Cutaneous Adverse Reactions to Valdecoxib Distinct From Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis

Ziemer, Mirjana; Wiesend, Christiane L.; Vetter, Robert; Weiss, Johannes M.; Blaschke, Sabine; Norgauer, Johannes; Mockenhaupt, Maja

doi:10.1001/archderm.143.6.711

Cited by 33 publications

(28 citation statements)

References 10 publications

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“…In the antipyretic, analgesic and antiphlogistic drug category, acetaminophen which was considered to be comparatively safe for people of all ages, and valdecoxib which was discontinued due to the occurrence of serious adverse events in May 2005, were detected as signals [23]. In the antibacterial agent category, azithromycin, which was linked with SJS in Japan in 2003, was detected as a signal.…”

Section: Discussionmentioning

confidence: 99%

Signal Detection of Drug Complications Applying Association Rule Learning for Stevens-Johnson Syndrome

Shirakuni¹,

Okamoto²,

Kawashita³

et al. 2009

J. Comput. Aided Chem.

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The adverse events induced by drugs have been complicated, when two or more drugs are administrated for a patient. We selected "Stevens-Johnson Syndrome (SJS)" as a research object, which is one of the severe skin manifestations. The data source is a database constructed by the Food and Drug Administration (FDA). FDA's post-marketing safety surveillance program is supported by the Adverse Event Reporting System (AERS). AERS is designed with a computerized information database. To analyze the relationships between the concurrent medication and SJS in this study, we applied association rule learning. Our purpose is to propose an efficient procedure that enables the detection of signals for drugs related to an adverse event, without assuming the involvement of a specific drug. We defined new value K for the evaluation of existing signal detection. Association rule was evaluated according to criterion K value. As a result, it was suggested to obtain a strong signal by combining two concomitant drugs. Association rule learning in this study was applicable for the analysis of the relationships between adverse events and pairs of drugs.

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Section: Discussionmentioning

confidence: 99%

Signal Detection of Drug Complications Applying Association Rule Learning for Stevens-Johnson Syndrome

Shirakuni¹,

Okamoto²,

Kawashita³

et al. 2009

J. Comput. Aided Chem.

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“…Idiosyncratic and drug-induced liver injury have been reported for these classes of compounds through postmarketing surveillance in patients (Olsson et al, 1992;Ziemer et al, 2007;Andrews and Daly, 2008). The underlying reason for these adverse reactions is at present unknown, but it has been speculated that reactive metabolite species are involved (Park et al, 2011).…”

Section: Reactive Metabolism Of Phenyl Methyl-isoxazolesmentioning

confidence: 99%

“…1), dicloxacillin, cloxacillin, and flucloxacillin, also contain this phenyl methyl-isoxazole fragment. Serious skin reactions, including erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been reported through postmarketing surveillance in patients receiving valdecoxib, although it is at present unknown what the root cause to these adverse drug reactions is (Ziemer et al, 2007). Even for the oxacillin derivatives, adverse drug reactions have been reported (Olsson et al, 1992;Andrews and Daly, 2008).…”

Section: Introductionmentioning

confidence: 99%

Novel Bioactivation Mechanism of Reactive Metabolite Formation from Phenyl Methyl-Isoxazoles

et al. 2012

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ABSTRACT:Recently, we described a series of phenyl methyl-isoxazole derivatives as novel, potent, and selective inhibitors of the voltage-gated sodium channel type 1.7 (Bioorg Med Chem Lett 21:3871-3876, 2011). The lead compound, 2-chloro-6-fluorobenzyl [3-(2,6-dichlorophenyl)-5-methylisoxazol-4-yl]carbamate, showed unprecedented GSH and cysteine reactivity associated with NADPH-dependent metabolism in trapping studies using human liver microsomes. Additional trapping experiments with close analogs and mass spectra and NMR analyses suggested that the conjugates were attached directly to the 5-methyl on the isoxazole moiety. We propose a mechanism of bioactivation via an initial oxidation of the 5-methyl generating a stabilized enimine intermediate and a subsequent GSH attack on the 5-methylene. Efforts to ameliorate reactive metabolite generation were undertaken to minimize the potential risk of toxicity. Formation of reactive metabolites could be significantly reduced or prevented by removing the 5-methyl, by N-methylation of the carbamate; by replacing the nitrogen with a carbon or removing the nitrogen to obtain a carboxylate; or by inserting an isomeric 5-methyl isoxazole. The effectiveness of these various chemical modifications in reducing GSH adduct formation is in line with the proposed mechanism. In conclusion, we have identified a novel mechanism of bioactivation of phenyl 5-methylisoxazol-4-yl-amines. The reactivity was attenuated by several modifications aimed to prevent the emergence of an enimine intermediate. Whether 5-methyl isoxazoles should be considered a structural alert for potential formation of reactive metabolites is dependent on their context, i.e., 4-nitrogen.

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“…In particular, cyclooxygenase-2 inhibitors are able to induce widespread erythematous target-like skin reactions with certain additional symptoms, especially dyspnea and facial edema, and often also more widespread dermal edema ( figure 5A). [Ziemer, et al, 2007] The exanthema is not accompanied by mucous membrane involvement and usually shows no or only very localized blisters (< 5% of the body surface). Histopathologically, biopsy specimens show a normal epidermis.…”

Section: Histologymentioning

confidence: 99%

“…A few lymphocytes may be found in the epidermis; which may in some cases focally be detached from the underlying skin as a result of severe edema in the papillary dermis. [Ziemer, et al, 2007] Another, essentially distinct, severe and potentially fatal condition is 'drug reaction with eosinophilia and systemic symptoms' (DRESS). Although clinically well characterized, histology has not been studied systematically for this disease entity and reported findings are not consistent.…”

Section: Histologymentioning

confidence: 99%

Severe Drug-Induced Skin Reactions: Clinical Pattern, Diagnostics and Therapy

Ziemer¹,

Mockenhaupt²

2011

Skin Biopsy - Perspectives

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Cutaneous Adverse Reactions to Valdecoxib Distinct From Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis

Cited by 33 publications

References 10 publications

Signal Detection of Drug Complications Applying Association Rule Learning for Stevens-Johnson Syndrome

Signal Detection of Drug Complications Applying Association Rule Learning for Stevens-Johnson Syndrome

Novel Bioactivation Mechanism of Reactive Metabolite Formation from Phenyl Methyl-Isoxazoles

Severe Drug-Induced Skin Reactions: Clinical Pattern, Diagnostics and Therapy

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