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Developmental toxicity of artesunate and an artesunate combination in the rat and rabbit

Clark, R. L., White, T. E. K., Clode, S. A., Gaunt, I., Winstanley, P. and Ward, Stephen ORCID: https://orcid.org/0000-0003-2331-3192 (2004) 'Developmental toxicity of artesunate and an artesunate combination in the rat and rabbit'. Birth Defects Research Part B-Developmental and Reproductive Toxicology, Vol 71, Issue 6, pp. 380-394.

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Abstract

The artemisinins are playing an increasingly important role in treating multidrug-resistant malaria. The artemisinin, artesunate, is currently in use in Southeast Asia and is advocated for use in Africa. In these areas, more than one million people die of malaria each year, with the highest mortality occurring in children and pregnant women. To test the developmental toxicity in ICH-compliant animal studies, embryofetal development studies were conducted in rats and rabbits treated with artesunate alone or a three-drug combination (CDA) consisting of chlorproguanil hydrochloride, Dapsone, and artesunate in the ratio 1.00:1.25:2.00. Developmental toxicity seen with CDA could be attributed to the administered dose of artesunate. The hallmark effect of artesunate exposure was a dramatic induction of embryo loss, apparent as abortions in rabbits and resorptions in both rats and rabbits. In addition, low incidences of cardiovascular malformations and a syndrome of skeletal defects were induced at or close to embryolethal doses of artesunate in both rats and rabbits. The cardiovascular malformations consisted of ventricular septal and vessel defects. The skeletal syndrome consisted of shortened and/or bent lonc, bones and scapulae, misshapen ribs, cleft sternebrae, and incompletely ossified pelvic bones. These developmental effects were observed largely in the absence of any apparent maternal toxicity. The no or low adverse effect levels were in the range of 5 to 7 mg/kg/day artesunate. Encouragingly, no adverse drug-related developmental effects have been observed in a limited number of pregnant women (more than 100 first trimester and 600 second and third trimester) treated with artemisinins, primarily artesunate. Investigations of the mechanism of developmental toxicity are ongoing to attempt to determine whether rats and rabbits are more sensitive to artemisinins than humans. (C) 2004 Wiley-Liss, Inc.

Item Type: Article
Uncontrolled Keywords: artesunate artemisinin malaria embryotoxicity teratogenicity malformations long bone heart artemisinin derivatives falciparum-malaria in-vitro pregnancy teratogenicity drug cyclophosphamide mechanism skeletogenesis neurotoxicity
Subjects: QV Pharmacology > QV 38 Drug action.
QV Pharmacology > Drug Standardization. Pharmacognosy. Medicinal Plants > QV 771 Standardization and evaluation of drugs
QW Microbiology and Immunology > QW 45 Microbial drug resistance. General or not elsewhere classified.
QW Microbiology and Immunology > Immune Responses > QW 700 Infection. Mechanisms of infection and resistance.
WC Communicable Diseases > Tropical and Parasitic Diseases > WC 750 Malaria
Faculty: Department: Groups (2002 - 2012) > Molecular & Biochemical Parasitology Group
Digital Object Identifer (DOI): https://doi.org/10.1002/bdrb.20027
Depositing User: Sarah Lewis-Newton
Date Deposited: 31 Jan 2012 14:33
Last Modified: 06 Feb 2018 13:03
URI: http://archive.lstmed.ac.uk/id/eprint/2127

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