Chronic toxicity in monkeys with the thiazolidinedione antidiabetic agent troglitazone.

The antidiabetic agent troglitazone was given to groups of 4 cynomolgus monkeys per sex at 300, 600, or 1200 mg/kg daily by gavage for 52 weeks. A group of 4 monkeys per sex received vehicle alone and served as controls. Emesis and soft stool or diarrhea occurred sporadically in all troglitazone-treated groups, but did not compromise animal health. There were no effects on body weight or food consumption, or ophthalmologic, electrocardiographic, or echocardiographic parameters. Erythrocyte count, hemoglobin, and hematocrit decreased 8% to 16% in males at all doses and serum cholesterol decreased 30% to 46% in both sexes at all doses. Urinary ketones were increased in several animals at 600 and 1200 mg/kg. Absolute and relative liver weights increased at all doses in both sexes by 40% to 71%. The only microscopic change attributable to troglitazone treatment was minimal to mild bile duct hyperplasia in males at all doses and in females at 600 and 1200 mg/kg. No differences in systemic exposure were apparent between sexes. Over the dose range tested, AUC(0-24) values were 27 to 102 micrograms.hr/ml of troglitazone, 401 to 2060 micrograms.hr/ml of its sulfate conjugate, and 34 to 312 micrograms.hr/ml of its quinone metabolite. Therefore, oral administration of troglitazone to monkeys at 300, 600, and 1200 mg/kg for 52 weeks resulted in significant systemic exposure, with only minimal gastrointestinal, hematologic, and hepatic effects.

Noninvasive polarimetric-based glucose monitoring: an in vivo study.

BACKGROUND: Since 1990, there has been significant research devoted toward development of a noninvasive physiological glucose sensor. In this article, we report on the use of optical polarimetry for the noninvasive measurement of physiological glucose concentration in the anterior chamber of the eye of New Zealand white (NZW) rabbits. METHOD: Measurements were acquired using a custom-designed laser-based optical polarimetry system in a total of seven NZW rabbits anesthetized using an isoflurane-only anesthesia protocol. Aqueous humor-based polarimetric measurements were obtained by coupling light through the anterior chamber of the eye. Blood glucose levels were first stabilized and then altered with intravenous dextrose and insulin administration and measured every 3-5 min with a standard glucometer and intermittently with a YSI 2300 glucose analyzer. Acquired polarimetric glucose signals are calibrated to measured blood glucose concentration. RESULTS: Based on a total of 41 data points, Clarke error grid analysis indicated 93% in zone A, 7% in zone B, and 0% in zones C and D, with reference concentrations between 93 and 521 mg/dl. Errors in prediction are shown to be related to gross movement of the rabbit during the procedures, incurring time-varying corneal birefringence effects that directly affect the measured polarimetric signal. These effects can be compensated for with appropriate design modifications. CONCLUSIONS: An optical polarimetry technique was used for in vivo physiological glucose monitoring. The technique demonstrated provides a basis for the development of a noninvasive polarimetric glucose monitor for home, personal, or hospital use.

An immunohistochemical approach to differentiate hepatic lipidosis from hepatic phospholipidosis in rats.

Hepatocellular vacuolation can be a diagnostic challenge since cytoplasmic accumulations of various substances (lipid, water, phospholipids, glycogen, and plasma) can have a similar morphology. Cytoplasmic accumulation of phospholipids following administration of cationic amphiphilic drugs (CAD) can be particularly difficult to differentiate from nonphosphorylated lipid accumulations at the light microscopic level. Histochemical methods (Sudan Black, Oil Red-O, Nile Blue, etc.) can be used to identify both nonphosphorylated and/or phosphorylated lipid accumulations, but these techniques require non-paraffin-embedded tissue and are only moderately sensitive. Thus, electron microscopy is often utilized to achieve a definitive diagnosis based upon the characteristic morphologic features of phospholipid accumulations; however, this is a low throughput and labor intense procedure. In this report, we describe the use of immunohistochemical staining for LAMP-2 (a lysosome-associated protein) and adipophilin (a protein that forms the membrane around non-lysosomal lipid droplets) to differentiate phospholipidosis and lipidosis, respectively in the livers of rats. This staining procedure can be performed on formalin-fixed paraffin embedded tissues, is more sensitive than histochemistry, and easier to perform than ultrastructural evaluation.