Drugs associated with reversible cerebral vasoconstriction syndrome: A pharmacovigilance study in vigiBase®.

BACKGROUND: Data on drug-induced reversible cerebral vasoconstriction syndrome (RCVS) are scarce. We aimed to describe RCVS characteristics with drugs previously identified as associated with RCVS and investigate potential signals related to other drugs. METHODS: VigiBase® was queried for all reports of RCVS until 31 May 2023. A descriptive study was performed on reports concerning drug classes known to precipitate RCVS. To identify new drugs, a disproportionality analysis was conducted. RESULTS: In total, 560 reports were included. RCVS occurred in patients aged between 45-64 years (40%) and 18-44 years (35%), mainly in females (72.5%). Drugs were antidepressants (38.4%), triptans (6.4%), nasal decongestants (3.7%) and immunosupressants (8.7%). In 50 cases, antidepressants were in association with drugs known to precipitate RCVS. The median time to onset was 195 days for antidepressants and much shorter (1-10 days) for triptans, nasal decongestants and immunosuppressants. The outcome was favorable in 87% of cases, and fatal in 4.4%. We found a disproportionality signal with 14 drugs: glucocorticoids, bupropion, varenicline, mycophenolic acid, aripiprazole, trazodone, monoclonal antibodies (erenumab, ustekinumab and tocilizumab), leuprorelin and anastrozole. CONCLUSIONS: The present study confirms the role of vasoconstrictors in the onset of RCVS, particularly when used in combination and found potential signals, which may help clinicians envisage an iatrogenic etiology of RCVS.

Leukoencephalopathy with transient splenial lesions related to 5-fluorouracil or capecitabine.

BACKGROUND: 5-Fluorouracil (5-FU) and its oral prodrug capecitabine have been rarely but consistently associated with acute central nervous system toxicity, including transient leukoencephalopathies involving the splenium of the corpus callosum. METHODS: We performed a retrospective search in the French Pharmacovigilance database (FPDB) (January 1985-July 2020) for adult patients affected by solid cancers who developed acute toxic leukoencephalopathies with splenial lesions following treatment with 5-FU or capecitabine. A comprehensive review of the literature helped to circumstantiate our findings. RESULTS: Our research in the FPDB identified six patients who, within 3 days from their first cycle of 5-FU or capecitabine, developed acute neurological symptoms, including gait ataxia (n = 4), dysarthria (n = 3), dysmetria (n = 2), headache (n = 2), and confusion (n = 2). Brain magnetic resonance imaging (MRI) showed T2/FLAIR (fluid-attenuated inversion recovery) hyperintensities in the corpus callosum, with diffusion restriction and no contrast enhancement, generally accompanied by additional alterations in the bilateral supratentorial white matter (n = 5). All patients discontinued the agent supposedly responsible for the toxicity and experienced full recovery after a median of 8.5 days from symptom onset. Control MRI showed a progressive normalization of acute MRI abnormalities. Literature review identified 26 cases with similar clinical and paraclinical characteristics. A single patient from the literature resumed 5-FU at a lower dose, with no recurrent toxicity. CONCLUSIONS: 5-FU and capecitabine might be responsible for acute leukoencephalopathies with transient splenial lesions that are generally reversible upon drug discontinuation. Resuming the agent responsible for toxicity might be feasible in selected cases, after having excluded dihydropyrimidine dehydrogenase deficiency, if expected benefits outweigh the risks.

Immediate-Type Hypersensitivity Cross-Reactions to Proton Pump Inhibitors: A Descriptive Study of Data from the French National Pharmacovigilance Database.

BACKGROUND: Proton pump inhibitors (PPIs) can trigger immediate-type hypersensitivity reactions (HSRs). Three main patterns of cross-reactivity have been identified: reactions to a single PPI, selective cross-reactions, and cross-reactions with all PPIs. Several hypotheses have been advanced, but no consensus has been reached. OBJECTIVE: We sought to identify immediate-type hypersensitivity cross-reactions to PPIs using real-world data about hypersensitivity testing from French pharmacovigilance cases. METHODS: Potentially relevant immediate-type HSRs reported from January 1985 to February 2015 were extracted from the French pharmacovigilance database using a standardized MedDRA query (SMQ). Cases describing skin tests or oral provocation tests (OPTs) performed with several PPIs that yielded at least one positive result were included. RESULTS: The SMQ extracted 2,119 cases, 38 of which were included in our study. Data collected from skin tests and OPTs indicated cross-reactions with all PPIs (n = 1), reactions to a single PPI (n = 14), or selective cross-reactions (n = 23). Esomeprazole, omeprazole, and pantoprazole concerned 78% of all selective cross-reactions. In more than half of the cases (55.3%), only 2 PPIs were tested. CONCLUSION: To the best of our knowledge, this PPI cross-reactivity study is the largest to date in terms of population size, describing 38 immediate-type HSRs to PPIs explored by skin tests or OPTs. This paucity of data belies the lack of standardized procedures for PPI hypersensitivity testing. It is likely that PPI HSR workups in everyday clinical practice are often incomplete. Further research to gain insight into selective cross-reactions between PPIs is needed. In the meantime, thorough workups should be completed when a PPI is suspected to have triggered an HSR, instead of routine contraindication to all PPIs.

Pleural adverse drugs reactions and protein kinase inhibitors: Identification of suspicious targets by disproportionality analysis from VigiBase.

AIMS: To evaluate the risk of pleural disorders (PD) associated with 33 protein kinase (PK) inhibitors (PKIs) through a disproportionality analysis and to identify which PKs and pathways are involved in PKI-induced PD. METHODS: To evaluate the risk of PD, reporting odds ratios (RORs) were calculated for 33 PKIs through data registered in the World Health Organization safety report database (VigiBase). We undertook a literature review to identify PKs that were possibly involved in PD caused by PKIs. Pearson correlation coefficients (r) between RORs and affinity data of 19 PKIs were calculated to identify the cellular target most likely to be involved in PKI-induced PD. RESULTS: A total of 235 110 individual case safety reports were extracted from the database for 33 available PKIs. Among these reports, 5001 concerned PD (2.1%). Significant and positive disproportionality for PD was found for 29 of 33 PKI included in our study with top values for dasatinib [ROR = 115.3; 95% confidence interval (CI): 110.1-120.8], bosutinib (ROR = 20.4; 95% CI: 15.8-26.4) and ponatinib (ROR = 12; 95% CI: 9.2-15.6). Correlation analyses between the product of dissociation constant and ROR highlighted possibly Lyn involvement in PD with PKI (r = 0.73, P = 0.0004). CONCLUSIONS: Our study showed that 28 of the 33 tested PKIs were associated with PD. Besides, the study highlighted the role of Lyn in PD caused by PKIs through an immune-mediated process.

Adverse Drug Reactions in Pediatric Emergency Medicine.

BACKGROUND: The pediatric population displays its own pharmacological characteristics, making children vulnerable to adverse drug reactions (ADRs). OBJECTIVE: To determine the incidence of ADRs among the pediatric emergency department (PED) population. METHODS: This is a descriptive, noncontrolled, prospective, and single-center study, during 4 consecutive months in the PED of Nantes University Hospital. RESULTS: Setting up active gathering of data on ADRs enabled 121 reports of 11 095 consultations at the emergency department, which corresponds to an ADR incidence of 1.09%. Digestive and cutaneous reactions made up the majority of reactions judged as being nonserious (53%) and were mainly found in children between 2 -11 years old. Of the serious ADRs, 25% were found in the 12-15-year-old age range because of the drug overdose. The main medications administered, which were responsible for the majority of the ADRs, were an equimolar mix of oxygen and nitrogen monoxide, amoxicillin, and acetaminophen. Three means of collecting data were possible: collecting files data, oral communication, or filling a form, the last being the most used method. CONCLUSIONS: This active data gathering shows the incidence and nature of the adverse effects as well as the age distribution in the PED population. It highlights the considerable misuse of medications among young teenagers and the high incidence of overmedication in the younger age group. This work also revealed the need for a better reporting system. Future joint studies should be carried out between clinical and pharmacological departments to optimize communication and the correct use of medications in children.

Pharmacology and pharmacovigilance of protein kinase inhibitors.

Protein kinase inhibitors experienced their advent in the 2000s. Their market introduction made it possible to constitute a class of targeted therapies administered orally. This name was chosen to mark a break with conventional chemotherapy drugs, but it is important to stress that these are multi-target drugs with complex affinity profiles. Adverse effects can be explained by direct interactions with their targets of interest, chosen for their indications (on-target) but also interactions with other targets (off-target). The adverse effect profiles of these drugs are therefore varied and it is possible to identify common profiles related to inhibitions of common targets. Identification of these targets has improved the global understanding of the pathophysiological mechanisms underlying the onset of adverse drug reactions as well as of the related diseases, and makes it possible to predict the adverse effect profile of new protein kinase inhibitors based on their affinities. In this review, we describe the main adverse drug reactions associated with protein kinase inhibitors, their frequency and their plausible mechanisms of action.

Severe poisoning with naproxen causing coagulopathy.

Non-steroidal anti-inflammatory drugs (NSAIDs) are well known for their most frequent side effects (digestive, renal and metabolic disorders) but are lesser known for other effects, such as coagulation disturbances. In this issue, we report the case of a 58-year-old woman who ingested 26 g of naproxen in a suicidal attempt and developed cardiovascular shock, hypocoagulability and thrombopenia. Her outcome was positive (extubation 3 days after admission [D3], correction of haemostatic disruptions on D5 and of thrombopenia on D6). Naproxen plasma concentration was at a toxic concentration of 1320 mg/L at 6 hours after drug ingestion. Only few cases of hypocoagulopathy are reported with the NSAIDs, and this is the first case that can be attributed to naproxen. A possible explanation of this phenomenon following naproxen ingestion is an inhibition of thromboxane A2, usually attributed to NSAIDs, combined with an inhibition of activation of downstream the cascade.

Cannabis and anticancer drugs: societal usage and expected pharmacological interactions - a review.

Cannabis is a plant that has been used for centuries to relieve a wide range of symptoms. Since the 1960s, interest in medical research into this plant has grown steadily. Already very popular for recreational use, a growing number of consumers not accustomed to using cannabis for psychoactive purposes have begun to use it as an alternative or complement to mainstream pharmaceutical medicines. The principal unsubstantiated or 'social' uses of cannabis are based mainly on data that is at best controversial, but usually not scientifically proven. The aim of this review was to identify the scientific basis and reasons that lead patients with cancer to consume cannabis, and also to identify whether there is a risk of interaction between cannabis and anticancer medicines through drug transporters (P-glycoprotein and other ATP-binding cassette superfamily members) Cytochromes P450 (3A, 1A, 2B, 2C, 2D families…) and glucuronyl transferases.

Renal thrombotic microangiopathy caused by interferon beta-1a treatment for multiple sclerosis.

Interferon beta-1a is available as an immunomodulating agent for relapsing forms of multiple sclerosis. Common side effects include flu-like symptoms, asthenia, anorexia, and administration site reaction. Kidney disorders are rarely reported. In this study we describe the case of a woman who has been undergoing treatment with interferon beta-1a for multiple sclerosis for 5 years. She developed a hemolytic-uremic syndrome with intravascular hemolysis in a context of severe hypertension. A kidney biopsy showed a thrombotic microangiopathy. This observation highlights an uncommon side effect of long-term interferon beta-1a therapy. Pathophysiological mechanisms leading to this complication might be explained by the antiangiogenic activity of interferon.