Toxicity and toxicokinetics of metformin in rats.

Metformin is a first-line drug for the treatment of type 2 diabetes (T2D) and is often prescribed in combination with other drugs to control a patient's blood glucose level and achieve their HbA1c goal. New treatment options for T2D will likely include fixed dose combinations with metformin, which may require preclinical combination toxicology studies. To date, there are few published reports evaluating the toxicity of metformin alone to aid in the design of these studies. Therefore, to understand the toxicity of metformin alone, Crl:CD(SD) rats were administered metformin at 0, 200, 600, 900 or 1200 mg/kg/day by oral gavage for 13 weeks. Administration of > or =900 mg/kg/day resulted in moribundity/mortality and clinical signs of toxicity. Other adverse findings included increased incidence of minimal necrosis with minimal to slight inflammation of the parotid salivary gland for males given 1200 mg/kg/day, body weight loss and clinical signs in rats given > or =600 mg/kg/day. Metformin was also associated with evidence of minimal metabolic acidosis (increased serum lactate and beta-hydroxybutyric acid and decreased serum bicarbonate and urine pH) at doses > or =600 mg/kg/day. There were no significant sex differences in mean AUC(0-24) or C(max) nor were there significant differences in mean AUC(0-24) or C(max) following repeated dosing compared to a single dose. The no observable adverse effect level (NOAEL) was 200 mg/kg/day (mean AUC(0-24)=41.1 microg h/mL; mean C(max)=10.3 microg/mL based on gender average week 13 values). These effects should be taken into consideration when assessing potential toxicities of metformin in fixed dose combinations.

Does pharmacotherapy for preterm labor sensitize the developing brain to environmental neurotoxicants? Cellular and synaptic effects of sequential exposure to terbutaline and chlorpyrifos in neonatal rats.

It is increasingly clear that environmental toxicants target specific human subpopulations. In the current study, we examined the effects of prior developmental exposure to a beta(2)-adrenoceptor agonist used to arrest preterm labor, terbutaline, on the subsequent effects of exposure to the organophosphate insecticide, chlorpyrifos (CPF). Neonatal rats were given terbutaline on postnatal day (PN) 2-5, followed by CPF on PN11-14. Although neither treatment affected growth or viability, each elicited alterations in indices of brain cell differentiation and cholinergic innervation in the immediate posttreatment period (PN15), persisting into adulthood (PN60). Biomarkers of brain cell number (DNA concentration and content), cell size (protein/DNA ratio) and neuritic projections (membrane/total protein) were affected by either agent alone, with patterns consistent with neuronal and neuritic damage accompanied by reactive gliosis. The combined exposure augmented these effects by both additive and synergistic mechanisms. Similarly, choline acetyltransferase (ChAT), a constitutive marker for cholinergic nerve terminals, was affected only by combined exposure to both terbutaline and CPF. Indices of cholinergic synaptic activity [hemicholinium-3 and m(2)-muscarinic acetylcholine receptor binding] showed impairment after exposure to either terbutaline or CPF but the effects were more severe when the treatments were combined. These findings suggest that terbutaline, like CPF, is a developmental neurotoxicant, and that its use in the therapy of preterm labor may create a subpopulation that is sensitized to the adverse neural effects of a subsequent exposure to organophosphate insecticides.

Terbutaline is a developmental neurotoxicant: effects on neuroproteins and morphology in cerebellum, hippocampus, and somatosensory cortex.

Beta(2)-adrenoceptor agonists, especially terbutaline, are widely used to arrest preterm labor, but they also cross the placenta to stimulate fetal beta-adrenoceptors that control neural cell differentiation. We evaluated the effects of terbutaline administration in neonatal rats, a stage of neurodevelopment corresponding to human fetal development. Terbutaline administered on postnatal days PN2 to 5 elicited neurochemical changes indicative of neuronal injury and reactive gliosis: immediate increases in glial fibrillary acidic protein and subsequent induction of the 68-kDa neurofilament protein. Quantitative morphological evaluations carried out on PN30 indicated structural abnormalities in the cerebellum, hippocampus, and somatosensory cortex. In the cerebellum, PN2 to 5 terbutaline treatment reduced the number of Purkinje cells and elicited thinning of the granular and molecular layers. The hippocampal CA3 region also displayed thinning, along with marked gliosis, effects that were restricted to females. In the somatosensory cortex, terbutaline evoked a reduction in the proportion of pyramidal cells and an increase in smaller, nonpyramidal cells; again, females were affected more than males. Although abnormalities were obtained with later terbutaline treatment (PN11 to 14), in general the effects were smaller than those seen with PN2 to 5 exposure. Our results indicate that terbutaline is a neurotoxicant that elicits biochemical alterations and structural damage in the immature brain during a critical period. These effects point to a causal relationship between fetal terbutaline exposure and the higher incidence of cognitive and neuropsychiatric disorders reported for the offspring of women receiving terbutaline therapy for preterm labor.

Does terbutaline damage the developing heart?

BACKGROUND: Beta(2)-Adrenoceptor (betaAR) agonists, such as terbutaline, are widely used to arrest preterm labor. They also cross the placenta where they stimulate receptors in fetal tissues, which in turn use betaAR input for trophic control of cell replication and differentiation. METHODS: As rats are altricial, we administered terbutaline in two different postnatal exposure periods (10 mg/kg given daily on Days 2-5 or 11-14). RESULTS: Hearts were examined twenty-four hours after the last dose and on postnatal day 30 for cardiac damage. Neither treatment paradigm caused an increase in cardiac abnormalities compared to controls but quantitative analysis of the number of nuclei indicated reductions in females. CONCLUSIONS: These findings do not support earlier case reports of outright myocardial necrosis after terbutaline tocolysis in human infants. Nevertheless, the significant statistical association between terbutaline and cardiac anomalies in epidemiological studies suggest that terbutaline may sensitize the developing heart to other insults that affect development.