Naslov
Effect of proguanil hydrochloride on DNA damage in human peripheral blood lymphocytes

Autori
Dinter, Domagoj ; Gajski, Goran ; Garaj Vrhovac, Vera

Vrsta, podvrsta i kategorija rada
Sažeci sa skupova, sažetak, znanstveni

Izvornik
Preceedings of 43rd Annual Scientific Meeting of Australasian Society of Clinical and Experimental Pharmacologists and Toxicologists / Hay, D ; Ngo, S. - Sydney : Australasian Society of Clinical and Experimental Pharmacologists and Toxicologists, 2009, 64-64

Skup
43rd Annual Scientific Meeting of Australasian Society of Clinical and Experimental Pharmacologists and Toxicologists (43 ; 2009)

Mjesto i datum
Sydney, Australija, 29.11.2009. - 02.12.2009

Vrsta sudjelovanja
Poster

Vrsta recenzije
Međunarodna recenzija

Ključne riječi
proguanil hydrochloride ; DNA damage ; alakline comet assay ; human blood lymphocytes ; metabolic activation

Sažetak
Proguanil hydrochloride is a chemical substance used for treatment and prevention of malaria caused by Plasmodium falciparum. It usually comes in fixed combination with atovaquone in ratio 1/2.5 per tablet. In this combimation for prophylactic treatment 100 mg of proguanil hydrochlorideis given once daily before entering malaria-endemic area and continued daily during the stay and for seven days after return. In treatment of malaria it is taken 400 mg of proguanil hydrochloride as a single dose daily for three consecutive days. Once taken it is metabolized to cycloguanil (via CYP2C19) and 4- chlorophenylbiguanide but pharmacological effect is primarily done by metabolite cycloguanil.Cycloguanil is dihydrofolate reductase inhibitor and by inhibition of this enzyme cycloguanil disrupts deoxythymidylate synthesis necessary for creation of DNA in malaria parasite. This study aimed to evaluate the effect of proguanil hydrochloride on dNA damage in human blod lymphocytes in vitro.Tetsing was done with and without metabolic activation (S9). Imapct on DNA was assesses with the alkaline comet assayas described by Singh et al (1985). We used two different concnetrations of proguanil hydrochloride obtained from the plasma concentrations ; 130 ng/ml used for prophylactic tretament and 520 ng/ml used in treatment of malaria. Results show that viability of human lymphocytes decreased in time and dose depenedent manner but statistically significant decrease was noticed only for 130 ng/ml treatments with metabolic activazion(S9) whereas 520 ng/ml treatments decreased viability with and without metabolic activation (S9) respectively. Comet assay parameters showed similar effects indicating that some damage to DNA molecule can occure after treatment with higher concentration of proguanil hydrochloride in lower expodure periods whereas after long exposure even concnetrations measured for prophylaxis can induce genetic alterations. It was also noticed that majority of DNA damaging effect is induced after metabolic activation (S9) indicating that principal metabolite cycloguanil has the major impact on DNA molecule. It is to be concluded that activity of proguanil hydrochloride is dependent upon the active metabolite cycloguanil and that patients monitoring shoul be conducted espacially among frequent travellers.

Izvorni jezik
Engleski

Znanstvena područja
Biologija

POVEZANOST RADA