Pyrimethamine with sulfadoxine

The use of the long-acting sulfonamides such as sulfadimethoxine and sulfadoxine is limited because of a high rate of hypersensitivity reactions. Sulfadoxine in combination with pyrimethamine is indicated for chloroquine-resistant falciparum malaria. 

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). 

Sulfonamides — Sulfadoxine or sulfadiazine is used with pyrimethamine. 

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. 

In Irian Jay a, a randomized, controlled trial (n = 105 88 children) of oral artesunate (4 mg/kg od for 3 days) with pyrimethamine (1.25 mg/kg) + sulfadoxine or pyrimethamine + sulfadoxine alone (same dose) showed reduced gametocyte carriage and reduced treatment failure rates (RR = 0.3 95% Cl = 0.1, 1.3) in the combination group (16). Self-limiting adverse events of combination treatment were mild diarrhea (2.1%), rashes (4.3%), and itching (2.1%). 

In a double-blind, randomized, placebo-controlled trial in Gambian children with uncomplicated falciparum malaria treated with pyrimethamine + sulfadoxine (25/ 500 mg n — 600) or pyrimethamine + sulfadoxine combined with two regimens of oral artesunate (4 mg/kg, n — 200 or 4 mg/kg od for 3 days, n — 200), there were mild adverse events, such as headache, anorexia, nausea, vomiting, abdominal pain, and diarrhea, in a high proportion of children (56%) (17). Combination treatment with... 

Instances of mefloquine resistance were reported in Tanzania in 1983, in Thailand in 1989, and in Africa (Malawi) in 1991. Resistance to combinations of mefloquine with sulfadoxine and pyrimethamine was reported in 1985 (SEDA-13, 808) (40 4). The possibility of crossresistance between mefloquine and halofantrine was raised in 1990 (SEDA-13, 808) (45). Currently there are extensive areas, including Thailand, Cambodia, Laos, Papua New Guinea, and Myanmar, where P. falciparum... 

Intermittent iron supplementation with pyrimethamine + sulfadoxine has been investigated in 328 anemic but symptom-free Kenyan children, who were randomly given either iron (ferrous fumarate suspension 6.25 g/1 twice a week) or placebo and pyrimethamine + sulfadoxine (25 mg and 1.25 mg/kg once every 4 weeks) or placebo (82 in each group) (6). After 12 weeks, those who took iron and pyrimethamine + sulfadoxine, iron alone, or pyrimethamine + sulfadoxine alone had higher hemoglobin concentrations than those who took the double placebo. No adverse effects were reported. 

In addition, sulfadoxine and pyrimethamine (Fansidar) are indicated in prophylaxis of malaria in individuals traveling to areas where chloroquine-resistant P. falciparum malaria is endemic. However, resistant strains may be encountered. Regardless of the prophylactic regimen used, it is still possible to contract malaria. Moreover, this combination has been used as a prophylactic agent in the prevention of Pneumocystis carinii pneumonia in patients with AIDS. 

FIGURE 107 Patients with a clinical diagnosis of AIDS should undergo long-term therapy with zidovudine (AZT, 1200 mg q. 4 hrs). Acyclovir may potentiate the beneficial effects of AZT. In addition, patients should be treated prophylactically for Pneumocystis carinii pneumonia such regimens include sulfadoxine and pyrimethamine (Fansidar), dapsone, or aerosolized pentamidine. Dextran sulfate is also useful because it blocks the binding of HIV to target cells. 

Sulfadoxine has a particularly long t (7-9 days). In combination with pyrimethamine (500 mg sulfadoxine plus 25 mg pyrimethamine as fansidar), it is used for prophylaxis and treatment of malaria caused by mefioquine-resistant strains of Plasmodium falciparum (see Chapter 39). Because of severe adverse reactions (e.g., Stevens-Johnson syndrome), the drug should be used for prophylaxis only where the risk of resistant malaria is high. 

A study in patients with AIDS found that zidovudine 250 mg four times daily did not adversely affeet the prevention of toxoplasma eneephalitis with pyrimethamine/sulfadoxine (Fansidar), one tablet twice weekly for up to 8 months. /w vitro and animal data have shown that the combination of zidovudine and pyrimethamine caused synergistic decreases in lymphocyte and neutrophil numbers. ... 

Observational studies During a surveillance period of 2 years, 1552 patients with uncomplicated P. falciparum malaria who had received sulfadoxine 4- pyrimethamine with artesunate on the Northern coast of Peru were followed up 8.8% reported at least one adverse effect, the most common being vomiting, nausea, headache, abdominal pain, dizziness, and fever there were no severe adverse effects [13 ]. 

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. 

ACTs are currently recommended artemether-lume-fantrine, artesunate + amodiaquine, artesunate + mefloquine, artesunate + sulfadoxine-pyrimethamine [1, 5]. In areas with amodiaquine and sulfadoxine-pyrimethamine resistance exceeding 20%, i.e., SE Asia, artesunate + mefloquine or artemether-lumefantrine should be used [1,5]. 

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. 

Malaria (doxycycline only) Prophylaxis of malaria due to Plasmodium falciparum in short-term travelers (less than 4 months) to areas with chloroquine and/or pyrimethamine-sulfadoxine resistant strains. 

VI.a.2.4. Diaminopyrimidines. Pyrimethamine is a dihydrofolate reductase inhibitor, like the biguanides, and is structurally related to trimethoprim. It is seldom used alone. Pyrimethamine in fixed combinations with dapsone or sulfadoxine is used for treatment and prophylaxis of chloroquine-resistant falciparum malaria. The synergistic activities of pyrimethamine and sulfonamides are similar to those of trimethoprim/sulfonamide combinations. Resistant strains of Plasmodium falciparum have appeared world wide. Prophylaxis against falciparum... 

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. 

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. 

A. Liposomal amphotericin B was approved by the US. Food and Drug Administration to treat visceral leishmaniasis. Pentavalent antimony compounds, pentamidine, amphotericin B, and aminosi-dine (paromomycin) have all been demonstrated efficacious here. The liposomal amphotericin appears to be better taken up by the reticuloendothelial system, where the parasite resides, and partitions less in the kidney, where amphotericin B traditionally manifests its toxicity. In addition to being better tolerated by patients, it has proved to be very effective in India, where resistance to antimony drugs is widespread. This patient appears to have acquired his infection there, where many infected patients develop darkening of the skin, hence the name kala-azar, or black sickness. Albendazole, an anthelmintic, has no role here. Atovaquone, a naphthoquinone, is used to treat malaria, babesiosis, and pneumocystosis. Pyrimethamine-sulfadoxine is used to treat malaria and toxoplasmosis. Proguanil inhibits the dihydrofolate reductase of malaria parasites and is used in combination with atovaquone. 

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... 

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