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Jack Uetrecht - One of the best experts on this subject based on the ideXlab platform.
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How Reactive Metabolites Induce an Immune Response That Sometimes Leads to an Idiosyncratic Drug Reaction
Chemical research in toxicology, 2016Co-Authors: Tiffany Cho, Jack UetrechtAbstract:Little is known with certainty about the mechanisms of Idiosyncratic Drug Reactions (IDRs); however, there is substantive evidence that reactive metabolites are involved in most, but not all, IDRs. In addition, evidence also suggests that most IDRs are immune mediated. That raises the question of how reactive metabolites induce an immune response that can lead to an IDR. The dominant hypotheses are the hapten and danger hypotheses. These are complementary hypotheses: a reactive metabolite can act as a hapten to produce neoantigens, and it can also cause cell damage leading to the release of danger-associated molecular pattern molecules that activate antigen presenting cells. Both are required for an immune response. In addition, Drugs may induce an immune response through inflammasome activation. We have found examples in which the ability to activate inflammasomes differentiated Drugs that cause IDRs from similar Drugs that do not. There are other hypotheses that do not involve an immune mechanism such a...
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Encyclopedia of Drug Metabolism and Interactions - Idiosyncratic Drug Reactions
Encyclopedia of Drug Metabolism and Interactions, 2012Co-Authors: Zbigniew W. Wojcinski, Jack UetrechtAbstract:Idiosyncratic Drug Reactions (IDRs) are adverse Drug Reactions that are not related to the known pharmacological properties of the Drug occur in only a small percentage of the population and do not show any apparent dose–response relationship. The unpredictable nature of IDRs together with the often serious adverse effects encountered pose a major health concern in the development and clinical usage of pharmaceuticals. The mechanism of IDRs is not clearly understood, and although several theories have been proposed, IDRs can be generally categorized mechanistically as either immune mediated or non-immune-mediated. There is circumstantial evidence that suggests that most Idiosyncratic Reactions are hypersensitivity Reactions initiated by the formation of chemically reactive metabolites that bind to proteins and induce an immune-mediated response. Investigations in animal models have had limited success owing to the unpredictability of IDRs in animals, which is similar to the situation in humans. However, IDRs in animals do share some similar characteristics and mechanisms observed in humans supporting the need for further study of animal models. Keywords: Idiosyncratic; Drug; Reaction; animal; models
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Characterization of a potential animal model of an Idiosyncratic Drug Reaction: nevirapine-induced skin rash in the rat.
Chemical research in toxicology, 2003Co-Authors: Jacintha M. Shenton, Munehiro Teranishi, Mones Abu-asab, Julie A. Yager, Jack UetrechtAbstract:Idiosyncratic Drug Reactions are difficult to study in humans due to their unpredictability. Unfortunately, this characteristic also hinders the development of animal models needed for mechanistic studies. Nevirapine, used to treat human immunodeficiency virus (HIV) infections, results in a severe Idiosyncratic skin rash in some patients. We found that nevirapine can also cause a significant rash in some strains of rats. At a dose of 150 mg/kg/day, the incidence in female Sprague-Dawley rats was 6/28 (21%), in female Brown Norway rats 32/32 (100%), and in female Lewis rats 0/6 (0%) while no male Sprague-Dawley or Brown Norway rats developed a rash. Female SJL mice 0/7 also did not develop nevirapine-induced skin lesions. The first sign of a Reaction in Brown Norway rats was red ears at days 7-10 followed by a rash with scabbing mainly on the back; this was a shorter time to onset than in Sprague-Dawley rats. Light microscopy of the skin revealed a primarily mononuclear inflammatory infiltrate and lesions typical of self-trauma. Immunohistochemistry results suggest that the infiltrate was composed of CD4 and CD8 T cells as well as macrophages. A lower dose of either 40 or 75 mg/kg/day did not lead to a rash and, in fact, 2 weeks of the lower doses induced tolerance to the 150 mg/kg/day dose in female Brown Norway rats. A dose of 100 mg/kg/day resulted in rash in 2/4 (50%) of female Brown Norway rats. Rechallenge of Brown Norway rats that had been allowed to recuperate after a nevirapine-induced rash led to red ears in less than 24 h followed by hair loss and occasional skin lesions. Although the skin rash was less evident on rechallenge, microscopically, the cellular infiltrate was more prominent, especially surrounding the hair follicles. Moreover, there were lesions of interface dermatitis with apoptosis and satellitosis, indicative of a cell-mediated immune attack on the epidermis. While systemic signs of illness did not accompany the rash on primary exposure, on rechallenge, the animals appeared generally unwell and this forced sacrifice after 2 weeks or less of treatment. Importantly, splenocytes isolated from rechallenged animals were able to transfer susceptibility to nevirapine-induced skin rash to naive female Brown Norway recipients, which was illustrated by a faster time to onset of rash in the recipients. The characteristics of this adverse Reaction are similar to that seen in humans; that is, it is Idiosyncratic in that it only occurs in some strains of animals, is delayed in onset, is more common in females, is dose-dependent, and appears to be immune-mediated. Therefore, it may represent a good animal model for the study of Idiosyncratic Drug Reactions.
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Is it possible to more accurately predict which Drug candidates will cause Idiosyncratic Drug Reactions
Current drug metabolism, 2000Co-Authors: Jack UetrechtAbstract:The unexpected occurrence of Idiosyncratic Drug Reactions during late clinical trials or after a Drug has been released can lead to a severe restriction in its use or failure to release/withdrawal. This leads to considerable uncertainty in Drug development and has led to attempts to try to predict a Drug's potential to cause such Reactions. It appears that most Idiosyncratic Drug Reactions are due to reactive metabolites; however, many Drugs that form reactive metabolites are associated with a very low incidence of Idiosyncratic Drug Reactions. Therefore. screening Drug for their ability to generate reactive metabolites is likely to cause the rejection of many good Drug candidates. There is evidence to suggest that an Idiosyncratic Drug Reaction is more likely if there is some "danger signal'. Thus Drugs that cause some degree of cell stress or damage may be more likely to lead to a high incidence of Idiosyncratic Drug Reactions. The exact nature of the putative danger signals is unknown. However, a screen of the effects of Drugs known to be associated with a high incidence of idiosyncatic Reactions using expression genomics and proteomics may reveal a pattern or patterns of mRNA and protein expression that predict which Drugs will cause a high incidence of Idiosyncratic Drug Reactions. Although Idiosyncratic Drug Reactions are not usually detected in animal tests because they are just as Idiosyncratic in animals as they are in humans, it is likely that Drug reactive metabolites would also cause similar cell stress in animals. It is more likely that in most cases it is differences in the immune response to the reactive metabolites that determine which individuals will develop an Idiosyncratic Reaction. If the expression of certain proteins in animals treated with a Drug candidate could be used as a screening method to predict a Drug's potential to cause a high incidence of Idiosyncratic Drug Reactions, it would greatly facilitate the development of safer Drugs.
Sepideh Elyasi - One of the best experts on this subject based on the ideXlab platform.
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Antibacterial antibiotic-induced Drug Reaction with eosinophilia and systemic symptoms (DRESS) syndrome: a literature review
European Journal of Clinical Pharmacology, 2020Co-Authors: Shiva Sharifzadeh, Amir Hooshang Mohammadpour, Ashraf Tavanaee, Sepideh ElyasiAbstract:Background Drug Reaction with eosinophilia and systemic symptoms syndrome (DRESS) is a delayed infrequent potentially life-threatening Idiosyncratic Drug Reaction. Aromatic anticonvulsants and allopurinol are the most frequent causative agents. However, various reports of antibiotic-induced DRESS are available. In this review, we try to summarize reports of antibacterial antibiotic-induced DRESS focusing on characteristics of DRESS induced by each antibiotic group. Methods The data were collected by searching PubMed/MEDLINE and ScienceDirect. The keywords used as search terms were “DRESS syndrome,” “Drug-induced hypersensitivity syndrome (DIHS),” “antibiotics,” “antimicrobial,” and names of various antimicrobial groups. Finally, 254 relevant cases with a definite or probable diagnosis of DRESS based on RegiSCAR criteria were found until 30 May 2020 and reviewed. Results and conclusion Totally, 254 cases of antibacterial antibiotic-induced DRESS are reported. Most of them are related to antituberculosis Drugs, vancomycin, and sulfonamides, respectively. Rash and fever were most frequent clinical findings. Eosinophilia and liver injury were the most reported hematologic and visceral organ involvement, respectively. Most of the patients are managed with systemic corticosteroids. The death occurred in 16 patients which most of them experienced liver or lung involvement. The reactivation of various viruses especially HHV-6 is reported in 33 cases. The mean latency period was 29 days. It is necessary to perform thorough epidemiological, genetic, and immunological studies, also systematic case review and causality assessment, as well as well-designed clinical trials for better management of antibiotic-induced DRESS.
F. J. Nellen - One of the best experts on this subject based on the ideXlab platform.
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A lethal case of the dapsone hypersensitivity syndrome involving the myocardium.
The Netherlands journal of medicine, 2016Co-Authors: R. M. Hoogeveen, T. Van Der Bom, H. H. De Boer, R. M. Thurlings, Bas S. Wind, H. J. C. De Vries, A. U. Van Lent, Ulrich Beuers, A. C. Van Der Wal, F. J. NellenAbstract:In the Netherlands dapsone is used for the treatment of dermatitis herpetiformis, leprosy and Pneumocystis jiroveci pneumonia and prophylaxis in case of cotrimoxazole allergy. An Idiosyncratic Drug Reaction, known as the dapsone hypersensitivity syndrome (DHS), appears in about 0.5-3.6% of persons treated with dapsone. DHS can be associated with fever, rash and systemic involvement. We present a 35-year-old woman who developed severe DHS seven weeks after starting dapsone. Six weeks after being discharged in a good clinical condition she died from fulminant myocarditis, 11 weeks after the first DHS symptoms and the discontinuation of dapsone.
Paolo Romanelli - One of the best experts on this subject based on the ideXlab platform.
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Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Syndrome
The Journal of clinical and aesthetic dermatology, 2013Co-Authors: Sonal Choudhary, Michael P. Mcleod, Daniele Torchia, Paolo RomanelliAbstract:Drug rash with eosinophilia and systemic symptoms syndrome is a severe Idiosyncratic Drug Reaction with a long latency period. It has been described using many terms; however, Drug rash with eosinophilia and systemic symptoms syndrome appears to be the most appropriate. This syndrome causes a diverse array of clinical symptoms, anywhere from 2 to 8 weeks after initiating the offending Drug. Standardized criteria for the diagnosis have been developed; however, their utility remains to be validated. Unfortunately, the management of Drug rash with eosinophilia and systemic symptoms syndrome is not well supported by strong evidence-based data.
M Chakroun - One of the best experts on this subject based on the ideXlab platform.
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hypersensitivity to amoxicillin after Drug rash with eosinophilia and systemic symptoms dress to carbamazepine and allopurinol a possible co sensitization
British Journal of Clinical Pharmacology, 2010Co-Authors: Nadia Ben Fredj, Karim Aouam, Amel Chaabane, A Toumi, Foued Ben Rhomdhane, Naceur A Boughattas, M ChakrounAbstract:Hypersensitivity syndrome, also known as Drug rash with eosinophilia and systemic symptoms (DRESS), is a serious Idiosyncratic Drug Reaction. It is associated with fever, skin eruption, eosinophilia and multiple organ involvement (lymph node enlargement, hepatitis, pneumonitis, renal dysfunction, pancreatitis, myositis, myocarditis, central nervous system manifestations and hyper- and/or hypothyroidism) [1].
