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1.
Preprint em Inglês | medRxiv | ID: ppmedrxiv-22269095

RESUMO

BackgroundACEi/ARB medications have been hypothesized to have potential benefit in COVID-19. Despite concern for increased ACE-2 expression in some animal models, preclinical and observational-retrospective and uncontrolled trials suggested possible benefit. Two RCTs of the ARB losartan from University of Minnesota showed no benefit yet safety signals for losartan in outpatient and hospitalized COVID-19 patients. COVID MED, started early in the pandemic, also assessed losartan in a RCT in hospitalized patients with COVID-19. MethodsCOVID MED was quadruple-blinded, placebo-controlled, multicenter randomized clinical trial (RCT). Hospitalized COVID-19 patients were randomized to receive standard care and hydroxychloroquine, lopinavir/ritonavir, losartan, or placebo. Hydroxychloroquine and lopinavir/ritonavir arms were discontinued after RCTs showed no benefit. We report data from the losartan arm compared to combined (lopinavir-ritonavir and placebo) and prespecified placebo-only controls. The primary endpoint was the NCOSS slope of change. Slow enrollment prompted early stopping. ResultsOf 432 screened patients, 14 were enrolled (3.5%), 9 received losartan and 5 combined control (lopinavir/ritonavir [N=2], placebo [N=3]); 1 hydroxychloroquine arm patient was excluded. Most baseline parameters were balanced. Treatment with losartan was not associated with a difference in NCOSS slope of change in comparison with combined control (p=0.4) or placebo-only control (p=0.05) (trend favoring placebo). 60-day mortality and overall AE and SAE rates were numerically but not significantly higher with losartan. ConclusionsIn this small blinded RCT in hospitalized COVID-19 patients, losartan did not improve outcome vs. control comparisons and was associated with adverse safety signals.

2.
Preprint em Inglês | medRxiv | ID: ppmedrxiv-22269069

RESUMO

BackgroundIn the beginning of the COVID-19 pandemic, many hospitalized patients received empiric hydroxychloroquine/chloroquine (HC/CQ). Although some retrospective-observational trials suggested potential benefit, all subsequent randomized clinical trials (RCTs) failed to show benefit and use generally ceased. Herein, we summarize key studies that clinicians advising patients on HC/CQs efficacy:safety calculus in hospitalized COVID-19 patients would want to know about in a practical one-stop-shopping source. MethodsPubmed and Google were searched on November 4, 2021. Search words included: COVID-19, hydroxychloroquine, chloroquine, in vitro, animal studies, clinical trials, and meta-analyses. Studies were assessed for import and included if considered impactful for benefit:risk assessment. ResultsThese searches led to inclusion of 12 in vitro and animal reports; 12 retrospective-observational trials, 19 interventional clinical trials (17 RCTs, 1 single-arm, 1 controlled but unblinded), and 51 meta-analyses in hospitalized patients. Inconsistent efficacy was seen in vitro and in animal studies for coronaviruses and nil in SARS-CoV-2 animal models specifically. Most retrospective-observational studies in hospitalized COVID-19 patients found no efficacy; QT prolongation and increased adverse events and mortality were reported in some. All RCTs and almost all meta-analyses provided robust data showing no benefit in overall populations and subgroups, yet concerning safety issues in many. ConclusionsHC/CQ have inconsistent anti-coronavirus efficacy in vitro and in animal models, and no convincing efficacy yet substantial safety issues in the overwhelming majority of retrospective-observational trials, RCTs, and meta-analyses in hospitalized COVID-19 patients. HC/CQ should not be prescribed for hospitalized COVID-19 patients outside of clinical trials. Key Summary PointsPreclinical hydroxychloroquine/chloroquine in vitro studies found inconsistent activity against coronaviruses including SARS-CoV-2. Preclinical hydroxychloroquine/chloroquine animals studies found inconsistent efficacy for coronaviruses in general and none for SARS-CoV-2. The overhwelming majority of RCTs and retrospective-observational trials found no benefit for hydroxychloroquine/chloroquine in hospitalized COVID-19 patients, and many found concerning safety signals. The majority of RCTs and retrospective-observational trials found no benefit for hydroxychloroquine/chloroquine in COVID-19 outpatients or for pre- or post-exposure prophylaxis, and some found concerning safety signals. The overwhelming majority of meta-analyses found no benefit for hydroxychloroquine/chloroquine in COVID-19 inpatients, outpatients, or for prophylaxis, and many found concerning safety signals.

3.
Preprint em Inglês | medRxiv | ID: ppmedrxiv-22269008

RESUMO

ImportanceResults from observational studies and randomized clinical trials (RCTs) have led to the consensus that hydroxychloroquine (HCQ) and chloroquine (CQ) are not effective for COVID-19 prevention or treatment. Pooling individual participant data (IPD), including unanalyzed data from trials terminated early, enables further investigation of the efficacy and safety of HCQ/CQ. ObjectiveTo assess efficacy of HCQ/CQ in patients hospitalized with COVID-19, both overall and in prespecified subgroups. Data SourcesClinicalTrials.gov was searched multiple times in May-June 2020. Principal investigators of US-based RCTs evaluating HCQ/CQ in hospitalized COVID-19 patients were invited to collaborate in this IPD meta-analysis. Study SelectionRCTs in which: (1) HCQ/CQ was a treatment arm; (2) patient informed consent and/or individual study IRB approval allowed for data sharing; (3) principal investigators/their institutions signed a data use agreement for the present study; and (4) the outcomes defined in this study were recorded or could be extrapolated. Data Extraction and SynthesisWherever possible, harmonized de-identified data were collected via a common template spreadsheet sent to each principal investigator, then shared via a secure online data sharing platform to create a pooled data set. When this was not possible, individual study data were harmonized and merged manually. Data were analyzed by fitting a prespecified Bayesian ordinal regression model and standardizing the resulting predictions. Main Outcome(s) and Measure(s)7-point ordinal scale, measured between day 28 and 35 post-enrollment. ResultsEight of 19 trials met eligibility criteria and agreed to participate. Patient-level data were available from 770 participants (412 HCQ/CQ vs 358 control). Baseline characteristics were similar between groups. We found no evidence of a difference in ordinal scores between days 28 and 35 post-enrollment in the pooled patient population (odds ratio, 0.97; 95% credible interval, 0.76-1.24; higher favors HCQ/CQ), and no convincing evidence of meaningful treatment effect heterogeneity among prespecified subgroups. Adverse event and serious adverse event rates were numerically higher with HCQ/CQ vs control (0.39 vs 0.29 and 0.13 vs 0.09 per patient, respectively). Conclusions and RelevanceThe findings of this IPD meta-analysis reinforce those of individual RCTs that HCQ/CQ is not efficacious for treatment of COVID-19 in hospitalized patients. Key PointsO_ST_ABSQuestionC_ST_ABSDoes hydroxychloroquine/chloroquine benefit hospitalized patients with COVID-19, overall or within prespecified subgroups? FindingsIn this individual participant data meta-analysis of 770 hospitalized COVID-19 patients across 8 clinical trials, we did not find evidence of a benefit of hydroxychloroquine/chloroquine, measured by a 7-point ordinal COVID-19 severity score at 28-35 days post-enrollment, in the pooled study population. We also found no substantial treatment effect heterogeneity among prespecified patient subgroups. MeaningThis study supports the consensus that hydroxychloroquine/chloroquine should not be used to treat hospitalized patients with COVID-19.

4.
Artigo em Inglês | MEDLINE | ID: mdl-35044458

RESUMO

CONTEXT: On March 19, 2020, President Trump endorsed using hydroxychloroquine for COVID-19 treatment, despite inconclusive evidence of the drug's effectiveness. This study sought to understand the influence of political preferences on prescription uptake by quantifying the relationship between a geographic area's partisan leaning and hydroxychloroquine prescription rates following Trump's endorsement. METHODS: The analysis used hydroxychloroquine prescriptions filled in 205 continental U.S. Designated Market Areas (DMAs) between March 1, 2018, and July 31, 2020, and percentage of votes for Donald Trump in the 2016 presidential election. Associations were estimated using an empirical strategy resembling difference-in-differences models. FINDINGS: Prior to President Trump's endorsement, mean weekly hydroxychloroquine prescription rates were similar across DMAs with the most and the least Trump vote percentages (0.56 and 0.49 scripts per 100,000). After Trump's endorsement, although both high- and low-Trump-supportive DMAs experienced sharp increases in weekly hydroxychloroquine prescription rates, results indicate a 1-percentage-point increase in share of Trump votes was associated with 0.013, or 2%, more weekly hydroxychloroquine prescriptions per 100,000 (b=0.013, t=2.20, p=.028). CONCLUSIONS: President Trump's endorsement of an untested therapy influenced prescribing behavior, especially when that endorsement aligned with communities' political leanings.

5.
medRxiv ; 2022 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-35043124

RESUMO

Importance: Results from observational studies and randomized clinical trials (RCTs) have led to the consensus that hydroxychloroquine (HCQ) and chloroquine (CQ) are not effective for COVID-19 prevention or treatment. Pooling individual participant data (IPD), including unanalyzed data from trials terminated early, enables further investigation of the efficacy and safety of HCQ/CQ. Objective: To assess efficacy of HCQ/CQ in patients hospitalized with COVID-19, both overall and in prespecified subgroups. Data Sources: ClinicalTrials.gov was searched multiple times in May-June 2020. Principal investigators of US-based RCTs evaluating HCQ/CQ in hospitalized COVID-19 patients were invited to collaborate in this IPD meta-analysis. Study Selection: RCTs in which: (1) HCQ/CQ was a treatment arm; (2) patient informed consent and/or individual study IRB approval allowed for data sharing; (3) principal investigators/their institutions signed a data use agreement for the present study; and (4) the outcomes defined in this study were recorded or could be extrapolated. Data Extraction and Synthesis: Wherever possible, harmonized de-identified data were collected via a common template spreadsheet sent to each principal investigator, then shared via a secure online data sharing platform to create a pooled data set. When this was not possible, individual study data were harmonized and merged manually. Data were analyzed by fitting a prespecified Bayesian ordinal regression model and standardizing the resulting predictions. Main Outcomes and Measures: 7-point ordinal scale, measured between day 28 and 35 post-enrollment. Results: Eight of 19 trials met eligibility criteria and agreed to participate. Patient-level data were available from 770 participants (412 HCQ/CQ vs 358 control). Baseline characteristics were similar between groups. We found no evidence of a difference in ordinal scores between days 28 and 35 post-enrollment in the pooled patient population (odds ratio, 0.97; 95% credible interval, 0.76-1.24; higher favors HCQ/CQ), and no convincing evidence of meaningful treatment effect heterogeneity among prespecified subgroups. Adverse event and serious adverse event rates were numerically higher with HCQ/CQ vs control (0.39 vs 0.29 and 0.13 vs 0.09 per patient, respectively). Conclusions and Relevance: The findings of this IPD meta-analysis reinforce those of individual RCTs that HCQ/CQ is not efficacious for treatment of COVID-19 in hospitalized patients. Key Points: Question: Does hydroxychloroquine/chloroquine benefit hospitalized patients with COVID-19, overall or within prespecified subgroups?Findings: In this individual participant data meta-analysis of 770 hospitalized COVID-19 patients across 8 clinical trials, we did not find evidence of a benefit of hydroxychloroquine/chloroquine, measured by a 7-point ordinal COVID-19 severity score at 28-35 days post-enrollment, in the pooled study population. We also found no substantial treatment effect heterogeneity among prespecified patient subgroups.Meaning: This study supports the consensus that hydroxychloroquine/chloroquine should not be used to treat hospitalized patients with COVID-19.

6.
J Mol Struct ; 1253: 132242, 2022 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-34975177

RESUMO

The recent outbreak of coronavirus disease (COVID-19) has rampaged the world with more than 236 million confirmed cases and over 4.8 million deaths across the world reported by the world health organization (WHO) till Oct 5, 2021. Due to the advent of different variants of coronavirus, there is an urgent need to identify effective drugs and vaccines to combat rapidly spreading virus varieties across the globe. Ferrocene derivatives have attained immense interest as anticancer, antifungal, antibacterial, and antiparasitic drug candidates. However, the ability of ferrocene as anti-COVID-19 is not yet explored. Therefore, in the present work, we have synthesized four new ferrocene Schiff bases (L1-L4) to understand the active sites and biological activity of ferrocene derivatives by employing various molecular descriptors, frontier molecular orbitals (FMO), electron affinity, ionization potential, and molecular electrostatic potential (MEP). A theoretical insight on synthesized ferrocene Schiff bases was accomplished by molecular docking, frontier molecular orbitals energies, active sites, and molecular descriptors which were further compared with drugs being currently used against COVID-19, i.e., dexamethasone, hydroxychloroquine, favipiravir (FPV), and remdesivir (RDV). Moreover, through the molecular docking approach, we recorded the inhibitions of ferrocene derivatives on core protease (6LU7) protein of SARS-CoV-2 and the effect of substituents on the anti-COVID activity of these synthesized compounds. The computational outcome indicated that L1 has a powerful 6LU7 inhibition of SARS-CoV-2 compared to the currently used drugs. These results could be helpful to design new ferrocene compounds and explore their potential application in the prevention and treatment of SARS-CoV-2.

7.
Artigo em Inglês | MEDLINE | ID: mdl-34995022

RESUMO

OBJECTIVES: The use of Hydroxychloroquine (HCQ) prophylaxis has been recommended by the National task force constituted by the Indian Council of Medical Research (ICMR) for the prevention of corona virus disease 2019 (COVID-19) among healthcare workers (HCWs). However, this recommendation was based essentially on the preclinical data and limited clinical experience. The aim of this study was to evaluate the efficacy and safety of HCQ as a pre-exposure prophylaxis for COVID-19 infection among Indian HCWs. METHODS: A cross-sectional study was conducted among HCWs of a tertiary care hospital in north India. The HCQ prophylaxis was initiated among 996 HCWs and they were followed up to 8 weeks for conversion to COVID-19 positive status and any adverse drug reaction (ADR). RESULTS: About 10.3% of the study participants were tested positive for COVID-19 which was comparable to the positivity rate among HCWs not taking HCQ prophylaxis (9.7%). CONCLUSIONS: HCQ was well tolerated at a weekly dose of 400 mg for 8 weeks but provided no additional benefit in prevention of COVID-19 among HCWs.

8.
Biomed Res Int ; 2022: 1522426, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35013710

RESUMO

Several therapeutic regimens for COVID-19 have been studied, such as combination antiviral therapies. We aimed to compare outcome of two types of combination therapies atazanavir/ritonavir (ATV/r) or lopinavir/ritonavir (LPV/r) plus hydroxychloroquine among COVID-19 patients. 108 patients with moderate and severe forms of COVID-19 were divided into two groups (each group 54 patients). One group received ATV/r plus hydroxychloroquine, and the other group received hydroxychloroquine plus LPV/r. Then, both groups were evaluated and compared for clinical symptoms, recovery rates, and complications of treatment regimens. Our findings showed a significant increase in bilirubin in ATV/r-receiving group compared to LPV/r receivers. There was also a significant increase in arrhythmias in the LPV/r group compared to the ATV/r group during treatment. Other findings including length of hospital stay, outcome, and treatment complications were not statistically significant. There is no significant difference between protease inhibitor drugs including ATV/r and LPV/r in the treatment of COVID-19 regarding clinical outcomes. However, some side effects such as hyperbilirubinemia and arrhythmia were significantly different by application of atazanavir or lopinavir.


Assuntos
Sulfato de Atazanavir/uso terapêutico , COVID-19/tratamento farmacológico , Lopinavir/uso terapêutico , Ritonavir/uso terapêutico , Idoso , Antivirais/uso terapêutico , Arritmias Cardíacas/induzido quimicamente , Arritmias Cardíacas/fisiopatologia , Bilirrubina/análise , COVID-19/metabolismo , Combinação de Medicamentos , Quimioterapia Combinada/métodos , Feminino , Hospitalização/tendências , Humanos , Hidroxicloroquina/uso terapêutico , Tempo de Internação/tendências , Masculino , Pessoa de Meia-Idade , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/patogenicidade , Resultado do Tratamento
9.
Muscle Nerve ; 2022 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-35040147

RESUMO

INTRODUCTION/AIMS: Coronavirus disease 2019(COVID-19) may have a more severe course in patients with myasthenia gravis(MG). We aimed to assess severity of the infection and factors contributing to its severity in a group of MG patients, most of whom were not hospitalized. METHODS: One hundred forty outpatients with MG followed between March 2020 and April 2021 were included. Patients were asked to respond to a brief questionnaire in person, by telemedicine or through electronic messages. RESULTS: Nineteen patients tested positive for COVID-19 by polymerase chain reaction. Two were asymptomatic. Of the seventeen symptomatic patients, eleven had mild symptoms. They either had no treatment or received antivirals, antibiotics and anticoagulants. Their myasthenia was well-controlled prior to infection and was unaffected by COVID-19. Three patients with moderate COVID-19 required hospitalization, but not intensive care, and had full recovery. Three other patients, the oldest in the cohort, had severe disease: One patient with a post-surgery myasthenic exacerbation prior to the infection needed intensive care without intubation, but recovered completely; two morbidly obese patients with comorbidities required intubation and died. Corticosteroids were increased in four of the six moderate/severely involved patients. Immunosuppressives(IS) were generally continued. Hydroxychloroquine(HCQ) for COVID-19 was used in one patient. DISCUSSION: The majority of the patients had mild COVID-19 and all but two patients recovered. The design of the study made it possible to capture mild cases. Having well-controlled MG prior to infection and absence of comorbidities likely affected the course of the infection favorably. IS did not influence the progression. This article is protected by copyright. All rights reserved.

10.
Arch Pharm (Weinheim) ; : e2100382, 2022 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-35040187

RESUMO

The outbreak of the coronavirus pandemic COVID-19 created by its severe acute respiratory syndrome corona virus-2 (SARS-CoV-2) variant, known for producing a very severe acute respiratory syndrome, has created an unprecedented situation by its continual assault around the world. The crisis caused by the SARS-CoV-2 variant has been a global challenge, calling to mitigate this unprecedented pandemic that has engulfed the whole world. Since the outbreak and spread of COVID-19, many researchers globally have been grappling to find new clinically trialed active drugs with anti-COVID-19 activity, from antimalarial drugs to JAK inhibitors, antiviral drugs, immune suppressants, and so forth. This article presents a brief discussion on the activity and synthesis of some active molecules such as favipiravir, hydroxychloroquine, pirfenidone, remdesivir, lopinavir, camostat, chloroquine, baricitinib, molnupiravir, and so forth, which are under trial.

11.
Artigo em Inglês | MEDLINE | ID: mdl-35040405

RESUMO

BACKGROUND: Drug discovery and development process is an expensive, complex, time-consuming and risky. There are different techniques involved in the drug development process which include random screening, computational approach, molecular manipulation and serendipitous research. Among these methods, the computational approach is considered as an efficient strategy to accelerate and economize the drug discovery process. OBJECTIVE: This approach is mainly applied in various phases of drug discovery process including target identification, target validation, lead identification and lead optimization. Due to increase in the availability of information regarding various biological targets of different disease states, computational approaches such as molecular docking, de novo design, molecular similarity calculation, virtual screening, pharmacophore-based modeling and pharmacophore mapping have been applied extensively. METHODS: Various drug molecules can be designed by applying computational tools to explore the drug candidates for treatment of Coronavirus infection. The world health organization has announced the novel corona virus disease as COVID-19 and declared it as pandemic globally on 11 February 2020. So, it is thought of interest to scientific community to apply computational methods to design and optimize the pharmacological properties of various clinically available and FDA approved drugs such as remdesivir, ribavirin, favipiravir, oseltamivir, ritonavir, arbidol, chloroquine, hydroxychloroquine, carfilzomib, baraticinib, prulifloxacin, etc for effective treatment of COVID-19 infection. RESULTS: Further, various survey reports suggest that the extensive studies are carried out by various research communities to find out the safety and efficacy profile of these drug candidates. CONCLUSION: This review is focused on the study of various aspects of these drugs related to their target sites on virus, binding interactions, physicochemical properties etc.

12.
Arthritis Res Ther ; 24(1): 21, 2022 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-35016701

RESUMO

BACKGROUND: Little is known about the safety of SARS-CoV-2 vaccination in patients with rheumatic musculoskeletal disease (RMD). We evaluated the occurrence of adverse events following immunization (AEFI) in RMD patients and heathy subjects who received anti-SARS-CoV-2 mRNA vaccine. METHODS: We performed a telephone interview collecting any adverse event (AE) following immunization (AEFI) that occurred in RMD patients and healthy controls after the two doses of mRNA vaccine including common local reactogenicity and systemic events (for example, fever, fatigue/malaise, joint and muscle pain). We also investigated the onset of new signs or symptoms of the RMD after the vaccination. RESULTS: We evaluated 126 patients with RMDs [105 females and 19 males, median age 51(IQR 17)] and 85 controls [62 females and 23 males, (median age 49 (20)]. Seventy patients (55.6%) were taking immunosuppressants, conventional synthetic (n=31, 43.3%) and/or biological [TNF inhibitors (n=49, 68.6%)], and 30 (23.8%) were taking hydroxychloroquine; treatment remained unchanged in 77% of patients. Eleven out of 126 patients and none of the 85 controls previously contracted COVID-19. The median follow-up from the completion of vaccination was 15 (3) weeks both in patients and controls. We reviewed 5 suspected cases confirming mild articular flares in 3 women (2.8) with inflammatory arthritis (2 psoriatic arthritis and 1 rheumatoid arthritis) while no disease reactivation was recorded in patients with connective tissue diseases; the incidence rate of RMD reactivation was 0.007 person/month. Multivariable logistic regression analysis showed similar frequencies of local and systemic AEFI in patients and controls with no effect of therapies or previous COVID-19. Local reaction-pain in the injection site-was the most frequently reported AEFI both in RMD and controls (71% and 75% of all the AEFI, respectively) after the first dose. Overall, up to 66% of patients experienced at least one AEFI at the second dose and up to 62% in the control group. Most of AEFI occurred within 2 days of vaccine administration. Two RMD patients developed pauci-symptomatic COVID-19 after the first dose of vaccine. CONCLUSION: The low incidence rate of disease reactivation and the similar AEFI occurrence compared to controls should reassure on mRNA vaccine safety in RMD patients.


Assuntos
COVID-19 , Doenças Musculoesqueléticas , Doenças Reumáticas , Vacinas contra COVID-19 , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doenças Reumáticas/tratamento farmacológico , SARS-CoV-2 , Exacerbação dos Sintomas , Vacinas Sintéticas
13.
Clin Nephrol Case Stud ; 10: 6-10, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35028280

RESUMO

. Acute tubular injury is the lesion most frequently described in this disease. However, four cases of ANCA-associated vasculitis (AAV) with COVID-19 with pauci-immune glomerulonephritis have recently been described. We report the case of an African woman, aged 70, in whom we diagnosed an AAV with pauci-immune glomerulonephritis in the context of COVID-19. She was treated with hydroxychloroquine and azithromycin for COVID-19. Corticosteroids and cyclophosphamide have been used for the treatment of vasculitis. The evolution was marked by the reappearance of COVID-19 one month after the beginning of an immunosuppressive therapy. The patient died a week later from respiratory failure. The occurrence of AAV during COVID-19 may not be due an unfortunate association but triggered by infection with SARS-CoV-2. The use of immunosuppressive therapy should be discussed due to the potential risk of reactivation or recurrence of the viral infection.

14.
PLoS One ; 17(1): e0261843, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35061735

RESUMO

INTRODUCTION: During the first wave of the coronavirus-disease 2019 (covid-19) pandemic in early 2020, hydroxychloroquine (HCQ) was widely prescribed in light of in vitro activity against severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2). Our objective was to evaluate in early 2020 the rate of French hospitalists declaring having prescribed HCQ to treat covid-19 patients outside any therapeutic trial, compare the reasons and the determinants for having prescribed HCQ or not. MATERIAL AND METHODS: A national inquiry submitted by email from May 7 to 25, 2020, to a sample of French hospitalists: doctors managing patients hospitalized for covid-19 in a French department of internal medicine or infectious diseases and identified in the directories of French hospitals or as a member of the French Infectious Diseases Society (SPILF). Primary outcome was the percentage of hospitalists declaring having prescribed HCQ to covid-19 patients. Secondary outcomes were reasons and determinants of HCQ prescription. RESULTS: Among 400 (22.8%) responding hospitalists, 45.3% (95% CI, 40.4 to 50.1%) declared having prescribed HCQ to covid-19 patients. Two main profiles were discerned: HCQ prescribers who did not raise its efficacy as a motive, and non-prescribers who based their decision on evidence-based medicine. Multivariate analysis retained the following prescription determinants (adjusted odds ratio; 95% confidence interval): a departmental procedure for HCQ prescription (8.25; 4.79 to 14.20), having prescribed other treatments outside a therapeutic trial (3.21; 1.81 to 5.71), prior HCQ prescription (2.75; 1.5 to 5.03) and HCQ prescribed within the framework of a therapeutic trial (0.56; 0.33 to 0.95). CONCLUSION: Almost half of the hospitalists prescribed HCQ. The physician's personality (questioning or not evidence-based-medicine principles in the context of the pandemic) and departmental therapeutic procedures were the main factors influencing HCQ prescription. Establishment of "therapeutic" procedures represents a potential means to improve the quality of therapeutic decision-making during a pandemic.

15.
J Assoc Physicians India ; 70(1): 11-12, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-35062802

RESUMO

BACKGROUND: Although hydroxychloroquine (HCQ) lacks benefit in patients with moderate-to-severe COVID-19, its role in asymptomatic and mildly symptomatic disease needs better elucidation. METHODS: This multi-centre cohort study included asymptomatic and mildly symptomatic, RT-PCR confirmed COVID-19 cases between 30 March and 20 May, 2020. Patients were categorized into two groups (HCQ-treated and untreated) based on exposure to HCQ. Dose of HCQ used was 400 mg twice daily (day one) followed by once daily for seven days. HCQ-untreated patients were managed supportively without any active antiviral or immunomodulatory therapy. Nasopharyngeal SARS-CoV-2 clearance by RT-PCR (primary outcome) was compared between HCQ-treated and untreated patients using Kaplan-Meier analysis and Cox proportional-hazards regression. Clinical efficacy and safety profile of HCQ were assessed (secondary outcomes). RESULTS: 162 patients [84 (51·9%) males; mean age 38·2 (15·2) years] were included. Forty-four (27·2%) patients had mild disease, rest 118 (72·8%) were asymptomatic. Seventy-five (46·3%) patients received HCQ. Median time to virological negativity was lesser in HCQ-treated (13 days) versus untreated patients (15 days) (logrank<0·001) in both asymptomatic and mildly symptomatic patients. Treatment with HCQ was the only independent predictor of virological negativity (hazardratio=2·24; adjusted p-value<0·001). Two (5·4%) mildly symptomatic patients progressed to severe disease within 24 hours (two doses) of HCQ initiation, compared to none in the HCQ-untreated group. Five HCQ-treated patients developed minor gastrointestinal side effects, not requiring drug discontinuation. CONCLUSION: HCQ reduced the time to virologic negativity (by 2 days) in asymptomatic and mildly symptomatic COVID-19, without any serious adverse events. However, no obvious clinical benefit was noted.

16.
J Cardiovasc Pharmacol Ther ; 27: 10742484211069479, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35006023

RESUMO

BACKGROUND: Several reports linked the use of repurposed drugs such as hydroxychloroquine (HCQ), azithromycin, lopinavir/ritonavir, and favipiravir with QT interval prolongation in patients with SARS-CoV2 infection. Little is known about the risk factors for QT interval prolongation in this population. We sought to describe the prevalence and identify the main risk factors associated with clinically significant corrected QT (QTc) prolongation in this population. METHODS: We conducted a retrospective analysis of critically ill patients who were admitted to our intensive care unit (ICU), had at least one electrocardiogram performed during their ICU stay, and tested positive for SARs-CoV-2. Clinically significant QTc interval prolongation was defined as QTc >500 milliseconds (ms). RESULTS: Out of the 111 critically ill patients with SARS-CoV-2 infection, QTc was significantly prolonged in 47 cases (42.3%). Patients with a clinically significant QTc prolongation had significantly higher proportions of history of cardiac diseases/surgery (22 [46.8%] vs. 10 [15.6%], P < .001), hypokalemia (10 [21.3] vs. 5 [7.8%], P = .04), and male gender (95% vs. 82.8%, P = .036) than patients with QTc ≤500 ms, respectively. A total of 46 patients (41.4%) received HCQ, 28 (25.2%) received lopinavir/ritonavir, and 5 (4.5%) received azithromycin. Multivariate logistic regression analysis showed that a history of cardiac disease was the only independent factor associated with clinically significant QTc prolongation (P = .004 for the likelihood-ratio test). CONCLUSION: The prevalence of clinically significant QTc prolongation in critically ill patients with SARS-CoV-2 infection was high and independent of drugs used. Larger prospective observational studies are warranted to elucidate independent risk factors associated with clinically significant QTc prolongation in this study population.

17.
Int J Antimicrob Agents ; : 106516, 2022 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-34999239

RESUMO

High concentrations of ivermectin demonstrated antiviral activity against SARS-CoV-2 in vitro. Aim of this study was to assess safety and efficacy of high-dose ivermectin in reducing viral load in individuals with early SARS-CoV-2 infection. Randomised, double-blind, multicentre, phase II, dose-finding, proof-of-concept clinical trial. Participants: adults recently diagnosed with asymptomatic/oligosymptomatic SARS-CoV-2 infection, providing informed consent. Exclusion criteria: pregnant or lactating women; CNS diseases; dialysis; severe medical condition with prognosis < 6 months; warfarin treatment; antiviral/chloroquine phosphate/hydroxychloroquine treatment. Participants were assigned according to a randomized permuted block procedure to one of the following arms with allocation ratio 1:1:1: placebo (arm A); single dose ivermectin 600 µg/kg plus placebo for 5 days (arm B); single dose ivermectin 1200 µg/kg for 5 days (arm C). Primary outcomes: serious adverse drug reactions (SADR) and change of viral load at Day 7. From 31th July, 2020 to 26th May, 2021, 32 participants were randomized to arm A, 29 to arm B and 32 to arm C. The recruitment was stopped on 10th June, because of a dramatic drop of cases. Eighty-nine participants were included in the safety analysis set, the change in viral load was calculated on 87 participants. No SADR were registered. The mean log10 viral load reduction was 2.9 in arm C (SD 1.6), 2.5 (2.2) in arm B and 2.0 (2.1) in arm A, with no significant differences (p=0.099 and 0.122 for C versus A and B versus A, respectively). High-dose ivermectin was safe, but did not prove efficacy to reduce viral load.

18.
Pharm Res ; 2022 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-35000036

RESUMO

PURPOSE: Chloroquine and hydroxychloroquine are effective against respiratory viruses in vitro. However, they lack antiviral efficacy upon oral administration. Translation of in vitro to in vivo exposure is necessary for understanding the disconnect between the two to develop effective therapeutic strategies. METHODS: We employed an in vitro ion-trapping kinetic model to predict the changes in the cytosolic and lysosomal concentrations of chloroquine and hydroxychloroquine in cell lines and primary human airway cultures. A physiologically based pharmacokinetic model with detailed respiratory physiology was used to predict regional airway exposure and optimize dosing regimens. RESULTS: At their reported in vitro effective concentrations in cell lines, chloroquine and hydroxychloroquine cause a significant increase in their cytosolic and lysosomal concentrations by altering the lysosomal pH. Higher concentrations of the compounds are required to achieve similar levels of cytosolic and lysosomal changes in primary human airway cells in vitro. The predicted cellular and lysosomal concentrations in the respiratory tract for in vivo oral doses are lower than the in vitro effective levels. Pulmonary administration of aerosolized chloroquine or hydroxychloroquine is predicted to achieve high bound in vitro-effective concentrations in the respiratory tract, with low systemic exposure. Achieving effective cytosolic concentrations for activating immunomodulatory effects and adequate lysosomal levels for inhibiting viral replication could be key drivers for treating viral respiratory infections. CONCLUSION: Our analysis provides a framework for extrapolating in vitro effective concentrations of chloroquine and hydroxychloroquine to in vivo dosing regimens for treating viral respiratory infections.

19.
Mol Divers ; 2022 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-35000060

RESUMO

Several existing drugs have gained initial consideration due to their therapeutic characteristics against COVID-19 (Corona Virus Disease 2019). Hydroxychloroquine (HCQ) was proposed as possible therapy for shortening the duration of COVID-19, but soon after this, it was discarded. Similarly, known antiviral compounds were also proposed and investigated to treat COVID-19. We report a pharmacophore screening using essential chemical groups derived from HCQ and known antivirals to search a natural compound chemical space. Molecular docking of HCQ under physiological condition with spike protein, 3C-like protease (3CLpro), and RNA-dependent RNA polymerase (RdRp) of SARS-CoV2 showed - 8.52 kcal/mole binding score with RdRp, while the other two proteins showed relatively weaker binding affinity. Docked complex of RdRp-HCQ is further examined using 100 ns molecular dynamic simulation. Docking and simulation study confirmed active chemical moieties of HCQ, treated as 6-point pharmacophore to screen ZINC natural compound database. Pharmacophore screening resulted in the identification of potent hit molecule [(3S,3aR,6R,6aS)-3-(5-phenylsulfanyltetrazol-1-yl)-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-yl]N-naphthalen-ylcarbamate from natural compound library. Additionally, a set of antiviral compounds with similar chemical scaffolds are also used to design a separate ligand-based pharmacophore screening. Antiviral pharmacophore screening produced a potent hit 4-[(1,5-dimethyl-3-oxo-2-phenylpyrazol-4-yl)-(2-hydroxyphenyl)methyl]-1,5-dimethyl-2-phenylpyrazol-3-one containing essential moieties that showed affinity towards RdRp. Further, both these screened compounds are docked (- 8.69 and - 8.86 kcal/mol) and simulated with RdRp protein for 100 ns in explicit solvent medium. They bind at the active site of RdRp and form direct/indirect interaction with ASP618, ASP760, and ASP761 catalytic residues of the protein. Successively, their molecular mechanics Poisson Boltzmann surface area (MMPBSA) binding energies are calculated over the simulation trajectory to determine the dynamic atomistic interaction details. Overall, this study proposes two key natural chemical moieties: (a) tetrazol and (b) phenylpyrazol that can be investigated as a potential chemical group to design inhibitors against SARS-CoV2 RdRp.

20.
Sci Total Environ ; : 153122, 2022 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-35063509

RESUMO

The city of Vitoria-Gasteiz was one of the probable first entrances of the SARS-CoV2 in Spain, one of the worst affected countries in the world during the first COVID 19 wave. Driven by the urgency of the situation, multiple drugs with antiviral activity were used off label. Sadly, most of these treatments were of little or no benefit and thus, the number of patients suffering from COVID-19 attended in intensive care units (ICUs) multiplied. After being administered to patients, a variable proportion of these drugs reach the environment where they may have detrimental effects, although this aspect is usually ignored by healthcare professionals. In this study we measured the patterns of hospital drug use in the city of Vitoria-Gasteiz (Spain) during the first COVID-19 wave pandemic, focusing on those with antiviral activity and those used in the ICUs. Subsequently, we measured concentrations of selected drugs in the city's wastewater treatment plant influent and effluent and estimated the potential risk for the environment. The hospital use of certain antivirals and drugs used for sedo-analgesia were dramatically increased during the first wave (cisatracurium was multiplied by 25 and lopinavir/ritonavir by 20). A mean of 1.632 daily defined doses of hydroxychloroquine were used during the period of February-May 2020. In this study we report the first positive detection of hydroxychloroquine ever in the environment. We also show the second positive report of lopinavir. Low risk was estimated for hydroxychloroquine, lopinavir and ritonavir (Risk quotients (RQ) <1), and medium risk for azithromycin (RQ 0f 0.146).

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