Risk of acute and serious liver injury associated to nimesulide and other NSAIDs: data from drug-induced liver injury case-control study in Italy

Aim: Drug-induced liver injury is one of the most serious adverse drug reactions and the most frequent reason for restriction of indications or withdrawal of drugs. Some nonsteroidal anti-inflammatory drugs (NSAIDs) were withdrawn from the market because of serious hepatotoxicity. We estimated the risk of acute and serious liver injury associated with the use of nimesulide and other NSAIDs, with a prevalence of use greater than or equal to 5%. Methods: This is a multicentre case–control study carried out in nine Italian hospitals from October 2010 to January 2014. Cases were adults, with a diagnosis of acute liver injury. Controls presented acute clinical disorders not related to chronic conditions, not involving the liver. Adjusted odds ratio (ORs) with 95% confidence interval (CI) were calculated initially with a bivariate and then multivariate analysis. Results: We included 179 cases matched to 1770 controls. Adjusted OR for acute serious liver injury associated with all NSAIDs was 1.69, 95% CI 1.21–2.37. Thirty cases were exposed to nimesulide (adjusted OR 2.10, 95% CI 1.28–3.47); the risk increased according to the length of exposure (OR > 30 days: 12.55, 95% CI 1.73–90.88) and to higher doses (OR 10.69, 95% CI 4.02–28.44). Risk of hepatotoxicity was increased also for ibuprofen, used both at recommended dosages (OR 1.92, 95% CI 1.13–3.26) and at higher doses (OR 3.73, 95% CI 1.11–12.46) and for ketoprofen ≥ 150 mg (OR 4.65, 95% CI 1.33–10.00). Conclusion: Among all NSAIDs, nimesulide is associated with the higher risk, ibuprofen and high doses of ketoprofen are also associated with a modestly increased risk of hepatotoxicity

Safety of COVID-19 vaccines in pregnancy: a VAERS based analysis

Purpose: Since vaccination against COVID-19 is recommended in pregnant people, we aimed to provide further evidence on the safety profile of COVID-19 vaccines in pregnancy. Methods: Data on COVID-19 vaccines adverse events following immunizations (AEFIs) in pregnant people were retrieved from the open-access Vaccine Adverse Event Reporting System (VAERS) from December 2020 to April 2022. Results: From December 2020 to April 1, 2022, a total of 4,869 reports involving pregnant women at COVID-19 vaccination were reported to VAERS. Among vaccines recipients, most belonged to the age group between 30 and 39 years old (3,029; 62.21%) and nearly half experienced an adverse event within 48 h of immunization (2,344; 48.14%). Overall, 21,816 suspected adverse reactions associated with COVID-19 vaccines were reported, and for as many as 80.43% of patients, they were described as non-serious. Most reactions occurred after administration of the mRNA-1273 (53.34%) and the BNT162b2 (40.68%) vaccines, while only a small proportion were related to the Johnson & Johnson’s vaccine (5.69%). The most common non-pregnancy specific adverse events were headache (482; 2.21%), fatigue (472; 2.16%), and pyrexia (436; 2.00%), while adverse pregnancy outcomes with the highest reporting rate were abortions spontaneous (762; 3.49%), and vaginal haemorrhage (229; 1.05%). Conclusion: This post-marketing survey on VAERS data have provided updated evidence on the safety of COVID-19 vaccines during pregnancy, thus supporting clinicians in recommending maternal immunization

Safety Profile of Molnupiravir in the Treatment of COVID-19: A Descriptive Study Based on FAERS Data

Concerns have been raised about the actual benefit and safety of molnupiravir, a new antiviral treatment for coronavirus disease 2019 (COVID-19). In order to provide additional evidence to support its use, we aimed to evaluate the real safety profile based on post-marketing pharmacovigilance data. Molnupiravir safety data were captured from the FDA Adverse Event Reporting System (FAERS). We performed a descriptive analysis of the baseline demographic characteristics of patients who experienced at least one adverse drug reaction (ADRs) related to molnupiravir, and then evaluated those most frequently reported. As of 31 March 2022, 612 reports of ADRs related to molnupiravir were submitted to the FDA, 301 (49.18%) were related to females and 281 (45.92%) to males. Most reports (524; 85.62%) were submitted by healthcare professionals and 345 (56.37%) concerned serious outcomes. The most common reported ADRs were diarrhoea (57; 4.51%), rash (36; 2.85), nausea (29; 2.30%), and COVID-19 pneumonia (22; 1.74%). The most frequent adverse reactions reported with molnupiravir in the U.S. post-marketing experience are consistent with the safety evaluation of the antiviral medicine. Even if no evident safety concerns emerged, an unexpectedly high rate of serious adverse reactions together with a few cases of potential new adverse reactions occurred

Drug-induced disseminated intravascular coagulation: a pharmacovigilance study on World Health Organization’s database

Background: Disseminated intravascular coagulation (DIC) occurs in several clinical conditions, including drug therapy. We aim to investigate the association between the administration of several drug classes and the onset of DIC by using the reports of Adverse Drug Reactions (ADR) collected in Vigibase, the World Health Organization (WHO) database of ADR. Methods: We collected reports of drug-related DIC from 1968 to September 2015, classified in Vigibase according to the MedDRA (Medical Dictionary for Regulatory Activities) term “Disseminated intravascular coagulation”. A disproportionality analysis using Reporting Odds Ratio (ROR) with 95% Confidence Interval (CI95%) was performed. Results: Overall, 4653 reports of drug-associated DIC were retrieved and the 75.9% of them was serious according to WHO seriousness criteria. DIC was significantly (ROR > 1, lower limit of CI95% > 1) associated with 88 drugs, mainly antineoplastic agents, antithrombotic agents and antibacterials for systemic use. Among of the most frequently reported individual drugs we found dabigatran (94 reports) ROR = 1.34 (CI95% 1.08–1.67), oxaliplatin and bevacizumab both with 75 reports and ROR = 1.77 (1.38–2.27) and 2.02 (1.57–2.61), respectively. Conclusion: A substantial number of drugs, widely used in the clinical practice, may be associated with the potential occurrence of DIC. For many of these drugs, the ADR is not acknowledged in the corresponding Summary of Product Characteristics. The high number of drugs involved underlines the importance of evaluate this condition such as an ADR that might occur during drug therapy

Safety profile of paediatric COVID-19 vaccines: An analysis of the US Vaccine Adverse Event Reporting System

Aim: To provide further evidence on the safety profile of COVID-19 vaccines in paediatrics by analysing the spontaneous reports of adverse effects related to these vaccines.Methods: Reports related to US paediatric population (from 0 to 17 years) vaccinated with authorised COVID-19 vaccines were extracted from Vaccine Adverse Event Reporting System from December 2020 to 17 November 2022. We conducted a descriptive analysis of Adverse Events Following Immunization (AEFI), calculating reporting rate of serious AEFIs and focusing on myocarditis and Guillain-Barre Syndrome after mRNA COVID-19 vaccines.Results: Overall, 52 720 reports were retrieved: 77% (40541)-Pfizer-BioNTech, 19% (10083)-Moderna, a small proportion for other vaccines 4% (2096). Most of AEFIs were non-serious and listed in corresponding SPCs. Of serious AEFIs, 96% were related to the Pfizer-BioNTech vaccine. Roughly 91% (47874) were related to people from 6 to 17 years, a small percentage of 9% (4773) to the younger group (0-5 years). In both groups, most of the reports were related to mRNA vaccines and the percentage of AEFIs experienced by females were similar to males.Conclusions: Data showed that events most frequently reported were non-serious and listed in the corresponding SPCs, extending the evidence of safety of COVID-19 vaccines authorised in the United States in children

Hormonal Signal Amplification Mediates Environmental Conditions during Development and Controls an Irreversible Commitment to Adulthood

Many animals can choose between different developmental fates to maximize fitness. Despite the complexity of environmental cues and life history, different developmental fates are executed in a robust fashion. The nematode Caenorhabditis elegans serves as a powerful model to examine this phenomenon because it can adopt one of two developmental fates (adulthood or diapause) depending on environmental conditions. The steroid hormone dafachronic acid (DA) directs development to adulthood by regulating the transcriptional activity of the nuclear hormone receptor DAF-12. The known role of DA suggests that it may be the molecular mediator of environmental condition effects on the developmental fate decision, although the mechanism is yet unknown. We used a combination of physiological and molecular biology techniques to demonstrate that commitment to reproductive adult development occurs when DA levels, produced in the neuroendocrine XXX cells, exceed a threshold. Furthermore, imaging and cell ablation experiments demonstrate that the XXX cells act as a source of DA, which, upon commitment to adult development, is amplified and propagated in the epidermis in a DAF-12 dependent manner. This positive feedback loop increases DA levels and drives adult programs in the gonad and epidermis, thus conferring the irreversibility of the decision. We show that the positive feedback loop canalizes development by ensuring that sufficient amounts of DA are dispersed throughout the body and serves as a robust fate-locking mechanism to enforce an organism-wide binary decision, despite noisy and complex environmental cues. These mechanisms are not only relevant to C. elegans but may be extended to other hormonal-based decision-making mechanisms in insects and mammals

Level of therapeutic innovation from the registration studies of the new drugs for the prophylaxis of migraine

What is known and objective: Migraine is one of the most prevalent and disabling medical illnesses. Preventive drugs are used to reduce the frequency, severity, and duration of attacks. Most patients were no longer on their medication due to contraindications or poor clinical response. Therefore, there is need for novel prophylactic agents for migraine. New preventive treatments are those of the class of calcitonin gene related peptide (CGRP)-targeting therapies. We aimed to assess the real level of therapeutic innovation of these new drugs. Methods: The information on the new drugs was collected from several documents, including the European public assessment reports. The level of therapeutic innovation was assessed with the algorithm published by some of us in 2006. Results: All new approved drugs (eptinezumab, galcanezumab, fremanezumab, erenumab) are indicated for the prophylaxis of migraine in adults who have at least four migraine days for month. All these drugs have been tested only in comparison to placebo. Their level of therapeutic innovation was only modest, that is, the lowest value of our algorithm. Discussion: The new monoclonal antibodies of the class of CGRP targeting therapies have been authorized with efficacy data only against placebo. They do not offer additional clinical benefits compared to available therapies for the prevention of migraine attacks, with the exception of a lower frequency of administration and a more rapid effect. All this assigns to these drugs only a modest role in therapy according to our algorithm for therapeutic innovation with a significantly higher cost than similar therapies

Evaluation of the safety profile of rotavirus vaccines: a pharmacovigilance analysis on American and European data

Rotaviruses (RVs) are the most common cause of severe diarrheal disease. To date two rotavirus oral vaccines are licensed: Rotarix and Rotateq. Our aim was to contribute to the post-marketing evaluation of these vaccines safety profile. We collected all RV vaccines-related reports of Adverse Events Following Immunization (AEFI) in US Vaccine Adverse Events Reporting System (VAERS) and VigiBase between January 2007 and December 2017. A disproportionality analysis using Reporting Odds Ratio (ROR) was performed. A total of 17,750 reports in VAERS and 6,358 in VigiBase were retrieved. In VAERS, 86.2% of the reports concerned RotaTeq, whereas in VigiBase 67.7% of them involved Rotarix. Across the databases, diarrhea (1,672 events in VAERS, 1,961 in VigiBase) and vomiting (1,746 in VAERS, 1,508 in VigiBase) were the most reported AEFIs. Noteworthy, the RV vaccines-intussusception pair showed a ROR greater than 20 in both databases. Some new potential safety signals emerged such as fontanelle bulging, hypotonic-hyporesponsive episode, livedo reticularis, and opisthotonus. Overall, our data show that most of the reported AEFIs are listed in the Summary of Product Characteristics (SPCs). However, there remains the need to investigate the potential safety signals arose from this analysis, in order to complete the description of the AEFIs

Real-life safety profile of mRNA vaccines for COVID-19: An analysis of VAERS database

Introduction: Since the first COVID-19 messenger RNA vaccines became available globally for emergency or conditional use, post-marketing surveillance activities have been implemented for the monitoring of any adverse events that might arise in daily clinical practice and were not detected earlier during clinical trials. Methods: Safety data concerning the BNT162b2 and the mRNA-1273 COVID-19 vaccines were collected from the Vaccine Adverse Event Reporting System (VAERS) for the period from December 2020 to October 15, 2021. In addition to a descriptive analysis of individuals who experienced an adverse event after vaccination, a case-non-case analysis was performed by using the Reporting Odds Ratio with 95 % confidence interval as statistical parameter for detecting differences in reporting rates between the two mRNA vaccines. Results: At the cut-off date, a total of 758,040 reports were submitted to VAERS, of which 439,401 were related to the Pfizer-BioNTech (BNT162b2) vaccine and 318,639 to the Moderna vaccine (mRNA-1273). Most common adverse events following immunization for both mRNA vaccines were headache, fatigue, pyrexia, dizziness, nausea, pain, chills, and pain in extremity. A disproportionality was found for BNT162b2 as compared with mRNA-1273 for some events of special interest, such as myocarditis [ROR 2.00; 95 % confidence interval (CI), 1.93–2.06], Bell's palsy (1.34; 1.29–1.39), and anaphylactic shock (3.23; 2.96–3.53). Conclusion: Even if some rare adverse events were identified, our survey of post-marketing surveillance has provided further evidence of the favourable safety profile of mRNA vaccines

Assessing the Association of Pioglitazone Use and Bladder Cancer Through Drug Adverse Event Reporting

OBJECTIVE\u2014To analyze the association between pioglitazone use and bladder cancer through a spontaneous adverse event reporting system for medications. RESEARCH DESIGN AND METHODS\u2014Case/noncase bladder cancer reports associated with antidiabetic drug use were retrieved from the U.S. Food and Drug Administration (FDA) Adverse Event Reporting System (AERS) between 2004 and 2009 and analyzed by the reporting odds ratio (ROR). RESULTS\u2014Ninety-three reports of bladder cancer were retrieved, corresponding to 138 drug reaction pairs (pioglitazone, 31; insulin, 29; metformin, 25; glimepiride, 13; exenatide, 8; others, 22). RORwas indicative of a definite risk for pioglitazone (4.30 [95%CI 2.82\u20136.52]), and a much weaker risk for gliclazide and acarbose, with very few cases being treated with these two drugs (6 and 4, respectively). CONCLUSIONS\u2014In agreement with preclinical and clinical studies, AERS analysis is consistent with an association between pioglitazone and bladder cancer. This issue needs constant epidemiologic surveillance and urgent definition by more specific studies