Pyrimethamine-chloroquine

Ziodvudine, quinacrine, amodiaquine, mepacrine, pyrimethamine, chloroquine, mebendazole... 

The sulfas also remain clinically useful in the treatment of chancroid, lymphogranuloma venereum, trachoma, inclusion conjunctivitis, and the fungus-related nocardiosis (7). In combination with pyrimethamine, they are recommended for toxoplasmosis (8) and have been used for chloroquine-resistant falciparium malaria (4,9). There has also been some use of sulfas for the prophylaxis of rheumatic fever. The sulfone, dapsone, remains an accepted treatment for all forms of leprosy (4). 

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. 

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. 

Antimalarial drugs are designed to prevent or treat malaria. Antimalarial drugs currently used for treatment for prophylaxis are mefloquine, primaquine, chloroquine, pyrimethamine, amodiaquin, quinine/quinidine, chloroguanide. 

Upon oral administration, quinine effectively acts in combination with pyrimethamine, sulfadiazine, and/or tetracycline for treating uncomplicated incidents of chloroquine-resistant forms of P. falciparum. Because of the many associated side effects, its use is extremely limited. Currently, the only indication for use is for forms of malaria that are resistant to other synthetic drugs. Synonyms of this drug are bronchopulmin, nicopriv, quinnam, and others. 

A combination of pyrimethamine, sulfonamide, and qninine is the dmg of choice for acute attacks of malaria and its chloroquine-resistant forms. 

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. 

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. 

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... 

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. 

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. 

Pyrimethamine is well absorbed after oral administration, with peak plasma levels occurring within 3 to 7 hours. An initial loading dose to saturate nonspecific binding sites is not required, as it is with chloroquine. However, the drug binds to tissues, and therefore, its rate of renal excretion is slow. Pyrimethamine has a half-life of about 4 days. Although the drug does undergo some metabolic alterations, the metabolites formed have not been totally identified. 

In areas where chloroquine-resistant P. falciparum is common, a combination of a rapidly acting blood schi-zonticide and pyrimethamine-sulfadoxine may be the treatment of choice. An acute attack of malaria caused... 

It is also used with pyrimethamine in chloroquine resistant malaria. 

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... 

Chloroquine-resistant Quinine Artemisinin derivatives Atovaquone-proguanil Mefloquine Pyrimethamine-sulfadoxine Antibacterials (e.g., clindamycin, doxycycline, sulfamethoxazole, or tetracycline] ... 

The major antimalarial agents are the 4-aminoquinoline derivative (e.g., chloroquine), 8-aminoquinoline derivative (e.g., primaquine), folic acid antagonist (e.g., pyrimethamine), and... 

Pyrimethamine is a fohc acid antagonist (antifol) with pharmacological actions similar to chlorguanide, methotrexate, and trimethoprim. Pyrimethamine may be used in combination with sulfadoxine for suppression and sulfadiazine for treatment of chloroquine-resistant Plasmodium falciparum. 

Note The main objective in the clinical management of patients suffering from an acute malaria attack is the prompt elimination of the parasite form responsible for the symptoms, that is, the asexual erythrocytic form. Drugs that are particularly effective in this regard are called schizontocidal or suppressive agents. They include such compounds as amodiaquine, chloroguanide, chloroquine, hydroxychloroquine, pyrimethamine, quinine, and tetracycline. 

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. 

Novartis Malaria Data from Gamo et al. (14), P. falciparum strains 3d7 (drug-susceptible), and W2 (chloroquine-, quinine-, pyrimethamine-, cycloguanil-, and sulfadoxine-resistant), obtained from MR4, were tested in an erythrocyte-based infection assay for susceptibility to inhibition of proliferation by selected compounds. 5,695... 

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. 

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