Developmental and reproductive toxicity studies on artemisone.

Abstract

BACKGROUND:

In order to justify clinical studies in women of child-bearing age with artemisone, a new artimisinin derivative, studies to assess fertility and early embryonic development in rats, developmental toxicity in rats and rabbits, and peri-post natal development in rats were performed.

METHODS AND RESULTS:

In the study on fertility and early embryonic development (dose levels 0-5-20-80 mg/kg bw/day), doses inducing clinical and organ toxicity were used. Only in severe toxicity conditions, a reduction of the number of estruses, a prolonged time to insemination, decreased numbers of corpora lutea, implantation sites, and viable fetuses were found. Two developmental toxicity studies were performed in rats (dose levels 0-1-2 mg/kg bw/day) and rabbits (dose levels 0-2.5-5.0-7.5 mg/kg bw/day). It was shown that rats were about 5 times more sensitive than rabbits. In rats, artemisone induced total litter loss (late resorptions) at 2 mg/kg body weight and above with an increased incidence of a common vascular variation and retarded ossification at this dose. In rabbits, maternal toxicity, abortion and a slightly increased incidence of cardiac ventricular septal defects was observed at 7.5 mg/kg body weight. In a pre- and postnatal developmental toxicity study in rats (dose levels 0-1-2-4 mg/kg bw/day), 4 mg/kg body weight artemisone induced clinical symptoms and affected postnatal survival, body weight gain in the F1 pups, and motor activity.

CONCLUSIONS:

In summary, artemisone was shown to be embryo- and fetotoxic and induced cardiac ventricular septal defects and retarded ossification in dosages where total litter loss and abortions were observed. However, no effect on reproductive and developmental parameters below severe toxic dosages could be observed.

• Authors: G Schmuck, A-M Klaus, F Krötlinger, F W Langewische
• Journal: Birth defects research. Part B, Developmental and reproductive toxicology (Birth Defects Res B Dev Reprod Toxicol) Vol. 86 Issue 2 Pg. 131-43 (Apr 2009) ISSN: 1542-9741 [Electronic] United States
• PMID: 19306395 (Publication Type: Comparative Study, Journal Article)
• Copyright: (c) 2009 Wiley-Liss, Inc.

Chemical References

• Antimalarials
• Artemisinins
• artemisone

Topics

• Abnormalities, Drug-Induced (etiology)
• Animals
• Antimalarials (administration & dosage, toxicity)
• Artemisinins (administration & dosage, toxicity)
• Body Weight (drug effects)
• Dose-Response Relationship, Drug
• Drug Evaluation, Preclinical
• Embryonic Development (drug effects)
• Female
• Fertility (drug effects)
• Fetal Resorption (chemically induced)
• Growth and Development (drug effects)
• Heart Septal Defects, Ventricular (chemically induced)
• Hematopoiesis, Extramedullary (drug effects)
• Infertility, Female (chemically induced)
• Organ Size (drug effects)
• Pregnancy
• Prenatal Exposure Delayed Effects
• Rabbits
• Rats
• Rats, Wistar
• Species Specificity
• Spleen (drug effects, embryology)
• Splenomegaly (chemically induced)