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Malaria Control During Mass Population Movements and Natural Disasters APPENDIX A Description of Antimalarial Drugs QUININE Quinine was first isolated from Chinchona bark in 1820 and has since been the fundamental chemotherapeutic tool for the treatment of malaria, especially severe disease. Quinine and its dextroisomer, quinidine, are rapidly acting schizontocides that target the erythrocytic asexual stages of all malaria parasites. It is available in both oral and parenteral preparations and can be used in infants and pregnant women. Side effects include nausea, dysphoria, blurred vision, and tinnitus and typically resolve after treatment has ended. P. falciparum from most areas of the world responds well to quinine; thus, shortened courses of quinine can be used in conjunction with a second drug to reduce the likelihood of quinine-associated side effects. P. falciparum from many areas of Southeast Asia requires full-course quinine treatment in conjunction with a second drug (see Table 3-3), such as tetracycline. CHLOROQUINE Chloroquine is a 4-aminoquinoline derivative of quinine first synthesized in 1934. Historically, it has been the drug of choice for the treatment of nonsevere or uncomplicated malaria and for chemoprophylaxis. Chloroquine acts primarily against erythrocytic asexual stages, although it has gametocidal properties. Because of widespread resistance to this drug,
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Malaria Control During Mass Population Movements and Natural Disasters 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 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. ANTIFOL COMBINATION DRUGS 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).
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Malaria Control During Mass Population Movements and Natural Disasters Another promising antifol combination, chlorproguanil and dapsone, is currently being tested in Africa and elsewhere. Also known as “LapDap,” this particular combination is innately more effective than sulfadoxine/ pyrimethamine (even in areas where resistance is present) and also has a much shorter elimination half-life, which may decrease the chances for development of resistance (Watkins et al., 1997; Mutabingwa et al., 2001). Conversely, the shorter half-life requires that it be given over 3 days rather than in a single dose. TETRACYCLINES Tetracycline and derivatives such as doxycycline are very potent antimalarials and are used for either treatment or prophylaxis. In areas where response to quinine has deteriorated, tetracyclines are often used in combination with quinine to improve cure rates. Tetracyclines are also used in conjunction with shortened courses of quinine to decrease the likelihood of quinine-associated side effects (provided parasites are susceptible to quinine). Tetracyclines should not be used during pregnancy, breast-feeding, or in children under age 8. Common side effects include nausea, vomiting, diarrhea, Candida superinfections, and photosensitivity. PRIMAQUINE Primaquine, an 8-aminoquinoline, is primarily used as a tissue schizonticide for the purpose of reducing the likelihood of relapse due to hypnozoites of P. vivax and P. ovale. Studies have shown that primaquine has reasonably good efficacy (74 percent against P. falciparum and 90 percent against P. vivax) when used for prophylaxis (Baird et al., 1995). Although it has activity against blood-stage asexual parasites, the concentrations required to achieve blood schizonticidal action are toxic; primaquine is also a potent gametocidal drug. People with glucose-6-phosphate dehydrogenase (G6PD) deficiencies can experience severe and potentially fatal hemolytic anemia if treated with primaquine. The most severe Mediterranean B variant and related Asian variants of G6PD deficiency can occur at high rates among some groups and in some regions; Kurdish Jews (62 percent), Saudi Arabia (13 percent), Myanmar (20 percent), and southern China (6 percent). Migration, mutation, and intermarriage have spread these variants throughout the world. Primaquine should not be used in pregnancy.
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Malaria Control During Mass Population Movements and Natural Disasters Tafenoquine, a synthetic primaquine analog, is currently being tested. It is highly effective against both liver and blood stages of malaria. Because of its long half-life (14 days versus 6 hours for primaquine), tafenoquine may prove to be a valuable chemoprophylactic drug (Lell et al., 2000). As for primaquine, tafenoquine can result in hemolysis among patients with G6PD deficiency. MEFLOQUINE Mefloquine is a quinoline-methanol derivative of quinine. Mefloquine can be used either therapeutically or prophylactically in most areas with multidrug-resistant malaria. Resistance to mefloquine, however, occurs frequently in parts of Southeast Asia; sporadic resistance has been reported in areas of Africa and South America. Mefloquine has been associated with a relatively high incidence of neuropsychiatric side effects when used at treatment doses but is otherwise well tolerated. Although not licensed for use during pregnancy and in very young infants, mefloquine appears to be safe and effective in both groups. HALOFANTRINE Halofantrine is a phenanthrene-methanol compound with activity against the erythrocytic stages of the malaria parasite. Its use has been especially recommended in areas with multidrug-resistant falciparum. Studies have indicated, however, that the drug can produce cardiac conduction abnormalities (specifically, prolongation of the PR and QT interval1), limiting its usefulness (Nosten et al., 1993). A subsequent study suggests that cardiac abnormalities are dose dependent and can be severe in patients with preexisting cardiopathy; the authors suggest that electrocardiography be conducted on all patients prior to treatment with halofantrine (Monlun et al., 1995). A micronized formulation has improved halofantrine’s poor oral bioavailability; however, it should be given on an empty stomach. Fatty foods dramatically increase absorption, increasing the risk of cardiac complications. Recrudescences can occur with one round of treatment, and, especially when treating nonimmune individuals, a second course should 1 PR and QT intervals are specific points on an electrocardiogram. They are the intervals between the P and R wave forms and between the Q and T wave forms, respectively.
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Malaria Control During Mass Population Movements and Natural Disasters be given 7 days later. Retreatment of patients who had failed mefloquine therapy with halofantrine was less successful than primary treatment with halofantrine, suggesting the possibility of clinical cross-resistance between the two drugs (Wongsrichanalai et al., 1992; ter Kuile et al., 1993). Halofantrine therapy after mefloquine or quinine therapy also increases the risk of cardiac problems. CLINDAMYCIN Clindamycin has some antimalarial activity but is a poor choice compared to the other available antimalarial drugs. It is a slow-acting schizonticide and should only be used in combination with a fast-acting schizonticide, such as quinine, especially when treating patients with little or no immunity to malaria (Pukrittayakamee et al., 2000b; Parola et al., 2001). Although clindamycin may be useful for treatment of pregnant women and very young children (Pukrittayakamee et al., 2000a) more effective drugs are available that can be used in these groups (such as mefloquine or even, perhaps, mefloquine + artesunate). ARTEMISININ COMPOUNDS A number of sesquiterpine lactone compounds have been synthesized from the plant Artemisia annua (artesunate, artemether, artether). Benefits of use for severe malaria include rapid parasite clearance times and faster fever resolution than occurs with quinine. Preliminary results of studies to determine if this faster action produces improved survival suggest that there is quicker improvement of coma following treatment with artemisinins (Taylor et al., 1993; Salako et al., 1994). When used alone, especially for durations of less than 5 to 7 days, recrudescence rates are high. For nonsevere malaria, artemisinins are most successfully used in combination with a second drug (Nosten et al., 1994a). The best-documented combination therapy is that using mefloquine and 3 days of artesunate. A fixed-dose preparation of lumefantrine and artemether is commercially available (Co-artem or Riamet). Lumefantrine (previously known as benflumetol) is an aryl-amino alcohol antimalarial compound. Although related chemically, in practice, lumefantrine does not appear to have cardiac effects similar to halofantrine (van Vugt et al., 1999). This combination is marketed in two packaging schemes: a six-dose (24-tablet) package for use by nonimmune patients, and a four-dose (16-tablet) package for use by
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Malaria Control During Mass Population Movements and Natural Disasters semiimmune patients. Until studies have conclusively shown adequate efficacy of the four-dose regimen among semiimmune populations, all patients should probably be treated with a full six-dose regimen (van Vugt et al., 2000). No data exist to prove the safety of lumefantrine use during pregnancy; thus, lumefantrine should not be used to treat pregnant women. ATOVAQUONE PLUS PROGUANIL (MALARONE) This drug is a fixed-dose antimalarial combination of 250 mg of atovaquone and 100 mg of proguanil. Atovaquone is a hydroxynaptho-quinone that is currently being used mostly to treat opportunistic infections in immunosuppressed patients. Because of a high incidence of recrudescence when used alone, atovaquone is given in combination with proguanil (Looareesuwan et al., 1996a; Radloff et al., 1996). Treatment is with 1,000 mg of atovaquone and 400 mg of proguanil daily for 3 days. Malarone is reportedly effective against erythrocytic forms of P. vivax (Looareesuwan et al., 1996a). Although there is some concern about resistance developing rapidly to this combination, Malarone currently appears to be highly effective against most drug-resistant malaria parasites. PYRONARIDINE Pyronaridine is a drug synthesized and used in China for over 20 years. While it was reportedly 100 percent effective in one trial in Cameroon, the drug was only 63 to 88 percent effective in Thailand (Ringwald et al., 1996; Looareesuwan et al., 1996b). Further testing is required before pyronaridine can be recommended for use.
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