Pharmacogenomics of Allopurinol and Sulfamethoxazole/Trimethoprim: Case Series and Review of the Literature

Adverse drug reactions (ADRs) remain a common and major problem in healthcare. Severe cutaneous adverse drug reactions (SCARs), such as Stevens–Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) with mortality rate ranges from 10% to more than 30%, can be life threatening. A number of recent studies demonstrated that ADRs possess strong genetic predisposition. ADRs induced by several drugs have been shown to have significant associations with specific alleles of human leukocyte antigen (HLA) genes. For example, hypersensitivity to abacavir, a drug used for treating of human immunodeficiency virus (HIV) infection, has been proposed to be associated with allele 57:01 of HLA-B gene (terms HLA-B∗57:01). The incidences of abacavir hypersensitivity are much higher in Caucasians compared to other populations due to various allele frequencies in different ethnic populations. The antithyroid drug- (ATDs- ) induced agranulocytosis are strongly associated with two alleles: HLA-B∗38:02 and HLA-DRB1∗08:03. In addition, HLA-B∗15:02 allele was reported to be related to carbamazepine-induced SJS/TEN, and HLA-B∗57:01 in abacavir hypersensitivity and flucloxacillin induced drug-induced liver injury (DILI). In this review, we summarized the alleles of HLA genes which have been proposed to have association with ADRs caused by different drugs.

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Immunohistopathological Findings of Severe Cutaneous Adverse Drug Reactions

Journal of Immunology Research ◽

10.1155/2017/6928363 ◽

2017 ◽

Vol 2017 ◽

pp. 1-5 ◽

Cited By ~ 7

Author(s):

Mari Orime

Keyword(s):

Adverse Drug Reactions ◽

Clinical Manifestations ◽

Hypersensitivity Syndrome ◽

Conclusive Evidence ◽

Stevens Johnson Syndrome ◽

Drug Reactions ◽

Drug Induced ◽

Cutaneous Manifestations ◽

Johnson Syndrome ◽

Systemic Symptoms

Diagnosis of severe cutaneous adverse drug reactions should involve immunohistopathological examination, which gives insight into the pathomechanisms of these disorders. The characteristic histological findings of erythema multiforme (EM), Stevens–Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN) provide conclusive evidence demonstrating that SJS/TEN can be distinguished from EM. Established SJS/TEN shows full-thickness, extensive keratinocyte necrosis that develops into subepidermal bullae. Drug-induced hypersensitivity syndrome (DIHS) and exanthema in drug reaction with eosinophilia and systemic symptoms (DRESS) each display a variety of histopathological findings, which may partly correlate with the clinical manifestations. Although the histopathology of DRESS is nonspecific, the association of two or more of the four patterns—eczematous changes, interface dermatitis, acute generalized exanthematous pustulosis- (AGEP-) like patterns, and EM-like patterns—might appear in a single biopsy specimen, suggesting the diagnosis and severe cutaneous manifestations of DRESS. Cutaneous dendritic cells may be involved in the clinical course. AGEP typically shows spongiform superficial epidermal pustules accompanied with edema of the papillary dermis and abundant mixed perivascular infiltrates. Mutations in IL36RN may have a definite effect on pathological similarities between AGEP and generalized pustular psoriasis.

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A Comprehensive Review of HLA and Severe Cutaneous Adverse Drug Reactions: Implication for Clinical Pharmacogenomics and Precision Medicine

Pharmaceuticals ◽

10.3390/ph14111077 ◽

2021 ◽

Vol 14 (11) ◽

pp. 1077

Author(s):

Chiraphat Kloypan ◽

Napatrupron Koomdee ◽

Patompong Satapornpong ◽

Therdpong Tempark ◽

Mohitosh Biswas ◽

...

Keyword(s):

Clinical Practice ◽

Precision Medicine ◽

Adverse Drug Reactions ◽

Drug Hypersensitivity ◽

Human Leukocyte ◽

Population Level ◽

Stevens Johnson Syndrome ◽

Drug Reactions ◽

Drug Induced ◽

Systemic Symptoms

Human leukocyte antigen (HLA) encoded by the HLA gene is an important modulator for immune responses and drug hypersensitivity reactions as well. Genetic polymorphisms of HLA vary widely at population level and are responsible for developing severe cutaneous adverse drug reactions (SCARs) such as Stevens–Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), maculopapular exanthema (MPE). The associations of different HLA alleles with the risk of drug induced SJS/TEN, DRESS and MPE are strongly supportive for clinical considerations. Prescribing guidelines generated by different national and international working groups for translation of HLA pharmacogenetics into clinical practice are underway and functional in many countries, including Thailand. Cutting edge genomic technologies may accelerate wider adoption of HLA screening in routine clinical settings. There are great opportunities and several challenges as well for effective implementation of HLA genotyping globally in routine clinical practice for the prevention of drug induced SCARs substantially, enforcing precision medicine initiatives.

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Intravenous N-acetylcysteine in severe cutaneous drug reaction treatment: A case series

SAGE Open Medical Case Reports ◽

10.1177/2050313x20934708 ◽

2020 ◽

Vol 8 ◽

pp. 2050313X2093470 ◽

Cited By ~ 1

Author(s):

Md Jahidul Hasan ◽

Raihan Rabbani

Keyword(s):

Toxic Epidermal Necrolysis ◽

Intravenous Immunoglobulin ◽

Adverse Drug Reactions ◽

Therapeutic Option ◽

Case Series ◽

High Rate ◽

Stevens Johnson Syndrome ◽

Drug Reactions ◽

Drug Induced ◽

Johnson Syndrome

Drug-induced serious adverse reaction is an unpleasant event with high rate of mortality. Stevens–Johnson Syndrome and toxic epidermal necrolysis are most common among the serious adverse drug reactions. There is no selective drug therapy for the management of serious adverse drug reactions-associated mucocutaneous blisters. The use of N-acetylcysteine in the treatment of mucocutaneous blisters has limited evidence worldwide. Three cases of toxic epidermal necrolysis or Stevens–Johnson Syndrome-associated mucocutaneous blisters are presented in this study where intravenous N-acetylcysteine (600 mg, every 8 h) was given in early hospitalization hours for the treatment of mucocutaneous fluid-filled blisters. Here, one patient with toxic epidermal necrolysis received intravenous immunoglobulin along with intravenous N-acetylcysteine and the other two patients (toxic epidermal necrolysis/Stevens–Johnson Syndrome) received only N-acetylcysteine intravenously. In response, mucocutaneous fluid-filled blisters stopped progressing within 48 h and were healed within 2 weeks of admission in the intensive care unit. Thus, intravenous N-acetylcysteine with or without having intravenous immunoglobulin in the treatment of serious adverse drug reactions-associated mucocutaneous blisters may be an effective therapeutic option for better clinical outcome.

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Cutaneous Adverse Drug Reactions

10.2310/tywc.1009 ◽

2018 ◽

Author(s):

Neil H. Shear ◽

Sandra Knowles ◽

Lori Shapiro

Keyword(s):

Adverse Drug Reaction ◽

Drug Reaction ◽

Toxic Epidermal Necrolysis ◽

Adverse Drug Reactions ◽

Skin Necrosis ◽

Drug Eruption ◽

Hypersensitivity Syndrome ◽

Stevens Johnson Syndrome ◽

Drug Reactions ◽

Cutaneous Eruption

An adverse drug reaction is defined as any noxious, unintended, and undesired effect of a drug that occurs at doses used in humans for prophylaxis, diagnosis, or therapy. A cutaneous eruption is one of the most common manifestations of an adverse drug reaction. This chapter reviews the epidemiology, etiology, diagnosis, clinical manifestations, and differential diagnosis of adverse drug reactions, as well as laboratory tests for them. Also discussed are the types of cutaneous eruption: exanthematous eruption, urticarial eruption, blistering eruption, pustular eruption, and others. The simple and complex forms of each type of eruption are reviewed. The chapter includes 4 tables and 12 figures. Tables present the warning signs of a serious drug eruption, clinical features of hypersensitivity syndrome reaction and serum sickness-like reaction, characteristics of Stevens-Johnson Syndrome and toxic epidermal necrolysis, and clinical pearls to identify anticoagulant-induced skin necrosis. Figures illustrate hypersensitivity syndrome reaction, a fixed drug eruption from tetracycline, pseudoporphyria from naproxen, linear immunoglobulin A disease induced by vancomycin, pemphigus foliaceus from taking enalapril, pemphigus vulgaris from taking penicillamine, toxic epidermal necrolysis after starting phenytoin therapy, acneiform drug eruption due to gefitinib, acute generalized exanthematous pustulosis from cloxacillin, coumarin-induced skin necrosis, a lichenoid drug eruption associated with ramipril, and leukocytoclastic vasculitis from hydrochlorothiazide. This chapter contains 106 references.

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Cutaneous reactions to drugs

Oxford Textbook of Medicine ◽

10.1093/med/9780198746690.003.0565 ◽

2020 ◽

pp. 5752-5760

Author(s):

Sarah Walsh ◽

Daniel Creamer ◽

Haur Yueh Lee

Keyword(s):

Adverse Drug Reactions ◽

Adverse Reactions ◽

Normal Function ◽

Stevens Johnson Syndrome ◽

Drug Reactions ◽

Drug Induced ◽

Drug Eruptions ◽

Fixed Drug ◽

Iatrogenic Illness ◽

Systemic Symptoms

Adverse reactions to medications are common and important cause of iatrogenic illness. Severe cutaneous adverse drug reactions include toxic epidermal necrolysis, Stevens–Johnson syndrome, drug reaction with eosinophilia and systemic symptoms, and acute generalized exanthematous pustulosis, which together constitute 2% of all adverse drug reactions and may be life-threatening. Less severe drug-induced skin reactions such as exanthems, urticaria, lichenoid drug rashes, and fixed drug eruptions are more common, sometimes termed benign cutaneous adverse reactions, and generally resolve without sequelae. Drugs may also cause adverse events due to alteration of the normal function of the skin or its appendages. This may take the form of photosensitivity, abnormal pigmentation, or disrupted growth of hair or nails.

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Bibliometric analysis of adverse drug reactions and pharmacovigilance research activities in Nepal

Therapeutic Advances in Drug Safety ◽

10.1177/2042098620922480 ◽

2020 ◽

Vol 11 ◽

pp. 204209862092248

Author(s):

Sunil Shrestha ◽

Krisha Danekhu ◽

Bhuvan KC ◽

Subish Palaian ◽

Mohamed Izham Mohamed Ibrahim

Keyword(s):

Bibliometric Analysis ◽

Adverse Drug Reactions ◽

Case Reports ◽

Research Performance ◽

Case Series ◽

Original Research ◽

Drug Reactions ◽

Drug Induced ◽

Scientific Publications ◽

Research Activities

Background: Bibliometric analyses have been used previously to study the measures of quality and impact of research performed in several health-related areas such as adverse drug reactions (ADRs) and pharmacovigilance (PV), etc. This method can assess the research performance of publications quantitatively and statistically. There is no evidence of bibilometric studies analyzing ADRs and PV from Nepal. Therefore, the present study aimed to assess scientific output on ADRs and PV-related research activities in Nepal using a bibliometric analysis of publications from 2004 January to December 2018, that is, 15 years. Methods: A systematic search was conducted in PubMed, Web of Science, Google Scholar, Scopus and Nepal Journal Online (NepJOL) databases. ‘Adverse Drug Reactions‘ or ‘ADRs‘ or ‘ADR‘ or ‘Adverse drug reaction‘ or ‘AE‘ or ‘Adverse Event‘ or ‘Drug-Induced Reaction‘ or ‘Pharmacovigilance‘ or ‘PV‘ and ‘Nepal‘. The search covered 15 years (January 2004 to December 2018) of study on ADRs and PV in Nepal. Only articles retrieved from databases were included, whereas published/unpublished drug bulletins, pharmacy newsletters and thesis were excluded. The articles thus retrieved were recorded, and thereafter analyzed. Word count code was used for the analysis of keywords used in the retrieved articles. Results: A total of 124 articles were retrieved, with the highest rate of publications in 2006 and 2007, with 16 papers each. Among the articles, 10 (8.1%) were published in Kathmandu University Medical Journal (KUMJ). Single papers were published in 38 different journals. Brief reports (1.6%), case reports (31.2%), case series (0.8%), education forums (0.8%), letters to the editor (5.6%), original research articles (41.9%), review articles (9.7%), short communications and short reports (8.1%) on ADRs and PV were recorded. Out of 124 papers, 52 (41.9%) were original research publications. The majority (74.1%) of research was done in the category of ADR incidence, types, prevention, and management, followed by policy and suggestions for strengthening national and regional pharmacovigilance centers of Nepal (14.5%). Conclusions: During the study years, there was an increase in scientific publications on drug safety. A total of 124 published articles were found during bibliometric analysis of ADRs and PV research activities in Nepal.

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Ciprofloxacin-Induced Bullae of the Lower Extremity: A Case of a Fixed Drug Reaction

Journal of the American Podiatric Medical Association ◽

10.7547/17-088 ◽

2019 ◽

Vol 109 (2) ◽

pp. 155-158 ◽

Cited By ~ 1

Author(s):

Anthony J. Mollica ◽

Albert J. Mollica ◽

Elaine Grant ◽

Ali Malik ◽

Marc Claydon

Keyword(s):

Drug Reaction ◽

Adverse Drug Reactions ◽

Hypersensitivity Syndrome ◽

Stevens Johnson Syndrome ◽

Adverse Side Effect ◽

Drug Reactions ◽

Johnson Syndrome ◽

Fixed Drug ◽

Cutaneous Drug Reactions ◽

Exanthematous Pustulosis

Cutaneous adverse drug reactions make up 1% to 2% of all adverse drug reactions. From these adverse cutaneous drug reactions, 16% to 21% can be categorized as fixed drug reactions (FDR). Fixed drug reactions may show diverse morphology including but not limited to the following: dermatitis, Stevens-Johnson syndrome, urticaria, morbilliform exanthema, hypersensitivity syndrome, pigmentary changes, acute generalized exanthematous pustulosis, photosensitivity, and vasculitis. An FDR will occur at the same site because of repeated exposure to the offending agent, causing a corresponding immune reaction. There are many drugs that can cause an FDR, such as analgesics, antibiotics, muscle relaxants, and anticonvulsants. The antibiotic ciprofloxacin has been shown to be a cause of cutaneous adverse drug reactions; however, the fixed drug reaction bullous variant is rare. This case study was published to demonstrate a rare adverse side effect to a commonly used antibiotic in podiatric medicine.

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Cutaneous Adverse Drug Reactions

10.2310/im.1009 ◽

2012 ◽

Author(s):

Neil H. Shear ◽

Sandra Knowles ◽

Lori Shapiro

Keyword(s):

Adverse Drug Reaction ◽

Drug Reaction ◽

Toxic Epidermal Necrolysis ◽

Adverse Drug Reactions ◽

Skin Necrosis ◽

Drug Eruption ◽

Hypersensitivity Syndrome ◽

Stevens Johnson Syndrome ◽

Drug Reactions ◽

Cutaneous Eruption

An adverse drug reaction is defined as any noxious, unintended, and undesired effect of a drug that occurs at doses used in humans for prophylaxis, diagnosis, or therapy. A cutaneous eruption is one of the most common manifestations of an adverse drug reaction. This chapter reviews the epidemiology, etiology, diagnosis, clinical manifestations, and differential diagnosis of adverse drug reactions, as well as laboratory tests for them. Also discussed are the types of cutaneous eruption: exanthematous eruption, urticarial eruption, blistering eruption, pustular eruption, and others. The simple and complex forms of each type of eruption are reviewed. The chapter includes 4 tables and 12 figures. Tables present the warning signs of a serious drug eruption, clinical features of hypersensitivity syndrome reaction and serum sickness-like reaction, characteristics of Stevens-Johnson Syndrome and toxic epidermal necrolysis, and clinical pearls to identify anticoagulant-induced skin necrosis. Figures illustrate hypersensitivity syndrome reaction, a fixed drug eruption from tetracycline, pseudoporphyria from naproxen, linear immunoglobulin A disease induced by vancomycin, pemphigus foliaceus from taking enalapril, pemphigus vulgaris from taking penicillamine, toxic epidermal necrolysis after starting phenytoin therapy, acneiform drug eruption due to gefitinib, acute generalized exanthematous pustulosis from cloxacillin, coumarin-induced skin necrosis, a lichenoid drug eruption associated with ramipril, and leukocytoclastic vasculitis from hydrochlorothiazide. This chapter contains 106 references.

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The Roles of Immunoregulatory Networks in Severe Drug Hypersensitivity

Frontiers in Immunology ◽

10.3389/fimmu.2021.597761 ◽

2021 ◽

Vol 12 ◽

Author(s):

Yun-Shiuan Olivia Hsu ◽

Kun-Lin Lu ◽

Yun Fu ◽

Chuang-Wei Wang ◽

Chun-Wei Lu ◽

...

Keyword(s):

Checkpoint Inhibitors ◽

Drug Hypersensitivity ◽

Human Leukocyte ◽

Hypersensitivity Syndrome ◽

Stevens Johnson Syndrome ◽

Hypersensitivity Reactions ◽

Drug Induced ◽

Johnson Syndrome ◽

Signaling Receptors ◽

Systemic Symptoms

The immunomodulatory effects of regulatory T cells (Tregs) and co-signaling receptors have gained much attention, as they help balance immunogenic and immunotolerant responses that may be disrupted in autoimmune and infectious diseases. Drug hypersensitivity has a myriad of manifestations, which ranges from the mild maculopapular exanthema to the severe Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms/drug-induced hypersensitivity syndrome (DRESS/DIHS). While studies have identified high-risk human leukocyte antigen (HLA) allotypes, the presence of the HLA allotype at risk is not sufficient to elicit drug hypersensitivity. Recent studies have suggested that insufficient regulation by Tregs may play a role in severe hypersensitivity reactions. Furthermore, immune checkpoint inhibitors, such as anti-CTLA-4 or anti-PD-1, in cancer treatment also induce hypersensitivity reactions including SJS/TEN and DRESS/DIHS. Taken together, mechanisms involving both Tregs as well as coinhibitory and costimulatory receptors may be crucial in the pathogenesis of drug hypersensitivity. In this review, we summarize the currently implicated roles of co-signaling receptors and Tregs in delayed-type drug hypersensitivity in the hope of identifying potential pharmacologic targets.

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