Question 10. Answered by Samantha

10. Discuss drug therapies against malaria.

Malaria: Is the most important of all protozoan diseases, perhaps the most important infectious disease (except maybe mycobacterium), causes 2.3% of global disease, caused by P.falciparum, P.vivax, P. malariae and P.ovale. Reemerging disease is falciparum. Natural immunity to malaria is imperfect – the fact which also translates into a major impediment for vaccine development. Even persons who have lived all their lives in endemic areas, and have evidence of strong humoral and cellular immunity may get infected. The difference is that clinical manifestations tend to be less severe that in non-immune persons. Chloriquine is the most widely used (and misused) drug for antimalarial chemoprophylaxis and treatment. Chloriquine, and other quinine-based drugs, enter the parasite’s food vacuole, where RBC hemoglobin is degraded for the nutrition of the parasite. Normally, toxic heme released by this degradation is detoxified and converted to harmless malarial pigment. Chloriquine blocks heme detoxification and kills the parasite. Chloriquine resistance occurs by mutation of a vacuolar membrane protein that causes Chloriquine to be pumped out of the food vacuole and permits heme detoxification to resume.

While Chloriquine originally was effective against all four species of Plasmodium infecting humans, most P.falciparum strains circulating in Africa, SE Asia, and South-America have developed resistance to this drug. The alternative drug-of-choice for Chloriquine-resistant P.falciparum used to be Fancidar (trade name for a combination drug). However, any of the malaria strains are now double resistant. In addition, Fansidar has potential unwanted side-effects. Currently, if an infection with P.falciparum is acquired in a geographic area known to host Chloriquine/Fancidar resistant malaria, a combination-therapy with newer alternative drugs is applied. However, the best preventative measure is not to be bitten by a mosquito in the first place. So apart from schemes of applying environmental insecticides and drainage to floodways (expensive), as a visitor to malaria-endemic areas can protect yourself by simply measures such as mosquito nets, insect-repellants and protective clothing. Many experimental vaccines are under development.

Patients infected with Chloriquine-resistant P.falciparum can be treated with other agents, such as Malarone (a fixed combination of atovaquone and proguanil), mefloquine, quinine, quinidine, halofantrine or artesunate. At present, P.falciparum cases acquired in areas where drug resistance is prevalent are usually treated in the United States with a combination of doxycycline and quinine, Malarone, or quinidine. Mefloquine, a quinine derivative, is also active against Chloriquine-resistant strains but is often toxic at treatment doses. However, it is a mainstay for chemoprophylaxis in travelers to most areas with Chloriquine-resistant malaria. Unfortunately, resistance to mefloquine has also been detected in parts of SE Asia, and travelers to that area are now being advised to take daily doxycycline to prevent infection. Although all of the antimalarials mentioned are effective in controlling acute infection caused by P.vivax or P.ovale, none is effective against the liver (hypnozoite/exo-erythrocytic) stages of those species. Primaquine, a derivative of quinine, is effective against the hypnozoite stages. It is used with Chloriquine to prevent late relapses associated with maturation of the hypnozoite to the tissue schizont stage and the subsequent release of infectious merozoites. However, Primaquine is more toxic than Chloriquine and causes nausea, vomiting and diarrhea. In patients with G6P deficiency, Primaquine induces hemolysis. Primaquine is not indicated for either P.falciparum or P.malariae infections because those parasites do not produce a dormant (hypnozoite) stage in the liver.