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EMBO Molecular Medicine Aug 2020Initially used as antimalarial drugs, hydroxychloroquine (HCQ) and, to a lesser extent, chloroquine (CQ) are currently being used to treat several diseases. Due to its... (Review)
Review
Initially used as antimalarial drugs, hydroxychloroquine (HCQ) and, to a lesser extent, chloroquine (CQ) are currently being used to treat several diseases. Due to its cost-effectiveness, safety and efficacy, HCQ is especially used in rheumatic autoimmune disorders (RADs), such as systemic lupus erythematosus, primary Sjögren's syndrome and rheumatoid arthritis. Despite this widespread use in the clinic, HCQ molecular modes of action are still not completely understood. By influencing several cellular pathways through different mechanisms, CQ and HCQ inhibit multiple endolysosomal functions, including autophagy, as well as endosomal Toll-like receptor activation and calcium signalling. These effects alter several aspects of the immune system with the synergistic consequence of reducing pro-inflammatory cytokine production and release, one of the most marked symptoms of RADs. Here, we review the current knowledge on the molecular modes of action of these drugs and the circumstances under which they trigger side effects. This is of particular importance as the therapeutic use of HCQ is expanding beyond the treatment of malaria and RADs.
Topics: Arthritis, Rheumatoid; Autoimmune Diseases; Chloroquine; Humans; Hydroxychloroquine; Lupus Erythematosus, Systemic
PubMed: 32715647
DOI: 10.15252/emmm.202012476 -
Therapie 2023
Topics: Humans; COVID-19; Hydroxychloroquine; COVID-19 Drug Treatment; SARS-CoV-2; Antiviral Agents; Treatment Outcome
PubMed: 37321943
DOI: 10.1016/j.therap.2023.06.003 -
The New England Journal of Medicine Aug 2020Coronavirus disease 2019 (Covid-19) occurs after exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). For persons who are exposed, the standard of... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Coronavirus disease 2019 (Covid-19) occurs after exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). For persons who are exposed, the standard of care is observation and quarantine. Whether hydroxychloroquine can prevent symptomatic infection after SARS-CoV-2 exposure is unknown.
METHODS
We conducted a randomized, double-blind, placebo-controlled trial across the United States and parts of Canada testing hydroxychloroquine as postexposure prophylaxis. We enrolled adults who had household or occupational exposure to someone with confirmed Covid-19 at a distance of less than 6 ft for more than 10 minutes while wearing neither a face mask nor an eye shield (high-risk exposure) or while wearing a face mask but no eye shield (moderate-risk exposure). Within 4 days after exposure, we randomly assigned participants to receive either placebo or hydroxychloroquine (800 mg once, followed by 600 mg in 6 to 8 hours, then 600 mg daily for 4 additional days). The primary outcome was the incidence of either laboratory-confirmed Covid-19 or illness compatible with Covid-19 within 14 days.
RESULTS
We enrolled 821 asymptomatic participants. Overall, 87.6% of the participants (719 of 821) reported a high-risk exposure to a confirmed Covid-19 contact. The incidence of new illness compatible with Covid-19 did not differ significantly between participants receiving hydroxychloroquine (49 of 414 [11.8%]) and those receiving placebo (58 of 407 [14.3%]); the absolute difference was -2.4 percentage points (95% confidence interval, -7.0 to 2.2; P = 0.35). Side effects were more common with hydroxychloroquine than with placebo (40.1% vs. 16.8%), but no serious adverse reactions were reported.
CONCLUSIONS
After high-risk or moderate-risk exposure to Covid-19, hydroxychloroquine did not prevent illness compatible with Covid-19 or confirmed infection when used as postexposure prophylaxis within 4 days after exposure. (Funded by David Baszucki and Jan Ellison Baszucki and others; ClinicalTrials.gov number, NCT04308668.).
Topics: Adult; Betacoronavirus; COVID-19; Canada; Coronavirus Infections; Double-Blind Method; Female; Humans; Hydroxychloroquine; Inhalation Exposure; Male; Middle Aged; Occupational Exposure; Pandemics; Pneumonia, Viral; Post-Exposure Prophylaxis; SARS-CoV-2; Treatment Failure; United States
PubMed: 32492293
DOI: 10.1056/NEJMoa2016638 -
JAMA Oct 2022
Topics: Antirheumatic Agents; Dose-Response Relationship, Drug; Eye Diseases; Humans; Hydroxychloroquine; Lupus Erythematosus, Systemic; Ophthalmology; Practice Guidelines as Topic; Risk; Symptom Flare Up
PubMed: 36112387
DOI: 10.1001/jama.2022.13591 -
European Journal of Preventive... Feb 2022
Topics: Humans; Hydroxychloroquine; SARS-CoV-2; COVID-19 Drug Treatment
PubMed: 33580785
DOI: 10.1093/eurjpc/zwaa165 -
Cell Reports. Medicine May 2023Genetic and in vivo evidence suggests that aberrant recognition of RNA-containing autoantigens by Toll-like receptors (TLRs) 7 and 8 drives autoimmune diseases. Here we...
Genetic and in vivo evidence suggests that aberrant recognition of RNA-containing autoantigens by Toll-like receptors (TLRs) 7 and 8 drives autoimmune diseases. Here we report on the preclinical characterization of MHV370, a selective oral TLR7/8 inhibitor. In vitro, MHV370 inhibits TLR7/8-dependent production of cytokines in human and mouse cells, notably interferon-α, a clinically validated driver of autoimmune diseases. Moreover, MHV370 abrogates B cell, plasmacytoid dendritic cell, monocyte, and neutrophil responses downstream of TLR7/8. In vivo, prophylactic or therapeutic administration of MHV370 blocks secretion of TLR7 responses, including cytokine secretion, B cell activation, and gene expression of, e.g., interferon-stimulated genes. In the NZB/W F1 mouse model of lupus, MHV370 halts disease. Unlike hydroxychloroquine, MHV370 potently blocks interferon responses triggered by specific immune complexes from systemic lupus erythematosus patient sera, suggesting differentiation from clinical standard of care. These data support advancement of MHV370 to an ongoing phase 2 clinical trial.
Topics: Humans; Mice; Animals; Toll-Like Receptor 7; Lupus Erythematosus, Systemic; Autoimmune Diseases; Hydroxychloroquine; Interferons
PubMed: 37196635
DOI: 10.1016/j.xcrm.2023.101036 -
Current Allergy and Asthma Reports Jan 2021Told from the viewpoint of rheumatologists, this review tells the story of hydroxychloroquine and its swift ascent to become a household name as a therapeutic strategy... (Review)
Review
PURPOSE OF REVIEW
Told from the viewpoint of rheumatologists, this review tells the story of hydroxychloroquine and its swift ascent to become a household name as a therapeutic strategy against the novel SARS-CoV-2 virus. This review describes the history, mechanisms, pharmacokinetics, therapeutic applications, and safety profile of hydroxychloroquine as an immunomodulatory and antiviral agent. It also summarizes the major studies that launched and assessed the use of hydroxychloroquine against COVID-19 infection.
RECENT FINDINGS
More recent literature calls into question the long-held dogma that endolysosomal alkalinization is the primary mode of action of hydroxychloroquine. Ongoing uncertainty about the multiple potential mechanisms contributing to the therapeutic effect of hydroxychloroquine in rheumatic and viral disease led to a natural avenue for exploration in the treatment of COVID-19. Taken as a whole, the literature does not support utilizing hydroxychloroquine to treat or prevent infection from the SARS-CoV-2 virus. This is, at least in part, due to the wide variability in hydroxychloroquine pharmacokinetics between patients and difficulty achieving adequate target tissue concentrations of hydroxychloroquine without encountering unacceptable toxicities. Hydroxychloroquine continues to be a routinely prescribed, well-tolerated, effective, and low-cost treatment for rheumatic disease. Its therapeutic versatility has led to frequent repurposing for other conditions, most recently as an investigative treatment against the SARS-CoV-2 virus. Despite overall negative findings, the intense study of hydroxychloroquine against COVID-19 infection has enhanced our overall understanding of how hydroxychloroquine operates in autoimmune disease and beyond.
Topics: Animals; Antiviral Agents; Humans; Hydroxychloroquine; Rheumatologists; SARS-CoV-2; COVID-19 Drug Treatment
PubMed: 33475900
DOI: 10.1007/s11882-020-00983-9 -
Journal of Medical Toxicology :... Jul 2020SARS-CoV-2 is a novel coronavirus that emerged in 2019 and is causing the COVID-19 pandemic. There is no current standard of care. Clinicians need to be mindful of the... (Review)
Review
SARS-CoV-2 is a novel coronavirus that emerged in 2019 and is causing the COVID-19 pandemic. There is no current standard of care. Clinicians need to be mindful of the toxicity of a wide variety of possibly unfamiliar substances being tested or repurposed to treat COVID-19. The United States Food and Drug Administration (FDA) has provided emergency authorization for the use of chloroquine and hydroxychloroquine. These two medications may precipitate ventricular dysrhythmias, necessitating cardiac and electrolyte monitoring, and in severe cases, treatment with epinephrine and high-doses of diazepam. Recombinant protein therapeutics may cause serum sickness or immune complex deposition. Nucleic acid vaccines may introduce mutations into the human genome. ACE inhibitors and ibuprofen have been suggested to exacerbate the pathogenesis of COVID-19. Here, we review the use, mechanism of action, and toxicity of proposed COVID-19 therapeutics.
Topics: Antiviral Agents; Betacoronavirus; COVID-19; Chloroquine; Coronavirus Infections; Humans; Hydroxychloroquine; Pandemics; Pneumonia, Viral; SARS-CoV-2; United States
PubMed: 32356252
DOI: 10.1007/s13181-020-00777-5 -
The Indian Journal of Tuberculosis Dec 2020COVID 19 infection is unarguably the worst pandemic of this century. Till date there is no promising drug and vaccine available to treat this deadly viral infection. In... (Review)
Review
COVID 19 infection is unarguably the worst pandemic of this century. Till date there is no promising drug and vaccine available to treat this deadly viral infection. In the early phase chloroquine phosphate and hydroxychloroquine sulphate have been used to fight this illness on the basis of handful observational and small randomized and small-randomized studies. The paucity of clinical evidences of an unequivocal beneficial effect of chloroquine and hydroxychloroquine on COVID-19 has resulted in the passionate use of the drug for moderate to severe cases only and stimulated the need for large clinical trials for this and other molecules. In this review, we describe in brief the mechanism of action, the clinical studies, factors for cardiac toxicity, guidelines and future directions for hydroxychloroquine use in management of COVID-19 infection.
Topics: Enzyme Inhibitors; Humans; Hydroxychloroquine; SARS-CoV-2; COVID-19 Drug Treatment
PubMed: 33308661
DOI: 10.1016/j.ijtb.2020.06.004 -
American Journal of Ophthalmology May 2020
Topics: Antiviral Agents; COVID-19; Chloroquine; Coronavirus Infections; Dose-Response Relationship, Drug; Humans; Hydroxychloroquine; Ophthalmology; Pandemics; Pneumonia, Viral; Retina
PubMed: 32247518
DOI: 10.1016/j.ajo.2020.03.028