Covid-19: US gives emergency approval to hydroxychloroquine despite lack of evidence

Lenzer, Jeanne

doi:10.1136/bmj.m1335

Cited by 113 publications

(108 citation statements)

References 3 publications

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“…In this highly demanding scenario of huge unmet need and steeply increasing morbidity and mortality of COVID-19, many government bodies and expert panels have recommended the use of chloroquine and HCQ for the prophylaxis and treatment of COVID-19. [14][15][16][17][18] Recent geopolitical and media coverage of the possibility of this drug usage in COVID-19 has caused a huge stir and expectations among laymen and medical fraternity alike. This has lead to countries engaging in mass production, exports and imports of this drug.…”

Section: Introductionmentioning

confidence: 99%

Review of Current Evidence of Hydroxychloroquine in Pharmacotherapy of COVID-19

Suranagi

Rehan

Goyal

2020

Preprint

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Purpose:The COVID-19 Pandemic has literally left the world breathless in the chase for Pharmacotherapy. With the vaccine approval likely more than a year away and novel drugs in early clinical trials, repurposing of existing drugs takes the center stage. A potential drug discussed both in geopolitical and global scientific community is hydroxychloroquine (HCQ). We intend to systematically weigh and analyze the existing evidence of HCQ in the light of published and pre-print data available so far. Methods: PubMed Ovid MEDLINE, EMBASE, Google scholar databases and official clinical trialRegistries of the United States, China, WHO ICTRP were electronically searched for studies for the use of HCQ in patients with COVID-19. Pre-proof article repositories like MedRxiv, BioRxiv, and ChemRxiv were also included in the search. The literature was critically appraised. Results:Total 71 articles were available as of 15 th April of which articles of relevance (three invitro studies, two open label non-randomized trials, two open label randomized control trials, one follow-up study, three reviews, ten short communications) and 88 clinical trials registered in three clinical trial registries were analyzed. HCQ seems to be efficient in inhibiting of SARS-CoV-2 in in-vitro cell lines; there is lack of strong evidence from human studies. Conclusions:The in-vitro cell culture based data of viral inhibition does not suffice for the use of hydroxychloroquine in the patients with COVID-19. Currently literature shows inadequate, low level evidence in human studies. Scarcity of safety and efficacy data warrants medical communities, health care agencies and governments across the world against the widespread use of HCQ in COVID-19 prophylaxis and treatment, until robust evidence becomes available.

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Section: Introductionmentioning

confidence: 99%

Review of Current Evidence of Hydroxychloroquine in Pharmacotherapy of COVID-19

Suranagi

Rehan

Goyal

2020

Preprint

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“…All these effects were accentuated by combining HCQ challenge with AZM. Furthermore, (5) The HCQ+AZM combination, but not HCQ alone, then went on to increase susceptibilities to ventricular arrhythmic events consistent with significant clinical cardiac safety risks. (6) Human in-silico modelling of ion channel effects of HCQ and AZM recapitulated the altered APDs but not the reduced conduction.…”

Section: Discussionmentioning

confidence: 99%

“…An initial nonrandomized open label clinical trial of 20 cases, had associated HCQ treatment with viral load reduction or disappearance in COVID-19 patients, effects reinforced by AZM (3). This subsequently prompted the US Food and Drugs Administration (FDA) authorization of emergency use of CQ or HCQ, alone or in combination with AZM in Covid-19 therapy (4,5). Currently, large number of trials of these combinations, with or without the addition of further drugs, are registered worldwide (1, 2).…”

Section: Introductionmentioning

confidence: 99%

Mechanistic insights into ventricular arrhythmogenesis of hydroxychloroquine and azithromycin for the treatment of COVID-19

Wang¹,

Tian

Lu³

et al. 2020

Preprint

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CLHH, HZ, ML and GLH are joint senior authors Article length: 6234 words, including figure legends and references, excluding abstract and acknowledgements 3 ABSTRACT Aims:We investigate mechanisms for potential pro-arrhythmic effects of hydroxychloroquine (HCQ) alone, or combined with azithromycin (AZM), in Covid-19 management supplementing the limited available experimental cardiac safety data. Methods:We integrated patch-clamp studies utilizing In Vitro ProArrhythmia Assay (CiPA) Schema IC50 paradigms, molecular modelling, cardiac multi-electrode array and voltage (RH237) mapping, ECG studies, and Ca 2+ (Rhod-2 AM) mapping in isolated Langendorff-perfused guinea-pig hearts with human in-silico ion current modelling. Results:HCQ blocked IKr and IK1 with IC50s (10±0.6 and 34±5.0 µM) within clinical therapeutic ranges, INa and ICaL at higher IC50s, leaving Ito and IKs unaffected. AZM produced minor inhibition of INa, ICaL, IKs, and IKr,, sparing IK1 and Ito. HCQ+AZM combined inhibited IKr and IK1 with IC50s of 7.7±0.8 µM and 30.4±3.0 µM, sparing INa, ICaL and Ito. Molecular modelling confirmed potential HCQ binding to hERG. HCQ slowed heart rate and ventricular conduction. It prolonged PR, QRS and QT intervals, and caused prolonged, more heterogeneous, action potential durations and intracellular Ca 2+ transients. These effects were accentuated with combined HCQ+AZM treatment, which then elicited electrical alternans, re-entrant circuits and wave break. Modelling studies attributed these to integrated HCQ and AZM actions reducing IKr and IK1, thence altering cell Ca 2+ homeostasis. Conclusions:Combined HCQ+AZM treatment exerts pro-arrhythmic ventricular events by synergetically inhibiting IKr, IKs with resulting effects on cellular Ca 2+ signalling, and action potential propagation and duration. These findings provide an electrophysiological basis for recent FDA cardiac safety guidelines cautioning against combining HCQ/AZM when treating Covid-19.

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“…In another small open-label nonrandomized clinical trial from France, it has been shown that HCQ is associated with the reduction of viral load (Gautret et al 2020). Accordingly, Food and Drug Administration has authorized clinicians in USA to prescribe HCQ for hospitalized patients with COVID-19 (Lenzer 2020). However, from a recent analysis of 368 patients in U.S. Veterans hospitals, it has been found that HCQ does not provide any benefit, but more side effects and deaths, indicating a possible HCQ puzzle in COVID-19.…”

Section: Hcq Therapy In Covid-19mentioning

confidence: 99%

Smooth or Risky Revisit of an Old Malaria Drug for COVID-19?

Pahan

2020

J Neuroimmune Pharmacol

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Hydroxychloroquine (HCQ) is an old medication for malaria. In addition to handling this parasitic disease, HCQ is also used to treat a number of autoimmune disorders including rheumatoid arthritis and systemic lupus erythematosus when other medications are not effective. Recently a new viral infection (COVID-19) is rocking the entire world so much that it has already taken more than 200,000 lives throughout the world within the last two months and the World Health Organization was forced to declare it as a pandemic on March 11, 2020. Interestingly, some reports indicate that this wonder drug may be also beneficial for COVID-19 and accordingly, many clinical trials have begun. Here, we discuss different modes of action (anti-inflammatory, antioxidant, inhibition of endosomal acidification, suppression of angiotensin-converting enzyme 2 or ACE2 glycosylation, etc.) of HCQ that might be responsible for its possible anti-COVID-19 effect. On the other hand, this review also makes an honest attempt to delineate mechanisms (increase in vasoconstriction, inhibition of autophagy, depletion of T cells, etc.) indicating how it may aggravate certain conditions and why caution should be taken before granting widespread repurposing of HCQ for COVID-19.

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Covid-19: US gives emergency approval to hydroxychloroquine despite lack of evidence

Cited by 113 publications

References 3 publications

Review of Current Evidence of Hydroxychloroquine in Pharmacotherapy of COVID-19

Review of Current Evidence of Hydroxychloroquine in Pharmacotherapy of COVID-19

Mechanistic insights into ventricular arrhythmogenesis of hydroxychloroquine and azithromycin for the treatment of COVID-19

Smooth or Risky Revisit of an Old Malaria Drug for COVID-19?

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