A Double-Blind, Randomized, Placebo-Controlled Study to Assess the Efficacy of a Nerve Support Formula on Neuropathic Pain in Individuals Suffering from Type II Diabetes Mellitus

References

• Hossain P, Kawar B, El Nahas M. Obesity and diabetes in the developing world—a growing challenge. N Engl J Med. 2007;356(3):213–215. doi:10.1056/NEJMp068177
   PubMed Web of Science ®Google Scholar
• Cho N, Shaw J, Karuranga S, et al. IDF diabetes atlas: global estimates of diabetes prevalence for 2017 and projections for 2045. Diabetes Res Clin Pract. 2018;138:271–281. doi:10.1016/j.diabres.2018.02.023
   PubMed Web of Science ®Google Scholar
• Yu OHY, Suissa S. Identifying causes for excess mortality in patients with diabetes: closer but not there yet. Diabetes Care. 2016;39(11):1851–1853. doi:10.2337/dci16-0026
   PubMedGoogle Scholar
• Bertoni AG, Krop JS, Anderson GF, Brancati FL. Diabetes-related morbidity and mortality in a national sample of US elders. Diabetes Care. 2002;25(3):471–475. doi:10.2337/diacare.25.3.471
   PubMed Web of Science ®Google Scholar
• Vinik AI, Nevoret M-L, Casellini C, Parson H. Diabetic neuropathy. Endocrinol Metab Clin. 2013;42(4):747–787. doi:10.1016/j.ecl.2013.06.001
   Google Scholar
• Feldman EL, Callaghan BC, Pop-Busui R, et al. Diabetic neuropathy. Nat Rev Dis Primers. 2019;5(1):1–18. doi:10.1038/s41572-019-0092-1
   PubMedGoogle Scholar
• Jensen MP, Chodroff MJ, Dworkin RH. The impact of neuropathic pain on health-related quality of life: review and implications. Neurology. 2007;68(15):1178–1182. doi:10.1212/01.wnl.0000259085.61898.9e
   PubMed Web of Science ®Google Scholar
• Galuppo M, Giacoppo S, Bramanti P, Mazzon E. Use of natural compounds in the management of diabetic peripheral neuropathy. Molecules. 2014;19(3):2877–2895. doi:10.3390/molecules19032877
   PubMedGoogle Scholar
• Didangelos T, Veves A. Treatment of diabetic cardiovascular autonomic, peripheral and painful neuropathy. Focus on the treatment of cardiovascular autonomic neuropathy with ACE inhibitors. Curr Vasc Pharmacol. 2020;18(2):158–171. doi:10.2174/1570161117666190521101342
   PubMedGoogle Scholar
• Iqbal Z, Azmi S, Yadav R, et al. Diabetic peripheral neuropathy: epidemiology, diagnosis, and pharmacotherapy. Clin Ther. 2018;40(6):828–849. doi:10.1016/j.clinthera.2018.04.001
   PubMed Web of Science ®Google Scholar
• Finnerup NB, Attal N, Haroutounian S, et al. Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis. Lancet Neurol. 2015;14(2):162–173. doi:10.1016/S1474-4422(14)70251-0
   PubMed Web of Science ®Google Scholar
• Forouzanfar F, Hosseinzadeh H. Medicinal herbs in the treatment of neuropathic pain: a review. Iran J Basic Med Sci. 2018;21(4):347. doi:10.22038/IJBMS.2018.24026.6021
   PubMed Web of Science ®Google Scholar
• Andrès E, Loukili NH, Noel E, et al. Vitamin B12 (cobalamin) deficiency in elderly patients. CMAJ. 2004;171(3):251–259. doi:10.1503/cmaj.1031155
   PubMed Web of Science ®Google Scholar
• Gupta JK, Sana QS. Potential benefits of MeCbl: a review. Austin J Pharmacol Ther. 2015;3(3):1076. ISSN: 2373-6208.
   Google Scholar
• Kikuchi M, Kashii S, Honda Y, Tamura Y, Kaneda K, Akaike A. Protective effects of MeCbl, a vitamin B12 analog, against glutamate-induced neurotoxicity in retinal cell culture. Invest Ophthalmol Vis Sci. 1997;38(5):848–854. PMID: 9112980.
   PubMedGoogle Scholar
• Didangelos T, Karlafti E, Kotzakioulafi E, et al. Vitamin B12 supplementation in diabetic neuropathy: a 1-year, randomized, double-blind, placebo-controlled trial. Nutrients. 2021;13(2):395. PMID: 33513879; PMCID: PMC7912007. doi:10.3390/nu13020395
   PubMedGoogle Scholar
• Xu Q, Pan J, Yu J, et al. Meta-analysis of MeCbl alone and in combination with lipoic acid in patients with diabetic peripheral neuropathy. Diabetes Res Clin Pract. 2013;101(2):99–105. doi:10.1016/j.diabres.2013.03.033
   PubMedGoogle Scholar
• Stevens MJ, Lattimer SA, Kamijo M, Van Huysen C, Sima AA, Greene DA. Osmotically-induced nerve taurine depletion and the compatible osmolyte hypothesis in experimental diabetic neuropathy in the rat. Diabetologia. 1993;36(7):608–614. doi:10.1007/BF00404069
   PubMedGoogle Scholar
• Li C, Cao L, Zeng Q, et al. Taurine may prevent diabetic rats from developing cardiomyopathy also by downregulating angiotensin II type2 receptor expression. Cardiovasc Drugs Ther. 2005;19(2):105–112. doi:10.1007/s10557-005-0443-x
   PubMedGoogle Scholar
• Obrosova IG, Fathallah L, Stevens MJ. Taurine counteracts oxidative stress and nerve growth factor deficit in early experimental diabetic neuropathy. Exp Neurol. 2001;172(1):211–219. doi:10.1006/exnr.2001.7789
   PubMedGoogle Scholar
• Pop-Busui R, Sullivan KA, Van Huysen C, et al. Depletion of taurine in experimental diabetic neuropathy: implications for nerve metabolic, vascular, and functional deficits. Exp Neurol. 2001;168(2):259–272. doi:10.1006/exnr.2000.7591
   PubMedGoogle Scholar
• Scarpini E, Doneda P, Pizzul S, et al. L-carnitine and ALCin human nerves from normal and diabetic subjects. J Peripher Nerv Syst. 1996;1(2);157–163.
   PubMedGoogle Scholar
• Ido Y, McHowat J, Chang KC, et al. Neural dysfunction and metabolic imbalances in diabetic rats: prevention by ALC. Diabetes. 1994;43:1469–1477. doi:10.2337/diab.43.12.1469
   PubMedGoogle Scholar
• Sima AA, Ristic H, Merry A, et al. The primary preventive and secondary interventionary effects of ALCon diabetic neuropathy in the bio-breeding Worcester rat. J Clin Invest. 1996;97:1900–1907. doi:10.1172/JCI118621
   PubMed Web of Science ®Google Scholar
• Lowitt S, Malone JI, Salem AF, Korthals J, Benford S. ALCcorrects the altered peripheral nerve function of experimental diabetes. Metabolism. 1995;44:677–680. doi:10.1016/0026-0495(95)90128-0
   PubMed Web of Science ®Google Scholar
• Stevens MJ, Lattimer SA, Feldman EL, et al. ALCdeficiency as a cause of altered nerve myo-inositol content, Na+/K+-ATPase activity and motor conduction velocity in the streptozotocin diabetic rat. Metabolism. 1996;45:865–872. doi:10.1016/S0026-0495(96)90161-4
   PubMed Web of Science ®Google Scholar
• Scarpini E, Sacilotto G, Baron P, Cusini M, Scarlata G. Effect of ALCin the treatment of painful peripheral neuropathies in HIV+ patients. J Peripher Nerv Syst. 1997;2:250–252.
   PubMedGoogle Scholar
• Schwedhelm E, Maas R, Freese R, et al. Pharmacokinetic and pharmacodynamic properties of oral L-citrulline and L-arginine: impact on nitric oxide metabolism. Br J Clin Pharmacol. 2008;65(1):51–59. PMID: 17662090; PMCID: PMC2291275. doi:10.1111/j.1365-2125.2007.02990.x
   PubMed Web of Science ®Google Scholar
• Stout JR, Cramer JT, Zoeller RF, et al. Effects of beta-alanine supplementation on the onset of neuromuscular fatigue and ventilatory threshold in women. Amino Acids. 2007;32:381–386. doi:10.1007/s00726-006-0474-z
   PubMed Web of Science ®Google Scholar
• Stout JR, Cramer JT, Mielke M, O’Kroy J, Torok DJ, Zoeller RF. Effects of twenty-eight days of beta-alanine and creatine monohydrate supplementation on the physical working capacity at neuromuscular fatigue threshold. J Strength Cond Res. 2006;20:928–931. doi:10.1519/R-19655.1
   PubMed Web of Science ®Google Scholar
• Harris RC, Tallon MJ, Dunnett M, et al. The absorption of orally supplied beta-alanine and its effect on muscle carnosine synthesis in human vastus lateralis. Amino Acids. 2006;30:279–289. doi:10.1007/s00726-006-0299-9
   PubMed Web of Science ®Google Scholar
• Shinohara T, Harada M, Ogi K, et al. Identification of a G protein-coupled receptor specifically responsive to β-alanine. J Biol Chem. 2004;279(22):23559–23564. doi:10.1074/jbc.M314240200
   PubMed Web of Science ®Google Scholar
• Low PA, Nickander KK, Tritschler HJ. The roles of oxidative stress and antioxidant treatment in experimental diabetic neuropathy. Diabetes. 1997;46:S38–S42. doi:10.2337/diab.46.2.S38
   PubMed Web of Science ®Google Scholar
• Cameron NE, Eaton SE, Cotter MA, Tesfaye S. Vascular factors and metabolic interactions in the pathogenesis of diabetic neuropathy. Diabetologia. 2001;44:1973–1988. doi:10.1007/s001250100001
   PubMed Web of Science ®Google Scholar
• Nagamatsu M, Nickander KK, Schmelzer JD, et al. Lipoic acid improves nerve blood flow, reduces oxidative stress and improves distal nerve conduction in experimental diabetic neuropathy. Diabetes Care. 1995;18:1160–1167. doi:10.2337/diacare.18.8.1160
   PubMed Web of Science ®Google Scholar
• Cameron NE, Cotter MA, Horrobin DH, Tritschler HJ. Effects of αlipoic acid on neurovascular function in diabetic rats: interaction with essential fatty acids. Diabetologia. 1998;41:390–399. doi:10.1007/s001250050921
   PubMed Web of Science ®Google Scholar
• Bock E, Schneeweiss J. Ein Beitrag zur Therapie der Neuropathia diabetica. Munch Med Wochenschr. 1959;43:1911–1912.
   Google Scholar
• Ziegler D, Nowak H, Kempler P, Vargha P, Low PA. Treatment of symptomatic diabetic polyneuropathy with the antioxidant alpha-lipoic acid: a meta-analysis. Diabet Med. 2004;21(2):114–121. PMID: 14984445. doi:10.1111/j.1464-5491.2004.01109.x
   PubMedGoogle Scholar
• Farvid MS, Homayouni F, Amiri Z, Adelmanesh F. Improving neuropathy scores in type 2 diabetic patients using micronutrients supplementation. Diabetes Res Clin Pract. 2011;93(1):86–94. doi:10.1016/j.diabres.2011.03.016
   PubMed Web of Science ®Google Scholar
• Farrar JT, Young JP Jr, LaMoreaux L, Werth JL, Poole RM. Clinical importance of changes in chronic pain intensity measured on an 11-point numerical pain rating scale. Pain. 2001;94(2):149–158. doi:10.1016/S0304-3959(01)00349-9
   PubMed Web of Science ®Google Scholar
• Spallone V, Morganti R, D’Amato C, Greco C, Cacciotti L, Marfia GA. Validation of DN4 as a screening tool for neuropathic pain in painful diabetic polyneuropathy. Diabet Med. 2012;29(5):578–585. PMID: 22023377. doi:10.1111/j.1464-5491.2011.03500.x
   PubMed Web of Science ®Google Scholar
• Valk GD, Nauta JJ, Strijers RL, Bertelsmann FW. Clinical examination versus neurophysiological examination in the diagnosis of diabetic polyneuropathy. Diabet Med. 1992;9(8):716‐21. doi:10.1111/j.1464-5491.1992.tb01879.x
   PubMedGoogle Scholar
• Kulseng‐Hanssen S, Borstad E. The development of a questionnaire to measure the severity of symptoms and the quality of life before and after surgery for stress incontinence. BJOG. 2003;110(11):983–988. doi:10.1111/j.1471-0528.2003.01406.x
   PubMedGoogle Scholar
• Use CfMPfH. Guideline on clinical investigation of medicinal products in the treatment of diabetes mellitus. CPMP/EWP/1080/00 Rev; 2011:1.
   Google Scholar
• Kim CH, Jeong SJ, Mok JO, Lee KY, Kim SR. Impact on quality of life in peoples with painful diabetic peripheral neuropathy. In17th European Congress of Endocrinology; BioScientifica; 2015:EP443.
   Google Scholar
• Vasudevan D, Naik MM, Mukaddam QI. Efficacy and safety of MeCbl, alpha lipoic acid and pregabalin combination versus pregabalin monotherapy in improving pain and nerve conduction velocity in type 2 diabetes associated impaired peripheral neuropathic condition.[MAINTAIN]: results of a pilot study. Ann Indian Acad Neurol. 2014;17:19. doi:10.4103/0972-2327.128535
   PubMedGoogle Scholar
• Prabhoo R, Panghate A, Dewda RP, More B, Prabhoo T, Rana R. Efficacy and tolerability of a fixed dose combination of MeCbl and pregabalin in the management of painful neuropathy. N Am J Med Sci. 2012;4:605–607. doi:10.4103/1947-2714.103336
   PubMedGoogle Scholar
• Dongre YU, Swami OC. Sustained-release pregabalin with MeCbl in neuropathic pain: an Indian real-life experience. Int J Gen Med. 2013;6:413–417. doi:10.2147/IJGM.S45271
   PubMedGoogle Scholar
• Han Y, Wang M, Shen J, et al. Differential efficacy of MeCbl and alpha-lipoic acid treatment on symptoms of diabetic peripheral neuropathy. Minerva Endocrinol. 2018;43(1):11–18. PMID: 27901334. doi:10.23736/S0391-1977.16.02505-0
   PubMed Web of Science ®Google Scholar
• Sharma C, Kaur I, Singh H, Grover IS, Singh J. A randomized comparative study of MeCbl, MeCbl plus pregabalin and MeCbl plus duloxetine in patients of painful diabetic neuropathy. Indian J Pharmacol. 2021;53(5):358–363. PMID: 34854403; PMCID: PMC8641739. doi:10.4103/ijp.ijp_1159_20
   PubMedGoogle Scholar
• Rolim LC, da Silva EM, Flumignan RL, Abreu MM, Dib SA. ALCfor the treatment of diabetic peripheral neuropathy. Cochrane Database Syst Rev. 2019;6(6):CD011265. PMID: 31201734; PMCID: PMC6953387. doi:10.1002/14651858.CD011265.pub2
   PubMedGoogle Scholar
• Shatanawi A, Momani MS, Al-Aqtash R, Hamdan MH, Gharaibeh MN. L-citrulline supplementation increases plasma nitric oxide levels and reduces arginase activity in patients with type 2 diabetes. Front Pharmacol. 2020;11:584669. PMID: 33414716; PMCID: PMC7783447. doi:10.3389/fphar.2020.584669
   PubMedGoogle Scholar
• Rauck R, Makumi CW, Schwartz S, et al. A randomized, controlled trial of gabapentin enacarbil in subjects with neuropathic pain associated with diabetic peripheral neuropathy. Pain Pract. 2013;13(6):485–496. doi:10.1111/papr.12014
   PubMed Web of Science ®Google Scholar
• Verret M, Lauzier F, Zarychanski R, et al. Perioperative use of gabapentinoids for the management of postoperative acute pain: a systematic review and meta-analysis. Anesthesiology. 2020;133(2):265–279. doi:10.1097/ALN.0000000000003428
   PubMed Web of Science ®Google Scholar
• Esposito C, Garzarella EU, Santarcangelo C, et al. Safety and efficacy of alpha-lipoic acid oral supplementation in the reduction of pain with unknown etiology: a monocentric, randomized, double-blind, placebo-controlled clinical trial. Biomed Pharmacother. 2021;144:112308. doi:10.1016/j.biopha.2021.112308
   PubMedGoogle Scholar
• Agathos E, Tentolouris A, Eleftheriadou I, et al. Effect of α-lipoic acid on symptoms and quality of life in patients with painful diabetic neuropathy. J Int Med Res. 2018;46(5):1779–1790. doi:10.1177/0300060518756540
   PubMed Web of Science ®Google Scholar
• Nexo E, Hoffmann-Lücke E. Holotranscobalamin, a marker of vitamin B-12 status: analytical aspects and clinical utility. Am J Clin Nutr. 2011;94(1):359S–65S. doi:10.3945/ajcn.111.013458
   PubMed Web of Science ®Google Scholar
• Alvarez M, Sierra OR, Saavedra G, Moreno S. Vitamin B12 deficiency and diabetic neuropathy in patients taking metformin: a cross-sectional study. Endocr Connect. 2019;8(10):1324–1329. doi:10.1530/EC-19-0382
   PubMed Web of Science ®Google Scholar
• Tehrani KHN. A study of nerve conduction velocity in diabetic patients and its relationship with tendon reflexes (T-reflex). Open Access Maced J Med Sci. 2018;6(6):1072. doi:10.3889/oamjms.2018.262
   PubMedGoogle Scholar
• Didangelos T, Karlafti E, Kotzakioulafi E, et al. Efficacy and safety of the combination of superoxide dismutase, alpha lipoic acid, vitamin B12, and carnitine for 12 months in patients with diabetic neuropathy. Nutrients. 2020;12(11):3254. doi:10.3390/nu12113254
   PubMed Web of Science ®Google Scholar