Since December 2019 SARS‐Cov‐2 was found responsible for the disease COVID‐19, which has spread worldwide. No specific therapies/vaccines are yet available for the treatment of COVID‐19. Drug ...repositioning may offer a strategy and a number of drugs have been repurposed, including lopinavir/ritonavir, remdesivir, favipiravir and tocilizumab. This paper describes the main pharmacological properties of such drugs administered to patients with COVID‐19, focusing on their antiviral, immune‐modulatory and/or anti‐inflammatory actions. Where available, data from clinical trials involving patients with COVID‐19 are reported. Preliminary clinical trials seem to support their benefit. However, such drugs in COVID‐19 patients have peculiar safety profiles. Thus, adequate clinical trials are necessary for these compounds. Nevertheless, while waiting for effective preventive measures i.e. vaccines, many clinical trials on drugs belonging to different therapeutic classes are currently underway. Their results will help us in defining the best way to treat COVID‐19 and reducing its symptoms and complications.
Linked Articles
This article is part of a themed issue on The Pharmacology of COVID‐19. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.21/issuetoc
Introduction
Although the European Medicines Agency (EMA) encourage coronavirus disease 2019 (COVID-19) vaccination in pregnant women, the scientific evidence supporting the use of COVID-19 vaccines ...during pregnancy is still limited.
Aim
We aimed to investigate adverse events following immunization (AEFI) with COVID-19 vaccines during pregnancy.
Methods
We retrieved Individual Case Safety Reports (ICSRs) related to the use of COVID-19 vaccines during pregnancy from the EudraVigilance database for the year 2021. We analyzed AEFI related to the mother and fetus/newborn. The reporting odds ratio (ROR) was computed to compare the reporting probability of spontaneous abortion between COVID-19 vaccines.
Results
During the study period, among 1,315,315 ICSRs related to COVID-19 vaccines, we retrieved 3,252 (0.25%) reports related to the use in pregnancy. More than half (58.24%) of ICSRs were submitted by non-healthcare professionals. Although the majority (87.82%) of ICSRs concerned serious AEFI, their outcomes were mostly favorable. In this study, 85.0% of total ICSRs referred to pregnant women (n = 2,764), while 7.9% referred to fetuses/newborns (n = 258). We identified 16,569 AEFI. Moreover, 55.16% were AEFI not related to pregnancy (mostly headache, pyrexia, and fatigue), while 17.92% were pregnancy-, newborn-, or fetus-related AEFI. Among pregnancy-related AEFI, the most reported was spontaneous abortion. Messenger RNA (mRNA) vaccines had a lower reporting probability of spontaneous abortion than viral vector-based vaccines (ROR 0.80, 95% CI 0.69–0.93). Moderna and Oxford-AstraZeneca vaccines had a higher reporting probability of spontaneous abortion (ROR 1.2, 95% CI 1.05–1.38 and ROR 1.26, 95% CI 1.08–1.47, respectively), while a lower reporting probability was found for Pfizer-BioNTech vaccine compared with all other COVID-19 vaccines (ROR 0.73, 95% CI 0.64–0.84). In addition, 5.8% of ICSRs reported a fatal outcome.
Conclusions
No strong insight of unknown AEFI associated with COVID-19 vaccination in pregnant women was observed. Considering the high risk associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, our analysis suggests that the benefits of COVID-19 vaccines during pregnancy outweigh the possible risks. However, it is important to continue monitoring the safety profile of COVID-19 vaccines in this subpopulation.
Despite the available evidence showing an association between cardiac arrhythmia and Immune Checkpoint Inhibitors (ICIs), few studies have compared this risk between ICIs.
We aim to evaluate ...Individual Case Safety Reports (ICSRs) of ICIs-induced cardiac arrhythmias and compare the reporting frequency of cardiac arrhythmias among ICIs.
ICSRs were retrieved from the European Pharmacovigilance database (Eudravigilance). ICSRs were classified based on the ICI reported (pembrolizumab, nivolumab, atezolizumab, ipilimumab, durvalumab, avelumab, cemiplimab, and dostarlimab). If more than one ICI was reported, the ICSR was classified as a combination of ICIs. ICSRs of ICI-related arrhythmias were described and the reporting frequency of cardiac arrhythmias was assessed by applying the reporting odds ratio (ROR) and its 95 % confidence interval (95 %CI).
A total of 1262 ICSRs were retrieved, of which 147 (11.65 %) were related to combinations of ICIs. A total of 1426 events of cardiac arrhythmias were identified. The three most reported events were atrial fibrillation, tachycardia, and cardiac arrest. Ipilimumab was associated with a reduced reporting frequency of cardiac arrhythmias compared to all other ICIs (ROR 0.71, 95 %CI 0.55–0.92; p = 0.009). Anti-PD1 was associated with a higher reporting frequency of cardiac arrhythmias than anti-CTLA4 (ROR 1.47, 95 %CI 1.14–1.90; p = 0.003).
This study is the first comparing ICIs for the risk of cardiac arrhythmias. We found that ipilimumab was the only ICI associated with a reduced reporting frequency. Further high-quality studies are needed to confirm our results.
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•Most events of cardiac arrhythmias were severe and fatal.•Ipilimumab had a lower reporting frequency of arrhythmia than all other ICIs.•ICIs may share different pharmacological feature in terms of cardiac arrhythmias•The CTLA4 pathway may be less critical in the heart.
Capillary leak syndrome (CLS) emerged as new adverse event after immunization (AEFI) associated to COVID-19 vaccination. CLS is a rare condition characterized by increased capillary permeability, ...resulting in hypoalbuminemia, hypotension, and edema mainly in the upper and lower limbs. Our pharmacovigilance study aims to evaluate the CLS onset following receipt of COVID-19 mRNA vaccines (mRNA-1273 and BNT162b2) compared to viral vector vaccines (Ad26.COV2-S and ChAdOx1-SARS-COV-2). We carried a cross-sectional study using all Individual Case Safety Reports (ICSRs) reporting a COVID-19 vaccine as suspected drug and CLS as AEFI, which were collected in the pharmacovigilance database EudraVigilance from January 1st, 2021, to January 14th, 2022. We applied the Reporting Odds Ratio (ROR) 95% CI for the disproportionality analysis. During our study period, CLS was described as AEFI in 84 out of 1,357,962 ICRs reporting a vaccine COVID-19 as suspected drug and collected in the EV database. Overall, the ICSR reported by CLS were mainly related to the viral vector COVID-19(ChAdOx1-SARS-COV-2 = 36; Ad26.COV2-S = 9). The mRNA COVID-19 vaccines were reported in 39 ICSRs (BNT162b2 =33; mRNA-1273 =6). Majority of ICSRs were reported by healthcare professionals (71.4%). Majority of the patients were adult (58.3%) and the female gender accounted in more than 65% of ICSRs referred both to classes vaccines. In particular, women were more represented in ICSRs referred to mRNA-1273 (83.3%) and to ChAdOx1-SARS-COV-2 (72.2%). The CLS outcome was more frequently favorable in mRNA ICSRs (33,3%) than the viral vector ones (13.3%). Among the ICSRs reporting CLS with unfavorable outcome, we found also 9 fatal cases (BNT162b2 = 1; ChAdOx1-SARS-COV-2 = 4; Ad26.COV2-S = 4). From disproportionality analysis emerged a lower CLS reporting probability after vaccination with mRNA vaccines compared to viral vector-based ones (ROR 0.5, 95% CI 0.3–0.7; p <0.001).Our findings, even if subject to the limitations of spontaneous reporting systems, suggest a small but statistically significant safety concern for CLS following receipt of COVID-19 viral vector vaccines, in particular with Ad26.COV2-S. Cytokine-release following T-cell activation could be involved in CLS occurrence, but a precise mechanism has been not yet identified. COVID-19 vaccines remain attentive as possible triggers of CLS.
The use of quinolones has been associated with the development of serious and persistent adverse drug reaction (ADR) mainly affecting muscles, joints and the nervous system. This risk has led the ...European Medicines Agency (EMA) to endorse some restrictions on the use of this class of antibiotic. Therefore, we performed a study to primary estimate the reporting probability of musculoskeletal, neurological, and psychiatric ADRs among quinolone generations using national data.
We retrieved Individual Case Safety Reports (ICSRs) with a quinolone as suspected drug among those reported through the Campania spontaneous reporting system from January 1
, 2001 to April 30
2019. Moreover, we retrieved national aggregated safety data from the online public report system (RAM system) for the period from January 1
, 2002 to March 31
, 2019. Risk factors were classified as "age greater than 60 years," "therapeutic indication," "renal failure," "organ transplantation," "use of corticosteroid," and "history of side effects". Reporting odds ratio (ROR) was computed to evaluate the reporting probability of musculoskeletal, neurological, or psychiatric events among quinolones generations.
A total of 87 ICSRs with a quinolone as suspected drug that reported at least one musculoskeletal, neurological, and psychiatric adverse event were identified in the Campania spontaneous reporting system. Forty-nine (56.3%) ICSRs reported risk factors (total risk factors 59). The most reported risk factor was "age greater than 60 years" (69.5%), followed by "therapeutic indication" (16.9%), "renal failure" (5.1%), "organ transplantation" (3.4%), "use of corticosteroid" (3.4%), and "history of side effects" (1.7%). Second-generation quinolones were associated with a lower reporting probability of musculoskeletal (ROR 0.70; 95% CI 0.63-0.79), neurological (ROR 0.81; 95% CI 0.73-0.90), and psychiatric (ROR 0.55; 95% CI 0.44-0.63) ADRs compared to the third generation of quinolones.
Our findings showed that third-generation quinolones were always associated with a higher reporting probability of musculoskeletal, neurological, and psychiatric ADRs compared to the second generation ones. Moreover, we described risk factors in more than half of our cases suggesting that the inappropriate use of quinolones is a phenomenon that may frequently predispose patients to the occurrence of these ADRs.
Atherosclerosis is a progressive inflammatory disease leading to mortality and morbidity in the civilized world. Atherosclerosis manifests as an accumulation of plaques in the intimal layer of the ...arterial wall that, by its subsequent erosion or rupture, triggers cardiovascular diseases. Diabetes mellitus is a well-known risk factor for atherosclerosis. Indeed, Type 2 diabetes mellitus patients have an increased risk of atherosclerosis and its associated-cardiovascular complications than non-diabetic patients. Sodium-glucose co-transport 2 inhibitors (SGLT2i), a novel anti-diabetic drugs, have a surprising advantage in cardiovascular effects, such as reducing cardiovascular death in a patient with or without diabetes. Numerous studies have shown that atherosclerosis is due to a significant inflammatory burden and that SGLT2i may play a role in inflammation. In fact, several experiment results have demonstrated that SGLT2i, with suppression of inflammatory mechanism, slows the progression of atherosclerosis. Therefore, SGLT2i may have a double benefit in terms of glycemic control and control of the atherosclerotic process at a myocardial and vascular level. This review elaborates on the anti-inflammatory effects of sodium-glucose co-transporter 2 inhibitors on atherosclerosis.
A potential risk of suicide associated with liraglutide or semaglutide treatments has recently emerged. Therefore, we decided to investigate the reporting probability of suicidal events among ...glucagon-like peptide-1 receptor agonists (GLP-1 RAs).
A retrospective pharmacovigilance study of the European Pharmacovigilance database was conducted for the period from 1 January 2018 to 10 July 2023. Disproportionality analyses (reporting odds ratio, ROR) were performed to assess the reporting probability of suicidal events among GLP-1 RAs.
A total of 230 reports of suicidal events were identified. The most reported GLP-1 RA was liraglutide (38.3%), followed by semaglutide (36.5%) and dulaglutide (16.1%). The most reported events were suicidal ideation (65.3%) and suicide attempt (19.5%). Disproportionality analysis found a higher reporting probability of suicidal events for semaglutide than dulaglutide (ROR, 2.05; 95%CI, 1.40-3.01) and exenatide (ROR, 1.81; 95%CI, 1.08-3.05). In the same way, liraglutide was associated with a higher reporting probability of suicidal events than dulaglutide (ROR, 3.98; 95%CI, 2.73-5.82) and exenatide (ROR, 3.52; 95%CI, 2.10-5.92). On the contrary, a lower reporting probability was found for semaglutide than liraglutide (ROR, 0.51; 95%CI, 0.38-0.69).
Suicidal events were mostly reported with semaglutide and liraglutide, which were also associated with significantly higher reporting probabilities compared to other GLP1 RAs. Although this study provides the reporting frequencies of suicide-related events with GLP-1 RAs, establishing causality requires further investigation, which will probably be addressed by the Pharmacovigilance Risk Assessment Committee of the European Medicine Agency in the future.
Introduction:
Ibrutinib, a Bruton’s tyrosine kinase (BTK) inhibitor, is authorized for the treatment of chronic lymphocytic leukemia (CLL). This study aims to explore the cardiac safety profile of ...ibrutinib in comparison with obinutuzumab.
Methods:
A retrospective pharmacovigilance study was conducted on data retrieved from the European pharmacovigilance database (Eudravigilance) from 1 January 2014 to 30 September 2022. To compare the reporting frequency of cardiovascular events among ibrutinib, obinutuzumab, and the combination of both.
Results:
A total of 2 291 CV cases were retrieved, of which 1965 were related to ibrutinib, 312 to obinutuzumab, and 14 to the combination. Most cases referred to patients aged ≥65 years (
N
= 1,454; 63.47%) and male (
N
= 1,497; 65.34%). Most cases were serious (
N
= 2,131; 93.02%). The most reported events were: atrial fibrillation (
N
= 913; 31.31%) and haemorrhage (
N
= 201; 6.89%). A higher reporting frequency of CV events was found when ibrutinib was compared to obinutuzumab (ROR, 3.22; 95% CI, 2.89-3.60) or combination (ROR, 1.77; 95% CI, 1.11-2.83). A lower reporting was observed when obinutuzumab was compared to combination (ROR, 0.55; 95% CI, 0.34-0.88).
Discussion:
A higher reporting frequency of CV events in patients exposed to ibrutinib in comparison with obinutuzumab was found. Further studies are needed to better explore the safety of ibrutinib.
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