A tea/vanadate decoction delivered orally over 14 months to diabetic rats induces long-term glycemic stability without organ toxicity.

Vanadium can induce potent hypoglycemic effects in type 1 and type 2 diabetes mellitus animals, but toxic adverse effects have inhibited the translation of these findings. Administration of vanadate in a black tea decoction has shown impressive hypoglycemic effects without evidence of toxicity in short-term studies. The purpose of this study was to investigate the hypoglycemic action and the toxic adverse effects of a tea/vanadate (T/V) decoction in diabetic rats over a 14-month treatment period. Streptozotocin-induced type 1 diabetes mellitus rats were orally gavaged with 40 mg sodium vanadate in a black tea decoction only when blood glucose levels were greater than 10 mmol/L. Glycemic status and liver and kidney function were monitored over 14 months. All of the diabetic rats in this treatment group (n = 25) required treatment with the T/V decoction at the start of the study to reduce blood glucose levels to less than 10 mmol/L. Diarrhea was uncommon among the T/V-treated animals during the first week of T/V treatment and was absent thereafter. There was no evidence of liver or kidney dysfunction or injury. From 2 to 6 months, fewer animals required the T/V treatment to maintain their blood glucose levels. After 9 months of treatment, none of the diabetic animals required any T/V to maintain their blood glucose levels at less than 10 mmol/L. Oral administration of a T/V decoction provides safe, long-acting hypoglycemic effects in type 1 diabetes mellitus rats. The typical glycemic signs of diabetes were absent for the last 5 months of the study.

Local variations in defect polarization and covalent bonding in ferroelectric Cu(2+)-doped PZT and KNN functional ceramics at the morphotropic phase boundary.

Cu(2+)-doped Pb[Zr(0.54)Ti(0.46)]O(3) (PZT) and Cu(2+)-doped [K(0.5)Na(0.5)]NbO(3) (KNN) ferroelectrics with a dopant concentration of 0.25 mol% were investigated by means of multi-frequency and multi-pulse electron paramagnetic resonance (EPR) spectroscopy. Through the use of high magnetic fields and pulsed microwave fields an enhanced resolution was achieved yielding valuable information about the structural distortion at the dopant site. The results obtained suggest that Cu(2+) substitutes for both systems as an acceptor centre for the perovskite B-site. For reasons of local charge compensation, different kinds of defect associates invoking one and two oxygen vacancies are formed. These two kinds of extended defects differ in their electric and elastic properties. The results obtained are analyzed in order to characterize differences of the local structure in the Cu(2+)-defect center for morphotropic phase boundary compositions between the two systems. In particular, it is found that Cu(2+)-doping in KNN creates 50% more oxygen vacancies than the same amount of copper in PZT. Furthermore, local differences in covalent and ionic bonding are monitored.

8-Substituted analogues of 3-(3-cyclopentyloxy-4-methoxy-benzyl)-8-isopropyl-adenine: highly potent and selective PDE4 inhibitors.

3-(3-Cyclopentyloxy-4-methoxy-benzyl)-8-isopropyl-adenine V11294 (1) has been identified as a lead structure, which selectively inhibits human lung PDE4 (436 nM) and is also active in a number of in vitro and in vivo models of inflammation. Here we describe the synthesis and pharmacology of a series of highly potent 8-[(benzyloxy)methyl]-substituted analogues, with potencies in the range 10-300 nM. In addition, several compounds showed interesting PDE4 subtype specificities, for example, the 3-thienyl derivative 5v, which showed 6-10 nM potency at PDE4B, D3, and D5 and a 20- to 200-fold selectivity over A and D2, respectively.

Intramolecular C-H insertions adjacent to sulfur for the diastereoselective synthesis of thienofuranones.

A new approach to the diastereoselective synthesis of thienofuranones is described in which an intramolecular 1,5-carbenoid C-H insertion adjacent to sulfur features as a key step.

Decreases in portal flow trigger a hepatorenal reflex to inhibit renal sodium and water excretion in rats: role of adenosine.

The regulation of renal sodium and water excretion through a hepatorenal reflex activated by the changes in hemodynamics of the portal circulation has been suggested. We hypothesize that the changes in intrahepatic blood flow and flow-related intrahepatic adenosine are involved in the control of renal water and sodium excretion by triggering a hepatorenal reflex. Anesthetized rats were instrumented to monitor the systemic, hepatic, and renal circulation. A vascular shunt connecting the portal vein and central vena cava was established to allow for control of the portal venous blood flow (PVBF). Urine was collected from the bladder. The effects of decreased PVBF on renal water and sodium excretion were compared in normal and hepatic denervated rats. Decreasing intrahepatic PVBF by half for 30 minutes decreased urine flow by 38% (12.1 +/- 1.1 vs. 7.5 +/- 0.7 microL. min(-1)) and urine sodium excretion by 44% (1.11 +/- 0.30 vs. 0.62 +/- 0.17 micromol. min(-1)). Renal arterial blood flow (RABF) and creatinine clearance were also reduced by the decreases in intrahepatic PVBF. Hepatic denervation, or intrahepatic administration of an adenosine receptor antagonist, 8-phenyltheophylline (8-PT), abolished the effects of decreasing PVBF on urine flow and sodium excretion. The data suggest that the decrease in intrahepatic PVBF triggers a hepatorenal reflex through the activation of adenosine receptors within the liver, thereby inhibiting renal water and sodium excretion. The water and sodium retention commonly seen in the hepatorenal syndrome may be related to intrahepatic adenosine accumulation resulting from the associated decrease in intrahepatic portal flow.