Risk assessment and therapeutic indices of artesunate and artelinate in Plasmodium berghei-infected and uninfected rats.
Artesunate (AS) is being developed as a potential agent for the treatment of severe and complicated malaria. A risk assessment of the therapeutic index and related hematological changes of AS and artelinate (AL) following daily intravenous injection for 3 days was conducted in Plasmodium berghei-infected and uninfected rats. The minimum doses of AS and AL for parasitemia suppression were 2.3 and 2.5 mg/kg, respectively, and the suppressive doses for half parasitemia (SD50) were 7.4 and 8.6 mg/kg, respectively. The maximum tolerated dose (MTD) for AS was 240 mg/kg with a therapeutic index of 32.6. The MTD for AL was 80 mg/kg with a therapeutic index of 9.3. Hematological changes were studied on days 1 and 8 after the final dosing. In both AS- and AL-treated rats, dose-dependent and rapidly reversible hematological changes (significant reductions in RBC, HCT, Hb, and reticulocyte levels) were seen in the peripheral blood. Bone marrow evaluation revealed a statistically significant reduction in the myeloid/erythroid ratio only at the highest dose of AS (240 mg/kg), albeit still within the normal ratio range (1.0-1.5:1.0). Looking at the respective therapeutic indices the authors have concluded that AS is much safer than AL. Both drugs induced hematological changes in rats that parallel the dose-dependent, reversible anemia and reticulocytopenia previously reported in animals and humans. However, no significant bone marrow depression was seen for either agent.
Xie
Lisa H
LH
Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Silver Spring, Maryland 20307-5100, USA.
Johnson
Todd O
TO
Weina
Peter J
PJ
Si
Yuanzheng
Y
Haeberle
Adam
A
Upadhyay
Ravi
R
Wong
Elaine
E
Li
Qigui
Q
D000740:Anemia / Q000139:chemically induced; D000818:Animals; D000962:Antimalarials / Q000008:administration & dosage / Q000633:toxicity*; D037621:Artemisinins / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D000077332:Artesunate; D001835:Body Weight / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004906:Erythrocyte Count; D005260:Female; D006400:Hematocrit; D008288:Malaria / Q000097:blood / Q000188:drug therapy* / Q000469:parasitology; D008297:Male; D020714:Maximum Tolerated Dose; D018512:Parasitemia / Q000188:drug therapy; D010962:Plasmodium berghei; D051381:Rats; D017207:Rats, Sprague-Dawley; D017701:Reticulocyte Count; D018570:Risk Assessment; D012717:Sesquiterpenes / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D012737:Sex Factors; D013810:Therapeutic Equivalency; D013997:Time Factors
D000962:Antimalarials; D037621:Artemisinins; D012717:Sesquiterpenes; C062768:artelinic acid; D000077332:Artesunate