Renal and hepatic nucleic acid metabolism in neonates: relation to experimental duration, chlorphentermine dose as well as subsequent withdrawal.

Daily oral administration of either 20, 40 or 60 mg/kg chlorphentermine for 7 days significantly increased liver and kidney DNA levels, which were not elevated further even after a 3 week treatment period. Although cessation of drug administration for 3 weeks resulted in a return of hepatic DNA levels to control values, a rise in renal DNA was still observed after this withdrawal period. Whereas 20 mg/kg chlorphentermine for 7 days failed to markedly alter the incorporation of thymidine into kidney and liver DNA, significant enhancement was noted in neonates receiving 40 or 60 mg/kg drug and quantitatively greater incorporation occurred when the agent was given for 21 days. While a signficant augmentation in nucleic acids synthesis was seen 1 week after animals were removed from 40 or 60 mg/kg anorectic, a restoration to control levels occurred after a 3 week abstinence period. Treatment with 20 mg/kg for 1 week followed by withdrawal resulted in a significant rise in the incorporation of thymidine into renal and hepatic DNA. In contrast, drug administration for 3 weeks followed by 21 days abstinence resulted in a return to control levels in the incorporation of thymidine into kidney and liver DNA, except for renal tissue removed from 20 mg/kg. Our data demonstrate that the chlorphentermine-induced alterations in renal and hepatic DNA metabolism are dose-dependent, related to duration of exposure as well as reversible.

Behavioural and neurochemical consequences of neonatal exposure to lead in rats.

Locomotor activity, lead content and concentrations of norepinephrine (NE), dopamine (DA), 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) in discrete brain regions were examined in rats given a fixed oral dose (50 microgram/pup) of inorganic lead from birth till weaning and then kept on water containing 80 ppm lead until either 8 or 12 weeks of age. Lead-exposed animals showed an increase (by 74 and 93 percent, respectively) in locomotor activity at 6 and 8 weeks of age. By 12 weeks, the motor activity returned to control values both in animals which were withdrawn from lead treatment at 8 weeks of age and in those continued on lead. Lead levels in brain at 8 weeks of age were highest in hypothalamus and striatum. Significant decreases in cortical NE, DA and 5-HT, mildbrain DA, striatal NE and hypothalamic DA and 5-HT were found in brains of 8 week-old hyperactive rats; in contrast, NE levels in the midbrain were elevated. Whereas the decreases in 5-HT remained unchanged, alterations in regional concentration of catecholamines were no longer evident in lead-exposed animals whose motor activity returned to normal by 12 weeks of age or in rats withdrawn from lead at age of 8 weeks. Alterations in regional levels of NE and DA appear to be associated with lead-induced increase in locomotor activity, while changes in 5-HT metabolism may result from a non-specific toxic effect of the metal.

Metformin-induced lactic acidosis: potentiation by ethanol.

Although lactic acidosis has been recognized as a potential hazard in biguanide therapy, this complication has been claimed to be extremely rare with dimethylbiguanide (DMBG) (metformin). In the present studies, using the fasted guinea pig, DMBG (125-500 mg/kg i.p.) caused marked dose-related changes in both plasma glucose (43-88% reduction) and blood lactate (3.5-13 fold increase). Lactate/pyruvate ratios were substantially increased. While i.p. doses of 100 mg/kg of DMBG or of 1 g/kg of ethanol produced no changes in plasma glucose, lactate or pyruvate, the two drugs administered conjointly at the indicated doses produced a 53% decrease in plasma glucose and 2 and 10-fold increases in pyruvate and lactate levels respectively, and correspondingly, an increase in the lactate/pyruvate ratio. Ethanol decay curves indicated that DMBG did not significantly influence the disappearance of ethanol from the blood. These results indicate that: (1) doses of DMBG which produce hypoglycemia are associated with lactic acidosis, and (2) this effect of DMBG can be markedly potentiated by ethanol.

Brain distribution and kinetics of desipramine in the rat.

Pharmacokinetics and regional as well as subcellular brain distribution of desipramine (DMI) were investigated in male rats after single and repeated intraperitoneal administration. After a single dose DMI enters brain rapidly, accumulates with increasing the dose, and attains concentrations about 20 times those seen in plasma. After repeated administration peak plasma and brain levels were 2.7 and 3.7 times, respectively, higher than after a single dose. No significant regional differences were found in brain distribution or disappearance half-lives of the drug. After chronic treatment the drug was preferentially retained in the P2 fraction of brain homogenate; this may reflect the critical portion of drug bound to sites responsible for its pharmacological action.