Clinical usefulness of intrathecal injection of methylcobalamin in patients with diabetic neuropathy
Ide H Fujiya S Asanuma Y Tsuji M Sakai H Agishi Y, Clin Ther (1987) 9(2):183-92
Seven men and four women with symptomatic diabetic neuropathy were treated with methylcobalamine (2,500 micrograms in 10 ml of saline) injected intrathecally. Treatment was begun when patients had good metabolic control, as determined by measurements of plasma glucose and hemoglobin, and was repeated several times with a one-month interval between injections. Three patients were re-treated one year after the last intrathecal injection. Symptoms in the legs, such as paresthesia, burning pains, and heaviness, dramatically improved. The effect appeared within a few hours to one week and lasted from several months to four years. The mean peroneal motor-nerve conduction velocity did not change significantly. The mean (+/- SD) concentration of methylcobalamin in spinal fluid was 114 +/- 32 pg/ml before intrathecal injection (n = 5) and 4,752 +/- 2,504 pg/ml one month after intrathecal methylcobalamin treatment (n = 11). Methylcobalamine caused no side effects with respect to subjective symptoms or characteristics of spinal fluid. These findings suggest that a high concentration of methylcobalamin in spinal fluid is highly effective and safe for treating the symptoms of diabetic neuropathy.
Aqub BA, Siddique A, Sulimani R.
Division of Neurology, King Khalid University Hospital, Riyadh, Saudi Arabia.
We studied the clinical and neurophysiological effects of methylcobalamin on patients with diabetic neuropathy. In a double-blind study, the active group showed statistical improvement in the somatic and autonomic symptoms with regression of signs of diabetic neuropathy. Motor and sensory nerve conduction studies showed no statistical improvement after 4 months. The drug was easily tolerated by the patients and no side effects were encountered.
Methylcobalamine (methyl-B12) Promotes Regeneration of Motor Nerve Terminals Degenerating in anterior gracile muscle of gracile axonal dystrophy (GAD) mutant mouse
Yamazaki K Oda K Endo C Kikuchi T Wakabayashi T, Neurosci Lett
(1994 Mar 28) 170(1):195-7
We examined the effects of methylcobalamin (methyl-B12, mecobalamin) on degeneration of motor nerve terminals in the anterior gracile muscle of gracile axonal dystrophy (GAD) mutant mice. GAD mice received orally methyl-B12 (1 mg/kg body wt/day) from the 40th day after birth for 25 days. In the distal endplate zone of the muscle, although most terminals were degenerated in both the untreated and methyl-B12-treated GAD mice, sprouts were more frequently observed in the latter. In the proximal endplate zone, where few degenerated terminals were seen in both groups of the mice, the perimeter of the terminals was increased and the area of the terminals was decreased significantly in the methyl-B12-treated GAD mice. These findings indicate that methyl-B12 promotes regeneration of degenerating nerve terminals in GAD mice.
Protective effects of a vitamin B12 analogue, methylcobalamin, against glutamate cytotoxicity in cultured cortical neurons
Akaike A Tamura Y Sato Y Yokota T, Eur J Pharmacol (1993 Sep 7) 241(1):1-6
The effects of methylcobalamin, a vitamin B12 analogue, on glutamate-induced neurotoxicity were examined using cultured rat cortical neurons. Cell viability was markedly reduced by a brief exposure to glutamate followed by incubation with glutamate-free medium for 1 h. Glutamate cytotoxicity was prevented when the cultures were maintained in methylcobalamin-containing medium. Glutamate cytotoxicity was also prevented by chronic exposure to S-adenosylmethionine, which is formed in the metabolic pathway of methylcobalamin. Chronic exposure to methylcobalamin and S- adenosylmethionine also inhibited the cytotoxicity induced by methyl-D-aspartate or sodium nitroprusside that releases nitric oxide. In cultures maintained in a standard medium, glutamate cytotoxicity was not affected by adding methylcobalamin to the glutamate-containing medium. In contrast, acute exposure to MK-801, a NMDA receptor antagonist, prevented glutamate cytotoxicity. These results indicate that chronic exposure to methylcobalamin protects cortical neurons against NMDA receptor-mediated glutamate cytotoxicity.
Effectiveness of different benfotiamine dosage regimens in the treatment of painful diabetic neuropathy.
Arzneimittelforschung 1999 Mar; 49(3): 220-4. Winkler G, Pal B, Nagybeganyi E, Ory I, Porochnavec M, Kempler P.
The therapeutic effectiveness of a benfotiamine (CAS 22457-89-2)-vitamin B combination (Milgamma-N), administered in high (4 x 2 capsules/day, = 320 mg benfotiamine/day) and medium doses (3 x 1 capsules/day), was compared to a monotherapy with benfotiamine (Benfogamma) (3 x 1 tablets/day, = 150 mg benfotiamine/day) in diabetic patients suffering from painful peripheral diabetic neuropathy (DNP). In a 6-week open clinical trial, 36 patients (aged 40 to 70 yrs) having acceptable metabolic control (HbA1c < 8.0%) were randomly assigned to three groups, each of them comprising 12 participants. Neuropathy was assessed by five parameters: the pain sensation (evaluated by a modified analogue visual scale), the vibration sensation (measured with a tuning fork using the Riedel-Seyfert method) and the current perception threshold (CPT) on the peroneal nerve at 3 frequencies: 5, 250 and 2000 Hz). Parameters were registered at the beginning of the study and at the end of the 3rd and 6th week of therapy. An overall beneficial therapeutic effect on the neuropathy status was observed in all three groups during the study, and a significant improvement in most of the parameters studied appeared already at the 3rd week of therapy (p < 0.01). The greatest change occurred in the group of patients receiving the high dose of benfotiamine (p < 0.01 and 0.05, resp., compared to the other groups). Metabolic control did not change over the study. It is concluded that benfotiamine is most effective in large doses, although even in smaller daily dosages, either in combination or in monotherapy, it is effective.
Exp Clin Endocrinol Diabetes 1996; 104(4): 311-6.
Stracke H, Lindemann A, Federlin K.
In a double-blind, randomized, controlled study, the effectiveness of treatment with a combination of Benfotiamine (an Allithiamine, a lipid-soluble derivative of vitamin B1 with high bioavailability) plus vitamin B6/B12 on objective parameters of neuropathy was studied over a period of 12 weeks on 24 diabetic patients with diabetic polyneuropathy. The results showed a significant improvement (p = 0.006) of nerve conduction velocity in the peroneal nerve and a statistical trend toward improvement of the vibration perception threshold. Long-term observation of 9 patients with verum over a period of 9 months support the results. Therapy-specific adverse effects were not seen. The results of this double-blind investigation, of the long-term observation and of the reports in the literature support the contention that the neurotropic benfotiamine-vitamin B combination represents a starting point in the treatment of diabetic polyneuropathy.
Benfotiamine blocks three major pathways of hyperglycemic damage and prevents experimental diabetic retinopathy.
Nat Med 2003 Mar; 9(3): 294-9. Hammes HP, Du X, Edelstein D, Taguchi T, Matsumura T, Ju Q, Lin J, Bierhaus A, Nawroth P, Hannak D, Neumaier M, Bergfeld R, Giardino I, Brownlee M.
Three of the major biochemical pathways implicated in the pathogenesis of hyperglycemia induced vascular damage (the hexosamine pathway, the advanced glycation end product (AGE) formation pathway and the diacylglycerol (DAG)-protein kinase C (PKC) pathway) are activated by increased availability of the glycolytic metabolites glyceraldehyde-3-phosphate and fructose-6-phosphate. We have discovered that the lipid-soluble thiamine derivative benfotiamine can inhibit these three pathways, as well as hyperglycemia-associated NF-kappaB activation, by activating the pentose phosphate pathway enzyme transketolase, which converts glyceraldehyde-3-phosphate and fructose-6-phosphate into pentose-5-phosphates and other sugars. In retinas of diabetic animals, benfotiamine treatment inhibited these three pathways and NF-kappaB activation by activating transketolase, and also prevented experimental diabetic retinopathy. The ability of benfotiamine to inhibit three major pathways simultaneously might be clinically useful in preventing the development and progression of diabetic complications.
Summary:Advanced glycation end product (AGE) has been linked to many age related illnesses such as cataract development, Alzheimer’s Disease, cardiovascular disease, strokes and reduced muscle function. In this study, benfotiamine was shown to inhibit (AGE) development which in turn leads to decresed risk for these diseases. Diabetics are at risk for AGE formation beyond normal levels.
Alpha Lipoic Acid
Ziegler D, Ametov A, Barinov A, et al. The SYDNEY 2 trial. Diabetes Care. 2006;29:2365-70]
OBJECTIVE: The aim of this trial was to evaluate the effects of alpha-lipoic acid (ALA) on positive sensory symptoms and neuropathic deficits in diabetic patients with distal symmetric polyneuropathy (DSP).
RESEARCH DESIGN AND METHODS: In this multicenter, randomized, double-blind, placebo-controlled trial, 181 diabetic patients in Russia and Israel received once-daily oral doses of 600 mg (n = 45) (ALA600), 1,200 mg (n = 47) (ALA1200), and 1,800 mg (ALA1800) of ALA (n = 46) or placebo (n = 43) for 5 weeks after a 1-week placebo run-in period. The primary outcome measure was the change from baseline of the Total Symptom Score (TSS), including stabbing pain, burning pain, paresthesia, and asleep numbness of the feet. Secondary end points included individual symptoms of TSS, Neuropathy Symptoms and Change (NSC) score, Neuropathy Impairment Score (NIS), and patients’ global assessment of efficacy.
RESULTS: Mean TSS did not differ significantly at baseline among the treatment groups and on average decreased by 4.9 points (51%) in ALA600, 4.5 (48%) in ALA1200, and 4.7 (52%) in ALA1800 compared with 2.9 points (32%) in the placebo group (all P < 0.05 vs. placebo). The corresponding response rates (>/=50% reduction in TSS) were 62, 50, 56, and 26%, respectively. Significant improvements favoring all three ALA groups were also noted for stabbing and burning pain, the NSC score, and the patients’ global assessment of efficacy. The NIS was numerically reduced. Safety analysis showed a dose-dependent increase in nausea, vomiting, and vertigo.
CONCLUSIONS: Oral treatment with Alpha-Lipoic Acid for 5 weeks improved neuropathic symptoms and deficits in patients with Distal Symmetric Polyneuropathy. An oral dose of 600 mg once daily appears to provide the optimum risk-to-benefit ratio.
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.
OBJECTIVE–To determine whether lipoic acid (LA) will reduce oxidative stress in diabetic peripheral nerves and improve neuropathy. RESEARCH DESIGN AND METHODS–We used the model of streptozotocin-induced diabetic neuropathy (SDN) and evaluated the efficacy of LA supplementation in improving nerve blood flow (NBF), electrophysiology, and indexes of oxidative stress in peripheral nerves affected by SDN, at 1 month after onset of diabetes and in age-matched control rats. LA, in doses of 20, 50, and 100 mg/kg, was administered intraperitoneally five times per week after onset of diabetes. RESULTS–NBF in SDN was reduced by 50%; LA did not affect the NBF of normal nerves but improved that of SDN in a dose-dependent manner. After 1 month of treatment, LA-supplemented rats (100 mg/kg) exhibited normal NBF. The most sensitive and reliable indicator of oxidative stress was reduction in reduced glutathione, which was significantly reduced in streptozotocin-induced diabetic and alpha-tocopherol-deficient nerves; it was improved in a dose-dependent manner in LA-supplemented rats. The conduction velocity of the digital nerve was reduced in SDN and was significantly improved by LA. CONCLUSIONS–These studies suggest that LA improves SDN, in significant part by reducing the effects of oxidative stress. The drug may have potential in the treatment of human diabetic neuropathy.
Ziegler D, Reljanovic M, Mehnert H, Gries FA. Exp Clin Endocrinol Diabetes. 1999; 107:421-430.
Diabetic neuropathy represents a major health problem, as it is responsible for substantial morbidity, increased mortality, and impaired quality of life. Near-normoglycaemia is now generally accepted as the primary approach to prevention of diabetic neuropathy, but is not achievable in a considerable number of patients. In the past two decades several medical treatments that exert their effects despite hyperglycaemia have been derived from the experimental pathogenetic concepts of diabetic neuropathy. Such compounds have been designed to improve or slow the progression of the neuropathic process and are being evaluated in clinical trials, but with the exception of alpha-lipoic acid (thioctic acid) which is available in Germany, none of these drugs is currently available in clinical practice. Here we review the current evidence from the clinical trials that assessed the therapeutic efficacy and safety of thioctic acid in diabetic polyneuropathy. Thus far, 15 clinical trials have been completed using different study designs, durations of treatment, doses, sample sizes, and patient populations. Within this variety of clinical trials, those with beneficial effects of thioctic acid on either neuropathic symptoms and deficits due to polyneuropathy or reduced heart rate variability resulting from cardiac autonomic neuropathy used doses of at least 600 mg per day. The following conclusions can be drawn from the recent controlled clinical trials. 1.) Short-term treatment for 3 weeks using 600 mg of thioctic acid i.v. per day appears to reduce the chief symptoms of diabetic polyneuropathy. A 3-week pilot study of 1800 mg per day given orally indicates that the therapeutic effect may be independent of the route of administration, but this needs to be confirmed in a larger sample size. 2.) The effect on symptoms is accompanied by an improvement of neuropathic deficits. 3.) Oral treatment for 4-7 months tends to reduce neuropathic deficits and improves cardiac autonomic neuropathy. 4.) Preliminary data over 2 years indicate possible long-term improvement in motor and sensory nerve conduction in the lower limbs. 5.) Clinical and postmarketing surveillance studies have revealed a highly favourable safety profile of the drug. Based on these findings, a pivotal long-term multicenter trial of oral treatment with thioctic acid (NATHAN I Study) is being conducted in North America and Europe aimed at slowing the progression of diabetic polyneuropathy using a clinically meaningful and reliable primary outcome measure that combines clinical and neurophysiological assessment.
Androne L, Gavan NA, Veresiu IA, Orasan R. In vivo effect of lipoic acid on lipid peroxidation in patients with diabetic neuropathy. In Vivo. 2000;14(2):327-330
BACKGROUND: The diabetic state, in both humans and experimental animals, is associated with oxidative stress. Lipid peroxidation of nerve membranes has been suggested as a mechanism by which peripheral nerve ischemia and hypoxia could cause neuropathy. Lipoic acid (LA) is a powerful inhibitor of iron-dependent lipid peroxidation and reactive oxygen species. The treatment of diabetic peripheral and cardiac autonomic neuropathy with LA is based on good clinical and experimental evidence.
MATERIALS AND METHODS: To investigate the magnitude of the oxidative stress, serum ceruloplasmin (Cp) and lipid peroxide (Lp) levels were measured in 10 patients with diabetic neuropathy, before and 70 days after treatment with single dose of 600 mg LA/day. For other 12 healthy age- and sex-matched control subjects the serum Cp and Lp levels were evaluated.
RESULTS: Our results show that hyperglycemia is a factor for an increase in serum ceruloplasmin in patients with diabetic neuropathy compared to healthy subjects (p < 0.0001). High serum ceruloplasmin (Cp) level in patients with diabetes may be related to antioxidant defense. The treatment of diabetic neuropathy with LA does not affect significantly the serum Cp activity. The serum Lp levels after LA administration were significantly lower (p < 0.005) than those before treatment.
CONCLUSIONS: The antioxidant therapy with R-ALA improves and may prevent diabetic neuropathy. This improvement is associated with a reduction in the indexes of lipid peroxidation. Oxidative stress appears to be primarily due to the processes of nerve ischemia and hyperglycemia autooxidation.