its usefulness is increasingly limited. Where chloroquine retains efficacy it can be safely used for treatment or prophylaxis of infants and pregnant women. Side effects are uncommon and not generally serious. These include nausea, headache, gastrointestinal disturbance, and blurred vision. Some patients, especially if dark skinned, experience pruritus.
Amodiaquine is a drug closely related to chloroquine that fell out of favor because of a high incidence of adverse reactions (including agranulocytosis and hepatitis), primarily when used for prophylaxis, and drug resistance patterns similar to chloroquine. This drug is currently being reevaluated, especially as a possible component in artesunate-containing combination-therapy regimens. Concern over toxicity remains, however.
These drugs are various combinations of dihydrofolate reductase inhibitors (proguanil, chlorproguanil, pyrimethamine, and trimethoprim) and sulfa drugs (dapsone, sulfalene, sulfamethoxazole, sulfadoxine, and others). Although these drugs have antimalarial activity when used alone, parasitological resistance can develop rapidly. When used in combination, they produce a synergistic effect on the parasite and can be effective even in the presence of resistance to the individual components. Typical combinations include sulfadoxine/pyrimethamine (Fansidar), sulfalene/pyrimethamine (Metakelfin), and sulfamethoxazole/trimethoprim (cotrimoxazole). Proguanil is often used in combination with chloroquine for prophylaxis in areas of moderate chloroquine resistance, although studies suggest that minimal additional benefit is derived, especially with prolonged exposure (Lobel et al., 1993; Steffen et al., 1993). Side effects are uncommon; however, severe allergic reactions can occur. When used prophylactically among American travelers, sulfadoxine/pyrimethamine has been associated with a high incidence of severe cutaneous reactions (1 per 5,000 to 8,000 users) and mortality (1 per 11,000 to 25,000 users; Miller et al., 1986). These side effects do not appear to occur as frequently when the drug is used for treatment. Concerns about sulfa drug use during pregnancy are outweighed by the known risks to mother and fetus of untreated malaria. Finally, use of folate supplementation concurrently with antifol antimalarials may increase the frequency of treatment failure (van Hensbroek et al., 1995).