amphotericin-b and Abnormalities--Drug-Induced

Nyotran is a liposomally encapsulated i.v. formulation of the antifungal polyene nystatin. This drug was evaluated in a series of reproductive toxicity studies, according to the guidelines outlined by the International Conference on Harmonization (ICH). A fertility and early embryonic development study (SEG I) and a prenatal and postnatal development (SEG III) study were conducted in rats, and embryo-fetal development (SEG II) studies were conducted in rats and rabbits. Nyotran was administered iv in all studies. In SEG I and SEG III, rats were administered daily doses of 0.5, 1.5, or 3.0 mg/kg Nyotran. In both studies, parental mortality and toxicity in the 3.0 mg/kg dose group necessitated the lowering of the high dose to 2.0 mg/kg/day. Parental toxicity, in the form of decreased body weights, decreased food consumption, and piloerection were also observed at the 1.5 mg/kg/day dose level in the SEG I and SEG III studies. Despite the parentally toxic doses in the SEG I study, there was no effect of Nyotran on F0 male or female fertility or early embryonic development of F1 offspring. In the SEG III study, lactational body weights of the F1 generation were decreased at all Nyotran dose levels. There was no effect on pre-wean developmental landmarks, but post-wean development was affected by Nyotran administration at all dosage levels. Preputional separation was delayed in the 1.5 and 3.0/2.0 mg/kg/day F1 offspring, auditory startle function was decreased in F1 females at all dose levels, and motor activity was decreased in male F1 offspring at all dose levels. However, there were no treatment-related effects on the subsequent mating of the F1 generation and resulting F2 offspring. In SEG II studies, rats and rabbits were also administered 0.5, 1.5, or 3.0 mg/kg/day of Nyotran during gestation. The high dose in these SEG II studies was not lowered, as the maternal animals were able to tolerate the shorter duration of dosing. Maternal effects in rabbits were observed only in the high-dose group and were limited to decreased food consumption and decreased absolute and relative liver weight. Decreased food consumption in high-dose dams and clinical weight loss in some animals at the mid- and high-dose levels evidenced maternal toxicity in rats. Nyotran did not have any effect on Caesarian section parameters in either rats or rabbits and no effect on the incidence of fetal malformations in rabbits. A statistically significant increase in mild hydrocephaly, obs

Topics: Abnormalities, Drug-Induced; Amphotericin B; Animals; Antifungal Agents; Behavior, Animal; Drug Carriers; Eating; Female; Liposomes; Liver; Male; Motor Activity; Nystatin; Organ Size; Pregnancy; Rabbits; Rats; Rats, Sprague-Dawley; Reproduction; Toxicity Tests

The embryotoxic action of amphotericin B and its methyl derivative was compared in rats after their intravenous and intraamniotic administration. The concentrations of amphotericin B and its methyl derivative in the amniotic cavity on days 13, 14 and 15 of pregnancy were 1.5 and 36 micrograms/ml, respectively. When administered intravenously during the preimplantation period the antibiotics had no embryotoxic action. Intravenous administration of amphotericin B in a dose of 500 micrograms/kg and its derivative in a dose of 2000 micrograms/kg during organ genesis induced a decrease in the craniocaudal size. In a dose of 3000 micrograms/kg administered intravenously the methyl derivative of amphotericin B induced an increase in postimplantation death rates. Administration of amphotericin B to the amniotic cavity had no damaging action. Administration of the methyl derivative on day 15 of pregnancy led to anomalous development of the lower extremities and slower ossification. The threshold doses by the embryotoxic action for intravenous administration are 500 micrograms/kg for amphotericin B and 2000 micrograms/kg for the methyl derivative. Administration of the antibiotics to the amniotic cavity revealed potential teratogenic properties of the amphotericin B methyl derivative.

Topics: Abnormalities, Drug-Induced; Amnion; Amphotericin B; Animals; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Fetal Death; Fetal Growth Retardation; Hindlimb; Injections; Injections, Intravenous; Pregnancy; Rats; Teratogens

Topics: Abnormalities, Drug-Induced; Adult; Amphotericin B; Blastomycosis; Female; Fetus; Humans; Infant, Newborn; Pregnancy; Pregnancy Complications, Infectious

Topics: Abnormalities, Drug-Induced; Amphotericin B; Animals; Drug-Related Side Effects and Adverse Reactions; Erythrocyte Count; Hematocrit; Hemoglobinometry; Pathology; Pregnancy; Research; Swine; Thalidomide; Toxicology