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Toxicology and Applied Pharmacology Mar 2021COVID-19 is a pandemic with no end in sight. There is only one approved antiviral agent but global stocks are deemed insufficient. Despite in vitro antiviral activity,...
COVID-19 is a pandemic with no end in sight. There is only one approved antiviral agent but global stocks are deemed insufficient. Despite in vitro antiviral activity, clinical trials of chloroquine and hydroxychloroquine were disappointing, and they may even impair outcomes. Chloroquine causes zebroid deposits reminiscent of Fabry disease (α-galactosidase A deficiency) and endothelial cells are key targets of COVID-19. We have explored the effect of chloroquine on cultured endothelial cells and its modulation by recombinant α-galactosidase A (agalsidase). Following dose-response studies, 0.5 μg/mL chloroquine was added to cultured human endothelial cells. Neutral red and Lysotracker were used to assess lysosomes. Cytotoxicity was evaluated by the 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide) - MTT assay and cell stress by assessing reactive oxygen species (ROS) and nitric oxide (NO). In endothelial cells, chloroquine induced dose-dependent cytotoxicity at in vitro test concentrations for COVID-19 therapy. At a sublethal concentration, chloroquine significantly induced the accumulation of acid organelles (P < 0.05), increased ROS levels, and decreased NO production (P < 0.05). These adverse effects of chloroquine on endothelial cell biology were decreased by agalsidase-β (P < 0.05). Chloroquine-induced endothelial cell cytotoxicity and stress is attenuated by agalsidase-β treatment. This suggests that endothelial cell injury may contribute to the failure of chloroquine as therapy for COVID-19 and may be at least in part related to causing dysfunction of the lysosomal enzyme α-galactosidase A.
Topics: Cell Survival; Cells, Cultured; Chloroquine; Endothelial Cells; Endothelium, Vascular; Fabry Disease; Humans; Lysosomes; Oxidative Stress; Pandemics; Reactive Oxygen Species; SARS-CoV-2; COVID-19 Drug Treatment
PubMed: 33484708
DOI: 10.1016/j.taap.2021.115412 -
American Journal of Clinical Pathology May 2021To present an index case and review the histologic and electron microscopic findings in chloroquine (CQ) and hydroxychloroquine (HCQ) myopathy, focusing primarily on... (Review)
Review
OBJECTIVES
To present an index case and review the histologic and electron microscopic findings in chloroquine (CQ) and hydroxychloroquine (HCQ) myopathy, focusing primarily on cardiomyopathy. CQ and HCQ are antimalarial drugs with disease-modifying activity in rheumatic diseases (DMARD) and now are among the most widely used DMARDs. Although they are rare, severe adverse effects caused mainly by deposition of intracellular metabolites in both cardiac and skeletal muscle have been described. Currently, both CQ and HCQ have been proposed to have efficacy for patients with coronavirus disease 2019, and several large centers in the United States and other countries have started clinical trials.
METHODS
A case of HCQ cardiotoxicity diagnosed on an endomyocardial biopsy is presented. A review of the pathology archives was performed to identify additional cases of CQ or HCQ myopathy, and histologic changes were recorded. A brief literature review with an emphasis on pathologic findings in myopathies was performed.
RESULTS
Including the index case, 4 cases of CQ or HCQ myopathy were identified. Light microscopic findings included vacuolated myopathy, and electron microscopic findings included myeloid bodies and curvilinear inclusion bodies.
CONCLUSION
CQ and HCQ myopathy can present following long-term administration of the drug. The pathologic findings are nonspecific and overlap with other vacuolated myopathies, necessitating careful correlation of the histologic changes with the patient's medical history.
Topics: Antimalarials; Antiviral Agents; COVID-19; Cardiomyopathies; Chloroquine; Humans; Hydroxychloroquine; COVID-19 Drug Treatment
PubMed: 33316045
DOI: 10.1093/ajcp/aqaa253 -
Journal of Molecular Cell Biology Jul 2021Since chloroquine (CQ) and hydroxychloroquine (HCQ) can inhibit the invasion and proliferation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in... (Review)
Review
Since chloroquine (CQ) and hydroxychloroquine (HCQ) can inhibit the invasion and proliferation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in cultured cells, the repurposing of these antimalarial drugs was considered a promising strategy for treatment and prevention of coronavirus disease (COVID-19). However, despite promising preliminary findings, many clinical trials showed neither significant therapeutic nor prophylactic benefits of CQ and HCQ against COVID-19. Here, we aim to answer the question of why these drugs are not effective against the disease by examining the cellular working mechanisms of CQ and HCQ in prevention of SARS-CoV-2 infections.
Topics: Antiviral Agents; COVID-19; Cell Proliferation; Chloroquine; Drug Repositioning; Humans; Hydroxychloroquine; SARS-CoV-2; COVID-19 Drug Treatment
PubMed: 33693723
DOI: 10.1093/jmcb/mjab016 -
Dermatologic Therapy Sep 2020For the last two decades, the outbreaks of diseases caused by coronaviruses and intermittent worldwide public health emergences have reminded us that they still... (Review)
Review
For the last two decades, the outbreaks of diseases caused by coronaviruses and intermittent worldwide public health emergences have reminded us that they still represent a severe threat to global health. The recent outbreak of corona virus disease 19 (COVID-19) highlighted the urgent need for effective treatment, and initiated rapid search for therapies, able to counter the most severe disease effects. Many aspects of COVID-19 pathogenesis are unknown, but complex interplay of direct viral damage and immune response dysregulation is underline. Intensive research is undergoing for therapeutic targets of virus and high-efficiency and low toxicity targeted drugs. There is no available specific antiviral treatment of this disease, therefore repurposing of drugs already available for the treatment of other viral and autoimmune diseases has been a part of research efforts. Well known anti-inflammatory properties of chloroquine and hydroxychloroquine, agents widely used in dermatology, made them potential candidates for the treatment of COVID-19. We review pathogenesis and clinical characteristic of COVID-19, as well as treatment options that have been under evaluation in past several months. In addition, we focus more on chloroquine and hydroxychloroquine, their pharmacological properties, clinical utility, and current recommendations for their use in COVID-19.
Topics: Antiviral Agents; COVID-19; Chloroquine; Dermatology; Drug Repositioning; Humans; Hydroxychloroquine; SARS-CoV-2; COVID-19 Drug Treatment
PubMed: 32542964
DOI: 10.1111/dth.13829 -
Current Heart Failure Reports Dec 2022The coronavirus disease 2019 (COVID-19) pandemic has popularized the usage of hydroxychloroquine and chloroquine (HCQ/CQ) as treatments for COVID-19. Previously used as... (Review)
Review
PURPOSE OF REVIEW
The coronavirus disease 2019 (COVID-19) pandemic has popularized the usage of hydroxychloroquine and chloroquine (HCQ/CQ) as treatments for COVID-19. Previously used as anti-malarial and now commonly used in rheumatologic conditions, preliminary in vitro studies have demonstrated these medications also have anti-viral properties. Retinopathy and neuromyopathy are well recognized complications of using these treatments; however, cardiotoxicity is under-recognized. This review will discuss the implications and cardiotoxicity of HCQ/CQ, their mechanisms of action, and their utility in COVID-19.
RECENT FINDINGS
Early clinical trials demonstrated a modest benefit of HCQ in COVID-19, causing a push for the usage of it. However, further large multi-center randomized control centers, demonstrated no benefit, and even a trend towards worse outcomes. The predominant cardiac complication observed with HCQ in COVID-19 was cardiac arrhythmias and prolonging of the QT interval. However, with chronic usage of HCQ/CQ, the development of heart failure (HF) and cardiomyopathy (CM) can occur. Although, most adverse cardiac events related to HCQ/CQ usage in COVID-19 were secondary to conduction disorders given the short duration of treatment, HCQ/CQ can cause CM and HF, with chronic usage. Given the insufficient evidence, HCQ/CQ usage in COVID-19 is not routinely recommended, especially with novel therapies now being developed and used. Additionally, usage of HCQ/CQ should prompt initial cardiac evaluation with ECG, and yearly monitoring, with consideration for advanced imaging if clinically warranted. The diagnosis of HCQ/CQ cardiomyopathy is important, as prompt cessation can allow for recovery when these changes are still reversible.
Topics: Humans; Hydroxychloroquine; Pandemics; SARS-CoV-2; Cardiotoxicity; Heart Failure; Chloroquine; COVID-19 Drug Treatment
PubMed: 36167917
DOI: 10.1007/s11897-022-00581-y -
Cell Biochemistry and Function Jun 2016Viruses from the Filoviridae family, as many other virus families, require an acidic pH for successful infection and are therefore susceptible to the actions of... (Review)
Review
Viruses from the Filoviridae family, as many other virus families, require an acidic pH for successful infection and are therefore susceptible to the actions of 4-aminoquinolines, such as chloroquine. Although the mechanisms of action of chloroquine clearly indicate that it might inhibit filoviral infections, several clinical trials that attempted to use chloroquine in the treatment of other acute viral infections - including dengue and influenza A and B - caused by low pH-dependent viruses, have reported that chloroquine had no clinical efficacy, and these results demoted chloroquine from the potential treatments for other virus families requiring low pH for infectivity. The present review is aimed at investigating whether chloroquine could combat the present Ebola virus epidemic, and also at exploring the main reasons for the reported lack of efficacy. Literature was sourced from PubMed, Scopus, Google Scholar, reference list of articles and textbooks - Fields Virology (Volumes 1and 2), the cytokine handbook, Pharmacology in Medicine: Principles and Practice, and hydroxychloroquine and chloroquine retinopathy. The present analysis concludes that (1) chloroquine might find a place in the treatment of Ebola, either as a monotherapy or in combination therapies; (2) the ineffectiveness of chloroquine, or its analogue, hydroxychloroquine, at treating infections from low pH-dependent viruses is a result of the failure to attain and sustain a steady state concentration sufficient to increase and keep the pH of the acidic organelles to approximately neutral levels; (3) to successfully treat filoviral infections - or other viral infections that emerge or emerged from low pH-dependent viruses - a steady state chloroquine plasma concentration of at least 1 µg/mL(~3.125 μM/L) or a whole blood concentration of 16 μM/L must be achieved and be sustained until the patients' viraemia becomes undetectable. These concentrations, however, do not rule out the efficacy of other, higher, steady state concentrations - although such concentrations might be accompanied by severe adverse effects or toxicities. The feasibility of the conclusion in the preceding texts has recently been supported by a subsequent study that shows that amodiaquine, a derivative of CQ, is able to protect humans infected with Ebola from death.
Topics: Chloroquine; Filoviridae; Filoviridae Infections; Hydrogen-Ion Concentration; Immunomodulation; Organelles; Tropism
PubMed: 27001679
DOI: 10.1002/cbf.3182 -
Travel Medicine and Infectious Disease 2021To synthesize findings from systematic reviews and meta-analyses on the efficacy and safety of chloroquine (CQ) and hydroxychloroquine (HCQ) with or without Azithromycin... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVE
To synthesize findings from systematic reviews and meta-analyses on the efficacy and safety of chloroquine (CQ) and hydroxychloroquine (HCQ) with or without Azithromycin for treating COVID-19, and to update the evidence using a meta-analysis.
METHODS
A comprehensive search was carried out in electronic databases for systematic reviews, meta-analyses and experimental studies which investigated the efficacy and safety of CQ, HCQ with or without Azithromycin to treat COVID-19. Findings from the reviews were synthesised using tables and forest plots and the quality effect model was used for the updated meta-analysis. The main outcomes were mortality, the need for intensive care services, disease exacerbation, viral clearance and occurrence of adverse events.
RESULTS
Thirteen reviews with 40 primary studies were included. Two meta-analyses reported a high risk of mortality, with ORs of 2.2 and 3.0, and the two others found no association between HCQ and mortality. Findings from two meta-analyses showed that HCQ with Azithromycin increased the risk of mortality, with similar ORs of 2.5. The updated meta-analysis of experimental studies showed that the drugs were not effective in reducing mortality (RR 1.1, 95%CI 1.0-1.3, I = 0.0%), need for intensive care services (OR 1.1, 95%CI 0.9-1.4, I = 0.0%), virological cure (OR 1.5, 95%CI 0.5-4.4, I = 39.6%) or disease exacerbation (OR 1.2, 95%CI 0.3-5.9, I = 31.9%) but increased the odds of adverse events (OR 12,3, 95%CI 2.5-59.9, I = 76.6%).
CONCLUSION
There is conclusive evidence that CQ and HCQ, with or without Azithromycin are not effective in treating COVID-19 or its exacerbation.
REGISTRATION
PROSPERO: CRD42020191353.
Topics: Antiviral Agents; Chloroquine; Humans; Hydroxychloroquine; SARS-CoV-2; Systematic Reviews as Topic; Treatment Outcome; COVID-19 Drug Treatment
PubMed: 34265436
DOI: 10.1016/j.tmaid.2021.102135 -
Daru : Journal of Faculty of Pharmacy,... Jun 2021Review and assess pharmaceutical and clinical characteristics of chloroquine including high-performance liquid chromatography (HPLC)-based methods used to quantify the... (Review)
Review
OBJECTIVE
Review and assess pharmaceutical and clinical characteristics of chloroquine including high-performance liquid chromatography (HPLC)-based methods used to quantify the drug in pharmaceutical products and biological samples.
EVIDENCE ACQUISITION
A literature review was undertaken on the PubMed, Science Direct, and Scielo databases using the following keywords related to the investigated subject: 'chloroquine', 'analytical methods', and 'HPLC'.
RESULTS
For more than seven decades, chloroquine has been used to treat malaria and some autoimmune diseases, such as lupus erythematosus and rheumatoid arthritis. There is growing interest in chloroquine as a therapeutic alternative in the treatment of HIV, Q fever, Whipple's disease, fungal, Zika, Chikungunya infections, Sjogren's syndrome, porphyria, chronic ulcerative stomatitis, polymorphic light eruption, and different types of cancer. HPLC coupled to UV detectors is the most employed method to quantify chloroquine in pharmaceutical products and biological samples. The main chromatographic conditions used to identify and quantify chloroquine from tablets and injections, degradation products, and metabolites are presented and discussed.
CONCLUSION
Research findings reported in this article may facilitate the repositioning, quality control, and biological monitoring of chloroquine in modern pharmaceutical dosage forms and treatments.
Topics: Animals; Antimalarials; Chloroquine; Chromatography, High Pressure Liquid; Humans
PubMed: 33738722
DOI: 10.1007/s40199-021-00391-y -
Annals of Palliative Medicine Mar 2021The novel coronavirus disease 2019 (COVID-19) was broken out in December 2019 and soon became a global health emergency. Effective treatment for COVID-19 is urgently... (Comparative Study)
Comparative Study
BACKGROUND
The novel coronavirus disease 2019 (COVID-19) was broken out in December 2019 and soon became a global health emergency. Effective treatment for COVID-19 is urgently needed. In the present study, we aimed to evaluate the antiviral effect of Arbidol vs. Chloroquine in treating COVID-19.
METHODS
We retrospectively analyzed 62 patients with COVID-19 diagnosed according to the guidelines for diagnosis and treatment of COVID-19 in China. They were divided into two groups depending on the antiviral drugs that they received. Participants in the Arbidol group (n=42) received 0.2 g Arbidol, tid for 10 days,and those in Chloroquine group (n=20) received 500 mg Chloroquine, bid for 10 days. The coronavirus negative conversion time and the length of hospital stay were analyzed and compared between the two groups.
RESULTS
There was no significant difference in demographic and clinical characteristics between the two groups. After antiviral treatment, the nasopharyngeal specimen negative conversion time of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the length of hospital stay in the Arbidol group were significantly shorter than those in the Chloroquine group (18.50 vs. 25.05 days, P=0.001; 23.52 vs. 28.75 days, P=0.001). Adverse events observed during the antiviral treatment period were comparable between the two groups. Overall, 3 (7.14%) participants in the Arbidol group and 4 (20.0%) in the Chloroquine group experienced adverse events during antiviral treatment.
CONCLUSIONS
These results suggest that Arbidol is advantageous over Chloroquine in terms of the SARS-CoV-2 negative conversion and the length of hospital stay in treating COVID-19 patients.
Topics: Antiviral Agents; China; Chloroquine; Humans; Indoles; Length of Stay; Retrospective Studies; COVID-19 Drug Treatment
PubMed: 33849115
DOI: 10.21037/apm-21-400 -
Frontiers in Cellular and Infection... 2024Malaria has always been a serious infectious disease prevalent in the world. Antimalarial drugs such as chloroquine and artemisinin have been the main compounds used to... (Review)
Review
BACKGROUND
Malaria has always been a serious infectious disease prevalent in the world. Antimalarial drugs such as chloroquine and artemisinin have been the main compounds used to treat malaria. However, the massive use of this type of drugs accelerates the evolution and spread of malaria parasites, leading to the development of resistance. A large number of related data have been published by researchers in recent years. CiteSpace software has gained popularity among us researchers in recent years, because of its ability to help us obtain the core information we want in a mass of articles. In order to analyze the hotspots and develop trends in this field through visual analysis, this study used CiteSpace software to summarize the available data in the literature to provide insights.
METHOD
Relevant literature was collected from the Web of Science Core Collection (WOSCC) from 1 January 2015 to 29 March 2023. CiteSpace software and Microsoft Excel were used to analyze and present the data, respectively.
RESULTS
A total of 2,561 literatures were retrieved and 2,559 literatures were included in the analysis after the removal of duplicates. An irrefutable witness of the ever-growing interest in the topic of antimalarial drug resistance could be expressed by the exponentially increased number of publications and related citations from 2015 to 2022, and its sustained growth trend by 2023. During the past 7 years, USA, Oxford University, and David A Fidock are the country, institution, and author with the most publications in this field of research, respectively. We focused on the references and keywords from literature and found that the research and development of new drugs is the newest hotspot in this field. A growing number of scientists are devoted to finding new antimalarial drugs.
CONCLUSION
This study is the first visual metrological analysis of antimalarial drug resistance, using bibliometric methods. As a baseline information, it is important to analyze research output published globally on antimalarial drug resistance. In order to better understand the current research situation and future research plan agenda, such baseline data are needed accordingly.
Topics: Humans; Antimalarials; Chloroquine; Bibliometrics; Folic Acid Antagonists; Malaria
PubMed: 38410722
DOI: 10.3389/fcimb.2024.1270060