Contraindications And Interactions

At very high doses, mefloquine causes teratogenesis and developmental abnormalities in rodents. Mefloquine is approved for use during pregnancy by the CDC and after the first trimester by the World Health Organization (WHO). However, there have been studies suggesting an increased rate of fetal loss with mefloquine use, especially during the first trimester. The evidence for mefloquine 's safety in pregnancy is not fully convincing, and alternatives should be sought. Pregnancy also should be avoided for 3 months after mefloquine use because of its prolonged t1/2. The drug is contraindicated for patients with a history of seizures, severe neuropsychiatric disturbances, or adverse reactions to quinoline antimalarials. Although mefloquine can be taken safely 12 hours after a last dose of quinine, taking quinine shortly after mefloquine can be very hazardous because the latter is eliminated so slowly. Treatment with or after halofantrine or within 2 months of prior mefloquine administration is contraindicated. Mefloquine reportedly increases the risk of seizures in epileptic patients controlled by valproate and may compromise adequate immunization by live typhoid vaccine. Caution is advised for use of mefloquine along with drugs that can perturb cardiac conduction. The WHO advises against mefloquine use for patients in occupations that require great dexterity, such as pilots.

Primaquine

Primaquine, in contrast with other antimalarials, acts on tissue stages (exoerythrocytic) of plas-modia in the liver to prevent and cure relapsing malaria. The structure of primaquine is shown in Figure 39—3.

ANTIMALARIAL ACTIONS Primaquine destroys primary and latent hepatic stages of P. vivax and P. ovale and thus has great clinical value for preventing relapses of P. vivax or P. ovale malaria. The drug will not treat ongoing attacks of malaria, even though it displays some activity against the erythrocytic stages. The 8-aminoquinolines exert a marked gametocidal effect against all four species of plasmodia that infect humans, especially P. falciparum. Some strains of P. vivax exhibit partial resistance to the action of primaquine, which makes it imperative that strict adherence to drug regimen be maintained.

MECHANISM OF ANTIMALARIAL ACTION Little is known about the antimalarial action of the 8-aminoquinolines. Primaquine may be converted to electrophiles that act as oxidation-reduction mediators, which may be the toxic moiety.

ABSORPTION, FATE, AND EXCRETION

Primaquine is only given orally. Absorption from the GI tract is nearly complete. After a single dose, the plasma concentration peaks within 3 hours and then falls with an elimination tia of

6 hours. The apparent volume of distribution is several times that of total-body water. Primaquine is metabolized rapidly; only a small fraction is excreted as the parent drug. The major metabolite in human plasma is 8-(3-carboxyl-1-methylpropylamino)-6-methoxyquinoline, which is eliminated more slowly and accumulates with multiple doses.

THERAPEUTIC USES Primaquine is used primarily for the terminal prophylaxis and radical cure of P. vivax and P. ovale (relapsing) malarias because of its high activity against their latent tissue forms. The compound is given together with a blood schizontocide, usually chloroquine, to eradicate erythrocytic stages of these plasmodia and reduce the possibility of emerging drug resistance. For terminal prophylaxis, primaquine regimens are initiated shortly before or immediately after leaving an endemic area (Table 39-1). Radical cure of P. vivax or P. ovale malaria can be achieved if the drug is given either during the long-term latent period of infection or during an acute attack. Studies also have shown efficacy in prevention of P. falciparum and P. vivax malaria when primaquine is taken prophylactically. The drug generally is well tolerated when taken for up to 1

year.

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