Neuromuscular DiseasesNeuromuscular DiseasesНервно-мышечные болезни2222-87212413-0443Publishing House ABV Press2410.17650/2222-8721-2014-0-3-6-12LECTURES AND REVIEWSЛЕКЦИИ И ОБЗОРЫAcetyl-L-carnitine improves pain, nerve regeneration, and vibratory perception in patients with chronic diabetic neuropathyПоложительное влияние ацетил-L-карнитина на болевой синдром, регенерацию нервов и вибрационное чувство у пациентов с хронической диабетической нейропатией. Анализ результатов двух рандомизированных плацебоконтролируемых исследованийA.F. SimaAnders
Russian Federation
CalvaniMenotti
Russian Federation
MehraMunish
Russian Federation
AmatoAntonino
Russian Federation
Departments of Pathology and Neurology, Wayne State University, Detroit, MISigma-Tau spA, Pomezia, Rome, ItalyMedifacts International, Rockville, MDSigma-Tau Research, Gaithersburg, MD19092014436121902201519022015Copyright ©; 2014, A.F. Sima A., Calvani M., Mehra M., Amato A.Copyright ©; 2014, A.F. Sima A., Calvani M., Mehra M., Amato A.2014A.F. Sima A., Calvani M., Mehra M., Amato A.A.F. Sima A., Calvani M., Mehra M., Amato A.https://creativecommons.org/licenses/by/4.0https://nmb.abvpress.ru/jour/article/view/24

Objective — we evaluated frozen databases from two 52‑week randomized placebocontrolled clinical diabetic neuropathy trials testing two doses of acetyl-l-carnitine (alc): 500 and 1,000 mg / day t. i. d.

Research design and methods — intention-to-treat patients amounted to 1,257 or 93 % of enrolled patients. Efficacy end points were sural nerve morphometry, nerve conduction velocities, vibration perception thresholds, clinical symptom scores, and a visual analogue scale for most bothersome symptom, most notably pain. The two studies were evaluated separately and combined.

Results — data showed significant improvements in sural nerve fiber numbers and regenerating nerve fiber clusters. Nerve conduction velocities and amplitudes did not improve, whereas vibration perception improved in both studies. Pain as the most bothersome symptom showed significant improvement in one study and in the combined cohort taking 1,000 mg alc.

Conclusions — these studies demonstrate that alc treatment is efficacious in alleviating symptoms, particularly pain, and improves nerve fiber regeneration and vibration perception in patients with established diabetic neuropathy.

acetyl-L-carnitinecarnitinnerve biopsymorphometry of the sural nerveC-fibersvibration senseelectromyographyhyperglycemianeuropathic paindiabetes mellitusdiabetic neuropathyацетил-L-карнитинкарнитинбиопсия нерваморфометрия икроножного нерваС-волокнавибрационное чувствоэлектромиографиягипергликемиянейропатическая больсахарный диабетдиабетическая нейропатия1. Sugimoto K., Murakawa Y., Sima A.A.F. Diabetic neuropathy: a continuing enigma. Diabetes Metab Res Rev2000;16:408–33.Sugimoto K., Murakawa Y., Sima A.A.F. Diabetic neuropathy: a continuing enigma. Diabetes Metab Res Rev2000;16:408–33.2. Sima A.A.F. New insights into the metabolic and molecular basis for diabetic neuropathy. Cell Mol Life Sci 2003;60:2445–64.Sima A.A.F. New insights into the metabolic and molecular basis for diabetic neuropathy. Cell Mol Life Sci 2003;60:2445–64.3. Dyck P.J., Thomas P.K. Diabetic polyneuropathy. In: Diabetic Neuropathy. Philadelphia: W.B. Saunders, 1999; p. 239–406.Dyck P.J., Thomas P.K. Diabetic polyneuropathy. In: Diabetic Neuropathy. Philadelphia: W.B. Saunders, 1999; p. 239–406.4. Sima A.A.F. Diabetic neuropathy: pathogenetic background, current and future therapies. Expert Rev Neurotherapeutics 2001;1:225–38.Sima A.A.F. Diabetic neuropathy: pathogenetic background, current and future therapies. Expert Rev Neurotherapeutics 2001;1:225–38.5. Fagius J., Brattberg A., Jameson S., Berne C. Limited benefits of treatment of diabetic polyneuropathy with an aldose reductase inhibitor: a 24-wk controlled trial. Diabetologia 1985;28:323–9.Fagius J., Brattberg A., Jameson S., Berne C. Limited benefits of treatment of diabetic polyneuropathy with an aldose reductase inhibitor: a 24-wk controlled trial. Diabetologia 1985;28:323–9.6. Sima A.A.F., Bril V., Nathaniel V. et al. Regeneration and repair of myelinated fibers in sural nerve biopsies from patients with diabetic neuropathy treated with an aldose reductase inhibitor. N Engl J Med 1988;319: 548–55.Sima A.A.F., Bril V., Nathaniel V. et al. Regeneration and repair of myelinated fibers in sural nerve biopsies from patients with diabetic neuropathy treated with an aldose reductase inhibitor. N Engl J Med 1988;319: 548–55.7. Boulton A.J.M., Levin S., Comstock J.A. A multicenter trial of the aldose reductase inhibitor tolrestat, in patients with symptomatic diabetic neuropathy. Diabetologia 1990;33:431–7.Boulton A.J.M., Levin S., Comstock J.A. A multicenter trial of the aldose reductase inhibitor tolrestat, in patients with symptomatic diabetic neuropathy. Diabetologia 1990;33:431–7.8. Macleod A.F., Boulton A.J.M., Owens D.R. et al. A multicenter trial of the aldose reductase inhibitor in patients with symptomatic diabetic peripheral neuropathy. Diabetes Metab 1992;8: 14 –20.Macleod A.F., Boulton A.J.M., Owens D.R. et al. A multicenter trial of the aldose reductase inhibitor in patients with symptomatic diabetic peripheral neuropathy. Diabetes Metab 1992;8: 14 –20.9. Pfeifer M.A., Schumer M.P., Gelber D.A. Aldose reductase inhibitors: the end of an era or the need for different trial design. Diabetes 1997;46:582–9.Pfeifer M.A., Schumer M.P., Gelber D.A. Aldose reductase inhibitors: the end of an era or the need for different trial design. Diabetes 1997;46:582–9.10. Ziegler D., Hanefeld M., Ruhnau K.-J. et al. Treatment of symptomatic diabetic polyneuropathy with the anti-oxidant α-lipoic acid. Diabetes Care 1999;22:1296–301.Ziegler D., Hanefeld M., Ruhnau K.-J. et al. Treatment of symptomatic diabetic polyneuropathy with the anti-oxidant α-lipoic acid. Diabetes Care 1999;22:1296–301.11. Scarpini E., Doneda P., Pizzul S. et al. L-carnitine and acetyl-L-carnitine in human nerves from normal and diabetic subjects. J Peripher Nerv Syst 1996;1:157–63.Scarpini E., Doneda P., Pizzul S. et al. L-carnitine and acetyl-L-carnitine in human nerves from normal and diabetic subjects. J Peripher Nerv Syst 1996;1:157–63.12. Ido Y., McHowat J., Chang K.C. et al. Neural dysfunction and metabolic imbalances in diabetic rats: prevention by acetyl-Lcarnitine. Diabetes 1994;43:1469–77.Ido Y., McHowat J., Chang K.C. et al. Neural dysfunction and metabolic imbalances in diabetic rats: prevention by acetyl-Lcarnitine. Diabetes 1994;43:1469–77.13. Sima A.A., Ristic H., Merry A. et al. The primary preventive and secondary interventionary effects of acetyl-L-carnitine on diabetic neuropathy in the bio-breeding Worcester rat. J Clin Invest 1996;97:1900–7.Sima A.A., Ristic H., Merry A. et al. The primary preventive and secondary interventionary effects of acetyl-L-carnitine on diabetic neuropathy in the bio-breeding Worcester rat. J Clin Invest 1996;97:1900–7.14. Williamson J.R., Arrigoni-Martelli E. The role of glucose-induced metabolic hypoxia and imbalances in carnitine metabolism in mediating diabetes-induced vascular dysfunction. Int J Clin Pharmacol Res 1992;12:247–52.Williamson J.R., Arrigoni-Martelli E. The role of glucose-induced metabolic hypoxia and imbalances in carnitine metabolism in mediating diabetes-induced vascular dysfunction. Int J Clin Pharmacol Res 1992;12:247–52.15. Stevens M.J., Lattimer S.A., Feldman E.L. t al. Acetyl-L-carnitine deficiency as a cause of altered nerve myo-inositol content, Na-/K--ATPase activity and motor conduction velocity in the streptocin diabetic rat. Metabolism 1996;45:865–72.Stevens M.J., Lattimer S.A., Feldman E.L. t al. Acetyl-L-carnitine deficiency as a cause of altered nerve myo-inositol content, Na-/K--ATPase activity and motor conduction velocity in the streptocin diabetic rat. Metabolism 1996;45:865–72.16. Lowitt S., Malone J.I., Salem A.F. et al. Acetyl-L-carnitine corrects the altered peripheral nerve function of experimental diabetes. Metabolism 1995;44:677–80.Lowitt S., Malone J.I., Salem A.F. et al. Acetyl-L-carnitine corrects the altered peripheral nerve function of experimental diabetes. Metabolism 1995;44:677–80.17. Scarpini E., Sacilotto G., Baron P. et al. Effect of acetyl-L-carnitine in the treatment of painful peripheral neuropathies in HIVpatients. J Peripher Nerv Syst 1997;2:250 –2.Scarpini E., Sacilotto G., Baron P. et al. Effect of acetyl-L-carnitine in the treatment of painful peripheral neuropathies in HIVpatients. J Peripher Nerv Syst 1997;2:250 –2.18. Onofrj M., Fulgente T., Melchionda D. et al. L-acetyl-carnitine as a new therapeutic approach for peripheral neuropathies with pain. Int J Clin Pharmacol Res 15:9–15.Onofrj M., Fulgente T., Melchionda D. et al. L-acetyl-carnitine as a new therapeutic approach for peripheral neuropathies with pain. Int J Clin Pharmacol Res 15:9–15.19. Quatraro A., Roca P., Donzella C. et al. Acetyl-L-carnitine for symptomatic diabetic neuropathy. Diabetologia 1995;38:123.Quatraro A., Roca P., Donzella C. et al. Acetyl-L-carnitine for symptomatic diabetic neuropathy. Diabetologia 1995;38:123.20. Report and recommendations of the San Antonio Conference on diabetic neuropathy. Diabetes 1988;37:1000–4.Report and recommendations of the San Antonio Conference on diabetic neuropathy. Diabetes 1988;37:1000–4.21. Laudadio C., Sima A.A.F. Design of controlled clinical trials for diabetic polyneuropathy. Semin Neurol 1996;16:187–91.Laudadio C., Sima A.A.F. Design of controlled clinical trials for diabetic polyneuropathy. Semin Neurol 1996;16:187–91.22. Sima A.A.F., Blaivas M. Peripheral neuropathies. In Neuropathology: The Diagnostic Approach. Garcia J., McKeevar P., Sima A.A.F., Eds. Philadelphia: Mosby, 1997, p. 765–809.Sima A.A.F., Blaivas M. Peripheral neuropathies. In Neuropathology: The Diagnostic Approach. Garcia J., McKeevar P., Sima A.A.F., Eds. Philadelphia: Mosby, 1997, p. 765–809.23. O’Brien P.C. Procedures for comparing samples with multiple endpoints. Biometrics 1984;40:1079–87.O’Brien P.C. Procedures for comparing samples with multiple endpoints. Biometrics 1984;40:1079–87.24. Arezzo J.C., Schaumburg H.H., Laudadio C. The Vibratron: a simple device for quantitative evaluation of tactile/vibratory sense (Abstract). Neurology 1985;35 (Suppl. 1):169.Arezzo J.C., Schaumburg H.H., Laudadio C. The Vibratron: a simple device for quantitative evaluation of tactile/vibratory sense (Abstract). Neurology 1985;35 (Suppl. 1):169.25. Greene D.A., Arezzo J.C., Brown M.D., the Zenarestat Study Group: Effect of aldose reductase inhibition on nerve conduction and morphometry in diabetic neuropathy. Neurology 1999;53:580–91.Greene D.A., Arezzo J.C., Brown M.D., the Zenarestat Study Group: Effect of aldose reductase inhibition on nerve conduction and morphometry in diabetic neuropathy. Neurology 1999;53:580–91.26. Bohning D. Computer-Assisted Analysis of Mixtures and Applications. New York: Chapman and Hall/CRC, 1999.Bohning D. Computer-Assisted Analysis of Mixtures and Applications. New York: Chapman and Hall/CRC, 1999.27. Burchiel K.J., Russel L.C., Lee R.P., Sima A.A.F. Spontaneous activity of primary afferent neurons in diabetic BB-Wistar rats: a possible mechanism of chronic pain. Diabetes 1985;34:1210–3.Burchiel K.J., Russel L.C., Lee R.P., Sima A.A.F. Spontaneous activity of primary afferent neurons in diabetic BB-Wistar rats: a possible mechanism of chronic pain. Diabetes 1985;34:1210–3.28. Dyck P.K., Lambert E.H., O’Brien P.C. Pain in peripheral neuropathy related to rate and kind of fiber degeneration. Neurology 1976;26:466–71.Dyck P.K., Lambert E.H., O’Brien P.C. Pain in peripheral neuropathy related to rate and kind of fiber degeneration. Neurology 1976;26:466–71.29. Kapur D. Neuropathic pain and diabetes. Diabetes Metab Res Rev 2003;19:9–15.Kapur D. Neuropathic pain and diabetes. Diabetes Metab Res Rev 2003;19:9–15.30. Singleton J.R., Smith A.G., Bromberg M.B. Increased prevalence of impaired glucose tolerance in patients with painful sensory neuropathy. Diabetes Care 2001;24:1448–53.Singleton J.R., Smith A.G., Bromberg M.B. Increased prevalence of impaired glucose tolerance in patients with painful sensory neuropathy. Diabetes Care 2001;24:1448–53.31. Murakawa Y., Zhang W., Pierson C.R. et al. Impaired glucose tolerance and insulinopenia in the GK-rat causes peripheral neuropathy. Diabetes Metab Res Rev 2002;18:473–83.Murakawa Y., Zhang W., Pierson C.R. et al. Impaired glucose tolerance and insulinopenia in the GK-rat causes peripheral neuropathy. Diabetes Metab Res Rev 2002;18:473–83.32. Kamiya H., Zhang W., Sima A.A.F. C-peptide prevents nociceptive sensory neuropathy in type 1 diabetes. Ann Neurol. In press.Kamiya H., Zhang W., Sima A.A.F. C-peptide prevents nociceptive sensory neuropathy in type 1 diabetes. Ann Neurol. In press.33. Chiechio S., Caricasole A., Barletta E. et al. L-acetylcarnitine induces analgesia by selectively up-regulating mGlu2 metabotropic glutamate receptors. Molecul Pharm 2002;61:1– 8.Chiechio S., Caricasole A., Barletta E. et al. L-acetylcarnitine induces analgesia by selectively up-regulating mGlu2 metabotropic glutamate receptors. Molecul Pharm 2002;61:1– 8.34. Tomlinson D.R., Fernyhough P., Diemal L.T. Role of neurotrophins in diabetic neuropathy and treatment with nerve growth factor. Diabetes 1997;46 (Suppl 2):543–9.Tomlinson D.R., Fernyhough P., Diemal L.T. Role of neurotrophins in diabetic neuropathy and treatment with nerve growth factor. Diabetes 1997;46 (Suppl 2):543–9.35. DiGiulio A.M., Gorio A., Bertelli A. et al. Acetyl-L-carnitine prevents substance P loss in the sciatic nerve and lumbar spinal cord of diabetic animals. Int J Clin Pharmacol Res 1992;12:243–6.DiGiulio A.M., Gorio A., Bertelli A. et al. Acetyl-L-carnitine prevents substance P loss in the sciatic nerve and lumbar spinal cord of diabetic animals. Int J Clin Pharmacol Res 1992;12:243–6.36. Woolf C.J., Mannison R.J. Neuropathic pain: etiology, symptoms, mechanisms and management. Lancet 1999;353:1959–64.Woolf C.J., Mannison R.J. Neuropathic pain: etiology, symptoms, mechanisms and management. Lancet 1999;353:1959–64.37. Woolf C.J., Shortland P., Coggeshall R.E. Peripheral nerve injury triggers central sprouting of myelinated afferents. Nature 1992;355:75–8.Woolf C.J., Shortland P., Coggeshall R.E. Peripheral nerve injury triggers central sprouting of myelinated afferents. Nature 1992;355:75–8.38. Sima A.A.F., Kamiya H. Insulin, C-peptide, and diabetic neuropathy. Sci Med 2004;10:308–19.Sima A.A.F., Kamiya H. Insulin, C-peptide, and diabetic neuropathy. Sci Med 2004;10:308–19.