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Risk Assessment and Therapeutic Indices of Artesunate and Artelinate in Plasmodium berghei–Infected and Uninfected Rats

Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Silver Spring, Maryland, USA

Todd O. Johnson

Pathology Department, Naval Medical Research Center, Silver Spring, Maryland, USA

Peter J. Weina
Yuanzheng Si
Adam Haeberle
Ravi Upadhyay
Elaine Wong
Qigui Li

Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Silver Spring, Maryland, USA

Correspondence: Address correspondence to Qigui Li, MD, PhD, Division of Experimental Therapeutics, Walter Reed Army Institute of Research, 503 Robert Grant Avenue, Silver Spring, MD 20307-5100, USA. E-mail:qigui.li{at}na.amedd.army.mil

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.

Key Words: Antimalarial • Artelinate • Artesunate • Rats • Risk Assessment • Therapeutic Index

International Journal of Toxicology, Vol. 24, No. 4, 251-264 (2005)
DOI: 10.1080/10915810591007229


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