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Antimalarial compounds have been used to treat skin diseases for more than a century. Three compounds, chloroquine (CQ), hydroxychloroquine (HCQ), and quinacrine (QE), have been most studied. The 4-aminoquinolines are a family of compounds derived from quinine, a naturally occurring alkaloid originally procured from the South American cinchona bark tree.1 CQ and HCQ, the principal members of this class of compounds, are the most often used for therapeutic use in dermatology. QE, classified as an acridine, has also been used in dermatologic therapy. Interestingly, the use of these medications for treatment and prophylaxis of malaria is waning due to increased resistance.
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The precise mechanisms by which antimalarial compounds exert their actions are still unknown. However, several discrete mechanisms for each compound have been determined. In the treatment of malaria, aminoquinolines concentrate in the Plasmodium digestive vacuole and prevent polymerization of toxic heme released during proteolysis of hemoglobin.2 Mechanisms by which these compounds influence skin diseases are varied and include, among others, their effects on antigen presentation, cytokines, toll-like receptors, and prostaglandins.
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CQ and HCQ are lipophilic weak bases that pass through plasma membranes in their protonated state, become trapped, and accumulate inside acidic vesicles such as lysosomes,1,3,4 accounting for their effects in Plasmodium. HCQ induces signs of lysosomal and mitochondrial membrane permeabilization.5 By raising intralysosomal pH from 4–6, acidic proteases become inactivated and subsequent proteolysis is inhibited. Subsequently, antigen processing and presentation by dendritic cells may be impaired because of an inability to digest these foreign antigens within the lysosomal compartment.6 Additionally, CQ has been shown to disrupt antigenic peptide loading on class II MHC molecules and subsequent presentation to the opposing T cell.1,7 Inhibition of calcium signaling within the T cell may be an additional mechanism.8 Conversely, CQ has been more recently shown to enhance human CD8+ T cell responses.9 QE inhibits Na-K adenosine triphosphatase activity ...