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in category pharmacology and therapeutics

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1: Observational Study on 255 Mechanically Ventilated Covid Patients at the Beginning of the USA Pandemic
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Posted 31 May 2021

Observational Study on 255 Mechanically Ventilated Covid Patients at the Beginning of the USA Pandemic
24,861 downloads medRxiv pharmacology and therapeutics

Leon G Smith, Nicolas Mendoza, Stephen Smith, David P Dobesh

Abstract Introduction: This observational study looked at 255 COVID19 patients who required invasive mechanical ventilation (IMV) during the first two months of the US pandemic. Through comprehensive, longitudinal evaluation and new consideration of all the data, we were able to better describe and understand factors affecting outcome after intubation. Methods: All vital signs, laboratory values, and medication administrations (time, date, dose, and route) were collected and organized. Further, each patient's prior medical records, including PBM data and available ECG, were reviewed by a physician. These data were incorporated into time-series database for statistical analysis. Results: By discharge or Day 90, 78.2% of the cohort expired. The most common pre-existing conditions were hypertension, (63.5%), diabetes (59.2%) and obesity (50.4%). Age correlated with death. Comorbidities and clinical status on presentation were not predictive of outcome. Admission markers of inflammation were universally elevated (>96%). The cohort's weight range was nearly 7-fold. Causal modeling establishes that weight-adjusted HCQ and AZM therapy improves survival by over 100%. QTc prolongation did not correlate with cumulative HCQ dose or HCQ serum levels. Discussion: This detailed approach gives us better understanding of risk factors, prognostic indicators, and outcomes of Covid patients needing IMV. Few variables were related to outcome. By considering more factors and using new methods, we found that when increased doses of co-administered HCQ and AZM were associated with >100% increase in survival. Comparison of absolute with weight-adjusted cumulative doses proves administration [≥]80 mg/kg of HCQ with > 1 gm AZM increases survival in IMV-requiring Covid patients by over 100%. According to our data, HCQ is not associated with prolongation. Studies, which reported QTc prolongation secondary to HCQ, need to be re-evaluated more stringently and with controls. The weight ranges of Covid patient cohorts are substantially greater than those of most antibiotic RCTs. Future clinical trials need to consider the weight variance of hospitalized Covid patients and need to study therapeutics more thoughtfully.

2: Hydroxychloroquine with or without azithromycin and in-hospital mortality or discharge in patients hospitalized for COVID-19 infection: a cohort study of 4,642 in-patients in France
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Posted 19 Jun 2020

Hydroxychloroquine with or without azithromycin and in-hospital mortality or discharge in patients hospitalized for COVID-19 infection: a cohort study of 4,642 in-patients in France
11,721 downloads medRxiv pharmacology and therapeutics

Emilie Sbidian, Julie Josse, Guillaume Lemaitre, Imke Mayer, Melodie Bernaux, Alexandre Gramfort, Nathanael Lapidus, Nicolas Paris, Antoine Neuraz, Ivan Lerner, Nicolas Garcelon, Bastien Rance, Olivier Grisel, Thomas Moreau, Ali Bellamine, Pierre Wolkenstein, Gael Varoquaux, Eric Caumes, Marc Lavielle, Armand Mekontso Dessap, Etienne Audureau

Objective To assess the clinical effectiveness of oral hydroxychloroquine (HCQ) with or without azithromycin (AZI) in preventing death or leading to hospital discharge. Design Retrospective cohort study. Setting An analysis of data from electronic medical records and administrative claim data from the French Assistance Publique - Hopitaux de Paris (AP-HP) data warehouse, in 39 public hospitals, Ile-de-France, France. Participants All adult inpatients with at least one PCR-documented SARS-CoV-2 RNA from a nasopharyngeal sample between February 1st, 2020 and April 6th, 2020 were eligible for analysis. The study population was restricted to patients who did not receive COVID-19 treatments assessed in ongoing trials, including antivirals and immunosuppressive drugs. End of follow-up was defined as the date of death, discharge home, day 28 after admission, whichever occurred first, or administrative censoring on May 4, 2020. Intervention Patients were further classified into 3 groups: (i) receiving HCQ alone, (ii) receiving HCQ together with AZI, and (iii) receiving neither HCQ nor AZI. Exposure to a HCQ/AZI combination was defined as a simultaneous prescription of the 2 treatments (more or less one day). Main outcome measures The primary outcome was all-cause 28-day mortality as a time-to-event endpoint under a competing risks survival analysis framework. The secondary outcome was 28-day discharge home. Augmented inverse probability of treatment weighted (AIPTW) estimates of the average treatment effect (ATE) were computed to account for confounding. Results A total of 4,642 patients (mean age: 66.1 +/- 18; males: 2,738 (59%)) were included, of whom 623 (13.4%) received HCQ alone, 227 (5.9%) received HCQ plus AZI, and 3,792 (81.7%) neither drug. Patients receiving "HCQ alone" or "HCQ plus AZI" were more likely younger, males, current smokers and overall presented with slightly more co-morbidities (obesity, diabetes, any chronic pulmonary diseases, liver diseases), while no major difference was apparent in biological parameters. After accounting for confounding, no statistically significant difference was observed between the "HCQ" and "Neither drug" groups for 28-day mortality: AIPTW absolute difference in ATE was +1.24% (-5.63 to 8.12), ratio in ATE 1.05 (0.77 to 1.33). 28-day discharge rates were statistically significantly higher in the "HCQ" group: AIPTW absolute difference in ATE (+11.1% [3.30 to 18.9]), ratio in ATE (1.25 [1.07 to 1.42]). As for the "HCQ+AZI" vs neither drug, trends for significant differences and ratios in AIPTW ATE were found suggesting higher mortality rates in the former group (difference in ATE +9.83% [-0.51 to 20.17], ratio in ATE 1.40 [0.98 to 1.81];p=0.062). Conclusions Using a large non-selected population of inpatients hospitalized for COVID-19 infection in 39 hospitals in France and robust methodological approaches, we found no evidence for efficacy of HCQ or HCQ combined with AZI on 28-day mortality. Our results suggested a possible excess risk of mortality associated with HCQ combined with AZI, but not with HCQ alone. Significantly higher rates of discharge home were observed in patients treated by HCQ, a novel finding warranting further confirmation in replicative studies. Altogether, our findings further support the need to complete currently undergoing randomized clinical trials.

3: Clinical observations of low molecular weight heparin in relieving inflammation in COVID-19 patients: A retrospective cohort study
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Posted 01 Apr 2020

Clinical observations of low molecular weight heparin in relieving inflammation in COVID-19 patients: A retrospective cohort study
10,598 downloads medRxiv pharmacology and therapeutics

Chen Shi, Cong Wang, Hanxiang Wang, Chao Yang, Fei Cai, Fang Zeng, Fang Cheng, Yihui Liu, Taotao Zhou, Bin Deng, Israel Vlodavsky, Jin-Ping Li, Yu Zhang

BackgroundOn March 11, 2020, the World Health Organization declared its assessment of COVID-19 as a global pandemic. Effective therapeutic drugs are urgently needed to improve the overall prognosis of patients, but currently no such drugs are available. MethodsPatients in the study were divided into a heparin and a control group based on whether low molecular weight heparin (LMWH) was used. D-dimer, C-reactive protein (CRP), peripheral blood lymphocyte percentage, interleukin-6, and other indices in 42 patients with novel coronavirus pneumonia were retrospectively analyzed to compare and evaluate the progress of patients before and after LMWH treatment. ResultsCompared to the control group, D-dimer levels in the heparin group significantly increased before treatment, and there was no significant difference after treatment. There was no significant difference in the change of CRP levels between the two groups of patients before and after LMWH treatment, and levels for both groups were significantly lower after, compared to before, treatment. Compared to the control group, patients in the heparin group had a higher percentage of lymphocytes after treatment and lower levels of interleukin-6; these differences were statistically significant. ConclusionsUnder conventional antiviral treatment regimens, LMWH can improve hypercoagulability, inhibit IL-6 release, and counteract IL-6 biological activity in patients. LMWH has potential antiviral effects and can help delay or block inflammatory cytokine storms. It can also increase the lymphocytes (LYM%)of patients and has the potential for treatment of COVID-19.

4: Role of pharmacist during the COVID-19 pandemic: a scoping review
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Posted 02 Jul 2020

Role of pharmacist during the COVID-19 pandemic: a scoping review
9,617 downloads medRxiv pharmacology and therapeutics

Marilia Berlofa Visacri, Isabel Vitoria Figueiredo, Tácio de Mendonça Lima

Abstract Background Since the start of the new Coronavirus (COVID-19) outbreak in December 2019, pharmacists worldwide are playing a key role adopting innovative strategies to minimize the adverse impact of the pandemic. Objectives To identify and describe core services provided by the pharmacist during the COVID-19 pandemic. Methods A literature search was performed in MEDLINE, Embase, Scopus, and LILACS for studies published between December 1st, 2019 and May 20th, 2020 without language restriction. Studies that reported services provided by pharmacists during the COVID-19 pandemic were included. Two independent authors performed study selection and data extraction with a consensus process. The pharmacist's intervention identified in the included studies were described based on key domains in the DEPICT v.2. Results A total of 1,189 records were identified, of which 11 studies fully met the eligibility criteria. Most of them were conducted in the United States of America (n=4) and China (n=4). The most common type of publication were letters (n=4) describing the workplace of the pharmacist in hospitals (n=8). These findings showed the different roles of pharmacists during the COVID-19 pandemic, such as disease prevention and infection control, adequate storage and drug supply, patient care and support for healthcare professionals. Pharmacists' interventions were mostly conducted for healthcare professionals and patients (n=7), through one-to-one contact (n=11), telephone (n=6) or video conference (n=5). The pharmacists' main responsibility was to provide drug information for healthcare professionals (n=7) as well as patient counseling (n=8). Conclusions A reasonable number of studies that described the role of the pharmacists during the COVID-19 pandemic were found. All studies reported actions taken by pharmacists, although without providing a satisfactory description. Thus, future research with more detailed description as well as an evaluation of the impact of pharmacist intervention is needed in order to guide future actions in this and-or other pandemic. Keywords: COVID-19; pharmacists; pharmaceutical services; review

5: All-cause mortality among patients treated with repurposed antivirals and antibiotics for COVID-19 in Mexico City: A Real-World Observational Study
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Posted 14 Oct 2020

All-cause mortality among patients treated with repurposed antivirals and antibiotics for COVID-19 in Mexico City: A Real-World Observational Study
8,673 downloads medRxiv pharmacology and therapeutics

Javier Mancilla-Galindo, Jorge Óscar García-Méndez, Jessica Márquez-Sánchez, Rodrigo Estefano Reyes-Casarrubias, Eduardo Aguirre-Aguilar, Héctor Isaac Rocha-González, Ashuin Kammar-García

AimTo evaluate all-cause mortality risk in patients with laboratory-confirmed COVID-19 in Mexico City treated with repurposed antivirals and antibiotics. MethodsThis real-world retrospective cohort study contemplated 395,343 patients evaluated for suspected COVID-19 between February 24 and September 14, 2020 in 688 primary-to-tertiary medical units in Mexico City. Patients were included with a positive RT-PCR for SARS-CoV-2; those receiving unspecified antivirals, excluded; and antivirals prescribed in <30 patients, eliminated. Survival and mortality risks were determined for patients receiving antivirals, antibiotics, both, or none. Results136,855 patients were analyzed; mean age 44.2 (SD:16.8) years; 51.3% were men. 16.6% received antivirals (3%), antibiotics (10%), or both (3.6%). Antivirals studied were Oseltamivir (n=8414), Amantadine (n=319), Lopinavir-Ritonavir (n=100), Rimantadine (n=61), Zanamivir (n=39), and Acyclovir (n=36). Survival with antivirals (73.7%, p<0.0001) and antibiotics (85.8%, p<0.0001) was lower than no antiviral/antibiotic (93.6%). After multivariable adjustment, increased risk of death occurred with antivirals (HR=1.72, 95%CI:1.61-1.84) in ambulatory (HR=4.7, 95%CI:3.94-5.62) and non-critical (HR=2.03, 95%CI:1.86-2.21) patients. Oseltamivir increased mortality risk in the general population (HR=1.72, 95%CI:1.61-1.84), ambulatory (HR=4.79, 95%CI:4.01-5.75), non-critical (HR=2.05, 95%CI:1.88-2.23), and pregnancy (HR=8.35, 95%CI:1.77-39.30); as well as hospitalized (HR=1.13, 95%CI:1.01-1.26) and critical patients (HR:1.22, 95%CI:1.05-1.43) after propensity score-matching. Antibiotics were a risk factor in general population (HR=1.13, 95%CI:1.08-1.19) and pediatrics (HR=4.22, 95%CI:2.01-8.86), but a protective factor in hospitalized (HR=0.81, 95%CI:0.77-0.86) and critical patients (HR=0.67, 95%CI:0.63-0.72). ConclusionsNo significant benefit for repurposed antivirals was observed; oseltamivir was associated with increased mortality. Antibiotics increased mortality risk in the general population but may increase survival in hospitalized and critical patients. WHAT IS ALREADY KNOWNO_LICurrent recommendations for using repurposed antivirals and antibiotics for COVID-19 are conflicting. C_LIO_LIFew antivirals (i.e. lopinavir-ritonavir) have been shown to provide no additional benefit for COVID-19 in clinical trials; other antivirals may be having widespread use in real-world settings without formal assessment in clinical trials. C_LIO_LIReal-world use of repurposed antivirals and antibiotics for COVID-19 in population-based studies have not been performed; important populations have been left largely understudied (ambulatory patients, pregnant women, and pediatrics). C_LI WHAT THIS STUDY ADDSO_LIThis is the first real-world observational study evaluating amantadine, rimantadine, zanamivir, and acyclovir for COVID-19; no registered studies to evaluate these drugs exist. Only one study has evaluated risk of death for oseltamivir. Lopinavir-ritonavir have been previously evaluated in clinical trials. C_LIO_LIRepurposed antivirals and antibiotics were commonly prescribed in 688 ambulatory units and hospitals of Mexico City despite unclear recommendations for their use out of clinical trials. C_LIO_LIOseltamivir was associated with increased mortality risk; other repurposed antivirals (zanamivir, amantadine, rimantadine, and acyclovir) had no significant and consistent impact on mortality. Antibiotics were associated with increased mortality risk in the general population but may increase survival in hospitalized and critical patients. C_LI

6: Therapeutic Application of Chloroquine in Clinical Trials for COVID-19
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Posted 27 Mar 2020

Therapeutic Application of Chloroquine in Clinical Trials for COVID-19
6,790 downloads medRxiv pharmacology and therapeutics

Divya RSJB Rana, Santosh Dulal

The novel corona virus disease -2019 (COVID-19) pandemic has caused a massive global public health havoc. Recent clinical trials carried out in China has found a promising therapeutic application of chloroquine and hydroxychloroquine for COVID-19. This study meticulously evaluated the various dosages of chloroquine and hydroxychloroquine utilized in clinical trials registered in Chinese and US clinical trial registries for the treatment of pneumonia caused by SARS-CoV-2.

7: The Approved Dose of Ivermectin Alone is not the Ideal Dose for the Treatment of COVID-19
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Posted 26 Apr 2020

The Approved Dose of Ivermectin Alone is not the Ideal Dose for the Treatment of COVID-19
6,103 downloads medRxiv pharmacology and therapeutics

Virginia D Schmith, Jie Zhou, Lauren RL Lohmer

Introduction: Caly, Druce (1) reported that ivermectin inhibited SARS-CoV-2 in vitro for up to 48 h using ivermectin at 5 uM. The concentration resulting in 50% inhibition (IC50, 2 uM) was >35x higher than the maximum plasma concentration (Cmax) after oral administration of the approved dose of ivermectin when given fasted. Method: Simulations were conducted using an available population pharmacokinetic model to predict total (bound and unbound) and unbound plasma concentration-time profiles after a single and repeat fasted administration of the approved dose of ivermectin (200 ug/kg), 60 mg, and 120 mg. Plasma total Cmax was determined and then multiplied by the lung:plasma ratio reported in cattle to predict the lung Cmax after administration of each single dose. Results: Plasma ivermectin concentrations of total (bound and unbound) and unbound concentrations do not reach the IC50, even for a dose level 10x higher than the approved dose. Even with higher exposure in lungs than plasma, ivermectin is unlikely to reach the IC50 in lungs after single oral administration of the approved dose (predicted lung: 0.0857 uM) or at doses 10x higher that the approved dose administered orally (predicted lung: 0.817 uM). Conclusions: The likelihood of a successful clinical trial using the approved dose of ivermectin is low. Combination therapy should be evaluated in vitro. Re-purposing drugs for use in COVID-19 treatment is an ideal strategy but is only feasible when product safety has been established and experiments of re-purposed drugs are conducted at clinically relevant concentrations.

8: Low blood sodium increases risk and severity of COVID-19: a systematic review, meta-analysis and retrospective cohort study
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Posted 22 May 2020

Low blood sodium increases risk and severity of COVID-19: a systematic review, meta-analysis and retrospective cohort study
4,779 downloads medRxiv pharmacology and therapeutics

Yi Luo, Yirong Li, Jiapei Dai

Background Novel coronavirus (SARS-CoV-2) infects human lung tissue cells through angiotensin-converting enzyme-2 (ACE2), and the body sodium is an important factor for regulating the expression of ACE2. Through a systematic review, meta-analysis and retrospective cohort study, we found that the low blood sodium population may significantly increase the risk and severity of SARS-CoV-2 infection. Methods We extracted the data of serum sodium concentrations of patients with COVID-19 on admission from the articles published between Jan 1 and April 28, 2020, and analyzed the relationship between the serum sodium concentrations and the illness severity of patients. Then we used a cohort of 244 patients with COVID-19 for a retrospective analysis. Results We identified 36 studies, one of which comprised 2736 patients.The mean serum sodium concentration in patients with COVID-19 was 138.6 mmol/L, which was much lower than the median level in population (142.0). The mean serum sodium concentration in severe/critical patients (137.0) was significantly lower than those in mild and moderate patients (140.8 and 138.7, respectively). Such findings were confirmed in a retrospective cohort study, of which the mean serum sodium concentration in all patients was 137.5 mmol/L, and the significant differences were found between the mild (139.2) and moderate (137.2) patients, and the mild and severe/critical (136.6) patients. Interestingly, such changes were not obvious in the serum chlorine and potassium concentrations. Conclusions The low sodium state of patients with COVID-19 may not be the consequence of virus infection, but could be a physiological state possibly caused by living habits such as low salt diet and during aging process, which may result in ACE2 overexpression, and increase the risk and severity of COVID-19. These findings may provide a new idea for the prevention and treatment of COVID-19.

9: Prioritisation of potential anti-SARS-CoV-2 drug repurposing opportunities based on ability to achieve adequate target site concentrations derived from their established human pharmacokinetics
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Posted 22 Apr 2020

Prioritisation of potential anti-SARS-CoV-2 drug repurposing opportunities based on ability to achieve adequate target site concentrations derived from their established human pharmacokinetics
4,571 downloads medRxiv pharmacology and therapeutics

Usman Arshad, Henry Pertinez, Helen Box, Lee Tatham, Rajith KR Rajoli, Paul Curley, Megan Neary, Joanne Sharp, Neill J Liptrott, Anthony Valentijn, Christopher David, Steve P Rannard, Paul O'Neill, Ghaith Aljayyoussi, Shaun H Pennington, Stephen A Ward, David J Back, Saye Khoo, Patrick G Bray, Giancarlo A Biagini, Andrew Owen

Many papers are emerging that describe the in vitro antiviral activity of drugs that may be repurposed for therapy or chemoprophylaxis against SARS-CoV-2. However, no comprehensive evaluation of these molecules in the context of the achievable plasma pharmacokinetics after administration of approved doses and schedules to humans has been conducted. Moreover, most publications have focussed on 50% maximum effective concentrations (EC50), which may be an insufficiently robust indicator of antiviral activity because of marked differences in the slope of the concentration-response curve between drugs. Accordingly, in vitro anti-SARS-CoV-2 activity data was digitised from all available publications up to 13th April 2020 and used to recalculate an EC90 value for each drug. EC90 values were then expressed as a ratio to the achievable maximum plasma concentrations (Cmax) reported for each drug after administration of the approved dose to humans (Cmax/EC90 ratio). Only 14 of the analysed drugs achieved a Cmax/EC90 ratio above 1 meaning that plasma Cmax concentrations exceeded those necessary to inhibit 90% of SARS-CoV-2 replication. A more in-depth assessment of these drugs demonstrated that only nitazoxanide, nelfinavir, tipranavir (boosted with ritonavir) and sulfadoxine achieved plasma concentrations above their anti-SARS-CoV-2 activity across their entire approved dosing interval at their approved human dose. For all drugs reported, the unbound lung to plasma tissue partition coefficient (KpUlung) was also simulated and used along with reported Cmax and fraction unbound in plasma to derive a lung Cmax/EC50 as a better indicator of potential human efficacy (lung Cmax/EC90 ratio was also calculable for a limited number of drugs). Using this parameter hydroxychloroquine, chloroquine, mefloquine, atazanavir (boosted with ritonavir), tipranavir (boosted with ritonavir), ivermectin, azithromycin and lopinavir (boosted with ritonavir) were all predicted to achieve lung concentrations over 10-fold higher than their reported EC50. This analysis was not possible for nelfinavir because insufficient data were available to calculate KpUlung but nitozoxanide and sulfadoxine were also predicted to exceed their reported EC50 by 3.1- and 1.5-fold in lung, respectively. The antiviral activity data reported to date is of variable quality and conducted under different conditions by different investigators. However, this analysis has prioritised candidates with the best chance for success in therapy or chemoprevention of Covid-19 based upon the currently available in vitro activity and human plasma pharmacokinetic data. Future studies should focus on EC90 values and discuss findings in the context of achievable exposures in humans, especially within target compartments such as the lung, in order to maximise the potential for success of proposed human clinical trials.

10: Hydroxychloroquine for the management of COVID-19: Hope or Hype? A Systematic review of the current evidence
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Posted 22 Apr 2020

Hydroxychloroquine for the management of COVID-19: Hope or Hype? A Systematic review of the current evidence
4,033 downloads medRxiv pharmacology and therapeutics

Umesh Devappa Suranagi, Harmeet Singh Rehan, Nitesh Goyal

Importance: The COVID-19 Pandemic has literally left the world breathless in the chase for pharmacotherapy. With vaccine and novel drug development in early clinical trials, repurposing of existing drugs takes the center stage. Objective: A potential drug discussed in global scientific community is hydroxychloroquine. We intend to systematically explore, analyze, rate the existing evidence of hydroxychloroquine in the light of published, unpublished and clinical trial data. Evidence review: PubMed Ovid MEDLINE, EMBASE, Google scholar databases, pre-proof article repositories, clinical trial registries were comprehensively searched with focused question of use of hydroxychloroquine in COVID-19 patients. The literature was systematically explored as per PRISMA guidelines. Findings: Total 156 articles were available as of 7th May 2020; of which 11 articles of relevance were analyzed. Three in-vitro studies were reviewed. Two open label non-randomized trials, two open label randomized control trials, one large observational study, one follow-up study and two retrospective cohort studies were systematically analyzed and rated by oxford CEBM and GRADE framework for quality and strength of evidence. Also 27 clinical trials registered in three clinical trial registries were analyzed and summarized. Hydroxychloroquine seems to be efficient in inhibiting SARS-CoV-2 in in-vitro cell lines. However, there is lack of strong evidence from human studies. It was found that overall quality of available evidence ranges from "very low" to "low". Conclusions and relevance: The in-vitro cell culture based data of viral inhibition does not suffice for the use of hydroxychloroquine in the patients with COVID-19. Current literature shows inadequate, low level evidence in human studies. Scarcity of safety and efficacy data warrants medical communities, health care agencies and governments across the world against the widespread use of hydroxychloroquine in COVID-19 prophylaxis and treatment, until robust evidence becomes available.

11: Benefits and Risks of Chloroquine and Hydroxychloroquine in The Treatment of Viral Diseases: A Meta-Analysis of Placebo Randomized Controlled Trials
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Posted 18 Apr 2020

Benefits and Risks of Chloroquine and Hydroxychloroquine in The Treatment of Viral Diseases: A Meta-Analysis of Placebo Randomized Controlled Trials
3,842 downloads medRxiv pharmacology and therapeutics

Jing Wang, Li Yu, Kefeng Li

Background and Objective: Recently, in the scramble to find drugs to treat COVID-19, chloroquine (CQ) and its derivative hydroxychloroquine (HCQ) have rapidly gained the public attention. In this study, we conducted a meta-analysis of randomized clinical trials (RCTs) to evaluate the efficacy and safety of CQ and HCQ in the treatment of viral diseases. Methods: We searched PubMed, EMBASE, Cochrane Central, Web of Science, Clinical Trials Registries, CNKI, Wanfang Data, CQVIP, and Preprint Servers through April 4, 2020, for randomized controlled trials (RCTs) that examined the efficacy and safety of CQ and HCQ against viral infection. We analyzed pooled data on the overall efficacy, the relative risks over the placebo, and the prevalence of adverse events. Trial sequential analysis (TSA) was also performed to evaluate the random errors in the meta-analysis. Potential moderators of drug-placebo efficacy differences were analyzed by meta-regression. Results: The analysis included 11 RCTs with 2613 adult patients. Both the plasma viral load (standard mean difference: 0.29, 95% CI: -1.19 - 1.76, P = 0.70) and the improvement of clinical symptoms (odds ratio: 2.36, 95% CI: 0.81 - 6.92, P = 0.11) were not different between the intervention and placebo arm. There was significant heterogeneity for the efficacy assessment, which was primarily explained by the age of patients and the sample size. Compared to the placebo, CQ and HCQ had increased risk of mild adverse events (risk ratio: 1.51, 95% CI: 1.35 - 1.70, P < 0.05, TSA adjusted 95% CI: 1.31 - 2.19), which were statistically significant in nervous, integumentary, and gastrointestinal systems. The most common adverse events were observed in the nervous system, with the pooled prevalence of 31.4% (95% CI: 10.5% - 56.7%). Conclusions: Insufficient data were available to support the antiviral efficacy of CQ and HCQ due to the high heterogeneity caused by the age of patients. Mild side effects are expected for the current antiviral dose regimens of CQ and HCQ. Treatment outcomes may be enhanced by better-selected patients based on age and well-controlled adverse events.

12: Analysis of Crowdsourced Metformin Tablets from Individuals Reveals Widespread Contamination with N-Nitrosodimethylamine (NDMA) in the United States
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Posted 26 May 2020

Analysis of Crowdsourced Metformin Tablets from Individuals Reveals Widespread Contamination with N-Nitrosodimethylamine (NDMA) in the United States
3,803 downloads medRxiv pharmacology and therapeutics

Qian Wu, Evgenia Kvitko, Amber Jessop, Shannon Williams, Ryan C Costantino, Kaury Kucera, David Y Light

Recent reports of metformin drug products contaminated with unacceptable levels of the probable human carcinogen N-Nitrosodimethylamine (NDMA) prompted a national sampling of post-market metformin drug products. To most broadly sample the market and minimize supply chain bias, metformin medication samples were crowdsourced directly from individuals across many states in the United States. 128 samples were received, and liquid chromatography-high resolution mass spectrometry tests for a panel of nitrosamines revealed significant levels of NDMA that trend with labeling company. 42% of all medication samples contained detectable levels of NDMA and, when scaled to maximum daily tablet dose, 36% of all medication samples contained NDMA levels exceeding the FDA daily acceptable intake limit. The highest NDMA detection from the tested samples was 1565 ng per tablet, which, when commonly taken four times a day, is 65 times the United States Food and Drug Administration (FDA) acceptable daily intake limit. Results underscore the need for immediate product recalls of tainted medications and an overall investigation of metformin manufacturing practices.

13: Risk of drug-induced Long QT Syndrome associated with the use of repurposed COVID-19 drugs: a systematic review
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Posted 24 Apr 2020

Risk of drug-induced Long QT Syndrome associated with the use of repurposed COVID-19 drugs: a systematic review
3,633 downloads medRxiv pharmacology and therapeutics

Veronique Michaud, Pamela Dow, Sweilem B Al Rihani, Malavika Deodhar, Meghan Arwood, Brian Cicali, Jacques Turgeon

The risk-benefit ratio associated with the use of repurposed drugs to treat 2019 SARS-CoV-2 related infectious disease (COVID-19) is complicated since benefits are awaited, not proven. A thorough literature search was conducted to source information on the pharmacological properties of 5 drugs and 1 combination (azithromycin, chloroquine, favipiravir, hydroxychloroquine, remdesivir, and lopinavir/ritonavir) repurposed to treat COVID-19. A risk assessment of drug-induced Long QT Syndrome (LQTS) associated with COVID-19 repurposed drugs was performed and compared to 23 well-known torsadogenic and 10 low torsadogenic risk compounds. Computer calculations were performed using pharmacokinetic and pharmacodynamic data, including affinity to block the rapid component of the delayed rectifier cardiac potassium current (IKr) encoded by the human ether-a-go-go gene (hERG), propensity to prolong cardiac repolarization (QT interval) and cause torsade de pointes (TdP). Seven different LQTS indices were calculated and compared. The U.S. Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database was queried with specific key words relating to arrhythmogenic events. Estimators of LQTS risk levels indicated a very high or moderate risk for all COVID-19 repurposed drugs with the exception for azithromycin, although cases of TdP have been reported with this drug. There was excellent agreement among the various indices used to assess risk of drug-induced LQTS for the 6 repurposed medications and 23 torsadogenic compounds. Based on our results, monitoring of the QT interval shall be performed when some COVID-19 repurposed drugs are used, as such monitoring is possible for hospitalized patients or with the use of biodevices for outpatients.

14: Clinical Outcomes and Plasma Concentrations of Baloxavir Marboxil and Favipiravir in COVID-19 Patients: an Exploratory Randomized, Controlled Trial
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Posted 05 May 2020

Clinical Outcomes and Plasma Concentrations of Baloxavir Marboxil and Favipiravir in COVID-19 Patients: an Exploratory Randomized, Controlled Trial
3,272 downloads medRxiv pharmacology and therapeutics

Yan Lou, Lin Liu, Yunqing Qiu

Background: Effective antiviral drugs for COVID-19 are still lacking. This study aims to evaluate the clinical outcomes and plasma concentrations of baloxavir marboxil and favipiravir in COVID-19 patients. Methods: Favipiravir and baloxavir acid were evaluated for their antiviral activity against SARS-CoV-2 in vitro before the trial initiation. We conducted an exploratory trial with 3 arms involving hospitalized adult patients with COVID-19. Patients were randomized assigned in a 1:1:1 ratio into baloxavir marboxil group, favipiravir group, and control group. The primary outcome was the percentage of subjects with viral negative by Day 14 and the time from randomization to clinical improvement. Virus load reduction, blood drug concentration and clinical presentation were also observed. The trial was registered with Chinese Clinical Trial Registry (ChiCTR 2000029544). Results: Baloxavir showed antiviral activity in vitro with the half-maximal effective concentration (EC50) of 5.48 M comparable to arbidol and lopinavir, but favipiravir did not demonstrate significant antiviral activity up to 100 M. Thirty patients were enrolled. The percentage of patients who turned viral negative after 14-day treatment was 70%, 77%, and 100% in the baloxavir, favipiravir, and control group respectively, with the medians of time from randomization to clinical improvement was 14, 14 and 15 days, respectively. One reason for the lack of virological effect and clinical benefits may be due to insufficient concentrations of these drugs relative to their antiviral activities. Conclusions: Our findings do not support that adding either baloxavir or favipiravir under the trial dosages to the existing standard treatment.

15: A Randomized, Single-blind, Group sequential, Active-controlled Study to evaluate the clinical efficacy and safety of α-Lipoic acid for critically ill patients with coronavirus disease 2019(COVID-19)
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Posted 21 Apr 2020

A Randomized, Single-blind, Group sequential, Active-controlled Study to evaluate the clinical efficacy and safety of α-Lipoic acid for critically ill patients with coronavirus disease 2019(COVID-19)
3,257 downloads medRxiv pharmacology and therapeutics

Ming Zhong, Aijun Sun, Ting Xiao, Ge Yao, Ling Sang, Xia Zheng, Jinyan Zhang, Xuejuan Jin, Lei Xu, Wenlong Yang, Peng Wang, Kai Hu, Dingyu Zhang, Junbo Ge

Object: To evaluate the clinical efficacy and safety of -Lipoic acid (ALA) for critically ill patients with coronavirus disease 2019 (COVID-19). Methods: A randomized, single-blind, group sequential, active-controlled trial was performed at JinYinTan Hospital, Wuhan, China. Between February 2020 and March 2020, 17 patients with critically ill COVID-19 were enrolled in our study. Eligible patients were randomly assigned in a 1:1 ratio to receive either ALA (1200 mg/d, intravenous infusion) once daily plus standard care or standard care plus equal volume saline infusion (placebo) for 7 days. All patients were monitored within the 7 days therapy and followed up to day 30 after therapy. The primary outcome of this study was the Sequential Organ Failure Estimate (SOFA) score, and the secondary outcome was the all-cause mortality within 30 days. Result: Nine patients were randomized to placebo group and 8 patients were randomized to ALA group. SOFA score was similar at baseline, increased from 4.3 to 6.0 in the placebo group and increased from 3.8 to 4.0 in the ALA group (P=0.36) after 7 days. The 30-day all-cause mortality tended to be lower in the ALA group (3/8, 37.5%) compared to that in the placebo group (7/9, 77.8%, P=0.09). Conclusion: In our study, ALA use is associated with lower SOFA score increase and lower 30-day all-cause mortality as compared with the placebo group. Although the mortality rate was two-folds higher in placebo group than in ALA group, only borderline statistical difference was evidenced due to the limited patient number. Future studies with larger patient cohort are warranted to validate the role of ALA in critically ill patients with COVID-19. Keywords: Pneumonia; COVID-19; SARS-CoV-2 ; -Lipoic acid

16: Hydroxychloroquine serum concentrations in non-critical care patients infected with SARS CoV 2
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Posted 23 Jun 2020

Hydroxychloroquine serum concentrations in non-critical care patients infected with SARS CoV 2
3,070 downloads medRxiv pharmacology and therapeutics

Alasdair P. MacGowan, Fergus Hamilton, Mark Bayliss, Liam Read, Marie Attwood, Alan Noel, Sally Grier, Anna Morley, David Arnold, Nick maskell

Hydroxychloroquine(HCQ) has been widely used to treat SARS-CoV-2 infection however HCQ pharmacokinetics in this condition have not been studied in non-critical care patient groups. Here we report the serum concentrations of HCQ in a small cohort of patients treated with HCQ as part of the RECOVERY trial.

17: Telmisartan for treatment of Covid-19 patients: an open randomized clinical trial. Preliminary report.
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Posted 11 Aug 2020

Telmisartan for treatment of Covid-19 patients: an open randomized clinical trial. Preliminary report.
3,039 downloads medRxiv pharmacology and therapeutics

Mariano Duarte, Facundo G Pelorosso, Liliana Nicolosi, M. Victoria Salgado, Hector Vetulli, Analia Aquieri, Francisco Azzato, Mauro Basconcel, Marcela Castro, Javier Coyle, Ignacio Davolos, Eduardo Esparza, Ignacio Fernandez Criado, Rosana Gregori, Pedro Mastrodonato, Maria Rubio, Sergio Sarquis, Fernando Wahlmann, Rodolfo Pedro Rothlin

Background. Covid-19 is associated with respiratory-related morbidity and mortality. Angiotensin receptor blockers (ARB) have been postulated as tentative pharmacological agents to treat Covid-19-induced inflammation. Methods. This is a randomized, two-arm, open, multicenter trial. Participants were 18 years or older and had been hospitalized with confirmed Covid-19 with 4 or fewer days since symptom onset. Exclusion criteria included intensive care unit admission prior to randomization and ARB or angiotensin converting enzyme inhibitors use. Treatment arm received telmisartan 80 mg bid during 14 days plus standard care; control arm received standard care. Primary outcome were differences in C-reactive protein levels at days 5 and 8. Secondary outcomes included time to discharge evaluated at 15 days and death at 30 days post randomization. Results. This interim analysis included 40 patients in telmisartan and 38 in control groups. CRP levels in the control and telmisartan groups were 51.1+/-44.8 mg/L vs 24.2+/-31.4 mg/L at day 5 (mean +/- SD; n=28 and n=32, p<0.05), and 41.6+/-47.6 mg/L vs 9.0+/-10.0 mg/L at day 8 (mean +/- SD; n=16 and n=13; p<0.05), respectively. Telmisartan treated patients had statistically significant lower time to discharge (log-rank test p=0.0124, median time: 15 days in control group vs 9 days in telmisartan group). Mortality at day 30 was 11.76% in control group vs 5.26% in telmisartan group (p=0.41). Conclusions. In this study, ARB telmisartan, a well-known inexpensive safe antihypertensive drug, administered in high doses, was superior to standard care demonstrating anti-inflammatory effects and improved morbidity in hospitalized patients infected with SARS -CoV-2 (NCT04355936).

18: National Consumption of Antimalarial Drugs and COVID-19 Deaths Dynamics : an Ecological Study
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Posted 24 Apr 2020

National Consumption of Antimalarial Drugs and COVID-19 Deaths Dynamics : an Ecological Study
3,008 downloads medRxiv pharmacology and therapeutics

Maxime Izoulet

COVID-19 (Coronavirus Disease-2019) is an international public health problem with a high rate of severe clinical cases. Several treatments are currently being tested worldwide. This paper focuses on anti-malarial drugs such as chloroquine or hydroxychloroquine, which have been currently reviewed by a systematic study as a good potential candidate and that has been reported as the most used treatment by a recent survey of physicians. We compare the dynamics of COVID-19 death rates in countries using anti-malaria drugs as a treatment from the start of the epidemic versus countries that do not, the day of the 3rd death and the following 10 days. We show that the first group have a much slower dynamic in death rates that the second group. This univariate analysis is of course only one additional piece of evidence in the debate regarding the efficiency of anti-malaria drugs, and it is also limited as the two groups certainly have other systemic differences in the way they responded to the pandemic, in the way they report death or in their population that better explain differences in dynamics (systematic differences that may also explain their choice to rely on anti-malaria drugs in the first place). Nevertheless, the difference in dynamics is so striking that we believe that the urgency context commands presenting the univariate analysis before delving into further analysis. In the end, this data might ultimately be either a piece of evidence in favor or anti-malaria drugs or a stepping stone in understanding further what other ecological aspects place a role in the dynamics of COVID-19 deaths.

19: Vaccines against Covid-19, venous thromboembolism, and thrombocytopenia. A population-based retrospective cohort study
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Posted 27 Jul 2021

Vaccines against Covid-19, venous thromboembolism, and thrombocytopenia. A population-based retrospective cohort study
2,809 downloads medRxiv pharmacology and therapeutics

Joan-Ramon Laporte, Ermengol Coma, Francesc Fina, Luis Garcia-Eroles, Xavier Vidal, Manuel Medina

BackgroundCovid-19 vaccines may increase the risk of venous thromboembolism (VTE), thrombocytopenia (TCP), and VTE associated with TCP. We aimed at estimating this risk by age and sex, after the first dose of both adenovirus vector-based and mRNA-based Covid-19 vaccines, and after the second dose of m-RNA vaccines. MethodsIn this population-based retrospective cohort study, we examined three groups: 1 662 719 people 10 years of age and over vaccinated with the first dose of a Covid-19 vaccine, 622 778 with the second dose, and 190 616 diagnosed of Covid-19 in the same period (between1 January 2021 and 18 April 2021). The rates of various clinical presentations of VTE and TCP were compared with those in the reference population (7 013 040 people served by the health care system in 2919). The two primary outcomes were the observed 21 day rate of a composite variable of cerebral venous sinus thrombosis, mesenteric thrombosis, portal vein thrombosis, or any venous thromboembolism (VTE) associated with thrombocytopenia (TCP), and the rate of any VTE associated with TCP (VTE+TCP). Analyses were standardised by age and sex. FindingsThe 21 day rate per 100 000 of the primary composite variable was 2{middle dot}15 in the reference population, 5{middle dot}65 following the first vaccine dose (standardised difference, 2{middle dot}53 (95 percent confidence interval, 1{middle dot}04- 4{middle dot}00), and 7{middle dot}23 following the second dose (standardised difference, 4{middle dot}07 (95 percent confidence interval, 1{middle dot}43-6{middle dot}70). The event rates of VTE+TCP and of all the secondary variables showed the same patterns. Excess event rates were higher in men than in women, and they were not especially increased in any particular age group. All Covid-19 vaccines were associated with increased rates of the outcome variables. Excess event rates were many-fold higher in the Covid-19 cohort. InterpretationWe observed small increases of rates of venous thromboembolism in usual and unusual anatomical sites and of thrombocytopenia in recipients of both adenovirus vector and mRNA vaccines against Covid-19. Excess rates were higher in men than in women and they were not particularly elevated in any specific age group. Research in contextO_ST_ABSEvidence before this studyC_ST_ABSCovid-19 increases the risk of venous thromboembolism (VTE) in common and in unusual anatomical sites, and the risk of thrombocytopenia (TCP). This risk increases with age. Case reports of VTE and TCP after Covid-19 vaccination with VaxZevria(R), an adenovirus vector Covid-19 vaccine, suggested that the risk concentrates in young women. One study based on systematic ascertainment found 11 excess VTE events per 100 000 first doses, but people over 65 years were excluded. It is not known whether mRNA-based Covid-19 vaccines are associated with increased risks of VTE and TCP. What this study addsRecipients of Covid-19 vaccines had increased rates of VTE in usual and in unusual anatomical sites, of TCP, and of VTE associated with TCP. These rates were many-fold lower than those in Covid-19 patients, they were two fold in men compared with women, and they were not concentrated in any particular age group. Both recipients of adenovirus vector-based and of mRNA-based Covid-19 vaccines had increased rates of VTE, TCP, and VTE associated with TCP, after the first dose and after the second dose. Our data should be considered when designing selective targeting of the various Covid-19 vaccines to different age groups in vaccination campaigns.

20: Drug-Drug interactions between COVID-19 treatments and antipsychotics drugs: integrated evidence from 4 databases and a systematic review
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Posted 08 Jun 2020

Drug-Drug interactions between COVID-19 treatments and antipsychotics drugs: integrated evidence from 4 databases and a systematic review
2,630 downloads medRxiv pharmacology and therapeutics

Beatriz Oda Plasencia-Garcia, Gonzalo Rodriguez-Menendez, Maria Isabel Rico-Rangel, Ana Rubio-Garcia, Jaime Torello-Iserte, Benedicto Crespo-Facorro

Relevance: Management of symptoms like anxiety, delirium and agitation cannot be neglected in COVID-19 patients. Antipsychotics are usually used for the pharmacological management of delirium, and confusion and behavioral disturbances. The selection of concomitant COVID-19 medications and antipsychotics should be evidence-based and closely monitored Objective: To systematically review evidence-based available on drug-drug interactions between COVID-19 treatments and antipsychotics. Evidence Review: Three databases were consulted: (a) Lexicomp Drug Interactions, (b) Micromedex Solutions Drugs Interactions, (c) Liverpool Drug Interaction Group for COVID-19 therapies. To acquire more information on QT prolongation and TdP, the CredibleMeds QTDrugs List was searched. Based on the information collected, the authors made a recommendation agreed to by consensus. In addition, a systematic review was conducted to find the clinical outcomes of drug-drug interactions between COVID-19 treatments and antipsychotics Results: The main interaction between COVID-19 drugs and antipsychotics are the risk of QT prolongation and TdP, and CYP interactions. Remdesivir, favipiravir, baricinitib, and anakinra can be used concomitantly with antipsychotics with no risk of drug-drug interaction (except for hematological risk with clozapine and baricinitib). Tocilizumab is rather safe to use in combination with antipsychotics, although it can restore the activity of CYP3A4 and therefore its substrate metabolism may increase. The most demanding COVID-19 treatments for co-administration with antipsychotics are chloroquine, hydroxychloroquine, azithromycin (all prolong QT interval) and lopinavir / ritonavir (CYP interaction and risk of QT prolongation). Conclusions: We urge to development of evidence-based guidelines that can help clinicians decide the safest treatment combination and monitoring necessary for each particular patient. The selection of concomitant COVID-19 medications and antipsychotics should be evidence-based and closely monitored.

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