Translational neuropharmacology and the appropriate and effective use of animal models.

This issue of the British Journal of Pharmacology is dedicated to reviews of the major animal models used in neuropharmacology to examine drugs for both neurological and psychiatric conditions. Almost all major conditions are reviewed. In general, regulatory authorities require evidence for the efficacy of novel compounds in appropriate animal models. However, the failure of many compounds in clinical trials following clear demonstration of efficacy in animal models has called into question both the value of the models and the discovery process in general. These matters are expertly reviewed in this issue and proposals for better models outlined. In this editorial, we further suggest that more attention be made to incorporate pharmacokinetic knowledge into the studies (quantitative pharmacology). We also suggest that more attention be made to ensure that full methodological details are published and recommend that journals should be more amenable to publishing negative data. Finally, we propose that new approaches must be used in drug discovery so that preclinical studies become more reflective of the clinical situation, and studies using animal models mimic the anticipated design of studies to be performed in humans, as closely as possible.

Determination of potato glycoalkaloids and their aglycone in blood serum by high-performance liquid chromatography. Application to pharmacokinetic studies in humans.

The development of a high-performance liquid chromatography (HPLC) method for the separation and quantification of potato glycoalkaloids and their aglycone solanidine in blood serum is reported. High selectivity was obtained by using solid-phase extraction followed by off-line dual-column HPLC. Injections were made via a sample enrichment column to achieve maximum sensitivity in the assay. The potato alkaloids in the HPLC effluents were detected by ultraviolet absorption at 200 nm. The detection limits were estimated to be 0.3 ng/ml of serum for each of the alkaloids. The method was used to study the pharmacokinetics of potato glycoalkaloids in humans. alpha-Solanine and alpha-chaconine were detected in all blood serum samples collected from seven volunteers 1-25 h after a meal of potatoes. Solanidine was detected in some samples, but there were no traces of the mono- or diglycosides. The average apparent biological half-lives for alpha-solanine and alpha-chaconine were 11 and 19 h, respectively.

Effects of dietary sodium selenite supplementation on salicylate-induced embryo- and fetotoxicity in the rat.

The effects of dietary supplementation with sodium selenite (3.0 or 4.5 ppm Se) for 8 weeks prior to and throughout gestation on sodium salicylate induced embryo- and fetotoxicity (resorptions, fetal deaths, malformations, fetal weight reduction) have been studied in the rat. Salicylate was administered either as daily intragastric bolus doses of 250 mg/kg on gestation days 6-13 (maternal peak and trough salicylate levels of 222-120 micrograms/ml whole-blood) or via constant rate intravenous infusion of 150 mg/kg/day on the same gestation days via implanted osmotic minipumps (stable average maternal blood salicylate level of 120 micrograms/ml = human antirheumatic concentration). Both gavage and infusion of salicylate resulted in an increase of resorptions and fetal deaths as well as a decrease of fetal body weights. Gavage with salicylate also produced about 50% malformed fetuses. Selenite did not protect against the embryotoxic effects of salicylate administered as intragastric bolus doses. However, selenite was found to significantly increase fetal survival rate in the infusion experiment, although it did not counteract the decrease of fetal body weight. In animals fed selenite only, no negative effects on fetal body development were noted. The protective effect of selenite against salicylate induced embryotoxicity is difficult to explain, since very little is known about the mechanisms of salicylate embryotoxicity and the biological effects of selenium. However, an interaction between selenium, via glutathione peroxidase, and salicylate at the level of prostaglandin synthesis could be possible.