Mode of Action

The complex mode of action of chloroquine can only be briefly described. For detailed discussions, consult the extensive literature (see Barthel et al. 1996, Zeidler 1995). Chloroquine is an amphiphilic molecule (lipophilic ring structure and hydrophilic side chain). This enables the incorporation in interphases such as phospholipid membranes. The weak basic antimalarials pass the membranes and are pro-tonated in the acidic environment of the lysosomes. As a result, they are unable to penetrate the membranes, and chloroquine accumulates. The following effects can be explained by this mechanism:

• In plasmodia, intralysosomal proteases are inhibited, and heme, toxic for plas-modia, accumulates.

• In lysosomes of human leukocytes, the binding of antigens (low-affine peptides) to the "major histocompatibility complex" is inhibited and, as a result, the stimulation of specific T cells is prevented.

• This inhibition of antigen processing also impairs the production of antibodies, the activity of natural killer cells, and the release of interleukin-1, -2 and tumor necrosis factor-a (Jeong et al. 2002).

Furthermore, chloroquine reduces the generation of reactive oxygen species by neu-trophils (Jancinova et al. 2001) and inhibits lymphocyte apoptosis (Liu et al. 2001).

In porphyria cutanea tarda, chloroquine forms complexes with the porphyrines, thus increasing their elimination with urine. In sarcoidosis, chloroquine inhibits the hydroxylation of 1,25,dihydroxy-vitamine D3, thus lowering the high plasma levels of vitamin D. In LE, a sunscreen effect and the inhibition of UV-induced activation of transcription factors are discussed.

Besides these immunologic effects, chloroquine and hydroxychloroquine inhibit the aggregation of thrombocytes without prolongation of the bleeding time (Espinola et al. 2002). Chloroquine increases the binding of insulin to its receptor, changes the metabolism of insulin in the liver, and thus amplifies the insulin action. Antimalari-als increase the number of low-density lipoprotein receptors and inhibit the hepatic synthesis of cholesterol, thus lowering total cholesterol, low-density lipoprotein cholesterol, and triglyceride concentrations. Chloroquine also increases the pain threshold, even in healthy persons. This could explain the subjective improvement in joint pain.

The mechanisms of action of quinacrine are multifaceted. They include some of the mentioned effects (inhibition of T-cell response, antioxidant, inhibition of platelet aggregation) as well as antiprostaglandin actions (phospholipase A2 inhibition), lysosome stabilization, blocking of photodynamic actions and increase in light tolerance, sclerosing actions [nonsurgical sterilization by quinacrine pellet instillation into the uterus (Benagiano 2001)], and antimicrobial properties (see references in: Wallace 1989). Quinacrine had a more powerful in vitro anti-inflammatory activity compared with chloroquine and hydroxychloroquine (Ferrante et al. 1986).

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