Developmental toxicity of temafloxacin hydrochloride in the long‐tailed macaque (Macaca fascicularis)

Abstract

The potential developmental toxicity of temafloxacin hydrochloride was studied in the long-tailed macaque (Macaca fascicularis). Ten animals in each of the three drug-treated groups (25, 50, and 100 mg/kg) were administered temafloxacin via nasogastric intubation during gestational days (GD) 20-50. A control group of ten animals received vehicle only. The dams were monitored daily for adverse physical signs and maternal blood samples were collected for analyses of serum progesterone (P), 17 beta-estradiol (E2), and chorionic gonadotropin (CG). In addition, the conceptus was monitored periodically by ultrasound during gestation to confirm growth and viability. Increased maternal toxicity (weight loss, anorexia, emesis) and embryolethality were observed at 100 mg/kg, and a no-observable-adverse-effect-level (NOAEL) of 50 mg/kg was established. The incidence of prenatal mortality was as follows: Control = 1/10 (10%); 25 mg/kg = 1/10 (10%); 50 mg/kg = 2/10 (20%); and 100 mg/kg = 5/10 (50%). Analysis of P, E2, and CG indicated no significant effect of treatment. In addition, no significant differences were observed in embryonic/fetal growth and development when compared to historical controls. No gross structural changes were observed in fetuses exposed to 50 or 100 mg/kg, although one fetus exposed to 25 mg/kg exhibited microphthalmia. This anomaly was considered spontaneous and, therefore, unrelated to treatment.

Developmental expression of Ki‐67 antigen and proliferating cell nuclear antigen in macaque placentas

“…By contrast, the rate of diametrical growth over the last third of gestation is greatly reduced (at 152 days the primary placenta increases to approximately 88 x 78 mm, secondary approximately 64 x 64 mm). Other studies are in agreement that macaque placentas continue to increase in weight throughout gestation (van Wagenen et al, 1965;Kerr et al, 1969)) increasing to approximately 55 g a t 100 days and 96 g at 152 days (Prahalada et al, 1985;Tarantal et al, 1990). Given this general information on growth parameters of macaque placentas, how do our present results regarding cytotrophoblast cell proliferation relate to placental morphogenesis?…”

“…Precise information on the rate of growth for the bi-discoidal macaque placenta is limited. Data from our own measurements and those of the California Regional Primate Research Center (unpublished), and published studies (Tarantal and Hendrickx, 1988;Tarantal et al, 1990) indicate that the rate of growth, in diameter, of macaque placentas is very rapid until approximately 100 days of gestation (primary placenta approximately 83 x 73 mm, secondary placenta approximately 61 x 49 mm). By contrast, the rate of diametrical growth over the last third of gestation is greatly reduced (at 152 days the primary placenta increases to approximately 88 x 78 mm, secondary approximately 64 x 64 mm).…”

Frequency of spontaneous congenital defects in rhesus and cynomolgus macaques

“…Another objective of updating our malformation data is to aid in the evaluation of spurious malformations in teratology (safety assessment) studies at the CRPRC. Occasionally, single defects have been observed in teratology studies carried out at the CRPRC [19,6,7,18,27,29,28]. Owing to the isolated nature of the malformation, and the lack of dose relationship or a biologically plausible mechanism for teratogenicity, these cases have all been attributed to a spontaneous or unknown cause rather than related to drug treatment.…”

Holoprosencephaly in a long‐tailed macaque (Macaca fascicularis): A case report

“…Although this period of embryonic development has generally been considered refractory to teratogenic agents, recent reports suggest that early insults can result in gross malformations. Prior studies have shown that exposure during gastrulation can result in craniofacial malformations such as those exhibited by the fetus described in this report [9,23]. Experimental studies indicate that interference with cell proliferation during gastrulation can be damaging to the mesoderm and the anterior neural plate.…”