Pyrimethamine in malaria

Ngouesse B, Basco LK, Ringwald P, Keundjian A, Blackett KN. Cardiac effects of amodiaquine and sulfadoxine-pyrimethamine in malaria-infected African patients. Am J Trop Med Hyg 2001 65(6) 711-16. 

As can be seen from Table 4.2, the plasmodial enzyme is inhibited by pyrimethamine at a concentration about 2000 times lower than that inhibiting the analogous mammalian enzymes. The concentration that inhibited the plasmodial enzyme corresponded to that achieved in the tissues after the usual prophylactic dose. These data established that the selective action of pyrimethamine in malaria is due to the extraordinary sensitivity of the enzyme in the parasite compared to the analogous enzyme in the host (Burchall and Hitchings, 1965). 

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... 

It is also used with pyrimethamine in chloroquine resistant malaria. 

Two cases of pulmonary eosinophilia attributed to dapsone were reported in 1998. Four cases had previously been reported, in which the fixed combination of dapsone and pyrimethamine (a malaria prophylactic) had been implicated, but only one previous report had implicated dapsone alone. 

Although the hematological complications of pyrimethamine are generally a consequence of therapeutic use, long-term prophylactic treatment with pyrimethamine and dapsone in malaria could well involve an increased risk of megaloblastic anemia in patients whose nutritional state is not optimal (SEDA-13, 812). 

Rahman M, Rahman R, Bangali M, Das S, Talukder MR, Ringwald P. Efficacy of combined chloroquine and sulfadoxine-pyrimethamine in uncompUcated Plasmodium falciparum malaria in Bangladesh. Trans R Soc Trop Med Hyg 2004 98(7) 438 1. 

Pulmonary reactions have been described with most sulfonamides. Pyrimethamine -I- sulfadoxine, used in malaria prophylaxis and treatment, also rarely causes pulmonary reactions (17-19). The sulfapyridine moiety of sulfasalazine, used in inflammatory bowel disease, can produce adverse pulmonary reactions (20). 

There are few absolute clinical indications for the use of sulphonamides. They have been used extensively in the past for urinary tract infections, though less now. They are used for certain respiratory infections, including that by Pneumocystis carnii, some sexually transmitted diseases (chlamidia. chancroid, trachoma), in drug-resistant malaria (with pyrimethamine), in inflammatory towel disease (sulfasalazine) and as silver sulfadiazine for topical application in infected burns. 

MECHANISMS OF ANTIMALARIAL ACTION AND RESISTANCE The 2,4-diaminopyrimidines inhibit dihydrofolate reductase of plasmodia at concentrations far lower than those required to inhibit the mammalian enzymes. The dihydrofolate reductase in malaria resides on the same polypeptide chain as thymidylate synthase and is not upregulated in the face of inhibition, which contributes to the selective toxicity of the antifolates. Synergism between pyrimethamine and the sulfonamides or sulfones has been attributed to inhibition of two steps in an essential metabolic pathway. 

Dihydropteroate synthase Sporozoans (eg, plasmodium, toxoplasma, and eimeria species) lack the ability to utilize exogenous folate and therefore possess enzymes for its synthesis these enzymes can be inhibited by drugs. Sulfonamides, which are antimetabolites of PABA, inhibit dihydropteroate synthase. Sequential blockade ctin be achieved with a sulfonamide and an inhibitor of dihydrofolate reductase (eg, pyrimethamine) such drug combinations are effective in malaria and toxoplasmosis. 

Pyrimethamine in conjunction with sulfadoxine (25mg 500mg), under the brand name Fansidar (Roche), has been used successfully as an antimalarial drug for those subjects who display sensitization towards chloroquine therapy in malaria. 

Peterson DS, Milhous WK, Wellems TE. Molecular basis of differential resistance to cycloguanil and pyrimethamine in Plasmodium felciparum malaria. Proc Natl Acad Sci USA 1990 87(8) 3018-3022. 

An isolated report describes a 22-month-old girl treated with phenytoin, sodium valproate and topiramate for epilepsy and then with quinine sulfate (initially intravenously, then orally) followed by a single dose of sul-fadoxine/pyrimethamine for malaria. Her malaria film became negative after 4 days of the 7-day quinine course. About 1 month later she was found to have recrudescent falciparum malaria, which was treated with quinine sulfate and then atovaquone/proguanil. Although it is possible that quinine resistance may have occurred, the authors also considered that enzyme induction by phenytoin may have led to suboptimal quinine levels. Although quinine does not appear to affect phenytoin levels, the isolated case report suggests that levels of quinine may be reduced in the presence of phenytoin and it would seem prudent to monitor carefully concurrent use. 

An example of sequential blocking is the use of a sulfadiazine with pyrimethamine 9.31) in toxoplasmosis, a protozoal disease (Wettingfeld, Rowe and Eyles, 1956). In this sequence, the sulfonamide blocks the incorporation of / -aminobenzoic acid into dihydrofolic acid, and the pyrimethamine prevents the reduction of this pteridine to tetrahydrofolic acid (Sections 9.3.2 and 9.3.3). In malaria, as early as 1959, Hurly made the observation that pyrimethamine and sulfadiazine potentiated one another to such a degree that the combination could actually cure Pl.falciparum infections. Thus, less than 0.1 m.e.d. (minimal effective dose) of pyrimethamine and 0.25 m.e.d. of sulfadiazine were, together, as effective as 1.0 m.e.d. of either drug separately. In current tropical medicine, Maloprim , a combination of pyrimethamine and dapsone 9.17) (the latter chosen because of its slow rate of excretion which matches that of pyrimethamine), forms an excellent replacement for chloroquine in cases of Pl.falciparum... 

Sheng WD, Jiddawi MS, Hong XQ, Abdulla SM (1997) Treatment of chloroquine-resistant malaria using pyrimethamine in combination with berberine, tetracycline or cotrimoxazole. East Afr Med J 74 283-284... 

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). 

Sulfonamides in combination with dihydrofolate reductase inhibitors are of continuing value. Pyrimethamine [58-14-0] (5) in combination with sulfonamides is employed for toxoplasmosis (7), and a trimethoprim (6)-sulfamethoxa2ole preparation is used not only for urinary tract infections but also for bmceUosis, cholera, and malaria. 

Other Infections. The slowly excreted sulfonamides (eg, sulfamethoxypyrida2ine, sulfadimethoxine) are used for treatment of minor infections such as sinusitis or otitis, or for prolonged maintenance therapy. Soluble sulfonamides are sometimes used for proto2oal infections in combination with other agents. Pyrimethamine, combined with sulfonamides, has been used for toxoplasmosis or leishmaniasis, and trimethoprim with sulfonamides has been used in some types of malaria. In nocardiosis, sulfonamides have been used with cycloserine [68-41-7] (17). 

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. 

In treating resistant forms of malaria, tetracycline is also nsed in combination with pyrimethamine, snlfonamides, snlfones, and dapsone, which is widely used for treating leprosy (as a rnle, in combination with pyrimethamine). 

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. 

Mutabingwa TK, Anthony D, Heller A, Hallett R, Ahmed J, Drakeley C et al. Amodiaquine alone, amodiaquine-i-sulfadoxine-pyrimethamine, amodi-aquine-i-artesunate, and artemether-lumefantrine for outpatient treatment of malaria in Tanzanian children a four-arm randomised effectiveness trial. Lancet 2005 365(9469) 1474-80. 

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