Genotoxic evaluation of the antimalarial drug, fansidar, in cultured human lymphocytes.
Fansidar (pyrimethamine-sulfadoxine) has been used extensively worldwide for the treatment of chloroquine resistant Plasmodium falciparum malaria, toxoplasmosis and Pneumocystis carinii pneumonia in patients with the acquired immunodeficiency syndrome. Because of the wide usage of pyrimethamine-sulfadoxine in developing countries and the lake of information from open literature and reports from manufacturers about the genotoxicity of such antimalarial drug, the present work was suggested. The possible genetic toxicity of fansidar has been evaluated in human peripheral blood lymphocyte cultures. The frequencies of sister-chromatid exchanges (SCE) and micronuclei (MN) were scored as genetic endpoints. Both tests covering a wide range of induced genetic damage as primary DNA damage, clastogenicity and aneugenicity. Cultures were set up by using blood samples from two healthy donors and the treatment was done using different fansidar concentrations ranging from 1:20 to 10:200 microg/ml. From our results, it appears that this drug is able to induce moderate genotoxic effects, as revealed by the increases found in SCE and MN frequencies in cultures from the two donors at the two highest concentrations tested (5:100 and 10:200 microg/ml). In addition, cyotoxic/cytostatic effects of fansidar were revealed by a decrease in the proliferative rate index (PRI) and in the cytokinesis block proliferation index (CBPI). Our findings suggest that the use of this drug should be restricted to situations where other antimalarial drugs cannot be used. The drug should never be given to pregnant women.
Abou-Eisha
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Department of Cell Biology, National Research Center, Dokki, Cairo, Egypt. aaboueisha@hotmail.com
Afifi
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D000818:Animals; D000962:Antimalarials / Q000009:adverse effects* / Q000494:pharmacology*; D002478:Cells, Cultured; D004249:DNA Damage / Q000187:drug effects; D004338:Drug Combinations; D005260:Female; D006801:Humans; D008214:Lymphocytes / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D015162:Micronucleus Tests; D009152:Mutagenicity Tests; D011247:Pregnancy; D011739:Pyrimethamine / Q000009:adverse effects* / Q000494:pharmacology*; D012854:Sister Chromatid Exchange; D013413:Sulfadoxine / Q000009:adverse effects* / Q000494:pharmacology*
D000962:Antimalarials; D004338:Drug Combinations; C001205:fanasil, pyrimethamine drug combination; D013413:Sulfadoxine; D011739:Pyrimethamine