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Aldose Reductase Inhibitors and Late Complications of Diabetes

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Summary

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 sorbinol 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 50–250mg 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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References

  • Beyer-Mears A, Cruz E. Reversal of diabetic cataract by sorbinil, an aldose reductase inhibitor. Diabetes 34: 15–21, 1985

    Article  PubMed  CAS  Google Scholar 

  • Beyer-Mears A, Ku L, Cohen MP. Glomerular polyol accumulation in diabetes and its prevention by oral sorbinil. Diabetes 33: 604–607, 1984

    Article  PubMed  CAS  Google Scholar 

  • Beyer-Mears A, Cruz E, Varagiannis E. Reversal of stage-1 sugar cataract by sorbinil, an aldose reductase inhibitor. Pharmacology 31: 88–96, 1985a

    Article  PubMed  CAS  Google Scholar 

  • Beyer-Mears A, Kelly K, Cruz E. Synergism of sorbinil and normal diet on reversal of stage-II sugar cataract. Pharmacology 31: 170–179, 1985b

    Article  PubMed  CAS  Google Scholar 

  • Beyer-Mears A, Cruz E, Edelist T, Varagiannis E. Diminished proteinuria in diabetes mellitus by sorbinil, an aldose reductase inhibitor. Pharmacology 32: 52–60, 1986

    Article  PubMed  CAS  Google Scholar 

  • Bron AJ. Screening for treatable diabetic retinopathy. British Medical Journal 290: 1025–1026, 1985

    Article  PubMed  CAS  Google Scholar 

  • Cayen MN, Hicks DR, Ferdinandi ES, Kraml M, Greselin E, et al. Metabolic disposition and pharmacokinetics of the aldose reductase inhibitor tolrestat in rats, dogs and monkeys. Drug Metabolism and Disposition 13: 412–419, 1985

    PubMed  CAS  Google Scholar 

  • Clements RS, Bell DSH. Complications of diabetes: prevalence, detection, current treatment, and prognosis. American Journal of Medicine 79 (Suppl. 5A): 2–7, 1985

    Article  PubMed  Google Scholar 

  • Cohen M. Aldose reductase inhibition, glomerular metabolism, and diabetic nephropathy. Diabetic Medicine 2: 203–206, 1985

    Article  PubMed  CAS  Google Scholar 

  • Cohen MP, Dasmahapatra A. Reduced glomerular Na/K ATPase in diabetes and its prevention by oral sorbinil. Clinical Research 32: 796A, 1984

    Google Scholar 

  • Crabbe MJC, Petcheg M, Burgess SEP, Cheng H. The penetration of sorbinil, an aldose reductase inhibitor, into lens, aqueous humour and erythrocytes of patients undergoing cataract extraction. Experimental Eye Research 40: 95–99, 1985

    Article  PubMed  CAS  Google Scholar 

  • Culebras A, Alió J, Herrera J-L, Pérez-López-Fraile MI. Effect of an aldose reductase inhibitor on diabetic peripheral neuropathy. Archives of Neurology 38: 133–134, 1981

    Article  PubMed  CAS  Google Scholar 

  • Cunha-Vaz JG, Mota CC, Leite EC, Faria Abreu JR, Ruas MA. Effect of aldose-reductase inhibitors on the blood-retinal barrier in early diabetic retinopathy. Diabetes 34 (Suppl. 1): 109A, 1985

    Article  Google Scholar 

  • Duchen LW, Anjorin A, Watkins PJ, Mackay JD. Pathology of autonomic neuropathy in diabetes mellitus. Annals of Internal Medicine 92 (Suppl.): 301–303, 1980

    PubMed  CAS  Google Scholar 

  • Ewing DJ, Campbell IW, Clarke BF. Assessment of cardiovascular effects in diabetic autonomic neuropathy and prognostic implications. Annals of Internal Medicine 92 (Suppl.): 308–311, 1980

    PubMed  CAS  Google Scholar 

  • Fagius J, Brattberg A, Jameson S, Berne C. Limited benefit of treatment of diabetic neuropathy with an aldose reductase inhibitor: a 24-week controlled trial. Diabetologia 28: 323–329, 1985

    Article  PubMed  CAS  Google Scholar 

  • Foulds G, O’Brien MM, Bianchine JR, Gabbay KH. Kinetics of an orally absorbed aldose reductase inhibitor, sorbinil. Clinical Pharmacology and Therapeutics 30: 693–700, 1981

    Article  PubMed  CAS  Google Scholar 

  • Gabbay KH, Spack N, Loo S, Hirsch HJ, Ackil AA. Aldose reductase inhibition: studies with alrestatin. Metabolism 28 (Suppl. 1): 471–476, 1979

    Article  PubMed  CAS  Google Scholar 

  • Gillon KRW, Hawthorne JN, Tomlinson DR. Myo-inositol and sorbitol metabolism in relation to peripheral nerve function in experimental diabetes in the rat: the effect of aldose reductase inhibition. Diabetologia 25: 365–371, 1983

    Article  PubMed  CAS  Google Scholar 

  • Gonzalez A-M, Sochor M, McLean P. The effect of an aldose reductase inhibitor (sorbinil) on the level of metabolites in lenses of diabetic rats. Diabetes 32: 482–485, 1983

    Article  PubMed  CAS  Google Scholar 

  • Gonzalez A-M, Sochor M, McLean P. Effect of sorbinil on lens metabolites in experimental diabetes. Diabetologia 27: 280A, 1984

    Google Scholar 

  • Greene DA, Lattimer SA. Action of sorbinil on diabetic peripheral nerve. Diabetes 33: 712–716, 1984

    Article  PubMed  CAS  Google Scholar 

  • Greene DA, Lattimer SA. The polyol pathway in dysfunction of diabetic peripheral nerve. Diabetic Medicine 2: 206–210, 1985

    Article  PubMed  CAS  Google Scholar 

  • Handelsman DJ, Turtle JR. Clinical trial of an aldose reductase inhibitor in diabetic neuropathy. Diabetes 30: 459–464, 1981

    Article  PubMed  CAS  Google Scholar 

  • Hicks DR, Krami M, Cayen MN, Dubuc J, Ryder S, et al. Tolrestat kinetics. Clinical Pharmacology and Therapeutics 36: 493–499, 1984

    Article  PubMed  CAS  Google Scholar 

  • Hotta N, Kakuta H, Fukasawa H, Kimura M, Koh N, et al. Effects of a fructose-rich diet and the aldose reductase inhibitor, ONO-2235, on the development of diabetic neuropathy in streptozotocin-treated rats. Diabetologia 28: 176–180, 1985

    PubMed  CAS  Google Scholar 

  • Jaspan JB, Herold K, Bartkus C. Effects of sorbinil therapy in diabetic patients with painful peripheral neuropathy and autonomic neuropathy. American Journal of Medicine 79 (Suppl. 5A): 25–37, 1985

    Google Scholar 

  • Judzewitsch RG, Jaspan JB, Polonsky KS, Weinberg CR, Halter JB. Aldose reductase inhibition improves nerve conduction velocity in diabetic patients. New England Journal of Medicine 308: 119–125, 1983

    Article  PubMed  CAS  Google Scholar 

  • Kador PF, Kinoshita JH. The identification of aldose reductase in the pathogenesis of diabetic complications: the background. Diabetic Medicine 2: 187–189, 1985

    Article  PubMed  CAS  Google Scholar 

  • Kikkawa R, Hatanaka I, Yasuda H, Kobayashi N, Shigeta Y, et al. Effect of a new aldose reductase inhibitor, (E)-3-carboxymethyl-5-[(2E)-methyl-3-phenylpropenylidene] rhodanine (ONO-2235) on peripheral nerve disorders in streptozotocin-diabetic rats. Diabetologia 24: 290–292, 1983

    Article  PubMed  CAS  Google Scholar 

  • Lehtinen J, Hyvönen K, Kilpeläinen H, Uusitupa M, Puhakainen E, et al. The effect of small dose of aldose reductase inhibitor (sorbinil) on diabetic neuropathy. Acta Neurologica Scandinavica 69 (Suppl. 98): 198, 1984

    Article  Google Scholar 

  • Lewin IG, O’Brien IAD, Morgan MH, Corrall RJM. Clinical and neurophysiological studies with the aldose reductase inhibitor, sorbinil, in symptomatic diabetic neuropathy. Diabetologia 26: 445–448, 1984

    Article  PubMed  CAS  Google Scholar 

  • Malone JI, Lowitt S, Harvey HC, Mandlow S. The effect of sorbinil (an aldose reductase inhibitor) upon red cell sorbitol and inositol. Diabetes 33 (Suppl.): 172A, 1984

    Article  Google Scholar 

  • O’Brien MM, Schofield PJ, Edwards MR. Inhibition of human brain aldose reductase and hexonate dehydrogenase by alrestatin and sorbinil. Journal of Neurochemistry 39: 810–814, 1982

    Article  PubMed  Google Scholar 

  • Pirart J. Diabetes mellitus and its degenerative complications: a prospective study of 4,400 patients observed between 1947 and 1973. Diabetes Case 1: 168–188, 1978

    Google Scholar 

  • Pitts NE, Vreeland F, Shaw GL, Peterson MJ, Mehta DJ, et al. Clinical experience with sorbinil — an aldose reductase inhibitor. Metabolism 35 (Suppl. 1): 96–100, 1986

    Article  PubMed  CAS  Google Scholar 

  • Popp-Snijders C, Lomecky-Janousek MZ, Schouten JA, van der Veen EA. Red cell sorbitol determined by capillary gas chromatography in type 1 (insulin-dependent) diabetic patients before and after sorbinil treatment. Diabetologia 25: 187, 1983

    Google Scholar 

  • Poulsom R, Mirrlees DJ, Earl De N, Heath H. The effects of an aldose reductase inhibitor upon the sorbitol pathway, fructose-1-phosphate and lactate in the retina and nerve of streptozotocin-diabetic rats. Experimental Eye Research 36: 751–760, 1983

    Article  PubMed  CAS  Google Scholar 

  • Puhakainen E, Säämänen A-M, Lehtinen J, Kilpeläinen H. The effect of aldose reductase inhibitor (sorbinil) on erythrocyte sorbitol concentration in diabetic neuropathy. Acta Endocrinologica 103 (Suppl. 257): Abstract 56, 1983

    Google Scholar 

  • Raskin P, Rosenstock J, Challis P, Ryder S, Mullane JF. Effect of tolrestat on red blood cell sorbitol levels in patients with diabetes. Clinical Pharmacology and Therapeutics 38: 625–630, 1985

    Article  PubMed  CAS  Google Scholar 

  • Sabiston DW. Diabetic retinopathy. New Ethicals, Sept: 17–18, 1983

  • Schouten JA, Heimans JJ, Popp-Snijders C, Boot H, van der Akker J, et al. A 3 month placebo-controlled, efficacy study of sorbinil for diabetic neuropathy. Diabetologia 27: 329A, 1984

    Google Scholar 

  • Simard-Duquesne N, Greselin E, Dubuc J, Dvornik D. The effects of a new aldose reductase inhibitor (tolrestat) in galactosemic and diabetic rats. Metabolism 34: 885–892, 1985

    Article  PubMed  CAS  Google Scholar 

  • Stribling D, Mirrlees DJ, Harrison HE, Earl DCN. Properties of ICI 128,436, a novel aldose reductase inhibitor, and its effects on diabetic complications in the rat. Metabolism 34: 336–344, 1985

    Article  PubMed  CAS  Google Scholar 

  • Tomlinson DR, Holmes PR, Mayer JH. Reversal, by treatment with an aldose reductase inhibitor, of impaired axonal transport and motor nerve conduction velocity in experimental diabetes mellitus. Neuroscience Letters 31: 189–193, 1982

    Article  PubMed  CAS  Google Scholar 

  • Tomlinson DR, Moriarty RJ, Mayer JH. Prevention and reversal of defective axonal transport and motor nerve conduction velocity in rats with experimental diabetes by treatment with the aldose reductase inhibitor sorbinil. Diabetes 33: 470–476, 1984

    Article  PubMed  CAS  Google Scholar 

  • Tomlinson DR, Townsend J, Fretten P. Prevention of defective axonal transport in streptozotocin-diabetic rats by treatment with ‘statil’ (ICI 128436), an aldose reductase inhibitor. Diabetes 34: 970–972, 1985

    Article  PubMed  Google Scholar 

  • Unakar NJ, Tsui JY. Inhibition of galactose-induced alterations in ocular lens with sorbinil Experimental Eye Research 36: 685–694, 1983

    Article  PubMed  CAS  Google Scholar 

  • Ward JD. Diabetic neuropathies: current concepts in prevention and treatment. Drugs 32: 279–289, 1986

    Article  PubMed  CAS  Google Scholar 

  • Watkins PJ. Pain and diabetic neuropathy. British Medical Journal 288: 168–169, 1984

    Article  PubMed  CAS  Google Scholar 

  • Williamson JR, Chang K, Rowold E, Mawel J, Tomlinson M, et al. Sorbinol prevents diabetes-induced increases in vascular permeability but does not alter collagen cross-linking. Diabetes 34: 703–705, 1985

    Article  PubMed  CAS  Google Scholar 

  • Young RJ, Ewing DJ, Clarke BF. A controlled trial of sorbinil, an aldose reductase inhibitor, in chronic painful diabetic neuropathy. Diabetes 32: 938–942, 1983

    Article  PubMed  CAS  Google Scholar 

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    Paul Benfield

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Benfield, P. Aldose Reductase Inhibitors and Late Complications of Diabetes. Drugs 32 (Suppl 2), 43–55 (1986). https://doi.org/10.2165/00003495-198600322-00010

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