Impact of Antenatal Exposure of Mice to Fenfluramine on Cardiac Development and Long-Term Growth of the Offspring

Abstract

The objective of this investigation was to determine, in a placebo-controlled manner, whether antenatal exposure to formulations of fenfluramine and dexfenfluramine impacted cardiac development and long-term growth of exposed mice offspring. One hundred forty-four CD-1 mice were randomized to six treatment groups (n=23 or 25) to obtain, per group, 5 gravids for killing on gestational day (GD) 15 and < or =10 deliveries for assessing growth of the offspring. Either fenfluramine preparation was administered in feed bars in two doses: 1 and 3.2 times the equivalent human daily dosage according to body surface area. The drugs were given from 2 weeks before mating until GD 15. The mice ingested each drug at target values, averaging 10.5+/-0.3 and 31.8+/-1.9 mg/kg/d for fenfluramine and 5.0+/-0.2 and 16.2+/-0.4 mg/kg/d for dexfenfluramine. The drug concentration was about 36% in the fetal brain compared with the adult brain. The maternal and the offspring hearts, including mitral and aortic valves, of fenfluramine-exposed mice were indistinguishable from the placebo-exposed mice. The duration of gestation and the litter size were the same between the treatment groups. The mean body weights, body lengths, and head circumferences and early functional testing did not differ significantly between the fenfluramine or dexfenfluramine-exposed offspring and the placebo-exposed offspring. There were no significant treatment differences in growth measured as body weights to PND 120. Neither fenfluramine formulation, given before conception and during gestation, impacted cardiac development and long-term growth of the mice offspring.

An in vivo murine model of rosiglitazone use in pregnancy

“…A murine model was selected for a short gestation time of 19 -20 days, for litter sizes, and for ease of care. The ICR/CD1 mouse was chosen because of the ease of timed pregnancy (24) and large litter size of 10 -15 pups (personal communication, Charles River Laboratories). The animals were maintained in a pathogen-free environment.…”

“…Therefore, oral gavage was chosen to most closely approximate clinical use of the drug (absorption from the gastrointestinal tract) and to confirm timely treatment and equivalent doses between animals, as described elsewhere (25,28). Dosing was based on a 25-g nonpregnant female, with no change in dose made throughout the study (24).…”

Selective serotonin reuptake inhibitor exposure alters osteoblast gene expression and craniofacial development in mice

“…SSRIs, which cause targeted inhibition of reuptake of serotonin from the postsynaptic to the presynaptic serotonergic neuron vesicles, have also been shown to impact overall craniofacial development (Moiseiwitsch, ; Alwan et al, ; Malm et al, ; El Marroun et al, ). Preclinical studies report a reduction in cranial size in offspring after administration of SSRI to pregnant mice (Rayburn et al, ; Olivier et al, ). There are similar reports in humans (Davidson et al, ; Dubnov‐Raz et al, ; El Marroun et al, ).…”

Cardiac Valvular Pathology: Comparative Pathology and Animal Models of Acquired Cardiac Valvular Diseases

“…Pregnant mice were given either compound in a feed formulation producing dose levels similar to or higher (approximately threefold) than the human clinical dose associated with valvulopathy. Gross and histologic examination of the hearts from the mothers and the pups at postnatal day 120 showed no evidence of changes in the valves of any group (Rayburn et al 2000). Key differences in the preceding studies may account for differential results and include differences in biology of rats and mice, route of administration, dose level, selected day for postnatal examination, and the administration of the fenfluramine-phentermine combination compared to fenfluramine or dexfenfluramine alone.…”

“…Follow-up studies have not been reported. Rayburn et al (2000) studied the effects of antenatal exposure of fenfluramine and dexfenfluramine on the cardiac development of CD-1 mice. Pregnant mice were given either compound in a feed formulation producing dose levels similar to or higher (approximately threefold) than the human clinical dose associated with valvulopathy.…”