
"publication_types": "D016428:Journal Article; D064888:Observational Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Danish register-based study on the association between specific antipsychotic drugs and fractures in elderly individuals.",
"title_normalized": "danish register based study on the association between specific antipsychotic drugs and fractures in elderly individuals"
} | [
{
"companynumb": "DK-JNJFOC-20170607599",
"fulfillexpeditecriteria": "1",
"occurcountry": "DK",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "HALOPERIDOL"
},
"drugadditional": "3",
... |
{
"abstract": "Progressive multifocal leukoencephalopathy (PML) represents a life-threatening demyelinating disorder of the brain caused by reactivation of a rare opportunistic infection with JC Polyomavirus. The aims of this study were to describe the incidence of a susceptibility-weighted imaging hypointense rim in patients with multifocal leukoencephalopathy and to explore the histologic correlates and prognostic value of the rim with regard to the clinical outcome.\n\n\n\nThis retrospective study included 18 patients with a definite diagnosis of progressive multifocal leukoencephalopathy. Ten patients were HIV-positive, 3 patients had natalizumab-associated progressive multifocal leukoencephalopathy, 1 patient had multiple myeloma, 3 patients had a history of lymphoma, and 1 was diagnosed with acute myeloid leukemia. Patients were divided into short- (up to 12 months) and long-term (>12 months) survivors. A total of 93 initial and follow-up MR imaging examinations were reviewed. On SWI, the presence and development of a hypointense rim at the periphery of the progressive multifocal leukoencephalopathy lesions were noted. A postmortem histologic examination was performed in 2 patients: A rim formed in one, and in one, there was no rim.\n\n\n\nA total of 73 progressive multifocal leukoencephalopathy lesions were observed. In 13 (72.2%) patients, a well-defined thin, linear, hypointense rim at the periphery of the lesion toward the cortical side was present, while in 5 (27.8%) patients, it was completely absent. All 11 long-term survivors and 2 short-term survivors presented with a prominent SWI-hypointense rim, while 5/7 short-term survivors did not have this rim.\n\n\n\nThe thin, uniformly linear, gyriform SWI-hypointense rim in the paralesional U-fibers in patients with definite progressive multifocal leukoencephalopathy might represent an end-point stage of the neuroinflammatory process in long-term survivors.",
"affiliations": "From the Departments of Biomedical Imaging and Image-Guided Therapy (M.M.T., J.B.) majda.thurnher@meduniwien.ac.at.;From the Departments of Biomedical Imaging and Image-Guided Therapy (M.M.T., J.B.).;Dermatology (A.R.).;Institute of Neurology (E.G.), University Hospital Vienna, Medical University of Vienna, Vienna, Austria.",
"authors": "Thurnher|M M|MM|0000-0001-9746-0932;Boban|J|J|0000-0001-9701-5484;Rieger|A|A|0000-0003-0340-0117;Gelpi|E|E|0000-0003-2948-4187",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.3174/ajnr.A6072",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0195-6108",
"issue": "40(6)",
"journal": "AJNR. American journal of neuroradiology",
"keywords": null,
"medline_ta": "AJNR Am J Neuroradiol",
"mesh_terms": "D000328:Adult; D000368:Aged; D001921:Brain; D005260:Female; D006801:Humans; D007968:Leukoencephalopathy, Progressive Multifocal; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D059906:Neuroimaging; D011379:Prognosis; D012189:Retrospective Studies; D066127:White Matter; D055815:Young Adult",
"nlm_unique_id": "8003708",
"other_id": null,
"pages": "994-1000",
"pmc": null,
"pmid": "31122919",
"pubdate": "2019-06",
"publication_types": "D016428:Journal Article",
"references": "7295586;29142146;28618066;22790246;21131916;23269104;24752885;22529995;19647202;23568998;28643229;29044417;25846998;29025774;26944139;25270052;28588577;27273076;29081415;24972818;18319157;20298966;26360519;28674518;11337345;26369555;25666327;29195086;27042682",
"title": "Susceptibility-Weighted MR Imaging Hypointense Rim in Progressive Multifocal Leukoencephalopathy: The End Point of Neuroinflammation and a Potential Outcome Predictor.",
"title_normalized": "susceptibility weighted mr imaging hypointense rim in progressive multifocal leukoencephalopathy the end point of neuroinflammation and a potential outcome predictor"
} | [
{
"companynumb": "AT-BIOGEN-2013BI030044",
"fulfillexpeditecriteria": "1",
"occurcountry": "AT",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "NATALIZUMAB"
},
"drugadditional": null,
... |
{
"abstract": "The CRUSADE, ACTION and ACUITY-HORIZONS bleeding scores have been derived using Caucasian patients, and little is known about which has the better predictive ability in Chinese patients, especially for patients with STEMI.Methods and Results:We retrospectively analyzed 2,208 consecutive STEMI patients undergoing primary PCI (PPCI). Major bleeding events were defined according to Bleeding Academic Research Consortium criteria (type 3 or 5). Predictive ability of the 3 scores was assessed using logistic regression and AUC. Unadjusted HR for 1-year death were determined on Cox proportional hazard modeling. The major bleeding rate was 2.4%. The AUC of the CRUSADE, ACTION and ACUTIY-HORIZONS models was 0.88 (95% CI: 0.84-0.92), 0.90 (95% CI: 0.87-0.94), and 0.78 (95% CI: 0.87-0.94). The calibration of the ACUTIY-HORIZONS model was not acceptable overall, or in the subgroup of access site (P<0.05). In the high-risk category, 1-year mortality was approximately 4-7-fold greater than in the low-risk category (CRUSADE: HR, 7.27; 95% CI: 3.30-16.02, P<0.001; ACTION: HR, 7.13; 95% CI: 2.19-15.41, P<0.001; ACUITY-HORIZONS: HR, 4.06; 95% CI: 1.62-10.16; P=0.003).\n\n\n\nThe CRUSADE and ACTION scores have greater predictive ability for in-hospital major bleeding than the ACUITY-HORIZONS risk score in Chinese STEMI patients undergoing PPCI. Mortality would increase with the transition from low- to high-risk category in 1 year.",
"affiliations": "Emergency and Critical Care Centre, Beijing An Zhen Hospital, Capital Medical University, Beijing Institute of Heart Lung and Blood Vessel Disease.;Emergency and Critical Care Centre, Beijing An Zhen Hospital, Capital Medical University, Beijing Institute of Heart Lung and Blood Vessel Disease.;Emergency and Critical Care Centre, Beijing An Zhen Hospital, Capital Medical University, Beijing Institute of Heart Lung and Blood Vessel Disease.;Emergency and Critical Care Centre, Beijing An Zhen Hospital, Capital Medical University, Beijing Institute of Heart Lung and Blood Vessel Disease.;Emergency and Critical Care Centre, Beijing An Zhen Hospital, Capital Medical University, Beijing Institute of Heart Lung and Blood Vessel Disease.;Emergency and Critical Care Centre, Beijing An Zhen Hospital, Capital Medical University, Beijing Institute of Heart Lung and Blood Vessel Disease.;Emergency and Critical Care Centre, Beijing An Zhen Hospital, Capital Medical University, Beijing Institute of Heart Lung and Blood Vessel Disease.",
"authors": "Liu|Ran|R|;Zheng|Wen|W|;Zhao|Guanqi|G|;Wang|Xiao|X|;Zhao|Xuedong|X|;Zhou|Shenghui|S|;Nie|Shaoping|S|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": "10.1253/circj.CJ-17-0760",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1346-9843",
"issue": "82(3)",
"journal": "Circulation journal : official journal of the Japanese Circulation Society",
"keywords": "Chinese; Hemorrhage; Risk score; ST-segment elevation myocardial infarction",
"medline_ta": "Circ J",
"mesh_terms": "D000368:Aged; D000792:Angiography; D044466:Asians; D002543:Cerebral Hemorrhage; D005260:Female; D006471:Gastrointestinal Hemorrhage; D006470:Hemorrhage; D006801:Humans; D008297:Male; D008875:Middle Aged; D062645:Percutaneous Coronary Intervention; D011237:Predictive Value of Tests; D012189:Retrospective Studies; D018570:Risk Assessment; D000072657:ST Elevation Myocardial Infarction",
"nlm_unique_id": "101137683",
"other_id": null,
"pages": "791-797",
"pmc": null,
"pmid": "29237990",
"pubdate": "2018-02-23",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Predictive Validity of CRUSADE, ACTION and ACUITY-HORIZONS Bleeding Risk Scores in Chinese Patients With ST-Segment Elevation Myocardial Infarction.",
"title_normalized": "predictive validity of crusade action and acuity horizons bleeding risk scores in chinese patients with st segment elevation myocardial infarction"
} | [
{
"companynumb": "CN-AGG-12-2017-1854",
"fulfillexpeditecriteria": "2",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ASPIRIN"
},
"drugadditional": null,
"dru... |
{
"abstract": "We investigated hyperglycemia due to atypical antipsychotics in cancer patients with delirium. Using patient records retrospectively, we investigated 189 cancer patients who were diagnosed with delirium between June 2008 and May 2009. One- hundred fifty-four of the 189 patients used atypical antipsychotics for delirium treatment. Three percent(5/154)of them were admitted with over 350 mg/dL blood glucose during their atypical antipsychotics treatment, however, all cases did not relate the adverse reaction of hyperglycemia with the use of antipsychotics. Most cancer patients with delirium used atypical antipsychotics, and the incidence of hyperglycemia was low.",
"affiliations": "Dept. of Pharmacy, Meiji Pharmaceutical University, Japan.",
"authors": "Suzuki|Shinya|S|;Ichida|Yasuhiko|Y|;Fujisawa|Daisuke|D|;Ogawa|Asao|A|;Uchitomi|Yosuke|Y|;Endo|Kazushi|K|;Izumi|Keishiro|K|",
"chemical_list": "D014150:Antipsychotic Agents",
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0385-0684",
"issue": "39(10)",
"journal": "Gan to kagaku ryoho. Cancer & chemotherapy",
"keywords": null,
"medline_ta": "Gan To Kagaku Ryoho",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014150:Antipsychotic Agents; D003693:Delirium; D005260:Female; D006801:Humans; D006943:Hyperglycemia; D008297:Male; D008875:Middle Aged; D009369:Neoplasms",
"nlm_unique_id": "7810034",
"other_id": null,
"pages": "1523-6",
"pmc": null,
"pmid": "23064064",
"pubdate": "2012-10",
"publication_types": "D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "Hyperglycemia due to atypical antipsychotics in cancer patients with delirium.",
"title_normalized": "hyperglycemia due to atypical antipsychotics in cancer patients with delirium"
} | [
{
"companynumb": "JP-LUPIN PHARMACEUTICALS INC.-2016-02605",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "QUETIAPINE"
},
"drugadditiona... |
{
"abstract": "OBJECTIVE\nPost-marketing surveillance is very important, especially for rare adverse drug reactions like QTc-prolongation and Torsade de Pointes (TdP). The objective of this study was to investigate the characteristics of Belgian cases of drug-related TdP reported in the EudraVigilance database.\n\n\nMETHODS\nThe EudraVigilance database was searched for Belgian post-marketing cases of TdP reported between December 2001-April 2015. These cases were identified with MedDRA preferred terms. Duplicate reports were excluded. Each included case report was reviewed to collect data about age, gender, seriousness, suspected drug, concomitant drugs, causality, and other known risk factors for QTc-prolongation.\n\n\nRESULTS\nBetween 2001 and 2015, only 31 cases coded as TdP were identified; 16 cases were also coded as 'prolonged QT' and 2 patients died. In total, 21 suspected drugs were implicated and most of them (N = 11) were part of list 1 of CredibleMeds. The most common suspected drugs were citalopram (N = 4) and amiodarone (N = 3). In 18 cases, a pharmacodynamic drug-drug interaction with risk of QTc-prolongation was present. Most patients (N = 25) had ≥2 other risk factors for QTc-prolongation.\n\n\nCONCLUSIONS\nOver 15 years, only a low number of Belgian cases of TdP were identified in the EudraVigilance database. In most case reports, multiple risk factors for QTc-prolongation could be detected. This illustrates that there is a clear underreporting of QTc-prolongation and TdP in Belgium. Initiatives are needed to improve the awareness and knowledge of health care professionals regarding the risk of QTc-prolongation and TdP, both to prevent cases of TdP and to stimulate the reporting of these cases.",
"affiliations": "a Department of Pharmaceutical and Pharmacological Sciences , KU Leuven - University of Leuven , Leuven , Belgium.;b Department of Cardiovascular Sciences , KU Leuven - University of Leuven , Leuven , Belgium.;d Department of Neurosciences , KU Leuven - University of Leuven , Leuven , Belgium.;b Department of Cardiovascular Sciences , KU Leuven - University of Leuven , Leuven , Belgium.;a Department of Pharmaceutical and Pharmacological Sciences , KU Leuven - University of Leuven , Leuven , Belgium.",
"authors": "Vandael|Eline|E|;Vandenberk|Bert|B|http://orcid.org/0000-0001-8296-920X;Vandenberghe|Joris|J|;Willems|Rik|R|http://orcid.org/0000-0002-5469-9609;Foulon|Veerle|V|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1080/17843286.2017.1300217",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1784-3286",
"issue": "72(6)",
"journal": "Acta clinica Belgica",
"keywords": "EudraVigilance; QTc-prolongation; Torsade de Pointes; pharmacovigilance; sudden cardiac death",
"medline_ta": "Acta Clin Belg",
"mesh_terms": "D000368:Aged; D001530:Belgium; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D016171:Torsades de Pointes",
"nlm_unique_id": "0370306",
"other_id": null,
"pages": "385-390",
"pmc": null,
"pmid": "28335691",
"pubdate": "2017-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Cases of drug-induced Torsade de Pointes: a review of Belgian cases in the EudraVigilance database.",
"title_normalized": "cases of drug induced torsade de pointes a review of belgian cases in the eudravigilance database"
} | [
{
"companynumb": "BE-CIPLA LTD.-2017BE27075",
"fulfillexpeditecriteria": "1",
"occurcountry": "BE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "OLANZAPINE"
},
"drugadditional": "3",
... |
{
"abstract": "OBJECTIVE\nTo report a case of acute pancreatitis in a patient receiving a combination formulation of irbesartan and hydrochlorothiazide (HCTZ).\n\n\nMETHODS\nA 33-year-old white woman developed acute pancreatitis 10 days after starting irbesartan 300 mg and hydrochlorothiazide 12.5 mg for treatment of hypertension. Her symptoms disappeared and serum concentrations of lipase and amylase returned to normal 2 days after irbesartan/HCTZ was discontinued. A search of MEDLINE (1990-September 2002) and the Australian Adverse Drug Reaction Advisory Committee database revealed 1 additional case of pancreatitis associated with irbesartan/HCTZ and 3 cases of pancreatitis associated with losartan.\n\n\nCONCLUSIONS\nAn objective causality assessment indicates that it is probable that pancreatitis was caused by the angiotensin II receptor antagonist irbesartan (and the same is probably true for losartan). It is less likely that the hydrochlorothiazide in irbesartan/HCTZ caused pancreatitis in our patient since the dose was lower than that usually associated with thiazide-induced pancreatitis. Angiotensin II receptors are thought to be important in regulation of pancreatic secretion and microcirculation, but the mechanism of pancreatitis induced by angiotensin II receptor antagonists remains unclear.\n\n\nCONCLUSIONS\nClinicians should be aware that irbesartan/HCTZ or losartan may cause acute pancreatitis. If abdominal pain develops, the medication should be discontinued and the patient investigated for acute pancreatitis.",
"affiliations": "Clinical Pharmacology and Toxicology, The Canberra Hospital, Woden, Australia.",
"authors": "Fisher|Alexander A|AA|;Bassett|Mark L|ML|",
"chemical_list": "D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents; D001713:Biphenyl Compounds; D004232:Diuretics; D004338:Drug Combinations; D049993:Sodium Chloride Symporter Inhibitors; D013777:Tetrazoles; D006852:Hydrochlorothiazide; D000077405:Irbesartan; D019808:Losartan",
"country": "United States",
"delete": false,
"doi": "10.1345/aph.1C099",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1060-0280",
"issue": "36(12)",
"journal": "The Annals of pharmacotherapy",
"keywords": null,
"medline_ta": "Ann Pharmacother",
"mesh_terms": "D000208:Acute Disease; D000328:Adult; D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents; D001713:Biphenyl Compounds; D004232:Diuretics; D004338:Drug Combinations; D005260:Female; D006801:Humans; D006852:Hydrochlorothiazide; D000077405:Irbesartan; D019808:Losartan; D010195:Pancreatitis; D049993:Sodium Chloride Symporter Inhibitors; D013777:Tetrazoles",
"nlm_unique_id": "9203131",
"other_id": null,
"pages": "1883-6",
"pmc": null,
"pmid": "12452749",
"pubdate": "2002-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Acute pancreatitis associated with angiotensin II receptor antagonists.",
"title_normalized": "acute pancreatitis associated with angiotensin ii receptor antagonists"
} | [
{
"companynumb": "AU-RANBAXY-2013R1-74254",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "HYDROCHLOROTHIAZIDE\\IRBESARTAN"
},
"drugadditi... |
{
"abstract": "We describe the first case of a novel treatment for a newly diagnosed glioblastoma (GBM) using superselective intraarterial cerebral infusion (SIACI) of cetuximab after osmotic disruption of the blood-brain barrier (BBB) with mannitol. A 51year-old female underwent craniotomy for removal of a right frontal GBM. Pathology confirmed EGFR amplification, and she underwent three treatments of SIACI of cetuximab to the tumor site. The first treatment was given within a week of starting standard of care chemoradiation (Stupp protocol), which is a combination of radiation treatment (2 Gy per/ day x 30 days, total of 60 Gy) and oral temozolomide (75 mg/m2). The second and third SIACI of cetuximab were administered 3 and 6 months later, while the patient continued on maintenance temozolomide. Post-radiation changes on MRI were stable, and there were no signs of recurrence at 4 and 6 months post-resection. Herein, we detail the technical aspects of this novel treatment paradigm and suggest that SIACI of cetuximab after BBB disruption using mannitol, combined with the standard of care chemoradiation therapy, may be an effective treatment method for newly diagnosed EGFR amplified glioblastoma.",
"affiliations": "Brain Tumor Center, Department of Neurosurgery, Lenox Hill Hospital, New York, NY, U.S.A.;Brain Tumor Center, Department of Neurosurgery, Lenox Hill Hospital, New York, NY, U.S.A.;Brain Tumor Center, Department of Neurosurgery, Lenox Hill Hospital, New York, NY, U.S.A.;Department of Radiology, Division of Neuroradiology, Lenox Hill Hospital, New York, NY, U.S.A.;Department of Radiology, Division of Neuroradiology, Lenox Hill Hospital, New York, NY, U.S.A.;Brain Tumor Center, Department of Neurosurgery, Lenox Hill Hospital, New York, NY, U.S.A.;Brain Tumor Center, Department of Neurosurgery, Lenox Hill Hospital, New York, NY, U.S.A.;Brain Tumor Center, Department of Neurosurgery, Lenox Hill Hospital, New York, NY, U.S.A.;Brain Tumor Center, Department of Neurosurgery, Lenox Hill Hospital, New York, NY, U.S.A.;Brain Tumor Center, Department of Neurosurgery, Lenox Hill Hospital, New York, NY, U.S.A.;Brain Tumor Center, Department of Neurosurgery, Lenox Hill Hospital, New York, NY, U.S.A.;Brain Tumor Center, 450 Lakeville Road, Lake Success, NY, U.S.A.;Brain Tumor Center, Department of Neurosurgery, Lenox Hill Hospital, New York, NY, U.S.A.;Brain Tumor Center, Department of Neurosurgery, Lenox Hill Hospital, New York, NY, U.S.A.",
"authors": "Kulason|Kay O|KO|;Schneider|Julia R|JR|;Chakraborty|Shamik|S|;Filippi|Christopher G|CG|;Pramanik|Bidyut|B|;Wong|Tamika|T|;Fralin|Sherese|S|;Tan|Karissa|K|;Ray|Ashley|A|;Alter|Rachel A|RA|;Ortiz|Rafael|R|;Demopoulos|Alexis|A|;Langer|David J|DJ|;Boockvar|John A|JA|",
"chemical_list": "D018906:Antineoplastic Agents, Alkylating; D000074322:Antineoplastic Agents, Immunological; D008353:Mannitol; D003606:Dacarbazine; D000068818:Cetuximab; D000077204:Temozolomide",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1359-4117",
"issue": "12(3)",
"journal": "Journal of experimental therapeutics & oncology",
"keywords": "Cetuximab; EGFR amplified; GBM; Intra arterial; SIACI; blood brain barrier disruption; glioblastoma multiforme; mannitol",
"medline_ta": "J Exp Ther Oncol",
"mesh_terms": "D015901:Angiography, Digital Subtraction; D018906:Antineoplastic Agents, Alkylating; D000074322:Antineoplastic Agents, Immunological; D001812:Blood-Brain Barrier; D001932:Brain Neoplasms; D002533:Cerebral Angiography; D000068818:Cetuximab; D059186:Chemoradiotherapy, Adjuvant; D017024:Chemotherapy, Adjuvant; D003399:Craniotomy; D003606:Dacarbazine; D019583:Dose Fractionation, Radiation; D005260:Female; D005909:Glioblastoma; D006801:Humans; D007261:Infusions, Intra-Arterial; D008279:Magnetic Resonance Imaging; D008353:Mannitol; D008875:Middle Aged; D000077204:Temozolomide; D016896:Treatment Outcome",
"nlm_unique_id": "9604933",
"other_id": null,
"pages": "223-229",
"pmc": null,
"pmid": "29790314",
"pubdate": "2018-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Superselective intraarterial cerebral infusion of cetuximab with blood brain barrier disruption combined with Stupp Protocol for newly diagnosed glioblastoma.",
"title_normalized": "superselective intraarterial cerebral infusion of cetuximab with blood brain barrier disruption combined with stupp protocol for newly diagnosed glioblastoma"
} | [
{
"companynumb": "US-TEVA-2018-US-905563",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ACETAMINOPHEN"
},
"drugadditional": "3",
... |
{
"abstract": "Malignancy is known to be one of the predisposing factors of cerebral venous thrombosis (CVT) due to its hypercoagulable state. CVT is a rare disorder which can lead to frequent misdiagnoses of brain metastases in such cases. We report here the case of a 35-year-old female with metastatic colon adenocarcinoma presenting with sudden neurological symptoms. Brain MRI and magnetic resonance venography confirmed the presence of CVT. She was treated with low molecular weight heparin followed by warfarin. She recovered and is doing well on warfarin after 5 months of diagnosis of CVT. CVT should be strongly suspected as a cause of neurological dysfunction in any case of disseminated malignancy including colon adenocarcinoma. Rapid diagnosis and initiation of therapy should be considered because of its favourable outcome.",
"affiliations": "Department of Medical Oncology, Dr. B. R. A. Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi 110029, India.",
"authors": "Iqbal|Nida|N|;Sharma|Atul|A|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1155/2013/109412",
"fulltext": "\n==== Front\nCase Rep Oncol MedCase Rep Oncol MedCRIM.ONCMEDCase Reports in Oncological Medicine2090-67062090-6714Hindawi Publishing Corporation 10.1155/2013/109412Case ReportCerebral Venous Thrombosis: A Mimic of Brain Metastases in Colorectal Cancer Associated with a Better Prognosis 0000-0002-0240-1575Iqbal Nida Sharma Atul *Department of Medical Oncology, Dr. B. R. A. Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi 110029, India*Atul Sharma: atul1@hotmail.comAcademic Editors: Y.-F. Jiao and Y. Yamada\n\n2013 13 6 2013 2013 1094126 5 2013 30 5 2013 Copyright © 2013 N. Iqbal and A. Sharma.2013This 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.Malignancy is known to be one of the predisposing factors of cerebral venous thrombosis (CVT) due to its hypercoagulable state. CVT is a rare disorder which can lead to frequent misdiagnoses of brain metastases in such cases. We report here the case of a 35-year-old female with metastatic colon adenocarcinoma presenting with sudden neurological symptoms. Brain MRI and magnetic resonance venography confirmed the presence of CVT. She was treated with low molecular weight heparin followed by warfarin. She recovered and is doing well on warfarin after 5 months of diagnosis of CVT. CVT should be strongly suspected as a cause of neurological dysfunction in any case of disseminated malignancy including colon adenocarcinoma. Rapid diagnosis and initiation of therapy should be considered because of its favourable outcome.\n==== Body\n1. Introduction\nCerebral venous thrombosis (CVT), that is, any thrombosis that occurs in intracranial veins or sinuses, [1] is a rare disorder affecting approximately 5 persons per million per year with huge regional variations [2]. It accounts for approximately 0.5% of all the strokes and most commonly affects young adults. Many disorders can either cause or just predispose to CVT. They include medical, surgical, and obstetrical causes of deep vein thrombosis, genetic and acquired prothrombotic disorders, cancer and hematological disorders, inflammatory systemic disorders, pregnancy and puerperium, infections, and local causes such as tumors, arteriovenous malformations, trauma, central nervous system infections, and infections of the ear, sinus, mouth, face, and neck [1]. Cerebral venous thrombosis has a wide spectrum of clinical manifestations and modes of onset that may mimic many other neurological disorders and lead to frequent misdiagnosis and delay in treatment. Before the advent of computed tomography (CT) and magnetic resonance imaging (MRI), CVT was usually diagnosed at autopsy. It has got a favourable outcome with case fatality of less than 10% [1]. Cerebral venous thrombosis is a rare paraneoplastic syndrome.\n\nHerein, we report a case of metastatic colorectal cancer who developed cerebral venous thrombosis while on chemotherapy.\n\n2. Case Report\nA 35-year-old female, a diagnosed case of metastatic colorectal adenocarcinoma, (Figure 1) was on palliative chemotherapy with capecitabine and irinotecan (CAPIRI) when she presented with the history of sudden onset of headache, blurring of vision, weakness of left side of body, and multiple episodes of vomitings. She had no history of hypertension, diabetes, pregnancy or use of oral contraceptives. On physical examination, she was conscious, oriented, and having mild dysarthria and grade 3 power of left side of the body. There were no signs of meningismus. Fundus examination revealed bilateral papilledema. Contrast enhanced CT scan of head revealed mild edema in right frontal lobe. Brain MRI revealed hemorrhagic infarct in right parietal lobe (Figure 2(a)), and magnetic resonance (MR) venography revealed occlusion of superior and inferior sagittal sinuses, both transverse sinuses, and bilateral sigmoid sinuses with thrombus (Figures 2(b) and 2(c)). Laboratory parameters revealed a normal complete blood count, sedimentation rate, blood sugar, lipid profile, and kidney and liver function tests. Electrocardiogram and echocardiography were also normal.\n\nTo rule out any coexisting prothrombotic condition, homocysteine levels, protein C, protein S, factor V, and antithrombin III were done which were within normal limits. For disease assessment, contrast enhanced CT scan of abdomen and pelvis was done which revealed the disease to be in complete remission. She was started on low molecular weight heparin. There was marked improvement in her symptoms, and she was discharged in stable condition on oral warfarin. She is doing well even after 5 months from the diagnosis of cerebral venous thrombosis.\n\n3. Discussion\nCerebrovascular events may be the first clinical manifestations in patients with underlying malignancy or may develop subsequently during the course. Systemic thrombosis like deep vein thrombosis or pulmonary embolism is well recognized in cancer patients, although CVTs are uncommon in cancer. Potential mechanisms for an association of cancer with cerebral venous thrombosis (CVT) include direct tumor compression, tumor invasion of cerebral sinuses, the hypercoagulable state associated with cancer, or the chemotherapeutic side effects [3–5]. Cerebral venous thrombosis has been reported to be associated with various cancers like squamous cell cervical cancer [6], non-Hodgkin's lymphoma [7], and breast cancer [8]. Cerebral sinus venous thrombosis associated with chemotherapy has so far been described in a patient with colon cancer treated with FOLFIRI/bevacizumab [9], in a patient with a brain tumor treated with temozolomide, focal brain radiotherapy plus bevacizumab [10], in an adolescent with Ewing sarcoma treated with cisplatin, ifosfamide, adriamycin, and vincristine [11], and in two patients of nonseminomatous germ cell tumor treated with cisplatin, bleomycin, and etoposide [12]. Like our case, a case of cerebral venous thrombosis in a patient of rectal cancer has been described, but that was associated with cerebral metastases also [13].\n\nCerebral venous thrombosis should always be kept in the differential diagnosis of any form of neurological symptoms in a patient with cancer even without cerebral metastases and even if the disease is in complete remission as in our case. As CVT has got a favourable outcome unlike other neurological syndromes, early diagnosis with MRI/MR venography and rapid institution of therapy with heparin should be considered.\n\nConflict of Interests\n The authors declare that they have no conflict of interests.\n\nFigure 1 H&E of colon showing invasive adenocarcinoma. \n\nFigure 2 Brain MRI and magnetic resonance (MR) venography (AP view). (a) Hemorrhagic infarction was noted in the right parietal lobe on T2-weighed imaging. (b), (c) MR venography showed occlusion of the superior and inferior sagittal sinuses, both transverse sinuses, and bilateral sigmoid sinuses.\n==== Refs\n1 Ferro JM Canhão P Stam J Bousser M-G Barinagarrementeria F Prognosis of cerebral vein and dural sinus thrombosis: results of the international study on cerebral vein and dural sinus thrombosis (ISCVT) Stroke 2004 35 3 664 670 2-s2.0-1442274806 14976332 \n2 Bousser M-G Ferro JM Cerebral venous thrombosis: an update The Lancet Neurology 2007 6 2 162 170 2-s2.0-33846264044 17239803 \n3 Raizer JJ DeAngelis LM Cerebral sinus thrombosis diagnosed by MRI and MR venography in cancer patients Neurology 2000 54 6 1222 1226 2-s2.0-0034724249 10746588 \n4 Rogers LR Cerebrovascular complications in patients with cancer Seminars in Neurology 2004 24 4 453 460 2-s2.0-11344291348 15637656 \n5 Astudillo L Lacroix-Triki M Cousin F Chevreau C A rarely diagnosed paraneoplastic syndrome: cerebral venous thrombosis Revue de Medecine Interne 2007 28 10 716 717 2-s2.0-34648846039 17587466 \n6 López-Peláez MF Millán JM De Vergas J Fatal cerebral venous sinus thrombosis as major complication of metastatic cervical mass: computed tomography and magnetic resonance findings Journal of Laryngology and Otology 2000 114 10 798 801 2-s2.0-0033727532 11127157 \n7 Enevoldson TP Ross Russell RW Cerebral venous thrombosis: new causes for an old syndrome? Quarterly Journal of Medicine 1990 77 284 1255 1275 2-s2.0-0025633775 2149767 \n8 Soda T Edagawa K Tsuji K Dehara M Nakajima Y Ito M A case of deep cerebral venous thrombosis associated with breast cancer Clinical Neurology 2008 48 9 646 650 2-s2.0-58949088372 19048947 \n9 Ozen A Cicin I Sezer A Dural sinus vein thrombosis in a patient with colon cancer treated with FOLFIRI/bevacizumab Journal of Cancer Research and Therapeutics 2009 5 2 130 132 2-s2.0-67749098105 19542672 \n10 Vargo JA Snelling BM Ghareeb ER Dural venous sinus thrombosis in anaplastic astrocytoma following concurrent temozolomide and focal brain radiotherapy plus bevacizumab Journal of Neuro-Oncology 2011 104 2 595 598 2-s2.0-80052631833 21221711 \n11 Unal E Yazar A Koksal Y Caliskan U Paksoy Y Kalkan E Cerebral venous sinus thrombosis in an adolescent with Ewing sarcoma Child’s Nervous System 2008 24 9 983 986 2-s2.0-49349088486 \n12 Papet C Gutzeit A Pless M Two cases of cerebral sinus venous thrombosis following chemotherapy for non-seminomatous germ cell tumor Case Reports in Oncology 2011 4 3 555 559 2-s2.0-84855317905 22220149 \n13 Tóth L Szakáll S Káposzta Z Udvardy M Cerebral deep vein thrombosis associated with rectal cancer Orvosi Hetilap 2000 141 46 2493 2496 2-s2.0-0034642130 11126682\n\n",
"fulltext_license": "CC BY",
"issn_linking": null,
"issue": "2013()",
"journal": "Case reports in oncological medicine",
"keywords": null,
"medline_ta": "Case Rep Oncol Med",
"mesh_terms": null,
"nlm_unique_id": "101581035",
"other_id": null,
"pages": "109412",
"pmc": null,
"pmid": "23840992",
"pubdate": "2013",
"publication_types": "D016428:Journal Article",
"references": "10746588;15637656;14976332;19542672;11126682;17587466;11127157;2149767;22220149;19048947;18481071;17239803;21221711",
"title": "Cerebral venous thrombosis: a mimic of brain metastases in colorectal cancer associated with a better prognosis.",
"title_normalized": "cerebral venous thrombosis a mimic of brain metastases in colorectal cancer associated with a better prognosis"
} | [
{
"companynumb": "IN-PFIZER INC-2021226642",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "IRINOTECAN HYDROCHLORIDE"
},
"drugadditional":... |
{
"abstract": "OBJECTIVE\nTo evaluate the incidence of new cases of psoriatic arthritis (PsA) in patients with plaque psoriasis receiving biologic drugs.\n\n\nMETHODS\nA retrospective study was performed on 434 psoriatic patients under biologic treatment, attending the Psoriasis Care Centre of Dermatology at the University Federico II of Naples from January 2011 to November 2015. As part of the routine clinical practice, assessment of disease activity was made at baseline, and every 3 months. PsA diagnosis was performed by a rheumatologist through clinical examination, evaluation of the CASPAR criteria, laboratory and radiological assessment.\n\n\nRESULTS\nOn the basis of the inclusion and exclusion criteria, we reviewed and analysed the clinical data of 327 patients with plaque psoriasis. The biologic drugs adalimumab, etanercept, infliximab and ustekinumab were prescribed to 116 (35.5%), 88 (27.0%), 27 (8.2%), and 96 (29.3%), respectively. We found that 22 out of 327 patients with plaque psoriasis developed PsA during treatment with biologic drugs. In particular, 6 (27.2%) PsA patients were under etanercept therapy, 10 (45.4%) under adalimumab, 4 (18.2%) under ustekinumab and 2 (9.2%) under infliximab.\n\n\nCONCLUSIONS\nThe results of this study show that in several psoriasis patients, biologic therapy may not be sufficient to prevent the onset of articular involvement. In most of the verified PsA cases, arthritis occurred in concomitance with severe cutaneous involvement.",
"affiliations": "Dermatology Unit, Department of Clinical Medicine and Surgery, University Federico II, Naples, Italy.;Dermatology Unit, Department of Clinical Medicine and Surgery, University Federico II, Naples, Italy.;Rheumatology Unit, Department of Clinical Medicine and Surgery, University Federico II, Naples, Italy.;Rheumatology Unit, Department of Clinical Medicine and Surgery, University Federico II, Naples, Italy.;Dermatology Unit, Department of Clinical Medicine and Surgery, University Federico II, Naples, Italy.;Dermatology Unit, Department of Clinical Medicine and Surgery, University Federico II, Naples, Italy.;Dermatology Unit, Department of Clinical Medicine and Surgery, University Federico II, Naples, Italy.;Rheumatology Unit, Department of Clinical Medicine and Surgery, University Federico II, Naples, Italy. rscarpa@unina.it.",
"authors": "Napolitano|Maddalena|M|;Balato|Nicola|N|;Caso|Francesco|F|;Costa|Luisa|L|;Megna|Matteo|M|;Cirillo|Teresa|T|;Balato|Anna|A|;Scarpa|Raffaele|R|",
"chemical_list": "D018501:Antirheumatic Agents; D000069285:Infliximab; D000069549:Ustekinumab; D000068879:Adalimumab; D000068800:Etanercept",
"country": "Italy",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0392-856X",
"issue": "35(1)",
"journal": "Clinical and experimental rheumatology",
"keywords": null,
"medline_ta": "Clin Exp Rheumatol",
"mesh_terms": "D000068879:Adalimumab; D000328:Adult; D000368:Aged; D018501:Antirheumatic Agents; D015535:Arthritis, Psoriatic; D018450:Disease Progression; D000068800:Etanercept; D005260:Female; D006801:Humans; D015994:Incidence; D000069285:Infliximab; D008297:Male; D008875:Middle Aged; D011565:Psoriasis; D012189:Retrospective Studies; D000069549:Ustekinumab",
"nlm_unique_id": "8308521",
"other_id": null,
"pages": "137-140",
"pmc": null,
"pmid": "27749221",
"pubdate": "2017",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Paradoxical onset of psoriatic arthritis during treatment with biologic agents for plaque psoriasis: a combined dermatology and rheumatology clinical study.",
"title_normalized": "paradoxical onset of psoriatic arthritis during treatment with biologic agents for plaque psoriasis a combined dermatology and rheumatology clinical study"
} | [
{
"companynumb": "IT-JNJFOC-20170217218",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "USTEKINUMAB"
},
"drugadditional": null,
... |
{
"abstract": "Gemcitabine therapy has been associated with radiation recall reactions when used in the treatment of carcinoma. We report four cases of hemodynamically significant pericardial effusion in patients with refractory lymphoma who were receiving gemcitabine, all of whom had a history of mediastinal radiation without subcarinal blocking. All four patients had pericardial abnormalities on echocardiography prior to receiving gemcitabine. Two patients required emergent surgical procedures. Of twenty other patients in our practice who received gemcitabine for refractory lymphoma without developing pericardial effusion, none had received prior direct radiation to the heart. The overall response rate of these 24 refractory lymphomas to gemcitabine-containing regimens was 46%. Although gemcitabine-based regimens have clear efficacy in refractory lymphoma, prior mediastinal radiation without subcarinal blocking may be a relative contraindication, especially in the presence of pericardial abnormalities on echocardiography. Physicians should be aware of the potential for developing a gemcitabine-induced radiation recall reaction resulting in hemodynamically significant pericardial effusion.",
"affiliations": "Abramson Cancer Center, Hospital of the University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA, 19104, USA.",
"authors": "Vogl|Dan T|DT|;Glatstein|Eli|E|;Carver|Joseph R|JR|;Schuster|Stephen J|SJ|;Stadtmauer|Edward A|EA|;Luger|Selina|S|;Nasta|Sunita D|SD|;Porter|David L|DL|;Elstrom|Rebecca|R|;Tsai|Donald E|DE|",
"chemical_list": "D003841:Deoxycytidine; C056507:gemcitabine",
"country": "United States",
"delete": false,
"doi": "10.1080/10428190500158649",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1026-8022",
"issue": "46(9)",
"journal": "Leukemia & lymphoma",
"keywords": null,
"medline_ta": "Leuk Lymphoma",
"mesh_terms": "D000328:Adult; D002305:Cardiac Tamponade; D003841:Deoxycytidine; D005260:Female; D006321:Heart; D006801:Humans; D008223:Lymphoma; D008297:Male; D008482:Mediastinum; D008875:Middle Aged; D010490:Pericardial Effusion; D011832:Radiation Injuries",
"nlm_unique_id": "9007422",
"other_id": null,
"pages": "1313-20",
"pmc": null,
"pmid": "16109609",
"pubdate": "2005-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Gemcitabine-induced pericardial effusion and tamponade after unblocked cardiac irradiation.",
"title_normalized": "gemcitabine induced pericardial effusion and tamponade after unblocked cardiac irradiation"
} | [
{
"companynumb": "US-PFIZER INC-2020437192",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "GEMCITABINE HYDROCHLORIDE"
},
"drugadditional"... |
{
"abstract": "Cytomegalovirus (CMV) is the most common opportunistic pathogen affecting renal transplant recipients, especially in the first months. CMV-seropositive renal transplant recipients (CMV R+) are at intermediate risk for CMV disease, but this risk is enhanced among CMV R+ receiving T-cell depleting induction, compared to CMV R+ receiving non-depleting induction. In this second group, data in favor of prophylactic antiviral treatment with valganciclovir to reduce CMV disease is sparse. In this retrospective and multicentric trial, we included 372 CMV R+ transplanted between January 2012 and April 2015 and receiving non-depleting induction. During the first year following transplantation, CMV disease occurred in 5/222 patients (2.25%) in the prophylaxis group and 9/150 (6%) in the no-prophylaxis group (difference +3.7; 95% CI: 0.5-8; P = .002 for non-inferiority). The incidence of allograft rejection and other infectious diseases was similar between the two groups. Graft and patient survival were similar at the end of follow-up. In conclusion, the absence of prophylaxis did not appear to have a deleterious effect for CMV diseases among CMV R+ receiving non-depleting induction.",
"affiliations": "Service de Néphrologie, CHU Pontchaillou, Rennes, France.;Service de Pharmacologie clinique et biologique, CHU Pontchaillou, Rennes, France.;Institut de Transplantation Urologie-Néphrologie, Centre Hospitalier Universitaire de Nantes, Nantes, France.;Service de Néphrologie et Immunologie Clinique, Centre Hospitalier Universitaire de Tours, Tours, France.;Service de Néphrologie, Hémodialyse et Transplantation Rénale, Centre Hospitalier Universitaire de Poitiers, Poitiers, France.;Service de Néphrologie, Centre Hospitaliser de Brest, Université de Bretagne Occidentale, Brest, France.;Service de Nephrologie-Dialyse-Transplantation, Centre Hospitalier Universitaire d'Angers, Angers, France.;Service de Néphrologie, CHU Pontchaillou, Rennes, France.;Service de Néphrologie, CHU Pontchaillou, Rennes, France.",
"authors": "Boulay|Hugoline|H|https://orcid.org/0000-0002-3600-1350;Oger|Emmanuel|E|;Cantarovich|Diego|D|;Gatault|Philippe|P|;Thierry|Antoine|A|;Le Meur|Yannick|Y|https://orcid.org/0000-0001-8913-415X;Duveau|Agnès|A|;Vigneau|Cécile|C|;Lorcy|Nolwenn|N|",
"chemical_list": "D000998:Antiviral Agents; D015774:Ganciclovir",
"country": "Denmark",
"delete": false,
"doi": "10.1111/tid.13541",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1398-2273",
"issue": "23(3)",
"journal": "Transplant infectious disease : an official journal of the Transplantation Society",
"keywords": "CMV disease prevention; kidney transplantation; valganciclovir",
"medline_ta": "Transpl Infect Dis",
"mesh_terms": "D000998:Antiviral Agents; D003587:Cytomegalovirus; D003586:Cytomegalovirus Infections; D015774:Ganciclovir; D006084:Graft Rejection; D006801:Humans; D016030:Kidney Transplantation; D012189:Retrospective Studies; D013601:T-Lymphocytes; D016896:Treatment Outcome",
"nlm_unique_id": "100883688",
"other_id": null,
"pages": "e13541",
"pmc": null,
"pmid": "33270341",
"pubdate": "2021-06",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Among CMV-positive renal transplant patients receiving non-T-cell depleting induction, the absence of CMV disease prevention is a safe strategy: A retrospective cohort of 372 patients.",
"title_normalized": "among cmv positive renal transplant patients receiving non t cell depleting induction the absence of cmv disease prevention is a safe strategy a retrospective cohort of 372 patients"
} | [
{
"companynumb": "FR-CHEPLA-C20211829_02",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "BASILIXIMAB"
},
"drugadditional": null,
... |
{
"abstract": "A 52-year-old African American male with a long history of poorly controlled hypertension presented to the emergency department (ED) with two days of genital edema and pain. During ED work-up, the patient developed sudden onset of non-pitting, non-pruritic, and non-urticarial upper lip edema. Review of his antihypertensive medication list revealed that he normally took benazepril, highly suggestive of a diagnosis of angiotensin-converting-enzyme inhibitor-related angioedema (ACEI-RA). We present the first reported case of penile ACEI-RA that progressed to involve the oropharynx. The ED management of the condition and some of the newer treatment options available for ACEI-RA is also briefly discussed.",
"affiliations": "Keck School of Medicine of the University of Southern California, Los Angeles County + University of Southern California (LAC+USC), Department of Emergency Medicine, Los Angeles, California.;Keck School of Medicine of the University of Southern California, Los Angeles County + University of Southern California (LAC+USC), Department of Emergency Medicine, Los Angeles, California.;Keck School of Medicine of the University of Southern California, Los Angeles County + University of Southern California (LAC+USC), Department of Emergency Medicine, Los Angeles, California.",
"authors": "Wagner|Jonathan G|JG|;Bench|Elias M|EM|;Plantmason|Lee|L|",
"chemical_list": "D000806:Angiotensin-Converting Enzyme Inhibitors; D001552:Benzazepines; C044946:benazepril",
"country": "United States",
"delete": false,
"doi": "10.5811/westjem.2015.8.28061",
"fulltext": "\n==== Front\nWest J Emerg MedWest J Emerg MedWestJEMWestern Journal of Emergency Medicine1936-900X1936-9018Department of Emergency Medicine, University of California, Irvine School of Medicine 10.5811/westjem.2015.8.28061wjem-16-1185Diagnostic AcumenCase ReportAn Unusual Case of Angiotensin-Converting-Enzyme Inhibitor-Related Penile Angioedema with Evolution to the Oropharynx Wagner Jonathan G. MDBench Elias M. BSPlantmason Lee MD, MPHKeck School of Medicine of the University of Southern California, Los Angeles County + University of Southern California (LAC+USC), Department of Emergency Medicine, Los Angeles, CaliforniaAddress for Correspondence: Jonathan G. Wagner, MD, Keck School of Medicine of the University of Southern California, Los Angeles County + University of Southern California (LAC+USC), Department of Emergency Medicine, 1200 N. State Street, Room 1011, Los Angeles, CA 90033. Email: jwagner@usc.edu.12 2015 18 11 2015 16 7 1185 1187 12 7 2015 19 8 2015 Copyright © 2015 Wagner et al.2015This is an open access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) License. See: http://creativecommons.org/licenses/by/4.0/A 52-year-old African American male with a long history of poorly controlled hypertension presented to the emergency department (ED) with two days of genital edema and pain. During ED work-up, the patient developed sudden onset of non-pitting, non-pruritic, and non-urticarial upper lip edema. Review of his antihypertensive medication list revealed that he normally took benazepril, highly suggestive of a diagnosis of angiotensin-converting-enzyme inhibitor-related angioedema (ACEI-RA). We present the first reported case of penile ACEI-RA that progressed to involve the oropharynx. The ED management of the condition and some of the newer treatment options available for ACEI-RA is also briefly discussed.\n==== Body\nINTRODUCTION\nAngioedema, one of the true airway emergencies, is a non-pitting, often asymmetric swelling of subcutaneous or submucosal tissues. Typically isolated to an oropharyngeal distribution, it can also affect the gastrointestinal tract, extremities, and genitalia.1 Angiotensin-converting-enzyme inhibitor-related angioedema (ACEI-RA) is the most common type of angioedema and can occur in both long- and short-term use of angiotensin-converting-enzyme inhibitor (ACEI) medications.1 Though ACEI-RA is well-described in the literature and not a rare disorder, angioedema of the penis has only been reported in three previous publications (four total cases overall).2–4 In each case, the symptoms were isolated to the genitalia without additional sites of involvement. Here we present the first known case of a patient with delayed-onset ACEI-RA that was initially isolated to the genitalia with evolvement to the oropharynx, and discuss possible etiologies and treatment options for emergency department (ED) management.\n\nCASE REPORT\nA 52-year-old African-American male with a past medical history of poorly controlled hypertension (due to intermittent medication compliance), alcohol abuse, and alcohol withdrawal was referred to the ED for two days of penile and scrotal edema and pain. The patient stated that he noted the non-pruritic, non-erythematous diffuse genital swelling two days prior, but had delayed seeking treatment as he assumed it would self-resolve. Due to increasing pain, he visited his primary care practitioner (PCP), who then immediately referred him to the ED for further evaluation. On interview, he denied recent sexual intercourse, allergies to latex/condoms, penile rings, painful erections, lotions or creams applied to the genital area, traumatic sexual injuries, penile discharge, or history of sexually transmitted infections. Additionally, the patient also denied any other new exposures, known allergies, history of similar symptoms that would suggest angioedema to the face, extremities, or genitals, or a family history of recurrent angioedema. The patient stated that he only knew the name of two of his five prescribed antihypertensive agents, hydrochlorothiazide and benazepril, both of which he had taken for at least 10 years. His benazepril dose had recently been increased from 20mg to 40mg, but he admitted to not taking any of his anti-hypertensive medications on the day of his ED visit. He also disclosed a daily average alcohol intake of “one gallon of vodka per day” and had consumed one pint that morning. A review of systems was negative for any other complaints, including fevers, chills, dysuria, hematuria, urinary retention, abdominal or back pain, respiratory symptoms, any sensation of facial, oral, or pharyngeal swelling, change in voice, or difficulty swallowing.\n\nOn physical examination, blood pressure was significantly elevated at 198/112mmHg, pulse was 87 beats per min, respiratory rate was 20 breaths per min, oral temperature was recorded at 98.4°F, and room air pulse oximetry saturation of 97%. His skin exam revealed no rashes, urticaria, or discolorations. The facial, oropharyngeal, cardiopulmonary, and abdominal examinations were within normal limits. Examination of the genitalia revealed edema isolated to the scrotum and uncircumcised penis. The edema was soft and non-pitting with no excessive warmth, erythema, induration, or other signs of local infection. The foreskin was partially retractable with no evidence of paraphimosis or balanoposthitis. The bladder was non-distended, there were no hernias, and scrotal contents were of normal size and consistency with no epididymal tenderness. There was no penile discharge or inguinal lymphadenopathy. The extremities did not exhibit any edema, erythema, or skin changes.\n\nED work-up revealed a normal urinalysis with no hematuria, proteinuria, or evidence of infection. The patient’s complete blood count, comprehensive metabolic panel, and prothrombin time were within normal limits and did not exhibit evidence of hypoalbuminemia, increased creatinine, or impaired hepatic function. The patient also did not exhibit any symptoms or physical exam findings suggestive of congestive heart failure, although an incidental right middle lobe pulmonary nodule was noted on the patient’s chest radiograph. The preliminary read of the testicular ultrasound described a small hydrocele, but no evidence of torsion, abscess, tumor, or varicocele. The patient’s blood pressure improved to 170/98 with subsequent stay in the ED and upon restarting his home dose of hydrochlorothiazide.\n\nWhile awaiting the formal read of his scrotal ultrasound, the patient developed anterior oropharyngeal edema isolated to his upper lip. On examination, there appeared to be no airway involvement and the patient denied change in voice, difficulty swallowing, or shortness of breath. Given the acute onset of oropharyngeal edema, the patient was given diphenhydramine 50mg IV, famotidine 40mg IV, and methylprednisolone 125mg IV for possible allergic reaction versus acute onset of angioedema. He was observed in the ED for six hours, without progression or significant improvement in symptoms, and discharged home with explicit instructions to discontinue his benazepril and to avoid all ACEIs and angiotensin receptor blockers (ARBs). It was recommended that the patient follow up with his PCP as soon as possible for medication reconciliation to optimize his blood pressure control and to return to the ED for any of the following symptoms: increased oropharyngeal swelling, respiratory difficulty, difficulty urinating, worsening penile pain, or paraphimosis. Four days later, he followed up with his PCP and his symptoms had completely resolved.\n\nDISCUSSION\nACEI-RA was first reported in 19845 and is now the leading cause of drug-induced angioedema, accounting for up to 30% of angioedema cases presenting to the ED.6 The incidence of angioedema in patients taking ACEI has been estimated at 0.68%,7 most commonly affecting the face, lips, tongue, and upper airway. Infrequently, it involves the gastrointestinal tract, extremities, and very rarely, the genitalia.1 While the majority of cases of ACEI-RA present within the first week of exposure, many patients will experience symptoms after years of ACEI therapy.8, 9 The most important risk factor for ACEI-RA is African descent, followed by previous angioedema episode, age >65 years, nonsteroidal anti-inflammatory drug (NSAID) use, female sex, history of drug-related rash, and seasonal allergies.1 Angioedema is divided into mast-cell mediated and bradykinin-associated angioedema (ACEI-RA), with a lack of pruritus or urticaria as the hallmark of bradykinin-associated angioedema.\n\nA clinical diagnosis of ACEI-RA should be considered in a patient with angioedema to a characteristic anatomic site, without pruritus or urticaria, and a history of ACEI exposure. In all patients who present to the ED with swelling to an affected area, it is paramount to differentiate angioedema from other causes of soft-tissue swelling (i.e. cellulitis, contact dermatitis, low oncotic states, etc.). ACEI-RA should be distinguished from mast-cell associated angioedema as ACEI-RA is minimally responsive to antihistamines, glucocorticoids, epinephrine, and lacks allergic symptoms.10\n\nThe mainstay of treatment for ACEI-RA, no matter the affected location, is the prompt discontinuation and future avoidance of all ACEIs, assessment of the airway, and supportive care. In those with suspected oropharyngeal involvement, the airway should be evaluated emergently, as up to 10% of patients will require intubation.11 In patients with progressive symptoms or those who will require advanced airway management imminently, medical management should be attempted. Icatibant, a synthetic bradykinin B2 receptor antagonist, has been shown to be effective for severe ACEI-RA if given within the first 10 hours of symptom onset.12 Medications approved for hereditary angioedema should also be considered in severe cases of ACEI-RA in which intubation is imminent. These include fresh frozen plasma, purified C1 inhibitor concentrate, and ecallantide.1 Patients with ACEI-RA should be given strict precautions to avoid all ACEIs in the future, as continued use is associated with increased recurrence and severity.13 The use of ARBs is controversial, as patients with ACEI-RA have a 1.5–10% risk of recurrent angioedema when switched to ARBs.14, 15 Those with penile angioedema should be instructed to avoid retraction of the foreskin to reduce the risk of paraphimosis.3\n\nImportantly, as seen in our case, penile angioedema can be associated with oropharynx involvement, and ED physicians should perform a thorough examination of the upper airway and educate their patients on the possibility of this potentially life-threatening complication. Patients in whom there is no disease progression, no involvement of the larynx, tongue, or elevation of the floor of the mouth can be discharged safely if they express understanding of the possible complications of ACEI-RA, have the ability to return promptly if necessary, and have follow up with a primary provider.\n\nThis case report, as well as the three previous publications describing genital angioedema as a presentation of ACEI-RA, demonstrates the importance of including angioedema in the differential for new onset penile or scrotal swelling. This case is the first to show that isolated genital angioedema can progress to involve the oropharynx, further underscoring the importance of airway evaluation in all patients in whom ACEI-RA is suspected and observation to ensure there are no additional complications. Following diagnosis, physicians can reassure patients that they are experiencing a drug reaction that is likely to resolve quickly without long-term complications, reducing significant anxiety and distress associated with acute swelling of the genitalia.\n\nSection Editor: Rick A. McPheeters, DO\n\nFull text available through open access at http://escholarship.org/uc/uciem_westjem\n\nConflicts of Interest: By the WestJEM article submission agreement, all authors are required to disclose all affiliations, funding sources and financial or management relationships that could be perceived as potential sources of bias. The authors disclosed none.\n==== Refs\nREFERENCES\n1 Lewis L Angioedema: etiology, pathophysiology, current and emerging therapies J Emerg Med 2013 45 789 23992848 \n2 Henson EB Bess DT Abraham L Penile angioedema possibly related to lisinopril Am J Health Syst Pharm 1999 56 1773 10512511 \n3 McCabe J Stork C Mailloux D Penile angioedema associated with use of angiotensin-converting-enzyme inhibitors and angiotensin II blockers Am J Health Syst Pharm 2008 65 420 18281733 \n4 Miller DG Sweis RT Toerne TS Penile angioedema developing after 3 years of ACEI therapy J Emerg Med 2012 43 273 22560272 \n5 Jett GK Captopril-induced angioedema: first report Ann Emerg Med 1984 13 489 6375478 \n6 Banerji A Clark S Blanda M Multicenter study of patients with angiotensin-converting-enzyme inhibitor-induced angioedema who present to the emergency department Ann Allergy Asthma Immunol 2008 100 327 18450117 \n7 Kostis JB Packer M Black HR Omapatrilat and enalapril in patients with hypertension: the Omapatrilat Cardiovascular Treatment vs. Enalapril (OCTAVE) trial Am J Hypertens 2004 17 103 14751650 \n8 Sabroe RA Black AK Angiotensin-converting enzyme (ACE) inhibitors and angio-oedema Br J Dermatol 1997 136 153 9068723 \n9 Malde B Regalado J Greenberger PA Investigation of angioedema associated with the use of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers Ann Allergy Immunol 2007 98 57 \n10 Bas M Greve J Stelter K Therapeutic efficacy of icatibant in angioedema induced by angiotensin-converting enzyme inhibitors: a case series Ann Emerg Med 2010 56 278 20447725 \n11 Grant NN Deeb ZE Chia SH Clinical experience with angiotensin-converting enzyme inhibitor-induced angioedema Otolaryngol Head Neck Surg 2007 137 931 18036423 \n12 Bas M Greve J Stelter K A randomized trial of icatibant in ACE-inhibitor-induced angioedema N Engl J Med 2015 372 418 25629740 \n13 Beltrami L Zanichelli A Zingale L Long-term follow-up of 111 patients with angiotensin-converting-enzyme inhibitor-related angioedema J Hypertens 2011 29 2273 21970934 \n14 Haymore BR Yoon J Mikita CP Risk of angioedema with angiotensin receptor blockers in patients with prior angioedema associated with angiotensin-converting-enzyme inhibitors: a meta-analysis Ann Allerg Asthma Immunol 2008 101 495 \n15 Beavers CJ Dunn SP Macaulay TE The role of angiotensin receptor blockers in patients with angiotensin-converting-enzyme inhibitor-induced angioedema Ann Pharmacotherap 2011 45 520\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1936-900X",
"issue": "16(7)",
"journal": "The western journal of emergency medicine",
"keywords": null,
"medline_ta": "West J Emerg Med",
"mesh_terms": "D000437:Alcoholism; D000799:Angioedema; D000806:Angiotensin-Converting Enzyme Inhibitors; D001552:Benzazepines; D006801:Humans; D008046:Lip; D008297:Male; D008875:Middle Aged; D009960:Oropharynx; D010409:Penile Diseases; D010413:Penis",
"nlm_unique_id": "101476450",
"other_id": null,
"pages": "1185-7",
"pmc": null,
"pmid": "26759679",
"pubdate": "2015-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "22560272;23992848;25629740;14751650;6375478;9068723;10512511;17225721;18036423;18281733;18450117;19055203;20447725;21427294;21970934",
"title": "An Unusual Case of Angiotensin-Converting-Enzyme Inhibitor-Related Penile Angioedema with Evolution to the Oropharynx.",
"title_normalized": "an unusual case of angiotensin converting enzyme inhibitor related penile angioedema with evolution to the oropharynx"
} | [
{
"companynumb": "US-PRINSTON PHARMACEUTICAL INC.-2016PRN00021",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": null,
"drugadditional": null,
"drugadministrationroute": null,
... |
{
"abstract": "Determination of the risk-benefit ratio associated with the use of novel coronavirus disease 2019 (COVID-19) repurposed drugs in older adults with polypharmacy is mandatory. Our objective was to develop and validate a strategy to assess risk for adverse drug events (ADE) associated with COVID-19 repurposed drugs using hydroxychloroquine (HCQ) and chloroquine (CQ), alone or in combination with azithromycin (AZ), and the combination lopinavir/ritonavir (LPV/r). These medications were virtually added, one at a time, to drug regimens of 12,383 participants of the Program of All-Inclusive Care for the Elderly. The MedWise Risk Score (MRSTM) was determined from 198,323 drug claims. Results demonstrated that the addition of each repurposed drug caused a rightward shift in the frequency distribution of MRSTM values (p < 0.05); the increase was due to an increase in the drug-induced Long QT Syndrome (LQTS) or CYP450 drug interaction burden risk scores. Increases in LQTS risk observed with HCQ + AZ and CQ + AZ were of the same magnitude as those estimated when terfenadine or terfenadine + AZ, used as positive controls for drug-induced LQTS, were added to drug regimens. The simulation-based strategy performed offers a way to assess risk of ADE for drugs to be used in people with underlying medical comorbidities and polypharmacy at risk of COVID-19 infection without exposing them to these drugs.",
"affiliations": "Tabula Rasa HealthCare Precision Pharmacotherapy Research & Development Institute, Orlando, FL 32827, USA.;Tabula Rasa HealthCare Precision Pharmacotherapy Research & Development Institute, Orlando, FL 32827, USA.;Tabula Rasa HealthCare Precision Pharmacotherapy Research & Development Institute, Orlando, FL 32827, USA.;Tabula Rasa HealthCare Precision Pharmacotherapy Research & Development Institute, Orlando, FL 32827, USA.;Tabula Rasa HealthCare Precision Pharmacotherapy Research & Development Institute, Orlando, FL 32827, USA.;Tabula Rasa HealthCare Precision Pharmacotherapy Research & Development Institute, Orlando, FL 32827, USA.;Tabula Rasa HealthCare Precision Pharmacotherapy Research & Development Institute, Orlando, FL 32827, USA.",
"authors": "Al Rihani|Sweilem B|SB|0000-0003-2415-4664;Smith|Matt K|MK|;Bikmetov|Ravil|R|;Deodhar|Malavika|M|;Dow|Pamela|P|;Turgeon|Jacques|J|0000-0002-7978-9280;Michaud|Veronique|V|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3390/jcm9082591",
"fulltext": "\n==== Front\nJ Clin Med\nJ Clin Med\njcm\nJournal of Clinical Medicine\n2077-0383 MDPI \n\n10.3390/jcm9082591\njcm-09-02591\nArticle\nRisk of Adverse Drug Events Following the Virtual Addition of COVID-19 Repurposed Drugs to Drug Regimens of Frail Older Adults with Polypharmacy\nhttps://orcid.org/0000-0003-2415-4664Al Rihani Sweilem B. 1† Smith Matt K. 1† Bikmetov Ravil 1† Deodhar Malavika 1 Dow Pamela 1 https://orcid.org/0000-0002-7978-9280Turgeon Jacques 12 Michaud Veronique 12* 1 Tabula Rasa HealthCare Precision Pharmacotherapy Research & Development Institute, Orlando, FL 32827, USA; srihani@trhc.com (S.B.A.R.); mksmith@trhc.com (M.K.S.); rbikmetov@trhc.com (R.B.); mdeodhar@trhc.com (M.D.); pdow@trhc.com (P.D.); jturgeon@trhc.com (J.T.)\n2 Faculty of Pharmacy, Université de Montréal, Montreal, QC H3C 3J7, Canada\n* Correspondence: vmichaud@trhc.com; Tel.: +856-938-8697† S.B.A.R., M.K.S., and R.B. contributed equally to this work.\n\n\n10 8 2020 \n8 2020 \n9 8 259108 7 2020 04 8 2020 © 2020 by the authors.2020Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).Determination of the risk–benefit ratio associated with the use of novel coronavirus disease 2019 (COVID-19) repurposed drugs in older adults with polypharmacy is mandatory. Our objective was to develop and validate a strategy to assess risk for adverse drug events (ADE) associated with COVID-19 repurposed drugs using hydroxychloroquine (HCQ) and chloroquine (CQ), alone or in combination with azithromycin (AZ), and the combination lopinavir/ritonavir (LPV/r). These medications were virtually added, one at a time, to drug regimens of 12,383 participants of the Program of All-Inclusive Care for the Elderly. The MedWise Risk Score (MRSTM) was determined from 198,323 drug claims. Results demonstrated that the addition of each repurposed drug caused a rightward shift in the frequency distribution of MRSTM values (p < 0.05); the increase was due to an increase in the drug-induced Long QT Syndrome (LQTS) or CYP450 drug interaction burden risk scores. Increases in LQTS risk observed with HCQ + AZ and CQ + AZ were of the same magnitude as those estimated when terfenadine or terfenadine + AZ, used as positive controls for drug-induced LQTS, were added to drug regimens. The simulation-based strategy performed offers a way to assess risk of ADE for drugs to be used in people with underlying medical comorbidities and polypharmacy at risk of COVID-19 infection without exposing them to these drugs.\n\nadverse drug eventsCOVID-19polypharmacyolder adultssimulation\n==== Body\n1. Introduction\nIn December 2019, an unidentified pneumonia was reported in Wuhan, China [1]. In response, the World Health Organization (WHO) declared an epidemiological alert on 31 December 2019 [1,2]. Within weeks, SARS-CoV-2, spread globally causing the coronavirus disease 2019 (COVID-19) pandemic. As of 5 August 2020, COVID-19 has been diagnosed in more than 18,601,795 patients and associated with over 702,045 deaths all over the world [3].\n\nHydroxychloroquine (HCQ), chloroquine (CQ), and remdesivir have received US Food and Drug Administration (FDA) emergency use authorization (EUA) based on preliminary results from numerous ongoing clinical trials [4,5]. The FDA has recently determined that the statutory criteria for issuance of an EUA for HCQ and CQ were no longer met. Several other medications are also being tested in numerous clinical trials [6]. So far, no repurposed drug, new drug nor vaccine has been approved as a therapy for COVID-19. However, remdesivir and dexamethasone show promise as COVID-19 treatment in severely ill hospitalized patients [7,8], while the search continues for a treatment that decreases symptoms or rate of severe complications in the community.\n\nIn addition to the lack of proven efficacy, the safety to use drugs such as HCQ or CQ has been questioned, and their safety when added to an existing drug regimen, in the context of COVID-19, has not been established yet [9]. In particular, cardiac safety issues including abnormal heart rhythms such as QT prolongation have been associated with HCQ, CQ and azithromycin (AZ) [10,11,12,13,14,15,16]. Serious dysrhythmias in patients with COVID-19 who were treated with HCQ or CQ, often in combination with AZ and other drugs that prolong the QTc interval, have been reported [17,18,19,20].\n\nTabula Rasa HealthCare (TRHC) has developed a proprietary medication risk score, the MedWise Risk Score (MRSTM), that uses algorithms to compute risk of adverse drug events (ADE) while considering five medication characteristics [21,22,23]: (1) computation of a drug regimen relative odds ratio for ADE using the FDA pharmacovigilance database (FDA Adverse Event Reporting System (FAERS)) [24], (2) anticholinergic cognitive burden (ACB) [25], (3) sedative burden (SB) [26,27,28], (4) drug-induced Long QT Syndrome (LQTS) burden [29,30], and (5) CYP450 drug interaction burden risk scores [31]. MRSTM is a predictive tool used by healthcare providers to assess patients’ likelihood of an ADE occurring; over 30 million individuals have been risk-stratified using this tool recently to direct pharmacists and health professional interventions for high-risk patients. [32] In addition to its association with the risk of ADE, higher MRSTM is associated with increased medical expenditures, more hospitalization, more emergency visits, and an increased hospital length of stay in patients with comorbidities and polypharmacy [21].\n\nPrograms of All-inclusive Care for the Elderly (PACE), organizations funded by the Centers for Medicare and Medicaid Services, provide supportive services to community-dwelling adults, age 55 and older, who require a “nursing home level of care” [33]. TRHC currently provides pharmacy services to about 100 PACE Centers in the United States, servicing close to 13,000 participants. With several chronic conditions, frail PACE participants clearly represent an at-risk population for COVID-19 infection and complication [34]. Furthermore, PACE participants serviced by TRHC receive on average about 12 different medications per day. Obviously, the addition of any new medication to this polypharmacy condition increases the risk of ADE.\n\nThe objective of our study was to assess the risk of ADE associated with the addition of the proposed COVID-19 repurposed drugs HCQ and CQ, alone or in combination with azithromycin (AZ), and with the clinically used combination of lopinavir/ritonavir (LPV/r), to the drug regimens of PACE participants. A simulation approach was used to avoid unnecessary exposure to these drugs in patients and to allow a controlled estimation of risk change by the virtual addition of these drugs, one at a time, to their drug regimen. Validation of such an approach could help estimate the risk of ADE for future repurposed drugs to be used in COVID-19 patients.\n\n2. Methods\n2.1. Subjects and Study Design\nIn this cohort study, drug insurance claims of individuals enrolled in PACE receiving pharmacy services from CareKinesis were used to perform predictive simulation analyses. The last available prescription drug claims in 2019 were used to determine the subjects’ baseline drug regimen (from 1 July 2019 and ending 31 December 2019) and to calculate their baseline MRSTM. Participants with no drug claims data available for the specified period of 2019 were excluded. Data elements analyzed were prescribed drugs, dose, age, sex, and medical claims with an International Statistical Classification of Diseases and Related Health Problems 10th Revision (ICD-10)-WHO Version for 2019 for the corresponding period in 2019. For data protection, date of birth was represented as a year value, and age over 90 years old was fixed at 89 years old. All participant-level data were anonymized before being made available for analysis in this study.\n\nThis research protocol was reviewed and approved by Biomedical Research Alliance of New York Institutional Review Board (BRANY IRB), an independent review board, prior to study initiation, and a waiver of authorization to use protected health information was granted (protocol #20-12-117-427). The study protocol was registered at the U.S. National Institutes of Health website (http://www.clinicaltrials.gov; NCT04339634).\n\n2.2. Medication Risk Score and Simulation Strategy\nA medication risk stratification was used to simulate the impact of different COVID-19 repurposed drugs on the MRS™ (see the Patent section of the manuscript for more details) [21,22,23,30]. The total MRSTM and the individual aggregated risk factors (FDA Adverse Event Reporting System (FAERS), anticholinergic cognitive burden (ACB), sedative burden (SB), drug-induced LQTS, and CYP450 drug interaction burden scores) were divided into sub-categories of Low risk, Moderate risk, and High risk. The range of the total MRSTM values is from 0 to 53 (no risk to highest risk). MRSTM risk groups are defined as follows: MRSTM values < 15 are classified into the Low-risk group, MRSTM values ≥15 to <20 into the Moderate-risk group, and MRSTM values ≥ 20 into the High-risk group.\n\nTo simulate the effects of a repurposed drug (or drug combination) on the MRSTM, a fictitious claim for the tested repurposed drug (or combination) was added to the database for each participant. If a participant was already taking the added drug under study, their daily dosage was set to the proposed dose of this drug for treating COVID-19. Following the addition of a repurposed drug (or drug combination), a new MRSTM was derived for each participant.\n\nA total of five repurposed drugs or drug combinations were tested, including HCQ (400 mg twice daily), HCQ with AZ (400 mg twice daily + 500 mg once daily), CQ (500 mg twice daily), CQ with AZ (500 mg twice daily + 500 mg once daily), and, LPV/r (400 mg twice daily + 100 mg twice daily). In particular, HCQ and CQ can cause QT prolongation and polymorphic ventricular tachycardia (torsade de pointes) [35,36]. With the LQTS risk score being part of the MRSTM [22,30], additional simulations were performed using known negative and positive controls for QT prolongation including fexofenadine and terfenadine, respectively (fexofenadine 180 mg/day; terfenadine 180 mg/day; and terfenadine 180 mg/day + AZ 500 mg/day) [37].\n\n2.3. Data Processing and Statistical Analysis\nTo perform the medication risk stratification, a webservice interface and customized scripts were used. The MRSTM were generated by processing prescribed drug claims using National Drug Codes (NDCs) as drug identifiers. Medication data were extracted and cleaned from errors and inconsistencies through quality and integrity analyses. Since NDCs can also be assigned to non-medications (e.g., medical devices and consumables), active medication data were further filtered to exclude such NDCs. Afterward, active medication data for each participant was filtered based on prescription dates and days’ supply, which include any possible refills.\n\nDescriptive population characteristics were measured, including means, standard deviations, and proportions as appropriate. For comparing the MRS™ and composite individual risk factors before and after addition of repurposed drugs into participants’ drug regimens, the Wilcoxon signed-rank test analysis was performed. To determine the statistical significance of participants moving to a higher risk stratification category (Low-to-Moderate, Low-to-High, or Moderate-to-High), the McNemar test and the Stuart–Maxwell test of marginal homogeneity were utilized (no participants moved to a lower risk score category). To determine if the MRS™ or a risk category were more influenced by one drug than by others, we used a Friedman test, followed by paired comparisons with the Wilcoxon signed-rank test. For all the Wilcoxon signed-rank tests, the ranks of zeros were included in calculating the statistic (implemented as zero method = ‘zsplit’ in SciPy 1.4.1). For the statistical analysis assessing the difference between female and male groups, the effect size was calculated using the method denoted f.\n\nThe diseases were identified by finding the ICD-10 codes with the highest number of participants, limiting the ICD-10 codes to the first three digits. When ICD-9 codes were still used, these codes were translated to the appropriate ICD-10 code, if possible.\n\nFor statistical significance, we considered p-values below 0.05 to be significant. A population’s mean score change of at least 1 point was considered significant, as reported by Bankes et al. [21]. To adjust for multiple comparisons, the Benjamini/Hochberg adjustment was applied. When the p-values were too low, a value of p < 0.0001 is indicated. Statistical analysis was performed in Python 3.7.6 using the pandas (v. 1.0.1) (open-source software fiscally sponsored by NumFOCUS, Austin, TX, USA), SciPy (v. 1.4.1)) (open-source software fiscally sponsored by NumFOCUS (Austin, TX, USA)), statsmodels (v. 0.11.0) (open-source software sponsored by Google (Menlo Park, CA, USA) and AQR Capital Management (Greenwich, CT, USA)), Matplotlib (v. 3.1.3) (open-source comprehensive library sponsored by NumFOCUS (Austin, TX, USA)), and seaborn packages (v. 0.10.0) (a Python data visualization library created by Michael Waskom (New York, NY, USA) and in R (v. 1.2.5019) (R foundation for statistical computing. RC Team. (Vienna, Austria) with the dplyr, data.table, sqldf, scales, ggplot2, and igraph packages. Microsoft SQL Server (v. 15) was used to manipulate and analyze large datasets.\n\n3. Results\n3.1. Participant Characteristics\nIn total, 198,323 prescribed drug claims from 12,383 PACE participants were included in our study. Participants’ demographic and clinical characteristics at baseline are described in Table 1. Overall, the mean age of the PACE participants was 76 years (SD ± 10), 67.4% were female, and the average number of prescribed drugs per day in their actual drug regimen was 11.8 (SD ± 5.7). The more frequently prescribed medications are listed in Supplementary Table S1. The most common diseases/symptoms observed in our PACE population were hypertension, dyslipidemia, pain, vitamin D deficiency, constipation, type 2 diabetes, gastro-esophageal reflux disorder (GERD), and chronic obstructive pulmonary disease (COPD). More details on the most common diseases with their corresponding prevalence are provided in Supplementary Table S2. The number of participants already taking HCQ, AZ, or LPV/r at baseline was 106, 125, and 5 respectively; no participant was taking CQ. At baseline, the mean MRSTM was 14.4 (SD ± 7.7), with 54.4%, 20.1%, and 25.5% of our PACE population having a Low, Moderate, and High MRSTM. The average number of prescribed drugs increased in each category of Low, Moderate, and High-risk groups (from 9 to 14 and to 17 drugs/day, respectively).\n\nConcomitant drugs that can potentially interact with the CYP450 metabolic pathway of HCQ, CQ, and LPV/r were investigated: HCQ is metabolized mainly by CYP2C8 (30%) and to a lesser extent by CYP3A4 and CYP2D6 (both isoforms contributing to 15% of its metabolic clearance); CQ is metabolized by CYP2C8 and CYP3A4 (35% and 15% of its metabolic clearance, respectively); lopinavir is mostly metabolized by CYP3A4 (90%); and ritonavir is a strong substrate that competitively inhibits CYP3A4 [38,39,40,41,42,43]. Frequencies of participants already taking drugs metabolized by CYP2C8, CYP3A4, and CYP2D6 are listed in Table 1. CYP3A4 and CYP2D6 represent two minor pathways for elimination of HCQ when considered separately; therefore, drug regimens simultaneously affecting both pathways have been taken into consideration. Common CYP2C8 interacting drugs found in our PACE population were ibuprofen, loperamide, trimethoprim, pioglitazone, primidone, repaglinide, and gemfibrozil (Supplementary Table S3). A total of 6.7% of participants were treated with either 1) a CYP2C8 inhibitor or a CYP2C8 high-affinity substrate drug (N = 693) or 2) a CYP2C8 inducer (N = 137); these drugs could significantly modulate HCQ and CQ plasma concentrations (increase or decrease plasma levels, respectively). In our PACE population, 415 (3.4%) participants were taking a drug regimen that could impede all metabolic pathways involved in HCQ disposition (a combination of CYP2C8, CYP3A4, and CYP2D6 significant interacting drugs).\n\n3.2. Simulated Effects of Repurposed Drugs for COVID-19 on MRS™\nIn Figure 1, violin plots illustrate the distribution and probability density of the MRS™ at baseline and after the virtual addition of the five repurposed drugs (one at a time, alone or in combination) into PACE participants’ drug regimens. Our simulation results show that the addition of repurposed drugs significantly enhanced the median MRSTM (by 2 to 7 points, p < 0.0001). The combination therapy of HCQ + AZ or CQ + AZ was associated with further increases of the MRSTM compared to HCQ and CQ alone (median, 20 and 19 vs. 17 and 16, respectively; p < 0.0001).\n\nThe impact of repurposed drugs on the frequency distribution of participants allocated to Low, Moderate, and High MRSTM groups is shown in Figure 2. The virtual addition of repurposed drugs was associated with a lower number of patients in the Low-risk group and a significant increase in the number of participants with a High MRSTM. Compared to the baseline situation, the percentage of participants in the High-risk group was augmented by 50%, 103%, 43%, 88%, and 120% with HCQ, HCQ + AZ, CQ, CQ + AZ, and LPV/r, respectively (p < 0.0001). A larger fraction of participants were moved to the High-risk group when the CQ + AZ or HCQ + AZ combination was added to their drug regimen compared to CQ and HCQ alone (p < 0.0001).\n\nFigure 3 shows the effects of the virtual addition of repurposed drugs on individual aggregated risk factors including FAERS, CYP450 drug interaction burden, ACB, and SB burden scores. As mentioned previously, the FAERS score uses the FDA Adverse Event Reporting System to compute risk of adverse drug events (ADE) which is based on computation of a drug regimen relative odds ratio for ADE using the FDA pharmacovigilance database. The median FAERS score was significantly increased with the virtual addition of repurposed drugs to participants’ drug regimens. The increase observed in FAERS values was of a similar magnitude for all repurposed drugs tested, with probability density estimates greater for HCQ + AZ, CQ + AZ, and LPV/r. The CYP450 drug interaction burden score was significantly higher following the virtual addition of LPV/r and HCQ (regardless of whether it was alone or combined with AZ) (Supplementary Table S4). The virtual addition of CQ into patients’ drug regimen also slightly affected the CYP450 drug interaction burden (Supplementary Table S4). Both ACB and SB risk scores were not affected following the virtual addition of repurposed drugs.\n\n3.3. Simulated Effects of Repurposed Drugs for COVID-19 on the LQTS Risk Score\nThe effects of virtually adding repurposed drugs on drug-induced LQTS risk scores was examined while performing additional simulations with terfenadine (a drug known to prolong the QT and cause torsade de pointes) and fexofenadine (used as negative control as fexofenadine is not associated with QT prolongation) [37]. As illustrated in Figure 4, all repurposed drugs and terfenadine demonstrated a significant increase in the drug-induced LQTS score. No change in LQTS score was observed following the virtual addition of fexofenadine. Our simulations showed that the addition of HCQ and CQ alone produced changes in the distribution of the drug-induced LQTS score to an extent similar to the one observed with terfenadine. The magnitude of changes with LPV/r was also comparable to the one observed with terfenadine. The HCQ, CQ, and terfenadine drugs combined with AZ were associated with the highest increases in the drug-induced LQTS risk score compared to baseline (Supplementary Table S4 and Figure 4).\n\nFigure 5 illustrates the number of participants with Moderate and High risk of drug-induced LQTS after virtual addition of repurposed drugs to their drug regimens. Percentage of PACE participants in the High drug-induced LQTS risk group increased by 81%, 192%, 81%, 189%, 89%, 89%, and 192% with HCQ, HCQ + AZ, CQ, CQ + AZ, LPV/r, terfenadine, and terfenadine + AZ. No change in the frequency distribution was observed following the addition of fexofenadine.\n\nThe contribution of sex as a covariable was evaluated during the LQTS simulation process. Figure 6 shows violin plots for the drug-induced LQTS risk score distribution and probability density estimates stratified by sex. Our results indicate that those drugs affecting the drug-induced LQTS risk have greater effects on females than on males (p < 0.05). The effect of size was assessed, and the analysis indicates that while all female–male differences are statistically significant, the addition of repurposed drugs or terfenadine, except for fexofenadine, increased the difference between females and males compared to the baseline (p < 0.0001).\n\nIn our studied population, commonly used drugs known to prolong the QT interval with a clear association with the induction of torsade de pointes were donepezil, escitalopram, and citalopram: more than 20% of PACE participants were taking one of these medications. The most commonly prescribed drugs contributing to the drug-induced LQTS risk are listed in Table 2.\n\n4. Discussion\nThe most vulnerable patients at risk for serious illness with COVID-19 are the older adults and individuals with hypertension, diabetes, cardiovascular diseases, chronic respiratory disease, and cancer [34,45,46]. Hence, PACE participants considered in our study are at increased risk since they are, on average, 76 years old and have common chronic conditions such as hypertension, type 2 diabetes, and COPD. Simultaneous use of multiple drugs, as observed in our PACE cohort (with a mean of 11.8 different drugs per day), is associated with an increased risk of multi-drug interactions and of ADE. The risk of using any of the proposed repurposed COVID-19 drugs in such an elderly population with polypharmacy has not been specifically evaluated in any prospective randomized clinical trials—this population is underrepresented in COVID-19 clinical trials. Although 80% of COVID-19-related deaths occur among people aged 65 and over [47], a recent review led by Harvard Medical School researchers showed that older adults are routinely excluded from clinical trials on COVID-19 treatment [48]. Similarly, in a recent randomized trial investigating whether HCQ could reduce COVID-19 in adult outpatients, the older population with comorbidities was underrepresented; the median age was 40 years, and 68% of participants reported no chronic medical conditions [49]. In addition, an exhaustive list of medications associated with potential QT prolongation was excluded, and such exclusion criteria would contribute to underestimating the risk of cardiac side effects in patients with polypharmacy. In search of benefit, one cannot overlook risk. Our approach represents a powerful strategy to estimate risk associated with drugs without exposing patients to potential ADE, including death.\n\nWe have demonstrated that the total MRSTM of PACE participants’ drug regimens was hypothetically increased following the virtual addition of any of all tested COVID-19 repurposed drugs. In older adults with polypharmacy, this hypothetical increase in MRSTM was primarily associated with an increase in CYP450 drug interaction burden and drug-induced LQTS scores. The MRSTM has been previously evaluated and validated in a sub-cohort of PACE participants as a medication risk prediction tool for ADE and medical outcomes including hospitalization, emergency department visits, and medical expenditure [21]. Bankes et al. reported that each point increase in the MRSTM was significantly associated with an increase of ADE (OR = 1.09), additional emergency visits (+3 visits/100 patients/year), and an extra yearly medical expenditure of $1037. A difference of 2 to 7 points in the median value of the MRSTM was observed in our study when repurposed drugs were virtually added to drug regimens. Even though a short treatment duration with repurposed drugs is considered, the anticipated consequences remain substantial. Further pharmacoeconomic analysis with prospective data will provide more accurate estimates.\n\nThe COVID-Safer study exploited a similar strategy by using retrospective data from hospitalized older adults with polypharmacy included in the primary MedSafer study, and they theoretically exposed this patient population cohort to a treatment of HCQ (5 days at a minimum dose of 600 mg daily) [50]. They identified possible drug–drug interactions as well as potential harmful outcomes such as increased toxicity of HCQ, risk of QTc prolongation or malignant cardiac arrhythmia, or risk of other adverse drug events requiring closer monitoring during therapy. Their cohort of patients was smaller including only 1001 unique patients compared to this current study. They identified that 59% (590) were receiving one or more medications that could potentially interact with HCQ, and of those, 43% (255) were flagged as potentially inappropriate by the MedSafer tool. In agreement with COVID-Safer study, a simulation strategy can be used preemptively to identify older patients with polypharmacy; these patients are often ineligible for therapeutic trials or treatment with medication under investigation at high risk of drug–drug interactions. Consequently, the frequency of potential ADEs is underestimated.\n\nWhile several aggregated factors are used to calculate the MRSTM, the significant increase in patients’ MRS™ after addition of repurposed drugs were mainly related to drug-induced LQTS and CYP450 drug interaction burden scores. No change in both the ACB and SB scores was observed: this finding was expected since these drugs are not known to show any pharmacologic properties on these risk factors.\n\nThe number of participants at high risk of drug-induced LQTS was significantly increased with the addition of any of the tested repurposed drugs. It is knowns that HCQ, CQ, and AZ can all prolong ventricular repolarization, as corroborated by studies raising concerns about the risk of arrhythmia and torsade de pointes with these drugs [11,12,13,14,15,16,51,52,53,54,55]. Based on the analysis of FAERS data, the relative odds ratio of QT prolongation/torsade de pointes for CQ, AZ, HCQ is 7.9, 2.6, 1.6, respectively. In April 2020, the FDA posted a drug safety communication against the use of HCQ and CQ for COVID-19 outside of hospital settings or clinical trials due to serious heart rhythms problems such as QT prolongation [9]. In the context of COVID-19, QT prolongation and risk of torsade de pointes have been identified and discussed for patients treated with HCQ or CQ, alone or with AZ: such observations support and validate results obtained through our simulation study [19,56,57,58,59]. Clinical trials in hospitalized COVID-19 infected patients have been terminated, or HCQ or CQ arms have been removed from their trials, for either safety or lack of efficacy issues [8,60].\n\nOur results indicate that the virtual addition of repurposed drugs to a patient’s drug regimen significantly augmented the drug-induced LQTS risk score compared to the actual drug regimen. Notably, the drug-induced LQTS risk factor was of a similar magnitude to the one observed with terfenadine, a drug removed from the market because of drug-induced LQTS [61]. No difference was observed using fexofenadine as a negative control for drug-induced LQTS. This finding suggests that a simulation strategy based on a medication risk score represents a preemptive tool to predict patients at higher risk of drug-induced LQTS before exposing patients to a medication. Female sex is also a known risk factor for drug-induced LQTS as studies have shown that women have a greater susceptibility to torsade de pointes than men [62,63,64]. Our simulation approach confirmed that female sex was associated with higher drug-induced LQTS risk score than male.\n\nThe incidence of drug-induced LQTS/torsade de pointes is low, and it remains difficult to estimate an accurate incidence number since cases of torsade de pointes often are not recognized or are unreported [65,66]. In the MRSTM, the High-risk, drug-induced LQTS category corresponds to a score for drugs known to prolong the QT interval and associated with torsade de pointes. The combination of certain conditions such as drug interactions with QT-prolonging drugs, drugs causing electrolyte disturbances, hypokalemia, and older age can lead to a High drug-induced LQTS risk score. At baseline, the prevalence of patients in the High drug-induced LQTS score group was 0.29%; this number increased to 0.54% when HCQ, CQ, LPV/r, or terfenadine were added to participants’ drug regimens. When HCQ, CQ, or terfenadine were combined with AZ, the simulation showed a 3-fold increase in the prevalence (0.87%) of drug regimens with a High drug-induced LQTS score.\n\nHCQ and CQ (alone or combined with AZ) are the oral repurposed COVID-19 therapeutic agents most studied in on-going clinical trials, followed by LPV/r. [67] As these medications are metabolized by various CYP450 isoforms, they carry the risk of causing or suffering from drug–drug interactions. The combination of LPV/r was associated with the highest increase in the CYP450 drug interaction burden score. It is well known that ritonavir has the potential to significantly interact with many medications: ritonavir can competitively inhibit the metabolism of CYP3A substrates and induce numerous CYP450 isoforms such as CYP1A2, CYP2B6, CYP2C9/19, and UGTs [41,43]. Consequently, ritonavir, as a perpetrator, has the potential to cause several drug interactions. Conversely, HCQ and CQ, which exhibit a low affinity for the isoforms involved in their metabolisms, will suffer from drug interactions (competitive inhibition) acting as a victim drug. Approximately 7% of our studied population received CYP2C8 medications that can affect HCQ and CQ exposure. Although HCQ is mainly metabolized by CYP2C8, together, CYP2D6 and CYP3A4 contribute to ~30% of its metabolic clearance. More than 50% of patients were simultaneously taking CYP3A4 and CYP2D6-interacting drugs which can impede one-third of the HCQ elimination pathway.\n\n5. Conclusions\nOur study used a simulation strategy based on a medication risk score assessment used clinically to improve drug safety and reduce risks of ADE in people with underlying medical comorbidities and polypharmacy. Besides the current repurposed drugs tested, our strategy can be applicable to any new drug being proposed to be used for COVID-19 or other clinical situations. As we do not know the benefit associated with some drugs, our approach allows for the estimation of risk in patients with polypharmacy.\n\n6. Patents\nThe MedWise Risk ScoreTM (MRSTM) used in the current study is subjected to two patent applications: WO2019089725 (Population-Based Medication Risk Stratification and Personalized Medication Risk Score) and WO2017213825 (Treatment Methods Having Reduced Drug-Related Toxicity and Methods of Identifying the Likelihood of Patient Harm from Prescribed Medications).\n\nIn patent WO2019089725, embodiments of the invention relate to a system and method for population-based medication risk stratification and are used for generating a personalized medication risk score. The system and method may pertain to a software that relates pharmacological characteristics of medications and patient’s drug regimen data into algorithms that (1) enable identification of high-risk patients for ADEs within a population distribution and (2) allow computation of a personalized medication risk score which provides personalized, evidence-based information for safer drug use to mitigate medication risks. In brief, embodiments of the invention include algorithms that look at multiple factors that influence a medication regimen’s likelihood of causing a negative health effect. The following factors are used to drive the software’s algorithms to determine risk in respect to patient’s medication regimen: a relative odd ratio for a drug regimen risk of ADE based on the FDA Adverse Event Reporting System, the indices of anticholinergic burden, the indices of sedation effects, the risk of QT-interval prolongation, and the competitive inhibition on specific CYP450 isoforms by the drug regimen. The combinatorial assessment of these individual risk factors provides a comprehensive approach to medication risk stratification at a population level, as well as the possibility of personalized medication risk mitigation at the individual level by interpreting a Personalized Medication Risk Score. Hence, the output of this assessment is a quantitative score that can be used to measure and stratify risk of the occurrence of ADE due to a particular medication regimen. This quantitative score also allows the identification of patients at higher risk for multi-drug interactions within a population and thus require medication risk mitigation more so than others. This identification ability is of high importance for care providers who seek to know which of their patients require immediate attention. Once these patients are recognized, the software tool provides a personalized snapshot of the risk factors described above, empowering the provider to mitigate their medication risk accurately and efficiently.\n\nTo ensure the accuracy of the invention, the scoring mechanisms have been validated against literature and clinical cases. The software has been applied to various healthcare population settings numbering more than 30 million patients. In these applications, various high-risk groupings were identified and criteria were generated for patients of the highest risk through statistical aggregation. The tool has been found to typically identify the top 15 to 20 percent of high-risk patients for each risk factor as well as identify the approximate top 5 to 15 percent of the population considered at highest risk. Not only were high-risk members of the population identified, but the embodiments of the invention generated personalized medication risk score snapshots, which empower health professionals to generate recommendations to mitigate the established risks. The description of this Medication Risk Score™ was first published by Cicali et al. and is currently used in the course of the Centers for Medicare and Medicaid Services (CMS) Enhanced Medication Therapy Management (EMTM) Pilot program with MedicareBlueRx [23,32]. Complete description of algorithms and methodology pertaining to this patent can be found at https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019089725&tab=PCTDESCRIPTION (N = 190 claims, 17 drawings).\n\nPatent WO2017213825 describes methods of determining whether specific drugs or patients carry an increased risk of causing or developing, respectively, long QT syndrome, or torsade de pointes and methods of treating such patients. The inventions provide a comprehensive approach that includes a number of factors that may influence a medication’s likelihood of causing drug-induced LQTS and/or torsade de pointes. In some embodiments, the Long QT-JT Index considers the scenario where a medication has the greatest chance of causing torsade de pointes—when a medication is the most “risky.” The following factors may be considered specific to each medication: (1) IC50 for block of IKr; (2) IC50 for block of IKs; (3) IC50 for block of Navl 5 (sodium) current; (4) IC50 for block of Cavl.2 (calcium) current; (5) Inhibition of hERG trafficking; (6) Cmax of the drug at a test Dose; (7) Maximum daily dose of the drug according to labeling; (8) Protein binding of the drug; and/or (9) Drug–drug interaction coefficient (DDIC). In some embodiments, the DDIC considers the pharmacokinetics of the medication, i.e., whether it has a high extraction ratio (low bioavailability) or low extraction ratio (high bioavailability), relative CYP450 enzymatic pathways involved in the clearance of the drug. While the medication-specific risk index will be helpful when scrutinizing a single medication, the reality is that patients take many medications and have individual risk factors that may predispose or protect them from QT prolongation and torsade de pointes (TdP). In some embodiments, a patient-specific Long QT-JT Score is provided that is dynamic based on the patient’s current conditions and concomitant medications.\n\nThe scoring mechanisms described in this patent have been validated against literature cases of known TdP. More than 50 cases of documented TdP have been identified due to medication use and/or medication interactions, and their risk score has been calculated based on the methods described. In such cases, the risk scores are generally above 10. The patent description contains 236 claims and 22 drawings.\n\nAcknowledgments\nThe authors would like to thank Dana Filippoli and Orsula Knowlton for their comprehensive review and comments pertaining to the contents of this manuscript.\n\nSupplementary Materials\nThe following are available online at https://www.mdpi.com/2077-0383/9/8/2591/s1, Table S1: The top 25 prescribed medications, Table S2: The most common diseases, Table S3: Concomitant CYP2C8-interacting drugs including CYP2C8 inhibitors, CYP2C8 inducers, and potential interacting CYP2C8 competitive substrates with HCQ or CQ, Table S4: The medication risk factor scores for each factor for the population under study at baseline and following the addition of COVID-19 repurposed drugs.\n\nClick here for additional data file.\n\n Author Contributions\nConceptualization, V.M. and J.T.; methodology, V.M., M.K.S., and R.B.; formal analysis, M.K.S., and R.B.; resources, V.M., J.T., and P.D.; data curation, M.K.S. and R.B.; writing—original draft preparation, S.B.A.R., M.K.S, M.D., P.D., V.M., and J.T.; writing—review and editing, V.M., P.D, and J.T.; visualization, M.K.S.; supervision, J.T. and V.M.; project administration, J.T., P.D., and V.M. All authors have read and agreed to the published version of the manuscript.\n\nFunding\nThis research received no external funding.\n\nConflicts of Interest\nAll authors are employees and shareholders of Tabula Rasa HealthCare. The authors have no other conflicts of interest to disclose.\n\nFigure 1 Violin plots of the MedWise Risk Score™ at baseline and after the virtual addition of repurposed drugs into Programs of All-inclusive Care for the Elderly (PACE) participants’ drug regimens. The white dots are the medians, and the colored areas are probability density estimates. p < 0.0001 compared to the baseline for all repurposed drugs. Abbreviations: HCQ, hydroxychloroquine; AZ, azithromycin; CQ, chloroquine; and LPV/r, lopinavir + ritonavir.\n\nFigure 2 Histogram showing the frequency of PACE participants in Low, Moderate, and High MRS™ categories by drug compared to the baseline. The green, orange, and red represent the Low-risk (MRSTM 0 to <15), Moderate-risk (MRSTM ≥ 15 to <20), and High-risk (MRSTM ≥ 20) group categories, respectively. Abbreviations: HCQ, hydroxychloroquine; AZ, azithromycin; CQ, chloroquine; and LPV/r, lopinavir + ritonavir.\n\nFigure 3 Violin plots showing the medication risk scores for individual factors including FDA Adverse Event Reporting System (FAERS), CYP450 drug interaction burden, anticholinergic burden, and sedative burden scores at baseline and after the virtual addition of repurposed drugs into PACE participants’ drug regimens. The white dots are the medians, and the colored areas are probability density estimates. Abbreviations: HCQ, hydroxychloroquine; AZ, azithromycin; CQ, chloroquine; and LPV/r, lopinavir + ritonavir.\n\nFigure 4 Violin plots showing the drug-induced Long QT Syndrome (LQTS) risk score factor at baseline and after the virtual addition of repurposed drugs into PACE participants’ drug regimens. Fexofenadine was used as a negative control and terfenadine alone and combined with AZ were used as positive controls on drug-induced LQTS score. The white dots are the medians, and the colored areas are probability density estimates. p < 0.0001 compared to the baseline for all repurposed drugs and terfenadine (alone and combined with AZ). Abbreviations: HCQ, hydroxychloroquine; AZ, azithromycin; CQ, chloroquine; and LPV/r, lopinavir + ritonavir.\n\nFigure 5 Histogram showing frequency of PACE patients in Low, Moderate, and High LQTS risk categories by drug compared to the baseline. The inset shows the High-risk categories. The green, orange, and red represent the Low-risk, Moderate-risk, and High-risk, respectively. Abbreviations: HCQ, hydroxychloroquine; AZ, azithromycin; CQ, chloroquine; and LPV/r, lopinavir + ritonavir.\n\nFigure 6 Violin plots showing the drug-induced LQTS risk score factor broken down by sex at baseline and after the virtual addition of repurposed drugs into PACE participants’ drug regimens. Fexofenadine and terfenadine (alone and combined with AZ) were used as negative and positive controls, respectively, on drug-induced LQTS scores. The white dots are the medians, and the colored areas are probability density estimates. Male and female are represented by blue and pink colors, respectively. p < 0.05 female vs. male for the baseline and for all repurposed drugs and controls. Size of effect, p < 0.0001 for all added drugs vs. the baseline, except for fexofenadine. Abbreviations: HCQ, hydroxychloroquine; AZ, azithromycin; CQ, chloroquine; LPV/r, lopinavir + ritonavir; m, male; and f, female.\n\njcm-09-02591-t001_Table 1Table 1 Demographic characteristics of the studied population.\n\nCharacteristics at Baseline\t\n\t\nTotal number of patients, n\t12,383\t\nAge (years); mean ± SD (range)\t76 ± 10\n(55 to 89)\t\nSex; male, N (%)\nfemale, N (%)\t4039 (32.6%)\n8344 (67.4%)\t\nNumber of drugs/day per patient; N ± SD (range)\t11.8 ± 5.7 (0–47)\t\nTotal MRSTM; mean ± SD (range)\t14.4 ± 7.7 (0–39)\t\n \n- Low-risk group *; N (%) mean ± SD\n\n\n\n\n\t6741 (54.4%)\n8.6 ± 3.7\t\n\n- Moderate-risk group *; N (%) mean ± SD\n\n\n\n\n\t2489 (20.1%)\n16.9 ± 1.4\t\n\n- High-risk group *; N (%) mean ± SD\n\n\n\n\n\t3153 (25.5%)\n24.8 ± 3.7\t\nPatients currently receiving prescribed drugs proposed for repurposing:\n- HCQ, N (%)\n\n- CQ, N (%)\n\n- AZ, N (%)\n\n- LPV/r, N (%)\n\n\t\n106 (0.9%)\n0\n125 (1.0%)\n5 (0.04%)\t\nPotential CYP450 drug-drug interactions, patients currently receiving:- CYP2C8 inhibitors or competitive substrates ŧ, N (%)\n\n- CYP2C8 inducers ŧ, N (%)\n\n- CYP3A4 inhibitors or competitive substrates ŧ, N (%)\n\n- CYP2D6 inhibitors or competitive substrates ŧ, N (%)\n\n- Combination of CYP3A4 + 2D6 inhibitors or competitive substratesŧ, N (%)\n\n- Combination of CYP2C8 + 3A4 + 2D6 inhibitors or competitive substrates ŧ,N (%)\n\n\t\n693 (5.6%)\n137 (1.1%)\n8952 (72%)\n7439 (60%)\n5861 (47%)\n415 (3.4%)\t\n* MRSTM risk groups are defined as follows: MRSTM values < 15 are classified into the Low-risk group, MRSTM values ≥ 15 to <20 into the Moderate-risk group, and MRSTM values ≥ 20 into the High-risk group. ŧ Competitive substrates are drugs exhibiting a high affinity for a respective isoform. Concomitant administration of these drugs with the weak-affinity substrates HCQ and CQ is associated with potentially significant drug interactions. LPV is also a weak substrate of CYP3A4, but since its administration was always with ritonavir, a strong inhibitor of CYP3A4, no additional inhibition and interaction were considered for LPV. However, ritonavir, when virtually added to a patient regimen, was considered as a perpetrator drug. ASA, acetylsalicylic acid; AZ, azithromycin; COPD, chronic obstructive pulmonary disease; CQ, chloroquine; HCQ, hydroxychloroquine; GERD, gastro-esophageal reflux disorder; LPV/r, lopinavir boosted with ritonavir; MRSTM, medication risk score; SD, standard deviation.\n\njcm-09-02591-t002_Table 2Table 2 Common prescribed drugs in our cohort of patients that can contribute to drug-induced LQTS/torsade de pointes. Risk categories depend on whether drugs can cause QT prolongation or torsade de pointes: the Long QT-JT index used to derive the LQTS risk score and CredibleMeds are presented.\n\nDrug Names\tNumber of Patients, N (%)\tLong QT-JT Index Category *\tCredibleMeds Category ŧ\t\nFurosemide\t2629 (21%)\tModerate\tConditional\t\nPantoprazole\t2402 (19%)\tModerate\tConditional\t\nSertraline\t1583 (12%)\tLow\tConditional\t\nTrazodone\t1479 (11%)\tHigh\tConditional\t\nFamotidine\t1422 (11%)\tModerate\tConditional\t\nOmeprazole\t1395 (11%)\tModerate\tConditional\t\nHydrochlorothiazide\t1359 (10%)\tModerate\tConditional\t\nDonepezil\t1073 (8%)\tModerate\tKnown\t\nMirtazapine\t1004 (8%)\tModerate\tPossible\t\nQuetiapine\t853 (6%)\tHigh\tConditional\t\nEscitalopram\t752 (6%)\tHigh\tKnown\t\nCitalopram\t681 (5%)\tHigh\tKnown\t\nRisperidone\t500 (4%)\tHigh\tConditional\t\nMirabegron\t429 (3%)\tLow\tPossible\t\nAripiprazole\t400 (3%)\tModerate\tPossible\t\nVenlafaxine\t380 (3%)\tHigh\tPossible\t\nFluoxetine\t357 (2%)\tModerate\tConditional\t\nOlanzapine\t270 (2%)\tLow\tConditional\t\nEsomeprazole\t216 (1%)\tModerate\tConditional\t\nAmiodarone\t212 (1%)\tHigh\tKnown\t\nOndansetron\t177 (1%)\tHigh\tKnown\t\nParoxetine\t182 (1%)\tModerate\tConditional\t\nLoperamide\t154 (1%)\tHigh\tConditional\t\n* Long QT-JT Index values ≤ 15 are associated with High risk of drug-induced LQTS, values 16–100 are associated with a Moderate risk, and values 101-999 are associated with Low risk. Patient-specific risk (Long QT-JT Score) is determined by using the drug-specific Long QT-JT Index combined with other factors such as age, sinus rhythm, use of diuretics, use of Class 1A,1C or III antiarrhythmic drugs, magnesium and potassium levels, and QT interval value [30]. ŧ CredibleMeds categories are described as follows: Known risk of torsade de pointes is drugs that prolong the interval and are clearly associated with a known risk of torsade de pointes. Conditional risk is drugs associated with torsade de pointes but only under certain conditions of their use or creating conditions that facilitate or induce torsade de pointes. Possible risk is drugs that can cause QT prolongation but have no clear evidence for a risk of torsade de pointes [44].\n==== Refs\nReferences\n1. European Center for Disease Prevention and Control Cluster of Pneumonia Cases Caused by a Novel Coronavirus, Wuhan, China. Rapid Risk Assessment Available online: http://wjw.wuhan.gov.cn/front/web/showDetail/2019123108989 (accessed on 22 July 2020) \n2. World Health Organization Pnemonia of an Unknown Cause. Emergencies Preparedness, Response Available online: https://www.who.int/csr/don/05-january-2020-pneumonia-of-unkown-cause-china/en/ (accessed on 5 June 2020) \n3. Johns Hopkins University and Medicine COVID-19 Dashboard by the Center for Systems Science and Engineering (CSSE) at Johns Hopkins University and Medicine Available online: https://coronavirus.jhu.edu/map.html (accessed on 5 August 2020) \n4. U.S. Food and Drug Administration Emergency Use Authorization (EUA) for Emergency Use of Remdesivir for the Treatment of Hospitalized 2019 Coronavirus Disease (COVID-19) Patients Available online: https://www.fda.gov/media/137564/download (accessed on 22 July 2020) \n5. U.S. Food and Drug Administration Request for Emergency Use Authorization For Use of Chloroquine Phosphate or Hydroxychloroquine Sulfate Supplied from the Strategic National Stockpile for Treatment of 2019 Coronavirus Disease. Revoked Available online: https://www.fda.gov/media/136534/download (accessed on 23 July 2020) \n6. Al Rihani S.B. Deodhar M. Michaud V. Turgeon J. Lucio E. Condon G. Dow P. Potential COVID-19 Treatment Options (Off-Label) Available online: https://trhc.spprdi.com/covid19/home (accessed on 7 July 2020) \n7. Grein J. Ohmagari N. Shin D. Diaz G. Asperges E. Castagna A. Feldt T. Green G. Green M.L. Lescure F.-X. Compassionate Use of Remdesivir for Patients with Severe Covid-19 N. Engl. J. Med. 2020 382 2327 2336 10.1056/NEJMoa2007016 32275812 \n8. COVID-19 Treatment Guidelines Panel Coronavirus Disease 2019 (COVID-19) Treatment Guidelines Available online: https://www.covid19treatmentguidelines.nih.gov/ (accessed on 27 July 2020) \n9. U.S. Food and Drug Administration FDA cautions against use of hydroxychloroquine or chloroquine for COVID-19 outside of the hospital setting or a clinical trial due to risk of heart rhythm problems Does not Affect FDA-Approved Uses for Malaria, Lupus, and Rheumatoid Arthritis U.S. Food and Drug Administration Washington, DC, USA 2020 \n10. Milberg P. Eckardt L. Bruns H.J. Biertz J. Ramtin S. Reinsch N. Fleischer D. Kirchhof P. Fabritz L. Breithardt G. Divergent proarrhythmic potential of macrolide antibiotics despite similar QT prolongation: Fast phase 3 repolarization prevents early afterdepolarizations and torsade de pointes J. Pharmacol. Exp. Ther. 2002 303 218 225 10.1124/jpet.102.037911 12235254 \n11. Huang B.H. Chi-hua W. Hsia C.-P. Yin Chen C. Azithromycin-induced torsade de pointes Pacing Clin. Electrophysiol. 2007 30 1579 1582 10.1111/j.1540-8159.2007.00912.x 18070319 \n12. Kezerashvili A. Khattak H. Barsky A. Nazari R. Fisher J.D. Azithromycin as a cause of QT-interval prolongation and torsade de pointes in the absence of other known precipitating factors J. Interv. Card. Electrophysiol. 2007 18 243 246 10.1007/s10840-007-9124-y 17546486 \n13. Demazière J. Fourcade J.M. Busseuil C.T. Adeleine P. Meyer S.M. Saïssy J.M. The hazards of chloroquine self prescription in west Africa J. Toxicol. Clin. Toxicol. 1995 33 369 370 10.3109/15563659509028925 7629906 \n14. Chen C.Y. Wang F.L. Lin C.C. Chronic hydroxychloroquine use associated with QT prolongation and refractory ventricular arrhythmia Clin. Toxicol. 2006 44 173 175 10.1080/15563650500514558 \n15. Morgan N.D. Patel S.V. Dvorkina O. Suspected hydroxychloroquine-associated QT-interval prolongation in a patient with systemic lupus erythematosus J. Clin. Rheumatol. 2013 19 286 288 10.1097/RHU.0b013e31829d5e50 23872551 \n16. O’Laughlin J.P. Mehta P.H. Wong B.C. Life threatening severe QTc prolongation in patient with systemic lupus erythematosus due to hydroxychloroquine Case Rep. Cardiol. 2016 4626279 10.1155/2016/4626279 27478650 \n17. Geleris J. Sun Y. Platt J. Zucker J. Baldwin M. Hripcsak G. Labella A. Manson D.K. Kubin C. Barr R.G. Observational study of hydroxychloroquine in hospitalized patients with Covid-19 N. Engl. J. Med. 2020 382 2411 2418 10.1056/NEJMoa2012410 32379955 \n18. Simpson T.F. Kovacs R. Stecker E.C. Ventricular arrhythmia risk due to hydroxychloroquine-azithromycin treatment for COVID-19 Available online: https://www.acc.org/latest-in-cardiology/articles/2020/03/27/14/00/ventricular-arrhythmia-risk-due-to-hydroxychloroquine-azithromycin-treatment-for-covid-19 (accessed on 5 June 2020) \n19. Chorin E. Dai M. Shulman E. Wadhwani L. Bar-Cohen R. Barbhaiya C. Aizer A. Holmes D. Bernstein S. Spinelli M. The QT interval in patients with COVID-19 treated with hydroxychloroquine and azithromycin Nat. Med. 2020 26 808 809 10.1038/s41591-020-0888-2 32488217 \n20. Chorin E. Wadhwani L. Magnani S. Dai M. Shulman E. Nadeau-Routhier C. Knotts R. Bar-Cohen R. Kogan E. Barbhaiya C. QT Interval Prolongation and Torsade de Pointes in Patients with COVID-19 Treated with Hydroxychloroquine/Azithromycin Heart Rhythm 2020 10.1016/j.hrthm.2020.05.014 32407884 \n21. Bankes D.L. Jin H. Finnel S. Michaud V. Knowlton C.H. Turgeon J. Stein A. Association of a novel medication risk score with adverse drug events and other pertinent outcomes among participants of the programs of all-inclusive care for the elderly Pharmacy 2020 8 87 10.3390/pharmacy8020087 32443719 \n22. Turgeon J. Michaud V. Cicali B. Population-Based Medication Risk Stratification and Personalized Medication Risk Score U.S. Patent WO2019089725 5 9 2019 \n23. Cicali B. Michaud V. Knowlton C.H. Turgeon J. Application of a novel medication-related risk stratification strategy to a self-funded employer population Benefits Q. 2018 34 49 55 \n24. Harpaz R. Haerian K. Chase H.S. Friedman C. Statistical mining of potential drug interaction adverse effects in FDA’s spontaneous reporting system Amia Annu. Symp. Proc. 2010 2010 281 285 21346985 \n25. Boustani M. Campbell N. Munger S. Maidment I. Fox C. Impact of anticholinergics on the aging brain: A review and practical application Aging Health 2008 4 311 320 10.2217/1745509X.4.3.311 \n26. Taipale H.T. Bell J.S. Uusi-Kokko M. Lönnroos E. Sulkava R. Hartikainen S. Sedative load among community-dwelling people aged 75 years and older: A population-based study Drugs Aging 2011 28 913 925 10.2165/11597800-000000000-00000 22054232 \n27. Linjakumpu T. Hartikainen S. Klaukka T. Koponen H. Kivelä S.L. Isoaho R. A model to classify the sedative load of drugs Int. J. Geriatr. Psychiatry. 2003 18 542 544 10.1002/gps.846 12789678 \n28. Taipale H.T. Hartikainen S. Bell J.S. A comparison of four methods to quantify the cumulative effect of taking multiple drugs with sedative properties Am. J. Geriatr. Pharm. 2010 8 460 471 10.1016/j.amjopharm.2010.10.004 \n29. Michaud V. Dow P. Al Rihani S.B. Deodhar M. Arwood M. Cicali B. Turgeon J. Risk of drug-induced Long QT Syndrome associated with the use of repurposed COVID-19 drugs: A systematic review medRxiv 2020 [published online ahead of print, 24 April 2020] 10.1101/2020.04.21.20066761 \n30. Turgeon J. Michaud V. Steffen L.E. Badea G. Treatment Methods Having Reduced Drug-Related Toxicity and Methods of Identifying the Likelihood of Patient Harm from Prescribed Medications U.S. Patent WO2017213825 14 12 2017 \n31. Doan J. Zakrzewski-Jakubiak H. Roy J. Turgeon J. Tannenbaum C. Prevalence and risk of potential cytochrome P450-mediated drug-drug interactions in older hospitalized patients with polypharmacy Ann. Pharm. 2013 47 324 332 10.1345/aph.1R621 \n32. MedicareBlueRx PDP Enhanced Medication Therapy Management (EMTM) Pilot Available online: https://www.yourmedicaresolutions.com/members/emtm-providers#:~:text=Enhanced%20Medication%20Therapy%20Management%20 (accessed on 7 July 2020) \n33. Centers for Medicare and Medicaid Services Program of All-Inclusive Care for the Elderly. Long Term Services & Supports Available online: https://www.medicaid.gov/medicaid/long-term-services-supports/program-all-inclusive-care-elderly/index.html (accessed on 22 July 2020) \n34. Wu C. Chen X. Cai Y. Xia J.a. Zhou X. Xu S. Huang H. Zhang L. Zhou X. Du C. Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan, China JAMA Intern. Med. 2020 180 934 943 10.1001/jamainternmed.2020.0994 32167524 \n35. Jankelson L. Karam G. Becker M.L. Chinitz L.A. Tsai M.-C. QT prolongation, torsades de pointes and sudden death with short courses of chloroquine or hydroxychloroquine as used in COVID-19: A systematic review Heart Rhythm 2020 1 8 10.1016/j.hrthm.2020.05.008 31916951 \n36. Szekely Y. Lichter Y. Shrkihe B.A. Bruck H. Oster H.S. Viskin S. Chloroquine-induced torsades de pointes in a patient with coronavirus disease 2019 Available online: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7198423/pdf/main.pdf (accessed on 6 August 2020) \n37. Woosley R.L. Chen Y. Freiman J.P. Gillis R.A. Mechanism of the cardiotoxic actions of terfenadine JAMA 1993 269 1532 1536 10.1001/jama.1993.03500120070028 8445816 \n38. Kim K.A. Park J.Y. Lee J.S. Lim S. Cytochrome P450 2C8 and CYP3A4/5 are involved in chloroquine metabolism in human liver microsomes Arch. Pharm. Res. 2003 26 631 637 10.1007/BF02976712 12967198 \n39. Lee J.Y. Vinayagamoorthy N. Han K. Kwok S.K. Ju J.H. Park K.S. Jung S.H. Park S.W. Chung Y.J. Park S.H. Association of polymorphisms of cytochrome P450 2D6 with blood hydroxychloroquine levels in patients with systemic lupus erythematosus Arthritis Rheumatol. 2016 68 184 190 10.1002/art.39402 26316040 \n40. Projean D. Baune B. Farinotti R. Flinois J.-P. Beaune P. Taburet A.-M. Ducharme J. In Vitro Metabolism of Chloroquine: Identification of CYP2C8, CYP3A4, and CYP2D6 as the Main Isoforms Catalyzing N-Desethylcholoroquine Formation Drug Metab. Dispos. 2003 31 748 754 10.1124/dmd.31.6.748 12756207 \n41. Yeh R.F. Gaver V.E. Patterson K.B. Rezk N.L. Baxter-Meheux F. Blake M.J. Eron J.J. Jr. Klein C.E. Rublein J.C. Kashuba A.D. Lopinavir/ritonavir induces the hepatic activity of cytochrome P450 enzymes CYP2C9, CYP2C19, and CYP1A2 but inhibits the hepatic and intestinal activity of CYP3A as measured by a phenotyping drug cocktail in healthy volunteers J. Acquir. Immune Defic. Syndr. 2006 42 52 60 10.1097/01.qai.0000219774.20174.64 16639344 \n42. Kumar G.N. Dykstra J. Roberts E.M. Jayanti V.K. Hickman D. Uchic J. Yao Y. Surber B. Thomas S. Granneman G.R. Potent inhibition of the cytochrome P-450 3A-mediated human liver microsomal metabolism of a novel HIV protease inhibitor by ritonavir: A positive drug-drug interaction Drug Metab. Dispos. 1999 27 902 908 10421617 \n43. U.S. Food and Drug Administration NOVIR (Ritonavir) [Drug Label] Available online: https://www.accessdata.fda.gov/drugsatfda_docs/label/2005/020659s034,020945s017lbl.pdf (accessed on 5 June 2020) \n44. Food and Drug Administration, HSS International Conference on Harmonisation; guidance on S7B Nonclinical Evaluation of the Potential for Delayed Ventricular Repolarization (QT Interval Prolongation) by Human Pharmaceuticals; availability. Notice Fed. Regist. 2005 70 61133 61134 16237859 \n45. Zhang J.J. Dong X. Cao Y.Y. Yuan Y.D. Yang Y.B. Yan Y.Q. Akdis C.A. Gao Y.D. Clinical characteristics of 140 patients infected with SARS-CoV-2 in Wuhan, China Allergy 2020 75 1730 1741 10.1111/all.14238 32077115 \n46. Zhou F. Yu T. Du R. Fan G. Liu Y. Liu Z. Xiang J. Wang Y. Song B. Gu X. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: A retrospective cohort study Lancet 2020 395 1054 1062 10.1016/S0140-6736(20)30566-3 32171076 \n47. Centers for Disease Control and Prevention Severe Outcomes Among Patients with Coronavirus Disease 2019 (COVID-19) Morb. Mortal. Wkly. Rep. 2020 27 3 69 343 346 \n48. Oakes B. Thompson K. Inouye S. Ageism Leaves Older Patients Out Of Important Clinical Trials For COVID-19, Says Harvard Researcher. WBUR Morning Edition Available online: https://www.wbur.org/commonhealth/2020/06/25/covid-19-coronavirus-ageism (accessed on 17 July 2020) \n49. Skipper C.P. Pastick K.A. Engen N.W. Bangdiwala A.S. Abassi M. Lofgren S.M. Williams D.A. Okafor E.C. Pullen M.F. Nicol M.R. Hydroxychloroquine in Nonhospitalized Adults With Early COVID-19 Available online: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7384270/pdf/aim-olf-M204207.pdf (accessed on 6 August 2020) \n50. Ross S.B. Wilson M.G. Papillon-Ferland L. Elsayed S. Wu P.E. Battu K. Porter S. Rashidi B. Tamblyn R. Pilote L. COVID-SAFER: Deprescribing guidance for hydroxychloroquine drug interactions in older adults J. Am. Geriatr. Soc. 2020 [published online ahead of print, 22 May, 2020] 10.1111/jgs.16623 32441771 \n51. Ray W.A. Murray K.T. Hall K. Arbogast P.G. Stein C.M. Azithromycin and the Risk of Cardiovascular Death N. Engl. J. Med. 2012 366 1881 1890 10.1056/NEJMoa1003833 22591294 \n52. World Health Organization The cardiotoxicity of antimalarials Proceedings of the Malaria Policy Advisory Committee Meeting Geneva, Switzerlan 22–24 March 2017 \n53. Simkó J. Csilek A. Karászi J. Lorincz I. Proarrhythmic potential of antimicrobial agents Infection 2008 36 194 206 10.1007/s15010-007-7211-8 18454341 \n54. Stas P. Faes D. Noyens P. Conduction disorder and QT prolongation secondary to long-term treatment with chloroquine Int. J. Cardiol. 2008 127 e80 e82 10.1016/j.ijcard.2007.04.055 17590456 \n55. De Olano J. Howland M.A. Su M.K. Hoffman R.S. Biary R. Toxicokinetics of hydroxychloroquine following a massive overdose Am. J. Emerg. Med. 2019 37 e2264 e2265 10.1016/j.ajem.2019.158387 \n56. Bessière F. Roccia H. Delinière A. Charrière R. Chevalier P. Argaud L. Cour M. Assessment of QT intervals in a case series of patients with coronavirus disease 2019 (COVID-19) infection treated with hydroxychloroquine alone or in combination with azithromycin in an intensive care unit JAMA Cardiol. 2020 e201787 [published online ahead of print, 1 May, 2020] 10.1001/jamacardio.2020.1787 \n57. Mercuro N.J. Yen C.F. Shim D.J. Maher T.R. McCoy C.M. Zimetbaum P.J. Gold H.S. Risk of QT Interval prolongation associated with use of hydroxychloroquine with or without concomitant azithromycin among hospitalized patients testing positive for coronavirus disease 2019 (COVID-19) JAMA Cardiol 2020 e201834 [published online ahead of print,1 May 2020] 10.1001/jamacardio.2020.1834 \n58. Gautret P. Lagiera J.C. Parolaa P. Thuan Hoanga V. Meddeba L. Mailhea M. Doudiera B. Courjone J. Giordanengoh V. Esteves Vieiraa V. Hydroxychloroquine and azithromycin as a treatment of COVID-19: Results of an openlabel non-randomized clinical trial Int. J. Antimicrob. Agents 2020 56 105949 10.1016/j.ijantimicag.2020.105949 32205204 \n59. Bauman J.L. Tisdale J.E. Chloroquine and hydroxychloroquine in the era of SARS—CoV2: Caution on their cardiac toxicity Pharmacotherapy 2020 40 387 388 10.1002/phar.2387 32285489 \n60. World Health Organization “Solidarity” Clinical Trial for COVID-19 Treatments Available online: https://www.who.int/emergencies/diseases/novel-coronavirus-2019/global-research-on-novel-coronavirus-2019-ncov/solidarity-clinical-trial-for-covid-19-treatments (accessed on 22 July 2020) \n61. Department of Health and Human Services Hoechst Marion Roussel, Inc. Baker Norton Pharmaceuticals, Inc. Terfenadine Proposal to Withdraw Approval of Two New Drug Applications and One Abbreviated New Drug Application; Opportunity for a Hearing Fed. Regist. 1997 62 1889 1892 \n62. Makkar R.R. Fromm B.S. Steinman R.T. Meissner M.D. Lehmann M.H. Female gender as a risk factor for torsades de pointes associated with cardiovascular drugs JAMA 1993 270 2590 2597 10.1001/jama.1993.03510210076031 8230644 \n63. Drici M.D. Knollmann B.C. Wang W.X. Woosley R.L. Cardiac actions of erythromycin: Influence of female sex JAMA 1998 280 1774 1776 10.1001/jama.280.20.1774 9842954 \n64. Gowda R.M. Khan I.A. Punukollu G. Vasavada B.C. Sacchi T.J. Wilbur S.L. Female preponderance in ibutilide-induced torsade de pointes Int. J. Cardiol. 2004 95 219 222 10.1016/j.ijcard.2003.04.034 15193823 \n65. Sarganas G. Garbe E. Klimpel A. Hering R.C. Bronder E. Haverkamp W. Epidemiology of symptomatic drug-induced long QT syndrome and torsade de pointes in Germany Europace 2014 16 101 108 10.1093/europace/eut214 23833046 \n66. Arunachalam K. Lakshmanan S. Maan A. Kumar N. Dominic P. Impact of drug induced long QT syndrome: A systematic review J. Clin. Med. Res. 2018 10 384 390 10.14740/jocmr3338w 29581800 \n67. U.S. National Library of Medicine Clinical Trial Search COVID-19, SARS-CoV-2 2020 Available online: https://clinicaltrials.gov/ct2/results?cond=COVID-19. (accessed on 20 July 2020)\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2077-0383",
"issue": "9(8)",
"journal": "Journal of clinical medicine",
"keywords": "COVID-19; adverse drug events; older adults; polypharmacy; simulation",
"medline_ta": "J Clin Med",
"mesh_terms": null,
"nlm_unique_id": "101606588",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "32785135",
"pubdate": "2020-08-10",
"publication_types": "D016428:Journal Article",
"references": "22591294;32407884;32441771;16615675;32380291;32936266;17546486;12756207;10421617;17590456;12789678;27478650;32438018;32171076;16237859;23482734;31477360;23872551;21346985;16639344;12967198;15193823;21335299;9842954;18454341;32379955;23833046;32167524;32077115;26316040;12235254;32285489;32443719;8445816;32275812;18070319;32214079;32936252;7629906;8230644;32488217;32205204;29581800;22054232",
"title": "Risk of Adverse Drug Events Following the Virtual Addition of COVID-19 Repurposed Drugs to Drug Regimens of Frail Older Adults with Polypharmacy.",
"title_normalized": "risk of adverse drug events following the virtual addition of covid 19 repurposed drugs to drug regimens of frail older adults with polypharmacy"
} | [
{
"companynumb": "US-OTSUKA-2020_025755",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ARIPIPRAZOLE"
},
"drugadditional": "3",
... |
{
"abstract": "Dolutegravir is an increasingly-used second-generation human immunodeficiency virus integrase strand transfer inhibitor. Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) syndrome has been described in several patients treated with raltegravir but to our knowledge, there is no previous report of DRESS syndrome associated with dolutegravir.",
"affiliations": "Department of Infectious Diseases, Saint-Pierre University Hospital, Université Libre de Bruxelles (ULB), Brussels, Belgium.;Department of Infectious Diseases, Saint-Pierre University Hospital, Université Libre de Bruxelles (ULB), Brussels, Belgium.;Department of Infectious Diseases, Saint-Pierre University Hospital, Université Libre de Bruxelles (ULB), Brussels, Belgium.",
"authors": "Martin|Charlotte|C|;Payen|Marie-Christine|MC|;De Wit|Stephane|S|",
"chemical_list": "D019380:Anti-HIV Agents; D019428:HIV Integrase Inhibitors; D006575:Heterocyclic Compounds, 3-Ring; D010078:Oxazines; D010879:Piperazines; D011728:Pyridones; C562325:dolutegravir",
"country": "England",
"delete": false,
"doi": "10.1177/0956462418764973",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0956-4624",
"issue": "29(10)",
"journal": "International journal of STD & AIDS",
"keywords": "Antiretroviral therapy; dolutegravir; human immunodeficiency virus; toxicity",
"medline_ta": "Int J STD AIDS",
"mesh_terms": "D019380:Anti-HIV Agents; D023241:Antiretroviral Therapy, Highly Active; D063926:Drug Hypersensitivity Syndrome; D004347:Drug Interactions; D004802:Eosinophilia; D005076:Exanthema; D017809:Fatal Outcome; D019428:HIV Integrase Inhibitors; D006575:Heterocyclic Compounds, 3-Ring; D006801:Humans; D008297:Male; D008875:Middle Aged; D010078:Oxazines; D010879:Piperazines; D011728:Pyridones",
"nlm_unique_id": "9007917",
"other_id": null,
"pages": "1036-1038",
"pmc": null,
"pmid": "29621952",
"pubdate": "2018-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Dolutegravir as a trigger for DRESS syndrome?",
"title_normalized": "dolutegravir as a trigger for dress syndrome"
} | [
{
"companynumb": "BE-VIIV HEALTHCARE LIMITED-BE2018067448",
"fulfillexpeditecriteria": "1",
"occurcountry": "BE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ETHAMBUTOL HYDROCHLORIDE"
},
"d... |
{
"abstract": "Gabapentin has been widely used to manage post-herpetic neuralgia, peripheral neuropathy, seizure disorders, alcohol use disorder (AUD), alcohol withdrawal, and insomnia. Although usually well tolerated, gabapentin has been reported to cause severe physiologic dependence and withdrawal. Tapering gabapentin in this context poses a significant clinical challenge, with little published information to date on meeting this challenge. This case highlights the need for patient-centered slow tapers in patients with severe gabapentin dependence and withdrawal. We present a 32-year-old female effectively treated for AUD with 1,200 mg daily dose of gabapentin, who developed gabapentin dependence and severe withdrawal. Recognizing her intolerance to gabapentin withdrawal after a brief accidental pause of medication, a taper plan was initiated using the framework of the BRAVO Protocol. On average, she reduced daily gabapentin dose by 100 mg per month until she reached 300 mg. The taper then slowed to 20-30 mg dose decrements per month. For the last 100 mg, she tapered down at 5 mg decrements every one to two weeks to 60 mg, at which point she discontinued gabapentin. The entire taper process took eighteen months. The BRAVO protocol outlines a safe and compassionate strategy. Originally developed for opioids and adapted to benzodiazepines, the use of the Bravo Protocol provides a framework for a gabapentin taper. For patients in whom gabapentin treatment leads to severe dependence and withdrawal, the BRAVO Protocol provides a practical, patient-centered framework for tapering.",
"affiliations": "Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, USA.;Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, USA.;Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, USA.",
"authors": "Deng|Huiqiong|H|0000-0001-9822-2856;Benhamou|Ori-Michael|OM|;Lembke|Anna|A|",
"chemical_list": "D014151:Anti-Anxiety Agents; D000077206:Gabapentin",
"country": "England",
"delete": false,
"doi": "10.1080/10550887.2021.1907502",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1055-0887",
"issue": "39(4)",
"journal": "Journal of addictive diseases",
"keywords": "Alcohol use disorder; BRAVO protocol; dependence; gabapentin; taper",
"medline_ta": "J Addict Dis",
"mesh_terms": "D000328:Adult; D000437:Alcoholism; D014151:Anti-Anxiety Agents; D000084862:Drug Tapering; D005260:Female; D000077206:Gabapentin; D006801:Humans; D013375:Substance Withdrawal Syndrome",
"nlm_unique_id": "9107051",
"other_id": null,
"pages": "575-578",
"pmc": null,
"pmid": "33783336",
"pubdate": "2021",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Gabapentin dependence and withdrawal requiring an 18-month taper in a patient with alcohol use disorder: a case report.",
"title_normalized": "gabapentin dependence and withdrawal requiring an 18 month taper in a patient with alcohol use disorder a case report"
} | [
{
"companynumb": "US-MYLANLABS-2021M1024737",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LISDEXAMFETAMINE"
},
"drugadditional": "3",
... |
{
"abstract": "A 14-year-old female with juvenile idiopathic arthritis presented with left-sided recurrent painful periorbital swelling of 5 months duration. MRI revealed enlargement of the left lacrimal gland with extensive inflammatory change involving the orbital and periorbital soft tissues. Lacrimal gland biopsy showed evidence of chronic inflammation, and she had intralesional steroid injection at the time of biopsy. She remained asymptomatic at 6-month follow-up visit. Although juvenile idiopathic arthritis is usually related to intraocular inflammation, it may rarely be associated with dacryoadenitis.",
"affiliations": "Department of Ophthalmology, University of California San Francisco, San Francisco, California, U.S.A.",
"authors": "Idowu|Oluwatobi O|OO|;Saifee|Murtaza|M|;Copperman|Thomas S|TS|;Kersten|Robert C|RC|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1097/IOP.0000000000001573",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0740-9303",
"issue": "36(3)",
"journal": "Ophthalmic plastic and reconstructive surgery",
"keywords": null,
"medline_ta": "Ophthalmic Plast Reconstr Surg",
"mesh_terms": "D000293:Adolescent; D001171:Arthritis, Juvenile; D001706:Biopsy; D003607:Dacryocystitis; D005260:Female; D006801:Humans; D007765:Lacrimal Apparatus; D008279:Magnetic Resonance Imaging",
"nlm_unique_id": "8508431",
"other_id": null,
"pages": "e63-e65",
"pmc": null,
"pmid": "31880684",
"pubdate": "2020",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Dacryoadenitis Associated With Juvenile Idiopathic Arthritis.",
"title_normalized": "dacryoadenitis associated with juvenile idiopathic arthritis"
} | [
{
"companynumb": "US-STRIDES ARCOLAB LIMITED-2021SP001068",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"drugadditiona... |
{
"abstract": "Among neonates of 22 to 29 weeks' gestational age (GA) who required mechanical ventilation for the treatment of respiratory distress syndrome (RDS) and clinically diagnosed pulmonary hypertension (PH), we tested our hypothesis that the association between early treatment with inhaled nitric oxide (iNO) and survival would vary according to birth size and GA.\n\n\n\nBecause iNO was not randomly prescribed to patients in this cohort, we used propensity score matching to pair a neonate who received iNO at a chronological age of ≤7 days with an unexposed neonate with similar baseline characteristics. The primary outcome was inhospital mortality, which we evaluated based on size for GA and GA strata using the Cox proportional hazards regression model.\n\n\n\nAmong 1,531 neonates who met study criteria, we created a propensity score matched cohort of 615 pairs of neonates (iNO-exposed and unexposed). The risk of inhospital mortality for iNO-exposed neonates was observed only in the minority (<10%) who were large for GA, though this finding did not persist when matching for illness severity.\n\n\n\nEarly treatment with iNO is not associated with survival in most extremely premature neonates with RDS and clinically diagnosed PH when stratified for birth size or GA.",
"affiliations": "Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, Minnesota.;Division of Neonatal Medicine, Mayo Clinic, Rochester, Minnesota.;Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota.;Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota.;Center for Research, Education and Quality, Pediatrix Medical Group, Sunrise, Florida.;Division of Neonatal Medicine, Mayo Clinic, Rochester, Minnesota.",
"authors": "Udland|Carley J|CJ|;Carey|William A|WA|;Weaver|Amy L|AL|;Mara|Kristin C|KC|;Clark|Reese H|RH|;Ellsworth|Kevin R|KR|",
"chemical_list": "D009569:Nitric Oxide",
"country": "United States",
"delete": false,
"doi": "10.1055/s-0039-1677799",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0735-1631",
"issue": "36(14)",
"journal": "American journal of perinatology",
"keywords": null,
"medline_ta": "Am J Perinatol",
"mesh_terms": "D000280:Administration, Inhalation; D001724:Birth Weight; D016208:Databases, Factual; D019115:Fasciitis, Necrotizing; D005320:Fetal Macrosomia; D005865:Gestational Age; D017052:Hospital Mortality; D006801:Humans; D006976:Hypertension, Pulmonary; D062071:Infant, Extremely Premature; D007231:Infant, Newborn; D007234:Infant, Premature; D007235:Infant, Premature, Diseases; D007236:Infant, Small for Gestational Age; D009569:Nitric Oxide; D057216:Propensity Score; D016016:Proportional Hazards Models; D012127:Respiratory Distress Syndrome, Newborn",
"nlm_unique_id": "8405212",
"other_id": null,
"pages": "1471-1480",
"pmc": null,
"pmid": "30674051",
"pubdate": "2019-12",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Birth Size and Gestational Age Specific Outcomes of Inhaled Nitric Oxide Therapy in Preterm Neonates with Clinically Diagnosed Pulmonary Hypertension.",
"title_normalized": "birth size and gestational age specific outcomes of inhaled nitric oxide therapy in preterm neonates with clinically diagnosed pulmonary hypertension"
} | [
{
"companynumb": "US-SYNEX-T202004470",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "NITRIC OXIDE"
},
"drugadditional": null,
... |
{
"abstract": "A young male schizophrenic presented with neuroleptic malignant syndrome (NMS). Risperidone was the probable precipitating agent. Rigidity and elevated CPK levels poorly responded to bromocriptine, but showed good response to dantrolene. The role of specific treatment and the differential response of the symptom clusters are discussed.",
"affiliations": "G. VENKATASUBRAMANIAN, MBBS., Junior Resident, Department of Psychiatry, National Institute of Mental Health and Neurosciences, Bangalore-560029.",
"authors": "Venkatasubramanian|G|G|;Yogananda|B H|BH|;Gangadhar|B N|BN|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": null,
"fulltext": "Indian Journal of Psychiatry, 2000, 42 (1), 101-103\nRISPERIDONE-INDUCED NEUROLEPTIC MALIGNANT\nSYNDROME : A CASE REPORT\nG. VENKATASUBRAMANIAN, B.H. YOGANANDA & B.N. GANGADHAR\nABSTRACT\nA young male schizophrenic presented with neuroleptic malignant syndrome (NMS).\nRisperidone was the probable precipitating agent. Rigidity and elevated CPK levels poorly responded\nto bromocriptine, but showed good response to dantrolene. The role of specific treatment and the\ndifferential response of the symptom clusters are discussed.\nKey words : NMS, risperidone, dantrolene and bromocriptine\nNeuroleptic malignant syndrome (NMS)\nis a rare, but potentially fatal and idiosyncratic\nreaction to neuroleptics (Delay & Deniker, 1968;\nHenderson & Wooten,1981; Morris etal, 1980).\nThis syndrome consists of extra-pyramidal signs\nof rigidity and tremor; autonomic signs of\nhyperthermia, labile blood pressure, tachycardia,\ntachypnea, fever and diaphoresis, cognitive\ndic\nturbances like confusion and altered\nsensorium; biochemical disturbances in the form\nof elevated creatine phosphokinase (CPK)\n(Delay & Deniker, 1968; Henderson & Wooten,\n1981). NMS has occurred mostly in patients\nreceiving typical antipsychotics (Shalev et\nal.,1989). There are reports of NMS following\natypical neuroleptics like risperidone, clozapine\n(Hasan & Buckley,1998) and olanzapine\n(Johnson & Bruxner.1998). We report a case of\nNMS involving risperidone and the usefulness\nof specific treatment, particularly bromocriptine\nand dantrolene.\nCASE REPORT\nMr.A, a 22 year old male, is a case of\nparanoid schizophrenia (DSM-IV) of four year\nduration with positive as well as negative\nsymptoms, and without any treatment. He was\nstarted on treatment with injection fluphenazine\ndecanoate 25 mg i.m. fortnightly (suspected poor\ncompliance) and chlorpromazine 400 mg PO/day.\nIn view of prominent negative symptoms, severe\nEPS and no perceptible improvement with above\ndrugs for four weeks, risperidone was started and\nwas increased to 4 mg/day gradually. Six days\nafter starting risperidone, the patient developed\nmild confusion and agitation. He left the hospital\nagainst medical advice. Three days later, the\npatient presented to the hospital with features of\ncognitive disturbances in the form of confusion\nand altered sensorium; autonomic instability in\nthe form of profuse diaphoresis, tachycardia (100-120 beats per min.), tachypnea (22-26 respirations\nper min), labile blood pressure (systolic varying\nbetween 130-150 mm Hg and diastolic varying\nbetween 90-100 mm Hg), fever (100 F);\nneuromuscular disturbances in the form of\ngeneralized, extreme rigidity and tremors He was\nwithout any documented infection The CPK level\nat the time of admission was 4438U/L. His WBC\ncount was 14,600 per cu. mm The results of\ncranial CT scan, chest X-ray, lumbar CSF\nanalysis, metabolic profile and urine analysis were\nwithin normal limits.\nA diagnosis of NMS (Levenson,1985)\nwas made. The antipsychotics were stopped and\n101\nG. VENKATASUBRAMANIAN ef al.\nsupportive care was instituted There was\nimprovement in his autonomic instability and CPK\nlevel decreased to 1908 U/L. Other clinical\nfeatures continued to worsen The patient was\nstarted on bromocriptine on the fourth day. After\n36 hours of treatment with bromocriptine (7.5 mg/\nday, PO) there was improvement in cognitive\ndisturbances But, the rigidity remained the same\nand the CPK level rose upto 2957 U/L. So the\npatients was started on dantrolene which was\ngradually increased upto 200 mg/day at the rate\nof 50 mg every two days. Bromocriptine was\nincreased upto 20 mg/day at the rate of 5 mg\nevery two days Neuromuscular disturbances\ndisappeared gradually over a period of 10 days\nand CPK level came down to 216 U/L. Dantrolene\nwas tapered and stop over two days because of\nabnormal liver function tests (elevation of serum\nglutamate oxaloacetate transferase, serum\nglutamate pyruvate transferase, and alkaline\nphosphatase levels) after starting the drug. With\nthe discontinuation of dantrolene, the rigidity reemerged and the CPK level rose from 216U/L\nto 918 U/L (Figure) As literature evidence favours\ndosage of bromocriptine upto 60 mg/day (Caroff\n&Mann, 1993), an attempt was made to increase\nbromocriptine It had to be aborted due to reemergence of symptoms like irritability and sleep\ndisturbances The rigidity continued to worsen and\nthe CPK level was increasing. Dantrolene was\nrestarted after five days and all signs improved\n* U M CMUMLmoowof imsnan\nFig Effect of Dantrolene on serum CPK Although, there was\nan mstantial initial drop in serum CPK. it rose again while\nthe patient was only on bromocriptine and began to fall only\nafter treatment with Dantrolene Stopping this drug led to CPK\nelevation which again responded to Dantrolene treatment\nand CPK level dropped down to 213 U/L in next\ntwo days Repetition of liver function tests after\nrestarting dantrolene did not show any\nabnormality. After ten days of patient being in a\nstable condition, bromocriptine and dantrolene\nwere tapered and stopped. The patient recovered\nfully without any residual deficit.\nDISCUSSION\nOur patient was on typical neuroleptics\nfor nearly one month before starting treatment\nwith risperidone The manifestations on NMS in\nthis case had been noticed within a week after\nstarting risperidone. It has been observed that\nmajority of patients (66%) who develop NMS do\nso within the first week of treatment with the\noffending agent (DSM-IV). It is likely, therefore,\nin this case risperidone was responsible in either\ncausing or precipitating NMS.\nWe suggest that the clinical features of\nNMS can be grouped into four clusters based on\ntheir response to treatment viz., autonomic\ndisturbances, cognitive disturbances,\nneuromuscular disturbances and biochemical\ndisturbances. Autonomic disturbances decreased\nwith the stoppage of antipsychotics and supportive\ncare. Cognitive disturbances were improved by\ntreatment with bromocriptine. Neuromuscular\ndisturbances and biochemical perturbations\nrequired dantrolene (Figure). Dantrolene is a\nskeletal muscle relaxant, which acts mostly\nthrough peripheral mechanism in improving the\nrigidity Two possible mechanisms have been\nimplicated for rigidity in NMS First one, which\npostulates the central dopaminergic blockade,\nmay not fully explain the rigidity in NMS, as\nbromocriptine, which is a dopamine agonist, was\nineffective. Second mechanism is the peripheral\none, which involves an impairment of the\nsarcoplasmic reticulum re-uptake of calcium in a\ngenetically abnormal muscle as is proven in\nmalignant hyperthermia (Bismuth et al. ,1984). Our\ncase report supports the latter mechanism, since\nthe rigidity continued to worsen when the patient\nwas on bromocriptine alone and it promptly\nimproved after the reinstitution of dantrolene.\n102\nRISPERIDONE-INDUCED NEUROLEPTIC MALIGNANT SYNDROME\nIn summary, risperidone can cause or\nprecipitate NMS. There may be different clusters\nof symptoms, which may not respond to\nconservative treatment alone. Specific treatment\nlike dantrolene may be necessary particularly\nfor neuromuscular disturbances.\nREFERENCE\nantipsychotics and the neuroleptic malignant\nsyndrome : a review and critique. American\nJournal of Psychiatry, 155, 1113-1116.\nHenderson,V.W. & Wooten,G.F.(1981)\nNeuroleptic Malignant Syndrome A\npathogenetic role for dopamine receptor\nblockade? Neurology, 31, 132-137.\nBismuth, C , de Rohan-Chabot, P.,\nGoulon, M & Raphael.J.C. (1984) Dantrolene -\nA new therapeutic approach to the neuroleptic\nmalignant syndrome. Acta Neurologica\nScandinavica, 70, (suppl. 100), 193-198.\nCaroff, S.N. & Mann, S.C. (1993)\nNeuroleptic malignant syndrome, Medical Clinics\nof North America, 77, 1, 185-202.\nDelay.J. & Deniker,P.(1968) Drug\ninduced extrapyramidal syndromes. In :\nHandbook of Clinical Neurology, Vol.6, (Eds.)\nVinken.P. & Bruyn.G.W., Amesterdam, North\nHolland : Diseases of Basal Ganglia, 248-266.\nHasan.S. & Buckley,P.(1998) Novel\nJohnson, V. & Bruxner, G. (1998)\nNeuroleptic malignant syndrome associated with\nolanzapine. Australian and New Zealand Journal\nof Psychiatry, 32, 884-886.\nLevenson,J.L.(1985) Neuroleptic\nmalignant syndrome. American Journal of\nPsychiatry, 142, 1137-1145.\nMorris, H.H., McCormick, W.F. &\nReinarz.J.A. (1980) Neuroleptic malignant\nsyndrome. Archives of Neurology, 37, 462-463.\nShalev.A., Hermesh.K. & Munitz.K.\n(1989) Mortality from neuroleptic malignant\nsyndrome. Journal of Clinical Psychiatry, 50,\n18-25.\nG VENKATASUBRAMANIAN. MBBS.Junior Resident. B.H. YOGANANDA, MD. SeniorResident &BN. GANGADHAR', MD,\nAdditional Professor. Department of Psychiatry, National Institute of Mental Health and Neurosciences, Bangalore-560029.\n* Correspondence\n103\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "0019-5545",
"issue": "42(1)",
"journal": "Indian journal of psychiatry",
"keywords": "NMS; dantrolene and bromocriptine; risperidone",
"medline_ta": "Indian J Psychiatry",
"mesh_terms": null,
"nlm_unique_id": "0013255",
"other_id": null,
"pages": "101-3",
"pmc": null,
"pmid": "21407918",
"pubdate": "2000-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Risperidone-induced neuroleptic malignant syndrome : a case report.",
"title_normalized": "risperidone induced neuroleptic malignant syndrome a case report"
} | [
{
"companynumb": "CN-MLMSERVICE-20220530-3583195-1",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "LORAZEPAM"
},
"drugadditional": "1",
... |
{
"abstract": "Combined anti-cytotoxic-T-lymphocyte antigen 4 and programmed cell death 1 blockade induced high rates of immune-related adverse events in patients with renal cell carcinoma. However, the safety of reinitiating anti-programmed cell death 1 monotherapy for patients who discontinued combination therapy due to immune-related adverse events is largely unknown.\nWe report the case of 74-year-old man who received combination therapy with anti-cytotoxic-T-lymphocyte antigen 4 and programmed cell death 1 inhibitors for advanced renal cell carcinoma. After three cycles of combination therapy, he complained severe immune-related adverse events including grade 3 nausea and anorexia, and grade 3 diarrhea, leading to discontinuation of the therapy. He started readministration of anti-programmed cell death 1 monotherapy at 41 weeks after discontinuation due to the new lung metastatic lesion. Importantly, he experienced only grade 1 diarrhea, which can be controlled with prednisolone.\nThe readministration of anti-programmed cell death 1 monotherapy with close monitoring can be an acceptable treatment even after discontinuation of combination therapy.",
"affiliations": "Department of Urology Osaka University Graduate School of Medicine Osaka Japan.;Department of Urology Osaka University Graduate School of Medicine Osaka Japan.;Department of Urology Osaka University Graduate School of Medicine Osaka Japan.;Department of Urology Osaka University Graduate School of Medicine Osaka Japan.;Department of Urology Osaka University Graduate School of Medicine Osaka Japan.;Department of Urology Osaka University Graduate School of Medicine Osaka Japan.;Department of Urology Osaka University Graduate School of Medicine Osaka Japan.;Department of Urology Osaka University Graduate School of Medicine Osaka Japan.",
"authors": "Maegawa|Yoko|Y|;Kato|Taigo|T|https://orcid.org/0000-0002-8681-1407;Fukuhara|Shinichiro|S|;Kiuchi|Hiroshi|H|;Imamura|Ryoichi|R|;Uemura|Motohide|M|;Nonomura|Norio|N|;Fujita|Kazutoshi|K|",
"chemical_list": null,
"country": "Australia",
"delete": false,
"doi": "10.1002/iju5.12173",
"fulltext": "\n==== Front\nIJU Case Rep\nIJU Case Rep\n10.1002/(ISSN)2577-171X\nIJU5\nIJU Case Reports\n2577-171X John Wiley and Sons Inc. Hoboken \n\n10.1002/iju5.12173\nIJU512173\nCase Report\nCase Report\nResumption of anti‐programmed cell death 1 monotherapy for severe immune‐related adverse events experienced patient with renal cell carcinoma\nRestart anti‐PD‐1 therapy for irAE patientsY Maegawa et al.Maegawa Yoko \n1\n Kato Taigo https://orcid.org/0000-0002-8681-1407\n1\n\n2\nkato@uro.med.oaska-u.ac.jp Fukuhara Shinichiro \n1\n Kiuchi Hiroshi \n1\n Imamura Ryoichi \n1\n Uemura Motohide \n1\n\n2\n Nonomura Norio \n1\n Fujita Kazutoshi \n1\n \n1 \nDepartment of\nUrology\nOsaka University Graduate School of Medicine\nOsaka\nJapan\n\n\n2 \nDepartment of\nUrological Immuno‐oncology\nOsaka University Graduate School of Medicine\nOsaka\nJapan\n\n* Correspondence: Taigo Kato M.D., Ph.D., Department of Urology, Osaka University Graduate School of Medicine, 2‐2 Yamadaoka, Suita, Osaka 565‐0871, Japan. Email: kato@uro.med.oaska-u.ac.jp\n\n25 6 2020 \n9 2020 \n3 5 10.1002/iju5.v3.5176 179\n13 4 2020 05 5 2020 12 5 2020 © 2020 The Authors. IJU Case Reports published by John Wiley & Sons Australia, Ltd on behalf of the Japanese Urological AssociationThis is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.Introduction\nCombined anti‐cytotoxic‐T‐lymphocyte antigen 4 and programmed cell death 1 blockade induced high rates of immune‐related adverse events in patients with renal cell carcinoma. However, the safety of reinitiating anti‐programmed cell death 1 monotherapy for patients who discontinued combination therapy due to immune‐related adverse events is largely unknown.\n\nCase presentation\nWe report the case of 74‐year‐old man who received combination therapy with anti‐cytotoxic‐T‐lymphocyte antigen 4 and programmed cell death 1 inhibitors for advanced renal cell carcinoma. After three cycles of combination therapy, he complained severe immune‐related adverse events including grade 3 nausea and anorexia, and grade 3 diarrhea, leading to discontinuation of the therapy. He started readministration of anti‐programmed cell death 1 monotherapy at 41 weeks after discontinuation due to the new lung metastatic lesion. Importantly, he experienced only grade 1 diarrhea, which can be controlled with prednisolone.\n\nConclusion\nThe readministration of anti‐programmed cell death 1 monotherapy with close monitoring can be an acceptable treatment even after discontinuation of combination therapy.\n\nimmune checkpoint inhibitorimmune‐related adverse event source-schema-version-number2.0cover-dateSeptember 2020details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:5.8.9 mode:remove_FC converted:03.09.2020\n\n\nMaegawa \nY \n, \nKato \nT \n, \nFukuhara \nS \n, et al.\nResumption of anti‐programmed cell death 1 monotherapy for severe immune‐related adverse events experienced patient with renal cell carcinoma\n. IJU Case Rep . 2020 ; 3 : 176 –179\n.\n==== Body\nAbbreviations & Acronyms\nCTcomputed tomography\n\nCTLA‐4cytotoxic‐T‐lymphocyte antigen 4\n\nICIimmune checkpoint inhibitor\n\nIpiipilimumab\n\nirAEimmune‐related adverse event\n\nNivonivolumab\n\nPD‐1programmed cell death 1\n\nPSLprednisolone\n\nRCCrenal cell carcinoma\n\n\nKeynote message\nThe safety of resuming anti‐PD‐1 monotherapy for patients who discontinued ICIs due to irAEs is still unknown. We report an instructive case with advanced RCC who carefully resumed anti‐PD‐1 inhibitor after discontinuation of dual CTLA‐4 and PD‐1 blockade due to severe irAEs.\n\n\n\n\nIntroduction\nICIs have revolutionized the field of cancer in recent years and remarkably improved the prognosis of several types of cancer.\n1\n As ICIs have been used over the years, a certain number of patients face discontinuation of ICIs due to severe and sometime life‐threatening irAEs.\n2\n Especially, combination of CTLA‐4 and PD‐1 inhibitors, ipilimumab and nivolumab, was shown to increase the incidence of irAEs compared to that of either monotherapy despite of the high response rate.\n3\n, \n4\n\n\n\nNormally, patients with high‐grade irAEs require discontinuation of both ipilimumab and nivolumab with the administration of corticosteroids. After treatment‐free duration, physicians often need to choose secondary treatment in the face of progressive disease. Considering that most severe toxicities occur within 3 months after initiation of combination therapy, readministration of anti‐PD‐1 monotherapy can be the optional treatment to achieve durable disease control. However, the safety and efficacy of resuming anti‐PD‐1 monotherapy is still largely unknown.\n\nHere, we report an instructive case with advanced RCC who carefully resumed anti‐PD‐1 inhibitor after discontinuation of dual CTLA‐4 and PD‐1 blockade due to severe irAEs.\n\nCase presentation\nA 74‐year‐old man with no significant medical history presented with his left clavicular pain. A chest X‐ray showed a neoplastic fracture in the left clavicle. Abdominal and chest CT examination revealed the renal mass with early enhancement in right kidney with 35 mm diameter (Fig. 1). In addition, CT scan showed osteolytic mass in the left clavicle, left iliac crest, and small nodule in middle lobe of the right lung (Fig. 1). It is the basic policy of our institution to recommend radical nephrectomy for clinical stage T1 and T2, and subsequently he underwent laparoscopic radical nephrectomy. The pathological examination showed clear cell RCC (Fuhrman grade 2) with tumor invasion of perirenal fat, leading to the diagnosis of stage pT3aN0M1. With a diagnosis of left clavicle and iliac bone metastasis, the patient received the treatment with zoledronic acid 4 mg intravenously every 4 weeks.\n\nFig. 1 Abdominal and chest CT scan at the first diagnosis. Abdominal and chest CT shows the renal mass with early enhancement in right kidney with 35 mm diameter (a), osteolytic mass in the left clavicle (b) and left iliac crest (c), and small nodule in middle lobe of the right lung (d).\n\nAccording to the International Metastatic RCC Database Consortium score, the patient was classified as poor risk (<1 year from time of diagnosis to systemic therapy, Karnofsky Performance Status 70, low hemoglobin value) and began to receive nivolumab plus ipilimumab combination therapy for his multiple metastatic sites.\n\nAfter one cycle of combination therapy, he felt listlessness of the right forearm and difficulty in speaking clearly. The brain magnetic resonance imaging showed a brain metastasis and cyber knife therapy was performed for brain metastasis (Fig. 2). In parallel with radiotherapy, the patient received the second course of the combination therapy. Two weeks later, he complained of grade 3 nausea and anorexia. He also experienced grade 3 diarrhea, grade 2 liver dysfunction, and grade 1 rash, leading to discontinuation of third course of combination therapy (Fig. 2). We suspected severe irAEs due to various symptoms, but we were unable to exclude the possibility of bacterial enteritis and started the administration of 40 mg (1 mg/kg per day) PSL for the patient. With the negative test result of fecal culture, the dose of PSL was increased to 80 mg and irAEs gradually improved within next 7 weeks. Finally, the dose of PSL was tapered to 7.5 mg. Metastatic sites maintained partial response for 30 weeks after the discontinuation of ICIs without any additional therapy (Fig. 3a). However, follow‐up CT examination showed the new lung metastatic lesion after 41 weeks after discontinuation (Fig. 3b) and we decided to start readministration of nivolumab monotherapy (Fig. 4). As a result, he experienced only grade 1 diarrhea after three cycles of nivolumab, which can be controlled with the temporary increasing dose of PSL. Importantly, any other irAEs such as nausea, anorexia, liver dysfunction, and rash did not appear after the introduction of nivolumab monotherapy.\n\nFig. 2 Clinical course of the case with severe irAEs induced by ipilimumab and nivolumab. After two cycles of combination therapy, the patient showed severe irAEs such as grade 3 nausea and anorexia, and grade 3 diarrhea. All symptoms gradually resolved within next 7 weeks after discontinuation of combination therapy and additional treatment of PSL.\n\nFig. 3 Sequential CT scans after discontinuation of combination therapy. (a) Abdominal CT scans show that the metastatic site of iliac bone maintained partial response for 30 weeks after the discontinuation of combination therapy without any additional therapy. After 41 weeks after discontinuation follow‐up, CT showed reduction of iliac bone metastatic sites. (b) Chest CT scan shows the new lung metastatic lesion at 41 weeks after discontinuation and the patient was diagnosed as progressive disease. The number of weeks indicates duration after the first initiation of combination therapy.\n\nFig. 4 Clinical course after the readministration of nivolumab for progressive disease. The patient experienced only grade 1 diarrhea after readministration of nivolumab. The symptom promptly resolved with temporary increasing dose of PSL.\n\nFollow‐up CT scan at 12 weeks after the introduction of nivolumab showed the increase in lung and iliac bone metastasis, leading to withdrawal of nivolumab and subsequent axitinib therapy.\n\nDiscussion\nImmunotherapy targeting immune checkpoint is now the most attractive therapy in cancer field.\n1\n Particularly, combination of ICIs expands the application to various types of cancer as the first‐line therapy because of the high response rate.\n5\n At the same time, it is undeniable that a certain population of patients are forced to discontinue combination therapy because of severe irAEs. However, there is no conclusive evidence that determine which second‐line therapy is suitable in patients with progressive disease after discontinuation of ICIs.\n\nIn this study, we report a patient who experienced severe irAEs while on combination therapy of ipilimumab and nivolumab, and were cautiously reinitiated with anti‐PD‐1 monotherapy after certain duration of discontinuation. Interestingly, at the reinitiation phase with nivolumab, the patient experienced only grade 1 diarrhea. Pollack et al. reported almost 40% of 80 melanoma patients who discontinued combination therapy experienced recurrent or clinically significant distinct (de novo) irAEs with anti‐PD‐1 monotherapy reinitiation.\n6\n They concluded that most of recurrent or distinct irAEs were low‐grade and manageable with corticosteroid treatment, while they had one case of grade 5 Steven–Johnson syndrome. In other study, the same or different irAEs occurred in 55% of patients with resuming anti‐PD‐1 or anti‐PD‐L1 therapy and were not found to be more severe than the first.\n7\n Given that major irAEs (e.g. colitis, hypophysitis) of combination therapy are largely associated with ipilimumab at the first line of treatment, anti‐PD‐1 resumption with careful monitoring of irAEs may be one of the options to achieve further clinical response, although further cases are needed to judge the efficacy of anti‐PD‐1 resumption.\n\nIn conclusion, with intent to “cure” for cancer, the readministration of anti‐PD‐1 monotherapy may be considered as a durable and feasible option for RCC patients who discontinued combination therapy.\n\nConflict of interest\nThe authors declare no conflict of interest.\n\nAcknowledgments\nThe authors thank the patient and his family, who participated in this case report, for their important contributions.\n==== Refs\nReferences\n1 \n\nHavel \nJJ \n, \nChowell \nD \n, \nChan \nTA \n. The evolving landscape of biomarkers for checkpoint inhibitor immunotherapy\n. Nat. Rev. Cancer \n2019 ; 19 : 133 –50\n.30755690 \n2 \n\nRotte \nA \n. Combination of CTLA‐4 and PD‐1 blockers for treatment of cancer\n. J. Exp. Clin. Cancer Res. \n2019 ; 38 : 255 .31196207 \n3 \n\nJohnson \nDB \n, \nBalko \nJM \n, \nCompton \nML \n\net al\nFulminant myocarditis with combination immune checkpoint blockade\n. N. Engl. J. Med. \n2016 ; 375 : 1749 –55\n.27806233 \n4 \n\nPostow \nMA \n, \nChesney \nJ \n, \nPavlick \nAC \n\net al\nNivolumab and ipilimumab versus ipilimumab in untreated melanoma\n. N. Engl. J. Med. \n2015 ; 372 : 2006 –17\n.25891304 \n5 \n\nMotzer \nRJ \n, \nRini \nBI \n, \nMcDermott \nDF \n\net al\nNivolumab plus ipilimumab versus sunitinib in first‐line treatment for advanced renal cell carcinoma: extended follow‐up of efficacy and safety results from a randomised, controlled, phase 3 trial\n. Lancet Oncol. \n2019 ; 20 : 1370 –85\n.31427204 \n6 \n\nPollack \nMH \n, \nBetof \nA \n, \nDearden \nH \n\net al\nSafety of resuming anti‐PD‐1 in patients with immune‐related adverse events (irAEs) during combined anti‐CTLA‐4 and anti‐PD1 in metastatic melanoma\n. Ann. Oncol. \n2018 ; 29 : 250 –5\n.29045547 \n7 \n\nSimonaggio \nA \n, \nMichot \nJM \n, \nVoisin \nAL \n\net al\nEvaluation of readministration of immune checkpoint inhibitors after immune‐related adverse events in patients with cancer\n. JAMA Oncol. \n2019 ; 5 : 1310 .\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2577-171X",
"issue": "3(5)",
"journal": "IJU case reports",
"keywords": "immune checkpoint inhibitor; immune‐related adverse event",
"medline_ta": "IJU Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101764958",
"other_id": null,
"pages": "176-179",
"pmc": null,
"pmid": "32914066",
"pubdate": "2020-09",
"publication_types": "D002363:Case Reports",
"references": "31169866;27806233;25891304;29045547;31427204;30755690;31196207",
"title": "Resumption of anti-programmed cell death 1 monotherapy for severe immune-related adverse events experienced patient with renal cell carcinoma.",
"title_normalized": "resumption of anti programmed cell death 1 monotherapy for severe immune related adverse events experienced patient with renal cell carcinoma"
} | [
{
"companynumb": "JP-BRISTOL-MYERS SQUIBB COMPANY-BMS-2018-114352",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "NIVOLUMAB"
},
"drugaddi... |
{
"abstract": "Serotonergic medications are used for the prevention and treatment of depression during pregnancy. Selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors (SNRIs) can cause poor neonatal adaptation, which has been attributed to withdrawal versus toxicity. Bupropion, a norepinephrine-dopamine reuptake inhibitor, is often used as an adjunctive agent to selective serotonin reuptake inhibitors or SNRIs for refractory depression. Quetiapine, an atypical antipsychotic, may also be used in more complex cases. When combined with serotonergic drugs, bupropion and quetiapine are associated with increased risk of serotonin syndrome in adults. We describe a neonate exposed to venlafaxine (an SNRI), bupropion, and quetiapine in utero who presented nearly immediately after birth with encephalopathy and abnormal movements. The severity and rapidity of symptoms may be attributable to potentiation of venlafaxine's serotonergic effects by bupropion and quetiapine. Neonatal providers should be aware of maternal medications and prepare for possible adverse effects, particularly from common psychotropic exposures.",
"affiliations": "University of Colorado School of Medicine, Aurora, Colorado; and michelle.brajcich@childrenscolorado.org.;University of Colorado School of Medicine, Aurora, Colorado; and.;Children's Hospital Colorado, Aurora, Colorado.;Children's Hospital Colorado, Aurora, Colorado.;Children's Hospital Colorado, Aurora, Colorado.",
"authors": "Brajcich|Michelle R|MR|;Palau|Mauricio A|MA|;Messer|Ricka D|RD|;Murphy|Michael E|ME|;Marks|Jill|J|",
"chemical_list": "D000928:Antidepressive Agents; D014179:Neurotransmitter Uptake Inhibitors; D016642:Bupropion; D000069348:Quetiapine Fumarate; D000069470:Venlafaxine Hydrochloride",
"country": "United States",
"delete": false,
"doi": "10.1542/peds.2019-2250",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0031-4005",
"issue": "147(2)",
"journal": "Pediatrics",
"keywords": null,
"medline_ta": "Pediatrics",
"mesh_terms": "D000928:Antidepressive Agents; D001714:Bipolar Disorder; D001927:Brain Diseases; D016642:Bupropion; D004359:Drug Therapy, Combination; D004409:Dyskinesia, Drug-Induced; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D014179:Neurotransmitter Uptake Inhibitors; D011247:Pregnancy; D011248:Pregnancy Complications; D000069348:Quetiapine Fumarate; D013313:Stress Disorders, Post-Traumatic; D000069470:Venlafaxine Hydrochloride",
"nlm_unique_id": "0376422",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "33504611",
"pubdate": "2021-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Why the Maternal Medication List Matters: Neonatal Toxicity From Combined Serotonergic Exposures.",
"title_normalized": "why the maternal medication list matters neonatal toxicity from combined serotonergic exposures"
} | [
{
"companynumb": "US-APOTEX-2021AP004771",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "VENLAFAXINE HYDROCHLORIDE"
},
"drugadditional": ... |
{
"abstract": "Methotrexate (MTX) is a commonly used anti-metabolite agent. Long-term MTX treatment can cause MTX-related lymphoproliferative disorder (MTX-LPD). T-cell LPDs comprise a small fraction of MTX-LPDs. Epstein-Barr virus (EBV)+ tumor cells are rarely detected in MTX-related T-cell LPDs (MTX T-LPDs). Therefore, there have been very few reports of EBV+ MTX T-LPD. We encountered a case of cutaneous MTX T-LPD with a unique cellular phenotype. The patient was a 71-year-old Japanese man with rheumatoid arthritis treated with MTX for 6 years. He was referred to our department with a 6-month history of red plaques and ulcerated lesions in both lower legs and a 2-week history of high fever and fatigue. Cutaneous specimens showed that medium-sized atypical lymphocytes were positive for CD3, CD4, CD30, CD56, and in situ hybridization for EBV-encoded RNA. The patient was diagnosed with cutaneous MTX T-LPD. Four months after discontinuation of MTX, the skin lesions had disappeared. This is the first report of cutaneous MTX T-LPD with CD4+CD30+CD56+EBV+ tumor cells.",
"affiliations": "Department of Dermatology, National Hospital Organization Sagamihara National Hospital Sagamihara, Kanagawa, Japan.;Department of Dermatology, National Hospital Organization Sagamihara National Hospital Sagamihara, Kanagawa, Japan.;Department of Dermatology, National Hospital Organization Sagamihara National Hospital Sagamihara, Kanagawa, Japan.;Department of Dermatology, National Hospital Organization Sagamihara National Hospital Sagamihara, Kanagawa, Japan.;Department of Rheumatology, National Hospital Organization Sagamihara National Hospital Sagamihara, Kanagawa, Japan.;Department of Rheumatology, National Hospital Organization Sagamihara National Hospital Sagamihara, Kanagawa, Japan.;Department of Rheumatology, National Hospital Organization Sagamihara National Hospital Sagamihara, Kanagawa, Japan.;Department of Diagnostic Pathology, National Hospital Organization Sagamihara National Hospital Sagamihara, Kanagawa, Japan.;Department of Diagnostic Pathology, National Hospital Organization Sagamihara National Hospital Sagamihara, Kanagawa, Japan.;Department of Dermatology, National Hospital Organization Sagamihara National Hospital Sagamihara, Kanagawa, Japan.",
"authors": "Omori|Issei|I|;Kawanabe|Ruriko|R|;Hashimoto|Yuki|Y|;Mitsui|Aya|A|;Kodama|Kako|K|;Nogi|Shinichi|S|;Tsuno|Hirotaka|H|;Horita|Ayako|A|;Saito|Ikuo|I|;Ohmatsu|Hanako|H|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2160-1992",
"issue": "11(2)",
"journal": "American journal of blood research",
"keywords": "Methotrexate; lymphoproliferative disorder; methotrexate-related T-cell lymphoproliferative disorder",
"medline_ta": "Am J Blood Res",
"mesh_terms": null,
"nlm_unique_id": "101569577",
"other_id": null,
"pages": "163-167",
"pmc": null,
"pmid": "34079630",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": "8026822;28380678;17117491;8656264;31257346;27335685;23560463;7674250;18461290;28676912;10955685",
"title": "Cutaneous methotrexate-related T-cell lymphoproliferative disorder with CD4, CD30, CD56, EBV-positive tumor cell infiltration: a case illustration and a brief review.",
"title_normalized": "cutaneous methotrexate related t cell lymphoproliferative disorder with cd4 cd30 cd56 ebv positive tumor cell infiltration a case illustration and a brief review"
} | [
{
"companynumb": "JP-ACCORD-228463",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"drugadditional": "3",
"dru... |
{
"abstract": "Spontaneous remission of primary hyperparathyroidism (PHPT) due to necrosis and haemorrhage of parathyroid adenoma, the so-called 'parathyroid auto-infarction' is a very rare, but previously described phenomenon. Patients usually undergo parathyroidectomy or remain under close clinical and biochemical surveillance. We report two cases of parathyroid auto-infarction diagnosed in the same tertiary centre; one managed surgically and the other conservatively up to the present time. Case #1 was a 51-year old man with PHPT (adjusted (adj.) calcium: 3.11 mmol/L (reference range (RR): 2.20-2.60 mmol/L), parathyroid hormone (PTH) 26.9 pmol/L (RR: 1.6-6.9 pmol/L) and urine calcium excretion consistent with PHPT) referred for parathyroidectomy. Repeat biochemistry 4 weeks later at the surgical clinic showed normal adj. calcium (2.43 mmol/L) and reduced PTH. Serial ultrasound imaging demonstrated reduction in size of the parathyroid lesion from 33 to 17 mm. Twenty months later, following recurrence of hypercalcaemia, he underwent neck exploration and resection of an enlarged right inferior parathyroid gland. Histology revealed increased fibrosis and haemosiderin deposits in the parathyroid lesion in keeping with auto-infarction. Case #2 was a 54-year-old lady admitted with severe hypercalcaemia (adj. calcium: 4.58 mmol/L, PTH 51.6 pmol/L (RR: 1.6-6.9 pmol/L)) and severe vitamin D deficiency. She was treated with intravenous fluids and pamidronate and 8 days later developed symptomatic hypocalcaemia (1.88 mmol/L) with dramatic decrease of PTH (17.6 pmol/L). MRI of the neck showed a 44 mm large cystic parathyroid lesion. To date, (18 months later), she has remained normocalcaemic. Learning points: Primary hyperparathyroidism (PHPT) is characterised by excess parathyroid hormone (PTH) secretion arising mostly from one or more autonomously functioning parathyroid adenomas (up to 85%), diffuse parathyroid hyperplasia (<15%) and in 1-2% of cases from parathyroid carcinoma. PHPT and hypercalcaemia of malignancy, account for the majority of clinical presentations of hypercalcaemia. Spontaneous remission of PHPT due to necrosis, haemorrhage and infarction of parathyroid adenoma, the so-called 'parathyroid auto-infarction', 'auto-parathyroidectomy' or 'parathyroid apoplexy' is a very rare in clinical practice but has been previously reported in the literature. In most cases, patients with parathyroid auto-infarction undergo parathyroidectomy. Those who are managed conservatively need to remain under close clinical and biochemical surveillance long-term as in most cases PHPT recurs, sometimes several years after auto-infarction.",
"affiliations": "Department of Diabetes and Endocrinology, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK.;Department of Diabetes and Endocrinology, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK.;Department of Diabetes and Endocrinology, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK.;Department of Diabetes and Endocrinology, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK.;Department of Histopathology, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK.;Department of Diabetes and Endocrinology, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK.;Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK.",
"authors": "Novodvorsky|Peter|P|;Hussein|Ziad|Z|;Arshad|Muhammad Fahad|MF|;Iqbal|Ahmed|A|;Fernando|Malee|M|;Munir|Alia|A|;Balasubramanian|Sabapathy P|SP|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": null,
"fulltext": "\n==== Front\nEndocrinol Diabetes Metab Case RepEndocrinol Diabetes Metab Case RepEDMEndocrinology, Diabetes & Metabolism Case Reports2052-0573Bioscientifica Ltd Bristol 10.1530/EDM-18-0136EDM180136Unique/Unexpected Symptoms or Presentations of a DiseaseTwo cases of spontaneous remission of primary hyperparathyroidism due to auto-infarction: different management and their outcomes P Novodvorsky, Z Hussein and othersRemission of PHPT due to auto-infarctionNovodvorsky Peter 12*Hussein Ziad 1*Arshad Muhammad Fahad 1Iqbal Ahmed 1Fernando Malee 3Munir Alia 12Balasubramanian Sabapathy P 241 Department of Diabetes and Endocrinology, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK2 Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK3 Department of Histopathology, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK4 Department of General Surgery, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UKCorrespondence should be addressed to P Novodvorsky; Email: p.novodvorsky@sheffield.ac.uk*(P Novodvorsky and Z Hussein contributed equally to this work)\n\n07 5 2019 2019 2019 18-013627 3 2019 12 4 2019 © 2019 The authors2019The authors This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License..Summary\nSpontaneous remission of primary hyperparathyroidism (PHPT) due to necrosis and haemorrhage of parathyroid adenoma, the so-called ‘parathyroid auto-infarction’ is a very rare, but previously described phenomenon. Patients usually undergo parathyroidectomy or remain under close clinical and biochemical surveillance. We report two cases of parathyroid auto-infarction diagnosed in the same tertiary centre; one managed surgically and the other conservatively up to the present time. Case #1 was a 51-year old man with PHPT (adjusted (adj.) calcium: 3.11 mmol/L (reference range (RR): 2.20–2.60 mmol/L), parathyroid hormone (PTH) 26.9 pmol/L (RR: 1.6–6.9 pmol/L) and urine calcium excretion consistent with PHPT) referred for parathyroidectomy. Repeat biochemistry 4 weeks later at the surgical clinic showed normal adj. calcium (2.43 mmol/L) and reduced PTH. Serial ultrasound imaging demonstrated reduction in size of the parathyroid lesion from 33 to 17 mm. Twenty months later, following recurrence of hypercalcaemia, he underwent neck exploration and resection of an enlarged right inferior parathyroid gland. Histology revealed increased fibrosis and haemosiderin deposits in the parathyroid lesion in keeping with auto-infarction. Case #2 was a 54-year-old lady admitted with severe hypercalcaemia (adj. calcium: 4.58 mmol/L, PTH 51.6 pmol/L (RR: 1.6–6.9 pmol/L)) and severe vitamin D deficiency. She was treated with intravenous fluids and pamidronate and 8 days later developed symptomatic hypocalcaemia (1.88 mmol/L) with dramatic decrease of PTH (17.6 pmol/L). MRI of the neck showed a 44 mm large cystic parathyroid lesion. To date, (18 months later), she has remained normocalcaemic.\n\nLearning points:\nPrimary hyperparathyroidism (PHPT) is characterised by excess parathyroid hormone (PTH) secretion arising mostly from one or more autonomously functioning parathyroid adenomas (up to 85%), diffuse parathyroid hyperplasia (<15%) and in 1–2% of cases from parathyroid carcinoma.\n\nPHPT and hypercalcaemia of malignancy, account for the majority of clinical presentations of hypercalcaemia.\n\nSpontaneous remission of PHPT due to necrosis, haemorrhage and infarction of parathyroid adenoma, the so-called ‘parathyroid auto-infarction’, ‘auto-parathyroidectomy’ or ‘parathyroid apoplexy’ is a very rare in clinical practice but has been previously reported in the literature.\n\nIn most cases, patients with parathyroid auto-infarction undergo parathyroidectomy. Those who are managed conservatively need to remain under close clinical and biochemical surveillance long-term as in most cases PHPT recurs, sometimes several years after auto-infarction.\n==== Body\nBackground\nPrimary hyperparathyroidism (PHPT) is characterised by excess parathyroid hormone (PTH) secretion arising mostly from one or more autonomously functioning parathyroid adenomas (up to 85%), parathyroid hyperplasia (<15%), and in 1–2% of cases from parathyroid carcinoma (1). PHPT with its prevalence of approximately 1:1000 (2, 3) is a relatively common condition and, together with hypercalcaemia of malignancy accounts for the majority of clinical presentations of hypercalcaemia. Parathyroidectomy has been considered the only definitive cure, however, watchful waiting with monitoring for the presence of end-organ damage is also warranted in selected cases (4). Over last decades, several cases of spontaneous remission of PHPT have been reported and attributed to spontaneous necrosis, haemorrhage and infarction of parathyroid adenoma and this phenomenon has been referred to as ‘parathyroid auto-infarction’, ‘auto-parathyroidectomy’ or ‘parathyroid apoplexy’ (5, 6, 7, 8, 9).\n\nIn this report we present two cases of spontaneous resolution of PHPT due to parathyroid auto-infarction, one of which was managed surgically and the other one conservatively. We discuss their outcomes, prognosis and the strategy for long-term management of patients with this presentation.\n\nCase #1, case presentation\nA 51-year-old man was referred to an endocrinologist by his general practitioner for further evaluation and management of suspected PHPT. He had a background of obesity, type 2 diabetes and ischaemic heart disease. His regular medications included metformin, aspirin, atorvastatin and glyceryl trinitrate spray when required. Three months prior to the referral he presented to his GP with pains and paraesthesia affecting left hand leading to a diagnosis of left carpal tunnel syndrome. There was no history of nephrolithiasis or bone fractures.\n\nCase #1, investigation\nIn the clinic, his blood pressure was 145/85 mmHg, height 185 cm, weight 144 kg with a BMI of 43.0 kg/m2. His biochemistry at the time of referral showed adjusted (adj.) serum calcium (Ca2+) of 3.11 mmol/L (reference range (RR): 2.20–2.60 mmol/L), parathyroid hormone (PTH) 26.9 pmol/L (RR: 1.6–6.9 pmol/L) (Fig. 1), phosphate 0.49 mmol/L (RR: 0.80–1.50 mmol/L), alkaline phosphatase 95 IU/L (RR: 30–130 IU/L), vitamin D levels of 32.9 nmol/L and the 24-h urine calcium excretion 18.2 mmol (RR: 2.5–7.5 mmol) with urine volume of 2280 mL. The ultrasound (US) of the neck detected a hypoechoic lobulated mass measuring 33 × 19 × 23 mm in keeping with an enlarged right inferior parathyroid gland (Fig. 2A and B). The dual scintigraphy with 99mTc sestamibi and 99Tc pertechnetate showed a subtle unmatched area in the region of the left inferior posterior thyroid lobe which was suggestive of a left inferior parathyroid adenoma, however.Figure 1 Case #1. Graph showing timeline of adjusted serum Ca2+ and PTH levels with annotated times of parathyroid auto-infarction and parathyroidectomy (red arrows). Reference range for adjusted serum Ca2+ (2.20–2.60 mmol/L) is annotated with red dotted lines and reference range for PTH (1.6–6.9 pmol/L) is annotated with black dotted lines.\n\n\nFigure 2 Case #1. (A and B) US neck scan prior to parathyroid adenoma auto-infarction (A. long axis, B. short axis). (C and D) US neck scan several weeks after the parathyroid adenoma auto-infarction (C. long axis, D. short axis). (A, B, C and D): Parathyroid adenoma marked by white cross marks, size in left bottom corners). (E) Histopathological specimen of infarcted parathyroid adenoma (H&E, 100×). Haemosiderin deposits and fibrosis can be observed.\n\n\n\n\nCase #1, treatment\nHe was subsequently referred for consideration of parathyroidectomy. Four weeks later, at his pre-operative assessment, his adj. Ca2+ levels reduced spontaneously to 2.43 mmol/L and PTH reduced to 8.7 pmol/L (Fig. 1). A repeated US scan showed a dramatic reduction of the lesion size to 17 × 5 × 10 mm (Fig. 2C and D). A US-guided aspiration followed and PTH in the aspirate was found to be 84.8 pmol/L confirming parathyroid origin of this lesion. At the same time, his diabetes was noted to be poorly controlled and required initiation of insulin therapy. Given these circumstances, he was initially managed conservatively with regular serum Ca2+ and PTH monitoring (Fig. 1). Seventeen months later, his adj. Ca2+ was noted to be elevated again at 2.75 mmol/L, PTH at 9.8 pmol/L and with his diabetes management now optimised, a decision was made to proceed with surgery. Twenty months after the suspected parathyroid auto-infarction, he had an uneventful bilateral neck exploration (due to discordant imaging studies as detailed above) and an enlarged right inferior parathyroid gland was identified and excised. The histopathological report noted increased fibrosis and haemosiderin deposits in the parathyroid gland in keeping with the previously suspected parathyroid haemorrhage and auto-infarction (Fig. 2E).\n\nCase #1, outcome and follow-up\nOn day 1 after surgery adj. serum Ca2+ was recorded at 2.31 mmol/L and PTH levels normalised as well (3.2 pmol/L). At the follow-up appointment 1.5 months after surgery his adj. Ca2+ was 2.24 mmol/L, PTH was 6.2 pmol/L, phosphate was 0.65 mmol/L, alkaline phosphatase was 92 IU/L and vitamin D was 36.3 nmol/L and he was continued on calcium and vitamin D supplementation (Adcal D3® 1 tablet BD). Bone densitometry (dual-energy X-ray absorptiometry – DXA) done 2.5 months after parathyridectomy gave T-scores of +1.4 in lumbar spine, +0.4 in total hip and −2.5 in distal 1/3 of the forearm, respectively. Recommendations to continue with Ca2+ and vitamin D supplements were made and he could be discharged to primary care 6 months after the surgery. The serum adj. Ca2+ levels continued to be normal 6.5 months after surgery at 2.42 mmol/L (shown as month 27 in Fig. 1) and 18.5 months after surgery 2.33 mmol/L (approx. month 39 in Fig. 1).\n\nCase #2, case presentation\nA 54-year-old lady of Afro-Carribean/mixed ethnic origin presented to Acute Medical Admissions Unit with a 3-month history of lethargy, weight loss and reduced oral intake. She didn’t report any significant past medical history and wasn’t taking any regular medications. There was no family history of any endocrine condition.\n\nCase #2, investigation\nOn admission, her BP was 127/72 mmHg, height was172 cm, weight was 75.2 kg, BMI was 25.4 kg/m2 and her biochemistry showed adj. serum Ca2+ of 4.58 mmol/L (RR: 2.20–2.60 mmol/L), PTH at 51.6 pmol/L (RR: 1.6–6.9 pmol/L) (Fig. 3), phosphate at 0.22 mmol/L (RR: 0.80–1.50 mmol/L), alkaline phosphatase at 167 IU/L (RR: 30–130 IU/L), borderline elevated serum creatinine at 83 µmol/L (RR: 44–80 µmol/L) and non-detectable vitamin D levels (<12.5 nmol/L) indicating the presence of PHPT with severe hypercalcaemia, hypophosphataemia and severe vitamin D deficiency. A computed tomography (CT) scan of thorax, abdomen and pelvis and the US scan of the neck were done within 48 h of her admission. The CT scan showed a 21 mm large right para-tracheal lesion with low density and of cystic nature (Fig. 4A). In addition, lucent bone lesions in T5 and T12 vertebrae, left ilium and left acetabulum were reported and subsequent assessment with magnetic resonance imaging (MRI) suggested these represented brown tumours secondary to PHPT. The US scan of the neck detected the presence of a heterogeneous lesion posteriorly and inferiorly to the right lobe of the thyroid with the largest dimension of 22 mm (Fig. 4B) and with no vascular flow within it. This lesion was identified as a right inferior parathyroid adenoma. US investigation of renal tract did not show any nephrolithiasis or nephrocalcinosis.Figure 3 Case #2. Graph showing timeline of adjusted serum Ca2+ and PTH levels. Presumed time of parathyroid auto-infarction is annotated with a red arrow. Reference range for adjusted serum Ca2+ (2.20–2.60 mmol/L) is annotated with red dotted lines and reference range for PTH (1.6–6.9 pmol/L) is annotated with black dotted lines.\n\n\nFigure 4 Case #2. (A) CT scan of chest abdomen and pelvis showing a 21 mm large right para-tracheal lesion with low density and of cystic nature (red arrow). (B) US neck scan, short axis, showing a heterogeneous lesion posteriorly and inferiorly to the thyroid (annotated with white cross marks, dimension in left bottom corner). (C and D) T1-weighed MRI imaging of the neck (C. coronal view, D. sagittal view) showing a 44 mm large mostly cystic lesion in the lower neck (red arrows). (E and F) SPECT-CT (E. axial view, F. coronal view) following pertechnetate and MIBI administration identified the auto-infarcted parathyroid adenoma to have very low level of MIBI activity.\n\n\n\n\nCase #2, treatment\nShe was treated with intravenous (IV) normal saline infusion, 90 mg of IV pamidronate and was commenced on high-dose vitamin D supplementation (cholecalciferol 40 000 units once weekly for 7 weeks). Following the initial treatment, adj. Ca2+ levels dropped significantly and 8 days after admission, she developed symptomatic hypocalcaemia (nadir adj. Ca2+ levels: 1.88 mmol/L with PTH at 17.6 pmol/L on day 10 post admission) which necessitated IV calcium administration (Fig. 3). A subsequent MRI neck with contrast identified a 44 mm large, apparently cystic lesion lying on the deep aspect of the right thyroid lobe; the medial aspect blending with tracheal wall pushing the trachea but with no airway compromise and its inferior aspect bulged into the apex of the right lung without any obvious infiltration (Fig. 4C and D). These findings were supportive of the clinical suspicion of parathyroid auto-infarction. Her serum Ca2+ levels normalised several days later and she could be discharged home on cholecalciferol 40 000 units once weekly for the total duration of 7 weeks together with Adcal D3® 2 tablets BD (i.e. 6 grams of Ca2+ carbonate and 1600 IU of cholecalciferol) daily. PTH levels normalised approximately 6 weeks after admission. She continued to be closely followed up in the endocrine outpatient clinic with initially monthly, later on with less frequent Ca2+ and PTH measurements (Fig. 3). Two months after the event, her vitamin D levels were recorded at 78 nmol/L. A SPECT-CT imaging following application of both MIBI and pertechnetate done 3 months after initial admission demonstrated a soft tissue density inferiorly to right thyroid lobe with very low level of MIBI activity (likely due to its cystic nature) and no pertechnetate uptake, further confirming the aetiology of this lesion as a parathyroid adenoma (Fig. 4E and F). At 6 months, the repeat MRI of the spine could not detect brown tumours anymore. At this stage, PTH levels were noted to be elevated again at 7.5 pmol/L, however, with normal adj. Ca2+ (2.39 mmol/L) and vitamin D levels (78.9 nmol/L) (Fig. 3). Similar laboratory findings were recorded at 11 months and at this stage the cystic parathyroid lesion could not be visualised on the US imaging anymore.\n\nCase #2, outcome and follow-up\nAt present, 18 months after the initial event, her adj. Ca2+ was recorded at 2.38 mmol/L and PTH at6.8 pmol/L and she has remained asymptomatic.\n\nDiscussion\nSpontaneous remission of PHPT due to necrosis, haemorrhage and infarction of parathyroid adenoma, the so-called ‘parathyroid auto-infarction’, ‘auto-parathyroidectomy’ or ‘parathyroid apoplexy’ is very rare in clinical practice but has been previously documented in the literature, the first report being published by Norris et al. in 1946 (5). Since then, more cases have been published (6, 7, 8, 9). In 1995, Nylen et al. (6) reviewed available literature and observed that presentations of parathyroid auto-infarction could be divided into two groups. In one group patients suddenly became normo- or hypocalcaemic and this was sometimes linked with mild neck pain or tenderness. Necrosis, in some cases with evidence of recent or old haemorrhage, was found on histopathological examination. In the other group, patients presented more acutely with severe neck and/or substernal pain and swelling with respiratory distress and dysphonia requiring surgical exploration. Extensive haematoma related to haemorrhage from parathyroid adenoma was found on histopathological examination (6). The authors went on to suggest a single unifying pathological process behind these presentations which begins acutely with necrosis and a degree of haemorrhage which determines the clinical presentation. In cases where haemorrhage is less severe, the process subsequently leads to fibrosis and cyst formation. The difference in the degree of haemorrhage was proposed as a defining feature for sub-classification of this disorder into three types: type 1: adenoma with necrosis without haemorrhage, type 2: adenoma with intra-capsular haemorrhage (or evidence thereof) and necrosis and type 3: adenoma with extracapsular haemorrhage (6). Parathyroid auto-infarction usually leads to acute and dramatic reduction of Ca2+ and PTH levels leading to remission of PHPT, however, in some cases, the decrease in Ca2+/PTH is much less pronounced and entirely asymptomatic (7). In most cases reported so far, surgical treatment was eventually indicated, with only a few cases reported in which conservative approach with regular clinical and biochemical follow-up was initially chosen. This might be due to contraindications for surgery or patient preference (8). In one case, PHPT recurred 7 years after the auto-infarction leading to parathyroidectomy, which was performed 8 years after the index event (8). This indicates that the clinical and biochemical surveillance has to be performed long term, perhaps life-long. The clinical observation that parathyroid auto-infarction doesn’t lead to a definitive cure may be likely explained by the presence of non-ischaemic adenomatous tissue having a potential to grow resulting in recurrence of hypercalcaemia at some stage.\n\nIn our report we describe two cases of spontaneous remission of PHPT due to parathyroid auto-infarction. None of the patients could remember any neck pain or discomfort around the presumed time of the event. Both patients were initially managed conservatively. In case #1 this was not only due to spontaneous normalisation of serum Ca2+, but also due to poorly controlled diabetes that required optimisation before surgery. Hypercalcaemia recurred 17 months later and he eventually underwent bilateral neck exploration 20 months after the index event. The histopathological findings showed fibrosis and haemosiderin deposits in keeping with parathyroid adenoma auto-infarction, type 2 as per Nylen et al.’s classification (6).\n\nIn case #2 we have continued with conservative management up to present date, i.e. 18 months after the index event. In this case, the dramatic improvement of severe hypercalcaemia leading to symptomatic hypocalcaemia requiring IV Ca2+ administration in line with the current Society for Endocrinology Endocrine Emergency Guidance on Management of Acute Hypocalcaemia (10). These changes in serum adj. Ca2+ levels were observed after administration of pamidronate in the setting of severe vitamin D deficiency. Given this, in addition to a parathyroid auto-infarction, a plausible differential diagnosis to this clinical scenario would be the effect of bisphosphonate in the presence of severe vitamin D deficiency. The timing of these events (nadir Ca2+ value on day 10 after pamidronate administration) would be supportive of this. Although it is entirely possible that the above mechanism contributed to the development of symptomatic hypocalcaemia, the dramatic decrease in serum PTH levels, the cystic character of the parathyroid lesion on MRI, and inability to visualise the previously clearly visible lesion on US imaging several months later is strongly suggestive of parathyroid auto-infarction that likely occurred several days after pamidronate infusion. To our knowledge, there is only one case published in the literature linking IV administration of a bisphosphonate with subsequent parathyroid auto-infarction. This report relates to a case of a parathyroid carcinoma arising from parathyroid hyperplasia (11). Importantly, we are unaware of any plausible physiological mechanism by which bisphosphonates could cause parathyroid auto-infarction. The widespread use of bisphosphonates versus the rare incidence of parathyroid auto-infarction suggests that bisphosphonate administration in these cases was likely to be coincidental.\n\nIn case#1 we had discordant results in localisation studies of the parathyroid adenoma. The US scan of the neck identified a large R inferior parathyroid adenoma, whereas the dual scintigraphy with 99mTc sestamibi (MIBI) and 99mTc pertechnetate showed a subtle unmatched area in the region of the left inferior posterior thyroid lobe. Thus, the MIBI findings were more subtle than the findings on US imaging and as they could not be confirmed in surgery they clearly represent a false positive finding. Discordant results in various imaging modalities of the parathyroid is a well described phenomenon (12). False-positive scintigraphic findings can be caused by a variety of conditions, the most common being solitary thyroid adenoma, followed by benign and malignant lesions of the neck, breast or lung, thymic lesions or reactive lymph nodes (13). Although the sensitivity of the 99mTc sestamibi scan is high in patients with solitary parathyroid adenomas, false-negative and -positive results of 99mTc sestamibi scanning are unavoidable. There are several factors that influence scintigrafic detection of parathyroid adenomas. Apart from size (weight), 99mTc sestamibi uptake also depends on the content of mitochondria-rich oxyphil cells, the expression of P-glycoprotein and the perfusion and functional activity of the adenoma (14). Although we are unable to provide more details on the histopathological and immunohistochemical analysis of the parathyroid adenoma specimen in case#1, we assume that the unfavourable properties in relation to the above characteristics have contributed to the fact that, despite its size, it was not picked up on the parathyroid scintigraphy. From clinical perspective, discordant localisation studies should lead to indication of bilateral neck exploration. If at exploration no discrete abnormality can be found at the presumed site of uptake, like in was in our case#1, this area is left alone.\n\nIn relation to the post-operative management in case#1, the biochemical picture of mild hypophosphataemia at 1.5 months after surgery (0.65 mmol/L, normal RR: 0.80–1.50 mmol/L) and PTH levels of 6.2 pmol/L in the upper end of normal RR (1.6–6.9 pmol/L) were attributed to be secondary to ongoing vitamin D deficiency (36.3 nmol/L). The possibility of persistent mild PHPT (for example due to a second adenoma and discordant localisation studies) after bilateral neck exploration and normal adjusted Ca2+ levels was considered as very unlikely and the patient was discharged to primary care.\n\nLastly, in case#1 FNA was used to confirm the aetiology of the lesion. The high detected PTH concentration (800 ng/L) was confirmatory of its parathyroid origin. Similarly to case#1, we considered the use of FNA, but the lesion could not be visualised on subsequent imaging; probably as a result of previous auto-infarction. It has to be noted that FNA does not form part of standard diagnostic workup in cases of suspected PHPT (4) and its indication in these circumstances is still a subject of debate. The unusual clinical behaviour of both presented cases, however, raised questions about the aetiology of the detected neck lesions and concerns were raised not to miss an alternative diagnosis (reactive lymph node, lymphoma). Both cases were discussed on the local endocrine multidisciplinary team (MDT) meetings and it was felt that the benefits of establishing the correct diagnosis outweighed the risks linked with the procedure itself including discomfort, pain or bleeding, but mainly the risk of tumour dissemination in cases of confirmed malignancy. The use of FNA under such and similar circumstances is based on our previous experience and has been reported by our group (15) as well as others (16, 17).\n\nIn summary, our current report adds to the already available amount of literature on cases of spontaneous PHPT remission due to parathyroid auto-infarction, provides a discussion on the possible approaches of clinical management and makes the wide readership aware of this rare, but well described phenomenon.\n\nDeclaration of interest\nThe authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.\n\nFunding\nThis research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.\n\nPatient consent\nThe authors confirm that written informed consent was obtained from both patients for publication of this article through their signatures on the consent form.\n\nAuthor contribution statement\nP N did a literature search and wrote the manuscript. Z H attended to patient #2, reviewed this case and reviewed the manuscript. M F A and A I reviewed the manuscript. M F acquired and reported the histopathological samples and reviewed the manuscript. A M is the consultant in charge for patient #2 and reviewed the manuscript. S B was the consultant in charge for patient #1, operated on patient #1 and reviewed the manuscript. Case #2 was presented by Z H and A M as a poster on the Society for Endocrinology BES annual meeting, 6th–11th November 2017, Harrogate, UK.\n\nAcknowledgements\nThe authors would like to thank to Dr Matthew Bull and Dr Christopher Johns from the Department of Radiology, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK for their help with interpretation of the scans.\n==== Refs\nReferences\n1 Bringhurst FR Demay MB Kronenberg HM \nHormones and disorders of mineral metabolism In Williams Textbook of Endocrinology , 13th ed, ch. 28, pp 1254 –1322 . Eds Melmed S , Pollonsky KS , Reed Larsen P & Kronenberg HM \nPhiladelphia : Elsevier , 2016 (10.1016/C2013-0-15980-6 )\n2 Wermers RA Khosla S Atkinson EJ Achenbach SJ Oberg AL Grant CS Melton LJ 3rd \nIncidence of primary hyperparathyroidism in Rochester, Minnesota, 1993–2001: an update on the changing epidemiology of the disease . Journal of Bone and Mineral Research \n2006 \n21 \n171 –177 . (10.1359/JBMR.050910 )16355286 \n3 Boonstra CE Jackson CE \nSerum calcium survey for hyperparathyroidism: results in 50,000 clinic patients . American Journal of Clinical Pathology \n1971 \n55 \n523 –526 . (10.1093/ajcp/55.5.523 )5090209 \n4 Bilezikian JP Brandi ML Eastell R Silverberg SJ Udelsman R Marcocci C Potts JT Jr \nGuidelines for the management of asymptomatic primary hyperparathyroidism: summary statement from the fourth International Workshop . Journal of Clinical Endocrinology and Metabolism \n2014 \n99 \n3561 –3569 . (10.1210/jc.2014-1413 )25162665 \n5 Norris EH \nPrimary hyperparathyroidism; a report of five cases that exemplify special features of this disease (infarction of a parathyroid adenoma; oxyphil adenoma) . Archives of Pathology \n1946 \n42 \n261 –273 .20999926 \n6 Nylen E Shah A Hall J \nSpontaneous remission of primary hyperparathyroidism from parathyroid apoplexy . Journal of Clinical Endocrinology and Metabolism \n1996 \n81 \n1326 –1328 . (10.1210/jcem.81.4.8636326 )8636326 \n7 Kovacs KA Gay JD \nRemission of primary hyperparathyroidism due to spontaneous infarction of a parathyroid adenoma. Case report and review of the literature . Medicine \n1998 \n77 \n398 –402 . (10.1097/00005792-199811000-00005 )9854603 \n8 Pereira FA Brandao DF Elias J JrPaula FJ \nParathyroid adenoma apoplexy as a temporary solution of primary hyperparathyroidism: a case report . Journal of Medical Case Reports \n2007 \n1 \n139 (10.1186/1752-1947-1-139 )18021421 \n9 Efremidou EI Papageorgiou MS Pavlidou E Manolas KJ Liratzopoulos N \nParathyroid apoplexy, the explanation of spontaneous remission of primary hyperparathyroidism: a case report . Cases Journal \n2009 \n2 \n6399 (10.1186/1757-1626-2-6399 )20184676 \n10 Turner J Gittoes N Selby P \nand the Society for Endocrinology Clinical Committee . SOCIETY FOR ENDOCRINOLOGY ENDOCRINE EMERGENCY GUIDANCE: Emergency management of acute hypocalcaemia in adult patients . Endocrine Connections \n5 \nG7 –G8 . (10.1530/EC-16-0056 )\n11 de Papp AE Kinder B LiVolsi V Gupta SM Stewart AF \nParathyroid carcinoma arising from parathyroid hyperplasia: autoinfarction following intravenous treatment with pamidronate . American Journal of Medicine \n1994 \n97 \n399 –400 . (10.1016/0002-9343(94)90312-3 )7942947 \n12 Mihai R Gleeson F Buley ID Roskell DE Sadler GP \nNegative imaging studies for primary hyperparathyroidism are unavoidable: correlation of sestamibi and high-resolution ultrasound scanning with histological analysis in 150 patients . World Journal of Surgery \n2006 \n30 \n697 –704 . (10.1007/s00268-005-0338-9 )16680585 \n13 Eslamy HK Ziessman HA \nParathyroid scintigraphy in patients with primary hyperparathyroidism: 99mTc sestamibi SPECT and SPECT/CT . RadioGraphics \n2008 \n28 \n1461 –1476 . (10.1148/rg.285075055 )18794320 \n14 Erbil Y Kapran Y Issever H Barbaros U Adalet I Dizdaroglu F Bozbora A Ozarmagan S Tezelman S \nThe positive effect of adenoma weight and oxyphil cell content on preoperative localization with 99mTc-sestamibi scanning for primary hyperparathyroidism . American Journal of Surgery \n2008 \n195 \n34 –39 . (10.1016/j.amjsurg.2007.01.040 )18082541 \n15 Truran P Stedman T Balasubramanian S Harrison BJ \nThe utility of ultrasound guided fine needle aspiration for PTH levels in challenging cases of primary hyperparathyroidism . In British Association of Endocrine and Thyroid Surgeons Annual Scientific Conference , pp S79 –S88 . Reading/Henley on Thames, UK , 2015 .\n16 Aydin C Polat SB Dellal FD Kaya C Dogan HT Turkolmez S Kilic M Ersoy R Cakir B \nThe diagnostic value of parathyroid hormone washout in primary hyperparathyroidism patients with negative or equivocal 99mTc-MIBI results . Diagnostic Cytopathology \n2019 \n47 \n94 –99 . (10.1002/dc.24065 )30461227 \n17 Abraham D Sharma PK Bentz J Gault PM Neumayer L McClain DA \nUtility of ultrasound-guided fine-needle aspiration of parathyroid adenomas for localization before minimally invasive parathyroidectomy . Endocrine Practice \n2007 \n13 \n333 –337 . (10.4158/EP.13.4.333 )17669707\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2052-0573",
"issue": "2019()",
"journal": "Endocrinology, diabetes & metabolism case reports",
"keywords": "2019; Adult; Alkaline phosphatase; Appetite reduction/loss; Bisphosphonates; Black - Caribbean; Bone; Bone mineral density; CT scan; Calcium; Calcium (serum); Calcium (urine); Calcium carbonate; Cholecalciferol; Creatinine (serum); Fatigue; Female; Fine needle aspiration biopsy; Fluid repletion; Histopathology; Hypercalcaemia; Hyperparathyroidism (primary); Hypophosphataemia; MRI; Male; May; PTH; Pamidronate; Paraesthesia; Parathyroid; Parathyroid adenoma; Parathyroidectomy; Phosphate (serum); SPECT scan; Saline; Sestamibi scan; Ultrasound scan; Unique/unexpected symptoms or presentations of a disease; United Kingdom; Urine 24-hour volume; Vitamin D; Weight loss; White",
"medline_ta": "Endocrinol Diabetes Metab Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101618943",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "31063971",
"pubdate": "2019-05-07",
"publication_types": "D016428:Journal Article",
"references": "16355286;16680585;17669707;18021421;18082541;18794320;20184676;20999926;25162665;27935815;30461227;5090209;7942947;8636326;9854603",
"title": "Two cases of spontaneous remission of primary hyperparathyroidism due to auto-infarction: different management and their outcomes.",
"title_normalized": "two cases of spontaneous remission of primary hyperparathyroidism due to auto infarction different management and their outcomes"
} | [
{
"companynumb": "GB-SUN PHARMACEUTICAL INDUSTRIES LTD-2019R1-215922",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PAMIDRONATE DISODIUM"
},
... |
{
"abstract": "BACKGROUND\nNonvitamin K antagonist oral anticoagulants may cause interstitial lung disease (ILD) similar to that seen for other cardiovascular drugs. The aim of this study was to determine trends and medical conditions associated with ILD in patients taking apixaban.\n\n\nMETHODS\nA single-center observational survey conducted between February 2013 and May 2015 examined patients who developed ILD after initiation of apixaban administration.\n\n\nRESULTS\nChest computed tomography showed that 4 (~.45%) out of approximately 870 apixaban users developed ILD. All patients were elderly Japanese men with decreased creatinine clearance who had nonvalvular atrial fibrillation. Three of the four were confirmed smokers, whereas three had a history of lung disease. Dyspnea occurred during the initial week after starting apixaban administration in 3 patients and at 90 days in 1 patient. All patients underwent methylprednisolone pulse therapy, with three requiring mechanical ventilation. Although 2 patients recovered, the other two died of respiratory failure.\n\n\nCONCLUSIONS\nDevelopment of ILD during anticoagulation with apixaban is not rare. When apixaban is administered in elderly high-risk patients, subjects need to be carefully monitored for respiratory symptoms. As drug-induced ILD is often reported in Japan, further studies that clarify if these types of cases are common in countries other than Japan will also need to be undertaken.",
"affiliations": "Department of Cerebrovascular Medicine, National Cerebral and Cardiovascular Center, Suita, Osaka, Japan. Electronic address: sny1139@ncvc.go.jp.;Department of Cerebrovascular Medicine, National Cerebral and Cardiovascular Center, Suita, Osaka, Japan.;Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center, Suita, Osaka, Japan.;Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center, Suita, Osaka, Japan.;Department of Cerebrovascular Medicine, National Cerebral and Cardiovascular Center, Suita, Osaka, Japan.;Department of Cerebrovascular Medicine, National Cerebral and Cardiovascular Center, Suita, Osaka, Japan.;Department of Cerebrovascular Medicine, National Cerebral and Cardiovascular Center, Suita, Osaka, Japan.;Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center, Suita, Osaka, Japan.;Department of Respiratory Medicine, Saiseikai Senri Hospital, Suita, Osaka, Japan.;Department of Respiratory Medicine, Saiseikai Senri Hospital, Suita, Osaka, Japan.;Department of Cerebrovascular Medicine, National Cerebral and Cardiovascular Center, Suita, Osaka, Japan.",
"authors": "Tomari|Shinya|S|;Homma|Kazunari|K|;Noguchi|Teruo|T|;Aiba|Takeshi|T|;Matsuki|Takayuki|T|;Suzuki|Rieko|R|;Koga|Masatoshi|M|;Takigami|Masao|M|;Tagawa|Hiroshi|H|;Hashimoto|Taisuke|T|;Toyoda|Kazunori|K|",
"chemical_list": "D000925:Anticoagulants; D005938:Glucocorticoids; D011720:Pyrazoles; D011728:Pyridones; C522181:apixaban; D008775:Methylprednisolone",
"country": "United States",
"delete": false,
"doi": "10.1016/j.jstrokecerebrovasdis.2016.03.036",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1052-3057",
"issue": "25(7)",
"journal": "Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association",
"keywords": "Adverse event; apixaban; factor Xa inhibitor; interstitial lung disease",
"medline_ta": "J Stroke Cerebrovasc Dis",
"mesh_terms": "D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000925:Anticoagulants; D017809:Fatal Outcome; D005938:Glucocorticoids; D006801:Humans; D007564:Japan; D008168:Lung; D017563:Lung Diseases, Interstitial; D008297:Male; D008775:Methylprednisolone; D020551:Pulse Therapy, Drug; D011720:Pyrazoles; D011728:Pyridones; D012121:Respiration, Artificial; D012307:Risk Factors; D012737:Sex Factors; D013997:Time Factors; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome",
"nlm_unique_id": "9111633",
"other_id": null,
"pages": "1767-1769",
"pmc": null,
"pmid": "27091686",
"pubdate": "2016-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D064888:Observational Study",
"references": null,
"title": "Development of Interstitial Lung Disease after Initiation of Apixaban Anticoagulation Therapy.",
"title_normalized": "development of interstitial lung disease after initiation of apixaban anticoagulation therapy"
} | [
{
"companynumb": "JP-PFIZER INC-2014310350",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PIPERACILLIN SODIUM\\TAZOBACTAM SODIUM"
},
"dr... |
{
"abstract": "Patients with lymphoma are predisposed to infection because of the immunocompromised state related to the disease itself and as a consequence of chemo-/radiotherapy. Here, we report a case of Herpes-simplex virus encephalitis (HSE) in an immunosuppressed patient with splenic marginal zone lymphoma (SMZL), a rare indolent variant of non-Hodgkin´s lymphoma (NHL). The course was complicated febrile neutropenia and HSV-1-related cerebral vasculitis causing progressive ischemic stroke. This case illustrates the expanding spectrum of atypical clinical and radiological manifestations of HSE in patients treated with myelotoxic drugs. Moreover, we summarize the few central nervous system manifestations of SMZL reported in the literature and discuss distinct causes of neurological deterioration in patients with NHL.",
"affiliations": "Department of Neurology, Franz Tappeiner Hospital, 39012 Merano, Italy.;Department of Neurology, Franz Tappeiner Hospital, 39012 Merano, Italy.;Department of Neurology, Franz Tappeiner Hospital, 39012 Merano, Italy.;Department of Neurology, Christian Doppler Medical Center, Paracelsus University Salzburg, 5020 Salzburg, Austria.;Department of Psychiatry, Psychotherapy and Psychosomatic Medicine, Christian Doppler Medical Center, Paracelsus University Salzburg, 5020 Salzburg, Austria.;Department of Neurology, Christian Doppler Medical Center, Paracelsus University Salzburg, 5020 Salzburg, Austria.",
"authors": "Nardone|Raffaele|R|;Carnicelli|Luca|L|;Brigo|Francesco|F|;Pikija|Slaven|S|;Hauer|Larissa|L|;Sellner|Johann|J|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3390/pathogens9030193",
"fulltext": "\n==== Front\nPathogens\nPathogens\npathogens\nPathogens\n2076-0817 MDPI \n\n10.3390/pathogens9030193\npathogens-09-00193\nCase Report\nCerebral HSV-1 Vasculitis as a Fatal Complication of Immunosuppression in Non-Hodgkin´s Lymphoma: A Case Report and Review of the Literature\nNardone Raffaele 12 Carnicelli Luca 1 Brigo Francesco 1 Pikija Slaven 2 Hauer Larissa 3 https://orcid.org/0000-0001-8749-5533Sellner Johann 245* 1 Department of Neurology, Franz Tappeiner Hospital, 39012 Merano, Italy; raffale.nardone@gmail.com (R.N.); luca.carnicelli@sabes.it (L.C.); dr.francescobrigo@gmail.com (F.B.)\n2 Department of Neurology, Christian Doppler Medical Center, Paracelsus University Salzburg, 5020 Salzburg, Austria; s.pikija@salk.at\n3 Department of Psychiatry, Psychotherapy and Psychosomatic Medicine, Christian Doppler Medical Center, Paracelsus University Salzburg, 5020 Salzburg, Austria; l.sellner@salk.at\n4 Department of Neurology, Klinikum rechts der Isar, Technische Universität München, 81675 München, Germany\n5 Department of Neurology, Krankenhaus Mistelbach-Gänserndorf, 2130 Mistelbach, Austria\n* Correspondence: j.sellner@salk.at; Tel.: +43-2572-9004-12850\n05 3 2020 \n3 2020 \n9 3 19323 1 2020 05 3 2020 © 2020 by the authors.2020Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).Patients with lymphoma are predisposed to infection because of the immunocompromised state related to the disease itself and as a consequence of chemo-/radiotherapy. Here, we report a case of Herpes-simplex virus encephalitis (HSE) in an immunosuppressed patient with splenic marginal zone lymphoma (SMZL), a rare indolent variant of non-Hodgkin´s lymphoma (NHL). The course was complicated febrile neutropenia and HSV-1-related cerebral vasculitis causing progressive ischemic stroke. This case illustrates the expanding spectrum of atypical clinical and radiological manifestations of HSE in patients treated with myelotoxic drugs. Moreover, we summarize the few central nervous system manifestations of SMZL reported in the literature and discuss distinct causes of neurological deterioration in patients with NHL.\n\nviral encephalitiscerebral vasculitisopportunistic infectionsplenic marginal cell lymphomaNon-Hodgkin´s lymphomaimmunosuppression\n==== Body\n1. Introduction\nSplenic marginal zone lymphoma (SMZL) is a rare indolent non-Hodgkin lymphoma (NHL) subtype that originates from B memory lymphocytes present in the marginal zone of secondary lymphoid follicles [1,2]. The median age at diagnosis of SMZL is 69 years and there is an association with hepatitis C infection in Southern Europe [3]. Patients usually present massive splenomegaly and bone marrow involvement with minimal or absent lymphadenopathy except for the spleen hilum [4]. Extranodal involvement incudes the bone marrow and the liver, whereas primary or secondary central nervous system (CNS) manifestations are extremely rare [5]. Of note, patients with lymphoma are predisposed to infection because of the immunosuppressed state related to the disease itself and chemo-/radiotherapy [6]. \n\nWhile the epidemiology of viral encephalitis is in constant turnover, Herpes-simplex virus (HSV) remains the most common pathogen of sporadic encephalitis (HSE) worldwide [7]. HSE is not regarded as an opportunistic infection. Notably, there is an increasing number of reports about HSE in immunosuppressed patients and treatment with immunotherapies approved for disease modification in multiple sclerosis (MS) is expanding [8,9,10,11]. HSE in patients on immunosuppressive treatment is associated with atypical clinical and radiological presentation and poorer outcome [12]. In this regard, prodromal symptoms such as fever and headache are less frequent in immunosuppressed patients and there is a higher chance of additional extratemporal location of lesions in the brainstem and the cerebellum or widespread cortical involvement. Moreover, an increasing number of patients have been reported to develop this condition following brain radiation or neurosurgical intervention, respectively [13,14]. \n\nHere, we describe the case of HSE with cerebral vasculitis causing progressive ischemic stroke in an immunosuppressed patient with SMZL. \n\n2. Case Study\nA 60 year old male patient was diagnosed with SMZL, an indolent B-cell NHL, stage IVB. The presenting symptoms included abdominal pain, fatigue and fever. His medical history included hypertension, hypercholesterinemia and ischemic cardiomyopathy. The CT scans showed splenomegaly (14 × 9 cm) and enlarged retroperitoneal lymph nodes (up to 15 mm). Bone marrow examination detected findings supportive of SMZL including CD20-positive malignant B cells and a lack of CD5 and CD30 expression. Two weeks before the scheduled therapy with R-CHOP (rituximab, cyclophosphamide, hydroxydaunorubicin, vincristin, prednisone), he was admitted with fever and abdominal pain. The work-up revealed progress of splenomegaly (17 × 11 cm) and new development of intrasplenic lesions consistent with splenic infiltration by the lymphoma. He was anemic and received erythrocyte concentrates. A radiation therapy was not performed. He then received treatment with R-CHOP and filgrastim, a biosimilar of Granulocyte colony-stimulating factor (G-CSF) with each course as shown in Figure 1. The time course of leukocyte dynamics is shown in Figure 1, and the nadir of the neutrophils was 130, 630 and 180 cell/µL, respectively. He was not lymphopenic the days before the start of R-CHOP therapy but had almost continuously grade 2-3 lymphopenia thereafter according to the Common Terminology Criteria for Adverse Events (CTAE) Grading system. \n\nShortly after the fourth R-CHOP cycle he sought medical help for nausea and emesis. He was diagnosed febrile neutropenia (grade 4 (130 cells/µL)). He developed sinusitis and persistent and high fever despite prophylaxis with broad-spectrum antibiotic and antifungal therapy. He was treated with 2 × 30 Mio U. filgrastim. His clinical condition further deteriorated and he reported headache and had recurrent episodes of reduced vigilance and confusion. In addition, epileptic seizures were observed. While brain magnetic resonance imaging (MRI) was unremarkable and electroencephalography (EEG) ruled out status epilepticus. The CSF examination revealed a lymphomononuclear pleocytosis of 230 cells/µL and increased blood-brain barrier (BBB) permeability (protein in CSF 203 mg/dL, upper limit 45 mg/dL). Empirical acyclovir (10 mg/kg iv every 8 hr) was started on suspicion for HSE, and later HSV-1 was confirmed by polymerase chain reaction (PCR) of CSF specimen. He fulfilled the diagnostic criteria for confirmed encephalitis [15]. The clinical condition improved under anticonvulsive and antiviral therapy, and the latter was given for 21 days. The hospital stay was 5 weeks, the last neutrophil count was 1320 cells/µL. \n\nEight weeks later he was readmitted for increasing confusion. He was still neutropenic (770 neutrophils/µL). CSF examination revealed a persistent mononuclear pleocytosis (19 cells/µL), BBB disruption and positive PCR for HSV-1. We performed another course of IV acyclovir for 14 days. Again, PCR was negative for common causes of opportunistic infections including cytomegalovirus (CMV), varicella-zoster virus (VZV), EBV and toxoplasmosis. The onconeural antibodies (anti-Hu, Yo, Ri, Ma, CV2 and amphiphysin), and autoimmune (anti-nuclear, -cardiolipin, ds-DNA, myeloperoxidase) as well as anti-N-methyl-D-aspartate receptor (NMDAR) antibodies were negative. \n\nBrain magnetic resonance imaging (MRI) disclosed a recent infarction of the left thalamus (Figure 2A). We observed new neurological symptoms over the next days with weakness and numbness on the left side, fluctuating cognitive function, mood and behavior. Brain MRI on day 7 from readmission showed further new ischemic lesions in the previously affected as well as additional vascular territories (Figure 2B,C). Conventional angiography revealed narrowing of intracerebral cerebral vessels consistent with vasculitis. The abnormalities were most prominent in the M2 segments of the left medial and the anterior cerebral artery (Figure 2D,E). High dose methylprednisolone (1g per day) was added for 7 days and acetylsalicylic acid switched to clopidogrel. There was no evidence for cardiac arrhythmia on Holter-ECG or cardiac thrombus or endocarditis on echocardiography. Yet, clinical deterioration was not halted and the patient died one month later in a palliative care setting. The approval by the local ethics committee is on file (415-EP/73/748-2017). \n\n3. Discussion\nOpportunistic CNS infections play a significant role in life-threatening chemotherapy- and radiation-related complications. Since the CSF cell count can be normal in immunocompromised individuals and the clinical presentation may be distinct, antiviral treatment on suspicion is commonly delayed [16]. Of note, immunocompromised patients have six times higher chance for an unfavorable outcome than patients with an unaltered immune system [12]. Myelotoxicity is a life-threatening complication of chemotherapy with R-CHOP. The risk for febrile neutropenia is 20% and the additional use of G-CSF was shown to allow the administration of maximal relative dose intensities [17]. Infections with Herpes-simplex and -zoster viruses are known complications of R-CHOP for treatment of B-cell lymphoma [18]. This case expands the spectrum as cerebral vasculitis in HSE, which is almost exclusively related to type 2 virus [19]. Epileptic seizures and ischemic stroke are risk factors for poor prognosis in HSE and presented in our patient [20]. The likelihood for an unfavorable outcome in patients with HSE is also higher with acute respiratory failure and intracranial hemorrhage. \n\nCerebral vasculitis or vasculopathies have not been described as a CNS manifestation or complication of SMZL Several studies corroborated that the risk of CNS involvement for indolent lymphomas was low. In a study of 1163 patients with low-grade non-Hodgkin’s lymphoma, the rate of patients with CNS involvement at 5 years was 2.8% [21]. Of note, CNS involvement has been reported in 7% of patients with low-grade non-Hodgkin’s lymphoma, which was associated with a transformation to high-grade malignancy in all these patients [22]. Such a biopsy-confirmed case was reported by Gao [23], where the secondary cerebral manifestation presented on MRI as a tumorous brain mass (2.1 × 2.2 cm). That radiological presentation contrasts our case with the presence of vascular alterations. The additional option beyond brain biopsy to verify a potential neoplastic origin of the cerebral lesion is positron emission tomography (PET) imaging, which was not performed in our patient. A patient with SMZL who developed focal neurological symptoms 3.5 years after diagnosis of the lymphoma was reported by Toennissen et al. [24]. MRI revealed four tumorous lesions and strong uptake on [18F] fluorodeoxyglucose (FDG) PET. The biopsy confirmed transformation to a diffuse large B-cell lymphoma and secondary CNS manifestation. Fadugba [25] reported a case of cerebral manifestation of SMZL, which was a cerebral mass with a 4-cm diameter and a large amount of cerebral edema, resulting in a midline shift. Wedgewood et al. [26] reported a patient with recurrence of SMCL as intracerebral dural mass. These dural manifestations may resemble a meningioma. Moreover, there are a few cases with clinical presentations related to meningeal lymphomatosis [27,28,29,30]. In our patient, cytology did not identify atypical cells in the CSF and there was no meningeal enhancement on MRI, which is frequently seen in the case of meningeal lymphomatosis. There are anecdotal reports about the efficacy of intrathecal treatment for these patients [31]. \n\nPersistent lymphopenia or marked drop of lymphocytes is a known risk factor for opportunistic CNS infection [32]. Of note, HSE has been reported not only after immunosuppressive therapy but also in multiple sclerosis (MS) by lymphocyte-lowering immunotherapies or interference with the migratory action of lymphocytes [10,33,34]. Neutrophils have an essential biological function for both innate and adaptive immune responses. Our patient had chemotherapy-induced febrile neutropenia and persistent grade 2-3 lymphopenia, which both are likely to have contributed to the development of HSE. Neutrophils play a role in the first line of host defense and are present in CSF in the early course of HSE [35]. While their exact role in the immunopathogenesis of HSE is unclear, neutrophils were critical for the control of replication and spread of the virus in an murine model of HSV-1 keratitis [36]. This effect is likely to be mediated by the release of oxygen and nitrogen reactive species as well as TNF-α. The latter activates caspase 8-dependent pathways, which can induce cell lysis and apoptosis of viral-infected epithelial cells [37]. \n\nUncomplicated HSE is treated for 2 weeks with intravenous acyclovir. In contrast, guidelines recommend intravenous acyclovir for 3 weeks in immunocompromised patients and a retap thereafter to exclude persistent infection [38]. In this regard, there is ongoing research to assess whether HSV strains in immunodeficient patients are more prone to developing acyclovir resistance [39]. With the development of ischemic stroke in territories supplied by distinct cerebral arteries in febrile neutropenia, we needed to rule out systemic, thoracic and abdominal infectious foci, endocarditis and cardiac arrhythmia as a potential embolic source. While his clinical presentation and subacute and fluctuating course was encephalitis-like and CSF consistent with intrathecal inflammation, we could not detect encephalitic lesions on conventional imaging during the initial stage of neurological symptoms. Of note, the mesial temporal lobe is the predilection site for brain lesions in HSE but an additional extratemporal location is more frequent in immunosuppressed patients [12]. The focal lesions seen in our patient, however, are of an ischemic nature and a consequence of widespread vasculitis of cerebral vessels. Infarction in infectious cerebral vasculitis can not only occur due to reduced cerebral blood flow caused by inflammation of the vessel wall but also vasospasm and arterio-arterial thrombosis [40]. Favorable effects by steroids may be particularly seen in patients with HSE-related cerebral vasculitis. As steroids have anti-inflammatory effects and could thus promote viral replication, some centers reserve this treatment for patients with brain edema and mass effect [41]. Moreover, there is no consensus regarding the steroid preparation and dosage, and some use a 4-day course of dexamethasone and others up to 7 days of methylprednisone. \n\nHowever, in addition to secondary CNS manifestation and HSV-1 related vasculitis, there are further causes of neurological deterioration in SMZL. Posterior leukoencephalopathy syndrome and vasoconstriction syndrome are clinical mimics of encephalitis, that show vascular alterations and has been reported in the context of lymphoma and with the oncological therapies used in our patient [42,43]. Ibrutinib, a Bruton’s tyrosine kinase inhibitor, has been increasingly widely used in relapsed and refractory SMZL. Cases of cryptococcal meningoencephalitis were confirmed for patients on this treatment [44]. In addition, in patients with myelotoxic adverse events, the entire range of opportunistic brain infection needs to be taken into account.\n\n4. Conclusions\nThere are various conditions which can cause neurological deterioration in patients with SMZL. The spectrum includes potentially reversible conditions such as encephalopathies and vasculopathies but also disorders with high mortality and morbidity including malignant transformation with secondary CNS manifestation and opportunistic infections. We described the rare case of HSV-1-related cerebral vasculitis causing progressive ischemic stroke, which developed as a complication of myelotoxicity by chemotherapy.\n\nAuthor Contributions\nConceptualization, R.N. and J.S.; analysis of data, R.N., L.C., F.B., S.P., L.H., J.S.; writing—original draft preparation, J.S.; writing—review and editing, R.N., L.C., F.B., S.P., L.H.; visualization, S.P. All authors have read and agreed to the published version of the manuscript.\n\nFunding\nThis research received no external funding. \n\nConflicts of Interest\nThe authors declare no conflicts of interest.\n\nFigure 1 (A) Time course of clinical events from diagnosis of splenic marginal zone lymphoma (SMZL) to febrile lymphopenia and Herpes-simplex virus encephalitis (HSE). (B,C) Temporary profile of white blood cells (WBC), neutrophils and lymphocytes. The lower limit for neutrophils and lymphocytes is depicted by a dotted horizontal line (1.5 × 1000 cells/µL and 1.1 × 1000 cells/µL)).\n\nFigure 2 (A) Fluid attenuated inversion recovery (FLAIR) MR axial images of the brain on second admission reveals acute infarction in the region of the left thalamus (white open arrow). (B) Seven days later additional FLAIR hyperintensities consistent with brain infarction were present in the region of the right putamen and in left juxtacortical frontal lobe (white open arrows). (C) The previous infarction also extended further rostral and affected white matter and U-fibers in the left frontal lobe and a portion of the left cingulate gyrus (white open arrows). (D) Anterior-posterior projection of early arterial phase of digital subtraction angiography (DSA) after selective left internal carotid catheterization showing multifocal segmental narrowing in the left superior (black arrow) and inferior (white arrow) M2 segments of the middle cerebral artery. Lateral DSA projection showing narrowing in left anterior cerebral artery (Panel E).\n==== Refs\nReferences\n1. Jiang M. Bennani N.N. Feldman A.L. Lymphoma classification update: B-cell non-Hodgkin lymphomas Expert Rev. Hematol. 2017 10 405 415 10.1080/17474086.2017.1318053 28395545 \n2. Vose J.M. Mantle cell lymphoma: 2017 update on diagnosis, risk-stratification, and clinical management Am. J. Hematol. 2017 92 806 813 10.1002/ajh.24797 28699667 \n3. Santos T.S.D. Tavares R.S. Farias D.L.C. Splenic marginal zone lymphoma: A literature review of diagnostic and therapeutic challenges Rev. Bras. Hematol. Hemoter. 2017 39 146 154 10.1016/j.bjhh.2016.09.014 28577652 \n4. Piris M.A. Onaindia A. Mollejo M. Splenic marginal zone lymphoma Best Pract. Res. Clin. Haematol. 2017 30 56 64 10.1016/j.beha.2016.09.005 28288718 \n5. Bayraktar S. Stefanovic A. Montague N. Davis J. Murray T. Lossos I.S. Central nervous system manifestations of marginal zone B-cell lymphoma Ann. Hematol. 2010 89 1003 1009 10.1007/s00277-010-0976-3 20440502 \n6. Weycker D. Chandler D. Barron R. Xu H. Wu H. Edelsberg J. Lyman G.H. Risk of infection among patients with non-metastatic solid tumors or non-Hodgkin’s lymphoma receiving myelosuppressive chemotherapy and antimicrobial prophylaxis in US clinical practice J. Oncol. Pharm. Pract. 2017 23 33 42 10.1177/1078155215614997 26568602 \n7. Boucher A. Herrmann J.L. Morand P. Buzele R. Crabol Y. Stahl J.P. Mailles A. Epidemiology of infectious encephalitis causes in 2016 Med. Mal. Infect. 2017 47 221 235 10.1016/j.medmal.2017.02.003 28341533 \n8. Saito M. Kiyozaki H. Obitsu T. Imoto H. Taniyama Y. Takata O. Rikiyama T. Herpes simplex virus-1 encephalitis induced by chemoradiotherapy and steroids in an esophageal cancer patient: A case report BMC Cancer 2016 16 233 10.1186/s12885-016-2255-8 26988237 \n9. Rommer P.S. Sellner J. Repurposing multiple sclerosis drugs: A review of studies in neurological and psychiatric conditions Drug Discov. Today 2019 24 1398 1404 10.1016/j.drudis.2019.05.009 31100209 \n10. Perini P. Rinaldi F. Puthenparampil M. Marcon M. Perini F. Gallo P. Herpes simplex virus encephalitis temporally associated with dimethyl fumarate-induced lymphopenia in a multiple sclerosis patient Mult. Scler. Relat. Disord. 2018 26 68 70 10.1016/j.msard.2018.09.009 30227312 \n11. Pfender N. Jelcic I. Linnebank M. Schwarz U. Martin R. Reactivation of herpesvirus under fingolimod: A case of severe herpes simplex encephalitis Neurology 2015 84 2377 2378 10.1212/WNL.0000000000001659 25957334 \n12. Tan I.L. McArthur J.C. Venkatesan A. Nath A. Atypical manifestations and poor outcome of herpes simplex encephalitis in the immunocompromised Neurology 2012 79 2125 2132 10.1212/WNL.0b013e3182752ceb 23136265 \n13. Chakraborty S. Donner M. Colan D. Fatal herpes encephalitis in a patient with small cell lung cancer following prophylactic cranial radiation—A case report with review of literature Anticancer Res. 2013 33 3263 3268 23898089 \n14. Mantero V. Cossu M. Rigamonti A. Fiumani A. Basilico P. Tassi L. Salmaggi A. HSV-1 encephalitis relapse after epilepsy surgery: A case report and review of the literature J. Neurovirol. 2019 10.1007/s13365-019-00796-1 \n15. Venkatesan A. Geocadin R.G. Diagnosis and management of acute encephalitis: A practical approach Neurol. Clin. Pract. 2014 4 206 215 10.1212/CPJ.0000000000000036 25110619 \n16. Jakob N.J. Lenhard T. Schnitzler P. Rohde S. Ringleb P.A. Steiner T. Wildemann B. Herpes simplex virus encephalitis despite normal cell count in the cerebrospinal fluid Crit. Care Med. 2012 40 1304 1308 10.1097/CCM.0b013e3182374a34 22067626 \n17. Gregory S.A. Case D.C. Jr. Bosserman L. Litwak D.L. Berry W.R. Kalman L.A. Belt R.J. Saven A. Fourteen-day CHOP supported with granulocyte colony-stimulating factor in patients with aggressive non-Hodgkin’s lymphoma: Results of a phase II study Clin. Lymphoma 2003 4 93 98 10.3816/CLM.2003.n.017 14556680 \n18. Ito K. Okamoto M. Inaguma Y. Okamoto A. Ando M. Ando Y. Tsuge M. Tomono A. Kakumae Y. Hayashi T. Influence of R-CHOP Therapy on Immune System Restoration in Patients with B-Cell Lymphoma Oncology 2016 91 302 310 10.1159/000449251 27682623 \n19. Hauer L. Pikija S. Schulte E.C. Sztriha L.K. Nardone R. Sellner J. Cerebrovascular manifestations of herpes simplex virus infection of the central nervous system: A systematic review J. Neuroinflamm. 2019 16 19 10.1186/s12974-019-1409-4 \n20. Modi S. Mahajan A. Dharaiya D. Varelas P. Mitsias P. Burden of herpes simplex virus encephalitis in the United States J. Neurol. 2017 264 1204 1208 10.1007/s00415-017-8516-x 28516331 \n21. Hollender A. Kvaloy S. Nome O. Skovlund E. Lote K. Holte H. Central nervous system involvement following diagnosis of non-Hodgkin’s lymphoma: A risk model Ann. Oncol. 2002 13 1099 1107 10.1093/annonc/mdf175 12176790 \n22. Bokstein F. Lossos A. Lossos I.S. Siegal T. Central nervous system relapse of systemic non-Hodgkin’s lymphoma: Results of treatment based on high-dose methotrexate combination chemotherapy Leuk. Lymphoma 2002 43 587 593 10.1080/10428190290012092 12002763 \n23. Gao X. Li J. Lin J. Liu D. Yu L. Wang Q. High-Grade Transformation in a Splenic Marginal Zone Lymphoma with a Cerebral Manifestation Am. J. Case Rep. 2017 18 611 616 10.12659/AJCR.903679 28566677 \n24. Thoennissen N.H. Keyvani K. Voelker H.U. Bremer J. Krug U. Muller-Tidow C. Koch P. Muller-Hermelink H.K. Berdel W.E. Splenic marginal zone lymphoma: Transformation to diffuse large B-cell lymphoma with isolated cerebral manifestation J. Clin. Oncol. 2008 26 4509 4511 10.1200/JCO.2008.17.6172 18802164 \n25. Fadugba O. Nguyen T.T. McGill J. Wagner-Johnston N. De novo large B-cell lymphoma in a parenchymal brain lesion: Evidence of clonal evolution from splenic marginal zone lymphoma J. Clin. Oncol. 2011 29 e234 e236 10.1200/JCO.2010.32.5811 21205746 \n26. Wedgwood A. Medeiros L.J. Romaguera J.E. CD20+ nodal marginal zone B-cell lymphoma with CD20-recurrence as an intracranial dural-based mass Leuk. Lymphoma 2006 47 2253 2256 10.1080/10428190600783288 17071504 \n27. Wada Y. Nishimura Y. Hashimoto K. A patient with splenic marginal zone lymphoma presenting with spastic paraplegia as the initial symptom Case Rep. Neurol. 2011 3 39 44 10.1159/000324446 21468362 \n28. Gotlib V. Singareddy S. Gergis U. Vakios J. Guevara E. Chadburn A. Yavorkovsky L.L. Patel A. Butt A. Nayak A. Leptomeningeal involvement in a patient with splenic lymphoma with villous lymphocytes Leuk. Lymphoma 2002 43 1337 1340 10.1080/10428190290026411 12153005 \n29. Bruna J. Martinez-Yelamos S. Alonso E. Romagosa V. Arruga J. Arruga J. Domingo A. Rojas-Marcos I. Petit J. Rubio F. Meningeal lymphomatosis as the first manifestation of splenic marginal zone lymphoma Int. J. Hematol. 2005 82 63 65 10.1532/IJH97.E0501 16105762 \n30. Yamazaki K. Shimizu S. Negami T. Sawada K. Nanasawa H. Ohta M. Konda S. Okuda K. Leukemic meningitis in a patient with splenic lymphoma with villous lymphocytes (SLVL). Meningitis as a possible initial manifestation of SLVL Cancer 1994 74 61 65 10.1002/1097-0142(19940701)74:1<61::AID-CNCR2820740111>3.0.CO;2-F 8004584 \n31. Angelopoulou M.K. Vassilakopoulos T.P. Konstantinou E. Boutsikas G. Asimakopoulos J.V. Triantafyllou E.F. Petevi K. Kanellopoulos A. Moschogiannis M. Pangalis G.A. Central nervous system involvement in primary bone marrow or splenic marginal zone lymphoma: Report of two cases and review of the literature Hematol. Oncol. 2019 37 219 222 10.1002/hon.2571 30592785 \n32. Weidauer S. Wagner M. Enkirch S.J. Hattingen E. CNS Infections in Immunoincompetent Patients: Neuroradiological and Clinical Features Clin. Neuroradiol. 2019 10.1007/s00062-019-00837-6 31538219 \n33. Rommer P.S. Milo R. Han M.H. Satyanarayan S. Sellner J. Hauer L. Illes Z. Warnke C. Laurent S. Weber M.S. Immunological Aspects of Approved MS Therapeutics Front. Immunol. 2019 10 1564 10.3389/fimmu.2019.01564 31354720 \n34. Haggiag S. Prosperini L. Galgani S. Pozzilli C. Pinnetti C. Extratemporal herpes encephalitis during natalizumab treatment: A case report Mult. Scler. Relat. Disord. 2016 10 134 136 10.1016/j.msard.2016.10.002 27919480 \n35. Jaijakul S. Salazar L. Wootton S.H. Aguilera E. Hasbun R. The clinical significance of neutrophilic pleocytosis in cerebrospinal fluid in patients with viral central nervous system infections Int. J. Infect. Dis. 2017 59 77 81 10.1016/j.ijid.2017.04.010 28435023 \n36. Tumpey T.M. Chen S.H. Oakes J.E. Lausch R.N. Neutrophil-mediated suppression of virus replication after herpes simplex virus type 1 infection of the murine cornea J. Virol. 1996 70 898 904 10.1128/JVI.70.2.898-904.1996 8551629 \n37. Amin I. Younas S. Afzal S. Shahid M. Idrees M. Herpes Simplex Virus Type 1 and Host Antiviral Immune Responses: An Update Viral Immunol. 2019 32 424 429 10.1089/vim.2019.0097 31599707 \n38. Solomon T. Michael B.D. Smith P.E. Sanderson F. Davies N.W. Hart I.J. Holland M. Easton A. Buckley C. Kneen R. Management of suspected viral encephalitis in adults—Association of British Neurologists and British Infection Association National Guidelines J. Infect. 2012 64 347 373 10.1016/j.jinf.2011.11.014 22120595 \n39. Karrasch M. Liermann K. Betz B.B. Wagner S. Scholl S. Dahms C. Sauerbrei A. Kunze A. Rapid acquisition of acyclovir resistance in an immunodeficient patient with herpes simplex encephalitis J. Neurol. Sci. 2018 384 89 90 10.1016/j.jns.2017.11.024 29249385 \n40. Carod Artal F.J. Clinical management of infectious cerebral vasculitides Expert Rev. Neurother. 2016 16 205 221 10.1586/14737175.2015.1134321 26689107 \n41. Bradshaw M.J. Venkatesan A. Herpes Simplex Virus-1 Encephalitis in Adults: Pathophysiology, Diagnosis, and Management Neurotherapeutics 2016 13 493 508 10.1007/s13311-016-0433-7 27106239 \n42. Kamiya-Matsuoka C. Paker A.M. Chi L. Youssef A. Tummala S. Loghin M.E. Posterior reversible encephalopathy syndrome in cancer patients: A single institution retrospective study J. Neurooncol. 2016 128 75 84 10.1007/s11060-016-2078-0 26900076 \n43. Ramachandran A. Klein R. Posterior reversible encephalopathy syndrome (PRES) after combination chemotherapy for lymphoma Am. J. Ther. 2014 21 e137 e142 10.1097/MJT.0b013e318262315b 23075577 \n44. Sun K. Kasparian S. Iyer S. Pingali S.R. Cryptococcal meningoencephalitis in patients with mantle cell lymphoma on ibrutinib Ecancermedicalscience 2018 12 836 10.3332/ecancer.2018.836 29910833\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2076-0817",
"issue": "9(3)",
"journal": "Pathogens (Basel, Switzerland)",
"keywords": "Non-Hodgkin´s lymphoma; cerebral vasculitis; immunosuppression.; opportunistic infection; splenic marginal cell lymphoma; viral encephalitis",
"medline_ta": "Pathogens",
"mesh_terms": null,
"nlm_unique_id": "101596317",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "32151046",
"pubdate": "2020-03-05",
"publication_types": "D002363:Case Reports",
"references": "28395545;25957334;31354720;28516331;28699667;27682623;30696448;23898089;29249385;31538219;31468470;30592785;25110619;23075577;26988237;18802164;16105762;27106239;21468362;8551629;30227312;12002763;20440502;22067626;28341533;26689107;28577652;22120595;27919480;28288718;17071504;12153005;26568602;23136265;28566677;14556680;29910833;31599707;12176790;28435023;8004584;21205746;26900076;31100209",
"title": "Cerebral HSV-1 Vasculitis as a Fatal Complication of Immunosuppression in Non-Hodgkin´s Lymphoma: A Case Report and Review of the Literature.",
"title_normalized": "cerebral hsv 1 vasculitis as a fatal complication of immunosuppression in non hodgkin s lymphoma a case report and review of the literature"
} | [
{
"companynumb": "IT-HIKMA PHARMACEUTICALS USA INC.-IT-H14001-20-51171",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CYCLOPHOSPHAMIDE"
},
... |
{
"abstract": "OBJECTIVE\nThis study determined the effect of the administration of perioperative ibuprofen 400 mg on tooth sensitivity caused by in-office bleaching.\n\n\nMETHODS\nA triple-blind, parallel-design, randomized clinical trial was conducted on 30 adults who received placebo or ibuprofen before and after bleaching. The drugs were administered three times per day for 48 hours; the first dose was given one hour prior to the bleaching treatment. Two bleaching sessions with 35% hydrogen peroxide gel were performed with a one-week interval. Tooth sensitivity was recorded on two scales: visual analogue and five-point verbal rating scale up to 48 hours after bleaching. The shade evaluation was performed with a visual shade guide and spectrophotometer, before and 30 days after bleaching. The absolute risk of tooth sensitivity and its intensity were evaluated by Fisher exact and Mann-Whitney tests, respectively. The shade changes were evaluated by Student's t-test.\n\n\nRESULTS\nBoth groups showed similar absolute risk of tooth sensitivity (p>0.05). Lower tooth sensitivity was observed in the experimental group only up to one hour postbleaching (p=0.04). Similar tooth sensitivity was observed in the other periods of time.\n\n\nCONCLUSIONS\nThe perioperative use of the anti-inflammatory ibuprofen was not able to avoid tooth sensitivity but reduced its intensity up to one hour after bleaching.",
"affiliations": null,
"authors": "Paula|E|E|;Kossatz|S|S|;Fernandes|D|D|;Loguercio|A|A|;Reis|A|A|",
"chemical_list": "D000894:Anti-Inflammatory Agents, Non-Steroidal; D006861:Hydrogen Peroxide; D007052:Ibuprofen",
"country": "United States",
"delete": false,
"doi": "10.2341/12-107-C",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0361-7734",
"issue": "38(6)",
"journal": "Operative dentistry",
"keywords": null,
"medline_ta": "Oper Dent",
"mesh_terms": "D000328:Adult; D000894:Anti-Inflammatory Agents, Non-Steroidal; D003807:Dentin Sensitivity; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D006861:Hydrogen Peroxide; D007052:Ibuprofen; D008297:Male; D010147:Pain Measurement; D059035:Perioperative Period; D014073:Tooth Bleaching; D014075:Tooth Discoloration",
"nlm_unique_id": "7605679",
"other_id": null,
"pages": "601-8",
"pmc": null,
"pmid": "23586657",
"pubdate": "2013",
"publication_types": "D016428:Journal Article; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "The effect of perioperative ibuprofen use on tooth sensitivity caused by in-office bleaching.",
"title_normalized": "the effect of perioperative ibuprofen use on tooth sensitivity caused by in office bleaching"
} | [
{
"companynumb": "US-JNJFOC-20150921719",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "IBUPROFEN"
},
"drugadditional": null,
"... |
{
"abstract": "We report the case of a patient with Rheumatoid Arthritis [RA] presenting with clinical-pathological and radiological features of Pulmonary Lymphomatoid Granulomatosis (PLG). This is a rare lung disorder characterized by multiple nodular lesions with lymphocytic invasion of vascular walls. We present one such case of PLG secondary to Methotrexate and Azathioprine therapy, who was successfully treated with Steroids and Rituximab. We wish to highlight the importance of lung biopsy in the diagnosis and the use of rituximab as a treatment modality for RA as well as PLG.",
"affiliations": "Department of Rheumatology, Nobles Hospital, Isle of Man, IM44RJ UK.;Department of Rheumatology, Nobles Hospital, Isle of Man, IM44RJ UK.;Department of Rheumatology, Nobles Hospital, Isle of Man, IM44RJ UK.",
"authors": "Barakat|Athar|A|;Grover|Karan|K|;Peshin|Rohit|R|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1186/2193-1801-3-751",
"fulltext": "\n==== Front\nSpringerplusSpringerplusSpringerPlus2193-1801Springer International Publishing Cham 25674479152510.1186/2193-1801-3-751Case StudyRituximab for pulmonary lymphomatoid granulomatosis which developed as a complication of methotrexate and azathioprine therapy for rheumatoid arthritis Barakat Athar athar.barakat@gov.im Grover Karan drkarangrover@gmail.com Peshin Rohit rohit.peshin@gov.im Department of Rheumatology, Nobles Hospital, Isle of Man, IM44RJ UK 18 12 2014 18 12 2014 2014 3 75117 10 2014 20 10 2014 © Barakat et al.; licensee Springer. 2014This article is published under license to BioMed Central Ltd. 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 credited.We report the case of a patient with Rheumatoid Arthritis [RA] presenting with clinical-pathological and radiological features of Pulmonary Lymphomatoid Granulomatosis (PLG). This is a rare lung disorder characterized by multiple nodular lesions with lymphocytic invasion of vascular walls. We present one such case of PLG secondary to Methotrexate and Azathioprine therapy, who was successfully treated with Steroids and Rituximab. We wish to highlight the importance of lung biopsy in the diagnosis and the use of rituximab as a treatment modality for RA as well as PLG.\n\nElectronic supplementary material\nThe online version of this article (doi:10.1186/2193-1801-3-751) contains supplementary material, which is available to authorized users.\n\nKeywords\nPulmonary Lymphomatoid granulomatosisRheumatoid arthritisRituximabissue-copyright-statement© The Author(s) 2014\n==== Body\nIntroduction\nWe report the case of a patient with Rheumatoid Arthritis [RA] presenting with clinical-pathological and radiological features of Pulmonary Lymphomatoid Granulomatosis (PLG). This is a rare lung disorder characterized by multiple nodular lesions with lymphocytic invasion of vascular walls. We present one such case of PLG secondary to Methotrexate and Azathioprine therapy, who was successfully treated with Steroids and Rituximab. We wish to highlight the importance of lung biopsy in the diagnosis and the use of rituximab as a treatment modality for RA as well as PLG.\n\nCase report\nA 60 year old lady with anti-CCP and sero-positive rheumatoid arthritis [RA] on methotrexate (MTX, 20 mg once weekly), hydroxycholroquine (HXQ, 200 mg twice daily), azathioprine (AZA, 50 mg twice daily), presented with a history of weight loss (2 stone in 6 months), poor appetite for 5 months, non-productive cough and non exertional shortness of breath of few days duration.\n\nExamination was unremarkable except for mouth ulcers, an erythematous rash with irregular borders above the upper lip and on trunk. There was no focal neurology. White cell count was elevated along with a predominantly raised neutrophil count, and CRP was elevated too. Biochemical profile was unremarkable.\n\nChest x-ray revealed increased coarse, linear shadowing in the mid- and lower zones, prominent hila, bilateral Kerley B lines, and a pleural reaction on the left. Nodular shadows were present bilaterally, the largest measuring 18 mm.\n\nMethotrexate and Azathioprine were discontinued. As concerns were raised about methotrexate lung disease, Folinic acid rescue was instituted and broad spectrum antibiotic cover with IV levofloxacin and oral clarithromycin therapy was commenced.\n\nCT scan revealed mediastinal (complex confluent subcarinal lymph node mass measuring 5.6 cm), aortopulmonary, paratracheal, right tracheobronchial, axillary, upper abdominal (1.5 cm), external ileac and right inguinal lymphadenopathy (largest 10.7 mm). There was widespread reticulonodular shadowing, subpleural consolidation and congestion of interlobular lymphatics. A small right pleural effusion and little pleural thickening/pleural reaction was reported in dependent parts of the left lower lobe (Figure 1).Figure 1 \nCT scan chest.\n\n\n\n\nLung function tests showed reduced diffusion (TLCO 62% of predicted), with no evidence of restrictive ventilatory defect.\n\nOur Differential included lymphoma, sarcoidosis, Wegener’s, pulmonary fibrosis and malignancy.\n\nLung biopsy conclusively diagnosed Pulmonary Lymphomatoid Granulomatosis [PLG]. EBV PCR was negative.\n\nAn opinion was sought from the haematologists who confirmed the diagnosis, malignancy was ruled out, and as the lung picture had improved considerably with steroids, it was agreed in an MDT setting that Rituximab could be used to treat both the RA and PLG.\n\nThe patient improved significantly on steroids (Figure 1) as well as rituximab infusions [dose 375 mg/m2 for 4 weeks]. The clinical response to treatment was very good, and a post-treatment CT chest shows complete resolution of lung changes.\n\nThe patient has been under surveillance for more than a year now with no recurrence of joint symptoms, lung complications or any extra articular complication. She has a very good quality of life now. The rituximab therapy really brought the disease as well as the PLG into remission.\n\nDiscussion\nPulmonary lymphomatoid granulomatosis (PLG) is a rare lung disorder characterized by multiple nodular lesions with lymphocytic invasion of vascular walls.\n\nIt is a nonspecific manifestation of conditions, including autoimmunity, immunodeficiency, infection, malignancy, lymphoproliferative disorder (Pittaluga et al. 2008; Katzenstein et al. 1979; Sordillo et al. 1982), can be secondary to immunosuppressive medications such as azathioprine, methotrexate, and imatinib where the disorder resolves after discontinuing medications (Katherine Martin et al. 2009; Kameda et al. 2007; Pfistershammer et al. 2010; Pisani and DeRemee 1990). It generally presents between 30 and 50 years, but any age group can be affected (Koss et al. 1986). It has been associated with Epstein-Barr virus infection in most cases (Pittaluga et al. 2008). Immune defects may lead to an abnormal host response to EBV infection (Pittaluga et al. 2008; Jaffe and Wilson 1997).\n\nLungs are most commonly involved (>90 percent) (Pittaluga et al. 2008) with or without skin and neurologic involvement. The commonest presenting picture includes fever, cough, rash/nodules, malaise, weight loss, neurologic abnormalities, dyspnoea, and chest pain (Katzenstein et al. 1979).\n\nLaboratory investigations are nonspecific, but pulmonary function test abnormalities can be characteristic (Katzenstein et al. 1979).\n\nChest radiography typically reveals multiple poorly defined nodules and/or masses in the mid- and lower-lung zones with possible diffuse reticular abnormalities (Jaffe and Wilson 1997; Katzenstein et al. 1979). Diagnosis requires the histopathologic triad of polymorphic lymphoid infiltrates, transmural infiltration of arteries and veins by lymphoid cells, and necrotic foci (not typical granulomas) within the lymphoid infiltrates (Pittaluga et al. 2008).\n\nThe prognosis varies (Katzenstein et al. 1979) from remission without treatment (Katzenstein et al. 1979; Jaffe and Wilson 1997) to death within 2 years from malignant lymphoma.\n\nTreatment differs according to symptoms, use of medication associated with PLG, extent of extrapulmonary involvement, and histopathologic grade. Medication implicated in the disorder should be stopped with repeated imaging over weeks to months (Pittaluga et al. 2008).\n\nTo our knowledge after literature search, this is the first case report of the use of Rituximab in treatment of PLG which had developed as a complication of DMARD therapy in a patient with RA.\n\nKey message\nLymphatoid granulomatosis is a rare lymphoproliferative disorder primarily affecting the lung, with variable clinical outcome.\n\nConsent\nWritten informed consent was obtained from the patient for the publication of this report and any accompanying images.\n\nAuthors’ original submitted files for images\nBelow are the links to the authors’ original submitted files for images.Authors’ original file for figure 1\n\n\n\nCompeting interests\n\nThe authors declare that they have no competing interests.\n\nAuthors’ contributions\n\nAll authors contributed equally in drafting, editing and submitting the final version of the script. All authors have read and approved the final manuscript.\n==== Refs\nReferences\nJaffe ES Wilson WH Lymphomatoid granulomatosis: pathogenesis, pathology and clinical implications Cancer Surv 1997 30 233 9547995 \nKameda H Okuyama A Tamaru J Itoyama S Iizuka A Takeuchi T Lymphomatoid granulomatosis and diffuse alveolar damage associated with methotrexate therapy in a patient with rheumatoid arthritis Clin Rheumatol 2007 26 9 1585 10.1007/s10067-006-0480-2 17200802 \nKatherine Martin L Porcu P Baiocchi RA Erter JW Chaudhury AR Primary central nervous system lymphomatoid granulomatosis in a patient receiving azathioprine therapy Clin Adv Hematol Oncol 2009 7 1 65 19274043 \nKatzenstein AL Carrington CB Liebow AA Lymphomatoid granulomatosis: a clinicopathologic study of 152 cases Cancer 1979 43 1 360 10.1002/1097-0142(197901)43:1<360::AID-CNCR2820430151>3.0.CO;2-8 761171 \nKoss MN Hochholzer L Langloss JM Wehunt WD Lazarus AA Nichols PW Lymphomatoid granulomatosis: a clinicopathologic study of 42 patients Pathology 1986 18 3 283 10.3109/00313028609059478 3785978 \nPfistershammer K Petzelbauer P Stingl G Mastan P Chott A Jager U Skrabs C Geusau A Methotrexate-induced primary cutaneous diffuse large B-cell lymphoma with an ‘angiocentric’ histological morphology Clin Exp Dermatol 2010 35 59 10.1111/j.1365-2230.2009.03293.x 19486063 \nPisani RJ DeRemee RA Clinical implications of the histopathologic diagnosis of pulmonary lymphomatoid granulomatosis Mayo Clin Proc 1990 65 151 10.1016/S0025-6196(12)65010-1 2304362 \nPittaluga S Wilson WH Jaffe ES World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues 2008 Lyon IARC Press \nSordillo PP Epremian B Koziner B Lacher M Lieberman P Lymphomatoid granulomatosis: an analysis of clinical and immunologic characteristics Cancer 1982 49 10 2070 10.1002/1097-0142(19820515)49:10<2070::AID-CNCR2820491019>3.0.CO;2-S 6978760\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2193-1801",
"issue": "3()",
"journal": "SpringerPlus",
"keywords": "Pulmonary Lymphomatoid granulomatosis; Rheumatoid arthritis; Rituximab",
"medline_ta": "Springerplus",
"mesh_terms": null,
"nlm_unique_id": "101597967",
"other_id": null,
"pages": "751",
"pmc": null,
"pmid": "25674479",
"pubdate": "2014",
"publication_types": "D016428:Journal Article",
"references": "19274043;2304362;19486063;9547995;17200802;3785978;6978760;761171",
"title": "Rituximab for pulmonary lymphomatoid granulomatosis which developed as a complication of methotrexate and azathioprine therapy for rheumatoid arthritis.",
"title_normalized": "rituximab for pulmonary lymphomatoid granulomatosis which developed as a complication of methotrexate and azathioprine therapy for rheumatoid arthritis"
} | [
{
"companynumb": "GB-ACCORD-028761",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "AZATHIOPRINE"
},
"drugadditional": null,
"dr... |
{
"abstract": "The precise etiology of oral lichen planus (OLP) is still unclear, but the existing evidence suggests that drug intake, virus infection, fungal infection, psychological disorders, and immunodeficiency are closely associated with the pathogenesis of OLP. We report a case of OLP accompanied with candidiasis induced by long-term use of antimicrobials for recurrent aphthous ulcer (RAU) and update the literature, to discuss the possible association between OLP and misuse of antimicrobials, and to inform general dentists and pharmacists the importance for practice with optimal antimicrobial stewardship. In this case, a 42-year-old man presented to Xiangya Stomatological Hospital with white reticular patterns spreading in the oral cavity for almost 1 year. He was diagnosed with OLP via histopathological examination. He had a 5-year history of RAU which occurred every 1-2 months, and he was given antimicrobials ingested or injected whenever the ulcers came up. Satisfactory treatment results were obtained by stopping the abuse of antimicrobials and local antifungal therapy. Meanwhile, the exacerbation and alleviation of OLP was closely related to the administration of antimicrobials. Combined with literature review, antimicrobial might contribute to the development of OLP by inducing candidiasis, a common side-effect of misuse of antimicrobials. Considering the seriousness of antimicrobial resistance and opportunistic infection, dentists should prescribe antimicrobials judiciously according to guidelines and evidence-based indications. Appropriate prescribing of antimicrobials is a professional responsibility to all dentists.",
"affiliations": "Xiangya Stomatological Hospital, Xiangya School of Stomatology, Central South University, Changsha 410008. liwenj@csu.edu.cn.;Xiangya Stomatological Hospital, Xiangya School of Stomatology, Central South University, Changsha 410008.;Xiangya Stomatological Hospital, Xiangya School of Stomatology, Central South University, Changsha 410008.;Xiangya Stomatological Hospital, Xiangya School of Stomatology, Central South University, Changsha 410008.;School of Stomatology, Peking University, Beijing 100081, China.;Xiangya Stomatological Hospital, Xiangya School of Stomatology, Central South University, Changsha 410008. chenjun1222@csu.edu.cn.",
"authors": "Li|Wenjie|W|;Gao|Xuyang|X|;Wang|Yuetong|Y|;Xu|Yiqi|Y|;Zhang|Xin|X|;Chen|Jun|J|",
"chemical_list": "D000935:Antifungal Agents",
"country": "China",
"delete": false,
"doi": "10.11817/j.issn.1672-7347.2021.200817",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1672-7347",
"issue": "46(6)",
"journal": "Zhong nan da xue xue bao. Yi xue ban = Journal of Central South University. Medical sciences",
"keywords": "Candida infection; misuse of antimicrobial; oral lichen planus; stewardship",
"medline_ta": "Zhong Nan Da Xue Xue Bao Yi Xue Ban",
"mesh_terms": "D000328:Adult; D000935:Antifungal Agents; D006801:Humans; D017676:Lichen Planus, Oral; D008297:Male; D009181:Mycoses; D013281:Stomatitis, Aphthous; D014777:Virus Diseases",
"nlm_unique_id": "101230586",
"other_id": null,
"pages": "666-672",
"pmc": null,
"pmid": "34275937",
"pubdate": "2021-06-28",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Oral lichen planus induced by long-term use of antimicrobials for recurrent aphthous ulcer: A case report and literature review.",
"title_normalized": "oral lichen planus induced by long term use of antimicrobials for recurrent aphthous ulcer a case report and literature review"
} | [
{
"companynumb": "CN-TEVA-2021-CN-1949908",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "FLUCONAZOLE"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nTo evaluate the safety and efficacy of the novel tenofovir prodrug, tenofovir alafenamide (TAF), as part of the first protease inhibitor-based single-tablet regimen (STR) for initial treatment of HIV-1 infection.\n\n\nMETHODS\nAntiretroviral therapy (ART)-naive adults with estimated glomerular filtration rate ≥ 70 mL/min were randomized 2:1 to receive the darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) STR (TAF: N = 103) or darunavir + cobicistat + emtricitabine/tenofovir disoproxil fumarate (TDF: N = 50) once daily with matched placebos for 48 weeks.\n\n\nRESULTS\nAt week 24, viral suppression (HIV-1 RNA <50 copies/mL) rates were similar (TAF 74.8% vs. TDF 74.0%). At week 48, rates were TAF 76.7% vs. TDF 84.0%; the difference was driven by higher rate of discontinuations in TAF (6.8%) vs. TDF (2%). Among those with virologic failure, none developed resistance. Most adverse events were of mild/moderate severity. The mean change in serum creatinine from baseline at week 48 was 0.06 mg/dL (95% confidence interval: 0.04 to 0.08) for TAF vs. 0.09 mg/dL (95% confidence interval: 0.05 to 0.14) for TDF (P = 0.053). The % change in retinol binding protein/Cr ratio was +9 (TAF) vs. +54 (TDF), P = 0.003; the % change in urine β-2 microglobulin/Cr ratio was -42.0 (TAF) vs. +2.3 (TDF), P = 0.002. The % change in hip bone mineral density (BMD) was -0.84 (TAF) vs. -3.82 (TDF), P < 0.001 and in spine BMD was -1.57 (TAF) vs. -3.62 (TDF), P = 0.003. There were no fractures in either group.\n\n\nCONCLUSIONS\nThe TAF arm had significantly improved renal and bone safety parameters: less proteinuria and less change in hip and spine BMD, consistent with results from a similarly designed study of the elvitegravir/C/F/TAF STR. This D/C/F/TAF STR offers a promising option for initial HIV treatment, with the high barrier to resistance of darunavir, and the potential for improved long-term renal and bone safety with TAF.",
"affiliations": "*Gordon Crofoot Research, Southern California Men's Medical Group/Men's Health Foundation, Assistant Professor of Clinical Medicine, Univeristy of California, Los Angeles, Los Angeles, CA; †Houston, TX; ‡Tarrant County Infectious Disease Associates, Fort Worth, TX; §Clinical Associate Professor in the Division of Allergy and Infectious Diseases, University of Washington School of Medicine, Seattle, WA; ‖Kaiser Permanente, Sacramento, CA; ¶Therapeutic Concepts, Houston, TX; #DCOL Center for Clinical Research, Longview, TX; **La Playa Medical Group and Clinical Research, San Diego, CA; ††Center for AIDS Research, The University of Alabama at Birmingham, Birmingham, AL; and ‡‡Gilead Sciences, Foster City, CA.",
"authors": "Mills|Anthony|A|;Crofoot|Gordon|G|;McDonald|Cheryl|C|;Shalit|Peter|P|;Flamm|Jason A|JA|;Gathe|Joseph|J|;Scribner|Anita|A|;Shamblaw|David|D|;Saag|Michael|M|;Cao|Huyen|H|;Martin|Hal|H|;Das|Moupali|M|;Thomas|Anne|A|;Liu|Hui C|HC|;Yan|Mingjin|M|;Callebaut|Christian|C|;Custodio|Joseph|J|;Cheng|Andrew|A|;McCallister|Scott|S|",
"chemical_list": "D019380:Anti-HIV Agents; D063065:Organophosphonates; D012367:RNA, Viral; D000068698:Tenofovir; C442442:tenofovir alafenamide; D000225:Adenine; D000409:Alanine",
"country": "United States",
"delete": false,
"doi": "10.1097/QAI.0000000000000618",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1525-4135",
"issue": "69(4)",
"journal": "Journal of acquired immune deficiency syndromes (1999)",
"keywords": null,
"medline_ta": "J Acquir Immune Defic Syndr",
"mesh_terms": "D000225:Adenine; D000328:Adult; D000409:Alanine; D019380:Anti-HIV Agents; D005260:Female; D015658:HIV Infections; D015497:HIV-1; D006801:Humans; D008297:Male; D063065:Organophosphonates; D012367:RNA, Viral; D000068698:Tenofovir",
"nlm_unique_id": "100892005",
"other_id": null,
"pages": "439-45",
"pmc": null,
"pmid": "25867913",
"pubdate": "2015-08-01",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Tenofovir Alafenamide Versus Tenofovir Disoproxil Fumarate in the First Protease Inhibitor-Based Single-Tablet Regimen for Initial HIV-1 Therapy: A Randomized Phase 2 Study.",
"title_normalized": "tenofovir alafenamide versus tenofovir disoproxil fumarate in the first protease inhibitor based single tablet regimen for initial hiv 1 therapy a randomized phase 2 study"
} | [
{
"companynumb": "US-CIPLA LTD.-2015US06544",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "TENOFOVIR ALAFENAMIDE"
},
"drugadditional": n... |
{
"abstract": "Melioidosis is caused by the tropical soil pathogen Burkholderia pseudomallei Infection, usually in the form of pneumonia, disproportionately affects people with a risk factor for immune dysregulation and mortality remains high even with treatment. Climate change and increasing rates of diabetes render the populations of endemic areas increasingly vulnerable to the disease, which is emerging as a serious global health threat. We present here a case of a 68-year-old man from northern Australia with sepsis and osteoarticular melioidosis of the hip, and explore the links between diabetes mellitus and melioidosis, particularly with respect to musculoskeletal infection.",
"affiliations": "Internal Medicine, Townsville University Hospital, Townsville, Queensland, Australia pierre.boyer@health.qld.gov.au.;Infectious Diseases, Townsville University Hospital, Townsville, Queensland, Australia.",
"authors": "Boyer|Pierre-Nicolas|PN|http://orcid.org/0000-0002-7012-4522;Woods|Marion L|ML|http://orcid.org/0000-0003-1094-9853",
"chemical_list": "D000900:Anti-Bacterial Agents",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2020-238200",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "13(12)",
"journal": "BMJ case reports",
"keywords": "bone and joint infections; diabetes; tropical medicine (infectious disease)",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000368:Aged; D000900:Anti-Bacterial Agents; D001315:Australia; D016957:Burkholderia pseudomallei; D003924:Diabetes Mellitus, Type 2; D004359:Drug Therapy, Combination; D006621:Hip Joint; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008554:Melioidosis; D015207:Osteoarthritis, Hip; D018805:Sepsis; D016896:Treatment Outcome",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "33370949",
"pubdate": "2020-12-21",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Burkholderia pseudomallei sepsis with osteoarticular melioidosis of the hip in a patient with diabetes mellitus.",
"title_normalized": "burkholderia pseudomallei sepsis with osteoarticular melioidosis of the hip in a patient with diabetes mellitus"
} | [
{
"companynumb": "AU-MYLANLABS-2021M1024813",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CEFTAZIDIME"
},
"drugadditional": "3",
... |
{
"abstract": "Psoriasis is an inflammatory skin disorder not uncommonly seen in pregnant patients. Several drugs have been approved for its treatment in non-pregnant patients, but special precautions are necessary when selecting a treatment plan during pregnancy to prevent harm to the fetus and child. This article reviews the treatment options for the treatment of psoriasis in the pregnant and lactating patient.",
"affiliations": "Department of Dermatology, University of Connecticut School of Medicine, Farmington, Connecticut 06030, USA.",
"authors": "Babalola|Olubukola|O|;Strober|Bruce E|BE|",
"chemical_list": "D000305:Adrenal Cortex Hormones; D009539:Nicotinic Acids; C086827:tazarotene; D016572:Cyclosporine; D008727:Methotrexate",
"country": "United States",
"delete": false,
"doi": "10.1111/dth.12073",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1396-0296",
"issue": "26(4)",
"journal": "Dermatologic therapy",
"keywords": "management; pregnancy; pregnancy dermatoses; psoriasis",
"medline_ta": "Dermatol Ther",
"mesh_terms": "D000305:Adrenal Cortex Hormones; D016572:Cyclosporine; D005260:Female; D006801:Humans; D008727:Methotrexate; D009539:Nicotinic Acids; D010789:Phototherapy; D011247:Pregnancy; D011248:Pregnancy Complications; D011565:Psoriasis",
"nlm_unique_id": "9700070",
"other_id": null,
"pages": "285-92",
"pmc": null,
"pmid": "23914885",
"pubdate": "2013",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": null,
"title": "Management of psoriasis in pregnancy.",
"title_normalized": "management of psoriasis in pregnancy"
} | [
{
"companynumb": "CN-ALKEM LABORATORIES LIMITED-CN-ALKEM-2019-03603",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "TRIAMCINOLONE ACETONIDE"
},
... |
{
"abstract": "Aphasia could be a manifestation of postoperative psychoemotional disorder. Early differential diagnosis is important.",
"affiliations": "Department of Anesthesiology and Perioperative Medicine Xijing Hospital Fourth Military Medical University Xi'an China.;Department of Anesthesiology and Perioperative Medicine Xijing Hospital Fourth Military Medical University Xi'an China.;Department of Anesthesiology and Perioperative Medicine Xijing Hospital Fourth Military Medical University Xi'an China.;Department of Anesthesiology and Perioperative Medicine Xijing Hospital Fourth Military Medical University Xi'an China.",
"authors": "Zhang|Junbao|J|;Yang|Manping|M|;Dong|Hailong|H|;Lu|Zhihong|Z|https://orcid.org/0000-0001-5639-4705",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1002/ccr3.3598",
"fulltext": "\n==== Front\nClin Case Rep\nClin Case Rep\n10.1002/(ISSN)2050-0904\nCCR3\nClinical Case Reports\n2050-0904 John Wiley and Sons Inc. Hoboken \n\n10.1002/ccr3.3598\nCCR33598\nCase Report\nCase Reports\nTransient aphasia following general anesthesia in patient undergoing laparoscopic gynecologic surgery: A case report and literature review\nZHANG et al.Zhang Junbao \n1\n Yang Manping \n1\n Dong Hailong \n1\n Lu Zhihong https://orcid.org/0000-0001-5639-4705\n1\ndeerlu23@163.com \n1 \nDepartment of Anesthesiology and Perioperative Medicine\nXijing Hospital\nFourth Military Medical University\nXi'an\nChina\n\n* Correspondence\n\nZhihong Lu, Department of Anesthesiology, Xijing Hospital, Fourth Military Medical University, Changle West Rd. 127, Xi'an, Shaanxi 710032, China.\n\nEmail: deerlu23@163.com\n\n02 12 2020 \n2 2021 \n9 2 10.1002/ccr3.v9.2634 637\n07 8 2020 16 10 2020 10 11 2020 © 2020 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.Abstract\nAphasia could be a manifestation of postoperative psychoemotional disorder. Early differential diagnosis is important.\n\nAphasia could be a manifestation of postoperative psychoemotional disorder. Early differential diagnosis is important.\n\n\n\naphasiacase reportgeneral anesthesialaparoscopic surgeryProject of Fourth Military Medical University2016TSB‐014National Natural Science Foundation of China 10.13039/501100001809816713038187102381871028National science foundation of Shaanxi Province2018SF‐277 source-schema-version-number2.0cover-dateFebruary 2021details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:5.9.7 mode:remove_FC converted:08.02.2021\n\n\nZhang \nJ \n, \nYang \nM \n, \nDong \nH \n, \nLu \nZ \n. Transient aphasia following general anesthesia in patient undergoing laparoscopic gynecologic surgery: A case report and literature review\n. Clin Case Rep .2021 ;9 :634 –637\n. 10.1002/ccr3.3598 \n\n\n\n\nFunding informationThe study received funding from National Natural Science Foundation of China (No. 81871028, 81871023, 81671303), Natural Science Foundation of Shaanxi Province (No. 2018SF‐277), and project of Fourth Military Medical University (No. 2016TSB‐014)\n==== Body\n1 INTRODUCTION\nThis case report describes a healthy 45‐year‐old woman who received total intravenous anesthesia for laparoscopic hysterectomy, and then exhibited postoperative transient aphasia. Droperidol was given and the patient resolved. The author hypothesized that aphasia is a manifestation of psychoemotional disorder. Early differential diagnosis is important.\n\nLaparoscopic gynecological surgery has been widely employed under general anesthesia. Although the safety and effectiveness of these techniques have greatly improved over the past decades, some problematic effects may still occur. Lithotomy position, Trendelenburg position, and CO2 pneumoperitoneum may increase the risk of neurologic complications.\n1\n, \n2\n, \n3\n, \n4\n There have been isolated case reports of psychogenic language disorder during surgery.\n5\n However, cognitive and neurologic complications after prolonged Trendelenburg position are extremely rare and more often reported in elderly patients, or those with underlying venous disease.\n6\n Furthermore, aphasia is rarely reported in perioperative settings. In this report, we present a patient who developed transient aphasia after extubation after laparoscopic hysterectomy. The patient provided written consent for this case report.\n\n2 CASE PRESENTATION\nA 45‐year‐old woman was admitted for laparoscopic hysterectomy under general anesthesia. She weighed 60 kg and was 162 cm tall. She had no history of psychiatric illness, medical disease, or drug abuse. Her physical examination did not reveal any significant findings. The preoperative electrocardiography and laboratory data, which included complete blood count, liver function, kidney function, and coagulation profile, were unremarkable.\n\nUpon arrival in the operating room, routine monitoring, including electrocardiograph (ECG) monitoring, noninvasive blood pressure, and pulse oximetry, was applied. Lactated Ringer's solution (500 mL) was rapidly infused intravenously during the induction of anesthesia. Scopolamine (0.3 mg) and dexamethasone (5 mg) were administered before induction. Propofol (2 mg/kg) and fentanyl (4 µg/kg) were used for induction. When the patient lost consciousness, 0.6 mg/kg of rocuronium was given to facilitate tracheal intubation. Anesthesia was maintained by the continuous infusion of propofol (6‐7 mg/kg/h) and remifentanil (0.15‐0.2 µg/kg/min). The patient was placed in the Trendelenburg position, and intra‐abdominal pressure was maintained at 11‐14 cmH2O during surgery. After surgery, the patient was extubated when spontaneous breathing and consciousness recovered. The surgery lasted 80 minutes. Neuromuscular blockade was monitored by TOF‐Watch, and no additional rocuronium was given during surgery.\n\nAfter extubation, the patient manifested symptoms of dyspnea, showing repeated effort to breathe. She was a little anxious but could obey loud verbal commands, such as opening the mouth and holding the anesthetist's hand. The TOF value was above 90% though our first concern was a possible weakness of muscle tone. We gave the patient neostigmine (0.04 mg/kg) and atropine (0.02 mg/kg). However, the patient became more anxious and irritable. We tried to pacify her with reassuring remarks that the surgery was successful and that she would be sent back to her husband soon. However, the patient frequently pointed to her throat, and we began to notice that she had difficulty speaking. She remained conscious and seemed to understand what we were saying to her. She tried to answer but could not utter a word. She could move her mouth, lips, tongue, head, and extremities upon command. Her pupils were equal in size and reactive to light. Her lungs were clear, and vital signs were stable. Arterial blood gas analysis showed no abnormal results. The patient asked for paper by gesture and wrote down the following words, “I want to speak, but I can't say a word” and “help me.” The patient was getting increasingly anxious, became uncooperative, and was in tears.\n\n3 DIAGNOSIS AND TREATMENT\nWe administered 2.5 mg of droperidol, and she fell asleep. When she woke up 20 minutes later, she could speak in a hoarse voice and was transferred to the ward. She became more peaceful when she saw her husband. After 4 hours, the patient was able to talk normally. The aphasia lasted for 1 hour, and the whole episode lasted for 5.5 hours. She told the anesthetist that she could recall the events during recovery and felt happy to be able to talk again. She recalled that approximately 4 years ago, she experienced an episode of transient aphasia after a bitter quarrel with her husband.\n\n4 OUTCOME AND FOLLOW‐UP\nA neurology consultation suggested that the patient should undergo more extensive studies before any definite diagnosis could be made. Therefore, imaging (MRI) was arranged immediately. No definite organic lesions were found in an MRI of the brain. She was discharged without sequelae on postsurgery day 3. She was followed up for 3 months, and no complications were reported.\n\n5 DISCUSSION\nThe differential diagnosis of such a clinical presentation of sudden and transient aphasia could be related to a residual effect of the anesthesia, transient ischemic attack (TIA), structural injury of vocal function,\n7\n or psychoemotional change.\n8\n, \n9\n The available literature on acute aphasia after anesthesia is limited.\n\nTransient ischemic attack is a transient neurological event that usually persists for minutes and can occur due to hypotension, hypoxia, or embolism. However, the patient did not have hypoxia or hypotension. Thromboembolism was considered because the patient was placed in the lithotomy position. Lithotomy position and CO2 pneumoperitoneum may result in increased lower extremity venous pressure during hysterectomy, representing a risk factor for deep venous thrombosis.\n10\n And it was reported that steep Trendelenburg, along with several other risk factors, increased the odds of venous thromboembolism formation by 2.4 [95% confidence interval (95% CI) 1.9‐5.0].\n11\n When TIA is suspected, the “ABCD2” score could be used for the assessment of early stroke risk (“ABCD2” score ≥ 4).\n12\n The “ABCD2” score in this patient was 3 (speech disturbance without weakness [1 point] and duration of symptoms > 60 minutes [2 points]). And the patient was with a Glasgow score of 15 and a normal MRI results after surgery. The patient was followed up for 3 months because there is a 10%‐20% risk of major stroke after TIA in the subsequent 3 months.\n13\n All the evidences supported that the patient did not suffer from TIA.\n\nThere are several reports of acute neurological events, including cerebral edema, in patients undergoing laparoscopic gynecological surgery.\n2\n, \n3\n Any rise in arterial carbon dioxide can possibly result in increased cerebral blood flow. A steep Trendelenburg position can alter the cerebral blood volume and, thus, increase intracranial pressure. Moreover, head‐down tilt causes cephalad fluid shift and increases capillary pressure in the head, leading to an increase in extracranial vascular pressure that may cause facial, laryngeal, pharyngeal edema, and nasal congestion.\n1\n, \n4\n However, in our case, the carbon dioxide levels were measured by capnography and were kept at the normal limit. The surgery lasted for 80 minutes, and no significant facial edema existed. Because MRI was normal, brain edema was not considered.\n\nResidual neuromuscular blockade could affect the speaking function. The patient could write down what she wanted to say, appropriately response to verbal command, indicating well‐reversed neuromuscular blockade. Structural injury, including the luxation of the arytenoid cartilage and laryngeal nerve injury, may occur after tracheal intubation and affect pronunciation.\n7\n, \n14\n, \n15\n The aphonia or aphasia in these cases is usually consistent and requires treatment. However, for our case the aphasia was transient, so structural damage was excluded. Pre‐existing neurologic disease should be screened for postoperative speaking dysfunction. Willson et al\n16\n reported a patient with hemiplegic migraine who developed atypical migraine with apneic spells, aphasia, and hemiparesis following general anesthesia. By history and MRI assessment, these possibilities were excluded in our case.\n\nPostoperative delirium may present as speaking disorder. Medications including midazolam and scopolamine have been proved to increase delirium.\n17\n, \n18\n And in a case of a healthy 12‐year‐old girl who received preoperative midazolam, Drobish et al\n19\n reported postoperative transient associative agnosia and expressive aphasia. The administration of flumazenil led to the immediate and lasting resolution of her symptoms. Confusion assessment method (CAM) is the most often used tool for delirium evaluation. The diagnosis of delirium by CAM requires the presence of features 1 (acute onset and fluctuation course) and 2 (inattention) and either 3 (disorganized thinking) or 4 (altered level of consciousness). Given the presentation as it is, the patient does not probably meet these criteria. Though the EEG was not recorded during the episode, the Brief Psychiatric Rating Scale of the patient was 10, which did not support the diagnosis of psychiatric disorder. Moreover, Broca's aphasia patient's cannot speak or write and with Wernicke's they can speak but cannot convey a clear message. The presentation of the patient may support that the aphasia is manifestation of psychological in nature. Droperidol was effective for the sedation of the patient; however, ruling out dangerous episodes by CT scan or MRI maybe important before droperidol administration.\n\nPsychogenic cognitive disturbance varies in presentation, including aphasia, aphagia, and quadriplegia.\n8\n, \n20\n, \n21\n In this case, the patient stayed awake and remembered the entire recovery process. The patient has a history of transient aphasia after a bitter quarrel with her husband 4 years ago. Stress and anxiety could have triggered her aphasia. She could be soothed by seeing her family, which highlights the importance of emotional support in treating perioperative psychogenic disorders. Enhanced pre‐operative education and early company of the family may improve the outcome.\n\n6 CONCLUSION\nIn summary, transient aphasia can occur after general anesthesia. The possibility of cerebral complications and the injury of the laryngeal‐pharyngeal structures should be ruled out in appropriate clinical settings. A previous history of psychoemotional disorder should not be dismissed when reviewing a patient preoperatively.\n\nCONFLICT OF INTEREST\nNone declared.\n\nAUTHOR CONTRIBUTION\nZL and HD: were the patient's anesthetists, reviewed the literature, and contributed to manuscript revision; JZ and MY: reviewed the literature and contributed to manuscript drafting; all authors issued final approval for the version to be submitted.\n\nETHICAL APPROVAL\nThe patient provided signed informed consent to the publishment of the case. All the procedures performed in this study were in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.\n\nACKNOWLEDGMENTS\nWe thoroughly appreciated the patient and her family for collaboration with us. Consent statement: Published with written consent of the patient.\n\nDATA AVAILABILITY STATEMENT\nData were not available for share.\n==== Refs\nREFERENCES\n1 \n\nDanic \nMJ \n, \nChow \nM \n, \nAlexander \nG \n, \nBhandari \nA \n, \nMenon \nM \n, \nBrown \nM \n. Anesthesia considerations for robotic‐assisted laparoscopic prostatectomy: a review of 1,500 cases\n. J Robot Surg . 2007 ;1 :119 ‐123\n.25484947 \n2 \n\nPandey \nR \n, \nGarg \nR \n, \nDarlong \nV \n, \nPunj \nJ \n, \nChandralekha \n. Hemiparesis after robotic laparoscopic radical cystectomy and ileal conduit formation in steep Trendelenburg position\n. J Robot Surg . 2012 ;6 :269 ‐271\n.27638287 \n3 \n\nPandey \nR \n, \nGarg \nR \n, \nDarlong \nV \n, \nPunj \nJ \n, \nChandralekha \nxxx \n, \nKumar \nA \n. Unpredicted neurological complications after robotic laparoscopic radical cystectomy and ileal conduit formation in steep trendelenburg position: two case reports\n. Acta Anaesthesiol Belg . 2010 ;61 :163 ‐166\n.21268573 \n4 \n\nPhong \nSV \n, \nKoh \nLK \n. Anaesthesia for robotic‐assisted radical prostatectomy: considerations for laparoscopy in the Trendelenburg position\n. Anaesth Intensive Care . 2007 ;35 :281 ‐285\n.17444322 \n5 \n\nNg \nKO \n, \nLee \nJF \n, \nMui \nWC \n. Aphonia induced by conversion disorder during a Cesarean section\n. Acta Anaesthesiol Taiwan . 2012 ;50 :138 ‐141\n.23026175 \n6 \n\nArvizo \nC \n, \nMehta \nST \n, \nYunker \nA \n. Adverse events related to Trendelenburg position during laparoscopic surgery: recommendations and review of the literature\n. Curr Opin Obstet Gynecol . 2018 ;30 :272 ‐278\n.29939851 \n7 \n\nChun \nEH \n, \nBaik \nHJ \n, \nChung \nRK \n, \nLee \nHJ \n, \nShin \nK \n, \nWoo \nJH \n. Arytenoid cartilage dislocation mimicking bilateral vocal cord paralysis: a case report\n. Medicine . 2017 ;96 :e8514.29137052 \n8 \n\nDrexler \nH \n, \nZaroura \nS \n, \nShapira \nY \n. Transient aphonia and quadriplegia during epidural anesthesia\n. Anesth Analg . 1985 ;64 :365 ‐366\n.3977096 \n9 \n\nParker \nWD \nJr\n, \nParker \nKC \n. Anesthesia‐related transient aphonia and quadriplegia\n. Anesth Analg . 1985 ;64 :1038 .4037393 \n10 \n\nLiu \nX \n, \nWang \nX \n, \nMeng \nX \n, \nWang \nH \n, \nAn \nZ \n. Effects of patient position on lower extremity venous pressure during different types of hysterectomy\n. J Obstet Gynaecol Res . 2015 ;41 :114 ‐119\n.25159605 \n11 \n\nPellino \nG \n, \nSciaudone \nG \n, \nCandilio \nG \n, \nDe Fatico \nGS \n, \nCanonico \nS \n, \nSelvaggi \nF \n. Predictors of venous thromboembolism after colorectal surgery in a single unit\n. Acta Chir Belg . 2015 ;115 :288 ‐292\n.26324031 \n12 \n\nMerwick \nA \n, \nKelly \nPJ \n. Transient ischaemic attack clinics and management of transient ischaemic attacks\n. Curr Opin Neurol . 2011 ;24 :50 ‐58\n.21150595 \n13 \n\nSylaja \nPN \n, \nHill \nMD \n. Current management of transient ischemic attack\n. Am J Cardiovasc Drugs . 2007 ;7 :67 ‐74\n.17355167 \n14 \n\nTakahoko \nK \n, \nIwasaki \nH \n, \nSasakawa \nT \n, \nSuzuki \nA \n, \nMatsumoto \nH \n, \nIwasaki \nH \n. Unilateral hypoglossal nerve palsy after use of the laryngeal mask airway supreme\n. Case Rep Anesthesiol . 2014 ;2014 :369563.25254120 \n15 \n\nUlusoy \nH \n, \nBesir \nA \n, \nCekic \nB \n, \nKosucu \nM \n, \nGeze \nS \n. Transient unilateral combined paresis of the hypoglossal nerve and lingual nerve following intubation anesthesia\n. Braz J Anesthesiol . 2014 ;64 :124 ‐127\n.24794456 \n16 \n\nWillson \nJ \n, \nKapur \nS \n. Apnoeic spells following general anaesthesia in a patient with familial hemiplegic migraine\n. Anaesthesia . 2007 ;62 :956 ‐958\n.17697227 \n17 \n\nAldecoa \nC \n, \nBettelli \nG \n, \nBilotta \nF \n, et al. European Society of Anaesthesiology evidence‐based and consensus‐based guideline on postoperative delirium\n. Eur J Anaesthesiol . 2017 ;34 :192 ‐214\n.28187050 \n18 \nEuropean Society of Anaesthesiology evidence‐based and consensus‐based guideline on postoperative delirium: erratum\n. Eur J Anaesthesiol . 2018 ;35 :718 ‐719\n.30063535 \n19 \n\nDrobish \nJK \n, \nKelz \nMB \n, \nDiPuppo \nPM \n, \nCook‐Sather \nSD \n. Emergence delirium with transient associative agnosia and expressive aphasia reversed by flumazenil in a pediatric patient\n. A A Case Rep . 2015 ;4 :148 ‐150\n.26035220 \n20 \n\nAdams \nAP \n, \nGoroszeniuk \nT \n. Hysteria. A cause of failure to recover after anaesthesia\n. Anaesthesia . 1991 ;46 :932 ‐934\n.1750593 \n21 \n\nKuczkowski \nKM \n, \nGoldsworthy \nM \n. Transient aphonia and aphagia in a parturient after induction of combined spinal‐epidural labor analgesia with subarachnoid fentanyl and bupivacaine\n. Acta Anaesthesiol Belg . 2003 ;54 :165 ‐166\n.12872435\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2050-0904",
"issue": "9(2)",
"journal": "Clinical case reports",
"keywords": "aphasia; case report; general anesthesia; laparoscopic surgery",
"medline_ta": "Clin Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101620385",
"other_id": null,
"pages": "634-637",
"pmc": null,
"pmid": "33598216",
"pubdate": "2021-02",
"publication_types": "D002363:Case Reports",
"references": "1750593;12872435;25159605;21268573;29939851;4037393;21150595;3977096;17355167;30063535;28187050;29137052;17697227;25484947;17444322;26324031;27638287;24794456;25254120;23026175;26035220",
"title": "Transient aphasia following general anesthesia in patient undergoing laparoscopic gynecologic surgery: A case report and literature review.",
"title_normalized": "transient aphasia following general anesthesia in patient undergoing laparoscopic gynecologic surgery a case report and literature review"
} | [
{
"companynumb": "CN-FRESENIUS KABI-FK202103895",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "PROPOFOL"
},
"drugadditional": null,
... |
{
"abstract": "To describe a case of retinal lymphoma presenting as an occlusive retinal vasculitis without vitritis that was exquisitely responsive to intravitreal dexamethasone implant (IVDI).\nA 66-year old male presented with decreased vision in the right eye and was diagnosed with occlusive retinal vasculitis and prominent cystoid macular edema though he lacked vitritis. A complete systemic workup for infectious, inflammatory, and infiltrative etiologies was unremarkable. Intravenous methylprednisolone and cyclophosphamide had no clinical effect. Due to persistent perivascular exudates and refractory macular edema, IVDI was administered with marked improvement in vision and clinical findings. Subsequent retinal vasculitis in the left eye responded to IVDI as well. The patient remained disease free for months while on weekly adalimumab. He then presented with acute vision loss in the left eye due to a lymphomatous subretinal infiltration and a new lesion in the corpus callosum. He has remained disease free for more than two years after intravitreal methotrexate injections and rituximab with an autologous stem cell transplant.\nLymphoma may present as an occlusive retinal vasculitis without vitritis and can be masked due to its response to IVDI.",
"affiliations": "Saint Louis University School of Medicine, St. Louis, MO, USA.;The Retina Institute, St. Louis, MO, USA.;Cole Eye Institute, Cleveland Clinic Foundation, Cleveland, OH, USA.;The Retina Institute, St. Louis, MO, USA.",
"authors": "Sonne|Scott J|SJ|;Shieh|Wen-Shi|WS|;Srivastava|Sunil K|SK|;Smith|Bradley T|BT|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.ajoc.2020.100777",
"fulltext": "\n==== Front\nAm J Ophthalmol Case Rep\nAm J Ophthalmol Case Rep\nAmerican Journal of Ophthalmology Case Reports\n2451-9936 Elsevier \n\nS2451-9936(18)30212-3\n10.1016/j.ajoc.2020.100777\n100777\nCase Report\nLymphoma masquerading as occlusive retinal vasculitis: A case study\nSonne Scott J. a Shieh Wen-Shi b Srivastava Sunil K. c Smith Bradley T. smithbradleythomas@msn.combd∗ a Saint Louis University School of Medicine, St. Louis, MO, USA\nb The Retina Institute, St. Louis, MO, USA\nc Cole Eye Institute, Cleveland Clinic Foundation, Cleveland, OH, USA\nd Washington University, Department of Ophthalmology and Visual Sciences, St. Louis, MO, USA\n∗ Corresponding author. 2201 S Brentwood Blvd, St. Louis, MO, 63144, USA. smithbradleythomas@msn.com\n10 6 2020 \n9 2020 \n10 6 2020 \n19 10077722 5 2018 11 5 2020 6 6 2020 © 2020 The Authors2020This 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 case of retinal lymphoma presenting as an occlusive retinal vasculitis without vitritis that was exquisitely responsive to intravitreal dexamethasone implant (IVDI).\n\nObservation\nA 66-year old male presented with decreased vision in the right eye and was diagnosed with occlusive retinal vasculitis and prominent cystoid macular edema though he lacked vitritis. A complete systemic workup for infectious, inflammatory, and infiltrative etiologies was unremarkable. Intravenous methylprednisolone and cyclophosphamide had no clinical effect. Due to persistent perivascular exudates and refractory macular edema, IVDI was administered with marked improvement in vision and clinical findings. Subsequent retinal vasculitis in the left eye responded to IVDI as well. The patient remained disease free for months while on weekly adalimumab. He then presented with acute vision loss in the left eye due to a lymphomatous subretinal infiltration and a new lesion in the corpus callosum. He has remained disease free for more than two years after intravitreal methotrexate injections and rituximab with an autologous stem cell transplant.\n\nConclusion and importance\nLymphoma may present as an occlusive retinal vasculitis without vitritis and can be masked due to its response to IVDI.\n\nKeywords\nLymphomaRetinal vasculitisOcclusive vasculitisIntravitreal dexamethasoneOzurdexUveitis\n==== Body\nIntroduction\nRetinal vasculitis is an inflammatory response characterized by perivascular inflammation that may result in vascular occlusion.1,2 Rarely primary vitreoretinal lymphoma can present as a retinal vasculitis though it often is accompanied by other signs and symptoms such as vitritis. A high suspicion is when the patient deviates from the expected clinical course.3,4\n\nWe describe a patient with presumed idiopathic occlusive retinal vasculitis that was resistant to conventional therapy with oral and intravenous (IV) steroids, as well as IV cyclophosphamide. Clinical and visual improvement occurred after a single intravitreal dexamethasone implant (IVDI), an FDA-approved treatment of non-infectious posterior uveitis.5 Recurrent cystoid macular edema in the fellow eye responded to several IVDI, but subsequently developed a subretinal infiltrate and biopsy revealed lymphoma. Magnetic resonance (MR) imaging of the brain also showed a new lesion in the splenium of the corpus callosum that was absent one year prior. This case demonstrates a profound effect of local steroid implantation, the protean manifestations of ocular lymphoma and the need for continued vigilance despite a seemingly successful treatment of suspected occlusive retinal vasculitis.\n\nCase report\nA 66-year old male presented with an abrupt decrease in right eye vision with an associated nasal field deficit. Visual acuity (VA) was 20/100 and 20/25 in the right and left eye, respectively. Pupillary response, intraocular pressures, and anterior segment exam was unremarkable. Fundus exam of the right eye showed periarteriolar exudates in the temporal macula with associated cystoid macular edema (CME) and subtle retinal whitening (Fig. 1). There was no vitritis or optic disc edema. The anterior and posterior exam of the left eye was normal. Angiographic studies of the right eye showed mild hyperfluorescence of the optic nerve, hyperfluorescence in the macula and vascular staining with peripheral nonperfusion. A thorough history and review of systems was obtained, revealing only asthma that required oral prednisone for episodic flares. Oral valacyclovir was initiated while awaiting laboratory results and a rheumatology consultation was obtained. At 1-week follow-up, VA declined to 20/200 in the right eye and was 20/20 in the left eye. Repeat fundus exam of the right eye showed worsening central macular edema, temporal retinal whitening, and intraretinal hemorrhages, while the left eye developed a new cotton-wool spot along the superior arcade. An aqueous tap was performed for PCR testing of VZV, HSV, CMV, and Toxoplasmosis, all of which were negative. The valacyclovir was discontinued and he was admitted for a 3-day course of intravenous methylprednisolone and a single 1g infusion of cyclophosphamide. The laboratory workup and rheumatologic consultation revealed no systemic etiology. (CBC, BMP, ESR, CRP, ACE, C- ANCA and P-ANCA, Rheumatoid factor, ANA, HLA-A29, HLA-B51 were within normal limits; FTA-ABS and HIV were non-reactive). Chest x-ray and brain MRI were also unremarkable.Fig. 1 Fundus photograph of the right eye showing perivascular exudates in the temporal macula with macular edema and retinal whitening in an otherwise healthy 66 yo male. There was no vitritis. (A) OCT demonstrates hyperreflectivity with cystoid macular edema and sub retinal fluid. (B). There is poor arterial fill after 30 seconds on fluorescein angiography. (C) Macular leakage is seen in later frames with vascular staining and peripheral nonperfusion. (D).\n\nFig. 1\n\nUpon discharge, the patient continued 325 mg of aspirin and 40mg of oral prednisone daily. Right eye VA was unchanged at 20/200 during follow-up at week 3 and OCT imaging showed persistent edema. IVDI was administered in the right eye. Ten days later, visual acuity improved to 20/60 with marked reduction of the central retinal thickness on OCT from 1067 μm to 282 μm (Fig. 2). The perivascular exudates also decreased (Fig. 2). The patient was gradually tapered off oral steroids and his visual acuity remained stable at 20/60 in the right eye following a single IVDI.Fig. 2 The perivascular exudates resolved 10 days after a single IVDI though there is persistent petechial hemorrhages, peripheral vascular sheathing and ischemic changes (A). Resolution of the macular edema and temporal thinning with disruption of outer retinal layers is noted on OCT. (B).\n\nFig. 2\n\nAt 4-month follow-up the patient presented with a temporal field cut in the left eye though his VA was 20/20. New perivascular exudates were noted in the nasal peripheral retina of the left eye (Fig. 3). The options of initiating therapy with biologics or local treatment with IVDI were discussed at length. A course of 60 mg oral prednisone was started instead. The patient underwent another evaluation by rheumatology for possible systemic association as well as the consideration of systemic therapy with adalimumab injections. An IVDI injection was administered in the left eye. Three weeks later, the perivascular exudates and retinal whitening resolved. The VA remained at 20/60 on the right and 20/20 on the left.Fig. 3 Fundus photo at 4 month follow up demonstrates new perivascular exudates in the nasal peripheral retina of the left eye without vitritis. He complained of temporal field loss though his visual acuity was 20/20.\n\nFig. 3\n\nHe developed recurrent CME with a decrease in vision while on weekly adalimumab without vasculitis. IVDI was administered two additional times with visual acuity improvement. Two months following the last IVDI and one year following initial presentation he had a sudden profound drop in left eye VA to 20/400. Examination showed a yellowish retinal lesion and hemorrhage (Fig. 4). OCT showed hyper-reflectivity and thickening of the neurosensory retina with underlying fluid. The patient was admitted for repeat high dose steroids and AC tap was repeated for PCR analysis. Repeat brain MRI showed a new lesion in the splenium of the corpus callosum, giving the clinical impression of demyelinating disease or possible lymphoma. Lumbar puncture was negative. A standard 3 port pars plana vitrectomy was performed. Diathermy was applied over the involved retina and yellowish exudate was aspirated and submitted to pathology along with a vitreous specimen. Cellular morphology showed large cell lymphoma consistent with the clinical suspicion. The specimen from the vitreous was paucicellular and negative for malignancy. Oncology recommended systemic induction therapy consisting of methotrexate, rituximab, and temozolomide followed by autologous hematopoietic stem cell therapy with cytarabine for one year. He also underwent 10 intravitreal injections of methotrexate 400 μg/0.1 ml in the left eye. The retinal lesion resolved (Fig. 5). The lesion in the splenium of the corpus callosum was successfully treated with systemic rituximab and autologous stem cell therapy. The right eye remained disease free throughout the entire course and maintained visual acuity at 20/50. The left eye remained 5/200 without lesion recurrence over one year following the last methotrexate injection. No systemic signs of lymphoma were evident more than 28 months after the initial presentation.Fig. 4 Fundus photo of left eye shows a large yellow lesion inferior to nerve with intraretinal hemorrhages and associated retinal detachment without vitritis. (A) OCT demonstrates full thickness involvement of the neurosensory retina and subretinal fluid. (B) Pathology of subretinal aspirate confirmed large cell lymphoma. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)\n\nFig. 4Fig. 5 Repeat photo shows resolution of lymphoma following 10 intraocular injections with methotrexate and systemic therapy with rituximab and autologous stem cells.\n\nFig. 5\n\nDiscussion\nPrimary vitreoretinal lymphoma often masquerades as vitritis leading to diagnostic delay or infiltrate the retina and sub retinal space.6 This case of ocular lymphoma is unique given the lack of vitritis and complete resolution of a vasculitis and CME after a single IVDI.3,4 Katoch et al. describe persistent vitritis in addition to vasculitis occurring prior to lymphomatous subretinal deposits.4 The present case differs in that there was no vitritis and the initial vasculitis was exquisitely responsive to IVDI. In a case of lymphoma causing an arterial occlusion Damato et al. hypothesized that primary vitreoretinal lymphoma results from hematogenous spread of systemic loci although it remains unclear why the disease remains limited to the CNS.7 Indeed, pathologic specimens have demonstrated its angiocentric distribution8, 9, 10, 11 Furthermore, ultra widefield fluorescein angiography may reveal vascular leakage prior to the development of other ocular manifestations.12 Differing degrees of perfusion status may explain the protean manifestations of primary vitreoretinal lymphoma in this case with subretinal infiltration of lymphomatous cells in the left eye, but not the right. However, this hypothesis remains unproven without the availability of corresponding pathologic specimens at each stage of disease presentation.\n\nThe effect of steroids on ocular lymphoma can cause delay in diagnosis or a falsely negative biopsy specimen.3,13,14 This case showed no response to systemic steroids. However, localized delivery of IVDI with its lack of dependency on perfusion resulted in profound and sustained resolution after one treatment in the right eye.15, 16, 17, 18, 19, 20 Natural history could have resulted in increasing subretinal infiltration that would have prompted earlier biopsy. However, the declining vision in the setting of a presumed occlusive inflammatory process with negative systemic workup led to the use of IVDI. Though spontaneous improvement of ocular lymphoma has been reported, it was not likely in this case given the immediate unequivocal improvement with IVDI and subsequent disease activity in the fellow eye.21\n\nIt is possible that our patient had an idiopathic inflammatory occlusive retinal vasculitis with subsequent lymphoma resulting from an induced immunosuppressed state. The link between immunosuppression and lymphoma is well documented and the use of cyclophosphamide and adalimumab in this patient was a risk factor for its development.22, 23, 24, 25, 26, 27 Although the lack of CNS findings on his initial MR may support this possibility, ocular lymphoma can predate cerebral disease in 42–92% of cases while only one third of cases have intracranial involvement at the time of presentation.28, 29, 30 A biopsy specimen was not obtained during the patient's initial presentation due to unequivocal resolution with a single IVDI. Likewise, his second eye had a vasculitis that responded to IVDI followed by two episodes of CME also responding to IVDI. Additionally, intraocular lymphoma has not been reported after use of anti-TNF therapy and cyclophosphamide has previously been used as part of a treatment algorithim for intraocular lymphoma.31 Nevertheless, this case underscores the need for continued vigilance when treating with immunosuppressants due to the risk of secondary malignancy.\n\nConclusions\nIn summary, we describe an interesting case of intraocular lymphoma presenting as a retinal vasculitis without vitritis and an exquisite sensitivity to IVDI. It underscores the need for continued vigilance despite an initial negative workup with initial successful treatment. Definitive biopsy should be considered when the clinical course changes or an expected response to treatment does not occur.\n\nPatient consent\nWritten consent to publish the case report was obtained. This report does not contain any protected health information (PHI) that could lead to the identification of the patient.\n\nFunding\nThis work was supported, in part, by 10.13039/100013779Retina Research & Development Foundation, St. Louis, MO.\n\nAuthorship\nAll authors attest that they meet the current ICMJE criteria for Authorship.\n\nDeclaration of competing interest\nNone of the authors have any financial disclosures.\n\nAppendix A Supplementary data\nThe following is the Supplementary data to this article:Multimedia component 1\nMultimedia component 1 \n\nAppendix A Supplementary data to this article can be found online at https://doi.org/10.1016/j.ajoc.2020.100777.\n==== Refs\nReferences\n1 Rosenbaum J.T. Ku J. Ali A. Patients with retinal vasculitis rarely suffer from systemic vasculitis Semin Arthritis Rheum 41 6 2012 859 865 22177107 \n2 Kwon S.J. Park D.H. Shin J.P. Frosted branch angiitis as ocular manifestation of Behçet's disease: unusual case report and literature review Kor J Ophthalmol 27 6 2013 466 469 \n3 Brown S.M. Jampol L.M. Cantrill H.L. Intraocular lymphoma presenting as retinal vasculitis Surv Ophthalmol 39 2 1994 133 140 7801221 \n4 Katoch D. Bansal R. Nijhawan R. Gupta A. Primary intraocular central nervous system lymphoma masquerading as diffuse retinal vasculitis BMJ Case Rep 30 2013 \n5 Lowder C. Belfort R. Jr. Lightman S. Dexamethasone intravitreal implant for noninfectious intermediate or posterior uveitis Arch Ophthalmol 129 5 2011 545 553 21220619 \n6 Grange L.K. Kouchouk A. Dalal M.D. Neoplastic masquerade syndromes in patients with uveitis Am J Ophthalmol 157 3 2014 526‐531 24211361 \n7 Damato B.E. Bever G.J. Afshar A.R. Rubenstein J.L. Insights from a case of vitreoretinal lymphoma Ocul Oncol Pathol 5 1 2019 13 19 30675472 \n8 Gass J.D. Trattler H.L. Retinal artery obstruction and atheromas associated with non-Hodgkin’s large cell lymphoma (reticulum cell sarcoma) Arch Ophthalmol 109 8 1991 1134 1139 1867559 \n9 Jack C.R. Jr. O'Neill B.P. Banks P.M. Reese D.F. Central nervous system lymphoma: histologic types and CT appearance Radiology 167 1 1988 211 215 3279454 \n10 Kohno T. Uchida H. Inomata H. Fukushima S. Takeshita M. Kikuchi M. Ocular manifestations of adult T-cell leukemia/lymphoma. A clinicopathologic study Ophthalmology 100 12 1993 1794 1799 8259276 \n11 Ridley M.E. McDonald H.R. Sternberg P. Jr. Blumenkranz M.S. Zarbin M.A. Schachat A.P. Retinal manifestations of ocular lymphoma (reticulum cell sarcoma) Ophthalmology 99 7 1992 1153 1161 1495797 \n12 Lavine J.A. Singh A.D. Sharma S. Ultra-widefield multimodal imaging of primary vitreoretinal lymphoma Retina 39 10 2019 1861 1871 30044267 \n13 Mulay K. Narula R. Honavar S.G. Primary vitreoretinal lymphoma Indian J Ophthalmol 63 3 2015 180 186 25971162 \n14 Whitcup S.M. de Smet M.D. Rubin B.I. Intraocular lymphoma. Clinical and histopathologic diagnosis Ophthalmology 100 9 1993 1399 1406 8371930 \n15 Saatci A.O. Ayhan Z. Takeş Ö. Yaman A. Bajin F.M. Single bilateral dexamethasone implant in addition to panretinal photocoagulation and oral azathioprine treatment in IRVAN syndrome Case Rep Ophthalmol 6 1 2015 56 62 25802506 \n16 Karagiannis D. Soumplis V. Georgalas I. Kandarakis A. Ranibizumab for idiopathic retinal vasculitis, aneurysms, and neuroretinitis: favorable results Eur J Ophthalmol 20 4 2010 792 794 20099231 \n17 Akesbi J. Brousseaud F.X. Adam R. Rodallec T. Nordmann J.P. Intravitreal bevacizumab (Avastin) in idiopathic retinitis, vasculitis, aneurysms and neuroretinitis Acta Ophthalmol 88 2 2010 e40 e41 19508455 \n18 Empeslidis T. Banerjee S. Vardarinos A. Konstas A.G. Dexamethasone intravitreal implant for idiopathic retinal vasculitis, aneurysms, and neuroretinitis Eur J Ophthalmol 23 5 2013 757 760 23661543 \n19 Fabiani C. Emmi G. Lopalco G. Intravitreal dexamethasone implant as an adjunct weapon for severe and refractory uveitis in behçet's disease Isr Med Assoc J 19 7 2017 415 419 28786255 \n20 Coşkun E. Celemler P. Kimyon G. Intravitreal dexamethasone implant for treatment of refractory behçet posterior uveitis: one-year follow-up results Ocul Immunol Inflamm 23 6 2015 437 443 26470764 \n21 Kase S. Namba K. Jin X.H. Kubota K.C. Ishida S. Spontaneous regression of intraocular lymphoma Ophthalmology 119 5 2012 1083 1084 \n22 Xu Y. Wang H. Zhou S. Risk of second malignant neoplasms after cyclophosphamide-based chemotherapy with or without radiotherapy for non-Hodgkin lymphoma Leuk Lymphoma 54 7 2013 1396 1404 23101661 \n23 Paul C. Le Tourneau A. Cayuela J.M. Epstein–Barr virus-associated lymphoproliferative disease during methotrexate therapy for psoriasis Arch Dermatol 133 7 1997 867 871 9236525 \n24 Pietersma F. Piriou E. van Baarle D. Immune surveillance of EBV-infected B cells and the development of non-Hodgkin lymphomas in immunocompromised patients Leuk Lymphoma 49 6 2008 1028 1041 18452077 \n25 Kasiskie B.L. Snyder J.J. Gilbertson D.T. Wang C. Cancer after kidney transplantation in the United States Am J Transplant 4 6 2004 905 913 15147424 \n26 Biggar R.J. Chaturvedi A.K. Goedert J.J. Engels E.A. AIDS-related cancer and severity of immunosuppression in persons with AIDS J Natl Cancer Inst 99 12 2007 962 972 17565153 \n27 Bernatsky S. Clarke A.E. Suissa S. Hematologic malignant neoplasms after drug exposure in rheumatoid arthritis Arch Intern Med 168 4 2008 378 381 18299492 \n28 Ferreri A.J. Blay J.Y. Reni M. Relevance of intraocular involvement in the management of primary central nervous system lymphomas Ann Oncol 13 4 2002 531 538 12056702 \n29 Cassoux N. Merle-Beral H. Leblond V. Ocular and central nervous system lymphoma: clinical features and diagnosis Ocul Immunol Inflamm 8 4 2000 243 250 11262654 \n30 Sagoo M.S. Mehta H. Swampillai A.J. Primary intraocular lymphoma Surv Ophthalmol 59 5 2014 503 516 24560125 \n31 Soussain C. Choquet S. Fourme E. Intensive chemotherapy with thiotepa, busulfan and cyclophosphamide and hematopoietic stem cell rescue in relapsed or refractory primary central nervous system lymphoma and intraocular lymphoma: a retrospective study of 79 cases Haematologica 97 11 2012 1751‐1756 22581000\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2451-9936",
"issue": "19()",
"journal": "American journal of ophthalmology case reports",
"keywords": "Intravitreal dexamethasone; Lymphoma; Occlusive vasculitis; Ozurdex; Retinal vasculitis; Uveitis",
"medline_ta": "Am J Ophthalmol Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101679941",
"other_id": null,
"pages": "100777",
"pmc": null,
"pmid": "32613135",
"pubdate": "2020-09",
"publication_types": "D002363:Case Reports",
"references": "22581000;11262654;17565153;12056702;24211361;1495797;23632616;22177107;24560125;19508455;3279454;15147424;8259276;18452077;25971162;24311935;22551603;30044267;21220619;25802506;7801221;26470764;30675472;23661543;9236525;20099231;28786255;1867559;8371930;23101661;18299492",
"title": "Lymphoma masquerading as occlusive retinal vasculitis: A case study.",
"title_normalized": "lymphoma masquerading as occlusive retinal vasculitis a case study"
} | [
{
"companynumb": "US-TEVA-2020-US-1810069",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drugadditional": "3",
... |
{
"abstract": "Erythropoietic protoporphyria (EPP) is a rare and usually autosomal dominant disorder characterized by ferrochelatase deficiency and accumulation of protoporphyrin in red blood cells (RBCs), skin, and liver. A small minority of patients develop severe liver dysfunction for which optimum treatment is lacking. Therapeutic plasma exchange (TPE) and RBC exchange (RCE) have been anecdotally reported to benefit patients with EPP and liver failure. A 50-year-old female with EPP developed severe liver dysfunction after knee replacement surgery and high-dose acetaminophen use. Liver biopsy showed cholestatic liver injury without fibrosis. A total of 20 TPE procedures, six RCE procedures, and then 14 more TPE procedures were performed as adjunctive therapy with the purpose of preventing progression to end-stage liver failure. After initial TPE, the plasma and RBC protoporphyrin levels decreased from 834.9 to 180.4 μg/dL (normal, ≤1 μg/dL), and from 3,905 to 2,879 μg/dL (normal, ≤80 μg/dL), respectively, without liver function improvement. RCE decreased RBC protoporphyrin levels from 2,879 to 1,225 μg/dL but plasma protoporphyrin increased from 180.4 to 1,044.1 μg/dL, and liver function failed to improve. Additional TPE again stabilized plasma protoporphyrin and improved RBC protoporphyrin levels but the patient ultimately died owing to end-stage liver disease complications. This case illustrates that TPE and RCE may improve the plasma and RBC biochemical markers of EPP activity but liver function abnormalities may persist and patients may still progress to liver failure either because of irreversible liver injury or independent pathobiological factors unrelated to EPP-induced hepatotoxicity.",
"affiliations": "Department of Pathology, Transfusion Medicine Division, Johns Hopkins Medical Institutions, Balimore, Maryland, USA. mpagano3@jhmi.edu",
"authors": "Pagano|Monica B|MB|;Hobbs|William|W|;Linenberger|Michael|M|;Delaney|Meghan|M|",
"chemical_list": "D018712:Analgesics, Non-Narcotic; D011524:Protoporphyrins; D000082:Acetaminophen",
"country": "United States",
"delete": false,
"doi": "10.1002/jca.21249",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0733-2459",
"issue": "27(6)",
"journal": "Journal of clinical apheresis",
"keywords": null,
"medline_ta": "J Clin Apher",
"mesh_terms": "D000082:Acetaminophen; D018712:Analgesics, Non-Narcotic; D019645:Arthroplasty, Replacement, Knee; D002780:Cholestasis, Intrahepatic; D016360:Clostridioides difficile; D018450:Disease Progression; D004761:Enterocolitis, Pseudomembranous; D017707:Erythrocyte Transfusion; D004912:Erythrocytes; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D017093:Liver Failure; D008875:Middle Aged; D010149:Pain, Postoperative; D010787:Photosensitivity Disorders; D010951:Plasma Exchange; D011183:Postoperative Complications; D046351:Protoporphyria, Erythropoietic; D011524:Protoporphyrins; D012772:Shock, Septic; D013203:Staphylococcal Infections",
"nlm_unique_id": "8216305",
"other_id": null,
"pages": "336-41",
"pmc": null,
"pmid": "22997063",
"pubdate": "2012",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Plasma and red cell exchange transfusions for erythropoietic protoporphyria: a case report and review of the literature.",
"title_normalized": "plasma and red cell exchange transfusions for erythropoietic protoporphyria a case report and review of the literature"
} | [
{
"companynumb": "US-RANBAXY-2013US-75689",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "NITROFURANTOIN"
},
"drugadditional": null,
... |
{
"abstract": "Oritavancin is a novel lipoglycopeptide with activity against Gram-positive organisms including streptococci, methicillin-resistant Staphylococcus aureus, vancomycin-resistant S aureus (VRSA), and vancomycin-resistant enterococci (VRE) [1-3]. The US Food and Drug Administration approved oritavancin as a single intravenous dose of 1200 mg for the treatment of acute bacterial skin and skin structure infections on the basis of 2 clinical trials demonstrating noninferiority compared with vancomycin [4, 5]. There are limited options for treatment of serious VRE infections. Monotherapy with daptomycin or tigecycline or linezolid may be sufficient in some cases, but combination therapy is often indicated for severe or complicated infections such as endocarditis. Several antibiotic combinations have been used in isolated case reports with some efficacy, including the following: high-dose ampicillin with an aminoglycoside [6], ampicillin with ceftriaxone or imipenem [7, 8], high-dose daptomycin with ampicillin and gentamicin [9] or with gentamicin and rifampin [10], daptomycin with tigecycline [11, 12], quinupristin-dalfopristin with high-dose ampicillin [13] or doxycycline and rifampin [14], and linezolid with tigecycline [15]. The limited efficacy, limited susceptibility, and extensive toxicities with many of these agents and combinations present barriers to effective treatment. Additional treatment options for VRE endocarditis would be valuable. Although oritavancin has been shown to have in vitro activity against some isolates of VRE, clinical data are lacking. We describe the first use of a prolonged course of oritavancin in the treatment of a serious VRE infection, prosthetic valve endocarditis.",
"affiliations": "Division of Infectious Diseases.;Divison of Infectious Diseases , St. Vincent's University Hospital , Elm Park, Dublin 4.;Department of Pharmacy , Brigham and Women's Hospital, Harvard Medical School , Boston, Massachusetts.;Divison of Infectious Diseases , Duke University Medical Center , Durham, North Carolina.",
"authors": "Johnson|Jennifer A|JA|;Feeney|Eoin R|ER|;Kubiak|David W|DW|;Corey|G Ralph|GR|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1093/ofid/ofv156",
"fulltext": "\n==== Front\nOpen Forum Infect DisOpen Forum Infect DisofidofidsOpen Forum Infectious Diseases2328-8957Oxford University Press 10.1093/ofid/ofv156ofv156Brief ReportsProlonged Use of Oritavancin for Vancomycin-Resistant Enterococcus faecium Prosthetic Valve Endocarditis Johnson Jennifer A. 1Feeney Eoin R. 3Kubiak David W. 2Corey G. Ralph 41 Division of Infectious Diseases2 Department of Pharmacy, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts3 Divison of Infectious Diseases, St. Vincent's University Hospital, Elm Park, Dublin 44 Divison of Infectious Diseases, Duke University Medical Center, Durham, North CarolinaCorrespondence: Jennifer A. Johnson, MD, Division of Infectious Disease, Brigham and Women's Hospital, 75 Francis Street, PBB-A4, Boston, MA 02115 (jjohnson30@partners.org).12 2015 29 10 2015 2 4 ofv15621 5 2015 14 10 2015 © The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America.2015This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.com.Oritavancin is a novel lipoglycopeptide with activity against Gram-positive organisms including streptococci, methicillin-resistant Staphylococcus aureus, vancomycin-resistant S aureus (VRSA), and vancomycin-resistant enterococci (VRE) [1–3]. The US Food and Drug Administration approved oritavancin as a single intravenous dose of 1200 mg for the treatment of acute bacterial skin and skin structure infections on the basis of 2 clinical trials demonstrating noninferiority compared with vancomycin [4, 5].\n\nThere are limited options for treatment of serious VRE infections. Monotherapy with daptomycin or tigecycline or linezolid may be sufficient in some cases, but combination therapy is often indicated for severe or complicated infections such as endocarditis. Several antibiotic combinations have been used in isolated case reports with some efficacy, including the following: high-dose ampicillin with an aminoglycoside [6], ampicillin with ceftriaxone or imipenem [7, 8], high-dose daptomycin with ampicillin and gentamicin [9] or with gentamicin and rifampin [10], daptomycin with tigecycline [11, 12], quinupristin-dalfopristin with high-dose ampicillin [13] or doxycycline and rifampin [14], and linezolid with tigecycline [15]. The limited efficacy, limited susceptibility, and extensive toxicities with many of these agents and combinations present barriers to effective treatment. Additional treatment options for VRE endocarditis would be valuable. Although oritavancin has been shown to have in vitro activity against some isolates of VRE, clinical data are lacking. We describe the first use of a prolonged course of oritavancin in the treatment of a serious VRE infection, prosthetic valve endocarditis.\n\nendocarditisenterococcioritavancinvancomycin-resistantVRE cover-dateFall 2015\n==== Body\nCASE REPORT\nA 73-year-old male with a bioprosthetic aortic valve placed 4 years previously, renal artery stenosis with stent placement, chronic kidney disease (creatinine clearance estimated at 22 mL/min), and spinal fusion at L5-S1 with hardware placement 1 year previously, presented with several months of malaise and weight loss. Blood cultures grew Enterococcus faecium, which was resistant to vancomycin but susceptible to daptomycin (Table 1). Treatment with intravenous daptomycin 8 mg/kg every other day was initiated. His bacteremia initially cleared but recurred after 48 hours. Tigecycline was added, and bacteremia resolved. Magnetic resonance imaging of the spine revealed slight displacement of the spinal hardware concerning for possible hardware loosening, although there were no definite findings of infection; surgical intervention was not pursued. Transthoracic and transesophageal echocardiograms showed no evidence of valvular vegetations. The patient continued parenteral antibiotic therapy with daptomycin and tigecycline. Eight weeks after initiation of intravenous antibiotic therapy, the patient was readmitted with Pseudomonas aeruginosa bacteremia and central venous catheter infection. The central venous catheter was removed, tigecycline and daptomycin were discontinued, and treatment with oral linezolid was initiated, which was discontinued 2 weeks later, the patient having completed a 10-week total antibiotic course.\nTable 1. Susceptibility Testing of Enterococcus faecium Isolates\n\nAntibiotic\tInitial Presentation\tFirst Recurrence (5 mo Later)\tSecond Recurrence (8 mo Later)\t\nAmpicillin\tKBD 6 mm (R)\tKBD 6 mm (R)\nMIC > 256 µg/mL (R)\tKBD 6 mm (R)\nMIC 256 µg/mL (R)\t\nVancomycin\tKBD 6 mm (R)\tKBD 6 mm (R)\tKBD 6 mm (R)\t\nGentamicin\tKBD 26 mm (Syn)\tKBD 26 mm (Syn)\tKBD 28 mm (Syn)\t\nStreptomycin\tKBD 21 mm (Syn)\tKBD 22 mm (Syn)\tKBD 26 mm (Syn)\t\nTetracycline\tKBD 6 mm (R)\tKBD 6 mm (R)\tKBD 6 mm (R)\t\nDoxycycline\t–\tKBD 12 mm\t–\t\nTelavancin\t–\tInitial: MIC > 32 µg/mL\nRepeat: MIC 0.19 µg/mL\tInitial: MIC 32 µg/mL\t\nLinezolid\tKBD 30 mm (S)\tKBD 31 mm (S)\tKBD 35 mm (R)\nMIC 0.75 µg/mL (S)\t\nDaptomycin\tMIC 4 µg/mL (S)\tInitial: MIC 4 µg/mL (S)\nRepeat: MIC 6 µg/mL (R)\tInitial: MIC 4 µg/mL (S)\t\nQuinupristin/dalfopristin\t–\tMIC 1.5 µg/mL (I)\t–\t\nTigecycline\tMIC 0.25 µg/mL\tInitial: MIC 0.19 µg/mL\nRepeat: MIC 0.25 µg/mL\tMIC 0.094 µg/mL\t\nOritavancin\t–\tMIC 0.5 µg/mL\tMIC 0.5 µg/mL\t\nAbbreviations: KBD, Kirby Bauer disk diffusion test; MIC, minimal inhibitory concentration; R, resistant; S, sensitive; Syn, synergy likely.\n\n\n\nApproximately 5 months after his initial presentation, the patient again presented with malaise and back pain. Blood cultures again grew vancomycin-resistant enterococci (VRE) (Table 1). Treatment with daptomycin and tigecycline was initiated, and blood cultures cleared after 3 days of bacteremia. However, VRE bacteremia recurred with a stuttering course, and susceptibility testing demonstrated daptomycin resistance (Table 1). Daptomycin was discontinued, therapy with linezolid and tigecycline was initiated, and subsequent blood cultures were negative. Transesophageal echocardiography again showed no evidence of cardiac valvular vegetation. Positron emission tomography-computed tomography showed slightly increased fludeoxyglucose uptake around the spinal hardware at L5-S1. Operative exploration of the spinal hardware was undertaken, and no evidence of spinal hardware infection was discovered. The patient continued outpatient therapy with oral linezolid and intravenous tigecycline, but this treatment was poorly tolerated with anorexia, nausea, thrombocytopenia, hyperlactatemia, and altered mental status. Although blood cultures remained negative, alternative antibiotic treatment was pursued. In vitro susceptibility testing of the VRE isolate, performed by JMI Laboratories (North Liberty, IA) by broth microdilution (CLSI M7-A09), showed an oritavancin minimal inhibitory concentration (MIC) of 0.5 µg/mL. At that time, oritavancin had not yet received US Food and Drug Administration (FDA) approval, so permission was obtained from the FDA and the institutional review board to initiate compassionate use of oritavancin for treatment of recurrent VRE bacteremia.\n\nOritavancin was initiated at a dose of 1200 mg every other day for 3 doses, and subsequently once weekly for 6 weeks. Linezolid and tigecycline were discontinued. The patient's appetite and strength improved, nausea and altered mental status resolved, and platelet count and lactate returned to normal. He was discharged home, returning weekly for intravenous oritavancin infusions in the outpatient infusion center. Complete blood count, blood urea nitrogen, creatinine, serum electrolytes, liver function tests (LFTs), blood cultures, serum oritavancin level (Table 2), and electrocardiogram were monitored weekly while on therapy. Blood cultures remained negative while on oritavancin, and he had no reported adverse effects from his infusions. An elevated activated partial thromboplastin time was noted, which was felt to be due to oritavancin interference with reagents in the testing kit and not clinically significant, as is currently noted in the US Prescribing Information [16]. He completed 7 weeks of treatment with oritavancin, following the 4 weeks of linezolid and tigecycline for the most recent episode of VRE bacteremia, and weekly blood cultures were negative throughout the antibiotic course.\nTable 2. Oritavancin Pharmacokinetic Data\n\nParameter\tValues/Estimates for This Patient\t\nTrough levelsa – this patient\tMean (range)\t\n Once weekly dosing\t 4.83 µg/mL (3.78–7.61)\t\n Twice weekly dosing\t 8.57 µg/mL (6.82–12.85)\t\nPeak levelsa – this patient\tMean (range)\t\n Once weekly dosing\t 124.19 µg/mL (114.79–133.58)\t\n Twice weekly dosing\t 90.39 µg/mL (67.02–113.91)\t\nPosttreatment drug levelsa – this patient\t\n 1 wk after completion of treatment\t 12.00 µg/mL\t\n 7 mo after completion of treatment\t 0.77 µg/mL\t\nCmaxb\t\n After 1st dose\t 114.79 µg/mL\t\n Average\t 100.00 µg/mL\t\n Highest\t 133.58 µg/mL\t\n Population mean from literaturec\t 138 µg/mL\t\n Population max from literaturec\t 319 µg/mL\t\nAUCb\t\n 0–48 h: this patient\t 2845 µg h/mL\t\n 0–48 h: population mean from literaturec\t 1390 µg h/mL\t\n 0–48 h: population max from literaturec\t 5370 µg h/mL\t\n 0–168 h: this patient\t 11 537 µg h/mL\t\nT1/2 alphab\t\n This patient\t 9.10 h\t\n Population mean from literaturec\t 2.29 h\t\n Population max from literaturec\t 6.97 h\t\nAbbreviations: AUC, area under the curve; max, maximum.\n\na Levels are reported of total plasma drug. The drug is 85% protein-bound, so free drug levels would be only 15% of the reported concentrations.\n\nb Formulas derived from References 16 and 17.\n\nc Population values from literature quoted from Reference 18.\n\n\n\nEight days after completion of the final dose of oritavancin, the patient was seen in follow-up and was feeling well. Blood cultures were collected and again grew VRE, with similar susceptibility test results (Table 1). He was admitted to the hospital and oritavancin was reinitiated at a dose of 1200 mg twice weekly, without additional loading doses given the proximity to the previous course and the now twice weekly dosing. The addition of gentamicin was attempted, but creatinine rose steadily with this, so gentamicin was discontinued after 4 days of treatment. Blood cultures initially cleared but subsequently were intermittently positive over the following 2 weeks. Transesophageal echocardiogram now showed worsening of aortic incompetence and mitral valve regurgitation, but without valvular vegetations. The patient underwent cardiac surgery for aortic and mitral valve replacements. Linezolid and tigecycline were restarted perioperatively. The excised prosthetic aortic valve grew VRE in culture, and the excised native mitral valve had evidence of healing endocarditis with cocci present on hematoxylin and eosin staining, although culture was negative.\n\nPostoperatively, the patient developed worsening anorexia, nausea, and rising lactate (2.2 mmol/L). Linezolid and tigecycline were discontinued on the 10th postoperative day, and oritavancin was continued at 1200 mg twice weekly. Again his symptoms improved. Blood cultures remained negative. He continued twice weekly infusions of oritavancin for 10 weeks postoperatively. In routine follow-up examination at 10 weeks postoperatively, he noted some anorexia and nausea, and LFTs revealed some new mild abnormalities: alanine aminotransferase 84 U/L (upper limit of normal = 50), aspartate aminotransferase 77 U/L (upper limit of normal = 50), alkaline phosphatase 333. Bilirubin was normal. In the absence of any other clear etiology for these new laboratory abnormalities, a concern for causal relationship with oritavancin was raised, and oritavancin was discontinued. Anorexia and nausea gradually improved. He did not have any other related adverse events during the oritavancin course. Liver function tests remained mildly abnormal for many months but resolved to normal at 11 months after completion of oritavancin therapy. Plasma oritavancin levels also remained detectable through 7 months after completion of oritavancin therapy. In clinical follow up, the patient has done well through 22 months after completion of oritavancin treatment. Blood cultures obtained 17 months after completion of oritavancin, in the setting of biliary disease, were negative.\n\nDISCUSSION\nThe options for treatment of resistant Gram-positive infections such as methicillin-resistant Staphylococcus aureus (MRSA) and VRE have significantly improved over the years with the advent of the oxazolidinone linezolid, the glycylcycline tigecyline, and the lipopeptide daptomycin. Nonetheless, resistance to all of these agents is well described, and intolerance or toxicities may limit their use. Oritavancin was initially developed because of its activity against both MRSA and VRE, but there has been no clinical data to support its use in VRE infections to date. This case demonstrates the tolerability of oritavancin at a high dose over a prolonged treatment course, and it provides preliminary evidence of clinical efficacy.\n\nIn this case, most other antibiotic options were not viable. The E faecium isolate had ampicillin MIC > 256 μg/mL, making β-lactams unlikely to be effective, even in combination therapy. Daptomycin therapy was unlikely to be effective given the rising MIC; recent data suggest that even VRE isolates with an MIC of 4 μg/mL may be difficult to treat effectively with daptomycin [17, 18]. The MIC for quinupristin-dalfopristin was intermediate. The patient was unable to tolerate linezolid or tigecycline due to severe side effects. Nephrotoxicity developed quickly with gentamicin therapy and was especially concerning given his underlying chronic kidney disease. Oritavancin presented a unique opportunity for this patient as a drug that might be efficacious and also expected to be well tolerated. The once, or later twice, weekly infusions via peripheral intravenous catheter were also favorable compared with the daily infusions by central venous catheter, which had been complicated by catheter-associated bloodstream infection earlier in his course.\n\nIn this case, the dosing regimen of oritavancin was determined by balancing safety with the goal of frontloading oritavancin exposure for the highest possible levels to treat a severe infection. Because oritavancin exerts concentration-dependent bactericidal activity and a long post-antibiotic effect [19, 20], the loading period over the first week was designed to impart the highest exposure safely over the initial portion of treatment. Although data suggests that the optimal MIC threshold for E faecium susceptibility to oritavancin is 0.25 μg/mL [1], the pharmacy team determined that at the loading dose schedule would maintain oritavancin plasma levels above 6–10 mL (total drug; 0.9–1.5 mg/L as free drug assuming 85% plasma protein binding) for the first 7 days of dosing, yielding early bacterial killing given the oritavancin MIC of 0.5 μg/mL for the VRE isolate in this case. Oritavancin is not renally cleared, nor is it associated with nephrotoxicity, so the dose was not adjusted for the patient's chronic kidney disease. A once-weekly dose frequency during the sustained dosing phase was anticipated to provide lasting coverage against Gram-positive pathogens during the entire dosing interval. Oritavancin exhibits a long post-antibiotic effect with bacterial inhibition even after plasma concentration has fallen below MIC. When bacteremia recurred shortly after completion of the first course of oritavancin, the dose was increased to twice weekly for the subsequent course with the hope of more effective bacterial killing at higher concentration and hope for sustained response. However, with both the once-weekly and twice-weekly dosing regimens, the trough levels of oritavancin remained low prior to each dose, which was reassuring for drug safety. In reviewing the available peak and trough levels, we were able to calculate some pharmacokinetic parameters of oritavancin as observed in this case [21, 22] (Table 2), which were similar to those reported in the literature from prior clinical trials with oritavancin [23]. Oritavancin is distributed into the tissues, stored, and then slowly eliminated by macrophages, so a prolonged posttreatment, detectable, plasma drug level was anticipated. Still, it is remarkable that the drug level 1 week after completion of the 10-week course were significantly higher than any earlier trough levels. This is likely due in part to the 3-compartment pharmacokinetics this drug exhibits, and there is likely a saturation effect from tissue accumulation [23, 24]. Furthermore, the detectable oritavancin levels at 7 months posttreatment highlight the prolonged effects of this drug, which was fortunately well tolerated by this patient.\n\nEfficacy of oritavancin is difficult to confirm in this case given the requirement for surgery and other antibiotics on several occasions over the course of illness. Nonetheless, the negative blood cultures throughout the initial course of oritavancin and the persistently negative blood cultures postoperatively support a potential clinical efficacy of oritavancin for treatment of VRE bacteremia. The recurrence of bacteremia immediately after completion of the initial oritavancin course and then intermittent bacteremia despite ongoing oritavancin are concerning for antibiotic failure, but this most likely represented ongoing unresolved source of infection, highlighting the importance of surgical management for this type of infection.\n\nCONCLUSIONS\nDespite this patient's age, multiple comorbid conditions, and active infection and complications, he tolerated oritavancin with no adverse events for the first 7 weeks of treatment. After 12 additional weeks of treatment, the patient developed mild nausea and LFT abnormalities, both of which slowly resolved over the following 11 months despite detectable bloodstream levels throughout this period. Although the optimal dosing regimen of oritavancin for serious VRE infections will require further investigation, this report provides valuable and encouraging information for the potential future use of oritavancin in serious infections due to enterococci.\n\nAcknowledgments\nPotential conflicts of interest. All authors: No reported conflicts.\n\nAll authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest.\n==== Refs\nReferences\n1 Arhin FF , Draghi DC , Pillar CM et al \nComparative in vitro activity profile of oritavancin against recent Gram-positive clinical isolates . Antimicrob Agents Chemother \n2009 ; 11 :4762 –71 .19738026 \n2 Mendes RE , Farrell DJ , Sader HS , Jones RN \nOritavancin microbiologic features and activity results from the surveillance program in the United States . Clin Infect Dis \n2012 ; 54 :S203 –13 .22431850 \n3 Ambrose PG , Drusano GL , Craig WA \nIn vivo activity of oritavancin in animal infection models and rationale for a new dosing regimen in humans . Clin Infect Dis \n2012 ; 54 :S220 –8 .22431852 \n4 Corey GR , Kabler H , Mehra P et al \nSingle-dose oritavancin in the treatment of acute bacterial skin infections . N Eng J Med \n2014 ; 370 :2180 –90 .\n5 Corey GR , Good S , Jiang H et al \nSingle-dose oritavancin versus 7–10 days of vancomycin for the treatment of gram-positive acute bacterial skin and skin structure infections: the SOLO II noninferiority study . Clin Infect Dis \n2015 ; 60 :254 –62 .25294250 \n6 Murray BE \nVancomycin-resistant enterococcal infections . N Engl J Med \n2000 ; 10 :710 –21 .10706902 \n7 Anthony SJ , Ladner J , Stratton CW et al \nHigh-level aminoglycoside-resistant enterococcus causing endocarditis successfully treated with a combination of ampicillin, imipenem and vancomycin . Scand J Infect Dis \n1997 ; 29 :628 –30 .9571747 \n8 Brandt CM , Rouse MS , Laue NW et al \nEffective treatment of multidrug-resistant enterococcal experimental endocarditis with combinations of cell wall-active agents . J Infect Dis \n1996 ; 173 :909 –13 .8603970 \n9 Arias CA , Torres HA , Singh KV et al \nFailure of daptomycin mono-therapy for endocarditis caused by an Enterococcus faecium strain with vancomycin-resistant and vancomycin-susceptible subpopulations and evidence of in vivo loss of the vanA gene cluster . Clin Infect Dis \n2007 ; 10 :1343 –6 .17968832 \n10 Stevens MP , Edmond MB \nEndocarditis due to vancomycin-resistant enterococci: case report and review of the literature . Clin Infect Dis \n2005 ; 8 :1134 –42 .16163631 \n11 Jenkins I \nLinezolid- and vancomycin-resistant Enterococcus faecium endocarditis: successful treatment with tigecycline and daptomycin . J Hosp Med \n2007 ; 2 :343 –4 .17935250 \n12 Schutt AC , Bohm NM \nMultidrug-resistant Enterococcus faecium endocarditis treated with combination tigecycline and high-dose daptomycin . Ann Pharmacother \n2009 ; 43 :2108 –12 .19887592 \n13 Bethea JA , Walko CM , Targos PA \nTreatment of vancomycin-resistant enterococcus with quinupristin/dalfopristin and high-dose ampicillin . Ann Pharmacother \n2004 ; 38 :989 –91 .15100393 \n14 Matsumura S , Simor AE \nTreatment of endocarditis due to vancomycin-resistant Enterococcus faecium with quinupristin/dalfopristin, doxycycline, and rifampin: a synergistic drug combination . Clin Infect Dis \n1998 ; 27 :1554 –6 .9868693 \n15 Polidori M , Nuccorini A , Tascini C et al \nVancomycin-resistant Enterococcus faecium (VRE) bacteremia in infective endocarditis successfully treated with combination daptomycin and tigecycline . J Chemotherapy \n2011 ; 23 :240 –1 .\n16 Oritavancin [package insert] . Parsippany, NJ : The Medicines Company ; 2014 .\n17 Munita JM , Mishra NN , Alvarez D et al \nFailure of high-dose daptomycin for bacteremia caused by daptomycin-susceptible Enterococcus faecium harboring LiaSR substitutions . Clin Infect Dis \n2014 ; 59 :1277 –80 .25107294 \n18 Moise PA , Sakoulas G , McKinnell JA et al \nClinical outcomes of daptomycin for vancomycin-resistant Enterococcus bacteremia . Clin Ther \n2015 ; 37 :1443 –53 .25982687 \n19 McKay GA , Beaulieu S , Arhin FF et al \nTime-kill kinetics of oritavancin and comparator agents against Staphylococcus aureus, Enterococcus faecalis and Enterococcus faecium . J Antimicrob Chemother \n2009 ; 63 :1191 –9 .19369269 \n20 Lehoux D , Arhin FF , Fadhil I et al \nOritavancin demonstrates rapid and sustained bactericidal activity in the rat granuloma pouch model of Staphyloccocus aureus infection [poster]. In: Presented at the 46th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) ; 2006 September 27–30; San Francisco, CA. Poster B-0404 .\n21 Bauer LA \nThe aminoglycoside antibiotics . In: Applied Clinical Pharmacokinetics , 2nd ed \nMcGraw Hill Medical ; 2008 : pp 97 –206 .\n22 Bauer LA \nVancomycin . In: Applied Clinical Pharmacokinetics , 2nd ed \nMcGraw Hill Medical ; 2008 : pp 207 –98 .\n23 Rubino CM , Bhavnani SM , Moek G et al \nPopulation pharmacokinetic analysis for a single 1,200-milligram dose of oritavancin using data from two pivotal phase 3 clinical trials . Antimicrobial Agents Chemother \n2015 ; 59 :3365 –72 .\n24 Van Bambeke F , Carryn S , Seral C et al \nCellular pharmacokinetics and pharmacodynamics of the glycopeptide antibiotic oritavancin (LY333328) in a model of J774 mouse macrophages . Antimicrob Agents Chemother \n2004 ; 48 :2853 –60 .15273091\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2328-8957",
"issue": "2(4)",
"journal": "Open forum infectious diseases",
"keywords": "VRE; endocarditis; enterococci; oritavancin; vancomycin-resistant",
"medline_ta": "Open Forum Infect Dis",
"mesh_terms": null,
"nlm_unique_id": "101637045",
"other_id": null,
"pages": "ofv156",
"pmc": null,
"pmid": "26677455",
"pubdate": "2015-12",
"publication_types": "D016428:Journal Article",
"references": "9868693;24897083;8603970;19887592;22431852;25982687;25294250;17968832;9571747;16163631;15273091;17935250;25824211;22431850;15100393;21803704;25107294;19738026;10706902;19369269",
"title": "Prolonged Use of Oritavancin for Vancomycin-Resistant Enterococcus faecium Prosthetic Valve Endocarditis.",
"title_normalized": "prolonged use of oritavancin for vancomycin resistant enterococcus faecium prosthetic valve endocarditis"
} | [
{
"companynumb": "US-MYLANLABS-2021M1034894",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "DAPTOMYCIN"
},
"drugadditional": "1",
... |
{
"abstract": "Neurologic complications are common after solid-organ transplantation, occurring in one-third of patients. Immunosuppression-related neurotoxicity (involving calcineurin inhibitors and corticosteroids), opportunistic central nervous system infections, seizures, and delirium are some of the causes of neurologic symptoms following solid-organ transplantation. An uncommon often missed complication posttransplantation involves buildup of ammonia levels that can lead to rapid clinical deterioration even when treated. Ammonia levels are not routinely checked due to the myriad of other explanations for encephalopathy in a transplant recipient. A treatment of choice for severe hyperammonemia involves renal replacement therapy (RRT), but there are no guidelines on the mode or parameters of RRT for reducing ammonia levels. Hyperammonemia in a transplant recipient poses specific challenges beyond the actual condition because the treatment (RRT) involves significant hemodynamic fluctuations that may affect the graft. In this review, we describe a patient with posttransplantation hyperammonemia and discuss the pathways of ammonia metabolism, potential factors underlying the development of hyperammonemia posttransplantation, and choice of appropriate therapeutic options in these patients.",
"affiliations": "Division of Nephrology, Department of Internal Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA. Electronic address: hseethapathy@bwh.harvard.edu.;Division of Nephrology, Department of Internal Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA.",
"authors": "Seethapathy|Harish|H|;Fenves|Andrew Z|AZ|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1053/j.ajkd.2019.03.419",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0272-6386",
"issue": "74(3)",
"journal": "American journal of kidney diseases : the official journal of the National Kidney Foundation",
"keywords": "Hyperammonemia; ammonia; bowel decontamination; continuous renal replacement therapy (CRRT); detoxification; hemodialysis (HD); kidney transplant; nitrogen scavengers; organ transplant",
"medline_ta": "Am J Kidney Dis",
"mesh_terms": "D006801:Humans; D022124:Hyperammonemia; D016377:Organ Transplantation; D011183:Postoperative Complications; D017582:Renal Replacement Therapy",
"nlm_unique_id": "8110075",
"other_id": null,
"pages": "390-398",
"pmc": null,
"pmid": "31040091",
"pubdate": "2019-09",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": null,
"title": "Pathophysiology and Management of Hyperammonemia in Organ Transplant Patients.",
"title_normalized": "pathophysiology and management of hyperammonemia in organ transplant patients"
} | [
{
"companynumb": "US-ASTELLAS-2019US035180",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional": "3",
... |
{
"abstract": "Vemurafenib and dabrafenib are both orally bioavailable small molecule agents that block mitogen activated protein kinase signalling in patients with melanoma and BRAF(V600E) mutation. Generalized hypersensitivity reactions to vemurafenib or dabrafenib have not been described. Continuing vemurafenib or dabrafenib therapy despite hypersensitivity reaction is especially important in patients with melanoma and BRAF(V600E) mutation, in whom this mutation plays a critical role in tumour growth. Desensitization protocols to overcome hypersensitivity reactions by gradual reintroduction of small amounts of the offending drug up to full therapeutic doses are available for many anti-cancer agents, including vemurafenib but, to the best of our knowledge, have not been reported for dabrafenib. We describe a patient with metastatic melanoma who developed Type I hypersensitivity reaction to vemurafenib and to subsequent treatment with dabrafenib, and who was successfully treated by drug desensitization which allowed safe prolonged continuation of dabrafenib. The development of hypersensitivity reactions for both dabrafenib and vemurafinib in the current case could be because these drugs have a similar chemical structure and cause a cross-reactivity. However, hypersensitivity reaction to a non-medicinal ingredient shared by the two drugs is also possible. Oral desensitization appears to be an option for patients with hypersensitivity Type I to dabrafenib. This approach may permit clinicians to safely administer dabrafenib to patients who experience hypersensitivity reactions to this life-prolonging medication.",
"affiliations": "Division of Oncology, Technion-Israel Institute of Technology, Haifa g_barsela@rambam.health.gov.il.;Division of Oncology, Technion-Israel Institute of Technology, Haifa.;Pharmacy Department, Technion-Israel Institute of Technology, Haifa.;Division of Oncology, Technion-Israel Institute of Technology, Haifa.;Department of Immunology, Rambam Health Care Campus and Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.",
"authors": "Bar-Sela|Gil|G|;Abu-Amna|Mahmoud|M|;Hadad|Salim|S|;Haim|Nissim|N|;Shahar|Eduardo|E|",
"chemical_list": "D000893:Anti-Inflammatory Agents; D000970:Antineoplastic Agents; D007093:Imidazoles; D010091:Oximes; D003907:Dexamethasone; D004155:Diphenhydramine; D048493:Proto-Oncogene Proteins B-raf; C561627:dabrafenib",
"country": "England",
"delete": false,
"doi": "10.1093/jjco/hyv086",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0368-2811",
"issue": "45(9)",
"journal": "Japanese journal of clinical oncology",
"keywords": "dabrafenib; desensitization; hypersensitivity reaction; vemurafenib",
"medline_ta": "Jpn J Clin Oncol",
"mesh_terms": "D000893:Anti-Inflammatory Agents; D000970:Antineoplastic Agents; D001932:Brain Neoplasms; D003888:Desensitization, Immunologic; D003907:Dexamethasone; D004155:Diphenhydramine; D004342:Drug Hypersensitivity; D005260:Female; D005720:Gamma Rays; D006801:Humans; D007093:Imidazoles; D008279:Magnetic Resonance Imaging; D008545:Melanoma; D008875:Middle Aged; D010091:Oximes; D020641:Polymorphism, Single Nucleotide; D049268:Positron-Emission Tomography; D048493:Proto-Oncogene Proteins B-raf; D012878:Skin Neoplasms; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "0313225",
"other_id": null,
"pages": "881-3",
"pmc": null,
"pmid": "26056325",
"pubdate": "2015-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Successful desensitization protocol for hypersensitivity reaction probably caused by dabrafenib in a patient with metastatic melanoma.",
"title_normalized": "successful desensitization protocol for hypersensitivity reaction probably caused by dabrafenib in a patient with metastatic melanoma"
} | [
{
"companynumb": "PHHY2015IL134540",
"fulfillexpeditecriteria": "1",
"occurcountry": "IL",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "DABRAFENIB MESYLATE"
},
"drugadditional": null,
... |
{
"abstract": "Collagenous enteritis is an uncommon small intestinal injury pattern with unclear pathogenesis. While it has been speculated that collagenous enteritis represents a form of refractory celiac disease, recent clinical studies suggest a potential link to exposure to the antihypertensive medication olmesartan. Here we hypothesized that the pathogenesis of collagenous enteritis involves both genetic and environmental factors. All subjects with biopsy-proven collagenous enteritis diagnosed between 2002 and 2015 were identified from 2 tertiary care medical centers. Human leukocyte antigen (HLA)-DQ genotyping was performed by polymerase chain reaction on archived tissue. Celiac disease serology, past medical history, medications, smoking history, demographics, histology, clinical management, and follow-up were recorded. A total of 32 subjects were included. In contrast to celiac disease, subjects with collagenous enteritis were mostly elderly (median age at diagnosis, 69 y; range, 33 to 84 y). Seventy percent of collagenous enteritis subjects harbored celiac disease susceptibility alleles HLA-DQ2/DQ8; however, only 1 subject had elevated serum levels of celiac disease-associated autoantibodies while on a gluten-containing diet. Furthermore, 56% of subjects were taking nonsteroidal anti-inflammatory drugs, 36% proton-pump inhibitors, 28% statins, and 32% olmesartan at the time of diagnosis. Discontinuation of olmesartan and treatments with steroids and/or gluten-free diet resulted in symptomatic and histologic improvement. Neither lymphoma nor collagenous enteritis-related death was seen in this cohort. Therefore, while collagenous enteritis shares similar HLA genotypes with celiac disease, the difference in demographics, the lack of celiac disease-associated autoantibodies, and potential link to medications as environmental triggers suggest the 2 entities are likely distinct in pathogenesis.",
"affiliations": "Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, MO.;Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, MO.;Department of Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, PA.",
"authors": "Kung|Vanderlene Liu|VL|;Liu|Ta-Chiang|TC|;Ma|Changqing|C|",
"chemical_list": "D047228:Angiotensin II Type 1 Receptor Blockers; D006683:HLA-DQ Antigens; C053186:HLA-DQ2 antigen; C109756:HLA-DQ8 antigen; D013256:Steroids; D003094:Collagen",
"country": "United States",
"delete": false,
"doi": "10.1097/PAS.0000000000001022",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0147-5185",
"issue": "42(4)",
"journal": "The American journal of surgical pathology",
"keywords": null,
"medline_ta": "Am J Surg Pathol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D047228:Angiotensin II Type 1 Receptor Blockers; D001706:Biopsy; D002446:Celiac Disease; D003094:Collagen; D064068:Collagenous Sprue; D055050:Diet, Gluten-Free; D004751:Enteritis; D005260:Female; D020022:Genetic Predisposition to Disease; D006683:HLA-DQ Antigens; D006801:Humans; D007421:Intestine, Small; D008297:Male; D008875:Middle Aged; D008923:Missouri; D010414:Pennsylvania; D010641:Phenotype; D012189:Retrospective Studies; D012307:Risk Factors; D013256:Steroids; D016896:Treatment Outcome",
"nlm_unique_id": "7707904",
"other_id": null,
"pages": "545-552",
"pmc": null,
"pmid": "29324472",
"pubdate": "2018-04",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Collagenous Enteritis is Unlikely a Form of Aggressive Celiac Disease Despite Sharing HLA-DQ2/DQ8 Genotypes.",
"title_normalized": "collagenous enteritis is unlikely a form of aggressive celiac disease despite sharing hla dq2 dq8 genotypes"
} | [
{
"companynumb": "US-MICRO LABS LIMITED-ML2019-00918",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "SIMVASTATIN"
},
"drugadditional": "3... |
{
"abstract": "BACKGROUND\nCor triatriatum sinister (CTS) is a rare congenital heart defect characterized by fibromuscular septation of the left atrium associated with atrial fibrillation (AF). The incidence of hemodynamically insignificant CTS in the AF ablation population and effect on ablation success are not known. Furthermore, little is known about the potential effect of CTS on arrhythmogenic substrate.\n\n\nOBJECTIVE\nWe define the incidence of hemodynamically insignificant CTS in patients undergoing AF ablation with RF and cryoballoon ablation, the technical challenges created by the left atrial partitioning, and the potentially arrhythmogenic effects of the membrane. We also review the literature of CA in patients with CTS.\n\n\nMETHODS\nFirst-time AF ablation cases at our institution over a 10-year period were screened to identify patients with CTS. Retrospective review was performed to obtain clinical characteristics and ablation data.\n\n\nRESULTS\nOf the 3953 consecutive patients undergoing initial AF ablation during the study period, four patients (0.10%) had CTS. Ablation was successful acutely in all patients. One patient had recurrent AF and required repeat ablation for a single procedure success rate of 75% and multi-procedure success rate of 100%. The CTS membrane was associated with low voltage zones in the two patients in whom it was measured and with substrate for macro-reentrant atrial tachycardia in one of these patients.\n\n\nCONCLUSIONS\nThe incidence of hemodynamically insignificant CTS in patients undergoing CA for AF is very low, but does not serve as a significant barrier to successful ablation as long as directed access to the superoposterior chamber is obtained.",
"affiliations": "Section of Clinical Cardiac Electrophysiology & Pacing, Division of Cardiology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina, USA.;Section of Clinical Cardiac Electrophysiology & Pacing, Division of Cardiology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina, USA.;Section of Clinical Cardiac Electrophysiology & Pacing, Division of Cardiology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina, USA.;Section of Clinical Cardiac Electrophysiology & Pacing, Division of Cardiology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina, USA.;Section of Clinical Cardiac Electrophysiology & Pacing, Division of Cardiology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina, USA.;Section of Clinical Cardiac Electrophysiology & Pacing, Division of Cardiology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina, USA.",
"authors": "Karimianpour|Ahmadreza|A|https://orcid.org/0000-0002-8450-8308;Cai|Amanda W|AW|;Cuoco|Frank A|FA|;Sturdivant|John Lacy|JL|;Litwin|Sheldon E|SE|;Wharton|John Marcus|JM|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1111/pace.14371",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0147-8389",
"issue": null,
"journal": "Pacing and clinical electrophysiology : PACE",
"keywords": null,
"medline_ta": "Pacing Clin Electrophysiol",
"mesh_terms": null,
"nlm_unique_id": "7803944",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34648196",
"pubdate": "2021-10-14",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": null,
"title": "Catheter ablation of atrial fibrillation in patients with cor triatriatum sinister; case series and review of literature.",
"title_normalized": "catheter ablation of atrial fibrillation in patients with cor triatriatum sinister case series and review of literature"
} | [
{
"companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2022R1-326979",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DOFETILIDE"
},
"drug... |
{
"abstract": "Dropped head syndrome (DHS) is a relatively rare condition, with a broad differential diagnosis. We report here a case of infantile nephrotic syndrome with DHS caused by severe hypokalemia. Electrocardiogram showed flat T- and U-waves. Multiple factors including recurrent diarrhea, prolonged diuretic and corticosteroid use, hypomagnesemia, poor intake, and malnutrition caused hypokalemia in the case. Head drop and flaccid weakness resolved completely after potassium and magnesium supplementation. Potassium levels should be monitored and corrected promptly in these settings.",
"affiliations": "Department of Pediatrics, Dayanand Medical College and Hospital, Ludhiana, Punjab, India.",
"authors": "Dhooria|G S|GS|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.4103/ijn.IJN_198_16",
"fulltext": "\n==== Front\nIndian J NephrolIndian J NephrolIJNIndian Journal of Nephrology0971-40651998-3662Medknow Publications & Media Pvt Ltd India IJN-28-38210.4103/ijn.IJN_198_16Case ReportHead Drop and Flaccid Weakness in Infantile Nephrotic Syndrome Dhooria G. S. Department of Pediatrics, Dayanand Medical College and Hospital, Ludhiana, Punjab, IndiaAddress for correspondence: Dr. G. S. Dhooria, Department of Pediatrics, Dayanand Medical College and Hospital, Ludhiana, Punjab, India. E-mail: gurdeep2005123@gmail.comSep-Oct 2018 28 5 382 384 Copyright: © 2018 Indian Journal of Nephrology2018This 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.Dropped head syndrome (DHS) is a relatively rare condition, with a broad differential diagnosis. We report here a case of infantile nephrotic syndrome with DHS caused by severe hypokalemia. Electrocardiogram showed flat T- and U-waves. Multiple factors including recurrent diarrhea, prolonged diuretic and corticosteroid use, hypomagnesemia, poor intake, and malnutrition caused hypokalemia in the case. Head drop and flaccid weakness resolved completely after potassium and magnesium supplementation. Potassium levels should be monitored and corrected promptly in these settings.\n\nKeywords:\nHypokalemianephrotic syndromeparalysis\n==== Body\nIntroduction\nDropped head syndrome (DHS) is characterized by severe weakness of the cervical paraspinal muscles, most commonly associated with neuromuscular disorders.[1] Although hypokalemia has been listed as a cause of DHS,[2] very few cases of hypokalemic weakness have been reported in children with nephrotic syndrome. Here, we report a case of infantile nephrotic syndrome who presented with sudden onset head drop and flaccid weakness due to hypokalemia. In this case, recurrent diarrhea, prolonged diuretic and corticosteroid use, poor intake, and malnutrition causing hypokalemia have been explained. The condition was rapidly reversed by potassium and magnesium supplementation.\n\nCase Report\nAn 18-month-old male infant, diagnosed as a case of steroid-resistant nephrotic syndrome, born of nonconsanguineous marriage, was admitted with complaints of not able to sit and head drop for 1 day.\n\nThe patient was diagnosed to be a case of infantile nephrotic syndrome at the age of 1 year with puffiness of face, edema feet, and oliguria. There was no renal dysfunction, hematuria, or hypertension. Family history of kidney disease was absent. He was treated with full dose steroid (2 mg/kg/day) for 4 weeks and additional 2 weeks with no remission. Renal biopsy showed minimal change disease with no deposits on immunofluorescence. He was started with cyclosporine A (6 mg/kg/day), alternate day steroids (1.5 mg/kg/day), oral enalapril and furosemide. Trough cyclosporine (C0) blood level after 4 weeks of initiation was 95 (target: 80–120 ng/ml). In the subsequent months, the patient was admitted twice, 5–7 days each with an interval of 2 weeks for infective diarrhea and treated with antibiotics, zinc, and fluid management. Diuretics were intentionally withheld and not restarted. Serum electrolytes at the time of last discharge were normal. The infant intake reduced to predominantly milk, due to cough, cold, and wheezing, few days before the weakness developed. There was no history of fever, dysuria, or vomiting. There was no history of weakness in the past. There was weight loss of 800 g (10% body weight) from previous hospital visit.\n\nOn admission, the infant was limp but conscious. General examination showed mild pallor and minimal pedal edema. Weight of the child was 7.4 kg (expected 10.5 kg, <3rd percentile WHO standards, Grade II malnutrition of Indian Academy of Pediatrics classification). Urine output was normal with approximately 1 ml/kg/h. Vital parameters were normal. Neurologically, the infant was conscious, but irritable. There was no cranial nerve palsy. There was head drop with weakness of extensors of neck. Tone was decreased in all the four limbs. He was able to sit only with support in tripod position [Figure 1]. Deep tendon reflexes were depressed and planters were absent. Other systemic examinations were normal.\n\nFigure 1 Head drop in the infant completely recovered after potassium supplementation. (a) Before correction. (b) After correction\n\nSuspecting hypokalemic paralysis, electrocardiogram (ECG) was done which showed flat T- and U-waves [Figure 2]. Investigations revealed hypokalemia (serum K+ = 2.1 mEq/L), hypocalcemia (corrected serum Ca = 6.9 mg/dl), hypomagnesemia (serum Mg = 1.6 mg/dl), hypoalbuminemia (serum albumin = 2.0 g/dl), and hypercholesteremia (serum cholesterol = 216 mg/dl) with blood urea of 3 mg/dl and serum creatinine of 0.12 mg/dl. Random blood sugar was 106 mg/dl and complete blood count was normal. Thyroid profile was normal.\n\nFigure 2 Electrocardiogram showing flat T- and U-waves (arrows) in the infant with hypokalemia\n\nArterial blood gas analysis was normal (pH = 7.40, HCO3− = 22.3 mmol/L, PCO2 = 36 mmHg, PO2 = 83.3 mmHg, and SaO2 = 95%) and urinary electrolytes (mEq/L) were Na: 9, K: 2.2, Cl: 12, creatinine: 5. Urinary K was <20 mEq/L with FeK of 2.5% (average 10%). Transtubular potassium gradient (TTKG) calculated was 0.5 (<4) ([urinary K × serum osmolality/serum K × urinary osmolarity] ×100), suggesting extrarenal losses. Spot urine protein creatinine ratio was 0.34 (normal <0.2). Spot calcium creatinine ratio was 0.34 (normal <0.8 for infants) and FeNa was 0.34 (normal <2). Urine routine and microscopy showed trace proteins and no white blood cells or red blood cells. Serum 25-hydroxyvitamin D3 level was 3 (normal = 9–37.6 ng/ml).\n\nThe patient was started on KCl infusion (4 mEq KCl in 100 ml fluid) along with injection MgSO4 50% 0.2 ml/kg intramuscular for 2 days; head drop improved rapidly and the patient completely recovered within 48 h. Repeat serum K+ level was normal (3.7 mEq/L). The patient was discharged on oral potassium supplement (syrup Potclor 20 mEq/15 ml) of 1 mEq/kg.\n\nDiscussion\nHypokalemic paralysis is defined as an acute-onset flaccid paralysis associated with low plasma potassium (<3.5 mEq/L).[3] The most common causes of hypokalemia are gastrointestinal loss (diarrhea, laxatives), renal loss (hyperaldosteronism, severe hyperglycemia, potassium-depleting diuretics, carbenicillin, sodium penicillin, and amphotericin B), intracellular shift (alkalosis), and malnutrition.[3] In the presence of hypokalemia, low urinary potassium <20 mmol/day suggests extrarenal loss or could be due to malnutrition (decreased oral intake), whereas urinary potassium >20 mmol/day suggests renal loss.[4] In the index case, urinary potassium and TTKG were low with no acidosis or alkalosis, ruling out renal losses such as renal tubular acidosis, Bartter syndrome, or primary hyperaldosteronism.\n\nThe major consequences of severe hypokalemia result from its effects on nerves and muscles (including the heart). Symptoms of mild hypokalemia are weakness, fatigue, paralysis, respiratory difficulty, constipation, paralytic ileus, and leg cramps; more severe hypokalemia will alter cardiac tissue excitability and conduction. Hypokalemia can produce ECG changes such as U-waves, T-wave flattening, and arrhythmias, particularly ventricular arrhythmias.[3] This infant had flat T- and U-waves on ECG, and head drop and flaccid weakness. The cause of hypokalemia was multifactorial as the patient had repeated episodes of diarrhea, poor intake/malnutrition, and was on medications such as loop diuretics and corticosteroids. The infant had a viral-induced wheeze, the possible use of oral salbutamol caused shift of potassium to precipitate the weakness in an already depleted infant.\n\nTypically, furosemide-induced hypokalemia is characterized by metabolic alkalosis, hypocalcemia, hypomagnesemia, high urine calcium creatinine ratio, and high urine sodium excretion, also termed “Pseudo–Bartter syndrome.”[5] Loop and thiazide diuretics deplete not only potassium but also magnesium. Oral potassium supplementation and/or potassium-sparing diuretics are used to recover from these losses.[6] Magnesium deficiency was also found in this case which could be explained with malnutrition, diuretic, and cyclosporine use. Renal allograft recipients receiving cyclosporine showed a significant reduction in serum magnesium levels and increased fractional excretion of magnesium, suggesting renal wasting.[7] Glucocorticoids, used in this patient for nephrotic syndrome, also cause renal sodium retention and potassium excretion with no increase in hydrogen excretion.[8]\n\nUnder normal circumstances, only minimal amounts of potassium are excreted through the intestine. In severe diarrhea, 90 mmol/24 h (<4 g of potassium) can be lost in stools, and in infants suffering from protein–energy malnutrition, potassium deficiency occurs when 10%–30% of body potassium is lost.[9] Repeated episodes of diarrhea, past diuretic use, and malnutrition might have caused chronic depletion of potassium stores.\n\nPotassium content of human milk is 15 mmol/L. Cow's milk contains 38 mmol/L of potassium and commercial formulae have around 18 mmol/L. The recommended adult potassium intake is 1875–5625 mg daily (10–28 g of KCl), while in infants <6 months, it is 350–925 mg (1.8 g of KCl) and in >6 months, it is 475–1275 (2.5 g of KCl). In children from 1 to 3 years, the recommended potassium intake is 550–1650 mg (3.2 g of KCl), and in 4–6 years, it is 775–2325 mg (4.5 g of KCl).[9] Our patient took only about 400 ml/day cow's milk (approximately 14 mmol/L) which was insufficient for his needs.\n\nTo our knowledge, only two cases of hypokalemia paralysis with nephrotic syndrome have been reported in literature till date, one had unusual combination of distal renal tubular acidosis with membranous nephropathy coupled with hypokalemic paralysis and medullary nephrocalcinosis.[410]\n\nOur case was an infant with steroid-resistant nephrotic syndrome who developed hypokalemic paralysis in the form of head drop and flaccid weakness secondary to multiple factors. The case highlights the need to monitor potassium levels with prolonged use of diuretics and steroids. Potassium deficiency should be anticipated, especially in cases with recurrent diarrhea and malnutrition.\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\nAcknowledgment\nWe acknowledge Professor Daljit Singh for his constant guidance and support.\n==== Refs\nReferences\n1 Sharan AD Kaye D Charles Malveaux WM Riew KD Dropped head syndrome: Etiology and management J Am Acad Orthop Surg 2012 20 766 74 23203936 \n2 Martin AR Reddy R Fehlings MG Dropped head syndrome: Diagnosis and management Evid Based Spine Care J 2011 2 41 7 23637681 \n3 Garg RK Malhotra HS Verma R Sharma P Singh MK Etiological spectrum of hypokalemic paralysis: A retrospective analysis of 29 patients Ann Indian Acad Neurol 2013 16 365 70 24101818 \n4 Sunder S Sathi S Venkataramanan K Verma H Bhardwaj M Rajesh J A rare case of type I renal tubular acidosis with membranous nephropathy presenting as hypokalemic paralysis Case Rep Nephrol Urol 2013 3 91 8 23898345 \n5 Ruisz W Stöllberger C Finsterer J Weidinger F Furosemide-induced severe hypokalemia with rhabdomyolysis without cardiac arrest BMC Womens Health 2013 13 30 23834955 \n6 Qavi AH Kamal R Schrier RW Clinical use of diuretics in heart failure, cirrhosis, and nephrotic syndrome Int J Nephrol 2015 2015 975934 26294976 \n7 Barton CH Vaziri ND Martin DC Choi S Alikhani S Hypomagnesemia and renal magnesium wasting in renal transplant recipients receiving cyclosporine Am J Med 1987 83 693 9 3314493 \n8 Mckay LI Cidlowski JA Kufe DW Pollock RE Weichselbaum RR Bast RC Gansler TS Holland JF Physiologic and pharmacologic effects of corticosteroids Holland-Frei Cancer Medicine 2003 6th ed Hamilton, ON BC Decker \n9 Indian Council of Medical Research 2009-2010 Jamai-Osmania, Hyderabad National Institute of Nutrition; Nutrient Requirements and Recommended Dietary Allowances for Indians; A Report of the Expert Group of the Indian Council of Medical Research 2009-2010 \n10 Koul PA Nephrotic syndrome and hypokalemic paralysis J Assoc Physicians India 1998 46 401\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "0971-4065",
"issue": "28(5)",
"journal": "Indian journal of nephrology",
"keywords": "Hypokalemia; nephrotic syndrome; paralysis",
"medline_ta": "Indian J Nephrol",
"mesh_terms": null,
"nlm_unique_id": "8914356",
"other_id": null,
"pages": "382-384",
"pmc": null,
"pmid": "30271001",
"pubdate": "2018",
"publication_types": "D002363:Case Reports",
"references": "11273334;23834955;3314493;23203936;24101818;23637681;26294976;23898345",
"title": "Head Drop and Flaccid Weakness in Infantile Nephrotic Syndrome.",
"title_normalized": "head drop and flaccid weakness in infantile nephrotic syndrome"
} | [
{
"companynumb": "IN-MYLANLABS-2018M1075184",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CYCLOSPORINE"
},
"drugadditional": "3",
... |
{
"abstract": "Bleomycin-induced lung injury is the most common chemotherapy-associated lung disease, and is linked with several histopathological patterns. Acute fibrinous and organising pneumonia (AFOP) is a relatively new and rare histological pattern of diffuse lung injury. We report the first known case of bleomycin-induced AFOP. A 36-year-old man with metastatic testicular cancer received three cycles of bleomycin, etoposide and cisplatin, before being transitioned to paclitaxel, ifosfamide and cisplatin. He subsequently presented with exertional dyspnoea, cough and pleuritic chest pain. CT of the chest demonstrated bilateral ground glass opacities with peribronchovascular distribution and pulmonary function tests demonstrated a restrictive pattern of lung disease with impaired diffusion. Transbronchial biopsy revealed intra-alveolar fibrin deposits with organising pneumonia, consisting of intraluminal loose connective tissue consistent with AFOP. The patient received high-dose corticosteroids with symptomatic and radiographic improvement. AFOP should be recognised as a histopathological variant of bleomycin-induced lung injury.",
"affiliations": "University of Texas Southwestern Medical Center, Dallas, Texas, USA.;University of Texas MD Anderson Cancer Center, Houston, TX.;University of Texas Southwestern Medical Center, Dallas, Texas, USA.",
"authors": "Gupta|Arjun|A|;Sen|Shiraj|S|;Naina|Harris|H|",
"chemical_list": "D000305:Adrenal Cortex Hormones; D001761:Bleomycin",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2016()",
"journal": "BMJ case reports",
"keywords": null,
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000305:Adrenal Cortex Hormones; D000328:Adult; D001761:Bleomycin; D018549:Cryptogenic Organizing Pneumonia; D003937:Diagnosis, Differential; D006801:Humans; D055370:Lung Injury; D008297:Male; D011014:Pneumonia; D012129:Respiratory Function Tests; D013736:Testicular Neoplasms; D016896:Treatment Outcome",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "27053543",
"pubdate": "2016-04-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "6208466;15992893;15685195;55502;2445461;1691067;12488299;16623365;12204055;1690503",
"title": "Acute fibrinous and organising pneumonia: a rare histopathological variant of chemotherapy-induced lung injury.",
"title_normalized": "acute fibrinous and organising pneumonia a rare histopathological variant of chemotherapy induced lung injury"
} | [
{
"companynumb": "US-PFIZER INC-2016375840",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ETOPOSIDE"
},
"drugadditional": null,
... |
{
"abstract": "In recent years, there has been an increase in the use of phosphodiesterase type 5 inhibitors (PDE5i) that are purchased from abroad without a doctor's diagnosis via the Internet or other means. We report six cases in which nonprescription use of PDE5i may have led to death. Among the four deceased individuals who were believed to have experienced sudden cardiac death, three (cases 1-3) had a history of cardiovascular disease, which is a contraindication, and the remaining case (case 4) involved combined use of multiple PDE5i. Sildenafil (0.063 µg/mL, 0.087 µg/mL) was detected in two of the four cases of sudden cardiac death. Tadalafil (0.096 µg/mL) was detected in one of the remaining two cases, and tadalafil (0.197 µg/mL) and vardenafil (0.011 µg/mL) were detected in the other case. Sildenafil (0.032 µg/mL), tadalafil (0.062 µg/mL), and ethanol were detected in a traffic accident case with a history of contraindications. In a case of asphyxiation by vomit aspiration, autopsy showed 90% stenosis in the anterior descending branch of the coronary artery, and sildenafil (0.063 µg/mL) was detected. To the best of our knowledge, this is the first report of postmortem blood levels of tadalafil and vardenafil likely contributing to the cause of death. Despite all the warnings about the dangers of using PDE5 inhibitors, cases of PDE5i contributing to death are still identified during autopsies. Therefore, raising public awareness of the risks of the risks associated with the imported drug use by individuals is necessary.",
"affiliations": "Department of Legal Medicine, Graduate School of Medicine, Chiba University, Inohana 1-8-1, Chuo-ku, Chiba City, Chiba 260-8670, Japan.;Department of Forensic Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokoyo 113-0033, Japan.;Department of Legal Medicine, Graduate School of Medicine, Chiba University, Inohana 1-8-1, Chuo-ku, Chiba City, Chiba 260-8670, Japan.;Department of Legal Medicine, Graduate School of Medicine, Chiba University, Inohana 1-8-1, Chuo-ku, Chiba City, Chiba 260-8670, Japan; Department of Forensic Medicine, Graduate School of Medicine, International University of Health and Werfare, Kozunomori 4-3, Narita City, Chiba 286-8686, Japan.;Department of Legal Medicine, Graduate School of Medicine, Chiba University, Inohana 1-8-1, Chuo-ku, Chiba City, Chiba 260-8670, Japan; Department of Forensic Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokoyo 113-0033, Japan.;Department of Legal Medicine, Graduate School of Medicine, Chiba University, Inohana 1-8-1, Chuo-ku, Chiba City, Chiba 260-8670, Japan; Department of Forensic Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokoyo 113-0033, Japan.;Department of Legal Medicine, Graduate School of Medicine, Chiba University, Inohana 1-8-1, Chuo-ku, Chiba City, Chiba 260-8670, Japan; Department of Forensic Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokoyo 113-0033, Japan.;Department of Legal Medicine, Graduate School of Medicine, Chiba University, Inohana 1-8-1, Chuo-ku, Chiba City, Chiba 260-8670, Japan; Department of Forensic Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokoyo 113-0033, Japan.",
"authors": "Nagasawa|Sayaka|S|;Saka|Kanju|K|;Yamagishi|Yoshikazu|Y|;Yajima|Daisuke|D|;Chiba|Fumiko|F|;Yamaguchi|Rutsuko|R|;Torimitsu|Suguru|S|;Iwase|Hirotaro|H|",
"chemical_list": "D058986:Phosphodiesterase 5 Inhibitors; D000069058:Vardenafil Dihydrochloride; D000068581:Tadalafil; D000068677:Sildenafil Citrate",
"country": "Ireland",
"delete": false,
"doi": "10.1016/j.legalmed.2020.101815",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1344-6223",
"issue": "48()",
"journal": "Legal medicine (Tokyo, Japan)",
"keywords": "Cardiovascular disorder; Erectile dysfunction; Nonprescription; Phosphodiesterase type 5 inhibitor; Postmortem redistribution",
"medline_ta": "Leg Med (Tokyo)",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002318:Cardiovascular Diseases; D000075203:Contraindications, Drug; D016757:Death, Sudden, Cardiac; D007172:Erectile Dysfunction; D005554:Forensic Medicine; D006801:Humans; D008297:Male; D008875:Middle Aged; D058986:Phosphodiesterase 5 Inhibitors; D012306:Risk; D012725:Sexual Behavior; D000068677:Sildenafil Citrate; D000068581:Tadalafil; D000069058:Vardenafil Dihydrochloride",
"nlm_unique_id": "100889186",
"other_id": null,
"pages": "101815",
"pmc": null,
"pmid": "33264696",
"pubdate": "2021-02",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Association between sexual activity-related death and non-prescription use of phosphodiesterase type 5 inhibitors.",
"title_normalized": "association between sexual activity related death and non prescription use of phosphodiesterase type 5 inhibitors"
} | [
{
"companynumb": "JP-ALKEM LABORATORIES LIMITED-JP-ALKEM-2021-00776",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "SILDENAFIL"
},
"druga... |
{
"abstract": "Thrombotic microangiopathy (TMA) is a rare complication of gemcitabine treatment. A 55-year-old man with a history of urothelial cancer underwent right ureteronephrectomy and palliative chemotherapy. The patient presented with dyspnea, generalized edema with foamy urine, and new-onset hypertension with acute kidney injury (AKI). Although AKI with oliguria was evident, thrombocytopenia and hemolytic anemia were not overt. To determine the cause of rapidly progressive azotemia, kidney biopsy was performed despite a single kidney and revealed chronic TMA. Microangiopathic hemolytic anemia and thrombocytopenia developed after renal biopsy. Diagnosed as gemcitabine-induced TMA, gemcitabine cessation and active treatment including steroids, plasmapheresis, and rituximab were carried out, but the patient׳s condition progressed to a dialysis-dependent state. Gemcitabine-induced TMA is often difficult to diagnose because of its variable clinical course. Therefore, heightened awareness of this potentially lethal complication of gemcitabine is essential; renal biopsy may be helpful.",
"affiliations": "Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.;Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.;Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.;Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.;Department of Pathology, Seoul National University College of Medicine, Seoul, Korea.;Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.;Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.",
"authors": "Ryu|Hyunjin|H|;Kang|Eunjeong|E|;Park|Seokwoo|S|;Park|Sehoon|S|;Lee|Kyoungbun|K|;Joo|Kwon Wook|KW|;Lee|Hajeong|H|",
"chemical_list": null,
"country": "Korea (South)",
"delete": false,
"doi": "10.1016/j.krcp.2015.06.001",
"fulltext": "\n==== Front\nKidney Res Clin PractKidney Res Clin PractKidney Research and Clinical Practice2211-91322211-9140Elsevier S2211-9132(15)30012-710.1016/j.krcp.2015.06.001Case ReportA case of gemcitabine-induced thrombotic microangiopathy in a urothelial tumor patient with a single kidney Ryu Hyunjin 1Kang Eunjeong 1Park Seokwoo 1Park Sehoon 1Lee Kyoungbun 2Joo Kwon Wook 1Lee Hajeong mdhjlee@gmail.com1∗1 Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea2 Department of Pathology, Seoul National University College of Medicine, Seoul, Korea∗ Corresponding author. Department of Internal Medicine, Seoul National University Hospital, 101, Daehak-ro, Jongno-gu, Seoul 03080, Korea. mdhjlee@gmail.com07 7 2015 12 2015 07 7 2015 34 4 237 240 24 4 2015 5 6 2015 11 6 2015 Copyright © 2015. The Korean Society of Nephrology. Published by Elsevier Ltd.2015This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Thrombotic microangiopathy (TMA) is a rare complication of gemcitabine treatment. A 55-year-old man with a history of urothelial cancer underwent right ureteronephrectomy and palliative chemotherapy. The patient presented with dyspnea, generalized edema with foamy urine, and new-onset hypertension with acute kidney injury (AKI). Although AKI with oliguria was evident, thrombocytopenia and hemolytic anemia were not overt. To determine the cause of rapidly progressive azotemia, kidney biopsy was performed despite a single kidney and revealed chronic TMA. Microangiopathic hemolytic anemia and thrombocytopenia developed after renal biopsy. Diagnosed as gemcitabine-induced TMA, gemcitabine cessation and active treatment including steroids, plasmapheresis, and rituximab were carried out, but the patient׳s condition progressed to a dialysis-dependent state. Gemcitabine-induced TMA is often difficult to diagnose because of its variable clinical course. Therefore, heightened awareness of this potentially lethal complication of gemcitabine is essential; renal biopsy may be helpful.\n\nKeywords\nGemcitabineThrombotic microangiopathyUrothelial carcinoma\n==== Body\nIntroduction\nGemcitabine is a nucleoside analogue of cytarabine, first approved by the US Food and Drug Administration in 1996. Its use has increased because of relatively mild complications. Currently, in combination with other chemotherapeutic agents, gemcitabine is included among first-line treatments in some adjuvant and palliative settings for non–small cell lung, ovarian, breast, and pancreatic cancers. In urothelial tumors, gemcitabine with cisplatin showed equal efficacy and less toxicity in elderly patients and currently, is a first-line regimen in advanced stages.\n\nThrombocytopenia and anemia are the most common complications of gemcitabine-induced myelosuppression. Mild proteinuria, microscopic hematuria, and elevated levels of blood urea nitrogen (BUN) and creatinine (Cr) can occur after gemcitabine treatment but are rarely of clinical significance. Nevertheless, gemcitabine-induced thrombotic microangiopathy (TMA) has been reported in a few cases and it can lead to persistent kidney failure with poor prognosis. The first case was reported in 1994; the currently known incidence of gemcitabine-induced TMA is 0.015–1.4% [1], [2]. The combination therapies with other chemotherapeutic agents including carboplatin, cisplatin, vinorelbine, tegafur, and docetaxel may increase the risk of TMA as discussed in previous studies [3], [4].\n\nThere have been reports that gemcitabine-induced TMA occurred in patients with urothelial cancer, but none of these included a nephrectomy case [5], [6], [7]. We report the case of gemcitabine-induced TMA in a patient with a single-kidney urothelial cancer, who eventually needed kidney biopsy for diagnosis.\n\nCase report\nA 55-year-old man, who had undergone palliative chemotherapy for urothelial carcinoma, was referred to nephrology for dyspnea and generalized edema for a month. One year previously, he was diagnosed with urothelial carcinoma when he visited a clinic on account of right flank pain. He received one cycle of neoadjuvant chemotherapy with gemcitabine/cisplatin but did not continue because of elevation of the liver enzyme level. After the neoadjuvant chemotherapy, thrombocytopenia developed (92,000/mm3), but the thrombocyte count returned to a normal level within 1 week. The final pathologic staging after right nephroureterectomy was T3Nx. Pathologic findings of the non–tumor-involved kidney tissue showed a normal glomerulus without significant tubular damage. At the time of surgery, his renal function was within the normal range. BUN and serum Cr (sCr) levels were 15 mg/dL and 1.2 mg/dL, respectively. Three months after surgery, multiple lymph node metastases were found on positron emission tomography, after completion of four cycles of palliative gemcitabine/cisplatin over 3 months. In each cycle, 35 mg/m2 of cisplatin and 1,500 mg/m2 of gemcitabine were injected. Cumulative doses of cisplatin and gemcitabine were 294 mg and 18,354 mg, respectively, including neoadjuvant and palliative chemotherapy.\n\nThe patient was hospitalized with dyspnea on exertion and generalized edema, developing during the final month of chemotherapy. He had gained 10 kg in 1 month and also reported foamy urine. He did not have a history of hypertension, but his blood pressure was elevated up to 164/110 mmHg. Daily urine output had decreased to less than 500 mL/day, and lower extremity pitting edema was prominent. The white blood cell count was 4,303/mm3, the hemoglobin level was 9.1 g/dL, and the platelet count was 133,000/mm3. BUN and sCr levels were elevated to 42 mg/dL and 3.4 mg/dL, respectively. Serologic test results were within the normal range, except for fluorescent antinuclear antibody titer positive at 1:40. Urinalysis showed 2+ albuminuria and microscopic hematuria. The spot urine protein-to-Cr ratio (g/g) was 15.32, and the albumin-to-Cr ratio (g/g) was 9.375. Shifting bilateral pleural effusions were found on chest radiography. On renal ultrasonography and abdominal computed tomography, the single left kidney measured 10.3 cm, without evidence of hydronephrosis. Interval decrease of multiple lymph node metastases was seen. On hospital day 3, hemodialysis was started because of worsening dyspnea and progressive azotemia. To differentiate the cause of rapidly progressive renal failure, we performed a kidney biopsy despite his single kidney.\n\nAfter the biopsy, anemia and thrombocytopenia worsened, with a hemoglobin level of 7.9 mg/dL and a platelet count of 98,000/mm3. Additional laboratory results were compatible with microangiopathic hemolytic anemia (MAHA), including decreased haptoglobin (8 mg/dL) and elevated plasma hemoglobin (10.5 mg/dL) levels, increased lactic acid dehydrogenase (533 IU/L) levels, and schistocytes on peripheral blood smears (Fig. 1). Ultimately, we demonstrated chronic TMA involvement of the kidney with endothelial hypercellularity and a tram-track appearance, combined with acute tubulitis from the kidney biopsy (Fig. 2).\n\nThe patient underwent steroid and rituximab therapy, with 16 sessions of plasmapheresis; however, his kidney failure did not recover, and he progressed to a dialysis-dependent state. Bone marrow biopsy was performed to check for an occult cause of refractory TMA, even after the intensive treatments, but did not show any abnormality. After 5 weeks of the treatments, thrombocytopenia began to recover, but urothelial carcinoma metastases progressed, and the patient is currently on second-line palliative chemotherapy with weekly taxol. The patient׳s clinical course and laboratory parameters are shown in Fig. 3.\n\nDiscussion\nTMA is a spectrum of diseases that includes thrombotic thrombocytopenic purpura and hemolytic uremic syndrome, characterized by glomerular microvascular endothelial injury. Anemia and thrombocytopenia occur as a result of MAHA, and other organs are often injured. In the kidney, TMA appears as endocapillary cell swelling, fibrin thrombi, platelet plugs, arterial intimal fibrosis, and membranoproliferation. Many chemotherapeutic agents, including mitomycin, bleomycin, cisplatin, and 5-fluorouracil, can induce TMA, but the precise pathophysiology is unknown. Since its initial use, a few cases of gemcitabine-induced TMA have been reported.\n\nThe incidence of gemcitabine-induced TMA varies between 0.015% (based on clinical trials) and 0.41% (from a single-center study) [1], [2]. Gemcitabine-induced TMA can occur at a cumulative dose of 2,450 mg/m2 and within 3 months after the first chemotherapy cycle, but the risk of occurrence seems to increase when the cumulative dose approaches 20,000 mg/m2 and more than 18 doses are administered [8]. Although kidney biopsy is necessary for confirmation, clinical manifestations, such as MAHA and thrombocytopenia with acute kidney injury (AKI), are sufficient for diagnosis in most cases. New or exacerbation of hypertension and proteinuria may appear before clinical manifestations. Neurologic and respiratory symptoms are often associated with gemcitabine-induced TMA [9]. Discontinuation of gemcitabine and plasmapheresis with steroids is the primary therapy for TMA. In some patients, dialysis is needed for AKI. Recently, rituximab treatment showed benefit in cases refractory to plasmapheresis and steroid therapy [9], [10].\n\nFor diagnosis of chemotherapy-induced TMA, various factors need to be considered when thrombocytopenia with AKI occurs during palliative treatment. Thrombocytopenia and anemia can occur with myelosuppression, and chemotherapy-induced tubulopathy and microangiopathy caused by disseminated cancer can induce AKI. Early diagnosis and proper management are important to improve prognosis and enable further cancer treatment, but differential diagnosis is often difficult based on clinical manifestations. In addition, the variable time course of gemcitabine-induced TMA presentation makes diagnosis more complicated.\n\nIn our case, gemcitabine-induced TMA presented acutely on a chronic course. From the patient׳s history, foamy urine with dyspnea and generalized edema appeared at least 1 month before admission, which was 7 months after the initial gemcitabine dose, and 3 months after the start of palliative therapy. The sCr level was only slightly elevated by 2 weeks after initial symptoms. Although AKI was overt, with oliguria at the time of the admission, thrombocytopenia and MAHA were not evident. For correct diagnosis and management, kidney biopsy was inevitable, despite the single kidney. Kidney pathology showed chronic TMA features. In this patient, thrombocytopenia and anemia recovered slowly, eventually requiring maintenance dialysis, even after active treatments including plasmapheresis and steroids. During the treatment of TMA, the cancer progressed, which suggested a poor prognosis.\n\nThis case highlights the importance of following blood pressure and urinalysis for new-onset hypertension and proteinuria for early diagnosis, when treating with gemcitabine. In patients with urothelial cancer, urinalysis with Cr testing should be performed routinely, with the caveat that various conditions can affect the result, including postoperative changes, tumor progression, and chemotherapy complications, as in this case. A high index of suspicion is required for early diagnosis, and biochemical tests associated with hemolysis should be considered.\n\nIn conclusion, we report a case of chronic TMA induced by gemcitabine that required kidney biopsy for diagnosis in a patient with a single kidney. Usually, TMA can be differentially diagnosed from MAHA features, thrombocytopenia, and other clinical manifestations, but sometimes, kidney biopsy is eventually needed to differentiate other causes. We should be aware of the importance of careful monitoring in renal function and be suspicious about TMA in patients with urothelial cancer with palliative gemcitabine treatments as in this case.\n\nConflicts of interest\nThe authors have no conflicts of interest to declare.\n\nFigure 1 Peripheral blood smear. The arrows indicate schistocytes.\n\nFigure 2 Light microscopy of renal biopsy. The arrows indicate endothelial hypercellularity with a tram-track appearance. Stains used were hematoxylin and eosin (A) and methenamine silver (B), with 400× magnification for both.\n\nFigure 3 Clinical course and laboratory data. BUN, blood urea nitrogen.\n==== Refs\nReferences\n1 Fung MC Storniolo AM Nguyen B Arning M Brookfield W Vigil J A review of hemolytic uremic syndrome in patients treated with gemcitabine therapy Cancer 85 1999 2023 2032 10223245 \n2 Muller S Schutt P Bojko P Nowrousian MR Hense J Seeber S Moritz T Hemolytic uremic syndrome following prolonged gemcitabine therapy: report of four cases from a single institution Ann Hematol 84 2005 110 114 15340761 \n3 Dasanu CA Gemcitabine: vascular toxicity and prothrombotic potential Expert Opin Drug Saf 7 2008 703 716 18983217 \n4 Zupancic M Shah PC Shah-Khan F Gemcitabine-associated thrombotic thrombocytopenic purpura Lancet Oncol 8 2007 634 641 17613425 \n5 Teixeira L Debourdeau P Zammit C Estival JL Pavic M Colle B Gemcitabine-induced thrombotic microangiopathy Presse Med 31 2002 740 742 12148351 \n6 Moya-Horno I Querol Ninerola R Bonfill Abella T Dalmau Portulas E Gallardo-Diaz E Saigi Grau E Pericay Pijaume C Haemolytic uraemic syndrome associated with gemcitabine Clin Transl Oncol 12 2010 381 383 20466623 \n7 Thomas JG Sethi S Norby SM Chronic thrombotic microangiopathy secondary to chemotherapy for urothelial carcinoma in a patient with a history of Wegener granulomatosis Am J Kidney Dis 57 2011 799 802 21411201 \n8 Zupancic M Shah PC Shah-Khan F Gemcitabine-associated thrombotic thrombocytopenic purpura Lancet Oncol 8 2007 634 641 17613425 \n9 Bharthuar A Egloff L Becker J George M Lohr JW Deeb G Iyer RV Rituximab-based therapy for gemcitabine-induced hemolytic uremic syndrome in a patient with metastatic pancreatic adenocarcinoma: a case report Cancer Chemother Pharmacol 64 2009 177 181 19116715 \n10 Gourley BL Mesa H Gupta P Rapid and complete resolution of chemotherapy-induced thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS) with rituximab Cancer Chemother Pharmacol 65 2010 1001 1004 20119714\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2211-9132",
"issue": "34(4)",
"journal": "Kidney research and clinical practice",
"keywords": "Gemcitabine; Thrombotic microangiopathy; Urothelial carcinoma",
"medline_ta": "Kidney Res Clin Pract",
"mesh_terms": null,
"nlm_unique_id": "101586778",
"other_id": null,
"pages": "237-40",
"pmc": null,
"pmid": "26779428",
"pubdate": "2015-12",
"publication_types": "D016428:Journal Article",
"references": "10223245;12148351;15340761;17613425;20466623;18983217;19116715;20119714;21411201",
"title": "A case of gemcitabine-induced thrombotic microangiopathy in a urothelial tumor patient with a single kidney.",
"title_normalized": "a case of gemcitabine induced thrombotic microangiopathy in a urothelial tumor patient with a single kidney"
} | [
{
"companynumb": "KR-ACCORD-037623",
"fulfillexpeditecriteria": "1",
"occurcountry": "KR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CISPLATIN"
},
"drugadditional": null,
"druga... |
{
"abstract": "BACKGROUND\nIfosfamide-based chemotherapy has already been the basis of three separate clinical trials. In this study, ifosfamide was administered to lung cancer patients who had failed to respond to previous chemotherapy, to assess its response rate and toxicity.\n\n\nMETHODS\nFrom January 1993 to December 1996, 21 patients were treated, including eight patients with small cell lung cancer (SCLC) and 13 with non-small cell lung cancer (NSCLC). Patients who had histocytologically confirmed lung cancer, were previously treated with chemotherapy, had a measurable lesion(s), were younger than 75 years of age, had an Eastern Cooperative Oncology Group performance status of 0-3 and adequate marrow, renal and liver function were eligible for inclusion in this study. For SCLC patients, ifosfamide 2.4 g/m2 intravenous (i.v.) infusion was given over 30 minutes on days 1-3 every four weeks. For NSCLC two regimens were used: IFL (ifosfamide 2 g/m2, 5-fluorouracil (FU) 600 mg/m2 and leucovorin 50 mg/m2 i.v. infusion on days 1-3 every four weeks) and LIFE (leucovorin 50 mg/m2, ifosfamide 1 g/m2, 5-FU 400 mg/m2 and epirubicin 12 mg/m2 i.v. infusion on days 1-3 every four weeks). For NSCLC patients, IFL was used for the first two years of treatment and LIFE was used in the last two treatment years. All patients were evaluated for treatment response and toxicity.\n\n\nRESULTS\nThe major toxic effect, myelosuppression (grade 3 or 4 leukopenia), occurred in 62.5% of SCLC patients and 23.1% of NSCLC patients during treatment, and in 62.5% and 10% of SCLC and NSCLC patients, respectively, throughout the course. Only one SCLC and one NSCLC patient experienced febrile neutropenia. One toxic death, attributed to febrile neutropenia, was documented in a patient with SCLC. Alopecia was ubiquitous. Other toxicities were uncommon and mild. The overall response rate was 50% in SCLC and 7.7% in NSCLC. The median time to disease progression was 61 days in SCLC and 47 days in NSCLC. Median survival was 172 days in SCLC and 173 days in NSCLC.\n\n\nCONCLUSIONS\nThe study results suggest that ifosfamide chemotherapy is active with an acceptable toxicity profile in previously treated SCLC patients. However, it lacks efficacy in NSCLC patients who have been previously treated.",
"affiliations": "Chest Department, Veterans General Hospital-Taipei, Taiwan, ROC.",
"authors": "Chen|Y M|YM|;Liu|J M|JM|;Wu|M F|MF|;Wu|H W|HW|;Lin|W C|WC|;Tsai|C M|CM|;Perng|R P|RP|;Whang-Peng|J|J|",
"chemical_list": "D015251:Epirubicin; D002955:Leucovorin; D005472:Fluorouracil; D007069:Ifosfamide",
"country": "China (Republic : 1949- )",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0578-1337",
"issue": "61(7)",
"journal": "Zhonghua yi xue za zhi = Chinese medical journal; Free China ed",
"keywords": null,
"medline_ta": "Zhonghua Yi Xue Za Zhi (Taipei)",
"mesh_terms": "D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D002289:Carcinoma, Non-Small-Cell Lung; D018288:Carcinoma, Small Cell; D015251:Epirubicin; D005260:Female; D005472:Fluorouracil; D006801:Humans; D007069:Ifosfamide; D002955:Leucovorin; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D016879:Salvage Therapy",
"nlm_unique_id": "0005327",
"other_id": null,
"pages": "389-96",
"pmc": null,
"pmid": "9699391",
"pubdate": "1998-07",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article",
"references": null,
"title": "Ifosfamide-based chemotherapy for previously treated lung cancer patients.",
"title_normalized": "ifosfamide based chemotherapy for previously treated lung cancer patients"
} | [
{
"companynumb": "TW-BAXTER-2016BAX011100",
"fulfillexpeditecriteria": "1",
"occurcountry": "TW",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "IFOSFAMIDE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nVentriculostomy-related infection with multidrug-negative strains are challenging to treat. We report the use of new antibiotics in such a case.\n\n\nMETHODS\nWe report the case of a neurosurgical intensive care unit patient who developed ventriculostomy-related infection with a multidrug-resistant Staphylococcus epidermidis. Vancomycin, recommended in such cases, was not used due to high minimal inhibitory concentrations and concerns for lack of pharmacokinetic/pharmacodynamic target attainment. Daptomycin and ceftaroline remained the only treatment options. Daptomycin was shown microbiologically ineffective after 10 treatment days, with undetectable cerebrospinal fluid (CSF) concentration. Ceftaroline, a novel beta-lactam agent to which the strain showed susceptibility, was thus used. Serum and CSF samples were assessed for antibiotic concentrations. Our results show that CSF bacterial clearance was obtained after 6 days of such treatment. Serum and CSF samplings showed low penetration ratios (2.6%-4.8%), probably due to mild inflammatory CSF profile, with CSF concentration at minimal inhibitory concentration level.\n\n\nCONCLUSIONS\nWe observed than even in the case of mild meningeal inflammation, ceftaroline penetration in CSF, although moderate, enabled efficient bacterial clearance and clinical efficacy, in adjunction to correct ventriculoperitoneal shunt management.",
"affiliations": "Department of Anesthesia and Surgical Intensive Care, Henri Mondor University Hospital of Paris, Paris XII School of Medicine, Créteil, France. Electronic address: ariane.roujansky@gmail.com.;Department of Anesthesia and Surgical Intensive Care, Henri Mondor University Hospital of Paris, Paris XII School of Medicine, Créteil, France.;Department of Microbiology, Henri Mondor University Hospital, Assitance Publique-Hôpitaux de Paris (APHP), University Paris-Est Créteil (UPEC), Créteil, France.;Department of Pharmacology, Henri Mondor University Hospital, Assitance Publique-Hôpitaux de Paris (APHP), University Paris-Est Créteil (UPEC), Créteil, France.;Department of Microbiology, Henri Mondor University Hospital, Assitance Publique-Hôpitaux de Paris (APHP), University Paris-Est Créteil (UPEC), Créteil, France; Groupe de Recherche Clinique IMPACT, Institut Mondor de la Recherche Biomédicale, Université Paris-Est Créteil, Créteil, France.",
"authors": "Roujansky|Ariane|A|;Martin|Mathieu|M|;Gomart|Camille|C|;Hulin|Anne|A|;Mounier|Roman|R|",
"chemical_list": "D000900:Anti-Bacterial Agents; D002511:Cephalosporins; C490727:T 91825; D017576:Daptomycin",
"country": "United States",
"delete": false,
"doi": "10.1016/j.wneu.2020.01.013",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1878-8750",
"issue": "136()",
"journal": "World neurosurgery",
"keywords": "CSF; Ceftaroline; Daptomycin; External ventricular drain; Multidrug-resistant bacteria; Ventriculostomy-related infection",
"medline_ta": "World Neurosurg",
"mesh_terms": "D061605:Administration, Intravenous; D000368:Aged; D000900:Anti-Bacterial Agents; D002511:Cephalosporins; D017576:Daptomycin; D024901:Drug Resistance, Multiple, Bacterial; D005260:Female; D006801:Humans; D019233:Retreatment; D013203:Staphylococcal Infections; D013212:Staphylococcus epidermidis; D013530:Surgical Wound Infection; D014696:Ventriculostomy",
"nlm_unique_id": "101528275",
"other_id": null,
"pages": "221-225",
"pmc": null,
"pmid": "31931253",
"pubdate": "2020-04",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Multidrug-Resistant Staphylococcus epidermidis Ventriculostomy-Related Infection Successfully Treated by Intravenous Ceftaroline after Failure of Daptomycin Treatment.",
"title_normalized": "multidrug resistant staphylococcus epidermidis ventriculostomy related infection successfully treated by intravenous ceftaroline after failure of daptomycin treatment"
} | [
{
"companynumb": "FR-MYLANLABS-2020M1032518",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CEFEPIME HYDROCHLORIDE"
},
"drugadditional": ... |
{
"abstract": "OBJECTIVE\nThe aim of the study was to evaluate HIV-1 viral load (VL) and inflammatory markers in cerebrospinal fluid (CSF) and neurocognitive performance in patients with neurocognitive impairment (NCI) while they were receiving tenofovir (TDF)/ emtricitabine (FTC)/efavirenz (EFV) and after switching to a regimen with enhanced central nervous system (CNS) penetrability.\n\n\nMETHODS\nThis was a prospective, single-arm pilot study. HIV-1-infected patients with plasma viral suppression and HIV-associated NCI on a regimen including TDF/FTC/EFV were switched to abacavir (ABC)/lamivudine (3TC)/maraviroc (MVC). The Global Deficit Score (GDS) was used to score cognitive function at baseline and 48 weeks after treatment switch. Both CSF and blood samples were taken at baseline and between weeks 24 and 36 after switching. HIV-1 RNA in plasma and CSF was determined by quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR). Inflammatory biomarkers in CSF were measured by enzyme-linked immunosorbent assay (ELISA).\n\n\nRESULTS\nA total of 71 patients receiving TDF/FTC/EFV were screened. Twelve of them (17%) had documented NCI, lacked the human leucocyte antigen (HLA)-B*57:01 haplotype and harboured Chemokine Receptor Type-5 (CCR5)-tropic virus. Eight patients had detectable HIV-1 RNA (between 2.7 and 41.6 HIV-1 RNA copies/mL) in CSF at baseline. All participants had elevated levels of neopterin and Monocyte Chemoattractant Protein 1 (MCP-1) in CSF at baseline. Eight out of 12 patients completed their follow-up assessment after treatment switch. The GDS decreased from 0.55 to 0.4 (P = 0.085). Median HIV-1 RNA in CSF decreased from 3.49 to 2.20 (P = 0.23). Among the inflammation markers in CSF, tumour necrosis factor (TNF)-α decreased significantly from median 0.51 to 0.35 pg/mL (P = 0.027), showing a correlation with the changes in neopterin, interferon (IFN)-γ and interleukin (IL)-6.\n\n\nCONCLUSIONS\nMost patients with NCI receiving TDF/FTC/EFV had low-level viraemia and/or increased inflammatory markers in CSF. Treatment switching to an MVC-containing regimen with better CNS penetration resulted in a trend towards improvement in neurocognitive status and reduced TNF-α concentrations in CSF.",
"affiliations": "Bellvitge University Hospital, Barcelona, Spain.;Fight AIDS Fundation-University Hospital Germans Trias i Pujol, Badalona, Spain.;AIDS Research Institute - IrsiCaixa, Health Sciences Research Institute of the Germans Trias i Pujol, UAB, Badalona, Spain.;Complex Sanitari Santa Tecla, URV, Tarragona, Spain.;Fight AIDS Fundation-University Hospital Germans Trias i Pujol, Badalona, Spain.;Bellvitge University Hospital, Barcelona, Spain.;Bellvitge University Hospital, Barcelona, Spain.;Bellvitge University Hospital, Barcelona, Spain.;AIDS Research Institute - IrsiCaixa, Health Sciences Research Institute of the Germans Trias i Pujol, UAB, Badalona, Spain.;AIDS Research Institute - IrsiCaixa, Health Sciences Research Institute of the Germans Trias i Pujol, UAB, Badalona, Spain.;Bellvitge University Hospital, Barcelona, Spain.",
"authors": "Tiraboschi|J M|JM|;Muñoz-Moreno|J A|JA|;Puertas|M C|MC|;Alonso-Villaverde|C|C|;Prats|A|A|;Ferrer|E|E|;Rozas|N|N|;Maso|M|M|;Ouchi|D|D|;Martinez-Picado|J|J|;Podzamczer|D|D|",
"chemical_list": "D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D015415:Biomarkers; D003521:Cyclopropanes; D015224:Dideoxynucleosides; D004338:Drug Combinations; D014409:Tumor Necrosis Factor-alpha; C492871:abacavir, lamivudine drug combination; D019259:Lamivudine; D000068698:Tenofovir; D000068679:Emtricitabine; C098320:efavirenz",
"country": "England",
"delete": false,
"doi": "10.1111/hiv.12243",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1464-2662",
"issue": "16(6)",
"journal": "HIV medicine",
"keywords": "HIV; antiretroviral therapy; central nervous system",
"medline_ta": "HIV Med",
"mesh_terms": "D000328:Adult; D000480:Alkynes; D019380:Anti-HIV Agents; D023241:Antiretroviral Therapy, Highly Active; D048588:Benzoxazines; D015415:Biomarkers; D003072:Cognition Disorders; D003521:Cyclopropanes; D015224:Dideoxynucleosides; D004338:Drug Combinations; D057915:Drug Substitution; D000068679:Emtricitabine; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D015658:HIV Infections; D015497:HIV-1; D006801:Humans; D019259:Lamivudine; D008297:Male; D008875:Middle Aged; D010865:Pilot Projects; D011446:Prospective Studies; D000068698:Tenofovir; D014409:Tumor Necrosis Factor-alpha; D019562:Viral Load",
"nlm_unique_id": "100897392",
"other_id": null,
"pages": "388-92",
"pmc": null,
"pmid": "25721471",
"pubdate": "2015-07",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Viral and inflammatory markers in cerebrospinal fluid of patients with HIV-1-associated neurocognitive impairment during antiretroviral treatment switch.",
"title_normalized": "viral and inflammatory markers in cerebrospinal fluid of patients with hiv 1 associated neurocognitive impairment during antiretroviral treatment switch"
} | [
{
"companynumb": "ES-CIPLA LTD.-2015ES01987",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LAMIVUDINE"
},
"drugadditional": null,
... |
{
"abstract": "Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is usually initiated by dental surgery, but is occasionally exacerbated by other antiresorptive (denosumab) and anti-angiogenic therapies, and in such cases is currently termed medication-related osteonecrosis of the jaws (MRONJ). The case of a 58-year-old female with breast cancer who developed multiple and ultimately fatal metastases despite 3 years of treatment with chemotherapeutic drugs and intravenous bisphosphonates, is presented herein. Her malignant disease worsened and she was started on mitoxantrone. She developed a severe adverse reaction to this drug soon after starting treatment. As well as diarrhoea and vomiting, she had a very aggressive gingival inflammation with multiple ulcerations in both jaws and wide areas of necrotic bone, affecting the attached gingiva, and seemingly unrelated to dental plaque. These ulcerations and the exposed necrotic bone persisted for more that 6 months, until her death. This report describes a case in which severe gingival ulcerations that occurred after mitoxantrone treatment for metastatic breast cancer were a local factor that initiated MRONJ.",
"affiliations": "Oral Medicine, Valencia University, Valencia, Spain; Service of Stomatology and Maxillofacial Surgery, University General Hospital, Valencia, Spain. Electronic address: bagan@uv.es.;Oral Medicine, Universidad Europea de Valencia, Valencia, Spain.;Service of Stomatology and Maxillofacial Surgery, University General Hospital, Valencia, Spain.;University College London, London, UK.",
"authors": "Bagan|J V|JV|;Bagan|L|L|;Poveda|R|R|;Scully|C|C|",
"chemical_list": "D000970:Antineoplastic Agents; D008942:Mitoxantrone",
"country": "Denmark",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0901-5027",
"issue": "45(3)",
"journal": "International journal of oral and maxillofacial surgery",
"keywords": "bisphosphonate; jaw osteonecrosis; mitoxantrone",
"medline_ta": "Int J Oral Maxillofac Surg",
"mesh_terms": "D000970:Antineoplastic Agents; D001943:Breast Neoplasms; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D007571:Jaw Diseases; D008875:Middle Aged; D008942:Mitoxantrone; D010020:Osteonecrosis",
"nlm_unique_id": "8605826",
"other_id": null,
"pages": "377-9",
"pmc": null,
"pmid": "26516027",
"pubdate": "2016-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Mitoxantrone as a contributing factor in medication-related osteonecrosis of the jaws.",
"title_normalized": "mitoxantrone as a contributing factor in medication related osteonecrosis of the jaws"
} | [
{
"companynumb": "PHHY2016ES019590",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ZOLEDRONIC ACID"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nAim of this review is to describe the role of clinical toxicology in the context of acute medicine. A special focus is put on antidotes and important aspects of diagnosis and therapy of acute intoxications. The data of the annual report of GIZ-Nord Poisons Centre is analyzed concerning the following aspects: what intoxications are relevant in acute medicine, are there special aspects in therapy, e.g. antidotes, and what antidotes are relevant? More over intoxication-related fatalities are analyzed.\n\n\nCONCLUSIONS\nIn 2015 the poisons centre was consulted in 33,000 cases of acute intoxications. The most important groups are drugs (e.g. antidepressants, beta blockers and calcium channel blockers), chemical products (e.g. products containing surfactant, corrosive substances and toxic alcohols like methanol), plants and recreational drugs. Intoxications are relevant in acute medicine. Some substances can cause fatal intoxications. Important antidotes are naloxone for opiods, acetylcystein for paracetamol, fomepizole and ethanol for toxic alcohols and diazepam for intoxications caused by chloroquine.",
"affiliations": "GIZ-Nord Poisons Centre, University Medical Centre, Georg August University Göttingen, Robert Koch Str. 40, D-37075 Göttingen, Germany. Electronic address: aschaper@giz-nord.de.;GIZ-Nord Poisons Centre, University Medical Centre, Georg August University Göttingen, Robert Koch Str. 40, D-37075 Göttingen, Germany.",
"authors": "Schaper|Andreas|A|;Ebbecke|Martin|M|",
"chemical_list": "D000931:Antidotes",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.ejim.2017.10.019",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0953-6205",
"issue": "45()",
"journal": "European journal of internal medicine",
"keywords": "Antidote; Chloroquine; Intoxication; Methanol; Paracetamol; Poisoning",
"medline_ta": "Eur J Intern Med",
"mesh_terms": "D000208:Acute Disease; D000931:Antidotes; D006801:Humans; D011039:Poison Control Centers; D011041:Poisoning; D012720:Severity of Illness Index",
"nlm_unique_id": "9003220",
"other_id": null,
"pages": "66-70",
"pmc": null,
"pmid": "29096991",
"pubdate": "2017-11",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": null,
"title": "Intox, detox, antidotes - Evidence based diagnosis and treatment of acute intoxications.",
"title_normalized": "intox detox antidotes evidence based diagnosis and treatment of acute intoxications"
} | [
{
"companynumb": "DE-ARBOR PHARMACEUTICALS, LLC-DE-2018ARB000300",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "GABAPENTIN ENACARBIL"
},
... |
{
"abstract": "BACKGROUND\nMedication-related adverse events, apart from causing significant morbidity and mortality, increase the healthcare cost burden and lead to early treatment discontinuations.\n\n\nOBJECTIVE\nKnowing the fact that cutaneous adverse drug reactions (cADRs) are most frequent, this study was conducted with an aim to describe their clinical profiles and preventive strategies.\n\n\nMETHODS\nAll adverse drug reaction (ADR) forms filled from January 2012 to January 2013 were scrutinised and forms with cADRs analysed and assessed for causality, preventability and severity.\n\n\nRESULTS\nOf 400 ADR forms, 109 included cADRs. Sixty-eight percent patients were males and mean ± SD age was 35 ± 18 years. Rash, Steven-Johnson syndrome and toxic epidermal necrolysis were the most common presentations. Most frequent culprit drugs included antibiotics and anti-inflammatory agents. Causality was probable or possible in majority. Ninety percent cases were \"not preventable\". Majority of the patients had mild to moderate reactions and recovered completely after medical management.\n\n\nCONCLUSIONS\nPharmacovigilance, with special attention to monitoring and reporting of cADRs must be encouraged. As major bulk of cADRs result from physician prescribed drugs, awareness on part of the physician can help in their timely detection and management, thereby restricting the associated damage.",
"affiliations": "Postgraduate Institute of Medical Sciences , Rohtak, Haryana , India.",
"authors": "Mittal|Niti|N|;Gupta|Mahesh|M|;Singla|Mohit|M|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.3109/15569527.2013.857678",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1556-9527",
"issue": "33(4)",
"journal": "Cutaneous and ocular toxicology",
"keywords": "Adverse reactions; causality; cutaneous; pharmacovigilance; preventability",
"medline_ta": "Cutan Ocul Toxicol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D002648:Child; D002675:Child, Preschool; D003875:Drug Eruptions; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D006801:Humans; D007194:India; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008875:Middle Aged; D060735:Pharmacovigilance; D015995:Prevalence; D012307:Risk Factors; D012737:Sex Factors; D012867:Skin; D062606:Tertiary Care Centers; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "101266892",
"other_id": null,
"pages": "289-93",
"pmc": null,
"pmid": "24517496",
"pubdate": "2014-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Cutaneous adverse drug reactions notified by pharmacovigilance in a tertiary care hospital in north India.",
"title_normalized": "cutaneous adverse drug reactions notified by pharmacovigilance in a tertiary care hospital in north india"
} | [
{
"companynumb": "IN-GLAXOSMITHKLINE-IN2014GSK038857",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ZIDOVUDINE"
},
"drugadditional": nul... |
{
"abstract": "Vincristine (VCR) is one of the main drugs of acute lymphoblastic leukemia (ALL) treatment. Azole antifungal medications are used for treatment or prophylaxis of invasive fungal infections in acute leukemia. Coadministration of these drugs increases the risk of VCR toxicity.\n\n\n\nWe presented a girl with ALL using posaconazole prophylaxis. She developed VCR toxicity that included tubulopathy, high blood pressure, neuropathic pain, difficulty walking, diffuse muscular weakness, constipation, abdominal pain.\n\n\n\nThere are limited data in children with ALL for posaconazole prophylaxis. We recommend that VCR side effects should be evaluated by careful monitoring of the patients who are on this combination therapy.",
"affiliations": "Department of Pediatrics, Division of Pediatric Hematology, Ankara University School of Medicine, Dikimevi, Ankara, Turkey.",
"authors": "Pekpak|Esra|E|;İleri|Talia|T|;İnce|Elif|E|;Ertem|Mehmet|M|;Uysal|Zümrüt|Z|",
"chemical_list": "D014230:Triazoles; D014750:Vincristine; C101425:posaconazole",
"country": "United States",
"delete": false,
"doi": "10.1097/MPH.0000000000001022",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1077-4114",
"issue": "40(5)",
"journal": "Journal of pediatric hematology/oncology",
"keywords": null,
"medline_ta": "J Pediatr Hematol Oncol",
"mesh_terms": "D015746:Abdominal Pain; D000293:Adolescent; D003248:Constipation; D005260:Female; D006801:Humans; D006973:Hypertension; D018908:Muscle Weakness; D009181:Mycoses; D009437:Neuralgia; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D014230:Triazoles; D014750:Vincristine",
"nlm_unique_id": "9505928",
"other_id": null,
"pages": "e309-e310",
"pmc": null,
"pmid": "29219892",
"pubdate": "2018-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Toxicity of Vincristine Combined With Posaconazole in Children With Acute Lymphoblastic Leukemia.",
"title_normalized": "toxicity of vincristine combined with posaconazole in children with acute lymphoblastic leukemia"
} | [
{
"companynumb": "TR-PFIZER INC-2017534633",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "POSACONAZOLE"
},
"drugadditional": "1",
... |
{
"abstract": "An overdose of the antiarrhythmic drug, lidocaine hydrochloride, was inadvertently administered to a patient through an arterial pressure monitoring apparatus, resulting in cardiac asystole. This medication error demonstrates to all anesthesia care team members the importance of preventing similar occurrences.",
"affiliations": "Division of Cardiothoracic Anesthesiology, University of Maryland School of Medicine, Baltimore, Maryland 21201-1595, USA. tgilbert@anes.umm.edu",
"authors": "Gilbert|T B|TB|",
"chemical_list": "D000779:Anesthetics, Local; D008012:Lidocaine",
"country": "United States",
"delete": false,
"doi": "10.1097/00000539-200112000-00041",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0003-2999",
"issue": "93(6)",
"journal": "Anesthesia and analgesia",
"keywords": null,
"medline_ta": "Anesth Analg",
"mesh_terms": "D000368:Aged; D000779:Anesthetics, Local; D001158:Arteries; D001795:Blood Pressure Determination; D002406:Catheterization, Peripheral; D006323:Heart Arrest; D006801:Humans; D008012:Lidocaine; D008297:Male; D008508:Medication Errors; D014160:Transducers, Pressure",
"nlm_unique_id": "1310650",
"other_id": null,
"pages": "1534-6, table of contents",
"pmc": null,
"pmid": "11726437",
"pubdate": "2001-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Cardiac arrest from inadvertent overdose of lidocaine hydrochloride through an arterial pressure line flush apparatus.",
"title_normalized": "cardiac arrest from inadvertent overdose of lidocaine hydrochloride through an arterial pressure line flush apparatus"
} | [
{
"companynumb": "US-BAXTER-2015BAX037973",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ASPIRIN"
},
"drugadditional": null,
... |
{
"abstract": "While this patient had osteoporosis, she hadn't experienced any recent trauma or falls that would explain her pain.",
"affiliations": "Department of Radiology, Eastern Virginia Medical School, Norfolk, VA, USA.;Department of Radiology, Eastern Virginia Medical School, Norfolk, VA, USA.;Department of Radiology, Eastern Virginia Medical School, Norfolk, VA, USA.",
"authors": "Trace|Anthony P|AP|;Hoang|Kimberly|K|;McMonagle|Joseph S|JS|",
"chemical_list": "D050071:Bone Density Conservation Agents; D004164:Diphosphonates",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0094-3509",
"issue": "66(6)",
"journal": "The Journal of family practice",
"keywords": null,
"medline_ta": "J Fam Pract",
"mesh_terms": "D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D005260:Female; D005264:Femoral Fractures; D006615:Hip; D006801:Humans; D008875:Middle Aged; D010024:Osteoporosis; D010146:Pain; D011859:Radiography",
"nlm_unique_id": "7502590",
"other_id": null,
"pages": "392-394",
"pmc": null,
"pmid": "28574525",
"pubdate": "2017-06",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Severe right hip pain.",
"title_normalized": "severe right hip pain"
} | [
{
"companynumb": "US-ROCHE-1992358",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "IBANDRONIC ACID"
},
"drugadditional": "1",
"... |
{
"abstract": "Mucormycosis is an invasive fungal infection (IFI) due to several species of saprophytic fungi, occurring in patients with underlying co-morbidities (including organ transplantation). During the ongoing Coronavirus disease 2019 (COVID-19) pandemic, there have been increasing reports of bacterial and fungal co-infections occurring in COVID-19 patients, including COVID-19 associated pulmonary aspergillosis (CAPA). We describe a case of mucormycosis occurring after COVID-19, in an individual who received a recent heart transplant for severe heart failure. Two months after heart transplant, our patient developed upper respiratory and systemic symptoms and was diagnosed with COVID-19. He was managed with convalescent plasma therapy and supportive care. Approximately three months after COVID-19 diagnosis, he developed cutaneous mucormycosis at an old intravascular device site. He underwent extensive surgical interventions, combined with broad-spectrum antifungal therapy. Despite the aggressive therapeutic measures, he died after a prolonged hospital stay. In this case report, we also review the prior well-reported cases of mucormycosis occurring in COVID-19 patients and discuss potential mechanisms by which COVID-19 may predispose to IFIs. Similar to CAPA, mucormycosis with COVID-19 may need to be evaluated as an emerging disease association. Clinicians should be vigilant to evaluate for invasive fungal infections such as mucormycosis in patients with COVID-19 infection.",
"affiliations": "Division of Infectious Diseases, Department of Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell Health, 400 Community Drive, Infectious Diseases Suite, 11030 Manhasset, NY, USA. Electronic address: akshay1210@gmail.com.;Division of Infectious Diseases, Department of Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell Health, 400 Community Drive, Infectious Diseases Suite, 11030 Manhasset, NY, USA. Electronic address: kchang6@northwell.edu.;Division of Infectious Diseases, Department of Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell Health, 400 Community Drive, Infectious Diseases Suite, 11030 Manhasset, NY, USA. Electronic address: iberlinrut@northwell.edu.;Division of Infectious Diseases, Department of Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell Health, 400 Community Drive, Infectious Diseases Suite, 11030 Manhasset, NY, USA. Electronic address: fwallach@northwell.edu.",
"authors": "Khatri|Akshay|A|;Chang|Kai-Ming|KM|;Berlinrut|Ilan|I|;Wallach|Frances|F|",
"chemical_list": "D000890:Anti-Infective Agents; D007166:Immunosuppressive Agents; D006886:Hydroxychloroquine",
"country": "France",
"delete": false,
"doi": "10.1016/j.mycmed.2021.101125",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1156-5233",
"issue": "31(2)",
"journal": "Journal de mycologie medicale",
"keywords": "Cardiac transplant; Coronavirus disease 2019 (COVID-19); Mucormycosis; Rhizopus microsporus; SARS-CoV-2; Zygomycosis",
"medline_ta": "J Mycol Med",
"mesh_terms": "D000368:Aged; D000890:Anti-Infective Agents; D016470:Bacteremia; D000086382:COVID-19; D055499:Catheter-Related Infections; D060085:Coinfection; D003131:Combined Modality Therapy; D000075203:Contraindications, Drug; D003646:Debridement; D003881:Dermatomycoses; D004198:Disease Susceptibility; D017809:Fatal Outcome; D006333:Heart Failure; D016027:Heart Transplantation; D006801:Humans; D006886:Hydroxychloroquine; D007116:Immunization, Passive; D007166:Immunosuppressive Agents; D007423:Intra-Aortic Balloon Pumping; D000072742:Invasive Fungal Infections; D008297:Male; D009091:Mucormycosis; D054843:Negative-Pressure Wound Therapy; D009894:Opportunistic Infections; D011183:Postoperative Complications; D012233:Rhizopus; D013530:Surgical Wound Infection",
"nlm_unique_id": "9425651",
"other_id": null,
"pages": "101125",
"pmc": null,
"pmid": "33857916",
"pubdate": "2021-06",
"publication_types": "D002363:Case Reports",
"references": "32972795;33331988;32983308;32473235;32844161;20218876;33207116;32719848;32860682;22247442;16020690;32105562;32585069;32678530;22247444;33145132;33229953;32737747;32307254;16080086",
"title": "Mucormycosis after Coronavirus disease 2019 infection in a heart transplant recipient - Case report and review of literature.",
"title_normalized": "mucormycosis after coronavirus disease 2019 infection in a heart transplant recipient case report and review of literature"
} | [
{
"companynumb": "US-DRREDDYS-SPO/USA/21/0137741",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional": "4",
... |
{
"abstract": "Breast cancer (BC) is the most frequent malignancy in both pre- and postmenopausal women. However, it is exceedingly rare in very young patients, and especially in adolescents. Herein, we report a case of an 18-year-old female diagnosed with invasive BC. The proband had been found to be negative for BC in close family members. A common BC genetic screening test for the Polish population did not detect any known founder mutations in the BRCA1 gene. Further evaluation identified a p.Ile157Thr (I157T) mutation in the CHEK2 gene, a p.Ala1991Val (A1991V) variant of unknown significance in the BRCA2 gene, p.Lys751Gln (K751Q) variant in the XPD (ERCC2) gene, and a homozygous p.Glu1008Ter (E1008*) mutation in the NOD2 gene. No other mutation had been found by next generation sequencing in major BC high-risk susceptibility genes BRCA1, BRCA2, as well as 92 other genes. To date, all these found alterations have been considered as low to moderate risk factors in the general population and moderate risk factors in younger women (<35 years of age). There are no previous articles relating low and moderate risk gene mutations to very young onset (below 20 years) BC with a fatal outcome. In our patient, a possible cumulative or synergistic risk effect for these 4 alterations, and a mutation in the NOD2 gene in particular, of which both presumably healthy parents were found to be carriers, is suggested.",
"affiliations": "a Department of Gynecology and Gynecologic Oncology , Medical University of Białystok , Białystok , Poland.;a Department of Gynecology and Gynecologic Oncology , Medical University of Białystok , Białystok , Poland.;b Department of Gynecology and Obstetrics, Faculty of Medicine , University of Warmia and Mazury , Olsztyn , Poland.;c II Department of Gynecology , Medical University of Lublin , Lublin , Poland.;d West Midlands Regional Genetics Laboratory , Birmingham Women's NHS Foundation Trust , Birmingham , UK.;e Medical Genetics Laboratory, DNA Research Center , Poznań , Poland.;e Medical Genetics Laboratory, DNA Research Center , Poznań , Poland.;g Department of Pediatrics, Gastroenterology and Allergology , Medical University of Białystok , Białystok , Poland.;e Medical Genetics Laboratory, DNA Research Center , Poznań , Poland.",
"authors": "Jóźwik|Maciej|M|0000-0001-9182-8791;Posmyk|Renata|R|;Jóźwik|Marcin|M|;Semczuk|Andrzej|A|;Gogiel-Shields|Magdalena|M|;Kuś-Słowińska|Marta|M|;Garbowicz|Magdalena|M|;Klukowski|Mark|M|;Wojciechowicz|Jacek|J|",
"chemical_list": "D024682:BRCA2 Protein; C551750:BRCA2 protein, human; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein; D043823:Taxoids; D004317:Doxorubicin; D003520:Cyclophosphamide; D064447:Checkpoint Kinase 2; C578634:CHEK2 protein, human; D051759:Xeroderma Pigmentosum Group D Protein; C497292:ERCC2 protein, human",
"country": "United States",
"delete": false,
"doi": "10.1080/15384047.2017.1416931",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1538-4047",
"issue": "19(7)",
"journal": "Cancer biology & therapy",
"keywords": "BRCA2 gene; CHEK2 gene; NOD2 gene; XPD gene; adolescent; breast cancer; next generation sequencing",
"medline_ta": "Cancer Biol Ther",
"mesh_terms": "D000293:Adolescent; D000971:Antineoplastic Combined Chemotherapy Protocols; D024682:BRCA2 Protein; D001943:Breast Neoplasms; D064447:Checkpoint Kinase 2; D003520:Cyclophosphamide; D004317:Doxorubicin; D017809:Fatal Outcome; D005260:Female; D006580:Genetic Carrier Screening; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D006801:Humans; D008113:Liver Neoplasms; D008175:Lung Neoplasms; D008297:Male; D009102:Multiple Organ Failure; D009154:Mutation; D053473:Nod2 Signaling Adaptor Protein; D010290:Parents; D043823:Taxoids; D051759:Xeroderma Pigmentosum Group D Protein",
"nlm_unique_id": "101137842",
"other_id": null,
"pages": "543-548",
"pmc": null,
"pmid": "29723101",
"pubdate": "2018-07-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't; D016454:Review",
"references": "24528374;19001605;24131591;25391773;21067385;24800916;25915596;22261811;18612148;19204208;21729660;25330149;19174449;18779615;16685590;17935274;21876083;24029122;11745185;8164038;24101192;16753742;24713400;10788334;22080245;27616075;23633450;17213823;8274138;16998506;19804603;16823163;16280055;15810020;15666202;12490742;21115855;16897426;20222998;11886005;16541315;19907646;20379847;28572259;17671126;19030985;20223031;25959805",
"title": "Breast cancer in an 18-year-old female: A fatal case report and literature review.",
"title_normalized": "breast cancer in an 18 year old female a fatal case report and literature review"
} | [
{
"companynumb": "PHHY2018PL026765",
"fulfillexpeditecriteria": "1",
"occurcountry": "PL",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "EVEROLIMUS"
},
"drugadditional": null,
"drug... |
{
"abstract": "Topiramate is a recognized cause of drug-induced acute angle-closure glaucoma. We describe a case presenting with bilateral acute angle-closure glaucoma caused by topiramate intake. Patient subsequently developed severe anterior uveitis caused by sulphonamide derivatives (acetazolamide and co-trimoxazole) due to cross-sensitivity, on two separate occasions. The present case also highlights the role of anterior segment optical tomography in diagnosis and follow-up. In a patient with known drug allergy to topiramate, other sulphonamide derivatives should be avoided to limit the ocular morbidity.",
"affiliations": "Guru Nanak Eye Centre, Maulana Azad Medical College, New Delhi, 110002, India, drskamal@gmail.com.",
"authors": "Kamal|Saurabh|S|;Yadava|Usha|U|;Kumar|Sushil|S|;Goel|Ruchi|R|",
"chemical_list": "D018696:Neuroprotective Agents; D013449:Sulfonamides; D000077236:Topiramate; D005632:Fructose",
"country": "Netherlands",
"delete": false,
"doi": "10.1007/s10792-013-9793-8",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0165-5701",
"issue": "34(2)",
"journal": "International ophthalmology",
"keywords": null,
"medline_ta": "Int Ophthalmol",
"mesh_terms": "D000328:Adult; D005260:Female; D005632:Fructose; D015812:Glaucoma, Angle-Closure; D006801:Humans; D018696:Neuroprotective Agents; D013449:Sulfonamides; D000077236:Topiramate; D014606:Uveitis, Anterior",
"nlm_unique_id": "7904294",
"other_id": null,
"pages": "345-9",
"pmc": null,
"pmid": "23749237",
"pubdate": "2014-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "11438067;16043677;14700673;21034312;20952855;14982912;21269432;14711721;20413935;15803424;8506919;9306054;22265151;17925516",
"title": "Topiramate-induced angle-closure glaucoma: cross-sensitivity with other sulphonamide derivatives causing anterior uveitis.",
"title_normalized": "topiramate induced angle closure glaucoma cross sensitivity with other sulphonamide derivatives causing anterior uveitis"
} | [
{
"companynumb": "PHHY2014IN078204",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TIMOLOL"
},
"drugadditional": null,
"drugadm... |
{
"abstract": "A 27-month-old girl with a history of congenital myopathy presented with two indurated, pink plaques involving the right arm and left thigh. Closer examination identified central puncta within these plaques, which reportedly occurred at sites of witnessed arachnid bites. After confirmation of the spider species as Trachelas tranquillus, she was treated to address cutaneous inflammation and suspected superinfection using oral and topical antibiotics as well as topical corticosteroid resulting in prompt resolution of her lesions. Trachelas tranquillus should be considered as a possible source of inflammatory spider bites that can become superinfected.",
"affiliations": "Department of Pediatrics, Section of Dermatology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.;The Poison Control Center, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.;Department of Anesthesiology and Critical Care Medicine, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.;Department of Pediatrics, Section of Dermatology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.",
"authors": "Smith|Robert J|RJ|http://orcid.org/0000-0001-9746-1230;Osterhoudt|Kevin|K|;Lin|Richard J|RJ|;Yan|Albert C|AC|",
"chemical_list": "D000900:Anti-Bacterial Agents; D005938:Glucocorticoids",
"country": "United States",
"delete": false,
"doi": "10.1111/pde.13677",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0736-8046",
"issue": "35(6)",
"journal": "Pediatric dermatology",
"keywords": "arachnid; arthropod; infection; spider bite; trachelas",
"medline_ta": "Pediatr Dermatol",
"mesh_terms": "D000818:Animals; D000900:Anti-Bacterial Agents; D002648:Child; D002675:Child, Preschool; D005260:Female; D005938:Glucocorticoids; D006801:Humans; D001098:Spider Bites; D013112:Spiders; D015163:Superinfection",
"nlm_unique_id": "8406799",
"other_id": null,
"pages": "e422-e424",
"pmc": null,
"pmid": "30230593",
"pubdate": "2018-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Trachelas tranquillus envenomation with presumed bacterial superinfection in a child.",
"title_normalized": "trachelas tranquillus envenomation with presumed bacterial superinfection in a child"
} | [
{
"companynumb": "US-009507513-1811USA009388",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "MOMETASONE FUROATE"
},
"drugadditional": nul... |
{
"abstract": "Metronidazole is commonly prescribed and has not been known to cause drug-induced immune thrombocytopenia. We have provided clinical and laboratory evidence with DDabs that metronidazole can cause drug-induced immune thrombocytopenia (DITP). Providers must be aware of metronidazole causing DITP because recognition of thrombocytopenia is critical and cessation of the drug should occur promptly.",
"affiliations": "Hematology Oncology Service Tripler Army Medical Center Hawaii 96859.;Hematology Oncology Service Tripler Army Medical Center Hawaii 96859.",
"authors": "Lew|Jeffrey|J|0000-0003-2516-2092;Berenberg|Jeffrey|J|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1002/ccr3.1334",
"fulltext": "\n==== Front\nClin Case RepClin Case Rep10.1002/(ISSN)2050-0904CCR3Clinical Case Reports2050-0904John Wiley and Sons Inc. Hoboken 10.1002/ccr3.1334CCR31334Case ReportCase ReportsMetronidazole caused profound drug‐induced immune thrombocytopenia J. Lew & J. BerenbergLew Jeffrey http://orcid.org/0000-0003-2516-2092Jeffrey.L.Lew.mil@mail.miljefflew007@gmail.com \n1\nBerenberg Jeffrey \n1\n\n1 \nHematology Oncology Service\nTripler Army Medical Center\nHawaii\n96859\n* Correspondence\n\nJeffrey Lew, Hematology Oncology Service, Tripler Army Medical Center, 1 Jarrett White Rd, HI 96859. Tel: 808 433 4925; Fax 808 433 1555; E‐mails: Jeffrey.L.Lew.mil@mail.mil; jefflew007@gmail.com\n15 12 2017 1 2018 6 1 10.1002/ccr3.2018.6.issue-1206 208 01 8 2017 01 10 2017 04 11 2017 Published 2017. This article is a U.S. Government work and is in the public domain in the USA. Clinical Case Reports published by John Wiley & Sons Ltd.This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.Key Clinical Message\nMetronidazole is commonly prescribed and has not been known to cause drug‐induced immune thrombocytopenia. We have provided clinical and laboratory evidence with DDabs that metronidazole can cause drug‐induced immune thrombocytopenia (DITP). Providers must be aware of metronidazole causing DITP because recognition of thrombocytopenia is critical and cessation of the drug should occur promptly.\n\nDrug‐dependent platelet‐reactive antibodiesdrug‐induced immune thrombocytopeniametronidazolethrombocytopenia source-schema-version-number2.0component-idccr31334cover-dateJanuary 2018details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:version=5.3.1 mode:remove_FC converted:17.01.2018\n\nClinical Case Reports \n2018 ; 6 (1 ): 206 –208\n==== Body\nIntroduction\nDrug‐induced immune thrombocytopenia (DITP) is a process in which a drug mediates platelet destruction via the host immune system. DITP can be life‐threatening if the causative drug is not identified and promptly discontinued. The incidence of DITP is estimated to affect 10 cases per 1 million 1. The typical time course of DITP is a drop in platelet count within 7 days of initiation of a new drug, or 2–3 days if the patient has been previously sensitized to the drug. When the drug is discontinued, platelets usually rise rapidly within 10 days. There are six known mechanisms DITP: hapten‐dependent antibody, drug‐dependent platelet antibody (DDabs), fibrin‐induced thrombocytopenia, drug‐specific antibody, autoantibody induction, and immune complex formation 2. This case documents metronidazole as a cause of drug‐dependent antibody‐mediated platelet destruction. DITP caused by DDabs is rare. Unlike hapten‐dependent antibodies that target covalent bonds between drug–platelet protein complexes, DDabs target hydrophobic interactions. A model described by Bougie postulated that the host's existing pool of immunoglobulins have weak interactions with platelet membrane glycoproteins. When an offending drug is introduced into the circulation, hydrophobic interactions form between drug and platelet glycoproteins. The high affinity of the Fc region of the circulating antibodies stimulates B cells to undergo proliferation, producing more antibodies and greater platelet destruction 3.\n\nCase Presentation\nA 68‐year‐old Caucasian male was hospitalized for a temporal lobe abscess and was treated with vancomycin, metronidazole, and cefepime. After 5 days of antibiotics, the patient underwent a mastoidectomy and drainage of the abscess. He was started on lovenox for DVT prophylaxis on day nine of antibiotics. After 12 days of antibiotic therapy, his platelet count began to decrease, dropping precipitously from 250 × 109/L to 140 × 109/L on day 13 and to 17 × 109/L on day 14 of antibiotics. The mean platelet volume was normal. He was asymptomatic and without the evidence of bleeding. Repeat platelet count using a citrated tube showed a platelet count of 7 × 109/L. Fibrin degradation products, fibrin d‐dimer, fibrinogen, prothrombin time (PT), partial thromboplastin time (PTT), and international normalized ratio (INR) were within normal limits. Peripheral blood smear showed a paucity of platelets, normal platelet size, and no schistocytes. Testing for heparin‐induced thrombocytopenia (HIT) with antiheparin PF4 antibodies was negative (Table 1). DITP was suspected, and antibiotics were changed to daptomycin and moxifloxacin. Over the next 4 days, platelets rose to above 150 × 109/L (Fig. 1). The patient's serum was sent to Blood Center of Wisconsin, where drug DDabs strongly positive to metronidazole and weakly positive to vancomycin were detected by flow cytometry (Table 2).\n\nTable 1 Workup for common causes of thrombocytopenia\n\nTest\tResult\t\nPlatelets in citrated tube\t9 × 109/L no platelet clumping\t\nPeripheral blood smear\tNo schistocytes, paucity of platelets\t\nFibrin degradation products\t<10 (<10) μg/mL\t\nFibrin D‐dimer\t1.14 (0–0.5) μg/mL FEU\t\nFibrinogen\t463 (196–468) mg/dL\t\nPT\t14.2 (11.7–14.2) sec\t\nPTT\t30 (24–36) sec\t\nINR\t1.1\t\nAntiheparin PF4 antibodies\tNegative\t\nJohn Wiley & Sons, LtdFigure 1 Platelet trend throughout hospital stay.\n\nTable 2 Drug‐dependent platelet antibody testing\n\n\tIgG result\tIgM result\t\nPatient's serum without drug\tNegative\tNegative\t\nCefepime\tNegative\tNegative\t\nMetronidazole\tPositive (Strong)\tNegative\t\nPantoprazole\tNegative\tNegative\t\nVancomycin\tPositive (Weak)\tNegative\t\nDrug‐dependent platelet antibody testing by flow cytometry reveals that in the presence of metronidazole IgG antibodies will be bound to the platelet surface and metronidazole forming a complex that will be removed from circulation. Vancomycin has the same interaction; however, it is weakly positive.\n\nJohn Wiley & Sons, LtdDiscussion\nMetronidazole is a commonly used antibiotic, and the medical literature has not reported a causal relationship between the drug and DITP. Although metronidazole was reported in the database for BloodCenter of Wisconsin for positive DDabs, there were no accompanying clinical data.\n\nReese et al. 4 used three systematic methods to identify DITP: case reports, positive drug‐dependent platelet antibodies, and reports cataloged in the United States Food and Drug Administration Adverse Event Reporting System (AERS) database 4. When examining pharmaceuticals in case reports, drugs were classified as having definite, probable, possible, or unlikely association with thrombocytopenia based on four clinical criteria. First, the suspected drug is administered prior to thrombocytopenia and recovery is complete and sustained after cessation of the drug. Second, the suspected drug is the only drug taken before the onset of thrombocytopenia, and other drugs are continued or reintroduced with a sustained normal platelet count. Third, all other potential causes of thrombocytopenia are reasonably excluded, and fourth, re‐exposure to the suspected drug results in recurrent thrombocytopenia. Based on these criteria, this case would represent a “possible” relationship to thrombocytopenia.\n\nThe second method was systematic searching through the AERS database with drugs of statistically significant reporting with keywords associated with thrombocytopenia (platelet destruction, idiopathic thrombocytopenic purpura, antiplatelet antibody positive). The third method consisted of reviewing peripheral blood samples submitted to BloodCenter of Wisconsin from 1995 to 2008 for positivity for DDabs.\n\nOf the drugs reviewed by the three systematic methods, 23 were found to both test positive in all three methods, with one drug, amiodarone, positive for the first two methods (Table 3) 5.\n\nTable 3 Twenty four implicated drugs for DITP identified by all three methods\n\nAbciximab\tIrinotecan\tRifampin\t\nAcetaminophen\tNaproxen\tSimvastatin\t\nAmiodaronea\n\tOxaliplatin\tSulfisoxazole\t\nAmpicillin\tPhenytoin\tTirofiban\t\nCarbamazepine\tPiperacillin\tTrimethoprim–Sulfamethoxazole\t\nEptifibatide\tQuinidine\tValproic acid\t\nEthambutol\tQuinine\tVancomycin\t\nHaloperidol\tRanitidine\t\t\nIbuprofen\t\t\t\na One Drug implicated by Methods 1 and 2.\n\nTable adapted from Reese et al. 4.\n\nJohn Wiley & Sons, LtdIn this case, two of four clinical criteria were fulfilled: The suspected drug was taken before the onset of thrombocytopenia, and recovery of thrombocytopenia was complete and sustained after the drug was discontinued after all other potential causes of thrombocytopenia were reasonably excluded. However, causality is further supported by IgG antibodies strongly positive in the presence of metronidazole. The combination of clinical criteria and confirmatory antibody testing strengthens the case for metronidazole as a cause of DITP.\n\nThere are limitations to establishing the causality of metronidazole and DITP in this case. The patient was never rechallenged with metronidazole after thrombocytopenia occurred; this was considered clinically risky. Additionally, vancomycin is a known cause of DITP, documented in case reports, DDab testing, and in the AERS database. Vancomycin was weakly positive for DDabs and may have contributed to the thrombocytopenia.\n\nConclusion\nMetronidazole as a cause of DITP has important clinical implications. In patients with thrombocytopenia on metronidazole, DITP should be considered in the differential diagnosis, and the antibiotic should be discontinued. The patient should be flagged as allergic to the drug, to prevent future exposures. The clinical role of DDab testing has not been firmly established, and DITP remains a clinical diagnosis, because there are few centers that offer DDab testing and laboratory protocols for DDab testing are not standardized between these centers 6.\n\nAuthorship\nJeffrey Lew MD, ACP associate, resident physician at Tripler Army Medical Center, and primary author of acquisition of data: involved in the analysis of data and drafting of the manuscript; Jeffrey Berenberg MD, MACP, Staff physician, Department of Hematology‐Oncology Service, Tripler Army Medical Center: involved in critical expertise, analysis, and revision of manuscript.\n\nAcknowledgements\nThe authors would like to thank Dale Vincent MD and Jordanna Hostler MD.\n==== Refs\nReferences\n1 \n\nvan den Bemt , P. M. \n, \nR. H. \nMeyboom \n, and \nA. C. \nEgberts \n. 2004 \nDrug‐induced immune thrombocytopenia . Drug Saf. \n27 :1243 –1252 .15588119 \n2 \n\nAster , R. H. \n, and \nD. W. \nBougie \n. 2007 \nDrug‐induced immune thrombocytopenia . N. Engl. J. Med. \n357 :580 –587 .17687133 \n3 \n\nBougie , D. W. \n, \nP. R. \nWilker \n, and \nR. H. \nAster \n. 2006 \nPatients with quinine‐induced immune thrombocytopenia have both “drug‐dependent” and “drug‐specific” antibodies . Blood \n108 :922 –927 .16861345 \n4 \n\nReese , J. A. \n, \nX. \nLi \n, \nM. \nHauben \n, \nR. H. \nAster \n, \nD. W. \nBougie \n, \nB. R. \nCurtis \n, et al. 2010 \nIdentifying drugs that cause acute thrombocytopenia: an analysis using 3 distinct methods . Blood \n116 :2127 –2133 .20530792 \n5 \n\nWarkentin , T. E. \n, and \nJ. A. M. \nAnderson \n. 2010 \nDITP causation: 3 methods better than 1? \nBlood \n116 :2002 –2003 .20864585 \n6 \n\nArnold , D. M. \n, \nS. \nKukaswadia \n, \nI. \nNazi \n, \nA. \nEsmail \n, \nL. \nDewar \n, \nJ. W. \nSmith \n, et al. 2013 \nA systematic evaluation of laboratory testing for drug‐induced immune thrombocytopenia . J. Thromb. Haemost. \n11 :169 –176 .23121994\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2050-0904",
"issue": "6(1)",
"journal": "Clinical case reports",
"keywords": "Drug‐dependent platelet‐reactive antibodies; drug‐induced immune thrombocytopenia; metronidazole; thrombocytopenia",
"medline_ta": "Clin Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101620385",
"other_id": null,
"pages": "206-208",
"pmc": null,
"pmid": "29375866",
"pubdate": "2018-01",
"publication_types": "D002363:Case Reports",
"references": "29375866;15588119;17687133;23121994;20530792;16861345;20864585",
"title": "Metronidazole caused profound drug-induced immune thrombocytopenia.",
"title_normalized": "metronidazole caused profound drug induced immune thrombocytopenia"
} | [
{
"companynumb": "US-FLAMINGO-001122",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "METRONIDAZOLE"
},
"drugadditional": "1",
"... |
{
"abstract": "OBJECTIVE\nThe primary objective was to evaluate the improvement in neuropsychiatric symptoms attributed to an antiretroviral drug after that drug was substituted with nevirapine. The secondary objective was to evaluate the impact on patient adherence and quality of life.\n\n\nMETHODS\nA prospective, observational study was carried out that included patients with HIV-1 plasma suppression for whom an antiretroviral drug was substituted with nevirapine because of central nervous system (CNS) side effects, a Pittsburgh Sleep Quality Index (PSQI) score > 5 or a Hospital Anxiety and Depression Scale (HADS) score ≥ 10, and who had not initiated psychoactive drug treatment during the prior 6 weeks. Evaluations were carried out at baseline and 1 and 3 months after the switch using the PSQI, HADS, Epworth Sleepiness Scale, Medical Outcomes Study-Short Form 30 items (MOS-SF-30) and Simplified Medication Adherence Questionnaire (SMAQ).\n\n\nRESULTS\nA total of 129 patients were included in the study. The drug substituted was mainly efavirenz (89.9%), and reasons for the switch included sleep disturbances (75.2%), anxiety (65.1%), depression (38.7%), attention disturbances (31%), and other reasons (31%), with a mean of 2.4 neuropsychiatric disturbances per patient. A statistically significant improvement was observed in all the tests evaluating neuropsychiatric symptoms and adherence at 1 and 3 months. The CD4 lymphocyte count remained stable (P = 0.096). Three (2.3%) patients had a detectable plasma HIV-1 RNA at the end of the study. Nine patients (6.9%) withdrew because of nevirapine-related toxicity (rash in seven patients and hypertransaminasaemia in two patients, none of which were > grade 2).\n\n\nCONCLUSIONS\nThe switch to nevirapine from a drug causing neuropsychiatric disturbances (primarily efavirenz) in subjects with virological suppression was effective in resolving those disturbances, with an improvement in all the parameters studied. This led to better adherence to treatment and quality of life, with no detrimental effect on their immunological and virological control.",
"affiliations": "Sant Pau i Santa Tecla Hospital, Tarragona, Spain.;Germans Trias i Pujol Universitary Hospital, 'Lluita contra la SIDA' Foundation, Badalona, Spain.;Sant Pau i Santa Tecla Hospital, Tarragona, Spain.;Vall d´Hebró Universitary Hospital, Barcelona, Spain.;Sant Pau i Santa Creu Hospital, Barcelona, Spain.;Granollers Hospital, Barcelona, Spain.;Hospital del Mar, Barcelona, Spain.;Santa María del Rosell Hospital, Cartagena, Spain.;Sant Pau i Santa Tecla Hospital, Tarragona, Spain.;Sant Pau i Santa Tecla Hospital, Tarragona, Spain.",
"authors": "Pedrol|E|E|;Llibre|J M|JM|;Tasias|M|M|;Currán|A|A|;Guardiola|J M|JM|;Deig|E|E|;Guelar|A|A|;Martínez-Madrid|O|O|;Tikhomirova|L|L|;Ramírez|R|R|;|||",
"chemical_list": "D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D018894:Reverse Transcriptase Inhibitors; D019829:Nevirapine; C098320:efavirenz",
"country": "England",
"delete": false,
"doi": "10.1111/hiv.12298",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1464-2662",
"issue": "16(10)",
"journal": "HIV medicine",
"keywords": "HIV; antiretroviral toxicity; antiretroviral treatment switch; efavirenz; neuropsychiatric symptoms; nevirapine",
"medline_ta": "HIV Med",
"mesh_terms": "D000328:Adult; D000368:Aged; D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D018791:CD4 Lymphocyte Count; D002493:Central Nervous System Diseases; D003521:Cyclopropanes; D057915:Drug Substitution; D005260:Female; D015658:HIV Infections; D006801:Humans; D008297:Male; D055118:Medication Adherence; D001523:Mental Disorders; D008875:Middle Aged; D019829:Nevirapine; D011446:Prospective Studies; D011788:Quality of Life; D018894:Reverse Transcriptase Inhibitors",
"nlm_unique_id": "100897392",
"other_id": null,
"pages": "628-34",
"pmc": null,
"pmid": "26238151",
"pubdate": "2015-11",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D064888:Observational Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Outcome of neuropsychiatric symptoms related to an antiretroviral drug following its substitution by nevirapine: the RELAX study.",
"title_normalized": "outcome of neuropsychiatric symptoms related to an antiretroviral drug following its substitution by nevirapine the relax study"
} | [
{
"companynumb": "ES-CIPLA LTD.-2015ES06600",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "NEVIRAPINE"
},
"drugadditional": null,
... |
{
"abstract": "Background Prolongation of the QTc interval may lead to life threatening arrhythmias. QTc prolongation is common in intensive care unit (ICU) patients. The objectives of this study were to identify the role of drug-drug interactions (DDIs) and other predictors (age, sex, cardiovascular diseases, and electrolyte abnormalities) in life threatening QTc prolongation in patients admitted to medical (M), surgical (S) and emergency (E) ICUs. Methods This prospective, observational study included patients above the age of 18 years who were admitted to SICU, EICU, and MICU at a tertiary respiratory referral center. Electrocardiogram (ECG) monitoring was performed during the first 5 days of ICU admission. Risk factors and DDIs which were anticipated to be associated with the prolongation of the QTc interval were assessed for all patients. Results Two hundred patients were included in the study. QTc prolongation occurred in 10.7% of patients and the majority of patients presenting with QTc prolongation had creatinine levels above 1.3 mg/dL during their 5 days of ICU admission. Incidence of pharmacodynamic (PD) DDIs was significantly higher in patients with QTc prolongation vs. other patients. Creatinine levels above 1.3 mg/dL and PD DDIs were associated with QTc prolongation during 5 days of ICU admission. Conclusions High serum creatinine and PD DDIs can increase the risk of QTc prolongation in patients admitted to the ICU. QTc interval measurements should be performed prior to initiation or after starting any drug that is associated with QT prolongation, specifically in patients with the known risk factors.",
"affiliations": "Department of Clinical Pharmacy, Faculty of Pharmacy, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.;Tracheal Diseases Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran.;Chronic Respiratory Diseases Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran.;Department of Clinical Pharmacy, Faculty of Pharmacy, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.;Tracheal Diseases Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran.",
"authors": "Hosseinpoor|Zeinab|Z|;Farzanegan|Behrooz|B|;Seyyedi|Seyyed Reza|SR|;Rajabi|Mehdi|M|;Baniasadi|Shadi|S|",
"chemical_list": "D003404:Creatinine",
"country": "Germany",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2363-8915",
"issue": "34(4)",
"journal": "Drug metabolism and personalized therapy",
"keywords": "QTc prolongation; creatinine levels; critically ill patients; drug-drug interactions (DDIs); intensive care unit (ICU)",
"medline_ta": "Drug Metab Pers Ther",
"mesh_terms": "D000328:Adult; D000368:Aged; D003404:Creatinine; D004347:Drug Interactions; D004562:Electrocardiography; D005260:Female; D006801:Humans; D007362:Intensive Care Units; D008133:Long QT Syndrome; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D012307:Risk Factors; D055815:Young Adult",
"nlm_unique_id": "101653409",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "31860464",
"pubdate": "2019-12-18",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": null,
"title": "Drug interactions and creatinine levels are associated with QTc prolongation in intensive care units: a prospective, observational study.",
"title_normalized": "drug interactions and creatinine levels are associated with qtc prolongation in intensive care units a prospective observational study"
} | [
{
"companynumb": "NVSC2020IR105490",
"fulfillexpeditecriteria": "1",
"occurcountry": "IR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "HALOPERIDOL"
},
"drugadditional": "3",
"drug... |
{
"abstract": "OBJECTIVE\nCalcineurin inhibitors are highly effective in patients with corticosteroid-refractory ulcerative colitis (UC). When therapy with calcineurin inhibitors fails, adalimumab can be considered to avoid colectomy. The efficacy and safety of this sequential alternative salvage therapy remain unknown. Therefore, the present study was performed to investigate the short- and long-term efficacy and safety of adalimumab after failure of calcineurin inhibitors in corticosteroid-refractory UC.\n\n\nMETHODS\nPatients with a corticosteroid-refractory flare of UC who did not respond to calcineurin inhibitors and received continuing salvage therapy with adalimumab were included in this retrospective, observational, single-centre study. The cumulative rates of colectomy were calculated using the Kaplan-Meier method. Clinical remission and response were evaluated based on the Rachmilewitz index. The cumulative rates of colectomy were calculated. Predictive factors for clinical remission and colectomy were identified. In the safety evaluation, any adverse event occurring after the administration of adalimumab was considered.\n\n\nRESULTS\nForty-one patients were enrolled; 78% had extensive colitis and 87% had moderate to severe colitis. Seventeen patients (41%) underwent colectomy during the follow-up period. At week 8, 26, and 52 after adalimumab injection, 27%, 39%, and 32% of patients achieved clinical remission, respectively. The adverse event rate was 17%, including one case of tuberculosis.\n\n\nCONCLUSIONS\nThe efficacy of adalimumab for calcineurin inhibitor-refractory UC was examined for the first time. Treatment with adalimumab avoided the need for colectomy in two-thirds of patients with corticosteroid-refractory UC in whom calcineurin inhibitors had failed. However, attention is needed to avoid adverse events, especially infection.",
"affiliations": "a Inflammatory Bowel Disease Center , Yokohama City University Medical Center , Yokohama , Japan.;a Inflammatory Bowel Disease Center , Yokohama City University Medical Center , Yokohama , Japan.;a Inflammatory Bowel Disease Center , Yokohama City University Medical Center , Yokohama , Japan.;a Inflammatory Bowel Disease Center , Yokohama City University Medical Center , Yokohama , Japan.;a Inflammatory Bowel Disease Center , Yokohama City University Medical Center , Yokohama , Japan.;a Inflammatory Bowel Disease Center , Yokohama City University Medical Center , Yokohama , Japan.;a Inflammatory Bowel Disease Center , Yokohama City University Medical Center , Yokohama , Japan.;c Department of Biostatistics , Yokohama City University Graduate School of Medicine , Yokohama , Japan.;a Inflammatory Bowel Disease Center , Yokohama City University Medical Center , Yokohama , Japan.;b Department of Gastroenterology , Yokohama City University Graduate School of Medicine , Yokohama , Japan.;a Inflammatory Bowel Disease Center , Yokohama City University Medical Center , Yokohama , Japan.",
"authors": "Nishio|Masafumi|M|http://orcid.org/0000-0002-1403-4784;Ishii|Yoshito|Y|;Hashimoto|Yu|Y|;Otake|Haruka|H|;Ogashiwa|Tsuyoshi|T|;Tsuda|Saya|S|;Yasuhara|Hisae|H|;Saigusa|Yusuke|Y|;Kimura|Hideaki|H|;Maeda|Shin|S|;Kunisaki|Reiko|R|",
"chemical_list": "D065095:Calcineurin Inhibitors; D013256:Steroids; D000068879:Adalimumab",
"country": "England",
"delete": false,
"doi": "10.1080/00365521.2018.1511825",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0036-5521",
"issue": "53(10-11)",
"journal": "Scandinavian journal of gastroenterology",
"keywords": "Ulcerative colitis; adalimumab; anti-tumour necrosis factor monoclonal antibodies; calcineurin inhibitor; colectomy; cyclosporine; remission; salvage; tacrolimus",
"medline_ta": "Scand J Gastroenterol",
"mesh_terms": "D000068879:Adalimumab; D000293:Adolescent; D000328:Adult; D000368:Aged; D065095:Calcineurin Inhibitors; D003082:Colectomy; D003093:Colitis, Ulcerative; D005260:Female; D006801:Humans; D007267:Injections; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D016016:Proportional Hazards Models; D012008:Recurrence; D012074:Remission Induction; D012189:Retrospective Studies; D016879:Salvage Therapy; D012720:Severity of Illness Index; D013256:Steroids; D017211:Treatment Failure; D055815:Young Adult",
"nlm_unique_id": "0060105",
"other_id": null,
"pages": "1236-1244",
"pmc": null,
"pmid": "30353757",
"pubdate": "2018",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": null,
"title": "Short- and long-term efficacy of adalimumab salvage therapy after failure of calcineurin inhibitors in steroid-refractory ulcerative colitis.",
"title_normalized": "short and long term efficacy of adalimumab salvage therapy after failure of calcineurin inhibitors in steroid refractory ulcerative colitis"
} | [
{
"companynumb": "JP-ABBVIE-18P-087-2540315-00",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ADALIMUMAB"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nTo report a case of dislodgement of an Iluvien (fluocinolone acetonide) intravitreal implant into the infusion cannula during pars plana vitrectomy for retinal detachment.\n\n\nMETHODS\nThe patient's surgery was video recorded, and the medical notes were reviewed retrospectively.\n\n\nRESULTS\nA patient developed a macula off retinal detachment over 1 year after intravitreal injection of Iluvien for diabetic maculopathy. The patient underwent pars plana vitrectomy, removal of implant, and successful retinal reattachment. Although we planned to remove the implant through a sclerostomy, we were not able to localize it after performing peripheral indented vitrectomy. As the intraocular pressure was fluctuating, we suspected that the implant might have dislodged into the infusion cannula. However, despite increasing the intraocular pressure to 60 mmHg and performing repeated fluid-air exchange, we could not eject the implant back into the vitreous cavity. Therefore, after completing the surgery safely, we flushed the infusion cannula with balanced salt solution and we found the implant.\n\n\nCONCLUSIONS\nIncreasing the intraocular pressure and performing fluid-air exchange were not sufficient to eject the implant probably because of the strong surface adherence between the infusion cannula and the implant's coating material. We, therefore, recommend removing and flushing the infusion cannula if the implant cannot be localized in the eye. In addition, clinicians should be aware that a fluctuating intraocular pressure might be the first sign of a partially blocked infusion cannula by the implant.",
"affiliations": "Birmingham and Midland Eye Centre, Birmingham, United Kingdom.",
"authors": "Andreatta|Walter|W|;Elaraoud|Ibrahim|I|;Mitra|Arijit|A|",
"chemical_list": "D004343:Drug Implants; D005938:Glucocorticoids; D005446:Fluocinolone Acetonide",
"country": "United States",
"delete": false,
"doi": "10.1097/ICB.0000000000000678",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1935-1089",
"issue": "14(3)",
"journal": "Retinal cases & brief reports",
"keywords": null,
"medline_ta": "Retin Cases Brief Rep",
"mesh_terms": "D000368:Aged; D000072601:Cannula; D004343:Drug Implants; D005260:Female; D005446:Fluocinolone Acetonide; D005938:Glucocorticoids; D006801:Humans; D007431:Intraoperative Complications; D058449:Intravitreal Injections; D012163:Retinal Detachment; D014792:Visual Acuity; D014821:Vitrectomy",
"nlm_unique_id": "101298744",
"other_id": null,
"pages": "215-217",
"pmc": null,
"pmid": "29210960",
"pubdate": "2020",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "DISLODGEMENT OF FLUOCINOLONE ACETONIDE INTRAVITREAL IMPLANT INTO THE INFUSION CANNULA DURING VITRECTOMY FOR RETINAL DETACHMENT.",
"title_normalized": "dislodgement of fluocinolone acetonide intravitreal implant into the infusion cannula during vitrectomy for retinal detachment"
} | [
{
"companynumb": "GB-ALIMERA SCIENCES LIMITED-GB-FL-2017-003720",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "FLUOCINOLONE ACETONIDE"
},
... |
{
"abstract": "Shoulder pain is very common in diabetic patients and often treated with steroid injections, with subsequent increases in blood glucose levels or the need for additional insulin being questioned. We report a case of significant and prolonged elevation of blood glucose levels and resultant insulin requirement in a type 1 diabetic man after a single 40 mg injection of triamcinolone for shoulder pain. Within 48 h, the shoulder pain as assessed by a visual analogue scale (0-10) was reduced to zero, but the elevated insulin requirements continued for 4 weeks after the injection. This finding suggests that steroid injections for shoulder pain in diabetics may not always be as safe as previously thought. We propose that medical practitioners advise their patients to monitor their glucose levels more carefully after such injections and that caution is exercised when considering administrating these injections to those who have poorly controlled blood glucose levels preinjection to avoid ketoacidosis.",
"affiliations": "London Hand Clinic, London, UK.;University of Oxford, Oxford, UK.",
"authors": "Povlsen|Bo|B|;Povlsen|Sebastian D|SD|",
"chemical_list": "D000893:Anti-Inflammatory Agents; D001786:Blood Glucose; D007328:Insulin; D013256:Steroids; D014221:Triamcinolone",
"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": "D000893:Anti-Inflammatory Agents; D001786:Blood Glucose; D003922:Diabetes Mellitus, Type 1; D016883:Diabetic Ketoacidosis; D006801:Humans; D007270:Injections, Intra-Articular; D007328:Insulin; D008297:Male; D020069:Shoulder Pain; D013256:Steroids; D014221:Triamcinolone",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "25199186",
"pubdate": "2014-09-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "14162532;16236742;11885825;18853221;8806252;11979014;15162102;16807669",
"title": "Steroid injection for shoulder pain causes prolonged increased glucose level in type 1 diabetics.",
"title_normalized": "steroid injection for shoulder pain causes prolonged increased glucose level in type 1 diabetics"
} | [
{
"companynumb": "GB-RANBAXY-2014R1-87952",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "TRIAMCINOLONE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nUse of certain antiseizure drugs (ASDs) during pregnancy increases the risk of major congenital malformations, while less is known about newer ASDs. Based on the safety of levetiracetam, brivaracetam may be similarly safe in pregnancy; however, no cases have been published to date.\n\n\nOBJECTIVE\nWe retrospectively identified three women with epilepsy treated with brivaracetam during pregnancy and described the maternal and neonatal outcomes.\n\n\nMETHODS\nWe reviewed the patients' medical records as well as the linked medical records of their infants to identify complications during pregnancy and delivery, neonatal complications, and evidence of major/minor congenital malformations.\n\n\nRESULTS\nOur series included one woman with idiopathic generalized epilepsy and two women with focal epilepsy (brivaracetam doses ranging from 50 to 200 mg daily). One patient with focal epilepsy experienced breakthrough seizures, and lamotrigine was added to brivaracetam. The other women had no neurologic complications during pregnancy. All three women had full-term deliveries without significant complications. Three healthy infants were born with Apgar scores of 9 and 9 and no major congenital malformations. Three minor congenital malformations were observed in two infants.\n\n\nCONCLUSIONS\nWhile the absence of major congenital malformations in these cases is encouraging, further data are needed to determine the safety of brivaracetam in pregnancy.",
"affiliations": "Department of Neurology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.;Department of Neurology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.;Department of Neurology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.;Department of Neurology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.;Department of Neurology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.;Department of Neurology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.",
"authors": "Paolini|Stephanie L|SL|https://orcid.org/0000-0001-6033-1491;Pilato|Madison|M|;Rajasekaran|Vijayalakshmi|V|;Waters|Janet F R|JFR|;Bagic|Anto|A|;Urban|Alexandra|A|",
"chemical_list": "D000927:Anticonvulsants; D011760:Pyrrolidinones; C482793:brivaracetam",
"country": "Denmark",
"delete": false,
"doi": "10.1111/ane.13222",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0001-6314",
"issue": "141(5)",
"journal": "Acta neurologica Scandinavica",
"keywords": "anticonvulsants; brivaracetam; pregnancy; teratogenicity",
"medline_ta": "Acta Neurol Scand",
"mesh_terms": "D000014:Abnormalities, Drug-Induced; D000328:Adult; D000927:Anticonvulsants; D004827:Epilepsy; D005260:Female; D006801:Humans; D007223:Infant; D011247:Pregnancy; D011248:Pregnancy Complications; D011256:Pregnancy Outcome; D011760:Pyrrolidinones; D012189:Retrospective Studies",
"nlm_unique_id": "0370336",
"other_id": null,
"pages": "438-441",
"pmc": null,
"pmid": "31943124",
"pubdate": "2020-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Outcomes in three cases after brivaracetam treatment during pregnancy.",
"title_normalized": "outcomes in three cases after brivaracetam treatment during pregnancy"
} | [
{
"companynumb": "US-MLMSERVICE-20200128-2139076-1",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "LEVETIRACETAM"
},
"drugadditional": nu... |
{
"abstract": "High-dose benzodiazepine (BZD) dependence represents an emerging and under-reported addiction phenomenon and is associated with reduced quality of life. To date there are no guidelines for the treatment of high-dose BZD withdrawal. Low-dose slow flumazenil infusion was reported to be effective for high-dose BZD detoxification, but there is concern about the risk of convulsions during this treatment. We evaluated the occurrence of seizures in 450 consecutive high-dose BZD dependence patients admitted to our unit from April 2012 to April 2016 for detoxification with low-dose slow subcutaneous infusion of flumazenil associated with routine anticonvulsant prophylaxis. In our sample, 22 patients (4.9%) reported history of convulsions when previously attempting BZD withdrawal. Only four patients (0.9%) had seizures during ( n = 2) or immediately after ( n = 2) flumazenil infusion. The two patients with seizures during flumazenil infusion were poly-drug misusers. The most common antiepileptic drugs (AEDs) used for anticonvulsant prophylaxis were either valproate 1000 mg or levetiracetam 1000 mg. Our data indicate that, when routinely associated with AEDs prophylaxis, low-dose slow subcutaneous flumazenil infusion represents a safe procedure, with low risk of seizure occurrence.",
"affiliations": "1 Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Verona, Italy.;2 Department of Medicine, Addiction Medicine Unit, Verona University Hospital, Verona, Italy.;2 Department of Medicine, Addiction Medicine Unit, Verona University Hospital, Verona, Italy.;1 Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Verona, Italy.;2 Department of Medicine, Addiction Medicine Unit, Verona University Hospital, Verona, Italy.;1 Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Verona, Italy.;1 Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Verona, Italy.;1 Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Verona, Italy.",
"authors": "Tamburin|Stefano|S|;Faccini|Marco|M|;Casari|Rebecca|R|;Federico|Angela|A|;Morbioli|Laura|L|;Franchini|Enrica|E|;Bongiovanni|Luigi Giuseppe|LG|;Lugoboni|Fabio|F|",
"chemical_list": "D014151:Anti-Anxiety Agents; D000927:Anticonvulsants; D000931:Antidotes; D006993:Hypnotics and Sedatives; D001569:Benzodiazepines; D005442:Flumazenil; D000077287:Levetiracetam; D014635:Valproic Acid; D010889:Piracetam",
"country": "United States",
"delete": false,
"doi": "10.1177/0269881117714050",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0269-8811",
"issue": "31(10)",
"journal": "Journal of psychopharmacology (Oxford, England)",
"keywords": "Benzodiazepine (BZD); detoxification; epilepsy; flumazenil; substance use disorders (SUD); treatment",
"medline_ta": "J Psychopharmacol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D014151:Anti-Anxiety Agents; D000927:Anticonvulsants; D000931:Antidotes; D001569:Benzodiazepines; D005260:Female; D005442:Flumazenil; D006801:Humans; D006993:Hypnotics and Sedatives; D000077287:Levetiracetam; D008297:Male; D008875:Middle Aged; D010889:Piracetam; D011788:Quality of Life; D012640:Seizures; D019966:Substance-Related Disorders; D014635:Valproic Acid; D055815:Young Adult",
"nlm_unique_id": "8907828",
"other_id": null,
"pages": "1369-1373",
"pmc": null,
"pmid": "28613124",
"pubdate": "2017-10",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Low risk of seizures with slow flumazenil infusion and routine anticonvulsant prophylaxis for high-dose benzodiazepine dependence.",
"title_normalized": "low risk of seizures with slow flumazenil infusion and routine anticonvulsant prophylaxis for high dose benzodiazepine dependence"
} | [
{
"companynumb": "IT-MYLANLABS-2017M1044290",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DIAZEPAM"
},
"drugadditional": "3",
... |
Subsets and Splits
No community queries yet
The top public SQL queries from the community will appear here once available.