Michael J. Peterson

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.

Components of variance for vibratory and thermal threshold testing in normal and diabetic subjects

Quantitative sensory testing (QST) is commonly used in the assessment of diabetic neuropathy. However, little data are available on the reliability of tactile and thermal testing devices. Reproducibility of QST measures between centers has not been previously reported. This study was designed to validate QST testing procedures and determine if these devices are suitable for large scale multicenter clinical trials. Finger and toe vibratory (Vf, Vt) and thermal (Tf, Tt) thresholds were determined for ten normal individuals by a two-alternative forced-choice procedure using the Optacon Tactile Tester (OTT) and Thermal Sensitivity Tester (TST). Threshold measurements were reproducible between technologists and had a day-to-day coefficient of variation of Vf 20%, Vt 23%, Tf 41%, and Tt 95%. Thresholds were determined for 140 normal individuals at six centers. Mean threshold values between centers were not significantly different. Center-to-center coefficients of variation (CV) were Vf 44%, Vt 45%, Tf 47%, and Tt 87%. There was no significant difference in threshold measures with regard to sex, side studied, presence of calluses, or skin temperature. Vf thresholds significantly correlated with age (p < 0.01). There was no correlation between either vibratory or thermal thresholds in normal individuals, and nerve conduction velocities (NCV). Thermal and vibratory thresholds were determined for 98 diabetic patients. Diabetic subjects without clinical evidence of neuropathy were not significantly different from normal individuals, but diabetic patients with neuropathy had increased thresholds compared to normals (p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Determinants of retinopathy progression in type 1 diabetes mellitus.

PURPOSE To determine the risk factors for retinopathy progression in type 1 (insulin-dependent) diabetes mellitus in a prospective cohort study. SUBJECTS AND METHODS Subjects were 485 participants in the Sorbinil Retinopathy Trial, a randomized trial of aldose reductase inhibition among patients aged 18 to 56 years with type 1 diabetes mellitus (duration of 1 to 15 years) and no or only mild retinopathy. Retinopathy progression, assessed by seven-field stereoscopic fundus photography, was defined as worsening by two or more levels on a standardized grading scale at the end of follow-up (median, 41 months). RESULTS The relative risks for retinopathy progression according to successively greater quintiles of total glycosylated hemoglobin level at baseline, after adjusting for age, diabetes duration, sorbinil assignment, and other variables, were 1.0, 2.0, 1.6, 3.7, and 4.4 (P trend <0.0001). Risk increased with greater baseline diastolic blood pressure: 1.0 for <70 mm Hg, 1.2 for 70 to 79 mm Hg, and 1.8 for > or =80 mm Hg (P for trend = 0.04). Diastolic blood pressure was a significant risk factor for progression in participants with mild baseline retinopathy (P for trend <0.02) but not in those without retinopathy at entry. Systolic blood pressure, by comparison, was not associated with progression. Baseline total cholesterol level was a marginally significant predictor of retinopathy progression when examined as a categorical variable (relative risks for increasing quartiles; 1.0, 1.6, 1.8, 1.9; P for trend = 0.03) but not when it was examined as a continuous variable or when hypercholesterolemic patients were compared with those with normal levels. Furthermore, when cholesterol levels were updated in subsequent visits, it was not a significant predictor of progression, and low density lipoprotein (LDL) cholesterol levels did not predict progression no matter how analyzed. Smoking was not associated with progression of retinopathy. CONCLUSIONS Levels of hyperglycemia and diastolic blood pressure predicted progression of retinopathy in type 1 diabetes mellitus. We found only a suggestion of an association between total cholesterol level (but not of LDL cholesterol level) and progression of retinopathy; resolution of this issue will require additional studies with larger sample sizes and longer follow-up.

Clinical experience with sorbinil—An aldose reductase inhibitor

A considerable volume of animal pharmacologic data support the view that increased flux through the polyol pathway provides a unifying hypothesis for the major complications of diabetes. An extensive clinical program has been established to verify the extrapolation of the animal pharmacologic findings to man. Clinical data accumulated to date confirm the biochemical and electrophysiologic effects, and encouraging evidence of a drug effect in diabetic neuropathy and retinopathy has already been observed. In the large, controlled safety data base already available, the long-term clinical use of sorbinil is devoid of significant adverse effects in terms of both subjective side effects and laboratory parameters. The only clinically important adverse reaction reported to date has been a hypersensitivity reaction in the early weeks of therapy, which is similar to that seen with other hydantoins.

Pharmacokinetics of the Aldose Reductase Inhibitor, Zopolrestat, in Humans

The pharmacokinetics of zopolrestat, an aldose reductase inhibitor that may be useful for the treatment of complications of diabetes, have been investigated using oral doses ranging from 50 to 1200 mg administered to healthy male volunteers. In a single‐dose study, Cmax, AUC(0–48), and urinary elimination of zopolrestat increased linearly with increasing dose. The amount of zopolrestat excreted unchanged in the urine within 48 hours ranged from 34 to 45% of the administered dose. Renal clearance ranged from 2.6 to 5.6 mL/min, and appeared to decrease as the dose was increased. In a 2‐week multiple dose study, the mean steady‐state minimum and maximum plasma concentrations, Cmin and Cmax, were 91.5 and 196 μg/mL for subjects administered 800 mg/day, and 131 and 281 μg/mL for subjects administered 1200 mg/day. Steady‐state AUC(0–24) was also dose proportional. The mean steady state half life of about 30.3 hours was consistent with the observed 2.2‐fold accumulation in plasma. Apparent oral clearance (Clpo) was 5.2 mL/min, and apparent volume of distribution (Vdss/F) was 12 L. Mean renal clearance was 2.2 mL/min, and approximately 45% of the administered dose was excreted into the urine at steady state. There was no effect of food consumption during dosing on the extent of absorption of zopolrestat. In in vitro studies, extensive, concentration‐dependent binding of zopolrestat to plasma proteins was observed. These data indicate that once‐daily dosing of zopolrestat will provide suitable exposure in the treatment of diabetic complications.

Sorbinil: A member of the novel class of spirohydantoin aldose reductase inhibitors☆

A decade ago, we discovered that spirohydantoins are a novel class of aldose reductase inhibitors characterized by very potent in vivo activity. This important discovery resulted from a systematic screening effort for in vitro activity against aldose reductase isolated from bovine lens and subsequent testing of active compounds for in vivo activity in a streptozotocin-diabetic rat model, measuring inhibition of sorbitol formation in sciatic nerve. In this in vivo model, spirohydantoins were clearly more potent than all known carboxylic acid-type aldose reductase inhibitors. Structure-activity studies in the spirohydantoin class demonstrated that potent in vitro and in vivo activity were obtained when the spiro junction was adjacent to an aromatic ring and when this junction was part of a 5- or 6-membered ring system fused to the aromatic ring. Excellent in vitro and in vivo activity was achieved in 6-halogenated chromane derivatives with the spirohydantoin group attached in the 4-position. In this series, biologic activity is highly stereospecific and associated with the S configuration. Sorbinil, the S isomer of the 6-fluoro derivative in this series, is one such example: it is 30 times more potent than its R isomer in vitro (IC50 0.15 v 4.4 mumol/L) and 100 times more potent in vivo (ED50 0.25 mg/kg po v 25 mg/kg po).

Aldose Reductase Inhibitors in Clinical Practice

SummaryExtensive animal data now exist to indicate potential benefit of sorbinil in the treatment of the major complications of diabetes mellitus. A clinical programme has been constructed to explore this therapeutic potential and encouraging evidence of drug effect has already been observed in patients with neuropathy and retinopathy. Two small preliminary studies in patients with painful neuropathy have shown that clinically significant reduction of pain was more frequently achieved with sorbinil than with placebo. A 6-month study of patients with retinopathy, using vitreous fluorophotometry as the criterion of retinal damage, showed significant (p=0.03) benefit for the sorbinil group compared with the placebo group. Drug evaluation in these areas is complex and difficult but it is anticipated that the accumulation of additional data will further substantiate the efficacy suggested by these early findings. The only clinically important adverse effect of sorbinil is the hypersensitivity reaction. This usually occurs during the initial weeks of therapy and is similar to that seen with phenytoin. The long term use of sorbinil is without significant adverse effects.

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.

Chapter 19. Anti-Diabetic Agents

Publisher Summary This chapter discusses studies focusing on anti-diabetic agents. Diabetes mellitus in humans is broadly classified in two types: the maturity onset type, characterized by a relative decrease in functional insulin, and the juvenile type in which there is a complete lack of insulin. Both groups suffer from the acute symptoms of diabetes, elevated fasting glycemia, glycosuria, glucose intolerance, and derangements in handling other substrates, in addition to the long-term complications of neuropathy, retinopathy, and microangiopathy. Recent studies on the morphology of the beta-cells of the pancreatic Islets of Langerhans—the cells responsible for synthesis, storage, and release of insulin—described the functional areas of synthesis and storage of insulin as well as some facets of the release of the stored hormone. Insulin is synthesized on the ribosomes and “packaged” in the Golgi apparatus to produce storage granules. When appropriately stimulated, these granules migrate to the outer edge of the beta-cell, possibly via the microtubular system, fuse with the cell membrane and expel their contents extracellularly by emiocytosis. The chapter highlights recent advances in anti-diabetic agents as well as concepts regarding the etiology of diabetic complications. The current methods of therapy are also elaborated.