Not All Sulfa Drugs Are Created Equal

Toler, Steven M.; Rodríguez, I.

doi:10.1345/aph.1e206

Cited by 4 publications

(6 citation statements)

References 12 publications

(10 reference statements)

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“…Indeed, the additional chemical structures condensed in the larger structural alerts identified by CWAS offered important mechanistic clues. For instance, the sulfonamide-containing antibacterials have been implicated with SJS, although sulfonamides alone do not induce SJS . Immunogenic reactions related to SJS have been attributed to the arylamine group within the sulfonylarylamine structural alert .…”

Section: Discussionmentioning

confidence: 99%

“…Immunogenic reactions related to SJS have been attributed to the arylamine group within the sulfonylarylamine structural alert . The supposed mechanism involves the metabolic transformation of the arylamine group into a reactive nitroso metabolite, which covalently binds to cellular macromolecules to initiate an immune response consistent with the hapten hypothesis. − Arylamines are generally rare among drugs due to their reactivity at the nitrogen site. Exceptions often contain electron-withdrawing groups in the para position to help stabilize the arylamine, such as sulfonamide-containing antibacterials, which involve a stabilizing p- sulfone group (SO 2 ) …”

Section: Discussionmentioning

confidence: 99%

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Chemistry-Wide Association Studies (CWAS): A Novel Framework for Identifying and Interpreting Structure–Activity Relationships

Low

Alves

Fourches

et al. 2018

J. Chem. Inf. Model.

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Quantitative Structure-Activity Relationships (QSAR) models are often seen as a “black box” because they are considered difficult to interpret. Meanwhile, qualitative approaches, e.g., structural alerts (SA) or read-across, provide mechanistic insight, which is preferred for regulatory purposes, but predictive accuracy of such approaches is often low. Herein, we introduce the Chemistry-Wide Association Study (CWAS) approach, a novel framework that both addresses such deficiencies and combines advantages of statistical QSAR and alert-based approaches. The CWAS framework consists of the following steps: (i) QSAR model building for an endpoint of interest; (ii) identification of key chemical features; (iii) determination of communities of such features disproportionately co-occurring more frequently in the active than in the inactive class; and (iv) assembling these communities to form larger (and not necessarily chemically connected) novel structural alerts with high specificity. As a proof-of-concept, we have applied CWAS to model Ames mutagenicity and Stevens-Johnson Syndrome (SJS). For the well-studied Ames mutagenicity dataset, we have identified 76 important individual fragments and assembled co-occurring fragments into SA both replicative of known as well as representing novel mutagenicity alerts. For the SJS dataset, we identified 29 important fragments and assembled co-occurring communities into SA including both known and novel alerts. In summary, we demonstrate that CWAS provides a new framework to interpret predictive QSAR models and derive refined structural alerts for more effective design and safety assessment of drugs and drug candidates.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Chemistry-Wide Association Studies (CWAS): A Novel Framework for Identifying and Interpreting Structure–Activity Relationships

Low

Alves

Fourches

et al. 2018

J. Chem. Inf. Model.

View full text Add to dashboard Cite

show abstract

“…For example, although it is known that sulfonamides alone do not induce SJS, 48 sulfonamides antibiotics have long been implicated with SJS 22 . Instead, studies have attributed immunogenic reactions related to SJS to an arylamine group within the sulfonylarylamine 49 structural alert (figure 3.1b).…”

Section: Discussionmentioning

confidence: 99%

“…Instead, studies have attributed immunogenic reactions related to SJS to an arylamine group within the sulfonylarylamine 49 structural alert (figure 3.1b). The purported mechanism involves the metabolic transformation of the arylamine group into a reactive nitroso metabolite that covalently binds to cellular macromolecules to initiate an immune response consistent with the hapten hypothesis 48–50 . Arylamines are generally rare among drugs due to their reactivity.…”

Section: Discussionmentioning

confidence: 99%

Cheminformatics-aided pharmacovigilance: application to Stevens-Johnson Syndrome

Low

Caster

Bergvall

et al. 2015

Journal of the American Medical Informatics Association

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Objective Quantitative Structure-Activity Relationship (QSAR) models can predict adverse drug reactions (ADRs), and thus provide early warnings of potential hazards. Timely identification of potential safety concerns could protect patients and aid early diagnosis of ADRs among the exposed. Our objective was to determine whether global spontaneous reporting patterns might allow chemical substructures associated with Stevens-Johnson Syndrome (SJS) to be identified and utilized for ADR prediction by QSAR models.Materials and Methods Using a reference set of 364 drugs having positive or negative reporting correlations with SJS in the VigiBase global repository of individual case safety reports (Uppsala Monitoring Center, Uppsala, Sweden), chemical descriptors were computed from drug molecular structures. Random Forest and Support Vector Machines methods were used to develop QSAR models, which were validated by external 5-fold cross validation. Models were employed for virtual screening of DrugBank to predict SJS actives and inactives, which were corroborated using knowledge bases like VigiBase, ChemoText, and MicroMedex (Truven Health Analytics Inc, Ann Arbor, Michigan).Results We developed QSAR models that could accurately predict if drugs were associated with SJS (area under the curve of 75%–81%). Our 10 most active and inactive predictions were substantiated by SJS reports (or lack thereof) in the literature.Discussion Interpretation of QSAR models in terms of significant chemical descriptors suggested novel SJS structural alerts.Conclusions We have demonstrated that QSAR models can accurately identify SJS active and inactive drugs. Requiring chemical structures only, QSAR models provide effective computational means to flag potentially harmful drugs for subsequent targeted surveillance and pharmacoepidemiologic investigations.

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“…is believed to play a crucial role in extreme cutaneous reactions to these medications. 9 Most adverse reactions to sulfonamide antibiotics appear aft er several doses have been taken, indicating that an immune response is involved. Once the arylamine groups are metabolized, they achieve reactivity and can elicit an immune response by acting as haptens.…”

Section: Case Reportmentioning

confidence: 99%

Acute Parotitis Induced by Trimethoprim/Sulfamethoxazole

Patel

Scheiner

2011

Ear Nose Throat J

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Adverse drug reactions to the sulfonamide antibiotics are uncommon. When they do occur, they usually manifest as a rash or urticaria. Our review of the recent literature found that while sialadenitis is listed as a possible side eff ect of sulfonamide use, no actual case has ever been reported until now. We describe a case of acute bilateral parotitis that arose as a side eff ect of sulfonamide antibiotic treatment. We also examine the relevance of such pathology to the proposed mechanisms of sialadenitis, and we briefl y discuss sulfonamide-induced pancreatitis. Lastly, we review the controversy over the possibility that some adverse drug reactions may be caused by crossreactivity among diff erent classes of sulfonamides.

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Not All Sulfa Drugs Are Created Equal

Cited by 4 publications

References 12 publications

Chemistry-Wide Association Studies (CWAS): A Novel Framework for Identifying and Interpreting Structure–Activity Relationships

Chemistry-Wide Association Studies (CWAS): A Novel Framework for Identifying and Interpreting Structure–Activity Relationships

Cheminformatics-aided pharmacovigilance: application to Stevens-Johnson Syndrome

Acute Parotitis Induced by Trimethoprim/Sulfamethoxazole

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