Mechanisms of action of hydroxychloroquine and chloroquine: implications for rheumatology

Schrezenmeier, Eva; Dörner, Thomas

doi:10.1038/s41584-020-0372-x

Cited by 1,127 publications

(1,276 citation statements)

References 144 publications

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“…This may progress to a cytokine storm, followed by multi-organ failure and potentially death. Both hydroxychloroquine and chloroquine have immunomodulatory effects and can suppress the increase of immune factors [29,30]. Bearing this in mind, it is possible that early treatment with either of the drugs may help prevent the progression of the disease to a critical, life-threatening state.…”

Section: Discussionmentioning

confidence: 99%

In Vitro Antiviral Activity and Projection of Optimized Dosing Design of Hydroxychloroquine for the Treatment of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)

Yao

Zhang

et al. 2020

Clinical Infectious Diseases

2,468

2,705

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Main point: Hydroxychloroquine was found to be more potent than chloroquine at inhibiting SARS-CoV-2 in vitro. Hydroxychloroquine sulfate 400 mg given twice daily for 1 day, followed by 200 mg twice daily for 4 more days is recommended to treat SARS-CoV-2 infection. AbstractBackground. The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) first broke out in Wuhan (China) and subsequently spread worldwide. Chloroquine has been sporadically used in treating SARS-CoV-2 infection. Hydroxychloroquine shares the same mechanism of action as chloroquine, but its more tolerable safety profile makes it the preferred drug to treat malaria and autoimmune conditions. We propose that the immunomodulatory effect of hydroxychloroquine also may be useful in controlling the cytokine storm that occurs late-phase in critically ill SARS-CoV-2 infected patients. Currently, there is no evidence to support the use of hydroxychloroquine in SARS-CoV-2 infection.Methods. The pharmacological activity of chloroquine and hydroxychloroquine was tested using SARS-CoV-2 infected Vero cells. Physiologically-based pharmacokinetic models (PBPK) were implemented for both drugs separately by integrating their in vitro data. Using the PBPK models, hydroxychloroquine concentrations in lung fluid were simulated under 5 different dosing regimens to explore the most effective regimen whilst considering the drug's safety profile.Results. Hydroxychloroquine (EC50=0.72 μM) was found to be more potent than chloroquine (EC50=5.47 μM) in vitro. Based on PBPK models results, a loading dose of 400 mg twice daily of hydroxychloroquine sulfate given orally, followed by a maintenance dose of 200 mg given twice daily for 4 days is recommended for SARS-CoV-2 infection, as it reached three times the potency of chloroquine phosphate when given 500 mg twice daily 5 days in advance. Conclusions.Hydroxychloroquine was found to be more potent than chloroquine to Downloaded from https://academic.oup.com/cid/advance-article-abstract/doi/10.1093/cid/ciaa237/5801998 by guest on 16 March 2020 4 / 25 inhibit SARS-CoV-2 in vitro.

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Section: Discussionmentioning

confidence: 99%

In Vitro Antiviral Activity and Projection of Optimized Dosing Design of Hydroxychloroquine for the Treatment of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)

Yao

Zhang

et al. 2020

Clinical Infectious Diseases

2,468

2,705

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“…Chloroquine and hydroxychloroquine are widely used anti-malarial drugs with well-known immunomodulatory properties that have extended their use to several immuno-rheumatological diseases including RA [83]. The ability of chloroquine to produce an anti-viral effect has been known since the late 1960s [84].…”

Section: Chloroquine/hydroxychloroquinementioning

confidence: 99%

COVID-19 infection and rheumatoid arthritis: Faraway, so close!

Favalli

Ingegnoli

Lucia

et al. 2020

Autoimmunity Reviews

424

454

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“…From mechanism perspective, HCQ as a weak base, accumulates within acidic vesicles, such as the lysosomes autophagosomes of phagocytic cells and changing local pH value, subsequently inhibits immune activation. 22 Multiple cellular functions and molecular pathways were partially inhibited, such as MHC class II expression, antigen presentation or Toll-like receptor-7, -9 signaling pathways and production of IL-1, IL-6, TNF, and IFNγ 22 . These shreds of evidence support the All rights reserved.…”

Section: Safetymentioning

confidence: 99%

Hydroxychloroquine in patients mainly with mild to moderate COVID–19: an open–label, randomized, controlled trial

Tang

Cao

Han

et al. 2020

Preprint

213

373

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Objectives To assess the efficacy and safety of hydroxychloroquine (HCQ) plus standard-of-care (SOC) compared with SOC alone in adult patients with COVID-19.Design Multicenter, open-label, randomized controlled trial.Setting 16 government-designated COVID-19 treatment centers in China through 11 to 29 in February 2020.Participants 150 patients hospitalized with COVID-19. 75 patients were assigned to HCQ plus SOC and 75 were assigned to SOC alone (control group).Interventions HCQ was administrated with a loading dose of 1, 200 mg daily for three days followed by a maintained dose of 800 mg daily for the remaining days (total treatment duration: 2 or 3 weeks for mild/moderate or severe patients, respectively). Main outcome measuresThe primary endpoint was the 28-day negative conversion rate of SARS-CoV-2. The assessed secondary endpoints were negative conversion rate at day 4, 7, 10, 14 or 21, the improvement rate of clinical symptoms within 28-day, normalization of C-reactive protein and blood lymphocyte count within 28-day. Primary and secondary analysis was by intention to treat. Adverse events were assessed in the safety population. ResultsThe overall 28-day negative conversion rate was not different between SOC plus HCQ and SOC group (Kaplan-Meier estimates 85.4% versus 81.3%, P=0.341). Negative conversion rate at day 4, 7, 10, 14 or 21 was also similar between the two groups. No different 28-day symptoms alleviation rate was observed between the two groups. A significant efficacy of HCQ on alleviating symptoms was observed when the confounding effects of anti-viral agents were removed in the post-hoc analysis (Hazard ratio, 8.83, 95%CI, 1.09 to 71.3). This was further supported by a significantly greater reduction of CRP (6.986 in SOC plus HCQ versus 2.723 in SOC,

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Mechanisms of action of hydroxychloroquine and chloroquine: implications for rheumatology

Cited by 1,127 publications

References 144 publications

In Vitro Antiviral Activity and Projection of Optimized Dosing Design of Hydroxychloroquine for the Treatment of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)

In Vitro Antiviral Activity and Projection of Optimized Dosing Design of Hydroxychloroquine for the Treatment of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)

COVID-19 infection and rheumatoid arthritis: Faraway, so close!

Hydroxychloroquine in patients mainly with mild to moderate COVID–19: an open–label, randomized, controlled trial

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