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"abstract": "Nasal extranodal natural killer/T-cell lymphoma (ENKL) is a rare clinical entity. It may, however, masquerade as a commonly encountered disease, such as sinusitis. A high index of clinical suspicion of nasal ENKL should be raised when there is inadequate clinical response despite appropriate therapeutic intervention of sinusitis. Biopsy would be warranted and crucial in those instances to make an accurate and timely diagnosis.",
"affiliations": "Division of Infectious Disease, Allegheny General Hospital, Allegheny Health Network, 420 East North Avenue, East Wing, Suite 407, Pittsburgh, PA 15212, USA.;Division of Infectious Disease, Allegheny General Hospital, Allegheny Health Network, 420 East North Avenue, East Wing, Suite 407, Pittsburgh, PA 15212, USA.",
"authors": "Min|Zaw|Z|https://orcid.org/0000-0002-5708-954X;Bhanot|Nitin|N|",
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"doi": "10.1155/2020/6646693",
"fulltext": "\n==== Front\nCase Rep Med\nCase Rep Med\nCRIM\nCase Reports in Medicine\n1687-9627 1687-9635 Hindawi \n\n10.1155/2020/6646693\nCase Report\nA Great Masquerader: Nasal Type, Extranodal Natural Killer/T-cell Lymphoma Presenting as Recalcitrant Bacterial Sinusitis and Periorbital Cellulitis\nhttps://orcid.org/0000-0002-5708-954XMin Zaw zaw.min@ahn.org Bhanot Nitin Division of Infectious Disease, Allegheny General Hospital, Allegheny Health Network, 420 East North Avenue, East Wing, Suite 407, Pittsburgh, PA 15212, USA\nAcademic Editor: Massimo Conese\n\n\n2020 \n15 12 2020 \n2020 66466938 10 2020 2 12 2020 8 12 2020 Copyright © 2020 Zaw Min and Nitin Bhanot.2020This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Nasal extranodal natural killer/T-cell lymphoma (ENKL) is a rare clinical entity. It may, however, masquerade as a commonly encountered disease, such as sinusitis. A high index of clinical suspicion of nasal ENKL should be raised when there is inadequate clinical response despite appropriate therapeutic intervention of sinusitis. Biopsy would be warranted and crucial in those instances to make an accurate and timely diagnosis.\n==== Body\n1. Introduction\nExtranodal natural killer/T-cell lymphoma (ENKL), nasal type, is a rare non-Hodgkin's lymphoma and was previously known as lethal midline granuloma or angiocentric lymphoma [1]. Sinusitis is a common disease and has been seen daily in clinical practice. ENKL is an aggressive lymphoma with poor outcome if delayed in diagnosis and therapy [1, 2]. When a patient with ENKL presents with persistent sinusitis or periorbital cellulitis, it may well be a missed diagnosis. A tissue biopsy for pathology is vital to reach an early diagnosis in conjunction with a heightened clinical suspicion and multidisciplinary approach to optimize clinical outcomes.\n\n2. Case Presentation\nA 52-year-old Caucasian male presented to his primary-care physician with a 2-month history of right-sided nasal congestion, fever, and purulent rhinorrhea. His past medical history was significant for gout and seasonal rhinitis. He denied intranasal cocaine use. Despite appropriate courses of oral antibiotics, the patient's symptoms progressed to headache and redness around the right eye. He was referred to an otorhinolaryngologist at that time. Physical examination revealed erythema and edema of the right periorbital tissues, upper and lower eyelids, and cheeks. On palpation, there was no fluctuant mass or exquisite tenderness over the right periorbital region or sinuses. Pupils, extraocular movements, and vision were all intact. The intranasal examination showed considerable swelling of the right middle meatus with purulent drainage. The computed tomography (CT) scan of sinuses showed 100% opacification of the right frontal and ethmoid sinuses, 50% opacification of the right maxillary sinus, and 20% opacification of the right sphenoidal sinus. There was no evidence of orbital or periorbital abscess or bony destruction. Routine laboratory workup was unremarkable. He was admitted to an outside hospital and treated with intravenous vancomycin and cefepime for presumed bacterial sinusitis. Functional endoscopic sinus surgery (FESS) was performed; the operative findings revealed thick yellow purulence and frontal/ethmoidal sinus abscesses. Intraoperative cultures revealed methicillin-sensitive Staphylococcus aureus (MSSA). Postoperatively, the patient felt better and the swelling and erythema around the right eye markedly decreased (see Figure 1). The patient was discharged to complete a 2-week course of oral cephalexin for MSSA bacterial sinusitis.\n\nHowever, 5 days into the oral antibiotic therapy, he experienced worsening of symptoms and was admitted to our institution. He was noted to have marked right periorbital edema with inability to completely open his right eye. Nasal washout on the right was performed. Thick mucinous discharge was noted. No specimens were taken for culture or pathology because it was thought to be severe MSSA bacterial sinusitis that failed outpatient oral antibiotic treatment. The patient was then discharged home with intravenous nafcillin for 2 weeks.\n\nDespite intravenous antibiotic therapy, the patient reported worsening right eye swelling and was readmitted 6 days into his course of intravenous antibiotics. The patient could not open his right eye due to extensive eyelid swelling. Marked periorbital erythema and extensive conjunctival chemosis were noted.\n\nMRI of the right orbit with IV gadolinium showed extensive fluid collection in the right frontal and ethmoidal sinuses and soft tissue swelling within the right orbit with right eye proptosis. MRI brain and MRI venogram with IV gadolinium failed to show intracranial extension or cerebral venous sinus thrombosis. The patient underwent an additional FESS of the right frontal and ethmoidal sinuses to optimize source control of the infection. There was no endoscopic finding suggestive of invasive fungal sinusitis. Cultures and biopsy from the sinus tissue were obtained this time. The former revealed the growth of Enterobacter cloacae for which ciprofloxacin was added to the antibiotic regimen. Fungal sinus tissue culture was negative. However, the patient continued to have worsening right periorbital edema, erythema, and chemosis despite on appropriate antibiotic therapy (see Figure 2).\n\nAntineutrophil cytoplasmic antibodies test (ANCA) was ordered to rule out ANCA-associated vasculitis or granulomatosis with polyangiitis, and it returned negative. Ophthalmology also evaluated the patient and their examination revealed a normal fundus with no optic nerve edema or venous congestion. The patient had the right anterior orbitotomy and dacryocystorhinostomy for better lacrimal drainage to alleviate periorbital swelling. Right orbital tissue biopsy for pathology was also obtained.\n\nThe right sinus as well as the orbital tissue pathology illustrated dense small atypical T cells with irregular nucleoli (see Figure 3), which were positive for natural killer cells or cytotoxic T-cell markers—CD2, CD3, and CD56 on the immunohistochemistry study. The neoplastic cells were negative for CD4, CD8, and CD7 on immunophenotype evaluation. Molecular detection of a clonal T-cell receptor (TCR) rearrangement was positive, confirming T-cell origin monoclonal expansion. In situ hybridization was strongly positive for Epstein–Barr virus (EBV) RNA (see Figure 4). Pathologic findings were suggestive of nasal type, extranodal natural killer/T-cell lymphoma. Blood EBV PCR was positive at 3,100 copies/mL (reference, <100 copies/mL). There was no lymphadenopathy or hepatosplenomegaly on CT chest, abdomen, and pelvis as well as no evidence of lymphoma in the bone marrow aspirate and biopsy. All findings were consistent with extranodal natural killer (NK)/T-cell lymphoma, nasal type.\n\nThe patient had completed 4 cycles of SMILE chemotherapy regimen (Steroids, Methotrexate, Ifosfamide, L-asparaginase, and Etoposide) and 20 sessions of radiation therapy. The right periorbital edema and erythema had almost resolved (see Figure 5). On surveillance imaging, contralateral jugular lymphadenopathy was noted. The patient subsequently had the lymph node biopsy, and the report revealed recurrent NK/T-cell lymphoma. He then underwent 3 cycles of pembrolizumab with complete clinical response. The patient eventually had the matched-unrelated donor peripheral blood stem cell transplant (MUD-PBSCT). It was complicated by severe GI graft-versus-host disease for which the patient was placed on a prolonged course of high-dose steroid therapy. Unfortunately, while on steroid therapy, the patient succumbed to severe Mycoplasma pneumoniae pneumonia 2 years after the initial diagnosis of nasal NK/T-cell lymphoma.\n\n3. Discussion\nExtranodal natural killer/T-cell lymphoma (EKNL) is a rare form of non-Hodgkin's lymphoma and is derived from natural killer (NK) cells or cytotoxic T-lymphocytes [1]. The most common body site of involvement in EKNL is the sinonasal region, and hence it is termed extranodal NK/T-cell lymphoma, nasal type [2]. This type of lymphoma was formerly known as lethal midline granuloma or angiocentric lymphoma [1]. Other organs involvement in EKNL includes salivary glands, skin, breast, gastrointestinal tract, spleen, or testes [2, 3]. The incidence of nasal NK/T-cell lymphoma is highest in Asia (China, Hong Kong, Korea, and Japan) and South America (Peru and Mexico) [1, 2]. It is a rare disease in North America and Europe [2]. Nasal EKNL is virtually always associated with EBV infection [1, 2].\n\nENKL, nasal type, usually affects the sinonasal region first with extension into the ipsilateral periorbital tissues [2–4]. Clinical manifestations of nasal ENKL include signs and symptoms of recurrent chronic sinusitis, periorbital swelling, chemosis, or proptosis [3, 4]. Rarely, there have been reported cases of periorbital involvement without sinusitis [5]. The diagnosis of nasal ENKL is almost always delayed because of its rarity and oftentimes treated as chronic or acute on chronic sinusitis during initial presentation.\n\nA sinus or orbital tissue biopsy is paramount for arriving at the correct diagnosis. ANCA-associated vasculitis, granulomatosis with polyangiitis, relapsing polychondritis, intranasal cocaine use, and sarcoidosis are important differential diagnoses. Clinical vigilance of nasal ENKL should be raised when there is sinusitis and/or periorbital cellulitis with slow or worsening clinical response to surgical intervention and appropriate antimicrobial therapy.\n\n4. Conclusion\nOur case illustrates the need to be aware of mimickers of sinusitis/periorbital cellulitis, such as nasal ENKL. Even if cultures are positive, the lack of clinical response or recurrence of sinus/orbital disease despite optimal antimicrobials and surgery should prompt clinicians to consider urgent tissue biopsy in order to rule out other potentially fatal disease processes.\n\nAcknowledgments\nWe gratefully thank Dr. Elias Y. Hilal, the otorhinolaryngologist, for his excellent patient's care and management and appreciate Dr. Mark Bunker, the pathologist, for high-resolution pathological slides. We also extend our thanks to the patient who provided us his generous and gracious consent for this publication of his case for medical education.\n\nData Availability\nNo data were used to support this study.\n\nConsent\nConsent was obtained from the patient.\n\nConflicts of Interest\nAll authors have no financial disclosures and no conflicts of interest regarding the publication of this article.\n\nFigure 1 Reduction of swelling and erythema was noted around the right paranasal sinuses and right eye after nasal washout.\n\nFigure 2 Exuberant periorbital edema, erythema, and superficial excoriation with serous drainage were noted over the right eye and right paranasal region.\n\nFigure 3 There were dense atypical lymphoid cells with irregular nucleoli (H&E stain, 400X).\n\nFigure 4 In situ hybridization was diffusely positive for Epstein–Barr virus (EBV) RNA.\n\nFigure 5 Significant resolution of the right periorbital edema and erythema was noted after 3 cycles of chemotherapy. The right eye was eventually able to fully open.\n==== Refs\n1 Swerdlow S. H. Campo E. Pileri S. A. The 2016 revision of the World Health Organization classification of lymphoid neoplasms Blood 2016 127 20 2375 2390 10.1182/blood-2016-01-643569 2-s2.0-84971566127 26980727 \n2 Tse E. Kwong Y. L. The diagnosis and management of NK/T-cell lymphomas Journal of Hematology & Oncology 2017 10 1 85 98 10.1186/s13045-017-0452-9 2-s2.0-85018524512 28410601 \n3 Zuhaimy H. Aziz H. A. Vasudevan S. Hui Hui S. Extranodal natural killer/T-cell lymphoma presenting as orbital cellulitis GMS Ophthalmology Cases 2017 7 p. Doc04 10.3205/oc000055 \n4 Termote K. Dierickx D. Verhoef G. Jorissen M. Tousseyn T. Mombaerts I. Series of extranodal natural killer/T-cell lymphoma, nasal type, with periorbital involvement Orbit 2014 33 4 245 251 10.3109/01676830.2014.902478 2-s2.0-84903726255 24831171 \n5 Al Shawabkeh M. i. A. Al Sulaiti M. Al Sa’ey H. Ganesan S. Nasal type extranodal natural killer/T (NK/T) cell lymphoma presenting as periorbital cellulitis: a case report American Journal of Case Reports 2016 17 934 938 10.12659/ajcr.899922 2-s2.0-85006162890\n\n",
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"title": "A Great Masquerader: Nasal Type, Extranodal Natural Killer/T-cell Lymphoma Presenting as Recalcitrant Bacterial Sinusitis and Periorbital Cellulitis.",
"title_normalized": "a great masquerader nasal type extranodal natural killer t cell lymphoma presenting as recalcitrant bacterial sinusitis and periorbital cellulitis"
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"abstract": "We present an atypical association of SCN2A epileptic encephalopathy with severe cortical dysplasia. SCN2A mutations are associated with epileptic syndromes from benign to extremely severe in absence of such macroscopic brain findings. Prenatal MRI (Magnetic Resonance Imaging) in a 32 weeks fetus, with US (Ultrasonography) diagnosis of isolated ventriculomegaly showed CNS (Central Nervous System) dysplasia characterized by lack of differentiation between cortical and subcortical layers, pachygyria and corpus callosum dysgenesis. Postnatal MRI confirmed the prenatal findings. On day 6 the baby presented a focal status epilepticus, partially controlled by phenobarbital, phenytoin, and levetiracetam. After three weeks a moderate improvement in seizure control has been achieved with carbamazepine. Exome sequencing detected a de novo heterozygous mutation in the SCN2A gene, encoding the αII-subunit of a sodium channel. The patient findings expand the phenotype spectrum of SCN2A mutations to epileptic encephalopathies with macroscopic brain developmental features.",
"affiliations": "Department of Radiological, Oncological and Pathological Sciences, Sapienza University of Rome, Policlinico Umberto I Hospital, Viale Regina Elena 324, Rome, Italy; Department of Experimental Medicine, Sapienza University of Rome, Policlinico Umberto I Hospital, Viale Regina Elena 324, Rome, Italy. Electronic address: silviabernardo@live.it.;Department of Experimental Medicine, Sapienza University of Rome, Policlinico Umberto I Hospital, Viale Regina Elena 324, Rome, Italy; IRCCS Casa Sollievo della Sofferenza, Mendel-laboratory, San Giovanni Rotondo, Italy. Electronic address: enrica.marchionni@uniroma1.it.;IRCCS Casa Sollievo della Sofferenza, Mendel-laboratory, San Giovanni Rotondo, Italy. Electronic address: s.prudente@css-mendel.it.;Department of Pediatrics, Child Neurology and Psychiatry, Sapienza University of Rome, Policlinico Umberto I Hospital, Viale Regina Elena 324, Rome, Italy. Electronic address: paola.deliso@uniroma1.it.;Department of Pediatrics, Child Neurology and Psychiatry, Sapienza University of Rome, Policlinico Umberto I Hospital, Viale Regina Elena 324, Rome, Italy. Electronic address: a.spalice@tiscali.it.;Department of Obstetrics, Gynecology and Urologic Sciences, Sapienza University of Rome, Policlinico Umberto I Hospital, Viale Regina Elena 324, Rome, Italy. Electronic address: antonella.giancotti@uniroma1.it.;Department of Radiological, Oncological and Pathological Sciences, Sapienza University of Rome, Policlinico Umberto I Hospital, Viale Regina Elena 324, Rome, Italy. Electronic address: lucia.manganaro@uniroma1.it.;Department of Experimental Medicine, Sapienza University of Rome, Policlinico Umberto I Hospital, Viale Regina Elena 324, Rome, Italy; IRCCS Casa Sollievo della Sofferenza, Mendel-laboratory, San Giovanni Rotondo, Italy. Electronic address: antonio.pizzuti@uniroma1.it.",
"authors": "Bernardo|Silvia|S|;Marchionni|Enrica|E|;Prudente|Sabrina|S|;De Liso|Paola|P|;Spalice|Alberto|A|;Giancotti|Antonella|A|;Manganaro|Lucia|L|;Pizzuti|Antonio|A|",
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"keywords": "Cortical dysplasia; Epileptic encephalopathy; Fetal MRI; Prenatal diagnosis; SCN2A",
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"title": "Unusual association of SCN2A epileptic encephalopathy with severe cortical dysplasia detected by prenatal MRI.",
"title_normalized": "unusual association of scn2a epileptic encephalopathy with severe cortical dysplasia detected by prenatal mri"
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"abstract": "To determine efficacy and safety of patient-controlled intravenous analgesia (PCIA) with tramadol and lornoxicam for postoperative analgesia, and its effects on surgical outcomes in patients following thoracotomy.The records of patients who underwent thoracotomy for lung resection between January 2014 and December 2014 at our institution were reviewed. The patients were divided into 2 groups according to postoperative pain treatment modalities. Patients of the patient-controlled epidural analgesia (PCEA) group (n = 63), received PCEA with 0.2% ropivacaine plus 0.5 μg/mL sufentanil, while patients in the PCIA group (n = 48), received PCIA with 5 mg/mL tramadol and 0.4 mg/mL lornoxicam. Data were collected for the quality of pain control, incidences of analgesia related side effects and pulmonary complications, lengths of thoracic intensive care unit stay and postoperative hospital stay, and in-hospital mortality.Pain at rest was always controlled well in both groups during the 4-day postoperative period. Patients in the PCIA group reported significantly higher pain scores on coughing and during mobilization in the first 2 postoperative days. The incidences of side effects and pulmonary complications, in-hospital mortality and other outcomes were similar between groups.PCIA with tramadol and lornoxicam can be considered as a safe and effective alternative with respect to pain control and postoperative outcomes for patients underwent thoracotomy.",
"affiliations": "Department of Anesthesiology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China..",
"authors": "Jin|Juying|J|;Min|Su|S|;Chen|Qibin|Q|;Zhang|Dong|D|",
"chemical_list": "D000701:Analgesics, Opioid; D000894:Anti-Inflammatory Agents, Non-Steroidal; D010894:Piroxicam; D014147:Tramadol; D000077212:Ropivacaine; D017409:Sufentanil; C059451:lornoxicam",
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"fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health 30762794MD-D-18-0851410.1097/MD.0000000000014538145383300Research ArticleObservational StudyPatient-controlled intravenous analgesia with tramadol and lornoxicam after thoracotomy A comparison with patient-controlled epidural analgesiaJin Juying MD∗Min Su MDChen Qibin MDZhang Dong MDGharaei. Helen Department of Anesthesiology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China..∗ Correspondence: Juying Jin, Department of Anesthesiology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China (e-mail: juyingjin@hotmail.com).2 2019 15 2 2019 98 7 e1453820 11 2018 15 1 2019 23 1 2019 Copyright © 2019 the Author(s). Published by Wolters Kluwer Health, Inc.2019This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0Abstract\nTo determine efficacy and safety of patient-controlled intravenous analgesia (PCIA) with tramadol and lornoxicam for postoperative analgesia, and its effects on surgical outcomes in patients following thoracotomy.\n\nThe records of patients who underwent thoracotomy for lung resection between January 2014 and December 2014 at our institution were reviewed. The patients were divided into 2 groups according to postoperative pain treatment modalities. Patients of the patient-controlled epidural analgesia (PCEA) group (n = 63), received PCEA with 0.2% ropivacaine plus 0.5 μg/mL sufentanil, while patients in the PCIA group (n = 48), received PCIA with 5 mg/mL tramadol and 0.4 mg/mL lornoxicam. Data were collected for the quality of pain control, incidences of analgesia related side effects and pulmonary complications, lengths of thoracic intensive care unit stay and postoperative hospital stay, and in-hospital mortality.\n\nPain at rest was always controlled well in both groups during the 4-day postoperative period. Patients in the PCIA group reported significantly higher pain scores on coughing and during mobilization in the first 2 postoperative days. The incidences of side effects and pulmonary complications, in-hospital mortality and other outcomes were similar between groups.\n\nPCIA with tramadol and lornoxicam can be considered as a safe and effective alternative with respect to pain control and postoperative outcomes for patients underwent thoracotomy.\n\nKeywords\nanalgesialornoxicampainpatient-controlledpostoperativethoracotomytramadolOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nThoracotomy is well recognized as one of the most painful surgical procedures. Adequate pain relief after thoracic surgery is of particular importance, not only for keeping the patient comfortable but also for reducing the incidence of postoperative complications.[1] Compared to systemic opioids, thoracic epidural analgesia (TEA) with local anesthetic and opioid has been demonstrated to provide superior post-thoracotomy pain management with minimum impairment of pulmonary function.[2,3] However, reduced pulmonary morbidity is primarily seen only in high-risk thoracic patients. So far, the benefits of TEA on the length of hospital stay and the in-hospital mortality are still controversial.[4,5] On the other hand, epidural catheterization may require additional anesthesia preparation time and may fail, may be contraindicated as well as associated with rare, but serious complications.[6,7] Therefore, intravenous analgesia is also widely used for pain control after thoracotomy due to its technical simplicity and safety.\n\nTramadol is a centrally acting analgesic with 2 different mechanisms of action. One enantiomer exerts a predominantly weak μ opioid effect, whereas the other inhibits norepinephrine and serotonin reuptake, activating descending monoaminergic inhibitory pathways.[8] Tramadol has been shown to offer a similar analgesic potential to opioid in patients receiving patient-controlled intravenous analgesia (PCIA) following thoracotomy. Its relative lack of sedative and respiratory depressive effects makes it especially suitable for analgesic use after thoracic surgery.[9]\n\nLornoxicam, a member of the oxicam group of nonsteroidal anti-inflammatory drugs (NSAIDs), was reported to improve postoperative pain control and decrease tramadol consumption as well as the incidence of side effects when administered with tramadol by PCIA after abdominal surgery.[10,11] Efficacy and safety of intravenous application of tramadol with NSAIDs have been documented in patients who have undergone the thoracic procedure.[12,13] However, no study has looked at post-thoracotomy pain control as well as postoperative outcomes of PCIA with tramadol and an NSAID compared to patient-controlled epidural analgesia (PCEA).\n\nAt our hospital, as an alternative technique to PCEA, tramadol has been administered in combination with lornoxicam by PCIA for pain management following thoracic surgery. Therefore, we performed this retrospective study primarily to examine the differences in postoperative pain intensity and side effects between patients who received PCIA or PCEA after thoracotomy for lung resection. A secondary aim was to determine whether postoperative outcomes differed significantly between the 2 analgesia regimens.\n\n2 Materials and methods\nFollowing the approval from our hospital's Ethics Committee (registration number: 2013-61), we reviewed the medical records of 124 consecutive patients who underwent elective posterolateral thoracotomy for lung resection between January 2014 and December 2014 at our institution. After excluding patients under 18 years of age, patients with a chronic pain condition or with regular consumption of opioids for more than 2 weeks preoperatively, and those had their epidural catheter dislodged within the first 2 days after surgery, the remaining 111 patients were included in this study. The patients were divided into 2 groups according to their postoperative pain treatment modalities. Patients in the PCEA group (n = 63), received PCEA with ropivacaine plus sufentanil, while patients in the PCIA group (n = 48), received PCIA with tramadol–lornoxicam combination.\n\nThe decision for postoperative analgesic modality was based on the outcomes of preoperative evaluation, and conversation between the attending anesthesiologist and patient about benefits and risks of both techniques. All patients gave written consent for the analgesic technique that was to be used.\n\nIn the PCEA group, a thoracic epidural catheter was placed at the level of T5-T7 using a loss of resistance technique before the induction of general anesthesia. The catheter was inserted cephalically 4 to 5 cm and fixed in place. A 3 mL test dose of 2% lidocaine was administered to exclude accidental intrathecal injection. Then an additional 1% ropivacaine 5 mL was administered. The level of sensory block was aimed at T2-T10, tested by pinprick method 20 minutes later. Epidural administration of 1% ropivacaine 5 mL was repeated every 60 minutes during surgery.\n\nGeneral anesthesia was induced with 2 to 3 mg/kg of propofol, 2 to 4 μg/kg of fentanyl, and a nondepolarizing muscle relaxant, either vecuronium (0.1 mg/kg) or atracurium (0.5 mg/kg) was used to facilitate endotracheal intubation with a double-lumen tube, and the lungs were ventilated with a mixture of 50% oxygen/air. Anesthesia was maintained with sevoflurane, fentanyl, and remifentanil as necessary. After completion of surgery, the double-lumen tube was removed and the patient was shifted to the postanesthetic care unit (PACU) for close observation for at least 2 hours, and then transferred to the thoracic intensive care unit (TICU).\n\nPostoperative pain treatments were initiated at the end of surgery. In the PCEA group, patients received a 0.2% ropivacaine solution with 0.5 μg/mL sufentanil. The epidural infusion was delivered at a rate of 3 to 5 mL/h with a 2 to 3 mL bolus and 20-minutes lockout interval. Patients in PCIA group received a 10-mL combination of 5 mg/mL tramadol and 0.4 mg/mL lornoxicam as a loading dose, followed by a continuous infusion at a rate of 1 to 2 mL/h, and a bolus of 1 to 2 mL with a lockout interval of 15 minutes.\n\nThe acute pain service (APS) is responsible for postoperative pain management at our Hospital. The visual analog scale (VAS) was used for assessing the degree of pain relief during patient controlled analgesia (PCA) treatment. The VAS ranged from 0 = no pain to 10 = unbearable pain. The nursing staff in the surgical ward measured pain intensity every 4 hours while the PCEA or PCIA was in use. The APS routinely reviewed each patient 2 times per day, and whenever necessary. VAS scores at rest, on coughing, and during mobilization (defining as changing body position) were recorded. If patients reported a pain score at rest equal to or greater than 4 on 2 consecutive time points, the ward nurse paged an APS member, who then visited the patient and adjusted the PCA settings as needed until the patient had a pain score at rest of less than 4, which was considered adequate analgesia. Supplemental morphine 5 to 10 mg was administered intravenously if the adjustment of the infusion pump still resulted in insufficient pain relief. Side effects of analgesia were also assessed daily. Antiemetic or antipruritic drugs were prescribed on an as-required basis. Ondansetron 4 to 8 mg was intravenously administered every 12 hours to treat nausea and vomiting. Intravenous diphenhydramine 20 mg was used every 12 hours for pruritus. The PCEA or PCIA protocol was maintained until patients were switched to oral analgesics. All patients were questioned as to their satisfaction with the quality of analgesia using a 4-point scale (0 = very unsatisfied, 1 = unsatisfied, 2 = satisfied, and 3 = very satisfied) at the end of PCA treatment period.\n\nPatients’ charts were analyzed for demographic data including gender, age, height, weight, American Society of Anesthesiologists (ASA) status, preoperative forced vital capacity (FVC) and forced expiratory volume in 1 second (FEV1), type and duration of surgery. Information about the maximum VAS values at rest, during coughing and mobilization in PACU, for the day of surgery (POD 0, from arrival in the TICU) and for postoperative days 1 (POD 1) through 4 (POD 4), and side effects of each analgesic modality including nausea and/or vomiting, pruritus (localized or generalized itching with or without treatment), oversedation (difficulty arousing the patient verbally), urine retention, hypotension (systolic blood pressure <90 mm Hg or >20% decrease from baseline), and respiratory depression (less than 9 breaths/min or apnea requiring naloxone and medication dose adjustment) were also collected. Additional parameters included requirement for supplemental intravenous morphine, duration of PCA use, patient satisfaction, occurrences of pulmonary complication as well as thoracic bleeding requiring reoperation, need for postoperative packed red blood cells (PRBCs) transfusion, lengths of TICU and postoperative hospital stay, and in-hospital mortality.\n\n2.1 Statistical analysis\nContinuous data are expressed as mean and standard deviation. Categorical data are described with percentages. Comparisons of continuous variables were performed using Student unpaired t test. Chi-square test was used to analyze categorical variables between the 2 groups. A P-value of less than .05 was considered statistically significant. All statistical analysis was performed with the use of SPPS 17.0 for Windows (SPSS Inc, Chicago, IL).\n\n3 Results\nThe 2 groups were similar with respect to gender, age, weight, and height. There were no differences in ASA status, preoperative FVC, FEV1, type, and duration of surgery between the groups (Table 1).\n\nTable 1 Patient characteristics, type and duration of surgery, duration of PCA use, requirement of supplementary morphine, and patient satisfaction.\n\nAs Figure 1 shows, the postoperative pain intensity decreased over time in both the PCEA group and PCIA group. Moreover, VAS scores were always below 4 at rest in the 2 groups during the 4-day postoperative period. In the PCIA group, patients reported significantly higher VAS values at rest in PACU and on the day of surgery when compared with the PCEA group. From POD1 through POD 4, pain control at rest was similar between the groups (Fig. 1A). Meanwhile, PCIA group had higher pain scores on coughing and during mobilization than the PCEA group in the first 2 days after surgery. From POD 3 to POD 4, pain scores during coughing and mobilization were comparable between the groups (Fig. 1B and C).\n\nFigure 1 Data expressed as mean ± standard deviation. ∗P < .05, compared with the PCEA group. VAS = visual analog scale, PACU = postanesthetic care unit, POD 0 = the day of surgery; POD1, POD2, POD3, and POD 4, first, second, third, and fourth postoperative day, PCEA = patient-controlled epidural analgesia with ropivacaine and sufentanil, PCIA = patient-controlled intravenous analgesia with tramadol and lornoxicam.\n\nSupplementary morphine was required during the study period in 21 patients (43.8%) in the PCIA group and 14 patients (22.2%) in the PCEA group. There was a significant difference between the 2 groups (P < .05). The duration of PCA use and patients overall satisfaction with postoperative analgesia were similar in both groups (Table 1).\n\nNo significant differences in the incidence of nausea and/or vomiting, pruritus, oversedation, urinary retention, and hypotension between the groups were found. During the period of study, none of the patients had respiratory depression in either group.\n\nAs shown in Table 2, the occurrence of postoperative pulmonary complications did not differ between the PCEA and the PCIA groups. There were no differences between the groups with regard to length of TICU, length of hospital stay, and in-hospital mortality. Two deaths occurred in the PCEA group. One patient died of ventricular arrhythmias on POD 5, and the other one died on POD 7 from respiratory failure. One patient in the PCIA died from severe pneumonia on POD 11.\n\nTable 2 Postoperative outcomes.\n\n4 Discussion\nThe present study suggests that although PCIA using tramadol and lornoxicam failed to provide as good pain relief as PCEA using sufentanil and ropivacaine in the early period following thoracic surgery, both analgesia modalities are effective on pain control at rest throughout the study period with similar incidences of side effects, pulmonary complication and in-hospital mortality.\n\nSevere acute pain after thoracotomy caused by surgical incision, stretch of ligaments, and placement of rib retractors in intercostal spaces and pleural manipulation is a normal response to all these insults. Inadequate pain control produces a restrictive pattern of respiration, which may lead to hypoxemia, retention of secretions, atelectasis, pneumonia, and respiratory failure.[14,15] Therefore, efficient pain relief has far-reaching consequences for short-term and long-term recovery.\n\nThere have been some studies that have evaluated the efficacy of intravenous tramadol combined with NSAIDs in post-thoracotomy pain management. Esme et al[12] demonstrated that the addition of flurbiprofen to systemic tramadol resulted in reduced postoperative pain, mean additional analgesic consumption, and postoperative inflammatory response. Another study prospectively collected data to compare TEA with intravenous tramadol plus ketorolac in fifty patients after thoracic procedure.[13] The authors found both analgesic techniques were able to maintain a good control of pain at rest with comparable incidence of side effects during the study period, whereas epidural analgesia showed more efficacy as for as incident pain relief.\n\nThere are several differences between our present research and previously published literature. First, both TEA and intravenous analgesia in our study were given in the form of PCA, which has been demonstrated to be able to provide better pain control with fewer adverse effects. Meanwhile, we used a low-dose background infusion in addition to PCA bolus because studies have shown this decreased the need for rescue analgesics and enhanced postoperative analgesia and patient satisfaction.[16,17] Second, in PCIA group, tramadol was administered in combination with lornoxicam, which is an NSAID that blocks constitutive cyclooxygenase-1 (COX-1) and inducible cyclooxygenase-2 (COX-2) and consequently inhibits the production of prostaglandins and reduces the development of sensitization process. Compared with other oxicams, lornoxicam has high-efficiency potential, good gastrointestinal tolerance, and a short plasma half-life of 3 to 5 hours. Moreover, it has also been reported not to exert a serious nephrotoxic effect.[18,19] Finally, as far as we know, this is the first study to compare the effect of PCIA using the combination of tramadol and an NSAID with PCEA on postoperative outcome.\n\nIn the present study, patients in the PCIA group reported higher pain scores on coughing and mobilization during the first 2 days after surgery when compared with the PCEA group. The possible explanation is the epidural administration of opioid provides segmental analgesia and improves the quality and duration of sensory block produced by local anesthetic.[20,21]\n\nDespite improved pain control with PCEA, overall patient satisfaction did not differ between the 2 groups. This underscores that patient satisfaction is influenced by complex factors. One important reason is the similar incidence of side effects between the 2 groups. It is notable that none of our patients developed respiratory depression, which probably attributes to the concurrent administration of 2 drugs with different modes of action in both groups. The synergistic effects could reduce the total amount of each drug needed, resulting in fewer unwanted side effects.[10,22]\n\nIncreased risk of bleeding is one of the major concerns with perioperative NSAIDs therapy.[23] In our study, there was no patient developed excessive bleeding and required reoperation in each group during the postoperative period. In addition, the percentage of patients requiring PRBCs transfusion after surgery was comparable in the 2 groups. These results were consistent with previous reports which have indicated that lornoxicam had no effect on postoperative bleeding, bleeding time, or blood transfusions requirements.[24,25]\n\nResearchers have compared the outcomes between TEA and intravenous analgesia after thoracic procedure. Some strongly suggest improved outcomes with the use of TEA, whereas others have found no improvement.[5,26–28] In the present study, we found the types of pain treatment did not affect the incidence of clinical respiratory complications, the length of hospital stay and in-hospital mortality. More studies are needed before definite conclusions can be drawn.\n\nA few limitations of our study should be mentioned. First of all, we cannot exclude the possibility of selection bias for the type of analgesia due to the retrospective nature of the study. Second, postoperative FVC and FEV1 values were not collected because pulmonary function test was not reperformed after surgery in all patients, so we were not able to examine the effects of PCEA and PCIA on lung function. Last, as perioperative coagulation profiles could not be obtained in this retrospective analysis, it is impossible for the authors to evaluate accurately the risk of postoperative bleeding associated with lornoxicam use.\n\nThis retrospective study has demonstrated that PCIA with tramadol and lornoxicam can be considered as a safe and effective alternative with respect to pain control and postoperative outcomes for patients underwent thoracic surgery. Certainly, collecting data in a prospective manner is required to verify the current results.\n\nAuthor contributions\nConceptualization: Juying Jin, Su Min.\n\nData curation: Juying Jin, Su Min.\n\nFormal analysis: Juying Jin.\n\nInvestigation: Juying Jin, Qibin Chen, Dong Zhang.\n\nMethodology: Juying Jin, Su Min.\n\nProject administration: Juying Jin, Qibin Chen, Dong Zhang.\n\nResources: Juying Jin, Su Min.\n\nSoftware: Su Min.\n\nSupervision: Su Min.\n\nValidation: Qibin Chen, Dong Zhang.\n\nVisualization: Qibin Chen, Dong Zhang.\n\nWriting – original draft: Juying Jin.\n\nWriting – review and editing: Juying Jin.\n\nAbbreviations: APS = acute pain service, ASA = American Society of Anesthesiologists, COX-1 = cyclooxygenase-1, COX-2 = cyclooxygenase-2, FEV1 = forced expiratory volume in 1 second, FVC = forced vital capacity, NSAIDs = nonsteroidal anti-inflammatory drugs, PACU = postanesthetic care unit, PCA = patient controlled analgesia, PCEA = patient-controlled epidural analgesia, PCIA = patient-controlled intravenous analgesia, POD = postoperative day, PRBCs = packed red blood cells, TEA = thoracic epidural analgesia, TICU = thoracic intensive care unit, VAS = visual analog scale.\n\nThe authors have no conflicts of interest to disclose.\n==== Refs\nReferences\n[1] Liu S Carpenter RL Neal JM \nEpidural anesthesia and analgesia. Their role in postoperative outcome . Anesthesiology \n1995 ;82 :1474–506 .7793661 \n[2] Joshi GP Bonnet F Shah R \nA systematic review of randomized trials evaluating regional techniques for postthoracotomy analgesia . Anesth Analg \n2008 ;107 :1026–40 .18713924 \n[3] Gottschalk A Cohen SP Yang S \nPreventing and treating pain after thoracic surgery . Anesthesiology \n2006 ;104 :594–600 .16508407 \n[4] Ballantyne JC Carr DB deFerranti S \nThe comparative effects of postoperative analgesic therapies on pulmonary outcome: cumulative meta-analyses of randomized, controlled trials . Anesth Analg \n1998 ;86 :598–612 .9495424 \n[5] Kampe S Weinreich G Darr C \nThe impact of epidural analgesia compared to systemic opioid-based analgesia with regard to length of hospital stay and recovery of bowel function: retrospective evaluation of 1555 patients undergoing thoracotomy . J Cardiothorac Surg \n2014 ;23 :175.\n[6] Moen V Dahlgren N Irestedt L \nSevere neurological complications after central neuraxial blockades in Sweden 1990–1999 . Anesthesiology \n2004 ;101 :950–9 .15448529 \n[7] Brull R McCartney CJ Chan VW \nNeurological complications after regional anesthesia: contemporary estimates of risk . Anesth Analg \n2007 ;104 :965–74 .17377115 \n[8] Budd K Langford R \nTramadol revisited . Br J Anaesth \n1999 ;82 :493–5 .10472210 \n[9] Erolçay H Yüceyar L \nIntravenous patient-controlled analgesia after thoracotomy: a comparison of morphine with tramadol . Eur J Anaesthesiol \n2003 ;20 :141–6 .12622499 \n[10] Kemal SO Sahin S Apan A \nComparison of tramadol, tramadol-metamizol and tramadol-lornoxicam administered by intravenous PCA in management of postoperative pain . Agri \n2007 ;19 :24–31 .18159576 \n[11] Kiliçkaya R Güleç E Ünlügenç H \nA comparative study of the efficacy of IV dexketoprofen, lornoxicam, and diclophenac sodium on postoperative analgesia and tramadol consumption in patients receiving patient-controlled tramadol . Turk J Anaesthesiol Reanim \n2015 ;43 :174–80 .27366491 \n[12] Esme H Kesli R Apiliogullari B \nEffects of flurbiprofen on CRP, TNF-α, IL-6, and postoperative pain of thoracotomy . Int J Med Sci \n2011 ;8 :216–21 .21448308 \n[13] Palermo S Gastaldo P Malerbi P \nPerioperative analgesia in pulmonary surgery . Minerva Anestesiol \n2005 ;71 :137–46 .15756154 \n[14] Ochroch EA Gottschalk A \nImpact of acute pain and its management for thoracic surgical patients . Thorac Surg Clin \n2005 ;15 :105–21 .15707349 \n[15] Senturk M \nAcute and chronic pain after thoracothomies . Curr Opin Anesth \n2005 ;18 :1–4 .\n[16] Komatsu H Matsumoto S Mitsuhata H \nComparison of patient-controlled epidural analgesia with and without background infusion after gastrectomy . Anesth Analg \n1998 ;87 :907–10 .9768792 \n[17] Guler T Unlugenc H Gundogan Z \nA background infusion of morphine enhances patient-controlled analgesia after cardiac surgery . Can J Anaesth \n2004 ;51 :718–22 .15310642 \n[18] Skjodt NM Davies NM \nClinical pharmacokinetics of lornoxicam. A short half-life oxicam . Clin Pharmacokinet \n1998 ;34 :421–8 .9646006 \n[19] Radhofer-Welte S Rabasseda X \nLornoxicam, a new potent NSAID with an improved tolerability profile . Drugs Today (Barc) \n2000 ;36 :55–76 .12879104 \n[20] Ginosar Y Riley ET Angst MS \nThe site of action of epidural fentanyl in humans: the difference between infusion and bolus administration . Anesth Analg \n2003 ;97 :1428–38 .14570661 \n[21] Kanai A Osawa S Suzuki A \nRegression of sensory and motor blockade, and analgesia during continuous epidural infusion of ropivacaine and fentanyl in comparison with other local anesthetics . Pain Med \n2007 ;8 :546–53 .17883739 \n[22] Tuncel G Ozalp G Savli S \nEpidural ropivacaine or sufentanil-ropivacaine infusions for post-thoracotomy pain . Eur J Cardiothorac Surg \n2005 ;28 :375–9 .16054823 \n[23] Møiniche S Rømsing J Dahl JB \nNonsteroidal antiinflammatory drugs and the risk of operative site bleeding after tonsillectomy: a quantitative systematic review . Anesth Analg \n2003 ;96 :68–77 .12505926 \n[24] Mazaris EM Varkarakis I Chrisofos M \nUse of nonsteroidal anti-inflammatory drugs after radical retropubic prostatectomy: a prospective, randomized trial . Urology \n2008 ;72 :1293–7 .18329071 \n[25] Karaman Y Kebapci E Gurkan A \nThe preemptive analgesic effect of lornoxicam in patients undergoing major abdominal surgery: a randomised controlled study . Int J Surg \n2008 ;6 :193–6 .18434268 \n[26] Wu CL Sapirstein A Herbert R \nEffect of postoperative epidural analgesia on morbidity and mortality after lung resection in medicare patients . J Clin Anesth \n2006 ;18 :515–20 .17126780 \n[27] Bauer C Hentz JG Ducrocq X \nLung function after lobectomy: a randomized, double-blinded trial comparing thoracic epidural ropivacaine/sufentanil and intravenous morphine for patient-controlled analgesia . Anesth Analg \n2007 ;105 :238–44 .17578981 \n[28] Meierhenrich R Hock D Kühn S \nAnalgesia and pulmonary function after lung surgery: is a single intercostal nerve block plus patient-controlled intravenous morphine as effective as patient-controlled epidural anaesthesia? A randomized non-inferiority clinical trial . Br J Anaesth \n2011 ;106 :580–9 .21296768\n\n",
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"title": "Patient-controlled intravenous analgesia with tramadol and lornoxicam after thoracotomy: A comparison with patient-controlled epidural analgesia.",
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"abstract": "OBJECTIVE\nTo advocate for high-dose steroids, not intravenous immunoglobulins (IVIG), as first-line treatment for Anti-glial fibrillary acidic protein (GFAP) associated meningoencephalomyelitis.\n\n\nBACKGROUND\nA novel IgG antibody against GFAP was associated with relapsing autoimmune meningoencephalomyelitis.\n\n\nMETHODS\nHere, we present an investigational case report to highlight continuing challenges in diagnosing and managing Anti-GFAP associated meningoencephalomyelitis.\n\n\nRESULTS\nOur 45-year-old Asian female presented to the emergency department with an acute onset low-grade fever and back pain associated with headaches, intermittent confusion, vision changes, and hand tremors. A review of systems identified no inciting factors. Past medical history was significant only for chronic Hepatitis B without significant viral load. Neurological exam was significant for decreased visual acuity, high-frequency hand tremor, and gait imbalance. Serum labs were within normal limits. Video electroencephalogram captured tremors without electrographical correlates. Cerebrospinal fluid analysis revealed lymphocytic leukocytosis, elevated protein, and reduced glucose. A wide range of infectious studies including bacterial, viral, and fungal cultures were negative. MRI brain and spine showed leptomeningeal enhancement. CT chest abdomen pelvis were negative. Patient continued to decline clinically, working diagnosis was possible paraneoplastic syndrome with pending laboratory results. She was given a five-day course of intravenous immunoglobulin as a therapeutic trial,hh however, her symptoms did not improve. A broader investigation with repeat lumbar puncture, imaging and serum laboratory failed to provide any additional information. She was treated symptomatically with minimal benefit. A trial of steroids was given with clinical improvement and continued stability. Paraneoplastic panels returned positive for high levels of Anti-GFAP antibody for confirmation of diagnosis.\n\n\nCONCLUSIONS\nAutoimmune GFAP astrocytopathy is a rare cause of meningoencephalomyelitis that remains difficult to diagnose despite emerging laboratory studies. Our case adds to the limited literature by proposing that high-dose steroids, not IVIG, should be the first-line treatment. Further investigations are underway to assess implications of this finding in disease pathophysiology and management.",
"affiliations": "University of California Irvine (UCI), Department of Neurology, Irvine CA, United States. Electronic address: esojourn@hs.uci.edu.;University of California Irvine (UCI), Department of Neurology, Irvine CA, United States.;University of California Irvine (UCI), Department of Neurology, Irvine CA, United States.;University of California Irvine (UCI), Department of Neurology, Irvine CA, United States.;University of California Irvine (UCI), Department of Neurology, Irvine CA, United States.",
"authors": "Heide|Elena S|ES|;Chaudhari|Amit|A|;Pirverdian|Ateena|A|;Lai|Samuel|S|;Courtney|Ardith|A|",
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"mesh_terms": "D001253:Astrocytes; D020274:Autoimmune Diseases of the Nervous System; D005260:Female; D005904:Glial Fibrillary Acidic Protein; D006801:Humans; D016756:Immunoglobulins, Intravenous; D008875:Middle Aged; D013256:Steroids",
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"title": "Failure of IVIG in steroid-responsive autoimmune glial fibrillary acidic protein astrocytopathy: A case report.",
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"abstract": "We report the case of a 56-year-old male patient, who over two decades, sequentially presented with a combination of clinical manifestations. These included thrombotic thrombocytopenic purpura (TTP), right leg deep vein thrombosis (DVT), and eventually constitutional symptoms, arthralgia, diffuse lymphadenopathy, pancytopenia, skin rash, pericarditis, and glomerulonephritis. Serologic tests and renal pathology uncovered a diagnosis of systemic lupus erythematosus (SLE), and immunosuppressive therapy was initiated. Soon after, the patient developed striking cytomegalovirus (CMV) viremia, requiring prolonged antiviral therapy and reduction of immunosuppression. Finally, an acute embolic stroke complicated the disease course. Prompt interventions allowed an excellent clinical outcome.",
"affiliations": "Department of Medicine, Hebrew University-Hadassah Medical Center, Jerusalem, Israel.;Department of Medicine, Hebrew University-Hadassah Medical Center, Jerusalem, Israel.;Department of Medicine, Hebrew University-Hadassah Medical Center, Jerusalem, Israel.;Department of Medicine, Hebrew University-Hadassah Medical Center, Jerusalem, Israel.;Department of Medicine, Hebrew University-Hadassah Medical Center, Jerusalem, Israel.;Department of Medicine, Hebrew University-Hadassah Medical Center, Jerusalem, Israel.;Department of Medicine, Hebrew University-Hadassah Medical Center, Jerusalem, Israel.",
"authors": "Kharouf|Fadi|F|https://orcid.org/0000-0002-3540-0341;Shahar|Sigal|S|;Hershkovitz|Yoav|Y|;Shaheen|Alaa|A|;Bayatra|Areej|A|;Kessler|Asa|A|https://orcid.org/0000-0001-6051-8192;Ishay|Yuval|Y|",
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"doi": "10.1155/2021/6654748",
"fulltext": "\n==== Front\nCase Rep Med\nCase Rep Med\nCRIM\nCase Reports in Medicine\n1687-9627 1687-9635 Hindawi \n\n10.1155/2021/6654748\nCase Report\nFrom TTP to Glomerulonephritis: A Lifetime of Lupus\nhttps://orcid.org/0000-0002-3540-0341Kharouf Fadi fadikharouf@hotmail.com\n1\n\n2\n Shahar Sigal \n1\n Hershkovitz Yoav \n1\n Shaheen Alaa \n1\n Bayatra Areej \n1\n https://orcid.org/0000-0001-6051-8192Kessler Asa \n1\n Ishay Yuval \n1\n\n3\n \n1Department of Medicine, Hebrew University-Hadassah Medical Center, Jerusalem, Israel\n\n2Rheumatology Unit, Hebrew University-Hadassah Medical Center, Jerusalem, Israel\n\n3Gastroenterology Unit, Hebrew University-Hadassah Medical Center, Jerusalem, Israel\nAcademic Editor: Marco Sebastiani\n\n\n2021 \n4 1 2021 \n2021 665474824 11 2020 26 12 2020 Copyright © 2021 Fadi Kharouf et al.2021This 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.We report the case of a 56-year-old male patient, who over two decades, sequentially presented with a combination of clinical manifestations. These included thrombotic thrombocytopenic purpura (TTP), right leg deep vein thrombosis (DVT), and eventually constitutional symptoms, arthralgia, diffuse lymphadenopathy, pancytopenia, skin rash, pericarditis, and glomerulonephritis. Serologic tests and renal pathology uncovered a diagnosis of systemic lupus erythematosus (SLE), and immunosuppressive therapy was initiated. Soon after, the patient developed striking cytomegalovirus (CMV) viremia, requiring prolonged antiviral therapy and reduction of immunosuppression. Finally, an acute embolic stroke complicated the disease course. Prompt interventions allowed an excellent clinical outcome.\n==== Body\n1. Introduction\nSystemic lupus erythematosus (SLE) is the prototypical systemic autoimmune disease, characterized by a wide spectrum of clinical manifestations, often exhibiting a relapsing-remitting course [1]. As treatment is based on immunosuppressive therapy, infections pose a major iatrogenic complication [2]. Here, we report a unique case of a middle-aged male, gradually presenting with a diverse constellation of systemic manifestations over a prolonged period. We discuss the clinical presentation, diagnostic implications, therapeutic decisions, and treatment complications.\n\n2. Case Presentation\nA 56-year-old male presented to the emergency department with a 2-month history of extreme weakness, fatigue, and anorexia. His past medical record was remarkable for a previous event of thrombotic thrombocytopenic purpura (TTP) 20 years earlier. He was then treated with plasmapheresis, aspirin, and corticosteroids, with complete recovery. 18 months thereafter, he was diagnosed with an unprovoked right leg deep vein thrombosis (DVT), for which no etiology was found. Noticeably, antiphospholipid antibodies (APLAs) were negative.\n\nSimilar constitutional symptoms had plagued the patient before. Several years prior to his current presentation, he was admitted for weakness and weight loss (30 kg over a few months). He then underwent a thorough investigation, including blood tests, whole-body computed tomography (CT), and positron emission tomography/CT (PET/CT). Diffuse hypermetabolic lymphadenopathy, involving axillary, abdominal, and retroperitoneal lymph nodes (LNs), was seen. Excisional biopsy of a pelvic LN (PN) and bone marrow (BM) biopsy were performed, both being unremarkable. Immune serologies sent at that time showed only a weakly positive antinuclear antibody (ANA). The differential diagnosis comprised a systemic infection, an indolent neoplastic process, and autoimmune lymphoproliferative syndrome (ALPS). None of these entities was proven however, leaving the patient undiagnosed despite regular follow-up. Thereafter, he spontaneously recovered, enjoying several uneventful years.\n\nUpon the patient's current admission, physical examination revealed mild bilateral leg edema and numerous lichen-like skin lesions (see Figure 1). Recurrent fever spikes of up to 39°C were recorded, with otherwise normal vital signs. Blood tests were extremely abnormal, showing pancytopenia, hypoalbuminemia, high creatinine levels, and elevated inflammatory markers (see Table 1). While whole-body CT displayed no noteworthy findings, PET/CT demonstrated widespread hypermetabolic lymphadenopathy and diffusely increased BM uptake. BM and groin LN biopsies were performed, again being noncontributory. Peripheral blood flow cytometry, however, showed a high proportion (7%) of double-negative (DN) T cells (negative for both CD4+ and CD8+). Blood cultures and broad bacterial and viral serologies were negative. The patient's urinalysis was significant for hematuria and proteinuria, and urine microscopy revealed red blood cell (RBC) casts, along with dysmorphic RBCs. 24-hour urine collection demonstrated nephrotic range proteinuria (3.9 g/d).\n\nDuring this time, the patient's clinical condition was one of the ongoing weakness, fatigue, and dyspnea. He also suffered from pleuritic chest pain and progressive, asymmetric leg edema. Further work-up directed at these complaints showed an extensive right leg DVT, elevated cardiac enzymes, and new-onset atrial fibrillation (AF). In addition, a small pericardial effusion was found on transesophageal echocardiography (TTE). Therapy with enoxaparin was started for his DVT and AF, and broad-spectrum antibiotic coverage was instituted for a suspected bacterial infection. Pericarditis was added to this ever-growing list of diagnoses.\n\nResults of ANA and anti-double-stranded deoxyribonucleic acid (anti-dsDNA) antibody were reported at this stage, both being strongly positive, along with low complement levels (see Table 2). Notably, APLAs were negative. In light of the patient's deteriorating renal function and active urinary sediment, kidney biopsy was performed. Lupus nephritis stages 3 and 5 (focal proliferative and membranous glomerulonephritis, respectively) were present on pathology. Biopsy of the skin lesions demonstrated immune complex (lupus band) deposition and a lichen planus-like pathological picture. The patient was thus diagnosed with SLE and started on high-dose corticosteroid therapy, hydroxychloroquine, mycophenolate mofetil, and ramipril, with impressive clinical and laboratory improvement. After a 4-week hospital stay, he was eventually discharged for follow-up at the rheumatology and nephrology outpatient clinics.\n\nLess than one month after discharge, the patient was readmitted due to a painful right calf ulcer, productive cough, and general weakness. Thorough work-up revealed significant cytomegalovirus (CMV) viremia (>925,000 copies/mL), with no signs of visceral involvement upon bronchoscopy, sigmoidoscopy, and ophthalmologic evaluation. The leg ulcer was attributed to postphlebitic syndrome, and biopsy of the ulcer was noncontributory. Cultures from both the ulcer and bronchoalveolar lavage fluid grew Pseudomonas aeroguinosa, and therapy with ciprofloxacin was started. Besides, mycophenolate mofetil and prednisone doses were reduced in an attempt to minimize immunosuppression, and intravenous ganciclovir therapy was initiated. The lack of clear signs of end-organ involvement has made it difficult to define the required duration of ganciclovir treatment, and the CMV viremia was monitored instead. Following the gradual elimination of viremia, antiviral therapy was stopped. Diligent wound care, compression stockings, and antibiotic treatment allowed stepwise healing of the ulcer.\n\nThree months later, the patient was again admitted for sudden-onset dysarthria and right-sided hemiparesis. Brain CT angiography showed left middle cerebral artery branch obstruction, consistent with an embolic etiology. An emergent thrombectomy was performed. TTE, transesophageal echocardiography (TEE), and carotid Doppler studies revealed no embolic source. Aspirin and high-dose statin were added, and the patient continued apixaban. Gradually, he was able to regain excellent functional capacity.\n\nAs of today, one year after his index presentation, the patient is well and suffers no residual neurologic deficits. His most recent labs, including blood counts, chemistry panels, complement levels, and urinalysis, are unremarkable. His proteinuria has declined to 170 mg/d, and CMV titers in blood are undetectable.\n\n3. Discussion\nOur patient was eventually diagnosed with SLE. Over 20 years, he presented with an assembly of disease manifestations, including hematologic, musculoskeletal, dermatologic, cardiac, and renal phenomena. Initially experiencing events of TTP and DVT, he went on to develop, over many years and in a relapsing-remitting manner, constitutional symptoms, arthralgia, lymphadenopathy, pancytopenia, skin lesions, pericarditis, and glomerulonephritis. Past immune serologies showed only a weakly positive ANA, with normal complement levels. The absence of classic lupus manifestations in the past obscured the diagnosis, and it was not until significant visceral involvement occurred many years thereafter, that the correct conclusions were drawn. In these days of extensive testing and follow-up, “the great pretender,” lupus, appears to present a lesser diagnostic dilemma than in the past. Atypical manifestations, combined with spontaneous disease remissions, may nonetheless obfuscate the clinical picture.\n\nConstitutional symptoms, including fatigue, anorexia, fever, and weight loss, are commonly seen in patients with SLE. Fatigue is a frequent, sometimes disabling, disease symptom. Its etiology is multifactorial and includes chronic inflammation, cytokine dysregulation, side effect of medications, comorbidities, and hormonal imbalances [3]. Fever occurs in 42–86% of SLE patients [4]. Its work-up can be challenging, and the disease occasionally presents as fever of unknown origin (FUO) [5].\n\nSLE is known to have myriad hematologic manifestations, many of which appeared in our case. Lymphadenopathy is a common, often unappreciated feature. LNs are usually soft and nontender and may fluctuate in size with disease exacerbations. Biopsy usually shows reactive hyperplasia [6]. 50% of patients with SLE develop anemia, usually due to chronic inflammation and iron deficiency, and less often due to autoimmune hemolysis [7]. White blood cell abnormalities are also common in lupus and include leukopenia, lymphopenia, and neutropenia [8]. Thrombocytopenia, when related to active disease, tends to be lower than 50,000/mm3 and usually necessitates aggressive therapy [9]. While TTP may be a rare manifestation of SLE, it is seldom the presenting feature [10]. Thrombosis, on the contrary, is a well-known finding in the disease and is multifactorial. Despite APLAs being the most important risk factor, 40% of SLE patients negative for these antibodies will still experience a thrombotic event. Other factors that contribute to thrombosis in lupus include inflammatory disease activity, medications, and traditional risk factors (including smoking, diabetes, and hypertension) [11]. Immunologically, it is noteworthy that SLE patients may have increased numbers of DN T cells in peripheral blood, probably driven by excessive T cell stimulation. These cells synthesize interleukins and can stimulate B cells, contributing to the pathogenesis of kidney damage, for instance [12].\n\nRegarding cardiac involvement, SLE can affect any layer of the heart. Pericardial effusion secondary to pericarditis is the most common manifestation [13]. Valvular heart disease is also well known in SLE. Left-sided valvular thickening is the predominant finding, followed by valvular vegetations, regurgitation, and stenosis [14]. It is worth mentioning that, in Libman–Sacks endocarditis complicating SLE, the sterile valvular vegetations have a greater tendency to embolize than in infective endocarditis, thus predisposing to neuropsychiatric disease, including ischemic stroke [15]. The latter is twice as common in SLE patients as compared to the general population. Contributing factors include embolic events, comorbidities (such as antiphospholipid syndrome and hypertension), systemic inflammation, and treatment complications [16]. AF, present in our case, is also known to be more common in SLE patients and is associated with increased mortality [17].\n\nSkin disease is a well-characterized feature of lupus. Chronic cutaneous lupus includes a lupus-lichen overlap entity [18]. In the majority of patients with systemic disease, immunofluorescence reveals deposits at the dermal-epidermal junction in normal non-sun-exposed skin and at sites of cutaneous lesions, the so-called lupus band test [19].\n\nRenal involvement remains one of the most devastating manifestations of SLE, with increased morbidity and mortality. Despite advances in management, 10% of the patients still progress to renal insufficiency and end-stage renal disease [20].\n\nComplications of immunosuppression are also represented in our case. CMV viremia dominated the clinical picture, necessitating reduction of immunosuppression and institution of prolonged intravenous antiviral therapy. The heavy immunosuppressive regimens used in systemic autoimmune diseases are known to predispose to opportunistic infections. These remain the most frequent cause of hospitalization, morbidity, and mortality in SLE patients. More than half of the infections are viral, the most common being herpes zoster [2]. No guidelines in the field of rheumatology advise in favor of prophylactic therapy against CMV upon heavy immunosuppression, as opposed to the recommendations in patients undergoing BM transplantation. In cases of symptomatic CMV disease, treatment involves both the minimization of immunosuppression and the institution of antiviral therapy, typically with oral valganciclovir or intravenous ganciclovir [21]. Duration of intravenous therapy is usually guided by the target organ, lacking in our patient.\n\nWe believe our case is educational in several aspects. First, the patient showed a remarkable mixture of systemic manifestations (see Figure 2), varying in severity, pattern, and timing, with the eventual diagnosis being made two decades after his initial presentation. Secondly, despite appropriate therapy, he went on to develop complications of the disease and its treatment, including DVT, AF, CMV viremia, and stroke. Finally, the correct utilization of the therapeutic armamentarium and the proper implementation of urgent interventions yielded an excellent outcome.\n\nAcknowledgments\nThe authors thank Professor Y. Ilan and Doctor H. Peleg for their important contribution to the patient's care.\n\nAbbreviations\nAF:Atrial fibrillation\n\nALPS:Autoimmune lymphoproliferative syndrome\n\nANA:Antinuclear antibody\n\nAnti-dsDNA:Anti-double-stranded deoxyribonucleic acid\n\nBM:Bone marrow\n\nC:Complement\n\nCMV:Cytomegalovirus\n\nCT:Computed tomography\n\nCRP:C-reactive protein\n\nDN:Double negative\n\nDVT:Deep vein thrombosis\n\nRBC:Red blood cell\n\nESR:Erythrocyte sedimentation rate\n\nFUO:Fever of unknown origin\n\nLN:Lymph node\n\nPET:Positron emission tomography\n\nSLE:Systemic lupus erythematous\n\nTEE:Transesophageal echocardiography\n\nTTE:Transthoracic echocardiography\n\nTTP:Thrombotic thrombocytopenic purpura.\n\nData Availability\nAll data used to support our findings are included within the article, and any additional data will be provided by the corresponding author upon reasonable request.\n\nConflicts of Interest\nThe authors declare that there are no conflicts of interest.\n\nFigure 1 Lichen planus-like lesions on the patient's back. On biopsy, the positive lupus band test was found, signifying immune complex deposition.\n\nFigure 2 Timeline of events in the patient's course over 20 years. AF: atrial fibrillation; CMV: cytomegalovirus; DVT: deep vein thrombosis, TTP: thrombotic thrombocytopenic purpura.\n\nTable 1 The patient's blood chemistry and counts upon admission.\n\nLab parameter\tValue\t\nCreatinine (μmol/L) (62–115)\t180\t\nAlbumin (g/L) (32–48)\t19\t\nLeukocytes (μL) (3,790–10,330)\t1,100\t\nHemoglobin (g/dL) (13.9–17.7)\t7.5\t\nPlatelets (μL) (166,000–389,000)\t62,000\t\nNeutrophils (μL) (1780–7,000)\t500\t\nLymphocytes (μL) (1,070–3,120)\t300\t\nESR (mm/hr) (1–20)\t62\t\nCRP (mg/dL) (0–0.5)\t2.7\t\nHaptoglobin (mg/dL) (3–200)\t296\t\nNormal range values appear in brackets. ESR: erythrocyte sedimentation rate; CRP: C-reactive protein.\n\nTable 2 The patient's immune serologies, completed during his admission.\n\nLab parameter\tValue\t\nANA (0/4)\t4/4\t\nAnti-DNA (U/mL) (<25)\t>200\t\nC3 (U/mL) (90–180)\t35\t\nC4 (mg/dL) (10–40)\t4\t\nCoombs test\tPositive\t\nNormal range values appear in brackets. ANA: antinuclear antibodies; Anti-DNA: anti-deoxyribonucleic acid; Anti-dsDNA: anti-double-stranded deoxyribonucleic acid; C: complement.\n==== Refs\n1 Tamirou F. Arnaud L. Talarico R. Systemic lupus erythematosus: state of the art on clinical practice guidelines RMD Open 2018 4 1 e000793 10.1136/rmdopen-2018-000793 2-s2.0-85057601284 \n2 Ginzler E. M. Dvorkina O. Infections in Systemic Lupus Erythematosus 2006 7th Philadelphia, PA, USA Lippincott, Williams & Wilkins \n3 Cleanthous S. Tyagi M. Isenberg D. Newman S. What do we know about self-reported fatigue in systemic lupus erythematosus? Lupus 2012 21 5 465 476 10.1177/0961203312436863 2-s2.0-84859293732 22345120 \n4 Font J. Cervera R. Ramos-Casals M. Clusters of clinical and immunologic features in systemic lupus erythematosus: analysis of 600 patients from a single center Seminars in Arthritis and Rheumatism 2004 33 4 217 230 10.1053/s0049-0172(03)00133-1 2-s2.0-1442348282 14978660 \n5 Cunha B. A. Lortholary O. Cunha C. B. Fever of unknown origin: a clinical approach American Journal of Medicine 2015 128 10 1138.e1 1138.e15 10.1016/j.amjmed.2015.06.001 2-s2.0-84941811214 \n6 Afzal W. Arab T. Ullah T. Teller K. Doshi K. J. Generalized lymphadenopathy as presenting feature of systemic lupus erythematosus: case report and review of the literature Journal of Clinical Medicine Research 2016 8 11 819 823 10.14740/jocmr2717w 27738484 \n7 Giannouli S. Voulgarelis M. Ziakas P. D. Anaemia in systemic lupus erythematosus: from pathophysiology to clinical assessment Annals of the Rheumatic Diseases 2006 65 2 144 148 10.1136/ard.2005.041673 2-s2.0-31144445839 16079164 \n8 Ng W. L. Chu C. M. WU A. K. L. Cheng V. C. C. Yuen K. Y. Lymphopenia at presentation is associated with increased risk of infections in patients with systemic lupus erythematosus QJM: An International Journal of Medicine 2006 99 1 37 47 10.1093/qjmed/hci155 2-s2.0-31144450174 16371405 \n9 Kuwana M. Kaburaki J. Okazaki Y. Miyazaki H. Ikeda Y. Concise report: two types of autoantibody-mediated thrombocytopenia in patients with systemic lupus erythematosus Rheumatology 2006 45 7 851 854 10.1093/rheumatology/kel010 2-s2.0-33745603994 16418192 \n10 Musio F. Bohen E. M. Yuan C. M. Welch P. G. Review of thrombotic thrombocytopenic purpurain the setting of systemic lupus erythematosus Seminars in Arthritis and Rheumatism 1998 28 1 1 19 10.1016/s0049-0172(98)80023-1 2-s2.0-0031821046 9726331 \n11 Al-Homood I. A. Thrombosis in systemic lupus erythematosus: a review article ISRN Rheumatology 2012 2012 6 428269 10.5402/2012/428269 \n12 Crispín J. C. Oukka M. Bayliss G. Expanded double negative T cells in patients with systemic lupus erythematosus produce IL-17 and infiltrate the kidneys The Journal of Immunology 2008 181 12 8761 8766 10.4049/jimmunol.181.12.8761 2-s2.0-58849162766 19050297 \n13 Bourré-Tessier J. Huynh T. Clarke A. Features associated with cardiac abnormalities in systemic lupus erythematosus Lupus 2011 20 14 1518 1525 10.1177/0961203311420318 2-s2.0-82955189318 21971202 \n14 Roldan C. A. Shively B. K. Crawford M. H. An echocardiographic study of valvular heart disease associated with systemic lupus erythematosus New England Journal of Medicine 1996 335 19 p. 1424 10.1056/nejm199611073351903 2-s2.0-0029821528 \n15 Roldan C. A. Sibbitt W. L. Jr. Qualls C. R. Libman-Sacks endocarditis and embolic cerebrovascular disease JACC: Cardiovascular Imaging 2013 6 9 p. 973 10.1016/j.jcmg.2013.04.012 2-s2.0-84883872990 24029368 \n16 Holmqvist M. Simard J. F. Asplund K. Arkema E. V. Stroke in systemic lupus erythematosus: a meta-analysis of population-based cohort studies RMD Open 2015 1 1 e000168 10.1136/rmdopen-2015-000168 2-s2.0-85018193112 \n17 Lim S. Y. Bae E. H. Han K. D. Systemic lupus erythematosus is a risk factor for atrial fibrillation: a nationwide, population-based study Clinical and Experimental Rheumatology 2019 37 6 1019 1025 30943134 \n18 Petri M. Orbai A. M. Alarcón G. S. Derivation and validation of systemic lupus international collaborating clinics classification criteria for systemic lupus erythematosus Arthritis & Rheumatology 2012 64 8 2677 2686 10.1002/art.34473 2-s2.0-84864470206 \n19 Smith C. D. Marino C. Rothfield N. F. The clinical utility of the lupus band test Arthritis & Rheumatism 1984 27 4 382 387 10.1002/art.1780270404 2-s2.0-0021278103 6608947 \n20 Ward M. M. Changes in the incidence of endstage renal disease due to lupus nephritis in the United States, 1996–2004 The Journal of Rheumatology 2009 36 1 63 67 10.3899/jrheum.080625 2-s2.0-58149502461 19004042 \n21 Kotton C. N. CMV: prevention, diagnosis and therapy American Journal of Transplantation 2013 13 s3 p. 24 10.1111/ajt.12006 2-s2.0-84877965931\n\n",
"fulltext_license": "CC BY",
"issn_linking": null,
"issue": "2021()",
"journal": "Case reports in medicine",
"keywords": null,
"medline_ta": "Case Rep Med",
"mesh_terms": null,
"nlm_unique_id": "101512910",
"other_id": null,
"pages": "6654748",
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"pmid": "33488735",
"pubdate": "2021",
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"references": "30564454;19004042;16079164;23347212;26093175;16418192;8875919;21971202;26719816;27738484;22553077;30943134;9726331;14978660;22900201;22345120;16371405;24029368;6608947;19050297",
"title": "From TTP to Glomerulonephritis: A Lifetime of Lupus.",
"title_normalized": "from ttp to glomerulonephritis a lifetime of lupus"
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"activesubstancename": "MYCOPHENOLATE MOFETIL"
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"abstract": "We report the case of a 53-year-old male patient with a medical history significant for paroxysmal atrial fibrillation, migraines with visual aura and non-obstructive coronary artery disease, who sustained a non-ST-elevation myocardial infarction a few hours after taking eletriptan as abortive therapy for migraine headaches. We believe this case implies a causal association between eletriptan and myocardial infarction, considering the timing of both drug intake and symptom onset. To the best of our knowledge this is the first reported myocardial infarction attributable to eletriptan overdose in a patient without obstructive coronary artery disease.",
"affiliations": "Western Connecticut Health Network, Danbury, CT, United States; Einstein Medical Center, Department of Cardiology, and Jefferson Medical College, Philadelphia, PA, United States. Electronic address: andremacdias@gmail.com.;Western Connecticut Health Network, Danbury, CT, United States.;University of Miami, Miller School of Medicine, Cardiology, United States.;University of Nevada School of Medicine, Cardiology, Las Vegas, NV, United States.",
"authors": "Dias|Andre|A|;Franco|Emiliana|E|;Hebert|Kathy|K|;Mercedes|Ana|A|",
"chemical_list": "D011759:Pyrrolidines; D017366:Serotonin Receptor Agonists; D014363:Tryptamines; C115647:eletriptan",
"country": "Portugal",
"delete": false,
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"issn_linking": "0870-2551",
"issue": "33(7-8)",
"journal": "Revista portuguesa de cardiologia : orgao oficial da Sociedade Portuguesa de Cardiologia = Portuguese journal of cardiology : an official journal of the Portuguese Society of Cardiology",
"keywords": "Acute myocardial infarction; Coronary vasospasm; Eletriptan; Eletriptano; Enfarte agudo do miocárdio; Vasoespasmo coronário",
"medline_ta": "Rev Port Cardiol",
"mesh_terms": "D006801:Humans; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction; D011759:Pyrrolidines; D017366:Serotonin Receptor Agonists; D014363:Tryptamines",
"nlm_unique_id": "8710716",
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"pmid": "25155004",
"pubdate": "2014",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Myocardial infarction after taking eletriptan.",
"title_normalized": "myocardial infarction after taking eletriptan"
} | [
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"companynumb": "US-PFIZER INC-2014256901",
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"occurcountry": "US",
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"activesubstancename": "ELETRIPTAN HYDROBROMIDE"
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"abstract": "Clinical data on the transfer of triptans into human breast milk remain scarce. In a lactation study including 19 breastfeeding women with migraine, we examined the excretion of six different triptans into milk. Following intake of a single dose, each participant collected seven breast milk samples at predefined intervals up to 24 hours after dose. Triptan concentrations in milk were measured using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Infant drug exposure was estimated by calculating the relative infant dose (RID). Twenty-two breast milk sample sets were obtained for sumatriptan (n = 8), rizatriptan (n = 5), zolmitriptan (n = 4), eletriptan (n = 3), almotriptan (n = 1) and naratriptan (n = 1). Based on the average concentration in milk throughout the day, estimated mean RIDs (with range in parenthesis) were as follows: eletriptan 0.6% (0.3%-0.8%), sumatriptan 0.7% (0.2%-1.8%), rizatriptan 0.9% (0.3%-1.4%), almotriptan 1.8% (-), zolmitriptan 2.1% (0.7%-5.3%) and naratriptan 5.0% (-). Infant drug exposure through breastfeeding appears to be low and indicates that use of the triptans in this study is compatible with breastfeeding. Naratriptan may not be first choice in breastfeeding mothers initiating triptans during the neonatal period.",
"affiliations": "Department of Laboratory Medicine, University Hospital of North Norway, Tromsø, Norway.;Pharmacoepidemiology and Drug Safety Research Group, Department of Pharmacy, University of Oslo, Oslo, Norway.;Department of Laboratory Medicine, University Hospital of North Norway, Tromsø, Norway.;Regional Medicines Information and Pharmacovigilance Centre (RELIS), University Hospital of North Norway, Tromsø, Norway.;Experimental and Clinical Pharmacology Research Group, Department of Medical Biology, Faculty of Health Sciences, UiT - The Arctic University of Norway, Tromsø, Norway.;Department of Clinical Pharmacology, St. Olav University Hospital, Trondheim, Norway.",
"authors": "Amundsen|Siri|S|https://orcid.org/0000-0002-2786-9852;Nordeng|Hedvig|H|https://orcid.org/0000-0001-6361-2918;Fuskevåg|Ole-Martin|OM|https://orcid.org/0000-0003-4733-0499;Nordmo|Elisabet|E|;Sager|Georg|G|https://orcid.org/0000-0003-1675-5881;Spigset|Olav|O|https://orcid.org/0000-0001-7902-9014",
"chemical_list": "D023303:Oxazolidinones; D010880:Piperidines; D011759:Pyrrolidines; D014230:Triazoles; D014363:Tryptamines; C409045:almotriptan; C115647:eletriptan; C089750:zolmitriptan; C093622:rizatriptan; C106783:naratriptan",
"country": "England",
"delete": false,
"doi": "10.1111/bcpt.13579",
"fulltext": null,
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"issn_linking": "1742-7835",
"issue": "128(6)",
"journal": "Basic & clinical pharmacology & toxicology",
"keywords": "breast milk; breastfeeding; lactation study; migraine; pharmacokinetics; relative infant dose; triptans",
"medline_ta": "Basic Clin Pharmacol Toxicol",
"mesh_terms": "D000328:Adult; D001942:Breast Feeding; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008881:Migraine Disorders; D008895:Milk, Human; D023303:Oxazolidinones; D010880:Piperidines; D011759:Pyrrolidines; D014230:Triazoles; D014363:Tryptamines",
"nlm_unique_id": "101208422",
"other_id": null,
"pages": "795-804",
"pmc": null,
"pmid": "33730376",
"pubdate": "2021-06",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Transfer of triptans into human breast milk and estimation of infant drug exposure through breastfeeding.",
"title_normalized": "transfer of triptans into human breast milk and estimation of infant drug exposure through breastfeeding"
} | [
{
"companynumb": "NO-ALKEM LABORATORIES LIMITED-NO-ALKEM-2021-01582",
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"occurcountry": "NO",
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"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "RIZATRIPTAN BENZOATE"
},
... |
{
"abstract": "Progressive neurological signs and symptoms, in immunocompromised individuals, could be due to progressive multifocal leukoencephalopathy (PML). We report the case of a patient who present a stroke unit with symptoms that were consistent initially with a posterior circulation stroke. Prior chemotherapy with Rituximab, for a lymphoma, had predisposed the patient to infection with the JC virus. Physicians need to be aware of the condition, and patients need to aware of these risks of chemotherapy.",
"affiliations": "Nottingham University Hospitals NHS Trust-Stroke, Nottingham, Nottinghamshire, UK.;Department Care of the Elderly, City Hospital, Nottingham NG5 1PB, UK.;Nottingham University Hospitals-Nottingham City Hospital, Nottingham NG5 1PB, UK.",
"authors": "Willott|Ruth H|RH|;Sunman|Wayne|W|;Munshi|Sunil K|SK|",
"chemical_list": "D000970:Antineoplastic Agents; D000069283:Rituximab",
"country": "England",
"delete": false,
"doi": "10.1093/ageing/afw052",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0002-0729",
"issue": "45(4)",
"journal": "Age and ageing",
"keywords": "ataxia; brain infarction; older people; posterior circulation; progressive multifocal leukoencephalopathy; rituximab; stroke",
"medline_ta": "Age Ageing",
"mesh_terms": "D000368:Aged; D000970:Antineoplastic Agents; D020520:Brain Infarction; D002526:Cerebellar Diseases; D003937:Diagnosis, Differential; D003951:Diagnostic Errors; D017809:Fatal Outcome; D006801:Humans; D016867:Immunocompromised Host; D007577:JC Virus; D007968:Leukoencephalopathy, Progressive Multifocal; D008279:Magnetic Resonance Imaging; D008297:Male; D011237:Predictive Value of Tests; D012307:Risk Factors; D000069283:Rituximab; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "0375655",
"other_id": null,
"pages": "564-5",
"pmc": null,
"pmid": "27056083",
"pubdate": "2016-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Progressive multifocal leukoencephalopathy masquerading as cerebellar infarction.",
"title_normalized": "progressive multifocal leukoencephalopathy masquerading as cerebellar infarction"
} | [
{
"companynumb": "GB-FRESENIUS KABI-FK201711234",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "FLUDARABINE PHOSPHATE"
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{
"abstract": "Hydroxychloroquine is a medication used to treat autoimmune conditions. Overdoses of hydroxychloroquine are uncommon, with most recommendations on monitoring drawing from experience with more common overdoses of the related drug chloroquine. We present a case of an adolescent with intentional overdose of approximately 12 g of hydroxychloroquine. The prominent clinical features were hypokalemia and widened QRS and QT intervals on the electrocardiogram. Therapy included epinephrine by intravenous drip and bicarbonate infusions along with supportive care and cardiac monitoring. The patient recovered without sequelae. Urine drug testing showed an absorbance alarm for one of the components of the institution drug of abuse screening panel, an oxycodone screen using an enzyme immunoassay. Analysis of two urine specimens collected during the hospitalization revealed hydroxychloroquine concentrations of greater than 500 mg/L (approximately 7.5 h after ingestion) and 130 mg/L (approximately 14 h after ingestion). Only the urine with greater than 500 mg/L hydroxychloroquine produced absorbance alarms on the drug of abuse testing. We separately analyzed the impact on 24 urine assays of varying concentrations of hydroxychloroquine spiked into de-identified pooled urine samples. For 6 of the assays (buprenorphine, cotinine, oxycodone, and tetrahydrocannabinol qualitative drug screens; microalbumin and urine myoglobin quantitative assays), hydroxychloroquine produced significant bias and/or instrument alarms. Overall, our study demonstrates that urine concentrations of hydroxychloroquine can reach very high concentrations (exceeding 500 mg/L) following overdose, with the potential to interfere with a range of urine assays including drug of abuse screening and microalbumin. Similar to previous reports, hydroxychloroquine overdose can produce hypokalemia and electrocardiographic abnormalities.",
"affiliations": "Department of Emergency Medicine, University of Iowa Hospitals and Clinics, 200 Hawkins Drive, Iowa City, IA, 52242, USA.;Department of Pathology, University of Iowa Hospitals and Clinics, 200 Hawkins Drive, Iowa City, IA, 52242, USA.;Department of Pathology, University of Iowa Hospitals and Clinics, 200 Hawkins Drive, Iowa City, IA, 52242, USA.;Department of Pathology, University of Iowa Hospitals and Clinics, 200 Hawkins Drive, Iowa City, IA, 52242, USA.",
"authors": "Radke|Joshua B|JB|;Kingery|Jennie M|JM|;Maakestad|Jon|J|;Krasowski|Matthew D|MD|",
"chemical_list": null,
"country": "Ireland",
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"doi": "10.1016/j.toxrep.2019.10.006",
"fulltext": "\n==== Front\nToxicol RepToxicol RepToxicology Reports2214-7500Elsevier S2214-7500(19)30098-810.1016/j.toxrep.2019.10.006ArticleDiagnostic pitfalls and laboratory test interference after hydroxychloroquine intoxication: A case report Radke Joshua B. aKingery Jennie M. bMaakestad Jon bKrasowski Matthew D. matthew-krasowski@uiowa.edub⁎a Department of Emergency Medicine, University of Iowa Hospitals and Clinics, 200 Hawkins Drive, Iowa City, IA, 52242, USAb Department of Pathology, University of Iowa Hospitals and Clinics, 200 Hawkins Drive, Iowa City, IA, 52242, USA⁎ Corresponding author at: University of Iowa Hospitals and Clinics, Department of Pathology, 200 Hawkins Drive, C-671 GH, Iowa City, IA 52242, USA. matthew-krasowski@uiowa.edu07 10 2019 2019 07 10 2019 6 1040 1046 14 2 2019 1 10 2019 4 10 2019 © 2019 The Authors2019This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Highlights\n• Hydroxychloroquine overdose can cause hypokalemia.\n\n• Hydroxychloroquine overdose can result in electrocardiographic abnormalities.\n\n• Hydroxychloroquine can interfere with urine chemistry and drug screening assays.\n\n• Urine concentrations of hydroxychloroquine can exceed 500 mg/L in acute overdose.\n\n\n\nHydroxychloroquine is a medication used to treat autoimmune conditions. Overdoses of hydroxychloroquine are uncommon, with most recommendations on monitoring drawing from experience with more common overdoses of the related drug chloroquine. We present a case of an adolescent with intentional overdose of approximately 12 g of hydroxychloroquine. The prominent clinical features were hypokalemia and widened QRS and QT intervals on the electrocardiogram. Therapy included epinephrine by intravenous drip and bicarbonate infusions along with supportive care and cardiac monitoring. The patient recovered without sequelae. Urine drug testing showed an absorbance alarm for one of the components of the institution drug of abuse screening panel, an oxycodone screen using an enzyme immunoassay. Analysis of two urine specimens collected during the hospitalization revealed hydroxychloroquine concentrations of greater than 500 mg/L (approximately 7.5 h after ingestion) and 130 mg/L (approximately 14 h after ingestion). Only the urine with greater than 500 mg/L hydroxychloroquine produced absorbance alarms on the drug of abuse testing. We separately analyzed the impact on 24 urine assays of varying concentrations of hydroxychloroquine spiked into de-identified pooled urine samples. For 6 of the assays (buprenorphine, cotinine, oxycodone, and tetrahydrocannabinol qualitative drug screens; microalbumin and urine myoglobin quantitative assays), hydroxychloroquine produced significant bias and/or instrument alarms. Overall, our study demonstrates that urine concentrations of hydroxychloroquine can reach very high concentrations (exceeding 500 mg/L) following overdose, with the potential to interfere with a range of urine assays including drug of abuse screening and microalbumin. Similar to previous reports, hydroxychloroquine overdose can produce hypokalemia and electrocardiographic abnormalities.\n\nKeywords\nArrhythmiasDrug overdose complicationsElectrocardiographyHydroxychloroquine adverse effectsHypokalemiaNorepinephrine therapeutic use\n==== Body\n1 Introduction\nHydroxychloroquine is a medication used to treat autoimmune conditions such as rheumatoid arthritis and systemic lupus erythematosus [[1], [2], [3], [4]]. Hydroxychloroquine and the related quinine derivatives chloroquine and amodiaquine have also been used for malaria treatment and prophylaxis, though this is becoming less common as rates of resistance to these drugs increase [[4], [5], [6], [7]]. Overdoses of hydroxychloroquine are rare, and most recommendations on monitoring and treatment of these patients reflect experiences with chloroquine overdoses, which are more commonly seen and usually more toxic [8]. Hydroxychloroquine was initially synthesized from chloroquine in 1946 to decrease the incidence of associated toxicities [9]. Chloroquine is estimated to be several times more toxic [10]; however, deaths have been reported from hydroxychloroquine overdose [11,12]. Published case reports of hydroxychloroquine toxicity are found as early as 1960 [13].\n\nHydroxychloroquine toxicity is largely due to its effects on the heart [4]. Sodium and potassium channel blockade result in QRS and QT prolongation, respectively, on the electrocardiogram (ECG). These prolonged intervals put patients at significant risk for dysrhythmias, included torsade de pointes and ventricular fibrillation. Other cardiac effects include delayed conduction as well as decreased contractility due to a negative inotropic effect [8]. These effects can lead to profound hypotension, dysrhythmias, and cardiovascular collapse [14].\n\nHypokalemia is usually seen with significant ingestions and is a result of decreased potassium efflux secondary to blockade of potassium membrane channels [15]. While these patients are often hypokalemic, the benefit from potassium supplementation is unclear. The low potassium likely does not represent a shortage of overall body stores but rather a shifting of the potassium to the intracellular compartment [8].\n\nOphthalmologic complications, specifically irreversible retinal injury, have been reported with chronic exposure to both chloroquine and hydroxychloroquine, but there are no reports of ophthalmologic complications after acute overdose as the toxicity is related to the overall total dosing and duration of these medications [16]. Some of the pathologic differences between chloroquine and hydroxychloroquine may be due to differences in binding to melanin [17].\n\nInterference with some laboratory testing has also been reported with hydroxychloroquine including drug of abuse immunoassays [18] and urine protein dipstick measurements [19,20]. We report a patient with acute overdose of hydroxychloroquine (approximately 12 g) who presented with cardiac symptoms, hypokalemia, electrocardiographic abnormalities, and interference with urine drug of abuse screening testing. We also investigated the impact of high concentrations of hydroxychloroquine on a variety of urine laboratory tests.\n\n2 Case history\nA 16 year old girl was transferred to our hospital after an intentional overdose of hydroxychloroquine. She ingested an estimated 60 hydroxychloroquine 200 mg tablets (12 g) at 20.00 in a suicide attempt. The medication belonged to her mother, and the patient had a similar presentation approximately 2 months prior after ingesting 20 hydroxychloroquine 200 mg tablets (4 g). The patient was also prescribed fluoxetine, risperidone, lamotrigine, and lisdexamfetamine dimesylate, but she denied any other ingestions.\n\nShe initially presented to another hospital and was drowsy but arousable with Glasgow Coma Scale score of 15 (out of maximum 15) and an initial heart rate (HR) of 88 beats per minute (bpm), respiratory rate of 24 per minute, and a blood pressure (BP) of 85/51 mm Hg. Her ECG taken approximately 2 h after ingestion showed sinus rhythm with HR of 91 bpm, QRS duration of 132 msec (normal range: 120 msec or less), and a corrected QT interval (QTc) of 728 msec (normal range: 440 msec or less; see Fig. 1). Her initial laboratory studies were notable for a plasma potassium of 3.0 mmol/L (normal range: 3.5–5.0 mmol/L) and a whole blood lactate of 2.5 mmol/L (normal range: 0.5–2.0 mmol/L). The anion gap was 11 (normal range: < 16). Urine potassium was 11.1 mmol/L (normal range: 25–126 mmol/L). Venous blood gas analysis revealed the following: pH 7.32 (normal range: 7.30–7.40) with a pCO2 of 49 mm Hg (normal range: 32–45 mm Hg) and HCO3 of 25 mmol/L (normal range: 22–26). The patient was given 3 L of normal saline.Fig. 1 Electrocardiogram (ECG) taken approximately 2 h after ingestion of hydroxychloroquine. The ECG shows sinus rhythm with a rate of 91 bpm, a QRS duration of 132 msec, and a corrected QT interval (QTc) of 728 msec.\n\nFig. 1\n\nThe regional Poison Center was contacted and recommended bicarbonate and epinephrine infusions. These were started, and she was transferred to our hospital for further management. On arrival to our hospital, her mental status and BP had improved, and she no longer required the epinephrine infusion. An ECG obtained shortly after arrival showed sinus rhythm with a rate of 82 bpm, and a QRS of 112 msec (see Fig. 2). The QTc was recorded by the machine as 320 msec but is closer to 600 msec by manual measurement. This error was likely the result of diffuse T wave flattening seen on her early ECGs. The bicarbonate infusion was continued, and she was admitted to the pediatric intensive care unit (PICU).Fig. 2 Electrocardiogram showing sinus rhythm with a rate of 82 bpm and a QRS of 112 msec. The QTc was recorded by the machine as 320 msec but is closer to 600 msec by manual measurement.\n\nFig. 2\n\nLaboratory studies in the PICU on arrival were notable for a potassium of 1.8 mmol/L and a white blood count of 15.5 k/mm3 (normal range: 3.7–10.5 k/mm3). The remainder of her laboratory studies, including blood gas analysis and routine toxicology tests, were unremarkable. Screening drug of abuse immunoassays were performed and was presumptive positive for amphetamines (explainable by known lisdexamfetamine prescription), but there was an absorbance alarm on the oxycodone immunoassay screen (this type of alarm occurs when substances in the specimen absorb light at the measured wavelength for the assay and produce a reading outside the analyzer photometer range). After it was hypothesized that the hydroxychloroquine may be interfering with the drug screens, her blood and urine was sent for quantification of hydroxychloroquine to a reference laboratory. Two separate urine samples and one blood sample were sent to specialized reference laboratory (NMS Labs, Willow Grove, PA, USA) for confirmatory testing by high performance liquid chromatography with tandem mass spectrometry (LC/MS/MS). The first urine, taken approximately 7.5 h after ingestion, had a hydroxychloroquine level of >500 mg/L (no reference range available). The second urine, taken about 14 h after ingestion, had a level of 130 mg/L. This sample tested negative for the urine drug screen panel, with no absorbance alarms. A blood sample was taken approximately 6 h after ingestion and showed a level of 10 mg/L (no clearly defined reference range, but reference laboratory result cited data that peak plasma concentrations of 0.41 +/- 0.13 mg/L were achieved approximately 2 h after a 400 mg hydroxychloroquine dose). The patient had a relatively uneventful hospital course. Her plasma potassium returned to normal range, her QRS and QTc prolongations on the ECG quickly resolved, and she was transferred to inpatient psychiatric care.\n\n3 Effects of hydroxychloroquine on laboratory urine assays\nWe investigated the effect on urine assays of hydroxychloroquine (Sigma-Aldrich) spiked into pools of de-identified urine specimens from the clinical laboratory. The 24 specific urine assays tested are summarized in Table 1. Four different urine specimen pools were tested in triplicate. Absorbance alarms and/or interference bias were clearly evident in 6 of the assays (Fig. 3, Fig. 4show representative data for each of these 6 drugs).Table 1 Urine assays analyzed in the present study.\n\nTable 1Assay\tAnalyzer\tVendor\tAssay version\tMethodology\tEffect of hydroxycholorquine?\t\nAmphetamines\tc502\tRoche\tAmphetamines II (AMPS) 2015-10 V9\tKIMS\tNo\t\nAmylase\tc701\tRoche\tα-Amylase EPS ver. 2 2015-08 V4\tEnzymatic, colorimetric\tNo\t\nBenzodiazepines\tc502\tRoche\tBenzodiazepines Plus 2016-08 V10\tKIMS\tNo\t\nBuprenorphine\tc502\tLin-Zhi\tBuprenorphine Enzyme Immunoassay 2018-04\tEIA\tYes, absorbance errors\t\nCalcium\tc701\tRoche\tCalcium Gen. 2 2014-02 V3\tPhotometric\tNo\t\nChloride\tc701\tRoche\tISE indirect Na, K, Cl Gen. 2 2016-01 V8\tIon-selective electrode\tNo\t\nCocaine metabolite\tc502\tRoche\tCocaine II 2014-03 V7\tKIMS\tNo\t\nCotinine\tc502\tThermo-Fisher\tDRI Cotinine Assay 2017-09\tEIA\tYes, positive bias and absorbance errors\t\nCreatinine\tc701\tRoche\tCreatinine plus ver. 2 2016-12 V9\tEnzymatic\tNo\t\nGlucose\tc701\tRoche\tGlucose HK Gen. 3 2016-06 V5\tHexokinase/UV\tNo\t\nhCG\tc602\tRoche\tHuman chorionic gonadotropin, STAT 2013-06 V16\tECLIA\tNo\t\nMagnesium\tc701\tRoche\tMagnesium Gen. 2 2017-06 V13\tColorimetric endpoint\tNo\t\nMicroalbumin\tc502\tRoche\tTina-quant Albumin 2015-08 V10\tImmunoturbidometric\tYes, biphasic biases\t\nMyoglobin\tc602\tRoche\tTina-quant myoglobin Gen. 2 2015-08 V6\tECLIA\tYes, negative bias\t\nNGAL\tc501\tBioporto\tNGAL 2015-09-RUO\tParticle-enhanced turbidimetric immunoassay\tNo\t\nOpiates\tc502\tRoche\tOpiate II 2014-07 V11\tKIMS\tNo\t\nOxycodone\tc502\tRoche\tOxycodone 2014-12 V7\tEIA\tYes, absorbance errors\t\npH\tc501\tRoche\tRoche SVTpH 190.2015-06 V2.0\tSpectrophotometric\tNo\t\nPhosphorus\tc701\tRoche\tPhospate (inorganic) ver. 2 2016-05 V8\tMolybdate/UV\tNo\t\nPotassium\tc701\tRoche\tISE indirect Na, K, Cl Gen. 2 2016-01 V8\tIon-selective electrode\tNo\t\nProtein\tc501\tRoche\tTotal Protein Gen. 2 2017-08 V10\tColorimetric\tNo\t\nSodium\tc701\tRoche\tISE indirect Na, K, Cl Gen. 2 2016-01 V8\tIon-selective electrode\tNo\t\nTHC\tc502\tRoche\tCannabinoids II 2014-03 V9\tKIMS\tYes, positive bias\t\nUrea nitrogen\tc701\tRoche\tUrea/BUN 2016-01 V6\tKinetic test, urease and glutamate dehydrogenase\tNo\t\nAbbreviations: ECLIA, electrochemiluminescence immunoassay; EIA, enzyme immunoassay; hCG, human chorionic gonadotropin; KIMS, kinetic interaction of microparticles in solution; NGAL, neutrophil gelatinase-associated lipocalin; THC, tetrahydrocannabinol; UV, ultraviolet.\n\nFig. 3 Representative examples of interference or errors produced by varying concentrations of hydroxychloroquine spiked in urine. (A) Buprenorphine and (B) cotinine screens shows decrease in relative absorbance relative to baseline from hydroxychloroquine concentrations ranging from 1 to 500 mg/L. For both assays, a hydroxychloroquine concentration of 1000 mg/L produces an absorbance error on the instrument. (C) Oxycodone screen shows no effect of hydroxychloroquine concentrations from 1 to 500 mg/L but does have an absorbance error at 1000 mg/L. See Table 1 for details on assay versions.\n\nFig. 3Fig. 4 Representative examples of interference produced by hydroxychloroquine spiked in urine. (A) Urine myoglobin (quantitative assay) shows negative bias from hydroxychloroquine, especially evident at hydroxychloroquine concentrations of 500 and 1000 mg/L. (B) Urine microalbumin (quantitative assay) shows biphasic interference, with negative bias evident at 1–100 mg/L and a positive bias at 1000 mg/L. (C) THC screen shows slight positive bias from hydroxychloroquine, especially at hydroxychloroquine concentrations of 500 and 1000 mg/L. See Table 1 for details on assay versions.\n\nFig. 4\n\nBuprenorphine, cotinine, and oxycodone qualitative screens all showed absorbance alarm at 1000 mg/L; buprenorphine and cotinine additionally showed negative bias related to control (not spiked with hydroxychloroquine) at all concentrations starting at 1 mg/L (Fig. 3). Oxycodone screen did not show any evident bias at hydroxychloroquine concentrations up to 500 mg/L but registered an absorbance alarm at 1000 mg/L.\n\nMyoglobin, microalbumin, and THC screen were examples of assays that showed evident bias but did not register any instrument alarm or error even up to 1000 mg/L (Fig. 4). A urine specimen pool with myoglobin concentration of 1008 ng/mL showed progressive negative bias with an apparent myoglobin concentration of 599 ng/mL when the sample was spiked with hydroxychloroquine concentration of 1000 mg/L (Fig. 4A). Microalbumin showed biphasic effects of hydroxychloroquine with negative bias at lower concentrations and a positive bias at higher concentrations (Fig. 4B); this was consistent across 4 urine specimen pools with varying baseline microalbumin concentrations. The THC screen showed slight positive bias (Fig. 4C); this would have potential to impact positive/negative results in specimens with baseline reactivity just below positive cutoff in the absence of hydroxychloroquine.\n\n4 Discussion\nToxicity from chloroquine or hydroxychloroquine is often apparent shortly after overdose, and cardiac arrest can be the first sign [21]. These medications are rapidly absorbed from the gastrointestinal tract which leads to early onset of symptoms, usually within the first 1–3 h, and as soon as 30 min after ingestion [8,14]. Despite the long half-life of hydroxychloroquine of around 50 days [22], the duration of effect is short and often less than 24 h due to redistribution of the drug into other tissues [14]. This time course was observed in our patient, who developed toxicity within 1–2 h, which resolved within 24 h.\n\nWhile seizures are well documented with chloroquine overdoses, there have been no reports in the literature of seizures after an overdose of hydroxychloroquine [23]. There have been reports of other neurologic symptoms, including generalized weakness, blurred vision, and vertigo [9,23]. A proximal myopathy has also been reported with therapeutic dosing, as well as overdose [9].\n\nHypokalemia has been previously reported with significant ingestions and is thought to be a result of decreased potassium efflux secondary to blockade of potassium membrane channels [15]. One retrospective study showed that the severity of toxicity was directly related to the degree of hypokalemia [24]. Some animal data, however, has shown that the hypokalemia may be protective against QRS widening and dysrhythmias [8]. While some amount of potassium replacement will likely be needed, this should be done with caution as rebound hyperkalemia is possible once toxicity is resolving and potassium redistributes [25].\n\nTreatment of both chloroquine and hydroxychloroquine focuses on good supportive care, including early mechanical ventilation and vasopressor support [9]. Other treatment options include potassium repletion, sodium bicarbonate, lipid emulsion, and high dose diazepam. No studies have looked specifically at which vasoactive agent is the most effective for these overdoses. Most of the cases described in the literature recommend using epinephrine. This seems reasonable given the improvements in both contractility and peripheral vascular resistance seen with epinephrine [26]. Norepinephrine may be a reasonable alternative, though it does not provide the same degree of inotropic support [26].\n\nSodium bicarbonate is frequently used in treatment of medications that cause QRS prolongation via sodium channel blockade. Its evidence for efficacy for chloroquine and hydroxychloroquine is limited. Animal studies show mild improvement in QRS duration and human case reports are limited by confounders such as co-ingestions and other therapies [27]. If sodium bicarbonate is used, caution should be taken as it may cause worsening of QT prolongation due to further intracellular shifting of potassium [8]. Hydroxychloroquine is highly lipophilic, so theoretically intravenous lipid emulsion would be beneficial. Data on efficacy, however, is lacking and limited to case reports [28]. While case reports describe the use of enhanced elimination techniques, such as hemodialysis, these are not thought to be beneficial due to high volumes of distribution and high protein binding for hydroxychloroquine [4,29].\n\nOne therapy that is unique to these overdoses is high dose diazepam. The initial data that this was derived from includes animal models and case reports of patients that were found to have less severe toxicity if they had overdosed on both chloroquine and diazepam [30]. Diazepam will help with sedation, as well as seizure treatment and prophylaxis, but otherwise the exact mechanism is unclear [8]. Hypotheses include a direct anti-dysrhythmia effect, a pharmacokinetic interaction between diazepam and chloroquine, and a central antagonistic effect [4]. While the benefit is unclear, in a case of severe life-threatening toxicity, it seems prudent to use a medication with minimal side effects such as diazepam [8].\n\nOur study demonstrates the potential for hydroxychloroquine to interfere with the performance of urine assays, either by causing interference bias or an instrument absorbance alarm. The ability to produce an absorbance alarm depends on the extent of light absorption by hydroxychloroquine at the measured wavelength(s) of the assay such as the 340 nm wavelength for the oxycodone screen in the present study. An alarm will register if the specimen yields a reading outside the measuring range of the photometer. Our subsequent in vitro analysis of urine specimens spiked with varying concentrations of hydroxychloroquine showed clear evidence of interference bias and/or absorbance alarm on 6 of 24 urine assays examined (buprenorphine, cotinine, oxycodone, and THC qualitative drug screens; microalbumin and urine myoglobin quantitative assays). The buprenorphine, cotinine, and oxycodone screens are all enzyme immunoassays. Buprenorphine and cotinine showed both negative bias at concentrations of 1–500 mg/L and also an absorbance alarm at 1000 mg/L. Oxycodone did not show bias at hydroxychloroquine concentrations up to 500 mg/L but registered an absorbance alarm at 1000 mg/L. This is consistent with the patient in the present case, where a urine specimen with hydroxychloroquine concentration exceeding 500 mg/L flagged an absorbance error for the oxycodone screen on urine drug screening ordered in the hospital. A urine specimen collected later, with a hydroxychloroquine concentration of 130 mg/L, did not flag any absorbance errors. Note that some categories of urine assays, such as those using ion-selective electrodes (chloride, potassium sodium), did not show any interference.\n\nA previous study did not show positive cross-reactivity (positive bias) of hydroxychloroquine up to 455 mg/L for the same buprenorphine enzyme immunoassay used in the present study but did show cross-reactivity for a buprenorphine CEDIA (cloned enzyme donor immunoassay) assay [18]. Our study showed inhibited signal (negative bias) and then an absorbance alarm at 1000 mg/L hydroxychloroquine. Two previous studies that examined cross-reactivity of various compounds with drug of abuse and therapeutic drug monitoring assays found that hydroxychloroquine has low structural similarity with common targets of these assays using computational chemistry methods, consistent with minimal ability to produce positive cross-reactivity (false positives) in assay package insert data [31,32]. This type of analysis suggests that interference produced by hydroxychloroquine is not due to structural similarity but instead other mechanisms such as absorption interference or chemical reaction with assay reagents. Given how commonly drug of abuse screening in used in the emergency department setting [33], understanding of potential interferences are important to avoid diagnostic confusion [34]. Overdoses such as hydroxychloroquine can cause additional challenges in producing cardiovascular symptoms (e.g., arrhythmias) that may overlap with common street drugs of abuse [[35], [36], [37]] or other ingestions such as caffeine [38] or tricyclic antidepressants [39].\n\nMyoglobin, microalbumin, and THC assays showed varying degrees of bias by hydroxychloroquine without instrument alarms. The interference of hydroxychloroquine on the microalbumin assay was biphasic across hydroxychloroquine concentrations. We did not see any interference with the Roche Total Protein assay; in contrast, two prior studies found hydroxychloroquine falsely elevated urine protein dipstick methods using tetrabromophenol blue [20] and pyrogallol red-molybdate methods [19]. The Roche protein assay used in the current operates using a colorimetric assay based on the biuret method [40].\n\n5 Conclusions\nThe present study shows that large overdoses of hydroxychloroquine have the potential to cause both electrocardiographic abnormalities and interference with urine laboratory assays. Urine concentrations of hydroxychloroquine can reach very high concentrations (exceeding 500 mg/L), with the potential to interfere with a range of urine assays including drug of abuse screening and microalbumin. As a future direction, it would be of interest to study hydroxychloroquine effects on more subtle effects such as metabolomics [36].\n\nFunding\nThe study was funded by internal funding from the University of Iowa Hospitals and Clinics Department of Pathology.\n\nDeclaration of Competing Interest\nNone of the authors have any conflict to report.\n\nAcknowledgements\nNone\n==== Refs\nReferences\n1 Hu C. Lu L. Wan J.P. Wen C. 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Vicaut E. Baud F.J. Hypokalaemia related to acute chloroquine ingestion Lancet 346 8979 1995 877 880 7564673 \n25 Clemessy J.L. Taboulet P. Hoffman J.R. Hantson P. Barriot P. Bismuth C. Baud F.J. Treatment of acute chloroquine poisoning: a 5-year experience Crit. Care Med. 24 7 1996 1189 1195 8674334 \n26 Hollenberg S.M. Vasoactive drugs in circulatory shock Am. J. Respir. Crit. Care Med. 183 7 2011 847 855 21097695 \n27 Bruccoleri R.E. Burns M.M. A literature review of the use of sodium bicarbonate for the treatment of QRS widening J. Med. Toxicol. 12 1 2016 121 129 26159649 \n28 Ten Broeke R. Mestrom E. Woo L. Kreeftenberg H. Early treatment with intravenous lipid emulsion in a potentially lethal hydroxychloroquine intoxication Neth. J. Med. 74 5 2016 210 214 27323674 \n29 McBeth P.B. Missirlis P.I. Brar H. Dhingra V. Novel therapies for myocardial irritability following extreme hydroxychloroquine toxicity Case Rep. Emerg. Med. 2015 2015 692948 \n30 Yanturali S. Aksay E. Demir O.F. Atilla R. Massive hydroxychloroquine overdose Acta Anaesthesiol. Scand. 48 3 2004 379 381 14982575 \n31 Krasowski M.D. Siam M.G. Iyer M. Ekins S. Molecular similarity methods for predicting cross-reactivity with therapeutic drug monitoring immunoassays Ther. Drug Monit. 31 3 2009 337 344 19333148 \n32 Krasowski M.D. Siam M.G. Iyer M. Pizon A.F. Giannoutsos S. Ekins S. Chemoinformatic methods for predicting interference in drug of abuse/toxicology immunoassays Clin. Chem. 55 6 2009 1203 1213 19342505 \n33 Lager P.S. Attema-de Jonge M.E. Gorzeman M.P. Kerkvliet L.E. Franssen E.J.F. Clinical value of drugs of abuse point of care testing in an emergency department setting Toxicol. Rep. 5 2018 12 17 29270362 \n34 Krasowski M.D. Pizon A.F. Siam M.G. Giannoutsos S. Iyer M. Ekins S. Using molecular similarity to highlight the challenges of routine immunoassay-based drug of abuse/toxicology screening in emergency medicine BMC Emerg. Med. 9 2009 5 19400959 \n35 Tsatsakis A. Docea A.O. Calina D. Tsarouhas K. Zamfira L.M. Mitrut R. Sharifi-Rad J. Kovatsi L. Siokas V. Dardiotis E. Drakoulis N. Lazopoulos G. Tsitsimpikou C. Mitsias P. Neagu M. A mechanistic and pathophysiological approach for stroke associated with drugs of abuse J. Clin. Med. 8 9 2019 \n36 Tsoukalas D. Alegakis A. Fragkiadaki P. Papakonstantinou E. Nikitovic D. Karataraki A. Nosyrev A.E. Papadakis E.G. Spandidos D.A. Drakoulis N. Tsatsakis A.M. Application of metabolomics: focus on the quantification of organic acids in healthy adults Int. J. Mol. Med. 40 1 2017 112 120 28498405 \n37 Wood K.E. McCarthy P.J. Krasowski M.D. A case series involving young children presenting with accidental ingestion of amphetamine based stimulants Toxicol. Rep. 5 2018 1129 1133 30510906 \n38 Willson C. The clinical toxicology of caffeine: a review and case study Toxicol. Rep. 5 2018 1140 1152 30505695 \n39 Giwa A. Oey E. The return of an old nemesis: survival after severe tricyclic antidepressant toxicity, a case report Toxicol. Rep. 5 2018 357 362 29854605 \n40 Weichselbaum T.E. An accurate and rapid method for the determination of proteins in small amounts of blood serum and plasma Am. J. Clin. Pathol. 10 1946 40 49 21027099\n\n",
"fulltext_license": "CC BY-NC-ND",
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"journal": "Toxicology reports",
"keywords": "Arrhythmias; Drug overdose complications; Electrocardiography; Hydroxychloroquine adverse effects; Hypokalemia; Norepinephrine therapeutic use",
"medline_ta": "Toxicol Rep",
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"nlm_unique_id": "101630272",
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"title": "Diagnostic pitfalls and laboratory test interference after hydroxychloroquine intoxication: A case report.",
"title_normalized": "diagnostic pitfalls and laboratory test interference after hydroxychloroquine intoxication a case report"
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"abstract": "Data are scarce on the prognosis of heart allograft antibody-mediated rejection (AMR) with cardiogenic shock (CS).\n\n\n\nWe performed a retrospective, single center, observational study. We included patients with biopsy-proven AMR and CS. We aimed to analyze the characteristics, treatment, and prognosis of patients treated for CS due to AMR. Patients alive after AMR were followed to analyze recurrences of AMR, graft function, and cardiac allograft vasculopathy (CAV).\n\n\n\nSeventeen patients met the inclusion criteria. Patients were mostly males (70%). Median age at diagnosis was 56 years, and median time between heart transplantation and AMR was 21 months. AMR was mostly due to high-level de novo class II DSA. Only 2 patients had past history of biopsy-proven AMR. Despite aggressive immunosuppressive therapies, in-hospital and 1-year mortality were as high as 76% and 82%, respectively. Four patients were discharged from hospital. Two of them were diagnosed with recurrent subclinical AMR: one died suddenly and the other presented rapidly progressive CAV.\n\n\n\nCS due to AMR occurred mostly in patients without history of AMR who developed de novo class II DSA. Despite aggressive conventional immunosuppressive therapies, prognosis after CS due to AMR was poor.",
"affiliations": "Department of Cardiac and Thoracic Surgery, Cardiology Institute, Pitié Salpêtrière Hospital, University of Paris VI, Paris, France.;Department of Cardiac and Thoracic Surgery, Cardiology Institute, Pitié Salpêtrière Hospital, University of Paris VI, Paris, France.;Department of Medical Intensive Care Unit, Cardiology Institute, Pitié Salpêtrière Hospital, University of Paris VI, Paris, France.;Department of Cardiac Anesthesia and Reanimation, Cardiology Institute, Pitié Salpêtrière Hospital, University of Paris VI, Paris, France.;Department of Pathology, Pitié Salpêtrière Hospital, University of Paris VI, Paris, France.;Department of Hemo-biotherapies, Pitié Salpêtrière Hospital, University of Paris VI, Paris, France.;Laboratory of Immunology and Histocompatibility, AP-HP, Saint Louis Hospital, Paris, France.;Department of Cardiac and Thoracic Surgery, Cardiology Institute, Pitié Salpêtrière Hospital, University of Paris VI, Paris, France.;Department of Cardiac and Thoracic Surgery, Cardiology Institute, Pitié Salpêtrière Hospital, University of Paris VI, Paris, France.",
"authors": "Coutance|Guillaume|G|0000-0003-4939-2175;Van Aelst|Lucas|L|;Hékimian|Guillaume|G|;Vidal|Charles|C|;Rouvier|Philippe|P|;Saheb|Samir|S|;Gautreau|Chantal|C|;Leprince|Pascal|P|;Varnous|Shaida|S|",
"chemical_list": "D007518:Isoantibodies",
"country": "Denmark",
"delete": false,
"doi": "10.1111/ctr.13253",
"fulltext": null,
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"issn_linking": "0902-0063",
"issue": "32(5)",
"journal": "Clinical transplantation",
"keywords": "alloantibody; antibody-mediated (ABMR); extracorporeal membrane oxygenation (ECMO); heart (allograft) dysfunction; rejection",
"medline_ta": "Clin Transplant",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D005260:Female; D005500:Follow-Up Studies; D006084:Graft Rejection; D006085:Graft Survival; D006331:Heart Diseases; D016027:Heart Transplantation; D006801:Humans; D007518:Isoantibodies; D008297:Male; D008875:Middle Aged; D011183:Postoperative Complications; D011379:Prognosis; D012189:Retrospective Studies; D012307:Risk Factors; D012770:Shock, Cardiogenic; D014019:Tissue Donors; D055815:Young Adult",
"nlm_unique_id": "8710240",
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"pubdate": "2018-05",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article; D064888:Observational Study",
"references": null,
"title": "Antibody-mediated rejection induced cardiogenic shock: Too late for conventional therapy.",
"title_normalized": "antibody mediated rejection induced cardiogenic shock too late for conventional therapy"
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"abstract": "We describe the case of a 53-year-old man who presented with abdominal pain, diarrhoea and hypomagnesaemia. The hypomagnesaemia proved to be due to gastrointestinal loss as urinary fractional excretion was very low, suggesting non-renal loss. Common causes were discarded and the hypomagnesaemia was attributed to chronic use of the proton pump inhibitor, omeprazole. As such, omeprazole was discontinued and an H2 blocker was given. Several days later the patient presented with upper gastrointestinal bleeding. CT scan demonstrated marked enlargement of the duodenum and proximal jejunum, and abnormal thickening and enhancement of the bowel wall. Urgent oesophagogastroduodenoscopy revealed coffee-ground and bloody contents in the distal oesophagus and stomach, and numerous ulcers along the duodenum and jejunum. A positron emission tomography-CT scan using GA 68-DOTANOC demonstrated increased uptake in the gastroduodenum junction, suggesting a neuroendocrine tumour. Pancreaticoduodenectomy was performed and tumour cells stained positive for gastrin, confirming the tentative diagnosis of Zollinger-Ellison syndrome.",
"affiliations": "Department of Internal Medicine H, Rambam Health Care Campus, Haifa, Israel.;Gastroenterology Institute, Rambam Health Care Campus, Haifa, Israel.;Infectious Diseases Unit and Internal Medicine H, Rambam Health Care Campus and the Rappaport's Faculty of Medicine, Technion, Haifa, Israel.;The B. Shine Rheumatology Unit and Internal Medicine H, Rambam Health Care Campus and the Rappaport's Faculty of Medicine, Technion, Haifa, Israel.",
"authors": "Eyal|Allon|A|;Sueissa|Alain|A|;Braun|Eyal|E|;Naffaa|Mohammad Ebrahim|ME|",
"chemical_list": "D054328:Proton Pump Inhibitors; D008274:Magnesium; D009853:Omeprazole",
"country": "England",
"delete": false,
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"issn_linking": "1757-790X",
"issue": "2014()",
"journal": "BMJ case reports",
"keywords": null,
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"mesh_terms": "D004379:Duodenal Neoplasms; D004381:Duodenal Ulcer; D015408:Gastrinoma; D006801:Humans; D008274:Magnesium; D008297:Male; D008875:Middle Aged; D009853:Omeprazole; D010438:Peptic Ulcer Hemorrhage; D054328:Proton Pump Inhibitors; D014883:Water-Electrolyte Imbalance; D015043:Zollinger-Ellison Syndrome",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "25274557",
"pubdate": "2014-10-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "23112541;23010681;22337212;23325090;20189276;22261919;11144036;23417896;19059523;17065651;23051182",
"title": "From hypomagnesaemia to Zollinger-Ellison syndrome: an adverse effect of a proton pump inhibitor.",
"title_normalized": "from hypomagnesaemia to zollinger ellison syndrome an adverse effect of a proton pump inhibitor"
} | [
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"activesubstancename": "BEZAFIBRATE"
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{
"abstract": "BACKGROUND\nPrimary hyperparathyroidism (PHPT) is uncommon among children with an incidence of 1:300,000. This diagnosis is often missed in children in contrast to adults where it is detected at a pre symptomatic stage due to routine blood investigations. Etiology of PHPT can be due to adenoma, hyperplasia or rarely carcinoma.\n\n\nMETHODS\nA 12 year old Sri Lankan girl presented with progressive difficulty in walking since 1 year. On examination she had bilateral genu valgum. Skeletal survey revealed valgus deformity of knee joints, bilateral subluxation of upper femoral epiphysis(SUFE), epiphyseal displacement of bilateral humeri, rugger jersey spine and subperiosteal bone resorptions in lateral aspects of 2nd and 3rd middle phalanges. There were no radiological manifestations of rickets. Metabolic profile revealed hypercalcemia with hypophosphatemia. Intact parathyroid hormone levels were elevated at 790 pg/ml. Vitamin D levels were deficient. She had low bone mineral density with Z score of -3.4. Vitamin D supplementation resulted in worsening of hypercalcemia without reduction in PTH levels. Tc 99 Sestamibi uptake scan showed abnormal tracer retention in left inferior pole of thyroid. A large parathyroid gland was removed with histology favoring parathyroid adenoma. Post operatively she developed hypocalcemia. Bilateral osteotomy was done for SUFE and further surgeries for correction of limb deformities planned.\n\n\nCONCLUSIONS\nPHPT in children is usually diagnosed late when irreversible organ damage has occurred. Children can present with non specific symptoms involving gastrointestinal, musculoskeletal, renal and neurological systems. PHPT can cause disarray in bone and epiphysis in children during pubertal growth spurt. Genu valgum and SUFE are rare skeletal manifestations in PHPT and only 10 cases of genu valgum and 9 cases of SUFE have been reported up to now. So far no cases have been reported on epiphyseal displacement of humeri. Awareness regarding the occurrence of these rare skeletal manifestations especially during puberty is important for early diagnosis to prevent irreversible outcomes.",
"affiliations": "Department of diabetes and endocrinology, National Hospital of Sri Lanka, Colombo, Sri Lanka. Maulee_80@yahoo.com.;Department of diabetes and endocrinology, National Hospital of Sri Lanka, Colombo, Sri Lanka.;Department of diabetes and endocrinology, National Hospital of Sri Lanka, Colombo, Sri Lanka.;Department of Radiology, National Hospital Sri Lanka, Colombo, Sri Lanka.;Orthopaedic Unit, National Hospital Sri Lanka, Colombo, Sri Lanka.",
"authors": "Arambewela|Maulee Hiromi|MH|;Liyanarachchi|Kamani Danushka|KD|;Somasundaram|Noel P|NP|;Pallewatte|Aruna S|AS|;Punchihewa|Gamini L|GL|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1186/s12902-017-0197-z",
"fulltext": "\n==== Front\nBMC Endocr DisordBMC Endocr DisordBMC Endocrine Disorders1472-6823BioMed Central London 19710.1186/s12902-017-0197-zCase ReportCase report: rare skeletal manifestations in a child with primary hyperparathyroidism Arambewela Maulee Hiromi Maulee_80@yahoo.com 1Liyanarachchi Kamani Danushka Liyanarachchi.kamani@gmail.com 1Somasundaram Noel P. noelsomasundaram@gmail.com 1Pallewatte Aruna S. Asp31263@hotmail.com 2Punchihewa Gamini L. gaminipunchihewa@yahoo.com 31 0000 0004 0556 2133grid.415398.2Department of diabetes and endocrinology, National Hospital of Sri Lanka, Colombo, Sri Lanka 2 0000 0004 0556 2133grid.415398.2Department of Radiology, National Hospital Sri Lanka, Colombo, Sri Lanka 3 0000 0004 0556 2133grid.415398.2Orthopaedic Unit, National Hospital Sri Lanka, Colombo, Sri Lanka 21 7 2017 21 7 2017 2017 17 458 9 2016 13 7 2017 © The Author(s). 2017\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nPrimary hyperparathyroidism (PHPT) is uncommon among children with an incidence of 1:300,000. This diagnosis is often missed in children in contrast to adults where it is detected at a pre symptomatic stage due to routine blood investigations. Etiology of PHPT can be due to adenoma, hyperplasia or rarely carcinoma.\n\nCase presentation\nA 12 year old Sri Lankan girl presented with progressive difficulty in walking since 1 year. On examination she had bilateral genu valgum. Skeletal survey revealed valgus deformity of knee joints, bilateral subluxation of upper femoral epiphysis(SUFE), epiphyseal displacement of bilateral humeri, rugger jersey spine and subperiosteal bone resorptions in lateral aspects of 2nd and 3rd middle phalanges. There were no radiological manifestations of rickets. Metabolic profile revealed hypercalcemia with hypophosphatemia. Intact parathyroid hormone levels were elevated at 790 pg/ml. Vitamin D levels were deficient. She had low bone mineral density with Z score of −3.4. Vitamin D supplementation resulted in worsening of hypercalcemia without reduction in PTH levels. Tc 99 Sestamibi uptake scan showed abnormal tracer retention in left inferior pole of thyroid. A large parathyroid gland was removed with histology favoring parathyroid adenoma. Post operatively she developed hypocalcemia. Bilateral osteotomy was done for SUFE and further surgeries for correction of limb deformities planned.\n\nConclusion\nPHPT in children is usually diagnosed late when irreversible organ damage has occurred. Children can present with non specific symptoms involving gastrointestinal, musculoskeletal, renal and neurological systems. PHPT can cause disarray in bone and epiphysis in children during pubertal growth spurt. Genu valgum and SUFE are rare skeletal manifestations in PHPT and only 10 cases of genu valgum and 9 cases of SUFE have been reported up to now. So far no cases have been reported on epiphyseal displacement of humeri. Awareness regarding the occurrence of these rare skeletal manifestations especially during puberty is important for early diagnosis to prevent irreversible outcomes.\n\nKeywords\nPrimary hyperparathyroidismPubertal growth spurtGenu valgumSlipped upper femoral epiphysisEpiphyseal displacement of humerusCase reportissue-copyright-statement© The Author(s) 2017\n==== Body\nBackground\nPrimary hyperparathyroidism (PHPT) is a common condition among adults. However it’s an uncommon disorder in children and adolescents associated invariably with delay in diagnosis. This is mainly attributed to incidental detection of hypercalcemia in routine blood investigations done in adults thus allowing diagnosis at an asymptomatic stage. In contrast diagnosis in children is often when they are symptomatic with target organ involvement. It is postulated that puberty may result in unmasking of certain skeletal manifestations which result due to PHPT.Table 1 Metabolic parameters before and after 3 months of vitamin D supplementation\n\n\tBefore vit D\tAfter vit D\t\nIonized calcium (1.12–1.32 mmol/l)\t1.5\t1.7\t\nCalcium/creatinine ratio\t0.06\t0.29\t\nALP (182–587 IU/L)\t3210\t2053\t\nIntact PTH (8–76 pg/ml)\t795\t892\t\nVitamin D (<30 nmol/l – deficiency, 30–79 nmol/l – insufficiency, 80–150 nmol/l - sufficiency)\t25\t110\t\n\n\n\nWe present a case of an adolescent with PHPT who presented with rare skeletal manifestations of genu valgum, bilateral SUFE and bilateral epiphyseal displacement of humeri.\n\nCase presentation\nA 12 year old Sri Lankan girl presented with crooked legs and progressive difficulty in walking for 1 year duration. She did not complain of any leg pain, joint pain or proximal muscle weakness. There was no history of trauma, fractures, abdominal pain, vomiting constipation, neck swelling or renal calculi. She had been relatively healthy up to now taking part in athletic events in school until the development of these symptoms. Her menses were regular following attaining menarche at the age of 11 years. She was a product of a non consanguineous marriage and both her siblings were healthy. Family history was nil of note for any renal disease or multiple endocrine neoplasia (MEN). Her diet was deficient in milk and meat products. Bilateral stapling of knees done 6 months back did not lead to any symptomatic resolution. On examination she had bilateral valgus deformities of the knees without any other clinical features of Rickets or dysmorphism. No other joint deformities were noted. Height and weight were age appropriate and she was in Tanner 2 in pubertal development. The rest of the systemic examination was normal.\n\nX ray imaging of the lower limbs revealed bilateral slipped upper femoral epiphysis (SUFE) and bilateral genu valgus deformity of the knees. As SUFE is associated with a wide range of endocrine and metabolic disorders she was screened for these diseases. Ionized calcium levels were 1.5 mmol/l (1–1.3 mmol/l) which was repeated and confirmed. Serum phosphate levels were low at 2.3 mg/dl (2.5–4.5 mg/dl). Serum Alkaline phosphate levels (ALP) were elevated at 3210 U/L (age matched reference range 182–587 U/L). Serum intact Parathyroid Hormone (PTH) levels were 796 pg/ml (8–76 pg/ml) indicating hyperparathyroidism. Calcium creatinine ratio was 0.06 (>0.02 suggestive if primary hyperparathyroidism). Vitamin D levels were 25 nmol/l (<30 nmol/l suggestive of deficiency). Anterior pituitary hormones inclusive of Thyroid function tests, 9 am Cortisol, Follicular Stimulating Hormone, Luteinizing Hormone, Prolactin and baseline hematological indices, serum electrolytes, renal and liver profile were all normal. A skeletal survey revealed evidence of epiphyseal displacement of bilateral humeral heads, rugger jersey spine and subperiosteal bone resorptions involving lateral aspects of 2nd and 3rd phalanges. There were no radiological features of rickets such as widening, cupping or fraying of the metaphysis. An ultrasound scan performed to detect a possible parathyroid adenoma failed to detect any masses. Ultrasound scan of abdomen did not show any evidence of nephrocalcinosis or renal calculi. Bone densitometry of spine revealed low bone mineral density with a Z score of −3.4. At this stage a differential diagnosis of Primary hyperparathyroidism (PHPT) with vitamin D deficiency or Tertiary hyperparathyroidism due to vitamin D deficiency was considered. It was decided to reassess her following adequate supplementation with vitamin D. She was treated with 50,000 IU of vitamin D2 weekly for 8 weeks followed by maintenance therapy of vitamin D3 1000 IU daily Table 1.\n\nAs adequate vitamin D supplementation failed to reduce the PTH levels a diagnosis of primary hyperparathyroidism was made. A Tc99 Sestamibi parathyroid scan revealed focal abnormal and persistent tracer retention in right inferior thyroid pole. As the diagnosis of PHPT was most likely due to parathyroid adenoma she underwent surgery where a large 2 × 3 cm parathyroid gland was removed from the right inferior pole of the thyroid gland. Ipsilateral parathyroid gland was atrophied. Histology favoured a parathyroid adenoma. Post operatively she developed perioral numbness and paresthesia in fingers. Serum ionized calcium levels were 0.8 mmol/l, serum intake PTH levels were 61 pg/ml with normal levels of magnesium 0.82 mmol/l (0.75–0.95 mmol/l) and phosphate 1.0 mmol/l (0.8–1.5 mmol/l). A probable diagnosis of hungry bone disease was made and she was treated with a single dose of intravenous calcium followed by oral calcium carbonate 3 g/day and calcitriol 2 μg/day with monitoring of serum calcium levels. She required calcium supplementation for 3 months following surgery. Bilateral osteotomy was performed for SUFE even prior to completion of metabolic evaluation as delay in treatment can have detrimental effects such as progression of the slippage and avascular necrosis. Series of surgeries for correction of limb deformities were planned following the improvement of quality of bone after treatment of PHPT (Figs. 1, 2, 3, 4, 5 and 6).Fig. 1 Bilateral genu valgus deformity\n\n\nFig. 2 X ray images showing bilateral SUFE and genu valgum\n\n\nFig. 3 X ray showing epiphyseal displacement of bilateral humeri\n\n\nFig. 4 X ray spine showing rugger jersey spine\n\n\nFig. 5 X ray hands showing sub periosteal resorption involving 2nd, 3rd middle phalanges\n\n\nFig. 6 Tc 99 Sestamibi scan showing abnormal, persistent tracer retention in right inferior pole of thyroid\n\n\n\n\nDiscussion\nPHPT is common disease among adults. However it’s occurrence is very rare among children and adolescents with about 200 cases reported worldwide up to now [1]. It’s incidence is estimated as 1 case per 300,000 live births [2]. PHPT in children has a bimodal age distribution occurring in very young and older children. In neonates and infants it can be due to inactivating mutations of the calcium sensing receptor gene on chromosome 3q which is inherited as an autosomal dominant disorder [3]. In older children it is caused by adenoma or hyperplasia of the gland and can be either familial (27–31%) or sporadic (65–70%).\n\nThe characteristic feature in older children is delayed presentation. Almost 80% of children are symptomatic and have end organ damage at the time of presentation [2, 4]. This is in contrast to adults where most of the cases of PHPT are diagnosed by incidental detection of hypercalcemia during routine investigations in asymptomatic patients. Children can present with various non specific symptoms involving gastrointestinal, musculoskeletal, renal and neurological systems due to hypercalcemia. Our patient presented with genu valgum. Skeletal survey revealed bilateral SUFE with bilateral genu valgum, displacement of epiphysis of bilateral humeri, rugger jersey spine and sub periosteal bone resorption involving radial aspects of phalanges in hand. Genu valgum is a rare presentation in children with PHPT with only 10 cases reported in literature. These 10 cases are summarized in an article on Genu valgum and primary hyperparathyroidism in children by Ramkumar et al. [5]. Most of these patients had genu valgum at presentation indicating an etiological link. All these patients had solitary parathyroid adenoma and none were reported vitamin D deficient. Genu valgum can also manifest in vitamin D deficiency which can also cause a similar clinical picture due to tertiary hyperparathyroidism. Our patient had biochemical evidence of vitamin D deficiency. However there were no other radiological features favoring vitamin D deficiency apart from bilateral SUFE which is known to occur in both vitamin D deficiency as well as hyperparathyroidism. Vitamin D deficiency alone is unlikely to cause genu valgum in children with PHPT. Adequate vitamin D supplementation resulted in worsening of hypercalcemia and failure of reduction in PTH levels. Tc 99 Sestamibi uptake scan demonstrated focal increase in uptake of tracer in the right inferior lobe of the thyroid for which she underwent surgery and removal of a parathyroid adenoma with clinical resolution. This was the case in the two patients encountered by Ramkumar et al. as well. The classic picture in the case of tertiary hyperparathyroidism would be parathyroid hyperplasia. Most of the cases of PHPT with genu valgum described so far have occurred in adolescence when a rapid growth spurt is expected. The exact mechanism of genu valgum in PHPT is unclear however it is postulated that PHPT has a direct effect on the growth plate during the pubertal growth spurt [6]. Similar phenomenon occurs in SUFE which is displacement of the capital femoral epiphysis caused by shear stress on a vulnerable physis during rapid growth in adolescence [7]. Although the exact pathogenesis is unclear many endocrine diseases such as hypothyroidism, administration of growth hormone, PHPT, panhypopituitarism and lately vitamin D deficiency have been contributory factors. These disorders result in abnormal growth and mineralization of cartilage thus predisposing to slippage of the vulnerable physis. Prevalences of these among 85 patients with SUFE were hypothyroidism in 40%, growth hormone deficiency in 25% and others in 35% [8]. PHPT causing SUFE is extremely rare with only 9 cases reported worldwide [9]. Madeira et al. reported the occurrence of genu valgum, SUFE and several painful skeletal manifestations in a teenager which was attributed to the rapid growth spurt during puberty [10]. Further to the development of genu valgum and SUFE, our patient had radiological evidence of epiphyseal displacement of bilateral humeri as well. This most likely can be attributed to the same mechanism of the effect of excess parathyroid hormone on the bone and epiphysis in a child going through the pubertal growth spurt. However there is no literature published to date describing epiphyseal displacement of humerus in association with PHPT.\n\nPHPT in our 12 year old patient was unmasked due to these skeletal deformities as she progressed through puberty. Apart from these she did not have any other clinical features suggestive of PHPT. Following excision of the parathyroid adenoma she developed biochemical resolution. However further surgeries will be required to correct the limb deformities.\n\nConclusion\nPHPT is a rare disease in children which is often diagnosed late once target organ involvement had developed. In contrast, adults with PHPT are incidentally detected in the asymptomatic phase during routine blood investigations. Apart from the well known skeletal manifestations, PHPT can affect the bone and epiphysis resulting in rare skeletal deformities such as genu valgum, SUFE and epiphyseal displacement especially during the pubertal growth spurt in adolescents. Having a high degree of suspicion when children and especially adolescents present with skeletal symptoms may aid in speedy diagnosis and prevention of detrimental long standing deformities.\n\nAbbreviations\nALPAlkaline phsophatase\n\nMENMultiple endocrine neoplasia\n\nPHPTPrimary hyperparathyroidism\n\nPTHParathyroid hormone\n\nSUFESubluxation of upper femoral epiphysis\n\nAcknowledgements\nDepartment of Radiology, National Hospital Sri Lanka.\n\nFunding\nNo funding was required for the reporting of this work.\n\nAvailability of data and materials\nThe datasets supporting the conclusions of this article is included within the article and in additional files.\n\nAuthors’ contributions\nDr. MHA, Dr. KDL, Dr. AMW, Dr. AP and Dr. GLP were involved in acquisition of data and drafting the manuscript. Dr. NPS participated in critically revising the manuscript and giving the final approval of the version to be published. All authors read and approved the final manuscript.\n\nEthics approval and consent to participate\nNot applicable.\n\nConsent for publication\nWritten informed consent was obtained from the patient’s legal guardian(s) for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nPublisher’s note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. Alagarathnam S Kurzawinski TR Aetiology, diagnosis and surgical treatment of primary hyperaparathyroidism in children: new trends Horm Res Paediatr 2015 83 365 375 10.1159/000381622 \n2. Mallet E Working group on calcium metabolism: primary hyperparathyroidism in neonates and childhood. The French experience (1984–2004) Horm Res 2008 69 180 188 18219222 \n3. Lietman SA Germain-Lee EL Levine MA Hypercalcemia in children and adolescents Curr Opin Pediatr 2010 22 508 515 10.1097/MOP.0b013e32833b7c23 20601885 \n4. Kollars J Zarroug AE van Heerden J Lteif A Stavlo P Suarez L Moir C Ishitani M Rodeberg D Primary hyperparathyroidism in pediatric patients Pediatrics 2005 115 974 980 10.1542/peds.2004-0804 15805373 \n5. Ramkumar S Kandasamy D Vijay MK Etal. Genu valgum and primary hyperparathyroidism in children. Int. J Case Rep Images 2014 5 6 401 407 10.5348/ijcri-201455-CS-10041 \n6. Rapaport D Ziv Y Rubin M Huminer D Dinstan M Primary hyperparathyroidism in children J Pediatr Surg 1986 21 5 395 397 10.1016/S0022-3468(86)80505-X 3712190 \n7. Herring JA Tachdjian MO Tachdjian’s pediatric orthopaedics 2008 Fourth Philadelphia Saunders 716 720 \n8. Loder RT Wittenberg B Desilva G Slipped capital femoral epiphysis associated with endocrine disorders J Paediatr Orthop 1995 15 3 349 356 10.1097/01241398-199505000-00018 \n9. El Scheich T Marquard J Westhoft B Approach to the management of slipped capital femoral epiphysis and primary hyperparathyroidism J Paediatr Endocinol Metab 2012 25 5–6 407 412 \n10. Madeira IR Machado M Maya MC Primary hyperparathyroidism associated to slipped capital femoral epiphysis in a teenager Arq Bras Endocrinol metabol 2005 49 2 314 318 10.1590/S0004-27302005000200021 16184263\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1472-6823",
"issue": "17(1)",
"journal": "BMC endocrine disorders",
"keywords": "Case report; Epiphyseal displacement of humerus; Genu valgum; Primary hyperparathyroidism; Pubertal growth spurt; Slipped upper femoral epiphysis",
"medline_ta": "BMC Endocr Disord",
"mesh_terms": "D001848:Bone Diseases, Developmental; D002648:Child; D005260:Female; D006801:Humans; D049950:Hyperparathyroidism, Primary; D011379:Prognosis",
"nlm_unique_id": "101088676",
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"title": "Case report: rare skeletal manifestations in a child with primary hyperparathyroidism.",
"title_normalized": "case report rare skeletal manifestations in a child with primary hyperparathyroidism"
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"abstract": "Thyroid function abnormalities after the use of selective serotonin reuptake inhibitors (SSRIs) have been reported in the extant literature, but the strength of this correlation is unclear and a commentary on its clinical significance is necessary. The one-week hospital course of a 16-year-old male presenting with worsening of major depressive disorder after the initiation of escitalopram was significant for the development of transient subclinical hypothyroidism (SCH). An analysis of the aberrant thyroid indices in the setting of escitalopram use was pursued. Data from previous studies suggesting similar events were reviewed in order to better characterize the nature of this association. The exact diagnostic criterion for SCH in the pediatric population has been undergoing reform and, based on the newer suggestions, our patient was assessed to have transient SCH. Thyroid hormone derangement following SSRI use has been reported in the past; however, the clinical implications of developing transient SCH in adolescent patients with major depression who are taking SSRIs is still unclear and not well understood at this time. The importance of having a better understanding of this potential interaction is marked by both the increased risk for suicidal ideation in the pediatric population with the use of SSRIs, as well as the confounding overlap of symptom presentation between hypothyroidism and major depressive disorder.",
"affiliations": "Psychiatry, Rush University Medical Center, Chicago, USA.;Psychiatry, Rush University Medical Center, Chicago, USA.;Child Psychiatry, Rush University Medical Center, Chicago, USA.",
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"fulltext": "\n==== Front\nCureusCureus2168-8184Cureus2168-8184Cureus Palo Alto (CA) 10.7759/cureus.5144Endocrinology/Diabetes/MetabolismInternal MedicinePsychiatryTransient Subclinical Hypothyroidism and Acute Suicidal Ideation Following Treatment with Escitalopram Muacevic Alexander Adler John R Bazigh Izza 1Dharmapuri Sanjaya 1Cosme Rosario M 2\n1 \nPsychiatry, Rush University Medical Center, Chicago, USA \n2 \nChild Psychiatry, Rush University Medical Center, Chicago, USA \nIzza Bazigh ibazigh@gmail.com15 7 2019 7 2019 11 7 e514428 6 2019 15 7 2019 Copyright © 2019, Bazigh et al.2019Bazigh et al.This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.This article is available from https://www.cureus.com/articles/21269-transient-subclinical-hypothyroidism-and-acute-suicidal-ideation-following-treatment-with-escitalopramThyroid function abnormalities after the use of selective serotonin reuptake inhibitors (SSRIs) have been reported in the extant literature, but the strength of this correlation is unclear and a commentary on its clinical significance is necessary.\n\nThe one-week hospital course of a 16-year-old male presenting with worsening of major depressive disorder after the initiation of escitalopram was significant for the development of transient subclinical hypothyroidism (SCH). An analysis of the aberrant thyroid indices in the setting of escitalopram use was pursued. Data from previous studies suggesting similar events were reviewed in order to better characterize the nature of this association.\n\nThe exact diagnostic criterion for SCH in the pediatric population has been undergoing reform and, based on the newer suggestions, our patient was assessed to have transient SCH. Thyroid hormone derangement following SSRI use has been reported in the past; however, the clinical implications of developing transient SCH in adolescent patients with major depression who are taking SSRIs is still unclear and not well understood at this time.\n\nThe importance of having a better understanding of this potential interaction is marked by both the increased risk for suicidal ideation in the pediatric population with the use of SSRIs, as well as the confounding overlap of symptom presentation between hypothyroidism and major depressive disorder. \n\nselective serotonin reuptake inhibitors (ssri)subclinical hypothyroidismecitalopramthyroid stimulating hormone (tsh)suicidal ideationadolescentside effectsThe content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus.\n==== Body\nIntroduction\nThe clinical implications of developing transient subclinical hypothyroidism (SCH) in patients with major depression who are taking selective serotonin reuptake inhibitors (SSRIs) have received little attention. The importance of having a better understanding of this potential interaction is marked by both the increased risk for suicidal ideation in the pediatric population with the use of SSRIs, as well as the confounding overlap of symptom presentation between hypothyroidism and major depressive disorder. SSRIs carry a Federal Drug Administration (FDA) black box warning for the increased risk of suicidal ideation in the pediatric population; yet, there is no current evidence-based understanding as to why this occurs.\n\nCase presentation\nDR was a 16-year-old adopted male who presented to the emergency department with the acute onset of suicidal ideation, culminating into a suicide attempt in the setting of recent worsening of depression following the initiation of escitalopram, 10 mg per day, 10 days earlier. He had no known medical history but did have a previous psychiatric history of attention deficit hyperactive disorder (ADHD) and major depressive episode (MDE). The patient was given a presumptive diagnosis of major depressive disorder (MDD), single and severe episode without psychotic features, and admitted for psychiatric stabilization.\n\nDR’s depressive symptoms began three months prior to his admission. In reference to that, he reported low mood, poor self-esteem manifesting in self-derogatory thoughts, guilt, anhedonia, social isolation/withdrawal, sleep disturbances, fatigue, poor concentration, academic performance decline, decreased appetite, and passive suicidal ideation. His depressive symptoms worsened 10 days before admission, noticeably in the context of the initiation of escitalopram that was prescribed by his primary care provider. \n\nThe adoptive parents confirmed DR’s history, providing supporting collateral information which reiterated their impression of DR as being depressed but stable prior to initiation of escitalopram. They reported that his symptoms were similar to a previous transient MDE when he was transitioning from middle school to high school. During that episode, DR pursued outpatient psychotherapy and the quick resolution of symptoms led to a reformulation of diagnosis as an adjustment reaction. The adoptive parents had little information on DR’s biologic family medical history aside from noting that his biologic mother died of hypothermia, as well as that DR was born in Siberia, Russia and adopted at the age of three.\n\nDuring his current presentation, his affect was flat, with a restricted range and low intensity. He expressed negativistic thinking and described feeling like “a burden on everyone,” as well as “not valuable or smart.” There were no clinical signs or symptoms of hypomania, mania, or psychosis and he denied ever having homicidal ideation or auditory/visual hallucinations. He denied any previous or active history of tobacco, alcohol, or illicit substance use. DR did acknowledge having multiple psychosocial stressors, including the recent termination of a romantic relationship. However, he did not attribute the acute onset of suicidal ideation to any particular triggering event other than a notable increase in rumination over negativistic thinking after starting escitalopram. \n\nDR’s workup after admission included baseline complete blood count (CBC), comprehensive metabolic panel (CMP), thyroid-stimulating hormone (TSH), vitamin D level, electrocardiography (ECG), and medication evaluation. The escitalopram was tapered towards discontinuation, given the concerns for the possibility of drug-induced suicidal ideation, and a trial of fluoxetine was then initiated. His lab work from the time of admission was remarkable only for a mild elevation of the TSH at 3.334 uIU/mL and a mild elevation of the low-density lipoprotein (LDL) at 103 mg/dL. Upon gathering further information during initial interviews after admission, it was revealed that DR had concerns about recently developing constipation, cold intolerance, and observing that his hair appeared to be falling out easily overnight. Based on these reports, as well as his laboratory results showing mild aberrations in thyroid function, an additional workup for consideration of hypothyroidism was pursued, including repeat TSH, free T3/T4, anti-thyroperoxidase (anti-TPO) antibody, anti-thyroglobulin (anti-TG) antibody, and lipid panel. His repeat thyroid labs (taken within three days of admission) showed that T4 was in the lower end of normal limits/borderline deficiency, T3 was in the upper end of normal limits, and TSH was trending down within normal limits, while anti-TPO and anti-TG antibodies were not present (See Table 1). The lipid panel revealed normal total cholesterol, triglyceride, and high-density lipoprotein (HDL) level, but a mildly elevated LDL level. DR’s subjective reports of symptoms were concerning, but the results of the lab work, although aberrant, were not revealing of a primary thyroid function abnormality and a consult with endocrinology was not pursued during his admission and rather given as an outpatient referral if his symptoms persisted. \n\nTable 1 Thyroid Laboratory Values \n(* Latest recommendations suggest TSH upper limit to be 2.5 uIU/ml)\n\nT3: triiodothyronine; TSH: thyroid-stimulating hormone\n\nReference Range and Units\t(Tg)Ab (O.O - 4.1 IU/L)\tTg (ng/mL)\tFree thyroxine (0.7 - 1.5 ng/dL)\tT3, Free (1.7 - 3.7 pg/mL)\tTSH (0.350 - 4.940 uIU/mL)*\t\n On admission\t \t \t \t \t3.344\t\nOn 3rd day of admission \t< 3.0\t2.5\t0.9\t2.9\t2.556\t\nWithin five days of transitioning to fluoxetine and the discontinuation of escitalopram, DR began showing marked improvement in depressive symptoms. He reported his mood was much improved, he had better appetite, less fatigue, improved sleep, and his suicidal ideation remitted. He noted a specific improvement in negativistic thinking and the absence of feelings of guilt which had previously been ruminative. Per staff reports, he was observed to have a progressive improvement in motivation and social participation within the milieu and during therapeutic programs. Upon acute stabilization, follow-up care was established outside of the hospital system, and he was discharged within seven days of his admission.\n\nDiscussion\nThyroid function abnormalities after the use of SSRIs have been reported in the extant literature but the clinical implications are still unclear. Normal TSH range is commonly accepted to be within 0.35 mU/l and 4.9 mU/l and experts suggest that the upper limit should be adjusted for the pediatric population to 2.5 mU/L [1-2]. DR had no known thyroid function abnormalities or other medical illness prior to the initiation of an SSRI. Based on the results of his thyroid function panel, and given the absence of anti-TPO/anti-TG antibodies, DR did not meet criteria for a diagnosis of primary hypothyroidism. While DR had very mild aberrations in his thyroid function panel results, he still met criteria for a diagnosis of SCH at the time of his admission based upon the elevation of his TSH, which appears to have been transient and resolved by the time of his discharge. SCH is defined by an elevation in TSH despite normal levels of serum-free thyroxine, without overt clinical symptoms [3]. SCH may be a result of medical illness or a transient reaction to a homeostatic process and has been associated with a variety of affective syndromes. There is also evidence in the literature to suggest a potential correlation between the initiation of SSRIs and the development of thyroid function abnormalities, such as was seen in DR, and appears to best explain the transience and resolution of his SCH after discontinuation of the SSRI [4-5].\n\nIt is commonly accepted that SSRI use in adolescents is marked by an initial increase in the risk of suicidal ideation and attempts possibly due to a transient increase in agitation or activation, which may induce already depressed individuals to follow through on existing suicidal thoughts or plans [6-7]. While there are studies that attempt to document this observation, there is a paucity of studies undertaken to uncover the neurobiological basis underlying this drug response in adolescents. Other alternative hypotheses assert a largely unfalsifiable logic that there is a direct SSRI cause-effect to negativistic thinking in some individuals. However, a specific pathophysiological mechanism(s) that underlie multiple systemic effects, which occurs as a result of the initiation of SSRIs, has yet to be fully characterized.\n\nConclusions\nOur case report aims to implant the idea of a possible cause-effect link between two macroscopic events observed after SSRI intake in children, i.e, the endocrine change and the neuropsychiatric change, and calls for an exploration of a possible cross-talk on the cellular level that may add evidence to this cause-effect relationship. Either way, a clinical commentary on the endocrine derangement following initiation of SSRIs and its potential role in enhancing the risk for worsening of depression in adolescents is warranted.\n\nThe authors have declared that no competing interests exist.\n\nHuman Ethics\nConsent was obtained by all participants in this study\n==== Refs\nReferences\n1 High and Low TSH Levels: What They Mean. Interpretations, Variations, and Controversies 7 2019 2019 http://www.verywellhealth.com/understanding-thyroid-blood-tests-low-or-high-tsh-3233198 \n2 The evidence for a narrower thyrotropin reference range is compelling J Clin Endocrinol Metab Wartofsky L Dickey RA 5483 5488 90 2005 https://academic.oup.com/jcem/article/90/9/5483/2838749 16148345 \n3 Subclinical hypothyroidism: an update for primary care physicians Mayo Clin Proc Fatourechi V 65 71 84 2009 https://www.mayoclinicproceedings.org/article/S0025-6196(11)60809-4/fulltext 19121255 \n4 Reversible escitalopram-induced hypothyroidism Gen Hosp Psychiatry Eker SS Akkaya C Ersoy C Sarandol A Kirli S 559 557 32 2010 https://www.sciencedirect.com/science/article/pii/S0163834310000046 \n5 Escitalopram-induced subclinical hypothyroidism. A case report Hormones (Athens) Mazokopakis EE Karefilakis CM Starakis IK 101 103 11 2012 https://link.springer.com/article/10.1007/BF03401543 22450350 \n6 Efficacy and safety of antidepressant drug treatment in children and adolescents Mol Psychiatry Henry A Kisicki MD Varley C 1186 1193 17 2012 https://www.nature.com/articles/mp2011150 22064376 \n7 SSRIs (selective serotonin reuptake inhibitors) and suicidality in adults, adolescents and children (Article in Dutch) Tijdschr Psychiatr Tandt H Audenaert K van Heeringen C 387 393 51 2009 http://www.tijdschriftvoorpsychiatrie.nl/assets/articles/articles_2793pdf.pdf 19517368\n\n",
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"keywords": "adolescent; ecitalopram; selective serotonin reuptake inhibitors (ssri); side effects; subclinical hypothyroidism; suicidal ideation; thyroid stimulating hormone (tsh)",
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"pubdate": "2019-07-15",
"publication_types": "D002363:Case Reports",
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"title": "Transient Subclinical Hypothyroidism and Acute Suicidal Ideation Following Treatment with Escitalopram.",
"title_normalized": "transient subclinical hypothyroidism and acute suicidal ideation following treatment with escitalopram"
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"abstract": "OBJECTIVE\nTo evaluate the effect of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) chemotherapy alone and of ABVD with mantle or mediastinal irradiation (RT) on the pulmonary function of patients with early-stage Hodgkin's disease.\n\n\nMETHODS\nBetween 1989 and 1993, 60 patients with clinical stage I to IIIA HD enrolled onto randomized trials at Memorial Sloan-Kettering Cancer Center (MSKCC) underwent prospective evaluation of pulmonary function. All patients received six cycles of ABVD, and 30 patients received mantle or mediastinal RT. Pulmonary function tests (PFTs) and symptom evaluation were conducted before, during, and after completion of chemotherapy and RT, and at various intervals thereafter. The median follow-up time was 30 months.\n\n\nRESULTS\nDuring chemotherapy, symptoms of cough and dyspnea on exertion developed in 32 of 60 patients (53%) and declines in pulmonary function occurred in 22 of 60 patients (37%). Discontinuation of bleomycin was necessary in 14 of 60 patients (23%). Following chemotherapy, there was a significant decline in median forced vital capacity (FVC) and diffusing capacity of carbon monoxide (DLCO). In patients who received mantle or mediastinal RT, there was a further decline in FVC following radiation therapy. At the most recent follow-up evaluation, five of 29 patients (18%) who received ABVD alone and nine of 30 (30%) who received ABVD and RT reported persistent mild pulmonary symptoms (P = .36), which did not significantly affect normal daily activity.\n\n\nCONCLUSIONS\nABVD chemotherapy induced acute pulmonary toxicity that required bleomycin dose modification in a substantial number of patients. The addition of RT resulted in a further decrease in FVC; however, this did not significantly affect the functional status of patients.",
"affiliations": "Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, NY,USA.",
"authors": "Hirsch|A|A|;Vander Els|N|N|;Straus|D J|DJ|;Gomez|E G|EG|;Leung|D|D|;Portlock|C S|CS|;Yahalom|J|J|",
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"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D001761:Bleomycin; D003606:Dacarbazine; D004317:Doxorubicin; D005260:Female; D006689:Hodgkin Disease; D006801:Humans; D008168:Lung; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D016896:Treatment Outcome; D014747:Vinblastine",
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"title": "Effect of ABVD chemotherapy with and without mantle or mediastinal irradiation on pulmonary function and symptoms in early-stage Hodgkin's disease.",
"title_normalized": "effect of abvd chemotherapy with and without mantle or mediastinal irradiation on pulmonary function and symptoms in early stage hodgkin s disease"
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"abstract": "OBJECTIVE\nTo report a patient developing fulminant liver failure while being treated with clarithromycin for pneumonia.\n\n\nMETHODS\nA 58-year-old white woman developed fulminant liver failure while being treated with the macrolide antibiotic clarithromycin for pneumonia. Comedication included N-acetylcysteine, atenolol, and isradipine. Other causes of liver failure, such as viral hepatitis, autoimmune hepatitis, toxins, and heart failure, were excluded by appropriate diagnostic means. All drugs were stopped, and the patient was transferred to another hospital for liver transplantation. She recovered spontaneously within several days, making transplantation unnecessary. A liver biopsy obtained 10 days after the initial presentation revealed centroacinar necrosis and beginning fibrous reorganization, compatible with recent centroacinar damage.\n\n\nCONCLUSIONS\nSince no other cause could be identified, liver injury was considered to be drug related. Fulminant liver failure has not previously been described with concomitant use of atenolol and N-acetylcysteine. Although isradipine has been associated with hepatocellular injury, there are no reports of fulminant liver failure with this agent, and our patient had been treated for >2 years without signs of toxicity. The most likely cause of liver failure in this patient was, therefore, clarithromycin, which undergoes hepatic metabolism and has been reported to cause fulminant hepatic failure. A second possibility is an interaction between clarithromycin and isradipine, potentially increasing the hepatic toxicity of isradipine.\n\n\nCONCLUSIONS\nClarithromycin may be a cause of fulminant liver failure either alone or by inhibiting the metabolism of other drugs.",
"affiliations": "Department of Internal Medicine, University Hospital, Basel, Switzerland.",
"authors": "Tietz|Andreas|A|;Heim|Markus H|MH|;Eriksson|Urs|U|;Marsch|Stephan|S|;Terracciano|Luigi|L|;Krähenbühl|Stephan|S|",
"chemical_list": "D000900:Anti-Bacterial Agents; D017291:Clarithromycin",
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"delete": false,
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"mesh_terms": "D000900:Anti-Bacterial Agents; D017291:Clarithromycin; D005260:Female; D006801:Humans; D017093:Liver Failure; D008111:Liver Function Tests; D008875:Middle Aged; D011014:Pneumonia",
"nlm_unique_id": "9203131",
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"title": "Fulminant liver failure associated with clarithromycin.",
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{
"abstract": "Despite improvement in survival of newly diagnosed adult precursor B-acute lymphoblastic leukemia/lymphoma (B-ALL), the results of relapsed/refractory disease are poor. Blinatumomab, a bispecific monoclonal antibody directed against CD19/CD3 show clinical activity against relapsed/refractory B-ALL and in minimal residual disease (MRD)-positive patients.We report our \"real-world\" experience with blinatumomab in patients with relapsed/refractory B-ALL.Twenty-one patients, at a median age 52 years with median disease duration of 10 months, were included. Indications for treatment were hematological relapse (n = 17), MRD positivity (n = 2), inability to continue intensive chemotherapy (n = 1), and bridging to a second alloSCT (n = 1). Blinatumomab was given as first salvage in 11 patients and after at least one prior salvage treatment in eight.Complete response (CR) was newly achieved in 47% and was maintained in 75% of patients with baseline CR. At a median follow-up of 12.4 months, 13 patients were alive, and 11 in CR. Median leukemia-free survival was 8.7 months, and median overall survival was 15.2 months. Median leukemia-free survival and overall survival were not reached in patients proceeding to alloSCT compared to 5.1 and 15.2 months, respectively, for patients who did not receive stem cell transplantation.Treatment was well tolerated with neurological events reported in two patients (10%) and GI events in three patients (14%). Cytokine storm was reported in four patients (19%).In conclusion, treatment with blinatumomab is effective and tolerable in adult patients with relapsed/refractory B-ALL outside of a clinical trial stetting.",
"affiliations": "Hematology Department, Shamir (Asaf Harofe) Medical Center, Zerifin, Israel. ariea@shamir.health.gov.il.;Department of Hematology and Bone Marrow transplantation, Rambam Health Care Campus, Haifa, Israel.;Institute of Hematology, Davidoff Cancer Center, Belinson Hospital, Rabin Medical Center, Petach-Tikva, Israel.;Institute of Hematology, Davidoff Cancer Center, Belinson Hospital, Rabin Medical Center, Petach-Tikva, Israel.;Bone Marrow Transplantation Unit, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.;Institute of Hematology, Faculty of Health Sciences, Soroka University Medical Center, Beer Sheba, Israel.;Soroka medical center, Beer Sheba, Israel.;Hematology Department, Shamir (Asaf Harofe) Medical Center, Zerifin, Israel.",
"authors": "Apel|Arie|A|http://orcid.org/0000-0001-6269-9994;Ofran|Yishai|Y|;Wolach|Ofir|O|;Shimony|Shai|S|;Ram|Ron|R|;Levi|Itai|I|;Zektser|Miri|M|;Koren-Michowitz|Maya|M|",
"chemical_list": "D018033:Antibodies, Bispecific; D018941:Antigens, CD19; D000951:Antigens, Neoplasm; D000074322:Antineoplastic Agents, Immunological; C000604811:CD19 molecule, human; D017252:CD3 Complex; D016207:Cytokines; C510808:blinatumomab",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00277-019-03854-0",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0939-5555",
"issue": "99(4)",
"journal": "Annals of hematology",
"keywords": "Blinatumomab; Minimal residual disease; Precursor B-acute lymphoblastic leukemia/lymphoma; Salvage therapy",
"medline_ta": "Ann Hematol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018033:Antibodies, Bispecific; D000918:Antibody Specificity; D018941:Antigens, CD19; D000951:Antigens, Neoplasm; D000074322:Antineoplastic Agents, Immunological; D017252:CD3 Complex; D003131:Combined Modality Therapy; D016207:Cytokines; D018572:Disease-Free Survival; D005260:Female; D005767:Gastrointestinal Diseases; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D018365:Neoplasm, Residual; D009422:Nervous System Diseases; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; D012008:Recurrence; D012074:Remission Induction; D012189:Retrospective Studies; D016879:Salvage Therapy; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "9107334",
"other_id": null,
"pages": "835-838",
"pmc": null,
"pmid": "32076826",
"pubdate": "2020-04",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Safety and efficacy of blinatumomab: a real world data.",
"title_normalized": "safety and efficacy of blinatumomab a real world data"
} | [
{
"companynumb": "IL-AMGEN-ISRSP2020068239",
"fulfillexpeditecriteria": "2",
"occurcountry": "IL",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "BLINATUMOMAB"
},
"drugadditional": null,
... |
{
"abstract": "Azathioprine is an immunosuppressant drug used in many dermatological and nondermatological pathologies. Azathioprine hypersensitivity syndrome (AHS) is a rare idiosyncratic reaction that is not related to dose or thiopurine methyltransferase activity. Up to half of cases of AHS can present with variable cutaneous manifestations besides fever, malaise and other systemic symptoms. It is important to be aware of AHS, as continuance or reintroduction of the drug can led to multiorgan failure and cardiovascular collapse.",
"affiliations": "Departments of Dermatology, Hospital Universitario Fundación Jiménez Díaz, Madrid, Spain.;Departments of Dermatology, Hospital Universitario Fundación Jiménez Díaz, Madrid, Spain.;Gastroenterology, Hospital Universitario Fundación Jiménez Díaz, Madrid, Spain.;Pathology, Hospital Universitario Fundación Jiménez Díaz, Madrid, Spain.;Pathology, Hospital Universitario Fundación Jiménez Díaz, Madrid, Spain.;Genetics, Hospital Universitario Fundación Jiménez Díaz, Madrid, Spain.;Departments of Dermatology, Hospital Universitario Fundación Jiménez Díaz, Madrid, Spain.;Departments of Dermatology, Hospital Universitario Fundación Jiménez Díaz, Madrid, Spain.",
"authors": "Moya-Martínez|C|C|https://orcid.org/0000-0002-0394-1282;Núñez-Hipólito|L|L|;Barrio-González|S|S|;Santonja|C|C|;Jo-Velasco|M|M|;Lorda-Sánchez|I|I|;Fariña-Sabaris|M C|MC|;Requena|L|L|https://orcid.org/0000-0002-1045-4810",
"chemical_list": "D007166:Immunosuppressive Agents; D001379:Azathioprine",
"country": "England",
"delete": false,
"doi": "10.1111/ced.14643",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0307-6938",
"issue": "46(6)",
"journal": "Clinical and experimental dermatology",
"keywords": null,
"medline_ta": "Clin Exp Dermatol",
"mesh_terms": "D001379:Azathioprine; D003937:Diagnosis, Differential; D063926:Drug Hypersensitivity Syndrome; D004487:Edema; D006801:Humans; D007166:Immunosuppressive Agents; D008297:Male; D008875:Middle Aged; D009504:Neutrophils; D012867:Skin",
"nlm_unique_id": "7606847",
"other_id": null,
"pages": "1097-1101",
"pmc": null,
"pmid": "33713349",
"pubdate": "2021-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Azathioprine hypersensitivity syndrome: report of two cases with cutaneous manifestations.",
"title_normalized": "azathioprine hypersensitivity syndrome report of two cases with cutaneous manifestations"
} | [
{
"companynumb": "AU-RISING PHARMA HOLDINGS, INC.-2021RIS000022",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "AZATHIOPRINE"
},
"drugad... |
{
"abstract": "We present a patient who had rheumatoid meningitis while on infliximab, a tumor necrosis factor alpha (TNF-α) inhibitor, which initially presented as transient ischemic attacks. Although our patient had been stable on infliximab for several years, her neurologic symptoms improved when her infliximab was held due to active infection and then recurred after reinitiation of therapy. Rheumatoid meningitis is exceedingly rare; however, there have been several other reports of rheumatoid meningitis developing in patients on TNF-α inhibitor therapy.",
"affiliations": "Baylor Scott & White Health, Temple, Texas.;Baylor Scott & White Health, Temple, Texas.;Baylor Scott & White Health, Temple, Texas.",
"authors": "Seago|Susan|S|;Stroberg|Edana|E|;Metting|Austin|A|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1080/08998280.2016.11929419",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0899-8280",
"issue": "29(2)",
"journal": "Proceedings (Baylor University. Medical Center)",
"keywords": null,
"medline_ta": "Proc (Bayl Univ Med Cent)",
"mesh_terms": null,
"nlm_unique_id": "9302033",
"other_id": null,
"pages": "204-6",
"pmc": null,
"pmid": "27034572",
"pubdate": "2016-04",
"publication_types": "D002363:Case Reports",
"references": "23802849;25198168;20656540;21962388;24584566;10449104;17549580;14677033;16981287;19046446",
"title": "Rheumatoid meningitis associated with infliximab.",
"title_normalized": "rheumatoid meningitis associated with infliximab"
} | [
{
"companynumb": "US-JNJFOC-20160406510",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "INFLIXIMAB"
},
"drugadditional": null,
... |
{
"abstract": "A 19-year-old man with a history of eczema was admitted to the emergency department following collapsing at home. The paramedics found him unresponsive with poor respiratory effort and a widespread erythematous rash. Anaphylaxis, thought to be secondary to flucloxacillin he had recently been prescribed, was diagnosed. Epinephrine, steroids and antihistamines were administered without clinical improvement. On arrival to hospital, constricted pupils were noted prompting the emergency physicians to consider opiate toxicity. Intravenous naloxone brought about an immediate recovery. His father subsequently disclosed that he had given his son one of his own fentanyl patches to alleviate the distressing symptoms of eczema. Although the patient had removed the patch prior to collapsing, he had suffered life-threatening opioid toxicity likely due to enhanced opiate absorption through eczematous skin. This case highlights the risks associated with fentanyl patches in patients with chronic skin conditions.",
"affiliations": "NHS Lothian, Edinburgh, UK.;National Poisons Information Service Edinburgh, NHS Lothian, Edinburgh, UK.",
"authors": "Doris|Mhairi K|MK|;Sandilands|Euan A|EA|",
"chemical_list": "D000701:Analgesics, Opioid; D009292:Narcotic Antagonists; D009270:Naloxone; D005283:Fentanyl",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2015()",
"journal": "BMJ case reports",
"keywords": null,
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000279:Administration, Cutaneous; D000701:Analgesics, Opioid; D004485:Eczema; D005283:Fentanyl; D006801:Humans; D008297:Male; D009270:Naloxone; D009292:Narcotic Antagonists; D012651:Self Medication; D057968:Transdermal Patch; D055815:Young Adult",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "25926584",
"pubdate": "2015-04-29",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "11524334;9010652;17882442;22835002;10668859",
"title": "Life-threatening opioid toxicity from a fentanyl patch applied to eczematous skin.",
"title_normalized": "life threatening opioid toxicity from a fentanyl patch applied to eczematous skin"
} | [
{
"companynumb": "GB-MYLANLABS-2015M1023015",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "FLUCLOXACILLIN"
},
"drugadditional": null,
... |
{
"abstract": "Many inflammatory bowel disease (IBD) patients do not respond to medical therapy. Tofacitinib is a first-in-class, partially selective inhibitor of Janus kinase, recently approved for treating patients with ulcerative colitis (UC). We describe our experience with the use of tofacitinib for treatment of patients with moderate-to-severe IBD.\n\n\n\nThis is a retrospective, observational study of the use of tofacitinib in IBD. Patients with medically resistant IBD were treated orally with 5 mg or 10 mg twice daily. Clinical response and adverse events were assessed at 8, 26, and 52 weeks. Objective response was assessed endoscopically, radiologically, and biochemically.\n\n\n\n58 patients (53 UC, 4 Crohn's, 1 pouchitis) completed at least 8 weeks of treatment with tofacitinib. 93% of the patients previously failed treatment with anti-TNF. At 8 weeks of treatment, 21 patients (36%) achieved a clinical response, and 19 (33%) achieved clinical remission. Steroid-free remission at 8 weeks was achieved in 15 patients (26%). Of the 48 patients followed for 26 weeks, 21% had clinical, steroid-free remission. Of the 26 patients followed for 12 months, 27% were in clinical, steroid-free remission. Twelve episodes of systemic infections were noted, mostly while on concomitant steroids. One episode of herpes zoster infection was noted during follow-up.\n\n\n\nIn this cohort of patients with moderate-to-severe, anti-TNF resistant IBD, tofacitinib induced clinical response in 69% of the patients. 27% were in clinical, steroid-free remission by 1 year of treatment. Tofacitinib is an effective therapeutic option for this challenging patient population.",
"affiliations": "Inflammatory Bowel Disease Center, University of Chicago Medicine, 5841 S. Maryland Ave, MC 4076, Chicago, IL, 60637, USA.;Inflammatory Bowel Disease Center, University of Chicago Medicine, 5841 S. Maryland Ave, MC 4076, Chicago, IL, 60637, USA.;Inflammatory Bowel Disease Center, University of Chicago Medicine, 5841 S. Maryland Ave, MC 4076, Chicago, IL, 60637, USA.;Inflammatory Bowel Disease Center, University of Chicago Medicine, 5841 S. Maryland Ave, MC 4076, Chicago, IL, 60637, USA.;Inflammatory Bowel Disease Center, University of Chicago Medicine, 5841 S. Maryland Ave, MC 4076, Chicago, IL, 60637, USA.;Inflammatory Bowel Disease Center, University of Chicago Medicine, 5841 S. Maryland Ave, MC 4076, Chicago, IL, 60637, USA.;Inflammatory Bowel Disease Center, University of Chicago Medicine, 5841 S. Maryland Ave, MC 4076, Chicago, IL, 60637, USA.;Inflammatory Bowel Disease Center, University of Chicago Medicine, 5841 S. Maryland Ave, MC 4076, Chicago, IL, 60637, USA.;Inflammatory Bowel Disease Center, University of Chicago Medicine, 5841 S. Maryland Ave, MC 4076, Chicago, IL, 60637, USA.;Inflammatory Bowel Disease Center, University of Chicago Medicine, 5841 S. Maryland Ave, MC 4076, Chicago, IL, 60637, USA. drubin@uchicago.edu.",
"authors": "Weisshof|Roni|R|;Aharoni Golan|Maya|M|;Sossenheimer|Philip H|PH|;El Jurdi|Katia|K|;Ollech|Jacob E|JE|;Pekow|Joel|J|;Cohen|Russel D|RD|;Sakuraba|Atsushi|A|;Dalal|Sushila|S|;Rubin|David T|DT|0000-0001-5647-1723",
"chemical_list": "D000075242:Janus Kinase Inhibitors; D010880:Piperidines; D011743:Pyrimidines; D011758:Pyrroles; C479163:tofacitinib",
"country": "United States",
"delete": false,
"doi": "10.1007/s10620-019-05492-y",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0163-2116",
"issue": "64(7)",
"journal": "Digestive diseases and sciences",
"keywords": "Inflammatory bowel disease; Jak inhibitors; Tofacitinib; Ulcerative colitis",
"medline_ta": "Dig Dis Sci",
"mesh_terms": "D000284:Administration, Oral; D000328:Adult; D003092:Colitis; D003093:Colitis, Ulcerative; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D000075242:Janus Kinase Inhibitors; D008297:Male; D008875:Middle Aged; D010880:Piperidines; D019449:Pouchitis; D011743:Pyrimidines; D011758:Pyrroles; D012074:Remission Induction; D012189:Retrospective Studies; D062606:Tertiary Care Centers; D013997:Time Factors; D016896:Treatment Outcome",
"nlm_unique_id": "7902782",
"other_id": null,
"pages": "1945-1951",
"pmc": null,
"pmid": "30734234",
"pubdate": "2019-07",
"publication_types": "D016428:Journal Article; D064888:Observational Study; D052061:Research Support, N.I.H., Extramural",
"references": "22062358;23964932;29850873;28467869;27780712;27787492;28630047;25047021;21407183;28209624;26966791;28164724;24943354;22001864;24480677;27988142;28593685",
"title": "Real-World Experience with Tofacitinib in IBD at a Tertiary Center.",
"title_normalized": "real world experience with tofacitinib in ibd at a tertiary center"
} | [
{
"companynumb": "US-PFIZER INC-2019066328",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "TOFACITINIB CITRATE"
},
"drugadditional": null... |
{
"abstract": "Donor-derived malignancy, particularly melanoma, is a rare but known complication of organ transplantation. Here we describe a case of metastatic melanoma in a deceased-donor kidney transplant recipient. After diagnosis, the patient was successfully treated with cessation of immunosuppression, explantation of the renal allograft, and novel melanoma therapies, including the mutation-targeted agents dabrafenib and trametinib and the immune checkpoint inhibitor nivolumab. These 2 new classes of melanoma therapy have revolutionized the course of metastatic melanoma, altering it from one of nearly certain mortality to one of potential cure. This case reviews the mechanisms of action of these therapies and reports our experience with them in the rare setting of donor-derived melanoma in a dialysis-dependent patient.",
"affiliations": "Division of Nephrology, Drexel University College of Medicine, Philadelphia, Pennsylvania. Electronic address: suzanne.boyle@drexelmed.edu.;Division of Medical Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania.;Division of Medical Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania.;Division of Transplant Surgery, Hahnemann University Hospital, Philadelphia, Pennsylvania.;Division of Transplant Surgery, Hahnemann University Hospital, Philadelphia, Pennsylvania.;Division of Transplant Surgery, Hahnemann University Hospital, Philadelphia, Pennsylvania.;Division of Nephrology, University of Virginia School of Medicine, Charlottesville, Virginia.",
"authors": "Boyle|S M|SM|;Ali|N|N|;Olszanski|A J|AJ|;Park|D J|DJ|;Xiao|G|G|;Guy|S|S|;Doyle|A M|AM|",
"chemical_list": "D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D007093:Imidazoles; D010091:Oximes; D011728:Pyridones; D011744:Pyrimidinones; D000077594:Nivolumab; C560077:trametinib; D064447:Checkpoint Kinase 2; C000605867:CHEK1 protein, human; C578634:CHEK2 protein, human; D000071877:Checkpoint Kinase 1; C561627:dabrafenib",
"country": "United States",
"delete": false,
"doi": "10.1016/j.transproceed.2017.06.007",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-1345",
"issue": "49(7)",
"journal": "Transplantation proceedings",
"keywords": null,
"medline_ta": "Transplant Proc",
"mesh_terms": "D064591:Allografts; D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D000071877:Checkpoint Kinase 1; D064447:Checkpoint Kinase 2; D006801:Humans; D007093:Imidazoles; D007668:Kidney; D007680:Kidney Neoplasms; D016030:Kidney Transplantation; D008113:Liver Neoplasms; D008175:Lung Neoplasms; D008297:Male; D008545:Melanoma; D008875:Middle Aged; D000077594:Nivolumab; D010091:Oximes; D011728:Pyridones; D011744:Pyrimidinones; D014019:Tissue Donors",
"nlm_unique_id": "0243532",
"other_id": null,
"pages": "1551-1554",
"pmc": null,
"pmid": "28838438",
"pubdate": "2017-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Donor-Derived Metastatic Melanoma and Checkpoint Inhibition.",
"title_normalized": "donor derived metastatic melanoma and checkpoint inhibition"
} | [
{
"companynumb": "US-ASTELLAS-2017US036555",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "DABRAFENIB"
},
"drugadditional": null,
... |
{
"abstract": "We present the cases of two pregnant women who developed severe respiratory compromise in mid pregnancy, one due to rapidly progressive interstitial lung disease associated with mixed connective tissue disease and one secondary to diffuse alveolar haemorrhage due to antiglomerular basement membrane disease. Both were treated with high-dose steroids followed by pulsed intravenous cyclophosphamide. Both women went onto have live births although one baby was growth restricted and preterm. Neither baby had any evidence of congenital abnormalities.",
"affiliations": "Women's Health Academic Centre, Guy's & St Thomas' Foundation Trust (GSTFT), St Thomas' Hospital, London, UK.;Department of Rheumatology, GSTFT, London, UK.;Department of Respiratory medicine, GSTFT, London, UK.",
"authors": "Nelson-Piercy|Catherine|C|;Agarwal|Sangita|S|;Lams|Boris|B|",
"chemical_list": "D000305:Adrenal Cortex Hormones; D007166:Immunosuppressive Agents; D003520:Cyclophosphamide",
"country": "England",
"delete": false,
"doi": "10.1136/thoraxjnl-2016-208441",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0040-6376",
"issue": "71(7)",
"journal": "Thorax",
"keywords": "Interstitial Fibrosis; Pulmonary vasculitis; Systemic disease and lungs",
"medline_ta": "Thorax",
"mesh_terms": "D000305:Adrenal Cortex Hormones; D000328:Adult; D019867:Anti-Glomerular Basement Membrane Disease; D001327:Autoimmune Diseases; D003520:Cyclophosphamide; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents; D017563:Lung Diseases, Interstitial; D008947:Mixed Connective Tissue Disease; D011247:Pregnancy; D011248:Pregnancy Complications; D011256:Pregnancy Outcome",
"nlm_unique_id": "0417353",
"other_id": null,
"pages": "667-8",
"pmc": null,
"pmid": "27033023",
"pubdate": "2016-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Lesson of the month: selective use of cyclophosphamide in pregnancy for severe autoimmune respiratory disease.",
"title_normalized": "lesson of the month selective use of cyclophosphamide in pregnancy for severe autoimmune respiratory disease"
} | [
{
"companynumb": "GB-PFIZER INC-2016374041",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"drugadditional": "3",
... |
{
"abstract": "Gabapentin is commonly used to treat neuropathic pain (pain due to nerve damage). This review updates a review published in 2014, and previous reviews published in 2011, 2005 and 2000.\n\n\n\nTo assess the analgesic efficacy and adverse effects of gabapentin in chronic neuropathic pain in adults.\n\n\n\nFor this update we searched CENTRAL), MEDLINE, and Embase for randomised controlled trials from January 2014 to January 2017. We also searched the reference lists of retrieved studies and reviews, and online clinical trials registries.\n\n\n\nWe included randomised, double-blind trials of two weeks' duration or longer, comparing gabapentin (any route of administration) with placebo or another active treatment for neuropathic pain, with participant-reported pain assessment.\n\n\n\nTwo review authors independently extracted data and assessed trial quality and potential bias. Primary outcomes were participants with substantial pain relief (at least 50% pain relief over baseline or very much improved on Patient Global Impression of Change scale (PGIC)), or moderate pain relief (at least 30% pain relief over baseline or much or very much improved on PGIC). We performed a pooled analysis for any substantial or moderate benefit. Where pooled analysis was possible, we used dichotomous data to calculate risk ratio (RR) and number needed to treat for an additional beneficial outcome (NNT) or harmful outcome (NNH). We assessed the quality of the evidence using GRADE and created 'Summary of findings' tables.\n\n\n\nWe included four new studies (530 participants), and excluded three previously included studies (126 participants). In all, 37 studies provided information on 5914 participants. Most studies used oral gabapentin or gabapentin encarbil at doses of 1200 mg or more daily in different neuropathic pain conditions, predominantly postherpetic neuralgia and painful diabetic neuropathy. Study duration was typically four to 12 weeks. Not all studies reported important outcomes of interest. High risk of bias occurred mainly due to small size (especially in cross-over studies), and handling of data after study withdrawal.In postherpetic neuralgia, more participants (32%) had substantial benefit (at least 50% pain relief or PGIC very much improved) with gabapentin at 1200 mg daily or greater than with placebo (17%) (RR 1.8 (95% CI 1.5 to 2.1); NNT 6.7 (5.4 to 8.7); 8 studies, 2260 participants, moderate-quality evidence). More participants (46%) had moderate benefit (at least 30% pain relief or PGIC much or very much improved) with gabapentin at 1200 mg daily or greater than with placebo (25%) (RR 1.8 (95% CI 1.6 to 2.0); NNT 4.8 (4.1 to 6.0); 8 studies, 2260 participants, moderate-quality evidence).In painful diabetic neuropathy, more participants (38%) had substantial benefit (at least 50% pain relief or PGIC very much improved) with gabapentin at 1200 mg daily or greater than with placebo (21%) (RR 1.9 (95% CI 1.5 to 2.3); NNT 5.9 (4.6 to 8.3); 6 studies, 1277 participants, moderate-quality evidence). More participants (52%) had moderate benefit (at least 30% pain relief or PGIC much or very much improved) with gabapentin at 1200 mg daily or greater than with placebo (37%) (RR 1.4 (95% CI 1.3 to 1.6); NNT 6.6 (4.9 to 9.9); 7 studies, 1439 participants, moderate-quality evidence).For all conditions combined, adverse event withdrawals were more common with gabapentin (11%) than with placebo (8.2%) (RR 1.4 (95% CI 1.1 to 1.7); NNH 30 (20 to 65); 22 studies, 4346 participants, high-quality evidence). Serious adverse events were no more common with gabapentin (3.2%) than with placebo (2.8%) (RR 1.2 (95% CI 0.8 to 1.7); 19 studies, 3948 participants, moderate-quality evidence); there were eight deaths (very low-quality evidence). Participants experiencing at least one adverse event were more common with gabapentin (63%) than with placebo (49%) (RR 1.3 (95% CI 1.2 to 1.4); NNH 7.5 (6.1 to 9.6); 18 studies, 4279 participants, moderate-quality evidence). Individual adverse events occurred significantly more often with gabapentin. Participants taking gabapentin experienced dizziness (19%), somnolence (14%), peripheral oedema (7%), and gait disturbance (14%).\n\n\n\nGabapentin at doses of 1800 mg to 3600 mg daily (1200 mg to 3600 mg gabapentin encarbil) can provide good levels of pain relief to some people with postherpetic neuralgia and peripheral diabetic neuropathy. Evidence for other types of neuropathic pain is very limited. The outcome of at least 50% pain intensity reduction is regarded as a useful outcome of treatment by patients, and the achievement of this degree of pain relief is associated with important beneficial effects on sleep interference, fatigue, and depression, as well as quality of life, function, and work. Around 3 or 4 out of 10 participants achieved this degree of pain relief with gabapentin, compared with 1 or 2 out of 10 for placebo. Over half of those treated with gabapentin will not have worthwhile pain relief but may experience adverse events. Conclusions have not changed since the previous update of this review.",
"affiliations": "Pain Research and Nuffield Department of Clinical Neurosciences (Nuffield Division of Anaesthetics), University of Oxford, Pain Research Unit, Churchill Hospital, Oxford, Oxfordshire, UK, OX3 7LE.",
"authors": "Wiffen|Philip J|PJ|;Derry|Sheena|S|;Bell|Rae F|RF|;Rice|Andrew Sc|AS|;Tölle|Thomas Rudolf|TR|;Phillips|Tudor|T|;Moore|R Andrew|RA|",
"chemical_list": "D000588:Amines; D000700:Analgesics; D003509:Cyclohexanecarboxylic Acids; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin",
"country": "England",
"delete": false,
"doi": "10.1002/14651858.CD007938.pub4",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1361-6137",
"issue": "6()",
"journal": "The Cochrane database of systematic reviews",
"keywords": null,
"medline_ta": "Cochrane Database Syst Rev",
"mesh_terms": "D000328:Adult; D000588:Amines; D000700:Analgesics; D002908:Chronic Disease; D059350:Chronic Pain; D003509:Cyclohexanecarboxylic Acids; D003929:Diabetic Neuropathies; D005356:Fibromyalgia; D000077206:Gabapentin; D006801:Humans; D009437:Neuralgia; D051474:Neuralgia, Postherpetic; D061366:Numbers Needed To Treat; D016032:Randomized Controlled Trials as Topic; D005680:gamma-Aminobutyric Acid",
"nlm_unique_id": "100909747",
"other_id": null,
"pages": "CD007938",
"pmc": null,
"pmid": "28597471",
"pubdate": "2017-06-09",
"publication_types": "D016428:Journal Article; D017418:Meta-Analysis; D013485:Research Support, Non-U.S. Gov't; D016454:Review; D000078182:Systematic Review",
"references": "1798430;7580659;23733529;28144823;18258368;25139589;19674449;25218827;16087911;16213659;23553508;16416358;20347225;19195785;22542023;25883095;15800228;25117131;24355386;10071116;23544056;16586190;21414722;19171730;20627575;16352376;15254060;26041754;21054455;27465317;19821395;24385423;19783099;17604592;23622761;21206180;20722677;8008402;21764514;23245607;8721797;20217150;19129523;25985142;20810214;23149085;22028777;23645858;19019057;21627766;27798973;18258369;22172618;22710756;21803546;26146793;22497967;26421677;9846778;26436601;19748185;22757655;28223849;21412914;10493324;17976220;20639294;18055266;18489611;23347230;23442783;18460194;17888574;19333167;3300460;28320937;23748119;12456446;25670518;17030096;27727431;15324820;26115203;19078655;22365541;19590476;12373695;19588419;16618472;11914310;23616031;28045473;18950449;21203440;23602345;20303665;20091515;24291734;22609141;23218569;26814307;19818485;8740611;17450066;16034978;18047869;8629879;19089502;27037091;19907043;12406532;18003941;17853395;15503108;23464879;16013891;22801243;20818838;24771480;23186035;23235657;18673529;25058164;22972149;24102928;19135492;15087796;16060401;22055553;27216018;22394606;11027910;19539427;23835590;22786518;21745832;28257927;12137213;19364730;10896633;19796802;9846777;24829909;19013718;28027389;25479151;18824466;16034857;11690735;15106126;9870574;15976235;28085183;19453961;19732374;19208243;20304558;28205574;25575710;16961166;27893485;18607580;21602106;26963844;23339030;17065896;20464764;15453912;24217986;21719618;12958120",
"title": "Gabapentin for chronic neuropathic pain in adults.",
"title_normalized": "gabapentin for chronic neuropathic pain in adults"
} | [
{
"companynumb": "PA-ALKEM LABORATORIES LIMITED-PA-ALKEM-2018-11103",
"fulfillexpeditecriteria": "1",
"occurcountry": "PA",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "GABAPENTIN"
},
"druga... |
{
"abstract": "Proton pump inhibitors (PPI) are widely used in patients with systemic sclerosis (SSc) due to the chronic gastroesophageal reflux. The authors report a female patient with a 9-year history of SSc and long-term use of omeprazole, who complained of paresthesia and asthenia for 12 months. Physical examination revealed clinical signs of hypocalcaemia confirmed by laboratory tests that also showed hypomagnesaemia. After exclusion of possible causes, hypomagnesaemia secondary to PPI was diagnosed and omeprazole was replaced by a histamine H2-receptor antagonist: ranitidine. Despite continuous magnesium supplementation, the reintroduction of PPI at a lower dose due to worsening of dyspeptic symptoms led to recurrence of hypomagnesaemia. After definitive suspension of PPI, reintroduction of ranitidine and optimisation of anti-reflux environmental measures, the patient stabilised. In conclusion, SSc patients using PPIs should have their magnesium and calcium serum levels measured periodically, and non-specific symptoms such as asthenia, generalised paresthesia or life-threatening manifestations (seizures, arrhythmias) should not be neglected.",
"affiliations": "Division of Rheumatology, University of São Paulo, São Paulo, Brazil. marianaortegaperez@gmail.com.",
"authors": "Perez|M O|MO|;Neves|E F V|EF|;Bortolai|C B C|CB|;Sampaio-Barros|P D|PD|;Andrade|Di C O|DC|;Seguro|L P C|LP|",
"chemical_list": "D054328:Proton Pump Inhibitors; D008274:Magnesium; D009853:Omeprazole",
"country": "Italy",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0392-856X",
"issue": "32(6 Suppl 86)",
"journal": "Clinical and experimental rheumatology",
"keywords": null,
"medline_ta": "Clin Exp Rheumatol",
"mesh_terms": "D000368:Aged; D005260:Female; D005764:Gastroesophageal Reflux; D006801:Humans; D006996:Hypocalcemia; D008274:Magnesium; D009853:Omeprazole; D054328:Proton Pump Inhibitors; D012595:Scleroderma, Systemic",
"nlm_unique_id": "8308521",
"other_id": null,
"pages": "S-225-7",
"pmc": null,
"pmid": "25068521",
"pubdate": "2014",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Hypomagnesaemia and hypocalcaemia in a patient with systemic sclerosis: role of proton pump inhibitors.",
"title_normalized": "hypomagnesaemia and hypocalcaemia in a patient with systemic sclerosis role of proton pump inhibitors"
} | [
{
"companynumb": "BR-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2015-BI-64813BI",
"fulfillexpeditecriteria": "1",
"occurcountry": "BR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "RANITIDINE\\RANITIDINE HYDROCHLORID... |
{
"abstract": "Conventional treatment of patients with adrenal insufficiency involves administration of glucocorticoids multiple times a day and has been associated with weight gain and metabolic impairment. The optimal glucocorticoid replacement therapy for these patients is highly debated because of the scarcity of evidence from randomised trials. We aimed to establish whether the timing and pharmacokinetics of glucocorticoid replacement therapy affect the metabolism and immune system of patients with adrenal insufficiency.\n\n\n\nWe did a single-blind randomised controlled trial at two reference university hospitals in Italy. Eligible patients (aged 18-80 years) with adrenal insufficiency were on conventional glucocorticoid therapy and had been stable for at least 3 months before enrolment. Patients were randomly assigned (1:1) with a computer-generated random sequence stratified by type of adrenal insufficiency and BMI to continue conventional glucocorticoid therapy (standard treatment group) or to switch to an equivalent dose of once-daily, modified-release oral hydrocortisone (switch treatment group). Outcome assessors were masked to treatment allocation. The primary outcome was bodyweight change from baseline to 24 weeks. Secondary outcomes included immune cell profiles, susceptibility to infections, and quality of life. Efficacy analyses included all patients who received at least one dose of the study drug. This trial is registered with ClinicalTrials.gov, NCT02277587.\n\n\n\nBetween March 1, 2014, and June 30, 2016, 89 patients with adrenal insufficiency were randomly assigned to continue standard glucocorticoid therapy (n=43) or to switch to once-daily, modified-release hydrocortisone (n=46). At 24 weeks, bodyweight reduction was superior in patients in the once-daily hydrocortisone group compared with those in the standard treatment group (-2·1 kg [95% CI -4·0 to -0·3] vs 1·9 kg [-0·1 to 3·9]; treatment difference -4·0 kg, 95% CI -6·9 to -1·1; p=0·008). Additionally, patients in the once-daily hydrocortisone group had more normal immune cell profiles, reduced susceptibility to infections, and improved quality of life compared with the standard glucocorticoid therapy group. We observed no difference in frequency or severity of adverse events between the two intervention groups, although a lower cumulative number of recurrent upper respiratory tract infections was observed with once-daily hydrocortisone than with standard treatment (17 vs 38; p=0·016). Most adverse events were mild; three serious adverse events occurred in each group, of which one adverse advent (arthritis) in the switch treatment group could be considered drug related.\n\n\n\nPatients with adrenal insufficiency on conventional glucocorticoid replacement therapy multiple times a day exhibit a pro-inflammatory state and weakened immune defence. Restoration of a more physiological circadian glucocorticoid rhythm by switching to a once-daily, modified-release regimen reduces bodyweight, normalises the immune cell profile, reduces recurrent infections, and improves the quality of life of patients with adrenal insufficiency.\n\n\n\nItalian Ministry of University and Research.",
"affiliations": "Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy. Electronic address: andrea.isidori@uniroma1.it.;Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy.;Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy.;Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Università Federico II di Napoli, Naples, Italy.;Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy.;Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy.;Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy.;Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy.;Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy.;Service of Medical Statistics and Information Technology, Fatebenefratelli Foundation for Health Research and Education, Rome, Italy.;Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy.;Department of Molecular Medicine, Pasteur Institute-Cenci Bolognetti Foundation, Sapienza University of Rome, Rome, Italy.;Department of Anatomical, Histological, Forensic and Orthopaedic Sciences, Sapienza University of Rome, Rome, Italy.;Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Università Federico II di Napoli, Naples, Italy.;Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Università Federico II di Napoli, Naples, Italy.;Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy.",
"authors": "Isidori|Andrea M|AM|;Venneri|Mary Anna|MA|;Graziadio|Chiara|C|;Simeoli|Chiara|C|;Fiore|Daniela|D|;Hasenmajer|Valeria|V|;Sbardella|Emilia|E|;Gianfrilli|Daniele|D|;Pozza|Carlotta|C|;Pasqualetti|Patrizio|P|;Morrone|Stefania|S|;Santoni|Angela|A|;Naro|Fabio|F|;Colao|Annamaria|A|;Pivonello|Rosario|R|;Lenzi|Andrea|A|",
"chemical_list": "D000893:Anti-Inflammatory Agents; D015415:Biomarkers; D005938:Glucocorticoids; D006854:Hydrocortisone",
"country": "England",
"delete": false,
"doi": "10.1016/S2213-8587(17)30398-4",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2213-8587",
"issue": "6(3)",
"journal": "The lancet. Diabetes & endocrinology",
"keywords": null,
"medline_ta": "Lancet Diabetes Endocrinol",
"mesh_terms": "D000293:Adolescent; D000309:Adrenal Insufficiency; D000328:Adult; D000368:Aged; D000893:Anti-Inflammatory Agents; D015415:Biomarkers; D001835:Body Weight; D002940:Circadian Rhythm; D004334:Drug Administration Schedule; D005260:Female; D005938:Glucocorticoids; D006801:Humans; D006854:Hydrocortisone; D007113:Immunity, Innate; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D011788:Quality of Life; D016037:Single-Blind Method; D055815:Young Adult",
"nlm_unique_id": "101618821",
"other_id": null,
"pages": "173-185",
"pmc": null,
"pmid": "29229498",
"pubdate": "2018-03",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Effect of once-daily, modified-release hydrocortisone versus standard glucocorticoid therapy on metabolism and innate immunity in patients with adrenal insufficiency (DREAM): a single-blind, randomised controlled trial.",
"title_normalized": "effect of once daily modified release hydrocortisone versus standard glucocorticoid therapy on metabolism and innate immunity in patients with adrenal insufficiency dream a single blind randomised controlled trial"
} | [
{
"companynumb": "IT-IMPAX LABORATORIES, INC-2018-IPXL-03333",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "HYDROCORTISONE"
},
"drugaddi... |
{
"abstract": "BACKGROUND\nAnthracyclines are effective drugs in pediatrics cancer treatment. However, anthracycline-induced cardiotoxicity (AIC) is a serious adverse drug reaction that affects the survival in patients treated for childhood cancer.\n\n\nMETHODS\nCase 1: Nine-year-old girl with stage IV Hodgkin lymphoma with 12 epirubicin doses and a cumulative dose of 576 mg/m2. After last chemotherapy dose, the patient was admitted with systemic inflammatory response, asthenia and adinamia. Echocardiography: LVEF of 22%, SF 11% and moderate mitral regurgitation. Patient died 2 days after diagnosed with dilated cardiomyopathy secondary to anthracyclines. Case 2: Fifteen-year-old girl with stage IV Burkitt lymphoma with two epirubicin doses and a cumulative dose of 90 mg/m2. After the last cycle, the patient developed several infectious foci. Echocardiography: LVEF of 49%, SF 20% and dilated left ventricle with septal flattening. Patient died 13 days after diagnosis of dilated cardiomyopathy by anthracyclines.\n\n\nCONCLUSIONS\nAIC is a problem in pediatric patients receiving anthracyclines, monitoring is essential to detect the onset of cardiac damage to provide an intervention to prevent heart failure progress.",
"affiliations": "Departamento de Farmacología, Centro de Investigación y de Estudios Avanzados, Instituto Politécnico Nacional, Ciudad de México, México. castelan@unam.mx.;Facultad de Estudios Superiores Zaragoza, Universidad Nacional Autónoma de México.;Hospital de Pediatría, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social.;Hospital de Pediatría, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social.;Hospital de Pediatría, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social; Centro de Adiestramiento en Investigación Clínica (CAIC), División de Investigación en Salud, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social/ Facultad de Medicina, Universidad Nacional Autónoma de México.",
"authors": "Vargas-Neri|Jessica Liliana|JL|;Castelán-Martínez|Osvaldo Daniel|OD|;de Jesús Estrada-Loza|María|M|;Betanzos-Cabrera|Yadira|Y|;Rivas-Ruiz|Rodolfo|R|",
"chemical_list": "D000903:Antibiotics, Antineoplastic; D015251:Epirubicin",
"country": "Mexico",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0443-5117",
"issue": "54(3)",
"journal": "Revista medica del Instituto Mexicano del Seguro Social",
"keywords": "Anthracycline; Cardiotoxicity; Chemotherapy; Heart failure",
"medline_ta": "Rev Med Inst Mex Seguro Soc",
"mesh_terms": "D000293:Adolescent; D000903:Antibiotics, Antineoplastic; D002311:Cardiomyopathy, Dilated; D066126:Cardiotoxicity; D002648:Child; D015251:Epirubicin; D017809:Fatal Outcome; D005260:Female; D006801:Humans",
"nlm_unique_id": "101243727",
"other_id": null,
"pages": "404-8",
"pmc": null,
"pmid": "27100990",
"pubdate": "2016",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Anthracycline-induced cardiotoxicity: report of fatal cases.",
"title_normalized": "anthracycline induced cardiotoxicity report of fatal cases"
} | [
{
"companynumb": "MX-PFIZER INC-2016234015",
"fulfillexpeditecriteria": "1",
"occurcountry": "MX",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "METHOTREXATE"
},
"drugadditional": null,
... |
{
"abstract": "Ruxolitinib is a novel inhibitor of the Janus kinase (JAK) pathway that has become available for the treatment of myelofibrosis. There are increasing reports of opportunistic infections associated with ruxolitinib therapy. We present a case of Pneumocystis jiroveci pneumonitis complicating ruxolitinib therapy. Clinicians should consider the use of pneumocystis prophylaxis when using ruxolitinib.",
"affiliations": "School of Medicine, University of Queensland, St Lucia, Queensland, Australia.;School of Medicine, University of Queensland, St Lucia, Queensland, Australia Department of Thoracic Medicine, The Wesley Hospital, Auchenflower, Queensland, Australia.;Department of Infectious Diseases, The Wesley Hospital, Auchenflower, Queensland, Australia.",
"authors": "Lee|Samantha C|SC|;Feenstra|John|J|;Georghiou|Paul R|PR|",
"chemical_list": "D009570:Nitriles; D011720:Pyrazoles; D011743:Pyrimidines; C540383:ruxolitinib; D053612:Janus Kinases",
"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": "D000368:Aged; D006801:Humans; D016867:Immunocompromised Host; D053612:Janus Kinases; D008297:Male; D009570:Nitriles; D045363:Pneumocystis carinii; D011020:Pneumonia, Pneumocystis; D055728:Primary Myelofibrosis; D011720:Pyrazoles; D011743:Pyrimidines",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "24891492",
"pubdate": "2014-06-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "24528917;23770777;23039051;23929216;23648912;23841743;23307549;24145312;23944322",
"title": "Pneumocystis jiroveci pneumonitis complicating ruxolitinib therapy.",
"title_normalized": "pneumocystis jiroveci pneumonitis complicating ruxolitinib therapy"
} | [
{
"companynumb": "AU-INCYTE CORPORATION-2014IN001770",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "RUXOLITINIB"
},
"drugadditional": nu... |
{
"abstract": "BACKGROUND\nAdenoid cystic carcinomas (ACCs) are malignant salivary gland tumors noteworthy for high rates of late failure with limited salvage therapy options. We have previously shown increased Akt signaling is common in ACC and the human immunodeficiency virus (HIV) protease inhibitor nelfinavir (NFV) inhibits in vitro tumor growth by suppressing Akt signaling. This phase II trial was conducted to determine progression-free survival in response to NFV in patients with recurrent/endstage ACC who have failed standard therapies.\n\n\nMETHODS\nEligible patients had recurrent or end-stage ACC and measureable disease per Response Evaluation Criteria in Solid Tumors (RECIST) criteria. NFV was provided at 1250 mg twice daily.\n\n\nRESULTS\nAmong 15 trial participants, median progression-free survival was 5.5 months (lower 95% bound 4.4 months). No patient achieved a RECIST partial or complete response to therapy.\n\n\nCONCLUSIONS\nNFV monotherapy does not result in a meaningful improvement in clinical outcomes among patients with recurrent ACC.",
"affiliations": "Department of Radiation Oncology, University of Iowa Hospitals and Clinics, Iowa City, Iowa.",
"authors": "Hoover|Andrew C|AC|;Milhem|Mohammed M|MM|;Anderson|Carryn M|CM|;Sun|Wenqing|W|;Smith|Brian J|BJ|;Hoffman|Henry T|HT|;Buatti|John M|JM|",
"chemical_list": "D019888:Nelfinavir",
"country": "United States",
"delete": false,
"doi": "10.1002/hed.23664",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1043-3074",
"issue": "37(5)",
"journal": "Head & neck",
"keywords": "Akt; adenoid cystic carcinoma; head and neck cancer; nelfinavir; salivary gland cancer",
"medline_ta": "Head Neck",
"mesh_terms": "D000328:Adult; D000367:Age Factors; D000368:Aged; D003528:Carcinoma, Adenoid Cystic; D002423:Cause of Death; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D005500:Follow-Up Studies; D006785:Hospitals, University; D006801:Humans; D007484:Iowa; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D019888:Nelfinavir; D011446:Prospective Studies; D018570:Risk Assessment; D012468:Salivary Gland Neoplasms; D012737:Sex Factors; D015996:Survival Rate; D016896:Treatment Outcome; D014481:United States",
"nlm_unique_id": "8902541",
"other_id": null,
"pages": "722-6",
"pmc": null,
"pmid": "24596143",
"pubdate": "2015-05",
"publication_types": "D016430:Clinical Trial; D017427:Clinical Trial, Phase II; D016428:Journal Article",
"references": "16861096;21547565;21697087;19412116;22271897;21216929;17761983;15238771;18509182;16757203;11513507;22425919;22540830;11410883;20594311;22564882;19097774;22759761;9607830;21355074;19480971;9307718;19729990",
"title": "Efficacy of nelfinavir as monotherapy in refractory adenoid cystic carcinoma: Results of a phase II clinical trial.",
"title_normalized": "efficacy of nelfinavir as monotherapy in refractory adenoid cystic carcinoma results of a phase ii clinical trial"
} | [
{
"companynumb": "US-PFIZER INC-2017169170",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "NELFINAVIR MESYLATE"
},
"drugadditional": null... |
{
"abstract": "BACKGROUND\nDigoxin intoxication results in predominantly digestive, cardiac and neurological symptoms. This case is outstanding in that the intoxication occurred in a nonagenarian and induced severe, extensively documented visual symptoms as well as dysphagia and proprioceptive illusions. Moreover, it went undiagnosed for a whole month despite close medical follow-up, illustrating the difficulty in recognizing drug-induced effects in a polymorbid patient.\n\n\nMETHODS\nDigoxin 0.25 mg qd for atrial fibrillation was prescribed to a 91-year-old woman with an estimated creatinine clearance of 18 ml/min. Over the following 2-3 weeks she developed nausea, vomiting and dysphagia, snowy and blurry vision, photopsia, dyschromatopsia, aggravated pre-existing formed visual hallucinations and proprioceptive illusions. She saw her family doctor twice and visited the eye clinic once until, 1 month after starting digoxin, she was admitted to the emergency room. Intoxication was confirmed by a serum digoxin level of 5.7 ng/ml (reference range 0.8-2 ng/ml). After stopping digoxin, general symptoms resolved in a few days, but visual complaints persisted. Examination by the ophthalmologist revealed decreased visual acuity in both eyes, 4/10 in the right eye (OD) and 5/10 in the left eye (OS), decreased color vision as demonstrated by a score of 1/13 in both eyes (OU) on Ishihara pseudoisochromatic plates, OS cataract, and dry age-related macular degeneration (ARMD). Computerized static perimetry showed non-specific diffuse alterations suggestive of either bilateral retinopathy or optic neuropathy. Full-field electroretinography (ERG) disclosed moderate diffuse rod and cone dysfunction and multifocal ERG revealed central loss of function OU. Visual symptoms progressively improved over the next 2 months, but multifocal ERG did not. The patient was finally discharged home after a 5 week hospital stay.\n\n\nCONCLUSIONS\nThis case is a reminder of a complication of digoxin treatment to be considered by any treating physician. If digoxin is prescribed in a vulnerable patient, close monitoring is mandatory. In general, when facing a new health problem in a polymorbid patient, it is crucial to elicit a complete history, with all recent drug changes and detailed complaints, and to include a drug adverse reaction in the differential diagnosis.",
"affiliations": "Division of Clinical Pharmacology, University Hospital of Lausanne, Bugnon 17-01, 1011, Lausanne, Switzerland. delphine.renard@chuv.ch.;Service de gériatrie et réadaptation gériatrique, CHUV, CUTR Sylvana, Ch. de Sylvana 10, 1066, Epalinges, Switzerland. eve.rubli@chuv.ch.;Département d'ophtalmologie, Université de Lausanne, Fondation Asile des Aveugles, Hôpital ophtalmique Jules-Gonin, av. de France 15, 1000, Lausanne 7, Switzerland. nathalie.voide@gmail.com.;Département d'ophtalmologie, Université de Lausanne, Fondation Asile des Aveugles, Hôpital ophtalmique Jules-Gonin, av. de France 15, 1000, Lausanne 7, Switzerland. francois.borruat@fa2.ch.;Division of Clinical Pharmacology, University Hospital of Lausanne, Bugnon 17-01, 1011, Lausanne, Switzerland. laura.rothuizen@chuv.ch.",
"authors": "Renard|Delphine|D|;Rubli|Eve|E|;Voide|Nathalie|N|;Borruat|François-Xavier|FX|;Rothuizen|Laura E|LE|",
"chemical_list": "D000889:Anti-Arrhythmia Agents; D004077:Digoxin",
"country": "England",
"delete": false,
"doi": "10.1186/s13104-015-1367-6",
"fulltext": "\n==== Front\nBMC Res NotesBMC Res NotesBMC Research Notes1756-0500BioMed Central London 136710.1186/s13104-015-1367-6Case ReportSpectrum of digoxin-induced ocular toxicity: a case report and literature review Renard Delphine +41 21 314 42 60delphine.renard@chuv.ch Rubli Eve +41 21 314 76 08eve.rubli@chuv.ch Voide Nathalie +41 21 626 88 50nathalie.voide@gmail.com Borruat François-Xavier +41 21 626 86 60francois.borruat@fa2.ch Rothuizen Laura E. +41 21 314 42 60laura.rothuizen@chuv.ch Division of Clinical Pharmacology, University Hospital of Lausanne, Bugnon 17-01, 1011 Lausanne, Switzerland Service de gériatrie et réadaptation gériatrique, CHUV, CUTR Sylvana, Ch. de Sylvana 10, 1066 Epalinges, Switzerland Département d’ophtalmologie, Université de Lausanne, Fondation Asile des Aveugles, Hôpital ophtalmique Jules-Gonin, av. de France 15, 1000 Lausanne 7, Switzerland 23 8 2015 23 8 2015 2015 8 36822 8 2014 18 8 2015 © Renard et al. 2015\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nDigoxin intoxication results in predominantly digestive, cardiac and neurological symptoms. This case is outstanding in that the intoxication occurred in a nonagenarian and induced severe, extensively documented visual symptoms as well as dysphagia and proprioceptive illusions. Moreover, it went undiagnosed for a whole month despite close medical follow-up, illustrating the difficulty in recognizing drug-induced effects in a polymorbid patient.\n\nCase presentation\nDigoxin 0.25 mg qd for atrial fibrillation was prescribed to a 91-year-old woman with an estimated creatinine clearance of 18 ml/min. Over the following 2–3 weeks she developed nausea, vomiting and dysphagia, snowy and blurry vision, photopsia, dyschromatopsia, aggravated pre-existing formed visual hallucinations and proprioceptive illusions. She saw her family doctor twice and visited the eye clinic once until, 1 month after starting digoxin, she was admitted to the emergency room. Intoxication was confirmed by a serum digoxin level of 5.7 ng/ml (reference range 0.8–2 ng/ml). After stopping digoxin, general symptoms resolved in a few days, but visual complaints persisted. Examination by the ophthalmologist revealed decreased visual acuity in both eyes, 4/10 in the right eye (OD) and 5/10 in the left eye (OS), decreased color vision as demonstrated by a score of 1/13 in both eyes (OU) on Ishihara pseudoisochromatic plates, OS cataract, and dry age-related macular degeneration (ARMD). Computerized static perimetry showed non-specific diffuse alterations suggestive of either bilateral retinopathy or optic neuropathy. Full-field electroretinography (ERG) disclosed moderate diffuse rod and cone dysfunction and multifocal ERG revealed central loss of function OU. Visual symptoms progressively improved over the next 2 months, but multifocal ERG did not. The patient was finally discharged home after a 5 week hospital stay.\n\nConclusion\nThis case is a reminder of a complication of digoxin treatment to be considered by any treating physician. If digoxin is prescribed in a vulnerable patient, close monitoring is mandatory. In general, when facing a new health problem in a polymorbid patient, it is crucial to elicit a complete history, with all recent drug changes and detailed complaints, and to include a drug adverse reaction in the differential diagnosis.\n\nKeywords\nDigoxinDrug intoxicationVision impairmentDyschromatopsiaPhotopsiaissue-copyright-statement© The Author(s) 2015\n==== Body\nBackground\nDigitalis glycosides’ long history in medical practice has been beautifully explored by English pharmacologist Jeff K. Aronson some 20 years ago. His in-depth study, centered on the work by 18th century English physician and scientist William Withering, shows that their narrow therapeutic margin has been recognized and dealt with for several thousand years [1].\n\nDigoxin is the main form of digitalis medically used in Switzerland today. It is extracted from the leaves of the plant Digitalis lanata. It combines with and reversibly inhibits the cell membrane Na+/K+-ATPase, inducing an increase in intracellular calcium, intracellular sodium, and extracellular potassium. In the heart, this leads to an increase in myocardium’s strength of contraction and excitability, as well as to a decrease in conduction and depolarization velocity in the atrio-ventricular node. Current indications to digoxin are restricted to second line treatment for paroxystic or permanent atrial fibrillation (AF), second line treatment for symptomatic heart failure with rapid AF, or as a last resort for severe, symptomatic systolic heart failure (left ventricular ejection fraction ≤40 %) [2, 3].\n\nPharmacological properties of digoxin are as follows: bioavailability 70–80 %, distribution volume 5–7 l/kg, poor protein binding (25 %), time to peak concentration 1 h, time to peak effect 6 h after oral administration. Metabolism is negligible and elimination essentially occurs through glomerular filtration, with a small contribution of tubular secretion involving P-glycoprotein. Digoxin has a long half-life (40 h; 100 h and beyond in kidney disease).\n\nUsual maintenance dosing is 0.25 mg qd. In kidney disease, empirical dose reductions are proposed accordingly, for example 50–75 % of usual dosing for a creatinine clearance (CrCl) of 50–100 ml/min according to the Cockroft-Gault formula, 30–50 % of usual dosing for a CrCl of 20–50 ml/min, and 20–30 % of usual dosing for a CrCl <20 ml/min. These are general guidelines only, as plasma creatinine is a poor indicator of kidney function in very ill or sarcopenic elderly people. Drug monitoring and scrupulous follow-up are mandatory in such cases.\n\nDigoxin toxicity predominantly manifests as digestive or neurological symptoms. Cardiac symptoms are less frequent but are related to the seriousness of digoxin poisoning, the overall rate of mortality being estimated at 25 %. Out of range potassium, calcium or magnesium levels can modulate digoxin action. Neurologic symptoms are multifold, including headache, confusion, somnolence, fatigue, restlessness and visual symptoms. Elderly patients are more susceptible to digoxin toxicity for a variety of reasons including kidney disease, a decrease in muscular mass, frequent polypharmacy (diuretics and amiodarone being the most frequent at-risk co-medication), and poor adherence due to sensory and cognitive impairment [4].\n\nThe earliest report of digitalis-associated ocular toxicity we could easily access was published in 1925 in the Boston Medical and Surgery Journal, ancestor of the New England Journal of Medicine [5]. According to the authors: “Sensory disturbances associated with an overdose of digitalis […] are met with rarely, and even then may easily be overlooked simply because their meaning is not clear.” They proceed with reporting the illness of a 55-year-old woman who, after 1 year of regularly taking digitalis, “developed an attack of failing vision. Everything appeared yellow before her eyes.” Later on, “She was unable clearly to distinguish objects and persons at a distance, and everything seemed to be bathed in a very intense glaring white light […]. The air seemed filled with yellow snow, and the grass appeared distinctly blue in color. The sky appeared green. At times she had double vision, […] at times she saw T shaped objects in the sky or any blank surface.” The authors conclude: “It may be that the condition of yellow vision is more common than we suppose and that more careful questioning of patients with toxic manifestations of digitalis will reveal this fact”.\n\nAs geriatricians, ophthalmologists, and clinical pharmacologists, we recently cared for an elderly woman suffering from several visual symptoms related to digoxin intoxication. We tell her story as a well documented case of digoxin ocular toxicity, as well as a reminder that the need for “careful questioning” still holds true in medical practice today.\n\nCase presentation\nA 91-year-old female patient, weight 56 kg, height 151 cm, was admitted to the emergency room (ER) of a tertiary hospital complaining about dysphagia, vomiting and blurry vision. She was in altered general condition but hemodynamically stable; detailed physical examination was unremarkable. Electrocardiography showed paced rhythm, 60/min. She felt so ill she repeatedly said she’d have to enter a nursing home.\n\nThe patient lived alone at home. She got daily help from her daughter and the local home care services, and sometimes made mistakes while managing her medication. She suffered from multiple co morbidities, including hypertension, hypercholesterolemia, type 2 diabetes, ischemic heart disease with heart failure, chronic kidney disease (creatinine clearance according to Cockroft-Gault formula, CrCl, 18 ml/min), gout, and indolent breast cancer. A pacemaker had been implanted 2 years earlier for permanent atrial fibrillation (AF) with insufficiently controlled ventricular rate. She had benefited from right eye cataract surgery. She was under the regular care of a general practitioner (GP), a nephrologist, a cardiologist, an ophthalmologist and an oncologist.\n\nHer medication consisted of acenocoumarol qd (dosing according to International Normalized Ratio, targeted range 2.0–3.0), metoprolol 100 mg qd, lisinopril 5 mg qd, torasemide 20 mg qd, simvastatin 20 mg qd, anastrozole 1 mg qd, ibandronate 150 mg monthly, lorazepam 0.5 mg qd, folate 5 mg qd, calcium 500 mg/cholecalciferol 400 IU bd, and zolpidem 5 mg qd as needed.\n\nDigoxin, 0.25 mg qd, and diltiazem, 90 mg qd, had been started exactly 1 month earlier by her cardiologist for AF with rapid ventricular response. In a letter to the GP sent 7 days after the patient was started on digoxin, the cardiologist mentioned the need for measuring the digoxin level and adapting the dosing, without specifying a deadline. He also reported intending atrioventricular node ablation therapy 5 weeks later.\n\nA detailed history given by the patient, her daughter, and the home care services revealed that on the 7th day after starting digoxin, the patient suffered a fall, which led her GP to stop diltiazem on the 8th day. On the 13th day, she had “digestive symptoms” and difficulty eating. From the 18th day on, she complained of significant loss of vision in both eyes, seeing “everything in white”.\n\nFive months previously, she had been routinely examined by her ophthalmologist. Visual acuity was 10/10 difficult in both eyes, and fundus examination disclosed the presence of slight retinal pigment epithelium changes compatible with early dry age-related macular degeneration (ARMD). On the 21th day of digoxin therapy, an emergency consultation at the eye clinic revealed decreased visual acuity in both eyes (4/10 OD and 5/10 OS), a mature cataract in the left eye and dry ARMD in both eyes. From then on, the patient lost 5 kg because of nausea and vomiting, and her vision remained severely impaired.\n\nHer symptoms varied from day to day but included blurry vision (she couldn’t read a printed text anymore), snowy vision (everything appeared to be bathed in a white light), a tendency to collide with objects on her right side, dyschromatopsia (she was seeing blue or purple spots when she closed her eyes, vivid colors appeared to be faded), formed visual hallucinations of little human figures that did not frighten her appearing either upon awakening (hypnopompic) or shortly before falling asleep (hypnagogic), and feeling as if she was on a fishing boat when lying in bed (proprioceptive illusions).\n\nDigoxin intoxication was suspected on admission 1 month after its initiation, and confirmed when the serum level was measured to be 5.7 ng/ml [0.8–2.0].1 Other relevant laboratory results were as follows (reference range in brackets): creatinine 183 µmol/l [44–80], sodium 144 mmol/l [135–145], potassium 4.0 mmol/l [3.5–4.6], calcium 2.41 mmol/l [2.10–2.50].\n\nDigoxin was definitively stopped, and further levels were as follows (all samples were taken at 6 am, day 0 = day of ER admission): Day 3: 4.0 ng/ml. Day 10: 1.1 ng/ml. Day 18: not to be detected. On this basis, we estimated the half-life to be approximately 80–90 h in this patient at that time. Chest radiography, brain computed tomography scan and oesogastric studies provided no contributive finding in explaining the symptoms.\n\nAfter digoxin withdrawal, nausea and vomiting were first to disappear in the next few days. Her general condition then improved, the patient gained weight and benefited from a hospital rehabilitation program.\n\nOn the 17th day after ER admission, a detailed ophthalmological examination was performed. Visual symptoms were persistent, including snowy and blurry vision, peripheral fixed photopsias and dyschromatopsia, all compatible with digoxin intoxication, as well as formed visual hallucinations occurring systematically when the patient fell asleep (hypnagogic visual hallucinations). Visual acuity was decreased in both eyes (4/10 OD with S−1.25, C−1.5 at 103° and 5/10 OS with S+1.25) and color vision testing with Ishihara pseudoisochromatic plates disclosed a severe red-green dyschromatopsia (only 1/13 plates correctly identified with either eye). Slit-lamp examination showed a pseudophakic OD and a mature corticonuclear OS cataract. Intraocular pressures were normal (12 mmHg OU). Funduscopy revealed normal optic nerve head with peripapillary atrophy OU, normal retinal vessels and bilateral minimal macular changes compatible with bilateral early dry ARMD. Computerised static perimetry (Octopus model 300) showed non-specific diffuse sensitivity loss consistent with bilateral diffuse retinopathy. Compared to our normative data for the age group, full-field photopic and scotopic ERGs confirmed a moderate diffuse dysfunction more pronounced for cones than rods (photopic and scotopic b-wave amplitude was decreased to 60 % of the lower normal values for the age). Qualitative interpretation of multifocal ERG disclosed a diffuse decrease of amplitude mostly in the central ten degrees.\n\nThe patient was finally discharged home 44 days after ER admission. She was still living at home 6 months after ER admission according to elicited follow-up. At that time, tests showed a subtle improvement of visual acuity (6/10 OD and 5/10 OS), persistent severe red-green dyschromatopsia (1/13 on Ishihara test OU), and a slight non significant amplitude increase on the multifocal ERG. Unfortunately, she denied further ophthalmologic examinations beyond follow-up at 6 months.\n\nDiscussion and literature review\nIn this patient, the time course and characteristics of the clinical evolution, and the constellation of symptoms were attributed with high probability to digoxin intoxication, notably in view of the elevated drug level (score of 9/13 according to the Naranjo Adverse Drug Reaction Probability Scale [6]).\n\nMany risk factors for these adverse drug reactions were present:A drug with a narrow therapeutic margin was administered at standard dosing with insufficient pre-defined follow-up strategy to a particularly vulnerable patient because of advanced age, polymorbidity, polymedication with questionable adherence, and pre-existing advanced kidney disease as well as functional and ocular impairment. Specific interacting drugs were diltiazem (which increases exposure to digoxin through uncertain mechanisms, possibly by inhibiting P-glycoprotein) and torasemide and lisinopril (which aggravate renal failure and the risk of dehydration and electrolyte imbalance).\n\nMany people were involved in the care of the patient, and her symptoms were, at least in the beginning, entirely non-specific. Loose communication between the cardiologist and the GP, dilution of responsibilities and failure to rapidly identify and incriminate drugs as a plausible cause were all elements that could contribute to the delay in diagnosing this potentially life-threatening intoxication.\n\n\n\nFurther discussion will focus on neurologic symptoms, with particular emphasis on visual symptoms.\n\nAlthough dysphagia was mentioned on admission, it is difficult to be positive it was really part of the clinical picture, because the patient then stopped complaining about it and later even denied having ever suffered from it. Two case reports describe dysphagia in digoxin intoxication in elderly women, but the clinical picture was more clear-cut [7, 8].\n\nProprioceptive illusions are described in another case report as “[the patient complained that] the room was hilly and that the bed was continuously sliding downhill” [9].\n\nDisturbances of vision during digoxin treatment are less common than cardiac or other non cardiac symptoms, but are considered by some authors to be more specific. In this patient, cardiac symptoms are likely to have been concealed by the implanted pacemaker. The spectrum of visual complaints include decreased visual acuity, central scotomas or visual field reduction, glare, photopsia most pronounced in daylight, photophobia, blurry or snowy vision, visual hallucinations, diplopia, and dyschromatopsia including xanthopsia (yellow vision), cyanopsia (blue vision) and chloropsia (green vision). Dyschromatopsia can be asymptomatic and revealed only by formal testing; several studies report a positive correlation between the total error score at testing and serum digoxin level. A more recent study in 30 elderly hospitalized patients receiving digoxin maintenance therapy compared to controls did not confirm this correlation, but the authors reported a high incidence of impaired color vision at serum digoxin levels considered therapeutic as well as supra-therapeutic, speaking for limited value of formal color vision testing for the detection of toxicity in the aged [10].\n\nThe mechanism underlying ocular symptoms is presumed to be related to Na+ K+ATPase inhibition but remains speculative [9, 11]. Ophthalmologic tests considered most useful to support a diagnosis of digoxin intoxication are photopic and scotopic ERG seeking for b-wave delayed implicit time and decreased b-wave amplitude.\n\nIn our patient, visual symptoms improved after stopping digoxin, yet some persisted for several weeks, long after drug levels became undetectable, and others had not resolved after 6 months. We offer several possible explanations for this. First, digoxin elimination was slow because of its high volume of distribution and prolonged half-life in this patient. It could also be hypothesized that serum digoxin levels more poorly correlate with certain specific pharmacodynamic effects (for example, duration of the effect may possibly vary according to different clearances from deep tissue compartments or variability in inhibition by digoxin of different Na /K+-ATPase isoforms in different body tissues). Second, the patient may have been more worried about and inclined to express ocular symptoms because of the attention given to them by clinicians. Third, the underlying eye diseases may themselves have evolved over the time. Eventually, the patient refused to continue ophthalmologic follow-up beyond 6 months hereby escaping longer monitoring.\n\nArbitrarily starting our literature review in the seventies, we found a total of 15 references to case reports of impaired vision during digoxin maintenance therapy or in situations of chronic supratherapeutic digoxin levels. These publications describe a total of 52 patients (Table 1), with only five cases described in more recent years (since 2000). Quality of documentation and degree of detail are highly unequal among studies, which does not allow for a quantitative analysis. As a whole, most patients are aged (>65-year-old), with only one patient being under 40. Ocular symptoms are numerous. Digoxin levels also vary greatly, but many are in the supratherapeutic or more clearly toxic range. Finally, full resolution is almost always witnessed over the course of 1–2 weeks, but here again follow-up is heterogeneous and often of short duration.Table 1 Synopsis of cases of visual symptoms in digoxin maintenance therapy or digoxin chronic intoxication published in Pubmed, 1974–2006\n\nReferences\tPatient(s) (F = female or M = male, age in years)\tDigoxin treatment (mg qd unless otherwise specified)\tTreatment duration\tOcular symptoms\tPrecipitating factors\tDigoxin level (ng/ml)\tSpecific ophthalmologic examination\tEvolution after stopping digoxin (or, in a few cases, significantly decreasing the dose)\t\nManninen [12]\tn = 5\n2 M, 3 F, 61–78\t0.15–0.75\tSeveral years\tIndistinct vision of objects\tNone detected\t1.3 (n = 1) 2.1–3.2 (n = 4)\tIshihara plates: “some degree of difficulty in seeing the plates for green–red vision”b\n\tFull resolution at 2 weeks\t\nVolpe and Soave [13]\tn = 3\n2 M, 1 F, 66–82\t\na\n\t\na\n\tYellow hue to objects, formed visual hallucinations (animals, people, household objects)\ta) a\n\nb) Dose increase to 0.375 mg bd\nc) a\n\ta) 5.0\nb) 6.5\nc) 2.7\tNot mentionedb\n\tFull resolution after drug level corrected\t\nAronson and Ford [11]\tn = 10 (experiment on subjects previously published)\tNot specified in this article\tNot specified in this article\t–\tNot specified in this article\tNot specified in this article\tFarnsworth-Munsell 100-Hue test (upper limit of normal for colour defect score = 140). “The median colour defect score in toxic patients (212) was significantly higher than that of controls (85), falling to the significantly lower value of 127 after withdrawal of digoxin […]\tFull resolution\t\nWeleber and Shults [14]\tM, 70\t0.25 four times daily\tAt least several months\tGlare sensitivity, dimming of vision, silver flashes in the form of rectangles in the right visual field, halos around lights, no yellow vision\tConcomitant quinidine sulfate administration\t3.5\tFarnsworth-Munsell 100-Hue error scores: 569 OD, 646 OS\nElectrooculogram: high initial light-to-dark ratios (3.50 OD, 3.20 OS)\nElectroretinogram: No detectable dark-adapted cone-mediated response (x wave). Light-adapted cone-mediated response (b wave) significantly subnormal and significantly prolonged in implicit time. Dark-adapted rod-mediated b wave significantly subnormal and prolonged in implicit time. Amplitude of the scotopic a wave (corneal negative peak) and bx wave (corneal positive peak) at maximal stimulus intensity subnormal.\tFull resolution after 2 weeks\t\nClosson [9]\tF, 84\t0.5\t38 months\tBlue, green and yellow veils floating everywhere, pleasant visions of trees, sun, etc. No color vision impairment.\tConcomitant hydrochlorothiazide and triamterene prescription for 2 days\t2.2\t\na\n\tFull resolution\t\nChuman and LeSage [15]\tn = 2\na) M, 79\nb) M, 61\ta) 0.25 and 0.125 on alternate days\nb) 0.125\t\na\n\ta) “Objects appearing more white than usual”\nb) Objects were seen as if they were in a fog and colors appeared to be faded\t\na\n\ta) 13.1\nb) 6\tFarnsworth-Munsell 100-Hue test error score:\na) 497\nb) 854\nIshihara plates:\na) 7 errors/failed\nb) 14 errors/failed\nAOH-R-R plate defects:\na) medium for green–red and blue-yellow\nb) strong for red-green and blue-yellow\t\na\n\t\nMerté et al. [16]\tn = 14, median age 72 years (prospective study comparing subjects with digoxin and digitoxin intoxication)\t\na\n\tAt least 6 weeks\tOne-third of patients complained about blurry vision, photopsia and impairment of color vision\t\na\n\tMedian digoxin level 2.98 (2.49–5.4)\tFarnsworth-Munsell 100-Hue test: median number of errors 170\tSignificant improvement, follow-up restricted to 8 days\t\nHobley and Lawrenson [17]\tF, 36\t0.25\t3 months\tScintillating visual field loss, in attacks each lasting about 20 min. No alteration in color vision\t\na\n\t<2\tFriedman Visual Field Analyser Mark II:\nrelative defect of visual field between 15 and 20 degrees in temporal field OD, and between 15 and 20 nasal field OS\nFarnsworth-Munsell 100-Hue error score:\n20 OD, 84 OS\nIshihara plates: results normal OU\tFull resolution\t\nPiltz et al. [18]\tn = 3\na) F, 88\nb) F, 78\nc) F, 58 (with retinitis pigmentosa and high myopia)\ta) 0.25\nb) 0.25\nc) 0.25\ta) a\n\nb) 2 months\nc) a\n\ta) Progressive, generalized “dimming” of vision OU\nb) decreased visual acuity bilaterally with snowy vision, obscuring vision of colors\nc) “extreme darkness of vision”\t\na\n\ta) 6.1\nb) 2.2\nc) 4.5\tElectroretinogram (ERG)\na) amplitude of dark adapted flash ERG decreased to ~ 20 % of normal OD, and 45 % of normal OS\nGoldman perimetry\nb) generalized depression of the field and 10-degree relative central scotoma to the I3E isopter OS\nIshihara plates\nb) correctly identified only the test plate\n(not all tests available for all patients; no specific tests mentioned for patient c)\ta) Partial resolution only at 3 months\nb) Full resolution at 1 month\nc) Full resolution\t\nButler et al. [19]\tn = 6\na) F, 76\nb) F, 79\nc) F, 82\nd) M, 75\ne) F, 85\nf) M, 66\ta) 0.25\nb) 0.25–0.75\nc) 0.25\nd) 0.375\ne) 0.25\nf) 0.25\t\na\n\ta) “Light through vertical blinds”\nb) Flashing lights temporally\nc) Yellow and white sparks dancing and swirling over whole visual field\nd) Flickering in periphery of vision\ne) Glare, brightness OD\nf) White glare, “snow on grass, trees”, decreased visual acuity and color discrimination\t\na\n\ta) 0.5–1.4\nb) 0.5–0.9\nc) 0.8\nd) 1.4–1.5\ne) 0.7\nf) 0.2\tElectroretinogram cone b-wave explicit time [ms]:\na) 30.0 OD, 28.8 OS\nb) 40 OD\nc) not done\nd) 37.6b\n\ne) 35.4b\n\nf) 36.4 OD, 36.0 OS\tFull resolution\t\nWolin [20]\tn = 2\na) F, 68\nb) F, 63\t\na\n\t\na\n\ta) Shimmering lights\nb) Blurred vision OU\t\na\n\ta) 1.7\nb) 1.0\tHumphrey automated visual field testing and fluorescein angiography:\na) not mentioned\nb) generalized depression OU with greater inferior than superior visual field lossb\n\ta) Full resolution in 2 weeks\nb) Partial resolution\t\nHonrubia et al. [21]\tM, 72\t\na\n\t2 months\tPhotopsia in the whole visual field\t\na\n\t2.75\tHumphrey automated visual field testing: normal (81 points) Farnsworth-Munsell 100-Hue test:\nnormal\tSignificant improvement after 3 days\t\nNagai et al. [22]\tn = 2\na) M, 72\nb) M, 54\t\na\n\t\na\n\tSevere decrease in visual acuity\t\na\n\t\na\n\tElectroretinogram (ERG):\n30 Herz-flicker ERG and photopic ERG: decreased amplitudeb\n\t\na\n\t\nGödecke-Koch et al. [23]\tF, 90 (severe eye disease after bilateral zoster infection)\t0.2\t\na\n\tVisual hallucinations (people, yellow hay, colored surfaces)\t\na\n\t1.9\t\na\n\tFull resolution\t\nOishi et al. [24]\tF, 72\t0.125\t1 year\tSudden onset of binocular photopsia in the periphery of visual fields\tDiarrhea with dehydration and hyperkaliemia\t1.7\t\na\n\tFull resolution in 2 weeks\t\n\nOD right eye, OS left eye, OU both eyes\n\n\naNo information available\n\n\nbNo further details or quantification available\n\n\n\nConclusion\nWe describe a case of digoxin intoxication in a patient at highest risk for this adverse outcome due to different endogenous and exogenous factors: advanced age, polymorbidity including severe chronic kidney disease, preexistent ocular disease, insufficient communication among carers and failure to include a drug-induced adverse reaction in the differential diagnosis. It is unique by its extensive description of ophthalmologic findings, over a 6 month follow-up. Above all, this case is a reminder of a complication of digoxin treatment to be considered by any treating physician. If digoxin is prescribed in a vulnerable patient, close monitoring is mandatory. In general, when facing a new health problem in a polymorbid patient, it is crucial to elicit a complete history, with all recent drug changes and detailed complaints, and to include a drug adverse reaction in the differential diagnosis.\n\nConsent\nWritten informed consent was obtained from the patient for publication of this case report. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\n1 The last time the patient had taken digoxin could not be determined with certainty, but was supposed to have been approximately 48 h prior to blood sampling.\n\nAuthors’ contributions\nDR handled the report to clinicians, the notification to pharmacovigilance authorities, and wrote the paper. ER cared for the patient, reported the adverse effect, and revised the paper. NV and FXB cared for the patient, wrote the parts of the case report pertaining to specific ophthalmology topics, and revised the paper. LER supervised the drug-induced adverse effect registration and revised the paper. All authors read and approved the final manuscript.\n\nAcknowledgements\nNone. This paper is a case report describing events having occurred in the natural course of a disease (adverse drug event) and state-of-the art medical care during the ensuing hospital stay. No research-oriented intervention was delivered to the patient. The ethics committee [Commission cantonale (VD) d’éthique de la recherche sur l’être humain, Lausanne, Switzerland] gave us a written approval for this publication.\n\nCompliance with ethical guidelines\nCompeting interests The authors declare that they have no competing interests.\n==== Refs\nReferences\n1. Aronson JK An account of foxglove and its medical uses 1785–1985 1985 Oxford Oxford University press \n2. McMurray JJ Adamopoulos S Anker SD Auricchio A Bohm M Dickstein K Falk V Filippatos G Fonseca C Gomez-Sanchez MA ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: the task force for the diagnosis and treatment of acute and chronic heart failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC Eur Heart J 2012 33 14 1787 1847 10.1093/eurheartj/ehs104 22611136 \n3. Camm AJ Lip GY De Caterina R Savelieva I Atar D Hohnloser SH Hindricks G Kirchhof P Guidelines-CPG ESCCfP, document R: 2012 focused update of the ESC guidelines for the management of atrial fibrillation: an update of the 2010 ESC guidelines for the management of atrial fibrillation—developed with the special contribution of the European Heart Rhythm Association Europace Eur Pacing Arrhythm Card Electrophysiol J Work Groups Card Pacing Arrhythm Card Cell Electrophysiol Eur Soc Cardiol 2012 14 10 1385 1413 \n4. Pautas E Lopez C Gouronnec A Gravelaine S Peyron I Lapostolle F Focus on digitalis intoxication in the elderly. Report of a case treated with digoxin-specific Fab antibody fragments Geriatrie et psychologie neuropsychiatrie du vieillissement 2012 10 4 355 363 23250015 \n5. Jackson HJ Zerfas LG A case of yellow vision associated with digitalis poisoning Boston Med Surg J 1925 192 890 893 10.1056/NEJM192505071921902 \n6. Naranjo CA Busto U Sellers EM Sandor P Ruiz I Roberts EA Janecek E Domecq C Greenblatt DJ A method for estimating the probability of adverse drug reactions Clin Pharmacol Ther 1981 30 2 239 245 10.1038/clpt.1981.154 7249508 \n7. Kelton JG Scullin DC Digitalis toxicity manifested by dysphagia JAMA J Am Med Assoc 1978 239 7 613 614 10.1001/jama.1978.03280340033007 \n8. Cordeiro MF Arnold KG Digoxin toxicity presenting as dysphagia and dysphonia BMJ 1991 302 6783 1025 10.1136/bmj.302.6783.1025 2039889 \n9. Closson RG Visual hallucinations as the earliest symptom of digoxin intoxication Arch Neurol 1983 40 6 386 10.1001/archneur.1983.04050060086017 6847447 \n10. Lawrenson JG Kelly C Lawrenson AL Birch J Acquired colour vision deficiency in patients receiving digoxin maintenance therapy Br J Ophthalmol 2002 86 11 1259 1261 10.1136/bjo.86.11.1259 12386084 \n11. Aronson JK Ford AR The use of colour vision measurement in the diagnosis of digoxin toxicity Q J Med 1980 49 195 273 282 6970370 \n12. Manninen V Letter: impaired colour vision in diagnosis of digitalis intoxication Br Med J 1974 4 5945 653 654 10.1136/bmj.4.5945.653-b 4280326 \n13. Volpe BT Soave R Formed visual hallucinations as digitalis toxicity Ann Intern Med 1979 91 6 865 866 10.7326/0003-4819-91-6-865 517886 \n14. Weleber RG Shults WT Digoxin retinal toxicity. Clinical and electrophysiological evaluation of a cone dysfunction syndrome Arch Ophthalmol 1981 99 9 1568 1572 10.1001/archopht.1981.03930020442007 7283806 \n15. Chuman MA LeSage J Color vision deficiencies in two cases of digoxin toxicity Am J Ophthalmol 1985 100 5 682 685 10.1016/0002-9394(85)90624-5 4061549 \n16. Merté H-J Hollwich F Naumann GOH Gloor B Farbsinnstörungen bei subtoxischen und toxischen Digoxin-und Digitoxinsereumkonzentrationen Klin Mbl Augenheilk 1988 193 622 626 10.1055/s-2008-1050308 3265458 \n17. Hobley A Lawrenson J Ocular adverse effects to the therapeutic administration of digoxin Ophthalmic Physiol Opt J Br Coll Ophthalmic Opt 1991 11 4 391 393 10.1111/j.1475-1313.1991.tb00241.x \n18. Piltz JR Wertenbaker C Lance SE Slamovits T Leeper HF Digoxin toxicity. Recognizing the varied visual presentations J Clin Neuro-Ophthalmol 1993 13 4 275 280 \n19. Butler VP Jr Odel JG Rath E Wolin MJ Behrens MM Martin TJ Kardon RH Gouras P Digitalis-induced visual disturbances with therapeutic serum digitalis concentrations Ann Intern Med 1995 123 9 676 680 10.7326/0003-4819-123-9-199511010-00006 7574223 \n20. Wolin MJ Digoxin visual toxicity with therapeutic blood levels of digoxin Am J Ophthalmol 1998 125 3 406 407 10.1016/S0002-9394(99)80161-5 9512168 \n21. Honrubia A Andres JM Alcaine F Bonasa E Fernandez J Lujan B Visual disorders induced by therapeutic levels of digoxin Archivos de la Sociedad Espanola de Oftalmologia 2000 75 1 55 56 11151114 \n22. Nagai N Ohde H Betsuin Y Matsukura S Kigasawa K Mashima Y Oguchi Y Two cases of digitalis toxicity with reversible and severe decrease of visual acuity Nippon Ganka Gakkai zasshi 2001 105 1 24 30 11210783 \n23. Godecke-Koch T Schlimme J Rada D Emrich HM Charles Bonnet syndrome in an elderly patient with bilateral vision loss, hyperthyroidism and relative digitalis overdose Der Nervenarzt 2002 73 5 471 474 10.1007/s001150101156 12078028 \n24. Oishi A Miyamoto K Kashii S Yoshimura N Photopsia as a manifestation of digitalis toxicity Can J Ophthalmol 2006 41 5 603 604 10.1016/S0008-4182(06)80031-1 17016533\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1756-0500",
"issue": "8()",
"journal": "BMC research notes",
"keywords": null,
"medline_ta": "BMC Res Notes",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000889:Anti-Arrhythmia Agents; D004077:Digoxin; D004596:Electroretinography; D005123:Eye; D005260:Female; D006801:Humans; D014792:Visual Acuity",
"nlm_unique_id": "101462768",
"other_id": null,
"pages": "368",
"pmc": null,
"pmid": "26298392",
"pubdate": "2015-08-23",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "12386084;12078028;11210783;4280326;621873;517886;6970370;7249508;7283806;6847447;4061549;3265458;2039889;1771077;8113441;7574223;9512168;17016533;22611136;11151114;23250015;22923145",
"title": "Spectrum of digoxin-induced ocular toxicity: a case report and literature review.",
"title_normalized": "spectrum of digoxin induced ocular toxicity a case report and literature review"
} | [
{
"companynumb": "CH-LUPIN PHARMACEUTICALS INC.-2016-01583",
"fulfillexpeditecriteria": "1",
"occurcountry": "CH",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "LISINOPRIL"
},
"drugadditiona... |
{
"abstract": "A 77-year-old man presented with an acute worsening of chronic back pain. CT showed dense bilateral adrenal glands suggestive of adrenal haemorrhage which was confirmed by MRI. Despite appropriate glucocorticoid replacement for adrenal insufficiency, 7 days after admission this patient suffered an adrenal crisis. Owing to the timely diagnosis, appropriate treatment was given and the patient survived. Large bilateral adrenal haemorrhage however, can lead to cardiovascular collapse and death if not appropriately diagnosed and managed promptly. Despite its rarity, bilateral adrenal haemorrhage should always be considered as a differential for back pain in the setting of an acute illness due to its potentially fatal consequences.",
"affiliations": "Keele University, Staffordshire, UK.",
"authors": "McGowan-Smyth|Sam|S|",
"chemical_list": "D005938:Glucocorticoids",
"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": "D000311:Adrenal Glands; D000309:Adrenal Insufficiency; D000368:Aged; D001416:Back Pain; D003937:Diagnosis, Differential; D005938:Glucocorticoids; D006470:Hemorrhage; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "24969071",
"pubdate": "2014-06-26",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "12788587;19776201;19223520;16259572;24031090;19168600;19282465;17307626",
"title": "Bilateral adrenal haemorrhage leading to adrenal crisis.",
"title_normalized": "bilateral adrenal haemorrhage leading to adrenal crisis"
} | [
{
"companynumb": "GB-TEVA-731409ISR",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "WARFARIN"
},
"drugadditional": "1",
"drugad... |
{
"abstract": "BACKGROUND\nInfliximab is a monoclonal anti-Tumor Necrosis Factor alpha-antibody (anti-TNFalpha) that has demonstrated its efficacy in the treatment of rheumatoid arthritis, Crohn's disease and psoriasis.\n\n\nMETHODS\nWe report the case of a 59 year-old woman with a 20-year history of rheumatoid arthritis consulting for an atypical erythematosus rash 18 months after her first infusion of infliximab. The rash was associated with inflammatory syndrome, incipient renal failure and high levels of antinuclear antibodies with the presence of anti-dsDNA antibodies. Lack of specificity in both skin manifestations and histology ruled out a diagnosis of drug-induced lupus. Discontinuation of treatment with infliximab resulted in improvement of all clinical signs together with a significant decrease of antinuclear antibody titers within six months.\n\n\nCONCLUSIONS\nInduction of antinuclear antibodies and/or anti-dsDNA antibodies is often seen in patients treated with TNFalpha inhibitors. Cases of true systemic lupus erythematosus or anti-TNFalpha-related eruption in a context of autoimmunity, as seen in our patient, have been reported only rarely. All cases were reversible upon discontinuation of treatment.",
"affiliations": "Service de Dermatologie, Hôpital Le Bocage, CHU, Dijon.",
"authors": "Jeudy|G|G|;Dutronc|Y|Y|;Galliot-Repkat|C|C|;Dupuis|J|J|;Jolimoy|G|G|;Lambert|D|D|;Collet|E|E|",
"chemical_list": "D000974:Antibodies, Antinuclear; D000911:Antibodies, Monoclonal; D000069285:Infliximab",
"country": "France",
"delete": false,
"doi": "10.1016/s0151-9638(07)91511-2",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0151-9638",
"issue": "134(3 Pt 1)",
"journal": "Annales de dermatologie et de venereologie",
"keywords": null,
"medline_ta": "Ann Dermatol Venereol",
"mesh_terms": "D000974:Antibodies, Antinuclear; D000911:Antibodies, Monoclonal; D001172:Arthritis, Rheumatoid; D006801:Humans; D007249:Inflammation; D000069285:Infliximab; D008297:Male; D008875:Middle Aged; D012871:Skin Diseases",
"nlm_unique_id": "7702013",
"other_id": null,
"pages": "268-71",
"pmc": null,
"pmid": "17389855",
"pubdate": "2007-03",
"publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "Infliximab-induced skin reaction with visceral manifestations and high levels of anti-DNA antibodies.",
"title_normalized": "infliximab induced skin reaction with visceral manifestations and high levels of anti dna antibodies"
} | [
{
"companynumb": "FR-JNJFOC-20190612154",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "INFLIXIMAB"
},
"drugadditional": "1",
"... |
{
"abstract": "BACKGROUND\nAn abscopal response describes radiotherapy-induced immune-mediated tumour regression at sites distant to the irradiated field. Granulocyte-macrophage colony-stimulating factor is a potent stimulator of dendritic cell maturation. We postulated that the exploitation of the pro-immunogenic effects of radiotherapy with granulocyte-macrophage colony-stimulating factor might result in abscopal responses among patients with metastatic cancer.\n\n\nMETHODS\nPatients with stable or progressing metastatic solid tumours, on single-agent chemotherapy or hormonal therapy, with at least three distinct measurable sites of disease, were treated with concurrent radiotherapy (35 Gy in ten fractions, over 2 weeks) to one metastatic site and granulocyte-macrophage colony-stimulating factor (125 μg/m(2) subcutaneously injected daily for 2 weeks, starting during the second week of radiotherapy). This course was repeated, targeting a second metastatic site. A Simon's optimal two-stage design was chosen for this trial: an additional 19 patients could be enrolled in stage 2 only if at least one patient among the first ten had an abscopal response. If no abscopal responses were seen among the first ten patients, the study would be deemed futile and terminated. The primary endpoint was the proportion of patients with an abscopal response (defined as at least a 30% decrease in the longest diameter of the best responding abscopal lesion). Secondary endpoints were safety and survival. Analyses were done based on intention to treat. The trial has concluded accrual, and is registered with ClinicalTrials.gov, number NCT02474186.\n\n\nRESULTS\nFrom April 7, 2003, to April 3, 2012, 41 patients with metastatic cancer were enrolled. In stage 1 of the Simon's two-stage design, ten patients were enrolled: four of the first ten patients had abscopal responses. Thus, the trial proceeded to stage 2, as planned, and an additional 19 patients were enrolled. Due to protocol amendments 12 further patients were enrolled. Abscopal responses occurred in eight (27·6%, 95% CI 12·7-47·2) of the first 29 patients, and 11 (26·8%, 95% CI 14·2-42·9) of 41 accrued patients (specifically in four patients with non-small-cell lung cancer, five with breast cancer, and two with thymic cancer). The most common grade 3-4 adverse events were fatigue (six patients) and haematological (ten patients). Additionally, a serious adverse event of grade 4 pulmonary embolism occurred in one patient.\n\n\nCONCLUSIONS\nThe combination of radiotherapy with granulocyte-macrophage colony-stimulating factor produced objective abscopal responses in some patients with metastatic solid tumours. This finding represents a promising approach to establish an in-situ anti-tumour vaccine. Further research is warranted in this area.\n\n\nBACKGROUND\nNew York University School of Medicine's Department of Radiation Oncology and Cancer Institute.",
"affiliations": "Department of Radiation Oncology, New York University School of Medicine, New York, NY, USA.;Department of Radiation Oncology, SUNY Downstate, New York, NY, USA.;Department of Medicine, New York University School of Medicine, New York, NY, USA.;Department of Medicine, New York University School of Medicine, New York, NY, USA.;Department of Radiology, New York University School of Medicine, New York, NY, USA.;Department of Radiation Oncology, New York University School of Medicine, New York, NY, USA.;Department of Radiology, New York University School of Medicine, New York, NY, USA.;Department of Radiology, New York University School of Medicine, New York, NY, USA.;Department of Radiology, New York University School of Medicine, New York, NY, USA.;Division of Biostatistics, New York University School of Medicine, New York, NY, USA.;Department of Radiation Oncology, New York University School of Medicine, New York, NY, USA; Department of Pathology, New York University School of Medicine, New York, NY, USA.;Department of Radiation Oncology, Weill Cornell Medical College, New York, NY, USA. Electronic address: formenti@med.cornell.edu.",
"authors": "Golden|Encouse B|EB|;Chhabra|Arpit|A|;Chachoua|Abraham|A|;Adams|Sylvia|S|;Donach|Martin|M|;Fenton-Kerimian|Maria|M|;Friedman|Kent|K|;Ponzo|Fabio|F|;Babb|James S|JS|;Goldberg|Judith|J|;Demaria|Sandra|S|;Formenti|Silvia C|SC|",
"chemical_list": "D016178:Granulocyte-Macrophage Colony-Stimulating Factor",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1470-2045",
"issue": "16(7)",
"journal": "The Lancet. Oncology",
"keywords": null,
"medline_ta": "Lancet Oncol",
"mesh_terms": "D000046:Academic Medical Centers; D000368:Aged; D003131:Combined Modality Therapy; D016001:Confidence Intervals; D018572:Disease-Free Survival; D019583:Dose Fractionation, Radiation; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D004334:Drug Administration Schedule; D005260:Female; D005500:Follow-Up Studies; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009369:Neoplasms; D009519:New York City; D018579:Patient Selection; D018714:Radiotherapy, Adjuvant; D018570:Risk Assessment; D018709:Statistics, Nonparametric; D016019:Survival Analysis; D016896:Treatment Outcome",
"nlm_unique_id": "100957246",
"other_id": null,
"pages": "795-803",
"pmc": null,
"pmid": "26095785",
"pubdate": "2015-07",
"publication_types": "D016430:Clinical Trial; D003160:Comparative Study; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Local radiotherapy and granulocyte-macrophage colony-stimulating factor to generate abscopal responses in patients with metastatic solid tumours: a proof-of-principle trial.",
"title_normalized": "local radiotherapy and granulocyte macrophage colony stimulating factor to generate abscopal responses in patients with metastatic solid tumours a proof of principle trial"
} | [
{
"companynumb": "US-SA-2015SA092246",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "GRANULOCYTE-MACROPHAGE COLONY-STIMULATING FACTOR"
},
... |
{
"abstract": "Hydralazine is a commonly used oral antihypertensive agent. We report a rare case of hydralazine-induced hepatotoxicity in the form of subacute hepatic necrosis. A 75-year-old African American woman presented with jaundice of 7-day duration. She was started on hydralazine 100 mg 3 times a day 10 weeks before presentation. On physical examination, scleral icterus was noted. Workup revealed elevated liver transaminases, alkaline phosphatase, and conjugated bilirubin. She had no history of liver disease, and liver function tests had been normal before starting hydralazine. Other etiologies, including viruses, common toxins, drugs, autoimmune, and copper-induced hepatitis, were excluded. Abdominal imaging studies did not show any evidence of intrahepatic or extrahepatic biliary ductal dilatation, and no pathologies were seen in the liver and pancreas. The patient's liver biopsy revealed extensive lobular hepatitis, significant necrosis, mixed inflammatory infiltrate, and no significant fibrosis, supporting a diagnosis of drug-induced liver injury. Hydralazine was immediately discontinued. She showed improvement of clinical and laboratory abnormalities within 5 days after discontinuation of hydralazine. To establish the diagnosis of hydralazine-induced liver injury, we used assessment tool outlined by the Council for International Organization of Medical Sciences (CIOMS) scale that led to \"high probable\" relationship. Although rare, clinically significant, and potentially life-threatening liver injury can result from use of hydralazine. Both clinical and histological presentations in our patient suggest acute liver injury. The hydralazine-induced hepatitis seems to be reversible as discontinuation of the drug improves clinical outcomes. We highly recommend monitoring of the liver function during hydralazine treatment.",
"affiliations": "Department of Internal Medicine, Providence Hospital, Washington, DC.",
"authors": "Harati|Hadi|H|;Rahmani|Maziar|M|;Taghizadeh|Sassan|S|",
"chemical_list": "D000959:Antihypertensive Agents; D006830:Hydralazine",
"country": "United States",
"delete": false,
"doi": "10.1097/MJT.0000000000000310",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1075-2765",
"issue": "23(5)",
"journal": "American journal of therapeutics",
"keywords": null,
"medline_ta": "Am J Ther",
"mesh_terms": "D000208:Acute Disease; D000368:Aged; D000959:Antihypertensive Agents; D001706:Biopsy; D056486:Chemical and Drug Induced Liver Injury; D002779:Cholestasis; D005260:Female; D006801:Humans; D006830:Hydralazine; D007565:Jaundice; D008111:Liver Function Tests",
"nlm_unique_id": "9441347",
"other_id": null,
"pages": "e1211-4",
"pmc": null,
"pmid": "26291593",
"pubdate": "2016",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Acute Cholestatic Liver Injury From Hydralazine Intake.",
"title_normalized": "acute cholestatic liver injury from hydralazine intake"
} | [
{
"companynumb": "US-ALKEM-001160",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "HYDROCHLOROTHIAZIDE"
},
"drugadditional": null,
... |
{
"abstract": "Donor-type aplasia (DTA) is a condition where an individual continues to be aplastic even after a successful engraftment of a hematopoeitic stem cell transplant with a majority of donor type cells in the bone marrow. This entity has been seen with varying frequency around the world, especially in Southeast Asia. However, its incidence in the Indian subcontinent remains fairly low. Here is a case of a 17-year-old child with DTA who had a 89% population of donor cells after a successful transplant and presented with recurrent severe aplastic anemia later. The patient eventually succumbed to his condition before a second transplant could be performed. The awareness about the seriousness of this relatively rare condition, therefore, needs to be emphasized.",
"affiliations": "Department of Pathology, ABVIMS and Dr. RML Hospital, New Delhi, India.;Department of Pathology, ABVIMS and Dr. RML Hospital, New Delhi, India.;Department of Pathology, ABVIMS and Dr. RML Hospital, New Delhi, India.",
"authors": "Majumder|A|A|;Misra|S|S|;Kumar|V|V|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.4103/jpgm.JPGM_988_20",
"fulltext": "\n==== Front\nJ Postgrad Med\nJ Postgrad Med\nJPGM\nJournal of Postgraduate Medicine\n0022-3859\n0972-2823\nWolters Kluwer - Medknow India\n\n34121669\nJPGM-67-235\n10.4103/jpgm.JPGM_988_20\nCase Report\nRecurrent aplastic anemia with donor-type aplasia: A rare occurrence in the Indian subcontinent\nMajumder A\nMisra S\nKumar V\nDepartment of Pathology, ABVIMS and Dr. RML Hospital, New Delhi, India\nAddress for correspondence: Dr. Kumar V, E-mail: vijaypgi1@gmail.com\nOct-Dec 2021\n01 6 2021\n67 4 235237\n23 8 2020\n06 12 2020\n30 12 2020\nCopyright: © 2021 Journal of Postgraduate Medicine\n2021\nhttps://creativecommons.org/licenses/by-nc-sa/4.0/ This 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.\nDonor-type aplasia (DTA) is a condition where an individual continues to be aplastic even after a successful engraftment of a hematopoeitic stem cell transplant with a majority of donor type cells in the bone marrow. This entity has been seen with varying frequency around the world, especially in Southeast Asia. However, its incidence in the Indian subcontinent remains fairly low. Here is a case of a 17-year-old child with DTA who had a 89% population of donor cells after a successful transplant and presented with recurrent severe aplastic anemia later. The patient eventually succumbed to his condition before a second transplant could be performed. The awareness about the seriousness of this relatively rare condition, therefore, needs to be emphasized.\n\nKEY WORDS:\n\nBone marrow transplant\nchimerism\ndonor-type aplasia\nhematology\nhematopoeitic stem cells\n==== Body\npmcIntroduction\n\nSevere Aplastic Anemia as defined by the modified Camitta criteria includes a marrow cellularity <25% (or 25–50% with <30% residual haematopoietic cells), plus at least 2 of: (i) neutrophils <500/μL, (ii) platelets <20.000/μL, (iii) reticulocyte count <20.000/μL. The widely accepted treatment of idiopathic severe aplastic anemia (SAA) in childhood is hematopoeitic stem cell transplant (HSCT) with a human leucocyte antigen (HLA) matched sibling donor (MSD) or a matched unrelated donor (MUD) along with concomitant immunosuppressive therapy (IST).[1] The natural expectation would be to attain a full donor chimerism of 100% or a high donor majority in a mixed chimeric picture to ensure complete engraftment. However, recent studies have shown that a mixed chimerism is favorable as it reduces the chance of acute graft vs host disease (GvHD).[2] In the recent years, there have been sporadic reported cases of a late graft failure after a successful transplant and engraftment of >6 months, usually after the stoppage of IST. Interestingly, some of these cases have shown to have a majority of donor cells in the marrow during this recurrence. This has been termed as donor-type aplasia (DTA).[3] This case highlights the importance of this relatively rare entity in this geographic area.\n\nCase Report\n\nHere we present the case of a 17-year-old male who was diagnosed as aplastic anemia in December 2018 (absolute neutrophil count 400/cu.mm, platelets 10000/cu.mm) and underwent bone marrow transplantation with a MSD on April 2019. The conditioning regimen offered was fludarabine (Flu) with reduced dose cyclophosphamide and anti-thymocyte globulin (ATG). The procedure was followed by successful engraftment and returning of blood counts to normal levels (Hemoglobin [Hb]: 12.1 gm/dl, total leucocyte count [TLC]: 5900/cu.mm, platelet count [PC]: 1.6 lakhs/cu.mm). Post-transplant IST was started in the form of cyclosporine (CsA) without ATG. The patient continued taking CsA without any obvious adverse effects for a year from April 2019 to March 2020. Repeat CBCs showed a stabilization of blood counts. Serial tests for chimerism done by short tandem repeats-polymerase chain reaction (STR-PCR) within the period May 2019 to February 2020 showed an average of 93% donor cells in the marrow (peak of 96%). After almost two and half months of stoppage of CsA, the patient's condition deteriorated in late May 2020. There were two episodes of bleeding from the nose and mouth and progressive pallor was noted. CBC showed the following parameters: Hb-5.6 gm/dl, TLC -3200/cu.mm, PC -30000/cu.mm. There was no history of trauma/viral infection. Bone marrow was sent for examination. The aspirate was hemodilute with few cellular trails showing trilineage hematopoiesis. The biopsy was hypoplastic with a cellularity of 20-25% [Figure 1a]. There was an apparent mild increase in lymphoid cells. Repeat bone marrow chimerism studies showed 89% donor cells [Figure 1b]. Packed red cells and platelet infusions were given for symptomatic relief. As the clinical condition continued to deteriorate rapidly, a second HSCT from the same sibling was planned with a clinical suspicion of DTA. No additional IST/medication was given. However, the patient succumbed to his critical illness before the second transplant could be attempted in June 2020.\n\nFigure 1 (a) Bone marrow biopsy showing pauci-cellular marrow spaces (black arrow) (H and E ×100). (b) Graph showing variation of donor cell percentage in sequential marrow-chimerism studies over a period of one-year post-transplant. (SD- standard deviation; CV- coefficient of variation)\n\nDiscussion\n\nDTA has been documented in cases occurring 8 months to 10 years post-transplant.[4] Its incidence varies from 5% to 26% in various studies.[56] A number of mechanisms have been theorized for the same. It is speculated that the destruction of the donor cells is more protracted than what was thought initially and that the “malignant” recipient clone eventually takes over the marrow again.[7] As in some cases the onset of DTA was seen along with an underlying viral infection, it is thought that a secondary infectious trigger which leads to the prolonged activation of pathogen specific T cells of recipient origin could also be the mechanism for aplasia. It is also of importance to note that although SAA is usually idiopathic, some cases of recurrence has been noted among MSDs.[8] Thus there is a possibility of a genetic role in such cases which warrants further investigations by whole genome sequencing. Patients after HSCT are also less responsive to indigenous erythropoietin, thereby worsening the state of anemia.[9] Other factors like low infused cell number, no IST prior to HSCT, preceding transfusion >40 times and inclusion of fludarabine therapy along with CsA were associated with the development of donor-type aplasia.[56]\n\nThe probable reasons for development of DTA in this particular case are varied. The patient underwent a high number of pre transplant transfusion (>40). Although viral markers were negative, subclinical viral infections could have caused a “second hit”, thereby leading to protracted recipient T-cell activation. Clonal evolution of the “aplastic clone” also remains a possible cause, warranting the need for whole genome studies in such patients. In addition to these, the exclusion of ATG from post-transplant regimen and a possible early withdrawal of CsA could be added causative factors here.\n\nA second HSCT from the primary donor remains the treatment of choice in patients of DTA. In some cases pre-transplant treatment by CD34 infusions, steroids, CsA, ATG, donor lymphocyte infusion (DLI), plasmapheresis, rituximab, sirolimus, or eltrmpobag may be used. Out of these, only eltrombopag has been reported to cause sustained improved cell counts. Occasional cases may even require a third transplant.[8] However, caution should be exercised because in spite of protective treatments, HSCT itself can cause a plethora of complications including GvHD, organ damage, infections, failure of stem cell transplant (primary and secondary) and rarely, hemolytic uremic syndrome and myelodysplasia.\n\nDTA is a relatively rare entity. Owing to the severity and possible fatal outcome, this condition should be borne in mind by clinicians and pathologists alike.\n\nDeclaration of patient consent\n\nThe authors certify that appropriate patient consent was obtained.\n\nFinancial support and sponsorship\n\nNil.\n\nConflicts of interest\n\nThere are no conflicts of interest.\n==== Refs\nReferences\n\n1 Samarasinghe S Veys P Vora A Wynn R Paediatric amendment to adult BSH Guidelines for aplastic anaemia Br J Haematol 2018 180 201 5 29285764\n2 Lawler M McCann SR Marsh JC Ljungman P Hows J Vandenberghe E Serial chimerism analyses indicate that mixed haemopoietic chimerism influences the probability of graft rejection and disease recurrence following allogeneic stem cell transplantation (SCT) for severe aplastic anaemia (SAA): Indication for routine assessment of chimerism post SCT for SAA Br J Haematol 2009 144 933 45 19183198\n3 Hama A Muramatsu H Narita A Kitazawa H Hamada M Kataoka S Risk factors for donor-type aplasia after bone marrow transplant in children with acquired bone marrow failure Blood 2017 130 Suppl 1 2461\n4 Eapen M Davies SM Ramsay NK Late graft rejection and second infusion of bone marrow in children with aplastic anaemia Br J Haematol 1999 104 186 8 10027732\n5 Jeong K Cho JH Cheon KR Jang HI Baek HJ Kook H Treatment and outcome of the patients with donor-type aplasia after bone marrow transplantation in children with aplastic anemia Blood 2015 126 4782\n6 Yoshida N Yagasaki H Yabe H Kikuchi A Kobayashi R Takahashi Y Donor-type aplasia after bone marrow transplantation in children with aplastic anemia: A nationwide retrospective study Blood 2012 120 959\n7 Dufour C Dallorso S Casarino L Corcione A Pistoia V Bacigalupo A Late graft failure 8 years after first bone marrow transplantation for severe acquired aplastic anemia Bone Marrow Transplant 1999 23 743 5 10218856\n8 Shaw A Passweg JR De La Fuente J Bajwa R Stein J Al-Zaben A Relapse of aplastic anemia with majority donor chimerism (donor-type aplasia) occurring late after bone marrow transplantation Biol Blood Marrow Transplant 2020 26 480 5 31733299\n9 Miller CB Jones RJ Zahurak ML Piantadosi S Burns WH Santos GW Impaired erythropoietin response to anemia after bone marrow transplantation Blood 1992 80 2677 82 1421381\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "0022-3859",
"issue": "67(4)",
"journal": "Journal of postgraduate medicine",
"keywords": "Bone marrow transplant; chimerism; donor-type aplasia; hematology; hematopoeitic stem cells",
"medline_ta": "J Postgrad Med",
"mesh_terms": null,
"nlm_unique_id": "2985196R",
"other_id": null,
"pages": "235-237",
"pmc": null,
"pmid": "34121669",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Recurrent aplastic anemia with donor-type aplasia: A rare occurrence in the Indian subcontinent.",
"title_normalized": "recurrent aplastic anemia with donor type aplasia a rare occurrence in the indian subcontinent"
} | [
{
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"activesubstancename": "FLUDARABINE PHOSPHATE"
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"abstract": "In this report, we describe a case of a patient with a clinical history of systemic sarcoidosis and psoriasis who developed biopsy-confirmed perforating and necrotizing cutaneous granulomas after 12 months of treatment with adalimumab, a tumor necrosis factor-alpha-inhibiting, anti-inflammatory, biologic medication, prescribed for the patient's psoriasis. Although rare reports of a \"sarcoidosis-like\" reaction associated with select tumor necrosis factor-alpha agents exist, to the best of our knowledge, perforating and necrotizing cutaneous granulomas after treatment with adalimumab has not been previously reported. Given the patient's history of systemic sarcoidosis, the differential diagnosis includes reactivation of latent sarcoidosis with adalimumab as a trigger.",
"affiliations": "Dermatology Section, Department of Medicine, VA Boston Healthcare System, MA.;Dermatology Section, Department of Medicine, VA Boston Healthcare System, MA.;Dermatopathology Section, Department of Pathology and Laboratory Medicine, VA Boston Healthcare System, MA.",
"authors": "Turkowski|Yana|Y|;Konnikov|Nellie|N|;Mahalingam|Meera|M|",
"chemical_list": "D000900:Anti-Bacterial Agents; D061067:Antibodies, Monoclonal, Humanized; D000068879:Adalimumab; D011241:Prednisone",
"country": "United States",
"delete": false,
"doi": "10.1097/DAD.0000000000001394",
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"issn_linking": "0193-1091",
"issue": "41(9)",
"journal": "The American Journal of dermatopathology",
"keywords": null,
"medline_ta": "Am J Dermatopathol",
"mesh_terms": "D000068879:Adalimumab; D000368:Aged; D000900:Anti-Bacterial Agents; D061067:Antibodies, Monoclonal, Humanized; D001707:Biopsy, Needle; D003131:Combined Modality Therapy; D064420:Drug-Related Side Effects and Adverse Reactions; D005500:Follow-Up Studies; D006099:Granuloma; D006801:Humans; D007150:Immunohistochemistry; D007866:Leg; D008297:Male; D009336:Necrosis; D011241:Prednisone; D011565:Psoriasis; D012008:Recurrence; D012507:Sarcoidosis; D012720:Severity of Illness Index; D016038:Skin Transplantation; D012883:Skin Ulcer; D013997:Time Factors; D014945:Wound Healing",
"nlm_unique_id": "7911005",
"other_id": null,
"pages": "661-666",
"pmc": null,
"pmid": "30839343",
"pubdate": "2019-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Necrotizing Granulomas in a Patient With Psoriasis and Sarcoidosis After Adalimumab-Medication-Induced Reaction or Reactivation of Latent Disease?",
"title_normalized": "necrotizing granulomas in a patient with psoriasis and sarcoidosis after adalimumab medication induced reaction or reactivation of latent disease"
} | [
{
"companynumb": "US-TEVA-2020-US-1193573",
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"activesubstancename": "ADALIMUMAB"
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... |
{
"abstract": "The objective of this study is to report a case of sertraline-induced rhabdomyolysis in a female patient with a history of depression. A 25-year-old Hispanic woman with a history of depression reported to the emergency department (ED) with a chief complaint of muscle swelling and soreness and dark urine. The patient's creatine phosphokinase was 15,103 U/L. Despite treatment with IV normal saline, the patient's symptoms persisted and the creatine phosphokinase continued to rise to a peak of 16,778 U/L on day 2. The patient reported completing a strenuous, although routine, exercise the day before arriving at the ED, and her medication history was only significant for sertraline. Of note, 6 weeks before her visit to the ED, sertraline was increased from 100 mg daily to 150 mg daily. The patient's rhabdomyolysis was attributed to sertraline in conjunction with recent exercise. Selective serotonin reuptake inhibitor (SSRI)-induced rhabdomyolysis has been documented in 5 case reports. Similar to most reports, our patient presented with rhabdomyolysis in the presence of both SSRI use and exercise. Unlike the majority of previous reports, our patient was not taking other medications with documented association to rhabdomyolysis and had performed routine exercise before presenting with rhabdomyolysis. Although the mechanism of SSRI-induced rhabdomyolysis is not known, a theory posits that sertraline may have a role in muscle contraction and relaxation, leading to shorter time to contracture and longer time of contraction. The use of sertraline and other SSRIs may be associated with development of rhabdomyolysis, especially in the presence of strenuous exercise.",
"affiliations": "1James J. Peters VA Medical Center, Bronx, NY; and 2Arnold and Marie Schwartz College of Pharmacy and Health Sciences, Long Island University, Brooklyn, NY.",
"authors": "Snyder|Mitchell|M|;Kish|Troy|T|",
"chemical_list": "D017367:Serotonin Uptake Inhibitors; D020280:Sertraline",
"country": "United States",
"delete": false,
"doi": "10.1097/MJT.0000000000000196",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1075-2765",
"issue": "23(2)",
"journal": "American journal of therapeutics",
"keywords": null,
"medline_ta": "Am J Ther",
"mesh_terms": "D000328:Adult; D005260:Female; D006801:Humans; D012206:Rhabdomyolysis; D017367:Serotonin Uptake Inhibitors; D020280:Sertraline",
"nlm_unique_id": "9441347",
"other_id": null,
"pages": "e561-5",
"pmc": null,
"pmid": "25581857",
"pubdate": "2016",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Sertraline-Induced Rhabdomyolysis: A Case Report and Literature Review.",
"title_normalized": "sertraline induced rhabdomyolysis a case report and literature review"
} | [
{
"companynumb": "US-CIPLA LTD.-2015US01041",
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"patient": {
"drug": [
{
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"activesubstance": {
"activesubstancename": "OLANZAPINE"
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... |
{
"abstract": "Based on the technical information that oral terbinafine must be used with caution in patients with pre-existing psoriasis or lupus erythematosus, the literature was summarized. Terbinafine belongs to the drugs able to induce subcutaneous lupus erythematosus (SCLE)-with a relatively high risk. The clinical picture of terbinafine-induced SCLE may be highly variable and can also include erythema exsudativum multiforme-like or bullous lesions. Thus, differentiation of terbinafine-induced Stevens-Johnson syndrome or toxic epidermal necrolysis may be difficult. Therefore, terbinafine should be prescribed with caution in patients who show light sensitivity, arthralgias, positive antinuclear antibodies or have a history of SLE or SCLE. Case reports include wide-spread, but mostly nonlife-threatening courses, which did not require systemic therapy with steroids or antimalarials in every case. Terbinafine is also able to induce or to aggravate psoriasis. The latency period seems to be rather short (<4 weeks). Terbinafine therefore is not first choice if a systemic therapy with antimycotics is indicated in a patient with psoriasis or psoriatic diathesis. Azole derivatives according to the guidelines may be used as an alternative.",
"affiliations": ", Hofmannstr. 11, 35444, Biebertal, Deutschland. peter.mayser@derma.med.uni-giessen.de.",
"authors": "Mayser|P|P|",
"chemical_list": "D000935:Antifungal Agents; D009281:Naphthalenes; D000077291:Terbinafine",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00105-016-3844-9",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0017-8470",
"issue": "67(9)",
"journal": "Der Hautarzt; Zeitschrift fur Dermatologie, Venerologie, und verwandte Gebiete",
"keywords": "Acute generalized exanthematous pustulosis; Antifungal agents; Erythema multiforme; Light sensitivity; Psoriasis",
"medline_ta": "Hautarzt",
"mesh_terms": "D000935:Antifungal Agents; D004305:Dose-Response Relationship, Drug; D003875:Drug Eruptions; D019317:Evidence-Based Medicine; D006801:Humans; D009281:Naphthalenes; D011565:Psoriasis; D000077291:Terbinafine; D016896:Treatment Outcome",
"nlm_unique_id": "0372755",
"other_id": null,
"pages": "724-31",
"pmc": null,
"pmid": "27455869",
"pubdate": "2016-09",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": "9764183;11369902;22458771;12786843;24880185;9990400;16760836;17854368;12718791;11559217;22937775;22998455;10804301;20627850;21888496;20461049;21039412;21091671;24452843;16319476;15146276;9640387;15844640;9674406;17854366;16533240;19049946;10494721;24820800;21790726;9146568;18441768;9990401;19874252;14739471;22998546;19762393;26021384;21564069;19549237;17805350;15840114;23217946;17297275;18833041;24278085;18564209",
"title": "Terbinafine : Drug-induced lupus erythematodes and triggering of psoriatic skin lesions.",
"title_normalized": "terbinafine drug induced lupus erythematodes and triggering of psoriatic skin lesions"
} | [
{
"companynumb": "DE-GLAXOSMITHKLINE-DE2016132917",
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"occurcountry": "DE",
"patient": {
"drug": [
{
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"activesubstance": {
"activesubstancename": "TERBINAFINE"
},
"drugadditional": "1",
... |
{
"abstract": "A 30-year-old right-handed man with a history of schizophrenia presented with 2 self-inflicted drywall screws in the skull. The patient was sleepy but easily arousable; blood tests showed he had taken methamphetamines. Computed tomography and computed tomography angiography of the head showed the frontal screw abutted left of the superior sagittal sinus, and the posterior screw went through the superior sagittal sinus with no extravasation of contrast material at either site. Both screws were removed with exposure of the sagittal sinus using U-shaped craniectomies. There was no bleeding on the removal of the screws. It appears the posterior screw entered between the leaflets of the sagittal sinus dura mater. The patient had returned to work without any sequelae 1 month after injury.",
"affiliations": "Department of Neurosurgery, Kaiser Permanente/University of California San Francisco, Sacramento, California, USA. Electronic address: kguppy@yahoo.com.;Department of Neurosurgery, Kaiser Permanente/University of California San Francisco, Sacramento, California, USA.",
"authors": "Guppy|Kern H|KH|;Ochi|Calvin|C|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.wneu.2017.11.134",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1878-8750",
"issue": "110()",
"journal": "World neurosurgery",
"keywords": "Drywall screws; Sagittal sinus; Self-inflicted",
"medline_ta": "World Neurosurg",
"mesh_terms": "D000328:Adult; D001863:Bone Screws; D020197:Head Injuries, Penetrating; D006801:Humans; D008297:Male; D012559:Schizophrenia; D016728:Self-Injurious Behavior; D054063:Superior Sagittal Sinus; D015898:Tomography Scanners, X-Ray Computed",
"nlm_unique_id": "101528275",
"other_id": null,
"pages": "323-325",
"pmc": null,
"pmid": "29191542",
"pubdate": "2018-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Self-Inflicted Drywall Screws in the Sagittal Sinus.",
"title_normalized": "self inflicted drywall screws in the sagittal sinus"
} | [
{
"companynumb": "US-RECORDATI RARE DISEASES-US-R13005-18-00003",
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"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "METHAMPHETAMINE"
},
"dru... |
{
"abstract": "Erythema nodosum leprosum is defined by the appearance of tender skin nodules, which can be accompanied by fever, joint pain, neuritis, edema, malaise and/or lymphadenopathy. The authors describe the case of a 19-year-old Angolan black woman, resident in Portugal for the last 10 years, diagnosed with Hansen's disease at the age of 12, irregular with follow-up and non-compliant with treatment. She was referred to our clinic with painful nodules and pustules on the upper limbs, diffuse facial infiltration with pustules and fever, after initiating minocycline with the intention of treating acne. Diagnosis of erythema nodosum leprosum was confirmed by the presence of acid-fast bacilli in the skin smear and also in skin biopsy. Minocycline was suspended and the patient was treated with systemic steroids, with prompt clinical improvement. Our case is reported to alert clinicians to this unusual presentation of erythema nodosum leprosum in a patient treated with highly bactericidal drugs that were not intended to treat Hansen's disease.",
"affiliations": "Clínica Universitária de Dermatologia, Hospital de Santa Maria (CHLN), Avenida Prof. Egas Moniz, 1649-035 Lisboa, Portugal. ritatravassos@gmail.com",
"authors": "Travassos|Ana Rita|AR|;Antunes|Joana|J|;Pacheco|David|D|;Almeida|Luís Soares|LS|;Filipe|Paulo|P|;Marques|Manuel Sacramento|MS|",
"chemical_list": "D007917:Leprostatic Agents; D011239:Prednisolone; D008911:Minocycline",
"country": "Slovenia",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1318-4458",
"issue": "21(2)",
"journal": "Acta dermatovenerologica Alpina, Pannonica, et Adriatica",
"keywords": null,
"medline_ta": "Acta Dermatovenerol Alp Pannonica Adriat",
"mesh_terms": "D000152:Acne Vulgaris; D001707:Biopsy, Needle; D004359:Drug Therapy, Combination; D004893:Erythema Nodosum; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007150:Immunohistochemistry; D007917:Leprostatic Agents; D015440:Leprosy, Lepromatous; D008911:Minocycline; D011239:Prednisolone; D018570:Risk Assessment; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "9422563",
"other_id": null,
"pages": "39-41",
"pmc": null,
"pmid": "23000940",
"pubdate": "2012",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Erythema nodosum leprosum associated with minocycline.",
"title_normalized": "erythema nodosum leprosum associated with minocycline"
} | [
{
"companynumb": "PHHY2012PT114367",
"fulfillexpeditecriteria": "1",
"occurcountry": "PT",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "MINOCYCLINE HYDROCHLORIDE"
},
"drugadditional": "1",
... |
{
"abstract": "Primary cancer of the vagina is a rare entity, comprising only 1-2% of all gynecologic malignancies. Infection of human papillomavirus, immunocompromised condition, and chronic irritation of the vagina by prolonged pessary usage are known to contribute to the development of vaginal cancer. We experienced a rare case of vaginal cancer that occurred after usage of a vaginal pessary while the patient was prescribed with oral prednisolone for idiopathic interstitial pneumonia. Previous reports of vaginal cancer that occurred after pessary usage are mostly neglected pessaries, but in this case the patient was managed properly. We suspect that her immunocompromised condition, as well as her pessary usage, may have accelerated the development of vaginal cancer. The presence of multiple risk factors could be related to the pathogenesis of vaginal cancer, and therefore proper management is required after pessary insertion for uterine prolapse treatment.",
"affiliations": "Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.;Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.;Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.;Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.;Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.;Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.;Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.;Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.",
"authors": "Akino|Nana|N|;Wada-Hiraike|Osamu|O|;Matsumoto|Yoko|Y|;Arimoto|Takahide|T|;Oda|Katsutoshi|K|;Kawana|Kei|K|;Osuga|Yutaka|Y|;Fujii|Tomoyuki|T|",
"chemical_list": null,
"country": "Australia",
"delete": false,
"doi": "10.1111/jog.12958",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1341-8076",
"issue": "42(6)",
"journal": "The journal of obstetrics and gynaecology research",
"keywords": "human papillomavirus; immunocompromised condition; uterine prolapse; vaginal cancer; vaginal pessary",
"medline_ta": "J Obstet Gynaecol Res",
"mesh_terms": null,
"nlm_unique_id": "9612761",
"other_id": null,
"pages": "748-751",
"pmc": null,
"pmid": "26914159",
"pubdate": "2016-06",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Vaginal cancer possibly caused by pessary and immunocompromised condition: Multiple risk factors may influence vaginal cancer development.",
"title_normalized": "vaginal cancer possibly caused by pessary and immunocompromised condition multiple risk factors may influence vaginal cancer development"
} | [
{
"companynumb": "JP-MYLANLABS-2016M1027269",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"drugadditional": null,
... |
{
"abstract": "We report a fatal case of neuroleptic malignant-like syndrome, which occurred as a consequence of paralytic bowel in a 72-year-old woman on treatment with antiparkinson medication.\nContrast enhanced computerized tomography of the chest and abdomen demonstrated the presence of paralytic bowel.\nThe patient died.\nPhysicians involved in the treatment of patients affected by Parkinson's disease should take into consideration the possibility of dopaminergic drug malabsorption due to paralytic bowel as a possible cause of neuroleptic malignant-like syndrome.\nClinical features of neuroleptic malignant-like syndrome (NMLS) in parkinsonian patients are similar to those of neuroleptic malignant syndrome (NMS), which is a potentially fatal condition associated with the withdrawal of antipsychotic medication.Paralytic bowel is a condition frequently impairing medication absorption in the absence of modifications to the normal daily intake of antiparkinson drugs.The present case report describes the fatal outcome of NMLS following paralytic bowel in a parkinsonian patient on levodopa and amantadine therapy.",
"affiliations": "Department of Emergency Medicine, Pineta Grande Hospital, Caserta, Italy.;Department of Emergency Medicine, Pineta Grande Hospital, Caserta, Italy.;Department of Emergency Medicine, Pineta Grande Hospital, Caserta, Italy.;Department of Emergency Medicine, Pineta Grande Hospital, Caserta, Italy.;LN Age, Roma, Italy.;Department of Emergency Medicine, Pineta Grande Hospital, Caserta, Italy.",
"authors": "Campa|Domenico|D|;Ariello|Manuela|M|;Castaldo|Rosaria|R|;Zibella|Francesco|F|;Ferrazza|Paolo|P|;Del Gaudio|Salvatore|S|",
"chemical_list": null,
"country": "Italy",
"delete": false,
"doi": "10.12890/2016_000368",
"fulltext": "\n==== Front\nEur J Case Rep Intern MedEur J Case Rep Intern MedEuropean Journal of Case Reports in Internal Medicine2284-2594SMC Media Srl 10.12890/2016_000368368-1-2783-1-10-20160518ArticlesA Fatal Case of Neuroleptic Malignant Syndrome After Paralytic Bowel in a Patient Taking Antiparkinson Medication Campa Domenico 1Ariello Manuela 1Castaldo Rosaria 1Zibella Francesco 1Ferrazza Paolo 2Del Gaudio Salvatore 1\n1 Department of Emergency Medicine, Pineta Grande Hospital, Caserta, Italy\n2 LN Age, Roma, Italy2016 18 5 2016 3 4 00036829 12 2015 08 2 2016 © EFIM 20162016This article is licensed under a Commons Attribution Non-Commercial 4.0 LicenseObjectives\nWe report a fatal case of neuroleptic malignant-like syndrome, which occurred as a consequence of paralytic bowel in a 72-year-old woman on treatment with antiparkinson medication.\n\nCase description\nContrast enhanced computerized tomography of the chest and abdomen demonstrated the presence of paralytic bowel.\n\nResults\nThe patient died.\n\nConclusions\nPhysicians involved in the treatment of patients affected by Parkinson’s disease should take into consideration the possibility of dopaminergic drug malabsorption due to paralytic bowel as a possible cause of neuroleptic malignant-like syndrome.\n\nLEARNING POINTS\nClinical features of neuroleptic malignant-like syndrome (NMLS) in parkinsonian patients are similar to those of neuroleptic malignant syndrome (NMS), which is a potentially fatal condition associated with the withdrawal of antipsychotic medication.\n\nParalytic bowel is a condition frequently impairing medication absorption in the absence of modifications to the normal daily intake of antiparkinson drugs.\n\nThe present case report describes the fatal outcome of NMLS following paralytic bowel in a parkinsonian patient on levodopa and amantadine therapy.\n\nNeuroleptic malignant-like syndrome (NMLS)Paralytic bowel (PB)Parkinson’s disease (PD)\n==== Body\nINTRODUCTION\nNeuroleptic malignant syndrome (NMS) is an idiosyncratic, rare and potentially fatal condition frequently associated with the withdrawal of antipsychotic medication[1]. The following symptoms are often described: persistent high temperature, stupor, autonomic and mental dysfunction, and rhabdomyolysis. Neuroleptic malignant-like syndrome (NMLS) is a clinically similar condition associated with sudden withdrawal of or abrupt reduction in dopamine agonists[2].\n\nParalytic bowel (PB) is a condition which frequently impairs medication absorption in the absence of modifications to the normal daily intake. NMLS caused by PB has not been widely described in the literature, although there is a relationship between NMS and gastroparesis.\n\nThe present report describes a case of NMLS in a parkinsonian patient on therapy with levodopa and amantadine who, due to the concomitant development of PB, experienced drug malabsorption leading to substantial withdrawal of dopamine agonist therapy.\n\nCASE DESCRIPTION\nA parkinsonian female patient aged 72 and bedridden for non-union of a femoral fracture, presented to the emergency department of our hospital with a 4-day history of high temperature (>39.5°C) and diffuse abdominal pain, distention and constipation without intestinal sounds. The patient’s relatives reported normal intake of her daily antiparkinson medication, consisting of levodopa and amantadine. At admission, the clinical picture was as follows: hyperpyrexia (axillary temperature 39.8°C), mild sinus tachycardia (112 bpm), blood pressure of 178/93 mmHg, oxygen saturation (SaO2) on pulse oximetry of 93%, and respiratory rate of 20. Abdominal bloating was noted on physical examination and mixed alkalosis was confirmed by arterial blood gas (ABG) analysis. Laboratory tests demonstrated the following abnormalities: increased total creatine phosphokinase (CPK) up to 614 mIU/ml, increased lactate dehydrogenase (LDH) up to 1034 IU/l, increased myoglobin up to 142 ng/ml, severe hypokalemia with serum potassium concentrations of 2.6 mEq/l, and an elevated white blood cell count (WBC) of 12,000.\n\nIn the following days, urine culture, viral tests and multiple blood cultures showed negative results, while chest and abdominal X-rays could not be used for diagnostic purposes as our patient could only rest in a dorsal recumbent position which made it hard to perform these investigations properly. Ceftriaxone prophylaxis (1 g twice a day) and fluid therapy were started and normal intake of the medications taken at home was maintained. However, the patient showed no improvement. Her high temperature persisted and was resistant to non-steroidal anti-inflammatory drugs (NSAIDs) and corticosteroids. After a further 4 days, the patient’s general condition worsened, and was accompanied by decreased diuresis and rhabdomyolysis confirmed by laboratory tests. Despite the renal impairment and rhabdomyolysis, a contrast enhanced computerized tomography (CT) scan of the chest and abdomen was performed after adequate hydration in order to exclude surgical pathology. The CT scan confirmed the presence of PB, with the consequent functional intestinal occlusion responsible for the malabsorption of antiparkinson drugs. Usually, a clinical examination together with an X-ray (orthostatic and clinostatic) of the abdomen or an abdominal echography is sufficient for the diagnosis of PB. However, in this case it was decided to proceed with the CT scan of the abdomen because it could be carried out more easily in the supine decubitus position and also because, in the radiological diagnosis of bowel obstructions, a CT scan has higher sensitivity and specificity than an X-ray and is better at detecting important diagnostic parameters such as the grade of occlusion and its localization.\n\nThe negative culture tests and persisting high temperature associated with a moderate increase in muscular enzymes suggested the administration of dantrolene (1 mg/kg IV) for 3 days and the suspension of calcium channel blockers, which led to prompt remission of fever. Intense fluid resuscitation was given as supportive therapy, with serial monitoring and correction of electrolyte disturbance. Nevertheless, in the following days oligo-anuria persisted and there was no response to fluid therapy, electrolyte correction or furosemide. Creatinine values gradually increased, resulting in renal failure with a stable CPK. The patient’s relatives refused dialysis and the patient died from irreversible cardiac arrest 9 days after admission.\n\nDISCUSSION\nNMS is a rare and potentially fatal complication occurring in patients treated with antipsychotic drugs. NMS should not be confused with malignant hyperthermia (MH) which is a rare (1/50,000), myopathic, familial condition, mostly characterized by autosomal dominant inheritance.\n\nThe diagnosis of NMS is clinical, according to the criteria given inTable 1. The presence of an altered state of consciousness, signs of modified autonomic functionality (such as blood pressure variations, tachycardia or perspiration), leukocytosis, or increased liver enzyme levels may furtherly support the diagnosis[3].\n\nNMLS, characterized by a clinical picture similar to that of NMS, may occur in patients affected by Parkinson’s disease (PD) as a possible reaction to a sudden withdrawal of or abrupt reduction in antiparkinsonian drugs, especially dopamine[4]. Indeed, in addition to the withdrawal of dopaminergic drugs, the occurrence of NMLS in PD patients has also been related to other conditions such as dehydration, intercurrent infection, use of cholinesterase inhibitors, a rapid switchover from bromocriptine to pergolide, constipation, and enteral nutrition, as well as to the deterioration of parkinsonian symptoms alone. Furthermore, it has been demonstrated that low levels of dopamine metabolite (homovanillic acid) in the cerebrospinal fluid may correlate with the occurrence of NMLS regardless of the dosage of levodopa[5].\n\nGiven the apparent normal daily intake of dopaminergic drugs, our patient presented with an atypical clinical picture, which suggested specific investigation of intestinal absorption should be carried out.\n\nCONCLUSIONS\nIn the absence of modifications in drug daily administration, reduced intestinal absorption may simulate drug withdrawal. Physicians involved in the treatment of PD patients should take into consideration the possibility of dopaminergic drug malabsorption due to PB as a possible cause of NMLS, as in the case reported here. A clinical picture broadly indicative of NMLS should suggest timely investigation of bowel functionality in order to exclude malabsorption issues, thus avoiding a delay in NMLS diagnosis which could result in a fatal outcome.\n\nAcknownledgements\nThe Authors would like to thank Dr. Capria Francesco and Dr. Melengu Ergena for help with scientific writing.\n\nConflicts of Interests: The Authors declare that there are no competing interests.\n\nTable 1 Neuroleptic malignant syndrome (NMS) diagnostic criteria\n\nNeuroleptic malignant syndrome (NMS) diagnostic criteria\t\nHyperthermia >100.4°F or >38.0°C on at least two occasions\t\nRigidity\t\nElevated creatine phosphokinase, at least 4 times the upper limit of normal\t\nSympathetic nervous system lability, defined as the presence of two or more of these features: elevated blood pressure, blood pressure fluctuation, diaphoresis or urinary incontinence, tachycardia and tachypnea\t\nNegative for infectious, toxic, metabolic and neurological causes\n==== Refs\nREFERENCES\n1 Thomas A Onofrj M Akinetic crisis, acute akinesia, neuroleptic malignant-like syndrome, parkinsonism-hyperpyrexia syndrome, and malignant syndrome are the same entity and are often independent of treatment withdrawal Mov Disord 2015 20 1671 author reply 1671–1672. \n2 Fiore S A neuroleptic malignant-like syndrome (NMLS) in a patient with Parkinson’s disease resolved with rotigotine: a case report Acta Biomed 2014 85 281 284 25567468 \n3 Berman BD Neuroleptic malignant syndrome: a review for neurohospitalists Neurohospitalist 2011 1 41 47 23983836 \n4 Ueda M Hamamoto M Biochemical alterations during medication withdrawal in Parkinson’s disease with and without neuroleptic malignant-like syndrome J Neurol Neurosurg Psychiatry 2011 71 111 113 \n5 Gurrera RJ An international consensus study of neuroleptic malignant syndrome diagnostic criteria using the Delphi method J Clin Psychiatry 2011 72 1222 1228 21733489\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2284-2594",
"issue": "3(4)",
"journal": "European journal of case reports in internal medicine",
"keywords": "Neuroleptic malignant-like syndrome (NMLS); Paralytic bowel (PB); Parkinson’s disease (PD)",
"medline_ta": "Eur J Case Rep Intern Med",
"mesh_terms": null,
"nlm_unique_id": "101648453",
"other_id": null,
"pages": "000368",
"pmc": null,
"pmid": "30755870",
"pubdate": "2016",
"publication_types": "D016428:Journal Article",
"references": "11413275;16149099;21733489;23983836;25567468",
"title": "A Fatal Case of Neuroleptic Malignant Syndrome After Paralytic Bowel in a Patient Taking Antiparkinson Medication.",
"title_normalized": "a fatal case of neuroleptic malignant syndrome after paralytic bowel in a patient taking antiparkinson medication"
} | [
{
"companynumb": "IT-TEVA-730761ACC",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FUROSEMIDE"
},
"drugadditional": "3",
"drug... |
{
"abstract": "BACKGROUND\nGeneralised convulsive status epilepticus (GCSE) should be treated quickly. Benzodiazepines are the only drug treatment available so far that is effective before admission to hospital. We assessed whether addition of the antiepileptic drug levetiracetam to the benzodiazepine clonazepam would improve prehospital treatment of GCSE.\n\n\nMETHODS\nWe did a prehospital, randomised, double-blind, phase 3, placebo-controlled, superiority trial to determine the efficacy of adding intravenous levetiracetam (2.5 g) to clonazepam (1 mg) in treatment of GCSE in 13 emergency medical service centres and 26 hospital departments in France. Randomisation was done at the Paris Descartes Clinical Research Unit with a list of random numbers generated by computer. Adults with convulsions lasting longer than 5 min were randomly assigned (1:1) by prehospital physicians to receive levetiracetam or placebo in combination with clonazepam. All physicians and paramedics were masked to group assignments. If the status epilepticus lasted beyond 5 min after drug injection, a second dose of 1 mg clonazepam was given. The primary outcome was cessation of convulsions within 15 min of drug injection. We analysed the modified intention-to-treat population that had received at least one injection of clonazepam and levetiracetam or placebo, excluding patients without valid consent and those randomised more than once. The trial is registered at EudraCT, number 2007-005782-35.\n\n\nRESULTS\nBetween July 20, 2009, and Dec 15, 2012, 107 patients were randomly assigned to receive placebo and 96 were assigned to receive levetiracetam. The trial was discontinued on Dec 15, 2012 when interim analysis showed no evidence of a treatment difference, and 68 patients in each group were included in the modified intention-to-treat analysis. Convulsions stopped at 15 min of drug injection in 57 of 68 patients (84%) receiving clonazepam and placebo and in 50 of 68 patients (74%) receiving clonazepam and levetiracetam (percentage difference -10.3%, 95% CI -24.0 to 3.4). Three deaths, 19 of 47 (40 %) serious adverse events, and 90 of 197 (46%) non-serious events were reported in the levetiracetam group, and four deaths, 28 of 47 (60%) serious events, and 107 of 197 (54%) non-serious events were reported in the placebo group.\n\n\nCONCLUSIONS\nThe addition of levetiracetam to clonazepam treatment presented no advantage over clonazepam treatment alone in the control of GCSE before admission to hospital. Future prehospital trials could assess the efficacy of clonazepam alone as a first-line treatment in status epilepticus and the efficacy of a second injection of clonazepam with another antiepileptic drug as second-line treatment.\n\n\nBACKGROUND\nUCB Pharma.",
"affiliations": "Assistance Publique-Hôpitaux de Paris (AP-HP), Pitié-Salpêtrière Hospital, Epilepsy Unit, and Brain and Spine Institute, Pitié-Salpêtrière Hospital and Université Pierre et Marie Curie, Paris, France. Electronic address: vincent.navarro@psl.aphp.fr.;AP-HP, Necker-Enfants Malades Hospital, SAMU 75, and Université Paris Descartes, Paris, France.;AP-HP, Paris Descartes Clinical Research Unit/Clinical Investigation Centre and Université Paris Descartes, France.;AP-HP, Necker-Enfants Malades Hospital, SAMU 75, and Université Paris Descartes, Paris, France.;AP-HP, Pitié-Salpêtrière Hospital, Neurological Intensive Care Unit, Paris, France.;AP-HP, Paris Descartes Clinical Research Unit/Clinical Investigation Centre and Université Paris Descartes, France.;AP-HP, Necker-Enfants Malades Hospital, SAMU 75, and Université Paris Descartes, Paris, France.;AP-HP, Pitié-Salpêtrière Hospital, Neurological Intensive Care Unit, Paris, France.;AP-HP, Paris Descartes Clinical Research Unit/Clinical Investigation Centre and Université Paris Descartes, France.;Assistance Publique-Hôpitaux de Paris (AP-HP), Pitié-Salpêtrière Hospital, Epilepsy Unit, and Brain and Spine Institute, Pitié-Salpêtrière Hospital and Université Pierre et Marie Curie, Paris, France.;AP-HP, Necker-Enfants Malades Hospital, SAMU 75, and Université Paris Descartes, Paris, France.",
"authors": "Navarro|Vincent|V|;Dagron|Christelle|C|;Elie|Caroline|C|;Lamhaut|Lionel|L|;Demeret|Sophie|S|;Urien|Saïk|S|;An|Kim|K|;Bolgert|Francis|F|;Tréluyer|Jean-Marc|JM|;Baulac|Michel|M|;Carli|Pierre|P|;|||",
"chemical_list": "D000927:Anticonvulsants; D000077287:Levetiracetam; D002998:Clonazepam; D010889:Piracetam",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1474-4422",
"issue": "15(1)",
"journal": "The Lancet. Neurology",
"keywords": null,
"medline_ta": "Lancet Neurol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000927:Anticonvulsants; D002998:Clonazepam; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D004632:Emergency Medical Services; D005260:Female; D006801:Humans; D000077287:Levetiracetam; D008297:Male; D008875:Middle Aged; D010889:Piracetam; D015990:Placebo Effect; D011446:Prospective Studies; D013226:Status Epilepticus; D016896:Treatment Outcome",
"nlm_unique_id": "101139309",
"other_id": null,
"pages": "47-55",
"pmc": null,
"pmid": "26627366",
"pubdate": "2016-01",
"publication_types": "D017428:Clinical Trial, Phase III; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Prehospital treatment with levetiracetam plus clonazepam or placebo plus clonazepam in status epilepticus (SAMUKeppra): a randomised, double-blind, phase 3 trial.",
"title_normalized": "prehospital treatment with levetiracetam plus clonazepam or placebo plus clonazepam in status epilepticus samukeppra a randomised double blind phase 3 trial"
} | [
{
"companynumb": "FR-ROCHE-1683635",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CLONAZEPAM"
},
"drugadditional": null,
"drug... |
{
"abstract": "Post-transplantation lymphoproliferative disorder (PTLD) is a complication of solid organ and hematopoietic stem cell transplantation. Cases with isolated central nervous system (CNS) disease are rare. Epstein-Barr virus (EBV) plays a causative role. We present a patient with EBV cerebellitis documented 5 months prior to development of primary CNS PTLD (PCNS-PTLD). This case report demonstrates progression from EBV CNS infection to lymphoproliferative disorder, highlighting the importance of serial clinical and imaging monitoring in transplant patients post-EBV CNS infection. PCNS-PTLD should always be considered in the differential diagnosis for transplant patients presenting with CNS symptoms, even in cases with no evidence of EBV viremia. Earlier diagnosis and appropriate treatment could result in improved outcomes.",
"affiliations": "Division of Neurology, Mayo Clinic Arizona, 13400 East Shea Boulevard, Scottsdale, AZ, 85259, USA. valenciasanchez.cristina@mayo.edu.;Otology & Neurotology Division, Stanford Ear Institute, 2452 Watson Ct Ste 1500, Palo Alto, CA, 94303, USA.;Division of Laboratory Medicine and Pathology, Mayo Clinic Arizona, 5777 East Mayo Boulevard, Phoenix, AZ, 85054, USA.;Division of Infectious Diseases, Mayo Clinic Arizona, 5777 East Mayo Boulevard, Phoenix, AZ, 85054, USA.;Division of Infectious Diseases, Mayo Clinic Arizona, 5777 East Mayo Boulevard, Phoenix, AZ, 85054, USA.;Division of Neurology, Mayo Clinic Arizona, 13400 East Shea Boulevard, Scottsdale, AZ, 85259, USA.",
"authors": "Valencia-Sanchez|Cristina|C|0000-0003-0116-8035;Steenerson|Kristen K|KK|;Kelemen|Katalin|K|;Orenstein|Robert|R|;Kusne|Shimon|S|;Grill|Marie F|MF|",
"chemical_list": "D000970:Antineoplastic Agents; D007166:Immunosuppressive Agents",
"country": "United States",
"delete": false,
"doi": "10.1007/s13365-018-0711-8",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1355-0284",
"issue": "25(2)",
"journal": "Journal of neurovirology",
"keywords": "Epstein-Barr virus encephalitis; Neurological complications solid organ transplant; Post-transplant lymphoproliferative disorder; Primary central nervous system lymphoma",
"medline_ta": "J Neurovirol",
"mesh_terms": "D000970:Antineoplastic Agents; D002490:Central Nervous System; D002493:Central Nervous System Diseases; D020031:Epstein-Barr Virus Infections; D017809:Fatal Outcome; D005260:Female; D004854:Herpesvirus 4, Human; D006801:Humans; D007166:Immunosuppressive Agents; D016030:Kidney Transplantation; D008223:Lymphoma; D008279:Magnetic Resonance Imaging; D008875:Middle Aged; D012008:Recurrence",
"nlm_unique_id": "9508123",
"other_id": null,
"pages": "280-283",
"pmc": null,
"pmid": "30607891",
"pubdate": "2019-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "10871255;11209035;11740719;17100717;17161283;18991070;20052713;20070626;20420644;23582985;23721553;27500242;28839616;7581154;9475119",
"title": "Post-transplant primary central nervous system lymphoma after Epstein-Barr virus cerebellitis.",
"title_normalized": "post transplant primary central nervous system lymphoma after epstein barr virus cerebellitis"
} | [
{
"companynumb": "US-ACCORD-131897",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drugadditional": null,
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{
"abstract": "Parry-Romberg syndrome (PRS) and linear sclerosis en coup de sabre (LScs) are rare, related, autoimmune conditions of focal atrophy and sclerosis of head and face which are associated with the development of focal epilepsy. The scarcity of PRS and LScs cases has made an evidence-based approach to optimal treatment of seizures difficult. Here we present a large systematic review of the literature evaluating 137 cases of PRS or LScs, as well as three new cases with epilepsy that span the spectrum of severity, treatments, and outcomes in these syndromes. Analysis showed that intracranial abnormalities and epileptic foci localized ipsilateral to the external (skin, eye, mouth) manifestations by imaging or EEG in 92% and 80% of cases, respectively. Epilepsy developed before external abnormalities in 19% of cases and after external disease onset in 66% of cases, with decreasing risk the further from the start of external symptoms. We found that over half of individuals affected may achieve seizure freedom with anti-seizure medications (ASMs) alone or in combination with immunomodulatory therapy (IMT), while a smaller number of individuals benefitted from epilepsy surgery. Although analysis of case reports has the risk of bias or omission, this is currently the best source of clinical information on epilepsy in PRS/LScs-spectrum disease. The paucity of higher quality information requires improved case identification and tracking. Toward this effort, all data have been deposited in a Synapse.org database for case collection with the potential for international collaboration.",
"affiliations": "Medical Scientist Training Program, University of Colorado, CU Anschutz Fitzsimons Building 13001 East 17th Place, Aurora, CO 80045, USA.;Medical Scientist Training Program, University of Colorado, CU Anschutz Fitzsimons Building 13001 East 17th Place, Aurora, CO 80045, USA.;Blue Sky Neurology, 499 E. Hampden Ave. Ste. 360 Englewood, CO 80113, USA.;Department of Neurology, University of Colorado, CU Anschutz Research Complex II, 12700 East 19th Avenue, Aurora, CO 80045, USA; Mayo Clinic Neurology and Neurosurgery, 13400 E Shea Blvd, Scottsdale, AZ 85259, USA. Electronic address: cornelia.drees@cuanschutz.edu.",
"authors": "Hixon|Alison M|AM|;Christensen|Elijah|E|;Hamilton|Robert|R|;Drees|Cornelia|C|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.yebeh.2021.108068",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1525-5050",
"issue": "121(Pt A)",
"journal": "Epilepsy & behavior : E&B",
"keywords": "Case series; Epilepsy; Linear scleroderma en coup de sabre; Parry–Romberg syndrome; Progressive hemifacial atrophy; Systematic literature review",
"medline_ta": "Epilepsy Behav",
"mesh_terms": "D001284:Atrophy; D004827:Epilepsy; D005150:Facial Hemiatrophy; D006801:Humans; D012594:Scleroderma, Localized; D012640:Seizures",
"nlm_unique_id": "100892858",
"other_id": null,
"pages": "108068",
"pmc": null,
"pmid": "34052630",
"pubdate": "2021-08",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't; D000078182:Systematic Review",
"references": null,
"title": "Epilepsy in Parry-Romberg syndrome and linear scleroderma en coup de sabre: Case series and systematic review including 140 patients.",
"title_normalized": "epilepsy in parry romberg syndrome and linear scleroderma en coup de sabre case series and systematic review including 140 patients"
} | [
{
"companynumb": "US-UCBSA-2021055943",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LACOSAMIDE"
},
"drugadditional": "3",
"dr... |
{
"abstract": "Systemic inflammatory diseases are related to an increased risk of lymphoproliferative disorders. Although inflammatory bowel disease (IBD) was also associated with these conditions, population-based studies failed to demonstrate this relationship, and most studies only identified a very small number of cases. In the last few years, concerns arose regarding the role of thiopurines and tumour necrosis factor-alpha (TNF-α)-blocking agents in the development of lymphoma, influencing therapeutic decisions in IBD patients. The aim of this study was to describe a case series of IBD patients who developed a lymphoproliferative disorder in our tertiary referral centre.\nThe clinical records of all IBD patients who were observed in our unit between January 2007 and December 2016 were retrospectively reviewed, and IBD subjects who were diagnosed with a lymphoproliferative disorder were selected. Clinical and demographic data regarding both conditions were collected.\nSix IBD patients were diagnosed with a lymphoma - 4 Hodgkin lymphomas and 2 B-cell non-Hodgkin lymphomas - of which 3 corresponded to primary colonic lymphomas. Immunohistochemical analysis detected the presence of Epstein-Barr virus in the tumour cells of 2 patients, both of them with Hodgkin lymphomas. Only 2 patients were previously treated with thiopurines or anti-TNF-α drugs; none of the remaining had any history of immunosuppressive treatment.\nDespite major attention being currently focused on the effect of treatment, which may play the main role in the increased susceptibility to lymphoma in IBD patients, and although it may be difficult to demonstrate, IBD itself may contribute to the development of lymphoproliferative disorders, particularly primary intestinal lymphomas.",
"affiliations": "Gastroenterology Department, Centro Hospitalar de Lisboa Central, Lisbon, Portugal.;Gastroenterology Department, Centro Hospitalar de Lisboa Central, Lisbon, Portugal.;Gastroenterology Department, Centro Hospitalar de Lisboa Central, Lisbon, Portugal.;Gastroenterology Department, Centro Hospitalar de Lisboa Central, Lisbon, Portugal.;Gastroenterology Department, Centro Hospitalar de Lisboa Central, Lisbon, Portugal.",
"authors": "Bernardes|Carlos|C|;Russo|Pedro|P|;Carvalho|Diana|D|;Saiote|Joana|J|;Ramos|Jaime|J|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000484440",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2387-1954",
"issue": "25(4)",
"journal": "GE Portuguese journal of gastroenterology",
"keywords": "Anti-TNF-α; Inflammatory bowel disease; Lymphoma; Lymphoproliferative disorders; Thiopurines",
"medline_ta": "GE Port J Gastroenterol",
"mesh_terms": null,
"nlm_unique_id": "101685861",
"other_id": null,
"pages": "175-178",
"pmc": null,
"pmid": "29998162",
"pubdate": "2018-06",
"publication_types": "D016428:Journal Article",
"references": "11677199;24070724;18024019;10632489;24444171;24938563;23891975;27196600;23721759;22271569;7883236;20888436;19837455;12687538;19795032;7388763",
"title": "Lymphoproliferative Disorders in Inflammatory Bowel Disease Patients: Is It the Drugs or the Disease.",
"title_normalized": "lymphoproliferative disorders in inflammatory bowel disease patients is it the drugs or the disease"
} | [
{
"companynumb": "PT-CELLTRION INC.-2018PT024538",
"fulfillexpeditecriteria": "1",
"occurcountry": "PT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "INFLIXIMAB"
},
"drugadditional": "3",
... |
{
"abstract": "Malakoplakia is a rare histiocytic disease first described in 1902 by Michaelis and Gutmann. It is associated with host immunocompromise including chronic inflammatory conditions, infectious conditions or malnutrition. Here, we report the case of uterine malakoplakia as a rare cause of postmenopausal bleeding in an immunocompromised patient.",
"affiliations": "Obstetrics and Gynaecology, The Royal Hospital for Women, Randwick, New South Wales, Australia.;Pathology, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia.;Obstetrics and Gynaecology, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia.;Obstetrics and Gynaecology, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia.",
"authors": "Kiely|Neill Paul|NP|;Anderson|Lyndal|L|;Arora|Harpreet|H|;Benness|Christopher|C|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2018-225642",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2018()",
"journal": "BMJ case reports",
"keywords": "gynecological cancer; menopause (including hrt); pathology; transplantation",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000368:Aged; D005260:Female; D006644:Histiocytes; D006801:Humans; D016867:Immunocompromised Host; D008287:Malacoplakia; D017698:Postmenopause; D014592:Uterine Hemorrhage",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "29991552",
"pubdate": "2018-07-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "12588449;17284117;18317211;2840796",
"title": "A novel cause of postmenopausal bleeding in an immunosuppressed patient.",
"title_normalized": "a novel cause of postmenopausal bleeding in an immunosuppressed patient"
} | [
{
"companynumb": "AU-ALKEM LABORATORIES LIMITED-AU-ALKEM-2018-06353",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"druga... |
{
"abstract": "Fibrodysplasia ossificans progressiva, a rare and severely disabling genetic condition, is characterized clinically by progressive ossification of skeletal muscle and connective tissue and congenital malformations of the great toes. Recurrent episodes of heterotopic ossification (flare-ups) lead to increasing loss of mobility as joints become progressively affected. We report the case of a young woman with fibrodysplasia ossificans progressiva who had recurrent, debilitating myoclonus that was refractory to conventional therapies but was relieved for prolonged periods after general anesthesia was administered.",
"affiliations": "From the *Department of Anesthesia, Division of Pediatric Anesthesia, Stanford University School of Medicine, Stanford; Departments of †Pediatrics and ‡Neurology, and §Department of Anesthesia, University of California San Francisco, San Francisco, California.",
"authors": "Char|Danton S|DS|;Hutchison|H Terry|HT|;Kitterman|Joseph A|JA|;Gregory|George A|GA|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1213/XAA.0000000000000037",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2325-7237",
"issue": "3(1)",
"journal": "A & A case reports",
"keywords": null,
"medline_ta": "A A Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101637720",
"other_id": null,
"pages": "6-8",
"pmc": null,
"pmid": "25612266",
"pubdate": "2014-07-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "General anesthesia treatment of propriospinal myoclonus in a patient with fibrodysplasia ossificans progressiva.",
"title_normalized": "general anesthesia treatment of propriospinal myoclonus in a patient with fibrodysplasia ossificans progressiva"
} | [
{
"companynumb": "PHHY2014US101361",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DIHYDROERGOTAMINE"
},
"drugadditional": null,
... |
{
"abstract": "In recent years the outcome of patients with multiple myeloma (MM) has significantly improved, due to new drugs. However, some agents, i.e. the alkylating drug melphalan, can be associated with an increased incidence of secondary malignancies. Myelodysplastic syndromes and acute myeloid leukemia are reported in the literature, and rarely acute lymphoblastic leukemia. Here we describe a unique case of a 56-years old female patient affected by MM since 2015 in complete remission after autologous stem cell transplant and in lenalidomide maintenance, who developed 2 years later mixed phenotype acute leukemia (MPAL). The patient, refractory to both lymphoblastic and myeloid acute leukemia regimens, achieved complete remission with bi-specific anti-CD19/anti-CD3 monoclonal antibody blinatumomab and with hypomethylating agent azacytidine plus the BCL-2 inhibitor venetoclax. She then underwent hematopoietic stem cell transplantation from HLA-identical sibling donor and she is still in complete remission after 9 months. To the best of our knowledge, there are no cases in the literature describing MPAL after autologous transplant for MM. Our patient was treated with blinatumomab and venetoclax and achieved complete remission 9 months from allogeneic transplant. The mechanism underlying the development of MPAL is not completely understood and therapies are still lacking. In this context the combination of blinatumomab, azacytidine and venetoclax successfully used in this patient may provide food for thought for further studies in this rare setting of patients.",
"affiliations": "Hematology Unit, University of Siena, Azienda Ospedaliera Universitaria Senese Siena, Italy.;Hematology Unit, University of Siena, Azienda Ospedaliera Universitaria Senese Siena, Italy.;Hematology Unit, University of Siena, Azienda Ospedaliera Universitaria Senese Siena, Italy.;Hematology Unit, University of Siena, Azienda Ospedaliera Universitaria Senese Siena, Italy.;Hematology Unit, University of Siena, Azienda Ospedaliera Universitaria Senese Siena, Italy.;Hematology Unit, University of Siena, Azienda Ospedaliera Universitaria Senese Siena, Italy.;Hematology Unit, University of Siena, Azienda Ospedaliera Universitaria Senese Siena, Italy.;Hematology Unit, University of Siena, Azienda Ospedaliera Universitaria Senese Siena, Italy.;Hematology Unit, University of Siena, Azienda Ospedaliera Universitaria Senese Siena, Italy.;Hematology Unit, University of Siena, Azienda Ospedaliera Universitaria Senese Siena, Italy.",
"authors": "Bacchiarri|Francesca|F|;Sammartano|Vincenzo|V|;Santoni|Adele|A|;Raspadori|Donatella|D|;Zappone|Elisabetta|E|;Defina|Marzia|M|;Ciofini|Sara|S|;Sicuranza|Anna|A|;Bocchia|Monica|M|;Gozzetti|Alessandro|A|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2160-1992",
"issue": "11(1)",
"journal": "American journal of blood research",
"keywords": "Mixed phenotype acute leukemia; multiple myeloma; secondary acute leukemia",
"medline_ta": "Am J Blood Res",
"mesh_terms": null,
"nlm_unique_id": "101569577",
"other_id": null,
"pages": "123-131",
"pmc": null,
"pmid": "33796400",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": "25555448;26283683;21266800;9118039;27864218;29076138;28742454;12764373;30828170;22571201;23380709;31080940;405642;19907437;24525202;23811785;27297582;22571202;32139010;20844566;26228379;29550836;21795746;24292625;30026571;24247655;31780415;18614782;27510179;24509509;29546454;24750307;29785311;20485373;23060579;27069254;31033213;31913151;22571200;22178548;31661160;27511158;22581002;30927976;24292623;22851973;25858895;3300761",
"title": "First reported case of secondary mixed phenotype acute leukemia after multiple myeloma.",
"title_normalized": "first reported case of secondary mixed phenotype acute leukemia after multiple myeloma"
} | [
{
"companynumb": "IT-SUN PHARMACEUTICAL INDUSTRIES LTD-2021RR-313970",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LENALIDOMIDE"
},
"dr... |
{
"abstract": "OBJECTIVE\nThis study sought to define thromboembolic risk and mortality in patients with heparin-induced thrombocytopenia (HIT) undergoing inferior vena cava filter (IVCF) placement, in light of the American Society of Hematology's 2018 guidelines against routine use of IVCFs in this population.\n\n\nMETHODS\nA total of 26 patients with HIT who received IVCFs were retrospectively reviewed, and the outcomes of this group were compared with those of 4,707 controls with either HIT or IVCFs alone and with reported outcomes in prior studies.\n\n\nRESULTS\nThe patient group demonstrated 6- and 12-month mortality rates of 26.9% and 30.8%, respectively, which did not differ significantly from those of the control groups and were in line with published mortality rates in the literature. The measured thromboembolic risk of 19.2% in the patient group was also within the range of published rates for patients with HIT or IVCF alone.\n\n\nCONCLUSIONS\nIVCF placement did not significantly increase the risk of thromboembolism or death in patients with HIT and may be a viable option in the subset of these patients who are not candidates for anticoagulation.",
"affiliations": "Department of Radiology, Massachusetts General Hospital, Boston, Massachusetts. Electronic address: mmoghbel@partners.org.;Section of Geriatric Medicine, Stanford University Medical Center, Stanford, California.;Department of Graduate Medical Education, Kaiser Permanente Santa Clara Medical Center, Santa Clara, California.;Department of Pulmonology & Critical Care, Kaiser Permanente Santa Clara Medical Center, Santa Clara, California.;Department of Hematology & Oncology, Kaiser Permanente Santa Clara Medical Center, Santa Clara, California.;Department of Radiology, Division of Vascular & Interventional Radiology, Kaiser Permanente Santa Clara Medical Center, Santa Clara, California.",
"authors": "Moghbel|Mateen C|MC|;Chen|Zeng|Z|;Liu|Chi-Mei|CM|;Rajan|Sudhir|S|;Vempaty|Hyma T|HT|;Wang|Stephen L|SL|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.jvir.2021.08.025",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1051-0443",
"issue": "32(12)",
"journal": "Journal of vascular and interventional radiology : JVIR",
"keywords": null,
"medline_ta": "J Vasc Interv Radiol",
"mesh_terms": null,
"nlm_unique_id": "9203369",
"other_id": null,
"pages": "1629-1634",
"pmc": null,
"pmid": "34547476",
"pubdate": "2021-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Thrombotic Risk Associated with Inferior Vena Cava Filter Placement in Patients with Heparin-Induced Thrombocytopenia.",
"title_normalized": "thrombotic risk associated with inferior vena cava filter placement in patients with heparin induced thrombocytopenia"
} | [
{
"companynumb": "US-Fresenius Kabi-FK202200780",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "3",
"activesubstance": {
"activesubstancename": "HEPARIN SODIUM"
},
"drugadditional": null... |
{
"abstract": "Metformin is increasingly being used a therapeutic option for the management of gestational diabetes mellitus (GDM). The aim of this study was to compare the maternal characteristics and perinatal outcomes of women with GDM treated with metformin (with or without supplemental insulin) with those receiving other management approaches. A retrospective, case-control study was carried out and 83 women taking metformin were matched 1:1 with women receiving insulin or diet and lifestyle modification alone. Women managed with diet and lifestyle modification had a significantly lower fasting plasma glucose (p < 0.001) and HbA1c (p < 0.01) at diagnosis of GDM. Furthermore, women managed with metformin had a higher early pregnancy body mass index (BMI) compared to those receiving insulin or diet and lifestyle modification (p < 0.001). There was no difference in mode of delivery, birth weight or incidence of large- or small-for-gestational-age neonates between groups. Women receiving glucose lowering therapies had a higher rate of neonatal hypoglycaemia (p < 0.05). The incidence of other adverse perinatal outcomes was similar between groups. Despite their greater BMI, women with metformin-treated GDM did not have an increased risk of adverse perinatal outcomes. Metformin is a useful alternative to insulin in the management of GDM.",
"affiliations": "Department of Diabetes, Endocrinology and Metabolism, Level 3, Acute Services Building, Royal North Shore Hospital, St Leonards, Sydney NSW 2065, Australia. rachel.mcgrath@sydney.edu.au.;Department of Diabetes, Endocrinology and Metabolism, Level 3, Acute Services Building, Royal North Shore Hospital, St Leonards, Sydney NSW 2065, Australia. sarah.glastras@sydney.edu.au.;Department of Diabetes, Endocrinology and Metabolism, Level 3, Acute Services Building, Royal North Shore Hospital, St Leonards, Sydney NSW 2065, Australia. emmasigrids@bigpond.com.;Department of Diabetes, Endocrinology and Metabolism, Level 3, Acute Services Building, Royal North Shore Hospital, St Leonards, Sydney NSW 2065, Australia. samantha.hocking@sydney.edu.au.;Department of Diabetes, Endocrinology and Metabolism, Level 3, Acute Services Building, Royal North Shore Hospital, St Leonards, Sydney NSW 2065, Australia. greg.fulcher@sydney.edu.au.",
"authors": "McGrath|Rachel T|RT|0000-0003-3453-058X;Glastras|Sarah J|SJ|;Scott|Emma S|ES|;Hocking|Samantha L|SL|0000-0002-2514-9392;Fulcher|Gregory R|GR|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3390/jcm7030050",
"fulltext": "\n==== Front\nJ Clin MedJ Clin MedjcmJournal of Clinical Medicine2077-0383MDPI 10.3390/jcm7030050jcm-07-00050ArticleOutcomes for Women with Gestational Diabetes Treated with Metformin: A Retrospective, Case-Control Study https://orcid.org/0000-0003-3453-058XMcGrath Rachel T. 123*Glastras Sarah J. 123Scott Emma S. 14Hocking Samantha L. 15Fulcher Gregory R. 121 Department of Diabetes, Endocrinology and Metabolism, Level 3, Acute Services Building, Royal North Shore Hospital, St Leonards, Sydney NSW 2065, Australia; sarah.glastras@sydney.edu.au (S.J.G.); emmasigrids@bigpond.com (E.S.S.); samantha.hocking@sydney.edu.au (S.L.H.); greg.fulcher@sydney.edu.au (G.R.F.)2 Northern Clinical School, University of Sydney, Sydney NSW 2065, Australia3 Kolling Institute of Medical Research, St Leonards, Sydney NSW 2065, Australia4 NHMRC Clinical Trials Centre, University of Sydney, Camperdown, Sydney NSW 2050, Australia5 Boden Institute, Charles Perkins Centre, University of Sydney, Camperdown, Sydney NSW 2006, Australia* Correspondence: rachel.mcgrath@sydney.edu.au; Tel.: +61-(2)-9463-1470; Fax: +61-(2)-9463-104509 3 2018 3 2018 7 3 5010 1 2018 08 3 2018 © 2018 by the authors.2018Licensee 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/).Metformin is increasingly being used a therapeutic option for the management of gestational diabetes mellitus (GDM). The aim of this study was to compare the maternal characteristics and perinatal outcomes of women with GDM treated with metformin (with or without supplemental insulin) with those receiving other management approaches. A retrospective, case-control study was carried out and 83 women taking metformin were matched 1:1 with women receiving insulin or diet and lifestyle modification alone. Women managed with diet and lifestyle modification had a significantly lower fasting plasma glucose (p < 0.001) and HbA1c (p < 0.01) at diagnosis of GDM. Furthermore, women managed with metformin had a higher early pregnancy body mass index (BMI) compared to those receiving insulin or diet and lifestyle modification (p < 0.001). There was no difference in mode of delivery, birth weight or incidence of large- or small-for-gestational-age neonates between groups. Women receiving glucose lowering therapies had a higher rate of neonatal hypoglycaemia (p < 0.05). The incidence of other adverse perinatal outcomes was similar between groups. Despite their greater BMI, women with metformin-treated GDM did not have an increased risk of adverse perinatal outcomes. Metformin is a useful alternative to insulin in the management of GDM.\n\ngestational diabetesmetformininsulinglycaemic controlperinatal outcomes\n==== Body\n1. Introduction\nThe incidence of gestational diabetes mellitus (GDM) is increasing in Australia and worldwide [1]. The latest diagnostic criteria recommended by the International Association of Diabetes and Pregnancy Study Groups (IADPSG) and endorsed by the Australasian Diabetes in Pregnancy Society (ADIPS) are more stringent than previous criteria and have led to an increase in the prevalence of GDM [2]. Following diagnosis, women with GDM routinely receive dietary education and lifestyle advice; with pharmacological therapy initiated if target blood glucose levels are not attained [3]. Importantly, treatment of GDM has been shown to significantly improve perinatal outcomes, with reductions in macrosomia, birth injury and neonatal death [4,5].\n\nA number of studies have demonstrated that treatment of GDM with metformin can lead to adequate glycaemic control and does not increase the risk of adverse perinatal outcomes [6,7]. The mechanism of action of metformin comprises suppression of hepatic gluconeogenesis and increasing insulin sensitivity, which mitigates hyperglycaemia. Moreover, metformin may be a more favourable alternative to insulin as it is weight neutral, is not associated with hypoglycaemia, avoids the need for injections and may make follow-up simpler [8]. A recent clinical trial found that treatment with metformin from 12 to 18 weeks of gestation reduced gestational weight gain but had no effect on the development of GDM or neonatal birth weight in a population of obese women [9]. Furthermore, a large, prospective clinical trial that randomised women with GDM to insulin or metformin found that metformin therapy was not associated with an increased risk of perinatal complications [10]. In addition, several meta-analyses have found no difference in perinatal outcomes for women with GDM treated with metformin or insulin [11,12]. Whilst efficacious for the majority of women, some women will require additional therapy with insulin to achieve target blood glucose levels; however, the dose of insulin needed is usually less than those managed with insulin therapy alone [10].\n\nDespite the above evidence, the use of metformin for the treatment of hyperglycaemia in pregnancy is not universally implemented and there is a lack of consensus in GDM management guidelines, dependent upon centre or location [13]. Moreover, a recent study found that metformin treatment in the first trimester of pre-gestational diabetes was associated with an increased risk of birth defects and pregnancy loss; however, these increased risks were attributed to hyperglycaemia rather than metformin therapy [14].\n\nAt our institution, the use of metformin for the treatment of GDM has been adopted as an alternative approach to insulin therapy in the management of hyperglycaemia in this population of women. Thus, the aim of the present study was to carry out an audit to assess and compare the maternal characteristics and perinatal outcomes of women with GDM treated with metformin (with or without supplemental insulin), in comparison to those treated solely with insulin or diet and lifestyle modification alone at our large tertiary referral hospital obstetric clinic in Sydney, Australia. This study will provide supplementary evidence of outcomes for women with GDM treated with metformin based upon our experience and the population of women that attended our institution. We hypothesise that our findings will support previous studies and show no increase in adverse perinatal outcomes for women treated with metformin in pregnancy.\n\n2. Materials and Methods\n2.1. Study Design\nA retrospective, observational, case-control study was conducted through a review of the medical records of women with GDM in singleton pregnancy that attended the multi-disciplinary Specialist Obstetric Clinic (SOC) at Royal North Shore Hospital, Sydney, Australia, from September 2012 to August 2016. Approval for this study was obtained from the Northern Sydney Local Health District Human Research Ethics Committee (Study Reference No. RESP/15/107) and was carried out in keeping with the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement for case-control studies [15].\n\n2.2. Diagnosis and Management of GDM\nGDM was diagnosed using a 75-g oral glucose tolerance test (OGTT) with two diagnostic criteria used throughout the study period: a fasting plasma glucose of ≥5.5 mmol/L or a 2-h plasma glucose of ≥7.8 mmol/L until the end of 2014, with new diagnostic criteria of a fasting plasma glucose ≥5.1 mmol/L, a 1-hour plasma glucose ≥10 mmol/L or a 2-h plasma glucose ≥8.5 mmol/L introduced in 2015, as endorsed by ADIPS [16]. At diagnosis of GDM, a diabetes nurse educator and dietician provided all women with group diabetes education and dietary advice. Dietary advice comprised information about a carbohydrate modified diet (30–45 g carbohydrate at main meals, 15–30 g carbohydrate at mid meals and encouragement to eat low glycaemic index carbohydrate). In addition, women were instructed to monitor their blood glucose levels 4 times daily using a blood glucose meter: fasting and 2-hs post breakfast, lunch and dinner. The standard model of care for women with GDM is to attend the SOC for review by an endocrinologist, and management was instituted dependent upon target blood glucose levels of <5.5 mmol/L fasting until 2014, ≤5.0 mmol/L fasting from 2015 and <6.7 mmol/L 2-h postprandially. If target blood glucose levels were not achieved with lifestyle and diet modification alone, pharmacological therapy was initiated. The use of metformin was dependent upon physician and patient preference. Further, if women failed to achieve adequate glycaemic control with metformin, treatment was intensified by the addition of insulin. Women managed with diet and lifestyle modification alone attended a midwife and diabetes educator-led diabetes education group session every 1–4 weeks.\n\nThe metformin group comprised women with GDM that were prescribed metformin as first-line therapy with/without the addition of insulin. Metformin was initiated at a dose of 500 mg twice daily and up-titrated to 2 g per day (where tolerated) if adequate glycaemic control was not achieved. Supplemental insulin was introduced if metformin was not sufficient to ameliorate hyperglycaemia. Women in the insulin-alone group were those who were prescribed insulin as their initial glucose lowering therapy. Insulin was commenced (Protaphane or Levemir and/or NovoRapid) depending upon the pattern of hyperglycaemia and the dose increased to achieve target fasting and postprandial blood glucose levels. Diet and lifestyle modification comprised non-pharmacological treatment as outlined above. Patients in the insulin and diet and lifestyle modification groups were individually matched in a 1:1 ratio to patients in the metformin group for age, previous history of GDM and gestational age at diagnosis of GDM.\n\n2.3. Data Collection\nData extracted from patient electronic medical records included maternal demographics (age, ethnicity, body mass index (BMI) recorded at the first visit to the antenatal clinic, family history of diabetes, previous history of GDM), gestational age at diagnosis of GDM, treatment regimen and the following perinatal outcomes: maternal outcomes—mode and timing of delivery, and neonatal outcomes—birth weight, gestational age at delivery, large-for-gestational-age (LGA; defined as birth weight >90th centile for gestational age and gender) [17], small-for-gestational-age (SGA; defined as birth weight <10th centile for gestational age and gender) [17], shoulder dystocia, respiratory distress, neonatal hypoglycaemia, jaundice, neonatal intensive care unit (NICU) admission, birth injury and neonatal death.\n\n2.4. Statistical Analysis\nTo compare differences in birth weight between women treated with metformin or insulin and based upon the results of Rowan et al. [10], a sample size of 3045 per group would be required. However, to detect difference in fasting blood glucose levels in women treated with metformin compared with insulin or diet alone (a secondary outcome of this study) and using the results of Corbould et al. [18], with power of 0.80 and α of 0.05, a sample size of 23 per group is needed.\n\nDifferences between groups were compared using Student’s independent t-test and one-way analysis of variance (ANOVA) for continuous data and chi-squared test and logistic regression for categorical data. Statistical analyses were carried out using GraphPad Prism Version 6 (GraphPad Software, La Jolla, CA, USA) and IBM SPSS Version 22 (IBM, Armonk, NY, USA). A p value of <0.05 was considered statistically significant.\n\n3. Results\n3.1. Study Population and Demographics\nDuring the time period of September 2012 to April 2016, 86 women were identified as taking metformin (with or without supplemental insulin) during singleton GDM pregnancy. Three of these women were subsequently excluded from the analysis as they were taking insulin prior to metformin. Thus, 83 women taking metformin were matched to those taking insulin or management with diet and lifestyle modification alone. The demographics of the groups are outlined in Table 1.\n\nWomen treated with metformin had a higher early pregnancy BMI compared to the insulin and diet and lifestyle-modification groups (p < 0.001). There was no difference in family history of diabetes between groups.\n\n3.2. Glycaemic Control\nWomen that were successfully managed with diet and lifestyle modification alone had a significantly lower fasting plasma glucose level on 75 g OGTT and HbA1c at diagnosis of GDM compared to women receiving metformin or insulin therapy (4.4 mmol/L vs. 4.9 mmol/L vs. 4.8 mmol/L, respectively; p < 0.0001 (Figure 1A) and 5.0% vs. 5.1% vs. 5.2%, respectively; p < 0.01 (Figure 1B)). There was no difference in the gestational age at which pharmacotherapy was initiated between the metformin and insulin groups (Table 1). In addition, the proportion of women taking metformin that required additional therapy with insulin to achieve targets was 42.2% (n = 35) and the mean gestational age at which insulin was added was 29.5 ± 5.7 weeks. There was no difference in the total daily dose of insulin at delivery for women in the metformin (and supplemental insulin) and insulin groups.\n\n3.3. Perinatal Outcomes\nThe maternal and neonatal outcomes for women taking metformin (with or without additional insulin) versus those taking insulin alone or managed with diet and lifestyle modification are outlined in Table 2. There was no difference in the rate of normal vaginal delivery, instrumental delivery or Caesarean section between groups. Women treated with glucose lowering therapies were delivered at a slightly earlier gestational age than women managed with lifestyle measures (p = 0.008). Furthermore, there was no difference in birth weight and a comparable incidence of SGA and LGA neonates was observed in each group. Following adjustment for early-pregnancy BMI, there was no association between GDM treatment and birth weight centile (p = 0.437) yet women managed with diet and lifestyle modification alone were less likely to have LGA neonates compared with women receiving pharmacotherapy (OR: 0.58; 95% CI: 0.358 to 0.940; p = 0.027). There was no difference in the likelihood of women managed with metformin (with or without supplemental insulin) or insulin having LGA neonates (OR: 0.548; 95% CI: 0.237 to 1.266; p = 0.159).\n\nThe rate of adverse perinatal outcomes was similar between groups. Infants of women treated with glucose-lowering therapies were more likely to experience neonatal hypoglycaemia (p = 0.039; Table 2). Of note, almost two thirds (61.5%) of the cases of neonatal hypoglycaemia in the metformin group were in women taking insulin in addition to metformin. For women treated with metformin alone, there was no difference in the rate of neonatal hypoglycaemia in comparison to the diet and lifestyle-modification group (10.4% vs. 6.1%; p = 0.497). There was also no difference in the incidence of shoulder dystocia, respiratory distress, jaundice, NICU admission, birth injury, birth defect or neonatal death in women treated with metformin compared to those managed with insulin or diet and lifestyle modification. The birth defects observed in each of the groups were tongue tie (metformin, n = 3; insulin, n = 1; diet and lifestyle modification, n = 3), left-lung sequestration (diet and lifestyle modification, n = 1), hypospadias (insulin, n = 1) and bilateral talipes (metformin, n = 1).\n\n4. Discussion\nThe results of the present analysis demonstrate that treatment of women with GDM with metformin gives rise to similar perinatal outcomes in comparison to women managed with insulin alone or diet and lifestyle modification alone. No difference was observed in the incidence of neonatal complications between groups, including respiratory distress, jaundice or birth defects; however, women treated with metformin and supplemental insulin or insulin alone were more likely to have infants experiencing neonatal hypoglycaemia, compared with those managed with lifestyle therapy alone. Lower fasting plasma glucose levels and HbA1c at diagnosis of GDM were associated with successful management without pharmacotherapy. Furthermore, women requiring glucose-lowering therapy were more likely to have LGA neonates than those managed with diet and lifestyle modification alone, indicating that hyperglycaemia requiring treatment is associated with an increased incidence of LGA neonates. In addition, women with a greater early-pregnancy BMI were more likely to be prescribed metformin therapy, which we speculate may be due to the beneficial effects of metformin on insulin resistance or the desire to avoid weight gain that may be incurred with insulin treatment.\n\nThe majority of guidelines recommend insulin for the treatment of hyperglycaemia in GDM [16,19]; however, there are several barriers towards insulin use in this population, namely an undesirable route of administration, the potential for weight gain (which may further compound and propagate hyperglycaemia) and the risk of hypoglycaemia [20]. Thus, metformin may be a more acceptable therapy for women with GDM. Studies have demonstrated that metformin is safe for use in pregnancy, with no significant differences in adverse neonatal outcomes such as respiratory distress and NICU admission [21]. The incidence of perinatal complications in the present study population are similar to that observed by Spaulonci et al. [22] and Goh et al. [23]. Treatment with metformin did not give rise to a reduction in prematurity, jaundice or NICU admission, as has been shown in previous reports [24]. This difference may result from the smaller sample size used. Alternatively, the absolute rate of adverse perinatal outcomes in our population was comparatively low and this may reflect optimal obstetric management, regardless of the therapy used to manage glycaemia in GDM.\n\nWomen prescribed metformin had a significantly higher early pregnancy BMI than the other groups suggesting that physicians may believe that metformin will be of most benefit to women that are overweight or obese who have a higher likelihood of significant insulin resistance. It has recently been shown that maternal weight gain in GDM is an independent predictor of macrosomia [25,26]. Therefore, optimisation of maternal weight prior to or early in pregnancy may avoid the need for pharmacologic interventions and improve perinatal outcomes, and the weight-neutral properties of metformin may be considered favourable for women with an elevated BMI. In addition, increased BMI in pregnancy has been shown to be associated with large-for-gestational-age neonates and maternal complications [27,28]; however, women in the metformin group did not display an increase in the incidence of adverse perinatal outcomes. A limitation of the present study is that we were unable to assess gestational weight gain, which has previously been shown to be a favourable outcome for women treated with metformin in pregnancy [11].\n\nIn women with mild GDM, metformin therapy alone is sufficient to achieve glycaemic targets [17,18]. In our population, just under half of the women treated with metformin required additional therapy with insulin for glycaemic control. This is a similar finding to other studies, wherein a significant proportion of women will not achieve glycaemic targets with metformin monotherapy alone [10,18]. We have recently observed that women with GDM treated with metformin who required pharmacological intervention earlier in pregnancy were more likely to need supplemental insulin as the pregnancy progressed [29].\n\nA recent meta-analysis demonstrated that use of metformin in pregnancy is not associated with an increased risk of short-term adverse outcomes and may have benefit in the postnatal period [30]. Furthermore, children of women exposed to metformin during GDM pregnancy were compared to those exposed to insulin at 6, 12 and 18 months of age and no difference was observed in early motor and linguistic skills and social development, although children in the metformin group were heavier [31]. In addition, the Metformin in Gestational Diabetes: The Offsrping Follow-Up (Mig-TOFU) study found similar outcomes for children of mothers treated with metformin in pregnancy [32,33]. It has been hypothesised that exposure to metformin in utero may be of benefit to children as it may increase insulin sensitivity from a young age and reduce metaboliccomplications [24]; however, longer term studies are required to confirm this assumption and to ensure the safety of metformin for neurodevelopment in children.\n\nA limitation of this study is the small sample size and the lack of statistical power for comparison of adverse perinatal outcome rates between groups; however, we tried to account for this by using well-matched controls to limit the potential for confounding and spurious results. It is possible that with a larger sample size, differences in perinatal outcomes may have been observed between groups, yet our results are in keeping with other studies that have examined outcomes post exposure to metformin in pregnancy [34]. The majority of studies examining metformin therapy in GDM have compared outcomes to women taking insulin, whereas we have employed an additional control group comprising women managed with diet and lifestyle modification alone. Both Goh et al. [23] and Corbould et al. [18] utilised a similar methodological approach and found no difference in neonatal outcomes between women treated solely with metformin, insulin or those who were diet-controlled. An additional limitation is that this was not a randomised study and therefore, metformin use was due to patient and/or physician preference.\n\nIn summary, treatment of GDM with metformin (with or without supplemental insulin) gives rise to similar perinatal outcomes to women managed solely with insulin or diet and lifestyle modification. Metformin is a useful alternative to insulin in the management of GDM, particularly in women with an elevated BMI. Our results also demonstrate that the use of metformin in an Australian GDM cohort has similar outcomes to other populations. With the results of long-term outcome studies examining the impact of metformin exposure in utero expected to be published in the near future, it is anticipated that the acceptance of metformin for the treatment of GDM will be further increased.\n\nAuthor Contributions\nR.T.M. collected and analysed data and wrote the first draft of the manuscript. S.J.G. and E.S.S. assisted with data analysis. R.T.M., S.L.H. and G.R.F. designed the study. All authors interpreted the data and reviewed/edited the manuscript.\n\nConflicts of Interest\nThe authors declare no conflict of interest.\n\nFigure 1 (A) Fasting plasma glucose (FPG) and 2-h plasma glucose post 75 g oral glucose tolerance test (OGTT) (2HrPG) for women diagnosed with GDM that were subsequently managed with metformin (Met), insulin (Ins) or diet and lifestyle modification (Diet). (B) HbA1c at diagnosis of GDM for women subsequently treated with metformin, insulin or diet and lifestyle modification. Results expressed as mean ± standard deviation. ** p < 0.01; *** p < 0.0001.\n\njcm-07-00050-t001_Table 1Table 1 Demographics and characteristics of women with gestational diabetes mellitus (GDM) managed with metformin, insulin or diet and lifestyle modification.\n\nMaternal Characteristics\tMetformin (n = 83)\tInsulin (n = 83)\tDiet and Lifestyle (n = 83)\tp\t\nMaternal age (years)\t33.1 ± 4.8\t33.5 ± 4.3\t33.1 ± 4.3\t0.858\t\nEthnicity\t\n\t\n\t\n\t\n\t\nCaucasian\t41.0% (n = 34)\t30.1% (n = 25)\t37.3% (n = 31)\t0.261\t\nSouth Asian\t26.5% (n = 22)\t34.9% (n = 29)\t18.1% (n = 15)\t-\t\nAsian\t21.7% (n = 18)\t24.1% (n = 20)\t32.5% (n = 27)\t-\t\nSouth-East Asian\t7.2% (n = 6)\t6.0% (n = 5)\t9.6% (n = 8)\t-\t\nMiddle Eastern\t2.4% (n = 2)\t4.8% (n = 4)\t1.2% (n = 1)\t-\t\nPacific Islander\t1.2% (n = 1)\t0\t0\t-\t\nAfrican\t0\t0\t1.2% (n = 1)\t-\t\nPrevious GDM\t13.3% (n = 11)\t13.3% (n = 11)\t13.3% (n = 11)\t0.999\t\nDiagnosis of GDM (weeks)\t23.6 ± 5.9\t24.0 ± 5.8\t24.0 ± 5.7\t0.880\t\nMaternal BMI (kg/m2)\t27.8 ± 8.0\t25.2 ± 6.3\t22.7 ± 2.9\t<0.0001\t\nFamily history of diabetes\t42.2% (n = 35)\t48.2% (n = 40)\t39.8% (n = 33)\t0.528\t\nGestational age at initiation of pharmacotherapy (weeks)\t27.1 ± 5.7\t28.0 ± 5.4\tN/A\t0.292\t\nGestational age at initiation of supplemental insulin (weeks)\t29.5 ± 5.7\tN/A\tN/A\t-\t\nTotal daily dose of insulin in units (before delivery)\t23.6 ± 19.6\t26.9 ± 24.2\tN/A\t0.779\t\njcm-07-00050-t002_Table 2Table 2 Maternal and neonatal outcomes for women receiving metformin in comparison to insulin or diet and lifestyle modification.\n\nPerinatal Outcomes\tMetformin (n = 83)\tInsulin (n = 83)\tDiet and Lifestyle (n = 82)\tp\t\nMaternal Outcomes\t\n\t\n\t\n\t\n\t\nMode of Delivery\t\n\t\n\t\n\t\n\t\nVaginal\t38.6% (n = 32)\t50.6% (n = 42)\t53.7% (n = 44)\t0.268\t\nInstrumental\t19.3% (n = 16)\t19.3% (n = 16)\t13.4% (n = 11)\t-\t\nCaesarean section\t42.2% (n = 35)\t30.1% (n = 25)\t32.9% (n = 27)\t-\t\nNeonatal Outcomes\t\n\t\n\t\n\t\n\t\nBirth weight (g)\t3289 ± 503\t3150 ± 497\t3228 ± 511\t0.140\t\nBirth weight centile\t61 ± 28.5\t52.8 ± 27.1\t53.7 ± 26.6\t0.089\t\nLarge-for-gestational-age\t21.7% (n = 18)\t14.5% (n = 12)\t8.5% (n = 7)\t0.059\t\nSmall-for-gestational-age\t4.1% (n = 3)\t4.1% (n = 3)\t5.6% (n = 4)\t0.758\t\nGestational age at delivery (weeks)\t38.6 ± 1.2\t38.4 ± 1.5\t38.9 ± 1.7\t0.008\t\nShoulder dystocia\t4.1% (n = 4)\t5.5% (n = 4)\t4.2% (n = 3)\t0.909\t\nRespiratory distress\t6.8% (n = 5)\t11.0% (n = 8)\t13.9% (n = 10)\t0.389\t\nNeonatal hypoglycaemia\t15.7% (n = 13)\t19.3% (n = 16)\t6.1% (n = 5)\t0.039\t\nJaundice\t21.7% (n = 18)\t18.1% (n = 15)\t14.6% (n = 12)\t0.501\t\nNICU admission\t14.5% (n = 12)\t14.5% (n = 12)\t7.3% (n = 6)\t0.268\t\nBirth injury\t0\t0\t0\t-\t\nBirth defect\t4.8% (n = 4)\t2.4% (n = 2)\t4.9% (n = 4)\t0.645\t\nNeonatal death\t0\t0\t1.2% (n = 1)\t-\n==== Refs\nReferences\n1. Moses R.G. Wong V.C. Lambert K. Morris G.J. San Gil F. The prevalence of hyperglycaemia in pregnancy in Australia Aust. N. Z. J. Obstet. Gynaecol. 2016 56 341 345 10.1111/ajo.12447 26914693 \n2. Moses R.G. Morris G.J. Petocz P. San Gil F. Garg D. The impact of potential new diagnostic criteria on the prevalence of gestational diabetes mellitus in Australia Med. J. Aust. 2011 194 338 340 21470082 \n3. Metzger B.E. Buchanan T.A. Coustan D.R. de Leiva A. Dunger D.B. Hadden D.R. Hod M. Kitzmiller J.L. Kjos S.L. Oats J.N. Summary and recommendations of the Fifth International Workshop-Conference on Gestational Diabetes Mellitus Diabetes Care 2007 30 Suppl. 2 S251 S260 10.2337/dc07-s225 17596481 \n4. Crowther C.A. Hiller J.E. Moss J.R. McPhee A.J. Jeffries W.S. Robinson J.S. Australian Carbohydrate Intolerance Study in Pregnant Women Trial Group Effect of treatment of gestational diabetes mellitus on pregnancy outcomes N. Engl. J. Med. 2005 352 2477 2486 10.1056/NEJMoa042973 15951574 \n5. Kwik M. Seeho S.K. Smith C. McElduff A. Morris J.M. Outcomes of pregnancies affected by impaired glucose tolerance Diabetes Res. Clin. Pract. 2007 77 263 268 10.1016/j.diabres.2006.12.004 17275121 \n6. Kitwitee P. Limwattananon S. Limwattananon C. Waleekachonlert O. Ratanachotpanich T. Phimphilai M. Nguyen T.V. Pongchaiyakul C. Metformin for the treatment of gestational diabetes: An updated meta-analysis Diabetes Res. Clin. Pract. 2015 109 521 532 10.1016/j.diabres.2015.05.017 26117686 \n7. Dhulkotia J.S. Ola B. Fraser R. Farrell T. Oral hypoglycemic agents vs insulin in management of gestational diabetes: A systematic review and metaanalysis Am. J. Obstet. Gynecol. 2010 203 457.e1 457.e9 10.1016/j.ajog.2010.06.044 20739011 \n8. Niromanesh S. Alavi A. Sharbaf F.R. Amjadi N. Moosavi S. Akbari S. Metformin compared with insulin in the management of gestational diabetes mellitus: A randomized clinical trial Diabetes Res. Clin. Pract. 2012 98 422 429 10.1016/j.diabres.2012.09.031 23068960 \n9. Syngelaki A. Nicolaides K.H. Balani J. Hyer S. Akolekar R. Kotecha R. Pastides A. Shehata H. Metformin versus Placebo in Obese Pregnant Women without Diabetes Mellitus N. Engl. J. Med. 2016 374 434 443 10.1056/NEJMoa1509819 26840133 \n10. Rowan J.A. Hague W.M. Gao W. Battin M.R. Moore M.P. Mi G.T.I. Metformin versus insulin for the treatment of gestational diabetes N. Engl. J. Med. 2008 358 2003 2015 10.1056/NEJMoa0707193 18463376 \n11. Balsells M. Garcia-Patterson A. Sola I. Roque M. Gich I. Corcoy R. Glibenclamide, metformin, and insulin for the treatment of gestational diabetes: A systematic review and meta-analysis BMJ 2015 350 h102 10.1136/bmj.h102 25609400 \n12. Zhao L.P. Sheng X.Y. Zhou S. Yang T. Ma L.Y. Zhou Y. Cui Y.M. Metformin versus insulin for gestational diabetes mellitus: A meta-analysis Br. J. Clin. Pharmacol. 2015 80 1224 1234 10.1111/bcp.12672 25925501 \n13. Donovan P.J. McIntyre H.D. Drugs for gestational diabetes Aust. Prescr. 2010 33 141 144 10.18773/austprescr.2010.066 \n14. Panchaud A. Rousson V. Vial T. Bernard N. Baud D. Amar E. De Santis M. Pistelli A. Dautriche A. Beau-Salinas F. Pregnancy outcomes in women on metformin for diabetes or other indications among those seeking teratology information services Br. J. Clin. Pharmacol. 2018 84 568 578 10.1111/bcp.13481 29215149 \n15. Von Elm E. Altman D.G. Egger M. Pocock S.J. Gøtzsche P.C. Vandenbroucke J.P. Initiative S. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: Guidelines for reporting observational studies Prev. Med. 2007 45 247 251 10.1016/j.ypmed.2007.08.012 17950122 \n16. ADIPS Consensus Guidelines for the Testing and Diagnosis of Gestational Diabetes Mellitus in Australia 2013 Available online: http://adips.org/downloads/ADIPSConsensusGuidelinesGDM-03.05.13VersionACCEPTEDFINAL.pdf (accessed on 10 May 2016) \n17. Villar J. Cheikh Ismail L. Victora C.G. Ohuma E.O. Bertino E. Altman D.G. Lambert A. Papageorghiou A.T. Carvalho M. Jaffer Y.A. Newborn Growth Consortium for the 21st C: International standards for newborn weight, length, and head circumference by gestational age and sex: The Newborn Cross-Sectional Study of the INTERGROWTH-21st Project Lancet 2014 384 857 868 10.1016/S0140-6736(14)60932-6 25209487 \n18. Corbould A. Swinton F. Radford A. Campbell J. McBeath S. Dennis A. Fasting blood glucose predicts response to extended-release metformin in gestational diabetes mellitus Aust. N. Z. J. Obstet. Gynaecol. 2013 53 125 129 10.1111/ajo.12018 23205962 \n19. American Diabetes Association 12. Management of Diabetes in Pregnancy Diabetes Care 2016 39 Suppl. 1 S94 S98 26696688 \n20. Singh A.K. Singh R. Metformin in gestational diabetes: An emerging contender Indian J. Endocrinol. Metab. 2015 19 236 244 10.4103/2230-8210.149317 25729685 \n21. Mesdaghinia E. Samimi M. Homaei Z. Saberi F. Moosavi S.G. Yaribakht M. Comparison of newborn outcomes in women with gestational diabetes mellitus treated with metformin or insulin: A randomised blinded trial Int. J. Prev. Med. 2013 4 327 333 23626890 \n22. Spaulonci C.P. Bernardes L.S. Trindade T.C. Zugaib M. Francisco R.P. Randomized trial of metformin vs insulin in the management of gestational diabetes Am. J. Obstet. Gynecol. 2013 209 34.e1 34.e7 10.1016/j.ajog.2013.03.022 23524173 \n23. Goh J.E. Sadler L. Rowan J. Metformin for gestational diabetes in routine clinical practice Diabet. Med. 2011 28 1082 1087 10.1111/j.1464-5491.2011.03361.x 21679232 \n24. Balani J. Hyer S.L. Rodin D.A. Shehata H. Pregnancy outcomes in women with gestational diabetes treated with metformin or insulin: A case-control study Diabet. Med. 2009 26 798 802 10.1111/j.1464-5491.2009.02780.x 19709150 \n25. Hillier T.A. Pedula K.L. Vesco K.K. Schmidt M.M. Mullen J.A. LeBlanc E.S. Pettitt D.J. Excess gestational weight gain: Modifying fetal macrosomia risk associated with maternal glucose Obstet. Gynecol. 2008 112 1007 1014 10.1097/AOG.0b013e31818a9779 18978099 \n26. Alberico S. Montico M. Barresi V. Monasta L. Businelli C. Soini V. Erenbourg A. Ronfani L. Maso G. Multicentre Study Group on Mode of Delivery in Friuli Venezia Giulia The role of gestational diabetes, pre-pregnancy body mass index and gestational weight gain on the risk of newborn macrosomia: Results from a prospective multicentre study BMC Pregnancy Childbirth 2014 14 23 10.1186/1471-2393-14-23 24428895 \n27. Sebire N.J. Jolly M. Harris J.P. Wadsworth J. Joffe M. Beard R.W. Regan L. Robinson S. Maternal obesity and pregnancy outcome: A study of 287,213 pregnancies in London Int. J. Obes. Relat. Metab. Disord. 2001 25 1175 1182 10.1038/sj.ijo.0801670 11477502 \n28. Usha Kiran T.S. Hemmadi S. Bethel J. Evans J. Outcome of pregnancy in a woman with an increased body mass index BJOG 2005 112 768 772 10.1111/j.1471-0528.2004.00546.x 15924535 \n29. McGrath R.T. Glastras S.J. Hocking S. Fulcher G.R. Use of metformin earlier in pregnancy predicts supplemental insulin therapy in women with gestational diabetes Diabetes Res. Clin. Pract. 2016 116 96 99 10.1016/j.diabres.2016.04.051 27321322 \n30. Butalia S. Gutierrez L. Lodha A. Aitken E. Zakariasen A. Donovan L. Short- and long-term outcomes of metformin compared with insulin alone in pregnancy: A systematic review and meta-analysis Diabet. Med. 2017 34 27 36 10.1111/dme.13150 27150509 \n31. Ijas H. Vaarasmaki M. Saarela T. Keravuo R. Raudaskoski T. A follow-up of a randomised study of metformin and insulin in gestational diabetes mellitus: Growth and development of the children at the age of 18 months BJOG 2015 122 994 1000 10.1111/1471-0528.12964 25039582 \n32. Rowan J.A. Rush E.C. Obolonkin V. Battin M. Wouldes T. Hague W.M. Metformin in gestational diabetes: The offspring follow-up (MiG TOFU): Body composition at 2 years of age Diabetes Care 2011 34 2279 2284 10.2337/dc11-0660 21949222 \n33. Wouldes T.A. Battin M. Coat S. Rush E.C. Hague W.M. Rowan J.A. Neurodevelopmental outcome at 2 years in offspring of women randomised to metformin or insulin treatment for gestational diabetes Arch. Dis. Child. Fetal Neonatal Ed. 2016 10.1136/archdischild-2015-309602 26912348 \n34. Ijas H. Vaarasmaki M. Morin-Papunen L. Keravuo R. Ebeling T. Saarela T. Raudaskoski T. Metformin should be considered in the treatment of gestational diabetes: A prospective randomised study BJOG 2011 118 880 885 10.1111/j.1471-0528.2010.02763.x 21083860\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2077-0383",
"issue": "7(3)",
"journal": "Journal of clinical medicine",
"keywords": "gestational diabetes; glycaemic control; insulin; metformin; perinatal outcomes",
"medline_ta": "J Clin Med",
"mesh_terms": null,
"nlm_unique_id": "101606588",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "29522471",
"pubdate": "2018-03-09",
"publication_types": "D016428:Journal Article",
"references": "21470082;19709150;27321322;15951574;26912348;26840133;11477502;25925501;17596481;25729685;27150509;29215149;23068960;25209487;26696688;21679232;21949222;23626890;26117686;25609400;23524173;23205962;26914693;20739011;17950122;25039582;18463376;15924535;24428895;18978099;17275121;21083860",
"title": "Outcomes for Women with Gestational Diabetes Treated with Metformin: A Retrospective, Case-Control Study.",
"title_normalized": "outcomes for women with gestational diabetes treated with metformin a retrospective case control study"
} | [
{
"companynumb": "AU-ALKEM LABORATORIES LIMITED-AU-ALKEM-2018-01542",
"fulfillexpeditecriteria": "2",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "METFORMIN HYDROCHLORIDE"
},
... |
{
"abstract": "BACKGROUND\nTreatment of trigeminal neuralgia can be challenging for many physicians; patients who do not respond to conventional treatments and traditional surgical approaches often continue to suffer with pain. The peripheral nerve stimulator (PNS) has been used to treat many chronic pain conditions, but few reports exist about its use to treat trigeminal neuralgia.\n\n\nMETHODS\nWe present the case of a patient with trigeminal neuralgia resistant to conventional techniques of pain management. Conservative pain management was attempted but was ineffective. As a result, a PNS was placed with minimally invasive surgery. Pain scores were recorded before and after the procedure, and the patient reported complete resolution of her pain.\n\n\nCONCLUSIONS\nPNS implantation can be a safe and effective method to treat trigeminal neuralgia. More research is needed to define its mechanism of action.",
"affiliations": "Department of Anesthesiology, University of Wisconsin School of Medicine and Public Health, Madison, WI.;Department of Anesthesiology, University of Cincinnati, Cincinnati, OH.;Department of Anesthesiology, University of Cincinnati, Cincinnati, OH.",
"authors": "Abd-Elsayed|Alaa A|AA|;Grandhi|Ravi|R|;Sachdeva|Harsh|H|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1524-5012",
"issue": "15(2)",
"journal": "The Ochsner journal",
"keywords": "Chronic pain; electric stimulation therapy; peripheral nerves; trigeminal neuralgia",
"medline_ta": "Ochsner J",
"mesh_terms": null,
"nlm_unique_id": "101125795",
"other_id": null,
"pages": "193-5",
"pmc": null,
"pmid": "26130986",
"pubdate": "2015",
"publication_types": "D002363:Case Reports",
"references": "22270735;205314;22996867;12441827;358067",
"title": "Effective Management of Trigeminal Neuralgia by Neurostimulation.",
"title_normalized": "effective management of trigeminal neuralgia by neurostimulation"
} | [
{
"companynumb": "US-ALKEM LABORATORIES LIMITED-US-ALKEM-2018-10302",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CARBAMAZEPINE"
},
"dr... |
{
"abstract": "OBJECTIVE\nTo examine the safety and efficacy of liquid risperidone to reduce duration of rages in children with severe mood dysregulation (SMD) or possible bipolar disorder (BP).\n\n\nMETHODS\nThe sample included 151 consecutive admissions of 5-12 year old children to a psychiatric inpatient unit. Diagnostic information and history of prior rage outbursts were obtained at admission. In hospital, a first rage was treated with seclusion. If a second rage occurred, the child was offered liquid risperidone to help him/her regain control. Durations of unmedicated and last medicated rage were compared. Rage frequency in children with SMD and several definitions of BP were compared.\n\n\nRESULTS\nAlthough 82 of 151 admissions were prompted by rages, rages occurred during only 49 hospitalizations and occurred more than once in only 24. In 16 multiply medicated children, duration of rages dropped from a baseline of 44.4 +/- 20.2 min to 25.6 +/- 12.5 min at the child's last dose. Neither SMD nor any definition of BP influenced rage response in this small sample. The average liquid risperidone dose was 0.02 mg/kg. All but two children also took atypical antipsychotics daily. In the evaluation of medicated rage episodes with standard rating scales, no extrapyramidal side effects, akathisia, or abnormal involuntary movements were observed, and the rate of sedation/sleepiness (7/67 = 10.4%) was similar and not significantly different from that observed during nonmedicated episodes (8/46 = 17.4%).\n\n\nCONCLUSIONS\nLiquid risperidone may be a safe and effective way to shorten the duration of rage episodes regardless of diagnosis. However, definitive conclusions cannot be drawn in the absence of a placebo control as children were also receiving other behavioral and psychopharmacologic treatments.",
"affiliations": "Division of Child and Adolescent Psychiatry, Stony Brook University School of Medicine, Stony Brook, NY 11794-8790, USA. gabrielle.carlson@stonybrook.edu",
"authors": "Carlson|Gabrielle A|GA|;Potegal|Michael|M|;Margulies|David|D|;Basile|Joann|J|;Gutkovich|Zinoviy|Z|",
"chemical_list": "D014150:Antipsychotic Agents; D019999:Pharmaceutical Solutions; D018967:Risperidone",
"country": "Denmark",
"delete": false,
"doi": "10.1111/j.1399-5618.2010.00793.x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1398-5647",
"issue": "12(2)",
"journal": "Bipolar disorders",
"keywords": null,
"medline_ta": "Bipolar Disord",
"mesh_terms": "D000284:Administration, Oral; D014150:Antipsychotic Agents; D001714:Bipolar Disorder; D002648:Child; D002673:Child, Hospitalized; D005260:Female; D006760:Hospitalization; D006801:Humans; D007297:Inpatients; D008297:Male; D019999:Pharmaceutical Solutions; D011889:Rage; D018967:Risperidone; D012890:Sleep; D016896:Treatment Outcome",
"nlm_unique_id": "100883596",
"other_id": null,
"pages": "205-12",
"pmc": null,
"pmid": "20402713",
"pubdate": "2010-03",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "17195735;8010362;19302766;12151468;1890103;11833634;16197929;7103676;12402570;17314717;16084859;17822344;4917967;12611821;9473921;2574607;1752851;19122014;19232024;12153826;17581453;17201611;16461861;19519263;11305699",
"title": "Liquid risperidone in the treatment of rages in psychiatrically hospitalized children with possible bipolar disorder.",
"title_normalized": "liquid risperidone in the treatment of rages in psychiatrically hospitalized children with possible bipolar disorder"
} | [
{
"companynumb": "US-JNJFOC-20130608011",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RISPERIDONE"
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"drugadditional": null,
... |
{
"abstract": "Missense variants in the SCN8A voltage-gated sodium channel gene are linked to early-infantile epileptic encephalopathy type 13, also known as SCN8A-related epilepsy. These patients exhibit a wide spectrum of intractable seizure types, severe developmental delay, movement disorders, and elevated risk of sudden unexpected death in epilepsy. The mechanisms by which SCN8A variants lead to epilepsy are poorly understood, although heterologous expression systems and mouse models have demonstrated altered sodium current properties. To investigate these mechanisms using a patient-specific model, we generated induced pluripotent stem cells from three patients with missense variants in SCN8A: p.R1872>L (Patient 1); p.V1592>L (Patient 2); and p.N1759>S (Patient 3). Using small molecule differentiation into excitatory neurons, induced pluripotent stem cell-derived neurons from all three patients displayed altered sodium currents. Patients 1 and 2 had elevated persistent current, while Patient 3 had increased resurgent current compared to controls. Neurons from all three patients displayed shorter axon initial segment lengths compared to controls. Further analyses focused on one of the patients with increased persistent sodium current (Patient 1) and the patient with increased resurgent current (Patient 3). Excitatory cortical neurons from both patients had prolonged action potential repolarization. Using doxycycline-inducible expression of the neuronal transcription factors neurogenin 1 and 2 to synchronize differentiation of induced excitatory cortical-like neurons, we investigated network activity and response to pharmacotherapies. Both small molecule differentiated and induced patient neurons displayed similar abnormalities in action potential repolarization. Patient induced neurons showed increased burstiness that was sensitive to phenytoin, currently a standard treatment for SCN8A-related epilepsy patients, or riluzole, an FDA-approved drug used in amyotrophic lateral sclerosis and known to block persistent and resurgent sodium currents, at pharmacologically relevant concentrations. Patch-clamp recordings showed that riluzole suppressed spontaneous firing and increased the action potential firing threshold of patient-derived neurons to more depolarized potentials. Two of the patients in this study were prescribed riluzole off-label. Patient 1 had a 50% reduction in seizure frequency. Patient 3 experienced an immediate and dramatic seizure reduction with months of seizure freedom. An additional patient with a SCN8A variant in domain IV of Nav1.6 (p.V1757>I) had a dramatic reduction in seizure frequency for several months after starting riluzole treatment, but then seizures recurred. Our results indicate that patient-specific neurons are useful for modelling SCN8A-related epilepsy and demonstrate SCN8A variant-specific mechanisms. Moreover, these findings suggest that patient-specific neuronal disease modelling offers a useful platform for discovering precision epilepsy therapies.",
"affiliations": "Department of Neurology, University of Michigan, Ann Arbor, MI, USA.;Department of Pharmacology, University of Michigan, Ann Arbor, MI, USA.;Department of Pharmacology, University of Michigan, Ann Arbor, MI, USA.;Department of Neurology, University of Michigan, Ann Arbor, MI, USA.;Department of Neurology, University of Michigan, Ann Arbor, MI, USA.;Department of Neurology, University of Michigan, Ann Arbor, MI, USA.;Department of Neurology, University of Michigan, Ann Arbor, MI, USA.;Child Neurology Services, Knoxville, TN, USA.;Department of Neurology, University of Alabama Birmingham School of Medicine, Birmingham, AL, USA.;Cook Children's Health Care System, Fort Worth, Texas, USA.;Department of Neurology, University of Michigan, Ann Arbor, MI, USA.;Department of Neurology, University of Michigan, Ann Arbor, MI, USA.",
"authors": "Tidball|Andrew M|AM|;Lopez-Santiago|Luis F|LF|;Yuan|Yukun|Y|;Glenn|Trevor W|TW|;Margolis|Joshua L|JL|;Clayton Walker|J|J|;Kilbane|Emma G|EG|;Miller|Christopher A|CA|;Martina Bebin|E|E|;Scott Perry|M|M|;Isom|Lori L|LL|;Parent|Jack M|JM|",
"chemical_list": "D062557:NAV1.6 Voltage-Gated Sodium Channel; C100681:SCN8A protein, human",
"country": "England",
"delete": false,
"doi": "10.1093/brain/awaa247",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0006-8950",
"issue": "143(10)",
"journal": "Brain : a journal of neurology",
"keywords": "developmental and epileptic encephalopathy; epileptogenesis; genetic epilepsy; induced pluripotent stem cell; voltage-gated sodium channel",
"medline_ta": "Brain",
"mesh_terms": "D000200:Action Potentials; D000293:Adolescent; D000328:Adult; D002648:Child; D004827:Epilepsy; D005260:Female; D014644:Genetic Variation; D006801:Humans; D057026:Induced Pluripotent Stem Cells; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008875:Middle Aged; D062557:NAV1.6 Voltage-Gated Sodium Channel; D009474:Neurons",
"nlm_unique_id": "0372537",
"other_id": null,
"pages": "3025-3040",
"pmc": null,
"pmid": "32968789",
"pubdate": "2020-10-01",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "23934111;30601941;29924991;22428025;23764284;1915583;29454965;22306606;28676574;30617209;22860217;3018617;25403753;25785782;14623733;23025758;26900580;28781079;22623668;26982737;30617258;12151762;22995823;16650134;26029160;17881658;11677002;31666522;8959995;25587899;20236142;23233385;20643904;9262334;22365152;25227913;11070180;8085162;24888894;29588963;25568300;24356715;30320153;28052116;11029626;26526995;26252990;19254928;18155774;11463511;23821540;27267376;27375106;24132240;24908486;27188845;24653680;29791859;23642365;30171078;21788423;28193882;21541342",
"title": "Variant-specific changes in persistent or resurgent sodium current in SCN8A-related epilepsy patient-derived neurons.",
"title_normalized": "variant specific changes in persistent or resurgent sodium current in scn8a related epilepsy patient derived neurons"
} | [
{
"companynumb": "US-DRREDDYS-USA/USA/21/0135300",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "PHENOBARBITAL"
},
"drugadditional": null... |
{
"abstract": "BACKGROUND\nThe majority of malignancies after transplantation appear to be virally mediated and of recipient origin. Donor-derived neoplasms occur early, whereas recipient-origin tumors typically occur many years after transplantation. Sarcomas are a relatively rare form of cancer. The etiology of sarcomas remains largely unknown, although some are linked to viruses, familial cancer syndromes, or therapeutic radiation exposure. Primary sarcomas are extremely rare, accounting for <0.1% of all native pancreatic malignancies. The involvement of the allograft itself in the tumor is rare.\n\n\nMETHODS\nA 53-year-old white woman (body mass index, 20.1 kg/m2) with a history of type 1 diabetes, chronic kidney disease, coronary artery disease, dyslipidemia, and pancreas-alone transplantation in 2007 was admitted with small bowel obstruction secondary to a mass in the head of the pancreas allograft, for which a laparotomy with allograft pancreatectomy was required. Histopathologic exam revealed a stage III high-grade unclassified spindle cell sarcoma positive for polyomavirus. After surgery, the patient was managed with close monitoring for disease recurrence. Her most recent scan was negative for recurrence at postoperative day 489.\n\n\nCONCLUSIONS\nWe report a previously unreported phenomenon of a soft tissue sarcoma arising in a pancreas allograft, likely of recipient origin and polyomavirus related. Standard treatment for sarcoma is wide excision of the tumor and close monitoring for recurrence. Systemic chemotherapy or radiotherapy is usually limited to advanced cases. Sarcomas may occur in a pancreas allograft. Allograft pancreatectomy and monitoring for recurrence is vital for a good outcome.",
"affiliations": "Division of Transplantation, Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana.;Department of Hematology and Oncology, Indiana University School of Medicine, Indianapolis, Indiana.;Transplant Division, Department of Nephrology, Indiana University School of Medicine, Indianapolis, Indiana.;Transplant Division, Department of Nephrology, Indiana University School of Medicine, Indianapolis, Indiana.;Division of Transplantation, Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana.;Division of Transplantation, Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana. Electronic address: jfridell@iupui.edu.",
"authors": "Nagaraju|S|S|;Grethlein|S J|SJ|;Vaishnav|S|S|;Sharfuddin|A A|AA|;Powelson|J A|JA|;Fridell|J A|JA|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.transproceed.2017.10.007",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-1345",
"issue": "49(10)",
"journal": "Transplantation proceedings",
"keywords": null,
"medline_ta": "Transplant Proc",
"mesh_terms": "D064591:Allografts; D003922:Diabetes Mellitus, Type 1; D005260:Female; D006801:Humans; D008875:Middle Aged; D016035:Pancreas Transplantation; D010190:Pancreatic Neoplasms; D027601:Polyomavirus Infections; D012509:Sarcoma; D014184:Transplantation, Homologous",
"nlm_unique_id": "0243532",
"other_id": null,
"pages": "2352-2354",
"pmc": null,
"pmid": "29198676",
"pubdate": "2017-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Case Report: Primary De Novo Sarcoma In Transplant Pancreas Allograft.",
"title_normalized": "case report primary de novo sarcoma in transplant pancreas allograft"
} | [
{
"companynumb": "US-DRREDDYS-USA/USA/17/0095581",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "SIROLIMUS"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nThis study evaluated the incidence of late cardiotoxicity after dose-dense and -intense adjuvant sequential doxorubicin (A), paclitaxel (T), and cyclophosphamide (C) for breast cancer (BC) with > or = 4 involved ipsilateral axillary lymph nodes.\n\n\nMETHODS\nPatients were enrolled from 1994 to 2001 after definitive BC surgery if > or =4 axillary nodes were involved. Planned treatment was A 90 mg/m(2) q 14 days x 3, T 250 mg/m(2) q 14 days x 3, C 3 g/m(2 )q 14 days x 3 with filgrastim (G) support. Left ventricular ejection fraction (LVEF) was monitored using equilibrium radionuclide angiography (ERNA) before the initiation of chemotherapy, and after three cycles of each chemotherapeutic agent. At a median follow-up of 7 years, we obtained ERNA scans on 32 patients to evaluate the long-term cardiotoxicity of this regimen.\n\n\nRESULTS\nEighty-five eligible patients enrolled on the treatment protocol. Clinical heart failure developed in one patient. Seven (8%) patients had LVEF < 50% at the end of therapy. No cardiac-related deaths occurred. Thirty-two (46%) of 69 surviving patients have consented to late cardiac imaging. At a median follow-up of 7 years, the median absolute change in LVEF from baseline was -5.5%; [range (-8%) to (+36%)], and from the end of chemotherapy was -2.0%; [range (-25%) to (+16%)]. Four patients (12%) had a LVEF < 50%; two of these four patients had an LVEF of < 50% at the end of chemotherapy.\n\n\nCONCLUSIONS\nLate development of asymptomatic decline in cardiac function may occur after dose-dense and -intense adjuvant therapy, but is uncommon.",
"affiliations": "Department of Internal Medicine, Section of Medical Oncology, Yale University School of Medicine, Yale Cancer Center, New Haven, CT 06520-8032, USA. maysa.abu-khalaf@yale.edu",
"authors": "Abu-Khalaf|Maysa M|MM|;Juneja|Vinni|V|;Chung|Gina G|GG|;DiGiovanna|Michael P|MP|;Sipples|Rebecca|R|;McGurk|Meghan|M|;Zelterman|Daniel|D|;Haffty|Bruce|B|;Reiss|Michael|M|;Wackers|Frans J|FJ|;Lee|Forrester A|FA|;Burtness|Barbara A|BA|",
"chemical_list": "D004317:Doxorubicin; D003520:Cyclophosphamide; D017239:Paclitaxel",
"country": "Netherlands",
"delete": false,
"doi": "10.1007/s10549-006-9413-7",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0167-6806",
"issue": "104(3)",
"journal": "Breast cancer research and treatment",
"keywords": null,
"medline_ta": "Breast Cancer Res Treat",
"mesh_terms": "D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D001943:Breast Neoplasms; D017024:Chemotherapy, Adjuvant; D003520:Cyclophosphamide; D004317:Doxorubicin; D004334:Drug Administration Schedule; D005260:Female; D005500:Follow-Up Studies; D006321:Heart; D006331:Heart Diseases; D006801:Humans; D008875:Middle Aged; D017239:Paclitaxel; D016896:Treatment Outcome",
"nlm_unique_id": "8111104",
"other_id": null,
"pages": "341-9",
"pmc": null,
"pmid": "17051423",
"pubdate": "2007-09",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Long-term assessment of cardiac function after dose-dense and -intense sequential doxorubicin (A), paclitaxel (T), and cyclophosphamide (C) as adjuvant therapy for high risk breast cancer.",
"title_normalized": "long term assessment of cardiac function after dose dense and intense sequential doxorubicin a paclitaxel t and cyclophosphamide c as adjuvant therapy for high risk breast cancer"
} | [
{
"companynumb": "US-AMGEN-USASP2019195097",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "DOXORUBICIN"
},
"drugadditional": null,
... |
{
"abstract": "A 71-year-old Japanese woman presented with progressive fatigue, lethargy, dysarthria and a gait disorder. Her laboratory data revealed hyponatremia (Na 101 mEq/L), and we started correcting her serum sodium level. Within a few days, she became comatose, bedridden, and was intubated. We diagnosed osmotic demyelination syndrome (ODS) and started performing plasma exchange (PE) on the 39th day of hospitalization. She fully recovered after starting PE, and was discharged on foot unassisted. PE can be a beneficial treatment in patients with chronic ODS.",
"affiliations": "Division of Nephrology, Department of Medicine, Tokyo Women's Medical University Yachiyo Medical Center, Japan.",
"authors": "Kumon|Saeko|S|;Usui|Ryosuke|R|;Kuzuhara|Shinzo|S|;Nitta|Kosaku|K|;Koike|Minako|M|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": "10.2169/internalmedicine.56.7491",
"fulltext": "\n==== Front\nIntern MedIntern. Med10.2169/internalmedicine.56.7491Internal Medicine0918-29181349-7235The Japanese Society of Internal Medicine 28321080Case ReportThe Improvement of the Outcome of Osmotic Demyelination Syndrome by Plasma Exchange Kumon Saeko 1Usui Ryosuke 1Kuzuhara Shinzo 2Nitta Kosaku 3Koike Minako 11 Division of Nephrology, Department of Medicine, Tokyo Women's Medical University Yachiyo Medical Center, Japan2 Division of Nephrology, Department of Medicine, Sekikawa Hospital, Japan3 Division of Nephrology, Department of Medicine, Tokyo Women's Medical University, JapanCorrespondence to Dr. Saeko Kumon, kumon.saeko@twmu.ac.jp\n\n15 3 2017 56 6 733 736 29 3 2016 4 7 2016 The Internal Medicine is an Open Access article distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view the details of this license, please visit (https://creativecommons.org/licenses/by-nc-nd/4.0/).A 71-year-old Japanese woman presented with progressive fatigue, lethargy, dysarthria and a gait disorder. Her laboratory data revealed hyponatremia (Na 101 mEq/L), and we started correcting her serum sodium level. Within a few days, she became comatose, bedridden, and was intubated. We diagnosed osmotic demyelination syndrome (ODS) and started performing plasma exchange (PE) on the 39th day of hospitalization. She fully recovered after starting PE, and was discharged on foot unassisted. PE can be a beneficial treatment in patients with chronic ODS. \n\nosmotic demyelination syndromehyponatremiaplasma exchange\n==== Body\nIntroduction\nOsmotic demyelination syndrome (ODS), which is also known as central pontine myelinolysis (CPM), has been found to occur after the rapid correction of severe hyponatremia (1). The clinical manifestations of ODS are known to develop for 2-6 days after a rapid elevation of the serum sodium level. The symptoms are often irreversible or only partially reversible, and they include dysarthria, dysphagia, tetraparesis, behavioral disturbances, lethargy, confusion, disorientation, and coma (2).\n\nWhen CPM develops after the rapid correction of hyponatremia, plasma exchange (PE) may be a beneficial therapy. Bibl et al. successfully treated three young female patients by intensive plasmapheresis soon after confirming a diagnosis of CPM (3). All three patients had undergone the correction of severe hyponatremia at 3-5 days before the onset of the neurological symptoms. Significant clinical improvement was obtained at one month after the start of plasmapheresis. We herein report a case of chronic ODS that was successfully treated by PE.\n\nCase Report\nA 71-year-old Japanese woman with hypertension and dyslipidemia was admitted for progressive dysarthria and gait disorder. She had experienced progressive fatigue and lethargy for a few weeks. She had been taking nifedipine CR (40 mg/day), imidapril (10 mg/day), valsartan (80 mg/day), rosuvastatin (2.5 mg/day), trichlormethiazide (4 mg/day), zolpidem (10 mg/day), teprenone (1.5 g/day), magnesium oxide (990 mg/day), torimebuchiren (300 mg/day), for a few years. She looked confused but was aware of her name, and the place and time. She denied any recent episodes of a cold or weight loss. She was 154 cm in height, and weighed 57 kg. Her vital signs were within the normal limits. She was slightly edematous in the lower extremities. There were numerous bruises all over her body as a result of repeated falls. A neurological examination revealed dysarthria, drooling and unsteadiness in balance and gait. The laboratory data on admission is shown in the Table; briefly, hyponatremia (Na 101 mEq/L), hypochloremia (Cl 68 mEq/L), and slight hypokalemia (K 3.5 mEq/L). Head computed tomography (CT) and brain magnetic resonance imaging (MRI) revealed no abnormalities, and electrocardiography (ECG) showed no evidence of arrhythmia. We suspected that her consciousness disorder was due to severe hyponatremia. Since her serum sodium level had fallen from 135 mEq/L at approximately one month before admission to 108 mEq/L a few days before admission to our hospital, we concluded that her hyponatremia had chronically progressed. We started correcting her serum sodium level with an intravenous infusion of normal saline by calculating the sodium dosage and infusion speed. On the second hospital day, her serum sodium level reached 108 mEq/L. She became alert and we allowed her to ingest meals that contained about 10 g of NaCl. On the third hospital day, her serum sodium level had risen to 120 mEq/L. Because we thought the correction was too rapid, we switched the intravenous drip infusion from normal saline to half saline. However, a few hours later, she was unable to follow our commands. Her serum sodium level was still 120 mEq/L and her serum phosphate level was 1.0 mg/dL. Her serum phosphate level was 2.5 mg/dL on the second day of hospitalization and decreased to 1.9 mg/dL on the morning of the third day. We prescribed sodium phosphate and water-soluble vitamins with saline or half saline to treat the deficiency while supplying few calories. At first, we suspected that her consciousness disturbance was due to delirium or ODS. After her consciousness deteriorated the following day, we performed head CT and brain MRI. We also consulted neurologists, who ruled out ODS based on the diagnostic imaging and physical findings. She became comatose, and rigidity was found in her extremities. A few hours later, we found her snoring, and gradually her oxygen saturation level started to fall. We performed tracheal intubation immediately for airway protection. Electroencephalography (EEG) and lumbar puncture did not help in making a diagnosis. Within 2 days, she became alert and was extubated. We found her having difficulty in expectorating sputum. Laryngoscopy resulted in a diagnosis of recurrent nerve palsy, and tracheotomy was performed. Spastic tetraparesis and deep tendon hyperreflexia were noted, and the Babinski reflex was observed. Her tetraparesis worsened day by day and it soon became difficult for her to stand, move her face, or swallow. The transient consciousness and respiratory disorder might have been due to refeeding syndrome or Wernicke encephalopathy. But we could hardly explain the progressive tetraparesis and recurrent nerve palsy after she became alert. On the 26th day of hospitalization, brain MRI revealed a fresh high signal region in the pons and the bilateral basal ganglia, which led us to make a diagnosis of ODS (Fig. 1). On the 39th day of hospitalization, we started consecutive PE, at a rate of 2-3 sessions per week for total of 6 sessions (Fig. 2). Since her body weight was 55 kg and her Hct value was 33%, her estimated plasma volume was 55×0.065×(1-0.33)=2.4 L. We exchanged a total volume of 3,840 mL of fresh frozen plasma (FFP) (approximately one and a half times the volume of her plasma; 2.4×1.5=3.6 L). Her spastic tetraparesis showed significant improvement after the start of PE therapy, and she was able to stand by herself and walk after the second session of PE. Laryngoscopy revealed improved vocal cord movement. We tried closing the tracheostoma on the 92nd day of hospitalization. The high signals in the pons and bilateral basal ganglia were reduced in size but remained after the completion of PE therapy (Fig. 1). She was able to eat and drink without aspirating, and walked on foot unassisted on the 111th day of hospitalization.\n\nTable. The Laboratory Findings.\n\nUrinalysis\t\t\tBlood chemistry\t\tImmunology\t\t\t\n specific gravity\t1.010\t\t HbAlc\t5.9\t%\t\t IgG\t937\tmg/dL\t\n pH\t6.0\t\t TP\t7.1\tg/dL\t\t IgA\t117\tmg/dL\t\n protein\t±\t\t AST\t90\tIU/L\t\t IgM\t72\tmg/dL\t\n occult blood\t2+\t\t ALT\t64\tIU/L\t\t CH50\t35\tIU/mL\t\nSediments\t\t\t LDH\t574\tIU/L\t\t C3\t68\tmg/dL\t\nRBC\t5-9\t/HPF\t CK\t2023\tIU/L\t\t C4\t28\tmg/dL\t\n\t\t\t BUN\t9.5\tmg/dL\t\t ANA\t×80\t\t\n uOSM\t202\tmOSM/kg\t Cr\t0.41\tmg/dL\t\t\t\t\t\n uUN\t229\tmg/dL\t Na\t101\tmEq/L\t\tOthers\t\t\t\n uNa\t14\tmEq/L\t K\t3.5\tmEq/L\t\t TSH\t1.63\tμIU/mL\t\n uK\t10.6\tmEq/L\t Cl\t68\tmEq/L\t\t free T3\t1.91\tpg/mL\t\n uCl\t21\tmEq/L\t Ca\t8.5\tmg/dL\t\t free T4\t1.75\tng/dL\t\n uCr\t37.4\tmg/dL\t TG\t41\tmg/dL\t\t hANP\t32.7\tpg/mL\t\n\t\t\t HDL\t102\tmg/dL\t\t PRA\t6.5\tng/mL/hr\t\nComplete blood count\t\t LDL\t35\tmg/dL\t\t aldosterone\t117\tpg/mL\t\n WBC\t11650\t/μL\t CRP\t0.74\tmg/dL\t\t ACTH\t28.9\tpg/mL\t\n Neutrophils\t80.4\t%\teGFR\t111.9\tmL/min/1.73m2\t cortisol\t20.3\tμg/dL\t\n Lymphocytes\t12.0\t%\tpOsm\t215\tmOSM/kg\t\t AVP\t2.6\tpg/mL\t\n Monocytes\t7.3\t%\t\t\t\t\tCoagulation\t\t\t\n Basophils\t0.0\t%\t\t\t\t\t PT (INR)\t0.96\t\t\n Eosinophils\t0.3\t%\tBlood gas analysis\t\t APTT\t27.6\tsec\t\n RBC\t439×104\t/µL\t pH\t\t7.48\t\t FDP\t<3\tμg/mL\t\n Hemoglobin\t13.5\tg/dL\t HCO3-\t\t24.6\tmEq/L\tInfection\t\t\t\n Hematocrit\t35.2\t%\t B.E.\t\t2.0\tmEq/L\tHBs antigen\t(-)\t\t\n Platelet\t23.3×104\t/µL\t anion gap\t9.0\tmEq/L\tHCV antibody\t(-)\t\t\n\t\t\t\t\t\tSTS\t(-)\t\t\nRBC: red blood cell, u-: urinary, OSM: osmolality, UN: urea nitrogen, Na: sodium, K: potassium, Cl: chrolide, Cr: creatinine,\n\nWBC: white blood cell, TP: total protein, AST: aspartate aminotransferase, ALT: alanine aminotransferase, LDH: lactate dehydrogenase,\n\nCK: creatine kinase, BUN: blood urea nitrogen, TG: tryglyceride, LDL: low density lipoprotein, CRP: C-reactive protein,\n\neGFR: estimated glomerular filtration rate, pOSM: plasma osmolality, B.E. bass excess, IgG/A/M: immunogloblin G/A/M, \n\nCH50: complement hemolytic activity, C3/C4: complement, ANA: anti-nuclear antibody, TSH: thyroid stimulating hormone, \n\nhANP: human atrial natriuretic peptide, PRA: plasma renin activity, ACTH: adrenocorticotrophic hormone, AVP: arginine vasopressin, \n\nPT (INR): thrombin time (international normalized ratio), APTT: activated partial thromboplastin time, \n\nFDP: fibrin and fibrinogen degradation products, HBs: hepatitis B surface, HCV.: anti-hepatitis C, STS: serological test for syphilis\n\nFigure 1. A fluid attenuated inversion recovery (FLAIR) sequence of brain MRI. The arrow shows the basal ganglia and pons in a time series.\n\nFigure 2. The clinical course.\n\nDiscussion\nThe laboratory findings on admission, including a serum osmolality of 215 mOsm and a serum sodium level of 108 mEq/L, showed hypoosmotic hyponatremia. The patient's lower limbs were slightly edematous on admission to the emergency department, but her chest X-ray showed a normal cardiac silhouette and no evidence of pleural fluid. A loss of appetite for a few days resulted in a fractional excretion of sodium value of 0.47% and a fractional excretion of urea nitrogen value of 33.9%, which indicated mild hypovolemia. The urinary sodium level was 64 mEq/L, and the urinary chrolide level was 88 mEq/L. Both the urinalysis findings and her serum human atrial natriuretic peptide level (32.7 pg/mL) ruled out severe hypovolemia. Hormonal tests revealed the patient was euthyroid. A rapid ACTH test showed no evidence of adrenocortical insufficiency, and a CRH/TRH/GnRH/GHRH tolerance test ruled out hypopituitarism. The serum AVP level of 2.6 pg/mL was high for an osmolality of 215 mOsm, and we suspected syndrome of inappropriate secretion of antidiuretic hormone (SIADH). No obvious cause of SIADH, such as malignancy, inflammatory disease, or central nervous system disorder was detected other than the physical stress caused by admission, and mental stress prior to admission. Her serum phosphate and potassium levels were slight decreased. An examination to investigate sodium and other electrolyte disorders, led to a diagnosis of hyponatremia due to thiazide diuretics. It is well-known that thiazide diuretics sometimes cause hyponatremia, and that it can happen after taking diuretics for a few years. Some drugs induce hyponatremia when taken with thiazide diuretics (4,5).\n\nThe etiology of ODS is not clear, but it is considered to be an iatrogenic disease that is caused by a rapid rise in the serum level of sodium (1). The damage to the blood-brain barrier by osmotic change is thought to result from the exposure of the brain to myelinotoxic substances (6,7). The speed at which the serum sodium level is corrected should be decided carefully when treating chronic hyponatremia; however, it is not unusual for the serum sodium level to differ from the expected values (2).\n\nThe re-induction of hyponatremia is reported to be beneficial for preventing ODS due to a rapid correction of hyponatremia (8,9). Other treatments, such as the administration of TRH, corticosteroids (6,10), immunoglobulins (11), and PE (3) were suggested by case reports. Minocycline is said to be effective in preventing ODS in the rat models (12). However, there are no proven, effective treatments for ODS. In the present case, it took more than one month to diagnose ODS. In the chronic phase of ODS, we could not expect the same effect of a re-lowering serum sodium level. Since plasma apheresis is known to be effective in treating demyelinating neuropathy (13), we decided to treat our patient using PE. The direct effects of PE on the blood-brain barrier have not been proven; however, her symptoms improved dramatically, immediately after the initiation of PE. The improvement of the nerve cells or neuron system is unlikely to occur with a single PE session. The previous case reports in which PE was shown to be beneficial in the treatment of acute-phase ODS indicate that the improvement of ODS-associated symptoms following PE could be explained by the removal of myelinotoxic substances, which are involved in the pathogenesis of ODS.\n\nOn the other hand, in the present case, the introduction of PE in the chronic phase improved her neurological symptoms, suggesting that myelinotoxic substances work not only as an exacerbating factor but also as a suppressor of neural activity. It has been reported that 31% of ODS patients died and that 31% required life-supporting therapy after one year of follow-up (14). There are likely to be cases that are thought to be uncurable in which physicians give up treatment after diagnosing ODS. Not all the cases require plasma exchange; however, it could be an effective treatment for chronic ODS.\n\nPE could therefore be a beneficial treatment for chronic ODS.\n\nThe authors state that they have no Conflict of Interest (COI).\n==== Refs\n1. Kleinschmidt-DeMasters BK , Norenberg MD \nRapid correction of hyponatremia causes demyelination: relation to central pontine myelinolysis . Science \n211 : 1068 -1070 , 1981 .7466381 \n2. Sterns RH , Cappuccio JD , Silver SM , Cohen EP \nNeurologic sequelae after treatment of hyponatremia: a multicenter perspective . J Am Soc Nephrol \n4 : 1522 -1530 , 1994 .8025225 \n3. Bibl D , Lampl C , Gabriel C , Jüngling G , Brock H , Köstler G \nTreatment of central pontine myelinolysis with therapeutic plasmapheresis . Lancet \n353 : 1155 , 1999 .\n4. Rodenburg EM , Hoorn EJ , Ruiter R , et al \nThiazide-associated hyponatremia: a population-based study . Am J Kidney Dis \n62 : 67 -72 , 2013 .23602191 \n5. Sardar GK , Eilbert WP \nSevere hyponatremia associated with thiazide diuretic use . J Emerg Med \n48 : 305 -309 , 2015 .25499401 \n6. Chang KY , Lee IH , Kim GJ , Cho K , Park HS , Kim HW \nPlasma exchange successfully treats central pontine myelinolysis after acute hypernatremia from intravenous sodium bicarbonate therapy . BMC Nephrol \n15 : 56 , 2014 .24708786 \n7. Corona G , Simonetti L , Giuliani C , Sforza A , Peri A \nA case of osmotic demyelination syndrome occurred after the correction of severe hyponatraemia in hyperemesis gravidarum . BMC Endocr Disord \n14 : 34 , 2014 .24725751 \n8. Gankam Kengne F , Soupart A , Pochet R , Brion JP , Decaux G \nRe-induction of hyponatremia after rapid overcorrection of hyponatremia reduces mortality in rats . Kidney Int \n76 : 614 -621 , 2009 .19606078 \n9. Yamada H , Takano K , Ayuzawa N , Seki G , Fujita T \nRelowering of serum Na for osmotic demyelinating syndrome . Case Rep Neurol Med \n2012 : 704639 , 2012 .22937357 \n10. King JD , Rosner MH \nOsmotic demyelination syndrome . Am J Med Sci \n339 : 561 -567 , 2010 .20453633 \n11. Murthy SB , Izadyar S , Dhamne M , Kass JS , Goldsmith CE \nOsmotic demyelination syndrome: variable clinical and radiologic response to intravenous immunoglobulin therapy . Neurol Sci \n4 : 581 -584 , 2013 .\n12. Suzuki H , Sugimura Y , Iwama S , et al \nMinocycline prevents osmotic demyelination syndrome by inhibiting the activation of microglia . J Am Soc Nephrol \n12 : 2090 -2098 , 2010 .\n13. Köller H , Kieseier BC , Jander S , Hartung HP \nChronic inflammatory demyelinating polyneuropathy . N Engl J Med \n352 : 1343 -1356 , 2005 .15800230 \n14. Louis G , Megarbane B , Lavoué S , et al \nLong-term outcome of patients hospitalized in intensive care units with central or extrapontine myelinolysis . Crit Care Med \n40 : 970 -972 , 2012 .22036854\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "0918-2918",
"issue": "56(6)",
"journal": "Internal medicine (Tokyo, Japan)",
"keywords": null,
"medline_ta": "Intern Med",
"mesh_terms": "D000368:Aged; D003711:Demyelinating Diseases; D005260:Female; D006801:Humans; D007010:Hyponatremia; D010951:Plasma Exchange; D013577:Syndrome",
"nlm_unique_id": "9204241",
"other_id": null,
"pages": "733-736",
"pmc": null,
"pmid": "28321080",
"pubdate": "2017",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "25499401;22491911;21030598;22937357;24708786;7466381;19606078;24725751;10209986;20453633;15800230;22036854;8025225;23602191",
"title": "The Improvement of the Outcome of Osmotic Demyelination Syndrome by Plasma Exchange.",
"title_normalized": "the improvement of the outcome of osmotic demyelination syndrome by plasma exchange"
} | [
{
"companynumb": "JP-MYLANLABS-2017M1023752",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "VALSARTAN"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nAdults with attention-deficit/hyperactivity disorder (ADHD) are at increased risk for both cigarette smoking and being overweight or obese. Although smoking cessation tends to result in weight increase, potentially initiating or exacerbating weight problems, adults with ADHD who are treated with osmotic release oral system methylphenidate (OROS-MPH) tend to lose weight. It is unclear how the use of OROS-MPH during a smoking-cessation attempt might affect the typical weight gain that accompanies cessation.\n\n\nMETHODS\nWe examined changes in weight and hunger during a smoking-cessation attempt in 215 adults with ADHD who completed a multisite, randomized, controlled trial and were randomized to either OROS-MPH (n = 107) or placebo (n = 108) (NCT #00253747). Both groups also received open-label transdermal nicotine replacement and counseling.\n\n\nRESULTS\nParticipants who received OROS-MPH lost an average of 1.6% of their body weight during the 11-week study, whereas those who received placebo gained an average of 1.3% of their weight (p < .001). Hunger ratings were lower in the OROS-MPH group (M = 1.1, SD = 0.8) than in the placebo group (M = 1.6, SD = 0.9; p < .001).\n\n\nCONCLUSIONS\nThe use of OROS-MPH during a smoking-cessation attempt prevents weight gain in adults with ADHD who substantially reduce or quit smoking. The potential utility of OROS-MPH in individuals with ADHD who are attempting to quit smoking and for whom weight gain would be problematic warrants further research.",
"affiliations": "Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati College of Medicine, Cincinnati, OH 45219, USA. Jaimee.Heffner@uc.edu",
"authors": "Heffner|Jaimee L|JL|;Lewis|Daniel F|DF|;Winhusen|Theresa M|TM|",
"chemical_list": "D008774:Methylphenidate",
"country": "England",
"delete": false,
"doi": "10.1093/ntr/nts152",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1462-2203",
"issue": "15(2)",
"journal": "Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco",
"keywords": null,
"medline_ta": "Nicotine Tob Res",
"mesh_terms": "D000284:Administration, Oral; D000328:Adult; D001289:Attention Deficit Disorder with Hyperactivity; D005260:Female; D006801:Humans; D008297:Male; D008774:Methylphenidate; D008875:Middle Aged; D009995:Osmosis; D016540:Smoking Cessation; D015430:Weight Gain",
"nlm_unique_id": "9815751",
"other_id": null,
"pages": "583-7",
"pmc": null,
"pmid": "22955246",
"pubdate": "2013-02",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D052061:Research Support, N.I.H., Extramural",
"references": "16373066;3954551;17222450;1932883;20492837;16137833;2848472;20966369;12745503;9801011;19023824;10868768;10710848;16085513;9086692",
"title": "Osmotic release oral system methylphenidate prevents weight gain during a smoking-cessation attempt in adults with ADHD.",
"title_normalized": "osmotic release oral system methylphenidate prevents weight gain during a smoking cessation attempt in adults with adhd"
} | [
{
"companynumb": "US-JNJFOC-20130113959",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "NICOTINE"
},
"drugadditional": null,
"d... |
{
"abstract": "OBJECTIVE\nTo report a case of Klebsiella pneumoniae carbapenemase (KPC)-producing K pneumoniae ventriculitis successfully treated with dual intraventricular plus systemic antibiotic therapy.\n\n\nMETHODS\nA 43-year-old woman with a ventriculoperitoneal shunt was transferred from a nursing home with fever, altered mental status, and leukocytosis. She was found to have KPC-producing K pneumoniae ventriculitis. Combination intraventricular antibiotic therapy with colistin and gentamicin plus systemic colistin and amikacin led to the resolution of infection.\n\n\nCONCLUSIONS\nUtilization of intraventricular or intrathecal antibiotics has been described in the literature for multidrug resistant (MDR) Gram-negative central nervous system (CNS) infections; however, none of the cases were caused by a KPC-producing organism. Given the pathogenicity and limited treatment options for this resistant organism, we utilized intraventricular colistin 10 mg and intraventricular gentamicin 10 mg in combination with systemic colistin and amikacin. An extensive literature search revealed several case reports and case series of documented MDR Acinetobacter baumanii CNS infections successfully treated with intraventricular colistin or aminoglycoside therapy with good tolerability. Additionally, recent pharmacokinetic analyses suggest improved cerebrospinal fluid (CSF) concentrations with direct CNS antimicrobial administration in combination with systemic therapy. Although our patient's cerebral spinal fluid cultures were cleared with dual intraventricular plus systemic therapy, she continued to deteriorate clinically because of her comorbid conditions and required hospice admission.\n\n\nCONCLUSIONS\nThis describes the first reported case of KPC-producing K pneumoniae ventriculitis microbiologically cured based on negative blood and CSF cultures with a combination of intraventricular and systemic therapy.",
"affiliations": "Alexian Brothers Medical Center, Elk Grove Village, IL, USA.",
"authors": "Nevrekar|Sonia|S|;Cunningham|Kathleen C|KC|;Greathouse|Kasey M|KM|;Panos|Nicholas G|NG|",
"chemical_list": "D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D005839:Gentamicins; D000583:Amikacin; D001618:beta-Lactamases; C063912:carbapenemase; D003091:Colistin",
"country": "United States",
"delete": false,
"doi": "10.1177/1060028013510487",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1060-0280",
"issue": "48(2)",
"journal": "The Annals of pharmacotherapy",
"keywords": "Klebsiella pneumoniae carbapenemase (KPC); intraventricular antimicrobials; ventriculitis",
"medline_ta": "Ann Pharmacother",
"mesh_terms": "D000328:Adult; D000583:Amikacin; D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D058565:Cerebral Ventriculitis; D003091:Colistin; D005260:Female; D005839:Gentamicins; D006801:Humans; D057967:Infusions, Intraventricular; D007710:Klebsiella Infections; D007711:Klebsiella pneumoniae; D001618:beta-Lactamases",
"nlm_unique_id": "9203131",
"other_id": null,
"pages": "274-8",
"pmc": null,
"pmid": "24259634",
"pubdate": "2014-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Dual intraventricular plus systemic antibiotic therapy for the treatment of Klebsiella pneumoniae carbapenemase-producing Klebsiella pneumoniae ventriculitis.",
"title_normalized": "dual intraventricular plus systemic antibiotic therapy for the treatment of klebsiella pneumoniae carbapenemase producing klebsiella pneumoniae ventriculitis"
} | [
{
"companynumb": "US-BAXTER-2014BAX072386",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "VANCOMYCIN"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nMycophenolate mofetil (MMF) and tacrolimus (TAC) are more potent than conventional immunosuppressive drugs, i.e. azathioprine, cyclosporin and prednisolone, and may be associated with an increase in the incidence of infections in the post-transplantation (post-tx) period. The aim of this study was to determine if the use of either or both of MMF and TAC for immunosuppression in renal transplant recipients increases the prevalence or modifies the clinical presentation of tuberculosis (TB), when compared with conventional therapy.\n\n\nMETHODS\nThe medical records of 443 adult patients who received a kidney transplant between 1994 and 2002 were reviewed retrospectively. Comparisons were made between patients who had conventional immunosuppressive treatments (cyclosporin, azathioprine and prednisolone) or an alternative regimen (including MMF, TAC or both).\n\n\nRESULTS\nWe found 20 patients (4.5%) to have post-tx TB. There were 13 cases of TB (age 38.9+/-10.6 years) among 328 patients who received conventional immunosuppressants (group I) (4.0%) and seven cases (age 24.2+/-7.4 years) among 115 (6.1%) who received an alternative immunosuppressive regimen (group II) (P>0.05). The patients in group II were younger than the patients in group I (P = 0.002). A significantly higher number of patients in group II developed TB within the first 6 months post-tx (P = 0.042). However, there was no significant difference between the two groups regarding clinical and radiographic presentations or outcomes.\n\n\nCONCLUSIONS\nImmunosuppression with TAC or MMF is associated with the development of TB earlier in the post-tx period and in younger patients.",
"affiliations": "Ege University Medical School, Chest Diseases Department, 35100, Bornova, Izmir, Turkey.",
"authors": "Atasever|Alev|A|;Bacakoglu|Feza|F|;Toz|Huseyin|H|;Basoglu|Ozen Kacmaz|OK|;Duman|Soner|S|;Basak|Kemal|K|;Guzelant|Asuman|A|;Sayiner|Abdullah|A|",
"chemical_list": "D007166:Immunosuppressive Agents; D016572:Cyclosporine; D011239:Prednisolone; D009173:Mycophenolic Acid; D001379:Azathioprine; D016559:Tacrolimus",
"country": "England",
"delete": false,
"doi": "10.1093/ndt/gfh691",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0931-0509",
"issue": "20(4)",
"journal": "Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association",
"keywords": null,
"medline_ta": "Nephrol Dial Transplant",
"mesh_terms": "D000328:Adult; D001379:Azathioprine; D016572:Cyclosporine; D005260:Female; D006801:Humans; D007165:Immunosuppression Therapy; D007166:Immunosuppressive Agents; D016030:Kidney Transplantation; D008297:Male; D009173:Mycophenolic Acid; D011239:Prednisolone; D012189:Retrospective Studies; D016559:Tacrolimus; D014376:Tuberculosis",
"nlm_unique_id": "8706402",
"other_id": null,
"pages": "797-802",
"pmc": null,
"pmid": "15703207",
"pubdate": "2005-04",
"publication_types": "D003160:Comparative Study; D016428:Journal Article",
"references": null,
"title": "Tuberculosis in renal transplant recipients on various immunosuppressive regimens.",
"title_normalized": "tuberculosis in renal transplant recipients on various immunosuppressive regimens"
} | [
{
"companynumb": "TR-ROCHE-1943770",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MYCOPHENOLATE MOFETIL"
},
"drugadditional": "3",
... |
{
"abstract": "Ischaemic digital ulcers (DUs) are an indicator of the severity of the microangiopathy in patients with systemic sclerosis (SSc). DUs are a frequent complication, affecting about 50% of patients with SSc, and are often recurrent. In cross-sectional studies involving patients with SSc, the frequency of ischaemic DUs was 12-16% with a major impact on hand function and quality of life. Effective therapy for DUs remains elusive. Intravenous iloprost has been demonstrated to have a positive effect on healing of active DUs. Bosentan, an oral endothelin receptor antagonist, only showed a benefit in preventing the occurrence of new DUs. Despite limited evidence, recent guidelines have recommended phosphodiesterase type 5 inhibitors as an option. Injection of botulinum toxin and digital sympathectomy have been increasingly used for ischaemic DUs. Here we present the complex case of a SSc patient already treated with sildenafil and bosentan in whom an active DU was successfully treated with botulinum toxin A. Despite the lack of a randomised controlled trial, results are encouraging for the use of botulinum toxin in the treatment of DUs and could perhaps help to avoid some amputations, as in the present case.",
"affiliations": "Vascular Medicine Department, Grenoble University Hospital, Grenoble, France.;UMR 1042-HP2, INSERM and University Grenoble-Alpes, Grenoble, France.;Hand Surgery Department, Grenoble Alps University Hospital, Grenoble, France.;Vascular Medicine Department, Grenoble University Hospital, Grenoble, France.;UMR 1042-HP2, INSERM and University Grenoble-Alpes, Grenoble, France.",
"authors": "Blaise|Sophie|S|;Roustit|Matthieu|M|;Forli|Alexandra|A|;Imbert|Bernard|B|;Cracowski|Jean-Luc|JL|",
"chemical_list": "D058986:Phosphodiesterase 5 Inhibitors; D013449:Sulfonamides; D000068677:Sildenafil Citrate; D019274:Botulinum Toxins, Type A; D016285:Iloprost; D000077300:Bosentan",
"country": "England",
"delete": false,
"doi": "10.1111/iwj.12742",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1742-4801",
"issue": "14(6)",
"journal": "International wound journal",
"keywords": "Botulinum toxin A; Digital ulcer; Raynaud phenomenon; Systemic sclerosis; Therapeutic",
"medline_ta": "Int Wound J",
"mesh_terms": "D061605:Administration, Intravenous; D000284:Administration, Oral; D000077300:Bosentan; D019274:Botulinum Toxins, Type A; D003430:Cross-Sectional Studies; D005260:Female; D005385:Fingers; D006801:Humans; D016285:Iloprost; D008875:Middle Aged; D058986:Phosphodiesterase 5 Inhibitors; D012595:Scleroderma, Systemic; D000068677:Sildenafil Citrate; D012883:Skin Ulcer; D013449:Sulfonamides; D016896:Treatment Outcome; D014945:Wound Healing",
"nlm_unique_id": "101230907",
"other_id": null,
"pages": "978-981",
"pmc": null,
"pmid": "28303689",
"pubdate": "2017-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "17985402;22247218;19487271;27478469;22204894;24369360;24124825;27941129;26173902;25995322",
"title": "Non-healing ischaemic digital ulcer in a systemic sclerosis patient: a challenging clinical case.",
"title_normalized": "non healing ischaemic digital ulcer in a systemic sclerosis patient a challenging clinical case"
} | [
{
"companynumb": "FR-ACTELION-A-CH2017-151459",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "BOSENTAN"
},
"drugadditional": null,
... |
{
"abstract": "Serotonin syndrome, characterized by autonomic, neuromuscular, and mental status changes, is an uncommon but well-established risk of psychotropic medications. The presentation can be highly variable, especially when triggered by agents with effects on additional neurotransmitters.1 The presence of a nonspecific prodrome has been reported but poorly characterized and can lead to misattribution of symptoms.2 We describe a case of serotonin syndrome with insidious onset in a boy treated with multiple medications for behavioral dysregulation.",
"affiliations": "Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York. Electronic address: lhutchis@montefiore.org.;Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York.;Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York.",
"authors": "Hutchison|Lisa|L|;Clark|Meredith|M|;Shaffer|Scott|S|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.jaac.2020.08.439",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0890-8567",
"issue": "60(2)",
"journal": "Journal of the American Academy of Child and Adolescent Psychiatry",
"keywords": null,
"medline_ta": "J Am Acad Child Adolesc Psychiatry",
"mesh_terms": "D002648:Child; D006801:Humans; D008297:Male; D001523:Mental Disorders; D020230:Serotonin Syndrome",
"nlm_unique_id": "8704565",
"other_id": null,
"pages": "201-202",
"pmc": null,
"pmid": "32949713",
"pubdate": "2021-02",
"publication_types": "D002363:Case Reports; D016422:Letter",
"references": null,
"title": "Insidious Onset of Serotonin Syndrome in a 6-Year-Old Boy.",
"title_normalized": "insidious onset of serotonin syndrome in a 6 year old boy"
} | [
{
"companynumb": "US-OTSUKA-2021_023807",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ARIPIPRAZOLE"
},
"drugadditional": "3",
... |
{
"abstract": "This case series describes three children with chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS), an inflammatory condition characterized by a relapsing-remitting disease course responsive to steroids. The patients (two males, age 3y and 13y; one female, age 14y) presented with ataxia, dysarthria, and multiple cranial neuropathies. All patients demonstrated bilateral nodular lesions with contrast enhancement in the brainstem and cerebellum on magnetic resonance imaging, and perivascular lymphocytes and macrophages infiltrates on brain biopsies. Despite an initially good response to corticosteroids, all patients eventually became steroid-dependent or -resistant, with frequent relapses on maintenance immunosuppressive therapy. Natalizumab and intravenous immunoglobulin stopped neurological disease progression in Patient 1 but he died at 17 years from respiratory complications. Patient 2 went into remission on infliximab and intravenous methylprednisolone for several months but was then diagnosed with Epstein-Barr virus driven B-cell lymphoma 3 years after symptom onset. Patient 3 failed to respond to treatment and died 4 years after diagnosis. CLIPPERS disease in children is aggressive, with poor response to immunotherapy. Earlier use of newer immunotherapeutic agents such as natalizumab may be beneficial. Potential side effects need to be considered carefully. WHAT THIS PAPER ADDS: Paediatric chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) appears a more severe condition than previously reported in adults. Aggressive treatment before neuroaxonal loss may be required for a better outcome.",
"affiliations": "Paediatric Neurology, Great Ormond Street Hospital for Children, London, UK.;Department of Paediatric Neurology, Leeds Teaching Hospitals NHS Trust, Leeds, UK.;Paediatric Neurology, Great Ormond Street Hospital for Children, London, UK.;Neuroradiology Department, Great Ormond Street Hospital for Children, London, UK.;Department of Histopathology, Great Ormond Street Hospital for Children, London, UK.;Department of Paediatric Neurology, St Georges Healthcare NHS Trust, London, UK.;Department of Paediatric Neurology, Leeds Teaching Hospitals NHS Trust, Leeds, UK.;Children's Neurosciences, Evelina London Children's Hospital at Guy's and St Thomas' NHS Foundation Trust, King's Health Partners Academic Health Science Centre, London, UK.;Paediatric Neurology, Great Ormond Street Hospital for Children, London, UK.;Paediatric Neurology, Great Ormond Street Hospital for Children, London, UK.",
"authors": "Sa|Mario|M|0000-0001-7555-1040;Green|Lydia|L|;Abdel-Mannan|Omar|O|;Chong|W K Kling|WKK|;Jacques|Thomas|T|;Clarke|Antonia|A|;Childs|Anne-Marie|AM|;Lim|Ming|M|;Hemingway|Cheryl|C|;Hacohen|Yael|Y|0000-0001-8490-9657",
"chemical_list": "D005938:Glucocorticoids; D008775:Methylprednisolone",
"country": "England",
"delete": false,
"doi": "10.1111/dmcn.13997",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0012-1622",
"issue": "61(4)",
"journal": "Developmental medicine and child neurology",
"keywords": null,
"medline_ta": "Dev Med Child Neurol",
"mesh_terms": "D000293:Adolescent; D000367:Age Factors; D002675:Child, Preschool; D002908:Chronic Disease; D004660:Encephalitis; D005260:Female; D005938:Glucocorticoids; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008775:Methylprednisolone; D011149:Pons",
"nlm_unique_id": "0006761",
"other_id": null,
"pages": "490-496",
"pmc": null,
"pmid": "30146710",
"pubdate": "2019-04",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Is chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) in children the same condition as in adults?",
"title_normalized": "is chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids clippers in children the same condition as in adults"
} | [
{
"companynumb": "GB-VISTAPHARM, INC.-VER201905-000236",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
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"activesubstancename": "AZATHIOPRINE"
},
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{
"abstract": "Treating patients with hemophilia and inhibitors is often problematic. The presence of inhibitors negatively impacts the effectiveness of treatment to achieve hemostasis especially in patients with hemophilia B, owing mainly to allergic reactions to factor IX (FIX) concentrates and the low success rate of immune tolerance therapy. A 9-month-old boy had intracranial hemorrhage and was diagnosed with hemophilia B. After replacement therapy, he developed inhibitors and an allergic reaction to FIX. Prophylactic therapy was initiated with recombinant activated factor VII (rFVIIa) and later switched to pdFVIIa/factor X (FX; 120 μg/kg as the FVII dose, every other day) because of a recurrence of intracranial hemorrhage. Since then, he remained well without life-threatening bleeding for more than 2 years. Our case suggests that pdFVIIa/FX may be useful for prophylactic therapy in hemophilia B complicated by inhibitors and allergic reaction to FIX concentrates.",
"affiliations": "Department of Hematology and Oncology, Nagano Children's Hospital, Azumino, Japan.;Department of Hematology and Oncology, Nagano Children's Hospital, Azumino, Japan.;Department of Hematology and Oncology, Nagano Children's Hospital, Azumino, Japan.;Department of Pediatrics, St. Marianna University School of Medicine Yokohama City Seibu Hospital, Yokohama, Japan.;Department of Hematology and Oncology, Nagano Children's Hospital, Azumino, Japan, sakasita@shinshu-u.ac.jp.",
"authors": "Uchida|Eriko|E|;Komori|Kazutoshi|K|;Kurata|Takashi|T|;Taki|Masashi|M|;Sakashita|Kazuo|K|",
"chemical_list": "D019774:Blood Coagulation Factor Inhibitors; D005164:Factor IX; D005170:Factor X; D015942:Factor VIIa",
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000508722",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0001-5792",
"issue": "144(3)",
"journal": "Acta haematologica",
"keywords": "Blood coagulation factor inhibitors; Factor VIIa; Factor X; Hemophilia B; Prophylaxis",
"medline_ta": "Acta Haematol",
"mesh_terms": "D019774:Blood Coagulation Factor Inhibitors; D005164:Factor IX; D015942:Factor VIIa; D005170:Factor X; D002836:Hemophilia B; D006470:Hemorrhage; D006801:Humans; D006967:Hypersensitivity; D007223:Infant; D008297:Male; D020641:Polymorphism, Single Nucleotide; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "0141053",
"other_id": null,
"pages": "293-296",
"pmc": null,
"pmid": "32702700",
"pubdate": "2021",
"publication_types": "D002363:Case Reports; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Prophylaxis Using a Mixture of Plasma-Derived Activated Factor VII and Factor X (pdFVIIa/FX) in a Patient with Hemophilia B Complicated by Inhibitors and Allergy to Factor IX Concentrates: A Case Report.",
"title_normalized": "prophylaxis using a mixture of plasma derived activated factor vii and factor x pdfviia fx in a patient with hemophilia b complicated by inhibitors and allergy to factor ix concentrates a case report"
} | [
{
"companynumb": "JP-PFIZER INC-202101407894",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "COAGULATION FACTOR IX RECOMBINANT HUMAN\\ISOPROPYL ALCOHOL"
... |
{
"abstract": "OBJECTIVE\nDrug-induced autoimmune hepatitis (DIAIH) remains poorly characterized. Our aim was to assess natural history and outcomes in DIAIH.\n\n\nMETHODS\nThis was a retrospective cohort study.\n\n\nRESULTS\nEighty-two patients with autoimmune hepatitis (AIH) were identified, 11 (13.4%) with DIAIH, implicated drugs being nitrofurantoin (n = 4), statins (n = 4), herbal remedies (n = 2) and diclofenac (n = 1). Female sex, acute onset, elevated serum globulins/immunoglobulin G, fibrosis stage (Ishak), cirrhosis at onset, moderate-severe portal inflammation, interface and lobular hepatitis, remission, relapse and poor outcome were similar in those with DIAIH and AIH (P > 0.05). The former were however more likely to be aged 60 years or more and take longer to relapse on immunosuppression discontinuation (P = <0.05). On Kaplan-Meier analysis, probability of poor outcome was similar in those with DIAIH and AIH (log-rank test, 0.339). On comparing those with (n = 4) and without nitrofurantoin (n = 7) DIAIH, the former were older, had longer duration of drug use prior to DIAIH diagnosis, higher fibrosis stage and were less likely to relapse upon immunosuppression discontinuation.\n\n\nCONCLUSIONS\nApproximately 15% of patients with AIH have DIAIH with similar outcomes, although the latter are older with a propensity for late relapse, mandating long-term follow up.",
"affiliations": "Departments of Medicine, Brighton and Sussex Medical School, Brighton, UK.;Department of Gastroenterology and Hepatology, Brighton and Sussex University Hospital, Brighton, UK.;Clinical and Investigation Research Unit, Brighton and Sussex University Hospital, Brighton, UK.;Department of Gastroenterology and Hepatology, Brighton and Sussex University Hospital, Brighton, UK.;Departments of Medicine, Brighton and Sussex Medical School, Brighton, UK.",
"authors": "Yeong|Tian T|TT|;Lim|Kok H J|KH|;Goubet|Stephanie|S|;Parnell|Nick|N|;Verma|Sumita|S|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1111/hepr.12532",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1386-6346",
"issue": "46(3)",
"journal": "Hepatology research : the official journal of the Japan Society of Hepatology",
"keywords": "drug-induced liver injury; herbal remedies; nitrofurantoin; statins",
"medline_ta": "Hepatol Res",
"mesh_terms": null,
"nlm_unique_id": "9711801",
"other_id": null,
"pages": "E79-88",
"pmc": null,
"pmid": "25943838",
"pubdate": "2016-03",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Natural history and outcomes in drug-induced autoimmune hepatitis.",
"title_normalized": "natural history and outcomes in drug induced autoimmune hepatitis"
} | [
{
"companynumb": "GB-BAUSCH-BL-2016-010090",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DICLOFENAC"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nOral mucositis is a common complication in pediatric cancer patients, affecting up to 80% of children. Due to neutropenia and disruption of the mucosal barrier, chemotherapy-induced oral mucositis is often complicated by super-infections.\n\n\nMETHODS\nA 16-years old male with stage 3 Burkitt's lymphoma developed chemotherapy induced oral mucositis grade 3 (according to WHO scale). Ulcers were quickly growing (reaching a maximum diameter of 3 cm) and became greyish in colour, resulting in dysphagia and pain. A swab of the lesions was taken and microbiological tests were performed. The sample grew for Raoultella planticola, an encapsulated Gram-negative bacterium whose full pathogenic potential still needs to be defined.\n\n\nMETHODS\nThe patient received antibiotic combination therapy with Amikacin and Ceftazidime for 8 days. Complete healing of the lesions and resolution of the symptoms were reached and he completed his antineoplastic therapy without further complications.\n\n\nRESULTS\nTwelve months after the infection, he is alive and well, with no oral complaints.\n\n\nCONCLUSIONS\nThis is the first report of a Raoultella planticola infection in a patient with chemotherapy induced oral mucositis. This type of infection must be added to the list of organisms to be considered when caring for these patients.",
"affiliations": "Department Oral Medicine and Paediatric Dentistry, Dental Clinic, University of Brescia, p.le Spedali Civili n.1, 25133, Brescia, Italy. elena.bardellini@unibs.it.;Department Oral Medicine and Paediatric Dentistry, Dental Clinic, University of Brescia, p.le Spedali Civili n.1, 25133, Brescia, Italy.;Paediatric Haematology-Oncology Unit, Spedali Civili di Brescia, Brescia, Italy.;Microbiology Department, Spedali Civili di Brescia, Brescia, Italy.;Department Oral Medicine and Paediatric Dentistry, Dental Clinic, University of Brescia, p.le Spedali Civili n.1, 25133, Brescia, Italy.",
"authors": "Bardellini|E|E|;Amadori|F|F|;Schumacher|R F|RF|;Foresti|I|I|;Majorana|A|A|",
"chemical_list": "D000900:Anti-Bacterial Agents; D000583:Amikacin; D002442:Ceftazidime",
"country": "England",
"delete": false,
"doi": "10.1007/s40368-017-0279-7",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1818-6300",
"issue": "18(3)",
"journal": "European archives of paediatric dentistry : official journal of the European Academy of Paediatric Dentistry",
"keywords": "Anti-neoplastic agents; Infection; Oral ulcer",
"medline_ta": "Eur Arch Paediatr Dent",
"mesh_terms": "D000293:Adolescent; D000583:Amikacin; D000900:Anti-Bacterial Agents; D002051:Burkitt Lymphoma; D002442:Ceftazidime; D004359:Drug Therapy, Combination; D004755:Enterobacteriaceae; D004756:Enterobacteriaceae Infections; D006801:Humans; D008297:Male; D013280:Stomatitis",
"nlm_unique_id": "101277157",
"other_id": null,
"pages": "215-218",
"pmc": null,
"pmid": "28349509",
"pubdate": "2017-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "22423899;20811592;10747132;22096135;17446297;14508842;11411716;22802099;23574552;6143213;20053705;26770234;25285133;23750582;9666015;15108222;23975584;24902523",
"title": "A new emerging oral infection: Raoultella planticola in a boy with haematological malignancy.",
"title_normalized": "a new emerging oral infection raoultella planticola in a boy with haematological malignancy"
} | [
{
"companynumb": "IT-ACCORD-068206",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "IFOSFAMIDE"
},
"drugadditional": null,
"drug... |
{
"abstract": "Ivermectin is safe and widely used for treating helminth infections. It also kills arthropods feeding on treated subjects, including malaria vectors. Thus, ivermectin mass drug administration as an additional tool for malaria control is being evaluated by WHO. As in vitro data, animal experiments and epidemiological observations suggest that ivermectin has a direct effect on the liver stages of the malaria parasite, this study was designed to assess the prophylactic effect of ivermectin on Plasmodium falciparum controlled human malaria infection.\n\n\n\nA total of 4 volunteers were randomised to placebo, and 8 volunteers were randomised to receive ivermectin 0.4 mg/kg, orally, once 2 h before being experimentally infected intravenously with 3200 P. falciparum sporozoites. The primary endpoint was time to parasitaemia detected by positive thick blood smear; RT-qPCR was performed in parallel.\n\n\n\nAll but one volunteer became thick blood smear positive between day 11 and day 12 after infection, and there was no significant effect of ivermectin on parasitaemia.\n\n\n\nIvermectin - at the dose used - has no clinically relevant activity against the pre-erythrocytic stages of P. falciparum.",
"affiliations": "Institute for Tropical Medicine, German Center for Infection Research, Tübingen, Germany.;Institute for Tropical Medicine, German Center for Infection Research, Tübingen, Germany.;Institute for Tropical Medicine, German Center for Infection Research, Tübingen, Germany.;Institute for Tropical Medicine, German Center for Infection Research, Tübingen, Germany.;Institute for Tropical Medicine, German Center for Infection Research, Tübingen, Germany.;Institute for Tropical Medicine, German Center for Infection Research, Tübingen, Germany.;Institute for Tropical Medicine, German Center for Infection Research, Tübingen, Germany.;Institute for Tropical Medicine, German Center for Infection Research, Tübingen, Germany.;Institute for Tropical Medicine, German Center for Infection Research, Tübingen, Germany.;Institute for Tropical Medicine, German Center for Infection Research, Tübingen, Germany.;Institute for Tropical Medicine, German Center for Infection Research, Tübingen, Germany.;Sanaria Inc., Rockville, MD, USA.;Sanaria Inc., Rockville, MD, USA.;Instituto de Salud Global, Barcelona, Spain.;Instituto de Salud Global, Barcelona, Spain.;Instituto de Salud Global, Barcelona, Spain.;Institute for Tropical Medicine, German Center for Infection Research, Tübingen, Germany.;Institute for Tropical Medicine, German Center for Infection Research, Tübingen, Germany.",
"authors": "Metzger|Wolfram G|WG|;Theurer|Antje|A|;Pfleiderer|Anne|A|;Molnar|Zsofia|Z|;Maihöfer-Braatting|Ditte|D|;Bissinger|Alfred L|AL|;Sulyok|Zita|Z|;Köhler|Carsten|C|;Egger-Adam|Diane|D|;Lalremruata|Albert|A|;Esen|Meral|M|;Lee Sim|Kim|K|;Hoffman|Stephen|S|;Rabinovich|Regina|R|;Chaccour|Carlos|C|;Alonso|Pedro|P|;Mordmüller|Benjamin G|BG|;Kremsner|Peter G|PG|",
"chemical_list": "D000962:Antimalarials; D007559:Ivermectin",
"country": "England",
"delete": false,
"doi": "10.1111/tmi.13357",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1360-2276",
"issue": "25(3)",
"journal": "Tropical medicine & international health : TM & IH",
"keywords": "Malaria; controlled human malaria infection; infection contrôlée du paludisme humain; ivermectin; ivermectine; malaria; paludisme",
"medline_ta": "Trop Med Int Health",
"mesh_terms": "D000328:Adult; D000962:Antimalarials; D005260:Female; D006801:Humans; D007559:Ivermectin; D016778:Malaria, Falciparum; D008297:Male; D000074381:Mass Drug Administration; D010963:Plasmodium falciparum; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "9610576",
"other_id": null,
"pages": "380-386",
"pmc": null,
"pmid": "31808594",
"pubdate": "2020-03",
"publication_types": "D016428:Journal Article; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Ivermectin for causal malaria prophylaxis: a randomised controlled human infection trial.",
"title_normalized": "ivermectin for causal malaria prophylaxis a randomised controlled human infection trial"
} | [
{
"companynumb": "DE-MYLANLABS-2020M1041839",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ATOVAQUONE\\PROGUANIL"
},
"drugadditional": "... |
{
"abstract": "Staphylococcal scalded skin syndrome is a condition which predominantly affects children and causes a spectrum of skin lesions. We present a case of a 2-month-old infant with complaints of fever and fragile blisters over the body. The mucosal areas were spared. The diagnosis of staphylococcal scalded skin syndrome was reached on clinical grounds and culture report. The patient responded well to the treatment, which included an antibiotic (cloxacillin), an analgesic (paracetamol), and hydration with intravenous fluids. He was discharged after 8 days, with almost complete resolution of his skin lesions. Having a high clinical suspicion for staphylococcal scalded skin syndrome, early diagnosis/treatment, and following robust hygiene measures are imperative for the effective management of staphylococcal scalded skin syndrome. More efforts are needed to develop novel therapies for staphylococcal scalded skin syndrome.",
"affiliations": "Department of Pharmacology, Postgraduate Institute of Medical Education and Research, Dr. Ram Manohar Lohia Hospital, New Delhi, India.;Department of Radiology, The University of Texas Health Science Center, San Antonio, TX, USA.;Department of Pediatrics, Richmond University Medical Center, Staten Island, NY, USA.",
"authors": "Meshram|Girish Gulab|GG|;Kaur|Neeraj|N|;Hura|Kanwaljeet Singh|KS|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1177/2050313X17750890",
"fulltext": "\n==== Front\nSAGE Open Med Case RepSAGE Open Med Case RepSCOspscoSAGE Open Medical Case Reports2050-313XSAGE Publications Sage UK: London, England 10.1177/2050313X1775089010.1177_2050313X17750890Case ReportStaphylococcal scalded skin syndrome: A pediatric dermatology case report Meshram Girish Gulab 1Kaur Neeraj 2Hura Kanwaljeet Singh 31 Department of Pharmacology, Postgraduate Institute of Medical Education and Research, Dr. Ram Manohar Lohia Hospital, New Delhi, India2 Department of Radiology, The University of Texas Health Science Center, San Antonio, TX, USA3 Department of Pediatrics, Richmond University Medical Center, Staten Island, NY, USAGirish Gulab Meshram, Department of Pharmacology, Postgraduate Institute of Medical Education and Research, Dr. Ram Manohar Lohia Hospital, New Delhi 110001, India. Email: drgirish23@yahoo.co.in04 1 2018 2018 6 2050313X1775089016 3 2017 30 11 2017 © The Author(s) 20182018SAGE PublicationsThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (http://www.creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).Staphylococcal scalded skin syndrome is a condition which predominantly affects children and causes a spectrum of skin lesions. We present a case of a 2-month-old infant with complaints of fever and fragile blisters over the body. The mucosal areas were spared. The diagnosis of staphylococcal scalded skin syndrome was reached on clinical grounds and culture report. The patient responded well to the treatment, which included an antibiotic (cloxacillin), an analgesic (paracetamol), and hydration with intravenous fluids. He was discharged after 8 days, with almost complete resolution of his skin lesions. Having a high clinical suspicion for staphylococcal scalded skin syndrome, early diagnosis/treatment, and following robust hygiene measures are imperative for the effective management of staphylococcal scalded skin syndrome. More efforts are needed to develop novel therapies for staphylococcal scalded skin syndrome.\n\nStaphylococcal scalded skin syndromedesmoglein-1superficial blisterscover-dateJanuary-December 2018\n==== Body\nIntroduction\nStaphylococcal scalded skin syndrome (SSSS) is a rare disorder with clinical features varying from superficial localized blisters to generalized exfoliation.1 The epidermolytic toxins (ETs) released by Staphylococcus aureus, particularly ETA and ETB, are thought to lyse desmoglein-1, present on desmosomes located in the strata granulosum of the epidermis, causing a loss of cell-to-cell adhesion between the keratinocytes, finally leading to intraepidermal splitting.2 SSSS predominantly affects neonates of 3–15 days of age, children less than 5 years of life, and adults with various comorbidities.3 We present a case of a 2-month-old infant with SSSS, emphasizing the role of early diagnosis/treatment and discussing the latest developments in the field.\n\nCase report\nA 2-month-old infant was presented to the pediatric outpatient department with erythematous blisters near the nose and mouth. The child was irritable and afebrile at that point of time. Systemic examination of the infant appeared unremarkable. The baby was born via normal vaginal home delivery, conducted by a traditional birth attendant of the village. Hence, Apgar scores at birth were not known. The mother was a primigravida and had no history of consumption of any drug during the past few months, except for iron and folic acid tablets. There was no history in the family of any blistering diseases. The HIV test was negative. Immunizations were complete for his age.\n\nWithin 24 h of admission, the infant developed a mild-grade fever; diffuse erythroderma; blisters on the chest, axilla, and gluteal region, which ruptured with minimal pressure; and desquamation of the skin. The lesions encompassed around 20% of his body area. Nikolsky’s sign was positive. The mucosa of the mouth and pharynx was not affected. The conjunctiva of both eyes did not show any signs of inflammation. At this point, the infant grew more irritable, refused to feed, and developed tachycardia (Figure 1). A diagnosis of SSSS was reached based on the history and clinical features. A skin biopsy was not requested as the clinical features were consistent with the diagnosis.\n\nFigure 1. 2-month-old infant with diffuse erythema and fragile blisters on the face, neck, and chest. Povidone-iodine ointment is applied on the blisters.\n\nAn intravenous (IV) catheter was introduced for the infusion of IV fluids. Parental cloxacillin 25 mg/kg/day in divided doses for every 6 h was initiated. Paracetamol was used for countering the fever and pain. The skin lesions were covered with sterile gauze dressings. Povidone-iodine ointment was applied on the blisters on the face (Figure 1). The blood counts were within the normal range. Prior initiating antibiotic therapy, cultures were obtained from the blood, nasopharynx, conjunctivae, umbilical stump, and skin lesions. The nasopharyngeal culture report, as obtained after 2 days, showed the growth of methicillin-sensitive Staphylococcus aureus (MSSA). Cultures from other sites were sterile. Meanwhile, the patient seemed to be responding well to the antibiotic as the desquamation had halted. After 8 days of therapy, the erythroderma completely resolved, and the skin lesions were healing with incrustations. The patient was subsequently discharged.\n\nIn order to identify the source of the MSSA strain, nasal swabs for microbiological cultures were collected from the parents of the child. However, their culture reports turned out to be negative for MSSA. The traditional birth attendant, who had conducted the delivery, could not be contacted for collecting culture samples. Immunofluorescence and genetic studies, in order to detect ET toxins and ET genes, were not performed due to the lack of material in our hospital setting.\n\nDiscussion\nSSSS is a rare disease with an incidence between 0.09 and 0.56 cases/ million.4 An infection with Staphylococcus aureus usually precedes SSSS. Staphylococcus aureus releases numerous toxins, which spread hematogenously from the locus of infection. Two ETs, particularly ETA and ETB, have been found to have an affinity toward the glycoprotein, desmoglein-1, present on desmosomes located in the zona granulosa layer of the skin. ETA and ETB lyse desmoglein-1, thereby destroying the cell-to-cell adhesion between the keratinocytes, leading to epidermolysis.1,2\n\nNeonates and children are at a higher risk for SSSS due to their undeveloped immune system to produce antibodies against the ETs and their inadequate renal capacity to excrete the pathogenic toxins.1,3 Similarly, immunocompromised adults or adults with renal diseases show a higher incidence of SSSS.4\n\nThe clinical features of SSSS comprise a prodromal phase in which there maybe fever and the child may become irritable. This is followed by the appearance of erythematous patches over the body, on which large superficial fragile blisters develop. When these blisters rupture, the skin appears reddish and scalded.1,3–5 All of these clinical features were observed in our patient.\n\nUsually, the diagnosis of SSSS is reached clinically with the help of culture reports, as we did in our case. However, if in doubt, diagnosis can be confirmed via skin biopsy, which shows intraepidermal cleavage without necrosis.4 Also, phage typing the Staphylococcus aureus is found to be useful, as almost 80% of the strains of Staphylococcus aureus causing SSSS belong to phage group II.3 Other sparingly used diagnostic tools are techniques measuring the titers of the ETs and isolating their gene sequences.1\n\nThe conditions which we considered in our differential diagnosis were toxic epidermal necrolysis (TEN) and bullous impetigo. A history of drug intake usually precedes TEN. The blistering skin lesions of TEN encompass more than 30% of the body surface area. Also, mucous membranes of the conjunctiva, mouth, trachea, esophagus, anus, and genitalia are involved.4,5 These features were absent in our patient. In bullous impetigo, a localized form of SSSS, the blistering lesions are restricted to the area of the skin infection. Also, cultures from the skin lesions produce growth of Staphylococcus aureus in bullous impetigo, which was not found in our case.4,5 All these points favored the diagnosis of SSSS.\n\nAs most strains of Staphylococcus aureus causing SSSS are methicillin-sensitive, penicillinase-resistant beta-lactam agents such as cloxacillin, dicloxacillin, oxacillin, flucloxacillin, and nafcillin are the first-line antibiotics. If the patient is not responding to these agents, then methicillin-resistant strains of Staphylococcus aureus (MRSA) should be suspected, for which vancomycin is the drug of choice. Topical therapy should constitute either fusidic acid and/or mupirocin as adjunct therapy at the site of blisters in an attempt to eradicate colonization. Exposed, damaged areas can be treated with emollients which sooth and moisturize the skin. Other important aspects to be addressed in the management of SSSS are temperature regulation, fluid resuscitation, analgesia, sterile dressing of the lesions, and prevention of secondary infections. Paracetamol is the analgesic of choice in cases of SSSS. Corticosteroids are contraindicated as they worsen the disease. With early diagnosis and management, mortality rate of SSSS is lower than 4% in children, and most skin lesions resolve by 2 weeks, as found in our patient.1,3–6\n\nHealthcare attendants and mothers, serving as asymptomatic carriers of Staphylococcus aureus, have been reported to be the source of several outbreaks of SSSS in pediatric units. Also, healthcare professionals, handling patients with SSSS, have been found to cross-contaminate other patients admitted in the unit.7 Hence, following robust hygiene measures, while treating SSSS patients and identifying/isolating suspected carriers at the earliest, is recommended to avert such outbreaks.\n\nWith the rise of MRSA strains and increase in the mortality rate of SSSS, some newer therapies have been investigated by researchers. Infusion of fresh frozen plasma (FFP) obtained from adults into children with SSSS has been found to be successful in a pediatric report. The use of FFP in SSSS is based on the buttress that adults more than 40 years develop antibodies against the causative ETs of SSSS.8 Also, infusion of IV immunoglobulins has been suggested to antagonize the ETs causing SSSS.9 Use of laxatives in order to excrete the pathogenic toxins of Staphylococcus aureus has been suggested in one report.10 There are reports suggesting better patient outcomes following the use of artificial skin substitutes over conventional sterile gauze dressings.11 However, there have been no clinical trials conducted to authenticate the abovementioned therapies. Although, theoretically developing desmoglein-1 antitoxins/analogues to antagonize the ETs causing SSSS should show superior results, no clinical or experimental studies exploring this therapy are available in the literature.1,12 Vaccines targeting Staphylococcus aureus have failed in the Phase III of clinical trials and face considerable hurdles in their development.13\n\nConclusion\nIn conclusion, although most cases of SSSS respond well to conventional therapy, it is a potentially fatal condition. Hence, early diagnosis, prompt treatment, and following robust hygiene measures are imperative for its successful management. More efforts are required to develop novel effective therapies for SSSS.\n\nDeclaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.\n\nEthical approval: Our institutions do not require ethical approval for reporting individual cases or case series.\n\nFunding: The author(s) received no financial support for the research, authorship, and/or publication of this article.\n\nInformed consent: Written informed consent was obtained from the legally authorized representative(s) for anonymized patient information to be published in this article.\n==== Refs\nReferences\n1 \nLadhani S \nRecent developments in staphylococcal scalded skin syndrome . Clin Microbiol Infect \n2001 ; 7 : 301 –307 .11442563 \n2 \nAmagai M Matsuyosih N Wang ZH et al \nToxin in bullous impetigo and staphylococcal scalded-skin syndrome targets desmoglein 1 . Nat Med \n2000 ; 6 : 1275 –1277 .11062541 \n3 \nLadhani S Evans RW \nStaphylococcal scalded skin syndrome . Arch Dis Child \n1998 ; 78 : 85 –88 .9534685 \n4 \nHandler MZ Schwartz RA \nStaphylococcal scalded skin syndrome: diagnosis and management in children and adults . J Eur Acad Dermatol Venereol \n2014 ; 28 : 1418 –1423 .24841497 \n5 \nPatel GK Finlay AY \nStaphylococcal scalded skin syndrome: diagnosis and management . Am J Clin Dermatol \n2003 ; 4 : 165 –175 .12627992 \n6 \nLamanna O Bongiorno D Bertoncello L et al \nRapid containment of nosocomial transmission of a rare community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) clone, responsible for the staphylococcal scalded skin syndrome (SSSS) . Ital J Pediatr \n2017 ; 43 : 5 .28061866 \n7 \nDavidson J Polly S Hayes PJ et al \nRecurrent staphylococcal scalded skin syndrome in an extremely low-birth-weight neonate . AJP Rep \n2017 ; 7 : e134 –e137 .28674637 \n8 \nTenenbaum T Hoehn T Hadzik B et al \nExchange transfusion in a preterm infant with hyperbilirubinemia, staphylococcal scalded skin syndrome (SSSS) and sepsis . Eur J Pediatr \n2007 ; 166 : 733 –735 .17109167 \n9 \nTakei S Arora YK Walker SM \nIntravenous immunoglobulin contains specific antibodies inhibitory to activation of T cells by staphylococcal toxin superantigens . J Clin Invest \n1993 ; 91 : 602 –607 .8432865 \n10 \nAydin D Alsbjorn B \nSevere case of staphylococcal scalded skin syndrome in a 5 -year-old child—case report . Clin Case Rep \n2016 ; 4 : 416 –419 .27099742 \n11 \nBartmans MG Dokter J den Hollander JC et al \nUse of skin substitute dressings in the treatment of staphylococcal scalded skin syndrome in neonates and young infants . Neonatology \n2011 ; 100 : 9 –13 .21150225 \n12 \nKong C Neoh H Nath S \nTargeting Staphylococcus aureus toxins: a potential form of anti-virulence therapy . Toxins \n2016 ; 8 : 72 .\n13 \nKurlenda J Grinholc M \nAlternative therapies in Staphylococcus aureus diseases . Acta Biochim Pol \n2012 ; 59 : 171 –184 .22577619\n\n",
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"abstract": "Embolization coil migration to the gastrointestinal tract is a rare complication. This report describes our experience of coil migration in the stomach and spontaneous excretion. A 77-year-old man, who was diagnosed with esophageal squamous cell carcinoma with multiple lymph node metastases, had a bleeding left gastric artery and splenic artery pseudoaneurysm associated with an abdominal lymph node mass, that was treated by coil embolization, after which the coil migrated into the stomach. Because there were no complications such as active bleeding or peritonitis, our patient was followed carefully, and excretion of the coil was documented. No standard management exists for migrated coils. Conservative treatment is an option, as in this case.",
"affiliations": "Department of General Medicine, IMSUT Hospital, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo108-8639, Japan.;Department of General Medicine, IMSUT Hospital, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo108-8639, Japan.;Department of General Medicine, IMSUT Hospital, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo108-8639, Japan.;Department of General Medicine, IMSUT Hospital, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo108-8639, Japan.;Department of General Medicine, IMSUT Hospital, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo108-8639, Japan.",
"authors": "Matsubara|Yasuo|Y|;Lim|Lay Ahyoung|LA|;Hijikata|Yasuki|Y|;Hirata|Yoshihiro|Y|;Yotsuyanagi|Hiroshi|H|",
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"fulltext": "\n==== Front\nRadiol Case Rep\nRadiol Case Rep\nRadiology Case Reports\n1930-0433 Elsevier \n\nS1930-0433(20)30159-X\n10.1016/j.radcr.2020.04.053\nEmergency Radiology\nEmbolization coil migration in the stomach and spontaneous excretion: a case report and review of the literature\nMatsubara Yasuo MD, PhDma-yasu@ims.u-tokyo.ac.jp⁎ Lim Lay Ahyoung MD, PhD Hijikata Yasuki MD, PhD Hirata Yoshihiro MD, PhD Yotsuyanagi Hiroshi MD, PhD Department of General Medicine, IMSUT Hospital, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo108-8639, Japan\n⁎ Corresponding author. ma-yasu@ims.u-tokyo.ac.jp\n26 5 2020 \n7 2020 \n26 5 2020 \n15 7 1018 1022\n10 4 2020 21 4 2020 21 4 2020 © 2020 The Authors. Published by Elsevier Inc. on behalf of University of Washington.2020This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Embolization coil migration to the gastrointestinal tract is a rare complication. This report describes our experience of coil migration in the stomach and spontaneous excretion. A 77-year-old man, who was diagnosed with esophageal squamous cell carcinoma with multiple lymph node metastases, had a bleeding left gastric artery and splenic artery pseudoaneurysm associated with an abdominal lymph node mass, that was treated by coil embolization, after which the coil migrated into the stomach. Because there were no complications such as active bleeding or peritonitis, our patient was followed carefully, and excretion of the coil was documented. No standard management exists for migrated coils. Conservative treatment is an option, as in this case.\n\nKeywords\nCoil embolizationMigrationStomach\n==== Body\nIntroduction\nAbdominal transcatheter arterial coil embolization has been used to treat hematemesis and prevent abdominal vessel bleeding in gastrointestinal (GI) ulcers, arterial aneurysms, and pseudoaneurysms [1,2]. Prophylactic coil embolization is also performed to minimize inadvertent misadministration to nearby structures in transarterial chemoembolization for hepatocellular carcinoma [3].\n\nBecause its high success rate has led to increased use of coil embolization, complications of coil embolization have been reported, including bleeding, infarction of normal structures, abscess formation, and coil migration [4], [5], [6]. Among these complications, migration to the GI tract is extremely rare.\n\nThis report describes our experience of treating a bleeding left gastric artery and splenic artery pseudoaneurysms associated with abdominal lymph node mass using coil embolization. The coil subsequently migrated into the stomach and was excreted spontaneously.\n\nCase report\nA 77-year-old man was diagnosed with esophageal squamous cell carcinoma and multiple lymph node metastases. An enlarged abdominal lymph node confirmed to contain an squamous cell carcinoma had invaded the posterior wall of the proximal stomach (Fig. 1). This ulcerative lesion was treated with proton pump inhibitor administration. Bloody stool appeared during the first course of chemotherapy, which consisted of DCF (docetaxel, 70 mg/m2 per day, day 1; cisplatin, 70 mg/m2 per day, day 1; fluorouracil (5-FU), 750 mg/m2 per day, days 1-5) repeated every 3 weeks. Abdominal computed tomography (CT) revealed bleeding from the left gastric artery, which was invaded by the mass (Fig. 2a). Transarterial embolization was performed on the left gastric artery with coils and N-butyl-2-cyanoacrylate. A splenic artery pseudoaneurysm that also penetrated the mass was treated with coils (Fig. 2b, c). After the patient's general condition improved, chemotherapy was restarted. CT and upper GI endoscopy revealed that the mass had decreased markedly in size and the embolization coil, used on the splenic artery, was exposed in the portion of the stomach where the mass had invaded (Fig 3) 2 months after embolization.Fig. 1 Computed tomography (a) and endoscopy (b) revealed an enlarged abdominal lymph node invading the posterior wall of the proximal stomach. The white arrow indicates the portion of the invasion (a).\n\nFig. 1 –Fig. 2 (a) Computed tomograph showing hemorrhage from the left gastric artery (white arrow), which was invaded by the enlarged abdominal lymph node. (b, c) Angiography before and after repeat embolization of the left gastric artery, and a splenic artery pseudoaneurysm (black arrows).\n\nFig. 2 –Fig. 3 About 2 months after embolization of the left gastric artery and a splenic artery aneurysm, computed tomography revealed the markedly shrinking mass (a). and endoscopy showed the coil eroding through the gastric wall (b).\n\nFig. 3 –\n\nThe patient responded partially to chemotherapy, which was continued. Follow-up endoscopy revealed a shallow ulcer and more extensive coil extrusion into the stomach (Fig. 4a). Five months after the embolization, the coil was not visible (Fig. 4b). At that time, coil migration was followed with x-ray examination, which demonstrated excretion of the coil.Fig. 4 (a) About 4 months after embolization, a strand of the wire extended into the stomach. (b) About 5 months after embolization, the coil was no longer visible in the stomach and was thought to have been excreted.\n\nFig. 4 –\n\nDiscussion\nVisceral artery pseudoaneurysms are caused by regional infection, inflammation, and trauma [7,8], and excessive hemorrhage from them can be life-threatening. Visceral artery aneurysms occur mainly in the splenic artery (60%-80%) and hepatic artery (14%-20%), whereas they occur rarely in the gastric artery (4%) [9]. In this case, inflammation by the lymph node mass might cause left gastric and splenic artery pseudoaneurysms, which were treated by coil embolization.\n\nMigration of an embolization coil into the GI tract is a rare complication [10,11]. Although the exact reason for coil migration is unclear, most migrations occur after endovascular embolization for pseudoaneurysms, and localized inflammatory events occur before coil migration in some cases [12,13]. In addition to the neoplastic inflammation, chemotherapy might damage the vessel [14] and provoke more inflammation [15], which could be a trigger of coil migration. Migration occurred as the mass shrank in our case.\n\nTo reduce the risk of coil migration, proximal and distal embolization without filling the aneurysm space had been reported [10,11,16]. Because pseudoaneurysms have thin walls, they are more fragile than adjacent normal vessels and can be a pathway for migration. However, sandwich embolization sometimes cannot be performed in the context of branched vessels that supply blood flow to the aneurysm without a main proximal and distal vessel route, as in this case.\n\nThere is no standard management for migrated coils [13,16], because there is insufficient information regarding coil migration. Some were removed endoscopically or surgically, and others were conservatively treated. Some coils passed spontaneously, although this is extremely rare [13,17]. Shah et al reported the case of migration of embolization coil passed per rectum after splenic artery pseudoaneurysm embolization in a patient with chronic pancreatitis, although the exact route of passage was unclear [17]. Because there was no active bleeding or peritonitis, our patient was carefully followed up, and excretion of the coil was documented. To the best of our knowledge, this is the first report of endoscopic follow-up of coil migration progress to the stomach.\n\nThere have been 7 reported cases of visceral artery coil migration into the stomach in the English literature. The clinical figures, including the present case (total 8 cases), are summarized in Table 1. Six patients had pseudoaneurysms or aneurysms, and 2 underwent prophylactic embolization. Most initial coil locations were the splenic artery and gastroduodenal artery or the right gastric artery, and sites of migration were the gastric body and gastric pylorus or the antrum, respectively. Two cases, both of which were pseudoaneurysms of the splenic artery, showed no complications. Migrations occurred from 3 weeks to 10 years. Surgery or endoscopic removal was performed in 5 cases, and conservative therapy was administered in 2 cases.Table 1 – Summary of reported cases of visceral artery coil migration into the stomach.\n\nTable 1Author\tAge\tSex\tUnderlying disease\tIndication of coil embolization\tLocation of initial coil deployment\tSite of coil migration\tComplications of coil migration\tTime from embolization\tTreatment\t\nCurrent case\t77\tM\tEsophageal cancer\tPseudoaneurysm\tSplenic artery\tGastric body\tNone\t2 months\tContinuation of PPI\t\nTakahashi et al [10]\t59\tM\tChronic pancreatitis\tPseudoaneurysm\tSplenic artery\tGastric body\tNone\t3 weeks\tOpen surgery\t\nDinter et al [6]\t82\tF\tGastric ulcer bleeding\tAneurysm\tCeliac artery\tGastric cardia\tAortogastric fistula\t10 years\tNone (death)\t\nBlitstein et al [18]\t67\tM\tHCC\tProphylactic embolization before TACE\tGDA\tGastric antrum\tAbdominal pain\t1 year\tPPI administration\t\n\t\t\t\t\tRGA\t\tAnorexia\t\t\t\nChang et al [19]\t63\tM\tHCC\tProphylactic embolization before TACE\tAccessory RGA\tGastric pylorus\tGastric ulcer bleeding\t2 years\tEndoscopic removal of coil and hemostasis\t\nSkipworth et al [11]\t55\tM\tChronic pancreatitis\tPseudoaneurysm\tGDA\tGastric pylorus\tAbdominal tenderness\t10 months\tNJ-nutrition and future surgery\t\n\t\t\t\t\t\t\tWeight loss\t\t\t\nTekola et al [12]\t48\tM\tRenal disease\tPseudoaneurysm\tSplenic artery\tGastric body\tAbdominal pain\t3 months\tOpen surgery\t\nPratap et al [20]\t65\tF\tNone\tAneurysm\tSplenic artery\tGastric body\tDyspepsia\t4 years\tLaparoscopic endoscopic combined surgery\t\n\t\t\t\t\t\t\tAnemia\t\t\t\nPPI, proton pump inhibitor; HCC, hepatocellular carcinoma; TACE, transarterial chemoembolization; GDA, gastroduodenal artery; RGA, right gastric artery.\n\n\n\nOur case is one of 2 rare cases showing no symptoms and only one conservative treatment case of coil migration after splenic artery embolization. Although it is difficult to make recommendations on management because of its rarity, a conservative treatment would be an option in cases without complications.\n\nCompeting interests: The authors declare that they have no conflicting interests to disclose\n==== Refs\nReferences\n1 Steckman M.L. Dooley M.C. Jaques P.F. Powell D.W. Major gastrointestinal hemorrhage from peripancreatic blood vessels in pancreatitis. Treatment by embolotherapy Dig Dis Sci 29 1984 486 497 6609804 \n2 Sato N. Yamaguchi K. Shimizu S. Morisaki T. Yokohata K. Chijiiwa K. Coil embolization of bleeding visceral pseudoaneurysms following pancreatectomy: the importance of early angiography Arch Surg 133 1998 1099 1102 9790208 \n3 Liu D.M. Salem R. Bui J.T. Courtney A. Barakat O. Sergie Z. Angiographic considerations in patients undergoing liver-directed therapy J Vasc Interv Radiol 16 2005 911 935 16002500 \n4 Falagas M.E. Nikou S.A. Siempos I.I. Infections related to coils used for embolization of arteries: review of the published evidence J Vasc Interv Radiol 18 2007 697 701 17538130 \n5 Lozier A.P. Connolly E.S. Jr. Lavine S.D. Solomon R.A. Guglielmi detachable coil embolization of posterior circulation aneurysms: a systematic review of the literature Stroke 33 2002 2509 2518 12364746 \n6 Dinter D.J. Rexin M. Kaehler G. Neff W. Fatal coil migration into the stomach 10 years after endovascular celiac aneurysm repair J Vasc Interv Radiol 18 2007 117 120 17296711 \n7 Carroccio A. Jacobs T.S. Faries P. Ellozy S.H. Teodorescu V.J. Ting W. Endovascular treatment of visceral artery aneurysms Vasc Endovascular Surg 41 2007 373 382 17942851 \n8 Nicholson A.A. Patel J. McPherson S. Shaw D.R. Kessel D. Endovascular treatment of visceral aneurysms associated with pancreatitis and a suggested classification with therapeutic implications J Vasc Interv Radiol 17 2006 1279 1285 16923974 \n9 Sousa J. Costa D. Mansilha A. Visceral artery aneurysms: review on indications and current treatment strategies Int Angiol 38 2019 381 394 (in eng) 31284707 \n10 Takahashi T. Shimada K. Kobayashi N. Kakita A. Migration of steel-wire coils into the stomach after transcatheter arterial embolization for a bleeding splenic artery pseudoaneurysm: report of a case Surg Today 31 2001 458 462 11381514 \n11 Skipworth J.R. Morkane C. Raptis D.A. Kennedy L. Johal K. Pendse D. Coil migration–a rare complication of endovascular exclusion of visceral artery pseudoaneurysms and aneurysms Ann R Coll Surg Engl 93 2011 e19 e23 21944789 \n12 Tekola B.D. Arner D.M. Behm B.W. Coil migration after transarterial coil embolization of a splenic artery pseudoaneurysm Case Rep Gastroenterol 7 2013 487 491 24348322 \n13 Sexton J.J. Whittaker D.R. A noninterventional management approach to endovascular coil migration into the sigmoid colon J Vasc Surg 61 2015 507 509 24239522 \n14 Rohatgi S. Jagannathan J.P. Rosenthal M.H. Kim K.W. Ramaiya N.H. Krajewski K.M. Vascular toxicity associated with chemotherapy and molecular targeted therapy: what should a radiologist know? AJR Am J Roentgenol 203 2014 1353 1362 25415715 \n15 Doll D.C. Yarbro J.W. Vascular toxicity associated with antineoplastic agents Semin Oncol 19 1992 580 596 1411655 \n16 Han Y.M. Lee J.Y. Choi I.J. Kim C.G. Cho S.J. Lee J.H. Endoscopic removal of a migrated coil after embolization of a splenic pseudoaneurysm: a case report Clin Endosc 47 2014 183 187 24765602 \n17 Shah N.A. Akingboye A. Haldipur N. Mackinlay J.Y. Jacob G. Embolization coils migrating and being passed per rectum after embolization of a splenic artery pseudoaneurysm, \"the migrating coil\": a case report Cardiovasc Intervent Radiol 30 2007 1259 1262 (in eng) 17882482 \n18 Blitstein M.K. Soares G.M. Dubel G.J. Coil migration into stomach after prophylactic coil embolization before transcatheter arterial chemoembolization Clin Gastroenterol Hepatol 7 2009 A26 \n19 Chang C.J. Hou M.C. Tseng H.S. Liao W.C. Lin H.C. Lee S.D. Bleeding gastric ulcer after prophylactic coiling of transarterial chemoembolization J Clin Gastroenterol 44 2010 588 591 20453659 \n20 Pratap A. Pokala B. Vargas L.M. Oleynikov D. Kothari V. Laparoscopic endoscopic combined surgery for removal of migrated coil after embolization of ruptured splenic artery aneurysm J Surg Case Rep 2018 rjx242 2018 29479413\n\n",
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"title": "Embolization coil migration in the stomach and spontaneous excretion: a case report and review of the literature.",
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"abstract": "Drug-induced pauci-immune crescentic glomerulonephritis has been described with several agents, including propylthiouracil, minocycline, D-penicillamine, and hydralazine. We present the case of a 60-year-old man who presented with rapidly progressive glomerulonephritis in the setting of recent use of trimethoprim-sulfamethoxazole complicated by the development of the Stevens-Johnson syndrome, and was found to have biopsy-proven pauci-immune crescentic glomerulonephritis and undetectable anti-neutrophilic cytoplasmic antibodies. We review the existing literature on the potential association between sulfonamides and hypersensitivity polyangiitis.",
"affiliations": "Division of Nephrology, Department of Medicine, St. Elizabeth's Medical Center, 736 Cambridge Street, Boston, MA, 02135, USA.;Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA.;Division of Nephrology, Department of Medicine, St. Elizabeth's Medical Center, 736 Cambridge Street, Boston, MA, 02135, USA. bertrand.jaber@steward.org.",
"authors": "Hegde|Shruti S|SS|;Bijol|Vanesa|V|;Jaber|Bertrand L|BL|",
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"title": "Pauci-immune crescentic glomerulonephritis associated with use of trimethoprim-sulfamethoxazole.",
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"abstract": "Acute hepatitis A viral (HAV) infection is rare in the liver transplant population due to recommended pre-transplant vaccinations. We report a case of acute hepatitis A infection in a liver transplant recipient. This individual had immunity to hepatitis A with protective IgG antibodies and presented with abnormal liver biochemistry in the post-transplant in-patient setting. Hepatitis A infection was confirmed by positive HAV IgM whereas other etiologies, including acute cellular rejection, were ruled out by laboratory tests and liver biopsies. He was treated conservatively with supportive care and liver enzymes recovered to normal baseline. Despite adequate pre-transplant immunity, in the post-transplant setting there may be loss of protective immunity due to profound immunosuppression and hence hepatitis A should remain an important differential diagnosis in the setting of acute hepatitis.",
"affiliations": "Division of Gastroenterology, University of British Columbia and the Liver Transplant Program, Vancouver General Hospital, Vancouver, Canada.;Division of Gastroenterology, University of British Columbia and the Liver Transplant Program, Vancouver General Hospital, Vancouver, Canada.;Faculty of Pharmaceutical Sciences, University of British Columbia and the Liver Transplant Program, Vancouver General Hospital, Vancouver, Canada.;Division of Gastroenterology, University of British Columbia and the Liver Transplant Program, Vancouver General Hospital, Vancouver, Canada.;Division of Gastroenterology, University of British Columbia and the Liver Transplant Program, Vancouver General Hospital, Vancouver, Canada.;BC Centre for Disease Control, University of British Columbia and the Liver Transplant Program, Vancouver General Hospital, Vancouver, Canada.;Department of Pathology and Laboratory Medicine, University of British Columbia and the Liver Transplant Program, Vancouver General Hospital, Vancouver, Canada.;Division of Gastroenterology, University of British Columbia and the Liver Transplant Program, Vancouver General Hospital, Vancouver, Canada.",
"authors": "Zhu|Julie|J|;Alalkim|Fatema|F|;Hussaini|Trana|T|;Erb|Siegfried R|SR|;Marquez|Vladimir|V|;Krajden|Mel|M|;Webber|Douglas|D|;Yoshida|Eric M|EM|",
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"fulltext": "\n==== Front\nSaudi J GastroenterolSaudi J GastroenterolSJGSaudi Journal of Gastroenterology : Official Journal of the Saudi Gastroenterology Association1319-37671998-4049Medknow Publications & Media Pvt Ltd India 30117491SJG-25-6710.4103/sjg.SJG_230_18Case ReportIn-hospital post-transplant acute hepatitis A viral (HAV) infection in a liver transplant recipient who was HAV seropositive pre-transplant Zhu Julie Alalkim Fatema Hussaini Trana 1Erb Siegfried R. Marquez Vladimir Krajden Mel 2Webber Douglas 3Yoshida Eric M. Division of Gastroenterology, University of British Columbia and the Liver Transplant Program, Vancouver General Hospital, Vancouver, Canada1 Faculty of Pharmaceutical Sciences, University of British Columbia and the Liver Transplant Program, Vancouver General Hospital, Vancouver, Canada2 BC Centre for Disease Control, University of British Columbia and the Liver Transplant Program, Vancouver General Hospital, Vancouver, Canada3 Department of Pathology and Laboratory Medicine, University of British Columbia and the Liver Transplant Program, Vancouver General Hospital, Vancouver, CanadaAddress for correspondence: Dr. Eric M. Yoshida, Vancouver General Hospital, Diamond Health Care Centre, 5th Floor, 2775 Laurel Street, Vancouver, British Columbia, V5Z 1M9, Canada. E-mail: eric.yoshida@vch.caJan-Feb 2019 25 1 67 70 Copyright: © 2018 Saudi Journal of Gastroenterology2018This 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.Acute hepatitis A viral (HAV) infection is rare in the liver transplant population due to recommended pre-transplant vaccinations. We report a case of acute hepatitis A infection in a liver transplant recipient. This individual had immunity to hepatitis A with protective IgG antibodies and presented with abnormal liver biochemistry in the post-transplant in-patient setting. Hepatitis A infection was confirmed by positive HAV IgM whereas other etiologies, including acute cellular rejection, were ruled out by laboratory tests and liver biopsies. He was treated conservatively with supportive care and liver enzymes recovered to normal baseline. Despite adequate pre-transplant immunity, in the post-transplant setting there may be loss of protective immunity due to profound immunosuppression and hence hepatitis A should remain an important differential diagnosis in the setting of acute hepatitis.\n\nAcute hepatitishepatitis A vaccinationhepatitis A viral infectionimmunosuppressionliver transplant\n==== Body\nINTRODUCTION\nLiver transplantation is the standard of care for patients with end-stage liver diseases. Pre-transplant vaccination series are recommended by most transplant centers to protect patients against hepatitis A and B in both pre- and post-transplant settings. It is believed that the presence of strong antibody titer pre-transplant, either from natural infection or past vaccination, confers immunity to hepatitis A viral (HAV) infection post-transplant. We report a case of acute HAV in a patient who had adequate pre-transplant anti-HAV antibodies and developed acute HAV in hospital, during the immediate post-transplant period in the context of immunosuppression.\n\nCASE PRESENTATION\nA 55-year-old man with decompensated alcoholic liver disease was transferred from a community hospital to our center for urgent liver transplant assessment. His past medical history was significant for recurrent hepatic encephalopathy, ascites, spontaneous bacterial peritonitis, and hepatorenal syndrome. His clinical status deteriorated rapidly requiring ICU admission for intubation, vasopressor support, and renal replacement therapy. Seventeen days later, Model for End-Stage Liver Disease (MELD) score was 40, and he received a liver transplant from a deceased donor who was seronegative for hepatitis A/B/C viruses. Post transplant, he received immunosuppression induction per standard protocol with basiliximab, mycophenolate mofetil, and tapering methylprednisolone followed by low dose tacrolimus. Pre-transplant serum hepatitis A IgG was positive and IgM was negative, which correlated with past immunity from either post natural infection or vaccination. The patient recalled having received a one-time hepatitis A viral (HAV) vaccination in 2001. Pre-transplant cytomegalovirus (CMV) IgG, herpes simplex virus (HSV), Epstein–Barr virus (EBV), and IgG serologies were positive. The results were negative for human immunodeficiency virus (HIV) serological testing. Pre-emptive screening via weekly CMV polymerase chain reaction (PCR) was started post-transplant as per institutional guidelines. His post-op complications were prolonged intubation, vancomycin resistant enterococcus (VRE), pneumonia, and septicemia. He had herpes simplex virus type 2 (HSV2) perineal ulcers and disseminated HSV2 limbic encephalitis without acute hepatitis that has been previously reported,[1] necessitating a 3-week course of intravenous acyclovir and percutaneous endoscopic gastrostomy (PEG) tube insertion for enteral nutrition. His other medications were levetiracetam 500 mg BID and trimethoprim-sulfamethoxazole three times a week. On POD 42, he was transferred to a community hospital for further recuperation. He had normal hepatic graft function during hospital-to-hospital transfer. It was noted that he had rising ALT and AST from baseline beginning around post-op day 105, which peaked on day 128.\n\nAfter the liver transplant, the patient had persistently low lymphocytes counts. On the day of hospital transfer, lymphocyte was at 0.8 × 109/L while neutrophil was at 1.3 × 109/L. Laboratory tests on POD 105 showed ALT 141 IU/L [<55 IU/L], AST 80 IU/L [<38 IU/L], GGT 21 IU/L [<55 IU/L], alkaline phosphatase 117 IU/L [<120 IU/L], total bilirubin 12 μmol/L [<20 μmol/L], total white blood cell count was low at 1.9 × 109/L, hemoglobin 96 g/L, platelet 112 × 109/L, and INR 0.8. On POD 128, blood tests were ALT 1042 IU/L, AST 441 IU/L, GGT 196 IU/L, ALP 355 IU/L, total bilirubin 21 μmol/L [Table 1]. Hepatitis A IgM level was >7 (positive) on POD 128. Serology for other infectious viral agents including hepatitis B, C, E, and CMV was negative. Autoimmune serology including IgG, smooth-muscle antibody, and nuclear antibody was normal. Doppler ultrasound showed normal biliary ductal system, patent portal vein, hepatic vein, and artery. Liver biopsies on POD 129 showed moderate lymphocytic infiltrate of portal triads, scattered plasma cells with focal interface activity, and lymphocytic lobulitis. There was only mild endotheliitis. It was consistent with an acute hepatitis with only coincidental mild acute cellular rejection, likely from hepatitis A infection with endothelial and bile duct damage en passant [Figures 1 and 2]. The predominant pathologic diagnosis was that of acute hepatitis. Due to persistent neutropenia, mycophenolate mofetil was held on POD31, restarted at 250 mg BID on POD 99, while tacrolimus was continued to target a trough level of 5-7. He was treated conservatively with supportive care and no escalation of immunosuppression medications. His liver enzymes eventually improved to normal. There were no HAV carriers identified in this case. At the time of HAV diagnosis, the patient had prolonged hospital stay and never returned home, and his HAV contacts remained undiscovered, although contaminated food from hospitals and outside of hospitals could be potential sources.\n\nTable 1 Post-transplant liver biochemistry\n\n\tALT (IU/L) [<55 IU/L]\tAST (IU/L) [<38 IU/L]\tTotal Bili (µmol/L) [<20 µmol/L]\tALP (IU/L) [<120 IU/L]\tGGT (IU/L) [<55 IU/L]\t\nJan 30 2018 (POD 105)\t100\t54\t6\t103\t17\t\nFeb 1\t141\t80\t12\t117\t21\t\nFeb 12\t518\t224\t14\t111\t22\t\nFeb 14\t624\t250\t11\t185\t76\t\nFeb 19\t968\t433\t18\t330\t181\t\nFeb 22 (POD 128)\t1042\t441\t21\t355\t196\t\nFeb 26\t884\t311\t15\t391\t219\t\nMar 16\t265\t106\t13\t236\t190\t\nMar 22\t168\t74\t17\t232\t168\t\nApr 4\t94\t41\t12\t166\t193\t\nPOD: Postoperative day, ALT: Alanine transaminase, AST: Aspartate transaminase, Total bili: Total bilirubin, ALP: Alkaline phosphatase, GGT: Gamma-glutamyltransferase\n\nFigure 1 Liver core portal triad at ×400 magnification. Haematoxylin and Eosin. Largely lymphocytic portal triadal inflammation with interface hepatitis and minor abnormalities of bile ducts/portal venules. Arrows: Open fat arrow-interface hepatitis. Open “thin” arrow: lymphocyte within bile duct epithelium. Solid arrow: rare eosinophilic leukocyte. White arrow-endothelial lifting in portal venule. Although acute cellular rejection (ACR) could have this appearance, it would be unusual to have interface hepatitis this close to the time of transplant. Also expect more eosinophilic leukocytes and more evidence of endotheliitis in ACR\n\nFigure 2 Liver core lobule at ×400 magnification. Haematoxylin and Eosin. Lymphocytic lobulitis. Arrow: lymphocytes in sinusoids. Lobulitis is distinctly rare in acute cellular rejection this close to the time of transplant\n\nDISCUSSION\nHepatitis A infection is a self-limited acute viral infection of the liver with oral-fecal route of transmission. At-risk populations include but are not limited to those from the endemic regions (India, Africa, and Middle-East countries), infants and children, those from poorly sanitized living conditions, and men who have sex with men.[2] The incidence of HAV has been significantly reduced in North America and endemic countries since hepatitis A vaccination for at-risk populations.[2] HAV infection is not endemic to Canada, however, there are reports of sporadic and outbreak cases of HAV, usually from contaminated food sources. HAV incubation time averages 28 days (range = 15 to 50 days).[3] Clinical presentation can be asymptomatic with abnormal liver biochemistry only, to presentations with nausea, vomiting, jaundice, dark urine, malaise, and right-sided abdominal pain.[4] Fulminant liver failure is rare, occurring in less than 1% of HAV cases. The diagnosis of HAV infection is made by positive anti-HAV IgM antibody titer, in conjunction with abnormal liver biochemistry.[5] In acute infection, ALT and AST can be greater than 1000 IU/L, with ALT characteristically higher than AST. The rise of transaminases generally precedes bilirubin elevation, and alkaline phosphatase can rise up to 400 IU/L. Anti-HAV IgM remains positive for 3 to 6 months after the onset of symptoms (i.e., jaundice), then becomes undetectable, although there have been unusual reports of prolonged persistent IgM antibody up to 200 days to 30 months after their initial infections.[6] False positive IgM is rare and the reported cases were from cross-reactive antibodies, other viral infections, non-Hodgkin's lymphoma, and cases of prolonged persistent IgM after HAV clearance.[7] Stool HAV RNA has a much shorter diagnostic window, becoming positive 2 to 3 weeks before and 1 week after the onset of clinical illness.[89] In our patient, a stool RNA by PCR performed at 1 month after the onset of illness, despite being negative, was falsely reassuring.\n\nHAV vaccination is 97% to 100% protective in healthy individuals. A booster dose is recommended 6 to 12 months post primary immunization, and the protective effect can last up to 17 years.[10] Primary HAV vaccination failures are extremely rare, especially in those vaccinated for the second time in 6 months following an initial dose. There are only a few case reports of primary HAV vaccination failure, including primary vaccination failure in an HIV positive individual.[1112]\n\nWhile most transplant programs will recommend hepatitis A and B vaccination series, many patients are still un-vaccinated pre-transplant. The conventional wisdom is that natural infection confers life-long immunity. Nevertheless, previously immune liver transplant patients may lose immunity to HAV due to immunosuppression. This was reported in a retrospective study where 18% and 29% of patients with previously detectable anti-HAV IgG from natural infection became anti-HAV IgG non-detectable at 1 and 2 years post transplant.[13] Anti-HAV IgG antibody loss may be caused by strong anti-rejection regimens given following liver transplant (LT). These immune-suppressing medications, including high-dose systemic steroids and mycophenolate mofetil, may decimate some memory B-cell pools. Mycophenolate mofetil has the unique ability to inhibit both B-cells and T-cells and, when used in combination with acyclovir, has been reported to further increase the area under the curve (AUC) and the maximal concentration of acyclovir.[1415] They can lead to severe leukopenia and neutropenia. Our patient had persistent lymphopenia and neutropenia, resulting in the temporary discontinuation of mycophenolate. A liver biopsy is not required for the diagnosis of acute HAV in otherwise healthy individuals. However, in early liver transplant setting with acute transaminase elevation, one of the most encountered scenarios is acute cellular rejection, which is managed by the escalation of immune-suppressants while viral hepatitis in LT setting is managed foremost, by reducing immune-suppressants and treating the underlying viral agent if possible. Therefore, a liver biopsy in this case was decisively useful. Our case showcased that HAV infection mimicked some features of the acute cellular rejection. The differences highlighted here were lobular and interface hepatitis, which are more common in acute HAV and less common in allograft rejection where marked endotheliitis and bile duct damage are pathonomonic. The degree of liver enzyme elevation was not explained by the incidental finding of mild acute rejection, but rather a consequence from acute hepatitis A infection, which was more compatible with the overall clinical picture. Similar to this case, there was another case report of hepatitis E virus (HEV) infection in LT mimicking acute rejection.[16] We also note that we did not treat our patient for acute graft rejection and his liver biochemistry normalized spontaneously. This is typical of an acute self-limited hepatitis such as HAV whereas untreated graft rejection would be expected to progress. This essentially confirms that the case was that of acute post-transplant HAV.\n\nThe American Transplant Society guideline recommends universal HAV vaccination for at-risk non-immune individuals, which include organ recipients, preferably before the transplant[17]; however, as our experience underscores, there is no absolute guarantee that HAV will not occur. Moreover, there is currently no guideline recommendation to routinely check antibody titers post-transplant to ensure adequate immunity. Another curious aspect of our case is that the acute HAV occurred in hospital. The infection control units of both our hospital and the community hospital where this occurred were notified, and no hospital workers have been identified as the source of infection. Presumably, the infection was transmitted from food items brought from outside the hospital. Our experience, which we suspect is the first reported post-transplant case to occur in a patient with pre-transplant anti-HAV (and happens as an in-patient), suggests that acute HAV needs to be screened for every post-transplant patient with a liver biochemical flare consistent with an acute hepatocellular process, regardless of the setting. Hepatitis A infection is an important differential diagnosis in the post LT population whenever acute hepatitis is suspected.\n\nDeclaration of patient consent\nThe authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.\n\nFinancial support and sponsorship\nNil.\n\nConflicts of interest\nThere are no conflicts of interest.\n==== Refs\nREFERENCES\n1 Zhu J Laghari M Hussaini T Marquez V Erb SR Yoshida EM Disseminated Herpes Simplex Virus 2 (HSV-2) Encephalitis in a Liver Transplant Recipient: Potential Implications for Liver Transplant Programs JAMMI 2018 Epub ahead of print \n2 Daniels D Grytdal S Wasley A Centers for Disease C, Prevention. Surveillance for acute viral hepatitis-United States, 2007 MMWR Surveill Summ 2009 58 1 27 \n3 Lemon SM Type A viral hepatitis. New developments in an old disease N Engl J Med 1985 313 1059 67 2413356 \n4 Lednar WM Lemon SM Kirkpatrick JW Redfield RR Fields ML Kelley PW Frequency of illness associated with epidemic hepatitis A virus infections in adults Am J Epidemiol 1985 122 226 33 3860002 \n5 American Medical A, American Nurses Association-American Nurses F, Centers for Disease C, Prevention, Center for Food S, Applied Nutrition F, et al . Diagnosis and management of foodborne illnesses: A primer for physicians and other health care professionals MMWR Recomm Rep 2004 53 1 33 \n6 Kao HW Ashcavai M Redeker AG The persistence of hepatitis A IgM antibody after acute clinical hepatitis A Hepatology 1984 4 933 6 6090293 \n7 Nainan OV Xia G Vaughan G Margolis HS Diagnosis of hepatitis a virus infection: A molecular approach Clin Microbiol Rev 2006 19 63 79 16418523 \n8 Koff RS Clinical manifestations and diagnosis of hepatitis A virus infection Vaccine 1992 10 Suppl 1 S15 7 1335649 \n9 Richardson M Elliman D Maguire H Simpson J Nicoll A Evidence base of incubation periods, periods of infectiousness and exclusion policies for the control of communicable diseases in schools and preschools Pediatr Infect Dis J 2001 20 380 91 11332662 \n10 Theeten H Van Herck K Van Der Meeren O Crasta P Van Damme P Hens N Long-term antibody persistence after vaccination with a 2-dose Havrix (inactivated hepatitis A vaccine): 20 years of observed data, and long-term model-based predictions Vaccine 2015 33 5723 7 26190091 \n11 Mor Z Lurie Y Katchman E A case of hepatitis A vaccination failure in an HIV-positive man who had sex with men in Israel Int J STD AIDS 2012 23 529 30 22844014 \n12 Elliott JH Kunze M Torresi J Hepatitis A vaccine failure Lancet 2002 359 1948 9 \n13 Arslan M Wiesner RH Poterucha JJ Gross JB Jr Zein NN Hepatitis A antibodies in liver transplant recipients: Evidence for loss of immunity posttransplantation Liver Transpl 2000 6 191 5 10719019 \n14 Gimenez F Foeillet E Bourdon O Weller S Garret C Bidault R Evaluation of pharmacokinetic interactions after oral administration of mycophenolate mofetil and valaciclovir or aciclovir to healthy subjects Clin Pharmacokinet 2004 43 685 92 15244498 \n15 Ritter ML Pirofski L Mycophenolate mofetil: Effects on cellular immune subsets, infectious complications, and antimicrobial activity Transpl Infect Dis 2009 11 290 7 19497072 \n16 Allaire M Bazille C Selves J Salame E Altieri M Hepatitis E virus infection mimicking acute graft rejection in a liver transplant recipient Clin Res Hepatol Gastroenterol 2018 Epub ahead of print \n17 Levitsky J Doucette K Practice ASTIDCo Viral hepatitis in solid organ transplantation Am J Transplant 2013 13 Suppl 4 147 68 23465008\n\n",
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"issue": "25(1)",
"journal": "Saudi journal of gastroenterology : official journal of the Saudi Gastroenterology Association",
"keywords": "Acute hepatitis; hepatitis A vaccination; hepatitis A viral infection; immunosuppression; liver transplant",
"medline_ta": "Saudi J Gastroenterol",
"mesh_terms": "D000208:Acute Disease; D003937:Diagnosis, Differential; D006506:Hepatitis A; D017957:Hepatitis A Virus, Human; D006801:Humans; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D007165:Immunosuppression Therapy; D008099:Liver; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged; D010166:Palliative Care; D016896:Treatment Outcome; D014611:Vaccination; D000073887:Vaccination Coverage",
"nlm_unique_id": "9516979",
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"pages": "67-70",
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"pmid": "30117491",
"pubdate": "2019",
"publication_types": "D002363:Case Reports",
"references": "10719019;11332662;12057583;1335649;15123984;15244498;16418523;19478727;19497072;22844014;23465008;2413356;26190091;29650438;3860002;6090293",
"title": "In-hospital post-transplant acute hepatitis A viral (HAV) infection in a liver transplant recipient who was HAV seropositive pre-transplant.",
"title_normalized": "in hospital post transplant acute hepatitis a viral hav infection in a liver transplant recipient who was hav seropositive pre transplant"
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"abstract": "Although evidence from animal and human studies indicates opioid analgesics increase susceptibility to infections, it is unclear whether the risk varies by specific opioid. We compared the risk of serious infection among patients initiating long-acting opioid analgesics with and without previously reported immunosuppressive properties.\n\n\n\nWe conducted a retrospective cohort study of Tennessee Medicaid enrollees age ≥18 years initiating long-acting opioids (1995-2015). Hospitalizations for serious infection were identified using validated coding algorithms. We used multivariable Poisson regression models to calculate adjusted incidence rate ratios (aIRR) and 95% confidence intervals (CI) to compare the infection risk among patients using long-acting opioids with known immunosuppressive properties (morphine, fentanyl, methadone) to the infection risk among patients using long-acting opioids without known immunosuppressive properties (oxycodone, oxymorphone, tramadol) accounting for demographics, opioid dose, comorbidities and pain conditions, medication use, frailty indicators, and healthcare encounter history using exposure propensity scores. We further compared users of individual long-acting opioids to long-acting morphine users (considered the prototypical immunosuppressive opioid).\n\n\n\nAmong the 61 240 patients initiating opioids with immunosuppressive properties and 22 811 patients initiating opioids without immunosuppressive properties, we identified 1906 serious infections. Nonimmunosuppressive opioid users had a lower rate of infections than immunosuppressive opioid users (aIRR:0.78 [CI: 0.66-0.91]). Among individual opioids, oxycodone users had a lower rate of infection than morphine users (aIRR:0.73 [CI: 0.60-0.89]). There were no significant differences in the infection risk between other opioids and morphine.\n\n\n\nThe risk of serious infections among long-acting opioid users varies by opioid type. Providers should carefully consider the risk of serious infections when making pain management decisions.",
"affiliations": "Department of Health Policy, Vanderbilt University Medical Center, Nashville, Tennessee.;Department of Health Policy, Vanderbilt University Medical Center, Nashville, Tennessee.;Department of Health Policy, Vanderbilt University Medical Center, Nashville, Tennessee.;Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.;Mid-South Geriatric Research Education and Clinical Center, VA Tennessee Valley Health Care System, Nashville, Tennessee.;Department of Health Policy, Vanderbilt University Medical Center, Nashville, Tennessee.;Department of Health Policy, Vanderbilt University Medical Center, Nashville, Tennessee.",
"authors": "Wiese|Andrew D|AD|;Griffin|Marie R|MR|;Schaffner|William|W|;Stein|C Michael|CM|;Greevy|Robert A|RA|;Mitchel|Edward F|EF|;Grijalva|Carlos G|CG|",
"chemical_list": "D000701:Analgesics, Opioid; D007166:Immunosuppressive Agents; D009020:Morphine; D008691:Methadone; D005283:Fentanyl",
"country": "United States",
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"doi": "10.1093/cid/ciy809",
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"issue": "68(11)",
"journal": "Clinical infectious diseases : an official publication of the Infectious Diseases Society of America",
"keywords": "opioid analgesics; serious infections",
"medline_ta": "Clin Infect Dis",
"mesh_terms": "D000328:Adult; D000368:Aged; D000701:Analgesics, Opioid; D059350:Chronic Pain; D005260:Female; D005283:Fentanyl; D006760:Hospitalization; D006801:Humans; D007166:Immunosuppressive Agents; D007239:Infections; D008297:Male; D008484:Medicaid; D008691:Methadone; D008875:Middle Aged; D009020:Morphine; D009293:Opioid-Related Disorders; D012189:Retrospective Studies; D012307:Risk Factors; D013714:Tennessee; D014481:United States",
"nlm_unique_id": "9203213",
"other_id": null,
"pages": "1862-1869",
"pmc": null,
"pmid": "30239630",
"pubdate": "2019-05-17",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural",
"references": "12383990;14585554;14585769;15289247;15629415;16764216;17504834;18363493;18543352;18685388;19906833;20543678;21083382;21149754;21524850;21728033;22091503;22747543;23787715;24482539;24598216;25587948;25599329;25686208;25960019;26337922;26473742;26987082;27299617;27487158;28213891;29435579;29896976;29921683;30178014",
"title": "Long-acting Opioid Use and the Risk of Serious Infections: A Retrospective Cohort Study.",
"title_normalized": "long acting opioid use and the risk of serious infections a retrospective cohort study"
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"abstract": "Nab-paclitaxel plus gemcitabine has become a standard treatment regimen in patients with metastatic pancreatic adenocarcinoma; however, retrospective data suggest that gemcitabine might be inefficient in 50-60% of patients and thus not an optimum regimen in combination with nab-paclitaxel. We did a phase 2 trial to assess the activity and safety of a new regimen of nab-paclitaxel plus simplified leucovorin and fluorouracil.\n\n\n\nWe did a non-comparative, multicentre, open-label, randomised phase 2 trial in 15 hospitals and institutions in France. Eligible participants were previously untreated patients with metastatic pancreatic adenocarcinoma (previous adjuvant chemotherapy after curative intent resection was allowed if the interval between the end of chemotherapy and relapse was more than 12 months). Patients had to have at least one measurable lesion assessed by CT scan or MRI and an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less. We randomly assigned participants (1:2) centrally to 28-day cycles of either gemcitabine plus nab-paclitaxel or simplified leucovorin and fluorouracil plus nab-paclitaxel. The randomisation was by minimisation, stratified by centre and ECOG performance status. Drugs were administered in each cycle as follows: nab-paclitaxel (125 mg/m2) and gemcitabine (1000 mg/m2) as 30-min intravenous infusions on days 1, 8, and 15; leucovorin (400 mg/m2) as a 120-min intravenous infusion on days 1 and 15; and fluorouracil (400 mg/m2) as a 5-min bolus intravenous infusion followed by a 46-h continuous intravenous infusion of 2400 mg/m2 on days 1 and 15. Patients continued treatment until unacceptable toxicity, disease progression, or patient withdrawal. The primary endpoint was progression-free survival at 4 months in the first 72 assessable patients in the leucovorin and fluorouracil group, with a target of 50% for the regimen to be deemed sufficiently active to warrant further study. We did the primary analysis on the modified intention-to-treat (ITT) population, defined as all randomly assigned and assessable patients regardless of their eligibility and received treatments. This trial is registered at ClinicalTrials.gov, number NCT01964534. The trial has ended and we report the final analysis here.\n\n\n\nBetween Dec 12, 2013, and Oct 31, 2014, we randomly assigned 114 patients to treatment: 75 patients to the leucovorin and fluorouracil group and 39 to the gemcitabine group. One patient in the leucovorin and fluorouracil group did not have a 4-month assessment, and was thus excluded from the modified ITT analysis. Median follow-up was 13·1 months (95% CI 12·5-14·1). At 4 months, 40 (56%, 90% CI 45-66) of 72 patients in the leucovorin and fluorouracil group were alive and free from disease progression (21 [54%, 40-68] of 39 patients in the gemcitabine group were also alive and progression-free at 4 months). Grade 3-4 adverse events occurred in 33 (87%) of 38 patients in the gemcitabine group and in 56 (77%) of 73 patients in the leucovorin and fluorouracil group, with different toxicity profiles. The most common grade 3-4 adverse events in the leucovorin and fluorouracil group were neutropenia without fever (17 [23%]), fatigue (16 [22%]), paraesthesia (14 [19%]), diarrhoea (nine [12%]), and mucositis (seven [10%]); in the gemcitabine group they were neutropenia without fever (12 [32%]), thrombocytopenia (seven [18%]), fatigue (eight [21%]), anaemia (five [13%]), increased alanine aminotransferase and aspartate aminotransferase concentrations (five [13%] for both), and paraesthesia (four [11%]). Two participants died; one in the leucovorin and fluorouracil group from septic shock, and one in the gemcitabine group from diabetes compensation with acidosis; these deaths were deemed to be not related to treatment. Treatment-related serious adverse events occurred in 28 (38%) of 73 patients in the leucovorin and fluorouracil group and in 14 (37%) of 38 in the gemcitabine group.\n\n\n\nNab-paclitaxel plus simplified leucovorin and fluorouracil fulfilled the primary endpoint in that more than the required 50% of our study population were progression-free at 4 months, with a tolerable toxicity profile. This regimen thus deserves further assessment in a phase 3 trial.\n\n\n\nGERCOR (Groupe Coopérateur Multidisciplinaire en Oncologie) and Celgene through grants to GERCOR.",
"affiliations": "Sorbonne Universités, UPMC Univ Paris 06, Paris, France; Department of Hepato-Gastroenterology, Groupe hospitalier Pitié Salpêtrière, Paris, France. Electronic address: jean-baptiste.bachet@aphp.fr.;Department of Digestive Oncology, Hôpital Beaujon, Paris, France.;Department of Hepato-Gastroenterology, Hôpital Privé Jean Mermoz, Lyon, France.;Department of Methodology and Quality of Life in Oncology, INSERM UMR 1098, Hôpital Universitaire de Besancon, Paris, France.;Department of Oncology, Institut Franco-Britannique, Levallois-Perret, Paris, France.;Department of Oncology, Hôpital Saint Antoine, Paris, France.;Department of Oncology, Institut Saint Catherine, Avignon, France.;Department of Oncology, Hôpital Layne Mont de Marsan, Mont de Marsan, France.;Department of Hepato-Gastroenterology, Hôpital Trousseau, Tours, France.;CHU La Timone, Marseille, France.;Department of Oncology, CHU Henri Mondor, Créteil, France.;Department of Hepato-Gastroenterology, CHU Avicenne, Bobigny, France.;Department of Oncology, Institut de cancérologie de L'Ouest Paul Papin, Angers, France.;Department of Gastroenterology and Digestive Oncology, Hôpital Européen Georges Pompidou, Paris, France.;Department of Hepato-Gastroenterology, CHU Robert Debré, Reims, France.;GERCOR (Groupe Coopérateur Multidisciplinaire en Oncologie), Paris, France.;Department of Methodology and Quality of Life in Oncology, INSERM UMR 1098, Hôpital Universitaire de Besancon, Paris, France.;Department of Oncology, Institut Mutualiste Montsouris, Paris, France.",
"authors": "Bachet|Jean-Baptiste|JB|;Hammel|Pascal|P|;Desramé|Jérôme|J|;Meurisse|Aurélia|A|;Chibaudel|Benoist|B|;André|Thierry|T|;Debourdeau|Philippe|P|;Dauba|Jérome|J|;Lecomte|Thierry|T|;Seitz|Jean-François|JF|;Tournigand|Christophe|C|;Aparicio|Thomas|T|;Meyer|Véronique Guerin|VG|;Taieb|Julien|J|;Volet|Julien|J|;Monier|Amandine|A|;Bonnetain|Franck|F|;Louvet|Christophe|C|",
"chemical_list": "C520255:130-nm albumin-bound paclitaxel; D000418:Albumins; D003841:Deoxycytidine; C056507:gemcitabine; D017239:Paclitaxel; D002955:Leucovorin; D005472:Fluorouracil",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/S2468-1253(17)30046-8",
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"keywords": null,
"medline_ta": "Lancet Gastroenterol Hepatol",
"mesh_terms": "D000230:Adenocarcinoma; D000368:Aged; D000369:Aged, 80 and over; D000418:Albumins; D000971:Antineoplastic Combined Chemotherapy Protocols; D003841:Deoxycytidine; D005260:Female; D005472:Fluorouracil; D006801:Humans; D057194:Intention to Treat Analysis; D002955:Leucovorin; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D017239:Paclitaxel; D010190:Pancreatic Neoplasms; D016019:Survival Analysis",
"nlm_unique_id": "101690683",
"other_id": null,
"pages": "337-346",
"pmc": null,
"pmid": "28397697",
"pubdate": "2017-05",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Nab-paclitaxel plus either gemcitabine or simplified leucovorin and fluorouracil as first-line therapy for metastatic pancreatic adenocarcinoma (AFUGEM GERCOR): a non-comparative, multicentre, open-label, randomised phase 2 trial.",
"title_normalized": "nab paclitaxel plus either gemcitabine or simplified leucovorin and fluorouracil as first line therapy for metastatic pancreatic adenocarcinoma afugem gercor a non comparative multicentre open label randomised phase 2 trial"
} | [
{
"companynumb": "FR-CELGENEUS-FRA-2017032521",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "PACLITAXEL"
},
"drugadditional": null,
... |
{
"abstract": "Complete heart block is rare in children and is usually owing to congenital abnormalities. These children are often pacemaker dependent. However, pacemaker complications can require emergency interventions, including external pacing. This case presents a child in complete heart block requiring external pacing and then discusses some of the literature behind such interventions.",
"affiliations": "From the Departments of Emergency Medicine.;Critical Care, Oregon Health and Science University, Portland, OR.",
"authors": "Jones|David|D|;Ran|Ran|R|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1097/PEC.0000000000001910",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0749-5161",
"issue": "35(9)",
"journal": "Pediatric emergency care",
"keywords": null,
"medline_ta": "Pediatr Emerg Care",
"mesh_terms": "D002304:Cardiac Pacing, Artificial; D002675:Child, Preschool; D005260:Female; D006323:Heart Arrest; D006327:Heart Block; D006801:Humans; D010138:Pacemaker, Artificial",
"nlm_unique_id": "8507560",
"other_id": null,
"pages": "e162-e163",
"pmc": null,
"pmid": "31425475",
"pubdate": "2019-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Transcutaneous Pacing of a 4-Year-Old Child.",
"title_normalized": "transcutaneous pacing of a 4 year old child"
} | [
{
"companynumb": "US-MYLANLABS-2019M1102517",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "EPINEPHRINE"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nUse of immunosuppressants and inflammatory bowel disease (IBD) may increase the risk of pneumonia caused by Pneumocystis jirovecii (PJP). We assessed the risk of PJP in a population-based cohort of patients with IBD treated with corticosteroids, immune-suppressive medications, and biologics.\n\n\nMETHODS\nWe performed a population-based cohort study of residents of Olmsted County, Minnesota, diagnosed with Crohn's disease (n = 427) or ulcerative colitis (n = 510) from 1970 through 2011. Records of patients were reviewed to identify all episodes of immunosuppressive therapies and concomitant PJP prophylaxis through February 2016. We reviewed charts to identify cases of PJP, cross-referenced with the Rochester Epidemiology Project database (using diagnostic codes for PJP) and the Mayo Clinic and Olmsted Medical Center databases. The primary outcome was risk of PJP associated with the use of corticosteroids, immune-suppressive medications, and biologics by patients with IBD.\n\n\nRESULTS\nOur analysis included 937 patients and 6066 patient-years of follow-up evaluation (median, 14.8 y per patient). Medications used included corticosteroids (520 patients; 55.5%; 555.4 patient-years of exposure), immunosuppressants (304 patients; 32.4%; 1555.7 patient-years of exposure), and biologics (193 patients; 20.5%; 670 patient-years of exposure). Double therapy (corticosteroids and either immunosuppressants and biologics) was used by 236 patients (25.2%), with 173 patient-years of exposure. Triple therapy (corticosteroids, immunosuppressants, and biologics) was used by 70 patients (7.5%) with 18.9 patient-years of exposure. There were 3 cases of PJP, conferring a risk of 0.2 (95% CI, 0.01-1.0) to corticosteroids, 0.1 (95% CI, 0.02-0.5) cases per 100 patient-years of exposure to immunosuppressants, 0.3 (95% CI, 0.04-1.1) cases per 100 patient-years of exposure to biologics, 0.6 (95% CI, 0.01-3.2) cases per 100 patient-years of exposure to double therapy, and 0 (95% CI, 0.0-19.5) cases per 100 patient-years of exposure to triple therapy. Primary prophylaxis for PJP was prescribed to 37 patients, for a total of 24.9 patient-years of exposure.\n\n\nCONCLUSIONS\nIn a population-based cohort of patients with IBD treated with corticosteroids, immunosuppressants, and biologics, there were only 3 cases of PJP, despite the uncommon use of PJP prophylaxis. Routine administration of PJP prophylaxis in these patients may not be warranted, although it should be considered for high-risk groups, such as patients receiving triple therapy.",
"affiliations": "Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota.;Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota.;Division of Infectious Disease, Mayo Clinic, Rochester, Minnesota.;Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota.;Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota.;Division of Infectious Disease, Mayo Clinic, Rochester, Minnesota.;Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota.;Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota.;Division of Gastroenterology, University of California San Diego, La Jolla, California.;Division of Pulmonary and Critical Care, Mayo Clinic, Rochester, Minnesota.;Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota. Electronic address: pardi.darrell@mayo.edu.",
"authors": "Cotter|Thomas G|TG|;Gathaiya|Nicola|N|;Catania|Jelena|J|;Loftus|Edward V|EV|;Tremaine|William J|WJ|;Baddour|Larry M|LM|;Harmsen|W Scott|WS|;Zinsmeister|Alan R|AR|;Sandborn|William J|WJ|;Limper|Andrew H|AH|;Pardi|Darrell S|DS|",
"chemical_list": "D007166:Immunosuppressive Agents",
"country": "United States",
"delete": false,
"doi": "10.1016/j.cgh.2016.11.037",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1542-3565",
"issue": "15(6)",
"journal": "Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association",
"keywords": "Calcineurin Inhibitors; Immunocompromised; Infliximab; Treatment",
"medline_ta": "Clin Gastroenterol Hepatol",
"mesh_terms": "D000328:Adult; D015331:Cohort Studies; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents; D015212:Inflammatory Bowel Diseases; D008297:Male; D008875:Middle Aged; D008910:Minnesota; D011020:Pneumonia, Pneumocystis; D018570:Risk Assessment; D055815:Young Adult",
"nlm_unique_id": "101160775",
"other_id": null,
"pages": "850-856",
"pmc": null,
"pmid": "28013116",
"pubdate": "2017-06",
"publication_types": "D016428:Journal Article",
"references": "21430193;15190141;15481319;20068560;17404870;17803871;20808846;24051931;19058233;15168804;26177704;23159830;15580408;9317088;17886285;23622345;15475754;23478805;21251557;16078322;11914999;19035972;22890223;10328575;22305027;20643496;15184529;17206702;8470640;23435401;17135309;24613021;21986616;26281787;9040337;15472531;15726101;17429728;19370790;21989472;15489347;8538233;21039834;10988193;7479194;8993860",
"title": "Low Risk of Pneumonia From Pneumocystis jirovecii Infection in Patients With Inflammatory Bowel Disease Receiving Immune Suppression.",
"title_normalized": "low risk of pneumonia from pneumocystis jirovecii infection in patients with inflammatory bowel disease receiving immune suppression"
} | [
{
"companynumb": "US-ACCORD-057426",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHOTREXATE"
},
"drugadditional": "3",
"dru... |
{
"abstract": "We present a case of a young lady with extreme involuntary weight loss and alarming constitutional symptoms found ultimately to be all due to a single medication's side effects. The objective of this case report is to alert physicians, especially in a primary care setting, that the side effects of a medication used mostly in a highly specialized field of neurology, sodium oxybate (SXB), can cause extreme involuntary weight loss in addition to chronic night sweats and symptoms of clinical depression.",
"affiliations": "Department of Medicine, Duke University Medical Center, 2301 Erwin Rd, 27703 Durham, NC, USA.;Department of Medicine, Duke University Medical Center, 2301 Erwin Rd, 27703 Durham, NC, USA.;Department of Medicine, Duke University Medical Center, 2301 Erwin Rd, 27703 Durham, NC, USA.",
"authors": "Noujaim|Michael G|MG|https://orcid.org/0000-0001-9329-5765;Mourad|Ahmad|A|;Clough|Jeffrey D|JD|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1155/2019/6537815",
"fulltext": "\n==== Front\nCase Rep MedCase Rep MedCRIMCase Reports in Medicine1687-96271687-9635Hindawi 10.1155/2019/6537815Case ReportSodium Oxybate: A Cause of Extreme Involuntary Weight Loss in a Young Lady https://orcid.org/0000-0001-9329-5765Noujaim Michael G. mgn9@duke.eduMourad Ahmad Clough Jeffrey D. Department of Medicine, Duke University Medical Center, 2301 Erwin Rd, 27703 Durham, NC, USAAcademic Editor: Bruno Megarbane\n\n2019 24 7 2019 2019 65378155 6 2019 1 7 2019 14 7 2019 Copyright © 2019 Michael G. Noujaim et al.2019This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.We present a case of a young lady with extreme involuntary weight loss and alarming constitutional symptoms found ultimately to be all due to a single medication's side effects. The objective of this case report is to alert physicians, especially in a primary care setting, that the side effects of a medication used mostly in a highly specialized field of neurology, sodium oxybate (SXB), can cause extreme involuntary weight loss in addition to chronic night sweats and symptoms of clinical depression.\n==== Body\n1. Background\nSodium oxybate (SXB) is a central nervous system depressant that primarily acts as a GABAB receptor agonist [1]. SXB was approved in 2002 for the treatment of excessive daytime sleepiness and cataplexy in patients with narcolepsy in the United States [1]. Its reported adverse effects include some weight loss (<12%) and depression (3–6%) [1].\n\n2. Case Report\nA 27-year-old female came to our primary care clinic with 64-pound unintentional weight loss over a 10-month period. Her associated symptoms included drenching night sweats, depressed mood, a lack of interest in performing her daily activities, and decreased energy. Her medical history was significant for polycystic ovarian syndrome, dysmenorrhea, and type 1 narcolepsy with hypnagogic/hypnopompic hallucinations and cataplexy. She had been followed by neurology long term for narcolepsy and was initially treated with methylphenidate (120 milligrams daily), subsequently transitioned to SXB (9 grams daily)—given its higher efficacy—approximately 10 months prior to her presentation. During this period, she endorsed eating her baseline three meals a day. She was not exercising at all and was losing weight on a daily basis. She weighed 205 pounds at the onset of her symptoms and weighed 142 pounds on current presentation. The patient denied any gastrointestinal symptoms including nausea, vomiting, or diarrhea. Her in-clinic PHQ-9 score was 9 points. The rest of her physical exam was notable for no palpable lymphadenopathy, a normal head, heart, chest, skin, and abdominal exam. She had had a recent normal pelvic exam and a normal pap smear from the prior year. Given our patient's unexplained weight loss and constitutional symptoms, an extensive workup was performed that included computed tomography scans of her chest, abdomen, and pelvis, complete blood count, comprehensive metabolic panel, thyroid profile, anti-nuclear antibody screen, C-reactive protein, sedimentation rate, lactate dehydrogenase, urinalysis, and peripheral blood smear. All of her laboratory testing and imaging studies were normal. Given negative testing and the temporal association of her symptoms with starting SXB, we decided to hold her SXB and scheduled follow-up at 3-week intervals. On initial follow-up, the patient's night sweats and depressive symptoms had resolved, and for the first time in almost a year, she had not lost any weight but instead had gained 3 pounds.\n\n3. Discussion\nWeight loss, to a certain extent, is a known adverse effect of SXB. A 2008 retrospective multicenter study included 54 patients who had been using SXB for at least 3 months and found an average weight loss of 7.5 pounds, with patients with cataplexy having the most significant loss in weight [2]. Only 1 of the 54 patients in this study exhibited extreme weight loss of 68 pounds [2]. A more recent retrospective follow-up study published in 2018 found that SXB use in narcolepsy caused a significant reduction in body mass index (BMI) [3]. They reported a mean BMI decrease of 2.56 kg/m2 in women and 0.84 kg/m2 in men who had been on SXB for at least 3 months [3].\n\nMedication adverse reactions were considered early on in our differential diagnosis. However, to our knowledge, the combination of extreme weight loss and severe constitutional symptoms due to SXB that our patient presented with has not been reported in the literature. As a result, given our patient's young age and concerning symptoms, we thought it was prudent to pursue an initial, limited yet thorough biochemical and radiological workup before trialing the patient off of SXB. Once our initial workup turned up negative, we made the decision to have our patient stop taking SXB with very close follow-up at no more than 1- to 2-week intervals. Had the patient continued to be symptomatic, we would have proceeded to more extensive testing such as positron emission tomography scanning as well as liver and bone marrow biopsies.\n\nUsing guidelines for reporting adverse drug reactions, we classify this as “dose related and time related [4].” Adverse drug reactions in this category are defined as an uncommon exaggerated pharmacologic response that are likely related to a cumulative dose of the drug with low potential for mortality [4]. Moreover, using the Naranjo algorithm for estimating the probability that this adverse reaction is due to SXB, we calculated a score of 9 points, indicating a definite link to SXB [5]. This case demonstrates the potential for SXB therapy in type 1 narcolepsy patients to cause extreme weight loss associated with other constitutional symptoms and depression. Furthermore, we highlight the importance of recognizing when to stop invasive testing and considering exaggerated adverse drug reactions in the workup of alarming symptoms in a young patient.\n\nConsent\nThe patient consent was obtained both verbally and in written format.\n\nConflicts of Interest\nThe authors declare that there are no conflicts of interest regarding the publication of this paper.\n\nAuthors' Contributions\nMGN treated the patient in clinic under the supervision of JC. MGN wrote the initial manuscript and literature review. MGN, AM, and JC reviewed and edited the manuscript.\n==== Refs\n1 UpToDate (Internet) Sodium Oxybate (Gamma Hydroxybutyrate): Drug Information 2019 Waltham, MA, USA UpToDate \n2 Husain A. M. Ristanovic R. K. Bogan R. K. Weight loss in narcolepsy patients treated with sodium oxybate Sleep Medicine 2009 10 6 661 663 10.1016/j.sleep.2008.05.012 2-s2.0-67349158754 19014899 \n3 Schinkelshoek M. S. Smolders I. M. Donjacour C. E. Decreased body mass index during treatment with sodium oxybate in narcolepsy type 1 Journal of Sleep Research 2019 28 3 e12684 10.1111/jsr.12684 \n4 Edwards I. R. Aronson J. K. Adverse drug reactions: definitions, diagnosis, and management The Lancet 2000 356 9237 1255 1259 10.1016/s0140-6736(00)02799-9 2-s2.0-0034619028 \n5 Naranjo C. A. Busto U. Sellers E. M. A method for estimating the probability of adverse drug reactions Clinical Pharmacology and Therapeutics 1981 30 2 239 245 10.1038/clpt.1981.154 2-s2.0-0019799332 7249508\n\n",
"fulltext_license": "CC BY",
"issn_linking": null,
"issue": "2019()",
"journal": "Case reports in medicine",
"keywords": null,
"medline_ta": "Case Rep Med",
"mesh_terms": null,
"nlm_unique_id": "101512910",
"other_id": null,
"pages": "6537815",
"pmc": null,
"pmid": "31428154",
"pubdate": "2019",
"publication_types": "D002363:Case Reports",
"references": "11072960;19014899;29504180;7249508",
"title": "Sodium Oxybate: A Cause of Extreme Involuntary Weight Loss in a Young Lady.",
"title_normalized": "sodium oxybate a cause of extreme involuntary weight loss in a young lady"
} | [
{
"companynumb": "US-JAZZ-2019-US-011979",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "SODIUM OXYBATE"
},
"drugadditional": "1",
... |
{
"abstract": "OBJECTIVE\nIn acute stroke, hypertension worsens outcomes. Guidelines do not mention a preferred antihypertensive agent. This present study aimed to compare the efficacy and safety of nicardipine and clevidipine in acute stroke.\n\n\nMETHODS\nThis retrospective review compared nicardipine with clevidipine for hypertension in acute stroke patients from March 17, 2015 to December 23, 2016. Ischemic and hemorrhagic stroke types were evaluated. Patients were excluded if under 18 years, had traumatic brain injury, had intracranial neoplasm, were on dialysis, had both study drugs during the stroke admission, or the study drug was infused for less than 1 hour. Efficacy outcomes were: time to goal blood pressure, percent time in goal, blood pressure range, and need for additional antihypertensive agents during the infusion. A composite of in-hospital death, 30-day readmission, rebleeding, ischemic to hemorrhagic conversion, and hematoma expansion were compared. Other clinical outcomes included length of intensive care unit and hospital stay, hypotension, bradycardia, tachycardia, onset of atrial fibrillation, and acute kidney injury.\n\n\nRESULTS\nMean time to goal blood pressure was 65.5 minutes and 65.8 minutes in the nicardipine and clevidipine group, respectively (P = .83). No efficacy outcome was significantly different between 2 groups after multivariate analysis.\n\n\nCONCLUSIONS\nBoth nicardipine and clevidipine are reasonable antihypertensive agents in stroke, although cost and volume restriction could differentiate preference.",
"affiliations": "Pharmacy Services Department, Community Hospital, Munster, Indiana.;Pharmacy Services Department, Memorial Medical center, Springfield, Illinois.;Department of Neurosurgery, Southern Illinois University School of Medicine, Springfield, Illinois.;Pharmacy Services Department, Memorial Medical center, Springfield, Illinois.;Department of Pharmacy Practice, Southern Illinois University, Edwardsville, Illinois.;Department of Neurosurgery, Southern Illinois University School of Medicine, Springfield, Illinois. Electronic address: fazeelmukhtar@gmail.com.",
"authors": "Rosenfeldt|Zachary|Z|;Conklen|Katelyn|K|;Jones|Breck|B|;Ferrill|Don|D|;Deshpande|Maithili|M|;Siddiqui|Fazeel M|FM|",
"chemical_list": "D000959:Antihypertensive Agents; D011725:Pyridines; C118563:clevidipine; D009529:Nicardipine",
"country": "United States",
"delete": false,
"doi": "10.1016/j.jstrokecerebrovasdis.2018.03.001",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1052-3057",
"issue": "27(8)",
"journal": "Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association",
"keywords": "Cerebrovascular disease; clevidipine; hypertension; nicardipine; outcomes",
"medline_ta": "J Stroke Cerebrovasc Dis",
"mesh_terms": "D000208:Acute Disease; D000368:Aged; D000959:Antihypertensive Agents; D002561:Cerebrovascular Disorders; D003430:Cross-Sectional Studies; D005260:Female; D006801:Humans; D006973:Hypertension; D008297:Male; D009529:Nicardipine; D011725:Pyridines; D012189:Retrospective Studies; D013997:Time Factors; D016896:Treatment Outcome",
"nlm_unique_id": "9111633",
"other_id": null,
"pages": "2067-2073",
"pmc": null,
"pmid": "29627171",
"pubdate": "2018-08",
"publication_types": "D003160:Comparative Study; D016428:Journal Article",
"references": null,
"title": "Comparison of Nicardipine with Clevidipine in the Management of Hypertension in Acute Cerebrovascular Diseases.",
"title_normalized": "comparison of nicardipine with clevidipine in the management of hypertension in acute cerebrovascular diseases"
} | [
{
"companynumb": "US-MYLANLABS-2018M1062145",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "NICARDIPINE"
},
"drugadditional": "3",
... |
{
"abstract": "Acute lymphoblastic leukemia (ALL) was diagnosed in a 13-year-old girl who had been treated previously for osteosarcoma of the left distal femur (23 months after her first cancer onset and 12 months after the end of treatment). The patient started chemotherapy for ALL and achieved complete remission; she is in continuous complete remission 5 years after the diagnosis of secondary ALL and 7 years after the onset of osteosarcoma.",
"affiliations": "Department of Pediatrics, University of Turin, Italy.",
"authors": "Miniero|R|R|;Barisone|E|E|;Vivenza|C|C|;Brach del Prever|A|A|;Besenzon|L|L|;Cordero di Montezemolo|L|L|;Madon|E|E|",
"chemical_list": "D014750:Vincristine; D004317:Doxorubicin; D015122:Mercaptopurine; D001215:Asparaginase; D002945:Cisplatin; D011241:Prednisone; D008727:Methotrexate; D003630:Daunorubicin",
"country": "England",
"delete": false,
"doi": "10.3109/08880019509029553",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0888-0018",
"issue": "12(2)",
"journal": "Pediatric hematology and oncology",
"keywords": null,
"medline_ta": "Pediatr Hematol Oncol",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D001215:Asparaginase; D002648:Child; D002945:Cisplatin; D003131:Combined Modality Therapy; D003630:Daunorubicin; D004317:Doxorubicin; D005260:Female; D005266:Femoral Neoplasms; D005500:Follow-Up Studies; D006801:Humans; D015122:Mercaptopurine; D008727:Methotrexate; D016609:Neoplasms, Second Primary; D012516:Osteosarcoma; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D011241:Prednisone; D011829:Radiation Dosage; D018714:Radiotherapy, Adjuvant; D012074:Remission Induction; D014750:Vincristine",
"nlm_unique_id": "8700164",
"other_id": null,
"pages": "185-8",
"pmc": null,
"pmid": "7626388",
"pubdate": "1995",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't; D016420:Comment",
"references": null,
"title": "Acute lymphoblastic leukemia in a girl treated for osteosarcoma.",
"title_normalized": "acute lymphoblastic leukemia in a girl treated for osteosarcoma"
} | [
{
"companynumb": "IT-PFIZER INC-2019114994",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CISPLATIN"
},
"drugadditional": null,
... |
{
"abstract": "The central nervous system is a common site of relapse in patients receiving crizotinib, which is presumed to be associated with the low concentration of crizotinib in the cerebrospinal fluid (CSF). Our patient received surgical treatment for anaplastic lymphoma kinase-positive stage IIA lung adenocarcinoma. His cancer recurred with brain metastases and carcinomatous meningitis. We started whole-brain radiation therapy (WBRT) and subsequently administered crizotinib. The concentration of crizotinib on day 15 in the plasma was 158 ng/mL, and that in the spinal fluid was 4.32 ng/mL. WBRT may elevate the CSF/plasma crizotinib concentration ratio; clinicians may therefore consider performing WBRT prior to crizotinib initiation.",
"affiliations": "Department of Internal Medicine, Division of Clinical Oncology and Respiratory Medicine, Shimane University Faculty of Medicine, Japan.;Department of Internal Medicine, Division of Clinical Oncology and Respiratory Medicine, Shimane University Faculty of Medicine, Japan.;Department of Internal Medicine, Division of Clinical Oncology and Respiratory Medicine, Shimane University Faculty of Medicine, Japan.;Department of Internal Medicine, Division of Clinical Oncology and Respiratory Medicine, Shimane University Faculty of Medicine, Japan.;Department of Internal Medicine, Division of Clinical Oncology and Respiratory Medicine, Shimane University Faculty of Medicine, Japan.;Department of Internal Medicine, Division of Clinical Oncology and Respiratory Medicine, Shimane University Faculty of Medicine, Japan.;Department of Molecular Pharmacology, National Cancer Center Research Institute, Japan.;Department of Internal Medicine, Division of Clinical Oncology and Respiratory Medicine, Shimane University Faculty of Medicine, Japan.",
"authors": "Okimoto|Tamio|T|;Tsubata|Yukari|Y|;Hotta|Takamasa|T|;Hamaguchi|Megumi|M|;Nakao|Mika|M|;Hamaguchi|Shun-Ichi|SI|;Hamada|Akinobu|A|;Isobe|Takeshi|T|",
"chemical_list": "D000970:Antineoplastic Agents; D000077547:Crizotinib; D000077548:Anaplastic Lymphoma Kinase",
"country": "Japan",
"delete": false,
"doi": "10.2169/internalmedicine.1072-18",
"fulltext": "\n==== Front\nIntern MedIntern. MedInternal Medicine0918-29181349-7235The Japanese Society of Internal Medicine 3033339410.2169/internalmedicine.1072-18Case ReportA Low Crizotinib Concentration in the Cerebrospinal Fluid Causes Ineffective Treatment of Anaplastic Lymphoma Kinase-positive Non-small Cell Lung Cancer with Carcinomatous Meningitis Okimoto Tamio 1Tsubata Yukari 1Hotta Takamasa 1Hamaguchi Megumi 1Nakao Mika 1Hamaguchi Shun-ichi 1Hamada Akinobu 2Isobe Takeshi 1\n1 Department of Internal Medicine, Division of Clinical Oncology and Respiratory Medicine, Shimane University Faculty of Medicine, Japan\n2 Department of Molecular Pharmacology, National Cancer Center Research Institute, JapanCorrespondence to Tamio Okimoto, okimoto@med.shimane-u.ac.jp\n\n17 10 2018 1 3 2019 58 5 703 705 22 2 2018 16 8 2018 Copyright © 2019 by The Japanese Society of Internal Medicine2019The Internal Medicine is an Open Access journal distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view the details of this license, please visit (https://creativecommons.org/licenses/by-nc-nd/4.0/).The central nervous system is a common site of relapse in patients receiving crizotinib, which is presumed to be associated with the low concentration of crizotinib in the cerebrospinal fluid (CSF). Our patient received surgical treatment for anaplastic lymphoma kinase-positive stage IIA lung adenocarcinoma. His cancer recurred with brain metastases and carcinomatous meningitis. We started whole-brain radiation therapy (WBRT) and subsequently administered crizotinib. The concentration of crizotinib on day 15 in the plasma was 158 ng/mL, and that in the spinal fluid was 4.32 ng/mL. WBRT may elevate the CSF/plasma crizotinib concentration ratio; clinicians may therefore consider performing WBRT prior to crizotinib initiation. \n\nanaplastic lymphoma kinasecentral nervous systemcerebrospinal fluidcrizotinibnon-small cell lung cancer\n==== Body\nIntroduction\nThe echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) fusion gene was first identified in 2007 by Soda et al., and they reported the gene rearrangement in 6.7% (5/75) of the examined patients who had non-small cell lung cancer (NSCLC) (1). Treatment with ALK-tyrosine kinase inhibitors (TKIs) showed superiority over chemotherapy, and ALK-TKIs are recommended for the first-line treatment of NSCLC patients positive for the ALK fusion protein.\n\nCrizotinib was the first drug approved for treating advanced ALK-positive NSCLC. Although alectinib showed a superior survival benefit compared to crizotinib, crizotinib is still a key drug for the treatment of ALK-positive NSCLC. Furthermore, crizotinib was approved for the treatment of advanced NSCLC with a ROS1 mutation.\n\nThe central nervous system (CNS) is a common site of relapse in patients with progressive disease who are receiving crizotinib (2). One possible reason for this is the low concentration of crizotinib in the cerebrospinal fluid (CSF). However, to date, there have only been three cases reported in the literature of a low crizotinib concentration in the CSF (3,4).\n\nWe herein report the fourth case of ALK-positive advanced NSCLC and carcinomatous meningitis.\n\nCase Report\nA 61-year-old man visited our hospital complaining of diplopia and incontinence. He had a history of stage IIA lung adenocarcinoma with EML4-ALK fusion, which was confirmed by immunohistochemistry and fluorescence in situ hybridization, treated by right lower lobectomy and adjuvant chemotherapy (cisplatin and vinorelbine). He also had a history of type C hepatitis and cirrhosis.\n\nA physical examination revealed left oculomotor nerve palsy and perianal sensory impairment. Meningeal irritation was not apparent. Computed tomography (CT) of the head showed a nodular lesion in his right posterior lobe, suggesting recurrence of lung cancer with brain metastasis (Figure a). A further examination using brain magnetic resonance imaging could not be performed because of tattoos present on his entire body other than his face, hands, and feet. A cytological analysis of the CSF revealed adenocarcinoma positivity, and reverse transcription-polymerase chain reaction revealed that this adenocarcinoma was positive for the ALK fusion gene. We clinically diagnosed the patient with brain metastasis of lung cancer and carcinomatous meningitis.\n\nFigure. Computed tomography findings of the brain metastasis. a) Relapse of brain metastasis and carcinomatous meningitis. Whole-brain radiation therapy (WBRT) was initiated. b) One month after performing WBRT and just prior to crizotinib initiation, progression of the metastatic lesion was observed. A cytological analysis of the cerebrospinal fluid (CSF) was positive for malignant cells. c) One month after crizotinib initiation, the response of the metastatic lesion was observed. A cytological analysis of the CSF was negative for malignant cells. d) One month after withdrawal of crizotinib, no remarkable change was observed.\n\nWe started the patient on whole-brain radiation therapy (WBRT). Despite the radiation therapy, his symptoms worsened, and he developed aspiration pneumonia. Head CT showed tumor progression after 1 month of radiation therapy (Figure b). We started administration of 250 mg crizotinib twice daily after improvement in the pneumonia. One month after crizotinib initiation, his diplopia improved, and head CT showed shrinkage of the metastatic lesion (Figure c). A cytological analysis of the CSF was now negative for malignant cells. Crizotinib concentrations in the CSF and plasma on day 15 were 4.32 ng/mL and 158 ng/mL, respectively. Despite the efficacy of this drug, we had to withdraw crizotinib due to grade 3 AST/ALT elevation two months after crizotinib initiation. The diplopia worsened, and disturbance of the consciousness was again observed. Head CT revealed no remarkable changes (Figure d). After improvement in side effects, we restarted crizotinib at 200 mg twice daily (80% dose). However, the patient's condition worsened, and he died of carcinomatous meningitis one month after re-administration.\n\nWe were unable to administer other ALK-TKIs because crizotinib was the only drug available for ALK-positive NSCLC at the time.\n\nThis study was approved by the Institutional Review Board of Shimane University and National Cancer Center Hospital. The crizotinib concentration was measured at the National Cancer Center Institute (UMIN000015840).\n\nDiscussion\nThis case had two important clinical findings. First, a low crizotinib concentration in the CSF was observed in our patient, consistent with the findings of the three previous ALK-positive NSCLC cases reported in the literature. Second, WBRT may slightly elevate the crizotinib concentration in the CSF.\n\nWith regard to the first finding, we noted in the present case that crizotinib concentrations in the CSF and plasma on day 15 were 4.32 ng/mL and 158 ng/mL, respectively; hence, the CSF-to-plasma concentration ratio was 0.026. Similarly, Costa et al. reported crizotinib concentrations in the CSF and plasma of 0.616 ng/mL and 237 ng/mL, respectively (3), and Metro et al. reported 2 patients with CSF crizotinib concentrations of 0.35 ng/mL and 0.80 ng/mL in the plasma and 587 ng/mL and 800 ng/mL in the plasma, respectively (4) (Table). In contrast, it has been reported that alectinib penetrates the CNS, and there is a linear relationship between alectinib concentrations in the CSF and plasma (5). Both crizotinib and alectinib are oil-soluble drugs; however, with regard to the oil/water coefficient, alectinib has a higher oil solubility than crizotinib (6,7). Although crizotinib is a substrate of the P-glycoprotein efflux transporter, alectinib is not (8). These characteristics contribute to the differences between crizotinib and alectinib in the CSF concentration and treatment outcome (9,10).\n\nTable. Crizotinib and Alectinib Concentrations in the CSF and Plasma.\n\n\t\tReference\t\tCSF\t\tPlasma\t\tCSF/plasma\t\tWBRT\t\nCrizotinib (ng/mL)\t\t3\t\t0.616\t\t237\t\t0.003\t\t+\t\n\t\t4\t\t0.35\t\t587\t\t0.0006\t\t-\t\n\t\t\t\t0.80\t\t800\t\t0.001\t\t+\t\n\t\tOur case\t\t4.32\t\t158\t\t0.026\t\t+\t\nAlectinib (nmol/L)\t\t5\t\t2.69\t\t3.12\t\t0.86\t\t\t\nCSF: cerebrospinal fluid, WBRT: whole-brain radiation therapy\n\nMetro et al. also suggested the possibility that WBRT elevates the crizotinib concentration in the CSF (4). The CSF and plasma crizotinib concentration ratios in the 4 published cases, including the present case, ranged between 0.0006 and 0.026. The patient who showed the smallest ratio had not received WBRT prior to crizotinib administration. This tendency was also observed in the present case, and similar trends were reported for HER2-positive breast cancer patients with brain metastases receiving the anti-HER2 monoclonal antibody trastuzumab (11). Stemmler et al. presented clinical evidence that the trastuzumab levels in the CSF are increased under conditions that impair the blood-brain barrier, such as radiotherapy. Although the median progression-free survival (PFS) after crizotinib treatment reported in a previous study was 10.9 months (12), we found that the re-administration of crizotinib did not show efficacy and resulted in a PFS of only approximately 2 months. It is presumed that the poor efficacy of re-administration is associated with an inadequate crizotinib concentration in the CSF rather than tolerance to crizotinib.\n\nWith regard to the ALK-TKIs approved by the Food and Drug Administration (FDA) to date, crizotinib and ceritinib are substrates of the P-glycoprotein efflux transporter, and alectinib is the only ALK-TKI that is not its substrate (13). Crizotinib is the only drug approved by the FDA for the treatment of advanced NSCLC with a ROS1 mutation. The half-maximum inhibitory concentration of crizotinib in vitro is reported to be 36-108 ng/mL (3,13), which is higher than that reported in the CSF. Although Costa et al. suggested that the CNS benefits even from low concentrations of crizotinib in the CSF (3), performing WBRT prior to crizotinib to elevate the drug concentration should be considered.\n\nConclusion\nCrizotinib remains a key drug for the treatment of NSCLC patients positive for ALK fusion protein or a ROS1 mutation. However, in the present case, the treatment attempt failed because the crizotinib concentration in the CSF was low, similar to the observations in the three previously reported cases. As WBRT may increase the crizotinib concentration in the CSF, clinicians should consider performing WBRT prior to crizotinib initiation.\n\n\nThe study was performed in accordance with the ethical standards established in the 1964 Declaration of Helsinki and its later amendments. The study was approved by the institutional review board of Shimane University and National Cancer Center. Informed consent was obtained from the patient described in the study.\n\n\nAuthor's disclosure of potential Conflicts of Interest (COI).\n\nTakeshi Isobe: Honoraria, Boehringer-Ingelheim, AstraZeneca and Pfizer.\n==== Refs\n1. \nSoda M , Choi YL , Enomoto M , et al \nIdentification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer . Nature \n448 : 561 -566 , 2007 .17625570 \n2. \nOu SH , Janne PA , Bartlett CH , et al \nClinical benefit of continuing ALK inhibition with crizotinib beyond initial disease progression in patients with advanced ALK-positive NSCLC . Ann Oncol \n25 : 415 -422 , 2014 .24478318 \n3. \nCosta DB , Kobayashi S , Pandya SS , et al \nCSF concentration of the anaplastic lymphoma kinase inhibitor crizotinib . J Clin Oncol \n29 : e443 -e445 , 2011 .21422405 \n4. \nMetro G , Lunardi G , Floridi P , et al \nCSF Concentration of crizotinib in two ALK-positive non-small-cell lung cancer patients with CNS metastases deriving clinical benefit from treatment . J Thorac Oncol \n10 : e26 -e27 , 2015 .25898960 \n5. \nGadgeel SM , Gandhi L , Riely GJ , et al \nSafety and activity of alectinib against systemic disease and brain metastases in patients with crizotinib-resistant ALK-rearranged non-small-cell lung cancer (AF-002JG): results from the dose-finding portion of a phase 1/2 study . Lancet Oncol \n15 : 1119 -1128 , 2014 .25153538 \n6. Xalkori interview form. 9th ed. Pfizer, Tokyo, 2017 (in Japanese).\n7. Alecensa interview form. 7th ed. Chugai Pharmaceutical, Tokyo, 2017 (in Japanese).\n8. \nKodama T , Hasegawa M , Takanashi K , Sakurai Y , Kondoh O , Sakamoto H \nAntitumor activity of the selective ALK inhibitor alectinib in models of intracranial metastases . Cancer Chemother Pharmacol \n74 : 1023 -1028 , 2014 .25205428 \n9. \nPeters S , Camidge DR , Shaw AT , et al \nAlectinib versus crizotinib in untreated ALK-positive non-small-cell lung cancer . N Engl J Med \n377 : 829 -838 , 2017 .28586279 \n10. \nHida T , Nokihara H , Kondo M , et al \nAlectinib versus crizotinib in patients with ALK-positive non-small-cell lung cancer (J-ALEX): an open-label, randomised phase 3 trial . Lancet \n390 : 29 -39 , 2017 .28501140 \n11. \nStemmler HJ , Schmitt M , Willems A , Bernhard H , Harbeck N , Heinemann V \nRatio of trastuzumab levels in serum and cerebrospinal fluid is altered in HER2-positive breast cancer patients with brain metastases and impairment of blood-brain barrier . Anti-cancer Drugs \n18 : 23 -28 , 2007 .17159499 \n12. \nSolomon BJ , Mok T , Kim DW , et al \nFirst-line crizotinib versus chemotherapy in ALK-positive lung cancer . N Engl J Med \n371 : 2167 -2177 , 2014 .25470694 \n13. \nKatayama R , Sakashita T , Yanagitani N , et al \nP-glycoprotein mediates ceritinib resistance in anaplastic lymphoma kinase-rearranged non-small cell lung cancer . EBioMedicine \n3 : 54 -66 , 2016 .26870817\n\n",
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"keywords": "anaplastic lymphoma kinase; central nervous system; cerebrospinal fluid; crizotinib; non-small cell lung cancer",
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"mesh_terms": "D000077192:Adenocarcinoma of Lung; D000077548:Anaplastic Lymphoma Kinase; D000970:Antineoplastic Agents; D001932:Brain Neoplasms; D003131:Combined Modality Therapy; D016371:Cranial Irradiation; D000077547:Crizotinib; D018450:Disease Progression; D017809:Fatal Outcome; D006801:Humans; D008175:Lung Neoplasms; D008297:Male; D055756:Meningeal Carcinomatosis; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local",
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"title": "A Low Crizotinib Concentration in the Cerebrospinal Fluid Causes Ineffective Treatment of Anaplastic Lymphoma Kinase-positive Non-small Cell Lung Cancer with Carcinomatous Meningitis.",
"title_normalized": "a low crizotinib concentration in the cerebrospinal fluid causes ineffective treatment of anaplastic lymphoma kinase positive non small cell lung cancer with carcinomatous meningitis"
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"abstract": "There is no standard therapy for recurrent anaplastic glioma (AG). Salvage therapies include alkylator-based chemotherapy, re-resection with or without carmustine implants, re-irradiation and bevacizumab. Bendamustine is a novel bifunctional alkylator with CNS penetration never previously evaluated in AG. Assess response and toxicity of bendamustine in recurrent AG in a phase II trial. Adults with radiation and temozolomide refractory recurrent AG were treated with bendamustine. A cycle of bendamustine was defined as two consecutive days of treatment (100 mg/m2/day) administered once every 4 weeks. Success of treatment was defined as progression free survival (PFS) at 6 months of 40 % or better. Twenty-six adults [16 males; 10 females: median age 40 years (range 30-65)] were treated, 12 at first recurrence and 17 at second recurrence. Prior salvage therapy included re-resection (14), chemotherapy (11) and re-radiation (2). Grade 3 treatment-related toxicities included lymphopenia (11 patients; Grade 4 in 3), myalgia, pneumonia, diarrhea, leukopenia, allergic reaction and thrombocytopenia in one patient each. One patient discontinued therapy due to toxicity. There were five instances of bendamustine dose delays all due to lymphopenia. There were no dose reductions due to toxicity. The median number of cycles of therapy was 3 (range 1-8). Best radiographic response was progressive disease in 12 (46 %), stable disease in 13 (50 %) and partial response in 1 (4 %). Median, 6- and 12-month PFS was 2.7 months (range 1-52), 27 and 8 % respectively. In patients with recurrent AG refractory to Z, bendamustine has manageable toxicity and modest single agent activity though not meeting pre-specified study criteria.",
"affiliations": "Division of Neuro-Oncology, Department of Neurology and Neurological Surgery, Fred Hutchinson Cancer Research Center, University of Washington, Seattle Cancer Care Alliance, 825 Eastlake Ave E, MS: G4-940, Seattle, WA, 98109, USA. chambemc@u.washington.edu.;Department of Neurosurgery, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.;Department of Neurology, University of Washington, Seattle, WA, USA.;Department of Neurology, Northwestern University, Chicago, IL, USA.",
"authors": "Chamberlain|Marc C|MC|;Colman|Howard|H|;Kim|Bryan T|BT|;Raizer|Jeffrey|J|",
"chemical_list": "D018906:Antineoplastic Agents, Alkylating; D003606:Dacarbazine; D000069461:Bendamustine Hydrochloride; D000077204:Temozolomide",
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"keywords": "Anaplastic glioma (AG); Bendamustine; Temozolomide refractory",
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"mesh_terms": "D000328:Adult; D000368:Aged; D018906:Antineoplastic Agents, Alkylating; D000069461:Bendamustine Hydrochloride; D001932:Brain Neoplasms; D003606:Dacarbazine; D019008:Drug Resistance, Neoplasm; D005260:Female; D005910:Glioma; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D011446:Prospective Studies; D016879:Salvage Therapy; D000077204:Temozolomide; D016896:Treatment Outcome",
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"title": "Salvage therapy with bendamustine for temozolomide refractory recurrent anaplastic gliomas: a prospective phase II trial.",
"title_normalized": "salvage therapy with bendamustine for temozolomide refractory recurrent anaplastic gliomas a prospective phase ii trial"
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"abstract": "Systemic absorption of oral vancomycin is poor due to the size of the molecule and its pharmacokinetics. It has an elimination half life of 5-11 hours in patients with normal renal function. We present a rare case of ototoxicity after oral vancomycin administration and detectable serum vancomycin levels 24 hours after cessation of vancomycin.\nA 42-year-old woman with a history of hypertension, diabetes mellitus, and previously treated Clostridium difficile colitis presented with abdominal pain and diarrhea for two weeks. Clostridium difficile infection was confirmed by PCR, and at the time of diagnosis and initiation of therapy, the patient had normal renal function. Vancomycin was initiated at a dose of 125 mg po q6h. After the third dose of oral vancomycin, the patient reported new symptoms of lightheadedness, sensations of \"buzzing\" and whistling of bilateral ears, and decreased perception of hearing described as \"clogged ears.\" The patient reported to the emergency department the next day due to worsening of these symptoms, and vancomycin dosing was reduced to every 8 hours; however, the patient reported the auditory symptoms persisted. On day three, vancomycin was discontinued with gradual resolution of symptoms over the next 12 hours. On day four, a serum random vancomycin level obtained 24 hours after the last dose was detectable at 2 mcg/dl. Temporal association of the patient's symptoms and improvement with cessation of therapy along with a detectable vancomycin level indicates systemic absorption of oral vancomycin with subsequent ototoxicity.\nThe potential for absorption of oral vancomycin is not well described and is attributed to compromised intestinal epithelium allowing for increased drug absorption. Few studies suggested that oral vancomycin may result in therapeutic or even potentially toxic levels of serum vancomycin in patients with impaired renal function. Ototoxicity may be a transient or permanent side effect of vancomycin therapy and is related to high serum levels. Symptoms usually resolve after decreasing the dose or cessation of vancomycin. No detectable serum vancomycin levels were found in 98% of the patients treated with oral vancomycin in a prospective study. The described case is unusual because despite normal renal function, the patient still developed ototoxicity, and systemic absorption of the drug was confirmed with a measurable vancomycin level approximately 24 hours after the drug was stopped. Additionally, the only other medication prescribed to the patient at the time of vancomycin administration was metformin at a dose of 500 mg po bid which has no known idiosyncratic interactions potentiating adverse side effects to vancomycin. This case reflects that some patients may be more susceptible to increased systemic absorption via the oral route, and the possibility for ototoxicity should be considered and discussed with patients while prescribing oral vancomycin.",
"affiliations": "Department of Internal Medicine, Bronx Lebanon Hospital Center, Bronx, NY, USA.;Department of Internal Medicine, Bronx Lebanon Hospital Center, Bronx, NY, USA.;Department of Internal Medicine, Bronx Lebanon Hospital Center, Bronx, NY, USA.;Department of Internal Medicine, Bronx Lebanon Hospital Center, Bronx, NY, USA.;Department of Internal Medicine, Bronx Lebanon Hospital Center, Bronx, NY, USA.",
"authors": "Gomceli|Umut|U|0000-0001-9946-1154;Vangala|Srija|S|;Zeana|Cosmina|C|0000-0002-8922-7150;Kelly|Paul J|PJ|;Singh|Manisha|M|0000-0002-4905-5403",
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"fulltext": "\n==== Front\nCase Rep Infect DisCase Rep Infect DisCRIIDCase Reports in Infectious Diseases2090-66252090-6633Hindawi 10.1155/2018/2980913Case ReportAn Unusual Case of Ototoxicity with Use of Oral Vancomycin http://orcid.org/0000-0001-9946-1154Gomceli Umut ugomceli@bronxleb.orgVangala Srija http://orcid.org/0000-0002-8922-7150Zeana Cosmina Kelly Paul J. http://orcid.org/0000-0002-4905-5403Singh Manisha Department of Internal Medicine, Bronx Lebanon Hospital Center, Bronx, NY, USAAcademic Editor: Larry M. Bush\n\n2018 3 7 2018 2018 298091310 12 2017 1 6 2018 Copyright © 2018 Umut Gomceli et al.2018This 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.Introduction\n Systemic absorption of oral vancomycin is poor due to the size of the molecule and its pharmacokinetics. It has an elimination half life of 5–11 hours in patients with normal renal function. We present a rare case of ototoxicity after oral vancomycin administration and detectable serum vancomycin levels 24 hours after cessation of vancomycin. \n\nCase Presentation\n A 42-year-old woman with a history of hypertension, diabetes mellitus, and previously treated Clostridium difficile colitis presented with abdominal pain and diarrhea for two weeks. Clostridium difficile infection was confirmed by PCR, and at the time of diagnosis and initiation of therapy, the patient had normal renal function. Vancomycin was initiated at a dose of 125 mg po q6h. After the third dose of oral vancomycin, the patient reported new symptoms of lightheadedness, sensations of “buzzing” and whistling of bilateral ears, and decreased perception of hearing described as “clogged ears.” The patient reported to the emergency department the next day due to worsening of these symptoms, and vancomycin dosing was reduced to every 8 hours; however, the patient reported the auditory symptoms persisted. On day three, vancomycin was discontinued with gradual resolution of symptoms over the next 12 hours. On day four, a serum random vancomycin level obtained 24 hours after the last dose was detectable at 2 mcg/dl. Temporal association of the patient's symptoms and improvement with cessation of therapy along with a detectable vancomycin level indicates systemic absorption of oral vancomycin with subsequent ototoxicity. \n\nDiscussion\n The potential for absorption of oral vancomycin is not well described and is attributed to compromised intestinal epithelium allowing for increased drug absorption. Few studies suggested that oral vancomycin may result in therapeutic or even potentially toxic levels of serum vancomycin in patients with impaired renal function. Ototoxicity may be a transient or permanent side effect of vancomycin therapy and is related to high serum levels. Symptoms usually resolve after decreasing the dose or cessation of vancomycin. No detectable serum vancomycin levels were found in 98% of the patients treated with oral vancomycin in a prospective study. The described case is unusual because despite normal renal function, the patient still developed ototoxicity, and systemic absorption of the drug was confirmed with a measurable vancomycin level approximately 24 hours after the drug was stopped. Additionally, the only other medication prescribed to the patient at the time of vancomycin administration was metformin at a dose of 500 mg po bid which has no known idiosyncratic interactions potentiating adverse side effects to vancomycin. This case reflects that some patients may be more susceptible to increased systemic absorption via the oral route, and the possibility for ototoxicity should be considered and discussed with patients while prescribing oral vancomycin.\n==== Body\n1. Introduction\n\nClostridium difficile infection (CDI) has become an increasingly common infection with the widespread use of the antibiotic therapy [1]. It is the most common cause of nosocomial diarrhea, yet the incidence of CDI in the community is also on the rise [2, 3]. Metronidazole is recommended for the treatment of patients with mild to moderate CDI and oral vancomycin for the treatment of patients with severe CDI and recurrent disease [2]. Oral vancomycin is predicted to be poorly absorbed from the gastrointestinal tract based on pharmacokinetic data [4]. However, prior reports have documented that oral vancomycin therapy may produce detectable serum concentrations in patients with severe colitis and renal failure [5, 6]. There are no reports of ototoxicity as a complication following administration of oral vancomycin. We report the first case of ototoxicity after administration of oral vancomycin in a patient with normal renal function.\n\n2. Case Presentation\nA 42-year-old woman with history of hypertension and diabetes mellitus presented to the outpatient clinic with abdominal pain and diarrhea for two weeks. The patient was recently treated with clindamycin for sinusitis. On examination, the patient appeared comfortable, afebrile, and had normal vital signs. There was mild tenderness reported on abdominal palpation, and the remainder of the physical examination was unremarkable. Clostridium difficile infection was confirmed by a positive stool toxin B PCR, and the patient was started on treatment with metronidazole. Due to complaints of nausea on day three of metronidazole use, the treatment was changed to oral vancomycin at 125 mg every 6 hours. At the time of initiation of therapy, the patient had creatinine of 0.6 mg/dL. After the third day of oral vancomycin, the patient reported new symptoms of lightheadedness, sensations of “buzzing and whistling” in both ears, as well as decreased perception of hearing described as “clogged ears.” The patient presented to the emergency department (ED) due to worsening of these symptoms, and the vancomycin dose was reduced to 125 mg every 8 hours. However, the reported symptoms persisted, and on day 5 of therapy, vancomycin was discontinued in the outpatient clinic. A random vancomycin level obtained 24 hours after the last dose of vancomycin, resulted as 2 mcg/mL. The patient's symptoms were also reported to be resolved within 24 hours after discontinuation of therapy. The temporal association of the patient's symptoms and improvement with cessation of therapy along with a detectable vancomycin level indicates systemic absorption of oral vancomycin with associated ototoxicity.\n\n3. Discussion\nCDI is a well-established cause of nosocomial diarrhea in hospitals and long-term care facilities leading to a large burden of cost [1]. The epidemiology of C. difficile-associated disease has changed in the last decade, and it is now an important pathogen in the community [1, 3]. In addition to an increasing incidence and virulence of infection, almost one fourth of patients have recurrent disease [7].\n\nVancomycin appears to be more efficacious than metronidazole for treatment of CDI [8]. Current treatment guidelines recommend use of oral vancomycin for severe disease and after the first recurrence of infection [2]. Poor absorption of oral vancomycin as predicted by pharmacokinetics forms the basis for use of oral vancomycin for colitis due to Clostridium difficile [5]. However, there are conflicting clinical data regarding the systemic absorption after oral administration. There are reported cases of detectable serum levels of vancomycin after oral administration in the setting of severe colitis and renal insufficiency [5, 9]. In one series of 10 cases treated with oral vancomycin, 4 had detectable levels ranging 1.0–3.1 mg/L. Out of the 4 patients, 1 had renal insufficiency [10]. In a prospective observational study including 85 patients, detectable vancomycin levels were observed in 68% cases. The observed risk factors for systemic exposure of the drug included ICU admission, over 10 days of therapy, presence of severe CDI, renal dysfunction, inflammatory conditions of the GI tract, and concomitant use of vancomycin retention enemas [6]. There are also reports indicating lack of systemic absorption of oral vancomycin [11]. In a recent pilot study including 8 children, 7 with inflammatory bowel disease and one with acute kidney injury, none had detectable levels of vancomycin after enteral administration [12]. A prospective study including 57 adults showed no detectable serum vancomycin in 98% of the patients treated with oral vancomycin. Furthermore, despite the fact that renal excretion is the dominant route of vancomycin clearance, systemic absorption did not occur even in patients with renal insufficiency [13]. Transient or permanent ototoxicity has rarely been described as a side effect of vancomycin therapy and is related to high serum vancomycin levels [4]. Symptoms usually resolve after decrease in dose or cessation of vancomycin. There is no reported case of ototoxicity associated with use of oral vancomycin. Our case is unusual because despite the absence of renal failure and other known risk factors for systemic exposure to vancomycin, the patient developed symptoms suggestive of ototoxicity. The patient was not concurrently taking other medications known to causing ototoxicity or with potential pharmacokinetic interactions with vancomycin. Systemic absorption was confirmed by a measurable vancomycin level of 2.0 mg/mL approximately 24 hours after the drug was stopped. Due to the time lag in obtaining the drug level, the peak serum level of vancomycin could have been significantly higher than the measured level. Using the adverse drug reaction probability calculation method described by Naranjo et al., our case would be considered a “probable” drug reaction due to oral vancomcyin [14].\n\n4. Conclusion\nOur case reflects that ototoxicity due to vancomycin can develop after oral administration in the absence of renal impairment or other reported risk factors for systemic absorption. The possibility of systemic absorption and possible ototoxicity should be considered and discussed with patients when prescribing oral vancomycin.\n\nAcknowledgments\nThis manuscript has been presented as a poster presentation in the New York Chapter ACP Resident and Medical Student Forum on November 14, 2015.\n\nConflicts of Interest\nThe authors declare that there are no conflicts of interest regarding the publication of this paper.\n==== Refs\n1 Evans C. T. Safdar N. Current trends in the epidemiology and outcomes of Clostridium difficile infection Clinical Infectious Diseases 2015 60 2 S66 S71 10.1093/cid/civ140 2-s2.0-84928923377 25922403 \n2 Cohen S. H. Gerding D. N. Johnson S. Clinical practice guidelines for Clostridium difficile infection in adults: 2010 update by the Society for Healthcare Epidemiology of America (SHEA) and the Infectious Diseases Society of America (IDSA) Infection Control & Hospital Epidemiology 2010 31 5 431 455 10.1086/651706 2-s2.0-77951026738 20307191 \n3 Chitnis A. S. Holzbauer S. M. Belflower R. M. Epidemiology of community-associated Clostridium difficile infection, 2009 through 2011 JAMA Internal Medicine 2013 173 14 1359 1367 10.1001/jamainternmed.2013.7056 2-s2.0-84880691277 23780507 \n4 Moellering R. C. Jr. Pharmacokinetics of vancomycin Journal of Antimicrobial Chemotherapy 1984 14 43 52 10.1093/jac/14.suppl_d.43 \n5 Spitzer P. G. Eliopoulos G. M. Systemic absorption of enteral vancomycin in a patient with pseudomembranous colitis Annals of Internal Medicine 1984 100 4 533 534 10.7326/0003-4819-100-4-533 6703548 \n6 Pettit N. N. DePestel D. D. Fohl A. L. Eyler R. Carver P. L. Risk factors for systemic vancomycin exposure following administration of oral vancomycin for the treatment of Clostridium difficile infection Pharmacotherapy 2015 35 2 119 126 10.1002/phar.1538 2-s2.0-84923300117 25689243 \n7 Kelly C. P. Lamont J. T. \nClostridium difficile -more difficult than ever New England Journal of Medicine 2008 359 18 1932 1940 10.1056/nejmra0707500 2-s2.0-55249105923 18971494 \n8 Zar F. A. Bakkanagari S. R. Moorthi K. M. A comparison of vancomycin and metronidazole for the treatment of Clostridium difficile -associated diarrhea, stratified by disease severity Clinical Infectious Diseases 2007 45 3 302 307 10.1086/519265 2-s2.0-34547133720 17599306 \n9 Matzke G. R. Halstenson C. E. Olson P. L. Systemic absorption of oral vancomycin in patients with renal insufficiency and antibiotic-associated colitis American Journal of Kidney Diseases 1987 9 5 422 425 10.1016/s0272-6386(87)80146-4 2-s2.0-0023201864 3578270 \n10 Armstrong C. J. Wilson T. S. Systemic absorption of vancomycin Journal of Clinical Pathology 1995 48 7 p. 689 10.1136/jcp.48.7.689-b 2-s2.0-0029064470 \n11 Tedesco F. Markham R. Gurwith M. Christie D. Bartlett J. G. Oral vancomycin for antibiotic-associated pseudomembranous colitis The Lancet 1978 2 8083 226 228 10.1016/s0140-6736(78)91741-5 2-s2.0-0018104816 \n12 Antoon J. W. Hall M. Metropulos D. Steiner M. J. Jhaveri R. Lohr J. A. A prospective pilot study on systemic absorption of oral vancomycin in children with colitis Journal of Pediatric Pharmacology and Therapeutics 2016 21 5 426 431 10.5863/1551-6776-21.5.426 27877096 \n13 Rao S. Kupfer Y. Pagala M. Chapnick E. Tessler S. Systemic absorption of oral vancomycin in patients with Clostridium difficile infection Scandinavian Journal of Infectious Diseases 2011 43 5 386 388 10.3109/00365548.2010.544671 2-s2.0-79954467511 21198337 \n14 Naranjo C. A. Busto U. Sellers E. M. A method for estimating the probability of adverse drug reactions Clinical Pharmacology and Therapeutics 1981 30 2 239 245 10.1038/clpt.1981.154 2-s2.0-0019799332 7249508\n\n",
"fulltext_license": "CC BY",
"issn_linking": null,
"issue": "2018()",
"journal": "Case reports in infectious diseases",
"keywords": null,
"medline_ta": "Case Rep Infect Dis",
"mesh_terms": null,
"nlm_unique_id": "101573243",
"other_id": null,
"pages": "2980913",
"pmc": null,
"pmid": "30057833",
"pubdate": "2018",
"publication_types": "D002363:Case Reports",
"references": "3578270;23780507;18971494;21198337;79026;6703548;7560186;17599306;7249508;27877096;25922403;6394577;25689243;20307191",
"title": "An Unusual Case of Ototoxicity with Use of Oral Vancomycin.",
"title_normalized": "an unusual case of ototoxicity with use of oral vancomycin"
} | [
{
"companynumb": "US-STRIDES ARCOLAB LIMITED-2019SP000402",
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"activesubstance": {
"activesubstancename": "CLINDAMYCIN"
},
"drugadditiona... |
{
"abstract": "BACKGROUND\nNeoadjuvant treatment has been reported to prolong survival in patients with potentially resectable pancreatic adenocarcinoma (PA). However, there are currently limited clinical results available using nab-paclitaxel and gemcitabine in PA. This paper compares the oncological results of patients affected by potentially resectable PA who underwent surgery first (SF) versus surgery following neoadjuvant treatment (NAT).\n\n\nMETHODS\nThis is an observational, comparative study whereby data were abstracted from a prospective database of patients affected by PA from 2007 to 2016.\n\n\nRESULTS\nWe included a total of 81 patients (36 SF and 45 NAT) which resulted in being preoperatively similar. Among the NAT patients, treatment was well tolerated and the resection rate was 68.8% (31/45 patients). There was a trend towards a higher R1 resection rate in the SF group compared with the NAT (13.8% vs 3.2%; p = 0.1). Median overall survival in the resected NAT group was higher (30.6 vs 22.1 months; p = 0.04). In the borderline resectable group, overall survival was found to be four times higher compared with SF (43.6 versus 13.5 months; p = 0.001).\n\n\nCONCLUSIONS\nThese data suggest that neoadjuvant treatment with gemcitabine/nab-paclitaxel is a safe and effective option for potentially resectable PA compared with the SF approach.",
"affiliations": "General Surgery Department, Sanchinarro HM University Hospital, CEU San Pablo University of Madrid, Spain. Electronic address: ielpo.b@gmail.com.;General Surgery Department, Sanchinarro HM University Hospital, CEU San Pablo University of Madrid, Spain.;General Surgery Department, Sanchinarro HM University Hospital, CEU San Pablo University of Madrid, Spain.;General Surgery Department, Sanchinarro HM University Hospital, CEU San Pablo University of Madrid, Spain.;General Surgery Department, Sanchinarro HM University Hospital, CEU San Pablo University of Madrid, Spain.;General Surgery Department, Sanchinarro HM University Hospital, CEU San Pablo University of Madrid, Spain.;General Surgery Department, Sanchinarro HM University Hospital, CEU San Pablo University of Madrid, Spain.;General Surgery Department, Sanchinarro HM University Hospital, CEU San Pablo University of Madrid, Spain.;General Surgery Department, Sanchinarro HM University Hospital, CEU San Pablo University of Madrid, Spain.;General Surgery Department, Sanchinarro HM University Hospital, CEU San Pablo University of Madrid, Spain.;General Surgery Department, Sanchinarro HM University Hospital, CEU San Pablo University of Madrid, Spain.;General Surgery Department, Sanchinarro HM University Hospital, CEU San Pablo University of Madrid, Spain.;General Surgery Department, Sanchinarro HM University Hospital, CEU San Pablo University of Madrid, Spain.;General Surgery Department, Sanchinarro HM University Hospital, CEU San Pablo University of Madrid, Spain.",
"authors": "Ielpo|Benedetto|B|;Caruso|Riccardo|R|;Duran|Hipolito|H|;Diaz|Eduardo|E|;Fabra|Isabel|I|;Malavé|Luis|L|;Ferri|Valentina|V|;Alvarez|Rafael|R|;Cubillo|Antonio|A|;Plaza|Carlos|C|;Lazzaro|Sara|S|;Kalivaci|Denis|D|;Quijano|Yolanda|Y|;Vicente|Emilio|E|",
"chemical_list": "C520255:130-nm albumin-bound paclitaxel; D000418:Albumins; D003841:Deoxycytidine; C056507:gemcitabine; D017239:Paclitaxel",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.suronc.2017.08.003",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0960-7404",
"issue": "26(4)",
"journal": "Surgical oncology",
"keywords": "Neoadjuvant treatment; Pancreatectomy; Pancreatic cancer",
"medline_ta": "Surg Oncol",
"mesh_terms": "D000230:Adenocarcinoma; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000418:Albumins; D000971:Antineoplastic Combined Chemotherapy Protocols; D003841:Deoxycytidine; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D017239:Paclitaxel; D010180:Pancreatectomy; D010190:Pancreatic Neoplasms; D011379:Prognosis; D011446:Prospective Studies; D015996:Survival Rate",
"nlm_unique_id": "9208188",
"other_id": null,
"pages": "402-410",
"pmc": null,
"pmid": "29113659",
"pubdate": "2017-12",
"publication_types": "D003160:Comparative Study; D016428:Journal Article",
"references": null,
"title": "A comparative study of neoadjuvant treatment with gemcitabine plus nab-paclitaxel versus surgery first for pancreatic adenocarcinoma.",
"title_normalized": "a comparative study of neoadjuvant treatment with gemcitabine plus nab paclitaxel versus surgery first for pancreatic adenocarcinoma"
} | [
{
"companynumb": "ES-CELGENEUS-ESP-2016030406",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
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{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "GEMCITABINE\\GEMCITABINE HYDROCHLORIDE"
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... |
{
"abstract": "We evaluated the efficacy of a post-grafting immunosuppressive regimen consisting of tacrolimus, methotrexate, and mycophenolate mofetil (MMF) in 21 adults (median age, 55 years) with poor-risk hematologic malignancy who underwent unrelated bone marrow transplantation after fludarabine-based reduced-intensity conditioning (RIC). In combination with intravenous tacrolimus and minidose methotrexate (5 mg/m2 on days 1, 3, and 6), MMF was orally administered at 30 mg/kg daily in three divided doses between days 7 and 27. All patients achieved neutrophil recovery with donor-type chimerism at a median of 19 days (range, 13-35). Cumulative incidences of grades II-IV and III-IV acute graft-versus-host disease (GVHD) were 33% (95% CI, 15-53%) and 5% (95% CI, 0.3-20%), respectively. Five of 20 evaluable patients developed extensive chronic GVHD. Toxicities associated with the use of MMF were acceptable, although one patient experienced intractable GVHD immediately after the cessation of MMF. With a median follow-up of 24 months, overall survival at 3 years was 38% (95% CI, 14-63%). No late graft failure was observed. In conclusion, post-transplant MMF combined with tacrolimus and methotrexate was well tolerated and conferred stable donor cell engraftment, low risk of severe acute GVHD, and encouraging overall survival in unrelated donor marrow transplantation after RIC regimens.",
"affiliations": "Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, 54 Shogoin Kawaharacho, Sakyo-ku, Kyoto, 606-8507, Japan.;Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, 54 Shogoin Kawaharacho, Sakyo-ku, Kyoto, 606-8507, Japan.;Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, 54 Shogoin Kawaharacho, Sakyo-ku, Kyoto, 606-8507, Japan. nohe@kuhp.kyoto-u.ac.jp.;Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, 54 Shogoin Kawaharacho, Sakyo-ku, Kyoto, 606-8507, Japan.;Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, 54 Shogoin Kawaharacho, Sakyo-ku, Kyoto, 606-8507, Japan.;Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, 54 Shogoin Kawaharacho, Sakyo-ku, Kyoto, 606-8507, Japan.;Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, 54 Shogoin Kawaharacho, Sakyo-ku, Kyoto, 606-8507, Japan.;Department of Hematology, Kokura Memorial Hospital, Kita-kyushu, Japan.;Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, 54 Shogoin Kawaharacho, Sakyo-ku, Kyoto, 606-8507, Japan.;Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, 54 Shogoin Kawaharacho, Sakyo-ku, Kyoto, 606-8507, Japan.;Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, 54 Shogoin Kawaharacho, Sakyo-ku, Kyoto, 606-8507, Japan.;Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, 54 Shogoin Kawaharacho, Sakyo-ku, Kyoto, 606-8507, Japan.;Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, 54 Shogoin Kawaharacho, Sakyo-ku, Kyoto, 606-8507, Japan.;Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, 54 Shogoin Kawaharacho, Sakyo-ku, Kyoto, 606-8507, Japan.;Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, 54 Shogoin Kawaharacho, Sakyo-ku, Kyoto, 606-8507, Japan.",
"authors": "Mizumoto|Chisaki|C|;Kanda|Junya|J|;Ichinohe|Tatsuo|T|;Ishikawa|Takayuki|T|;Matsui|Masashi|M|;Kadowaki|Norimitsu|N|;Kondo|Tadakazu|T|;Imada|Kazunori|K|;Hishizawa|Masakatsu|M|;Kawabata|Hiroshi|H|;Nishikori|Momoko|M|;Yamashita|Kouhei|K|;Takaori-Kondo|Akifumi|A|;Hori|Toshiyuki|T|;Uchiyama|Takashi|T|",
"chemical_list": "D009173:Mycophenolic Acid; D016559:Tacrolimus; D008727:Methotrexate",
"country": "Japan",
"delete": false,
"doi": "10.1007/s12185-009-0306-5",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0925-5710",
"issue": "89(4)",
"journal": "International journal of hematology",
"keywords": null,
"medline_ta": "Int J Hematol",
"mesh_terms": "D000208:Acute Disease; D000328:Adult; D000368:Aged; D016026:Bone Marrow Transplantation; D002908:Chronic Disease; D004305:Dose-Response Relationship, Drug; D006086:Graft vs Host Disease; D006801:Humans; D007938:Leukemia; D008727:Methotrexate; D008875:Middle Aged; D009173:Mycophenolic Acid; D015996:Survival Rate; D016559:Tacrolimus; D019172:Transplantation Conditioning",
"nlm_unique_id": "9111627",
"other_id": null,
"pages": "538-545",
"pmc": null,
"pmid": "19363648",
"pubdate": "2009-05",
"publication_types": "D016428:Journal Article",
"references": "17580263;16443519;18084333;7533411;12209350;10561185;17192496;12010826;9108426;11090046;9753033;17391494;15983549;12791654;16144801;10204198;17162215;8943876;15300236;7581076;11369628;17580257;16251851;11294511;16597592;18058141;1887253;15459007;9458011;12842990;11489799;11380402;2185339;12080355;12907447;11698269;17468773;18315786;16193083;11548843;12838284;17483064",
"title": "Mycophenolate mofetil combined with tacrolimus and minidose methotrexate after unrelated donor bone marrow transplantation with reduced-intensity conditioning.",
"title_normalized": "mycophenolate mofetil combined with tacrolimus and minidose methotrexate after unrelated donor bone marrow transplantation with reduced intensity conditioning"
} | [
{
"companynumb": "JP-SA-2014SA111006",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "WHOLE BLOOD"
},
"drugadditional": null,
"... |
{
"abstract": "OBJECTIVE\nTo report a patient who developed severe exacerbation of type 2 diabetes mellitus after the initiation of olanzapine therapy.\n\n\nMETHODS\nA 54-year-old African-American woman developed severe glucose dysregulation 12 days after the initiation of olanzapine. Prior to starting olanzapine therapy, the patient's diabetes was controlled by diet modification with a glycosylated hemoglobin of 6.5%. During olanzapine therapy, blood glucose concentrations could not be regulated despite use of antidiabetic agents, insulin, and dietary interventions. The patient also gained a total of 13 kg. Two weeks after discontinuation of all antipsychotic medications (olanzapine, quetiapine), the patient's blood glucose concentrations became better regulated and remained better controlled until discharge.\n\n\nCONCLUSIONS\nAll atypical antipsychotics are associated with weight gain. Obesity is a well-documented risk factor for developing type 2 diabetes mellitus. Currently there are only six published reports that implicate olanzapine as being associated with glucose dysregulation. The exact cause of glucose dysregulation with olanzapine is unclear, but weight gain does not seem to be the sole etiology. It has been hypothesized that serotonin (5-HT1A) antagonism may decrease the responsiveness of the pancreatic beta-cells. This would then result in inappropriately low insulin secretion and, therefore, hyperglycemia. Based on the Naranjo probability scale, the likelihood that olanzapine caused the glucose dysregulation in our patient was possible.\n\n\nCONCLUSIONS\nAlthough olanzapine has shown greater clinical efficacy and is associated with fewer extrapyramidal side effects than typical antipsychotics, it may produce exacerbation or new emergence of diabetes mellitus. Further examination of the incidence and etiology of glucose dysregulation after the initiation of olanzapine therapy is necessary.",
"affiliations": "College of Pharmacy, University of Texas at Austin, and Texas Department of Mental Health and Mental Retardation, 78712, USA.",
"authors": "Bettinger|T L|TL|;Mendelson|S C|SC|;Dorson|P G|PG|;Crismon|M L|ML|",
"chemical_list": "D014150:Antipsychotic Agents; D001786:Blood Glucose; D001569:Benzodiazepines; D010890:Pirenzepine; D000077152:Olanzapine",
"country": "United States",
"delete": false,
"doi": "10.1345/aph.19327",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1060-0280",
"issue": "34(7-8)",
"journal": "The Annals of pharmacotherapy",
"keywords": null,
"medline_ta": "Ann Pharmacother",
"mesh_terms": "D014150:Antipsychotic Agents; D001569:Benzodiazepines; D001786:Blood Glucose; D003924:Diabetes Mellitus, Type 2; D005260:Female; D006801:Humans; D008875:Middle Aged; D000077152:Olanzapine; D010890:Pirenzepine; D013997:Time Factors; D015430:Weight Gain",
"nlm_unique_id": "9203131",
"other_id": null,
"pages": "865-7",
"pmc": null,
"pmid": "10928397",
"pubdate": "2000",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Olanzapine-induced glucose dysregulation.",
"title_normalized": "olanzapine induced glucose dysregulation"
} | [
{
"companynumb": "US-MACLEODS PHARMACEUTICALS US LTD-MAC2022034408",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "OLANZAPINE"
},
"drugad... |
{
"abstract": "Chronic pain is associated with higher rates of psychiatric comorbidity, including substance use disorders. Patients with chronic pain often require opioids for their pain relief. Often, clinicians are reluctant to prescribe opioids to patients with chronic pain due to fear of patients becoming dependent on opioids. Diagnosing opioid addiction in chronic pain with comorbid prescription opioid use is challenging, as some of the symptoms of addiction overlap with those of physical dependence. A 28-year-old female presented with a history of recurrent abdominal pain beginning at the age of 16 years. The patient was diagnosed with chronic pancreatitis and was prescribed tramadol orally or injections for pain. The patient started experiencing craving with repeated administration of tramadol. She started using it daily and increased her dose to about 6-7 ampoules per day. She also developed complications due to injections. She was not able to work due to her pain, as well as injection use. She would go to multiple chemist shops for getting herself injected with tramadol injections. She also developed depressive symptoms in this period. Due to abdominal pain, the patient was admitted in the gastroenterology ward, from where she was shifted to the psychiatry ward for the management of opioid misuse and depressive symptoms. The patient was diagnosed to be suffering from opioid dependence syndrome with depressive episodes, for which she was provided tablet buprenorphine 14 mg/day dose along with tablet sertraline 150 mg/day. The case demonstrates several challenges in the diagnosis and management of opioid dependence and chronic pain when they occur simultaneously.",
"affiliations": "Department of Psychiatry, All India Institute of Medical Sciences, New Delhi, India.;Department of Psychiatry, All India Institute of Medical Sciences, New Delhi, India.;Department of Psychiatry, All India Institute of Medical Sciences, New Delhi, India.;Department of Psychiatry, All India Institute of Medical Sciences, New Delhi, India.;Department of Onco-Anaesthesis, Pain and Palliative Care, IRCH, All India Institute of Medical Sciences, New Delhi, India.;Department of Psychiatry, All India Institute of Medical Sciences, New Delhi, India.;Department of Psychiatry, All India Institute of Medical Sciences, New Delhi, India.",
"authors": "Kathiresan|Preethy|P|;Rao|Ravindra|R|;Joshi|Tanmay|T|;Bhad|Roshan|R|;Bhatnagar|Sushma|S|;Deb|Koushik Sinha|KS|;Chadda|Rakesh Kumar|RK|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.4103/IJPC.IJPC_232_19",
"fulltext": "\n==== Front\nIndian J Palliat Care\nIndian J Palliat Care\nIJPC\nIndian Journal of Palliative Care\n0973-1075 1998-3735 Wolters Kluwer - Medknow India \n\nIJPC-26-544\n10.4103/IJPC.IJPC_232_19\nCase Report\nChronic Noncancer Pain and Opioid Addiction: Diagnostic and Management Challenges\nKathiresan Preethy Rao Ravindra Joshi Tanmay Bhad Roshan Bhatnagar Sushma 1 Deb Koushik Sinha Chadda Rakesh Kumar Department of Psychiatry, All India Institute of Medical Sciences, New Delhi, India\n1 Department of Onco-Anaesthesis, Pain and Palliative Care, IRCH, All India Institute of Medical Sciences, New Delhi, India\nAddress for correspondence: Dr. Ravindra Rao, 4096, Department of Psychiatry, 4th Floor, Teaching Block, All India Institute of Medical Sciences, New Delhi - 110 029, India. E-mail: drrvrao@gmail.com\nOct-Dec 2020 \n19 11 2020 \n26 4 544 547\n21 12 2019 31 12 2019 Copyright: © 2020 Indian Journal of Palliative Care2020This 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.Chronic pain is associated with higher rates of psychiatric comorbidity, including substance use disorders. Patients with chronic pain often require opioids for their pain relief. Often, clinicians are reluctant to prescribe opioids to patients with chronic pain due to fear of patients becoming dependent on opioids. Diagnosing opioid addiction in chronic pain with comorbid prescription opioid use is challenging, as some of the symptoms of addiction overlap with those of physical dependence. A 28-year-old female presented with a history of recurrent abdominal pain beginning at the age of 16 years. The patient was diagnosed with chronic pancreatitis and was prescribed tramadol orally or injections for pain. The patient started experiencing craving with repeated administration of tramadol. She started using it daily and increased her dose to about 6–7 ampoules per day. She also developed complications due to injections. She was not able to work due to her pain, as well as injection use. She would go to multiple chemist shops for getting herself injected with tramadol injections. She also developed depressive symptoms in this period. Due to abdominal pain, the patient was admitted in the gastroenterology ward, from where she was shifted to the psychiatry ward for the management of opioid misuse and depressive symptoms. The patient was diagnosed to be suffering from opioid dependence syndrome with depressive episodes, for which she was provided tablet buprenorphine 14 mg/day dose along with tablet sertraline 150 mg/day. The case demonstrates several challenges in the diagnosis and management of opioid dependence and chronic pain when they occur simultaneously.\n\nChronic-noncancer-painopioid dependencephysical dependence\n==== Body\nINTRODUCTION\nChronic pain is defined as pain that either persists for or recurs for longer than 3 months.[12] Pain is one of the most prominent causes of years lived with disability and is associated with poor quality of life.[3] Chronic pain is also associated with higher rates of psychiatric comorbidity, including substance use disorders.[4] Patients with chronic pain often require opioids for their pain relief. Often, clinicians are reluctant to prescribe opioids to patients with chronic pain due to fear of patients becoming dependent on opioids. At times, this reluctance leads to underdosing with opioids, and results in partial improvement in pain, leading to dissatisfaction among patients.[5] This dilemma further deepens when a patient with chronic pain develops an addiction to the prescribed opioids. Diagnosing addiction in such cases is also challenging, as some of the symptoms of addiction overlap with those of physical dependence. The case presented below highlights some of the challenges one faces in the diagnosis and management of a patient with chronic pain who developed dependence to the opioid prescribed for the management of pain.\n\nCASE REPORT\nA 28-year-old married female educated up to Grade 12, belonging to the Hindu nuclear family of middle socioeconomic status, presented with a history of recurrent abdominal pain beginning at the age of 16 years. The abdominal pain was severe in nature originating in the epigastrium and left hypochondrium, further radiating to back and associated with vomiting. The pain used to get aggravated on the consumption of food for around 2 h, and relieved on bending forwards. The pain was episodic in nature, with each episode occurring once in 2–3 months and lasting for 3–4 days at a time. The patient was diagnosed to have chronic pancreatitis by a gastroenterology specialist and was prescribed pancreatic enzymes three times daily, along with tramadol 50 mg orally or injection as and when required for severe pain. The patient used to take Tramadol 50 mg orally or intravenously once in 2–3 months during episodes of severe pain. Around 2011, the patient underwent lateral pancreaticojejunostomy and was completely pain free following surgery for the next 2 years. Thereafter, in 2013, she again started to have similar pain as before and was given similar treatment (injection tramadol SOS for severe pain), which she would take once in 2–3 months. Two years later, the patient developed intermittent low mood, which gradually increased to persistent pervasive sadness of mood along with other depressive symptoms of moderate severity.\n\nIn 2017, when she had been again given injection tramadol intravenously for pain relief, the patient also experienced improvement in her mood and felt a sense of relaxation, which she liked. She continued getting herself injected with tramadol for pain relief daily for the next 1 week. However, after 1 week of continuous injection, the patient started to develop an intense desire to experience the relaxing effects of tramadol. Hence, she started to complain of pain (despite not having pain) to her family and got herself injected with tramadol daily. She started using one ampoule daily initially; however, she increased the dose gradually to 6–7 ampoules per day for 10 months, as she would not have the same effects with the previous dose. On days when she could not take the injection, she developed withdrawals in the form of severe anxiety, body ache, restlessness, lacrimation, and irritability, which used to get relieved only after taking the injection tramadol. She started to have repeated thoughts about when and where she can go and get herself injected again and started to neglect her household responsibilities, because of which her children had to shoulder the burden of household chores. She used to get herself injected always the help of trained persons such as doctors or chemists. She used to go to different medical shops in a single day itself to get injected and would spend even up to1 h waiting and convincing the local chemist or doctor to inject her under the plea of having severe abdominal pain. She developed scarring of veins, extravasation of injection leading to swelling, and seizures two to three times, despite which she continued to use the injections. She would be remorseful for her injection use behavior and think of stopping multiple times; however, she would not be able to control the use of injection tramadol.\n\nThe patient's depressive symptoms also persisted in the same intensity in this period. She also started to report of persistent abdominal pain daily, following which she was admitted to the gastroenterology department at the authors' institution. The patient continued to ask for tramadol injections in the gastroenterology ward and reported of depressive symptoms to the treating team, following which the patient was referred to the psychiatry department. In view of comorbid depressive symptoms and daily tramadol use, the patient was shifted to the psychiatry ward for further assessment and management.\n\nTHE DIAGNOSTIC CONUNDRUM – ADDICTION OR PHYSICAL DEPENDENCE?\nIn general, patients with comorbid chronic pain and misuse of prescribed opioids present a diagnostic challenge. On the face of it, the patient had opioid-related tolerance, withdrawals, and craving, which can point to a diagnosis of opioid dependence syndrome (ODS) (as per the International Classification of Diseases, [ICD]-10 criteria). However, it should be remembered here that daily use of prescribed opioids for a long-term can itself lead to physical dependence in the form of tolerance and withdrawal, due to the pharmacological property of the drug.[67] Similarly, patients who have not been given adequate pain relief may demand for more opioids, which might be mistaken to be “drug-seeking behavior” by the patient (“pseudoaddiction”).[89] Patients might also have a strong desire to take the drug to have a relief in withdrawal symptoms, which can be considered as “craving,” though the patient may not be “addicted” to opioids.[10] In such a situation, it becomes difficult to assess whether the patient has only physical dependence or “addiction” to opioids. Some studies show that neither the ICD-10 or Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV criteria are appropriate to diagnose “addiction” in chronic patients who are prescribed opioids for pain relief.[11] Similarly, the criteria laid down in DSM-5 for diagnosing opioid use disorder may not always apply to chronic pain who are on prescribed opioids.[12]\n\nA consensus document from the American Academy of Pain Medicine, the American Pain Society, and the American Society of Addiction Medicine specialists have listed impaired control over drug use, compulsive use, continued use despite harm, and craving as addiction criteria.[13] The present case had all these factors –inability to reduce or stop her use even when she wanted to, continued use despite complications in the form of vein complications and seizures. She neglected her household responsibilities and spent a large amount of time in procuring and injecting the drug. She had a craving for the “high” obtained after injecting tramadol, because of which she used to take tramadol even on days when she did not have pain. These symptoms helped us in making a diagnosis of “ODS” in the patient. Literature also mentioned other patient-related behaviors (aberrant drug-related behaviors) such as frequent loss or report of theft of opioid medication, stealing or borrowing drugs, and forging prescriptions as indicative of opioid misuse in a patient with chronic pain.[1415] In our case, these behaviors were not exhibited or indeed required, as the patient was able to access her opioid of choice (tramadol) relatively easily at the neighborhood pharmacist shops or registered medical practitioners.\n\nMANAGEMENT-RELATED CHALLENGES\nManagement of opioid dependence syndrome\nThe patient also posed challenges related to management. The first challenge was to manage ODS or opioid addiction. The strategies followed in cases of ODS not complicated by the presence of chronic pain include management of acute withdrawals alone, long-term opioid antagonist maintenance, or long-term opioid agonist maintenance treatment (OAMT). Of these, evidence overwhelmingly favors OAMT over the other two strategies, and consequently, most guidelines advocate the use of OAMT (also called opioid substitution therapy), unless otherwise indicated.[16]\n\nThe management of ODS in those with chronic noncancer pain poses a challenge for clinicians. Complete avoidance of opioids due to fear of addiction can lead to undertreatment of pain, leading to significant distress and reduced quality of life for patients. At the same time, the use of opioids without due diligence can lead to addiction in vulnerable patients. Indeed, it is a double-edged sword. There is limited literature or guidelines for the management of opioid dependence with comorbid pain.[17] The available literature, however, indicates the effectiveness of OAMT in managing both opioid dependence and pain. Of the two most commonly used medications (buprenorphine and methadone), guidelines and literature usually prefer buprenorphine for the treatment of opioid dependence with comorbid chronic noncancer pain due to its better safety profile including lesser chances of overdose and other adverse events such as corrected QT prolongation or respiratory depression compared to methadone, the other OAMT medicine.[18] In our case, we used buprenorphine as OAMT starting with 4 mg/day and gradually increased in dose to 14 mg/day. With this, the patient did not experience any opioid withdrawals, while opioid craving was present only intermittently. The dose of buprenorphine was increased to 16 mg/day; however, the patient developed urinary retention at this dose, due to which the dose was lowered to 14 mg/day. Opioid craving was managed by nonpharmacological therapies.\n\nManagement of comorbid psychiatric illnesses\nDetailed assessment for psychiatric illnesses was carried out after admission in the psychiatric ward. It was noted that the patient also fulfilled the criteria of emotionally unstable personality disorder. The patient also suffered from emotional neglect in childhood along with physical abuse by her stepmother in childhood. The patient's father also had a problem with alcohol use. There were significant interpersonal problems between the patient and her husband, not only due to the patient's illnesses but also due to her husband's daily alcohol use. The management of such cases poses additional challenges as every disorder potentially affects the course and outcome of the other. Studies have also found that the presence of such factors can increase the likelihood of a patient misusing opioids when given for chronic pain relief. The factors identified in most literature include concomitant psychiatric illnesses such as depression or anxiety disorders, history of substance use disorder, social instability, younger age, family history of substance use disorder, and history of sexual abuse.[1920] Our patient had most of these risk factors, which could have led her to misuse the prescribed opioid and develop opioid addiction.\n\nThe patient's depressive episode was managed with tablet sertraline in dose of up to 150 mg daily. Joint sessions were taken with the patient and her husband to address interpersonal issues, and the husband was offered to seek help for his alcohol use problem. Emotionally Unstable Personality Disorder was addressed through nonpharmacological strategies along with the use of tablet aripiprazole 15 mg/day.\n\nManagement of chronic pain\nThe presence of continued pain in a patient with opioid dependence or while on treatment with OAMT medicines leads to both diagnostic and management challenges. There is a degree of mistrust among clinicians when a patient with opioid dependence reports pain and requests for increase in dose of opioids.[2122] There is a tendency to ascribe complaints of pain to an attempt to increase the dose of opioids received. In our case, the patient's generalized body pain subsided on starting buprenorphine. The pancreatic pain also reduced but did not subside completely. Ultrasound of the whole abdomen showed multiple calcific foci in the body, head, and tail of the pancreas with prominent pancreatic duct (2.6 mm). Pain charting showed a baseline pain severity of 40/100 on Visual Analog Score (VAS), with exacerbation in pain severity after meals to 80/100 on VAS for around 2–3 h. Pancreatic enzymes were increased to six tablets per day, with which there was initial improvement by around 20% for the initial 2 days, but again pain got aggravated. Patient's craving for opioids also would increase during the episodes of severe pain. The vitals charting showed an increase in systolic blood pressure (BP) by 20 mm Hg from baseline and increase in pulse rate by around 20 beats/min from the baseline, during the episodes of severe pain. However, such increase in BP and pulse rate can also occur during craving. Hence, a consultation from the pain clinic was sought. A diagnostic, temporary local celiac plexus block was performed, with which there was a significant improvement in pain by around 90% and improvement in craving for about a week. The local celiac plexus block was repeated after a week with which there was 90% improvement in pain once again. The patient was also given tablet gabapentin in doses of 900 mg/day for pain. With all these measures, there was a persistent decrease in pain to around 10–20/100 VAS.\n\nAt the time of discharge, the patient was euthymic, her craving for opioids had reduced to 40/100 on VAS, and her pain had reduced to 20/100 on VAS.\n\nCONCLUSION\nThe diagnosis and management of patients with comorbid opioid dependence and chronic noncancer pain is a challenge, which requires multidisciplinary treatment and collaboration with various departments. The challenge is for both the addiction treatment as well as pain management specialists. This case aptly illustrates this diagnostic and management challenges. There is a need for further research on the best ways to approach and manage such cases in a multidisciplinary setting.\n\nDeclaration of patient consent\nThe authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.\n\nFinancial support and sponsorship\nNil.\n\nConflicts of interest\nThere are no conflicts of interest.\n==== Refs\nREFERENCES\n1 Treede RD Rief W Barke A Aziz Q Bennett MI Benoliel R A classification of chronic pain for ICD-11 Pain 2015 156 1003 7 25844555 \n2 World Health Organization International Statistical Classification of Diseases and Related Health Problems (11th Revision) ICD-11 – Mortality and Morbidity Statistics World Health Organization 2018 [Last accessed on 2019 Jun 21] Available from: https://icdwhoint/browse11/l-m/en#/http://idwhoint/icd/entity/1581976053 \n3 Monti S Caporali R Chronic pain: The burden of disease and treatment innovations Reumatismo 2015 67 35 44 26492961 \n4 Hooten WM Chronic pain and mental health disorders: Shared neural mechanisms, epidemiology, and treatment Mayo Clin Proc 2016 91 955 70 27344405 \n5 Cornett EM Budish R Latimer D Hart B Urman RD Kaye AD Management of challenging pharmacologic issues in chronic pain and substance abuse disorders Anesthesiol Clin 2018 36 615 26 30390782 \n6 Ballantyne JC LaForge KS Opioid dependence and addiction during opioid treatment of chronic pain Pain 2007 129 235 55 17482363 \n7 Christie MJ Cellular neuroadaptations to chronic opioids: Tolerance, withdrawal and addiction Br J Pharmacol 2008 154 384 96 18414400 \n8 Weissman DE Haddox JD Opioid pseudoaddiction: An iatrogenic syndrome Pain 1989 36 363 6 2710565 \n9 Bell K Salmon A Pain, physical dependence and pseudoaddiction: Redefining addiction for 'nice' people? Int J Drug Policy 2009 20 170 8 18768306 \n10 Juurlink DN Dhalla IA Dependence and addiction during chronic opioid therapy J Med Toxicol 2012 8 393 9 23073725 \n11 Højsted J Nielsen PR Guldstrand SK Frich L Sjøgren P Classification and identification of opioid addiction in chronic pain patients Eur J Pain 2010 14 1014 20 20494598 \n12 Gorfinkel L Voon P Wood E Klimas J Diagnosing opioid addiction in people with chronic pain BMJ 2018 362 k3949 30242012 \n13 Savage SR Joranson DE Covington EC Schnoll SH Heit HA Gilson AM Definitions related to the medical use of opioids: Evolution towards universal agreement J Pain and Symptom Management 2003 26 655 67 \n14 Arthur J Hui D Safe Opioid Use: Management of Opioid-Related Adverse Effects and Aberrant Behaviors Hematol Oncol Clin North Am 2018 32 387 403 29729776 \n15 Webster LR Webster RM Predicting aberrant behaviors in opioid-treated patients: Preliminary validation of the Opioid Risk Tool Pain Med 2005 6 432 42 16336480 \n16 World Health Organization United Nations Office on Drugs and Crime, Joint United Nations Programme on HIV/AIDS.Substitution Maintenance Therapy in the Management of Opioid Dependence and HIV/AIDS Prevention: WHO/UNODC/UNAIDS Position Paper 2004 Geneva World Health Organization \n17 Voon P Karamouzian M Kerr T Chronic pain and opioid misuse: A review of reviews Subst Abuse Treat Prev Policy 2017 12 36 28810899 \n18 Kahan M Wilson L Mailis-Gagnon A Srivastava A National Opioid Use Guideline Group. Canadian guideline for safe and effective use of opioids for chronic noncancer pain: Clinical summary for family physicians. Part 2: Special populations Can Fam Physician 2011 57 1269 76 e419-28 22084456 \n19 Turk DC Swanson KS Gatchel RJ Predicting opioid misuse by chronic pain patients: A systematic review and literature synthesis Clin J Pain 2008 24 497 508 18574359 \n20 Volkow ND McLellan AT Opioid abuse in chronic pain – Misconceptions and Mitigation Strategies N Engl J Med 2016 374 1253 63 27028915 \n21 Quinlan J Cox F Acute pain management in patients with drug dependence syndrome Pain Rep 2017 2 e611 29392226 \n22 Buchman DZ Ho A Illes J You present like a drug addict: Patient and clinician perspectives on trust and trustworthiness in chronic pain management Pain Med 2016 17 1394 406 26759389\n\n",
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"issue": "26(4)",
"journal": "Indian journal of palliative care",
"keywords": "Chronic-noncancer-pain; opioid dependence; physical dependence",
"medline_ta": "Indian J Palliat Care",
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"title": "Chronic Noncancer Pain and Opioid Addiction: Diagnostic and Management Challenges.",
"title_normalized": "chronic noncancer pain and opioid addiction diagnostic and management challenges"
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"abstract": "There has been growing concern surrounding the use of unconfined power morcellation in laparoscopic surgeries for uterine leiomyoma due to its associated risks and long-term clinical sequelae, including parasitic leiomyomas and disseminated peritoneal leiomyomatosis (DPL). We present a case of DPL resulting from previous laparoscopic morcellation and a review of the existing literature. DPL is a potentially devastating consequence of unconfined laparoscopic morcellation in the surgical management of uterine fibroids. A multidisciplinary approach is recommended in the management of DPL, especially in cases of multivisceral involvement. Clinical caution ought to be exercised when using power morcellators; when unavoidable, confined laparoscopic morcellation offers a promising mitigation and should be adopted if practicable.",
"affiliations": "Department of Hepatopancreatobiliary and Transplant Surgery, Singapore General Hospital, Singapore.;Department of Hepatopancreatobiliary and Transplant Surgery, Singapore General Hospital, Singapore.;Department of Colorectal Surgery, Singapore General Hospital, Singapore.;Division of Obstetrics and Gynaecology, KK Women's and Children's Hospital, Singapore.;Department of Obstetrics and Gynaecology, Singapore General Hospital, Singapore.;Department of Anatomical Pathology, Singapore General Hospital, Singapore.;Department of Hepatopancreatobiliary and Transplant Surgery, Singapore General Hospital, Singapore.",
"authors": "Tan|Hwee Leong|HL|;Koh|Ye Xin|YX|;Chew|Min Hoe|MH|;Wang|Junjie|J|;Lim|Jason Shau Khng|JSK|;Leow|Wei Qiang|WQ|;Lee|Ser Yee|SY|",
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"issue": "60(12)",
"journal": "Singapore medical journal",
"keywords": "disseminated peritoneal leiomyomatosis; laparoscopic morcellation; parasitic leiomyoma",
"medline_ta": "Singapore Med J",
"mesh_terms": "D000328:Adult; D018450:Disease Progression; D005260:Female; D006801:Humans; D007044:Hysterectomy; D010535:Laparoscopy; D007889:Leiomyoma; D018231:Leiomyomatosis; D000069577:Morcellation; D010534:Peritoneal Neoplasms; D014057:Tomography, X-Ray Computed; D014594:Uterine Neoplasms",
"nlm_unique_id": "0404516",
"other_id": null,
"pages": "652-654",
"pmc": null,
"pmid": "31889207",
"pubdate": "2019-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "26943477;21719004;26234998;25395465;27125448;25331441;17651554;29783003;28586771;18617593;26802909;25218993;9252927",
"title": "Disseminated peritoneal leiomyomatosis: a devastating sequelae of unconfined laparoscopic morcellation.",
"title_normalized": "disseminated peritoneal leiomyomatosis a devastating sequelae of unconfined laparoscopic morcellation"
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"companynumb": "SG-TOLMAR, INC.-20SG020172",
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"activesubstancename": "LEUPROLIDE ACETATE"
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"abstract": "Thrombotic microangiopathic syndromes are characterized by thrombus formation leading to microangiopathic hemolytic anemia, thrombocytopenia, and end-organ injury that most often affects the kidney and brain. Patients with thrombotic microangiopathy can also present with cardiac involvement, which has been shown to worsen their prognosis. We describe the case of a 46-year-old woman who presented with acute congestive heart failure as a manifestation of catastrophic antiphospholipid syndrome, which is characterized by rapidly progressing multiorgan involvement. Targeted therapy improved our patient's cardiomyopathy and saved her life. Increased recognition of thrombotic microangiopathy as an underlying pathophysiologic mechanism in heart failure and initiation of timely treatment may help to prevent death in patients with thrombotic microangiopathy.",
"affiliations": null,
"authors": "Tulai|Iulia M|IM|;Penciu|Oana M|OM|;Raut|Raymond|R|;Rudinskaya|Alla|A|",
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"issue": "46(1)",
"journal": "Texas Heart Institute journal",
"keywords": "Acute disease; cytomegalovirus infections/complications; heart failure/diagnosis/etiology; lupus erythematosus, systemic/complications/pathology; thrombotic microangiopathies/diagnosis/etiology; treatment outcome",
"medline_ta": "Tex Heart Inst J",
"mesh_terms": "D000208:Acute Disease; D016736:Antiphospholipid Syndrome; D001706:Biopsy; D018618:Echocardiography, Doppler, Color; D004562:Electrocardiography; D005260:Female; D006333:Heart Failure; D006801:Humans; D008875:Middle Aged; D057049:Thrombotic Microangiopathies",
"nlm_unique_id": "8214622",
"other_id": null,
"pages": "48-52",
"pmc": null,
"pmid": "30833839",
"pubdate": "2019-02",
"publication_types": "D002363:Case Reports",
"references": "19790130;3334284;18250089;19175494;1315712;3907317;15866258;25119611",
"title": "Catastrophic Antiphospholipid Syndrome Presenting as Congestive Heart Failure in a Patient with Thrombotic Microangiopathy.",
"title_normalized": "catastrophic antiphospholipid syndrome presenting as congestive heart failure in a patient with thrombotic microangiopathy"
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"companynumb": "US-APOTEX-2019AP011888",
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"abstract": "Defects in the surfactant biosynthesis are associated with respiratory distress syndrome, commonly occurring in premature infants due to lung immaturity. However, interstitial lung diseases have also been observed in full-term infants with mutations in the SFTPC, SFTPB, NKX2-1, or ABCA3 genes, involved in the surfactant metabolism. Herein, we report a newborn baby with neonatal respiratory distress and diffuse lung disease caused by ABCA3 mutation. The baby died at 5 weeks of age after developing pulmonary hypertension. Genomic DNA was analyzed for four genes involved in surfactant metabolism out of which the c. 4545C>G (p.Tyr1515*) homozygous mutation in exon 29 of ABCA3 was identified which is one of the most frequent mutation causing lethal neonatal respiratory failure in a term neonate. This case study emphasizes the importance of raising awareness about this diagnosis in the clinical settings for fruitful outcomes in health-care delivery.",
"affiliations": "Department of Pediatrics, Security Forces Hospital, Alfaisal University, Riyadh, Saudi Arabia.;Department of Pediatrics, Creteil Intercommunal Hospital, France.;Research Center, King Fahad Medical City, Riyadh, Saudi Arabia.;Genetic Department, Henri Mondor Hospital, France.;Department of Pediatrics, NICU, Security Forces Hospital, Riyadh, Saudi Arabia.;Genetic Department, Henri Mondor Hospital, France.",
"authors": "AlAnazi|AlNashmi|A|;Epaud|Ralph|R|;Heena|Humariya|H|;de Becdelievre|Alix|A|;Miqdad|Abeer Mohammad|AM|;Fanen|Pascale|P|",
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"doi": "10.4103/atm.ATM_386_16",
"fulltext": "\n==== Front\nAnn Thorac MedAnn Thorac MedATMAnnals of Thoracic Medicine1817-17371998-3557Medknow Publications & Media Pvt Ltd India ATM-12-21310.4103/atm.ATM_386_16Case ReportThe most frequent ABCA3 nonsense mutation -p.Tyr1515* (Y1515X) causing lethal neonatal respiratory failure in a term neonate AlAnazi AlNashmi Epaud Ralph Pr.1Heena Humariya 2de becdelievre Alix 3Miqdad Abeer Mohammad 4Fanen Pascale Pr.3Department of Pediatrics, Security Forces Hospital, Alfaisal University, Riyadh, Saudi Arabia1 Department of Pediatrics, Creteil Intercommunal Hospital, France2 Research Center, King Fahad Medical City, Riyadh, Saudi Arabia3 Genetic Department, Henri Mondor Hospital, France4 Department of Pediatrics, NICU, Security Forces Hospital, Riyadh, Saudi ArabiaAddress for correspondence: Dr. AlNashmi AlAnazi, Department of Pediatrics, Security Forces Hospital, Alfaisal University, Riyadh, Saudi Arabia. E-mail: alnashmialanazi@gmail.comJul-Sep 2017 12 3 213 215 22 11 2016 11 1 2017 Copyright: © 2017 Annals of Thoracic Medicine2017This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.Defects in the surfactant biosynthesis are associated with respiratory distress syndrome, commonly occurring in premature infants due to lung immaturity. However, interstitial lung diseases have also been observed in full-term infants with mutations in the SFTPC, SFTPB, NKX2-1, or ABCA3 genes, involved in the surfactant metabolism. Herein, we report a newborn baby with neonatal respiratory distress and diffuse lung disease caused by ABCA3 mutation. The baby died at 5 weeks of age after developing pulmonary hypertension. Genomic DNA was analyzed for four genes involved in surfactant metabolism out of which the c. 4545C>G (p.Tyr1515*) homozygous mutation in exon 29 of ABCA3 was identified which is one of the most frequent mutation causing lethal neonatal respiratory failure in a term neonate. This case study emphasizes the importance of raising awareness about this diagnosis in the clinical settings for fruitful outcomes in health-care delivery.\n\nInterstitial lung diseaseneonatal respiratory failurepediatric pulmonology\n==== Body\nDefects in the surfactant biosynthesis are associated with respiratory distress syndrome, which commonly occurs in premature infants due to lung immaturity. However, inherited surfactant metabolism disorders may cause a similar presentation in full-term newborns along with interstitial lung diseases (ILDs) in older children and adults. ILD have been observed in full-term infants with mutations in the SFTPC, SFTPB, NKX2-1, or ABCA3 genes, which are involved in the surfactant biosynthesis.[12] ABCA3 is a member of the ATP-binding cassette (ABC) transporter family which encodes membrane proteins involved in the transport of compounds across biologic membranes. ABCA3 is a 1704-amino-acid protein highly expressed in alveolar epithelial cells at the limiting membrane of lamellar bodies[3] and is crucial for AT2 cells homeostasis, lipid composition (importation of phospholipids in lamellar bodies) and protein maturation of surfactant.[4] More than 150 recessive mutations of the ABCA3 gene have been reported in newborn babies with respiratory failure and in older children or adults with ILD.[5] We report here a full-term infant with severe respiratory failure after 8 days of life, in whom we identified an ABCA3 null mutation at the homozygous state, namely, p. Tyr1515* (Y1515X). This truncating mutation causes a total loss of function of the ABCA3 protein.\n\nCase Report\nOur patient was from a consanguineous family (parents were first cousins) originating from Saudi Arabia. One older sister was asymptomatic, but there was a familial history since one sibling had died at 5 days of life due to meconium aspiration syndrome and bilateral pneumothorax with persistent pulmonary hypertension of the newborn [Figure 1].\n\nFigure 1 Pedigree of the family and identification of the homozygous mutation\n\nThe index patient was a full-term baby boy delivered normally with a weight of 3.74 kg after an uneventful pregnancy. Within the first few hours of life, he developed severe respiratory distress and required invasive ventilation. Chest radiograms at first few hours showed diffuse reticular granularity and air bronchograms [Figure 2] due to which the baby received three doses of exogenous surfactant (4 ml/kg) as standard first-line treatment but with only transient improvement. Although the blood cultures were negative, the boy remained ventilated with worsening of the chest radiogram and developed pulmonary hypertension despite receiving intravenous corticosteroids (dexamethasone) treatment (0.1 mg/kg/dose once daily for 2 weeks). As the baby's condition worsened, the respiratory failure occurred due to the hypoxemia initially and at later stages due to CO2 retention. Ultimately, he needed more respiratory support and was put on high-frequency ventilation with inhaled nitric oxide at 20 ppm.\n\nFigure 2 The chest X-ray images of the neonate\n\nDue to the family history, genetic analysis of genes associated with surfactant metabolism disorders was performed. Informed consent was obtained from the parents according to the current regulations. Genomic DNA was extracted from a peripheral blood ethylenediaminetetraacetic acid sample. The four genes involved in surfactant metabolism deficiency were explored by Sanger sequencing of all coding exons and their intronic flanking regions: SFTPC (NM_003018.3), SFTPB (NM_00542.3),NKX2-1 (NM_001079668), and ABCA3 (NM_001089.2). Sequence variations' pathogenicity was evaluated in silico on Alamut Visual version 2.7 software (Interactive Biosoftwares, Rouen, France). No mutation was detected in the SFTPC, SFTPB, and NKX2-1 genes, however, we identified the c.4545C>G (p. Tyr1515*) mutation in homozygosity in exon 29 of ABCA3 [Figure 1]. This substitution of a tyrosine codon by a premature stop codon is predicted to lead to a truncated protein.\n\nAfter the genetic result of ABCA3-related surfactant, metabolism disorder was obtained, another course of dexamethasone was given without any further improvement. The baby deceased at the age of 5 weeks.\n\nDiscussion\nPulmonary surfactant constitutes a tensioactive film covering the alveolar lumen and is necessary to avoid alveolar collapse during dynamic compression and decompression. The hydrophobic surfactant proteins SP-B and SP-C play a role in innate host lung defense and are transported to and stored in lamellar bodies-the secretory organelles of AT2 cells where they undergo posttranslational maturation before secretion at the epithelial surface.[4] Mature SP-B and SP-C interact with phospholipids to confer tension-active properties to the pulmonary surfactant.\n\nFour genes have mainly been implicated in genetic abnormalities of the surfactant: SFTPB, SFTPC, NKX2-1, and ABCA3, encoding respectively the specific proteins of the surfactant SP-B and SP-C, the transcription factor NKX2-1 which regulates the transcription of SFTPB, SFTPC, and ABCA3 genes. As with SP-B deficiency, ABCA3 deficiency is now recognized as the most frequent cause of genetic surfactant metabolism disorder[6] and should be suspected in full-term infants with severe neonatal respiratory distress syndrome refractory to conventional treatment[578] ABCA3 deficiency leads to abnormal lamellar bodies' structure and abnormal surfactant lipid composition, associated with impaired processing of SP-B and SP-C protein.[910] Total loss of function leads to dramatic progress with neonatal distress syndrome and death within the 1st year of life whereas residual ABCA3 function is associated with milder disease.[5] Most mutations are unique, which can make the genetic counseling difficult in the families, especially in the case of missense mutations (amino acid substitution) where phenotype-genotype correlation is unknown. However, some are considered “frequent,” as they have been reported among multiple patients as is the case for the p. Glu292Val (E292V) mutation which is the most frequent mutation in a population of European descent.[11] Similarly, p. Tyr1515* mutation in the ABCA3 gene seemed to be more frequent in the Middle East,[5] as it was recently described in 18 consanguineous families originating from Middle East region. In our extensive study, although it was considered as a null mutation (no residual function of ABCA3) no functional study was performed. Unfortunately, no bronchoalveolar lavage was available for our patient hence neither mRNA nor SP studies could be carried out to determine if nonsense-mediated mRNA decay degraded abnormal transcribed mRNA or if it was translated into a truncated protein. However, this mutation was located at the end of the functional nucleotide binding domain 2, which binds adenosine triphosphate and allows channel gating and lipid transport. Such mutation at the homozygous state is thought to cause a complete absence of functional ABCA3 protein and thus a severe defect in surfactant biosynthesis.\n\nNeonate respiratory distress due to impaired surfactant metabolism is a rare condition, and most clinical centers examine very few cases. Therefore, the ChILD-EU (ILD in children) collaboration recently published guidelines to diagnose the disease and to treat it when it is possible.[12] Besides oxygen therapy, usual treatment suggestions include methylprednisolone, hydroxychloroquine, and azithromycin. However, in case of neonatal presentation, where rapid intubation and ventilation is required, respiratory failure often leads to death or lung transplantation is performed where available. Our case drew similarities to all 19 p. Tyr1515* homozygous patients described recently with patients presenting with severe respiratory distress syndrome and death before 3 months of age.[5] Since ABCA3 is a large gene of 30 coding exons, so the molecular analysis is time-consuming. In such cases with a frequent mutation according to geographic origin, the mutation could be searched for as a first rapid step of the study, followed by analysis of all exons. This could help expedite the therapeutic approach or the ending of the care resulting in the reduced burden on the health-care resources of a country. This case also illustrates the need for genetic analysis in patients presenting with ILD. Indeed, in this consanguineous family, two children died of surfactant metabolism deficiency before 1 month of life. Elucidating the molecular cause of the disease in families is of tremendous importance for genetic counseling and mandatory prenatal diagnosis to prevent further pregnancies and toward achieving better health outcomes. Genetic studies of all SPs, not only ABCD3, should be studied in suspected cases because the presentations of the different SPs deficiencies may be overlapping. Moreover, ABCA3 gene mutation is important because it might ultimately obviate the need for lung biopsy with improved patient outcomes in these cases.[13]\n\nThe findings from this case report emphasize the need to perform genetic analysis in newborns with severe respiratory distress to adapt a better therapeutic approach along with timely genetic counseling.\n\nConclusions\np. Tyr1515* (Y1515X) is one of the most frequent mutations in exon 29 of ABCA3, usually leading to death within the 1st months. Appropriate prenatal diagnosis will help to deliver specific patient care and better outcomes. Similarly, mandatory genetic counseling is of remarkable importance to prevent further pregnancies and hence achieve better health outcomes. This case study aims to act as stepping stone to raise awareness of genetic counseling among parents as well as health-care providers.\n\nFinancial support and sponsorship\nNil.\n\nConflicts of interest\nThere are no conflicts of interest.\n==== Refs\n1 Mukhtar GM Al Otaibi WH Al-Mobaireek KF Al-Saleh S Adenosine triphosphate-binding cassette member A3 gene mutation in children from one family from Saudi Arabia Ann Thorac Med 2016 11 227 9 27512515 \n2 Wambach JA Yang P Wegner DJ Heins HB Kaliberova LN Kaliberov SA Functional characterization of ATP-binding cassette transporter A3 mutations from infants with respiratory distress syndrome Am J Respir Cell Mol Biol 2016 55 716 21 27374344 \n3 Wittmann T Schindlbeck U Höppner S Kinting S Frixel S Kröner C Tools to explore ABCA3 mutations causing interstitial lung disease Pediatr Pulmonol 2016 51 1284 94 27177387 \n4 Bush A Cunningham S de Blic J Barbato A Clement A Epaud R European protocols for the diagnosis and initial treatment of interstitial lung disease in children Thorax 2015 70 1078 84 26135832 \n5 Wambach JA Casey AM Fishman MP Wegner DJ Wert SE Cole FS Genotype-phenotype correlations for infants and children with ABCA3 deficiency Am J Respir Crit Care Med 2014 189 1538 43 24871971 \n6 Flamein F Riffault L Muselet-Charlier C Pernelle J Feldmann D Jonard L Molecular and cellular characteristics of ABCA3 mutations associated with diffuse parenchymal lung diseases in children Hum Mol Genet 2012 21 765 75 22068586 \n7 Whitsett JA Wert SE Weaver TE Alveolar surfactant homeostasis and the pathogenesis of pulmonary disease Annu Rev Med 2010 61 105 19 19824815 \n8 Wert SE Whitsett JA Nogee LM Genetic disorders of surfactant dysfunction Pediatr Dev Pathol 2009 12 253 74 19220077 \n9 Garmany TH Wambach JA Heins HB Watkins-Torry JM Wegner DJ Bennet K Population and disease-based prevalence of the common mutations associated with surfactant deficiency Pediatr Res 2008 63 645 9 18317237 \n10 Cheong N Zhang H Madesh M Zhao M Yu K Dodia C ABCA3 is critical for lamellar body biogenesis in vivo J Biol Chem 2007 282 23811 7 17540762 \n11 Hartl D Griese M Interstitial lung disease in children – Genetic background and associated phenotypes Respir Res 2005 6 32 15819986 \n12 Shulenin S Nogee LM Annilo T Wert SE Whitsett JA Dean M ABCA3 gene mutations in newborns with fatal surfactant deficiency N Engl J Med 2004 350 1296 303 15044640 \n13 Yamano G Funahashi H Kawanami O Zhao LX Ban N Uchida Y ABCA3 is a lamellar body membrane protein in human lung alveolar type II cells FEBS Lett 2001 508 221 5 11718719\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "1998-3557",
"issue": "12(3)",
"journal": "Annals of thoracic medicine",
"keywords": "Interstitial lung disease; neonatal respiratory failure; pediatric pulmonology",
"medline_ta": "Ann Thorac Med",
"mesh_terms": null,
"nlm_unique_id": "101280721",
"other_id": null,
"pages": "213-215",
"pmc": null,
"pmid": "28808495",
"pubdate": "2017",
"publication_types": "D002363:Case Reports",
"references": "26135832;18317237;15044640;15819986;19220077;27177387;22068586;27374344;19824815;17540762;24871971;11718719;27512515",
"title": "The most frequent ABCA3 nonsense mutation -p.Tyr1515* (Y1515X) causing lethal neonatal respiratory failure in a term neonate.",
"title_normalized": "the most frequent abca3 nonsense mutation p tyr1515 y1515x causing lethal neonatal respiratory failure in a term neonate"
} | [
{
"companynumb": "SA-BAUSCH-BL-2017-023667",
"fulfillexpeditecriteria": "1",
"occurcountry": "SA",
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"actiondrug": "6",
"activesubstance": {
"activesubstancename": "DEXAMETHASONE"
},
"drugadditional": null,
... |
{
"abstract": "Ibrutinib is a Bruton's tyrosine kinase (BTK) inhibitor approved for second-line treatment for mantle cell lymphoma (MCL), chronic lymphocytic leukemia (CLL), and Waldenström macroglobulinemia. Ibrutinib use has been linked to increased incidence of atrial fibrillation and hypertension in multiple studies. Other forms of cardiac toxicities have also been reported in isolated case reports. Bradycardia and asystole have not been associated with ibrutinib use in the past.\nWe present a case of a 76-year-old female with no prior cardiac history, who initiated treatment with ibrutinib for relapsing mantle cell lymphoma and was noted to have symptomatic bradycardia, greater than 20 second long pauses on her cardiac monitor requiring placement of a permanent pacemaker.\nThis is the first case associating bradycardia and asystole with tyrosine kinase inhibitor use. Irreversible inhibition of certain cardioprotective tyrosine kinases has been a growing topic of research in oncology therapeutics.",
"affiliations": "Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA, USA.;Department of Cardiac Electrophysiology, Virginia Commonwealth University, Richmond, VA, USA.;Department of Cardiac Electrophysiology, Virginia Commonwealth University, Richmond, VA, USA.;Department of Cardiac Electrophysiology, Virginia Commonwealth University, Richmond, VA, USA.",
"authors": "Mathur|Kanupriya|K|0000-0002-2790-5796;Saini|Aditya|A|;Ellenbogen|Kenneth A|KA|;Shepard|Richard K|RK|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1155/2017/7304021",
"fulltext": "\n==== Front\nCase Rep Oncol MedCase Rep Oncol MedCRIONMCase Reports in Oncological Medicine2090-67062090-6714Hindawi 10.1155/2017/7304021Case ReportProfound Sinoatrial Arrest Associated with Ibrutinib http://orcid.org/0000-0002-2790-5796Mathur Kanupriya kanupriya405@gmail.com\n1\nSaini Aditya \n2\nEllenbogen Kenneth A. \n2\nShepard Richard K. \n2\n\n1Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA, USA\n2Department of Cardiac Electrophysiology, Virginia Commonwealth University, Richmond, VA, USAAcademic Editor: Josep M. Ribera\n\n2017 10 12 2017 2017 73040219 8 2017 13 11 2017 Copyright © 2017 Kanupriya Mathur et al.2017This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Background\n Ibrutinib is a Bruton's tyrosine kinase (BTK) inhibitor approved for second-line treatment for mantle cell lymphoma (MCL), chronic lymphocytic leukemia (CLL), and Waldenström macroglobulinemia. Ibrutinib use has been linked to increased incidence of atrial fibrillation and hypertension in multiple studies. Other forms of cardiac toxicities have also been reported in isolated case reports. Bradycardia and asystole have not been associated with ibrutinib use in the past. \n\nCase Report\n We present a case of a 76-year-old female with no prior cardiac history, who initiated treatment with ibrutinib for relapsing mantle cell lymphoma and was noted to have symptomatic bradycardia, greater than 20 second long pauses on her cardiac monitor requiring placement of a permanent pacemaker. \n\nConclusion\n This is the first case associating bradycardia and asystole with tyrosine kinase inhibitor use. Irreversible inhibition of certain cardioprotective tyrosine kinases has been a growing topic of research in oncology therapeutics.\n==== Body\n1. Background\nIbrutinib (Imbruvica, Pharmacyclics, Inc.) is a Bruton's tyrosine kinase (BTK) inhibitor approved for use in patients with mantle cell lymphoma (MCL), chronic lymphocytic leukemia (CLL), and Waldenström macroglobulinemia. Ibrutinib use has been linked to increased incidence of atrial fibrillation and hypertension in multiple studies [1–4]. Other forms of cardiac toxicities have also been reported in isolated case reports [5]. We report a case of recurrent and profound sinus arrest in a patient treated with ibrutinib for MCL.\n\n2. Case Report\nA 76-year-old Caucasian female with a past medical history of mantle cell lymphoma (MCL), hypertension, and gastroesophageal reflux disease presented to the hospital with intractable nausea and vomiting of one week duration. With regard to treatment of her MCL, she had failed first-line treatment with bendamustine-rituximab following which she had received R-CHOP (rituximab, cyclophosphamide, vincristine, and prednisolone) chemotherapy. However, due to her advancing disease detected by positron emission tomography imaging and lymph node biopsy, she was started on ibrutinib 560 mg daily 11 days ago. She took the medication for 8 days after which she could not tolerate it due to intractable nausea and vomiting. She was unable to tolerate any of her other medications and quit taking all of them 5 days prior to admission. Her other home medications were reviewed, which included atorvastatin 20 mg daily, carvedilol 3.125 mg twice daily, citalopram 10 mg daily, and lisinopril 5 mg daily. While in the hospital, she continued to have nausea for two more days. During this time, her potassium (K+) level was low (range: 2.4–3.2 meq/L), and she received K+ replacement. In the first 48 hours of hospitalization, she experienced 2 episodes of brief syncope lasting a few seconds and sinus pauses (up to 6 seconds), which appeared to be vagally mediated, as they occurred immediately after an episode of retching or coughing. Her baseline 12-lead electrocardiogram showed normal sinus rhythm with normal PR interval and preexisting right bundle branch block with QRS duration of 138 milliseconds. She had no prior history of syncope, bradycardia, or any cardiac illness. She had no family history of sudden cardiac death. At the time of the event, she was not on any medications known to have a potential to cause bradycardia. Transthoracic echocardiogram revealed an ejection fraction of 60–65% and was otherwise normal.\n\nBy the third day of hospitalization, her symptoms had resolved and she was able to tolerate solid food with no difficulty. Her electrolytes were in normal range. However, she suddenly had a witnessed syncopal episode correlating with 26 seconds of sinoatrial arrest noted on telemetry (Figure 1). The episode was abrupt in onset. The patient was in bed and was talking to her nurse when she had this syncopal episode. She regained her baseline level of consciousness after the episode with no residual deficits. Cardiology consult was obtained, and a permanent pacemaker was planned. While awaiting pacemaker implantation, she developed two more symptomatic episodes of abrupt onset sinus pauses over next 24 hours without any trigger. A dual-chamber permanent pacemaker was implanted the next day. Patient was not given ibrutinib again.\n\n3. Discussion\nIbrutinib is a Bruton's tyrosine kinase (BTK) inhibitor that has been approved as a second-line agent for refractory/relapsedMCL. In November 2013, the Food and Drug Administration (FDA) granted accelerated approval to ibrutinib for the treatment of patients with MCL who have received at least one prior therapy. This approval was based on the results of an international multicenter trial of 111 patients with previously treated MCL which demonstrated favorable efficacy of the medication [1]. The common adverse events reported are diarrhea, fatigue, nausea, vomiting, peripheral edema, dyspnea, constipation, upper respiratory tract infection, and pneumonia in addition to hematological adverse events like neutropenia, thrombocytopenia, anemia, and bleeding.\n\nThere has been growing interest in cardiac side effects of tyrosine kinase inhibitors. Ibrutinib use particularly has been linked with cardiac manifestations, but the commonly associated condition with this drug is atrial fibrillation. In one study, 6-month, 1-year, and 2-year cumulative incidences of AF in patients with MCL who were treated with ibrutinib were 5.6%, 7.2%, and 14.2%, respectively [3]. In trials of ibrutinib in CLL patients, AF incidence of 5–7.7% has been reported [4]. The RESONATE trial for chronic lymphocytic leukemia showed a 10-fold increase in atrial fibrillation in patients treated with ibrutinib as compared to ofatumumab [6]. Life-threatening ventricular arrhythmias and sudden cardiac death were recently reported in a compilation of cases by Lampson et al. [7]. Ibrutinib is an irreversible tyrosine kinase inhibitor. Although the mechanism of cardiac toxicities of ibrutinib remains uncertain, it is possible that this at least in part may be due to irreversible inhibition of certain protective tyrosine kinases which may have a key role in cardiac function and electrophysiological properties. The irreversible inhibition may also explain why manifestations can occur even when the drug is withdrawn. According to one hypothesis, ibrutinib inhibits the protective PI3k-Akt signaling pathway, which may play a role in cardiac side effects of the medication [8]. TEC pathway inhibition is another plausible mechanism that may contribute to ibrutinib's cardiac toxicity, as referred by Tang et al. in 2017 [9]. One case of new onset cardiomyopathy and ventricular tachycardia has been reported with ibrutinib use [8]. The exact spectrum of cardiac manifestations of the medication as well as relation to dose and duration of therapy remains to be studied.\n\nA detailed cardiovascular safety report, published in the Drug Safety journal in 2015, describes the common cardiac effects associated with tyrosine kinase inhibitors (25 medications) approved for several oncologic indications. These include hypertension, pulmonary hypertension, bleeding, arterial and venous thrombosis, congestive heart failure, QT prolongation and associated arrhythmias, sudden death, and syncope. To our knowledge, this is the first case report of recurrent profound bradycardia due to paroxysmal sinoatrial arrest in a patient treated with ibrutinib. The authors would like to emphasize that it is possible our patient had previously undiagnosed sick sinus syndrome or autonomic dysfunction, which may have been the cause of sinus pauses and syncope. However, in light of recent use of ibrutinib in our patient, a medication that has been linked to cardiac side effects as well as with absence of any history of prior syncopal or presyncopal symptoms, the hypothesis that ibrutinib use resulted in profound depression of the sinus node or aggravated preexisting subclinical sinus node dysfunction has to be entertained.\n\n4. Conclusion\nWith ever-expanding indications for chemotherapeutic agents and immunomodulators, the clinician must remain vigilant for unknown and rare systemic manifestations that may be associated with their use. Some of these effects may be potentially life-threatening. Our case highlights the need for further studies aimed at providing mechanistic insights into cardiac toxicities of ibrutinib.\n\nConflicts of Interest\nThe authors declare that they have no conflicts of interest.\n\nFigure 1 Telemetry recording from the time of syncopal event in our patient demonstrating sinoatrial arrest and a 26-second pause. Notice the absence of any atrial activity during the pause indicating this is sinus pause rather than AV block. The telemetry marks some tremor artifact during the event erroneously as atrial activity (A) which is another important finding to recognize.\n==== Refs\n1 Wang M. L. Rule S. Martin P. Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma New England Journal of Medicine 2013 369 6 507 516 10.1056/NEJMoa1306220 2-s2.0-84881225049 23782157 \n2 Leong D. P. Caron F. Hillis C. The risk of atrial fibrillation with ibrutinib use: a systematic review and meta-analysis Blood 2016 128 1 138 140 10.1182/blood-2016-05-712828 27247135 \n3 Lee H. J. Chihara D. Wang M. Mouhayar E. Kim P. Ibrutinib-related atrial fibrillation in patients with mantle cell lymphoma Leukemia and Lymphoma 2016 57 12 2914 2916 10.3109/10428194.2016.1169408 2-s2.0-84963805026 27087288 \n4 Thompson P. A. Lévy V. Tam C. S. Atrial fibrillation in CLL patients treated with ibrutinib. An international retrospective study British Journal of Haematology 2016 175 3 462 466 10.1111/bjh.14324 2-s2.0-84992463341 27611233 \n5 Wallace N. Wong E. Cooper D. Chao H. A case of new-onset cardiomyopathy and ventricular tachycardia in a patient receiving ibrutinib for relapsed mantle cell lymphoma Clinical Case Reports 2016 4 12 1120 1121 10.1002/ccr3.719 27980745 \n6 Byrd J. C. Brown J. R. O’Brien S. Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia New England Journal of Medicine 2014 371 3 213 223 10.1056/NEJMoa1400376 2-s2.0-84904252369 24881631 \n7 Lampson B. L. Yu L. Glynn R. J. Ventricular arrhythmias and sudden death in patients taking ibrutinib Blood 2017 129 18 2581 2584 10.1182/blood-2016-10-742437 28223277 \n8 Shah R. R. Morganroth J. Update on cardiovascular safety of tyrosine kinase inhibitors: with a special focus on QT interval, left ventricular dysfunction and overall risk/benefit Drug Safety 2015 38 8 693 710 10.1007/s40264-015-0300-1 2-s2.0-84938211683 26008987 \n9 Tang C. P. S. McMullen J. Tam C. Cardiac side effects of Bruton tyrosine kinase (BTK) inhibitors Leukemia and Lymphoma 2017 1 11 10.1080/10428194.2017.1375110\n\n",
"fulltext_license": "CC BY",
"issn_linking": null,
"issue": "2017()",
"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": "7304021",
"pmc": null,
"pmid": "29375920",
"pubdate": "2017",
"publication_types": "D002363:Case Reports",
"references": "27247135;23782157;27087288;27611233;28223277;27980745;24881631;28901789;26008987",
"title": "Profound Sinoatrial Arrest Associated with Ibrutinib.",
"title_normalized": "profound sinoatrial arrest associated with ibrutinib"
} | [
{
"companynumb": "US-JNJFOC-20180316785",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CITALOPRAM HYDROBROMIDE"
},
"drugadditional": nul... |
{
"abstract": "Clonidine is a central alpha-2 agonist well known to produce a syndrome of bradycardia and hypotension in overdose. However, few examples of overt clinical clonidine toxicity secondary to cutaneous absorption have been reported. We report a case of unintentional systemic clonidine toxicity in an adult because of a compounded preparation of clonidine applied to a degraded skin barrier. A 35-year-old male suffered a motorcycle accident 48 hours before presentation resulting in an abrasion to his distal left leg. On the day of presentation, he self-treated the wound by repeated application of a family member's pain-relieving cream. Later he was found confused and unable to stand by a family member. The family member recognized the thick visible coat of cream as the likely cause and decontaminated the patient while calling 911. Prehospital vitals were notable for a blood pressure of 80/30 mm Hg and heart rate of 38 beats per minute. In the emergency department, the patient was resuscitated with intravenous fluids with resultant normalization of blood pressure. Upon later review, the cream was determined to have been created by a local compounding pharmacy for the use in neuropathic pain and was labeled to contain clonidine, lidocaine, ketamine, and gabapentin. Cutaneous absorption of the pain cream was greatly increased because of loss of skin integrity. Military physicians and compounding pharmacies should ensure that patients are aware of the proper application of compounded creams and the potential risk for systemic toxicity with overuse or degraded skin.",
"affiliations": "Division of Clinical Toxicology, Department of Emergency Medicine, Virginia Commonwealth University Health Sys tem, Richmond, VA, 23219, USA.;Division of Clinical Toxicology, Department of Emergency Medicine, Virginia Commonwealth University Health Sys tem, Richmond, VA, 23219, USA.",
"authors": "Downs|John W|JW|;Cumpston|Kirk L|KL|",
"chemical_list": "D000077206:Gabapentin; D003000:Clonidine",
"country": "England",
"delete": false,
"doi": "10.1093/milmed/usaa284",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0026-4075",
"issue": "186(3-4)",
"journal": "Military medicine",
"keywords": null,
"medline_ta": "Mil Med",
"mesh_terms": "D000328:Adult; D003000:Clonidine; D004244:Dizziness; D004339:Drug Compounding; D005076:Exanthema; D000077206:Gabapentin; D006801:Humans; D008297:Male",
"nlm_unique_id": "2984771R",
"other_id": null,
"pages": "e451-e453",
"pmc": null,
"pmid": "33005940",
"pubdate": "2021-02-26",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "\"Road Rash\" and Dizziness: A Case of Hemodynamically Significant Topical Clonidine Toxicity.",
"title_normalized": "road rash and dizziness a case of hemodynamically significant topical clonidine toxicity"
} | [
{
"companynumb": "US-MYLANLABS-2021M1034319",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "GABAPENTIN"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nTo report the case of a patient who presented with rare necrotizing esophagitis related to cefazolin-associated coagulopathy. A review of the literature is also provided.\n\n\nMETHODS\nA 53-year-old male patient was admitted for management of septicemia and femur osteomyelitis. Long-term cefazolin treatment was initiated after cultures and sensitivity revealed methicillin-sensitive Staphylococcus aureus. The patient was given intravenous cefazolin 2 g every 24 hours. On day 15 of cefazolin treatment, the patient presented to the emergency department complaining of black coffee ground emesis. On upper-gastrointestinal endoscopy, the patient was determined to have necrotizing esophagitis. He was found to have an international normalized ratio (INR) of 8.11 and prothrombin time (PT) of 89.2 s. Intravenous vitamin K, fresh frozen plasma, and packed red blood cells were administered. The INR was rechecked 4 hours later and found to have decreased to 1.55 with a PT of 17 s. The patient did not have medical conditions or take medications that could have caused bleeding.\n\n\nCONCLUSIONS\nBased on the Naranjo algorithm, it was determined that cefazolin had a \"probable\" relationship. Increased bleeding risk has been associated with other cephalosporins, although much less commonly with cefazolin. Possible mechanisms and implications are discussed.\n\n\nCONCLUSIONS\nHigh-risk patients being treated with cefazolin therapy should be monitored for potentially severe adverse events, including bleeding and necrotizing esophagitis.",
"affiliations": "Purdue University, West Lafayette, IN, USA.;Indiana University Arnett Hospital, Lafayette, IN, USA.;Purdue University, West Lafayette, IN, USA Indiana University Arnett Hospital, Lafayette, IN, USA kaakehy@purdue.edu.",
"authors": "Barnes|Tyler|T|;Yan|Shiqing|S|;Kaakeh|Yaman|Y|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1177/1060028014537038",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1060-0280",
"issue": "48(9)",
"journal": "The Annals of pharmacotherapy",
"keywords": "black esophagus; bleeding; cefazolin sodium; coagulopathy; hemorrhage; hypoprothrombinemia; international normalized ratio; necrotizing esophagitis; renal failure",
"medline_ta": "Ann Pharmacother",
"mesh_terms": null,
"nlm_unique_id": "9203131",
"other_id": null,
"pages": "1214-1218",
"pmc": null,
"pmid": "24847158",
"pubdate": "2014-09",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Necrotizing Esophagitis and Bleeding Associated With Cefazolin.",
"title_normalized": "necrotizing esophagitis and bleeding associated with cefazolin"
} | [
{
"companynumb": "US-BAXTER-2014BAX051839",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "INSULIN ASPART"
},
"drugadditional": null,
... |
{
"abstract": "Leptomeningeal carcinomatosis is a rare but serious complication of solid tumors such as melanoma, breast and lung cancer, as well as gastrointestinal carcinomas. Its clinical manifestation is highly variable, presenting as radicular pain with or without neurological deficits, as well as with headaches and hallucinatory irritation symptoms. Leptomeningeal carcinomatosis is often misdiagnosed, which delays treatment. Here we report a rare case of a patient with BRAF-mutated microsatellite stable colon carcinoma with lymphatic and skeletal metastases, who developed neurological symptoms one month after the initial diagnosis of malignancy. Based on the cytological detection of tumor cells in the cerebrospinal fluid, a leptomeningeal carcinomatosis was diagnosed, despite normal findings on MRI. Intrathecal chemotherapy with methotrexate, combined with intensive systemic immunochemotherapy, resulted in a good partial remission of the underlying malignant disease. However, approximately 8 months after the start of therapy, the patient developed progressive leptomeningeal carcinomatosis and died a few weeks later.",
"affiliations": "Klinik für Innere Medizin - Gastroenterologie, Diabetologie und Endokrinologie, Kemperhof Koblenz, Gemeinschaftsklinikum Mittelrhein.;Klinik für Innere Medizin - Gastroenterologie, Diabetologie und Endokrinologie, Kemperhof Koblenz, Gemeinschaftsklinikum Mittelrhein.;Klinik für diagnostische und interventionelle Radiologie, Kemperhof Koblenz, Gemeinschaftsklinikum Mittelrhein.;Institut für Pathologie, Koblenz.;Klinik für Innere Medizin - Gastroenterologie, Diabetologie und Endokrinologie, Kemperhof Koblenz, Gemeinschaftsklinikum Mittelrhein.",
"authors": "Höblinger|Aksana|A|;Weber|Stephanie|S|;Tschirner|Florian|F|;Kröber|Stefan|S|;Streetz|Konrad|K|",
"chemical_list": "D000970:Antineoplastic Agents; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D008727:Methotrexate",
"country": "Germany",
"delete": false,
"doi": "10.1055/s-0043-109025",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0044-2771",
"issue": "55(7)",
"journal": "Zeitschrift fur Gastroenterologie",
"keywords": null,
"medline_ta": "Z Gastroenterol",
"mesh_terms": "D000970:Antineoplastic Agents; D003110:Colonic Neoplasms; D017809:Fatal Outcome; D006801:Humans; D055756:Meningeal Carcinomatosis; D008727:Methotrexate; D018895:Microsatellite Repeats; D048493:Proto-Oncogene Proteins B-raf",
"nlm_unique_id": "0033370",
"other_id": null,
"pages": "667-674",
"pmc": null,
"pmid": "28709170",
"pubdate": "2017-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Leptomeningeal carcinomatosis as a rare metastatic spreading of BRAF-mutated microsatellite stable colon cancer.",
"title_normalized": "leptomeningeal carcinomatosis as a rare metastatic spreading of braf mutated microsatellite stable colon cancer"
} | [
{
"companynumb": "DE-BAUSCH-BL-2017-024539",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "FLUOROURACIL"
},
"drugadditional": null,
... |
{
"abstract": "Two male travelers with histories of gout and hazardous alcohol consumption, presented with a triad of severe culture-positive disseminated gonococcal infection, crystal-positive polyarticular gout, and gonococcal soft tissue collections, following unprotected sexual contact in The Philippines. Both men initially attributed symptoms to gout, since their usual joints were affected, but clinical deterioration occurred with self-administration of anti-inflammatory agents alone. The clinical courses were severe and protracted, requiring aggressive management of infection with prolonged intravenous antimicrobials and repeated surgery, and prolonged anti-inflammatory agents for gout. Joint symptom onset in each case occurred within a week of sexual exposure in conjunction with hazardous alcohol ingestion. We speculate that acute dissemination of infection to previously damaged joints triggered polyarticular gout, with progressive infection, exacerbated by unopposed anti-inflammatory agents and delayed antibiotics. Disseminated gonococcal infection can occur with polyarticular gout and delays in recognition and treatment, including while traveling, can lead to severe disease from both.",
"affiliations": "Division of Medicine, Royal Darwin Hospital, Darwin, Australia.;Division of Medicine, Royal Darwin Hospital, Darwin, Australia.;Global and Tropical Health Division, Menzies School of Health Research, Darwin, Australia.;Global and Tropical Health Division, Menzies School of Health Research, Darwin, Australia.",
"authors": "Smith|Emma L|EL|;Hodgetts|Kay E|KE|;Ralph|Anna P|AP|;Anstey|Nicholas M|NM|",
"chemical_list": "D000900:Anti-Bacterial Agents",
"country": "United States",
"delete": false,
"doi": "10.4269/ajtmh.18-0589",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0002-9637",
"issue": "100(1)",
"journal": "The American journal of tropical medicine and hygiene",
"keywords": null,
"medline_ta": "Am J Trop Med Hyg",
"mesh_terms": "D000428:Alcohol Drinking; D000900:Anti-Bacterial Agents; D001315:Australia; D006069:Gonorrhea; D006073:Gout; D006801:Humans; D007596:Joints; D008297:Male; D008875:Middle Aged; D009344:Neisseria gonorrhoeae; D010679:Philippines; D012720:Severity of Illness Index; D014057:Tomography, X-Ray Computed; D000076082:Travel-Related Illness; D016896:Treatment Outcome",
"nlm_unique_id": "0370507",
"other_id": null,
"pages": "209-212",
"pmc": null,
"pmid": "30457099",
"pubdate": "2019-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "25792538;7620028;1504159;8722952;28116187;12062998;2287942;14088465;22919521;19697211;29108466;8088928;16136359;6431620;24777471;23630956;6787219;23095086;8972665;12119340;23920397",
"title": "Case Report: Severe Disseminated Gonococcal Infection with Polyarticular Gout: Two Cases in Older Travelers.",
"title_normalized": "case report severe disseminated gonococcal infection with polyarticular gout two cases in older travelers"
} | [
{
"companynumb": "AU-MYLANLABS-2019M1109807",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "INDOMETHACIN"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nToday, women who have undergone liver transplantation enjoy better health, so they encounter more frequently the possibility of living pregnancy. Many questions about the safety of pregnancy are pending. This study analyzes pregnancy outcomes in women with a liver transplant managed at Policlinico Universitario \"A.Gemelli.\"\n\n\nRESULTS\nWe identified 17 childbirths in 13 women who had undergone a liver transplant. Causes of transplant include congenital or acquired disorders. The mean age at transplant was 22 ± 9 years, mean maternal age at delivery was 33 ± 5 years, and transplant-to-pregnancy interval was 12 ± 6 years. The mean gestational week was 36.1 ± 3.5. All women had normal liver function after pregnancy. Immunosuppressive therapy before and during pregnancy included tacrolimus (n = 8), cyclosporine (n = 5) and mycophenolate mofetil (n = 1). No maternal death was registered. Maternal complications included increase of aspartate transaminase and alanine transaminase, graft deterioration requiring liver retransplantation, increase of bile acids (n = 1), itch (n = 1), and anemia (n = 1). Twelve women had a high adherence to an immunosuppressive regimen during pregnancy. A woman with poor compliance continued therapy with mycophenolic acid during pregnancy, showing preterm birth (25th week) with fetal respiratory failure. Another woman continued therapy with tacrolimus during breastfeeding without adverse effects.\n\n\nCONCLUSIONS\nLiver transplant does not influence women's fertility; during pregnancy, we report low rates of minor graft complications and no major issues. There are no adverse effects on babies. An evaluation by a multidisciplinary team is recommended. Compliance to an immunosuppressive regimen is fundamental to ensure the stability of graft function and to prevent graft deterioration in pregnancy. Moreover, it is suggested to avoid teratogenic drugs, such as mycophenolic acid.",
"affiliations": "Fondazione Policlinico Universitario \"A. Gemelli\" IRCCS, Università Cattolica del Sacro Cuore, Department of General Surgery, General Surgery and Liver Transplant Unit, Rome, Italy.;Fondazione Policlinico Universitario \"A. Gemelli\" IRCCS, Università Cattolica del Sacro Cuore, Department of General Surgery, General Surgery and Liver Transplant Unit, Rome, Italy. Electronic address: pascale.marco.maria@gmail.com.;Fondazione Policlinico Universitario \"A. Gemelli\" IRCCS, Università Cattolica del Sacro Cuore, Department of General Surgery, General Surgery and Liver Transplant Unit, Rome, Italy.;Fondazione Policlinico Universitario \"A. Gemelli\" IRCCS, Università Cattolica del Sacro Cuore, Department of General Surgery, General Surgery and Liver Transplant Unit, Rome, Italy.;Fondazione Policlinico Universitario \"A. Gemelli\" IRCCS, Università Cattolica del Sacro Cuore, Department of General Surgery, General Surgery and Liver Transplant Unit, Rome, Italy.;Fondazione Policlinico Universitario \"A. Gemelli\" IRCCS, Università Cattolica del Sacro Cuore, Department of General Surgery, General Surgery and Liver Transplant Unit, Rome, Italy.",
"authors": "Nure|Edria|E|;Pascale|Marco Maria|MM|;Frongillo|Francesco|F|;Franco|Antonio|A|;Bianco|Giuseppe|G|;Agnes|Salvatore|S|",
"chemical_list": "D007166:Immunosuppressive Agents",
"country": "United States",
"delete": false,
"doi": "10.1016/j.transproceed.2019.02.071",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-1345",
"issue": "51(9)",
"journal": "Transplantation proceedings",
"keywords": null,
"medline_ta": "Transplant Proc",
"mesh_terms": "D000328:Adult; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007166:Immunosuppressive Agents; D007231:Infant, Newborn; D016031:Liver Transplantation; D011247:Pregnancy; D011256:Pregnancy Outcome; D055815:Young Adult",
"nlm_unique_id": "0243532",
"other_id": null,
"pages": "2948-2951",
"pmc": null,
"pmid": "31627912",
"pubdate": "2019-11",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Pregnancy After Liver Transplant: Neonatal Outcomes and Long-Term Maternal Follow-up.",
"title_normalized": "pregnancy after liver transplant neonatal outcomes and long term maternal follow up"
} | [
{
"companynumb": "NVSC2019IT035838",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "MYCOPHENOLIC ACID"
},
"drugadditional": null,
... |
{
"abstract": "The objective of the present study was to determine the mitochondrial toxicity mechanisms of linezolid-related hyperlactatemia. Five patients on a long-term schedule of linezolid treatment were studied during the acute phase of hyperlactatemia and after clinical recovery and lactate normalization following linezolid withdrawal. Mitochondrial studies were performed with peripheral blood mononuclear cells and consisted of measurement of mitochondrial mass, mitochondrial protein synthesis homeostasis (cytochrome c oxidase [COX] activity, COX-II subunit expression, COX-II mRNA abundance, and mitochondrial DNA [mtDNA] content), and overall mitochondrial function (mitochondrial membrane potential and intact-cell oxidative capacity). During linezolid-induced hyperlactatemia, we found extremely reduced protein expression (16% of the remaining content compared to control values [100%], P < 0.001) for the mitochondrially coded, transcribed, and translated COX-II subunit. Accordingly, COX activity was also found to be decreased (51% of the remaining activity, P < 0.05). These reductions were observed despite the numbers of COX-II mitochondrial RNA transcripts being abnormally increased (297%, P = 0.10 [not significant]) and the mitochondrial DNA content remaining stable. These abnormalities persisted even after the correction for mitochondrial mass, which was mildly decreased during the hyperlactatemic phase. Most of the mitochondrial abnormalities returned to control ranges after linezolid withdrawal, lactate normalization, and clinical recovery. Linezolid inhibits mitochondrial protein synthesis, leading to decreased mitochondrial enzymatic activity, which causes linezolid-related hyperlactatemia, which resolves upon discontinuation of linezolid treatment.",
"affiliations": "Mitochondrial Research Laboratory, Muscle Research Unit, Internal Medicine Department, Hospital Clinic of Barcelona, Villarroel 170, 08036 Barcelona, Catalonia, Spain.",
"authors": "Garrabou|Glòria|G|;Soriano|Alejandro|A|;López|Sònia|S|;Guallar|Jordi P|JP|;Giralt|Marta|M|;Villarroya|Francesc|F|;Martínez|Jose A|JA|;Casademont|Jordi|J|;Cardellach|Francesc|F|;Mensa|Josep|J|;Miró|Oscar|O|",
"chemical_list": "D000081:Acetamides; D000900:Anti-Bacterial Agents; D007773:Lactates; D023303:Oxazolidinones; D011500:Protein Synthesis Inhibitors; D012313:RNA; D004247:DNA; D003576:Electron Transport Complex IV; D000069349:Linezolid",
"country": "United States",
"delete": false,
"doi": "10.1128/AAC.01190-06",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0066-4804",
"issue": "51(3)",
"journal": "Antimicrobial agents and chemotherapy",
"keywords": null,
"medline_ta": "Antimicrob Agents Chemother",
"mesh_terms": "D000081:Acetamides; D000328:Adult; D000368:Aged; D000900:Anti-Bacterial Agents; D004247:DNA; D004579:Electron Transport; D003576:Electron Transport Complex IV; D005260:Female; D006801:Humans; D007773:Lactates; D000069349:Linezolid; D008137:Longitudinal Studies; D008297:Male; D008564:Membrane Potentials; D008928:Mitochondria; D023303:Oxazolidinones; D010084:Oxidation-Reduction; D011500:Protein Synthesis Inhibitors; D012313:RNA",
"nlm_unique_id": "0315061",
"other_id": null,
"pages": "962-7",
"pmc": null,
"pmid": "17194826",
"pubdate": "2007-03",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "16575728;16306535;16723564;16603396;942051;2461737;1692359;1677065;7955428;11381588;11803505;12054921;12115113;12205079;12510056;12659607;12730138;14526764;14583875;15040536;15117929;15288827;15307017;15317746;7525553;9606056;15577406;15909253;16127068;16619168",
"title": "Reversible inhibition of mitochondrial protein synthesis during linezolid-related hyperlactatemia.",
"title_normalized": "reversible inhibition of mitochondrial protein synthesis during linezolid related hyperlactatemia"
} | [
{
"companynumb": "KR-ALKEM LABORATORIES LIMITED-KR-ALKEM-2018-01808",
"fulfillexpeditecriteria": "1",
"occurcountry": "KR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LINEZOLID"
},
"drugad... |
{
"abstract": "Programmed death-1 (PD-1) inhibitors are among the immunotherapies that have revolutionized our approach to treating several cancers. These novel agents act by blocking PD-1 receptor/PD-1 ligand interactions that would otherwise allow tumor cells to evade host immune destruction by inhibiting response of cytotoxic T-lymphocytes. They are overall well tolerated, though they have been associated with a constellation of immune mediated adverse events (irAEs).\nWe present a case of rare nivolumab mediated adverse events in a patient with nodular recurrence of melanoma. The patient presented with rhabdomyolysis and shortly thereafter developed a constellation of immune-mediated organ derangements. This case further demonstrates the utility and effectiveness of steroid therapy in the setting of irAEs despite our patient's eventual poor clinical outcome. While PD-1 inhibitors have revolutionized the treatment of several cancers, they require vigilance by the clinician for early detection and treatment of uncommon but potentially fatal irAEs.\nPD-1 inhibitors are now widely used in a multitude of cancer types including melanoma, advanced non-small cell lung cancer, metastatic renal cell carcinoma, and Hodgkin lymphoma amongst others. While these agents are often well tolerated, they are associated with a unique profile of immune-related toxicities that can cause significant morbidity and mortality. Education of both patients and healthcare providers is essential for diagnosis and treatment of these adverse events early in their course. This case highlights the uncommon but potentially serious PD-1-associated toxicity of myopathy and rhabdomyolysis along with other organ involvement and is directly applicable to use of these agents in patients with advanced cancers.",
"affiliations": "1Loma Linda University, 11175 Campus Circle, Loma Linda, CA 92354 USA.;2Loma Linda University, 11234 Anderson St, Loma Linda, CA 92354 USA.;2Loma Linda University, 11234 Anderson St, Loma Linda, CA 92354 USA.;1Loma Linda University, 11175 Campus Circle, Loma Linda, CA 92354 USA.;1Loma Linda University, 11175 Campus Circle, Loma Linda, CA 92354 USA.",
"authors": "Pourhassan|Hoda Z|HZ|0000-0003-3862-4612;Tryon|David|D|;Schaeffer|Brett|B|;Mirshahidi|Hamid|H|;Wong|John|J|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1186/s40164-019-0140-2",
"fulltext": "\n==== Front\nExp Hematol OncolExp Hematol OncolExperimental Hematology & Oncology2162-3619BioMed Central London 14010.1186/s40164-019-0140-2Case ReportAutoimmune rhabdomyolysis and a multiorgan display of PD-1 inhibitor induced immune related adverse events during treatment of metastatic melanoma http://orcid.org/0000-0003-3862-4612Pourhassan Hoda Z. hpourhassan@llu.edu 1Tryon David dtryon@llu.edu 2Schaeffer Brett bschaeffer@llu.edu 2Mirshahidi Hamid HMirshah@llu.edu 1Wong John JOWong@llu.edu 11 0000 0000 9852 649Xgrid.43582.38Loma Linda University, 11175 Campus Circle, Loma Linda, CA 92354 USA 2 0000 0000 9852 649Xgrid.43582.38Loma Linda University, 11234 Anderson St, Loma Linda, CA 92354 USA 10 9 2019 10 9 2019 2019 8 209 5 2019 25 7 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\nProgrammed death-1 (PD-1) inhibitors are among the immunotherapies that have revolutionized our approach to treating several cancers. These novel agents act by blocking PD-1 receptor/PD-1 ligand interactions that would otherwise allow tumor cells to evade host immune destruction by inhibiting response of cytotoxic T-lymphocytes. They are overall well tolerated, though they have been associated with a constellation of immune mediated adverse events (irAEs).\n\nCase presentation\nWe present a case of rare nivolumab mediated adverse events in a patient with nodular recurrence of melanoma. The patient presented with rhabdomyolysis and shortly thereafter developed a constellation of immune-mediated organ derangements. This case further demonstrates the utility and effectiveness of steroid therapy in the setting of irAEs despite our patient’s eventual poor clinical outcome. While PD-1 inhibitors have revolutionized the treatment of several cancers, they require vigilance by the clinician for early detection and treatment of uncommon but potentially fatal irAEs.\n\nConclusions\nPD-1 inhibitors are now widely used in a multitude of cancer types including melanoma, advanced non-small cell lung cancer, metastatic renal cell carcinoma, and Hodgkin lymphoma amongst others. While these agents are often well tolerated, they are associated with a unique profile of immune-related toxicities that can cause significant morbidity and mortality. Education of both patients and healthcare providers is essential for diagnosis and treatment of these adverse events early in their course. This case highlights the uncommon but potentially serious PD-1-associated toxicity of myopathy and rhabdomyolysis along with other organ involvement and is directly applicable to use of these agents in patients with advanced cancers.\n\nKeywords\nPD-1NivolumabMelanomaImmunotherapyImmune mediated adverse eventsMyopathyRhabdomyolysisissue-copyright-statement© The Author(s) 2019\n==== Body\nIntroduction\nThe development of immune checkpoint inhibitors has added a remarkable tool for treatment of patients with advanced cancers. Programmed death-1 (PD-1) inhibitors, like nivolumab, are often described as well tolerated, but have a unique toxicity profile that can be severe and potentially affect multiple organs [1–3]. The most common adverse events involve the skin, GI tract, liver, lungs, and endocrine glands, however, a few cases have been reported involving the heart, eyes, and muscles [1, 2, 4–7]. High-grade musculoskeletal immune-related adverse events (irAEs) are less common and infrequently reported. There is evidence showing that PD-1 inhibitor combination therapy can lead to similar immune-related adverse events as well [8, 9]. Here we report a case of rhabdomyolysis caused by monotherapy with nivolumab in a patient with nodal recurrence of melanoma.\n\nCase\nAn 85-year-old man with nodal recurrence of melanoma was admitted to the hospital with generalized weakness and myalgias one week after receiving his second dose of nivolumab. Prior to initiating treatment, patient was described as a very active gentleman with proficient performance status and otherwise good health. He was being treated with 240 mg Nivolumab given day 1 and 15 of 28 day cycles. After completing his first cycle of nivolumab, he began experiencing generalized weakness, myalgia, and fatigue. These symptoms were both persistent and progressive until he became immobile and unable to care for himself leading to emergency room presentation.\n\nOn initial evaluation he denied fevers, chest pain, nausea, vomiting, or abdominal pain. He did elicit feeling extremely weak, lightheaded with muscle soreness since his last nivolumab infusion. He was having shortness of breath with exertion and at rest for the past 5 days. He was also having difficulty maintaining balance, experiencing blurry vision, and dry coughs. He had otherwise been active and healthy prior to symptom onset with medical history notable only for hypertension, atrial fibrillation, gastric reflux and coronary artery disease. His labs were most notable for elevated liver enzymes, decreased TSH and elevated free T4. He was also found to have troponin leak, elevated CK-MB and pro BNP concerning for NSTEMI and new onset diastolic heart failure. EKG showed rate-controlled Atrial fibrillation, but no ST changes. Chest x-ray was remarkable for cardiomegaly, pulmonary edema, and a left lung consolidation with effusion. Urine analysis showed large blood.\n\nFollowing admission to cardiology service he was found to have elevated CK and given concern for rhabdomyolysis, he was transferred to the medical intensive care unit and treated with aggressive intravenous fluids. In context of diastolic heart failure and volume overload patient required intubation. Hematology/Oncology was consulted and determined the constellation of symptoms to be irAEs of nivolumab (Table 1). Ophthalmology evaluation including limited eye exam on sedation was notable for keratoconjunctivitis and bilateral abduction deficit. Complete rheumatologic evaluation was negative for other causes of rhabdomyolysis and entire myositis panel was unremarkable. Endocrine workup did not reveal primary endocrine abnormality. Treatment with high dose steroid therapy was started and led to eventual improvement in abnormal laboratory findings (Fig. 1). Despite this, patient continued to deteriorate. He was unable to be weaned from the ventilator and the decision was made to withdraw supportive care.Table 1 Nivolumab and immune related adverse events\n\nirAEs associated with nivolumab\tPatient findings\t\nMyalgias and arthralgias\tRhabdomyolysis\t\nHyperthyroidism\tElevated TSH\t\nOcular side effects\tKeratoconjunctivitis\t\nHepatotoxicity\tTransaminitis\t\nMyocarditis\tTroponin leak\t\nPleural effusion\tLeft lung consolidation with effusion\t\nMyasthenia Gravis\tProgressive weakness (related?)\t\n\nFig. 1 a Decline in AST/ALT levels following initiation of steroid therapy (orange arrow). b Correction of hyperthyroid state with decline in free T4 and recovery of TSH following initiation of steroid therapy (orange arrow). c Decline in CK following initiation of steroid therapy (orange arrow). C1D1, cycle 1 day 1; C2D15, cycle 2 day 15; HD, hospital day\n\n\n\n\nDiscussion\nThe development of immune checkpoint inhibitors has changed the management of several types of cancer. Nivolumab and Pembrolizumab, PD-1 monoclonal antibody inhibitors, became FDA-approved for treatment of advanced melanoma in 2014 [10]. As of April 2018, Nivolumab is also approved for treatment of advanced non-small cell lung cancer, metastatic renal cell carcinoma, Hodgkin lymphoma, urothelial carcinoma, metastatic colorectal cancer, hepatocellular carcinoma, and head and neck cancers [10]. And in May 2017, pembrolizumab was approved for the treatment of adult and pediatric patients with unresectable or metastatic, microsatellite instability-high (MSI-H) or mismatch repair deficient tumors. This was the FDA’s first tissue/site-agnostic approval [11].\n\nPD-1 inhibitors act by blocking PD-1 receptor/PD-1 ligand interactions that would otherwise allow tumor cells to evade host immune destruction by inhibiting response of cytotoxic T-lymphocytes [12, 13]. Preventing PD-1 receptor/ligand inhibition enhances host immune response to the tumor. PD-1 inhibitors are often described as well-tolerated, with lower risk of treatment-related adverse events than standard cytotoxic therapy [1, 3]. However, the unique mechanism of action of these immunologic agents can create a distinct toxicity profile caused by excessive T-lymphocyte stimulation. These toxicities are known as immune-related adverse events. The exact pathophysiology for these events is unknown but is presumed to be brought on by a combination of autoreactive T cells, autoantibodies, and/or proinflammatory cytokines such as inrerlekin-17 [14, 15]. The most common side effects involve the skin, gastrointestinal tract, liver, lungs, and endocrine glands, although immune related adverse events could potentially affect any organ [1, 2, 4, 5]. Adverse events are mostly low grade, however high-grade events causing significant morbidity and mortality do occur [1, 2, 4, 5]. Overall, it is not thought that specific tumor types are more or less prone to IAEs as validated through systemic reviews by De Valasco et al. and Khoja et al. However, the latter review did find that tumor histology could perhaps play a role. Patients with melanoma experienced higher incidence of GI and skin irAEs but lower rates of pneumonitis in comparison to NSCLC. Melanoma patients had higher rates of arthritis and myalgias than those with RCC [16, 17]. However, these differences were not adjusted for patient factors such as smoking history and age and could perhaps be additive factors.\n\nIn the case presented, musculoskeletal symptoms and rhabdomyolysis were the most prominent findings at presentation. Myalgias and arthralgias are commonly reported adverse events with PD-1 inhibitors, with incidences described as high as 14% [5, 8, 18, 19]. High-grade musculoskeletal side effects are also documented but reporting of musculoskeletal adverse events is inconsistent and incomplete in the literature. Nivolumab-induced myopathy leading to rhabdomyolysis is not commonly reported and is not discussed in many of the landmark studies and meta-analyses on PD-1 inhibitors [3, 5, 8, 19, 20]. The exact frequency of Nivolumab-related myopathy and rhabdomyolysis is not known. Our review of the literature revealed nine reported cases of rhabdomyolysis attributed to nivolumab monotherapy [21–24] and four cases associated with Nivolumab in combination with ipilimumab [6, 7, 9, 25].\n\nPrevious cases reporting Nivolumab-related myositis demonstrated myocyte necrosis and extensive infiltration of T-lymphocytes on muscle biopsy [6, 23]. This is consistent with the mechanism of misdirected T-lymphocyte stimulation seen to cause other immune-related adverse events [12, 13]. Cases of myasthenia gravis caused by Nivolumab have also been reported, and several have had concomitant rhabdomyolysis [24, 26–28]. The severe weakness and vision changes seen in this case could fit with an associated myasthenia gravis but testing for acetylcholine receptor antibody was not performed.\n\nCardiac irAEs are also observed and can be potentially fatal. They can have a variety of manifestations including myocarditis, cardiomyopathy, cardiac fibrosis, heart failure, and cardiac arrest [29, 30]. Analysis of the WHO database revealed 101 individual case safety reports of severe myocarditis following initiation of immune checkpoint inhibitor therapy. 57% of these cases were in patients receiving ant PD-1 monotherapy and in cases with dosing information 64% had received only 1 or two doses of therapy at the time of symptom onset [31]. While neither a significant drop in left ventricular ejection fraction nor chest pain were observed, the elevated troponin and CK-MB seen in this patient may indicate some degree of associated myocarditis [6, 27, 28].\n\nOcular side effects are uncommon, but include iritis, uveitis, conjunctivitis, keratoconjunctivitis, episcleritis, neuromyolytis optica, and ophthalmoplegia [7, 13, 18, 28]. A full ophthalmologic workup was not able to be performed due to the severity of other illnesses and inability to participate in active exam. However, an initial eye exam demonstrated keratoconjunctivitis and follow up exam was concerning for bilateral abduction defect. Interestingly, a recent case series describing PD-1 inhibitor associated myopathies found that 4 of 8 reported patients with PD-1 inhibitor-associated myopathy and rhabdomyolysis also had ptosis or ophthalmoparesis, and 2 of them had AChR antibodies and were diagnosed with concomitant myasthenia gravis [24]. Despite the uncommon nature of ocular side effects, it is important to recognize that symptoms of eye pain or blurry vision in patients taking PD-1 inhibitors should prompt an ophthalmologic evaluation.\n\nAnother suspected immune-related adverse event was the patient’s hyperthyroidism. Endocrine adverse events are seen frequently with immune checkpoint inhibitors, and the rate of thyroid disorders associated with nivolumab is reported to be up to 18% [32, 33]. Hypothyroidism is more prevalent than hyperthyroidism [2, 33]. Prior to this admission, our patient had no documented history of thyroid disease. Testing for thyroid peroxidase antibody was positive, indicating that this patient may have had early Hashimoto’s thyroiditis in a hyperthyroid state. In our case, thyroid function improved rapidly with steroid therapy.\n\nThe combination of findings seen in this case as well as the timeline of symptom onset strongly suggest nivolumab-induced irAEs as the cause of symptoms and clinical presentation. This patient developed acute onset of severe weakness, rhabdomyolysis, hyperthyroidism, and blurry vision. He had no medical history of these issues prior to taking nivolumab. No other causes, including rheumatologic or primary endocrine disease related, could be identified for these findings. None of his other active medications had been implicated in rhabdomyolysis. Symptoms started approximately two weeks after the initial cycle of nivolumab and the day after the second cycle. This fits with the finding that most immune-related adverse events occur within 3–6 months of initiation of therapy and can occur within weeks [2]. In addition, the patient’s thyroid dysfunction and rhabdomyolysis responded well to steroid therapy, as would be expected with immune-related adverse events, further solidifying concern for an immune-related etiology.\n\nThe treatment of immune-related adverse events associated with PD-1 inhibitors depends on the organ involved and the severity of symptoms. For high-grade adverse events that necessitate reversal of immune-related toxicity, high dose steroids are recommended (prednisone 1–2 mg/kg PO daily or methylprednisolone 1–2 mg/kg IV daily) [18, 34]. Immunotherapy should be discontinued for grade 4 or recurrent grade 3 adverse events [34]. PD-1-associated immune-related adverse events typically respond well to steroids and resolve within 6–12 weeks [34].\n\nThese immune related adverse events have recently been defined on a much greater scale. The authors of a September 2018 study retrospectively queried a World Health Organization (WHO) pharmacovigilance database (Vigilyze) comprising more than 16 million adverse drug reactions, and records from seven academic centers [35]. This study found that Anti–PD-1/PD-L1 monotherapy in fact does have a wide distribution of fatal irAEs and underscored the very real risk of complications and death associated with immunotherapies. However, importantly, it also put into perspective the fatality rates of other common oncological interventions such as chemotherapy, stem cell transplantation and other targeted therapies which confer comparable if not greater risk of treatment related fatality.\n\nConclusion\nPD-1 inhibitors are a remarkable tool for treatment of patients with advanced cancers. While these agents are often well tolerated, they are associated with a unique profile of immune-related toxicities that can cause significant morbidity and mortality. Education of both patients and healthcare providers is essential for diagnosis and treatment of these adverse events early in their course. This case highlights the uncommon but potentially serious PD-1-associated toxicity of myopathy and rhabdomyolysis. It also demonstrates the broad spectrum of organ systems that can be affected by immune therapy. Further studies are needed to determine the prevalence of these events and identify methods to predict and prevent their occurrence.\n\nAbbreviations\nPD1programmed death-1\n\nirAEsimmune mediated adverse events\n\nTSHthyroid stimulating hormone\n\nT4thyroxine\n\nCK-MBcreatine kinase-muscle/brain\n\nBNPbrain natriuretic peptide\n\nNSTEMInon-ST elevated myocardial infarction\n\nEKGelectrocardiogram\n\nCKcreatine kinase\n\nMSI-Hmicrosatellite instability-high\n\nNSCLCnon-small cell lung cancer\n\nRCCrenal cell carcinoma\n\nWHOWorld Health Organization\n\nPOper os\n\nPublisher's Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAcknowledgements\nNot applicable.\n\nAuthors’ contributions\nHP was directly involved in patient care and management, was a major contributor in writing the manuscript, edited and updated all references, created figures and tables and completed final manuscript edits. All authors read and approved the final manuscript.\n\nFunding\nNo funding has been received in relation to this article.\n\nAvailability of data and materials\nNot applicable.\n\nEthics approval and consent to participate\nNot applicable.\n\nConsent for publication\nNot applicable.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n==== Refs\nReferences\n1. Nishijima TF Safety and tolerability of PD-1/PD-L1 inhibitors compared with chemotherapy in patients with advanced cancer: a meta-analysis Oncologist. 2017 22 4 470 479 10.1634/theoncologist.2016-0419 28275115 \n2. Michot JM Immune-related adverse events with immune checkpoint blockade: a comprehensive review Eur J Cancer 2016 54 139 148 10.1016/j.ejca.2015.11.016 26765102 \n3. Weber JS Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial Lancet Oncol 2015 16 375 384 10.1016/S1470-2045(15)70076-8 25795410 \n4. Hofmann Lars Cutaneous, gastrointestinal, hepatic, endocrine, and renal side-effects of anti-PD-1 therapy Eur J Cancer 2016 60 190 209 10.1016/j.ejca.2016.02.025 27085692 \n5. Wang P-F Chen Y Song S-Y Immune-related adverse events associated with anti-PD-1/PD-L1 treatment for malignancies: a meta-analysis Front Pharmacol 2017 8 730 10.3389/fphar.2017.00730 29093678 \n6. Johnson DB Balko JM Compton ML Fulminant myocarditis with combination immune checkpoint blockade N Engl J Med. 2016 375 18 1749 1755 10.1056/NEJMoa1609214 27806233 \n7. Alnabulsi R Complete ophthalmoplegia in Ipilmumab and Nivolumab combination treatment for metastatic melanoma Orbit. 2018 30 1 4 \n8. Larkin J Chiarion-Sileni V Gonzalez R Combined nivolumab and ipilimumab or monotherapy in untreated melanoma N Engl J Med 2015 373 23 34 10.1056/NEJMoa1504030 26027431 \n9. Bilen MA Acute rhabdomyolysis with severe polymyositis following ipilimumab-nivolumab treatment in a cancer patient with elevated anti-striated muscle antibody J Immunother Cancer. 2016 4 36 10.1186/s40425-016-0139-8 27330809 \n10. U.S. Food and Drug Administration. U.S. Department of Health and Human Services. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/125554s058lbl.pdf. Accessed 7/29/18.\n11. U.S. Food and Drug Administration. U.S. Department of Health and Human Services. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/125514s014lbl.pdf. Accessed 12/10/18.\n12. Ohaegbulam KC Assal A Lazar-Molnar E Yao Y Zang X Human cancer immunotherapy with antibodies to the PD-1 and PD-L1 pathway Trends Mol Med 2015 21 1 24 33 10.1016/j.molmed.2014.10.009 25440090 \n13. Ribas A Releasing the brakes on cancer immunotherapy N Engl J Med 2015 373 1490 1492 10.1056/NEJMp1510079 26348216 \n14. Postow MA Sidlow R Hellmann MD Immune-related adverse events associated with immune checkpoint blockade N Engl J Med 2018 378 158 168 10.1056/NEJMra1703481 29320654 \n15. Esfahani K Miller WH Jr Reversal of autoimmune toxicity and loss of tumor response by interleukin-17 blockade N Engl J Med 2017 376 1989 1991 10.1056/NEJMc1703047 28514612 \n16. Pillai RN Behera M Owonikoko TK Comparison of the toxicity pro le of PD-1 versus PD-L1 inhibitors in non-small cell lung cancer: a systematic analysis of the literature Cancer 2018 124 271 277 10.1002/cncr.31043 28960263 \n17. Khoja L Day D Wei-Wu Chen T Tumour- and class-speci c patterns of immune-related adverse events of immune checkpoint inhibitors: a systematic review Ann Oncol 2017 28 2377 2385 10.1093/annonc/mdx286 28945858 \n18. Spain L Management of toxicities of immune checkpoint inhibitors Cancer Treat Rev 2016 44 51 60 10.1016/j.ctrv.2016.02.001 26874776 \n19. Robert C Long GV Brady B Nivolumab in previously untreated melanoma without BRAF mutation N Engl J Med 2015 372 320 330 10.1056/NEJMoa1412082 25399552 \n20. El Osta B Not all immune-checkpoint inhibitors are created equal: meta-analysis and systematic review of immune-related adverse events in cancer trials Crit Rev Oncol Hematol 2017 119 1 12 10.1016/j.critrevonc.2017.09.002 29065979 \n21. Katsuya S A case of nivolumab-induced severe mononeuropathy multiplex and rhabdomyolysis Case Rep Med 2017 2017 1093858 29312452 \n22. Shirai T Acetylcholine receptor binding antibody-associated myasthenia gravis and rhabdomyolysis induced by nivolumab in a patient with melanoma Jpn J Clin Oncol 2016 46 1 86 88 10.1093/jjco/hyv158 26491202 \n23. Chen Q Fatal myocarditis and rhabdomyolysis induced by nivolumab during the treatment of type B3 thymoma Clin Toxicol (Phila) 2018 56 7 667 671 10.1080/15563650.2017.1401079 29126352 \n24. Liewluck T PD-1 inhibitor-associated Myopathies: emerging Immune-mediated Myopathies J Immunother 2018 41 4 208 211 10.1097/CJI.0000000000000196 29200081 \n25. Shah M Myositis as an adverse event of immune checkpoint blockade for cancer therapy Semin Arthritis Rheum. 2018 48 4 736 740 10.1016/j.semarthrit.2018.05.006 29909921 \n26. Bastianeet E Immunotherapy and targeted therapies in older patients with advanced melanoma; Young International Society of Geriatric Oncology review paper J Geriatr Oncol. 2019 10 3 389 397 10.1016/j.jgo.2018.06.009 30025821 \n27. Suzuki S Nivolumab-related myasthenia gravis with myositis and myocarditis in Japan Neurology. 2017 89 11 1127 1134 10.1212/WNL.0000000000004359 28821685 \n28. Zimmer L Neurological, respiratory, musculoskeletal, cardiac and ocular side-effects of anti-PD-1 therapy Eur J Cancer 2016 60 210 225 10.1016/j.ejca.2016.02.024 27084345 \n29. Mahmood SS Fradley MG Cohen JV Myocarditis in patients treated with immune checkpoint inhibitors J Am Coll Cardiol 2018 71 1755 1764 10.1016/j.jacc.2018.02.037 29567210 \n30. Suter TM Ewer MS Cancer drugs and the heart: importance and management Eur Heart J. 2013 34 1102 1111 10.1093/eurheartj/ehs181 22789916 \n31. Moslehi JJ Salem JE Sosman JA Increased reporting of fatal immune checkpoint inhibitor-associated myocarditis Lancet 2018 391 933 10.1016/S0140-6736(18)30533-6 \n32. Sznol M Endocrine-related adverse events associated with immune checkpoint blockade and expert insights on their management Cancer Treat Rev 2017 58 70 76 10.1016/j.ctrv.2017.06.002 28689073 \n33. González-Rodríguez E Rodríguez-Abreu D Immune checkpoint inhibitors: review and management of endocrine adverse events Oncologist 2016 21 7 804 816 10.1634/theoncologist.2015-0509 27306911 \n34. Nagai H Optimal management of immune-related adverse events resulting from treatment with immune checkpoint inhibitors: a review and update Int J Clin Oncol. 2018 23 3 410 420 10.1007/s10147-018-1259-6 29516216 \n35. Wang DY Salem J Cohen JV Fatal toxic effects associated with immune checkpoint inhibitorsa systematic review and meta-analysis JAMA Oncol. 2018 4 12 1721 1728 10.1001/jamaoncol.2018.3923 30242316\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2162-3619",
"issue": "8()",
"journal": "Experimental hematology & oncology",
"keywords": "Immune mediated adverse events; Immunotherapy; Melanoma; Myopathy; Nivolumab; PD-1; Rhabdomyolysis",
"medline_ta": "Exp Hematol Oncol",
"mesh_terms": null,
"nlm_unique_id": "101590676",
"other_id": null,
"pages": "20",
"pmc": null,
"pmid": "31516766",
"pubdate": "2019",
"publication_types": "D002363:Case Reports",
"references": "22789916;25399552;25440090;25795410;26027431;26348216;26491202;26765102;26874776;27084345;27085692;27306911;27330809;27806233;28275115;28514612;28689073;28821685;28945858;28960263;29065979;29093678;29126352;29200081;29312452;29320654;29381409;29516216;29536852;29567210;29909921;30025821;30242316",
"title": "Autoimmune rhabdomyolysis and a multiorgan display of PD-1 inhibitor induced immune related adverse events during treatment of metastatic melanoma.",
"title_normalized": "autoimmune rhabdomyolysis and a multiorgan display of pd 1 inhibitor induced immune related adverse events during treatment of metastatic melanoma"
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"abstract": "In patients undergoing catheter ablation (CA) for atrial fibrillation (AF), the use of uninterrupted direct oral anticoagulants (DOACs) is the current protocol. This study evaluated bleeding complications following the uninterrupted use of 4 DOACs in patients undergoing CA for AF without any change in the dosing regimen. Moreover, we assessed differences between once- and twice-daily DOAC dosing in patients undergoing CA for AF who continued on DOACs without any change in the dosing regimen. This study was a retrospective single-center cohort study of consecutive patients. All patients continued DOACs without interruption or changes to the dosing schedule, even in the case of morning procedures. The primary endpoint was the incidence of major bleeding events within the first 30 days after CA. In all, 710 consecutive patients were included in the study. Bleeding complications were less frequent in the uninterrupted twice- than once-daily DOACs group. However, the incidence of cardiac tamponade across all DOACs was low (0.98%; 7/710), suggesting that uninterrupted DOACs without changes to the dosing regimen may be an acceptable strategy. The rate of total bleeding events, including minor bleeding (12/710; 1.6%), was also satisfactory. Uninterrupted DOACs without any change in dosing regimen for patients undergoing CA for AF is acceptable. Bleeding complications may be less frequent in patients receiving DOACs twice rather than once daily.",
"affiliations": "Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo Tokyo Japan.;Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo Tokyo Japan.;Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo Tokyo Japan.;Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo Tokyo Japan.;Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo Tokyo Japan.;Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo Tokyo Japan.;Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo Tokyo Japan.;Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo Tokyo Japan.;Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo Tokyo Japan.;Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo Tokyo Japan.;Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo Tokyo Japan.;Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo Tokyo Japan.",
"authors": "Oshima|Tsukasa|T|;Fujiu|Katsuhito|K|;Matsunaga|Hiroshi|H|;Matsuda|Jun|J|;Matsubara|Takumi|T|;Saga|Akiko|A|;Yoshida|Yuriko|Y|;Shimizu|Yu|Y|;Hasumi|Eriko|E|;Oguri|Gaku|G|;Kojima|Toshiya|T|;Komuro|Issei|I|",
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"doi": "10.1253/circrep.CR-20-0139",
"fulltext": "\n==== Front\nCirc Rep\nCirc Rep\nCirculation Reports\n2434-0790\nThe Japanese Circulation Society\n\n10.1253/circrep.CR-20-0139\nOriginal article\nArrhythmia/Electrophysiology\nUninterrupted Direct Oral Anticoagulants Without a Change in Regimen for Catheter Ablation for Atrial Fibrillation Is an Acceptable Protocol\nOshima Tsukasa MD, PhD 1\nFujiu Katsuhito MD, PhD 1 2\nMatsunaga Hiroshi MD, PhD 1\nMatsuda Jun MD, PhD 1\nMatsubara Takumi MD, PhD 1\nSaga Akiko MD, PhD 1\nYoshida Yuriko MD 1\nShimizu Yu MD, PhD 1\nHasumi Eriko MD, PhD 1\nOguri Gaku MD, PhD 1\nKojima Toshiya MD, PhD 1\nKomuro Issei MD, PhD 1\n1) Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo Tokyo Japan\n2) Department of Advanced Cardiology, School of Medicine, The University of Tokyo Tokyo Japan\nI.K. is a member of Circulation Reports’ Editorial Team.\n\nMailing address Katsuhito Fujiu, MD, PhD\n\nDepartment of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655Japanfujiu-tky@umin.ac.jp\n30 7 2021\n10 9 2021\n3 9 481487\n24 12 2020\n13 6 2021\n23 6 2021\nCopyright © 2021, THE JAPANESE CIRCULATION SOCIETY\n2021\nThe Japanese Circulation Society\n一般社団法人 日本循環器学会\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This article is licensed under a Creative Commons [Attribution-NonCommercial-NoDerivatives 4.0 International] license.\nBackground: In patients undergoing catheter ablation (CA) for atrial fibrillation (AF), the use of uninterrupted direct oral anticoagulants (DOACs) is the current protocol. This study evaluated bleeding complications following the uninterrupted use of 4 DOACs in patients undergoing CA for AF without any change in the dosing regimen. Moreover, we assessed differences between once- and twice-daily DOAC dosing in patients undergoing CA for AF who continued on DOACs without any change in the dosing regimen.\n\nMethods and Results: This study was a retrospective single-center cohort study of consecutive patients. All patients continued DOACs without interruption or changes to the dosing schedule, even in the case of morning procedures. The primary endpoint was the incidence of major bleeding events within the first 30 days after CA. In all, 710 consecutive patients were included in the study. Bleeding complications were less frequent in the uninterrupted twice- than once-daily DOACs group. However, the incidence of cardiac tamponade across all DOACs was low (0.98%; 7/710), suggesting that uninterrupted DOACs without changes to the dosing regimen may be an acceptable strategy. The rate of total bleeding events, including minor bleeding (12/710; 1.6%), was also satisfactory.\n\nConclusions: Uninterrupted DOACs without any change in dosing regimen for patients undergoing CA for AF is acceptable. Bleeding complications may be less frequent in patients receiving DOACs twice rather than once daily.\n\nKey Words: Atrial fibrillation\nCatheter ablation\nComplication\nDirect oral anticoagulants\nTwice-daily administration\n==== Body\npmcAtrial fibrillation (AF) is the most common sustained arrhythmia. The prevalence of AF increases with age; although AF affects 2.0% of the general population, this rate increases up to 10% at 80 years of age.1 The population aging is worldwide. Therefore, the number of patients with AF is likely to increase in the future.\n\nCommon medical treatment for AF was anticoagulant therapy to prevent ischemic events.2,3 However, some studies recently demonstrated the superiority of catheter ablation (CA) compared with drug therapy, not only in the case of paroxysmal AF, but also in persistent AF (PeAF).4 Moreover, a recent study showed that CA is superior to drug therapy for patients with reduced ejection fraction.5 These results should lead to an increase in the number of patients who undergo CA for AF in the future.\n\nVitamin K antagonists (VKA) have been used for more than 50 years to prevent ischemic events in AF.3,6 However, in 2010, the use of 4 direct anticoagulants (DOACs), namely dabigatran, rivaroxaban, apixaban, and edoxaban, started.7,8 Studies comparing each of the DOACs and VKA showed the superiority or non-inferiority of each DOAC both in preventing ischemic events and in reducing bleeding events.7–10 Therefore, the use of these 4 DOACs has increased relative to the use of VKA; in fact, it is believed that, in future, the use of DOACs will increase compared with the use of VKA.11,12\n\nThe uninterrupted use of VKA has been recommended rather than switching to heparin infusion 2–5 days before ablation.13,14 Recent trials comparing the uninterrupted use of the 4 DOACs to uninterrupted VKA clearly showed the safety and effectiveness of each DOAC over VKA, especially a significant reduction in bleeding events in some trials.15–18\n\nHowever, in some of these trials, patients received once-daily DOACs in the evening of the day of the procedure, not in the morning.15,18 In Japan, most patients receive once-daily DOACs in the morning. Therefore, the safety of uninterrupted DOACs without any change in dosing regimen in patients undergoing CA for AF, particularly if the once-daily DOAC is received in the morning, remains unclear. In this study we evaluated bleeding complications in consecutive patients who underwent CA for AF without any change in the DOAC dosing regimen throughout all procedures.\n\nMethods\n\nCA for AF was performed without discontinuation of DOACs, even if they were taken in the morning on the day of the procedure, in all consecutive cases. Moreover, all once-daily DOACs were administrated in the morning before CA and were not shifted to the evening on the day of CA. This study is a retrospective single-center cohort study of consecutive patients who underwent AF ablation. All data were collected from electronic medical records.\n\nAnticoagulant Management\n\nAll consecutive patients who underwent CA for AF took DOACs unless they had severe renal dysfunction which is a contraindication for DOACs. The type of DOAC was decided by individual attending physicians. All patients were on anticoagulants for >4 weeks before CA. The once-daily DOACs (rivaroxaban and edoxaban) were taken in the morning, not in the evening, by all patients. Left atrial thrombi were evaluated before ablation by transesophageal echocardiography or computed tomography in all patients whose CHADS2 scores were >1. Thrombi were evaluated in PeAF and long-standing PeAF (LSPeAF) patients even if their CHADS2 score was 0.\n\nOff-label underdosing of dabigatran was defined in the present study as a dose <220 mg/day. This definition of off-label underdosing of dabigatran included the 150-mg/day on-label dose in the US.\n\nA bolus of 5,000 IU heparin was administered before transseptal puncture, just after puncture of the femoral vein. Patient were also given a continuous infusion of heparin 1,000 IU/h. During the procedure, the activated clotting time was maintained at 300–350 s. After ablation was completed, protamine sulfate was administered to reverse the effects of heparin.\n\nAfter each procedure, the same kind of anticoagulant was administered for at least 4 weeks. Therefore, 4 weeks before and after CA, including on the day of the procedure, all patients continued to take the same kind of DOAC in the morning (and evening in the case of patients taking DOACs twice daily).\n\nNone of the patients in the present study switched to another kind of DOACs during the observation periods. There was no significant difference in periprocedural anticoagulant management among different DOAC types.\n\nAblation Procedure\n\nIn cases of radiofrequency CA, extensive encircling pulmonary vein isolation (PVI) guided by intracardiac echocardiography and contact force was performed. If PVI was insufficient to sustain sinus rhythm, linear ablation (mitral isthmus linear ablation, left atrium [LA] roof linear ablation, or LA anterior linear ablation), ablation of complex fractionated atrial electrocardiograms, ganglionated plexi ablation, and/or superior vena cava isolation was added. In patients with PeAF or LSPeAF, if AF was not terminated, electric cardioversion was performed to restore sinus rhythm.\n\nIn cases of balloon ablation, including cryoballoon, hot balloon, and laser balloon, the 4 pulmonary veins (PVs) were isolated one by one. Touch-up ablation with radiofrequency was added if the isolation was not achieved after 2 sessions of balloon ablation.\n\nATP and isoproterenol were administered to disclose dormant conduction of the PV and non-PV triggers.\n\nAdverse Events\n\nAll adverse events throughout the periprocedural period and within the first 30 days after CA were recorded and analyzed. Adverse events included bleeding, defined as greater than Type 3 bleeding based on the Bleeding Academic Research Consortium (BARC), cardiac tamponade, and ischemic events. Bleeding included overt bleeding plus a decrease in hemoglobin >3 g/dL, overt bleeding requiring transfusion, intracerebral hemorrhage detected by imaging or during autopsy, and bleeding requiring surgical intervention.\n\nIschemic events included ischemic stroke, non-central nervous system systemic embolism, and myocardial infarction. Stroke was defined as the sudden onset of a focal neurologic deficit in a consistent location with the territory of the major cerebral artery. Systemic embolism was defined as acute vascular occlusion of an extremity or organ detected by imaging or surgery.\n\nStatistical Analysis\n\nAll continuous variables are expressed as the mean±SD, and were assessed using the Mann-Whitney U test. Categorical data are presented as frequencies and percentages, and the significance of differences between groups was evaluated using Chi-squared or Fisher’s exact tests. Two-sided P<0.05 was considered to be statistically significant. Multivariate analysis was used to assess and collect statistical data to explain the relationship between different variables associated with a result.\n\nEthical Considerations\n\nThe study protocol conformed to the Declaration of Helsinki and was reviewed and approved by the Institutional Review Board of The University of Tokyo (No. 2650).\n\nResults\n\nBaseline Characteristics\n\nIn all, 710 patients with AF underwent CA (Table 1). The mean age was 65.1±11.9 years. At baseline, the edoxaban group had a smaller percentage of female patients (20.1%) compared with the other groups (dabigatran, 29.5%; rivaroxaban, 32.0%; apixaban, 31.4%; P=0.041). The apixaban group had a higher age, specifically a higher percentage of elderly (>75 years old) patients (32.8%) than in the other groups (dabigatran, 14.7%; rivaroxaban, 17.3%; edoxaban, 16.5%; P<0.0001). Because of a higher percentage of elderly patients and a higher percentage of patients with a history of stroke/transient ischemic attack (TIA), the apixaban group had a CHA2DS2-VASC score. Conversely, there were no significant differences in the HAS-BLED score among groups. There was a higher frequency of balloon ablation in the dabigatran group than in the other groups (P=0.0304). Table 1. Baseline Characteristics According to DOAC Used\n\n \tDabigatran\n(n=88)\tRivaroxaban\n(n=237)\tApixaban\n(n=216)\tEdoxaban\n(n=169)\tP value\t\nAge (years)\t63.4±10.8\t64.4±11.7\t66.9±11.8\t64.1±12.6\t0.019\t\nFemale sex\t26 (29.5)\t77 (32.4)\t68 (31.4)\t34 (20.1)\t0.035\t\nPAF\t53 (60.2)\t110 (46.4)\t104 (48.1)\t70 (41.4)\t0.039\t\nPeAF\t22 (25.0)\t73 (30.8)\t69 (31.9)\t61 (36.0)\t0.330\t\nLSPeAF\t4 (4.5)\t21 (8.8)\t18 (8.3)\t14 (8.2)\t0.634\t\nAT/AFL\t9 (10.2)\t33 (13.9)\t25 (11.5)\t24 (14.2)\t0.711\t\nBody weight (kg)\t65.3±11.3\t65.5±12.9\t64.0±12.3\t66.3±13.4\t0.428\t\nOperator experience >5 years\t85 (96.5)\t220 (92.8)\t197 (91.2)\t146 (86.3)\t0.031\t\nAM procedure\t41 (46.5)\t101 (42.6)\t121 (56.2)\t87 (51.4)\t0.033\t\nTime from DOAC to procedure (h)\t4.3±2.3\t4.4±2.2\t3.8±2.1\t4.0±2.2\t0.031\t\nDOAC dose\t\n Appropriate dose\t83 (94.4)\t212 (89.5)\t196 (90.8)\t145 (85.8)\t0.003\t\n Off-label underdose\t5 (5.6)\t25 (10.5)\t20 (9.2)\t24 (14.2)\t0.170\t\n Regular dose\t83 (94.4)\t170 (71.7)\t164 (75.9)\t101 (59.7)\t0.003\t\nCHA2DS2-VASc score\t2.2±1.61\t2.09±1.37\t2.61±1.75\t2.23±1.64\t0.005\t\nHeart failure\t12 (13.6)\t32 (13.5)\t42 (19.4)\t31 (18.3)\t0.278\t\nHypertension\t51 (57.9)\t126 (53.1)\t124 (57.4)\t105 (62.1)\t0.350\t\nAge ≥75 years\t13 (14.7)\t41 (17.3)\t71 (32.8)\t28 (16.5)\t<0.001\t\nDiabetes\t15 (17.0)\t39 (16.4)\t44 (20.3)\t37 (21.8)\t0.494\t\nPrevious stroke/TIA\t10 (11.3)\t14 (5.9)\t28 (12.9)\t13 (7.6)\t0.052\t\nVascular disease\t12 (13.6)\t20 (8.4)\t31 (14.3)\t21 (12.4)\t0.234\t\nHAS-BLED score\t1.39±1.02\t1.33±0.99\t1.55±1.05\t1.5±1.13\t0.127\t\nAbnormal renal/liver function\t5 (5.68)\t18 (7.59)\t18 (8.33)\t9 (5.33)\t0.564\t\nPrevious bleeding\t2 (2.27)\t7 (2.95)\t2 (0.93)\t6 (3.55)\t0.350\t\nAntiplatelet therapy or alcohol\t10 (11.3)\t17 (7.1)\t32 (14.8)\t25 (14.7)\t0.041\t\nLVEF (%)\t62.9±9.3\t62.5±10.2\t60.9±12.1\t60.2±13.3\t0.160\t\nLAD (mm)\t40.7±7.87\t40.6±6.31\t40.9±6.59\t40.7±6.57\t0.975\t\nCKD\t29 (32.9)\t81 (34.1)\t77 (35.6)\t56 (33.1)\t0.951\t\neGFR\t67.9±15.7\t66.3±15.6\t65.5±15.7\t66.7±17.1\t0.696\t\nBalloon ablation\t16 (18.1)\t19 (8.02)\t17 (7.87)\t16 (9.47)\t0.030\t\nValues are presented as the mean±SD or n (%). AM, ante meridiem; AT/AFL, atrial tachycardia/atrial flutter; CKD, chronic kidney disease; DOAC, direct oral anticoagulant; LAD, left atrial diameter; LSPeAF, long-standing persistent atrial fibrillation; LVEF, left ventricular ejection fraction; PAF, paroxysmal atrial fibrillation; PeAF, persistent atrial fibrillation; TIA, transient ischemic attack.\n\nComparing patients receiving twice-daily DOACs (dabigatran and apixaban; n=304) and those receiving once-daily DOACs (rivaroxaban and edoxaban; n=406) revealed a significantly higher CHA2DS2-VASC score in the twice- than once-daily group (2.49±1.72 vs. 2.15±1.49, respectively; P=0.0085) due to the higher percentage of elderly patients and the higher frequency of stroke history (Table 2). There were no significant differences in other characteristics, including the timing of the procedure, appropriate dose ratio, and off-label underdosing ratio. Table 2. Baseline Characteristics According to Twice- or Once-Daily DOAC Dosing\n\n \tTwice-daily dosing\n(n=304)\tOnce-daily dosing\n(n=406)\tP value\t\nAge (years)\t66.0±11.7\t64.1±12.2\t0.0462\t\nFemale sex\t94 (30.9)\t110 (27.0)\t0.315\t\nPAF\t157 (51.6)\t180 (44.3)\t0.057\t\nPeAF\t91 (29.9)\t134 (33.0)\t0.415\t\nLSPeAF\t22 (7.2)\t35 (8.6)\t0.577\t\nAT/AFL\t34 (11.1)\t57 (14.0)\t0.307\t\nBody weight (kg)\t64.4±12.1\t65.7±13.1\t0.177\t\nOperator experience >5 years\t282 (92.7)\t366 (90.1)\t0.23\t\nAM procedure\t162 (53.2)\t188 (46.3)\t0.069\t\nTime from DOAC to procedure (h)\t4.0±2.2\t4.2±2.2\t0.082\t\nDOAC dose\t\n Appropriate dose\t279 (91.8)\t357 (88.0)\t0.14\t\n Off-label underdose\t25 (8.2)\t49 (12.0)\t0.107\t\nCHA2DS2-VASc score\t2.49±1.72\t2.15±1.49\t0.0043\t\nHeart failure\t54 (17.7)\t63 (15.5)\t0.474\t\nHypertension\t175 (57.5)\t231 (56.9)\t0.878\t\nAge ≥75 years\t84 (27.6)\t69 (17.0)\t0.0009\t\nDiabetes\t59 (19.4)\t76 (18.7)\t0.847\t\nPrevious stroke/TIA\t38 (12.5)\t27 (6.65)\t0.0085\t\nVascular disease\t43 (14.1)\t41 (10.1)\t0.101\t\nHAS-BLED score\t1.5±1.04\t1.4±1.06\t0.186\t\nAbnormal renal/liver function\t23 (7.5)\t27 (6.6)\t0.805\t\nPrevious bleeding\t4 (1.3)\t13 (3.2)\t0.137\t\nAntiplatelet therapy or alcohol\t42 (13.8)\t42 (10.3)\t0.16\t\nLVEF (%)\t61.5±11.4\t61.6±11.6\t0.916\t\nLAD (mm)\t40.8±6.96\t40.6±6.41\t0.74\t\nCKD\t106 (34.8)\t137 (33.7)\t0.81\t\neGFR\t66.2±15.7\t66.4±516.2\t0.84\t\nBalloon ablation\t33 (10.8)\t35 (8.6)\t0.367\t\nValues are presented as the mean±SD or n (%). Abbreviations as in Table 1.\n\nComplications\n\nThere were no fatal events or intracranial bleeding events in any group. There was a low frequency of cardiac tamponade among all patients (0.99%; 7/710). Cardiac tamponade occurred in 4 (1.6%) patients in the rivaroxaban group and in 3 (1.7%) patients in the edoxaban group; it did not occur in either the dabigatran or apixaban groups (P=0.13; Table 3). Other bleeding complications, including pericardiac effusion, puncture site hematoma, and intraperitoneal hemorrhage requiring blood transfusion due to a drop in hemoglobin >3 mg/dL, occurred in 1 (0.4%) patient in the apixaban group and in 4 (2.3%) patients in the edoxaban group. None of these bleeding complications were recorded in either the dabigatran or rivaroxaban groups (P=0.035). In total, bleeding complications occurred in 4 (1.6%) patients in the rivaroxaban group, in 1 (0.4%) patient in the apixaban group, and in 7 (4.1%) patients in the edoxaban group. There were bleeding complications in the dabigatran group (P=0.022). Stroke and TIA occurred in 1 (0.4%) patient in the rivaroxaban group and in 2 (1.1%) patients in the edoxaban group; there were no events of stroke/TIA recorded in either the dabigatran or apixaban groups (P=0.306; Table 3). Other ischemic events, including non-central nervous system systemic embolism and myocardial infarction, were not reported. There were significant differences in overall complications among the 4 groups, as indicated in Table 3. Table 3. Complications According to Direct Oral Anticoagulant Used\n\n \tDabigatran\n(n=88)\tRivaroxaban\n(n=237)\tApixaban\n(n=216)\tEdoxaban\n(n=169)\tP value\t\nTotal bleeding complications\t0 (0)\t4 (1.6)\t1 (0.4)\t7 (4.1)\t0.0224\t\n Cardiac tamponade\t0 (0)\t4 (1.6)\t0 (0)\t3 (1.7)\t0.1307\t\n Other bleeding complications\t0 (0)\t0 (0)\t1 (0.4)\t4 (2.3)\t0.0356\t\nStroke/transient ischemic attack\t0 (0)\t1 (0.4)\t0 (0)\t2 (1.1)\t0.306\t\nTotal no. complications\t0 (0)\t5 (2.1)\t1 (0.4)\t9 (5.3)\t0.0043\t\nValues are presented as n (%).\n\nComparing the twice- and once-daily DOACs groups revealed that cardiac tamponade occurred in 7 (1.7%) patients in the once-daily group, but not at all in the twice-daily group (P=0.022). There was a significantly higher incidence of total bleeding events in the once- than twice-daily group (11 [2.7%] vs. 1 [0.3%], respectively; P=0.016; Table 4). There was no significant difference in ischemic events between these 2 groups (Table 4). Overall complications tended to occur more frequently in the once- than twice-daily group (P=0.0016; Table 4). Details of each case of complications are presented in Table 5. Table 4. Bleeding and Stroke Complications According to Twice- or Once-Daily Direct Oral Anticoagulant Dosing\n\n \tTwice-daily dosing\n(n=304)\tOnce-daily dosing\n(n=406)\tP value\t\nTotal bleeding complications\t1 (0.3)\t11 (2.7)\t0.016\t\n Cardiac tamponade\t0 (0)\t7 (1.7)\t0.0221\t\n Other bleeding complications\t1 (0.3)\t4 (0.9)\t0.398\t\nStroke/transient ischemic attack\t0 (0)\t3 (0.7)\t0.264\t\nTotal no. complications\t1 (0.3)\t11 (2.7)\t0.016\t\nValues are presented as n (%).\n\nTable 5. Details of Patients With Complications\n\nAge\n(years)\tSex\tType\nof AF\tType of\nDOAC\tAppropriate\ndose\tOff-label\nunderdosing\tProcedure\tProcedure\ntimingA\tCHA2DS2-\nVASc\tHAS-\nBLED\tComplication\tComplication\ntiming\tIntervention\tOutcome\tOperator experience\n>5 years\t\n85\tF\tPAF\tApixaban\t1\t0\tRFCA (PVI+CTI)\tPM (9)\t3\t2\tRetroperitoneal hematoma\tDay 2\tTransfusion\tSurvive\tY\t\n49\tM\tPeAF\tEdoxaban\t1\t0\tRFCA (PVI+linear)\tAM (2)\t0\t0\tTIA\tDay 2\tNone\tSurvive\tY\t\n56\tF\tPeAF\tRivaroxaban\t0\t1\tRFCA (PVI+linear)\tPM (8)\t3\t1\tCT, CI\tDay 0\tSurgical repair\tSurvive\tY\t\n72\tM\tPeAF\tEdoxaban\t0\t1\tRFCA (PVI+linear+CTI)\tPM (6)\t3\t3\tPericardial effusion\tDay 0\tPericardiocentesis\tSurvive\tY\t\n61\tM\tPAF\tEdoxaban\t0\t1\tRFCA (PVI+CTI)\tPM (6)\t2\t1\tCT\tDay 0\tSurgical repair\tSurvive\tN\t\n57\tM\tPAF\tEdoxaban\t1\t0\tRFCA (PVI)\tPM (6)\t0\t0\tTIA\tDay 0\tNone\tSurvive\tN\t\n72\tM\tPAF\tEdoxaban\t1\t0\tRFCA (PVI)\tAM (2)\t4\t2\tRetroperitoneal hematoma\tDay 2\tTransfusion\tSurvive\tN\t\n59\tM\tPeAF\tEdoxaban\t1\t0\tRFCA (PVI+SVCi+CTI)\tAM (2)\t0\t0\tAtriovenous fistula, puncture site hematoma\tDay 5\tPressure hemostasis\tSurvive\tY\t\n83\tF\tPAF\tEdoxaban\t1\t0\tRFCA (PVI)\tPM (10)\t7\t2\tPuncture site hematoma\tDay 1\tTransfusion\tSurvive\tY\t\n73\tF\tPAF\tRivaroxaban\t1\t0\tBalloon ablation+CTI\tAM (2)\t2\t1\tCT\tDay 0\tPericardiocentesis\tSurvive\tY\t\n81\tM\tPAF\tEdoxaban\t1\t0\tRFCA (PVI)\tPM (7)\t6\t5\tCT\tDay 0\tPericardiocentesis\tSurvive\tY\t\n72\tM\tPAF\tEdoxaban\t1\t0\tRFCA (PVI+CTI)\tPM (6)\t1\t1\tCT\tDay 0\tSurgical repair\tSurvive\tY\t\n67\tF\tPAF\tRivaroxaban\t0\t1\tRFCA (PVI)\tPM (6)\t3\t1\tCT\tDay 0\tPericardiocentesis\tSurvive\tY\t\n71\tM\tPAF\tRivaroxaban\t1\t0\tRFCA (PVI+CTI)\tAM (2)\t1\t1\tCT\tDay 0\tPericardiocentesis\tSurvive\tY\t\nAThe procedure-started timings are shown as AM (in the morning) or PM (afternoon), with the duration (h) between DOAC administration and the procedure. AF, atrial fibrillation; CI, cerebral infarction; CT, cardiac tamponade; CTI, cavotricuspid isthmus ablation; DOAC, direct oral anticoagulant; F, female; M, male; N, no; PVI, pulmonary vein isolation; RFCA, radiofrequency catheter ablation; SVCi, superior vena cava isolation; TIA, transient ischemic attack; Y, yes.\n\nMultivariate analysis revealed that once-daily DOAC was the only independent predictor of complications (Table 6). Table 6. Multivariate Analysis of Predictors of Complications\n\n \tP valure\t\nTwice-daily dosing\t0.0269\t\nAge >75 years\t0.882\t\nFemale sex\t0.864\t\nOperator experience >5 years\t0.4\t\nAM procedure\t0.92\t\nAppropriate dose\t0.81\t\nOff-label underdosing\t0.22\t\nHypertension\t0.125\t\nDiabetes\t0.767\t\nPrevious stroke/TIA\t0.696\t\nAntiplatelet therapy or alcohol consumption\t0.502\t\nChronic kidney disease\t0.664\t\nBalloon ablation\t0.935\t\nAM, ante meridiem; TIA, transient ischemic attack.\n\nDiscussion\n\nThere is no doubt that uninterrupted DOACs have been used in AF ablation.15,17,18 However, decisions as to how the DOAC regimen is handled on the day of CA for AF are left to the discretion of medical staff. There is question as to whether once-daily DOACs should be shifted to the evening on the day of the procedure.\n\nIn this study, there was no change in the timing of administration and the type of DOAC from 4 weeks before to 4 weeks after CA, including on the day of the procedure. Specifically, all consecutive patients continued to take the same sort of DOAC they had been receiving in the morning (and evening in the case of twice-daily DOACs). There is a neutralizing antibody, idarucizumab, available for dabigatran, and it is highly effective in bleeding events, as shown by some studies.19,20 Therefore, the switch to dabigatran from other kinds of DOACs may be potentially safer. However, a change in the kind of DOAC during the perioperative period may increase the risk of human error, such as erroneous administration. Therefore, we did not change the kinds of DOACs or their administration.\n\nCardiac tamponade, a major life-threatening complication, has been evaluated as a representative bleeding event in previous uninterrupted DOAC with CA studies.21,22 In those studies, the frequency of cardiac tamponade under CA for AF with uninterrupted DOAC ranged from 0% (0/123) to 1.6% (1/64), with a mean of 0.66% (22/3,323).21,22 Currently, an incidence of cardiac tamponade of <1% seems to be acceptable during CA for AF.22 Considering the results of the previous studies and the complication rate of 0.98% (7/710, Table 4) in the present study, the uninterrupted use of DOACs without any change in the dosage regimen during CA for AF may be acceptable.\n\nHowever, cardiac tamponade and bleeding events were significantly lower in the twice- than once-daily group (Table 3). Fortunately, all patients with these complications recovered without any aftereffects with appropriate treatment, including observation only, epicardial drainage, or cardiac surgery. Thus, we do not expect to prevent administration of once-daily DOACs in the morning on the day of CA for AF.\n\nThe mean age and the proportion of patients >75 years of age were higher in the apixaban group (Table 1). Age is one of the risk factors for cardiac tamponade during ablation.23 However, bleeding complications were not increased in the apixaban group, suggesting the safety and effectiveness of uninterrupted apixaban. There were no complications, including bleeding events and ischemic events, in the dabigatran group. However, the frequency of balloon ablation in the dabigatran group was significantly higher than in the other groups. Balloon ablation can reduce cardiac tamponade compared with radiofrequency ablation; therefore, we cannot directly conclude that uninterrupted dabigatran is safe and effective, based on the findings of the present study.24\n\nThe baseline CHA2DS2-VASc score differed between the once- and twice-daily groups because of the higher frequency of elderly patients and history of stroke in the latter group. However, bleeding complications were significantly less frequent in the twice-daily DOAC group. Moreover, even after multivariate analysis, once-daily DOAC use was an independent predictor of bleeding complications. Therefore, twice-daily DOAC may be safer than once-daily DOACs in the context of CA for AF.\n\nThe specific feature of blood concentrations may be one reason why the once-daily DOAC regimen was associated with a higher incidence of complications. There is a significant difference in blood concentrations between peak and baseline with once-daily DOACs. The high peak concentration of once-daily DOACs might be associated with the higher rate of complications.\n\nStudy Limitations\n\nOne limitation of this study is that it was a retrospective study. In addition, the subjects in this study were exclusively Japanese, and the dosage of DOACs in Japan differs compared with other countries. Therefore, randomized double-blind multicenter trials are required to prove whether there is a difference between the 4 DOACs in terms of their effectiveness and safety.\n\nConclusions\n\nThe uninterrupted use of DOACs without any changes in the dosage in patients undergoing CA for AF was acceptable. However, bleeding complications may be less frequent in the patients receiving twice-daily DOACs than in those receiving once-daily DOACs.\n\nSources of Funding\n\nThis research did not receive any specific grant from funding agencies in the public, commercial, on not-for-profit sectors.\n\nDisclosures\n\nK.F. and I.K. have each received lecture fees from Bayer Healthcare, Boehringer Ingelheim, Bristol-Meyers Squibb, and Daiichi-Sankyo. I.K. is a member of Circulation Reports’ Editorial Team. The remaining authors have no conflicts of interest to disclose.\n\nIRB Information\n\nThis study was approved by the Institutional Review Board of The University of Tokyo (Reference no. 2659).\n\nAcknowledgments\n\nWe thank Ms. Takahashi Michiko for her excellent data collection.\n\nData Availability\n\nThe deidentified participant data will not be shared.\n==== Refs\nReferences\n\n1. Zoni-Berisso M, Lercari F, Carazza T, Domenicucci S. Epidemiology of atrial fibrillation: European perspective. 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"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2434-0790",
"issue": "3(9)",
"journal": "Circulation reports",
"keywords": "Atrial fibrillation; Catheter ablation; Complication; Direct oral anticoagulants; Twice-daily administration",
"medline_ta": "Circ Rep",
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"pages": "481-487",
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"pubdate": "2021-09-10",
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"title": "Uninterrupted Direct Oral Anticoagulants Without a Change in Regimen for Catheter Ablation for Atrial Fibrillation Is an Acceptable Protocol.",
"title_normalized": "uninterrupted direct oral anticoagulants without a change in regimen for catheter ablation for atrial fibrillation is an acceptable protocol"
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"abstract": "To investigate the effects of diazepam on ventilatroy control, hypoxic and hypercapnic ventilatory responses were studied in 8 normal subjects before and after 10 mg of intramuscular diazepam. There was no significant change in either resting minute ventilation or resting end-tidal CO2 tension, but depression of hypoxic ventilatory response was observed 15 (60% of control) and 30 min (53% of control) after diazepam (p less than 0.05). No significant depression of hypercapnic ventilatory response was noted 70 to 130 min after diazepam. In view of the depression of hypoxic ventilatory response by diazepam in normal subjects, adverse responses along these lines should be considered in patients with impaired ventilatory function, such as chronic airways obstruction, and in those encountering acute hypoxemia.",
"affiliations": null,
"authors": "Lakshminarayan|S|S|;Sahn|S A|SA|;Hudson|L D|LD|;Weil|J V|JV|",
"chemical_list": "D003975:Diazepam",
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"doi": "10.1002/cpt1976202178",
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"issn_linking": "0009-9236",
"issue": "20(2)",
"journal": "Clinical pharmacology and therapeutics",
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"medline_ta": "Clin Pharmacol Ther",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D003975:Diazepam; D005260:Female; D006801:Humans; D006935:Hypercapnia; D000860:Hypoxia; D008297:Male; D012119:Respiration; D013997:Time Factors",
"nlm_unique_id": "0372741",
"other_id": null,
"pages": "178-83",
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"pubdate": "1976-08",
"publication_types": "D016428:Journal Article; D013487:Research Support, U.S. Gov't, P.H.S.",
"references": null,
"title": "Effect of diazepam on ventilatory responses.",
"title_normalized": "effect of diazepam on ventilatory responses"
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"abstract": "OBJECTIVE\nAcetaminophen (APAP) hepatotoxicity is related to the formation of N-acetyl-p-benzoquinone imine (NAPQI), which is detoxified through conjugation with reduced glutathione (GSH). Ophthalmic acid (OA) is an analogue of GSH in which cysteine is replaced with 2-aminobutyrate. Metabolomics studies of mice with APAP-induced acute liver failure (APAP-ALF) identified OA as a marker of oxidative stress and hepatic GSH consumption. The aim of the current study was to determine whether OA is detectable in APAP-ALF human patients either early (day 2) or late (day 4) and whether OA levels were associated with in-hospital survival in the absence of liver transplant.\n\n\nMETHODS\nSerum samples from 130 APAP-ALF patients (82 survivors, 48 non-survivors) were analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and correlated with clinical data from the United States Acute Liver Failure Study Group (US ALFSG) Registry (2004-2011).\n\n\nRESULTS\nSurvivors had significantly lower admission bilirubin (4.2 vs. 5.7 mg/dl) and lactate levels (3.3 vs. 6.5 μmol/l, p<0.05 for all). During the first 7 days of the study, survivors were less likely to require mechanical ventilation (55% vs. 88%), vasopressor support (9.8% vs. 67%) or renal replacement therapy (26% vs. 63%, p< 0.001 for all). Non-survivors were more likely to have detectable OA levels early (31% vs. 15%, p = 0.034) and late (27% vs. 11%, p = 0.02). However there were no significant differences in mean OA levels between non-survivors and survivors (early 0.48 vs. 0.36, late 0.43 vs. 0.37, P > 0.5 for all).\n\n\nCONCLUSIONS\nOA was detectable more frequently in APAP-ALF non-survivors but mean OA levels were not associated with survival. The routine clinical administration of N-acetyl cysteine could replenish GSH levels and prevent OA production.",
"affiliations": "Department of Laboratory Medicine, Pathology, University of Alberta, Edmonton, Canada.;Department of Laboratory Medicine, Pathology, University of Alberta, Edmonton, Canada; Department of Physiology, University of Alberta, Edmonton, Canada.;Department of Public Health Sciences, Medical University of South Carolina, Charleston, South Carolina, United States of America.;Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.;Department of Physiology, University of Alberta, Edmonton, Canada.;Divisions of Hepatology and Critical Care Medicine, University of Alberta, Edmonton, Canada.",
"authors": "Kaur|Gurnit|G|;Leslie|Elaine M|EM|;Tillman|Holly|H|;Lee|William M|WM|;Swanlund|Diane P|DP|;Karvellas|Constantine J|CJ|;|||",
"chemical_list": "D009842:Oligopeptides; D000082:Acetaminophen; C016632:ophthalmic acid",
"country": "United States",
"delete": false,
"doi": "10.1371/journal.pone.0139299",
"fulltext": "\n==== Front\nPLoS OnePLoS ONEplosplosonePLoS ONE1932-6203Public Library of Science San Francisco, CA USA 2640717010.1371/journal.pone.0139299PONE-D-15-16050Research ArticleDetection of Ophthalmic Acid in Serum from Acetaminophen-Induced Acute Liver Failure Patients Is More Frequent in Non-Survivors Ophthalmic Acid in Acute Liver FailureKaur Gurnit \n1\nLeslie Elaine M. \n1\n\n2\nTillman Holly \n3\nLee William M. \n4\nSwanlund Diane P. \n2\nKarvellas Constantine J. \n5\n*US Acute Liver Failure Study Group \n¶\n\n1 \nDepartment of Laboratory Medicine, Pathology, University of Alberta, Edmonton, Canada\n\n2 \nDepartment of Physiology, University of Alberta, Edmonton, Canada\n\n3 \nDepartment of Public Health Sciences, Medical University of South Carolina, Charleston, South Carolina, United States of America\n\n4 \nDivision of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America\n\n5 \nDivisions of Hepatology and Critical Care Medicine, University of Alberta, Edmonton, Canada\nVilla Erica Editor\nUniversity of Modena & Reggio Emilia, ITALY\nCompeting Interests: The authors have declared that no competing interests exist.\n\nConceived and designed the experiments: CJK EML. Performed the experiments: EML DPS GK. Analyzed the data: CJK HT EML GK. Contributed reagents/materials/analysis tools: EML DPS GK. Wrote the paper: GK EML WML HT DPS CJK. Guarantor of this manuscript submission: CJK. Reviewed and approved the final manuscript: GK EML HT WML DS CJK.\n\n¶ Complete membership in the US Acute Liver Failure Study group can be found in the Acknowledgments\n\n* E-mail: dean.karvellas@ualberta.ca25 9 2015 2015 10 9 e013929915 4 2015 12 9 2015 © 2015 Kaur et al2015Kaur et alThis is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.Background/Aim\nAcetaminophen (APAP) hepatotoxicity is related to the formation of N-acetyl-p-benzoquinone imine (NAPQI), which is detoxified through conjugation with reduced glutathione (GSH). Ophthalmic acid (OA) is an analogue of GSH in which cysteine is replaced with 2-aminobutyrate. Metabolomics studies of mice with APAP-induced acute liver failure (APAP-ALF) identified OA as a marker of oxidative stress and hepatic GSH consumption. The aim of the current study was to determine whether OA is detectable in APAP-ALF human patients either early (day 2) or late (day 4) and whether OA levels were associated with in-hospital survival in the absence of liver transplant.\n\nMethods\nSerum samples from 130 APAP-ALF patients (82 survivors, 48 non-survivors) were analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and correlated with clinical data from the United States Acute Liver Failure Study Group (US ALFSG) Registry (2004–2011).\n\nResults\nSurvivors had significantly lower admission bilirubin (4.2 vs. 5.7 mg/dl) and lactate levels (3.3 vs. 6.5 μmol/l, p<0.05 for all). During the first 7 days of the study, survivors were less likely to require mechanical ventilation (55% vs. 88%), vasopressor support (9.8% vs. 67%) or renal replacement therapy (26% vs. 63%, p< 0.001 for all). Non-survivors were more likely to have detectable OA levels early (31% vs. 15%, p = 0.034) and late (27% vs. 11%, p = 0.02). However there were no significant differences in mean OA levels between non-survivors and survivors (early 0.48 vs. 0.36, late 0.43 vs. 0.37, P > 0.5 for all).\n\nConclusion\nOA was detectable more frequently in APAP-ALF non-survivors but mean OA levels were not associated with survival. The routine clinical administration of N-acetyl cysteine could replenish GSH levels and prevent OA production.\n\nThe study was sponsored by NIH grant U-01 58369 (from NIDDK). It was also supported by a grant from the Transplant Fund Value Added and the Canadian Institutes of Health Research [Grant MOP-272075]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Data AvailabilityDue to ethical restrictions imposed by the authors' Institutional Review Board, data is available upon request to all interested researchers with proper permission/approval. Interested researchers may contact Angela Bowling, administrative lead of the United States Actue Liver Failure Study Group (angela.bowling@utsouthwestern.edu) to request data. Data is also available upon request with permission via the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and data appear on clinicaltrials.gov (identifier: NCT00518440). Requests for a copy of the database may also be made through the NIDDK webpage: (https://www.niddkrepository.org/studies/aalf/?query=acute%20liver%20failure).Data Availability\nDue to ethical restrictions imposed by the authors' Institutional Review Board, data is available upon request to all interested researchers with proper permission/approval. Interested researchers may contact Angela Bowling, administrative lead of the United States Actue Liver Failure Study Group (angela.bowling@utsouthwestern.edu) to request data. Data is also available upon request with permission via the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and data appear on clinicaltrials.gov (identifier: NCT00518440). Requests for a copy of the database may also be made through the NIDDK webpage: (https://www.niddkrepository.org/studies/aalf/?query=acute%20liver%20failure).\n==== Body\nIntroduction\nAcute liver failure (ALF) is defined by the occurrence of encephalopathy and synthetic dysfunction within 8 weeks of the first symptoms of liver disease [1, 2]. In the United States and United Kingdom, acetaminophen (APAP) overdose is the leading cause of ALF [3, 4]. APAP metabolism occurs in the liver, predominantly through glucuronide and sulfate conjugation. A small amount of the APAP dose is catalyzed by cytochrome P450 2E1 (CYP2E1) to form the reactive intermediate species, N-acetyl-p-benzoquinone imine (NAPQI), which can then be detoxified by glutathione (GSH) conjugation. Resulting cysteine and mercapturic acid conjugates can then be eliminated via the urine. If APAP doses are excessive, rapid depletion of GSH from the liver will occur. GSH is an endogenous tripeptide, composed of γ-glutamate, cysteine and glycine, with cysteine being the limiting amino acid. The cysteine can be replaced by 2-aminobutyrate, forming ophthalmic acid (OA), which is effluxed into the systemic circulation from the liver. Treatment of APAP-induced ALF is through the administration of N-acetyl cysteine (NAC) therapy. This elevates cellular cysteine levels, allowing for GSH synthesis [5]. Metabolomics studies of mice undergoing APAP induced ALF have identified OA as a marker for oxidative stress and hepatic GSH depletion [6]. The aim of this study was to determine firstly whether the human serum concentrations of OA were detectable in patients with APAP-ALF and secondly whether OA levels were associated with subsequent clinically relevant outcomes (21-day survival) and hence be a potential biomarker in APAP-ALF.\n\nMaterials and Methods\nStudy Design\nWe performed a case-control study of a total of 130 APAP-ALF patients enrolled by the US ALFSG registry between March 2004 and August 2011. The authors’ Institutional Review Board (IRB)/Health research ethics boards of all enrolling US ALFSG sites (University of Texas Southwestern, University of Washington, Yale University, Medical University of South Carolina, University of Alabama, University of California Los Angeles, University of California San Francisco, Northwestern University, University of Michigan, University of Pennsylvania, Virginia Commonwealth University, Emory, The Ohio State University, University of Kansas, University of Alberta) have approved all research and all clinical investigation has been conducted according to the principles expressed in the Declaration of Helsinki. Consent/assent were obtained from all patients/their next of kin for collection of data in the US ALFSG registry and healthy controls. Patient records/information was anonymized and de-identified prior to use in this analysis. Participants who were medically competent provided written informed consent to participate in this study. In cases when patients were unable to provide written consent (critical illness, hepatic encephalopathy) written assent was obtained by the next of kin. Upon regaining capacity, patients were given the option to withdraw written consent. In those cases, data were not included in the registry. Documentation of participant consent/assent is kept in duplicate at individual sites of the US ALFSG (as above). Health research ethics boards/ Institutional review boards at all sites of the US ALFSG have approved this consent procedure (as above).\n\nParticipants\n\nInclusion criteria were: 1) evidence of ALF due to APAP toxicity according to the enrollment criteria for the ALFSG (see operational definitions) and 2) age ≥18 years; and 3) Grade I to IV HE during the first seven days of study admission (West Haven Criteria; see below). Exclusion criteria were: 1) Cirrhosis and 2) patients < 18 years.\n\nOperational Definitions\nFor the purposes of this study, ALF is defined as International normalized ratio (INR) ≥ 1.5 and HE within the first 26 weeks of liver disease in a patient with an acute hepatic insult [2]. HE grade is defined by the West Haven Criteria (simplified) as follows; grade 1 ~ any alteration in mentation, grade 2 being somnolent or obtunded but easily rousable or presence of asterixis, grade 3 being rousable with difficulty and, grade 4: unresponsive to deep pain [7, 8].\n\nData Sources and Collection\nData were collected prospectively as part of the US ALFSG and retrospectively analyzed. Prior to February 2010, each individual site prospectively sent case report forms to the University of Texas Southwestern for entry into a central database. Following this date, individual sites entered data electronically into a central database housed at the ALFSG Data Coordinating Center at the Medical University of South Carolina (Charleston, USA). Registry data assessed in this study included demographics (age, race, sex), etiology of ALF, hematology and biochemistry, requirement for organ support and therapies on day of admission or during first 7 days, and outcome data (21-day survival).\n\nSolvents and Reagents\nHPLC-grade acetonitrile, HPLC-grade methanol, and formic acid were purchased from Fisher Scientific (Fair Lawn, NJ). Water was purified using a Milli-Q water purification system (Millipore, Molsheim, France). OA was purchased from Bachem (Bupendorf, Switzerland). All other chemicals and reagents used were of analytical grade.\n\nPatient Serum Sample\nPatient samples were acquired from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) BioSample Repository. A total of 260 samples from 130 patients that had suffered APAP-induced ALF were analyzed. Patient blood samples were collected on Day 2 and Day 4 from when the patients were admitted into hospital (Day 0). At Day 21, 82 patients were alive and 48 deceased. A total of 25 healthy control serum samples were acquired from the Centre of Excellence for Gastrointestinal Inflammation and Immunity Research (CEGIIR), University of Alberta for comparison of OA levels in serum from APAP-induced ALF patients. Serum samples from four other healthy controls recruited from the University of Alberta were used for preparation of standards (as described below).\n\nPreparation of Ophthalmic Acid Standards\nOA solutions were prepared in water to achieve concentrations ranging from 0.05 μM to 10 μM. The standard curve was made up of the following concentrations: 0.05 μM, 0.1 μM, 0.3 μM, 0.5 μM, 1 μM, 3 μM, 5 μM, 10 μM. Serum samples (48 μl) from healthy human volunteers (with OA levels below the limit of detection) were spiked with these concentrations of OA (2 μl) and processed as described previously, in order to achieve a standard curve [9]. Briefly, OA was extracted from human samples (25 μl) using ice cold methanol (75 μl). Samples were vortexed and centrifuged at 16,000g for 20 min. The supernatant was collected and speed vacuumed to dryness. Contents were then dissolved in 50 μl of water and vortexed before analysis. Water (48 μl), was also spiked in an identical manner without extraction to act as quality control. Fresh standard curves were prepared for each analysis.\n\nUPLC-quadrupole linear ion trap MS conditions\nA quadrupole linear ion trap mass spectrometer (4000 QTRAP, Applied Biosystems/MDS SCIEX, Toronto, Canada) was coupled with an Agilent UPLC system (Agilent Technologies, Waldbronn, Germany). The QTRAP-MS conditions were set as previously described [10]. The HSS T3 (C18) column (2.1 mm x 150 mm), with a 1.8 μm particle size was used. The autosampler and the column oven were kept at 4°C and 60°C respectively. The flow rate was 0.35 ml/min and the mobile phase consisted of Solvent A and Solvent B. Solvent A was made up of 0.1% Formic Acid, 2% Acetonitrile and 98% Water. Solvent B was made up of 0.1% Formic Acid, 2% Water and 98% Acetonitrile; gradient elution conditions were set as previously described (New and Chan, 2008). The injection volume was 3 μl. OA was profiled using an m/z transition of 290.1 to 161.1. Data were analyzed using Analyst 1.6.2 software (Applied Biosystems).\n\nStatistical Analysis\nStatistical analysis was performed using IBM SPSS version 22 (2014) and SAS version 9.2 (SAS Institute, North Carolina, USA). In the event of missing values, data were not replaced or estimated. Data were analyzed using descriptive statistics to characterize demographics and other clinical variables. Categorical variables were compared using the Chi-square test or Fisher’s exact test (< 5 subjects). For continuous variables, normally distributed variables were reported as means with standard deviations (SD) and compared by Student’s t-test. Non-normally distributed continuous data were reported as medians with inter-quartile ranges (IQR) and compared by Wilcoxon rank sum test. Survival was defined as the dichotomous outcome, alive at 21-days after enrolment into the Registry. A two-sided significance level of <0.05 was used for all comparisons.\n\nResults\nDemographic, biochemical and therapeutic characteristics of all APAP-ALF patients (n = 130) are shown in Table 1. Survivors (n = 82) were significantly younger (mean 36 (SD 13) vs. 42(15) years) than non-survivors (n = 48) with no differences in gender or sex. On study admission (Table 1), hematological indicators were similar apart from median platelet count (survivors 140 vs. controls 116; p = 0.009). Survivors had significantly lower admission bilirubin (4.2 vs. 5.7 mg/dl; p = 0.001), creatinine (1.4 vs. 2.3 mg/dl, p = 0.049) and lactate levels (3.3 vs. 6.5 μmol/l, p = 0.003).\n\n10.1371/journal.pone.0139299.t001Table 1 Demographic, Clinical and Biochemical Parameters in 130 Acetaminophen-induced Acute Liver Failure patients.\n\tSurvivors (n = 82)\tNon-survivors (n = 48)\t\t\n\tN\tNumber % or median (IQR)\tN\tNumber % or median (IQR)\tP value\t\n\nAge\n\t82\t36 (13)\t48\t42 (15)\t\n0.007\n\t\n\nSex (female)\n\t82\t62\t48\t34\t0.55\t\n\nRace\n\t82\t\t48\t\t0.36\t\nWhite\t\t66\t\t39\t\t\nAfrican-American\t\t7\t\t8\t\t\nOther\t\t5\t\t1\t\t\n\nAdmission biochemistry\n\t\t\t\t\t\t\nWhite Blood count (x109/L)\t81\t9.3 (6.4–13.7)\t48\t9.3 (7.0–13.3)\t0.87\t\nPlatelet count (x109/L)\t81\t140 (91–196)\t48\t116 (61–164)\t0.009\t\nInternationalized Ratio (INR)\t82\t2.7 (1.8–4.3)\t46\t3.2 (2.0–4.3)\t0.19\t\nALT (IU/L)\t79\t3346(1920–6894)\t48\t3211(1246–6355)\t0.53\t\nBilirubin (mg/dl)\t79\t4.2 (2.3–5.7)\t48\t5.7 (3.7–8.2)\t0.001\t\npH\t70\t7.4 (7.3–7.5)\t45\t7.4 (7.3–7.5)\t0.73\t\nAmmonia (venous; μmol/L)\t38\t94 (78–136)\t17\t75 (60–126)\t0.23\t\nCreatinine (mg/dL)\t82\t1.4 (0.8–3.1)\t47\t2.3 (1.0–3.8)\t\n0.049\n\t\nLactate (mmol/L)\t56\t3.3 (2.1–6.3)\t35\t6.5 (3.9–11.0)\t\n0.003\n\t\n\nAdmitted to Intensive Care\n\t82\t75 (91%)\t48\t47 (98%)\t0.48\t\n\nNAC\n\t82\t75 (91%)\t48\t44 (92%)\t0.75\t\n\nOrgan support (7-days)\n\t\t\t\t\t\t\nMechanical ventilation\t82\t45 (55%)\t48\t42 (88%)\t<0.001\t\nVasopressors\t82\t8 (9.8%)\t48\t32 (67%)\t<0.001\t\nRenal Replacement therapy\t82\t21 (26%)\t48\t30 (63%)\t\n<0.001\n\t\n\nICP therapies (7 days)\n\t\t\t\t\t\t\nMannitol\t82\t14 (17%)\t48\t19 (40%)\t\n0.006\n\t\nHypertonic saline\t82\t6 (7.3%)\t48\t4 (8.3%)\t\n1.0\n\t\nBarbiturates\t82\t10 (12%)\t48\t9 (19%)\t\n0.33\n\t\nHypothermia\t82\t8 (9.8%)\t48\t7 (15%)\t\n0.43\n\t\nSedatives\t\t\t\t\t\t\n\nICP monitor\n\t81\t9 (11%)\t45\t8 (18%)\t0.29\t\nHE Grade (median IQR)\t82\t2(1–4)\t48\t3(2–4)\t0.17\t\n\nHE Grade III/IV\n\t82\t39 (48%)\t48\t31 (65%)\t0.26\t\n\nOA level detectable\n\t\t\t\t\t\t\n\nEarly (μmol/L)\t80\t12 (15%)\t48\t15 (31%)\t0.034\t\n\nLate (μmol/L)\t82\t9 (11%)\t48\t13 (27%)\t0.018\t\n\nOA level\n\t\t\t\t\t\t\n\nEarly (μmol/L)\t80\t0.36(1.65)\t48\t0.48 (1.45)\t0.69\t\n\nLate (μmol/L)\t82\t0.37(1.53)\t48\t0.43 (0.92)\t0.79\t\n\nAbbreviations: INR, international normalized ratio; ALT, alanine aminotransferase; AST, aspartate aminotransferase\n\n7-days: Values refer to therapies at any time during the 7-days of study.\n\nDuring the first 7 study days, survivors were less likely to require mechanical ventilation (55% vs. 88%), vasopressor support (9.8% vs. 67%) or renal replacement therapy (26% vs. 63%, p< 0.001 for all comparisons). Survivors were less likely to receive mannitol to treat intracranial hypertension (ICH) (17% vs. 40%, p = 0.006) but not other ICH directed therapies. There were no significant differences in requirements for invasive intracranial pressure monitoring (11% vs. 18%), median worst hepatic coma grade (West Haven) (2(1–4) vs. 3(2–4)) or number of patients with worst coma grade III or IV (48% vs. 65%; p>0.15 for all comparisons).\n\nNon-survivors were more likely to have detectable OA levels early (day 1 or 2: 31% vs. 15%, p = 0.034) and late (day 3 or 4; 27% vs. 11%, p = 0.018). However there were no statistically significant differences for overall mean levels between non-survivors and survivors (early 0.48 vs. 0.36, late 0.43 vs. 0.37, P > 0.5 for both) (Table 1). The range of detectable OA levels for the healthy controls, the survivors (early and late) and non-survivors (early and late) are shown in Fig 1. The lower limit of detection was 0.02 μM. Samples that fell below the limit of detection were set to 0 for data analysis. The mean OA level for the healthy human control group was 0.18 μM with a range from 0 μM to 1.18 μM. The survivors from both the early and late groups had a range of detectable OA levels from 0 μM to 2.47 μM and 0 μM to 4.09 μM respectively. OA levels were higher in non-survivors with a range of 0 μM to 3.77 μM and 0 μM to 3.12 μM in the early and late groups respectively, however statistical significance was not reached. This was also attributed to the fact that a large proportion of samples did not fall within the detectable range.\n\n10.1371/journal.pone.0139299.g001Fig 1 Ophthalmic acid levels in healthy controls compared with surviving and non-surviving APAP-induced ALF patients at Day 2 (early) and Day 4 (late).\nBlood samples were collected for 130 patients with APAP-induced ALF on Day 2 and Day 4 after admission into hospital; at Day 21, there were 82 survivors and 48 non-survivors. Serum OA levels were quantified using UPLC-MS-MS. The data are shown as a Box and Whiskers plot with boxes representing the interquartile range, lines representing the entire range, and data points representing the outliers. No statistically significant differences were found between groups using Chi-squared test.\n\nDiscussion\nSummary of key results\nIn this retrospective case control study of 130 APAP-ALF patients from the US ALFSG, OA was detectable more frequently in APAP-ALF non-survivors however OA was detected in only a minority of patients (~30%). Mean OA levels (early or late) were not predictive of outcome in APAP-ALF patients. These results might be explained by the use of therapeutic NAC increasing cellular cysteine levels allowing for GSH synthesis and reducing OA synthesis. Increased OA levels do not appear to predict outcome in APAP-ALF patients.\n\nGeneralizability/Significance of Results\nIn this analysis, OA levels were detectable more frequently in APAP-ALF patients that died but not universally detected nor were mean levels correlated with outcome. We speculate that the lack of discriminatory power of OA in the human APAP-ALF setting is due to several reasons. Firstly, when patients intentionally overdose on APAP, they do not necessarily seek medical attention immediately after ingestion (some patients may present several days later). Given that the turnover rate of OA is rapid (peak serum levels in mice occurred 1 hour post-APAP dose with OA levels becoming similar to untreated animals after 6 hours) [6], the late presentation of patients after APAP overdose could result in reduced serum OA levels. Our results could imply that the use of NAC mitigates ongoing OA production. This is supported by the recent finding that OA levels are significantly elevated in patients with non-hepatic steatosis (who would not receive NAC therapy) [11]. There are also several confounding medical interventions in APAP-ALF patients that could potentially confound serum OA levels including dialysis/renal replacement therapy, oliguria/anuria, nutritional status and support (e.g. parenteral or enteral) and possibly other co-existent medical problems (e.g. bacteremia/sepsis).\n\nThese results are complementary to previous literature that shows NAC therapy increases cellular cysteine levels allowing for GSH synthesis and preventing OA synthesis. Previous well-documented clinical studies have demonstrated that NAC was beneficial in APAP-ALF through repletion of GSH, improved oxygen transport, improved hemodynamic status and reduced incidence of intracranial hypertension [12, 13]. Nonetheless, serum OA levels do not appear to yield clinically significant information regarding prognosis beyond traditional criteria based on hepatic synthetic activity (INR, Bilirubin, Factor V) [14, 15], severity of hepatic necrosis [16] or hepatic encephalopathy/coma grade.\n\nStudy limitations\nThis study has several limitations that warrant consideration. It is a retrospective case control study which has potential bias due to selection of appropriate cases (non-survivors) and controls (survivors). We were unable to acquire matched numbers of APAP-survivors and non-survivors. While we did have healthy controls for comparison in our OA assay, we did not have access to serum samples from critically ill patients without ALF as controls. We do not believe that this would have had a significant impact on study conclusions. We did not have data on the exact timing of APAP ingestion for each patient compared to admission to hospital or amount ingested but practically speaking this is exceedingly difficult in clinical practice given that some patients may have had staggered APAP toxicity (i.e. not a single large ingestion but ongoing daily use of APAP). Finally, given that NAC is standard of care in suspected APAP toxicity, APAP-ALF, we did not have access to a significant number of patients with APAP-ALF in the absence of NAC. Despite these limitations, we believe this study has significant merit because to our knowledge it is the only study to examine serum OA levels in humans in APAP-ALF.\n\nConclusions\nOA was detectable more frequently in APAP-ALF non-survivors but mean OA levels were not associated with survival. The routine clinical administration of N-acetyl cysteine could diminish OA production and prevent OA from being a clinically useful biomarker in APAP-ALF.\n\nKey Points\nOphthalmic acid (OA) is an analogue of GSH in which cysteine is replaced with 2-aminobutyrate.\n\nOA was detectable more frequently in acetaminophen-induced acute liver failure non-survivors\n\nMean OA levels were not associated with survival.\n\nSupporting Information\nS1 STROBE Checklist STROBE guideline for reporting retrospective studies.\nThis file contains the STROBE guideline for reporting case control studies format used for the current study[17] (BMJ 2007).\n\n(DOC)\n\nClick here for additional data file.\n\n The authors would like to thank Dr. Nancy Zhang (nanoFAB Facility, University of Alberta) for assistance with setting up the UPLC-MS-MS method. Maimoona Tariq is thanked for assistance with sample preparation and processing. The Lead author/ Principal investigator of the United States Acute liver Failure study group is Dr. William M. Lee (Division of Digestive Diseases, University of Texas Southwestern; email: william.lee@utsouthwestern.edu). Current principal co-investigators and institutions participating in the United States Acute Liver Failure Study Group are as follows:\nAnne M. Larson MD; Division of Hepatology, University of Texas Southwestern, Dallas, TX\n\nIris Liou, M.D., Division of Hepatology, University of Washington, Seattle, WA.\n\nOren Fix, M.D., Division of Hepatology, University of California, San Francisco, CA.\n\nMichael Schilsky, M.D., (Division of Digestive Diseases/Transplant: Yale University, New Haven, CT);\n\nDaniel Ganger, M.D., Division of Hepatology, Northwestern University, Chicago, IL;\n\nSteven H.B. Han, M.D., University of California, Los Angeles, CA;\n\nRobert Fontana, M.D., Division of Hepatology, University of Michigan, Ann Arbor, MI;\n\nBrendan McGuire, M.D., Division of Hepatology, University of Alabama, Birmingham, AL;\n\nAdrian Reuben, M.B.B.S., Division of Hepatology, Medical University of South Carolina, Charleston, SC;\n\nDavid Koch, MD, Division of Hepatology, Medical University of South Carolina, Charleston, SC;\n\nRajender Reddy, M.D., Division of Hepatology, University of Pennsylvania, Philadelphia, PA;\n\nR. Todd Stravitz, M.D., Division of Hepatology, Virginia Commonwealth University, Richmond, VA;\n\nJames Hanje, Division of Hepatology, Ohio State University, Columbus, OH.\n\nJody Olson, Division of Hepatology and Critical Care, University of Kansas, Kansas City, KA\n\nRam Subramanian, Divisions of Hepatology and Critical Care, Emory, Atlanta, GA\n\nConstantine J. Karvellas, Divisions of Hepatology and Critical Care, University of Alberta, Edmonton, Canada.\n\nThe University of Texas Southwestern Administrative Group included Grace Samuel, Ezmina Lalani, Carla Pezzia, and Corron Sanders, Ph.D., Nahid Attar, Linda S. Hynan, Ph.D., and the Medical University of South Carolina Data Coordination Unit included Valerie Durkalski, Ph.D., Wenle Zhao, Ph.D., Jaime Speiser, Catherine Dillon, Holly Battenhouse and Michelle Gottfried.\n\n\n\n\nAbbreviations\nALFacute liver failure\n\nAPAPacetaminophen\n\nHEhepatic encephalopathy\n\nGSHglutathione\n\nINRinternational normalized ratio\n\nMAPmean arterial pressure (mm Hg)\n\nMELDmodel for end stage liver disease score\n\nMVmechanical ventilation\n\nOAophthalmic acid\n\nRRTrenal replacement therapy\n\nUPLC-MS-MSultraperformance liquid chromatography tandem mass spectrometry\n==== Refs\nReferences\n1 \nO'Grady JG , Williams R . Classification of acute liver failure . Lancet . 1993 ;342 (8873 ):743 .8103845 \n2 \nO'Grady JG , Schalm SW , Williams R . Acute liver failure: redefining the syndromes . Lancet . 1993 ;342 (8866 ):273 –5 . .8101303 \n3 \nFagan E , Wannan G . Reducing paracetamol overdoses . BMJ . 1996 ;313 (7070 ):1417 –8 . .8973219 \n4 \nLarson AM , Polson J , Fontana RJ , Davern TJ , Lalani E , Hynan LS , et al\nAcetaminophen-induced acute liver failure: results of a United States multicenter, prospective study . Hepatology . 2005 ;42 (6 ):1364 –72 . .16317692 \n5 \nLu SC . Regulation of hepatic glutathione synthesis: current concepts and controversies . FASEB journal: official publication of the Federation of American Societies for Experimental Biology . 1999 ;13 (10 ):1169 –83 . .10385608 \n6 \nSoga T , Baran R , Suematsu M , Ueno Y , Ikeda S , Sakurakawa T , et al\nDifferential metabolomics reveals ophthalmic acid as an oxidative stress biomarker indicating hepatic glutathione consumption . The Journal of biological chemistry . 2006 ;281 (24 ):16768 –76 . 10.1074/jbc.M601876200 \n.16608839 \n7 \nAtterbury CE , Maddrey WC , Conn HO . Neomycin-sorbitol and lactulose in the treatment of acute portal-systemic encephalopathy. A controlled, double-blind clinical trial . Am J Dig Dis . 1978 ;23 (5 ):398 –406 . Epub 1978/05/01. .354373 \n8 \nConn HO , Lieberthal MM , editors. The hepatic coma syndromes and lactulose . Baltimore : Williams & Wilkins ; 1979 .\n9 \nGeenen S , Michopoulos F , Kenna JG , Kolaja KL , Westerhoff HV , Wilson I . HPLC-MS/MS methods for the quantitative analysis of ophthalmic acid in rodent plasma and hepatic cell line culture medium . Journal of pharmaceutical and biomedical analysis . 2011 ;54 (5 ):1128 –35 . 10.1016/j.jpba.2010.11.038 \n.21176868 \n10 \nNew LS , Chan EC . Evaluation of BEH C18, BEH HILIC, and HSS T3 (C18) column chemistries for the UPLC-MS-MS analysis of glutathione, glutathione disulfide, and ophthalmic acid in mouse liver and human plasma . Journal of chromatographic science . 2008 ;46 (3 ):209 –14 . .18334086 \n11 \nCarretero A , Leon Z , Garcia-Canaveras JC , Zaragoza A , Gomez-Lechon MJ , Donato MT , et al\nIn vitro/in vivo screening of oxidative homeostasis and damage to DNA, protein, and lipids using UPLC/MS-MS . Analytical and bioanalytical chemistry . 2014 ;406 (22 ):5465 –76 . 10.1007/s00216-014-7983-5 \n.24969468 \n12 \nKeays R , Harrison PM , Wendon JA , Forbes A , Gove C , Alexander GJ , et al\nIntravenous acetylcysteine in paracetamol induced fulminant hepatic failure: a prospective controlled trial . BMJ . 1991 ;303 (6809 ):1026 –9 . 1954453 \n13 \nHarrison PM , Wendon JA , Gimson AE , Alexander GJ , Williams R . Improvement by acetylcysteine of hemodynamics and oxygen transport in fulminant hepatic failure . The New England journal of medicine . 1991 ;324 (26 ):1852 –7 . 10.1056/NEJM199106273242604 \n.1904133 \n14 \nO'Grady JG , Alexander GJ , Hayllar KM , Williams R . Early indicators of prognosis in fulminant hepatic failure . Gastroenterology . 1989 ;97 (2 ):439 –45 . Epub 1989/08/01. .2490426 \n15 \nBernuau J , Goudeau A , Poynard T , Dubois F , Lesage G , Yvonnet B , et al\nMultivariate analysis of prognostic factors in fulminant hepatitis B . Hepatology . 1986 ;6 (4 ):648 –51 . .3732998 \n16 \nDonaldson BW , Gopinath R , Wanless IR , Phillips MJ , Cameron R , Roberts EA , et al\nThe role of transjugular liver biopsy in fulminant liver failure: relation to other prognostic indicators . Hepatology . 1993 ;18 (6 ):1370 –6 . .8244261 \n17 \nvon Elm E , Altman DG , Egger M , Pocock SJ , Gotzsche PC , Vandenbroucke JP , et al\nStrengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies . BMJ . 2007 ;335 (7624 ):806 –8 . 10.1136/bmj.39335.541782.AD \n17947786\n\n",
"fulltext_license": "CC BY",
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"issue": "10(9)",
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"mesh_terms": "D000082:Acetaminophen; D000328:Adult; D016022:Case-Control Studies; D003710:Demography; D005260:Female; D006801:Humans; D017114:Liver Failure, Acute; D008297:Male; D009842:Oligopeptides; D017741:Survivors",
"nlm_unique_id": "101285081",
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"pubdate": "2015",
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"references": "8244261;8973219;10385608;16317692;16608839;17947786;18334086;21176868;24969468;354373;3732998;2490426;1904133;1954453;8101303;8103845",
"title": "Detection of Ophthalmic Acid in Serum from Acetaminophen-Induced Acute Liver Failure Patients Is More Frequent in Non-Survivors.",
"title_normalized": "detection of ophthalmic acid in serum from acetaminophen induced acute liver failure patients is more frequent in non survivors"
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"abstract": "There is no effective treatment for recurrent glioblastoma (GB) when temozolomide-based radiochemotherapy fails. In theory, intra-arterial (IA) delivery of cytotoxic agents could achieve higher drug concentrations in tumors compared to intravenous injection. Moreover, choosing a highly lipid-soluble drug could make the most of the first-pass effect. Here, we evaluated idarubicin (IDA), a lipophilic anthracycline, in an in vitro assay using four human GB cell lines and compared it with 11 other drugs previously used for the IA treatment of brain tumors. Despite impressive in vitro cytotoxicity, IA IDA did not produce a beneficial effect in 2 patients with recurrent GB.",
"affiliations": "Department of Medical Oncology, University Hospital, Amiens, France.;Department of Medical Oncology, University Hospital, Amiens, France.;Department of Radiology, University Hospital, Amiens, France.;Department of Radiology, University Hospital, Amiens, France.;Department of Radiology, University Hospital, Amiens, France.;Department of Medical Oncology, University Hospital, Amiens, France.;Department of Medical Oncology, University Hospital, Amiens, France.",
"authors": "Chehimi|Mohamad|M|;Boone|Mathieu|M|;Chivot|Cyril|C|;Deramond|Hervé|H|;Constans|Jean-Marc|JM|;Ly|Mony Chenda|MC|;Chauffert|Bruno|B|",
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"fulltext": "\n==== Front\nCase Rep OncolCase Rep OncolCROCase Reports in Oncology1662-6575S. 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 10.1159/000448654cro-0009-0499Case ReportIntra-Arterial Delivery of Idarubicin in Two Patients with Glioblastoma Chehimi Mohamad aBoone Mathieu aChivot Cyril bDeramond Hervé bConstans Jean-Marc bLy Mony Chenda aChauffert Bruno a*aDepartment of Medical Oncology, University Hospital, Amiens, FrancebDepartment of Radiology, University Hospital, Amiens, France*Bruno Chauffert, Department of Medical Oncology, University Hospital, FR-80054 Amiens (France), E-Mail chauffert.bruno@chu-amiens.frMay-Aug 2016 30 8 2016 30 8 2016 9 2 499 505 25 7 2016 25 7 2016 Copyright © 2016 by S. Karger AG, Basel2016This article is licensed under the Creative Commons Attribution-NonCommercial-4.0 International License (CC BY-NC) (http://www.karger.com/Services/OpenAccessLicense). Usage and distribution for commercial purposes requires written permission.There is no effective treatment for recurrent glioblastoma (GB) when temozolomide-based radiochemotherapy fails. In theory, intra-arterial (IA) delivery of cytotoxic agents could achieve higher drug concentrations in tumors compared to intravenous injection. Moreover, choosing a highly lipid-soluble drug could make the most of the first-pass effect. Here, we evaluated idarubicin (IDA), a lipophilic anthracycline, in an in vitro assay using four human GB cell lines and compared it with 11 other drugs previously used for the IA treatment of brain tumors. Despite impressive in vitro cytotoxicity, IA IDA did not produce a beneficial effect in 2 patients with recurrent GB.\n\nKey Words\nGlioblastomaIdarubicinIntra-arterial chemotherapy\n==== Body\nIntroduction\nNo effective treatment exists against recurrent glioblastoma (GB) when the standard first-line treatment using a temozolomide-based radiochemotherapy fails. Bevacizumab and lomustine increased progression-free survival, but their impact on overall survival is controversial [1]. There is no defined third-line treatment. Intra-arterial (IA) delivery of cytotoxic drugs has been explored over decades, but with no significant results to date [for review, see 2]. IA studies commonly use the same drugs as for i.v. delivery (melphalan, carboplatin, methotrexate, and temozolomide). Drugs are not specifically selected in order to exploit the concentration/antitumor effect anticipated by using IA delivery. Drugs have to be rapidly and irreversibly taken up during their first pass through the tissue circulation [3]. Moreover, the selected drug should be highly cytotoxic against targeted tumor cells. Here, we evaluated the in vitro cytotoxicity of idarubicin (IDA), a lipophilic anthracycline, using four human GB cell lines. Encouraging in vitro data led us to evaluate IDA by the IA route in patients with recurrent GB.\n\nResults\nIn vitro Results\nIDA cytotoxicity was compared to 11 other antineoplastic drugs previously used for IA chemotherapy in GB or brain metastases in 4 human GB cell lines (fig. 1). Briefly, U87MG, CGL-1 CGL-3 or CGL-8 cells were seeded in complete culture medium and grown for 48 h in cell-culture plates. U87-MG cells were obtained from American Type Culture Collection (Manassas, Va., USA). The CGL-1, CGL-3 and CGL-9 cell lines were established from resected GB from 3 different patients and kindly donated by Dr. Philipe Genne (Oncodesign, Dijon, France). Subconfluent cells were incubated for 30 min with antitumor drugs at one selected concentration, then washed and grown again for 7 days in drug-free culture medium. The selected drug concentration was calculated assuming an unilateral carotid blood flow of 0.33 liter/min (10 liters in 30 min) and taking into account the dose usually given i.v. in patients with various tumors (table 1). The 30-min duration of in vitro exposure was selected since it was tolerated by patients receiving intracarotid infusion. A colorimetric assay was used to quantify drug-induced cell death. Surviving cells adherent to the bottom of the well were fixed with pure ethanol and stained with crystal violet dye. The dye was eluted with 33% acetic acid. Absorbance was determined by spectrophotometry (UVM 340; Bioserv) at 570 nm wavelength. Percent cell survival was calculated as optical density in treated wells/optical density in control wells ×100.\n\nNinety percent or more of the cells from the 4 human GB cell lines were killed after a 30-min exposure to 3 µg/ml IDA. This is an achievable concentration in the brain blood flow for a 30-mg dose of IDA. Other drugs were active less consistently.\n\nCase Presentations\nThe impressive in vitro results led us to design a phase 1 study of IDA administration via intracarotid delivery (IDACAR) to treat recurrent GB. The IDACAR trial was approved on January 12, 2012, by the ethics committee (Comité de Protection des Personnes Nord-Ouest 2) and registered under EUDRACT No. 2011-004176-11. A dose increase was planned. After femoral puncture under local anesthesia, the catheter was placed into a carotid branch (S1, A1 or M 1, depending on the tumor localization) and above the ophthalmic artery in order to minimize ocular complications. Whole perfusion of the tumor was checked by angiography. IDA (1 mg/ml in saline solution) was infused in the carotid blood flow by an electric pump over 30 min. Patients were kept conscious and regularly asked to speak and move their limbs.\n\nPatient 1\nA 56-year-old female had a history of resected colon adenocarcinoma in 2004. She was referred for behavioral disorders. A right frontal tumor with cystic contingent was evidenced by MRI. Partial resection of a GB was done in October 2010, followed by 60-Gy radiotherapy with concomitant and adjuvant temozolomide for 6 months. Disease recurred in November 2011 and progressed on MRI despite 3 months of bevacizumab. WHO status was 2 at inclusion with a mild left hemiparesis. The catheter was placed into the superficial branch of the middle cerebral artery that mainly irrigated the tumor. No adverse effects were observed during the IA injection of 22 mg IDA (12 mg/m2) over 30 min. Anisocoria, worsening of the left hemiparesis, and severe cognitive impairment occurred at day 3 after IA infusion. The neurological degradation was considered to be a case of irreversible and severe toxicity, although tumor progression could not be completely ruled out considering the MRI at day 28 (fig. 2). A grade III leuconeutropenia occurred at day 7 despite granulocyte colony-stimulating factor (G-CSF). Grade I anemia and thrombocytopenia were also recorded. The patient died 42 days after IA IDA due to disease progression.\n\nPatient 2\nA 57-year-old female had an expansive sustentorial left occipital tumor. Complete resection of a GB in January 2009 was followed by 60-Gy radiotherapy with concomitant and adjuvant temozolomide for 6 months. Disease progressed in November 2011, and the patient received bevacizumab until March 2012. WHO status was 1 at inclusion. A catheter was placed into the posterior cerebral artery, and 21 mg IDA were infused IA over 30 min. No adverse effects occurred during the IA injection. Grade III leuconeutropenia was registered at day 7 nadir despite G-CSF. The neurological status and WHO status remained stable for 30 days. MRI evaluation on day 28 showed tumor stability according to the Response Assessment in Neuro-Oncology (RANO) Criteria. The patient refused a second IA injection and died 26 weeks after treatment due to disease progression.\n\nConsidering the possible grade IV neurological toxicity in the first patient and the lack of clinical benefit in both patients, the Independent Data Monitoring Committee (IDMC) recommended to stop the trial.\n\nDiscussion\nWe reported here for the first time the IA delivery of IDA in 2 patients with recurrent GB. Our in vitro results were in agreement with previous papers. Schott and Robert [4] compared growth inhibition, DNA synthesis inhibition, and cell incorporation of eight anthracyclines in a model of doxorubicin-sensitive and -resistant rat C6 GB cells. They found that new anthracyclines, including IDA, were more potent than the reference drugs (daunorubicin and doxorubicin) in rat GB cells. They observed reduced cross-resistance of IDA, pirarubicin and 4′-deoxy-4′-iododoxorubicin in a doxorubicin-resistant cell line. Among these anthracyclines, only IDA still remains available for clinical treatment of acute myeloid leukemias. Kuffel et al. [5] evaluated the growth-inhibitory and DNA-damaging activities of IDA, daunorubicin, doxorubicin, and epirubicin against human tumor cell lines, including the U87-MG human GB cell line. IDA was 2–5 times more potent than the other three anthracycline analogs. Considering that IDA is more lipophilic than other anthracyclines and more cytotoxic in glioma cell lines, Boogerd et al. [6] found a significant uptake of IDA and its major metabolite idarubicinol by the brain tumor tissue from 1 patient with a brain metastasis from breast cancer and from 4 patients with malignant glioma after a single oral dose of IDA (25–45 mg/m2). Based on these preclinical data, a phase II trial was performed in children with progressive brain tumors [7]. i.v. IDA (18 mg/m2) was followed by G-CSF. Most patients developed progressive disease. Grade III/IV hematopoietic toxicities were common. The authors concluded that it is unlikely that IDA will be useful for the treatment of primary central nervous system tumors by the i.v. route.\n\nIn parallel to GB, we performed an experimental study to select the best candidate drug for transarterial chemoembolization of hepatocellular carcinoma (HCC). The SNU-398, HepG2, and SNU-449 human HCC cell lines were exposed to doxorubicin, epirubicin, IDA, mitoxantrone, carboplatin, cisplatin, oxaliplatin, 5-fluorouracil, gemcitabine, mitomycin C, or paclitaxel for 30 min. IDA was the most active drug against all three HCC cell lines [8]. A phase I trial of IDA loaded on eluting beads for chemoembolization produced encouraging results in 21 patients with HCC and liver cirrhosis (response rate of 52% and 28% of complete responses) [9].\n\nConsidering the experimental data from our study and others about the strong in vitro antineoplasic activity of IDA and arguing that IA delivery could theoretically increase the tumor drug concentration by a factor of 5–10, we designed the IDACAR trial in recurrent GB. In contrast to HCC, clinical results were disappointing in our 2 GB patients. Neither of the 2 patients displayed a response on MRI, and irreversible grade IV neurological toxicity was suspected in the first patient. Many hypotheses can be proposed to explain the discrepancy between the in vitro and the clinical results. Selecting a drug that is potent on GB cells in vitro is not enough to improve the antitumor effect in patients. Heterogeneity of perfusion into the complex angioarchitecture of GB, reduced drug penetration due to the residual blood-brain barrier, and drug streaming in the locally accelerated blood flow and a number of other technical and pharmacological pitfalls remain to be solved in order to improve the IA treatment of brain tumors [2]. Moreover, the lack of experimental models of GB in big animals greatly hinders progress.\n\nStatement of Ethics\nThe authors have no ethical conflicts to disclose.\n\nDisclosure Statement\nThe authors have no conflicts of interest to declare.\n\nAcknowledgment\nThis work was funded by an internal grant from the University Hospital of Amiens, France.\n\nFig. 1 In vitro colorimetric assay of 12 chemotherapeutic agents using four human GB cell lines. Bars indicate the mean of 3 wells (standard deviation <10%).\n\nFig. 2 Gadolinium-enhanced T1-weighted MRI before and 28 days after the IA delivery of IDA in Patient 1.\n\nTable 1 Calculations of drug concentrations for the in vitro cytotoxicity assay\n\nDrug\tDose for i.v. use, mg\tConcentration for the in vitro assay, mg/l\t\nIdarubicin\t30\t3\t\nDoxorubicin\t60\t6\t\nCisplatin\t150\t15\t\nCarboplatin\t800\t80\t\nMethotrexate\t100\t10\t\nRaltitrexed\t6\t0.6\t\n5-fluorouracil\t1,000\t100\t\nGemcitabine\t2,000\t200\t\nBCNU (carmustine)\t200\t20\t\nEtoposide\t300\t30\t\nPaclitaxel\t300\t30\t\nMitomycin C\t30\t3\t\nBlood flow in the selected carotid artery was estimated to be at 0.33 ml/min (10 liters in 30 min). The selected drug doses were in the range of those used by i.v. route for various tumors.\n==== Refs\nReferences\n1 Taal W Oosterkamp HM Walenkamp AM Dubbink HJ Beerepoot LV Hanse MC Buter J Honkoop AH Boerman D de Vos FY Dinjens WN Enting RH Taphoorn MJ Van den Berkmortel FW Jansen RL Brandsma D Bromberg JE Van Heuvel I Vernhout RM Van der Holt B van den Bent MJ Single-agent bevacizumab or lomustine versus a combination of bevacizumab plus lomustine in patients with recurrent glioblastoma (BELOB trial): a randomised controlled phase 2 trial Lancet Oncol 2014 15 943 953 25035291 \n2 Ellis JA Banu M Hossain SS Singh-Moon R Lavine SD Bruce JN Joshi S Reassessing the role of intra-arterial drug delivery for glioblastoma multiforme treatment J Drug Deliv 2015 2015 405735 26819758 \n3 Dedrick RL Arterial drug infusion: pharmacokinetic problems and pitfalls J Natl Cancer Inst 1988 80 84 89 3278123 \n4 Schott B Robert J Comparative cytotoxicity, DNA synthesis inhibition and drug incorporation of eight anthracyclines in a model of doxorubicin-sensitive and -resistant rat glioblastoma cells Biochem Pharmacol 1989 38 167 172 2910297 \n5 Kuffel MJ Reid JM Ames MM Anthracyclines and their C-13 alcohol metabolites: growth inhibition and DNA damage following incubation with human tumor cells in culture Cancer Chemother Pharmacol 1992 30 51 57 1586980 \n6 Boogerd W Tjahja IS Van de Sandt MM Beijnen JH Penetration of idarubicin into malignant brain tumor tissue J Neurooncol 1999 44 65 69 10582671 \n7 Dreyer ZE Kadota RP Stewart CF Friedman HS Mahoney DH Kun LE McCluggage CW Burger PC Kepner J Heideman RL Pediatric Oncology Group Phase 2 study of idarubicin in pediatric brain tumors: Pediatric Oncology Group study POG 9237 Neuro Oncol 2003 5 261 267 14565163 \n8 Boulin M Guiu S Chauffert B Aho S Cercueil JP Ghiringhelli F Krause D Fagnoni P Hillon P Bedenne L Guiu B Screening of anticancer drugs for chemoembolization of hepatocellular carcinoma Anticancer Drugs 2011 22 741 748 21487286 \n9 Boulin M Hillon P Cercueil JP Bonnetain F Dabakuyo S Minello A Jouve JL Lepage C Bardou M Wendremaire M Guerard P Denys A Grandvuillemin A Chauffert B Bedenne L Guiu B Idarubicin-loaded beads for chemoembolisation of hepatocellular carcinoma: results of the IDASPHERE phase I trial Aliment Pharmacol Ther 2014 39 1301 1313 24738629\n\n",
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"issue": "9(2)",
"journal": "Case reports in oncology",
"keywords": "Glioblastoma; Idarubicin; Intra-arterial chemotherapy",
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"title": "Intra-Arterial Delivery of Idarubicin in Two Patients with Glioblastoma.",
"title_normalized": "intra arterial delivery of idarubicin in two patients with glioblastoma"
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"abstract": "We performed a retrospective chart review of three patients with hypomyopathic dermatomyositis and rapidly progressive interstitial lung disease. The patients were Japanese women of 71, 69, and 65 years of age. Two patients were anti-melanoma differentiation-associated gene 5 (anti-MDA5) antibody-positive and 1 was anti-aminoacyl-tRNA synthetase (anti-ARS) antibody-positive. Their respiratory statuses deteriorated despite the administration of glucocorticoid, calcineurin inhibitors, and intravenous cyclophosphamide therapy. We subsequently administered rituximab. The anti-ARS antibody-positive patient survived, while 2 anti-MDA5 antibody-positive patients died.",
"affiliations": "Department of Rheumatology, Japanese Red Cross Kumamoto Hospital, Japan.;Division of Rheumatology, Teikyo University Chiba Medical Center, Japan.",
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"doi": "10.2169/internalmedicine.56.7956",
"fulltext": "\n==== Front\nIntern MedIntern. MedInternal Medicine0918-29181349-7235The Japanese Society of Internal Medicine 2856660510.2169/internalmedicine.56.7956Case ReportDermatomyositis with Rapidly Progressive Interstitial Lung Disease Treated with Rituximab: A Report of 3 Cases in Japan Tokunaga Kenichiro 1Hagino Noboru 21 Department of Rheumatology, Japanese Red Cross Kumamoto Hospital, Japan2 Division of Rheumatology, Teikyo University Chiba Medical Center, JapanCorrespondence to Dr. Kenichiro Tokunaga, kentoku71@hotmail.co.jp\n\n1 6 2017 56 11 1399 1403 6 7 2016 26 9 2016 Copyright © 2017 by The Japanese Society of Internal Medicine2017The Internal Medicine is an Open Access article distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view the details of this license, please visit (https://creativecommons.org/licenses/by-nc-nd/4.0/).We performed a retrospective chart review of three patients with hypomyopathic dermatomyositis and rapidly progressive interstitial lung disease. The patients were Japanese women of 71, 69, and 65 years of age. Two patients were anti-melanoma differentiation-associated gene 5 (anti-MDA5) antibody-positive and 1 was anti-aminoacyl-tRNA synthetase (anti-ARS) antibody-positive. Their respiratory statuses deteriorated despite the administration of glucocorticoid, calcineurin inhibitors, and intravenous cyclophosphamide therapy. We subsequently administered rituximab. The anti-ARS antibody-positive patient survived, while 2 anti-MDA5 antibody-positive patients died. \n\nanti-ARS antibodyanti-MDA5 antibodydermatomyositisinterstitial lung diseaserituximabanti-PL-12 antibody\n==== Body\nIntroduction\nDermatomyositis (DM) is an autoimmune disease that mainly affects the skin and proximal muscles. It is occasionally complicated by interstitial lung disease (ILD). Immunosuppressive agents including glucocorticoids (GCs), calcineurin inhibitors (CNi; e.g. tacrolimus [Tac] and cyclosporine A [CyA]), and intravenous cyclophosphamide (IVCY) have been recommended for the treatment of this condition based on the results of observational studies, which have shown the variable efficacy of these treatments (1,2). The disease is associated with a high rate of mortality (1).\n\nAnti-aminoacyl-tRNA synthetase (anti-ARS) antibodies, particularly non-Jo-1 (anti-PL-7 and anti-PL-12) antibodies, are strongly associated with the development of ILD (3). Some DM patients with ILD present progressive deterioration in pulmonary disease (rapidly progressive ILD; RP-ILD). The condition of these patients is characterized by mild myositis, palmar papules, fever, a negative or low antinuclear antibody titer, and a very high mortality rate (1). A recent study suggested that RP-ILD is strongly associated with clinically amyopathic DM and the presence of anti-melanoma differentiation-associated gene 5 (anti-MDA5) antibodies (4,5). In addition, a high ferritin titer is suspected to be a poor prognostic factor in DM patients with RP-ILD (6,7).\n\nThe pharmacological treatment of DM is based on the administration of high doses of GC over long periods, often in combination with another immune-modulating agent (most often methotrexate or azathioprine). Other immunomodulators include CyA, Tac, and mycophenolate mofetil; treatment with high doses of intravenous immunoglobulin has also been described. Despite these treatments, most patients experience persistent muscle weakness or a relapse when the medication is tapered. During the past year, some case series showed the beneficial effects of rituximab (RTX) treatment in anti-ARS antibody-positive DM patients (7-11). In addition, an anti-MDA5 antibody-positive patient displaying the mucocutaneous manifestations of DM who was refractory to IVCY treatment but who improved after the administration of RTX (12), and the successful treatment of 2 anti-MDA5 antibody-positive patients with RTX were recently reported (13,14). However, the efficacy of RTX treatment in DM patients with RP-ILD, including anti-MDA5 antibody-positive patients is still not clear.\n\nWe assessed the clinical and serological responses of DM patients with RP-ILD to RTX.\n\nWe performed a retrospective chart review of 3 DM patients with RP-ILD who were treated with RTX in our department from February 2014 to February 2015. The present study was performed in accordance with the Declaration of Helsinki, and informed consent was obtained from all of the patients or their next of kin. We collected clinical data, including the age of onset, sex, disease duration, medications, and respiratory status, their laboratory test results (including the creatine kinase [CK] and ferritin levels and autoantibody type), as well as the chest radiography and computed tomography (CT) findings.\n\nTreatment protocol\nIn addition to their pre-existing immunosuppressive therapy (GC, CNi, and IVCY) RTX (375 mg/m2) was administered weekly to the patients with a deteriorating respiratory status.\n\nCase Reports\nCase 1\nA 71-year-old Japanese woman developed fever and dry cough of 2 weeks' duration. Although she was prescribed antibiotics by her physician, her symptoms did not improve and she developed a rash. She was subsequently referred to our clinic.\n\nA physical examination revealed late inspiratory crackles bilaterally in the basilar lung area, purpura on the extensor side of the elbows, and erythema with pruritus on her anterior chest. There was no pain on palpation of her muscles, and her manual muscle test (MMT) parameters were not decreased. Chest CT showed ground-glass opacities (Fig. 1). We administered methylprednisolone (mPSL; 1 g) for 3 days, Tac (Trough level: 5-10 ng/mL) from the 2nd day of hospitalization, and IVCY (750 mg [500 mg/m2]) on the 3rd day of hospitalization. However, her respiratory status continued to worsen. We therefore administered IVCY (500 mg) on the 22nd and 36th days and RTX (600 mg [375 mg/m2]) on the 38th and 45th days. She did not improve and died on the 51st day of hospitalization. She was anti-MDA5 antibody-positive (Fig. 2).\n\nCase 2\nA 69-year-old Japanese woman was admitted with a rash of the extremities, dyspnea on exertion, and polyarthralgia of 3 weeks in duration. She did not have respiratory distress, desaturation, or muscle weakness, but did display hyperkeratosis on the palmar side of her fingers and Gottron's sign. A laboratory analysis revealed a slightly elevated CK level of 225 U/L and a ferritin level of 219 ng/mL. Chest CT showed interstitial lung disease (Fig. 1).\n\nWe started intravenous mPSL (1 g pulses) for 3 days and CyA (150 mg/day), followed by prednisolone (PSL; 50 mg daily [1 mg/kg], gradually tapered to 30 mg). Her symptoms improved, and she was discharged on the 17th day after hospitalization. She was anti-MDA5 antibody-positive. At a visit 12 days after her initial discharge, she showed slight respiratory distress with decreased oxygen saturation (SpO2) at 95% in ambient air and her cutaneous symptoms had worsened. Her ferritin level of 263 ng/mL was slightly elevated. Chest CT showed worsening interstitial shadows (Fig. 1). Although Gram staining of her sputum revealed no specific findings, empiric antibiotics were administered. Subsequently, intravenous mPSL therapy (60 mg/day) was initiated. In addition, we administered IVCY [650 mg (500 mg/m2)] on the 2nd day of hospitalization) and RTX [500 mg [375 mg/m2)] on the 4th day. The patient's condition showed further deterioration and mPSL (1 g/day pulses for 3 days) treatment was initiated from the 6th day. Her respiratory state and chest CT findings continued to worsen. IVCY [1,000 mg (750 mg/m2)] was therefore administered on the 8th day and the patient was and was intubated and RTX [500 mg (375 mg/m2)] was administered on the 11th day. On the 12th day, continuous hemodiafiltration was started and tocilizumab (8 mg/kg) was administered; her ferritin level was 1,930 ng/mL. However, the patient did not respond and died on the 18th day after re-admission to hospital (Fig. 3).\n\nCase 3\nA 65-year-old Japanese woman developed fever, cough, and dyspnea of 6 weeks in duration. She was initially treated with antibiotics for presumed pneumonia by her physician. Her symptoms did not improve. Moreover, a rash and edema appeared on her extremities, and she developed polyarthralgia. She was then referred to our clinic.\n\nHer body temperature was 38.5°C, respiratory rate was 20 breaths/min, and her SpO2 was 98% in ambient air. A physical examination revealed late inspiratory crackles bilaterally in the basilar lung area, no decreases in her MMT parameters, and urticarial lesions on her trunk and extremities. Laboratory tests revealed a CK level of 399 U/L and a ferritin level of 853 ng/mL. Chest CT showed interstitial shadows (Fig. 1). We started mPSL (1 g pulses for 3 days) from admission, followed by CyA (100 mg/day) from the 2nd day of hospitalization. However, her SpO2 level began to deteriorate, and we administered IVCY [750 mg (500 mg/m2)] on the 5th day. On the 5th day, the chest CT findings suggested that her condition had deteriorated (Fig. 1); we therefore administered RTX [500 mg (375 mg/m2)] on the 7th day, followed by mPSL (1 g for 3 days) from the 8th day. The patient started showing signs of improvement, so mPSL (1 g for 3 days) was administered from the 13th day, and RTX (500 mg) was administered weekly for 4 weeks, IVCY (750 mg) was administered biweekly for 6 treatments, and mPSL was tapered to 20 mg daily and then switched to PSL (20 mg) with a tapering dosage regime. The patient's respiratory status continued to improve and she was discharged with domiciliary oxygen therapy (1 L/min) on the 114th day. She was anti-PL-12 antibody-positive.\n\nDiscussion\nWe reported the cases of 3 DM patients with RP-ILD (Table); 2 of the patients died, while 1 survived. The patient who survived was anti-ARS antibody (anti-PL-12 antibody)-positive. Both patients who died were anti-MDA5-antibody positive. The outcome of DM with RP-ILD in anti-MDA5 antibody-positive patients was very poor in spite of early intensive care including treatment with GC, CNi, IVCY, and RTX.\n\nSome case series have suggested that RTX had beneficial effects in anti-ARS antibody-positive DM patients. Our findings were in line with those results in that the anti-PL-12 antibody-positive patient survived. However, there are few reports describing the successful treatment of anti-MDA5 antibody-positive patients with RTX (12-14). In our report, in spite of intensive care, including the administration of RTX, the 2 anti-MDA5 antibody-positive patients died.\n\nFigure 1. Chest computed tomography images of the patients at admission, before the first administration of rituximab (RTX), and after the series of RTX treatments.\n\nFigure 2. CyA: cyclosporine A, IVCY: intravenous cyclophosphamide, mPSL: methylprednisolone, MMF: mycophenolate mofetil, RTX: rituximab, Tac: tacrolimus\n\n\nFigure 3. CyA: cyclosporine A, IVCY: intravenous cyclophosphamide, mPSL: methylprednisolone, RTX: rituximab, Tac: tacrolimus, TCZ: tocilizumab\n\nTable. The Clinical Characteristics and Treatments of the 3 Patients.\n\nCase\tAge, sex\tDisease duration, weeks\tSpecific antibody\tPrevious treatment\tRTX cycles, n\tConcomitant treatment with different RTX cycles\tSerum ferritin(ng/mL), Baseline/Post-RTX\tSerum KL-6(U/mL), Baseline/Post-RTX\tVital status\t\n1\t2\t3\t4\t\n1\t71, F\t2\tAnti-MDA5\tmPSL 1 g→mPSL 60 mg IVCY Tac→CyA\t2\tCyA\tCyA\t\t\t507/1,740\t991/NA\tD\t\n2\t69, F\t8\tAnti-MDA5\tmPSL 1 g→mPSL 60 mg CyA IVCY\t2\tCyA, IVCY\tIVCY\t\t\t219/1,930\t922/1,520\tD\t\n3\t65, F\t6\tAnti-PL-12\tmPSL 1 g→mPSL 60 mg CyA→Tac IVCY\t4\tTac, IVCY\tTac, IVCY\tTac, IVCY\tCyA, IVCY\t853/476\t529/987\tA\t\nA: alive, Anti-MDA5: anti-melanoma differentiation-associated gene 5 (MDA5) antibody, CyA: cyclosporine A, D: dead, F: female, IVCY: intravenous cyclophosphamide, mPSL: methylprednisolone, NA: not applicable, RTX: rituximab, Tac: tacrolimus\n\nThe prognosis of anti-MDA5 antibody-positive DM patients with RP-ILD is very poor, in spite of early detection and intensive care. However, the beneficial effects of RTX in the treatment of anti-MDA5 antibody-positive DM patients have been reported. RTX was not administered at the start of treatment in our clinic; thus, outcome of the two cases in our study cannot be used to definitively characterize the efficacy of RTX in DM patients with RP-ILD.\n\nAlthough the number of patients in our report is too small to draw definite conclusions, it has some interesting clinical implications. There is a report that the anti-MDA5 antibody titer and ferritin and IL-18 concentrations are useful for the evaluation of the response of anti-MDA5 antibody-positive DM patients to the treatment of ILD (15). The serum ferritin concentrations in the 3 patients in our case series support this hypothesis (Table). Notably, in Case 2, the ferritin level increased as the patient's clinical status deteriorated, after the administration of RTX. In addition, the outcomes of the patients in our study reflected that anti-MDA5 positivity is associated with poor prognosis.\n\nEarly and intensive treatment and close monitoring are critical when treating DM patients with RP-ILD. However, new treatments are needed.\n\n\nThe authors state that they have no Conflict of Interest (COI).\n\nAcknowledgement\nWe would like to thank Takao Fujii of the Department for the Control of Rheumatic Diseases, Graduate School of Medicine, Kyoto University, and Ran Sasai and Yuji Hosono of the Department of Rheumatology and Clinical Immunology, Graduate School of Medicine, Kyoto University, for the measurement of the antibody data.\n==== Refs\n1. \nKameda H , Nagasawa H , Ogawa H , et al \nCombination therapy with corticosteroids, cyclosporin A, and intravenous pulse cyclophosphamide for acute/subacute interstitial pneumonia in patients with dermatomyositis . J Rheumatol \n32 : 1719 -1726 , 2005 .16142867 \n2. \nKurita T , Yasuda S , Oba K , et al \nThe efficacy of tacrolimus in patients with interstitial lung diseases complicated with polymyositis or dermatomyositis . Rheumatology \n54 : 39 -44 , 2015 .24764266 \n3. \nLabirua A , Lundberg IE \nInterstitial lung disease and idiopathic inflammatory myopathies: progress and pitfalls . Curr Opin Rheumatol \n22 : 633 -638 , 2010 .20827201 \n4. \nSato S , Hirakata M , Kuwana M , et al \nAutoantibodies to a 140-kd polypeptide, CADM-140, in Japanese patients with clinically amyopathic dermatomyositis . Arthritis Rheum \n52 : 1571 -1576 , 2005 .15880816 \n5. \nGono T , Kawaguchi Y , Satoh T , et al \nClinical manifestation and prognostic factor in anti-melanoma differentiation-associated gene 5 antibody-associated interstitial lung disease as a complication of dermatomyositis . Rheumatology \n49 : 1713 -1719 , 2010 .20498012 \n6. \nGono T , Kawaguchi Y , Hara M , et al \nIncreased ferritin predicts development and severity of acute interstitial lung disease as a complication of dermatomyositis . Rheumatology \n49 : 1354 -1360 , 2010 .20385617 \n7. \nMarie I , Dominique S , Janvresse A , Levesque H , Menard JF \nRituximab therapy for refractory interstitial lung disease related to antisynthetase syndrome . Respir Med \n106 : 581 -587 , 2012 .22280877 \n8. \nSem M , Molberg O , Lund MB , Gran JT \nRituximab treatment of the anti-synthetase syndrome: a retrospective case series . Rheumatology \n48 : 968 -971 , 2009 .19531628 \n9. \nUnger L , Kampf S , Lüthke K , Aringer M \nRituximab therapy in patients with refractory dermatomyositis or polymyositis: differential effects in a real-life population . Rheumatology \n53 : 1630 -1638 , 2014 .24706995 \n10. \nAndersson H , Sem M , Lund MB , et al \nLong-term experience with rituximab in antisynthetase syndrome-related interstitial lung disease . Rheumatology \n54 : 1420 -1428 , 2015 .25740830 \n11. \nAggarwal R , Bandos A , Reed AM , et al \nPredictors of clinical improvement in rituximab-treated refractory adult and juvenile dermatomyositis and adult polymyositis . Arthritis Rheum \n66 : 740 -749 , 2014 .\n12. \nClottu A , Laffitte E , Prins C , Chizzolini C \nResponse of mucocutaneous lesions to rituximab in a case of melanoma differentiation antigen 5-related dermatomyositis . Dermatology \n225 : 376 -380 , 2012 .23428928 \n13. \nWatanabe R , Ishii T , Araki K , et al \nSuccessful multi-target therapy using corticosteroid, tacrolimus, cyclophosphamide, and rituximab for rapidly progressive interstitial lung disease in a patient with clinically amyopathic dermatomyositis . Mod Rheumatol \n26 : 465 -466 , 2016 .25698368 \n14. \nYamaguchi K , Yamaguchi A , Uchida M , et al \nA case of anti-MDA5-positive rapidly progressive interstitial lung disease in a patient with clinically amyopathic dermatomyositis ameliorated by rituximab, in addition to standard immunosuppressive treatment . Mod Rheumatol \n2015 (Epub ahead od print).\n15. \nGono T , Sato S , Kawaguchi Y , et al \nAnti-MDA5 antibody, ferritin and IL-18 are useful for the evaluation of response to treatment in interstitial lung disease with anti-MDA5 antibody-positive dermatomyositis . Rheumatology \n51 : 1563 -1570 , 2012 .22589330\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "0918-2918",
"issue": "56(11)",
"journal": "Internal medicine (Tokyo, Japan)",
"keywords": "anti-ARS antibody; anti-MDA5 antibody; anti-PL-12 antibody; dermatomyositis; interstitial lung disease; rituximab",
"medline_ta": "Intern Med",
"mesh_terms": "D000368:Aged; D000604:Amino Acyl-tRNA Synthetases; D001323:Autoantibodies; D065095:Calcineurin Inhibitors; D003520:Cyclophosphamide; D003882:Dermatomyositis; D005260:Female; D005938:Glucocorticoids; D006801:Humans; D007155:Immunologic Factors; D000072640:Interferon-Induced Helicase, IFIH1; D007564:Japan; D017563:Lung Diseases, Interstitial; D012189:Retrospective Studies; D000069283:Rituximab",
"nlm_unique_id": "9204241",
"other_id": null,
"pages": "1399-1403",
"pmc": null,
"pmid": "28566605",
"pubdate": "2017",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "20498012;22280877;16142867;24706995;25740830;20385617;23428928;22589330;15880816;25698373;25698368;24574235;19531628;20827201;24764266",
"title": "Dermatomyositis with Rapidly Progressive Interstitial Lung Disease Treated with Rituximab: A Report of 3 Cases in Japan.",
"title_normalized": "dermatomyositis with rapidly progressive interstitial lung disease treated with rituximab a report of 3 cases in japan"
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