Fansidar - Pyrimethamine

In Britain, the retrospective reported rate for serious reactions with Maloprim was one in 9100, the incidence of blood dyscrasias being one in 20 000. These figures are lower than those reported with Fansidar (pyrimethamine + sulfadoxine) (SEDA-16, 309). 

Liver function abnormalities with Fansidar (pyrimethamine + sulfadoxine) vary from raised serum transaminase activities to more marked disturbances, with jaundice and granulomatous hepatitis. An occasional case of fatal hepatic failure has been reported this was the case in a young white American woman who had taken three doses of Fansidar with chloroquine (SEDA-12,242). Hepatic symptoms may be part of a vasculitis sjmdrome or can be seen in association with skin reactions (SEDA-13, 241). 

Sulfonamide and/or pyrimethamine sensitivity, pregnancy, and G6PD deficiency are contraindications. Use in young infants is considered inadvisable the history of an 8-month-old infant with P. falciparum malaria who developed high fever, tachycardia, hypotension, chills, jaundice, and splenomegaly 48 hours after a single parenteral dose of Fansidar (pyrimethamine + sulfadoxine) (SEDA-16, 309) seems to confirm the wisdom of this advice. It has been advocated that Fansidar should not be used prophylactically if exposure to malaria will last less then 3 weeks, in view of the incidence of severe skin reactions during the first month. 

The success of quinine inspired the search for other antimalarials. The greatest impetus for the development of synthetic dmgs came this century when the two World Wars intermpted the supply of cinchona bark to the combatants. A stmcturally related 4-quinolinemethanol is mefloquine (65, Lariam [51773-92-3]) which now serves as an effective alternative agent for chloroquine-resistant P. falciparum. This is a potent substance that requires less than one-tenth the dose of quinine to effect cures. There are some untoward side effects associated with this dmg such as gastrointestinal upset and dizziness, but they tend to be transient. Mefloquine is not recommended for use by those using beta-blockers, those whose job requires fine coordination and spatial discrimination, or those with a history of epilepsy or psychiatric disorders. A combination of mefloquine with Fansidar (a mixture of pyrimethamine and sulfadoxine) is known as Fansimef but its use is not recommended. Resistance to mefloquine has been reported even though the compound has not been in wide use. 

Pyrimethamin-Heyl (Heyl) comb. Fansidar (Roche)-comb. 

Fansidar is the fixed dose combination of pyrimethamine with sulfadoxine. This formulation is well absorbed with peak plasma levels of the components 2-8 hours after dosing. 

Knowledge of local resistance patterns is important to determine the treatment regimen. There is increasing chloroquine and pyrimethamine-sulfado-xine (Fansidar) resistance in Africa and in some areas at the border of Thailand there is resistance for almost all antimalarial drugs including halofantrine, mefloquine and quinine. In these areas only the artemisinin derivatives (artemether, arteether, arte-sunate, dihydroartemisinin) are effective. 

Nebulized pentamidine at the dosage of 300 mg every two weeks should be used in patients with a CD4-I- count less than 100 mm if systemic therapy cannot be tolerated. Sulfadoxine/pyrimethamine (Fansidar), one tablet given once or twice a week, is useful in patients in whom compliance is considered to be a problem. However, it has been associated with hepatotoxicity, Stevens-Johnson syndrome and toxic epidermal necrolysis. 

Sulfonamides, such as sulfadiazine, in combination with pyrimethamine, are considered the treatment of choice of symptomatic toxoplasmosis. Patients should be well hydrated to prevent crystalluria this problem may be reduced with the use of triple sulfas (trisulfapyrimidine). Some regimens have included a sulfonamide (sul-fadoxine) in combination with pyrimethamine (Fansidar) for the treatment of chloroquine-resistant malaria caused by P. falciparum. 

The combined use of sulfonamides or sulfones with dihydrofolate reductase inhibitors, such as trimethoprim Bactrim, Septra) or pyrimethamine Fansidar), s, a good example of the synergistic possibilities that exist in multiple-drug chemotherapy. This type of impairment of the parasite s metabolism is termed sequential blockade. Using drugs that inhibit at two different points in the same biochemical pathway produces parasite lethality at lower drug concentrations than are possible when either drug is used alone. 

Sulfadoxine is the only long-acting sulfonamide currently available in the USA and only as a combination formulation with pyrimethamine (Fansidar), a second-line agent in treatment for malaria (see Chapter 52). 

Pyrimethamine and sulfadiazine have been used for treatment of leishmaniasis and toxoplasmosis. In falciparum malaria, the combination of pyrimethamine with sulfadoxine (Fansidar) has been used (see Chapter 52). 

Sulfadoxine-pyrimethamine (Fansidar) Folate antagonist combination Treatment of infections with some chloroquine-resistant P falciparum, including combination with artesunate intermittent preventive therapy in endemic areas... 

In many areas, resistance to folate antagonists and sulfonamides is common for P falciparum and less common for P vlvax. Resistance is due primarily to mutations in dihydrofolate reductase and dihydropteroate synthase, with increasing numbers of mutations leading to increasing levels of resistance. At present, resistance seriously limits the efficacy of sulfadoxine-pyrimethamine (Fansidar) for the treatment of malaria in most areas, but in Africa most parasites exhibit only moderate resistance, such that antifolates appear to continue to offer preventive efficacy against malaria. Because different mutations may mediate resistance to different agents, cross-resistance is not uniformly seen. 

The sulfones and sulfonamides synergize with the inhibitors of dihydrofolate reductase, and the combinations have been effective in controlling malaria, toxoplasmosis, and coccidiosis. Fansidar, a combination of sulfadoxine and pyrimethamine, has been successful in controlling some strains of chloroquine-resistant Plasmodium falciparum malaria (see Chapter 53 Antiprotozoal Drugs). However, reports of Fansidar resistance have increased in recent years. New inhibitors effective against the sulfonamide-resistant 7,8-dihydropteroate synthase are needed. 

Pharmacokinetics When a chloroquine-resistant organism is encountered, therapy usually consists of a combination of quinine, pyrimethamine, and a sulfonamide. All are administered orally. [Note fansidar, a combination of pyrimethamine and sulfa-doxime is used.] Taken orally, quinine is well distributed throughout the body and can reach the fetus across the placenta. Alkalinization of the urine decreases its excretion. 

A quinine satf 600 mg 8-hourly by mouth for 7 days followed by pyrimethamine plus sulfadoxine (Fansidar) 3 tablets as a single dose. Where there is resistance to Fansidar, doxycycline 200 mg, should be given after the course of quinine daily for at least 7 days. This additional therapy is necessary as quinine alone tends to be associated with a higher rate of relapse. 

Pyrimethamine acts synergistically with suifadoxine (as Fansidar) to inhibit folic acid metabolism (see antifols, above) suifadoxine is excreted in the urine. The combination is chiefly used with quinine to treat acute attacks of malaria caused by susceptible strains of Plasmodium falciparum a single dose of pyrimethamine 75 mg plus suifadoxine 1.5 g (3 tablets) usually suffices. 

The combined use of Fansidar (sulfadoxine + pyrimethamine) with chloroquine has been reported to result in more severe adverse reactions (50). However, an increased risk has not been reported in recent studies (51). 

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