-
Neuropathy
Support Formula
-
- Clinical Trials
There have been numerous studies over the
last several years that have shown the effectiveness of the
ingredients found in the Neuropathy Support Formula. We have
compiled several of these studies along with the results so that
you can find out for yourself that the ingredients in the
Neuropathy Support Formula can help reduce or eliminate the
symptoms of your neuropathy. Along
with numerous clinical studies, we have received hundreds
testimonials from satisfied users.
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Methyl B12
Clinical Studies
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.
Yaqub 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.
Watanabe T Kaji R Oka N Bara W
Kimura J, J Neurol Sci (1994 Apr) 122(2):140-3
Despite intensive searches for
therapeutic agents, few substances have been convincingly
shown to enhance nerve regeneration in patients with
peripheral neuropathies. Recent biochemical evidence
suggests that an ultra-high dose of methylcobalamin
(methyl-B12) may up-regulate gene transcription and thereby
protein synthesis. We examined the effects of ultra-high
dose of methyl-B12 on the rate of nerve regeneration in rats
with acrylamide neuropathy, using the amplitudes of compound
muscle action potentials (CMAPs) after tibial nerve
stimulation as an index of the number of regenerating motor
fibers. After intoxication with acrylamide, all the rats
showed equally decreased CMAP amplitudes. The animals were
then divided into 3 groups; rats treated with ultra-high
(500 micrograms/kg body weight, intraperitoneally) and low
(50 micrograms/kg) doses of methyl- B12, and saline-treated
control rats. Those treated with ultra-high dose
showed significantly faster CMAP recovery than
saline-treated control rats, whereas the low-dose group
showed no difference from the control. Morphometric analysis
revealed a similar difference in fiber density between these
groups. Ultra-high doses of methyl-B12 may be of
clinical use for patients with peripheral neuropathies.
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 Methylcobalamine, A Vitamin B12
Analogue, Against Glutamate-induced Neurotoxicity in Retinal
Cell Culture
Kikuchi M Kashii S Honda Y Tamura Y Kaneda K Akaike, Invest
Ophthalmol Vis Sci (1997 Apr) 38(5):848-54
Purpose: To examine the
effects of methylcobalamine on glutamate- induced
neurotoxicity in the cultured retinal neurons. Methods:
Primary cultures obtained from the fetal rat retina
(gestation days 16 to 19) were used for the experiment. The
neurotoxicity was assessed quantitatively using the trypan
blue exclusion method. Results: Glutamate neurotoxicity was
prevented by chronic exposure to methylcobalamine and S-adenosylmethionine
(SAMe), which is formed in the metabolic pathway of
methylcobalamin. Chronic exposure to methylcobalamine and
SAMe also inhibited the neurotoxicity induced by sodium
nitroprusside that release nitric oxide. By contrast, acute
exposure to methylcobalamine did not protect retinal neurons
against glutamate neurotoxicity. Conclusions:
Chronic administration of methylcobalamine protects cultured
retinal neurons against N-methyl-D- aspartate-receptor-mediated
glutamate neurotoxicity, probably by altering the membrane
properties through SAMe-mediated methylation.
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):1-6The
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.
Benfotiamine Clinical Studies
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.
Pharmacokinetics of thiamine
derivatives especially of benfotiamine.
Int J Clin Pharmacol Ther 1996 Feb;
34(2): 47-50. Loew D.
Pharmacokinetic data of orally
administered lipid-soluble thiamine analogues like
benfotiamine are reviewed and assessed. It is quite
clear that benfotiamine is absorbed much better than
water-soluble thiamine salts: maximum plasma levels
of thiamine are about 5 times higher after
benfotiamine, the bioavailability is at maximum about 3.6
times as high as that of thiamine hydrochloride and
better than other lipophilic thiamine derivates. The
physiological activity (alphaETK) increased only after
benfotiamine was given. Due to its excellent pharmacokinetic
profile benfotiamine should be preferred in
treatment of relevant indications.
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 inhibits
intracellular formation of advanced Glycation end products
in vivoDiabetes. 2000
May; 49(Suppl1): A143(P583). Lin J, Alt A, Liersch J,
Bretzel RG, Brownlee MA, Hammes HP.
We have demonstrated previously that
intracellular formation of the advanced glycation end
product (AGE) N-[Epsilon]-(carboxymethyl)lysine (CML)
inversely correlates with diabetic vascular complications
independently from glycemia (Diabetologia 42, 603, 1999).
Here, we studied the effect of benfotiamine, a lipid-soluble
thiamine derivative with known AGE-inhibiting properties
in-vitro on the intracellular formation of (CML) and
methylglyoxal-derived AGE in red blood cells. Blood was
collected from 6 Type 1 diabetic patients (2m, 4f, age 31.8
± 5.5 years; diabetes duration 15.3 ± 7.0 years) before and
after treatment with 600 mg/day benfotiamine for 28 days. In
addition to HbA1c (HPLC), CML and methylglyoxal were
measured using specific antibodies and a quantitative blot
technique. While treatment with benfotiamine did not affect
HbA1c levels (at entry: 7.18 ± 0.86%; at conclusion 6.88 ±
0.88%; p not significant), levels of CML decreased by 40%
(737 ± 51 arbitrary units/mg protein (AU) vs 470 ± 86 AU;
p<0.01). The levels of intracellular methylglyoxal
were reduced by almost 70% (1628 ± AU vs 500 ± 343
AU; p<0.01). The data indicate that thiamine derivatives are
effective inhibitors of both intracellular glycoxidation and
AGE formation.
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.
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.
Koltai MZ. In Gries FA, Federlin K.
Benfotiamin in the Therapy of Polyneuropathy.
New York: Georg Thieme Verlag, 1998;
45-9.
Experimentally-induced diabetes of the
dog leads to disturbances in the autonomous neurological
function of the heart after approximately 3 months of
continuously- observed diabetes. As signs of autonomic
cardiac neuropathy, the heart rate variability and Valsalva
ratio clearly fell in the untreated diabetic animals. Oral
benfotiamine, administered from the sixth day after
diabetes-induction, prevented or at least delayed these
changes. According to the results, treatment with
fat-soluble benfotiamine can play an important role in the
therapy and prevention of cardiac autonomic neuropathy,
apart from any effect on diabetic metabolic disturbances.
Alpha-Lipoic Acid Clinical Studies
Ziegler D, Ametov A, Barinov A, et al.
The SYDNEY 2 trial. Diabetes Care. 2006;29:2365-70]
http://www.ncbi.nlm.nih.gov/pubmed/17065669
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.
Ziegler D, Gries FA. Diabetes. 1997;46 (suppl
2):S62–66.
http://www.ncbi.nlm.nih.gov/pubmed/9285502
Antioxidant treatment has been shown
to prevent nerve dysfunction in experimental diabetes,
providing a rationale for a potential therapeutic value in
diabetic patients. The effects of the antioxidant alpha-lipoic
acid (thioctic acid) were studied in two multicenter,
randomized, double-blind placebo-controlled trials. In the
Alpha-Lipoic Acid in Diabetic Neuropathy Study, 328 patients
with NIDDM and symptomatic peripheral neuropathy were
randomly assigned to treatment with intravenous infusion of
alpha-lipoic acid using three doses (ALA 1,200 mg; 600 mg;
100 mg) or placebo (PLAC) over 3 weeks. The total symptom
score (TSS) (pain, burning, paresthesia, and numbness) in
the feet decreased significantly from baseline to day 19 in
ALA 1,200 and ALA 600 vs. PLAC. Each of the four individual
symptom scores was significantly lower in ALA 600 than in
PLAC after 19 days (all P < 0.05). The total scale of the
Hamburg Pain Adjective List (HPAL) was significantly reduced
in ALA 1,200 and ALA 600 compared with PLAC after 19 days
(both P < 0.05). In the Deutsche Kardiale Autonome
Neuropathie Studie, patients with NIDDM and cardiac
autonomic neuropathy diagnosed by reduced heart rate
variability were randomly assigned to treatment with a daily
oral dose of 800 mg alpha-lipoic acid (ALA) (n = 39) or
placebo (n = 34) for 4 months. Two out of four parameters of
heart rate variability at rest were significantly improved
in ALA compared with placebo. A trend toward a favorable
effect of ALA was noted for the remaining two indexes. In
both studies, no significant adverse events were observed.
In conclusion, intravenous treatment with alpha-lipoic acid
(600 mg/day) over 3 weeks is safe and effective in reducing
symptoms of diabetic peripheral neuropathy, and oral
treatment with 800 mg/day for 4 months may improve cardiac
autonomic dysfunction in NIDDM.
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.
http://care.diabetesjournals.org/content/18/8/1160.abstract
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.
Packer L, Kraemer K, Rimbach G.
Nutrition. 2001;17(10):888-895.
http://www.ncbi.nlm.nih.gov/pubmed/11684397
Alpha-lipoic acid (LA) and its reduced
form, dihydrolipoic acid, are powerful antioxidants. LA
scavenges hydroxyl radicals, hypochlorous acid,
peroxynitrite, and singlet oxygen. Dihydrolipoic acid also
scavenges superoxide and peroxyl radicals and can regenerate
thioredoxin, vitamin C, and glutathione, which in turn can
recycle vitamin E. There are several possible sources of
oxidative stress in diabetes including glycation reactions,
decompartmentalization of transition metals, and a shift in
the reduced-oxygen status of the diabetic cells. Diabetics
have increased levels of lipid hydroperoxides, DNA adducts,
and protein carbonyls. Available data strongly suggest that
LA, because of its antioxidant properties, is particularly
suited to the prevention and/or treatment of diabetic
complications that arise from an overproduction of reactive
oxygen and nitrogen species. In addition to its antioxidant
properties, LA increases glucose uptake through recruitment
of the glucose transporter-4 to plasma membranes, a
mechanism that is shared with insulin-stimulated glucose
uptake. Further, recent trials have demonstrated that LA
improves glucose disposal in patients with type II diabetes.
In experimental and clinical studies, LA markedly reduced
the symptoms of diabetic pathologies, including cataract
formation, vascular damage, and polyneuropathy. To develop a
better understanding of the preventative and therapeutic
potentials of LA, much of the current interest is focused on
elucidating its molecular mechanisms in redox dependent gene
expression.
Ziegler D, Reljanovic M, Mehnert H, Gries
FA. Exp Clin Endocrinol Diabetes. 1999; 107:421-430.
http://www.ncbi.nlm.nih.gov/pubmed/10595592
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.
Melhem MF, Craven PA, Derubertis FR.
Effects of dietary supplementation of alpha-lipoic acid on
early glomerular injury in diabetes mellitus. J Am Soc
Nephrol. 2001;12:124-133.
http://www.ncbi.nlm.nih.gov/pubmed/11134258
Antioxidants, in particular vitamin E
(VE), have been reported to protect against diabetic renal
injury. alpha-Lipoic acid (LA) has been found to attenuate
diabetic peripheral neuropathy, but its effects on
nephropathy have not been examined. In the present study,
parameters of glomerular injury were examined in
streptozotocin diabetic rats after 2 mo on unsupplemented
diets and in diabetic rats that received the lowest daily
dose of dietary LA (30 mg/kg body wt), VE (100 IU/kg body
wt), or vitamin C (VC; 1 g/kg body wt), which detectably
increased the renal cortical content of each antioxidant.
Blood glucose values did not differ among the diabetic
groups. At 2 mo, inulin clearance, urinary albumin
excretion, fractional albumin clearance, glomerular volume,
and glomerular content of immunoreactive transforming growth
factor-beta (TGF-beta) and collagen alpha1 (IV) all were
significantly increased in unsupplemented D compared with
age-matched nondiabetic controls. With the exception of
inulin clearance, LA prevented or significantly attenuated
the increase in all of these glomerular parameters in D, as
well as the increases in renal tubular cell TGF-beta seen in
D. At the dose used, VE reduced inulin clearance in D to
control levels but failed to alter any of the other indices
of glomerular injury or to suppress renal tubular cell TGF-beta
in D. VC suppressed urinary albumin excretion, fractional
albumin clearance, and glomerular volume but not glomerular
or tubular TGF-beta or glomerular collagen alpha1 (IV)
content. LA but not VE or VC significantly increased renal
cortical glutathione content in D. These data indicate that
LA is effective in the prevention of early diabetic
glomerular injury and suggest that this agent may have
advantages over high doses of either VE or VC.
Lynch MA. Nutr Neurosci.
2001;4(6):419-438.
http://www.ncbi.nlm.nih.gov/pubmed/11843262
In the past decade or so, a convincing
link between oxidative stress and degenerative conditions
has been made and with the knowledge that oxidatiye changes
may actually trigger deterioration in cell function, a great
deal of energy has focussed on identifying agents which may
have possible therapeutic value in combating oxidative
changes. One agent which has received attention, because of
its powerful antioxidative effects, particularly in neuronal
tissue, is lipoic acid.
Melhem MF, Craven PA, Liachenko J, et al.
Alpha-lipoic acid attenuates hyperglycemia and prevents
glomerular mesangial matrix expansion in diabetes. J Am Soc
Nephrol. 2002;13:108-116.
http://www.ncbi.nlm.nih.gov/pubmed/11752027
Previous studies demonstrated that 2
mo of dietary supplementation with alpha-lipoic acid (LA)
prevented early glomerular injury in non-insulin-treated
streptozotocin diabetic rats (D). The present study examined
the effects of chronic LA supplementation (30 mg/kg body wt
per d) on nephropathy in D after 7 mo of diabetes. Compared
with control rats, D developed increased urinary excretion
of albumin and transforming growth factor beta, renal
insufficiency, glomerular mesangial matrix expansion, and
glomerulosclerosis in association with depletion of
glutathione and accumulation of malondialdehyde in renal
cortex. LA prevented or ameliorated all of these changes in
D. Because chronic LA supplementation also attenuated
hyperglycemia in D after 3 mo, its effects on renal injury
were compared with treatment of rats with sufficient insulin
to maintain a level of glycemic control for the entire 7-mo
period (D-INS) equivalent to that observed with LA during
the final 4 mo. Despite superior longitudinal glycemic
control in D-INS, urinary excretion of albumin and
transforming growth factor beta, glomerular mesangial matrix
expansion, the extent of glomerulosclerosis, and renal
cortical malondialdehyde content were all significantly
greater, whereas cortical glutathione content was lower than
corresponding values in D given LA. Thus, the renoprotective
effects of LA in D were not attributable to improved
glycemic control alone but also likely reflected its
antioxidant activity. The combined antioxidant and
hypoglycemic actions of LA both may contribute to its
utility in preventing renal injury and other complications
of diabetes.
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
http://www.ncbi.nlm.nih.gov/pubmed/10836205
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 auto-oxidation.
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