Chloroquine phosphate

Chloroquine phosphate, a 4-aminoquinoline compound, has been a cornerstone in the treatment of malaria since its clinical introduction in 19479. Originally perceived as too toxic, its reevaluation during World War II led to its widespread adoption due to its efficacy and tolerability9. Beyond its antimalarial properties, chloroquine has been repurposed for a variety of diseases, including rheumatoid arthritis, systemic lupus erythematosus, and various skin conditions2. Its potential extends to the treatment of viral infections such as COVID-19 and as an adjunct in cancer therapies469. This comprehensive analysis will delve into the mechanism of action of chloroquine phosphate and its applications across different fields.

Chloroquine's primary mechanism involves the elevation of intracellular pH levels, which disrupts processes such as protein degradation in lysosomes, macromolecule assembly in endosomes, and post-translational protein modification in the Golgi apparatus5. This disruption affects antigen processing in antigen-presenting cells, leading to a diminished immune response against autoantigenic peptides, which is particularly relevant in autoimmune diseases5. Additionally, chloroquine has been shown to activate Akt, a protein kinase that stimulates glucose uptake and glycogen synthase, suggesting its potential as a therapeutic agent for type 2 diabetes mellitus3. The drug's lysosomotropic properties also contribute to its immunomodulatory and anti-inflammatory effects, which are leveraged in the treatment of various diseases24.

Rheumatoid Arthritis

Chloroquine phosphate has demonstrated immunosuppressive effects in rheumatoid arthritis (RA), improving clinical, functional, and laboratory indices, including the reduction of rheumatoid factor titers1. Its ability to interfere with antigen processing in macrophages and other antigen-presenting cells underpins its utility in managing RA5.

Dermatological and Immunological Diseases

The drug's immunomodulatory and anti-inflammatory actions have made it beneficial for treating dermatological and immunological conditions, such as lupus erythematosus and skin diseases2. Chloroquine's effects on lysosomal activity and autophagy contribute to its therapeutic roles in these diseases7.

Infectious Diseases

Chloroquine has shown efficacy in treating COVID-19 associated pneumonia in clinical trials, leading to its recommendation for inclusion in treatment guidelines in China6. It has also been effective in managing severe infectious mononucleosis, demonstrating a symptomatic response upon administration8.

Cancer Therapies

Recent studies suggest that chloroquine can sensitize cancer cells to cell-killing effects from radiation and chemotherapeutic agents, potentially enhancing the efficacy of conventional cancer therapies9. Its lysosomotropic property is crucial for this increased efficacy and specificity.

Antiviral Activity

Chloroquine has been identified as an effective inhibitor of SARS-CoV replication in vitro, with its antiviral activity being significantly higher than its cytostatic activity, suggesting its potential for immediate use in the prevention and treatment of SARS-CoV infections10.