Immunosuppressant drugs like Etanercept, Mycophenolate mofetil, Sirolimus, Cyclosporine and Rituximab can weaken the immune system and make patients susceptible to SARS nCoV-2 virus. These drugs make immunocompromised persons more vulnerable to complications associated with COVID-19. Moreover, it can also increase the mortality and morbidity, as a weakened immune system can lead to longer duration of infection. This study discusses the guidelines on immunosuppressant drugs and its associated risk factors with COVID-19, issued by the U.S CDC (Centers for Disease Control and Prevention), WHO (World Health Organisation), U.S FDA (Food and Drug Administration) and other accredited global health organisations. Moreover, it also includes information about pharmaceutical properties, mechanism of action, COVID-19 associated risk factors, adverse drug reactions, contraindications and drug-drug interactions. Our study will help government partners and international health organisations to better understand COVID-19 health risks associated with immunosuppressants. Increased public awareness about effective drug therapy for autoimmune diseases, cancer treatment, immunocompromised and organ transplant patients will help lower the mortality and morbidity associated with the disease amid COVID-19 pandemic.

Objective: Hyperuricemia increases the risk of gout and cardiovascular diseases. Obesity increase the risk of hyperuricemia while weight loss (>5 kg) has been reported to decrease urate. The effects of orlistat on serum uric acid is still controversial. The aim of this meta-analysis was to evaluate the influence of orlistat on serum uric acid level in adults. Methods: Relevant studies, published up to May 2020, were searched systematically through PubMed/Medline, Scopus, and Google Scholar. All relevant randomized controlled clinical trials were included. Meta-analysis was performed using random-effect model. Subgroup analysis, sensitivity analysis, and meta-regression were also carried out Results: Overall 7 trials (9 dataset) that enrolled 1786 subjects were included. Orlistat showed in significant change in serum uric acid level (Difference in means: -17.661μmol, 95% CI: -31.615 to -3.707, P=0.01). A low heterogeneity observed across the studies (I^2 = 25.119%). After categorizing studies on the basis of duration and sample size the effect of orlistat on serum uric acid was significant. The results of meta-regression were showed that significant relationships were not found between orlistat and serum uric acid in duration of intervention. Conclusion: We found a significant reduction in serum uric acid following orlistat therapy in adults.

Fatma Zgolli 1 2, Imen Aouinti 1 2, Ons  Charfi1 2, Sarrah Kastalli1 2, Daghfous Riadh1 2, Sihem EL Aidli 1 2, Ghozlane Lakhoua 1 21National Center Chalbi Belkahia of Pharmacovigilance, 9 Avenue du Dr Zouhaier Essafi 1006, Tunis, Tunisia.2University of Tunis El Manar, Faculty of Medicine, Research unit: UR17ES12, 15 Rue Djebel Lakhdhar, La Rabta, 1007, Tunis, Tunisia.Leukocytoclasticvasculitis (LCV) is a hypersensitivity vasculitis. It may be secondary to infections, drugs, collagen tissue disorders, and malignities(1). Drug-induced LCV represents approximately 10-15% of LCV cases (2). Calcium channel blockers are little involved in this skin impairment. In fact, only few cases of LCV induced by amlodipine and diltiazem LCV were reported (3-5).We report herein an exceptional case of LCV induced by lercanidipine (LER). It was notified in the Tunisian National Centre of Pharmacovigilance.An 87-year-old woman was treated with flecainide and bisoprolol during ten years for cardiac disease. In 2016, she started LER (10 milligram per day). Seven months later, in January 2017, she developed a polymorphic and pruritic cutaneous eruption limited to forearms and legs. A symptomatic treatment (dermocoticoids and antihistamincs) was initiated without improvement of the eruption. Skin examination showed an erythematous maculopapular eruption, necrotic and purpuric lesions and ulcerations. The rest of the physical examination was normal. Laboratory findings showed an accelerated erythrocyte sedimentation rate and a high level of C-Reactive Protein (82mg/l), the serum protein electrophoresis was normal. The diagnosis of vasculitis was suspected by dermatologists. A skin biopsy was performed and revealed characteristic perivascular neutrophilic infiltrates, a leukocytoclasis and extravasated erythrocytes in favour of LCV. The responsibility of LER was suspected and this medication was stopped. The other drugs were continued. The pruritus and cutaneous lesions started to subside few days later after the drug cessation. Symptoms had completely resolved in two weeks.LCV is the inflammation of small blood vessels.Its clinical features are generally a palpable purpura on gravity-dependent body parts. Also it can occur as urticaria, ulcers, nodules or haemorrhagic bullae (6). It is diagnosed by histopathological evaluation of the biopsy from the lesion.LCV is idiopathic up to 50% of the cases.  Infections and drugs are the most common triggers for secondary LCV. Drug-induced LCV is approximately 10-15% of cases (2). Merkel PA had defined drug-induced LCV as “any case of inflammatory vasculitis in which a specific drug is established as a causal agent of disease when other forms of vasculitis are excluded” (7). The onset is typically 1 to 3 weeks after drug initiation (2).The exact pathogenesis of drug-induced LCV remains unclear, but studies suggest that the offending drug may act as a hapten, which stimulates antibody production and immune complex formation. These immune complexes are subsequently deposited in postcapillaryvenules leading to complement activation and vascular damage (8).More than 100 drugs are implicated as causes of drug-induced LCV. Commonly, offending drugs include antibiotics such as beta-lactams, erythromycin, clindamycin, vancomycin, sulfonamides, and other molecules such as furosemide, allopurinol, NSAIDs, amiodarone, gold, thiazides, phenytoin, beta-blockers, TNF-alpha inhibitors, selective serotonin reuptake inhibitors, metformin, warfarin, valproic acid, among many others (2).In our case, the responsibility of LER was retained in front of the onset of the reaction after a compatible delay (seven months after beginning the treatment), and mainly the improvement of the condition after drug withdrawal. According to Naranjo probability scale, the score was 4 (9).In literature, calcium channel blockers are little involved in this skin impairment. After a MEDLINE search (vasculitis, drug-induced vasculitis, leucocytoklasis, calcium channel blockers, lercanidipine, amlodipine, nifedipine, diltiazem), we have only found few cases of LCV induced by amlodipine and diltiazem(3–5). Concerning LER, only one previous case of an enalapril-LER combination induced LCV was reported (10). But, no cases are available on drug-induced LCV associated with LER only. Thus, this is the first reported case of LCV induced by LER.The drug-induced LCV therapeutic approach is based on antigen removal and the treatment of the cutaneous lesions. Withdrawal of the precipitating drug and minimization of stasis by compression, elevation, and use of non steroidal anti-inflammatory drugs are employed. Antihistamines, systemic corticosteroids or other immunosuppressant may be required when the cutaneous lesions are progressive (6,8).This report is, to the best of our knowledge, the first case of LCV induced by LER. Considering the wide use of LER in hypertensive population, prescribers should be aware of the possibility of occurrence of cutaneous LCV as a side effect of this drug.References:1) Goeser MR, Laniosz V, Wetter DA. A Practical Approach to the Diagnosis, Evaluation, and Management of Cutaneous Small-Vessel Vasculitis. Am J ClinDermatol 2014;15(4):299-306.(2) Baigrie D, Bansal P, Goyal A, et al. LeukocytoclasticVasculitis (Hypersensitivity Vasculitis. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2020.(3) del Río Fernández MC, Plagaro Cordero ME, de FrutosArribas JF, del PozoRomán T, Martín Escudero JC. Leukocytoclasticvasculitis in relation to amlodipine administration. Rev ClinEsp 1995;195(10):738-9.(4) Sheehan-Dare RA, Goodfield MJ. Severe cutaneous vasculitis induced bydiltiazem. Br J Dermatol 1988;119(1):134.(5) Lachapelle J-M, Ramelet A-A. Exercise-induced vasculitis and amlodipine. Louvain Med 2014;133:103-6.(6) Ha YJ, Han YJ, Choi YW, Myung KB, Choi HY. Sibutramine (Reductil®)-Induced Cutaneous LeukocytoclasticVasculitis: A Case Report. Ann Dermatol 2011;23(4):544-7.(7) Merkel PA. Drug-induced vasculitis. Rheum Dis Clin North Am. 2001;27(4):849-862.(8) Gupta M. Levetiracetam-induced leukocytoclasticvasculitis. Indian J Pharmacol. 2017;49(1):124-6.(9) Naranjo CA, Busto U, Sellars EM, et al. A method for estimating the probability of adverse drug reactions. ClinPharmacolTher 1981; 30: 239-45(10) Ouni B, Fathallah N, Ben‐Sayed N, Slim R, Abdessayed N, Anoun J, et al. Enalapril‐lercanidipine combination induced leukocytoclasticvasculitis: A case report. Br J ClinPharmacol 2020; 10.1111/bcp.14346.

Aim: The aim of this study was to develop a population pharmacokinetic (PPK) model in Chinese children for intravenous busulfan, and to develop a novel busulfan dosing regimen to support better area under the concentration-time curve (AUC) targeting. Methods: We collected busulfan concentration-time samples from 69 children who received intravenous busulfan prior to allogeneic hematopoietic stem cell transplantation (allo-HSCT). A population pharmacokinetic model for busulfan was developed by nonlinear mixed effect modelling and was validated by an external dataset (n=14). A novel busulfan dosing regimen was developed through simulation on 1000 patients. Limited Sampling Strategy (LSS) was established by the Bayesian forecasting. Absolute Prediction Error (APE), Mean Absolute Prediction Error (MAPE) and relative Root Mean Squared Error (rRMSE) were calculated to evaluate predictive accuracy. Results: A one-compartment model with first-order elimination best described the data. GSTA1 genotypes, BSA and AST were found to be significant covariates of Bu clearance, and BSA had remarkable impact of the volume. Moreover, recommended dose regimens for children with different GSTA1 genotypes and BSA were developed with a perfect AUC targeting. A two-point LSS, two hours and four hours after dosing, behaved well with acceptable prediction precision. Conclusion: This study developed a PPK model for busulfan that firstly incorporated GSTA1 genotypes in an Asian pediatric population. We recommend a BSA-based dosing for personalizing busulfan therapy in pediatric population. Additionally, an optimal LSS (C2h and C4h) provides convenience for therapeutic drug monitoring (TDM) in the future.

Aim: To assess the feasibility of converting electronic medical records (EMR) into the Observational Medical Outcomes Partnership-Common Data Model (OMOP-CDM) schema and potential for subsequent analyses relating to drug safety. Methods: The EMRs belonging to a tertiary care facility from 2013 to 2016 were mapped onto the OMOP-CDM schema. Vocabulary mappings were applied to translate source data values into OMOP-CDM terminologies. Existing analytic codes from a previous study were modified and applied to conduct an illustrative analysis involving oral anticoagulants (OACs) to mimic analyses that may be part of a typical benefit-risk assessment. A novel visualization is proposed to represent comparative efficacy, safety and utilization in one chart. Results: Records of 245,561 unique patients were mapped onto the OMOP-CDM. The CDM and analytic code templates simplified the data analysis for the illustrative example. Of 132 patients identified, a majority were warfarin users (76.5%), followed by rivaroxaban (19.7%) and apixaban (3.8%). Following six months of follow up, differences in cumulative incidence of bleeding and thromboembolic events were observable. The proposed visualization may facilitate collective evaluation of differences relating to utilization, efficacy and safety of drugs of interest. Conclusion: OMOP-CDM conversion of RWD may be useful for gleaning insights on comparative drug utilization, efficacy and safety for risk-benefit assessments in post-market regulatory settings.

Health and specifically Medication Literacy is important in patient empowerment and in empowering patients and families as effective partners in ensuring optimal health outcomes. While there has is a reasonable body of evidence on this for adults, there has been very little work on medication literacy for children, specifically in terms of effective interventions. Adopting agreed upon nomenclature and developing and validating children's specific instruments -- such as infographics - will be important in moving forward, especially when these instruments can be actively incorporated into eHealth initiatives.

Introduction Irrational medicine use is proportionately higher in low and middle-income countries like Sierra Leone. This study aims at exploring the structure, functions, and challenges of Drug, and Therapeutics Committees (DTC) recently piloted in Sierra Leone. Method A two-phase mixed-method study design was used in this study. Firstly, a cross-sectional survey using an online questionnaire to assess the structure, indicators, and challenges of DTC . In phase two, a semi-structured interview was used to get deeper insights into the key issues that emerged from the survey. Participants were mainly pharmacists in-charge at the hospitals where the DTC program hasbeen established. MS Excel 2019 and NVivo version 12 were respectively used for data management and analysis. Results DTCs mostly had a minimum of ten members consisting of a mix of both medical and hospital administrative staff. The main functions of DTC are ensuring rational medicines use, monitoring, and reporting adverse drug reactions. All but one hospital had subcommittees that are either effective or nonfunctional. The main challenges in DTC functions and maintenance were funding (n=6), DTC decision implementation (n=4), and unmotivated members (n=4). Strategies suggested to improve DTC at public hospitals and nationwide include; resource allocation, monitoring, and evaluating DTC functions and capacity building of its members. Conclusion DTC present a compelling opportunity towards achieving rational medicines use at the hospital level in Sierra Leone. Nonetheless, lack of funding, operational resources, are significant limitations. Policymakers must note these drawbacks whilst expanding DTC programs to other hospitals in Sierra Leone.

Kedaling tablets is an extract of with Corydalis yanhusuo W.T. Wang and used to coronary heart disease, angina pectoris, myocardial infarction with no previously well documented hepatotoxicity. We report the first case of kedaling tablets-related drug-induced liver injury (DILI), which highlights the need for clinician awareness regarding potential hepatotoxicity of kedaling tablets, particularly among patients with pre-existing liver disease.

Early studies suggesting that chloroquine (CQ) and hydroxychloroquine (HCQ) could benefit coronavirus patients brought these old medicines back to the spotlight. This led to an increase in demand and price, turning their counterfeiting a pharmacovigilance issue worldwide. Meanwhile, lack of evidence on effectiveness and safety concerns have reduced their clinical trials in severe COVID-19 cases. Despite the knowledge that CQ and HCQ toxic effects are stereo specific rather than their therapeutic effects, these drugs are available only as racemates. In this context, this work brings a discussion about chiral switching to their eutomers so that CQ and HCQ distomers would become impurities, what may be a viable alternative to test new dose-response curves. Even if it is proven that the use of pure CQ and HCQ enantiomers are useless against COVID-19, chiral switching would certainly improve safety and efficacy in the treatment of many autoimmune inflammatory diseases, benefiting chronic users of these drugs.

Introduction The ORBITA trial of PCI versus a placebo procedure for patients with stable angina was conducted across 6 sites in the United Kingdom via home monitoring and telephone consultations. Patients underwent detailed assessment of medication adherence which allowed us to measure the efficacy of the implementation of the optimisation protocol and interpretation of the main trial endpoints. Methods Prescribing data were collected throughout the trial. Self-reported adherence was assessed, and urine samples collected at pre-randomisation and at follow-up for direct assessment of adherence using HPLC MS/MS. Results Self-reported adherence was >96% for all drugs in both treatment groups at both stages. The percentage of samples in which drug was detected at pre-randomisation and at follow-up in the PCI vs. OMT groups respectively was: clopidogrel, 96% vs. 90% and 98% vs. 94%; atorvastatin, 95% vs. 92% and 92% vs. 91%; perindopril, 95% vs. 97% and 85% vs. 100%; bisoprolol, 98% vs. 99% and 96% vs. 97%; amlodipine, 99% vs. 99% and 94% vs. 96%; nicorandil, 98% vs. 96% and 94% vs. 92%; ivabradine, 100% vs. 100% and 100% vs. 100%; and ranolazine, 100% vs. 100% and 100% vs. 100%. Conclusions Adherence levels were high throughout the study when quantified by self-reporting methods and similarly high proportions of drug were detected by urinary assay. The results indicate successful implementation of the optimisation protocol delivered by telephone, an approach that could serve as a model for treatment of chronic conditions, particularly as consultations are increasingly conducted online.

Aims: These last years, pharmacists gained more and more importance in the clinical support of patients. However, few studies have explored the clinical outcomes of a pharmaceutical intervention on chronic patients. Methods: A randomized controlled study single blinded, evaluating the impact of a single pharmaceutical interview on hypertension, type 2 diabetes and hypercholesterolemia patients not reaching the therapeutic objectives despite a drug therapy. Patients in the intervention group were interviewed by a pharmacist who provided patient education on pathology management and advice on how to deal with the pathology on a daily basis, and identified any prescription problems. The primary outcome was the proportion of patients reaching the therapeutic objectives for blood pressure, glycated hemoglobin level and low-density lipoprotein cholesterol level at the three-month follow up consultation. Results: Seventy-three patients completed the study. In the control group, 33.3% patients reached the therapeutic objectives with the usual care versus 61.7% in the intervention group (p=0.015). The intervention was significantly more effective on patients with more than five different drugs prescribed (+16.7% vs +60.0%; p=0.005) and with a high education level (+29.4% vs +68.8%; p=0.024). A much lower rate of type 2 diabetes patients reached the therapeutic objectives whatever the group. Interestingly, the efficacy of the intervention did not depend on the number of chronic diseases or age after adjustment for the number of different drugs prescribed. Conclusions: There is a concrete clinical and public health impact of a single pharmaceutic interview, especially on polypharmacy patients with hypertension or hypercholesterolemia.

Aim COVID-19 outbreak spread all over the world and created a public health catastrophe. Here, we have aimed to conduct a systematic review and meta-analysis on remdesivir use for COVID-19. Methods We searched Pubmed, Pubmed Central, Scopus, Embase, clinicaltrials.gov, and preprint sites and identified ten studies for qualitative and four studies for quantitative analysis using PRISMA guidelines. The quantitative synthesis was performed using fixed and random effect models in RevMan 5.4. Heterogeneity was assessed using the I-squared (I2) test. Results Comparing remdesivir group with placebo or standard of care (SOC) group, remdesivir reduces 14 days mortality (OR 0.61, CI 0.41- 0.91), need of mechanical ventilation (OR 0.73, CI 0.54-0.97), and overall severe adverse effects (OR 0.69, 95% CI 0.54 to 0.88). There is better clinical improvement on day 28 (OR 1.59, CI 1.06- 2.39); day 14 clinical recovery (OR 1.48, CI 1.19-1.84); day 14 discharge rate (OR 1.41, CI 1.15-1.73) among remdesivir groups. Earlier clinical improvement (MD -2.51, CI -4.16 to -0.85); and clinical recovery (MD -4.69, CI -5.11 to -4.28) seen among remdesivir group. While no difference on 28 days mortality rate; discharge rate; overall adverse effect. Longer course (10 days) of remdesivir showed higher discharge rate at day 14 (OR 2.11, CI 1.50-2.97), but there are significantly higher rates of serious adverse effects, and drug discontinuation than the shorter course. Conclusion Remdesivir showed a better 14 days mortality profile, clinical recovery, and discharge rate. Overall clinical improvement and clinical recovery were earlier among remdesivir group.

Objective Investigate the antihemorrhagic effect of intravenous perioperative tranexamic acid in hysterectomy for benign gynecological diseases. Study Design A prospective randomized case-control study was carried out in the Department of Obstetrics and Gynaecology, PGIMS, Rohtak, on 150 patients planned for hysterectomy for benign conditions. The women were randomized into two groups- Group I and Group II, with 75 subjects in each group. Group I was not be given any drug, while Group II was given TXA as intravenous bolus injection of 10mg/kg (maximum 1g) for 10 min about 30 min before incision. Unpaired ‘t’ test and ANOVA test were used to calculate the difference of means of quantitative variables. An association was significant if the p-value < 0.05. Results Intraoperative blood loss was reduced in the group given tranexamic acid preoperatively (mean loss 489.07± 279.248 ml) v/s the control group (mean loss 539.93 ± 211.08ml) (p<0.05). This result was particularly significant in the subjects who underwent vaginal hysterectomy (mean loss 364.58 ± 108.53ml in Group II v/s 278.91 ± 118.34ml in Group I; p<0.05). The incidence of transfusion of blood or blood products intraoperative to postoperative day seven was significantly reduced in the tranexamic acid group (0.47 vs. 0.23, P = .02). Conclusion The results show that preoperative intravenous tranexamic acid reduces the total blood loss irrespective of the route of hysterectomy and the number of perioperative transfusions. No incidences of serious adverse events occurred. Thus, tranexamic acid should be considered as a prophylactic treatment before benign hysterectomy.

Aim Patients on anti-tuberculosis (anti-TB) therapy are at risk of drug-induced liver injury (DILI). MicroRNA-122 (miR-122) and cytokeratin-18 (K18) are exploratory DILI biomarkers. To explore their utility in this global context, circulating miR-122 and K18 concentrations were measured in UK and Ugandan populations on anti-TB therapy for mycobacterial infection. Methods European patients receiving anti-TB therapy were recruited at the Royal Infirmary of Edinburgh, UK (ALISTER-ClinicalTrials.gov Identifier: NCT03211208). African patients with HIV-TB coinfection, receiving anti-TB and anti-retroviral therapy (ART), were recruited at the Infectious Diseases Institute, Kampala, Uganda (SAEFRIF-NCT03982277). Serial blood samples, demographic and clinical data were collected. MiR-122 was quantified using PCR. K18 was quantified using the M65 ELISA. Results The study had 235 participants (healthy volunteers (n=28); ALISTER: active TB (n=30), latent TB (n=88), non-tuberculous mycobacterial infection (n=25); SAEFRIF: HIV-TB coinfection (n=64)). In the absence of DILI, there was no difference in miR-122 and K18 across the groups. Both miR-122 and K18 correlated with alanine transaminase activity (ALT) (miR-122: r=0.52, 95%CI=0.42-0.61, P<0.0001. K18: r=0.42, 95%CI=0.34-0.49, P<0.0001). There were two DILI cases: baseline ALT was 18 and 28 IU/L, peak ALT 431 and 194 IU/L; baseline K18 58 and 219 U/L, peak K18 1247 and 3490 U/L; baseline miR-122 4 and 17 fM, peak miR-122 60 and 336 fM, respectively. Conclusion In European and African patients treated with anti-TB therapy miR-122 and K18 correlated with ALT and increased with DILI. Further work should determine the diagnostic and prognostic utility of miR-122 and K18 in this global context-of-use.

Introduction: Encorafenib (BraftoviTM) is indicated for the treatment of adult patients with unresectable or metastatic melanoma with a BRAF V600 mutation, in combination with binimetinib (Mektovi ®). According to the product label of encorafenib, there are no specific treatment recommendations in case of an overdose. Case presentation: We report on a 63 year old man who ingested a double dose (900 mg) of encorafenib for 16 days. He developed overall minor chronic intoxication symptoms such as upset stomach, bloating, occasional vomiting and muscle pain. Based on the most occurring adverse events of encorafenib, liver values, kidney function parameters and QTc interval were measured. Kidney function parameters were normal, whereas liver values were slightly increased and QTc slightly prolonged. The plasma concentration 3 hours after the last dose was 2110 ng/mL. Conclusion: We describe the course of a case with a chronic toxicity during 16 days of double dose of encorafenib as well as the followed approach, which could be taken into account when treating a patient with encorafenib intoxication.

A high concentration of oxalate is associated with an increased risk of kidney calcium oxalate (CaOx) stones. Because humans lack enzymes that metabolize oxalate, the degradation of exogenous oxalate mainly depends on oxalate-degrading enzymes from the intestinal microbiome. Epidemiologic cohort studies have demonstrated that the imbalance of intestinal oxalate-degrading bacteria caused by antibiotics is closely linked to the occurrence and formation of CaOx implicated renal stones, but the mechanism of action remains poorly characterized. Here, based on clinical sample analysis, we report that the imbalance of Lactobacillus and oxalate decarboxylase (OxDC) is involved in CaOx kidney stones. Next, by analyzing the crystal structure of OxDC derived from L. farciminis, we reveal the mechanism of oxalate metabolism. Finally, through experiments in vivo and in vitro, we identify that Zn2+ can be used as an external factor to improve the activity of OxDC and protect Lactobacillus, confirming the preventive effect of Zn2+ on stones aggravated by antibiotics. Collectively, our findings illustrate the association of CaOx stones, Lactobacillus and OxDC, and provide some new recommendations for the prevention of CaOx kidney stones.

The development of specific drug therapy for children was a paradigm changing event that transformed paediatric medical practice. However a series of tragedies involving drug treatment for children resulted in a gap developing between drug regulation and practice, with the majority of drugs used in child health care being used “off label” rendering children therapeutic orphans. Over the past two decades changes in drug regulation led by the US FDA and followed by the European Union’s EMA have led to substantial changes in how new drugs with potential use in children are studied and labelled. While these changes have substantially improved labeling for new drugs, there has been much less progress with older drugs. As well while the unique challenges of conducting clinical research in children have been addressed by novel clinical trial designs, many of these innovations have not been translated into approaches accepted for the drug approval process. The regulations applying to the need for paediatric studies currently are only applicable in the United States and the European Union, and there is less impetus for paediatric labeling in other jurisdictions. This impacts on a number of issues beyond labeling, including the availability of child-friendly formulations. Finally the impact of Brexit on paediatric drug studies in the UK remains unclear and subject to on-going negotiations between the UK government and the European Union.

AIM: This study aimed to assess the pharmacokinetics, tolerability, safety and exploratory analgesic efficacy of a novel water-soluble oro-buccal nanoparticle spray of a cannabis-based medicine in advanced cancer patients with unrelieved pain. METHODS: The study was a non-blinded single arm, single escalating dose (n=5) [2.5 mg Δ9-THC and 2.5 mg CBD) and multiple escalating doses (up to 5.5 doses)] of a two-stage pilot study in patients diagnosed with advanced cancers and intractable pain (n=25). RESULTS: As the cannabis-based medicine dose increased, maximum plasma concentrations of all analytes were approximately proportional to dose. The bioavailability of Δ9-THC and CBD in this water-soluble nanoparticle formulation was approximately twice the bioavailability reported for Δ9-THC/CBD formulation with ethanol. The water-soluble formulation in the current study resulted in a higher median (min, max) bioavailability of Δ9-THC than CBD (AUC from 2.5 mg each of Δ9-THC and CBD was 1.71 ng mL.h-1 (1.1, 6.6) and 0.65 ng mL.h-1 (0.49. 4.1), respectively). Analyte accumulation was not observed. In a subgroup of patients diagnosed with breast and prostate cancer with bone metastases, mean pain scores improvement from baseline was 40% (unadjusted) and 33% adjusted for rescue medication use. For all patients the most commonly reported adverse events were mild or moderate drowsiness affecting 11 (44%) and 4 (6%) patients, respectively and nausea and vomiting that affected 18 (72%) patients. CONCLUSIONS: The water-soluble cannabis-based medicine (NanaBisTM) provided acceptable bioavailability for Δ9-THC and CBD, appeared safe and tolerable in cancer with uncontrolled pain with preliminary evidence of analgesic efficacy.

Timely intravenous (IV) to oral antimicrobial switch (IV-oral-switch) is a key antimicrobial stewardship (AMS) strategy. A retrospective audit was undertaken to determine concordance with IV-oral-switch guidelines in the context of a long-standing, tightly regulated AMS program. Data from 107 general medical and surgical patients in an Australian hospital were analysed. Median duration of IV antimicrobial courses before switching to oral therapy was 3 days (interquartile range, 2.25-5.00). Timely IV-oral-switch occurred in 57% (n=61) of patients. The median delay to switching was 0 days (IQR 0 to 1.25). In most courses (92/106, 86.8%), the choice of oral alternative after switching was appropriate. In 45% (47/105) of courses, total duration of therapy (IV plus oral) exceeded the recommended duration by >1.0 day. Excessive IV antimicrobial duration was uncommon at a hospital with a tightly regulated AMS program. Total duration of therapy was identified as an AMS target for improvement.

Background and aim: The search for early and emergency effective treatments for COVID-19 infection may have led to loss of sight of treatments safety. In addition, characteristics of drug-drug interactions (DDIs)-related adverse drug reactions (ADRs) in COVID-19 patients have not yet been studied in depth. The aim of the present case-series study is to describe clinical and pharmacological characteristics of SARS-CoV-2 inpatients, focusing on ADRs, particularly those related to DDIs. Methods: We evaluated all reports of COVID-19 medications-related ADRs collected within the COVID-19 Units of Careggi University Hospital, Florence (Italy), between January 1st and 31st May 2020. Information regarding COVID-19 medications, patients’ demographic and clinical characteristics, concomitant drugs, ADRs description and outcome, were collected. Each case was evaluated for the causality assessment and to identify the presence of DDIs. Results: During the study period, 23 Caucasian patients (56.5% males, mean age 76.1 years) experienced one or more ADRs. The majority of them were exposed to polypharmacy and 17.4% presented concomitant conditions. ADRs were referred to cardiovascular, psychiatric and gastrointestinal disorders. The most frequently reported preferred term was QT prolongation (mean QT interval 496.1 msec). ADRs improved or resolved completely in 60.8% of cases. For all patients, a case-by-case evaluation revealed the presence of one or more DDIs, especially those related to pharmacokinetic interactions. Conclusions: Despite the small number of patients, our evidence underline the clinical burden of DDIs in SARS-CoV-2 inpatients and the risk of unexpected and uncommon psychiatric ADRs.

Aims: Emodepside is an anthelmintic, originally developed for veterinary use. We investigated the safety, pharmacokinetics, relative bioavailability and dose linearity of four oral formulations of emodepside in healthy male subjects. Methods: Three randomised, parallel‐group, controlled, Phase I studies were conducted using various oral formulations, involving 79 subjects in ten cohorts in the single-ascending-dose study, 24 subjects in three ascending-dose cohorts in the multiple-ascending-dose study and 77 subjects in seven different cohorts in the relative bioavailability study. Pharmacokinetics and safety assessments were performed up to 21, 30 and 7 days, respectively. Results: As a liquid service formulation, emodepside was rapidly absorbed under fasting conditions, with dose-proportional increases in plasma concentrations at doses from 1 mg to 40 mg. The half-life during the first 24 hours after dosing was around 11 hours, followed by a terminal elimination half-life > 500 hours. Emodepside was less bioavailable in the fed state. The rate of absorption was slower and Cmax was lower with the amorphous solid dispersion tablets compared to the liquid service formulation. Emodepside was well tolerated overall with no major safety concerns. Conclusion: These Phase I studies with various dosage forms revealed a pharmacokinetic profile suggesting good tissue distribution of emodepside and a long terminal half‐life. A 15 mg dose with the gastrosoluble tablet is predicted to provide exposure that will achieve the target concentration for clinical efficacy. These data enabled us to select a field-adapted tablet formulation that will open the way for further clinical development of emodepside in individuals with onchocerchiasis.

One form known as pain modulation is the phenomenon of inhibiting pain using a prior pain stimulus. The term CPM (conditioned pain modulation) is used to describe this phenomenon in humans. Serotonin pathways work as both anti- and pro-nociceptive pathways. Ondansetron is a 5HT3 receptor antagonist routinely used to prevent postoperative nausea and vomiting. Therefore, this study’s objective was to evaluate ondansetron’s effect on mechanical and thermal pain thresholds, as well as CPM in humans. 17 volunteers, who were randomly selected and double-blinded, participated in the research. They received an intravenous solution containing 1 - NaCl at 0.9%, in a volume of 20 mL; 2 - NaCl at 0.9% and 8 mg ondansetron in a volume of 20 mL. Using the quantitative sensory test (QST), we obtained the thresholds for detecting warm and cold; pain thresholds to hot and cold; the pressure pain threshold. CPM was evaluated using the parallel paradigm in which two identical nociceptive test stimuli were induced before and simultaneous to a conditioned nociceptive stimulus. Thirty minutes after the intervention, we redid the tests. We repeated the tests one week later but using the different solution so that each participant was their own control (crossover). We used the Wilcoxon test to compare the variables. Ondansetron, intravenously, improved CPM (p<0.05) and influenced thermal detection thresholds (heat and cold p < 0.05). There is evidence that the results related to the antagonism of the 5HT-3 receptor by ondansetron, occur through inhibition of facilitating descending pathways, improving the CPM.

Aim To provide a comprehensive/updated evaluation of the effect of ACEIs/ARBs on COVID-19 related-clinical outcomes, including exploration of inter-class differences between ACEIs and ARBs. Methods This was a systematic review/meta-analysis conducted in Medline (OVID), Embase, Scopus, Cochrane library and medRxiv from inception to 22nd May-2020. English studies that evaluated the effect of ACEIs/ARBs among patients with COVID-19 were included. The study outcomes included any COVID-19 related-clinical outcomes. Studies’ quality was appraised using the Newcastle-Ottawa Scale. Data were analysed using the random-effects modelling stratified by ACEIs/ARBs, ACEIs, and ARBs. Heterogenicity was assessed using I2 statistic. Several sub-group analyses were conducted to explore the impact of potential confounders. Results Out of the identified 452 studies, 27 studies were eligible for inclusion. The pooled analyses showed non-significant associations between ACEIs/ARBs and death (OR:0.97, 95%CI:0.75,1.27), ICU admission (OR:1.09;95%CI:0.65,1.81), death/ICU admission (OR:0.67; 95%CI:0.52,0.86), risk of COVID-19 infection (OR:1.01; 95%CI:0.93,1.10), severe infection (OR:0.78; 95%CI:0.53,1.15) and hospitalisation (OR:1.15; 95%CI:0.81,1.65). However, the sub-group analyses indicated different results such as significant association between ACEIs/ARBs and hospitalisation among USA studies (OR:1.59; 95%CI:1.03,2.44), peer-reviewed (OR:1.93, 95%CI:1.38,2.71), good quality and studies which reported adjusted measure of effect (OR:1.30, 95%CI:1.10,1.50). Significant differences were found between ACEIs and ARBs with the latter being significantly associated with lower risk of acquiring COVID-19 infection (OR:0.24; 95%CI: 0.17,0.34). Conclusions High-quality evidence exist for the effect of ACEIs/ARBs on some COVID-19 clinical outcomes. For the first time, we provided evidence, albeit of low quality, on inter-class differences between ACEIs and ARBs for some of the reported clinical outcome.

Abstract Patients at risk of severe forms of COVID 19 share metabolic disturbances, diabetes, hypertension, among which dysregulation of antioxydant defence mechanisms and orientation toward Th17 immunological response are predisposing factors for severe cellular lesions of Covid infection. We propose to act on NrF2, so as to protect tissues from oxydative burst, and cellular lesions characteristic of hyperinflammation of Covid 19. Bardoxolone acts upon Nrf2 and represses NfKappa B. It has been evaluated in diabetic nephropathy, but some patients suffered from overhydration and cardiac failure (Beacon study). In Covid infection, benefit-risk equation is different from long term use of this drug in diabetic nephropathy, in a disease potentialy lethal in a couple of weeks, with a short term risk of overhydration which could be seen as quite negligeable with a daily monitoring of weight. We advocate for an evaluation of Bardoxolone in recently infected Covid patients, with severe-Covid19-risk, in a framework of a strict evaluation of their cardio-vascular risk.