Abstract. The goal of the present study was to examine the utility of the conscious dog model by assessing the QT-interval-prolonging potential of ten positive compounds that have been reported to induce QT interval prolongation in clinical use and seven negative compounds considered not to have such an effect. Three doses of test compounds or vehicle were administered orally to male beagle dogs (n = 4), and telemetry signals were recorded for 24 h after administration. All positive compounds (astemizole, bepridil, cisapride, E-4031, haloperidol, MK-499, pimozide, quinidine, terfenadine, and thioridazine) caused a significant increase in the corrected QT (QTc) interval, with a greater than 10% increase achieved at high doses. In contrast, administration of negative compounds (amoxicillin, captopril, ciprofloxacin, diphenhydramine, nifedipine, propranolol, and verapamil) did not produce any significant change in the QTc interval, with the exception of nifedipine that may have produced an overcorrection of the QTc interval due to increased heart rate. The estimated plasma concentrations of the positive compounds that caused a 10% increase in the QTc interval were in good agreement with the plasma / serum concentrations achieved in humans who developed prolonged QT interval or torsade de pointes (TdP). Although careful consideration should be given to the interpretation of QT data with marked heart rate change, these data suggest that an in vivo QT assay using the conscious dog is a useful model for the assessment of QT interval prolongation by human pharmaceuticals. Supplementary material (Appendix): available only at http://dx

To clarify the relationship between intracellular concentrations of methylmalonic acid and metabolic and growth inhibition in vitamin B,,deficient rats, hepatic methylmalonic acid levels were assayed and inhibition of glucose and glutamic acid metabolism by methylmalonic acid was studied in isolated hepatocytes. Vitamin B,,deficient rats (14 weeks old) excreted more urinary methylmalonic acid and had lower body weights than the control rats. Hepatic methylmalonic acid levels (3-6 (SD 1.30)-5.3 (SD 0.51) pmol/g tissue; 7.9 (SD 290)-11-8 (SD 1-14) mM) were increased and correlated with the extent of the growth retardation during vitamin B,,deficiency. Isolated hepatocytes and mitochondria from normally fed rats were labelled with ["Cc(Ullglucose and [14C(LJ)]glutamic acid respectively, in the presence or absence of Sm-methylmalonic acid. Although methylmalonic acid did not atTect the incorporation of "C into protein and organic acid fractions in the hepatocytes, it inhibited 14C02 formation (an index of glucose oxidation by the Krebs cycle) by 25 % and incorporation of I4C into the amino acid fraction by 30%. In the mitochondria, methylmalonic acid inhibited "CO, formation (indicating glutamic acid oxidation by the Krebs cycle) by 70%, but not the incorporation of I4C into the protein fraction. The incorporation of I4C into the organic acid fraction was significantly stimulated by the addition of methylmalonic acid. These results indicate that the unusual accumulation of methylmalonic acid caused by vitamin B,,deficiency disrupts normal glucose and glutamic acid metabolism in rat liver, probably by inhibiting the Krebs cycle.

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-Although the toxic effects of citrate including hemodynamic and cardiovascular changes result from a decrease in ionized calcium levels in serum due to chelating action, these effects of citrate on blood coagulation have not yet been fully clarified. The present study examines whether serum citrate and ionized calcium levels affect whole blood clotting time in rats using the test tube method in which citrate is administered by rapid intravenous infusion. Citrate was infused via the tail vein into 10 rats at 3, 4 or 5 mmol/kg/hr for 1 hr, and then whole blood clotting time, serum citrate and ionized calcium levels were determined. Whole blood clotting time did not significantly change at citrate infusion rates of 3 and 4 mmol/kg/hr. However, at 5 mmol/kg/hr, whole blood clotting time was significantly prolonged by a factor of 2.1 relative to the untreated group, when the serum citrate level was 10.03 ± 1.39 mmol/l (59.0-fold higher than that in the untreated group) and the serum-ionized calcium level was 0.29 ± 0.02 mmol/ l (0.2-fold lower than that in the untreated group). These results suggest that whole blood clotting time is significantly prolonged in rats with severe ionized hypocalcemia.

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