Ivermectin role in COVID-19 treatment (IRICT): single-center, adaptive, randomized, double-blind, placebo-controlled, clinical trial.

BACKGROUND: To investigate the efficacy and safety of ivermectin compared to hydroxychloroquine and placebo in hospitalized moderate to severe COVID-19 patients. RESEARCH DESIGN AND METHODS: The study was an adaptive, randomized, double-blinded, controlled, single-center trial. The study was a series of 3-arm comparisons between two different investigational therapeutic agents (ivermectin and hydroxychloroquine) and a placebo. There was interim monitoring to allow early stopping for futility, efficacy, or safety. RESULTS: Ivermectin decreased survival time from 29 to 18.3 days (HR, 9.8, 95%CI, 3.7-26.2), while it did not shorten the recovery time (HR, 1.02, 95%CI, 0.69-1.5). Subgroup analysis showed an association between ivermectin-related mortality and baseline oxygen saturation level. Moreover, stratified groups showed higher risk among patients on high flow O2. Hydroxychloroquine delayed recovery from 10.1 to 12.5 days (HR, 0.62, 95%CI, 0.4-0.95) and non-significantly decreased survival time from 29 to 26.8 days (HR, 1.47, 95%CI, 0.73-2.9). However, 3 months mortality rates were increased with hydroxychloroquine (RR, 2.05, 95%CI, 1.33-3.16). Neither ivermectin nor hydroxychloroquine increased adverse events and demonstrated safety profile compared to placebo. CONCLUSIONS: The study recommends against using either ivermectin or hydroxychloroquine for treatment of COVID-19 in hospitalized patients with any degree of severity. Clinical trial registration: www.clinicaltrials.gov identifier is: NCT04746365.

Carbapenems consumption and Klebsiella resistance in intensive care units in Egypt: A study to evaluate the effect of an antimicrobial stewardship program.

Background: The high prevalence of carbapenem-resistant Klebsiella imposes optimizing antibiotic consumption. We aimed to evaluate the impact of antibiotic stewardship program on carbapenem consumption and the Klebsiella resistance. Method: We retrospectively evaluated critically ill patients with isolated Klebsiella species from Elaraby hospital, Egypt during the period from April 2017 to January 2019. We collected data related to carbapenems consumption and Klebsiella clinical isolates with their antimicrobial susceptibility. Based on susceptibility, Klebsiella isolates were classified into sensitive, extended spectrum beta-lactamase (ESBL) producer, and carbapenem-resistant Klebsiella (CRK), respectively. Our primary outcome was the change in carbapenems consumption after implementing the program, while the secondary outcomes were the changes in the incidence of CRK. Results: The study included 205 patients with isolated Klebsiella species during the study period. The antibiotic stewardship program started in March 2018. Out of the 205 patients, 61 patients (29.8%) represented the pre-intervention sample, and 144 patients (70.2%) represented the post-intervention sample. Applying the antibiotic stewardship program was associated with a significant decrease in the carbapenems consumption from 38.9 to 26.6 defined daily dose/1000 patient-days (p = 0.02). The incidence of CRK was decreased from 85.25% of total Klebsiella isolates to 48.6% (p < 0.001). Klebsiella species were more likely to be in a lower category of resistance after applying the program with an odds ratio of 6.3 (2.88-13.73) using ordinal logistic regression. Conclusion: Applying the antibiotic stewardship program could reduce the unnecessary carbapenems use in the ICU with a subsequent decrease in the emergence of the Klebsiella-resistant strains.

Double-blind, randomized, placebo-controlled pilot study of the phosphodiesterase-3 inhibitor cilostazol as an adjunctive to antidepressants in patients with major depressive disorder.

AIMS: Cilostazol (CLS) has shown antidepressant effect in cardiovascular patients, post-stroke depression, and animal models through its neurotrophic and antiinflammatory activities. Consequently, we aimed to investigate its safety and efficacy in patients with MDD by conducting double-blind, randomized, placebo-controlled pilot study. METHODS: 80 participants with MDD (DSM-IV criteria) and Hamilton Depression Rating Scale (HDRS) score >20 were treated with CLS 50 mg or placebo twice daily plus escitalopram (ESC) 20 mg once daily for six weeks. Patients were evaluated by HDRS scores (weeks 0, 2, 4, and 6). Serum levels of CREB1, BDNF, 5-HT, TNF-α, NF- κB, and FAM19A5 were assessed pre- and post-treatment. RESULTS: Co-administration of CLS had markedly decreased HDRS score at all-time points compared to the placebo group (p < 0.001). Early improvement, response, and remission rates after 6 weeks were significantly higher in the CLS group (90%, 90%, 80%, respectively) than in the placebo group (25%, 65%, 50% respectively) (p < 0.001). Moreover, the CLS group was superior to the placebo group in modulation of the measured neurotrophic and inflammatory biomarkers. CONCLUSION: CLS is safe and effective short-term adjunctive therapy in patients with MDD with no other comorbid conditions. Trial registration ID:NCT04069819.

The AMPK modulator metformin as adjunct to methotrexate in patients with rheumatoid arthritis: A proof-of-concept, randomized, double-blind, placebo-controlled trial.

BACKGROUND: Metformin (MET) may exert anti-rheumatic effects and reduce cartilage degradation through its immunomodulatory and anti-inflammatory actions. METHODS: This was a double-blind placebo-controlled study, 120 adult patients with active rheumatoid arthritis (RA) were randomized to receive MET (1000 mg) or placebo daily with methotrexate (MTX, 7.5 mg/week) for 12 weeks. American College of Rheumatology (ACR)20, ACR50, and ACR70 response rates, Disease Activity Score in 28 joints (DAS-28), and drug safety were the efficacy endpoints. Serum levels of TNF-α, IL-1ß, IL-6, IL-10, IL-17A, NF-κB, TGG-ß1, MDA together with gene expression of AMPK and IGF-IR were assessed before and after the therapy. RESULTS: A total of 80.8% of the patients in the MET group, compared with 54.7% in placebo group, met the criteria of ACR20 response after 12 weeks (P = 0.001). Statistically significant enhancements in the DAS28-3 (CRP) were observed after 4 and 8 weeks for the MET group compared with placebo and were sustained after 12 weeks. MET group showed statistically significant increase in percentage of patients achieving DAS remission after 12 weeks (P = 0.015). Significant improvements in ACR50, ACR70, Health Assessment Questionnaire Disability Index (HAQ-DI), and DAS28-3 (CRP) were also reported. MET was well-tolerated, and no serious adverse effects were reported in both groups. Furthermore, the MET group was superior in improving the measured parameters compared to the placebo. CONCLUSIONS: MET improved the anti-rheumatic effect of MTX; suggesting it to be a beneficial adjuvant in patients with RA. Trial registration ID: NCT04068246.

Efficacy and safety of remdesivir in hospitalized Covid-19 patients: Systematic review and meta-analysis including network meta-analysis.

Remdesivir is an antiviral agent that has shown broad-spectrum activity, including against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Clinical trials investigating the role of remdesivir in coronavirus disease 2019 (Covid-19) reported conflicting results. This study aimed to systematically review the best available evidence and synthesize the results. Several electronic databases were searched for candidate studies up to 12 October 2020. Studies eligible for meta-analysis were selected based on the inclusion criteria. Primary outcomes are the recovery and mortality rates, while secondary outcomes are the safety profile of remdesivir. The main effective measures are the rate ratio (RR) and rate difference (RD). Four clinical trials and one observational study were included. Remdesivir treatment for 10 days increased the recovery rate on day 14 by 50% among severe Covid-19 patients (RR = 1.5, 95%CI = 1.33-1.7), while on day 28 it was increased by 14% among moderate and severe Covid-19 patients (RR = 1.14, 95%CI = 1.06-1.22). Additionally, remdesivir decreased the mortality rate on day 14 by 36% among all patients (RR = 0.64, 95%CI = 0.45-0.92) but not on day 28 (RR = 1.05, 95%CI = 0.56-1.97). Nonmechanically ventilated Covid-19 patients showed better response to remdesivir in the recovery (RR = 0.3, 95%CI = 0.13-0.7) and mortality (RR = 2.33, 95%CI = 1.24-4.4) rates on day 14. Remdesivir reduced serious adverse effects by absolute 6% and no significant Grade 3 or 4 adverse effects were reported. At this early stage of the pandemic, there is evidence that remdesivir can be safely administered for hospitalized Covid-19 patients. It improves the recovery rate in both moderate and severe patients but, the optimal effect is achieved for those who are severely affected but not mechanically ventilated.

Hydroxychloroquine for treatment of nonsevere COVID-19 patients: Systematic review and meta-analysis of controlled clinical trials.

Being a pandemic and having a high global case fatality rate directed us to assess the evidence strength of hydroxychloroquine efficacy in treating coronavirus disease-2019 (COVID-19) arising from clinical trials and to update the practice with the most reliable clinical evidence. A comprehensive search was started in June up to 18 July, 2020 in many databases, including PubMed, Embase, and others. Of 432 studies found, only six studies fulfilled the inclusion criteria, which includes: clinical trials, age more than 12 years with nonsevere COVID-19, polymerase chain reaction-confirmed COVID-19, hydroxychloroquine is the intervention beyond the usual care. Data extraction and bias risk assessment were done by two independent authors. Both fixed-effect and random-effect models were utilized for pooling data using risk difference as a summary measure. The primary outcomes are clinical and radiological COVID-19 progression, severe acute respiratory syndrome coronavirus-2 clearance in the pharyngeal swab, and mortality. The secondary outcomes are the adverse effects of hydroxychloroquine. Among 609 COVID-19 confirmed patients obtained from pooling six studies, 294 patients received hydroxychloroquine and 315 patients served as a control. Hydroxychloroquine significantly prevents early radiological progression relative to control with risk difference and 95% confidence interval of -0.2 (-0.36 to -0.03). On the other hand, hydroxychloroquine did not prevent clinical COVID-19 progression, reduce 5-day mortality, or enhance viral clearance on days 5, 6, and 7. Moreover, many adverse effects were reported with hydroxychloroquine therapy. Failure of hydroxychloroquine to show viral clearance or clinical benefits with additional adverse effects outweigh its protective effect from radiological progression in nonsevere COVID-19 patients. Benefit-risk balance should determine the hydroxychloroquine use in COVID-19.

Topiramate for smoking cessation: Systematic review and meta-analysis.

INTRODUCTION: Topiramate is an antiepileptic drug that has been used for many labeled and off-labeled indications. It may be useful in reducing withdrawal symptoms of various addictive agents such as alcohol, cocaine, cannabis and smoking. To date, some studies have examined the effectiveness of topiramate for smoking cessation. The present review aims to synthesize the results from those studies and determine topiramate effectiveness in smoking cessation. METHODS: A comprehensive search was conducted in the databases: PubMed/Medline, Cochrane, Egyptian Knowledge Bank, and Google Scholar. All clinical trials that examined the effect of topiramate, compared with the placebo, on smoking cessation rate were included. Statistical analysis using fixed effect models, heterogeneity and sensitivity analysis were conducted using RevMan 5.3. RESULTS: Five trials met the inclusion criteria and were included in the meta-analysis. Topiramate non-significantly increased prolonged smoking abstinence rate (OR=1.19, 95% CI: 0.57-2.5) compared with the placebo. On the other hand, topiramate significantly increased the abstinence rate at weeks 4, 6, 8 and 12 (OR=3.07, 95% CI: 1.19-7.93; OR=4.03, 95% CI: 1.98-8.2; OR=2.29, 95% CI: 1.23-4.28; and OR=2.45, 95% CI: 1.37-4.39; respectively) compared with the placebo. CONCLUSIONS: Based on the five trials, where publication bias cannot be excluded, the current evidence is not sufficient to show a significant difference to favor topiramate in prolonged smoking cessation over the placebo, although the 12th week point prevalence favored topiramate.