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1.
PLoS One ; 17(4): e0266337, 2022.
Article in English | MEDLINE | ID: covidwho-1779766

ABSTRACT

The COVID-19 pandemic caused by SARS-CoV-2 has resulted in an urgent need for identifying potential therapeutic drugs. In the first half of 2020 tropic antimalarial drugs, such as chloroquine (CQ) or hydroxochloroquine (HCQ) were the focus of tremendous public attention. In the initial periods of the pandemic, many scientific results pointed out that CQ/HCQ could be very effective for patients with severe COVID. While CQ and HCQ have successfully been used against several diseases (such as malaria, autoimmune disease and rheumatic illnesses); long term use of these agents are associated with serious adverse effects (i.e. inducing acute kidney injury, among many others) due to their role in blocking autophagy-dependent self-degradation. Recent experimental and clinical trial data also confirmed that there is no sufficient evidence about the efficient usage of CQ/HCQ against COVID-19. By using systems biology techniques, here we show that the cellular effect of CQ/HCQ on autophagy during endoplasmic reticulum (ER) stress or following SARS-CoV-2 infection results in upregulation of ER stress. By presenting a simple mathematical model, we claim that although CQ/HCQ might be able to ameliorate virus infection, the permanent inhibition of autophagy by CQ/HCQ has serious negative effects on the cell. Since CQ/HCQ promotes apoptotic cell death, here we confirm that addition of CQ/HCQ cannot be really effective even in severe cases. Only a transient treatment seemed to be able to avoid apoptotic cell death, but this type of therapy could not limit virus replication in the infected host. The presented theoretical analysis clearly points out the utility and applicability of systems biology modelling to test the cellular effect of a drug targeting key major processes, such as autophagy and apoptosis. Applying these approaches could decrease the cost of pre-clinical studies and facilitate the selection of promising clinical trials in a timely fashion.


Subject(s)
COVID-19 , Autophagy , COVID-19/drug therapy , Chloroquine/pharmacology , Chloroquine/therapeutic use , Humans , Hydroxychloroquine/adverse effects , Pandemics , SARS-CoV-2 , Systems Biology
2.
Brain Behav Immun ; 87: 59-73, 2020 07.
Article in English | MEDLINE | ID: covidwho-1719339

ABSTRACT

As of April 15, 2020, the ongoing coronavirus disease 2019 (COVID-2019) pandemic has swept through 213 countries and infected more than 1,870,000 individuals, posing an unprecedented threat to international health and the economy. There is currently no specific treatment available for patients with COVID-19 infection. The lessons learned from past management of respiratory viral infections have provided insights into treating COVID-19. Numerous potential therapies, including supportive intervention, immunomodulatory agents, antiviral therapy, and convalescent plasma transfusion, have been tentatively applied in clinical settings. A number of these therapies have provided substantially curative benefits in treating patients with COVID-19 infection. Furthermore, intensive research and clinical trials are underway to assess the efficacy of existing drugs and identify potential therapeutic targets to develop new drugs for treating COVID-19. Herein, we summarize the current potential therapeutic approaches for diseases related to COVID-19 infection and introduce their mechanisms of action, safety, and effectiveness.


Subject(s)
Coronavirus Infections/therapy , Pneumonia, Viral/therapy , Adrenal Cortex Hormones/therapeutic use , Angiotensin-Converting Enzyme 2 , Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Antibodies, Monoclonal, Humanized/therapeutic use , Anticoagulants/therapeutic use , Antimalarials/therapeutic use , Antiviral Agents/therapeutic use , Betacoronavirus , Bevacizumab/therapeutic use , COVID-19 , COVID-19 Vaccines , Chloroquine/therapeutic use , Coronavirus Infections/drug therapy , Coronavirus Infections/prevention & control , Humans , Hydroxychloroquine/therapeutic use , Immunization, Passive , Immunoglobulins, Intravenous/therapeutic use , Immunologic Factors/therapeutic use , Interferons/therapeutic use , Janus Kinase Inhibitors/therapeutic use , Killer Cells, Natural , Medicine, Chinese Traditional , Mesenchymal Stem Cell Transplantation , Nitric Oxide/therapeutic use , Pandemics , Peptidyl-Dipeptidase A , SARS-CoV-2 , Spike Glycoprotein, Coronavirus , Trace Elements/therapeutic use , Viral Vaccines/therapeutic use , Vitamins/therapeutic use , Zinc/therapeutic use
3.
Clin Med Res ; 19(4): 179-182, 2021 12.
Article in English | MEDLINE | ID: covidwho-1581437

ABSTRACT

Objective: To assess the effect of chloroquine and hydroxychloroquine on cytokine release syndrome (CRS) in adult patients with coronavirus disease 2019 (COVID-19) having mild to moderate symptoms.Methods: This blinded, placebo-controlled, randomized study was conducted in the Department of Medicine, Pak Emirates Military Hospital Rawalpindi, from June 1-15, 2020. A total of 150 hospitalized patients were enrolled after diagnoses with COVID-19 through reverse transcription polymerase chain reaction (RT-PCR). They were divided into three groups: hydroxychloroquine plus general care (HGC, n=50), chloroquine plus general care (CGC, n=50); and only general care (OGC, n=50). The HGC group received treatment with hydroxychloroquine 400 mg every 12 hours for day one and 200 mg for the next 4 days. The CGC group received treatment with chloroquine 250 mg every 12 hours for 7 days. The OGC group was kept as a control with only general care. After 12 days, the patients were screened for development of CRS through detection of interleukin 6 (IL-6) in serum samples by using Roche cobas e411 electrochemiluminescence immunoassay analyzer.Results: The mean duration from onset of symptoms to randomization was 7.65 days (SD = 3.287 days; range, 2-15 days). The mean age of patients was 37.57 (range 19-63) years. Results showed that out of a total 150 patients, only 10 patients (6%, mean=1.93; CI=1.89-1.97, P=0.651) developed CRS in all study groups. Four patients (8%) developed CRS in the HGC group, 2 patients (4%) in the CGC group, and 4 patients (8%) in the OGC group. There was no significant difference in the mean level of CRS among study groups.Conclusion: Administration of hydroxychloroquine and chloroquine has no effect in reducing the development of CRS in patients with COVID-19 having mild to moderate symptoms.


Subject(s)
COVID-19 , Hydroxychloroquine , Adult , Antiviral Agents/therapeutic use , COVID-19/drug therapy , Chloroquine/therapeutic use , Cytokine Release Syndrome , Humans , Hydroxychloroquine/therapeutic use , Middle Aged , SARS-CoV-2 , Treatment Outcome , Young Adult
4.
J Med Virol ; 93(12): 6737-6749, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1544327

ABSTRACT

Chloroquine or its derivative hydroxychloroquine (HCQ) combined with or without azithromycin (AZ) have been widely investigated in observational studies as a treatment option for coronavirus 2019 (COVID-19) infection. The network meta-analysis aims to summarize evidence from randomized controlled trials (RCTs) to determine if AZ or HCQ is associated with improved clinical outcomes. PubMed and Embase were searched from inception to March 7, 2021. We included published RCTs that investigated the efficacy of AZ, HCQ, or its combination among hospitalized patients with COVID-19 infection. The outcomes of interest were all-cause mortality and the use of mechanical ventilation. The pooled odds ratio was calculated using a random-effect model. A total of 10 RCTs were analyzed. Participant's mean age ranged from 40.4 to 66.5 years. There was no significant effect on mortality associated with AZ plus HCQ (odds ratio [OR] = 0.562 [95% confidence interval {CI}: 0.168-1.887]), AZ alone (OR = 0.965 [95% CI: 0.865-1.077]), or HCQ alone (OR = 1.122 [95% CI: 0.995-1.266]; p = 0.06). Similarly, based on pooled effect sizes derived from direct and indirect evidence, none of the treatments had a significant benefit in decreasing the use of mechanical ventilation. No heterogeneity was identified (Cochran's Q = 1.68; p = 0.95; τ2 = 0; I2 = 0% [95% CI: 0%-0%]). Evidence from RCTs suggests that AZ with or without HCQ was not associated with a significant effect on the mortality or mechanical ventilation rates in hospitalized patients with COVID-19. More research is needed to explore therapeutics agents that can effectively reduce the mortality or severity of COVID-19.


Subject(s)
Antiviral Agents/therapeutic use , Azithromycin/therapeutic use , COVID-19/drug therapy , Hydroxychloroquine/therapeutic use , Adult , Aged , Chloroquine/therapeutic use , Female , Humans , Male , Middle Aged , Network Meta-Analysis , Randomized Controlled Trials as Topic , Respiration, Artificial/methods
5.
Mol Med Rep ; 24(6)2021 12.
Article in English | MEDLINE | ID: covidwho-1504040

ABSTRACT

The spread of the novel severe acute respiratory syndrome coronavirus 2 (SARS­CoV­2) emerged suddenly at the end of 2019 and the disease came to be known as coronavirus disease 2019 (COVID­19). To date, there is no specific therapy established to treat COVID­19. Identifying effective treatments is urgently required to treat patients and stop the transmission of SARS­CoV­2 in humans. For the present review, >100 publications on therapeutic agents for COVID­19, including in vitro and in vivo animal studies, case reports, retrospective analyses and meta­analyses were retrieved from PubMed and analyzed, and promising therapeutic agents that may be used to combat SARS­CoV­2 infection were highlighted. Since the outbreak of COVID­19, different drugs have been repurposed for its treatment. Existing drugs, including chloroquine (CQ), its derivative hydroxychloroquine (HCQ), remdesivir and nucleoside analogues, monoclonal antibodies, convalescent plasma, Chinese herbal medicine and natural compounds for treating COVID­19 evaluated in experimental and clinical studies were discussed. Although early clinical studies suggested that CQ/HCQ produces antiviral action, later research indicated certain controversy regarding their use for treating COVID­19. The molecular mechanisms of these therapeutic agents against SARS­CoV2 have been investigated, including inhibition of viral interactions with angiotensin­converting enzyme 2 receptors in human cells, viral RNA­dependent RNA polymerase, RNA replication and the packaging of viral particles. Potent therapeutic options were reviewed and future challenges to accelerate the development of novel therapeutic agents to treat and prevent COVID­19 were acknowledged.


Subject(s)
COVID-19/therapy , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/therapeutic use , Alanine/analogs & derivatives , Alanine/therapeutic use , Animals , Antimalarials/therapeutic use , Antiviral Agents/therapeutic use , COVID-19/diagnosis , Chloroquine/therapeutic use , Drugs, Chinese Herbal/therapeutic use , Humans , Hydroxychloroquine/therapeutic use , Immunization, Passive , SARS-CoV-2/isolation & purification
6.
Arthritis Rheumatol ; 73(12): 2151-2160, 2021 12.
Article in English | MEDLINE | ID: covidwho-1482112

ABSTRACT

Hydroxychloroquine (HCQ) and chloroquine (CQ) are well-established medications used in treating systemic lupus erythematosus and rheumatoid arthritis, as well as skin conditions such as cutaneous lupus erythematosus. In rare cases, arrhythmias and conduction system abnormalities, as well as cardiomyopathy, have been reported in association with HCQ/CQ use. Recently, however, the corrected QT interval (QTc)-prolonging potential of these medications, and risk of torsade de pointes (TdP) in particular, have been highlighted in the setting of their experimental use for COVID-19 infection. This report was undertaken to summarize the current understanding of HCQ/CQ cardiac toxicity, describe QTc prolongation and TdP risks, and discuss areas of priority for future research. A working group of experts across rheumatology, cardiology, and dermatology performed a nonsystematic literature review and offered a consensus-based expert opinion. Current data clearly indicate that HCQ and CQ are invaluable medications in the management of rheumatic and dermatologic diseases, but they are associated with QTc prolongation by directly affecting cardiac repolarization. Prescribing clinicians should be cognizant of this small effect, especially in patients taking additional medications that prolong the QTc interval. Long-term use of HCQ/CQ may lead to a cardiomyopathy associated with arrhythmias and heart failure. Risk and benefit assessment should be considered prior to initiation of any medication, and both initial and ongoing risk-benefit assessments are important with regard to prescription of HCQ/CQ. While cardiac toxicity related to HCQ/CQ treatment of rheumatic diseases is rarely reported, it can be fatal. Awareness of the potential adverse cardiac effects of HCQ and CQ can increase the safe use of these medications. There is a clear need for additional research to allow better understanding of the cardiovascular risk and safety profile of these therapies used in the management of rheumatic and cutaneous diseases.


Subject(s)
Antimalarials/therapeutic use , COVID-19/drug therapy , Cardiotoxicity/etiology , Chloroquine/therapeutic use , Hydroxychloroquine/therapeutic use , Antimalarials/adverse effects , Chloroquine/adverse effects , Humans , Hydroxychloroquine/adverse effects
8.
Am J Chin Med ; 48(6): 1263-1277, 2020.
Article in English | MEDLINE | ID: covidwho-1365228

ABSTRACT

In December 2019, a novel coronavirus SARS-CoV-2, causing the disease COVID-19, spread from Wuhan throughout China and has infected people over 200 countries. Thus far, more than 3,400,000 cases and 240,000 deaths have occurred worldwide, and the coronavirus pandemic continues to grip the globe. While numbers of cases in China have been steadying, the number of infections outside China is increasing at a worrying pace. We face an urgent need to control the spread of the COVID-19 epidemic, which is currently expanding to a global pandemic. Efforts have focused on testing antiviral drugs and vaccines, but there is currently no treatment specifically approved. Traditional Chinese medicine (TCM) is grounded in empirical observations and the Chinese people use TCM to overcome these sorts of plagues many times in thousands of years of history. Currently, the Chinese National Health Commission recommended a TCM prescription of Qing-Fei-Pai-Du-Tang (QFPDT) in the latest version of the "Diagnosis and Treatment guidelines of COVID-19" which has been reported to provide reliable effects for COVID-19. While doubts about TCM still exist today, this review paper will describe the rationalities that QFPDT is likely to bring a safe and effective treatment of COVID-19.


Subject(s)
Anti-Inflammatory Agents/therapeutic use , Antiviral Agents/therapeutic use , Coronavirus Infections/drug therapy , Drugs, Chinese Herbal/therapeutic use , Pneumonia, Viral/drug therapy , Adrenal Cortex Hormones/therapeutic use , Antibodies, Monoclonal, Humanized/therapeutic use , Betacoronavirus , COVID-19 , Chloroquine/therapeutic use , Coronavirus Infections/immunology , Cytokine Release Syndrome/drug therapy , Cytokine Release Syndrome/immunology , Drug Combinations , Humans , Indoles/therapeutic use , Janus Kinase Inhibitors/therapeutic use , Lopinavir/therapeutic use , Medicine, Chinese Traditional , Pandemics , Pneumonia, Viral/immunology , Ritonavir/therapeutic use , SARS-CoV-2
9.
PLoS One ; 16(8): e0256035, 2021.
Article in English | MEDLINE | ID: covidwho-1359100

ABSTRACT

BACKGROUND: Chloroquine was promoted as a COVID-19 therapeutic early in the pandemic. Most countries have since discontinued the use of chloroquine due to lack of evidence of any benefit and the risk of severe adverse events. The primary aim of this study was to examine if administering chloroquine during COVID-19 imposed an increased risk of ischemic heart injury or heart failure. METHODS: Medical records, laboratory findings, and electrocardiograms of patients with COVID-19 who were treated with 500 mg chloroquine phosphate daily and controls not treated with chloroquine were reviewed retrospectively. Controls were matched in age and severity of disease. RESULTS: We included 20 patients receiving chloroquine (500 mg twice daily) for an average of five days, and 40 controls. The groups were comparable regarding demographics and biochemical analyses including C-reactive protein, thrombocytes, and creatinine. There were no statistically significant differences in cardiac biomarkers or in electrocardiograms. Median troponin T was 10,8 ng/L in the study group and 17.9 ng/L in the control group, whereas median NT-proBNP was 399 ng/L in patients receiving chloroquine and 349 ng/L in the controls. CONCLUSIONS: We found no increased risk of ischemic heart injury or heart failure as a result of administering chloroquine. However, the use of chloroquine to treat COVID-19 outside of clinical trials is not recommended, considering the lack of evidence of its effectiveness, as well as the elevated risk of fatal arrythmias.


Subject(s)
Antiviral Agents/adverse effects , Biomarkers/analysis , Chloroquine/analogs & derivatives , Heart Failure/etiology , Heart Injuries/etiology , Aged , Antiviral Agents/therapeutic use , C-Reactive Protein/analysis , COVID-19/drug therapy , COVID-19/pathology , COVID-19/virology , Case-Control Studies , Chloroquine/adverse effects , Chloroquine/therapeutic use , Creatinine/analysis , Electrocardiography , Female , Heart Failure/metabolism , Heart Injuries/metabolism , Humans , Male , Middle Aged , Natriuretic Peptide, Brain/analysis , Peptide Fragments/analysis , Retrospective Studies , SARS-CoV-2/isolation & purification , Severity of Illness Index , Troponin T/analysis
10.
S Afr Med J ; 111(8): 720-723, 2021 Jun 08.
Article in English | MEDLINE | ID: covidwho-1355170

ABSTRACT

Herbal medicines made from the bark of the Cinchona tree, and later quinine, have been widely used for centuries to treat medical conditions such as tropical malaria. More recently, chloroquine (CQ) and its synthetic derivatives have been used as antimalarials and to treat systemic lupus erythematosus, rheumatoid arthritis, and in the past 14 months or so, COVID-19 pneumonia. Anecdotal evidence and the erratic covering through social media of its potential efficacy in the treatment of COVID-19 pneumonia have resulted in the widespread off-label use of CQ in South Africa and worldwide. This study aimed to show that access to CQ as a chronic medication for rheumatic and musculoskeletal diseases was limited during the COVID-19 pandemic, and that this resulted in an increased incidence of flares in these patients, affecting their morbidity and potentially leading to mortality.


Subject(s)
Chloroquine/pharmacology , Rheumatology/standards , Ambulatory Care Facilities/organization & administration , Ambulatory Care Facilities/statistics & numerical data , Antirheumatic Agents/pharmacology , Antirheumatic Agents/therapeutic use , COVID-19/drug therapy , Chloroquine/therapeutic use , Humans , Musculoskeletal Diseases/drug therapy , Rheumatic Diseases/drug therapy , Rheumatology/methods , Rheumatology/statistics & numerical data
11.
Eur J Pharmacol ; 908: 174374, 2021 Oct 05.
Article in English | MEDLINE | ID: covidwho-1322083

ABSTRACT

The efficacy of corticosteroids and its use for the treatment of SARS-CoV-2 infections is controversial. In this study, using data sets of SARS-CoV-2 infected lung tissues and nasopharyngeal swabs, as well as in vitro experiments, we show that SARS-CoV-2 infection significantly downregulates DUSP1 expression. This downregulation of DUSP1 could be the mechanism regulating the enhanced activation of MAPK pathway as well as the reported steroid resistance in SARS-CoV-2 infection. Moreover, chloroquine, an off labeled COVID-19 drug is able to induce DUSP1 and attenuate MAPK pathway; and is expected to improve sensitivity to steroid treatment. However, further mechanistic studies are required to confirm this effect.


Subject(s)
COVID-19/drug therapy , Chloroquine/pharmacology , Dual Specificity Phosphatase 1/genetics , Glucocorticoids/pharmacology , p38 Mitogen-Activated Protein Kinases/metabolism , Adult , Aged , COVID-19/pathology , COVID-19/virology , Case-Control Studies , Cells, Cultured , Chloroquine/therapeutic use , Datasets as Topic , Down-Regulation/drug effects , Drug Resistance/drug effects , Drug Resistance/genetics , Drug Synergism , Dual Specificity Phosphatase 1/metabolism , Fibroblasts , Glucocorticoids/therapeutic use , Healthy Volunteers , Humans , Lung/cytology , Lung/pathology , MAP Kinase Signaling System/drug effects , MAP Kinase Signaling System/genetics , Middle Aged , Nasopharynx/virology , Off-Label Use , Primary Cell Culture , SARS-CoV-2/isolation & purification , SARS-CoV-2/pathogenicity
12.
Pharmacol Res ; 158: 104904, 2020 08.
Article in English | MEDLINE | ID: covidwho-1318936

ABSTRACT

The anti-malarial drugs chloroquine (CQ) and primarily the less toxic hydroxychloroquine (HCQ) are currently used to treat autoimmune diseases for their immunomodulatory and anti-thrombotic properties. They have also been proposed for the treatment of several viral infections, due to their anti-viral effects in cell cultures and animal models, and, currently, for the treatment of coronavirus disease 2019 (COVID-19), the pandemic severe acute respiratory syndrome caused by coronavirus 2 (Sars-Cov-2) infection that is spreading all over the world. Although in some recent studies a clinical improvement in COVID-19 patients has been observed, the clinical efficacy of CQ and HCQ in COVID-19 has yet to be proven with randomized controlled studies, many of which are currently ongoing, also considering pharmacokinetics, optimal dosing regimen, therapeutic level and duration of treatment and taking into account patients with different severity degrees of disease. Here we review what is currently known on the mechanisms of action of CQ and HCQ as anti-viral, anti-inflammatory and anti-thrombotic drugs and discuss the up-to-date experimental evidence on the potential mechanisms of action of CQ/HCQ in Sars-Cov2 infection and the current clinical knowledge on their efficacy in the treatment of COVID-19 patients. Given the role of iron in several human viral infections, we also propose a different insight into a number of CQ and HCQ pharmacological effects, suggesting a potential involvement of iron homeostasis in Sars-Cov-2 infection and COVID-19 clinical course.


Subject(s)
Betacoronavirus/drug effects , Chloroquine/pharmacology , Chloroquine/therapeutic use , Coronavirus Infections/drug therapy , Homeostasis/drug effects , Hydroxychloroquine/pharmacology , Hydroxychloroquine/therapeutic use , Iron/metabolism , Pneumonia, Viral/drug therapy , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , COVID-19 , Coronavirus Infections/metabolism , Humans , Pandemics , Pneumonia, Viral/metabolism , SARS-CoV-2
13.
Afr J Prim Health Care Fam Med ; 13(1): e1-e8, 2021 Jun 15.
Article in English | MEDLINE | ID: covidwho-1296009

ABSTRACT

BACKGROUND: As the search for effective treatment of coronavirus disease 2019 (COVID-19) infection continues, the public opinion around the potential use of chloroquine (CQ) in treating COVID-19 remains mixed. AIM: To examine opinion and uptake of CQ for treating COVID-19 in the sub-Saharan African (SSA) region. SETTING: This study was conducted through an online survey software titled SurveyMonkey. METHODS: Anonymous online survey of 1829 SSA countries was conducted during the lockdown period using Facebook, WhatsApp and authors' networks. Opinion and uptake of CQ for COVID-19 treatment were assessed using multivariate analyses. RESULTS: About 14% of respondents believed that CQ could treat COVID-19 and of which, 3.2% took CQ for COVID-19 treatment. Multivariate analyses revealed that respondents from Central (adjusted odds ratios [aOR]: 2.54, 95% confidence interval [CI] 1.43, 4.43) and West Africa (aOR: 1.79, 95% CI 1.15, 2.88) had higher odds of believing that CQ could treat COVID-19. Respondents from East Africa reported higher odds for uptake of CQ for COVID-19 than Central, Western and Southern Africans. Knowledge of the disease and compliance with the public health advice were associated with both belief and uptake of CQ for COVID-19 treatment. CONCLUSION: Central and West African respondents were more likely to believe in CQ as a treatment for COVID-19 whilst the uptake of the medication during the pandemic was higher amongst East Africans. Future intervention discouraging the unsupervised use of CQ should target respondents from Central, West and East African regions.


Subject(s)
COVID-19/drug therapy , Chloroquine/therapeutic use , Hydroxychloroquine/therapeutic use , Pandemics/prevention & control , Adolescent , Adult , Africa South of the Sahara , Communicable Disease Control , Female , Health Knowledge, Attitudes, Practice , Humans , Male , Middle Aged , Public Opinion , SARS-CoV-2 , Surveys and Questionnaires , Young Adult
14.
Biomolecules ; 11(7)2021 07 06.
Article in English | MEDLINE | ID: covidwho-1295755

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the etiological agent of the coronavirus disease 2019 (COVID-19) pandemic, which has been a topic of major concern for global human health. The challenge to restrain the COVID-19 pandemic is further compounded by the emergence of several SARS-CoV-2 variants viz. B.1.1.7 (Alpha), B.1.351 (Beta), P1 (Gamma) and B.1.617.2 (Delta), which show increased transmissibility and resistance towards vaccines and therapies. Importantly, there is convincing evidence of increased susceptibility to SARS-CoV-2 infection among individuals with dysregulated immune response and comorbidities. Herein, we provide a comprehensive perspective regarding vulnerability of SARS-CoV-2 infection in patients with underlying medical comorbidities. We discuss ongoing vaccine (mRNA, protein-based, viral vector-based, etc.) and therapeutic (monoclonal antibodies, small molecules, plasma therapy, etc.) modalities designed to curb the COVID-19 pandemic. We also discuss in detail, the challenges posed by different SARS-CoV-2 variants of concern (VOC) identified across the globe and their effects on therapeutic and prophylactic interventions.


Subject(s)
COVID-19 Vaccines/therapeutic use , COVID-19/therapy , SARS-CoV-2 , Animals , Antibodies, Monoclonal, Humanized/therapeutic use , Antimalarials/therapeutic use , Antiviral Agents/therapeutic use , COVID-19/drug therapy , COVID-19/immunology , COVID-19/prevention & control , Chloroquine/therapeutic use , Dexamethasone/therapeutic use , Disease Management , Glucocorticoids/therapeutic use , Humans , Immunization, Passive , Mesenchymal Stem Cell Transplantation , SARS-CoV-2/drug effects , SARS-CoV-2/immunology
16.
Int Immunopharmacol ; 95: 107493, 2021 Jun.
Article in English | MEDLINE | ID: covidwho-1263296

ABSTRACT

The novel coronavirus disease (COVID-19) a global pandemic outbreak is an emerging new virus accountable for respiratory illness caused by SARS-CoV-2, originated in Wuhan city, Hubei province China, urgently calls to adopt prevention and intervention strategies. Several viral epidemics such as severe acute respiratory syndrome coronavirus (SARS-CoV) in 2002 to 2003 and H1N1 influenza in 2009 were reported since last two decades. Moreover, the Saudi Arabia was the epicenter for Middle East respiratory syndrome coronavirus (MERS-CoV) in 2012. The CoVs are large family with single-stranded RNA viruses (+ssRNA). Genome sequence of 2019-nCoV, shows relatively different homology from other coronavirus subtypes, categorized in betacoronavirus and possibly found from strain of bats. The COVID-19 composed of exposed densely glycosylated spike protein (S) determines virus binding and infiltrate into host cells as well as initiate protective host immune response. Recently published reviews on the emerging SARS-CoV-2 have mainly focused on its structure, development of the outbreak, relevant precautions and management trials. Currently, there is an urgency of pharmacological intervention to combat this deadly infectious disease. Elucidation of molecular mechanism of COVID-19 becomes necessary. Based on the current literature and understanding, the aim of this review is to provide current genome structure, etiology, clinical prognosis as well as to explore the viral receptor binding together functional insight of SARS-CoV-2 infection (COVID-19) with treatment and preventive measures.


Subject(s)
COVID-19/etiology , SARS-CoV-2/genetics , SARS-CoV-2/pathogenicity , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/therapeutic use , Alanine/analogs & derivatives , Alanine/therapeutic use , Animals , COVID-19/diagnosis , COVID-19/drug therapy , COVID-19/transmission , COVID-19 Vaccines/therapeutic use , Chloroquine/therapeutic use , Genome, Viral , Humans , Receptors, Coronavirus/chemistry , Receptors, Coronavirus/genetics , SARS-CoV-2/chemistry , SARS-CoV-2/drug effects , Virus Attachment
18.
Aging (Albany NY) ; 12(12): 11224-11237, 2020 06 17.
Article in English | MEDLINE | ID: covidwho-1251837

ABSTRACT

With the outbreak of coronavirus disease-19 (COVID-19), Changsha faced an increasing burden of treating the Wuhan migrants and their infected patients. This study is a retrospective, single-center case series of the 238 consecutive hospitalized patients with confirmed COVID-19 at the First Hospital of Changsha city, China, from 01/21 to 02/14, 2020; the final date of follow-up was 02/27, 2020. Of 238 patients 43.7% visited Wuhan, 58.4% got in touch with Wuhan people, and 47.5% had contacted with diagnosed patients. 37.8% patients had family members infected. 190 cases had mild / general disease, and 48 cases had severe / critical disease. Compared to mild or general patients, more severe or critical patients visited Wuhan (59.6% vs 40.2%; P=0.02) and contacted with Wuhan people (74.5% vs 55.0%; P=0.02). All patients received antiviral treatment, including Lopinavir / Ritonavir (29.3%), Interferon (14.6%) and their combination (40.6%), Arbidol (6.7%), Xuebijing (7.1%) and Chloroquine phosphate (1.3%). Severe and critical patients received glucocorticoid, Gamma-globulin and oxygen inhalation. Some received mechanic ventilation support. As of 02/27, 161 patients discharged. The median length of hospital stay was 13 days. The 10-, 14-, 20- and 28-day discharge rate was 19.1%, 42.8%, 65.0% and 76.4%, respectively. No hospital-related transmission was observed.


Subject(s)
Antiviral Agents/therapeutic use , Betacoronavirus , Coronavirus Infections/epidemiology , Coronavirus Infections/therapy , Pneumonia, Viral/epidemiology , Pneumonia, Viral/therapy , Respiration, Artificial , Adult , Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , COVID-19 , China/epidemiology , Chloroquine/analogs & derivatives , Chloroquine/therapeutic use , Drug Combinations , Drugs, Chinese Herbal/therapeutic use , Female , Glucocorticoids/therapeutic use , Hospitalization , Humans , Immunologic Factors/therapeutic use , Indoles/therapeutic use , Interferons/therapeutic use , Lopinavir/therapeutic use , Male , Middle Aged , Oxygen/therapeutic use , Pandemics , Retrospective Studies , Ritonavir/therapeutic use , SARS-CoV-2 , gamma-Globulins/therapeutic use
19.
Food Chem Toxicol ; 151: 112106, 2021 May.
Article in English | MEDLINE | ID: covidwho-1235893

ABSTRACT

The review summarizes chloroquine (CQ) and its safer derivative hydroxychloroquine (HCQ) and its utility in Covid-19. Recently this well-established drug made its way back to the headlines during the SARS-CoV-2 pandemic. This led to an upsurge in the scientific arena with multiple research and review articles along with expert opinions and commentaries. The HCQ has received mixed judgements so far about its efficacy to be used in Covid-19 patients in a limited trial conducted all across the Globe. The purpose of our article is to put forth the history, pharmacodynamics, and pharmacokinetics, along with the existing studies favouring and disapproving the role of HCQ in the treatment of Covid-19. We grouped HCQ use at three stages, this includes HCQ for i. prophylactic use by asymptomatic health workers or peoples at higher risk; ii. patients having mild symptoms; iii. patients with extreme symptoms. The review critically discusses the underlying plausible reasons and mechanisms exploring HCQ in prophylactic management or treatment of SARS-CoV-2. Furthermore, we have critically analysed the reported pharmacokinetic parameters and compiled the proponent, opponent, or neutral opinions on the use of HCQ in Covid-19. Authors discretion is to conduct more studies considering the optimal dosing regimen and pharmacokinetics assessment.


Subject(s)
Antiviral Agents/therapeutic use , COVID-19/drug therapy , Hydroxychloroquine/therapeutic use , Animals , Antiviral Agents/adverse effects , COVID-19/prevention & control , Chloroquine/adverse effects , Chloroquine/therapeutic use , Humans , Hydroxychloroquine/adverse effects , Pandemics
20.
J Pharmacol Exp Ther ; 377(2): 265-272, 2021 05.
Article in English | MEDLINE | ID: covidwho-1234275

ABSTRACT

Drug-induced long QT syndrome (LQTS) is an established cardiac side effect of a wide range of medications and represents a significant concern for drug safety. The rapidly and slowly activating delayed rectifier K+ currents, mediated by channels encoded by the human ether-a-go-go-related gene (hERG) and KCNQ1 + KCNE1, respectively, are two main currents responsible for ventricular repolarization. The common cause for drugs to induce LQTS is through impairing the hERG channel. For the recent emergence of COVID-19, caused by severe acute respiratory syndrome coronavirus 2, several drugs have been investigated as potential therapies; however, there are concerns about their QT prolongation risk. Here, we studied the effects of chloroquine, hydroxychloroquine, azithromycin, and remdesivir on hERG channels. Our results showed that although chloroquine acutely blocked hERG current (IhERG), with an IC50 of 3.0 µM, hydroxychloroquine acutely blocked IhERG 8-fold less potently, with an IC50 of 23.4 µM. Azithromycin and remdesivir did not acutely affect IhERG When these drugs were added at 10 µM to the cell culture medium for 24 hours, remdesivir increased IhERG by 2-fold, which was associated with an increased mature hERG channel expression. In addition, these four drugs did not acutely or chronically affect KCNQ1 + KCNE1 channels. Our data provide insight into COVID-19 drug-associated LQTS and cardiac safety concerns. SIGNIFICANCE STATEMENT: This work demonstrates that, among off-label potential COVID-19 treatment drugs chloroquine, hydroxychloroquine, azithromycin, and remdesivir, the former two drugs block hERG potassium channels, whereas the latter two drugs do not. All four drugs do not affect KCNQ1 + KCNE1. As hERG and KCNQ1 + KCNE1 are two main K+ channels responsible for ventricular repolarization, and most drugs that induce long QT syndrome (LQTS) do so by impairing hERG channels, these data provide insight into COVID-19 drug-associated LQTS and cardiac safety concerns.


Subject(s)
Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , Azithromycin/pharmacology , COVID-19/drug therapy , Chloroquine/pharmacology , ERG1 Potassium Channel/antagonists & inhibitors , Hydroxychloroquine/pharmacology , Adenosine Monophosphate/pharmacology , Adenosine Monophosphate/therapeutic use , Alanine/pharmacology , Alanine/therapeutic use , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/therapeutic use , Antimalarials/pharmacology , Antimalarials/therapeutic use , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Azithromycin/therapeutic use , COVID-19/metabolism , Chloroquine/therapeutic use , Dose-Response Relationship, Drug , ERG1 Potassium Channel/metabolism , HEK293 Cells , Humans , Hydroxychloroquine/therapeutic use , Potassium Channel Blockers/pharmacology , Potassium Channel Blockers/therapeutic use
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