A prodrug form of cycloguanil
Proguanil is a prodrug form of the antimalarial agent cycloguanil .1 Proguanil is metabolized by the cytochrome P450 (CYP) isoforms CYP2C19 and CYP3A to form cycloguanil in human liver microsomes. It is active against chloroquine- and quinine-resistant strains of P. falciparum alone or in combination with atovaquone with EC50 values ranging from 0.22 to 2.67 and 0.37 to 1.6 ?M, respectively.2 It reduces parasitemia in a mouse model of P. berghei infection with a minimum effective dose (MED) of 32 mg/kg.3 Formulations containing proguanil have been used in combination with atovaquone for the prevention and treatment of malaria.
1.Birkett, D.J., Rees, D., Anderson, T., et al.In vitro proguanil activation to cycloguanil by human liver microsomes is mediated by CYP3A isoforms as well as by S-mephenytoin hydroxylaseBr. J. Clin. Pharmacol.37(5)413-420(1994) 2.Thapar, M.M., Gupta, S., Spindler, C., et al.Pharmacodynamic interactions among atovaquone, proguanil and cycloguanil against Plasmodium falciparum in vitroTrans. R. Soc. Trop. Med. Hyg.97(3)331-337(2003) 3.Black, R.H., and Ray, A.P.Experimental studies of the potentiation of proguanil and pyrimethamine by dapsone using Plasmodium berghei in white miceAnn. Trop. Med. Parasitol.71(2)131-139(1977)
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Cell experiment: |
Sertoli cells obtained from sixteen to eighteen day-old-rats are cultured and treated with 0.3 μM to 10 μM of proguanil for 5 days after which Sertoli cell viability and nuclei integrity are determined. Also, the genetic expressions of transferrin and Glial cell line-derived neurotrophic factor are assessed[4]. |
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Animal experiment: |
Rats: Groups of ten to twelve-week-old rats are administered proguanil (2.9 mg/kg body weight) daily for 5 days and 6 weeks respectively. Thereafter, body and reproductive organ weights are taken, sperm parameters are analyzed, while the histology of the testis and epididymis are carried out. Also, serum levels of testosterone, luteinizing hormone and follicle stimulating hormone are determined[4]. |
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参考文献: [1]. Pudney M, et al. Atovaquone and proguanil hydrochloride: a review of nonclinical studies. J Travel Med. 1999 May;6 Suppl 1:S8-12. |
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