Ciglitazone, 5-[4-(1-methylcyclohexylmethoxy) benzyl]-thiazolidine-2,4-dione, is a new hypoglycemic agent orally active in the obese-hyperglycemic animal models. In C57BL/6J-ob/ob mice, treatment with 100 mg/kg ciglitazone for 2 days elicited a drastic fall in blood glucose. It also decreased plasma insulin, triglycerides, and free fatty acids and food intake without affecting the body weight. Its hypoglycemic activity was independent of its effect on food intake. Regranulation of islet beta-cells and increased pancreatic insulin content were observed in ob/ob mice treated for 41-44 days with 100 mg/kg/day ciglitazone. Ciglitazone showed no effect on food intake, blood glucose, or pancreatic islet beta-cells in a group of lean C57BL/6J-+/? mice concomitantly treated at a dose of 150 mg/kg/day. In C57BL/KsJ-db/db mice, ciglitazone decreased blood glucose and food intake. The untreated db/db mice lost weight despite hyperphagia, whereas the ciglitazone-treated db/db mice gained weight. In the spontaneously diabetic Chinese hamsters, ciglitazone showed no significant effect on food intake, body weight, blood glucose, or insulin content in either plasma or pancreas, but it lowered plasma lipids. In normal rats, ciglitazone failed to affect fasting blood glucose but improved glucose tolerance without increasing insulin secretory response to glucose. In streptozotocin-diabetic rats, it showed no effect on blood glucose or glycemic response to exogenous insulin. The hypoglycemic activity of ciglitazone was specific for obese-hyperglycemic and insulin-resistant animals.
The relationship between phasic systolic and diastolic coronary blood flow and its transmural distribution has been studied in 29 Yucatan miniature pigs at rest and during heavy exercise, with and without adenosine infusion (1.5 mg . kg-1 . min-1) and with and without a subtotal coronary artery occlusion. Altered factors that affected coronary flow included vascular resistance, perfusion pressure, myocardial oxygen demand, and extra-vascular pressure. The data indicate that, at rest, endomural perfusion is significantly dependent on diastolic blood flow. However, the ability of the myocardial vessels to autoregulate during systole as well as during diastole was clearly shown with the use of adenosine infusion. This ability to regulate flow intrinsically appeared to transcend the endocardial dependency on diastolic perfusion under certain stressful conditions, e.g., during heavy exercise, when the diastolic duration was significantly reduced. Systolic transmural perfusion may then become a significant factor in meeting the blood flow demands of the myocardium. However, due to gradients in vascular resistance, perfusion pressure, and oxygen demand, the coronary reserve of the epicardium appears to be greater than that of the endocardium under any condition.
Coronary collateral blood flow was measured in 7 miniature pigs, exercise trained (ET) for 10 mo by running about 35 km/wk, and in 10 sedentary control pigs (SC). In acute, open-chest preparations, radiolabeled (85SR, 141CE, or 51Cr) microspheres, 15 +/- 5 micron in diameter, were injected into the left atrium during each of three conditions: control (C), total occlusion of the left circumflex artery (TO), and TO plus mechanically elevated aortic pressure (TOP). Blood flow to the circumflex bed during control condition in ET and SC was 0.36 +/- 0.07 (SE) and 0.43 +/- 0.10 ml.g-1.min-1, respectively. During TO, circumflex flow in ET and SC fell to 0.05 +/- 0.01 and 0.06 +/- 0.01 ml.g-1.min-1, respectively. In the presence of TOP, left circumflex flow in ET and SC rose to 0.11 +/- 0.04 and 0.11 +/- 0.02 ml.g-1.min-1, respectively. Blood flow to the tissue bed of the left anterior descendens was the same in both groups of pigs under all conditions. Thus, 10 mo of endurance exercise training seems to have no effect on the development of coronary collaterals in the left ventricles of pig hearts.
Few inhibitors of the RNase H function associated with the HIV-1 reverse transcriptase have been discovered to date. We observed that three novenamines, U-34445, U-35122, and U-35401, are specific inhibitors of the HIV-1 RT RNase H function. All three compounds are strong amphiphiles and contain one ionizable group. Hence, a priori, in aqueous solutions the inhibitors might exist in at least four different physical states, namely protonated monomers, ionized monomers, protonated micelles, and ionized micelles. The three inhibitors all yielded anomalous dose-response curves, indicating that the four molecular species have different inhibitory potentials. In order to identify the inhibitory species, the amphiphilic properties of these compounds were studied. It was established that in alkaline solutions, around pH 8, all compounds are ionized and form micelles at concentrations above their CMC. Both the protonated and the ionized forms of these molecules form stable insoluble monomolecular layers at the air/water interface. The anomalies of the dose-response curves can be resolved by taking into account the fact that, in solution, the relative proportion of these molecules in each physical state depends on the pH and on their analytical concentration. Thus interpreted, the results indicate that RNase H is inhibited only by the ionized micellar form of these compounds and not by their monomeric form. Around their pKa (approximately pH 5), the three compounds reproducibly form uniformly sized, self-emulsified colloidal particles that may be used as an efficient drug delivery system.
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