Recent studies have highlighted the potential of chloroquine and hydroxychloroquine as first-line rescue treatments for hospitalized patients with SARS-CoV-2, despite limited clinical data supporting their efficacy, optimal dosage, treatment duration, and potential adverse effects.
Background of Chloroquine and Hydroxychloroquine
Originally used to treat and prevent malaria, chloroquine and hydroxychloroquine were approved by the FDA in 1949 and 1955, respectively. These 4-aminoquinolones are characterized by their ability to accumulate in lysosomes, which plays a role in their therapeutic effects. They have a long half-life of 40-60 days and a large volume of distribution in the blood.
Mechanism of Action
Chloroquine and hydroxychloroquine work by accumulating in lysosomes, raising the pH and stabilizing them. This process inhibits eosinophil and neutrophil chemotaxis and phagocytic activity. They also reduce complement-mediated hemolysis, prevent MHC class II-mediated autoantigen presentation, and decrease cell-mediated immunity by inhibiting the production of interleukin-1 and plasma cell synthesis.
Additionally, hydroxychloroquine can accumulate in endosomes, inhibiting toll-like receptor signaling and reducing the production of proinflammatory cytokines.
Role in SARS-CoV-2 Treatment
One way SARS-CoV-2 enters cells is through ACE2, which chloroquine and hydroxychloroquine can block by reducing its glycosylation, inhibiting viral entry. They also increase endosomal pH, potentially inactivating enzymes the virus needs for replication. Their benefits may also stem from their ability to block IL-6, a proinflammatory cytokine believed to contribute to acute respiratory distress syndrome.
Interestingly, chloroquine has also been shown to facilitate the entry of zinc ions into cells. Zinc is a potent inhibitor of coronavirus RNA polymerase, further aiding in viral suppression.
Side Effects
Despite the potential benefits, chloroquine and hydroxychloroquine have several side effects, including:
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GI upset
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Retinal toxicity with long-term use
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Hypoglycemia
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Cardiomyopathy
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QT prolongation and ventricular arrhythmias
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Renal and liver toxicity
Cutaneous effects like pruritus, morbilliform rashes, psoriasis flares, and blue-black hyperpigmentation (in approximately 25% of users) have also been reported.
Clinical Trials and Emergency Use Authorization
In February 2020, China reported the first clinical results of chloroquine treatment for COVID-19. On March 20, the FDA issued an Emergency Use Authorization for hydroxychloroquine and chloroquine for hospitalized patients with COVID-19, despite biases and limitations in the initial studies.
Current Research and Shortage
As of April 2020, the ORCHID trial at Vanderbilt University began assessing the safety and efficacy of hydroxychloroquine in treating COVID-19. The trial aims to determine the effects of hydroxychloroquine on acute respiratory distress syndrome.
However, the shortage of chloroquine and hydroxychloroquine has become a major concern for patients with dermatologic and rheumatologic diseases who rely on these drugs to remain in remission.
While chloroquine and hydroxychloroquine show potential in the treatment of COVID-19, more well-controlled, randomized studies are essential to assess their long-term safety and efficacy. Proper funding and distribution of these medications will be crucial for both hospitalized and non-hospitalized patients.
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