Cycloguanil HCl, the active metabolite of proguanil, is a dihydrofolate-reductase (DHFR) inhibitor and acts on malaria schizonts in erythrocytes and hepatocytes. A partial cross-resistance between pyrimethamine and cycloguanil that is based on similar amino acid substitutions in dihydrofolate reductase and suggest that two or three mutations, including at least Asn-108, may be necessary for cycloguanil resistance, whereas a single Asn-108 mutation is sufficient for pyrimethamine resistance[1]. The combination of atovaquone and cycloguanil yielded corresponding mean sigmaFICs of 3.70 and 2.11, indicating antagonism. The EC50 and EC90 values for proguanil alone were not influenced by RPMI-1640 medium with low concentrations of paraaminobenzoic acid and folic acid (LPLF culture medium), whereas the EC50 and EC90 values for cycloguanil were more than 10 times lower in LPLF medium than in normal RPMI-1640 medium[2]. Cycloguanil (2.5 micrograms/ml) combined with a noninhibitory concentration of sulfadiazine (25 micrograms/ml) inhibited T. gondii more than cycloguanil alone[3].
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