Antimalarials

The causative agents of malaria are plasmodia, unicellular organisms (Order Hemosporidia, Class Protozoa). The infective form, the sporozoite, is inoculated into skin capillaries when infected female Anopheles mosquitoes (A) suck blood from humans. The sporozoites invade liver parenchymal cells, where they develop into primary tissue schizonts. These give rise to numerous merozoites that enter the blood. The preerythrocytic stage is asymptomatic. In blood, the parasite enters erythrocytes (erythrocytic stage), where it again multiplies by schizogony, resulting in the formation of more merozoites. Rupture of the infected erythrocytes releases the merozoites and pyrogens. A fever attack ensues and more erythrocytes are infected. The generation period for the next crop of merozoites determines the interval between fever attacks. With Plasmodium vivax and P. ovale, there can be a parallel multiplication in the liver (paraerythrocytic stage). Moreover, some sporozoites may become dormant in the liver as “hypnozoites” before entering schizogony.

Different antimalarials selectively kill the parasite’s different developmental forms. The mechanism of action is known for some agents: Chloroquine and quinine accumulate within the acidic vacuoles of blood schizonts and inhibit polymerization of heme released from digested hemoglobin, free heme being toxic for the schizonts. Pyrimethamine in-

via its active metabolite cycloguanil. The sulfonamide sulfadoxine inhibits synthesis of dihydrofolic acid (p.274). Dihydrofolate reductase is also blocked by cycloguanil, the active form of proguanil. Atoquavone suppresses synthesis of pyrimidine bases, probably by interfering with mitochondrial electron transport. Artemesinin derivatives (artemether, artesunate) originate from the East Asian plant Qinghaosu (Artemisia sp.) Its antischizontal effect appears to involve a re-

action between heme iron and the epoxide group of these compounds.

Antimalarial drug choice takes tolerability and plasmodial resistance into account.

Tolerability. The oldest antimalarial, quinine, has the smallest therapeutic margin. All newer agents are rather well tolerated.

Plasmodium falciparum, responsibleforthe most dangerous form of malaria, is particularly prone to develop drug resistance. The prevalence of resistant strains rises with increasingfrequencyofdruguse.Resistancehas been reported for chloroquine and also the combination pyrimethamine/sulfadoxine.

Drug choice for antimalarial chemoprophylaxis. In areas with a risk of malaria, continuous intake of antimalarials affords the best protection against the disease, though not against infection. Primaquine would be effective against primary tissue schizonts of all plasmodial species; however, it is not used for long-term prophylaxis because of unsatisfactory tolerability and the risk of plasmodial resistance. Instead, prophylactic regimens employ agents against blood schizonts. Depending on the presence of resistant strains, use can be made of chloroquine, and/or proguanil, mefloquine, the tetracycline doxycycline, as well as the combination of atoquavone and proguanil.

These drugs do not prevent the (symp- tom-free) hepatic infection but only the dis- ease-causing infection of erythrocytes (“suppression therapy”). On a person’s return from an endemic malaria region, a two-week course of primaquine is adequate for eradication of the late hepatic stages (P. vivax and

P. ovale).

Protection from mosquito bites (with nets, skin-covering clothes, etc.) is a very important prophylactic measure.

Therapy. Antimalarial therapy employs the same agents, in addition to the combinations of artemether plus lumefantrine or pyrimethamine plus sulfadoxine.

Other Tropical Diseases

In addition to malaria, other tropical diseases and their treatment will be considered for the following reasons. (1) Owing to the tremendous growth in global travel, inhabitants of temperate climatic zones have become exposed to the hazard of infection with tropical disease pathogens. (2) The spread of some tropical diseases is of unimaginable dimensions, with humans victims numbering in the millions. The pharmacotherapeutic possibilitiesknown to date will be presented.

Amebiasis. The causative agent, Entamoeba histolytica, lives and multiplies in the colon (symptom: diarrhea), its cyst form residing also in the liver among other sites. In tropical regions, up to half the population can be infested, transmission occurring by the fe- cal–oral route. The most effective treatment against both intestinal infestation and systemic disease is administration of metronidazole. If monotherapy fails, combination therapy with chloroquine, emetine or tetracyclines may be indicated.

Leishmaniasis. The causative agents are flagellated protozoa that are transmitted by sand flies to humans. The parasites are taken up into phagocytes, where they remain in phagolysosomes and multiply until the cell dies and the parasites can infect new cells. Symptoms: A visceral form, known as kalaazar, and cutaneous or mucocutaneous forms exist (A). An estimated 12 million humans are affected. Therapy is dif cult; pentavalent antimonial compounds, such as stibogluconate, must be given for extended periods. Adverse effects are pronounced.

Trypanosomiasis. The pathogens, Trypanosoma brucei (sleeping sickness) and T. cruzi (Chagas disease), are flagellated protozoa. T. brucei (C) is transmitted by the tsetse fly, distributed in West and East Africa. An initial stage (swelling of lymph nodes, malaise, hepatosplenomegaly, among others) is followed by invasion of the CNS with lethargy,

extrapyramidal motor disturbances, Parkin- son-like signs, coma, and death. Therapy: Long-term suramine i.v. or pentamidine(less effective); arsenicals (e.g., melarsoprol, highly toxic), when the CNS is involved. T. cruzi is confined to Central and South America and transmitted by blood-sucking reduviid bugs. These parasites preferentially infiltrate the cardiac musculature, where they cause damage to muscle fibers and the specialized conducting tissue. Death results from cardiac failure. Therapy: unsatisfactory.

Schistosomiasis (bilharziasis) (see also p.292). The causative organisms are trematodes with a complex life cycle that need (aquatic) snails as intermediate hosts. Freeswimming larval cercariae penetrate the intact skin of humans. The adult worms (Schistosoma mansoni, D) livein thevenousvasculature. Occurrence: tropical countries rich in aquatic habitats. About 200 million humans are af icted. Therapy: praziquantel, 10– 40 mg/kg,singledose,ishighlyeffectivewith minimal adverse effects. Substancesreleased from decaying worms may cause problems.

Filariasis. In its microform, Wuchereria bancrofti istransmittedbymosquitoes;theadult parasites live in the lymph system and cause inflammations and blockage of lymph drainage leading to elephantiasis in extreme cases (B). Therapy: diethylcarbamazepine for several weeks; adverse reactions are chiefly due to products from disintegrating worms.

Onchocerciasis (“River Blindness”). The causative organism is Onchocerca volvulus, a filaria transmitted by black flies (genus Simulium). The adult parasites (several centimeters long) form tangles and proliferating nodules (onchocercomas) in the skin and have a particular propensity for invading the eyeball, resulting in blindness. About 20 million people inhabiting banks of fast-flow- ing rivers are af icted with river blindness. Therapy: ivermectin (0.15 mg/kg, single dose); adverse reactions are in part caused by disintegrating worms.