Pyrimethamine antimalarial

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. 

The folate antagonists, pyrimethamine and sulfadiazine, inhibit the parasite s DHFR/TS synthase enzyme complex and the DHPS, respectively (Fig. 4) (see antimalarial drugs). To avoid deficiency of folic acid in patients treated with antifolate antagonists, folinic acid supplementation is recommended to reduce bone-marrow suppression. 

Alkaloids 39 and 40, which are enantiomers of one another and are both used as antimalarial agents, inhibited GST Pl-1 in the single-digit micromolar range (IC50 = 4 and 1 pM, respectively), indicating that the chirality of the secondary alcohol does not play a significant role in this activity. Pyrimethamine (41),... 

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. 

Different antimalarials selectively kill the parasite s different developmental forms. The mechanism of action is known for some of them pyrimethamine and dapsone inhibit dihydrofolate reductase (p. 273), as does chlorguanide (proguanil) via its active metabolite. The sulfonamide sulfadoxine inhibits synthesis of dihydrofolic acid (p. 272). Chlo-roquine and quinine accumulate within the acidic vacuoles of blood schizonts and inhibit polymerization of heme, the latter substance being toxic for the schizonts. 

Antimalarial therapy employs the same agents and is based on the same principles. The blood-schizonticidal halofantrine is reserved for therapy only. The pyrimethamine-sulfadoxine combination may be used for initial selftreatment. 

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. 

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. 

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. 

In addition to its antimalarial effects, pyrimethamine is indicated (in combination with a sulfonamide) for the treatment of toxoplasmosis. The dosage required is 10 to 20 times higher than that employed in malarial infections. 

Other examples of pyrimidine-based pharmaceuticals include busipirone 1130, used to treat anxiety disorders, piribedil 1131 used for Parkinson s disease, epirizole 1132, a nonsteroidal antinflammatory (NSAID), pyrimethamine 1133, an antimalarial, minoxidil 1134, which is used for treating alopecia (male baldness), primidone 1135, which is used as an antiepileptic agent, and pyrantel pamoate 1136, which is used as an antiparasitic. 

Trimethoprim is a pyrimidine derivative (diaminopyrimidine) related to antimalarial drug pyrimethamine, which selectively inhibits bacterial dihydrofolate reductase, necessary for the conversion of dihydrofolate to tetrahydrofolic acid. Sulfonamides act by inhibiting the incorporation of PABA into dihydrofolate by bacteria. A combination of... 

A drug that is a weak base can be defined as a neutral molecule that can form a cation (a positively charged molecule) by combining with a proton. For example, pyrimethamine, an antimalarial drug, undergoes the following association-dissociation process ... 

Toxoplasmosis Lymph nodes many organs and tissues Pyrimethamine-sulfadiazine [see antimalarial drugs] other antibacterials [clindamycin] Trimethoprim-sulfamethoxazole another agent [azithromycin, clarithromycin, atovaquone, or dapsone]... 

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. 

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... 

Of interest is a recently described yeast-based, nutrient-dependent viability screen for inhibitors of protozoal dihydrofolate reductase (DHFR) [43,44], Antiprotozoal activity of DHFR inhibitors is well known, and DHFR- yeast complemented with the DHFR gene derived from the malaria parasite P. falciparum have been used to characterize the molecular pharmacology of resistance to the antimalarial DHFR inhibitors pyrimethamine and cycloguanil [45,46], The subsequent development of a screen was based on the demonstration that the protozoal... 

Therapy. Antimalarial therapy employs the same agents, in addition to the combinations of artemether plus lumefantrine or pyrimethamine plus sulfadoxine. 

PHENYTOIN ANTIMALARIALS -PYRIMETHAMINE 1. i efficacy of phenytoin 2. t antifolate effect 1. Uncertain 2. Additive effect 1. Care with co-administration t dose of antiepileptic if T incidence of fits 2. Monitor FBC closely the effect may take a number of weeks to occur... 

---