The causative agents of malaria are Plasmodia, unicellular organisms belonging to the 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 sporo-zoites invade liver parenchymal cells where they develop into primary tissue schizonts. After multiple fission, these schizonts produce numerous mero-zoites that enter the blood. The pre-erythrocytic stage is symptom free. 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. When the sexual forms (gametocytes) are ingested by a feeding mosquito, they can initiate the sexual reproductive stage of the cycle that results in a new generation of transmittable sporozoites.
Different antimalarials selectively kill the parasite's different developmental forms. The mechanism of action is known for some of them: pyrimethamine and dapsone inhibit dihydrofolate reductase (p. 273), as does chlorguanide (proguanil) via its active metabolite. The sulfonamide sulfadoxine inhibits synthesis of dihydrofolic acid (p. 272). Chlo-roquine and quinine accumulate within the acidic vacuoles of blood schizonts and inhibit polymerization of heme, the latter substance being toxic for the schizonts.
Antimalarial drug choice takes into account tolerability and plasmodial resistance.
Tolerability. The first available antimalarial, quinine, has the smallest therapeutic margin. All newer agents are rather well tolerated.
Plasmodium (P.) falciparum, responsible for the most dangerous form of malaria, is particularly prone to develop drug resistance. The incidence of resistant strains rises with increasing frequency of drug use. Resistance has been reported for chloroquine and also for the combination pyrimethamine/ sulfadoxine.
Drug choice for antimalarial chemoprophylaxis. In areas with a risk of malaria, continuous intake of antima-larials affords the best protection against the disease, although not against infection. The drug of choice is chloroquine. Because of its slow excretion (plasma ti/2 = 3d and longer), a single weekly dose is sufficient. In areas with resistant P. falciparum, alternative regimens are chloroquine plus pyri-methamine/sulfadoxine (or proguanil, or doxycycline), the chloroquine analogue amodiaquine, as well as quinine or the better tolerated derivative meflo-quine (blood-schizonticidal). Agents active against blood schizonts do not prevent the (symptom-free) hepatic infection, only the disease-causing infection of erythrocytes ("suppression therapy"). On return from an endemic malaria region, a 2 wk course of primaquine is adequate for eradication of the late hepatic stages (P. vivax and P. ovale).
Protection from mosquito bites (net, skin-covering clothes, etc.) is a very important prophylactic measure.
Antimalarial therapy employs the same agents and is based on the same principles. The blood-schizonticidal halofantrine is reserved for therapy only. The pyrimethamine-sulfadoxine combination may be used for initial self-treatment.
Drug resistance is accelerating in many endemic areas; malaria vaccines may hold the greatest hope for control of infection.
Chemotherapy of Malignant Tumors
A tumor (neoplasm) consists of cells that proliferate independently of the body's inherent "building plan." A malignant tumor (cancer) is present when the tumor tissue destructively invades healthy surrounding tissue or when dislodged tumor cells form secondary tumors (metastases) in other organs. A cure requires the elimination of all malignant cells (curative therapy). When this is not possible, attempts can be made to slow tumor growth and thereby prolong the patient's life or improve quality of life (palliative therapy). Chemotherapy is faced with the problem that the malignant cells are endogenous and are not endowed with special metabolic properties.
Cytostatics (A) are cytotoxic substances that particularly affect proliferating or dividing cells. Rapidly dividing malignant cells are preferentially injured. Damage to mitotic processes not only retards tumor growth but may also initiate apoptosis (programmed cell death). Tissues with a low mitotic rate are largely unaffected; likewise, most healthy tissues. This, however, also applies to malignant tumors consisting of slowly dividing differentiated cells. Tissues that have a physiologically high mitotic rate are bound to be affected by cytostatic therapy. Thus, typical adverse effects occur:
Loss of hair results from injury to hair follicles; gastrointestinal disturbances, such as diarrhea, from inadequate replacement of enterocytes whose life span is limited to a few days; nausea and vomiting from stimulation of area postrema chemoreceptors (p. 330); and lowered resistance to infection from weakening of the immune system (p. 300). In addition, cytostatics cause bone marrow depression. Resupply of blood cells depends on the mitotic activity of bone marrow stem and daughter cells. When myeloid proliferation is arrested, the short-lived granulocytes are the first to be affected (neutropenia), then blood platelets (thrombopenia) and, finally, the more long-lived erythrocytes (anemia). Infertility is caused by suppression of spermatogenesis or follicle maturation. Most cytostatics disrupt DNA metabolism. This entails the risk of a potential genomic alteration in healthy cells (mutagenic effect). Conceivably, the latter accounts for the occurrence of leukemias several years after cytostatic therapy (carcinogenic effect). Furthermore, congenital malformations are to be expected when cytostatics must be used during pregnancy (teratogenic effect).
Cytostatics possess different mechanisms of action.
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