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

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 long 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.

Relationship Between Bent Long Bones, Bent Scapulae, and Wavy Ribs: Malformations or Variations?

“…When data were available on more than one species with the same agent, the concordance of responses varied. In the case of artesunate (Clark et al, 2004), both rats and rabbits showed wavy ribs and short/bent long bones. However, in the case of the pesticide S-53482 (Kawamura et al, 1995), rats showed wavy ribs and bent scapulae but rabbits showed no effect.…”

“…Bent scapulae and shortened and bent long bones (in the absence of gross limb defects) were reported in the presence of wavy ribs in studies conducted in both rats and mice, and in one case in rabbits (Clark et al, 2004). When data were available on more than one species with the same agent, the concordance of responses varied.…”

“…Three studies included a comparative examination in rats and rabbits of the effects of agents that caused wavy ribs, bent long bones and scapulae. Hayasaka et al (1984) and Kawamura et al (1995) found effects in rats but not in rabbits, while Clark et al (2004) reported only a few cases of wavy ribs and long bone changes at birth at dose levels with low maternal toxicity, but high embryolethality in both species.…”

“…Studies in which the response level was <10% were included if long bone and/or scapular defects or skeletal defects in general were noted. A search of the literature since 2006 revealed a few additional studies, particularly studies published on the artemisinins by Clark et al (2004Clark et al ( , 2008 and White and Clark (2008). In addition, spontaneous and chemically induced effects in the Han Wistar rat (Mitchard and Stewart, 2014) and changes as a result of a corticotrophin-releasing hormone (CRF-1) antagonist (De Schaepdrijver et al, 2014) were included.…”

Effect of interaction of magnetic nanoparticles of Fe3O4 and artesunate on apoptosis of K562 cells

“…Recently, several studies showed that ART could inhibit the growth of various carcinoma cell lines [1][2][3] and suppress tumor cell proliferation by inducing apoptosis, 4 indicating that ART may be a promising novel candidate for leukemia therapy. However, a variety of lines of evidence indicate that ART inhibited cell proliferation in a dose-dependent manner, and a high concentration of ART induced embryo toxicity, [5][6][7] reversible renal damage toxicity, 8 and toxicity to bone development, 9 which limit the usefulness of ART. To minimize side effects associated with dosage during chemotherapy, a promising approach is to combine a conventional chemotherapy with new strategies to maximize efficacy of tumor treatment through inducing cell apoptosis.…”