epalrestat and Cardiovascular-Diseases

To evaluate the effect of long-term administration of an aldose reductase inhibitor on diabetic cardiovascular autonomic neuropathy, 22 subjects with non-insulin dependent diabetes mellitus (NIDDM, 11 men and 11 women, mean age; 64.8 +/- 7.8 years, duration of diabetes; 18.3 +/- 5.6 years) were administered epalrestat, one type of aldose reductase inhibitor, for 36 months. The changes in the coefficient of variation of the R-R interval (CV(R R)) during rest and the QTc interval were compared with 43 age-matched NIDDM (controls). During the study, the CV(R R) value gradually decreased in the controls, while it slightly increased in subjects treated with epalrestat. After 36 months, the CV(R R) value (2.31 +/- 1.09%) in subjects treated with epalrestat was significantly (P < 0.05) higher than that (1.84 +/- 0.75%) in the controls. There were no significant differences in QTc intervals in both groups. These results suggest that long-term administration of an aldose reductase inhibitor may be available for cardiac autonomic neuropathy in even relatively older diabetic subjects with long duration.

Topics: Aged; Aged, 80 and over; Aldehyde Reductase; Autonomic Nervous System Diseases; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Electrocardiography; Enzyme Inhibitors; Female; Humans; Male; Middle Aged; Rhodanine; Statistics, Nonparametric; Thiazolidines

Diabetes mellitus is the major risk factor for cardiovascular disorders. Aldose reductase, the rate-limiting enzyme of the polyol pathway, plays a key role in the pathogenesis of diabetic complications. Accordingly, inhibition of this enzyme is emerging as a major therapeutic strategy for the treatment of hyperglycemia-induced cardiovascular pathologies. In this study, we describe a series of 5(6)-substituted benzofuroxane derivatives, 5a-k,m, synthesized as aldose reductase inhibitors. Besides inhibiting efficiently the target enzyme, 5a-k,m showed additional NO donor and antioxidant properties, thus emerging as novel multi-effective compounds. The benzyloxy derivative 5a, the most promising of the whole series, showed a well-balanced, multifunctional profile consisting of submicromolar ALR2 inhibitory efficacy (IC50=0.99±0.02 μM), significant and spontaneous NO generation properties, and excellent hydroxyl radical scavenging activity. Computational studies of the novel compounds clarified the aldose reductase inhibitory profile observed, thus rationalizing structure-activity relationships of the whole series.

Topics: Animals; Benzoxazoles; Cardiovascular Diseases; Diabetes Complications; Humans; Liver; Models, Molecular; Molecular Docking Simulation; Rats

We present a diabetic patient with long-standing constipation complicated by paralytic ileus and septic shock. She successfully recovered from a critical condition, and her diabetes was well controlled. However, the constipation did not improve even after the administration of conventional medications. Epalrestat, an aldose reductase inhibitor (ARI), improved her bowel motility and autonomic cardiovascular dysfunction, as evident from her heart rate and blood pressure response. Gastroenteropathy is a major diabetic complication which may cause disturbed bowel motility leading to serious enterobacterial infections, thus, its amelioration is important. ARI may be beneficial in the treatment of diabetic gastroenteropathy refractory to conventional therapies.

Topics: Aldehyde Reductase; Autonomic Nervous System Diseases; Cardiovascular Diseases; Constipation; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Enzyme Inhibitors; Female; Gastrointestinal Motility; Hemodynamics; Humans; Intestinal Pseudo-Obstruction; Middle Aged; Rhodanine; Shock, Septic; Thiazolidines