Abstract Aims Bruton’s tyrosine kinase inhibitors (BTKIs), including first-generation ibrutinib, second-generation acalabrutinib, and zanubrutinib may have certain mechanisms of action (MOAs) related to adverse effects (AEs) on the cardiovascular system. We aimed to evaluate the cardiac AEs of BTKIs reported to the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) and to compare the differences in cardiovascular toxicity of ibrutinib, acalabrutinib, and zanubrutinib. Methods Only primary suspect drugs from the FAERS database were extracted from January 2013 to December 2022 across all indications of FDA-approved BTKIs. Disproportionality was measured by reporting odds ratios (RORs) and information components (ICs). An additional disproportionality analysis was also performed from January 2020 to December 2022. Results A total of 10,353 cases involving ibrutinib, acalabrutinib and zanubrutinib were included. Ibrutinib was significantly associated with the incidence of cerebrovascular accidents, myocardial infarction and other thrombotic events. Acalabrutinib was associated with new signals, including cardiac failure, ventricular extrasystoles, pulmonary edema and angina pectoris, and hypertension and myocardial infarction were found in additional analyses. Furthermore, acalabrutinib was characterized by a much earlier onset of cardiovascular events. Only atrial fibrillation was associated with zanubrutinib use. Acalabrutinib and zanubrutinib had lower ROR values for cardiac AEs, and fewer signals for these two drugs compared with ibrutinib. Conclusion This study indicated that new AEs were not clearly noted on the label for acalabrutinib. It is suggested that the cardiovascular risks of BTKIs remain a concern and worth attention as next-generation BTKIs are discovered and developed.

Mitotane is the only drug approved for treating adrenocortical carcinoma (ACC) by the FDA since 1959, despite the controversy regarding its efficacy in prolonging patient survival. This drug has cytotoxic effects on tumor tissue by inducing cell death and antisecretory effects on adrenal cells by inhibiting the synthesis of adrenocortical steroids involved in the pathogenesis of ACC. To reach the therapeutic plasma concentration, high doses of mitotane are usually necessary, which may result in several adverse effects. This suggests that important pharmacological features are involved in the mechanisms of action of this drug, such as first pass metabolism, tissue accumulation, and extensive time needed for drug elimination. However, few studies have reported the pharmacological aspects of mitotane, and they did not provide sufficient evidence regarding monitoring mitotane’s therapeutic effects. Therefore, this review summarized the chemistry, pharmacokinetics and pharmacodynamics, therapeutic effects, toxic effects, and new perspectives of mitotane treatment that are currently under investigation. Understanding the pharmacological profile of mitotane can improve the monitoring and efficacy of this drug in ACC treatment and can further provide useful information for the development of new drugs with specific action against ACC with fewer adverse effects.

Objectives. The aim of this systematic review is to assess the effects of community pharmacist-led interventions to optimize the use of antibiotics and identify which interventions are most effective. Methods. This review was conducted according to the PRISMA-P guidelines (PROSPERO: CRD42020188552). PubMed, EMBASE and the Cochrane Central Register of Controlled Trials were searched for (randomised) controlled trials. Included interventions were required to target antibiotic use, be set in the community pharmacy context and be pharmacist-led. Primary outcomes were quality of antibiotic supply and adverse effects while secondary outcomes included patient reported outcomes. Risk of bias was assessed using the ‘Cochrane suggested risk of bias criteria’ and narrative synthesis of primary outcomes conducted. Results. Seventeen studies were included covering in total 3,822 patients (mean age 45.6 years, 61.9% female). Most studies used educational interventions. Three studies reported on primary outcomes, twelve on secondary outcomes and two on both. Three studies reported improvements in quality of dispensing where interventions led to more intensive symptom assessment and a reduction of OTC or wrong choice antibiotic supply. Some interventions led to higher consumer satisfaction, effects on adherence were mixed. All studies had unclear or high risks of bias across at least one domain, with large heterogeneity between studies. Conclusions. Our review suggests some possible positive results from pharmacist-led interventions, but the role of the pharmacist needs to be expanded. This review should be interpreted as exploratory research, as more high-quality research is needed. Authors did not receive funding for the review.

Introduction: Prazosin is an antihypertensive medication which can be used to help with post-traumatic stress disorder (PTSD) symptoms. Little data is currently available on its safety in pregnancy. Objective: To assess the fetal and pregnancy safety associated with Prazosin exposures in early Pregnancy. Methods: Subjects were 11 patients who took Prazosin during pregnancy and were counselled at the FRAME clinic in London Health Sciences Centre (Ontario, Canada) between January 1, 2000 to December 31, 2021. Data on their other exposures and pregnancy outcomes were collected from medical records and through telephone questionnaires. Results: It was found that 6 /11 (54.5%) subjects did not report any adverse outcomes and were uneventful pregnancies. There were 2 miscarriages. Birthweights were within the normal range for the remaining 9 pregnancies. Adverse events reported were consistent with background population expectation, including: 1 postpartum hemorrhage, 1 case of preeclampsia, 1 preterm birth, 2 NICU admissions, and 2 caesarean sections. Discussion / Conclusion: For these 11 subjects, pregnancy outcomes after exposure to Prazosin were consistent with typical outcomes from unexposed pregnancies. More data are needed to conclude that Prazosin is safe for use in pregnant subjects. However, the lack of adverse effects above baseline is reassuring to future patients who may be unintentionally exposed to Prazosin while pregnant. Therefore, this study contributes valuable data toward monitoring safety of Prazosin in Pregnancy.

Abstract Background: Propofol may result in hypotension, bradycardia, and loss of protective reflexes, especially in elderly patients, while esketamine, a N-methyl-D-aspartate receptor antagonists, has analgesic, anaesthetic and sympathomimetic properties and is known to cause less cardiorespiratory depression. We hypothesized that esketamine may reduce the median effective concentration (EC50) of propofol and cause more stable haemodynamic responses during gastrointestinal endoscopy in elderly patients. Methods: Ninety elderly patients, aged 65-89 years, undergoing gastrointestinal endoscopy were randomly assigned into three groups: SK0.25 group (0.25 mg/kg esketamine), SK0.5 group (0.5 mg/kg esketamine) and saline control group. Anaesthesia was achieved by target-controlled infusion of propofol with an initial plasma concentration of 2.5 μg/ml with different bolus doses of esketamine during gastrointestinal endoscopy. The EC50 of propofol for gastrointestinal endoscopy was determined by using an up-and-down method of Dixon with an adjacent concentration gradient at 0.5μg/mL to prohibit purposeful movements. Cardiovascular parameters were also measured and recorded. Results: Propofol EC50 and its 95% confidence interval for gastrointestinal endoscopy in elderly patients were 1.71 (1.15-2.27) μg/mL in SK0.5 group, 2.45 (1.85-3.05) μg/mL in SK0.25 group and 3.69 (2.59-4.78) μg/mL in control group respectively (P < 0.05). The average percent change to baseline mean arterial pressure (MBP) was -19.7 (7.55), -15.2 (7.14) and -10.1 (6.73) with P＜0.001, in the control group, the SK0.25 group and the SK0.5 group, respectively. Conclusions: Combination medication of propofol with esketamine reduced the propofol EC50 during gastrointestinal endoscopy in elderly patients and caused more stable haemodynamic responses compared with single administration of propofol.

Several cases of herpes zoster (HZ) following mRNA COVID-19 vaccination (BNT162b2 and mRNA-1273) have been reported, and first epidemiological evidences suggest an increased risk. We used the worldwide pharmacovigilance database VigiBase to describe HZ cases following mRNA COVID-19 vaccination. We performed disproportionality analyses (case/non-case statistical approach) to assess the relative risk of HZ reporting in mRNA COVID-19 vaccine recipients compared to influenza vaccine recipients and according to patient age. Until 30th June 2021, of 716,928 reports about mRNA COVID-19 vaccines, we found 7,728 HZ cases. When compared to influenza vaccines, mRNA COVID-19 vaccines were associated with a significantly higher reporting of HZ (reporting odds-ratio 1.9, 95%CI [1.8-2.1]). Furthermore, we found a reduced risk of reporting HZ among under 40 year-old persons compared to older persons (reporting odds-ratio 0.39, 95%CI [0.36-0.41]). For the first time, we could assess at a global level the risk of HZ after mRNA COVID-19 vaccination.

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been declared a global pandemic and urgent treatment and prevention strategies are needed. Nitazoxanide, an anthelmintic drug has been shown to exhibit in vitro activity against SARS-CoV-2. The present study used physiologically-based pharmacokinetic (PBPK) modelling to inform optimal doses of nitazoxanide capable of maintaining plasma and lung tizoxanide exposures above the reported nitazoxanide SARS-CoV-2 EC90. Methods: A whole-body PBPK model was validated against available pharmacokinetic data for healthy individuals receiving single and multiple doses between 500–4000 mg with and without food. The validated model was used to predict doses expected to maintain tizoxanide plasma and lung concentrations above the nitazoxanide EC90 in >90% of the simulated population. PopDes was used to estimate an optimal sparse sampling strategy for future clinical trials. Results: The PBPK model was successfully validated against the reported human pharmacokinetics. The model predicted optimal doses of 1200 mg QID, 1600 mg TID, 2900 mg BID in the fasted state and 700 mg QID, 900 mg TID and 1400 mg BID when given with food. For BID regimens an optimal sparse sampling strategy of 0.25, 1, 3 and 12h post dose was estimated. Conclusion: The PBPK model predicted tizoxanide concentrations within doses of nitazoxanide already given to humans previously. The reported dosing strategies provide a rational basis for design of clinical trials with nitazoxanide for the treatment or prevention of SARS-CoV-2 infection.

Reactivation of the scar resulting from intracutaneous injection of Bacillus Calmette-Guérin (BCG) is a common specific reaction in Kawasaki’s Disease. It has also sporadically been associated with viral infections, Multisystem Inflammatory Syndrome in Children, influenza vaccination and mRNA COVID-19 vaccination. Since the start of the COVID-19 vaccination campaign in January 2021, the Netherlands Pharmacovigilance Centre Lareb has received 22 case reports of BCG reactivation after vaccination with a COVID-19 vaccine. In 20 case reports it concerned mRNA COVID-19 vaccines Moderna (14) and Pfizer (6). In 2 case reports the viral vector COVID-19 vaccine AstraZeneca was administered. Erythema and pain were the most frequently reported symptoms and the size of the inflammation was between 1.5 to 5 cm. BCG reactivation occurred with a median time to onset of 2 days after the second or booster COVID-19 vaccination, whereas the median time to onset was 7 days after the first COVID-19 vaccination. None of the BCG reactivations were treated. The exact mechanism of the occurrence of this specific reaction remains unknown, however involvement of heat shock protein 65 is suggested. BCG reactivation is a non-serious, self-limiting reaction that can occur after vaccination with both mRNA and viral vector COVID-19 vaccines.

The deployment of artesunate for severe malaria and the artemisinin combination therapies (ACTs) for uncomplicated malaria has been a major advance in antimalarial therapeutics. These drugs have reduced treated mortality, accelerated recovery, and reduced treatment failure rates and transmission from the treated infection. These drugs remain highly effective against falciparum malaria in most malaria endemic areas but significant resistance has emerged in the Greater Mekong subregion of Southeast Asia. Resistance to artemisinin was followed by resistance in the ACT partner drugs, and fit multidrug resistant parasite lineages have now spread widely across the region. ACTs are highly effective against P. vivax and the other malaria species. Recent studies show that radical curative regimens of primaquine (to prevent relapse) can be shortened to seven days, and that the newly introduced single dose tafenoquine is an alternative, although the currently recommended dose is insufficient in Southeast Asia and Oceania. Targeted malaria elimination using focal mass treatments with dihydroartemisinin-piperaquine have proved safe and effective malaria elimination accelerators, but progress overall towards malaria elimination is very slow. Indeed since 2015 overall malaria case numbers globally have risen.

Globally, more than 200 million women become pregnant each year, most of whom receive medications despite limited information on their safe use during pregnancy. The paucity of drug safety data on pregnant and breastfeeding women stems from the routine exclusion of this population from clinical trials due to scientific, ethical, regulatory and legal concerns. Consequently, at the time of initial drug approval, there may be scant safety data to inform the drug benefit-risk balance to the mother, foetus, or infant. Although momentum is growing to include this underrepresented population in clinical trials, most information on drug exposure outcomes comes from data collected in the post-marketing setting. Regulatory guidance and legislation on medication use in pregnancy and breastfeeding were reviewed globally by TransCelerate IGR PV Pregnancy and Breastfeeding Team. ICH standards and CIOMS guidelines served as benchmarks for national safety regulations and guidance. The landscape assessment identified a lack of harmonisation of global regulations on research in pregnant and breastfeeding women. This editorial focuses on the ambiguities and lack of harmonisation in global regulations on post-marketing pregnancy and breastfeeding safety studies. There is currently no ICH standard to guide these types of safety studies and, in most regions reviewed, there are no clear regulations or guidance on when and how to conduct them. While a challenging undertaking, greater clarity and harmonisation would facilitate more timely completion of post-marketing pregnancy safety studies that would ultimately generate the critical data needed to optimize benefit-risk decisions for pregnant and breastfeeding women.

Aim: This systematic review aims to assess the safety profile of oxcarbazepine during pregnancy. Methods: Observational studies that included women who took oxcarbazepine anytime during pregnancy were included in our systematic review. The review did not include non-English articles, reviews, meta-analyses, case reports, and animal studies. Different online sources such as MEDLINE, Cochrane library, Virtual Health Library, etc. were searched for published and unpublished literature. Assessment of the risk of bias in observational studies was done using the Newcastle-Ottawa Scale. The meta-analyses were performed using a random-effect model. GRADE was used for the evaluation of the quality of evidence for the primary outcomes. Results: We included 19 cohort studies with a total number of 5,071,137 patients, of which 2,450 were exposed to oxcarbazepine either as monotherapy or polytherapy. The summary odds ratio (OR) was 1.69 (95% CI, 0.95-2.98) for congenital malformations following in-utero exposure to oxcarbazepine as compared to the control group of unexposed patients [seven studies (n=625)], and was 1.19 (95% CI, 0.67-2.12) when compared to those following lamotrigine (LTG) exposure during pregnancy [3 studies (n=591)]. In total, three studies (n=770) reported the association between in-utero oxcarbazepine exposure and fetal/perinatal deaths. The meta-analysis yielded a summary OR of 3.33 (95% CI, 1.70-6.51). Significance: Our systematic review will help healthcare providers and guideline developers regarding the treatment of epilepsy and other neurological disorders during pregnancy. More cohort studies with a higher sample size concerning oxcarbazepine use in pregnant patients are required to truly assess the in-utero safety profile of the drug.

Aims In light of the recent safety concerns relating to NSAID use in COVID-19, we sought to evaluate cardiovascular and respiratory complications in patients taking NSAIDs during acute lower respiratory tract infections. Methods We carried out a systematic review and meta-analysis of randomised controlled trials and observational studies. Studies of adult patients with short-term NSAID use during acute lower respiratory tract infections, including bacterial and viral infections, were included. Primary outcome was all-cause mortality. Secondary outcomes were cardiovascular, renal and respiratory complications. Results In total, eight studies including two randomised controlled trials, three retrospective and three prospective observational studies enrolling 44140 patients were included. Five of the studies were in patients with pneumonia, two in patients with Influenza, and one in patients with acute bronchitis. There was uncertainty as to the effects on mortality (RR 0.87 [0.63, 1.18]), but pleuro-pulmonary complications were more common with NSAID use (RR 2.62 [1.96, 3.50]). However, all studies exhibited high risks of bias, primarily due to lack of adjustment for confounding variables. Cardiovascular outcomes were not reported by any of the included studies. Conclusion Short-term NSAID use during acute lower respiratory tract infections was associated with more pleuro-pulmonary complications although this may be due to confounding by indication. There remains significant uncertainty on the effects on mortality. Such results should be interpreted cautiously given the very low quality of evidence. Mechanistic and clinical studies addressing the captioned subject are urgently needed, especially in relation to COVID-19.

Abstract Interleukin 6 (IL-6) is a circulating cytokine that is implicated in a range of inflammatory diseases. However, the broad effects of IL-6 receptor (IL-6R) signalling on other circulating cytokines is not known. Using summary-level data from genome-wide association studies, we leveraged genetic variants that proxy IL-6R signalling in two-sample Mendelian randomization analyses to investigate effects on levels of 40 circulating cytokines. Increased genetically proxied IL-6R signalling was associated with reduced levels of 10 circulating interleukins, chemokines, and growth factors. The findings from this study support feedback effects of IL-6R signalling on reducing levels of a range of circulating cytokines and identify compensatory mechanisms that may be modulating its inflammatory effects. These results provide novel insight into the mechanisms by which IL-6R signalling may be contributing to inflammatory and autoimmune diseases.

Abstract Aim: To compare the effectiveness and safety of two high-intensity atorvastatin doses (40mg vs. 80mg) among acute coronary syndrome (ACS) patients. Methods: This retrospective observational cohort study using real-world data included patients admitted with ACS to the Heart Hospital in Qatar between January 1, 2017 and December 31, 2018. The primary endpoint was a composite of cardiovascular disease (CVD)-associated death, non-fatal ACS, and non-fatal stroke. Cox proportional hazard regression analysis was used to determine the association between the two high-intensity atorvastatin dosing regimens and the primary outcome at 1 month and 12 months post-discharge. Results: Of the 626 patients included in the analyses, 475 (75.9%) received atorvastatin 40mg, while 151 (24.1%) received atorvastatin 80mg following ACS. Most of the patients were Asian (73%), male (97%) with a mean age of 50 years, and presented with ST-elevation myocardial infarction (60%). The incidence of the primary effectiveness outcome did not differ between the atorvastatin 40mg and 80mg groups at 1 month (0.8% vs. 1.3%; aHR= 0.59, 95% CI 0.04-8.13, p= 0.690) and at 12 months (3.2% vs. 4%; aHR= 0.57, 95% CI 0.18-1.80, p= 0.340). Similarly, the use of the two doses of atorvastatin resulted in comparable safety outcomes, including liver toxicity, myopathy, and rhabdomyolysis with an event rate of < 1% in both groups. Conclusion: The use of atorvastatin 40mg in comparison to atorvastatin 80mg in patients with ACS resulted in similar cardiovascular effectiveness and safety outcomes.

Aims In the absence of a commonly agreed dosing protocol based on pharmacokinetic considerations, the dose and treatment duration for hydroxychloroquine (HCQ) COVID-19 disease currently vary across national guidelines and clinical study protocols. We have used a model-based approach to explore the relative impact of alternative dosing regimens proposed in different dosing protocols for hydroxychloroquine in COVID-19. Methods We compared different PK exposures using Monte Carlo simulations based on a previously published population pharmacokinetic model in patients with rheumatoid arthritis, externally validated using both independent data in lupus erythematous patients and recent data in French COVID-19 patients. Clinical efficacy and safety information from COVID-19 patients treated with HCQ were used to contextualize and assess the actual clinical value of the model predictions. Results Literature and observed clinical data confirm the variability in clinical responses in COVID-19 when treated with the same fixed doses. Confounding factors were identified that should be taken into account for dose recommendation. For 80% of patients, doses higher than 800mg day on D1 followed by 600mg daily on following days might not be needed for being cured. Limited adverse drug reactions have been reported so far for this dosing regimen, most often confounded by co-medications, comorbidities or underlying COVID-19 disease effects. Conclusion Our results were clear indicating the unmet need for characterization of target PK exposures to inform HCQ dosing optimization in COVID-19. Dosing optimization for HCQ in COVID-19 is still an unmet need. Efforts in this sense are a prerequisite for best the benefit/risk balance.

RP7214 is a potent and selective inhibitor of human mitochondrial enzyme dihydroorotate dehydrogenase (DHODH). This paper describes the results from a Phase 1 study that evaluated safety and pharmacokinetics of single and multiple ascending doses (SAD and MAD) and the food effect of RP7214 in healthy subjects. Target engagement of DHODH was also evaluated. A randomized, double-blind, placebo-controlled trial of single-dose (100, 200, and 400 mg QD) and multiple doses (200 and 400 mg BID for 7 days) followed by food effect at a single dose of 200 mg was conducted. A total of 18 healthy volunteers (HVs) (6 subjects in each of three cohorts) in the SAD part, 12 (6 subjects each in two cohorts) in the MAD part, and 12 in the food effect study were enrolled. RP7214 was well tolerated at all dose levels. None of the subjects reported any RP7214-related adverse events. RP7214 showed dose-proportional pharmacokinetics after single and multiple dosing. Steady-state concentrations were reached within about 3–6 days. The mean plasma half-life of RP724 at steady-state was approximately 13h. RP7214 showed accumulation on multiple dosing.. Food did not impact the absorption of RP7214. RP7214 showed dose-dependent inhibition of DHODH as measured by analyzing accumulating DHO levels, confirming target engagement. The rapid absorption and high systemic exposure of RP724 with a favorable safety profile shows the potential for the development of RP7214 in SARS-CoV-2 infection and acute myeloid leukemia. (NCT04680429). Keywords: RP7214, dihydroorotate dehydrogenase, SAD, MAD, HV

There is a growing interest in the psychiatric properties of the dissociative anesthetic ketamine, as single doses have been shown to have fast-acting mood-enhancing and anxiolytic effects, which persist for up to a week after the main psychoactive symptoms have diminished. Therefore, ketamine poses potential beneficial effects in patients with refractory anxiety disorders, where other conventional anxiolytics have been ineffective. Ketamine is a non-competitive antagonist of the N-methyl-D-aspartate (NMDA) glutamate receptor, which underlies its induction of pain relief and anaesthesia. However, the role of NMDA receptors in anxiety reduction is still relatively unknown. To fill this paucity in the literature, this systematic review assesses the evidence that ketamine significantly reduces refractory anxiety and discusses to what extent this may be mediated by NMDA receptor antagonism. We highlight the temporary nature of the anxiolytic effects and discuss the high discrepancy among the study designs regarding many fundamental factors such as administration routes, complementary treatments, and other treatments.

Proposals for SARS-CoV-2 virus vaccination priorities in the UK and in many other countries are heavily influenced by epidemiological models, which use outcome measures such as deaths or hospitalisation. Limiting the values under consideration to those attributable to the direct effects of infection has the advantage of simplifying the models and the process of decision-making. However, the consequences of the pandemic extend beyond outcomes directly attributable to SARS-CoV-2 infection. The alternative to vaccination (in addition the threat of illness and death) is restrictions on educational and work opportunities, access to services, recreational activities, affiliations and relationships with others, freedom of movement (including escaping abusive relationships), and other determinants of human experience. Capability theory gives emphasis to the freedoms that individuals have to express themselves (in doings and beings). Restrictions on freedoms restrict our capabilities. Capability theory has been used to provide a framework for the evaluation and comparison of international development approaches and in the evaluation of public health policy. There is a clustering of disadvantages associated with this pandemic that adds to pre-existing inequalities. Much of the disadvantage engendered in the SARS-CoV-2 pandemic is left out when public health policy is based on a limited range of metrics. Acknowledging the impact of policy across the range of human freedoms at both a national and international level has the potential to improve policy, facilitate the mitigation of direct and indirect adverse consequences, and improve public confidence in vaccine deployment strategies.