Antifolates antimalarial

Roper, C., R. Pearce, B. Bredenkamp, J. Gumede, C. Drakeley, F. Mosha, D. Chandramohan, and B. Sharp. 2003. Antifolate Antimalarial Resistance in Southeast Africa A Population-Based Analysis. Lancet 361 1174—1181. 

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. 

VI.a.2.3. Quinine alkaloids. The quinine alkaloids include quinine and quinidine. Quinidine, the dextrorotatory diastereoisomer of quinine, is mainly used for the parenteral treatment of cardiac arrhythmias but it can be an alternative antimalarial in regions where Plasmodium falciparum is resistant to both chloroquine and antifolate-sulfonamide combinations. 

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... 

METHOTREXATE ANTIMALARIALS -PYRIMETHAMINE t antifolate effect of methotrexate Pyrimethamine should not be used alone and is combined with sulfadoxine. Pyrimethamine and methotrexate synergistically induce folate deficiency Although the toxic effects of methotrexate are more frequent with high doses of methotrexate, it is necessary to do an FBC, liver and renal function tests before starting treatment even with low doses, repeating these tests weekly until therapy is stabilized and thereafter every 2-3 months. Patients should be advised to report symptoms such as sore throat and fever immediately, and also any gastrointestinal discomfort. A profound drop in white cell count or platelet count warrants immediate stoppage of methotrexate therapy and initiation of supportive therapy... 

ANTIBIOTICS- SULPHONAMIDES, TRIMETHOPRIM ANTIMALARIALS -PYRIMETHAMINE T antifolate effect Additive effect Monitor FBC closely the effect may take a number of weeks to occur... 

The folic acid biosynthesis has been extensively explored to design effective antimalarials. A number of classes of compounds have been developed, which interfere with different steps of the folate synthesis in plasmodia [14]. These antimalarials, which are collectively known as antifolates, may be broadly divided in three groups. 

The chemotherapy and prophylaxis of malaria have been undermined by the development of worldwide resistance of P. falciparum to the 4-aminoquinoline chloroquine, first observed in the 1960s, as well as resistance to the antifolates pyrimethamine and cycloguanil. Resistance to quinine and other more recently developed drugs, for example mefloquine, have also been reported [4, 5]. The search for alternative antimalarials is one of the main themes of this chapter. 

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. 

Describe the pharmacodynamic and pharmacokinetic properties of the major antimalarial drugs (chloroquine, mefloquine, quinine, primaquine, and the antifolate agents). 

Five 2, 4-diaminopyrimidines (antifolics with antimalarial effects) received from Dr. G. H. Hitchings, Burroughs Wellcome Co., (U.S.A.) Inc., Tuckahoe, N. Y., were tested in place of methotrexate in the system shown in Figure 4, each compound in the concentrations shown at the top of Table 5. It was first tested alone (C), then in combination with 5 mM uridine (C + U), and finally in combination also with 0.5 mM thymidine (C + U + T). 

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