Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tolrestat is an aldose reductase inhibitor that is undergoing extensive clinical investigation for the treatment of diabetic complications including polyneuropathy. As part of a larger European trial, we report here the results from a single clinical center on the efficacy of tolrestat in patients with confirmed diabetic neuropathy. The trial was conducted in two phases: a 6-month double-blind, placebo-controlled phase, and a 6-month open-label phase in which most patients were treated with tolrestat. Following the double-blind phase, motor and sensory nerve conduction velocity had significantly deteriorated in the placebo group, which did not occur during treatment with tolrestat. Deterioration of vibration threshold also occurred during placebo treatment and did not occur with tolrestat. During the open-label phase, motor nerve condition velocity and vibration threshold improved with tolrestat. Moreover, the deterioration of motor nerve conduction velocity and vibration threshold that had occurred in patients initially treated with placebo, was stopped during open-label treatment with tolrestat.
J Diabetes Complications
PMID:Long-term effects of tolrestat on symptomatic diabetic sensory polyneuropathy. 156 58

To analyze the effects of sorbitol accumulation on the survival and growth of epithelial cells from rabbit renal inner medulla, cloning efficiency (an index of cell viability) was measured at normal and high glucose and NaCl concentrations and when sorbitol accumulation was prevented by Tolrestat and Sorbinil, which inhibit aldose reductase. With PAP-HT25 cells grown to near confluence, high NaCl increases aldose reductase activity, causing enough rise in cell sorbitol concentration to balance most of the increased osmolality of the high extracellular NaCl. Inhibition of aldose reductase prevents both the increased enzyme activity and sorbitol accumulation in a dose-related manner. Paralleling this, colony-forming efficiency is not affected by the inhibitors at a normal NaCl concentration but is greatly reduced when extracellular NaCl is high. On the other hand, high glucose levels, as occur in diabetes, increase sorbitol content well above the concentration required for osmotic balance and inhibit colony-forming efficiency. Under those conditions, aldose reductase inhibitors lower cell sorbitol and reverse (at 300-350 mosmol/kgH2O) or reduce (at 500-550 mosmol/kgH2O) the decrease in colony-forming efficiency caused by high glucose. Thus sorbitol accumulation is necessary for osmoregulation when induced by high osmolality but is harmful when induced by high glucose.
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PMID:Effects of NaCl, glucose, and aldose reductase inhibitors on cloning efficiency of renal medullary cells. 210 52

Aldose reductase (AR) mRNA levels increase when dog lens epithelial cells are exposed to hypertonic conditions. Hybridization of mRNA to an AR cDNA, using Northern and slot blots, showed that AR mRNA is elevated at least fourfold when primary dog lens epithelial cells are grown in media (300 mosmol kg-1) supplemented with 150 mM NaCl (600 mosmol kg-1 final). A time course showed an increase in AR mRNA of approximately twofold by 24 hr with a maximum increase of between four- and eightfold by 48 hr. AR mRNA remained elevated for the duration of the experiment, 8 days. The addition of Tolrestat, an inhibitor of aldose reductase, had no effect on the increased level of AR mRNA in these hypertonically stressed cells. Cells grown in media supplemented with 250 mM sorbitol also showed a substantial increase in AR mRNA. These data indicate, as in other cell types, the lens, a target tissue of diabetes, responds to hypersomotic stress with an induction of AR expression and suggests that AR may play a role in intracellular osmotic regulation.
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PMID:Increase in aldose reductase mRNA in dog lens epithelial cells under hypertonic conditions. 211 55

The effect of the aldose reductase inhibitor, tolrestat, on red blood cell (RBC) sorbitol levels was studied in 23 patients with diabetes after oral dosing with tolrestat, 25 or 100 mg b.i.d. The mean (+/- SE) RBC sorbitol levels (measured 12 hours after the preceding dose) after 3, 7, and 13 days of dosing decreased after both dose levels. After 25 mg tolrestat the RBC sorbitol levels fell from 25.1 +/- 4.0 to 20.0 +/- 5.7 nmol/gm hemoglobin (21%) and after 100 mg tolrestat the level fell from 26.7 +/- 3.7 to 11.4 +/- 1.7 nmol/gm hemoglobin (57%; P less than 0.001). This latter RBC sorbitol concentration is similar to levels in individuals without diabetes. At both dosage levels the maximum decrease in RBC sorbitol levels occurred after only 3 days of dosing. Tolrestat had no effect on plasma glucose or hemoglobin A1 concentrations. The overall mean plasma unbound drug concentration measured 12 hours after 100 mg tolrestat (11.7 +/- 3.0 ng/ml; 3.3 X 10(-8) mol/L) was similar to the median inhibitory level (3 X 10(-8) mol/L) of tolrestat for sorbitol accumulation in human RBCs incubated in a high-glucose medium. Our results demonstrate the systemic bioavailability of tolrestat and its aldose reductase inhibitory activity in erythrocytes of patients with diabetes.
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PMID:Effect of tolrestat on red blood cell sorbitol levels in patients with diabetes. 406 65

The kinetics of tolrestat, a potent inhibitor of aldose reductase, were examined. Serum concentrations of tolrestat and of total 14C were measured after dosing normal subjects and subjects with diabetes with 14C-labeled tolrestat. In normal subjects, tolrestat was rapidly absorbed and disappearance from serum was biphasic. Distribution and elimination t 1/2s were approximately 2 and 10 to 12 hr, respectively, after single and multiple doses. Unchanged tolrestat accounted for the major portion of 14C in serum. Radioactivity was rapidly and completely excreted in urine and feces in an approximate ratio of 2:1. Findings were much the same in subjects with diabetes. In normal subjects, the kinetics of oral tolrestat were independent of dose in the 10 to 800 mg range. Repetitive dosing did not result in unexpected cumulation. Tolrestat was more than 99% bound to serum protein; it did not compete with warfarin for binding sites but was displaced to some extent by high concentrations of tolbutamide or salicylate.
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PMID:Tolrestat kinetics. 647 35

It has been demonstrated that activation of aldose reductase (AR; EC 1.1.1.21) in diabetic tissues plays an important role in the pathogenesis of diabetic complications. In the present study, the effects of non-enzymatic glycation of recombinant human AR (rhAR) on enzyme activity and affinity for its substrate (glyceraldehyde), co-factor (NADPH) and inhibitors (ARI; Sorbinil, Tolrestat, AL-1576 and Statil) were examined. Although rhAR was successfully non-enzymatically glycated with HPLC-purified [3H]D-glucose, the Michaelis constant (Km) and catalytic efficiency (Kcat/Km) for glyceraldehyde, the Km for NADPH and the inhibitor constant (Ki) for ARI did not change. These results suggest that the mechanism of AR activation and its insensitivity to inhibition observed in diabetic tissues cannot be attributed to its non-enzymatic glycation.
Diabetes Res Clin Pract 1995 Mar
PMID:The effect of non-enzymatic glycation on recombinant human aldose reductase. 755 97

This study examined the effects of hyperglycemia and treatment with the aldose reductase inhibitor, Tolrestat, on the pain behavior evoked by injection of formalin into the dorsum of a single hind paw. In control rats, injection of formalin (50 microliters of a 5% solution) evoked two phases of flinching of the injected paw (phases 1 and 2), separated by a quiescent period. Four weeks of streptozotocin-induced diabetes or galactose intoxication did not alter the frequency of flinching during either of the active phases but significantly (P < 0.001 and P < 0.05, respectively) enhanced flinch frequency during the quiescent period. Concurrent treatment with Tolrestat (50 mg/kg/day by gavage) during hyperglycemia prevented the accumulation of the polyol pathway metabolites sorbitol and fructose in the nerve and spinal cord of streptozotocin-diabetic rats and also significantly (P < 0.05) reduced the enhanced flinching of diabetic rats during the quiescent period. These data demonstrate that hyperglycemia induces a period of Tolrestate-preventable hyperalgesia in a paradigm that is used to model persistent pain and suggest that exaggerated flux through aldose reductase may initiate changes in nociceptive pathways that could contribute to some of the pain states experienced by patients with diabetic neuropathy.
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PMID:Tolrestat treatment prevents modification of the formalin test model of prolonged pain in hyperglycemic rats. 783 91

We describe two patients with type 2 diabetes who presented with abdominal pain secondary to thoracic polyradiculopathy. In the first patient abdominal pain occurred in association with marked abdominal distension; extensive negative gastrointestinal investigations were performed before the correct diagnosis was made by electromyography showing thoracic paraspinal muscle denervation. In the second case, truncal sensory symptoms alone were evident at the time of diagnosis of diabetes mellitus. While muscle laxity was absent, extensive paraspinal muscle denervation was detected. Tolrestat, an aldose reductase inhibitor, was associated with good clinical response of symptoms due to peripheral neuropathy and thoracic polyradiculopathy. The pathogenesis of thoracic polyradiculopathy is uncertain but is likely to be the result of multiple infarcts along the course of thoracic spinal nerves accounting.
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PMID:Thoracic polyradiculopathy--abdominal wall swelling and sensory symptoms in diabetes mellitus. 796 Jun 57

The clinical efficacy of an aldose reductase (AR) inhibitor in diabetic polyneuropathy depends on its bioavailability at the site(s) of AR in peripheral nerves. Accordingly, the link between the concentration of the AR inhibitor, tolrestat, and the extent of its inhibition of the AR-catalyzed polyol production was investigated in sciatic nerves of galactosemic rats. Tolrestat was administered by gavage (1 x 150 mg/kg, or 5, and 15 mg/kg/day for 15 days to attain steady state as estimated from the 53-h half-life of tolrestat determined in rat nerve); subsequently, at six time intervals, ranging from 4 to 59 days, rats were given access for 4 days to a 20% galactose diet, and killed. At every time point, the composite tolrestat concentration in the nerve correlated with the percentage decrease in nerve galactitol (r = 0.857, p = 0.0015). Because the latter should reflect the extent of nerve AR inhibition by tolrestat, the concentration of "free" tolrestat available at the site(s) of AR in the nerve was estimated from the tolrestat concentration/percent AR inhibition plot obtained in vitro. The estimated amount of tolrestat present at the site(s) of nerve AR represented 0.4% of the composite tolrestat concentration measured in the nerve. The results support the view that the effectiveness of an AR inhibitor in peripheral nerve depends on its pharmacokinetics in the nerve, i.e., on its uptake, nonspecific binding to cellular constituents, and elimination.
J Diabetes Complications
PMID:Tolrestat pharmacokinetics in rat peripheral nerve. 816 82

Cultured bovine retinal capillary pericytes (BRP) were used to investigate the effect of an aldose reductase inhibitor, tolrestat, and an inhibitor of advanced glycation end products (AGE) formation, aminoguanidine, on glucose toxicity. Glucose at high concentration reduced the replicative activity of pericytes in a dose-dependent manner. Tolrestat completely inhibited the production of sorbitol in cells exposed to a high concentration of glucose but failed to protect the cells from glucose toxicity. These results suggest that sorbitol accumulation in cells is probably not the major mechanism for glucose toxicity. In contrast, the addition of aminoguanidine at 10 mM concentration to the culture media protected pericytes from glucose toxicity. The degree of protected pericytes from glucose toxicity. The degree of protection was dose-dependent and evident at aminoguanidine concentration as low as 1 mM. The drug was only slightly toxic to BRP but induced morphological changes in pericytes with the loss of cellular processes and decreased cell spreading. This may suggest some action of aminoguanidine on the pericyte cytoskeleton. High concentration of glucose significantly increased the level of early glycation but not fluorescent AGE formation on BRP proteins. This was inhibited by the addition of aminoguanidine suggesting that glycation of cellular/membrane proteins and other mechanisms may play an important role in the toxic action of high glucose levels in cultured pericytes.
Diabetes 1994 Jun
PMID:The effect of aminoguanidine and tolrestat on glucose toxicity in bovine retinal capillary pericytes. 819 60


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