sorbinil and alrestatin

Despite numerous attempts over 16 years, the results of aldose reductase inhibitor (ARI) trials for the treatment of diabetic neuropathy have not proven efficacy. This paper reviews each of the ARI trials, examines confounding factors, and proposes a future course. The confounding factors considered are pharmacokinetics (ARI penetration of human nerve), length of trial (in terms of the natural history of diabetic neuropathy), trial endpoints (reversibility or slowing of progression), reproducibility of clinical measurements (in terms of power calculations), standardization and quality control of endpoints, and clinically meaningful differences in endpoints. We conclude that ARIs are most likely to have a beneficial effect in the management of diabetic distal symmetrical polyneuropathy and autonomic neuropathy but that the clinical role of ARIs is to slow the progression of diabetic neuropathy rather than to reverse it. Future trials should be designed with adequate statistical power, with consideration of the variability of the endpoint measurements for long enough duration, and with rigorous quality control to definitively confirm the utility of ARIs in the treatment of diabetic distal symmetrical polyneuropathy and autonomic neuropathy.

Topics: Aldehyde Reductase; Autonomic Nervous System; Diabetic Neuropathies; Enzyme Inhibitors; Humans; Imidazoles; Imidazolidines; Isoquinolines; Naphthalenes; Phthalazines; Time Factors

To update readers on research being conducted with the aldose reductase inhibitor (ARI) tolrestat in treating complications of diabetes mellitus. The article briefly describes early investigations with other ARIs and reviews the more recent studies of tolrestat. In addition, the article gives readers a simplified overview of the biochemical background pertinent to the use of these agents.. A MEDLINE search was performed to identify articles relating to the clinical use of, and research involving, the following ARIs: sorbinil, alrestatin, ponalrestat, and tolrestat. In addition, pharmaceutical manufacturers were contacted in an attempt to obtain data relating to ongoing investigations.. Review articles and clinical trials of sorbinil, alrestatin, and ponalrestat were included. Articles dealing with clinical trials of tolrestat were selected from the MEDLINE search. As there were only a few trials, all studies identified were included. No additional written data were available from the manufacturers.. ARIs, which when first introduced were proclaimed to be major advances in treating diabetic complications, have never produced the expected results. Problems with efficacy and toxicity relegated most of this class of agents to historical interest. One compound, tolrestat, has continued to be tested and has potential clinical application. To date, the extent of benefit that has been realized in tolrestat-treated patients is small to moderate. Improvements have occurred in paresthesia and neuropathy, but unfortunately, not in pain symptoms. Adverse effects have been minor and are primarily confined to elevations of hepatic alanine aminotransferase. Additional clinical trials are being conducted with this agent.. Tolrestat is the only one of the original ARIs still undergoing clinical trials. Results so far have been encouraging, but by no means definitive, for improvement in some aspects of diabetic neuropathy. Information from ongoing investigations is necessary before the true usefulness of tolrestat therapy can be determined.

Topics: Aldehyde Reductase; Clinical Trials as Topic; Diabetes Complications; Diabetes Mellitus; Humans; Imidazoles; Imidazolidines; Isoquinolines; Naphthalenes; Phthalazines

Despite numerous attempts over 16 years, the results of aldose reductase inhibitor (ARI) trials for the treatment of diabetic neuropathy have not proven efficacy. This paper reviews each of the ARI trials, examines confounding factors, and proposes a future course. The confounding factors considered are pharmacokinetics (ARI penetration of human nerve), length of trial (in terms of the natural history of diabetic neuropathy), trial endpoints (reversibility or slowing of progression), reproducibility of clinical measurements (in terms of power calculations), standardization and quality control of endpoints, and clinically meaningful differences in endpoints. We conclude that ARIs are most likely to have a beneficial effect in the management of diabetic distal symmetrical polyneuropathy and autonomic neuropathy but that the clinical role of ARIs is to slow the progression of diabetic neuropathy rather than to reverse it. Future trials should be designed with adequate statistical power, with consideration of the variability of the endpoint measurements for long enough duration, and with rigorous quality control to definitively confirm the utility of ARIs in the treatment of diabetic distal symmetrical polyneuropathy and autonomic neuropathy.

Topics: Aldehyde Reductase; Autonomic Nervous System; Diabetic Neuropathies; Enzyme Inhibitors; Humans; Imidazoles; Imidazolidines; Isoquinolines; Naphthalenes; Phthalazines; Time Factors

Kinetic patterns of inhibition of homogenous human kidney aldose reductase (AR, EC 1.1.1.21) and aldehyde reductase II (AR II, EC 1.1.1.19) by statil, ICI 105552 [1-(3,4-dichlorobenzyl)-3-methyl-1,2-dihydro-2-oxoquinol-4-yl acetic acid], tolrestat, alrestatin, chromone carboxylic acid (CCA), quercetin, phenobarbital and sorbinil were studied. On the basis of the kinetic nature of inhibition, the inhibitors were classified into four distinct categories. For aldose reductase, sorbinil and phenobarbital were noncompetitive (NC; category I) and CCA and alrestatin were uncompetitive (UC; category II) to both the aldehyde substrate and NADPH. Quercetin and ICI 105552 were NC to the aldehyde and UC to NADPH (category III) and tolrestat and statil were UC to the aldehyde and NC to NADPH (category IV). For AR II, sorbinil and alrestatin were category I inhibitors, ICI 105552 and statil belong to category II, phenobarbital, tolrestat and CCA to category III, and quercetin to category IV. To determine the specificity of inhibition, the ratios of the inhibition constants (Kii) for AR and AR II were calculated. A lower ratio indicates greater specificity. With aldehyde as the varied substrate the specificity ratios were: statil less than ICI 105552 less than alrestatin less than tolrestat less than quercetin less than CCA less than sorbinil less than phenobarbital, and with NADPH as the varied substrate, ICI 105552 less than statil less than alrestatin less than tolrestat less than quercetin less than CCA less than sorbinil less than phenobarbital. For AR, double-inhibition plots generated for one inhibitor from each kinetic category versus sorbinil showed that AR inhibitors of categories I-III bind to the same site on the protein molecule as sorbinil. However, tolrestat seemed to bind to a site different from the sorbinil binding site. For AR II, inhibitors from all the four categories appeared to bind to the same inhibitor binding site.

Topics: Aldehyde Reductase; Aldehydes; Carbohydrate Dehydrogenases; Chromones; Humans; Imidazoles; Imidazolidines; Isoquinolines; Kidney; Kinetics; Naphthalenes; Phenobarbital; Phthalazines; Quercetin; Quinolones; Substrate Specificity; Sugar Alcohol Dehydrogenases

5-Isothiocyanatoalrestatin (1b) and 5-azidoalrestatin (1c) were prepared synthetically and examined as potential affinity and photoaffinity inhibitors of rat lens aldose reductase. Both compound 1b and 1c under appropriate conditions at 10(-4) M produced a 70% irreversible inactivation of aldose reductase within 1 min. The enzyme could, in part, be protected by preincubation with sorbinil 2, a known potent inhibitor of aldose reductase.

Topics: Affinity Labels; Aldehyde Reductase; Animals; Dose-Response Relationship, Drug; Imidazoles; Imidazolidines; Isoquinolines; Rats; Structure-Activity Relationship; Sugar Alcohol Dehydrogenases

Aldose reductase (alditol:NADP+ 1-oxidoreductase, EC 1.1.1.21) has been partially purified from human erythrocytes by DEAE-cellulose (DE-52) column chromatography. This enzyme is activated severalfold upon incubation with 10 microM each glucose 6-phosphate, NADPH, and glucose. The activation of the enzyme was confirmed by following the oxidation of NADPH as well as the formation of sorbitol with glucose as substrate. The activated form of aldose reductase exhibited monophasic kinetics with both glyceraldehyde and glucose (Km of glucose = 0.68 mM and Km of glyceraldehyde = 0.096 mM), whereas the native (unactivated) enzyme exhibited biphasic kinetics (Km of glucose = 9.0 and 0.9 mM and Km of glyceraldehyde = 1.1 and 0.14 mM). The unactivated enzyme was strongly inhibited by aldose reductase inhibitors such as sorbinil, alrestatin, and quercetrin, and by phosphorylated intermediates such as ADP, glycerate 3-phosphate, glycerate 1,3-bisphosphate, and glycerate 2,3-trisphosphate. The activated form of the enzyme was less susceptible to inhibition by aldose reductase inhibitors and phosphorylated intermediates.

Topics: Aldehyde Reductase; Diabetes Mellitus; Enzyme Activation; Erythrocytes; Glucose; Glyceraldehyde; Humans; Imidazoles; Imidazolidines; Isoquinolines; Kinetics; NADP; Quercetin; Sorbitol; Sugar Alcohol Dehydrogenases

Topics: Aldehyde Reductase; Animals; Cattle; Diabetes Mellitus, Experimental; Galactitol; Isoquinolines; Lens, Crystalline; Naphthalenes; Rats; Sorbitol; Sugar Alcohol Dehydrogenases

The tricyclic ring structure of several of the aldose reductase inhibitors indicates that they could be detected by optical spectroscopy in certain ocular tissues. Four of these compounds (Quercetin, Quercitrin, AY22-284, and Sorbinil) were investigated with respect to their UV absorption, fluorescence, and phosphorescence characteristics. All absorb in the UV wavelength and have measurable fluorescence (room temperature) and phosphorescence characteristics (77 K). The phosphorescence characteristics were utilized to monitor for the presence of Quercetin, Quercitrin, and AY22-284 in rat, rabbit, and human lenses incubated with each of the inhibitors. Following IP injection, rat and rabbit lenses were removed and subjected to phosphorescence spectroscopy for these three reagents. AY22-284 gave the sharpest and clearest phosphorescence spectra with emission wavelengths well removed from intrinsic lens phosphorescence. It can be detected in the extracted ocular lens within 30 minutes after in vivo IP administration, as well as in vitro lens incubations. The spectral data correlate well with aldose reductase inhibitor levels in such lenses as measured by a biochemical technique. Similar data were obtained with Quercitrin. Sorbinil was best monitored by fluorescence spectroscopy and could be detected in the lens following in vivo administration, as well as in vitro lens incubations.

Topics: Aldehyde Reductase; Animals; Imidazoles; Imidazolidines; In Vitro Techniques; Isoquinolines; Lens, Crystalline; Quercetin; Rabbits; Rats; Spectrometry, Fluorescence; Spectrophotometry, Ultraviolet; Sugar Alcohol Dehydrogenases

Human brain aldose reductase and hexonate dehydrogenase are inhibited by alrestatin (AY 22,284) and sorbinil (CP 45,634). Inhibition by alrestatin is noncompetitive for both enzymes, and slightly stronger for hexonate dehydrogenase (KI values 52-250 microM) than for aldose reductase (KI values 170-320 microM). Sorbinil inhibits hexonate dehydrogenase far more potently than aldose reductase, KI values being 5 5 microM for hexonate dehydrogenase and 150 microM for aldose reductase. The inhibition of hexonate dehydrogenase by sorbinil is noncompetitive with respect to both aldehyde and NADPH substrates, and is thus kinetically similar to the inhibition by alrestatin. However, sorbinil inhibition of aldose reductase is uncompetitive with respect to glyceraldehyde and noncompetitive with NADPH as the varied substrate. Inhibition of human brain aldose reductase by these two inhibitors is much less potent than that reported for the enzyme from other sources.

Topics: Aldehyde Reductase; Brain; Carbohydrate Dehydrogenases; Humans; Imidazoles; Imidazolidines; Isoquinolines; Kinetics; Parasympatholytics; Sugar Alcohol Dehydrogenases

The susceptibility of human lens aldose reductase (HLAR), human placental aldose reductase (HPAR), and rat lens aldose reductase (RLAR) to inhibition by 10 structurally diverse inhibitors is compared. Significant differences in the susceptibility of these enzymes was observed; however, no trends could be predicted. In general, HPAR appeared to be less susceptible to inhibition than either HLAR or RLAR, with the susceptibility of HLAR being more similar to RLAR than to HPAR. These findings indicate that the evaluation of aldose reductase inhibitors for potential clinical use may require the use of human aldose reductase from the appropriate target tissue.

Topics: Aldehyde Reductase; Animals; Cataract; Chromones; Female; Humans; Imidazoles; Imidazolidines; Isoquinolines; Lens, Crystalline; Placenta; Pregnancy; Quercetin; Rats; Sugar Alcohol Dehydrogenases; Sugar Alcohols