Teratogenesis of calcium valproate in rabbits

Abstract

The calcium salt of valproic acid (Valontin) has been proposed for use in the treatment of absence, myoclonic, and tonic clonic seizures of the primarily generalized type. The present study was conducted to determine the teratogenic potential of calcium valproate in rabbits. Groups of 20 Dutch-belted rabbits were given oral doses of 50, 150, or 350 mg/kg on days 6-18 of gestation. A reference group was given 350 mg/kg sodium valproate and control groups were untreated or given vehicle alone. Animals were observed daily and body weights were recorded on gestation days 0, 6, 13, 18, and 30. Litter and fetal parameters were evaluated following uterotomies on day 30. No drug-related clinical signs or deaths occurred. Postimplantation loss and the incidence of malformed vertebrae and ribs, rudimentary or absent pollices, and extra vertebrae and ribs were increased at 350 mg/kg with both calcium and sodium salts of valproic acid. At the 150-mg/kg dose level, calcium valproate markedly increased the incidence of supernumerary ribs. No teratogenic or embryotoxic effects were seen with calcium valproate at 50 mg/kg. These data indicate that the sodium and calcium salts of valproic acid exhibit teratogenic potential in rabbits.

Antiepileptic Drugs and Pregnancy Outcomes

“…Abnormal number or shape of ribs, vertebrae, number of ossification points in the digits or abnormal ossification of craniofacial bones were the most frequently reported. Similar results were obtained in the rabbit, with an increased frequency of axial and appendicular skeletal abnormalities observed following administration of 350 mg/kg/day doses of either calcium or sodium valproate [Petrere et al, 1986]. Beside skeletal defects, high doses of VPA also induced craniofacial, skeletal and cardiac defects as well as intrauterine growth retardation in rhesus monkeys [Hendrickx et al, 1988].…”

Structural Effects and Neurofunctional Sequelae of Developmental Exposure to Psychotherapeutic Drugs: Experimental and Clinical Aspects

“…Neural, renal, cardiac, urogenital, and musculoskeletal abnormalities have been found in rabbits (Petrere et al, 1986), rodents (Kao et al, 1981;Ong et al, 1983), and nonhuman primates (Mast et al, 1986). In humans, in utero exposure to valproic acid has been associated with neural, craniofacial, cardiovascular, and musculoskeletal defects (Table 3) (Jager-Roman et al, 1986;Winter, 1987;Kozma, 2001).…”

Tetramethylcyclopropyl analogue of the leading antiepileptic drug, valproic acid: Evaluation of the teratogenic effects of its amide derivatives in NMRI mice

“…The teratogenic activity of VPA has been established in mice; a single injection with VPA on day 8 of gestation caused a high percentage of exencephaly, which is the murine anterior NTD equivalent of human anencephaly (Kao et al, 1981;Menegola et al, 1996). Because other animal species, such as rats and rabbits, are not susceptible to VPA-induced NTDs (Petrere et al, 1986;Menegola et al, 1996), the mice model system is used for the in vivo evaluation of AED-induced NTD potency. Another commonly observed teratogenic effect caused by VPA is skeletal abnormality, which has been detected in many species, including humans, rhesus monkeys, mice, rats, and rabbits (Kao et al, 1981;Ong et al, 1983;Petrere et al, 1986;Vorhees, 1987;Binkerd et al, 1988;Hendrickx et al, 1988).…”

“…Because other animal species, such as rats and rabbits, are not susceptible to VPA-induced NTDs (Petrere et al, 1986;Menegola et al, 1996), the mice model system is used for the in vivo evaluation of AED-induced NTD potency. Another commonly observed teratogenic effect caused by VPA is skeletal abnormality, which has been detected in many species, including humans, rhesus monkeys, mice, rats, and rabbits (Kao et al, 1981;Ong et al, 1983;Petrere et al, 1986;Vorhees, 1987;Binkerd et al, 1988;Hendrickx et al, 1988). In rodents, the region of the axial skeleton affected by VPA treatment depends on when in the developmental stage the rodent is exposed to VPA (Collins et al, 1991;Menegola et al, 1998).…”