Abstract Objectives: To assess the efficacy and safety of oral glucokinase activator (GKA) in the treatment of type 2 diabetes mellitus(T2DM). Methods: We searched PubMed, ClinicalTrails, Cochrane Library, Web of Science, and CNKI and collected randomized controlled trials (RCTs) of glucokinase activator in the treatment of T2DM. Revman5.3 software was used to do the meta-analysis. And the risk of bias in the included RCTs was evaluated according to the Cochrane tool. Results: Seven double-blind RTCs were included in the final analysis, with a total of 762 patients. Regarding the efficacy, GKAs significantly reduced fasting blood glucose (mean difference -0.71, 95% CI: -1.11 to -0.31, based on 459 patients from 5 literatures), and glycated hemoglobin also significantly reduced (mean difference: -0.65%, 95% CI: -0.82 to -0.48, based on 570 patients from 4 literatures). Regarding safety, GKAs did not affect the total rate of adverse events(AEs) (relative risk(RR) 1.11, 95% CI: 0.95 to 1.30, P = 0.19), but increased the risk of hypoglycemia (RR 1.81, 95% CI: 1.35 to 2.42, P < 0.0001). And the risk of diarrhea (RR 1.59, 95% CI: 0.7 to 3.65, P = 0.26), headache (RR 0.96, 95% CI: 0.41-2.21, P = 0.60) and nausea (RR 2.23, 95% CI: 0.55-9.12, P = 0.24) were not significantly increased in GKAs group. Conclusions: Oral GKAs combined with metformin has an obvious hypoglycemic effect on T2DM and good tolerance. Further clinical studies are still necessary to explore its long-term efficacy and safety. Keywords: Glucokinase; Glucokinase activator; Type 2 diabetes; Meta-analysis

Aim. Repurposing strategies to address the COVID-19 pandemic have been accelerated. As both pregnant and pediatric patients are likely to be excluded from most planned investigations, the list of repurposed options and the available data on these drugs and vaccines provides a baseline risk assessment and identifies gaps for targeted investigation. Methods. Clinical trials have been searched and reviewed; twenty-three repurposed drugs and drug combinations and 9 candidate vaccines have been assessed regarding the availability of relevant data in pediatrics and pregnant women and to evaluate expected or unanticipated risk. Results. Thirteen of the repurposed drugs or drug combinations are indicated for use in pediatrics in some age category albeit for indications other than COVID-19; 10 of these are indicated for use in pregnant women. Even in cases where these drugs are indicated in the populations, source data from which safety and or dosing could be extrapolated for use in COVID-19 is sparse. Vaccine trials are ongoing and generally exclude pregnant women; only in a few instances have pediatric subgroups been planned for enrollment. Data from individual case studies and RWD may suggest that subpopulations of both pediatric patients and pregnant women may be more at risk, particularly those in an increased inflammatory state. Conclusion. In conjunction with more prospective collaboration, plans are evolving to ensure that we will be better prepared to address similar situations especially in pediatrics and pregnant women where experience is limited and actual practice relies heavily on leveraging data from other populations and indications.

BACKGROUND AND PURPOSE Mass drug administration of ivermectin has been proposed as a possible malaria elimination tool. Ivermectin exhibits a mosquito-lethal effect well beyond its biological half-life, suggesting the presence of active slowly eliminated metabolites. EXPERIMENTAL APPROACH Human liver microsomes, primary human hepatocytes, and whole blood from healthy volunteers given oral ivermectin were used to identify ivermectin metabolites by ultra-high performance liquid chromatography coupled with high resolution mass spectrometry. The molecular structures of metabolites were determined by mass spectrometry and verified by nuclear magnetic resonance. Pure cytochrome P450 enzyme isoforms were used to elucidate the metabolic pathways. KEY RESULTS Thirteen different metabolites (M1-M13) were identified after incubation of ivermectin with human liver microsomes. Three (M1, M3, and M6) were the dominant metabolites found in microsomes, hepatocytes, and blood from volunteers after oral ivermectin administration. The chemical structure defined by LC-MS/MS and NMR indicated that M1 is 3″-O-demethyl ivermectin, M3 is 4-hydroxymethyl ivermectin, and M6 is 3″-O-demethyl, 4-hydroxymethyl ivermectin. Metabolic pathway evaluations with characterized cytochrome P450 enzymes showed that M1 was produced by CYP3A4 and CYP3A5, and that M3 and M6 were produced by CYP3A4. CONCLUSIONS AND IMPLICATIONS Demethylated and hydroxylated ivermectin are the main human metabolites in vivo. Further study to characterize their pharmacokinetic properties and mosquito-lethal activity is now needed.

Background and Purpose: Hypertensive vascular remodeling (VR) is responsible for end-organ damage and is the result of increased extracellular matrix accumulation and excessive vascular smooth muscle cell (VSMC) proliferation. MicroRNA-26a (miR-26a), a non-coding small RNA, is involved in multiple cardiovascular diseases. We aimed to validate the effect and mechanisms of miR-26a in hypertensive VR. Experimental Approach: Spontaneously hypertensive rats (SHRs) were injected intravenously with recombinant adeno-associated virus-miR-26a. In vitro experiments, angiotensin II (AngII)-induced VSMCs were transfected with miR-26a mimic or inhibitor. Key Results: We found miR-26a downregulated in the thoracic aorta and plasma of SHRs. Overexpression of miR-26a inhibited extracellular matrix deposition by targeting connective tissue growth factor (CTGF) and mitigated VSMC proliferation by regulating the enhancer of zeste homolog 2 (EZH2)/p21 pathway both in vitro and in vivo. AngII-mediated Smad3 activation suppressed miR-26a expression, which in turn promoted Smad3 activation via targeted regulation of Smad4, leading to further downregulation of miR-26a. Conclusion and Implications: Our study reveals that AngII stimulates a Smads/miR-26a positive feedback loop, which further reduces miR-26a expression, leading to collagen production and VSMC proliferation and consequently, VR. MiR-26a has an antagonistic effect on hypertensive VR and can be a strategy for treating hypertensive VR.

Patients in sub-Saharan Africa generally have poor anticoagulation control. We review the potential reasons for this poor control, as well as the potential solutions. Challenges include the affordability and centralisation of anticoagulation care, problems with access to medicines and INR monitoring, the lack of locally-validated standardized dosing protocols, and low levels of anticoagulation knowledge among health care workers and patients. Increasing numbers of patients will need anticoagulation in the future because of the epidemiological transition in the region. We propose that locally-developed “warfarin care bundles” which address multiple anticoagulation challenges in combination may be the most appropriate solution in this setting currently.

Aim: To determine the risk factors of valproic acid (VPA)-induced tremor, with particular attention on characterizing cerebellar atrophy and identifying tremor-susceptible gene mutations. Methods: Epileptic patients taking VPA were divided into two groups, a tremor and a non-tremor group, based on self-reported or clinically assessed tremors. A mutation of rs9652490 in the leucine-rich repeat and immunoglobulin domain-containing Nogo-receptor-interacting protein 1 (LINGO-1) gene was determined by Sanger sequencing. Cerebellar atrophy was assessed and various cerebellar dimensions were measured on magnetic resonance imaging (MRI) scans. Results: Among 200 subjects enrolled, 181 were included for analysis (mean age 33.28±11.78 years old, male:female=2.77:1). In the tremor group, the percentage of females (p=0.036), positive tremor family history (p=0.001), and incidence of polytherapy (p=0.034), treatment duration (>12 months [p=0.013] or >24 months [p=0.008]), and daily dosage (>1,000 mg/d; p=0.003) of VPA, were significantly higher than in the non-tremor group. Treatment with VPA magnesium (p=0.030), alone or in combination with carbamazepine (p=0.040), reduced the incidence of tremor. Furthermore, 176 gene sequencing results ruled out any significant difference between the two groups in the mutation of rs9652490 within LINGO-1 (p=0.443); 86 subjects’ MRI scans indicated no significant differences in the ratio of cerebellar atrophy or the cerebellar-dimension values (p>0.05). However, mutation of rs9652490 within LINGO-1 was correlated with increased cerebellar atrophy (p=0.001), reduced cerebellar-hemisphere thickness (p=0.025), and right-cerebellar-hemisphere longitudinal diameter (p=0.047). Conclusion: Our cohort indicated risk and protective factors of VPA-induced tremor. Although mutation of rs9652490 within LINGO-1 correlated with cerebellar atrophy, neither was correlated with VPA-induced tremors.

Aim: Augmented Renal Clearance (ARC) is a common phenomenon among critically ill patients and create sub-therapeutic concentrations of antibiotics, due to an increase in renal clearance of them. We evaluated the Pharmacokinetic and Pharmacodynamic (PK/PD) properties of recommended doses of meropenem in critically ill patients with ARC. Methods: Adult critically ill patients with confirmed ARC, based on 12-hour Creatinine Clearance (CrCl) (≥130 ml/min/1.73 m2), who received standard doses of meropenem enrolled. Two blood samples were gathered from each participant, at the steady-state time, to determination of peak and trough concentrations. Serum concentrations of meropenem were measured by High-Performance Liquid Chromatography (HPLC) with Ultra-Violet (UV) detector. Results: From eighteen paired samples (peak and trough concentrations) that were obtained from 16 critically ill patients, peak concentrations were significantly lower in group 1 (received meropenem 1g every 8 hours) than group 2 (received meropenem 2g every 8 hours) (mean ±SD, 5.95 ±3.39 µg/mL vs. 11.93± 4.18 µg/mL, respectively, p= 0.005). Trough concentration were sub-threshold (< 2 µg/mL) in 10 patients of group 1 (83.3%) and 3 patients of group 2 (50%). ft > MIC ≥ 50% was achieved in 83.3% of patients in both groups whereas 16.6% of patients of group 1 and 33.3% of patients of group 2 had ft> MIC= 100%. Conclusion: ARC is an essential cause of sub-therapeutic concentrations of meropenem in critically ill patients, and higher than the recommended doses of meropenem administered as an intermittent infusion may be necessary to achieve the PD targets and improve efficacy.

Baricitinib is a promising drug in COVID-19 pneumonia. The aim of this study is to compare the clinical outcome of moderate-to-severe COVID-19 pneumonia treated with baricitinib with or without a loading dose. This prospective case-control study enrolled 37 adult patients where 17 patients (control) received baricitinib at 4 mg oral daily dose and 20 patients (case) received an additional single 8 mg oral loading dose. The median day to gain blood oxygen saturation level ≥ 95% (in room air) and return in normal breathing function were lower in case group than the control group [29.4% (n = 17)/10% (n = 20), P < 0.05; 11.8% (n = 17)/5% (n = 20), P > 0.05), respectively]. The requirement of intensive care unit and mechanical ventilation support were higher in control group than the case group. Thus, an additional loading dose of baricitinib revealed better clinical outcome in COVID-19 pneumonia.

Haemophilia A and B are rare bleeding disorders. Over the past decades, they have been transformed from debilitating diseases to manageable conditions. However, several challenges and unmet needs remain in the treatment of the haemophilia limiting the QoL of the patients. These challenges are now being addressed by EHL recombinant factors, rebalancing and substitution therapies. Gene therapy and genome editing show promise for a definite clinical cure. Herein, we provide an overview of new therapeutic opportunities for haemophilia and their advances and limitations. The database on human medicines from EMA was used and data from rare disease (orphan) designations and EPARs were retrieved for the analysis. Clinical Trial databases were used to query all active studies on haemophilia. Gene therapy medicinal products based on AAV and lentiviral vectors are in development and clinical trials have reported substantial success in ameliorating bleeding tendency in haemophilia patients. The prospect of gene editing for correction of the underlying mutation is on the horizon with considerable potential. We are entering an era of innovation and abundance in treatment options for those affected by bleeding disorders but issues still remain about the affordability and accessibility to patients, the long-term durability, safety and efficacy.

Aim: To evaluate clinical vertebral fractures after denosumab discontinuation in patients with breast cancer. Methods: To evaluate the occurrence of clinical vertebral fractures after denosumab discontinuation, we conducted a retrospective chart review to identify patients with a history of breast cancer who were treated with denosumab between June 1, 2010 and July 18, 2018 at Memorial Sloan Kettering Cancer Center. We identified 335 postmenopausal female patients and one male patient with nonmetastatic breast cancer who received at least two doses of denosumab (60 mg) and had received their final denosumab injection at least 6.5 months earlier. Results: The median age of patients was 62 years (54–69). Patients received between two and 13 denosumab doses before drug discontinuation. The majority of patients (310; 92.3%) were also treated with aromatase inhibitors. Of the 194 patients with baseline bone-density data, 50 (25.8%) had normal bone density, 97 (50.0%) had osteopenia, and 47 (24.2%) had osteoporosis. The median follow-up duration from the last denosumab dose was 18.5 months (12.5–23.5). We identified one case of spontaneous vertebral fractures after denosumab stoppage. We found no cases of osteonecrosis of the jaw or atypical femur fracture. A majority of patients (88%) had a gap in denosumab dosing. Conclusions: Patients with breast cancer—especially those taking aromatase inhibitors—taking denosumab should be warned of the risks of delaying denosumab. Larger prospective studies are needed to fully evaluate the risks of stopping or delaying denosumab

Coronavirus disease of 2019 (COVID-19) is a public health emergency of international concern caused by a novel coronavirus, i.e., Severe Acute Respiratory Syndrome Coronavirus -2 (SARS-CoV-2). Since it is a new virus, an effective remedy against the virus is yet unknown. SARS-CoV-2 is a member of order nidovirales, family coronaviridae. Previously known treatment strategies against Middle East Respiratory Syndrome and Severe Acute Respiratory Syndromes are being tested for their effectiveness against SARS-CoV-2. Thus, various clinical and observational studies aimed at identifying potential therapies against the disease. In our study, we reviewed various drugs along with their mechanism of action including anti-virals, anti-bacterials, glucocorticoids, ACE inhibitors, anti retrovirals, anti-malarials, monoclonal antibodies, plasma and many more. Individual drugs are described and evaluated for their potential to treat SARS-CoV-2 infection. This study offers a brief review of the findings of trials conducted so far. Dexamethasone, convalescent plasma therapy, tocilizumab, remdesivir and combination therapies are found to be beneficial against SARS-CoV-2.

We suggest that patients with COVID-19 may be at higher risk for selenium deficiency and, therefore, their selenium status should be assessed. Moreover, we suggest incorporating selenium supplementation to enhance their immune response and reduce the SARS-CoV-2 virulence.

Introduction: Pharmacist’s knowledge about different aspects of this pandemic is crucial because it influence their role and contribution as a frontline health care provider, as pharmacies and most of the pharmacy practice sectors are kept open even during lockdowns providing counseling, patient care. Pharmacist can provide valuable services during COVID-19 pandemic, these services may include: provide reliable information on the disease, participate in public education on preventive measures, referring of suspected cases, insuring continuous supply of medicine. Methods: A web-based, cross-sectional study, conducted using survey instrument to obtain responses from Sudanese pharmacists during the period from 26th of May to 3rd of June 2020. A 14-item survey instrument was developed. The web-based cross-sectional study was carried out among Sudanese pharmacists. A self-reported structured questionnaire was divided into three sections: demographic characteristics, questions assessing the knowledge, and one question for the pharmacist contribution during the pandemic. Results: The study showed that 51.1% of pharmacists have good knowledge about the COVID-19. The work experience and education level significantly (P<0.05) influence pharmacist knowledge. Majority of pharmacists contribute to different activities during the pandemic, e.g. providing patients with transmission information (94%), Provide factual and reliable information on the diseases symptoms (93.1%), providing patients with prevention information (91.1%). Conclusion: The study identified that pharmacists have good knowledge about COVID-19 pandemic Also pharmacists contributed in many activities as a frontline health care provider during this pandemic.

Aim: To investigate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of the highly selective oral p38α/β MAP-kinase inhibitor Org 48775-0, a first-in-human study was conducted. Methods: In the SAD study part, an oral dose of Org 48775-0 ranging from 0.3 mg to 600 mg was evaluated in healthy males. In the MAD study part, dose levels of 30, 70 and 150 mg were evaluated with dosing for six consecutive days, twice daily. Both studies were performed in a double-blind, randomized, placebo-controlled, cross-over fashion and evaluated pharmacokinetics (PK), pharmacodynamics (PD; inhibition of LPS-induced TNFα release) and routine clinical and laboratory data. Moreover, the effect of a standardized fat meal on PK and PD parameters of Org 48775-0 was evaluated, and PK and PD parameters of Org 48775-0 were compared between healthy males and postmenopausal females. Results: All adverse events observed in the SAD and MAD cohorts were mild, transient and completely reversible without medical intervention. Pharmacokinetics were linear up to single dose s of 400 mg. Org 48775-0 doses equal to and greater than 30 mg significantly inhibited LPS-induced TNFα release (42.3% increase in inhibition, 95% CI=-65.2; -4.3) compared to placebo. In the MAD study, Org 48775-0 treatment inhibited the LPS-induced TNFα release during the entire steady state period. Levels of inhibition amounted 30-75% for 30 mg, 53-80% for 70 mg, and 77-92% for 150 mg Org 48775-0. Conclusion: This study demonstrates that Org 48775-0 has the capacity to significantly inhibit MAP-kinase activity in humans, without raising safety concerns.

As of March, 2020, Corona Virus disease 2019 (COVID-19) has catapulted to the status of a pandemic. Its rapid spread has initiated a worldwide search for appropriate therapeutics targeting the causative SARS-CoV-2 virus. Till now, the management of critical COVID-19 patients mainly revolves around the supportive therapies of supplemental oxygen and ventilatory support. However, pharmacotherapy and immunotherapy specifically intended to halt SARS-CoV-2 from exerting its effects are increasingly being incorporated into treatment regimens. COVID-19 patient care continues to evolve as the available drugs are being thoroughly investigated for their potential antiviral effects and new therapies, such as vaccines, are being developed. The list of pre-existing therapeutics that show promise against SARS-CoV-2 includes anti-virals like Remdesivir, plasma therapy, traditional Chinese medicine (TCM), anticoagulants, antibiotics, corticosteroids and several other investigational agents such as vitamin supplements and thymosin alpha one. In this comprehensive, updated review we will highlight the major prospective therapies that are currently in the arsenal against COVID-19 and where they stand in the treatment recommendations as well as a brief look at the challenges faced in Pakistan. With this review we not only hope to disseminate the accurate, recent information regarding these therapies, but also discuss the reliability of the clinical trials that have designated them to be useful against COVID-19.

The disbalance of the renin-angiotensin system was suggested to play an important role in the pathogenesis of the COVID-19 disease. Previously it has been shown that ACE2 expression in downregulated in the murine model in response to SARS-CoV infection and may be also induced by the recombinant spike protein alone. We hypothesize that the soluble SARS-CoV-2 spike protein S1 subunits shed from the infected cells and from the virions in vivo may bind to the ACE2 receptor and trigger ACE2 downregulation. Decreased ACE2 activity on the background of the constant or increased ACE activity in the lungs may lead to the prevalence of angiotensin II effects over angiotensin(1-7) connected to increased thrombosis, inflammation and pulmonary damage.

Objective: To analyze the current situation of clinical trials of drugs with indications for children in China in order to provide references for research and development of drugs for children and in formulating relevant policies. Methods: Drug clinical trials with indications for children registered before January 9, 2020 were retrieved based on the drug clinical trial registration and information publicity platform. The data were extracted and statistically analyzed by excel 2010 and SPSS 22.0, respectively. Results: There were 256 clinical trials of drugs with indications for children, which accounted for 2.61% of the total registered trials. The overall average annual growth rate of the number of trials from 2007 to 2019 was 43.30% (P=0.0000). The host company and the lead organization were mainly located in the eastern and northern parts of China. There were 67 trials (26.17%) with children as subjects; 102 trials (39.84%) with research drugs only for children; the drug type was mainly the chemical drug, and indications mainly included infections, nervous and mental diseases and respiratory diseases. Conclusion: The prospects associated with pediatric drug development are positive, but it still needs new incentives or technical guidance to further promote.

Glucocorticoids are highly effective medicines in the treatment of inflammatory disorders. However they cause severe dose-related adverse reactions, particularly where taken systemically for prolonged periods. Systemic glucocorticoids are therefore given at dosage sufficient to control the disease, then withdrawn as fast as is possible to minimise dose-related adverse effects without losing disease control. End-of-use adverse reactions present a major challenge in the withdrawal of long term (>3 weeks) glucocorticoids. Suppression of the hypothalamic-pituitary-adrenal (HPA) axis causes adrenal insufficiency, which is potentially life threatening and can become symptomatic as treatment is withdrawn. Adrenal insufficiency can be extremely difficult to differentiate from ‘glucocorticoid withdrawal syndrome’, where patients experience symptoms despite adequate adrenal function, and from psychological dependence. Long term systemic glucocorticoids should therefore be withdrawn slowly. The rate at which the dose is tapered should initially be determined by treatment requirements of the underlying disease. Once physiological doses (prednisolone 7.5mg or equivalent) are reached, the rate of reduction is determined by rate of HPA recovery and need for exogenous glucocorticoid cover while endogenous secretion recovers. If symptoms prevent treatment withdrawal, HPA testing should be used to look for adrenal insufficiency. Patients with adrenal insufficiency require physiological doses of glucocorticoids for adrenal replacement, which may be lifelong if the HPA axis fails to recover.

Introduction: Though there is currently no approved treatment for COVID-19, potential medications include lopinavir and doxycycline. Lopinavir is a broad-spectrum protease inhibitor successfully used during the SARS outbreak. Doxycycline is an antibiotic with immunomodulatory effects, which successfully treats dengue hemorrhagic fever. Comparing lopinavir combined with doxycycline with other commonly implemented COVID-19 treatment regimens is of medical significance. Methods: We conducted a retrospective study comparing two cohorts. One cohort strictly adhered to a treatment protocol of lopinavir combined with doxycycline (Lop/Dox), while the other cohort (Others) applied protocols based on combinations of favipiravir, hydroxychloroquine, and azithromycin. The outcomes evaluated were death from coronavirus and intubation. Results: During the study period, 161 and 114 patients were followed in the Lop/Dox cohort and the Others cohort, respectively. The Lop/Dox cohort was older and had lower O2 saturation at admission. The proportion of patients needing intubation did not differ between the cohorts (Lop/Dox, 15∙5%; Others, 16∙7%). The overall fatality rate likewise did not differ (12∙4%) in Lop/Dox and 8∙7% in the Others cohort). Older age and elapsed time between the onset of symptoms and hospitalization, O2 saturation at admission, and the lymphocyte to white blood cell ratio were independent risk factors for poor outcomes of the illness. Conclusion: This study showed that lopinavir plus doxycycline therapy is an effective treatment amongst moderate to severe COVID-19 patients.

Associations between colorectal cancer (CRC) survival and mutations in mediator of MAPK/ERK (RAS-BRAF-MEK-ERK) and PIK3CA/AKT signaling pathways have been reported. The objective of this study was to evaluate the influence of mutations in the EGFR pathway (KRAS, NRAS, BRAF and PIK3CA) on overall survival in CRC. We conducted a retrospective observational cohort study comprising 194 paraffin tumor samples from patients diagnosed with colorectal cancer were analyzed for KRAS codons 12, 13 and 61, NRAS codons 12, 13 and 61, BRAF and PIK3CA exons 9 and 20 gene mutations. Multivariate analysis confirmed that patients with ECOG of 0 presented lower risk of death (HR = 0.17, CI95%, 0.10 -0.31, p = 1656.10-9) compared to a higher ECOG (Table 4). The only independent genetic association was between PIK3CA20 mutation (H1047Y; rs121913281) and higher risk of death (HR = 8.93, CI95%, 1.20-66.57, p = 0.03268). No association was found between the rest of the mutations analyzed and overall survival. To explore the effect of mutations in patients with different degrees of ECOG, a stratified analysis was performed. Multivariate analysis in patients with ECOG 0 group confirmed the association between mutations of PIK3CA and an increased risk of death: E545K (HR = 5.49, CI95%, 1.28-23.51, p = 0.021720) and H1047Y (HR = 53.49; %, 4.63-617.40, p = 0.001429). In conclusion, our results show PIK3CA gene mutations may predict the overall survival of CRC patients, positioning PIK3CA as a potential biomarker for survival in CRC.

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.

Background: An understanding of deprescribing processes in primary care is an important step in designing policy initiatives and healthcare systems to optimise appropriate antidepressant discontinuation. Aim: To explore GPs perceptions and experiences of discontinuing antidepressants. Design and setting: Following ethical approval, a qualitative study was undertaken with GPs affiliated with a University education and research network for general practice in Ireland. Method: Semi-structured interviews undertaken with a purposive sample of GPs (n=10) between July 2019 and March 2020, were transcribed and analysed using Braun and Clarkes (2013) thematic analysis framework. Results: Five themes emerged: Clinical dilemmas; personalised therapy; medication tapering toolkit; talk therapy and concerns around tapering. GPs described being less likely to engage in deprescribing in those with recurrent depression, older patients and those with comorbidities. Fear associated with patient relapse was described by all participants. GPs felt limited access to psychological services impacted on care and that prompts to review might facilitate deprescribing. Conclusions: GPs are confident in their role of managing mild to moderate depression in the community and deprescribing antidepressants. This study provides an insight into factors that influence GPs decisions to deprescribe antidepressants and the barriers and facilitators for GPs in this role.

COVID-19 is the global-pandemic targets human-lung-ACE2 that converts Angiotensin-II to (1-7) peptide causing vasodilatation. Vasoconstriction caused by Angiotensin-II is produced from Angiotensin-I by ACE1. The vaso-status maintains blood-pressure/vascular-health of the individuals which is demolished in Covid-19 infection manifesting aldosterone/salt-deregulations/inflammations/endothelial-dysfunctions/hyper-hypo- tension, sepsis/hypovolemic-shock and vessel-thrombosis/coagulations. These cause comorbidity patients. Here, nigellidine, an indazole-alkaloid was analyzed by molecular-docking for binding to different Angiotensin-binding-proteins (enzymes, ACE1(6en5)/ACE2(4aph)/receptors, AT1(6os1)/AT2(5xjm)) and COVID-19 spike-glycoprotein(6vsb). Data suggest that nigellidine strongly binds to the spike-protein at the hinge-region/active-site-opening which may hamper proper-binding of nCoV2-ACE2 surface. Nigellidine strongly (-7.54 kcal/mol, -211.76, Atomic-Contact-Energy; ACE-value) binds (>known-binderEGCG; -4.53 and Theaflavin-di-gallate; -2.85) in the Angiotensin-II binding-site/entry-pocket at ACE2 with Ki 8.68 and 8.3 µmol. Further, Nigellidine showed strong-binding (best Ki, 50.93µmol/binding-energy -5.48 kcal/mol) to both mono- and multi-meric ACE1-forms. Moreover, this compound binds Angiotensin-receptors, AT1/AT2 (Ki, 42.79/14.22 µmol, binding-energy, -5.96/-6.61 kcal/mol) at active-sites, respectively. Here, we first-time report that nigellidine can block all angiotensin-binding proteins where, the Angiotensin-bonded amino acids were more or less similar/analogous and effectively blocked by nigellidine. The ACEs-blocking could restore Angiotensin-level and restrict vaso-turbulence in Covid-infected patients and receptor-blocking might stop inflammatory/vascular impairment. Further, nigellidine may slowdown the vaso-fluctuations due to Angiotensin deregulations in Covid-infected patients. Angiotensin II-ACE2 binding (ACE-value -294.81) is more favorable than nigellidine-ACE2. Contrarily, nigellidine-ACE1 binding-energy/Ki are lower than nigellidine-ACE2 values indicating a balanced-state between constriction-dilatation. It is also noticed that nigellidine binds to the viral-spike, closer proximity to its ACE2 binding-domain. Taken together, Covid-infected-patients/elderly-patients/comorbid-patients (with hypertensive/diabetic/cardiac/renal impairment, counting >90% of non-survivors) could be greatly benefited.

Introduction We reviewed the types of monoclonal antibodies being repurposed for COVID-19 therapeutics, the clinical outcomes and adverse effects so as to provide evidence the bedside physicians, the health policy-makers and the general public could employ in the COVID-19 management protocol. Methods This systematic review was conducted following the guidelines of Preferred Reporting Items for Systematic Reviews and Meta-Analyses. The Joanna Briggs Institute’s critical appraisal checklists for evaluation of the quality of studies were employed to assess the quality of the different types of primary studies included in the review. Results Our search strategy identified 396 potentially relevant articles which decreased to 322 after duplicates were removed. 281 articles were screened out due to lack of relevance. The full text of the remaining 41 relevant papers were retrieved for full text evaluation after which only 19 studies from eight countries met our eligibility criteria and were included in the review. Majority (42%) of the studies emanated from Italy. Also, 94.7% of the studies used tocilizumab. A total of 698 patients were included in all the studies with a male/female ratio of 1.94:1. 78.9% of the studies stated patients’ co-morbidities which include hypertension (80%), diabetes mellitus (73.3%), cardiovascular disease (53.3%) and obesity (26.7%). 75.9% of the patients recovered. Adverse effects reported included viral myocarditis, bacteraemia, candidaemia and invasive aspergillosis. Conclusion Monoclonal antibodies, especially tocilizumab and eculizumab hold some promise in the treatment of the disease but controlled clinical trials using them as monotherapy are needed to further evaluate this finding.