Naomi Jessurun

Relationship Between Structural Alerts in NSAIDs and Idiosyncratic Hepatotoxicity: An Analysis of Spontaneous Report Data from the WHO Database

BackgroundIdiosyncratic drug reactions such as hepatotoxicity and blood dyscrasias represent one of the major causes of drug withdrawal from the market. According to the reactive metabolite (RM) concept, this may be due to the metabolic activation of structural alerts (SAs), functionalities in the drug molecule that are susceptible to bioactivation resulting in RMs. The relationship, however, between metabolic activation of SAs in drugs with in vivo toxicity measured as disproportionate reporting of adverse drug reactions (ADRs) to the WHO VigiBase™ database has never been studied.ObjectiveThe objective of this study was to investigate whether reported associations of hepatotoxicity between NSAIDs with SAs and NSAIDs with mitigated SAs are disproportionately present in the ADR reporting VigiBase™ database of the WHO collaborating center (the Uppsala Monitoring Centre). The extent of disproportionality of these associations is compared with associations of NSAIDs and hemorrhage, an ADR not associated with the forming of RMs.MethodsWe calculated the reporting odds ratios for five NSAIDs [bromfenac (withdrawn), lumiracoxib (withdrawn), diclofenac, ibuprofen, and naproxen] associated with the MedDRA preferred terms: hepatic failure, hepatic function abnormal, hepatic necrosis, and hepatitis. The disproportionality of the association of these ADRs is compared with the preferred term hemorrhage.ResultsThe results show that hepatotoxicity is more disproportionately reported in the WHO database for NSAIDs with SAs (bromfenac, lumiracoxib, diclofenac) than for NSAIDs where SAs are mitigated (ibuprofen and naproxen). This difference in reporting between NSAIDs with SAs and with mitigated SAs is not observed for the ADR hemorrhage, an ADR not associated with the forming of RMs.ConclusionsThis study shows that although spontaneous reports have many limitations, the findings are in line with previous research on the reactive metabolite concept. Whether SAs and the number of SAs in the NSAIDs actually play a role in the observed hepatotoxicity must be investigated in future studies.

Adverse drug reactions of haloperidol used in critically ill children for the treatment of delirium

Clinical Pharmacology & Therapeutics (2013) 93, S88–S122. doi:10.1038/clpt.2012.258

Muscle spasms: an unexpected adverse drug reaction of pemetrexed?:

In this report we describe a 53-year-old woman with advanced non-small cell lung cancer, treated with pemetrexed and cisplatin combination therapy, followed by pemetrexed monotherapy. The patient developed severe muscle spasms at least twice, shortly after administration of pemetrexed monotherapy. A possible explanation for this observation is that in combination with cisplatin therapy, the patient was hyperhydrated before administration to promote renal excretion and reduce toxicity. Pemetrexed is also renally excreted, which supports the finding that toxicity did not occur when the patient was hyperhydrated. After discontinuation of pemetrexed the symptoms did not reoccur. All aspects of this case point to a possible relationship between pemetrexed and an adverse drug reaction (ADR). We conclude that muscle spasms are a rare, but possibly dose-related ADR of pemetrexed-based therapy.

Inhibition of CYP2D6 with low dose (5 mg) paroxetine in patients with high 10-hydroxynortriptyline serum levels - a review of routine practice

Netherlands Pharmacovigilance Centre Lareb, ‘s-Hertogenbosch, The Netherlands, Department of Pharmacy: Pharmacotherapy and Pharmaceutical Care, University of Groningen, Groningen, The Netherlands, Department of Pharmacy, University of Utrecht, Utrecht, The Netherlands, Reinier van Arkelgroep, ‘s-Hertogenbosch, The Netherlands, Jeroen Bosch Hospital, ‘s-Hertogenbosch, The Netherlands, Department of General Practice & Elderly Care Medicine/EMGO Institute for Health and Care Research, VU University Medical Center Amsterdam, The Netherlands, and Utrecht Institute for Pharmaceutical Sciences, Division of Pharmacoepidemiology & Clinical Pharmacology, Utrecht University, Utrecht, The Netherlands

Advanced Age and Female Sex As Risk Factors for High Anion Gap Metabolic Acidosis After a Drug Interaction Between Paracetamol and Flucloxacillin: A Case Series

Conflict of Interest: No author listed on this manuscript has declared any conflict of interest. Author Contributions: Bose-Brill, Pressler-Vyrda, Taylor: study concept and design. Belanger, Kobe, Ballenger, Kretovics: participant recruitment, data collection and preparation. Bose-Brill, Belanger, Kobe, Pressler-Vyrda: data analysis. Bose-Brill, Belanger, Kretovics, Ballenger, PresslerVyrda, Taylor: data interpretation. Bose-Brill, Belanger, Kretovics, Pressler-Vyrda: manuscript preparation. Sponsor’s Role: There was no sponsor for this study.