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Query: UMLS:C0030193 (pain)
 261,466 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Neuropathy is the most common and perhaps the most devastating complication associated with diabetes. Although many theories regarding the pathogenesis of diabetic neuropathies have been proposed, the most popular theory focuses on the accumulation of sorbitol in the nerve cell through the "polyol pathway." Treatment for diabetic neuropathy remains inadequate. Newer agents such as the aldose reductase inhibitors show some promise in halting and perhaps reversing the pathogenesis of this complication; however, these agents remain investigational. Currently, the most reasonable approach involves the use of agents to control pain and other symptoms associated with this progressive disease.
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PMID:Drug therapy of diabetic neuropathy. 158 3

Increased flux through the polyol pathway mediated by the enzyme aldose reductase may be associated with the development of diabetic neuropathy. Fifty-four diabetic patients (median age 56 yr, range 25-65 yr) with chronic neuropathic symptoms were randomly allocated to placebo or aldose reductase inhibition (300 or 600 mg ponalrestat ICI 128436) groups for 24 wk. Patients with vibration perception thresholds (VPTs) greater than 35 V at the great toe or thermal difference thresholds (TTs) greater than 10 degrees C on the dorsum of the foot were excluded from the trial. No significant changes were observed in symptoms of pain, numbness, or paresthesia between ponalrestat and placebo groups, and there were no improvements in VPT or TT at several sites. Posterior tibial nerve conduction velocity changed from 35.3 +/- 4.9 m/s at baseline to 33.4 +/- 4.0 m/s at 24 wk (NS) with placebo compared with 37.6 +/- 5.6 vs. 37.2 +/- 8.7 m/s (NS) with 300 mg ponalrestat and 34.5 +/- 6.1 vs. 36.2 +/- 6.8 m/s (NS) with 600 mg ponalrestat. Further studies are indicated with intervention at an earlier stage in the evolution of neuropathy and for longer periods.
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PMID:Clinical and neurophysiological studies of aldose reductase inhibitor ponalrestat in chronic symptomatic diabetic peripheral neuropathy. 190 8

Studies of the effect of sorbinil, an aldose reductase inhibitor, in human diabetic neuropathy have shown improvements in motor and sensory nerve conduction velocity and somatosensory evoked potentials, and a reduction in neuropathic pain. Improvements in motor and sensory deficits have also been detected clinically. These effects occurred after the administration of sorbinil for relatively short periods. However, more prolonged treatment may be necessary to achieve a therapeutic response in some patients. The results of tests of cardiac autonomic (vagal) function improved with the administration of sorbinil for 6 weeks. The most notable finding was a reduction in resting heart rate. Improvements in both clinical and test measures, related to autonomic and somatic nerve function, have reversed on withdrawal of sorbinil and improved again on renewal of administration. Toxic manifestations of sorbinil were infrequent, almost invariably mild, and readily reversible.
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PMID:Pharmacological inhibition of aldose reductase in human diabetic neuropathy. 243 59

Clinical investigations with the aldose reductase inhibitor sorbinil in patients with peripheral neuropathy due to diabetes are described. After an improvement in motor and sensory nerve conduction velocities was demonstrated in asymptomatic diabetic patients taking sorbinil (compared with velocities during a placebo period), 11 patients with painful diabetic neuropathy were treated with sorbinil for three weeks without alterations in diabetic management or control. Therapy was placebo-controlled in a single-blind fashion in eight patients. Pain (assessed by or on a zero to 20 rating scale), which had been constant for many months before entry into the study and unresponsive to numerous medications, improved from a mean score of 16 to 8 and returned when the drug was discontinued. Objective improvement in sensation and strength were observed in some cases. Improvements in nerve conduction velocity and cardiac autonomic function were also documented. Cardiac autonomic neuropathy was studied in 36 patients in a double-blind, placebo-controlled, randomized, noncrossover trial. Patients received one 250-mg sorbinil tablet or one placebo tablet daily for six weeks, after a one-week baseline period. Glycemic control did not change during the study period, as indicated by unaltered glycohemoglobin levels. Response was assessed by expiration-inspiration ratios, obtained on electrocardiography during six cycles per minute respiration, and by resting minimal heart rate, both measures of vagal function. In the sorbinil-treated group, expiration-inspiration ratios improved from 1.074 +/- 0.012 to 1.096 +/- 0.020 (p less than 0.03). There was a slight decrease in the ratios in the placebo-treated group, from 1.112 +/- 0.023 to 1.105 +/- 0.023 (not significant). The difference between the Week 0 to Week 6 changes in each group was significant (p less than 0.01). Resting minimal heart rate decreased in the sorbinil-treated group from 76.4 +/- 2.3 to 66.8 +/- 2.8 +/- 2.4 beats per minute (p less than 0.001), with a mean change of 10 +/- 2. In the placebo-treated group, heart rate was unchanged (77.9 +/- 3.9 to 77.5 +/- 3.3 beats per minute). The two-sample t test of the within-group differences was also significant (p less than 0.001). The changes in both expiration-inspiration ratios and resting minimal heart rate are consistent with a sorbinil-related improvement in cardiac parasympathetic nerve function. Several isolated cases of apparent sorbinil-related improvements in autonomic symptoms have been observed.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Effects of sorbinil therapy in diabetic patients with painful peripheral neuropathy and autonomic neuropathy. 300 Jan 76

Diabetic neuropathy is a common complication of diabetes mellitus with significant morbidity and mortality. Hyperglycemia with its secondary metabolic, vascular, and enzymatic consequences is most likely to be the predominant cause. The clinical manifestations includes a wide range of somatic and autonomic syndromes. Painful diabetic neuropathy may require symptomatic treatment. The precise role of therapies such as continuous subcutaneous insulin therapy and aldose reductase inhibitors remains to be clarified.
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PMID:Peripheral diabetic neuropathy. 305 62

Neuropathy and retinopathy are two potentially serious late complications of diabetes. There is accumulating evidence that the development of these conditions is closely related to increased activity of the polyol pathway, which occurs in certain tissues as a consequence of long term hyperglycaemia. Symptomatic diabetic neuropathy may appear as one of many forms and is frequently accompanied by pain. Diabetic retinopathy is a progressive degeneration of the retina that represents one of the major causes of blindness in the developed world. A good prognosis for either of these conditions is believed to rely on early diagnosis and optimisation of glycaemic control as they become less reversible with progression of cellular damage. A new approach to the treatment of these and other late complications of diabetes may be offered by recently developed drugs, such as sorbinil, that inhibit the enzyme aldose reductase. In various animal models of late complications of diabetes sorbinil and other aldose reductase inhibitors have been shown to reverse some of the biochemical and physiological changes believed to underlie these complications. These include prevention or reversal of the accumulation of sorbitol and depletion of myo-inositol in nerve, lens and renal glomeruli. Sorbinil also counteracts the slowing of nerve conduction velocities, reverses the structural changes of Sipple stages I and II cataracts and prevents proteinuria in diabetic rats. Orally administered sorbinil is absorbed rapidly and reaches steady state plasma concentrations after 6 to 10 days' administration. Its elimination half-life is long (38-52 hours) and much greater than that of another aldose reductase inhibitor, tolrestat (10-12 hours). Within the dose range 50-250 mg about one-third of administered sorbinil appears in the urine as unchanged drug. In the small number of clinical studies of diabetic patients with neuropathies sorbinil has demonstrated limited therapeutic effects. There is now a requirement for studies of its prophylactic use and its therapeutic use in patients with diabetic neuropathy in the early stages of development.
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PMID:Aldose reductase inhibitors and late complications of diabetes. 309 44

Diabetic nerve damage leads to a wide variety of unpleasant problems: painful sensations, muscle weakness, numb feet predisposing to ulcers, impotence, and a series of distressing effects due to autonomic dysfunction. At present, there is no single effective treatment for the many clinical syndromes--each of which may well have a different cause. Improved blood glucose control must remain the first line of treatment, hopefully to improve nerve structure and function but also to raise the pain threshold. A variety of sedatives and analgesics may also help some patients. Inhibition of the enzyme aldose reductase with resultant interference with neural sorbitol and myo-inositol metabolism would seem to have a good theoretical basis in therapy, and detailed results of long term clinical trials of aldose reductase inhibitors such as sorbinil and tolrestat are awaited with interest. Their role in the future could be more important in prevention of nerve damage than in attempting to reverse gross end-stage nerve destruction. In diabetic subjects with loss of pain sensation in the foot due to neuropathy or in the more advanced state of foot ulceration, intensive educational and clinical efforts should be exerted to prevent this distressing and common problem. In the future, a more detailed understanding of the biochemical abnormalities occurring in nerves and their effect on nerve function, structure and vasculature may lead to more satisfactory and logical treatments for this the commonest single complication of diabetes.
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PMID:Diabetic neuropathies. Current concepts in prevention and treatment. 353 Jul 5

11 patients with severely painful diabetic neuropathy previously unresponsive to numerous drugs were treated with an aldose reductase inhibitor ('Sorbinil'--Pfizer CP 45, 634); 8 also received a placebo. Response was assessed according to a 0-20 graphic rating scale for pain and by tests for motor and sensory nerve conduction velocities (NCV) and cardiac autonomic nerve function. 8 patients had moderate to marked relief of symptoms, generally beginning on the 3rd or 4th day of medication, 2 had equivocal responses, and 1 had no change. Each of 4 patients with diabetic amyotrophy reported striking improvement in pain and mild to moderate improvement in proximal leg muscle strength; 2 of these noticed improved sensory perception in their feet. Objective evidence of improved muscle strength was obtained in each of these 4 patients and of improved sensation in 3. On stopping medication, pain worsened in 7 of 8 responders, although generally with some delay, suggesting a carry over effect. During the course of treatment autonomic nerve function improved significantly in 6 of 7 patients tested and across the group, and NCV improved in 4 of 7 tested. Both of these variables deteriorated after withdrawal of the drug. A correlation between NCV response and clinical response was apparent. Very little toxicity was observed. These observations suggest that aldose reductase inhibitors may be important in the treatment of symptomatic somatic and autonomic neuropathies complicating diabetes.
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PMID:Treatment of severely painful diabetic neuropathy with an aldose reductase inhibitor: relief of pain and improved somatic and autonomic nerve function. 613 1

A double-blind, randomized, placebo-controlled cross-over trial of the aldose reductase inhibitor sorbinil was undertaken in 15 patients (age 35-68 yr) with chronic painful diabetic neuropathy. Treatment was evaluated by subjective pain responses, clinical examination, vibration perception threshold, motor and sensory nerve electrophysiology, and cardiovascular reflex tests of autonomic nerve function. Among the many measurements, only pain, tendon reflex scores, and sural sensory potential amplitude improved significantly during sorbinil administration, while scores of clinical sensory examination deteriorated. Four patients experienced an idiosyncratic reaction that rapidly recovered on discontinuing the drug. This study suggests that aldose reductase inhibitor treatment with suggests that aldose reductase inhibitor treatment with sorbinil may have an effect on symptomatic diabetic neuropathy in man.
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PMID:A controlled trial of sorbinil, an aldose reductase inhibitor, in chronic painful diabetic neuropathy. 622 86

The clinical efficacy of epalrestat (150 mg/day, 50 mg tid, po; A group), an aldose reductase inhibitor, was evaluated in 196 patients with diabetic neuropathy by a double-blind study using placebo (9 mg/day, 3 mg tid, po; P group) as a control for 12 weeks. The disappearance rates of upper limb spontaneous pain were 42.9% and 12.0% in the A and P groups, respectively, and those of lower limb spontaneous pain 48.6% and 22.6%, thus being significantly higher in the A group (p < 0.05, logrank-test). The motor nerve conduction velocity of the peroneal nerve significantly increased only in the A group (delta 1.6 +/- 0.6 m/sec, p < 0.01, paired t-test), and the extent of increase in that of the median nerve was significantly greater in the A group than in the P group (p < 0.05). Thresholds of vibratory sensation and autonomic nerve function were also significantly improved in the A group (p < 0.05). The data were reanalyzed by dividing patients into two groups according to their HbA1c values. The improvement ratings of subjective symptoms and of nerve function tests for cases with HbA1c > or = 7.5% were both significantly different between the A and P groups, with the improvement rate being higher in the A group, and also higher as compared to the analysis for cases with HbA1c < 7.5%.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effects of an aldose reductase inhibitor, epalrestat, on diabetic neuropathy. Clinical benefit and indication for the drug assessed from the results of a placebo-controlled double-blind study. 757 7


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