Thrombotic events are common during COVID-19 infection. Aspirin might be beneficial. Objective: Systematic review and meta-analysis of deaths in users and non-users of aspirin. Data sources: Pubmed Medline, Google scholar, Clinicaltrials.gov, Cochrane, to June 8, 2021, Study selection: Studies providing adjusted or matched evaluation of association of exposure to aspirin and death in COVID-19 patients were included. Data extraction and synthesis: Data were used as published, as Odds ratio, hazard ratio or relative risks and 95% CI from which log(OR) and SE were recalculated. These were entered in an inverse variance odds ratios random-effects model, using RevMan 5.4 (the Cochrane Collaboration). Main outcomes and measure: The prespecified outcome studied was death. Results: Nine studies (8 observational, one interventional) included 14989 patients exposed to aspirin and 15857 unexposed. Overall Odds Ratio of death in aspirin exposed patients in a random effects model was 0.63, 95% confidence interval [0.40-0.99], I2 94%. Using a fixed-effect model did not change much the result (0.76 [0.71-0.81], removing the Recovery trial (OR 0.43 [0.38-0.49], I271%, or the two largest studies (0.66 [0.47-0.93], I2 38%) reduced heterogeneity without materially altering the results. The funnel plot showed no evident publication bias Conclusion: this meta-analysis suggests that the use of aspirin may be associated with a lower risk of death in COVID-19. Considering the results of the Recovery Study, it would appear preferable to continue aspirin in patients who have a non-covid indication, but possibly useless to add it if they don’t.

Aims: To evaluate the efficacy, effectiveness, and safety of integrase inhibitors in the treatment of HIV/AIDS in patients coinfected with tuberculosis (TB). Methods: Clinical trials or observational studies were included. The searches were performed in the MEDLINE, EMBASE, LILACS, COCHRANE, Web of Science, Scopus, and CINAHL databases using the terms “HIV”, “AIDS”, “tuberculosis”, “raltegravir potassium”, “dolutegravir”, “elvitegravir”, “bictegravir”, “integrase inhibitor”, and their respective synonyms. The methodological quality of the studies was independently assessed using the Cochrane risk of bias and Newcastle Ottawa scales. Results: Reports from three randomised clinical trials and a historical cohort were included. Patients coinfected with TB and HIV/AIDS showed a good response to TB treatment, which was above 85% in all arms of the evaluated studies. As a primary outcome, the HIV viral load suppression rates at week 48 were greater than 60% in all arms. The therapies evaluated in patients coinfected with TB and HIV/AIDS were also proven to be safe. However, there was no statistically significant difference in the efficacy outcomes between the efavirenz and integrase inhibitor arms, and regarding safety outcomes, there were few events compared with the total. Furthermore, the certainty of the evidence of the outcomes assessed was low, indicating that future research is likely to have an important impact on this estimate. Conclusion: Integrase inhibitors are effective and well tolerated, being an alternative to efavirenz in clinical protocols. However, more studies with high quality evidence are needed on the use of this treatment in health systems.

Leflunomide is a prodrug for teruflunomide and used for rheumatic diseases. Teriflunomide is considered to be teratogenic and should be avoided in pregnancy. We describe a case of teriflunomide exposure up to the third trimester of pregnancy. A healthy baby was delivered, despite substantial drug exposure. Multiple washout procedures were required to reduce teriflunomide concentrations below the safe target concentration 0.02 mg/L.

Malignant hyperthermia (MH) is a rare life-threatening response that triggered by exposure to specific anesthetics commonly used during surgery interventions. Dantrolene is a well-known drug which used as first-line therapy for MH. A 14-year-old Chinese boy with a mutation in RYR1 whose muscle biopsy diagnosis was central core disease (CCD) occurred MH after cervical spine surgery underwent general anesthesia without volatile anesthetics or succinylcholine. The MH crisis treatment workflow was started and intravenous dantrolene was used soon which combined with sequent continuous veno-venous hemofiltration (CVVH) and plasma exchange (PE) therapy. We explored the pharmacokinetics of dantrolene during the treatment and the results showed that a one-compartment model with first-order absorption and elimination was sufficient to characterize dantrolene pharmacokinetics. The clearance estimate for dantrolene was 0.43 mL/(min*kg) and volume of distribution was 0.61 L/kg. The clearance of dantrolene was significantly affected by CVVH and PE.

Background: For diseases with a genetic cause genomics can deliver improved diagnostics and facilitate access to targeted treatments. Drug pharmacodynamics and pharmacokinetics are often dependent on genetic variation underlying these processes. As pharmacogenomics comes of age it may be the first way in which genomics is utilised at a population level. Still required is guidance and standards of how genomic information can be communicated within the health record, and how clinicians should be alerted to variation impacting the use of medicines. Methods: The Professional Record Standards Body commissioned by National Health Service England developed guidance on using pharmacogenomics information in clinical practice. We conducted research with those implementing pharmacogenomics in England and internationally to produce guidance and recommendations for a systems-based approach. Results: A consensus viewpoint is that systems need to be in place to ensure the safe provision of pharmacogenomics information that is curated, actionable and up-to-date. Standards should be established with respect to notification and information exchange, which could impact new or existing prescribing and these must be in keeping with routine practice. Alerting systems should contribute to safer practices. Conclusion: Ensuring pharmacogenetics information is available to make use of medicines safer will require major effort of which this guidance is a beginning. Standards are required to ensure useful genomic information within the health record can be communicated to clinicians in the right format and times to be actioned successfully. A multidisciplinary group of stakeholders must be engaged in developing pharmacogenomic standards to support the most appropriate prescribing.

As human spaceflight continues with extended mission durations, the demand of effective and safe drugs is going to increase. To date, the medications used during missions (for space motion sickness, sleep disturbances, allergies, pain and sinus congestion) are administered under the assumption that they act similarly as on the Earth. During spaceflights however fluid shifts, muscle and bone loss, immune system dysregulation and changes in the gastrointestinal tract and metabolism are documented. These alterations may change the pharmacokinetics (PK) and pharmacodynamics. The information gained from bed-rest studies and from inflight observations is partial and demonstrates variability in drug PK. The objectives of this review are to report: i) the impact of the space environmental stressors on human physiology in relation to PK; ii) the state-of-the-art on experimental data in space and/or in ground-based models; iii) the validation of ground-based models for PK studies; and iv) the identification of possible research gaps.

X-linked adrenoleukodystrophy (X-ALD) is an inherited, neurodegenerative rare disease that can result in devastating symptoms of blindness, gait disturbances, and spastic quadriparesis due to progressive demyelination. Typically, the disease progresses rapidly, causing death within the first decade of life. With limited treatments available, efforts to determine an effective therapy that can alter disease progression or mitigate symptoms have been undertaken for many years, particularly through drug repurposing. Repurposing has generally been guided through clinical experience and small trials. At this time, none of the drug candidates have been approved for use, which may be due, in part, to the lack of pharmacokinetic/pharmacodynamic (PK/PD) information on the repurposed medications in the target patient population. Greater consideration for the disease pathophysiology, drug pharmacology, and potential drug-target interactions, specifically at the site of action, would improve drug repurposing and facilitate development. Although there is a good understanding of X-ALD pathophysiology, the absence of information on drug targets, pharmacokinetics, and pharmacodynamics hinders the repurposing of drugs for this condition. Incorporating advanced translational and clinical pharmacological approaches in preclinical studies and early stages clinical trials will improve the success of repurposed drugs for X-ALD as well as other rare diseases.

Aims: Baclofen is widely used for spastic disorders, and most recently for addictive disorders. The first signals of baclofen abuse occurred in the last decade. This study aims to assess the motives, diversion sources and routes of administration associated with the non-medical use of baclofen and examine health problems related to the non-medical use of baclofen. Methods: Spontaneous reports of baclofen abuse reported to the addictovigilance center of East France were analyzed. A literature search was simultaneously conducted using PubMed®, Web of Sciences®, and Google Scholar® databases. Both searches were performed in February 2021 without a time limit. Results: Forty-six cases were analysed (33-from the literature review and 13-from addictovigilance base). Baclofen’s non-medical use mainly affected male subjects with addictive history, but cases of primary abuse in subjects without any substance abuse history were also observed. Euphoria search was the most common reason for misuse. Route of administration included oral, snorting and sublingual use. Physicians were a common source for misused baclofen, but cases involving illegal sources were also observed. Most of the patients misusing baclofen presented serious complications, mainly represented by neurological and respiratory disturbances. Physical and psychological dependence to baclofen was observed in three persons. Conclusion: Although baclofen abuse remains relatively infrequent or (most likely) underestimated, this study helped to confirm the intrinsic abuse potential of baclofen and make visible the baclofen-abuse-related health harms. Careful consideration and benefit-risk analysis should be employed when prescribing baclofen, and emergency departments should be aware of baclofen dangers in abuse situations.

Introduction: Free-of-charge (FoC) medicine schemes are increasingly available and allow access to investigational treatments outside clinical trials or in advance of licensing or NHS commissioning. Methods: We retrospectively reviewed FoC medicine schemes evaluated between 2013 and 2019 by a single NHS trust and a regional drug and therapeutics committee (DTC). The details of each locally reviewed FoC scheme, and any nationally available MHRA Early Access to Medicines Scheme (MHRA EAMS) in the same period, were recorded and categorised. Results: Most FoC schemes (95%) allowed access to medicines intended to address an unmet clinical need. Over 7 years, 90% were company-FoC schemes and 10% were MHRA EAMS that were locally reviewed. Phase 3 clinical trial data were available for 44% of FoC schemes; 37% had phase 2 data; and 19% were supported only by phase 1, retrospective observational studies, or pre-clinical data. Utilisation of company-FoC schemes increased on average by 50% per year, while MHRA EAMS showed little growth. Conclusion: Company-FoC medicine schemes are increasingly common. This may indicate a preference for pharmaceutical companies to independently co-ordinate schemes. Motivations for company-FoC schemes remain unclear and many provide access to treatments that are yet to be evaluated in appropriately conducted clinical trials, and whose efficacy and risk of harm remain uncertain. There is no standardisation of this practice and there is no regulatory oversight. Moreover, no standardised data collection framework is in place that could demonstrate the utility of such programmes in addressing unmet clinical need or allow generation of further evidence.

Brigatinib was recently approved for the treatment of anaplastic lymphoma kinase-positive non-small cell lung cancer and is dosed according to a one-dose-fits-all paradigm. We aimed to identify a pharmacokinetically-guided precision dosing strategy to improve treatment response with brigatinib through simulations using a previously published pharmacokinetic-pharmacodynamic model. Dosing strategies explored were the approved 180mg QD, the highest tolerable dose tested in clinical trials: 240mg QD, and two precision dosing strategies targeting the median trough concentrations following 180mg QD, and 240mg QD. We investigated the impact of alternative dosing regimens on progression-free survival (PFS), overall survival (OS), and the probability of developing a grade ≥2 rash or grade ≥2 amylase increase. Median PFS and OS increased by 1.6 and 7.8 months, respectively between the currently approved dosing strategy and precision dosing to the median trough concentration of the 240mg dosing strategy, with only a minor increase in the probability of developing toxicity.

Aims: To assess the impact of cytochrome P450 (CYP) 2C19 polymorphisms on the clinical efficacy and safety of voriconazole. Methods: We systematically searched PubMed, EMBASE, CENTRAL, ClinicalTrials.gov, and three Chinese databases from their inception to March 18, 2021 using a predefined search algorithm to identify relevant studies. Studies that reported voriconazole-treated patients and information on CYP2C19 polymorphisms were included. The efficacy outcome was success rate. The safety outcomes included overall adverse events, hepatotoxicity and neurotoxicity. Results: A total of 20 studies were included. Intermediate metabolizers (IMs) and Poor metabolizers (PMs) were associated with increased success rates compared with normal metabolizers (NMs) (risk ratio (RR): 1.18, 95% confidence interval (CI): 1.03~1.34, I2=0%, p=0.02; RR: 1.28, 95%CI: 1.06~1.54, I2=0%, p=0.01). PMs were at increased risk of overall adverse events in comparison with NMs and IMs (RR: 2.18, 95%CI: 1.35~3.53, I2=0%, p=0.001; RR: 1.80, 95% CI: 1.23~2.64, I2=0%, p=0.003). PMs demonstrated a trend towards an increased incidence of hepatotoxicity when compared with NMs (RR: 1.60, 95%CI: 0.94~2.74, I2=27%, p=0.08), although there was no statistically significant difference. In addition, there was no significant association between CYP2C19 polymorphisms and neurotoxicity. Conclusions: IMs and PMs were at a significant higher success rate in comparison with NMs. PMs were significantly associated with an increased incidence of all adverse events compared with NMs and IMs. Researches are expected to further confirm these findings. Additionally, the relationship between hepatotoxicity and CYP2C19 polymorphisms deservers clinical attention.

Aldosterone binds to the mineralocorticoid receptor (MR), a transcription factor of the nuclear receptor family, present in the kidney and in various other non-epithelial cells including the heart and the vasculature (Cannavo et al., 2018). Indeed, extra-renal pathophysiological effects of this hormone have been characterized, extending its actions to the cardiovascular (CV) system (Messaoudi et al., 2012). A growing body of clinical and pre-clinical evidence suggests that MR activation plays an important pathophysiological role in CV remodeling by promoting cardiac hypertrophy, fibrosis, arterial stiffness, as well as in inflammation and oxidative stress (Bauersachs et al., 2015). The following review article outlines the role of MR in CV disease with a focus on myocardial remodeling and heart failure (HF) including clinical trials as well as cellular and animal studies.

Aim To describe the antiepileptic drug (AED) prescription pattern in pregnant women and women of childbearing age in the 2010-2019 period in the Lombardy region, Italy. Methods The Lombardy region administrative healthcare databases (2010-2019) were analysed. AEDs were classified as drugs belonging to the N03A subgroup of the Anatomical Therapeutic Chemical Classification System. Women 15-49 years old were considered as women of childbearing age, while exposure during pregnancy was estimated taking into account the 12 months before delivery (International Classification of Diseases, Ninth Revision, Clinical Modification, ICD-9-CM codes in the diagnosis record from 650 to 659). Results During 2019, 16,605 women of childbearing age (prevalence: 14.8‰) received at least one AED prescription. Pregabalin was the most widely used antiepileptic in women of childbearing age (22.3%), followed by valproic acid (20.0%). The prevalence of AED prescription in pregnant women was 3.8‰, and levetiracetam and lamotrigine (16.6%) were the most commonly prescribed drugs. The prevalence of AED prescription did not change from 2010 to 2019 in women of childbearing age or in pregnant women. Valproic acid was one of the most used AEDs in pregnancy until 2016, after which its prescription declined from 19% to 14% of AED users. Conclusions Despite the decrease in valproic acid prescription over time, this drug is still among the most used AEDs, in particular in women of childbearing age. Educational interventions for healthcare professionals and women are needed in order to reduce the risk of unplanned pregnancy.

Favipiravir is one of the repurposed antiviral medications for the treatment of SARS-CoV-2 infection. Since the dosing regimen is a prominent factor for the success of the antiviral therapy, this prospective observational study aimed to characterize the pharmacokinetic characteristics of favipiravir in COVID-19 patients. Adult patients (n=21) hospitalized for mild to moderate COVID-19 with a positive RT-PCR test, and assigned for favipiravir treatment were included. Favipiravir was administered for 5 days, with a loading dose of 3200 mg and a 1200 mg/day maintenance dose. Serial blood samples were collected on Day-2 and Day-4 of the therapy. Laboratory findings of the patients and in-hospital mortality were assessed. Favipiravir concentrations exhibited high variations and a significant decrease during the treatment of COVID-19. The median favipiravir trough concentration (C0-trough) on Day-2 was 21.26 µg/mL whereas it decreased significantly to 1.61 µg/mL on Day-4, the area under the concentration versus time curve decreased from 345.6 µg.h/mL to 108.6 µg.h/mL, respectively. Gender seems significant to affect favipiravir concentrations. Day-2-C0-trough of female patients was significantly higher than male patients. Of the 5 patients that died, 4 were male with a significant increase in ferritin levels from Day-0 to Day-5 compared to surviving patients. In addition, there was a significant decrease in D-dimer and CRP levels in the surviving patients. Our findings indicate that favipiravir concentrations show significant changes during the treatment of COVID-19. Therapeutic drug monitoring may best guide dose adjustments in patients that do not respond to treatment with favipiravir.

Background and purpose: Cancer patients are always complicated with vein thromboembolism, thus the combination of anticoagulants with anti-cancer drugs has profound foundations. This study aimed to assess the safety of rivaroxaban comminating with three tyrosine kinase inhibitors (TKIs) in cancer patients. Experimental Approach: The inhibition of three TKIs on CYP2J2- and CYP3A4-mediated rivaroxaban metabolism was first screened and then reversible and mechanism-dependent inhibitory kinetic constants were determined. Molecular docking was conducted to reveal the interactions between TKIs and CYP2J2 and CYP3A4. Finally, pharmacokinetic parameters of cancer patients were used to assess the safety. Key Results: Imatinib and gefitinib significantly reversibly inhibited CYP2J2- and CYP3A4-mediated rivaroxaban metabolism, while sunitinib only showed reversible inhibition of CYP3A4, not CYP2J2. Three TKIs also showed time-dependent inactivation of CYP3A4. Notably, sunitinib had the strongest inactivation effect on CYP3A4 than the other TKIs with a 4.00-fold IC50 shift, however, a slight effect on CYP2J2. Docking simulations revealed the relation of inhibitory activity to ChemScore. Additionally, drug-drug interaction risks of combinations were assessed using pharmacokinetic data of cancer patients. Imatinib, which showed the strongest inhibition, was predicted to cause a 114–244% increase in rivaroxaban exposure. Conclusion and Implications: Imatinib was predicted to have a moderate DDI risk when was combined with rivaroxaban. These results provide evidence for medication guidance when combining rivaroxaban with TKIs for cancer patients, and also give new insight for the DDI assessment involving rivaroxaban.

Antidepressants are not safe during pregnancy and in women of child bearing age.Alain Braillon (1), Susan Bewley(2), Aubrey Blumsohn(3), Florian Naudet (4) Jean-Louis Montastruc(5), Joel R Lexchin(6)(1) Previously senior consultant, Amiens, France braillon.alain@gmail.com(2) Department of Women & Children’s Health, King’s College London, London, UK(3) Previously Senior Lecturer in Medicine, University of Sheffield, Sheffield, UK(4) University of Rennes 1, Rennes, France Clinical Investigation Center (INSERM 1414) and Adult Psychiatry Department, Rennes University Hospital, Rennes, France(5) Medical and Clinical Pharmacology, University Hospital-Faculty of Medicine, Toulouse, France(6) School of Health Policy and Management Faculty of Health, York University, Toronto, Ontario, CanadaCorrespondanceAlain Braillon, 27 rue Voiture, 80000 Amiens, France. braillon.alain@gmail.com757 w + 9 ref. (Limit 800 words + 10 references)Keywords: risk minimization measures; drug safety; serotonin reuptake inhibitors; teratogenicity; developmental disorders; post-partum hemorrhage; EBMNo fundingCoI: Alain Braillon, JL and SB are among industry independent experts on Jeanne Lenzer’s list (https://jeannelenzer.com/list-independent-experts). SB chairs Healthwatch, a charity promoting science and integrity in healthcare (https://www.healthwatch-uk.org/) and her interests are declared at https://www.whopaysthisdoctor.org/doctor/58/active. JL received payments for writing a brief in an action for side effects of a drug for Michael F. Smith, Lawyer and a second brief on the role of promotion in generating prescriptions for Goodmans LLP in 2017-2020. He is a member of the Foundation Board of Health Action International. He receives royalties from University of Toronto Press and James Lorimer & Co. Ltd. for books he has written.Cabaillot and colleagues’ pharmaco-epidemiological study of antidepressants use during pregnancy in France raises a number of questions about the validity of their conclusions.(1)Firstly, what is their basis for making the claim that “[selective serotonin-norepinephrine reuptake inhibitors] appear to be safe in pregnant women”?(1) This claim ignores significant evidence to the contrary:a) the odds ratio for maternal use of serotonin reuptake inhibitor antidepressants (SRIs) (we use SRI to refer to both serotonin-norepinephrine reuptake inhibitors and so-called ‘selective’ serotonin reuptake inhibitors as selectivity is restricted to the experimental setting) during the first trimester of pregnancy and the presence of congenital heart defects is 1.57 (95% CI 1.25–1.97) for paroxetine, 1.36 (95% CI 1.08–1.72) for fluoxetine and 1.29 (95% CI 1.14–1.45) for sertraline.(2) Further, observational studies reported developmental disorders that are in line with experimental studies and with human infant MRI studies: SRIs exposure has an association with changes in brain structure, white matter microstructure, brain connectivity, and cerebral metabolism, particularly in brain regions critical to emotional processing;(3)b) previous warnings about SRIs’ harms in core clinical journals were overlooked;(4,5)c) post-partum hemorrhage, a serious SRI complication acknowledged by Cabaillot and colleagues, is a very serious issue; with cardiovascular conditions it is the most common underlying causes of pregnancy-related death.(6)Secondly, Cabaillot et al misrepresent the references that they cite in their statement that “[selective serotonin-norepinephrine reuptake inhibitors] are recommended by the National Agency for Health and Medicines (ANSM) and the 2018 International Cochrane Review International Publications ”?(1)a) the link for the recommendation (ref. 19 in Cabaillot et al) does not work and the summary of product characteristics for fluoxetine warns “Overall, the data suggest that the risk of cardiovascular malformation in children after maternal exposure to fluoxetine is approximately 2/100 … Fluoxetine should not be used during pregnancy unless the clinical condition of the patient requires treatment with fluoxetine and justifies the potential risk to the fetus”.(7)b) the Cochrane Review (ref. 20 in Cabaillot et al) is about postnatal depression, not pregnancy. It concluded: “Due to the limitations of the current evidence base, such as the low statistical power of the included studies, it is not possible to draw any clear conclusions about the effectiveness of antidepressants for the prevention of postnatal depression.”Thirdly, Cabaillot and colleagues should provide data (malformations, deprescription) according to the various classes of antidepressants and their princeps. The risk of malformations varies among antidepressant classes and within classes, e.g., it is highest for SRIs containing paroxetine.(2)Fourthly, the widespread prescribing of antidepressants in France may be the result of France’s universal healthcare scheme consistently refusing to reimburse effective psychotherapy. In contrast is the 2008 Improving Access to Psychological Therapies strategy in England that provides free and direct access to psychotherapy without barriers.(8)Overplaying benefits and downplaying harms are not serving the patient’s interests. All prescribers must be warned that antidepressants have not been shown to be risk free during pregnancy, either for the woman or her fetus. Quantitative explanation of the degree of risk expressed in easily understood terms such as number needed to harm must be provided, not binary assertions of apparent “safety” based on a value judgment only women should make. The well documented harms of SRIs during pregnancy contrast with purported benefits _a limited effectiveness of SRIs in the general population and no controlled trials during pregnancy. Available SRI vs placebo trials are short-term (6-8 weeks) and although the decreases in depression scores are statistically significant, their clinical relevance is doubtful.(9) In contrast, many patients with depression respond to judicious ‘watchful waiting’ and psychotherapies successfully treat most episodes of even persistent depression. These interventions are evidence-based in real-life settings: their benefits persist over the long term (improving self-esteem, agency, and social functioning and, they are safe.(9) Evidence based psychosocial interventions must be the preferred initial option in treating depression, especially in women of child bearing age as many pregnancies are unintended.(4)Regulatory agencies must implement and monitor a series of risk minimization measures for SRIs as for other teratogens: a) an assessment of each woman’s potential to become pregnant; b) shared decision making about the risks of antidepressant treatment in general and specifically during pregnancy, and an explanation about the need for effective contraception throughout treatment; c) informed pregnancy testing before and during treatment as needed; d) a ‘risk acknowledgement form’, in which the woman and prescriber confirm that appropriate counselling has been given and understood. Finally, prescription of antidepressants during pregnancy should be recorded in specific registries to closely monitor clinical outcomes.References1. Cabaillot A, Bourset A, Mulliez A et al. Trajectories of antidepressant drugs during pregnancy: A cohort study from a community-based sample. Br J Clin Pharmacol. 2021;87(3):965-987.doi: 10.1111/bcp.14449.2. De Vries C, Gadzhanova S, Sykes MJ, Ward M, Roughead E. A Systematic Review and Meta-Analysis Considering the Risk for Congenital Heart Defects of Antidepressant Classes and Individual Antidepressants. Drug Saf. 2020;44(3):291-312.doi: 10.1007/s40264-020-01027-x3. Lugo-Candelas C, Cha J, Hong S, et al. Associations Between Brain Structure and Connectivity in Infants and Exposure to Selective Serotonin Reuptake Inhibitors During Pregnancy. JAMA Pediatr. 2018; 172(6):525-533. doi: 10.1001/jamapediatrics.2017.5227.4. Braillon A, Bewley S. Prescribing in pregnancy shows the weaknesses in pharmacovigilance. BMJ. 2018;361:k2334. doi: 10.1136/bmj.k2334.5. Braillon A, Bewley S. The easy misuse of antidepressants during pregnancy is depressing. Br J Clin Pharmacol. 2018;84(10):2445-2446. doi: 10.1111/bcp.13713.6. Davis NL, MPH, Smoots AN, Goodman, DA. Pregnancy-Related Deaths: Data from 14 U.S. Maternal Mortality Review Committees, 2008-2017. Maternal Mortality Review Data-Brief. 2019. Available at https://www.cdc.gov/reproductivehealth/maternal-mortality/erase-mm/MMR-Data-Brief_2019-h.pdf Accessed 27 May 2020.7. French National Agency for Health and Medicines (ANSM). Fluoxetine: Summary of Product Characteristics. 3 April 2016. Available at http://agence-prd.ansm.sante.fr/php/ecodex/rcp/R0278605.htm Accessed 27 May 2021.8. Thornicroft G. Improving access to psychological therapies in England. Lancet. 2018;391(10121):636-637. doi: 10.1016/S0140-6736(17)32158-X.9. Braillon A, Lexchin J, Noble JH, Menkes D, M’sahli L, Fierlbeck K, Blumsohn A, Naudet F. Challenging the promotion of antidepressants for nonsevere depression. Acta Psychiatr Scand. 2019;139(3):294-295. doi: 10.1111/acps.13010.

Background: 64 million pharmacy filled multicompartment medication compliance aids (MCAs) are dispensed by pharmacies in England each year as a method to improve medication adherence. Despite the widespread use of MCAs and evidence that their use may be associated with harm there is no national consensus regarding MCA provision by acute hospital Trusts in England. Aim: To determine current practice for initiation and supply of MCAs in acute hospital Trusts in England and the potential consequences for patients and hospitals. Methods: A 26 item survey was distributed to all acute hospital Trusts in England. The questionnaire covered policy, initiation, supply and review of MCAs; alternatives offered; and pharmacy staffing and capacity related to MCAs. Results: 72 out of 138 (52%) Trusts responded to the survey. 60/70 (86%) had a policy for the provision of MCAs. 33/55 (60%) that supplied MCAs on discharge supplied a different prescription length for MCA vs. non-MCA prescriptions. 49/55 (89%) Trusts provided only one brand of MCA. 47/55 (85%) MCA-supplying Trusts identified frequent difficulties with MCAs and 13/55 (24%) reported employing staff specifically to complete MCAs. 30/35 (86%) MCA-initiating Trusts had an assessment process for initiation, with care agency request as the most common reason. Conclusion: There is a lack of a national approach to MCA provision and initiation by acute hospital Trusts in England. This leads to significant variation in care and has the potential to put MCA users at an increased risk of medication related harm.

Aims: KA2237, an oral, potent and selective, inhibitor of the PI3K β and δ isoforms, was evaluated for safety, tolerability and pharmacokinetics (PK) in patients with B-cell lymphoma. KA2237 is metabolised by CYP3A4/5 but also demonstrated mechanism-based inhibition (MBI) of CYP3A4/5. An MBI mechanistic dynamic model was used to predict drug accumulation after repeat dosing of KA2237. This model, along with clinical safety data, was used to guide safe dose escalation. Methods: An open-label, single arm, dose escalation study was carried out in patients, dosed orally with KA2237 at 50, 100, 200 and 400 mg once daily. Complete plasma profiles were obtained on Day 1 and Day 14 of dosing and pre-dose (Cmin) samples were obtained on Days 2-7. The MBI model was validated and used to calculate drug levels and predict potential drug accumulation during dose escalation. Results: KA2237 elimination half-life was around 20-30 h, compatible with once daily dosing regimens. The accumulation of KA2237 was around 4-fold after the highest dose of 400 mg and around 3-fold after administration of 200 mg, which is considered the maximum tolerated dose (MTD). The MBI model accurately predicted this accumulation. Conclusions: Drugs that demonstrate MBI and potential auto-inhibition can be successfully developed, provided that models are developed to assess the extent of accumulation prior to the start of FIH clinical studies. This, along with the close monitoring of drug levels and clinical safety data can be used to guide dose escalation and lead to the safe conduct of clinical studies.

A case of acute necrotising pancreatitis following the second dose of Pfizer-BioNTech COVID-19 mRNA vaccineAs of 22 June 2021, there have been about 400,000,000 doses of the Pfizer-BioNTech COVID-19 mRNA vaccine administered world-wide. At this time, 176 cases of pancreatitis have been reported in pharmacovigilance reports submitted to the WHO.1 No epidemiological link between the Pfizer-BioNTech COVID-19 mRNA vaccine and pancreatitis has been reported. We report a case of acute necrotising pancreatitis following the second dose of the Pfizer-BioNTech COVID-19 mRNA vaccine. This case has been reported to the New Zealand Pharmacovigilance Centre and the patient has consented to publication of the case report.A 43-year-old, NZ European male was diagnosed with acute necrotising pancreatitis 10 hours following the administration of his second Pfizer-BioNTech COVID-19 mRNA vaccine. He has a background of atopy with seasonal rhinitis, eczema and asthma, all of which are ‘mild’. He takes no regular medications and takes as needed melatonin 2 mg nocte, cetirizine 10 mg for hay fever, and betamethasone and emollient cream for dermatitis. He has no family history of note and works in a senior professional role. He drinks six standard units of alcohol per week, has never been a tobacco smoker and does not use recreational drugs – and his employer undertakes regular drug testing.He had a previous episode of pancreatitis in 2011, precipitated by high alcohol intake during a holiday abroad. He is otherwise previously well. There is no family history of note, his father was a smoker and died of lung cancer in his 60s, his mother is well, he has two siblings and three children all of whom are well. He is not aware of any diseases of note in his extended family.In May 2021 he received his second dose of Pfizer-BioNTech COVID-19 mRNA vaccine, he was well at that time. Four hours after the dose he had two 330ml bottles of 5% alcohol beer with his dinner. Six hours after the dose he became unwell with nausea, epigastric pain, and vomiting. Ten hours after the dose blood tests on admission to hospital included: white cell count 18.5 x109/L (4 - 11), neutrophils 15.5 x109/L (1.9 - 7.5), lymphocytes 0.8 x109/L (1.0 - 4.0), CRP <3 mg/L (<5), lipase 23,750 U/L (10 – 70), and triglycerides 3.3 mmol/L. Acute pancreatitis was diagnosed. An ultrasound scan showed pancreatitis without evidence of cholelithiasis. He subsequently deteriorated and a computer tomography (CT) scan on 17 May, day 9 of the illness, showed severe necrotising pancreatitis with collections.During the admission under a specialist hepatobiliary surgical team, known causes of pancreatitis were excluded including: steroid use, trauma, family history of autoimmune conditions, and infection. He did not have the risk factors of obesity, smoking or heavy alcohol consumption. He had the risk factor of a previous episode of acute pancreatitis. The incidence of pancreatitis in New Zealand Europeans in this age group is approximately 50 per 100,000 per year.2 Idiopathic cases represent about 15% of these.Using the Naranjo criteria, the pancreatitis being ’caused’ by the Pfizer-BioNTech COVID-19 mRNA vaccine score was 6 ‘probable’.3 Clinical case discussion (including a hepatobiliary surgeon, gastroenterologist and clinical pharmacologist) concluded that while idiopathic pancreatitis could not be excluded, the onset of symptoms and findings were consistent with an acute precipitating event around the time the second vaccine dose was administered.In addition to the 176 cases reported in VigiBase™, searches of PubMed and Google Scholar™ identified two published case reports of pancreatitis following the Pfizer-BioNTech COVID-19 mRNA vaccine. These were following administration of the first dose of the Pfizer-BioNTech COVID-19 mRNA vaccine. In one case symptoms developed several hours after vaccine administration and the other several days after vaccine administration.4,5Acute pancreatitis is a rare in patients with COVID-19 but characteristic patterns of illness have been reported.6 This raises the possibility that an immune response to either the virus or the vaccine could have common sequalae.This case of acute pancreatitis was temporally associated with the Pfizer-BioNTech COVID-19 mRNA vaccine suggesting a causal link. The characteristics of pancreatitis cases associated with the Pfizer-BioNTech COVID-19 mRNA vaccine should be examined to see if a consistent pattern is present.VigiAccess™ http://www.vigiaccess.org/ - accessed June 24, 2021.Pendharkar SA, Mathew J, Zhao J, Windsor JA, Exeter J, Petrov MS. Ethnic and geographic variations in the incidence of pancreatitis and post- pancreatitis diabetes mellitus in New Zealand: a nationwide population- based study. 2017;130(1450):14.Naranjo CA, Busto U, Sellers EM, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther . 1981;30(2):239-245. doi:10.1038/clpt.1981.154Cieślewicz A, Dudek M, Krela-Kaźmierczak I, Jabłecka A, Lesiak M, Korzeniowska K. Pancreatic Injury after COVID-19 Vaccine—A Case Report. Vaccines . 2021;9(6):576. doi:10.3390/vaccines9060576Parkash O, Sharko A, Farooqi A, Ying GW, Sura P. Acute Pancreatitis: A Possible Side Effect of COVID-19 Vaccine. Cureus . Published online April 28, 2021. doi:10.7759/cureus.14741Bircakova B, Bruha R, Lambert L, Grusova G, Michalek P, Burgetova A. A bimodal pattern of the onset of COVID-19 related acute pancreatitis supports both the cytotoxic and immune-related pathogenesis – a systematic review. Scand J Gastroenterol . 2021;56(7):870-873. doi:10.1080/00365521.2021.1922751

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.

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.

Aim: To conduct the first systematic synthesis of existing evidence reviews on interventions to enhance medication safety in RACS, to establish and compare their effectiveness. Method: This umbrella review included examination of meta-analyses, scoping and systematic reviews. Four electronic databases (MEDLINE, EMBASE, CINAHL, and The Cochrane library database of Systematic Reviews) were explored for eligible reviews. Those meeting the inclusion criteria were critically appraised using the JBI Critical Appraisal Instrument for Systematic reviews and Research Syntheses by two authors. Results: Fourteen reviews covering 166 unique, primary studies were included. Interventions were grouped according to type: medication review (n= 12); staff education (n= 8); multidisciplinary team meetings (n= 6); computerised clinical decision support systems (n= 5); and transferring medicines information between health care settings (n= 1). Most reviews showed mixed evidence to support interventions’ effectiveness, due to the significant heterogeneity between original research studies in respect to sites, samples sizes and intervention periods. However, in all intervention categories, pharmacists’ collaboration with other health care professionals was most beneficial, showing definitive evidence for improving medication safety and quality of prescribing in RACS. The evidence suggests that combining two or more interventions is the most promising approach, despite this presenting implementation barriers in the resource-limited environments of many RACS, and methodological challenges in identifying the precise contribution of individual interventions, when implemented concurrently. Conclusion: Health stakeholders should explore a combination of at least two interventions, such as medication review and staff education, to improve medication safety in RACS.

Aim This Phase I open label study examined pharmacokinetics, safety, and tolerability of escalating doses of a combination cannabinoid medication (1:1 ratio THC:CBD) in patients with chronic non-cancer pain (CNCP) on high dose opioid analgesia. Methods Nine people with CNCP and oral morphine equivalent daily dose of ≥60mg were recruited. Blood concentrations of THC, 11-hydroxytetrahydrocannabinol (OH-THC), 11-nor-9-carboxy-tetrahydrocannabinol (COOH-THC) and CBD were assayed weekly. Concentrations were measured after a single dose of 2.5mg THC/2.5mg CBD up to 12.5mg THC/12.5mg CBD on Day 29. Follow-up was on Day 36 after 7 day washout. Secondary outcome data encompassed pain, mood, and sleep parameters. Results The parent THC, CBD, OH-THC, COOH-THC were detected at most time points. In general, the concentration of all analytes increased until 2 hours post-administration, decreasing to approximately pre-dose concentrations by 8 hrs. There was considerable inter- and intra-individual variability. The study medication was well tolerated. Eight participants reported at least one Adverse Event (AE), with a total of 62 AEs; most common were euphoric mood, headache, and agitation, none classified as severe. There was no significant change to pain severity self-ratings, nor use of pain medications. Improvements in pain interference scores, mood, and some sleep parameters were observed. Conclusion The THC:CBD formulation was tolerated well in a CNCP patient group. Between-participant variability supports personalized dosing and “start low-go slow” titration. Improvements in pain, mood, and sleep parameters suggest that on relatively low dosages clinical effects are apparent. To validate and quantify findings a comparison placebo group study is needed.

Aim: To determine the safety of Coenzyme Q10 (CoQ10) in breast cancer patients receiving doxorubicin treatment. Methods: Phase I randomized, placebo-controlled, cross-over, dose-finding pharmacokinetic study among women with stage I-III breast cancer receiving 4 cycles of doxorubicin plus cyclophosphamide. The study was designed to test the maximum tolerated dose of CoQ10 using up to 1200 mg/day. Eligible patients were randomized to Arm A (CoQ10 after Cycle 3, followed by placebo after Cycle 4) or Arm B (placebo after cycle 3, followed by CoQ10 after cycle 4). CoQ10 concentrations and total antioxidant capacity (TAC) were measured before and after chemotherapy cycles. Non-compartmental pharmacokinetic parameters of doxorubicin and its active metabolites were measured with and without CoQ10. Paired t-tests assessed intra-patient differences in pharmacokinetic parameters, serum CoQ10 concentrations, TAC and adverse events. Results: Six patients received 300 mg/day of CoQ10 [Arm A (n=3), Arm B (n=3)]. One patient received 600 mg/day of CoQ10 but was discontinued due to non-adherence. Serum CoQ10 concentrations were increased in patients receiving 300 mg/day (mean±SD change: CoQ10, 1.6±0.9 ug/mL; placebo, -0.01±0.3 ug/mL; P=0.01). There were no clinically significant pharmacokinetic interactions between 300 mg/day CoQ10 and doxorubicin and no differences in TAC or adverse events during treatment and nontreatment periods. The trial was closed early due to slow accrual. Conclusions: 300 mg/day of CoQ10 with doxorubicin did not change doxorubicin pharmacokinetics and was not associated with treatment-related adverse events. Future studies should evaluate the long-term effects of CoQ10 at 300 mg/day and safety studies should examine higher doses.