Pyrimethamine with dapsone

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). 

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). 

Dapsone and pyrimethamine should be used in patients that cannot tolerate sulfamethoxazole/trimethoprim with a CD4 count less than... 

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). 

Dapsone (alone or in combination with pyrimethamine) can cause methemoglobinemia and hemolytic anemia. These complications tend to be dose-related and are more often encountered in G6PD-deficient subjects (SEDA-18, 287). 

Dapsone is also the drug of choice for dermatitis herpetiformis and is sometimes used with pyrimethamine for treatment of malaria and with trimethoprim for PCP. 

When the CD4 count of this patient fell below 200/pL. prophylaxis against pneumocystis pneumonia was instituted. The currently recommended therapy is double-strength trimethoprim-sulfamethoxazole or dapsone. Alternative prophylactic regimens include aerosolic pentamidine, dapsone plus pyrimethamine, and atovaquone. Primary prophylaxis against toxoplasmosis is normally recommended with CD4 cell counts below 100/pL in AIDS patients who are IgG antibody-positive. Trimethoprim-sulfamethoxazole plus dapsone is also prophylactic against toxoplasmosis. With the continued decline in CD4 cells, exacerbation of candidal infection may occur despite use of clotrimazole troches, necessitating treatment with fluconazole or itraconazole. 

A large number of diphenylsulfone analogues have been developed for the treatment of leprosy. Incidentlly one such member chemically known as 4,4 -diaminodiphenyl sulfone (dapsone) exhibited prophylactic activity against resistant/ falciparum. Dapsone in conjimction with pyrimethamine has been effectively used in the treatment of malaria due to chloroquine resistant P. falciparum. 

Haemoglobinuria after a single dose treatment with dapsone and pyrimethamine for falciparum malaria in a patient with glucose-6-phosphate dehydrogenase deficiency. 

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... 

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... 

Maloprim, the fixed dose combination of pyrimethamine with dapsone, is not recommended for routine prophylaxis because of the potential for fatal agranulocytosis. 

Pyrimethamine may also be combined with other antimalarials such as artemisinin derivatives, but these regimens should only be used if the malarial parasites are not resistant to the specific drugs in the regimen.13 Pyrimethamine can also be combined with a sulfonamide drug such as dapsone, sulfadiazine, or sulfamethoxazole to treat protozoal infections that cause toxoplasmosis, or fungal infections that cause Pneumocystis pneumonia.These agents are administered orally. 

Pyrimethamine is combined with dapsone (Malo-prim) (see p. 271) for prophylaxis of Plasmodium falciparum malaria. 

Since chlorproguanil + dapsone exerts lower resistance pressure on Plasmodium falciparum than does pyrimethamine -I- sulfadoxine, a randomized trial in outpatients with uncomplicated falciparum malaria was conducted in Africa in 910 children (1). Treatment failure was more common... 

When the pyrimethamine + dapsone combination was used in the prophylaxis of Pneumocystis jiroveci pneumonia in 173 patients with AIDS, there was anemia in about 20, and in all 117 cases for which data were available, serum haptoglobin concentrations had fallen (SEDA-18, 287). 

Skin rashes are uncommon with the combination of pyrimethamine + dapsone. A lichen planus type of skin reaction has been described (11). 

Thong BY, Leong KP, Chug HH. Hypersensitivity syndrome associated with dapsone/pyrimethamine (Maloprim) antimalaria chemoprophylaxis. Ann Allergy Asthma Immunol 2002 88(5) 527-9. 

Pyrimethamine is a folic acid antagonist that for many years has been used as an antimalarial drug [193-195], specially for chloroquine-resistant P. falciparum. Due to its synergistic activity, pyrimethamine also has been used, in combination with sulfadiazine or dapsone for the treatment or prophylaxis of cerebral toxoplasmosis or PCP in patients with AIDS [196]. 

Attempts to prevent evolution of resistance have led to investigations of various other combinations of anilines for therapeutic use. Examples include Pyrimethamine (131) with sulfadiazine (119), and trimethoprim (126) with dapsone (32). 

Later as a result of the investigation of Archibold and Ross [33a] and others, it has been shown that dapsone (and its repository forms) could clear the blood from trophozoites of different plasmodium spp. The sensitivity of the different species of parasites varied P. falciparum is very sensitive, while P. vivax is less so. Their action, as with sulphonamides, is mainly against the blood stages with marginal activity against primary (pre-erythrocytic) tissue forms and no activity against sexual and latent tissue forms. It has also been shown that dapsone potentiated the action of pyrimethamine, and a combination of the two markedly delayed the development of... 

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. 

Sulfonamides or sulfones usually account for most toxicity associated with coadministration of these antifolate drugs (see Chapter 43). The combination of pyrimethamine (25 mg) and sulfa-doxine (500 mg) (fansidar) causes severe and even fatal cutaneous reactions in up to 1 in 5000 people. This combination also has been associated with serum sickness-type reactions, urticaria, exfoliative dermatitis, and hepatitis. Pyrimethamine-sulfadoxine is contraindicated in individuals with previous reactions to sulfonamides, lactating mothers, and infants <2 months of age. Administration of pyrimethamine with dapsone (MALOPRIM, unavailable in the U.S.), occasionally has been associated with agranulocytosis. Higher doses pyrimethamine (75 mg daily) used along... 

Sulfonamides having a free j )-amino group are readily assayed by titration with nitrous acid. The sulfonamide function may also be titrated with base, such as lithium methoxide. The majority of the sulfas listed in the U.S. Pharmacopeia XXII, however, are assayed by chromatographic methods, particularly high performance liquid chromatography (49). Sulfonamides for which assays are listed in the U.S. Pharmacopeia XXII-National Formulary XVII include the following sulfacetamide, sulfabenzamide, sulfadiazine, sulfadoxine, sulfamerazine, sulfamethazine, sulfamethizole, sulfamethoxazole, sulfapyridine, sulfasalazine, sulfathiazole, sulfinpyrazone, sulfis ox azole, sulfisoxazole acetyl, sulfisoxazole diolamine, sulfoxone, triple sulfa, dapsone, and various combinations with prednisolone, pyrimethamine, and trimethoprim. 

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