| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
From the Departments of Internal Medicine (Dr. Greene) and Biostatistics (Dr. Brown), University of Michigan, Ann Arbor, MI; and the Department of Neuroscience (Dr. Arezzo), Albert Einstein College of Medicine, Yeshiva University, Bronx, NY.
Address correspondence and reprint requests to Dr. Douglas A. Greene, 3920 Taubman Center, Box 0354, University of Michigan Medical Center, Ann Arbor, MI 48109-0354.
OBJECTIVE: To determine whether the aldose reductase inhibitor (ARI) zenarestat improves nerve conduction velocity (NCV) and nerve morphology in diabetic peripheral polyneuropathy (DPN).
METHODS: A 52-week, randomized, placebo-controlled, double-blinded, multiple-dose, clinical trial with the ARI zenarestat was conducted in patients with mild to moderate DPN. NCV was measured at baseline and study end. Contralateral sural nerve biopsies were obtained at 6 weeks and at the study’s end for nerve sorbitol measurement and computer-assisted light morphometry to determine myelinated nerve fiber density (number of fibers/mm2 cross-sectional area) in serial bilateral sural nerve biopsies.
RESULTS: Dose-dependent increments in sural nerve zenarestat level and sorbitol suppression were accompanied by significant improvement in NCV. In a secondary analysis, zenarestat doses producing >80% sorbitol suppression were associated with a significant increase in the density of small-diameter (<5 µm) sural nerve myelinated fibers.
CONCLUSIONS: Aldose reductase pathway inhibition improves NCV slowing and small myelinated nerve fiber loss in DPN in humans, but >80% suppression of nerve sorbitol content is required. Thus, even low residual levels of aldose reductase activity may be neurotoxic in diabetes, and potent ARIs such as zenarestat may be required to stop or reverse progression of DPN.
This article has been cited by other articles:
|
|
 |
|
  P. J. Dyck, J. E. Norell, H. Tritschler, K. Schuette, R. Samigullin, D. Ziegler, E. J. Bastyr III, W. J. Litchy, and P. C. O'Brien Challenges in Design of Multicenter Trials: End points assessed longitudinally for change and monotonicity Diabetes Care, October 1, 2007; 30(10): 2619 - 2625. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. R. Drel, N. Mashtalir, O. Ilnytska, J. Shin, F. Li, V. V. Lyzogubov, and I. G. Obrosova The Leptin-Deficient (ob/ob) Mouse: A New Animal Model of Peripheral Neuropathy of Type 2 Diabetes and Obesity Diabetes, December 1, 2006; 55(12): 3335 - 3343. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Hotta, Y. Akanuma, R. Kawamori, K. Matsuoka, Y. Oka, M. Shichiri, T. Toyota, M. Nakashima, I. Yoshimura, N. Sakamoto, et al. Long-Term Clinical Effects of Epalrestat, an Aldose Reductase Inhibitor, on Diabetic Peripheral Neuropathy: The 3-year, multicenter, comparative Aldose Reductase Inhibitor-Diabetes Complications Trial Diabetes Care, July 1, 2006; 29(7): 1538 - 1544. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. G. Smith, J. Russell, E. L. Feldman, J. Goldstein, A. Peltier, S. Smith, J. Hamwi, D. Pollari, B. Bixby, J. Howard, et al. Lifestyle Intervention for Pre-Diabetic Neuropathy. Diabetes Care, June 1, 2006; 29(6): 1294 - 1299. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Misawa, S. Kuwabara, K. Kanai, N. Tamura, M. Nakata, S. Sawai, K. Yagui, and T. Hattori Aldose reductase inhibition alters nodal Na+ currents and nerve conduction in human diabetics Neurology, May 23, 2006; 66(10): 1545 - 1549. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Kakinoki, S. Sekimoto, S. Yuki, T. Ohgami, M. Sejima, K. Yamagami, and K.-i. Saito Orally Active Neurotrophin-Enhancing Agent Protects Against Dysfunctions of the Peripheral Nerves in Hyperglycemic Animals Diabetes, March 1, 2006; 55(3): 616 - 621. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V Bansal, J Kalita, and U K Misra Diabetic neuropathy Postgrad. Med. J., February 1, 2006; 82(964): 95 - 100. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. Bril, R. A. Buchanan, and the Ranirestat Study Group* Long-Term Effects of Ranirestat (AS-3201) on Peripheral Nerve Function in Patients With Diabetic Sensorimotor Polyneuropathy Diabetes Care, January 1, 2006; 29(1): 68 - 72. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Vinik Use of Antiepileptic Drugs in the Treatment of Chronic Painful Diabetic Neuropathy J. Clin. Endocrinol. Metab., August 1, 2005; 90(8): 4936 - 4945. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Li, V. R. Drel, C. Szabo, M. J. Stevens, and I. G. Obrosova Low-Dose Poly(ADP-Ribose) Polymerase Inhibitor-Containing Combination Therapies Reverse Early Peripheral Diabetic Neuropathy Diabetes, May 1, 2005; 54(5): 1514 - 1522. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. D. Davis, L. Kiers, L. MacGregor, M. Quinn, J. Arezzo, M. Green, M. Rosenthal, M. Chia, M. Michael, P. Bartley, et al. A Randomized, Double-Blinded, Placebo-Controlled Phase II Trial of Recombinant Human Leukemia Inhibitory Factor (rhuLIF, Emfilermin, AM424) to Prevent Chemotherapy-Induced Peripheral Neuropathy Clin. Cancer Res., March 1, 2005; 11(5): 1890 - 1898. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. A.F. Sima, M. Calvani, M. Mehra, A. Amato, and for the Acetyl-l-Carnitine Study Group Acetyl-L-Carnitine Improves Pain, Nerve Regeneration, and Vibratory Perception in Patients With Chronic Diabetic Neuropathy: An analysis of two randomized placebo-controlled trials Diabetes Care, January 1, 2005; 28(1): 89 - 94. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. G. Obrosova, P. Pacher, C. Szabo, Z. Zsengeller, H. Hirooka, M. J. Stevens, and M. A. Yorek Aldose Reductase Inhibition Counteracts Oxidative-Nitrosative Stress and Poly(ADP-Ribose) Polymerase Activation in Tissue Sites for Diabetes Complications Diabetes, January 1, 2005; 54(1): 234 - 242. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Uehara, S.-I. Yamagishi, S. Otsuki, S. Chin, and S. Yagihashi Effects of Polyol Pathway Hyperactivity on Protein Kinase C Activity, Nociceptive Peptide Expression, and Neuronal Structure in Dorsal Root Ganglia in Diabetic Mice Diabetes, December 1, 2004; 53(12): 3239 - 3247. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. Bril, R. A. Buchanan, and the AS-3201 Study Group Aldose Reductase Inhibition by AS-3201 in Sural Nerve From Patients With Diabetic Sensorimotor Polyneuropathy Diabetes Care, October 1, 2004; 27(10): 2369 - 2375. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Ziegler Polyneuropathy in the diabetic patient--update on pathogenesis and management Nephrol. Dial. Transplant., September 1, 2004; 19(9): 2170 - 2175. [Full Text] [PDF]
|
|
|
|
 |
|
 A. M. Vincent, J. W. Russell, P. Low, and E. L. Feldman Oxidative Stress in the Pathogenesis of Diabetic Neuropathy Endocr. Rev., August 1, 2004; 25(4): 612 - 628. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. J.M. Boulton, R. A. Malik, J. C. Arezzo, and J. M. Sosenko Diabetic Somatic Neuropathies Diabetes Care, June 1, 2004; 27(6): 1458 - 1486. [Full Text] [PDF]
|
|
|
|
|
|
D. Sigaudo-Roussel, C. Demiot, B. Fromy, A. Koitka, G. Leftheriotis, P. Abraham, and J. L. Saumet Early Endothelial Dysfunction Severely Impairs Skin Blood Flow Response to Local Pressure Application in Streptozotocin-Induced Diabetic Mice Diabetes, June 1, 2004; 53(6): 1564 - 1569. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. J. Brown, S. J. Bird, S. Watling, H. Kaleta, L. Hayes, S. Eckert, and H. L. Foyt Natural Progression of Diabetic Peripheral Neuropathy in the Zenarestat Study Population Diabetes Care, May 1, 2004; 27(5): 1153 - 1159. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. Bril, Y. Ono, and R. A. Buchanan Sural Nerve Sorbitol in Patients With Diabetic Sensorimotor Polyneuropathy Diabetes Care, May 1, 2004; 27(5): 1160 - 1163. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Kallinikos, M. Berhanu, C. O'Donnell, A. J. M. Boulton, N. Efron, and R. A. Malik Corneal Nerve Tortuosity in Diabetic Patients with Neuropathy Invest. Ophthalmol. Vis. Sci., February 1, 2004; 45(2): 418 - 422. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. F. Johnson, R. W. Nesto, M. A. Pfeifer, W. R. Slater, A. I. Vinik, D. A. Chyun, G. Law, F. J.Th. Wackers, and L. H. Young Cardiac Abnormalities in Diabetic Patients With Neuropathy: Effects of aldose reductase inhibitor administration Diabetes Care, February 1, 2004; 27(2): 448 - 454. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. M Setter, R K. Campbell, and C. J Cahoon Biochemical Pathways for Microvascular Complications of Diabetes Mellitus Ann. Pharmacother., December 1, 2003; 37(12): 1858 - 1866. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Thrainsdottir, R. A. Malik, L. B. Dahlin, P. Wiksell, K. F. Eriksson, I. Rosen, J. Petersson, D. A. Greene, and G. Sundkvist Endoneurial Capillary Abnormalities Presage Deterioration of Glucose Tolerance and Accompany Peripheral Neuropathy in Man Diabetes, October 1, 2003; 52(10): 2615 - 2622. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Malik Failure to define the pathogenesis and treatment of human diabetic neuropathy The British Journal of Diabetes & Vascular Disease, March 1, 2003; 3(2): 107 - 111. [Abstract] [PDF]
|
|
|
|
|
|
V. Asnaghi, C. Gerhardinger, T. Hoehn, A. Adeboje, and M. Lorenzi A Role for the Polyol Pathway in the Early Neuroretinal Apoptosis and Glial Changes Induced by Diabetes in the Rat Diabetes, February 1, 2003; 52(2): 506 - 511. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z. T. Bloomgarden Neuropathy, Womens' Health, and Socioeconomic Aspects of Diabetes Diabetes Care, June 1, 2002; 25(6): 1085 - 1094. [Full Text] [PDF]
|
|
|
|
 |
|
 S. Yagihashi, S.-I. Yamagishi, R.-i. Wada, M. Baba, T. C. Hohman, C. Yabe-Nishimura, and Y. Kokai Neuropathy in diabetic mice overexpressing human aldose reductase and effects of aldose reductase inhibitor Brain, December 1, 2001; 124(12): 2448 - 2458. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Hotta, T. Toyota, K. Matsuoka, Y. Shigeta, R. Kikkawa, T. Kaneko, A. Takahashi, K. Sugimura, Y. Koike, J. Ishii, et al. Clinical Efficacy of Fidarestat, a Novel Aldose Reductase Inhibitor, for Diabetic Peripheral Neuropathy: A 52-week multicenter placebo-controlled double-blind parallel group study Diabetes Care, October 1, 2001; 24(10): 1776 - 1782. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Q. Yang, R. Kaji, T. Takagi, N. Kohara, N. Murase, Y. Yamada, Y. Seino, and H. Bostock Abnormal axonal inward rectifier in streptozocin-induced experimental diabetic neuropathy Brain, June 1, 2001; 124(6): 1149 - 1155. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Nakayama, J. Nakamura, Y. Hamada, S. Chaya, R. Mizubayashi, Y. Yasuda, H. Kamiya, N. Koh, and N. Hotta Aldose Reductase Inhibition Ameliorates Pupillary Light Reflex and F-Wave Latency in Patients With Mild Diabetic Neuropathy Diabetes Care, June 1, 2001; 24(6): 1093 - 1098. [Abstract] [Full Text]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
