Charles E. Aldinger

Red blood cell sorbitol as an indicator of polyol pathway activity: inhibition by sorbinil in insulin-dependent diabetic subjects

In a double-blind crossover study of 15 diabetic patients, elevated red blood cell (RBC) sorbitol levels were reduced by oral doses of the potent aldose reductase inhibitor, sorbinil (250 mg o.d.), to near-normal ranges. In diabetic rats with severe hyperglycemia, oral sorbinil (5 mg/kg) dramatically reduced (80–90%) sorbitol levels in tissues without affecting blood glucose; the RBC dose-response curve was similar to that in lens and sciatic nerve. In streptozotocin-treated rats with varying degrees of diabetes sorbitol levels in the lens, sciatic nerve, and RBC were elevated in proportion to the degree of hyperglycemia. RBC sorbitol levels in these animals were positively correlated with the levels in lens and sciatic nerve. These results establish that orally administered sorbinil is effective in lowering elevated sorbitol levels, and strongly suggest that the reduction seen in RBC sorbitol levels in human diabetic subjects is likely to reflect comparable effects of the drug in less accessible tissues associated with the long-term complications of diabetes.

Molecular Characterization of Novel and Selective Peroxisome Proliferator-Activated Receptor α Agonists with Robust Hypolipidemic Activity in Vivo

The nuclear receptor peroxisome proliferator-activated receptor α (PPARα) is recognized as the primary target of the fibrate class of hypolipidemic drugs and mediates lipid lowering in part by activating a transcriptional cascade that induces genes involved in the catabolism of lipids. We report here the characterization of three novel PPARα agonists with therapeutic potential for treating dyslipidemia. These structurally related compounds display potent and selective binding to human PPARα and support robust recruitment of coactivator peptides in vitro. These compounds markedly potentiate chimeric transcription systems in cell-based assays and strikingly lower serum triglycerides in vivo. The transcription networks induced by these selective PPARα agonists were assessed by transcriptional profiling of mouse liver after short- and long-term treatment. The induction of several known PPARα target genes involved with fatty acid metabolism were observed, reflecting the expected pharmacology associated with PPARα activation. We also noted the down-regulation of a number of genes related to immune cell function, the acute phase response, and glucose metabolism, suggesting that these compounds may have anti-inflammatory action in the mammalian liver. Whereas these compounds are efficacious in acute preclinical models, extended safety studies and further clinical testing will be required before the full therapeutic promise of a selective PPARα agonist is realized.

Applicability of red blood cell sorbitol measurements to monitor the clinical activity of sorbinil

Increased flux of glucose through the polyol pathway with resultant resultant accumulation of tissue sorbitol is implicated in the pathogenesis of the chronic complications of diabetes. Sorbinil is a potent inhibitor of aldose reductase (the first enzyme in the polyol pathway) and has been shown to normalize sorbitol levels in relevant tissues (eg, nerve, kidney, lens) of experimentally-induced diabetic animals. The purpose of this study was to identify a relatively noninvasive method of monitoring the intrinsic (or biochemical) efficacy of sorbinil in diabetic man. Specifically, the objective was to identify a readily accessible tissue that would be reflective of polyol pathway activity and the activity of sorbinil in clinically relevant but less accessible tissues. Based on several previous studies, which demonstrated that sorbitol accumulation in human red blood cells (RBCs) was a function of ambient glucose concentrations, either in vitro or in vivo, our investigations were conducted to determine if RBC sorbitol accumulation would correlate with sorbitol accumulation in lens and nerve tissue of diabetic rats; the effect of sorbinil in reducing sorbitol levels in lens and nerve tissue of diabetic rats would be reflected by changes in RBC sorbitol; and sorbinil would reduce RBC sorbitol in diabetic man.

Dihydropyridines: a new class of angiotensin II antagonists

Abstract The syntheses and biological activities of dihydropyridine angiotensin II (AII) antagonists are described. Compounds such as 12 are examples of a new, structurally distinct class of AT(in1-selective agents.