Pyrimethamine Trimethoprim

The recommendations for the treatment of EPM using pyrimethamine, trimethoprim and sulfadiazine were originally based on the use of these drugs for the treatment of malaria and toxoplasmosis in humans. Either pyrimethanune or trimethoprim in combination with sulfadiazine or sulfamethoxazole have been used with some success and have gained widespread acceptance as the treatment of choice for EPM. Pyrimethamine and trimethoprim are diaminopyrimidine antimicrobial agents that inhibit dihydrofolate reductase (DHFR see Ch. 2). These agents interfere with... 

Lindsay D S, Dubey J P 1999 Determination of the activity of pyrimethamine, trimethoprim, sulfonamides, and combinations of pyrimethamine and sulfonamides against Sarcocystis neurona in cell cultures. Veterinary Parasitology 82 205-210... 

The reverse situation exists for the antimalarial drug pyrimethamine." Trimethoprim does have some affinity for human folate reducta.se. and this i.s the cause of some of the toxic effects of the drug. 

Enzyme source Pyrimethamine Trimethoprim Cycloguanil Methotrexate... 

Like pyrimethamine, trimethoprim is a potent inhibitor of dihydrofolate reductase. It has... 

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). 

The methylation of deoxyuridine monophosphate (dUMP) to thymidine monophosphate (TMP), catalyzed by thymidylate synthase, is essential for the synthesis of DNA. The one-carbon fragment of methy-lene-tetrahydrofolate is reduced to a methyl group with release of dihydrofolate, which is then reduced back to tetrahydrofolate by dihydrofolate reductase. Thymidylate synthase and dihydrofolate reductase are especially active in tissues with a high rate of cell division. Methotrexate, an analog of 10-methyl-tetrahydrofolate, inhibits dihydrofolate reductase and has been exploited as an anticancer drug. The dihydrofolate reductases of some bacteria and parasites differ from the human enzyme inhibitors of these enzymes can be used as antibacterial drugs, eg, trimethoprim, and anti-malarial drugs, eg, pyrimethamine. 

Folate metabolism Sulphonamides (also ) Trimethoprim Pyrimethamine Trimetrexate / Inhibit folate synthesis Inhibits dihydrofolate reductase Inhibits dihydrofolate reductase Inhibits dihydrofolate reductase Not present in mammalian cells Mammalian enzyme not inhibited Mammalian enzyme not inhibited Toxicity overcome with leucovorin... 

Impairs proximal tubular secretion of creatinine ° Cimetidine, pyrimethamine, and trimethoprim... 

Methotrexate (eukaryotic) Trimethoprim (prokaryotic) Pyrimethamine (protozoal)... 

This sol-gel procedure is an elaboration on well established entrapment methods [29], but with the added advantage of stability and better flow properties. Interestingly, none of the examples presented thus far demonstrate competitive behavior between multiple ligands (i.e. displacement) in the FAC analysis of trimethoprim and pyrimethamine a reversed order of elution based on is described, but this could simply be due to the shift towards an on-rate limited situation for higher affinity compounds, as described earlier. Erosion of dynamic competition between ligands could occur if the sol-gel allows convective mixing of the entrapped protein however the bimodal pore structure of these materials would... 

Rapidly dividing cells need an abundant supply of dTMP for DNA synthesis, and this creates a need for dihydrofolate reductase activity. Specific dihydrofolate reductase inhibitors have become especially useful as antibacterials, e.g. trimethoprim, and antimalarial drugs, e.g. pyrimethamine. 

In combination with pyrimethamine or trimethoprim, sulfanilamides are active with respect to a few protozoal infections, including Toxoplasma, Plasmodium falciparum, and Pneumocystis carinii. 

The diaminopyrimidines trimethoprim and pyrimethamine are synthetic, antibacterial drags and inhibitors of dihydrofolate reductase that are used both independently as well as in combination with sulfanilamides, in particular, with sulfamethoxazole (cotrimoxazole, bactrim, biseptol, sulfatrim, and many others). 

A while later, pyrimethamine (33.1.60) was suggested as a result of intensive research of antimetabolites of folic acid. Trimethoprim (33.1.51) is the result of later research. The structural similarity of these drugs with the pteridine fragment of folic acid undoubtedly determines their affinity with binding regions of dihydrofolate reductase. 

Folate deficiency can be dietary, especially in the eiderly, due to increased demand like in pregnancy, or due to maiabsorption syndromes. Agents which can cause folic acid deficiency with long-term use include phenytoin, oral contraceptives, isoniazid and glucocorticosteroids. In rare instances the use of dihydrofolate reductase inhibitors like trimethoprim, methotrexate or pyrimethamine can contribute to the occurrence of folate deficiency. Folinic acid can circumvent the need for the inhibited dihydrofolate reductase. 

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... 

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

Pyrimethamine (Daraprim) is the best of a number of 2,4-diaminopyrimidines that were synthesized as potential antimalarial and antibacterial compounds. Trimethoprim (Proloprim) is a closely related compound. 

Whereas the sulfonamides and sulfones inhibit the initial step whereby PABA and the pteridine moiety combine to form dihydropteroic acid (see Chapter 44), pyrimethamine and trimethoprim inhibit the conversion of dihydrofolic acid to tetrahydrofoUc acid, a reaction... 

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. 

---