The following info may not be what the original poster had in mind, but it
seems on-topic. The first couple items are specific to B12 and nerves. Below
that are some general neuropathy references -- this list is about 1/20th of
my current list, which itself is obviously just a small fraction of the
current articles on the topic. No single article makes the case for
regeneration, of course. (And I certainly didn't take the time to include
just the articles that support any particular view in the list below.) Like
any other subject, an experienced individual will draw his or her own
conclusions based on the subset of research he or she reads.

However, since you are a clinician, the best source of info regarding optic
nerve regeneration in human patients would be for you to search out and
befriend a high quality physician working on the alternative medical side
who could share his or her clinical experiences with you. Caveat: starting
off with the typical allopathic negative bias against alternative treatments
might cause you to reject anything an alternative practitioner might say,
even if that practitioner is very competent. Unfortunately, there may not be
such a practitioner in your area. But expand your radius, and you will
eventually find someone who is getting better results than you in terms of
vision restoration ("[I] have not seen one [of my patients] with improvement
in their optic nerves."), and the best results will probably be coming from
an alternative medicine physician. (Another caveat to any patients seeking
alternative treatments: the practitioners in alternative medicine range from
very bad to very good, and the deviation in competency may be greater than
the range for conventional practitioners.)

If one examines the trends in medical thinking from the last 20+ years,
alternative medicine is often seen leading the way in the clinical
understanding/treatment of chronic diseases. Just think about cardiovascular
disease, for example. Many alternative practitioners made strong statements
against the use of margarine (trans fatty acids, etc.) at least 20 years
ago, while the main stream medical establishment promoted its use (which we
now know was a mistake). Alternative practitioners were also the first to
seriously investigate the role of oxidation (free radical) damage in
cardiovascular disease, and this has been a fruitful avenue. In fact, the
original thinking about cholesterol's role is now completely outdated, and
the most up-to-date view is very similar to what many alternative
practitioners were saying twenty years ago. Any heart disease patient who
went to a good alternative physician twenty years ago would today be far
better off than a similar patient who went to a conventional allopathic
physician. I suspect the same will be said in the future about glaucoma. (I
also suspect this view will infuriate most conventional allopathic
physicians, but that's life.)

Nerve Regeneration with Methylcobalamin
Ultra-high dose methylcobalamin promotes nerve regeneration in experimental
acrylamide neuropathy. 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.

Protective effects of methylcobalamin, 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 methylcobalamin 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 methylcobalamin and S-adenosylmethionine (SAMe),
which is formed in the metabolic pathway of methylcobalamin. Chronic
exposure to methylcobalamin and SAMe also inhibited the neurotoxicity
induced by sodium nitroprusside that release nitric oxide. By contrast,
acute exposure to methylcobalamin did not protect retinal neurons against
glutamate neurotoxicity. Conclusions: Chronic administration of
methylcobalamin protects cultured retinal neurons against N-methyl-D-
aspartate-receptor-mediated glutamate neurotoxicity, probably by altering
the membrane properties through SAMe-mediated methylation.

Vitamins for seeing
COMPR. THER. (USA), 1990, 16/4 (62)

It has long been known that an inadequate diet lacking in certain essential
vitamins can cause ocular disorders. On an Egyptian papyrus dated about 1500
BC, it is recorded that liver was used as a food to cure night blindness.
Healthy eyes depend on a well-balanced diet. Vitamin A maintains the normal
function of the epithelial cells of the eye and is essential for the
synthesis of visual photosensitive pigments. Deficiencies of vitamin A lead
to clinical manifestations including night blindness, conjunctival
pigmentation, and dry eyes. The B vitamins are important for maintaining
good vision. Vitamin B1 (thiamine) deficiency produces optic nerve
dysfunction. Vitamin B12 deficiency can produce vascular changes in the
retina. Deficiency of riboflavin (part of the B complex) has been implicated
in the formation of cataracts and may also be a factor in producting
xerophthalmia (dry eyes). Vitamin C is necessary to prevent scurvy. The
scorbutic manifestations in the eyes are bleeding from the lids,
conjunctiva, anterior chamber, and retina. Vitamin C deficiency may also be
a factor in cataract formation. Finally, vitamin K deficiency causes retinal
hemorrhages in neonates. Deficiencies of vitamin D and E have not been shown
to have a negative effect on the visual process, but vitamin E therapy
improves retrolental fibroplasia (retinopathy of prematurity).

     ABSTRACTS

           Abuaisha BB., 1998. Acupuncture for the treatment of chronic
painful peripheral diabetic neuropathy: a long-term study.
           Anon.., 1998. Monograph:Alpha-Lipoic Acid.
           Backonja MM., 2002. Use of anticonvulsants for treatment of
neuropathic pain.
           Cameron NE., 1996. Interaction between oxidative stress and
gamma-linolenic acid in impaired neurovascular function of diabetic rats.
           Cameron NE., 1997. Metabolic and vascular factors in the
pathogenesis of diabetic neuropathy.
           Chu CC., 1998. Chronic inorganic mercury induced peripheral
neuropathy.
           CNFIT., 1995. Epidemic optic neuropathy in Cuba--clinical
characterization and risk factors. The Cuba Neuropathy Field Investigation
Team.
           de la Cruz JP., 1993. Antiplatelet effect of pentoxifylline in
human whole blood.
           Dines KC., 1996. Effectiveness of natural oils as sources of
gamma-linolenic acid to correct peripheral nerve conduction velocity
abnormalities in diabetic rats: modulation by thromboxane A2 inhibition.
           Fang C., 1997. Expression of constitutive cyclo-oxygenase
(COX-1) in rats with streptozotocin-induced diabetes; effects of treatment
with evening primrose oil or an aldose reductase inhibitor on COX-1 mRNA
levels.
           Flint H., 2000. Pentoxifylline effects on nerve conduction
velocity and blood flow in diabetic rats.
           Ford I., 2001. The effects of treatment with alpha-lipoic acid
or evening primrose oil on vascular hemostatic and lipid risk factors, blood
flow, and peripheral nerve conduction in the streptozotocin-diabetic rat.
           Franconi F., 1995. Plasma and platelet taurine are reduced in
subjects with insulin-dependent diabetes mellitus: effects of taurine
supplementation.
           Galantino ML., 1999. Use of noninvasive electroacupuncture for
the treatment of HIV-related peripheral neuropathy: a pilot study.
           Gara II., 1993. [The effect of pentoxifylline and nicergoline on
the systemic and cerebral hemodynamics and on the blood rheological
properties in patients with an ischemic stroke and atherosclerotic lesions
of the major cerebral arteries]
           Gaur SP., 1993. Effect of anti-platelet therapy (aspirin +
pentoxiphylline) on plasma lipids in patients of ischaemic stroke.
           Gupta R., 1998. Oral zinc therapy in diabetic neuropathy.
           Hansen SH., 2001. The role of taurine in diabetes and the
development of diabetic complications.
           Hibi C., 1997. [Aldose reductase inhibitor SNK-860]
           Hipkiss AR., 1998. Pluripotent protective effects of carnosine,
a naturally occurring dipeptide.
           Hotta N., 1990. Current progress in clinical trials of aldose
reductase inhibitors in Japan.
           Jain SK., 2000. Lipoic acid decreases lipid peroxidation and
protein glycosylation and increases (Na(+) + K(+))- and Ca(++)-ATPase
activities in high glucose-treated human erythrocytes.
           Kuwabara S., 2001. Intravenous methylcobalamin treatment for
uremic and diabetic neuropathy in chronic hemodialysis patients.
           Malik RA., 2000. Can diabetic neuropathy be prevented by
angiotensin-converting enzyme inhibitors?
           Manzella D., 2001. Chronic administration of pharmacologic doses
of vitamin E improves the cardiac autonomic nervous system in patients with
type 2 diabetes.
           Martinello F., 1998. Supplemental therapy in isolated vitamin E
deficiency improves the peripheral neuropathy and prevents the progression
of ataxia.
           Mellegers MA., 2001. Gabapentin for neuropathic pain: systematic
review of controlled and uncontrolled literature.
           Mikhailov VV., 1983. [Mechanism of the effect of methylcobalamin
on the recovery of neuromuscular functions in mechanical and toxin
denervation]
           Nakamura J., 1998. Polyol pathway hyperactivity is closely
related to carnitine deficiency in the pathogenesis of diabetic neuropathy
of streptozotocin-diabetic rats.
           Reljanovic M., 1999. Treatment of diabetic polyneuropathy with
the antioxidant thioctic acid (alpha-lipoic acid): a two year multicenter
randomized double-blind placebo-controlled trial (ALADIN II). Alpha Lipoic
Acid in Diabetic Neuropathy.
           Rowbottom DG., 1998. The case history of an elite
ultra-endurance cyclist who developed chronic fatigue syndrome.
           Sagara M., 1996. Inhibition of development of peripheral
neuropathy in streptozotocin-induced diabetic rats with N-acetylcysteine.
           Scarpini E., 1997. Effect of acetyl-L-carnitine in the treatment
of painful peripheral neuropathies in HIV+ patients.
           Singleton CK., 2001. Molecular mechanisms of thiamine
utilization.
           Surtees R., 1993. Biochemical pathogenesis of subacute combined
degeneration of the spinal cord and brain.
           Terada R., 1998. Effects of propionyl-L-carnitine on cardiac
dysfunction in streptozotocin-diabetic rats.
           Venters HD., 1999. A new mechanism of neurodegeneration: a
proinflammatory cytokine inhibits receptor signaling by a survival peptide.
           Yamatsu K., 1976. [Pharmacological studies on degeneration and
regeneration of the peripheral nerves. (2) Effects of methylcobalamin on
mitosis of Schwann cells and incorporation of labeled amino acid into
protein fractions of crushed sciatic nerve in rats]
           Ziegler D., 1995. Treatment of symptomatic diabetic peripheral
neuropathy with the anti-oxidant alpha-lipoic acid. A 3-week multicentre
randomized controlled trial (ALADIN Study).
           Ziegler D., 1999. Treatment of symptomatic diabetic
polyneuropathy with the antioxidant alpha-lipoic acid: a 7-month multicenter
randomized controlled trial (ALADIN III Study). ALADIN III Study Group.
Alpha-Lipoic Acid in Diabetic Neuropathy.
           Ziegler D., 1999. Alpha-lipoic acid in the treatment of diabetic
polyneuropathy in Germany: current evidence from clinical trials.

           Acupuncture for the treatment of chronic painful peripheral
diabetic neuropathy: a long-term study.

           Abuaisha BB, Costanzi JB, Boulton AJ. Department of Medicine,
Manchester Royal Infirmary, University of Manchester, UK.

           Diabetes Res Clin Pract. 1998 Feb;39(2):115-21.

           Forty-six diabetic patients with chronic painful peripheral
neuropathy were treated with acupuncture analgesia to determine its efficacy
and long-term effectiveness. Twenty-nine (63%) patients were already on
standard medical treatment for painful neuropathy. Patients initially
received up to six courses of classical acupuncture analgesia over a period
of 10 weeks, using traditional Chinese Medicine acupuncture points.
Forty-four patients completed the study with 34 (77%) showing significant
improvement in their primary and/or secondary symptoms (P < 0.01). These
patients were followed up for a period of 18-52 weeks with 67% were able to
stop or reduce their medications significantly. During the follow-up period
only eight (24%) patients required further acupuncture treatment. Although
34 (77%) patients noted significant improvement in their symptoms, only
seven (21%) noted that their symptoms cleared completely. All the patients
but one finished the full course of acupuncture treatment without reported
or observed side effects. There were no significant changes either in the
peripheral neurological examination scores, VPT or in HbA1c during the
course of treatment. These data suggest that acupuncture is a safe and
effective therapy for the long-term management of painful diabetic
neuropathy, although its mechanism of action remains speculative.

           Monograph:Alpha-Lipoic Acid.

           Anon.

           Altern Med Rev 1998 Aug;3(4):308-11

           Alpha-Lipoic acid is a potent antioxidant in both fat- and
water-soluble mediums. Furthermore, its antioxidant activity extends to both
the oxidized form and its reduced form. DHLA is capable of regenerating
ascorbic acid from dehydroascorbic acid, directly regenerating vitamin C and
indirectly regenerating vitamin E. Researchers have found lipoic acid to
increase intracellular glutathione levels as well as Coenzyme Q10.
Clinically, it appears lipoic acid has the potential to prevent diabetes,
influence glucose control, and prevent chronic hyperglycemia associated
complications such as neuropathy and cataracts. Lipoic acid may also be
useful in the treatment of glaucoma, ischemia-reperfusion injury, amanita
mushroom poisoning, and cellular oxidative damage.

           Use of anticonvulsants for treatment of neuropathic pain.

           Backonja MM. Department of Neurology, University of Wisconsin
Hospital and Clinics, Room H6/574, 600 Highland Avenue, Madison, WI
53792-5132, USA. backonja@neurology.wisc.edu

           Neurology. 2002 Sep 10;59(5 Suppl 2):S14-7.

           Emerging evidence from animal models of neuropathic pain
suggests that many pathophysiologic and biochemical changes occur in the
peripheral and central nervous system. Similarities between the
pathophysiologic phenomena observed in some epilepsy models and in
neuropathic pain models justify the use of anticonvulsants in the
symptomatic management of neuropathic pain. Positive results from laboratory
and clinical trials further support such use. Carbamazepine was the first of
this class of drugs to be studied in clinical trials and has been longest in
use for treatment of neuropathic pain. Clinical trial data support its use
in treating trigeminal neuralgia, but data for treatment of painful diabetic
neuropathy are less convincing. Use of newer anticonvulsants has marked a
new era in the treatment of neuropathic pain. Gabapentin has demonstrated
efficacy, specifically in painful diabetic neuropathy and postherpetic
neuralgia. Lamotrigine has been reported to be effective in relieving pain
from trigeminal neuralgia refractory to other treatments, HIV neuropathy,
and central post-stroke pain. Results from clinical trials of phenytoin are
equivocal. Zonisamide's mechanisms of action suggest that it would be
effective in controlling neuropathic pain symptoms. Other anticonvulsants,
including lorazepam, valproate, topiramate, and tiagabine, have also been
under investigation. Anecdotal experience provides support for studies with
oxcarbazepine and levetiracetam for treating neuropathic pain. Evidence
supporting the efficacy of anticonvulsants in treatment of such pain is
evolving. Additional clinical trials should provide information that will
better define their role in neuropathic pain.

           Interaction between oxidative stress and gamma-linolenic acid in
impaired neurovascular function of diabetic rats.

           Cameron NE, Cotter MA. Department of Biomedical Sciences,
University of Aberdeen, Scotland, United Kingdom.

           Am J Physiol 1996 Sep;271(3 Pt 1):E471-6

           Nerve conduction and perfusion deficits in diabetic rats depend
on increased oxidative stress and impaired n-6 essential fatty acid
metabolism, which are corrected by free radical scavenger and
gamma-linolenic acid (GLA)-rich oil treatments, respectively. We
investigated the interaction between these mechanisms on conduction velocity
and endoneurial blood flow by use of low-dose antioxidant (BM15.0639) and
GLA treatments, alone and in combination. After 8 wk of
streptozotocin-induced diabetes, sciatic motor conduction velocity was 20.9%
reduced. Treatment with GLA or BM15.0639 for the final 2 wk corrected this
deficit by 18.5 and 20.0%, respectively; however, joint treatment caused
71.5% improvement, corresponding to a 7.5-fold amplification of individual
drug effects. A 48.3% deficit in sciatic nutritive endoneurial blood flow
was corrected by 34.8 and 24.8% with GLA and BM15.0639 treatments,
respectively. With joint treatment, the flow improvement of 72.5% was
greater than expected from individual drug effects, indicating a
facilitatory interaction. Thus the synergistic effect of combined
antioxidant and n-6 essential fatty acid treatment could potentially provide
increased therapeutic power against diabetic neuropathy.

           Metabolic and vascular factors in the pathogenesis of diabetic
neuropathy.

           Cameron NE, Cotter MA. Department of Biomedical Sciences,
University of Aberdeen, Scotland, U.K.

           Diabetes 1997 Sep;46 Suppl 2:S31-7

           Reduced nerve perfusion is an important factor in the etiology
of diabetic neuropathy. Studies in streptozotocin-induced diabetic rats show
that nerve conduction velocity (NCV) and blood flow deficits are corrected
by treatment with vasodilator drugs, with angiotensin II and endothelin-1
antagonists being particularly important. The AT1 antagonist ZD7155 also
prevents diabetic deficits in regeneration following nerve damage,
indicating that hypoperfusion is an important limitation for nerve repair.
Metabolic changes include high polyol pathway flux, increased advanced
glycosylation, elevated oxidative stress, and impaired omega-6 essential
fatty acid metabolism. Aldose reductase inhibitors (ARIs) restore NCV via
their effects on perfusion. ARI action probably depends on blocking the
conversion of glucose to sorbitol, thus preventing depletion of vasa
nervorum glutathione, an important endogenous free radical scavenger. Free
radicals cause vascular endothelium damage and reduced nitric oxide
vasodilation. Inhibition of advanced glycosylation and autoxidation
(autoxidative glycosylation), major sources of free radicals, by
aminoguanidine or transition metal chelators, corrects neurovascular
dysfunction. Evening primrose oil supplies gamma-linolenic acid (GLA) to
improve vasodilator eicosanoid synthesis in diabetes, correcting nerve blood
flow and NCV deficits. Interactions between some of these mechanisms have
therapeutic implications. Thus, combined ARI and evening primrose oil
treatment produced a 10-fold amplification of NCV and blood flow responses.
Similarly, GLA effects are markedly enhanced when given in combination with
ascorbate as ascorbyl-GLA. Thus, metabolic abnormalities combine to produce
deleterious changes in nerve perfusion that make a major contribution to the
etiology of diabetic neuropathy. The potential importance of multi-action
therapy is stressed.

           Chronic inorganic mercury induced peripheral neuropathy.

           Chu CC, Huang CC, Ryu SJ, Wu TN. Department of Neurology, Chang
Gung Memorial Hospital and Chang Gung University, Taipei, Taiwan.

           Acta Neurol Scand. 1998 Dec;98(6):461-5.

           We report the clinical features, electrophysiological studies,
and morphometric analysis of sural nerve pathology in a patient with
polyneuropathy due to inorganic mercury intoxication. He developed slowly
progressive generalized paralysis of all limbs after 3 months ingestion of
herb drugs which contained mercuric sulfate. Electrophysiologic studies
revealed axonal polyneuropathy involving both motor and sensory fibers.
Sural nerve biopsy demonstrated axonal degeneration with demyelination and a
predominant loss of large myelinated fibers. His muscle strength showed only
mild improvement after 2 years' follow-up. We concluded that inorganic
mercury exposure may induce severe axonal sensorimotor polyneuropathy in
humans and that neurological deficits may persist in severe cases.

           Epidemic optic neuropathy in Cuba--clinical characterization and
risk factors. The Cuba Neuropathy Field Investigation Team.

           CNFIT.

           N Engl J Med 1995 Nov 2;333(18):1176-82

           BACKGROUND. From 1991 to 1993, epidemic optic and peripheral
neuropathy affected more than 50,000 people in Cuba. The number of new cases
decreased after the initiation of vitamin supplementation in the population.
In September 1993, Cuban and U.S. investigators conducted a study to
characterize and identify risk factors for the optic form of the syndrome.
METHODS. We conducted ophthalmologic and neurologic examinations, assessed
exposure to potential toxins, administered a semiquantitative food-frequency
questionnaire, and assessed serum measures of nutritional status in 123
patients with severe optic neuropathy, matched for sex and age to randomly
chosen normal subjects. RESULTS. In the case patients, prominent clinical
features were subacute loss of visual acuity with field defects, diminished
color vision, optic-nerve pallor, and decreased sensitivity to vibration and
temperature in the legs. Tobacco use, particularly cigar smoking, was
associated with an increased risk of optic neuropathy. The risk was reduced
among subjects with higher dietary intakes of methionine, vitamin B12,
riboflavin, and niacin and higher serum concentrations of antioxidant
carotenoids. The risk was also reduced among subjects who raised chickens at
home or had relatives living overseas--factors that may be indirect measures
of increased food availability. CONCLUSIONS. The epidemic of optic and
peripheral neuropathy in Cuba between 1991 and 1993 appears to be linked to
reduced nutrient intake caused by the country's deteriorating economic
situation and the high prevalence of tobacco use.

           Antiplatelet effect of pentoxifylline in human whole blood.

           de la Cruz JP, Romero MM, Sanchez P, Sanchez de la Cuesta F.
Department of Pharmacology and Therapeutics, School of Medicine, University
of Malaga, Spain.

           Gen Pharmacol 1993 May;24(3):605-9

           1. Pentoxifylline inhibits platelet aggregation in whole blood
more than in platelet-rich plasma. 2. An inhibition of the erythrocyte
uptake of adenosine contributes to the antiaggregatory effect of
pentoxifylline.

           Effectiveness of natural oils as sources of gamma-linolenic acid
to correct peripheral nerve conduction velocity abnormalities in diabetic
rats: modulation by thromboxane A2 inhibition.

           Dines KC, Cotter MA, Cameron NE. Department of Biomedical
Sciences, University of Aberdeen, Marischal College, Scotland, UK.

           Prostaglandins Leukot Essent Fatty Acids 1996 Sep;55(3):159-65

           Reduced nerve conduction velocity (NCV) in experimental diabetes
can be prevented by evening primrose oil (EP), which is rich in
gamma-linolenic acid (GLA). This study examined the efficacy of natural GLA
sources, blackcurrant (BC), borage (BO) and fungal (FU) oils, compared with
EP, in correcting motor and sensory NCV deficits in streptozotocin-diabetic
rats, and any potential contribution of thromboxane (TX) A2 synthesis using
the TX antagonist, ZD1542, alone and jointly with GLA-rich oils. Sciatic
motor NCV, 20% reduced by 8 weeks of diabetes, was partially (16%) corrected
by 2 weeks ZD1542 treatment. 1% BC, BO, FU and EP dietary supplementation
caused 11%, 32%, 41% and 53% NCV ameliorations, respectively. A 2% EP diet,
more closely matching the GLA intake from the other oils, caused 67%
correction. Joint oil/ZD1542 treatment produced further motor NCV
improvements for BC and, particularly, BO. A 13% sensory saphenous NCV
deficit in diabetic rats was ameliorated by 31%, 24%, 49%, 81%, 70% and 94%
for ZD1542, BC, BO, FU, EP and 2% EP, respectively. Joint ZD1542-oil
treatment further improved NCV, particularly for BO. Therefore, efficacy
against experimental diabetic neuropathy is not predictable from the GLA
content of natural oils, EP consistently outperforming BC, BO and FU.
Increased TXA2 with diabetes made a minor contribution to NCV deficits, but
blockade improved the response to BO.

           Expression of constitutive cyclo-oxygenase (COX-1) in rats with
streptozotocin-induced diabetes; effects of treatment with evening primrose
oil or an aldose reductase inhibitor on COX-1 mRNA levels.

           Fang C, Jiang Z, Tomlinson DR. Department of Pharmacology, St.
Bartholomew's, London, UK.

           Prostaglandins Leukot Essent Fatty Acids 1997 Feb;56(2):157-63

           Altered prostanoid metabolism participates in the pathogenesis
of diabetic complications. The rate-limiting enzyme in the control of
prostanoid metabolism is constitutive cyclo-oxygenase (COX-1). This study
examined the possibility that altered prostanoid metabolism derives from
altered COX-1 expression in those tissues from diabetic rats, with
characteristic changes in prostanoid production and related haemodynamics.
This account also describes a procedure for estimation of minute amounts of
COX-1 mRNA by reverse transcription and competitive polymerase chain
reaction (RT-cPCR) amplification. In streptozotocin-diabetic rats (STZ-D, 55
mg/kg body weight), compared with age-matched controls, the level of COX-1
mRNA (in attomoles/micrograms tRNA +/- 1SD) was significantly decreased in
sciatic nerve (0.50 +/- 0.26 versus 0.89 +/- 0.32 in controls; P < 0.05) and
thoracic aorta (3.99 +/- 1.67 versus 8.80 +/- 2.37 in controls; P < 0.05).
There were no differences in COX-1 mRNA in diabetic and control rat kidney
and retina, though there was a trend towards increased expression with
diabetes in the latter. Evening primrose oil (EPO) treatment increased COX-1
mRNA in nerve and retina to levels in diabetic rats that were higher than
those of non-diabetic controls (1.21 +/- 0.28 for nerve and 0.065 +/- 0.017
for retina, where control retinae gave 0.031 +/- 0.020-see above for nerve).
Treatment of diabetic rats with an aldose reductase inhibitor was without
effect on COX-1 mRNA levels in the tissues examined. This study demonstrates
that the changes in COX-1 mRNA levels in diabetic rats are organ specific
and suggests that altered prostanoid metabolism can, in part, be explained
by altered COX-1 expression. Apart from providing arachidonate as substrate
for COX, EPO stimulates COX-1 expression in some tissues.

           Pentoxifylline effects on nerve conduction velocity and blood
flow in diabetic rats.

           Flint H, Cotter MA, Cameron NE. Department of Biomedical
Sciences, Institute of Medical Sciences, University of Aberdeen,
Foresterhill, Scotland, UK.

           Int J Exp Diabetes Res 2000;1(1):49-58

           Pentoxifylline has several actions that improve blood rheology
and tissue perfusion and may therefore potentially be applicable to diabetic
neuropathy. The aims of this study were to ascertain whether 2 weeks of
treatment with pentoxifylline could correct nerve conduction velocity and
blood flow deficits in 6-week streptozotocin-diabetic rats and to examine
whether the effects were blocked by co-treatment with the cyclooxygenase
inhibitor, flurbiprofen, or the nitric oxide synthase inhibitor,
NG-nitro-L-arginine. Diabetic deficits in sciatic motor and saphenous
sensory nerve conduction velocity were 56.5% and 69.8% corrected,
respectively, with pentoxifylline treatment. Sciatic endoneurial blood flow
was approximately halved by diabetes and this deficit was 50.4% corrected by
pentoxifylline. Flurbiprofen co-treatment markedly attenuated these actions
of pentoxifylline on nerve conduction and blood flow whereas
NG-nitro-L-arginine was without effect. Thus, pentoxifylline treatment
confers neurovascular benefits in experimental diabetic neuropathy, which
are linked at least in part to cyclooxygenase-mediated metabolism.

           The effects of treatment with alpha-lipoic acid or evening
primrose oil on vascular hemostatic and lipid risk factors, blood flow, and
peripheral nerve conduction in the streptozotocin-diabetic rat.

           Ford I, Cotter MA, Cameron NE, Greaves M. Departments of
Medicine & Therapeutics, University of Aberdeen, Aberdeen, Scotland.

           Metabolism 2001 Aug;50(8):868-75

           Oxidative stress and defective fatty acid metabolism in diabetes
may lead to impaired nerve perfusion and contribute to the development of
peripheral neuropathy. We studied the effects of 2-week treatments with
evening primrose oil (EPO; n = 16) or the antioxidant alpha-lipoic acid
(ALA; n = 16) on endoneurial blood flow, nerve conduction parameters,
lipids, coagulation, and endothelial factors, in rats with
streptozotocin-induced diabetes. Compared with their nondiabetic
littermates, untreated diabetic rats had impaired sciatic motor and
saphenous sensory nerve-conduction velocity (NCV; P <.001), reduced
endoneurial blood flow (P <.001), and increased serum triglycerides (P
<.01), cholesterol (P < 0.01), plasma factor VII (P <.0001), and von
Willebrand factor (vWF; P <.0001). Plasma fibrinogen and serum high-density
lipoprotein concentrations were not significantly different. Treatment with
either ALA or EPO effectively corrected the deficits in NCV and endoneurial
blood flow. ALA was associated with marked and statistically significant
decreases in fibrinogen, factor VII, vWF, and triglycerides (P <.01, paired
t tests before v after treatment). In contrast, EPO was associated with
significant (P <.05) increases in fibrinogen, factor VII, vWF,
triglycerides, and cholesterol and a significant decrease in high-density
lipoprotein. Changes in levels of coagulation factors and lipids,
qualitatively similar to those found with EPO, were obtained with a diet
containing sunflower oil (to control for calorific and lipid content) or
with a normal diet alone. Blood glucose and hematocrit levels were not
significantly altered by treatments. These data suggest that although both
ALA and EPO improve blood flow and nerve function, their actions on vascular
factors differ. The marked effects of ALA in lowering lipid and hemostatic
risk factors for cardiovascular disease indicate potential antithrombotic
and antiatherosclerotic actions that could be of benefit in human diabetes
and merit further study. Copyright 2001 by W.B. Saunders Company

           Plasma and platelet taurine are reduced in subjects with
insulin-dependent diabetes mellitus: effects of taurine supplementation.

           Franconi F, Bennardini F, Mattana A, Miceli M, Ciuti M, Mian M,
Gironi A, Anichini R, Seghieri G. Institute of Biochemistry, University of
Sassari, Italy.

           Am J Clin Nutr 1995 May;61(5):1115-9

           Plasma and platelet taurine concentrations were assayed in 39
patients with insulin-dependent diabetes mellitus (IDDM) and in 34 control
subjects matched for age, sex, and both total and protein-derived daily
energy intake. Platelet aggregation induced by arachidonic acid in vitro at
baseline and after oral taurine supplementation (1.5 g/d) for 90 d was also
studied. Plasma and platelet taurine concentrations (mean +/- SEM) were
lower in diabetic patients (65.6 +/- 3.1 mumol/L, or 0.66 +/- 0.07 mol/g
protein) than in control subjects (93.3 +/- 6.3 mumol/L, or 0.99 +/- 0.16
mol/g protein, P < 0.01). After oral supplementation, both plasma and
platelet taurine concentrations increased significantly in the diabetic
patients, reaching the mean values of healthy control subjects. The
effective dose (mean +/- SEM) of arachidonic acid required for platelets to
aggregate was significantly lower in diabetic patients than in control
subjects (0.44 +/- 0.07 mmol compared with 0.77 +/- 0.02 mmol, P < 0.001,
whereas after taurine supplementation it equaled the mean value for healthy
control subjects (0.72 +/- 0.04 mmol). In in vitro experiments, taurine
reduced platelet aggregation in diabetic patients in a dose-dependent
manner, whereas 10 mmol taurine/L did not modify aggregation in healthy
subjects.

           Use of noninvasive electroacupuncture for the treatment of
HIV-related peripheral neuropathy: a pilot study.

           Galantino ML, Eke-Okoro ST, Findley TW, Condoluci D.
Neuromusculoskeletal Institute, Department of Physical Medicine and
Rehabilitation, School of Osteopathic Medicine, University of Medicine and
Dentistry of New Jersey, Stratford 08084, USA. galantinoml@stockton.edu

           J Altern Complement Med. 1999 Apr;5(2):135-42.

           OBJECTIVES: The main objective of this study was to test the
hypothesis that low-voltage non-invasive electroacupuncture will improve the
condition of neuropathic human immunodeficiency virus (HIV)/acquired
immunodeficiency syndrome (AIDS) patients.

           DESIGN: A prospective study using HIV/AIDS patients who had
antiretroviral drug-induced neuropathy. Eleven patients were enrolled, but
complete data was obtained from only 7. Non-invasive skin electrodes were
placed on leg acupuncture points BL60, ST36, K1, LIV3, and low-voltage
current passed for 20 minutes every day for 30 days. Patients were assessed
preintervention and postintervention with MOS-HIV 30-item instrument
questionnaire and tibial H-reflex was similarly recorded from the right calf
muscle.

           RESULTS: There was improvement in the condition of all 7
patients. They felt much better and reported feelings of increased physical
strength. Outcomes on MOS-HIV 30-item instrument showed significant overall
improvement in functional activities (pre 33+/-10, post 38.4+/-9.6, p = 0.02
MANOVA). This was confirmed by postintervention H-reflex parameters; H-max
and direct muscle response (M-response) amplitudes were potentiated in
relation to pretreatment values (H-max: pre = 1.19+/-1.2, post = 2.68+/-1.9,
p<0.05; M-response: pre = 0.93+/-1.1, post = 2.34+/-1.8, p<0.05); M-response
latency decreased in relation to pretreatment value (pre = 9.7+/-1.8, post =
7.8+/-1.9, p<0.01).

           CONCLUSION: The results support the hypothesis that low-voltage
electroacupuncture will improve the condition of the neuropathic HIV/AIDS
patient.

           [The effect of pentoxifylline and nicergoline on the systemic
and cerebral hemodynamics and on the blood rheological properties in
patients with an ischemic stroke and atherosclerotic lesions of the major
cerebral arteries] [Article in Russian]

           Gara II.

           Zh Nevropatol Psikhiatr Im S S Korsakova 1993;93(3):28-32

           Pentoxifylline versus nicergoline therapy has been studied in 56
patients with atherosclerosis of major cerebral arteries who had ischemic
apoplexy. Pentoxifylline enhances circulation primarily in the stenotic
vessels, while nicergoline in the intact cerebral arteries. The former is
more potent in inducing antiaggregation inhibiting spontaneous platelet and
red cell aggregation and reducing blood viscosity. The results of the study
suggest better response in case of pentoxifylline treatment of patients with
hypo- and eukinetic circulation, while in nicergoline treatment hyperkinetic
hemodynamics patients benefit more in view of the drug cardiodepressive
activity.

           Effect of anti-platelet therapy (aspirin + pentoxiphylline) on
plasma lipids in patients of ischaemic stroke.

           Gaur SP, Garg RK, Kar AM, Srimal RC. Department of Pharmacology
and Clinical & Experimental Medicine Central Drug Research Institute,
Lucknow.

           Indian J Physiol Pharmacol 1993 Apr;37(2):158-60

           Twenty-one patients of ischaemic stroke were put on prolonged
administration of antiplatelet drugs (aspirin 320 mg once daily with
pentoxiphylline 400 mg thrice daily). The serum lipids along with other
biochemical parameters were estimated before starting the treatment and
after completion of 2 months of therapy. No significant changes were
observed in any of the biochemical parameters including lipid profile except
in serum high density lipoprotein (HDL) which increased significantly (<
0.05) after 2 months therapy. It is concluded that 2 months antiplatelet
therapy has no adverse metabolic effect in patients of ischaemic stroke and
the raised serum HDL may contribute to cerebral protective effect.

           Oral zinc therapy in diabetic neuropathy.

           Gupta R, Garg VK, Mathur DK, Goyal RK. Dept. of Medicine, JLN
Medical College and Associated Group of Hospital, Ajmer, Rajasthan-305 001.

           J Assoc Physicians India. 1998 Nov;46(11):939-42.

           The present double blind randomized study was conducted on 50
subjects; 20 age and sex matched healthy controls (Group--I); 15 patients of
diabetes mellitus with neuropathy who received placebo for 6 weeks
(Group--IIA); and 15 patients of diabetes mellitus with neuropathy who were
given supplemental zinc sulphate (660 mg) for 6 weeks (Group--IIB). Serum
zinc level, fasting blood sugar (FBS) and post prandial blood sugar (PPBS)
levels and motor nerve conduction velocity (MNCV) were estimated on day 0
and after 6 weeks in all subjects. Serum zinc levels were significantly low
(p < 0.001) in group IIA and IIB as compared to healthy controls (Group--I)
at baseline. After 6 weeks the change in pre and post therapy values of FBS,
PPBS and MNCV (median and common peroneal nerve) were highly significant (P
= < 0.001) for group IIB alone with insignificant change (P = > 0.05) in
group IIA. No improvement (P = > 0.05) in autonomic dysfunction was observed
in either groups. Therefore, oral zinc supplementation helps in achieving
better glycemic control and improvement in severity of peripheral neuropathy
as assessed by MNCV.

           The role of taurine in diabetes and the development of diabetic
complications.

           Hansen SH. Department of Clinical Biochemistry, Rigshospitalet,
Copenhagen University Hospital, Denmark. shhansen@rh.dk

           Diabetes Metab Res Rev 2001 Sep-Oct;17(5):330-46

           The ubiquitously found beta-amino acid taurine has several
physiological functions, e.g. in bile acid formation, as an osmolyte by cell
volume regulation, in the heart, in the retina, in the formation of
N-chlorotaurine by reaction with hypochlorous acid in leucocytes, and
possibly for intracellular scavenging of carbonyl groups. Some animals, such
as the cat and the C57BL/6 mouse, have disturbances in taurine homeostasis.
The C57BL/6 mouse strain is widely used in diabetic and atherosclerotic
animal models. In diabetes, the high extracellular levels of glucose disturb
the cellular osmoregulation and sorbitol is formed intracellularly due to
the intracellular polyol pathway, which is suspected to be one of the key
processes in the development of diabetic late complications and associated
cellular dysfunctions. Intracellular accumulation of sorbitol is most likely
to cause depletion of other intracellular compounds including osmolytes such
as myo-inositol and taurine. When considering the clinical complications in
diabetes, several links can be established between altered taurine
metabolism and the development of cellular dysfunctions in diabetes which
cause the clinical complications observed in diabetes, e.g. retinopathy,
neuropathy, nephropathy, cardiomyopathy, platelet aggregation, endothelial
dysfunction and atherosclerosis. Possible therapeutic perspectives could be
a supplementation with taurine and other osmolytes and low-molecular
compounds, perhaps in a combinational therapy with aldose reductase
inhibitors. Copyright 2001 John Wiley & Sons, Ltd.

           [Aldose reductase inhibitor SNK-860] [Article in Japanese]

           Hibi C.

           Sanwa Kagaku Kenkyusho Co., Ltd., Research and Development
Section.

           Nippon Rinsho 1997 Nov;55 Suppl:212-5

           No abstract available.

           Pluripotent protective effects of carnosine, a naturally
occurring dipeptide.

           Hipkiss AR, Preston JE, Himsworth DT, Worthington VC, Keown M,
Michaelis J, Lawrence J, Mateen A, Allende L, Eagles PA, Abbott NJ.
Molecular Biology and Biophysics Group, King's College London, Strand,
United Kingdom. alan.hipkiss@kcl.ac.uk

           Ann N Y Acad Sci 1998 Nov 20;854:37-53

           Carnosine is a naturally occurring dipeptide
(beta-alanyl-L-histidine) found in brain, innervated tissues, and the lens
at concentrations up to 20 mM in humans. In 1994 it was shown that carnosine
could delay senescence of cultured human fibroblasts. Evidence will be
presented to suggest that carnosine, in addition to antioxidant and oxygen
free-radical scavenging activities, also reacts with deleterious aldehydes
to protect susceptible macromolecules. Our studies show that, in vitro,
carnosine inhibits nonenzymic glycosylation and cross-linking of proteins
induced by reactive aldehydes (aldose and ketose sugars, certain triose
glycolytic intermediates and malondialdehyde (MDA), a lipid peroxidation
product). Additionally we show that carnosine inhibits formation of
MDA-induced protein-associated advanced glycosylation end products (AGEs)
and formation of DNA-protein cross-links induced by acetaldehyde and
formaldehyde. At the cellular level 20 mM carnosine protected cultured human
fibroblasts and lymphocytes, CHO cells, and cultured rat brain endothelial
cells against the toxic effects of formaldehyde, acetaldehyde and MDA, and
AGEs formed by a lysine/deoxyribose mixture. Interestingly, carnosine
protected cultured rat brain endothelial cells against amyloid peptide
toxicity. We propose that carnosine (which is remarkably nontoxic) or
related structures should be explored for possible intervention in
pathologies that involve deleterious aldehydes, for example, secondary
diabetic complications, inflammatory phenomena, alcoholic liver disease, and
possibly Alzheimer's disease.

           Current progress in clinical trials of aldose reductase
inhibitors in Japan.

           Hotta N, Kakuta H, Ando F, Sakamoto N. Third Department of
Internal Medicine, Nagoya University School of Medicine, Japan.

           Exp Eye Res 1990 Jun;50(6):625-8

           In addition to the results of our clinical trial of epalrestat
in diabetic retinopathy (the open study), the current progress in the
clinical trials of aldose reductase inhibitors for the 'triopathy' of
complications (neuropathy, retinopathy and nephropathy) in Japan is
reported. No data from the placebo-controlled double-blind studies in Japan
are shown because a detailed analysis of the effects of epalrestat on
diabetic neuropathy and retinopathy is now under way. However, it must be
stressed that in the phase III placebo-controlled double-blind studies in
neuropathy and retinopathy, epalrestat was effective.

           Lipoic acid decreases lipid peroxidation and protein
glycosylation and increases (Na(+) + K(+))- and Ca(++)-ATPase activities in
high glucose-treated human erythrocytes.

           Jain SK, Lim G. Department of Pediatrics, Louisiana State
University Health Sciences Center, Shreveport, LA 71130, USA.
sjain@lsuhsc.edu

           Free Radic Biol Med. 2000 Dec;29(11):1122-8.

           Lipoic acid supplementation has been found to be beneficial in
preventing neurovascular abnormalities in diabetic neuropathy. Insufficient
(Na(+) + K(+))-ATPase activity has been suggested as a contributing factor
in the development of diabetic neuropathy. This study was undertaken to test
the hypothesis that lipoic acid reduces lipid peroxidation and glycosylation
and can increase the (Na(+) + K(+))- and Ca(++)-ATPase activities in high
glucose-exposed red blood cells (RBC). Washed normal human RBC were treated
with normal (6 mM) and high glucose concentrations (45 mM) with 0-0.2 mM
lipoic acid (mixture of S and R sterioisomers) in a shaking water bath at 37
degrees C for 24 h. There was a significant stimulation of glucose
consumption by RBC in the presence of lipoic acid both in normal and high
glucose-treated RBC. Lipoic acid significantly lowered the level of glycated
hemoglobin (GHb) and lipid peroxidation in RBC exposed to high glucose
concentrations. High glucose treatment significantly lowered the activities
of (Na(+) + K(+))- and Ca(++)-ATPases of RBC membranes. Lipoic acid addition
significantly blocked the reduction in activities of (Na(+) + K(+))- and
Ca(++)-ATPases in high glucose- treated RBC. There were no differences in
lipid peroxidation, GHb and (Na(+) + K(+))- and Ca(++)-ATPase activity
levels in normal glucose-treated RBC with and without lipoic acid. Thus,
lipoic acid can lower lipid peroxidation and protein glycosylation, and
increase (Na(+) + K(+))- and Ca(++)-ATPase activities in high-glucose
exposed RBC, which provides a potential mechanism by which lipoic acid may
delay or inhibit the development of neuropathy in diabetes.

           Intravenous methylcobalamin treatment for uremic and diabetic
neuropathy in chronic hemodialysis patients.

           Kuwabara S, Nakazawa R, Azuma N, Suzuki M, Miyajima K, Fukutake
T, Hattori T. Department of Neurology, Chiba University School of Medicine.

           Intern Med 1999 Jun;38(6):472-5

           OBJECT: To study the effects of the intravenous administration
of methylcobalamin, an analogue of vitamin B12, for uremic or
uremic-diabetic polyneuropathy in patients who are receiving maintenance
hemodialysis. An ultra-high dose of vitamin B12 has been reported to promote
peripheral nerve regeneration in experimental neuropathy.

           METHODS: Nine patients received a 500 microg methylcobalamin
injection 3 times a week for 6 months. The effects were evaluated using
neuropathic pain grading and a nerve conduction study.

           RESULTS: Serum concentrations of vitamin B12 were ultra-high
during treatment due to the lack of urinary excretion. After 6 months of
treatment, the patients' pain or paresthesia had lessened, and the ulnar
motor and median sensory nerve conduction velocities showed significant
improvement. There were no side effects.

           CONCLUSION: Intravenous methycobalamin treatment is a safe and
potentially beneficial therapy for neuropathy in chronic hemodialysis
patients.

           Can diabetic neuropathy be prevented by angiotensin-converting
enzyme inhibitors?

           Malik RA.

           Ann Med 2000 Feb;32(1):1-5

           The incidence of diabetes and its complications is increasing to
staggering proportions. Presently the WHO estimates an overall prevalence of
130 million, but by 2025 there will be 300 million individuals with diabetes
mellitus. The incidence of diabetic neuropathy approaches 50% in most
diabetic populations; there is no treatment, and its consequences in the
form of foot ulceration and amputation are financially punishing for health
care providers. Attempts to develop treatments have faltered for want of an
understanding of the aetiology of diabetic neuropathy. As a consequence,
1999 saw the demise of two further compounds: recombinant growth factor by
Roche-Genentech and the aldose reductase inhibitor zopolrestat, by Pfizer,
both had reached phase III clinical trials. They joined an impressive list
of at least 30 other compounds which have reached phase III clinical trials
and failed to establish efficacy. The need to establish a viable treatment
for human diabetic neuropathy is absolutely paramount. To provide a rational
answer as to whether angiotensin-converting enzyme (ACE) inhibitors can
prevent human diabetic neuropathy, two major issues need addressing: 1) Does
vascular dysfunction cause human diabetic neuropathy? 2) Can ACE inhibitors
ameliorate diabetic vascular dysfunction and hence neuropathy?
Epidemiological studies support a strong association between neuropathy,
retinopathy and nephropathy. Microangiopathy is deemed as the root cause of
both nephropathy, and retinopathy and mounting evidence provides support for
a vascular basis of diabetic neuropathy. ACE inhibitors appear to correct
many of the abnormalities associated with the vascular dysfunction found in
diabetes. Thus effective ACE inhibition impacts very positively on
cardiovascular outcomes in patients with ischaemic heart disease,
particularly in diabetic patients. ACE inhibition also prevents the
development and progression of incipient and established diabetic
nephropathy and delays progression of background retinopathy. Quinapril
improves measures of diabetic autonomic neuropathy. Our recent study has
demonstrated a significant improvement in peripheral neuropathy following 12
months of treatment with the ACE inhibitor trandolapril.

           Chronic administration of pharmacologic doses of vitamin E
improves the cardiac autonomic nervous system in patients with type 2
diabetes.

           Manzella D, Barbieri M, Ragno E, Paolisso G. Department of
Geriatric Medicine and Metabolic Diseases, Second University of Naples,
Italy.

           Am J Clin Nutr 2001 Jun;73(6):1052-7

           BACKGROUND: Type 2 diabetes is associated with elevated
oxidative stress and declines in antioxidant defense. The disease is also
characterized by an imbalance in the ratio of cardiac sympathetic to
parasympathetic tone. Antioxidants, vitamin E in particular, may have
beneficial effects on the cardiac autonomic nervous system through a decline
in oxidative stress.

           OBJECTIVE: We investigated the possible effects of vitamin E on
the cardiac autonomic nervous system, as assessed by analysis of heart rate
variability, in patients with type 2 diabetes and cardiac autonomic
neuropathy.

           DESIGN: In a double-blind randomized controlled trial, 50
patients with type 2 diabetes were assigned to treatment with vitamin E (600
mg/d) or placebo for 4 mo.

           RESULTS: The anthropometric characteristics of the patients
remained unchanged throughout the study. Chronic vitamin E administration
was associated with decreases in concentrations of glycated hemoglobin (P <
0.05), plasma insulin (P < 0.05), norepinephrine (P < 0.03), and epinephrine
(P < 0.02); a lower homeostasis model assessment index (P < 0.05); and
improved indexes of oxidative stress. Furthermore, vitamin E administration
was associated with increases in the R-R interval (P < 0.05), total power (P
< 0.05), and the high-frequency component of heart rate variability (HF; P <
0.05) and decreases in the low-frequency component (LF; P < 0.05) and the
ratio of LF to HF (P < 0.05). Finally, change in the plasma vitamin E
concentration was correlated with change in the LF-HF ratio (r = -0.43, P <
0.04) independently of changes in the homeostasis model assessment index and
plasma catecholamines concentrations.

           CONCLUSIONS: Chronic vitamin E administration improves the ratio
of cardiac sympathetic to parasympathetic tone in patients with type 2
diabetes. Such an effect might be mediated by a decline in oxidative stress.

           Supplemental therapy in isolated vitamin E deficiency improves
the peripheral neuropathy and prevents the progression of ataxia.

           Martinello F, Fardin P, Ottina M, Ricchieri GL, Koenig M,
Cavalier L, Trevisan CP. Department of Neurological and Psychiatric
Sciences, University of Padua, Italy.

           J Neurol Sci 1998 Apr 1;156(2):177-9

           A 24-year-old male, who suffered since childhood from a
progressive form of ataxia associated with peripheral neuropathy, was found
severely deficient in serum vitamin E. He walked with bilateral aid and
presented severe dysmetria of the limbs and dysarthric speech; muscular
strength and trophism were slightly diminished in the distal muscles of four
limbs and there was hypotonia of the arms; he presented absent deep tendon
reflexes, bilateral Babinski's sign, reduced proprioception at four limbs,
pes cavus and fasciculations of the tongue. Intestinal fat malabsorption and
other gastrointestinal or haematological conditions associated with
deficiency of this vitamin were ruled out. In this patient, after 2 years of
a daily supplement of high doses of vitamin E, a further progression of the
disease was not observed and, moreover, the neurophysiological
characteristics of his neuropathy appeared clearly improved. A longitudinal
evaluation of serum vitamin E levels showed values in the normal range after
13 months of therapy. The patient had molecular genetic analysis of
chromosome 8 and was found homozygous for the unusual mutation 513insTT in
the alpha-tocopherol transfer protein gene.

           Gabapentin for neuropathic pain: systematic review of controlled
and uncontrolled literature.

           Mellegers MA, Furlan AD, Mailis A. University of Maastricht, The
Netherlands.

           Clin J Pain. 2001 Dec;17(4):284-95.

           OBJECTIVE: To assess the efficacy/effectiveness and side effects
of gabapentin for the treatment of neuropathic pain. DESIGN: Systematic
review of the literature. METHODS: Extensive search of several electronic
databases located both controlled and uncontrolled studies. Efficacy was
assessed through meta-analysis of randomized controlled trials (RCTs),
whereas the effectiveness of gabapentin in uncontrolled studies was assessed
via a novel system of dichotomous classification of "bad" versus "good"
results.

           FINDINGS: Thirty-five papers involving 727 patients with
multiple neuropathic pain conditions met the inclusion criteria. The
meta-analysis of the 2 high-quality, placebo-controlled RCTs showed positive
effect of gabapentin in diabetic neuropathy and post-herpetic neuralgia. The
addition of 2 low-quality, placebo-controlled RCTs did not alter the
magnitude or direction of observed effect. The uncontrolled studies
demonstrated positive effect on pain in different neuropathic syndromes, as
well as benefit on different types of neuropathic pain; highest dose
administered and rate-of-dose escalation showed wide variability between
prescribers. Fewer and less severe side effects were reported in the
uncontrolled studies.

           CONCLUSIONS: Gabapentin seems to be effective in multiple
painful neuropathic conditions. The variable prescribing patterns of the
uncontrolled studies raise the suspicion that effectiveness may be reduced
if one limits administration of the drug to very low doses, whereas rapid
dose escalation may be associated with increased central nervous system side
effects. Well-designed controlled trials may provide insight into
differential symptom sensitivity to the drug.

           [Mechanism of the effect of methylcobalamin on the recovery of
neuromuscular functions in mechanical and toxin denervation] [Article in
Russian]

           Mikhailov VV, Mikhailov VV, Avakumov VM.

           Farmakol Toksikol 1983 Nov-Dec;46(6):9-12

           It has been shown in experiments on rats that daily
administration of methylcobalamine in a dose of 50 micrograms/100 g bw
produces marked activation of the regeneration of mechanically damaged axons
of motoneurons. Systematic administration of the drug has a protective
action on the development of neuromuscular transmission blockade induced by
botulinum toxoid.

           Polyol pathway hyperactivity is closely related to carnitine
deficiency in the pathogenesis of diabetic neuropathy of
streptozotocin-diabetic rats.

           Nakamura J, Koh N, Sakakibara F, Hamada Y, Hara T, Sasaki H,
Chaya S, Komori T, Nakashima E, Naruse K, Kato K, Takeuchi N, Kasuya Y,
Hotta N. The Third Department of Internal Medicine, Nagoya University School
of Medicine, Nagoya, Japan.

           J Pharmacol Exp Ther 1998 Dec;287(3):897-902

           To investigate the relationship between polyol pathway
hyperactivity and altered carnitine metabolism in the pathogenesis of
diabetic neuropathy, the effects of an aldose reductase inhibitor,
[5-(3-thienyl) tetrazol-1-yl]acetic acid (TAT), and a carnitine analog,
acetyl-L-carnitine (ALC), on neural functions and biochemistry and
hemodynamic factors were compared in streptozotocin-diabetic rats.
Significantly delayed motor nerve conduction velocity, decreased R-R
interval variation, reduced sciatic nerve blood flow and decreased
erythrocyte 2, 3-diphosphoglycerate concentrations in diabetic rats were all
ameliorated by treatment with TAT (administered with rat chow containing
0.05% TAT, approximately 50 mg/kg/day) or ALC (by gavage, 300 mg/kg/day) for
4 weeks. Platelet hyperaggregation activity in diabetic rats was diminished
by TAT but not by ALC. TAT decreased sorbitol accumulation and prevented not
only myo-inositol depletion but also free-carnitine deficiency in diabetic
nerves. On the other hand, ALC also increased the myo-inositol as well as
the free-carnitine content without affecting the sorbitol content. These
observations suggest that there is a close relationship between increased
polyol pathway activity and carnitine deficiency in the development of
diabetic neuropathy and that an aldose reductase inhibitor, TAT, and a
carnitine analog, ALC, have therapeutic potential for the treatment of
diabetic neuropathy.

           Treatment of diabetic polyneuropathy with the antioxidant
thioctic acid (alpha-lipoic acid): a two year multicenter randomized
double-blind placebo-controlled trial (ALADIN II). Alpha Lipoic Acid in
Diabetic Neuropathy.

           Reljanovic M, Reichel G, Rett K, Lobisch M, Schuette K, Moller
W, Tritschler HJ, Mehnert H. University of Clinic for Diabetes,
Endocrinology and Metabolic Diseases Vuk Vrhovac, Medical faculty,
University of Zagreb, Coratia.

           Free Radic Res. 1999 Sep;31(3):171-9.

           Short-term trials with the antioxidant thioctic acid (TA) appear
to improve neuropathic symptoms in diabetic patients, but the long-term
response remains to be established. Therefore, Type 1 and Type 2 diabetic
patients with symptomatic polyneuropathy were randomly assigned to three
treatment regimens: (1) 2 x 600(mg of TA (TA 1200), (2) 600)mg of TA plus
placebo (PLA) (TA 600) or (3) placebo and placebo (PLA). A trometamol salt
solution of TA of 1200 or 600 mg or PLA was intravenously administered once
daily for five consecutive days before enrolling the patients in the oral
treatment phase. The study was prospective, PLA-controlled, randomized,
double-blind and conducted for two years. Severity of diabetic neuropathy
was assessed by the Neuropathy Disability Score (NDS) and
electrophysiological attributes of the sural (sensory nerve conduction
velocity (SNCV), sensory nerve action potential (SNAP)) and the tibial
(motor nerve conduction velocity (MNCV), motor nerve distal latency (MNDL))
nerve. Statistical analysis was performed after independent reviewers
excluded all patients with highly variable data allowing a final analysis of
65 patients (TA 1200: n = 18, TA 600: n = 27; PLA: n = 20). At baseline no
significant differences were noted between the groups regarding the
demographic variables and peripheral nerve function parameters for these 65
patients. Statistically significant changes after 24 months between TA and
PLA were observed (mean +/- SD) for sural SNCV: +3.8 +/- 4.2 m/s in TA 1200,
+3.0+/-3.0m/s in TA 600, -0.1+/-4.8m/s in PLA (p < 0.05 for TA 1200 and TA
600 vs. PLA); sural SNAP: +0.6+/-2.5 microV in TA 1200, +0.3+/-1.4 microV in
TA 600, -0.7 +/- 1.5 microV in PLA (p = 0.076 for TA 1200 vs. PLA and p <
0.05 for TA 600 vs. PLA), and in tibial MNCV: +/- 1.2 +/- 3.8 m/s in TA
1200, -0.3 +/- 5.2 m/s in TA 600, 1.5 +/- 2.9 m/s in PLA (p < 0.05 for TA
1200 vs. PLA). No significant differences between the groups after 24 months
were noted regarding the tibial MNDL and the NDS. We conclude that in a
subgroup of patients after exclusion of patients with excessive test
variability throughout the trial, TA appeared to have a beneficial effect on
several attributes of nerve conduction.

           The case history of an elite ultra-endurance cyclist who
developed chronic fatigue syndrome.

           Rowbottom DG, Keast D, Green S, Kakulas B, Morton AR. Department
of Human Movement, University of Western Australia, Nedlands, Australia.

           Med Sci Sports Exerc. 1998 Sep;30(9):1345-8.

           An elite ultra-endurance athlete, who had previously undergone
physiological and performance testing, developed chronic fatigue syndrome
(CFS). An incremental cycling exercise test conducted while he was suffering
from CFS indicated decreases in maximum workload achieved (Wmax; -11.3%),
the maximum oxygen uptake (VO2max; -12.5%), and the anaerobic threshold
(AT; -14.3%) compared to pre-CFS data. A third test conducted after the
athlete had shown indications of significant improvement in his clinical
condition revealed further decreases in Wmax (-7.9%), VO2max (-10.2%) and AT
(-8.3%). These data, along with submaximal exercise data and muscle biopsy
electron microscopic analyses, suggest that the performance decrements were
the result of detraining, rather than an impairment of aerobic metabolism
due to CFS per se. These data may be indicative of central, possibly
neurological, factors influencing fatigue perception in CFS sufferers.

           Inhibition of development of peripheral neuropathy in
streptozotocin-induced diabetic rats with N-acetylcysteine.

           Sagara M, Satoh J, Wada R, Yagihashi S, Takahashi K, Fukuzawa M,
Muto G, Muto Y, Toyota T. Third Department of Internal Medicine, Tohoku
University School of Medicine, Sendai, Japan.

           Diabetologia 1996 Mar;39(3):263-9

           N-acetylcysteine (NAC) is a precursor of glutathione (GSH)
synthesis, a free radical scavenger and an inhibitor of tumour necrosis
factor alpha (TNF). Because these functions might be beneficial in diabetic
complications, in this study we examined whether NAC inhibits peripheral
neuropathy. Motor nerve conduction velocity (MNCV) was significantly
decreased in streptozotocin-induced-diabetic Wistar rats compared to control
rats. Oral administration of NAC reduced the decline of MNCV in diabetic
rats. Structural analysis of the sural nerve disclosed significant reduction
of fibres undergoing myelin wrinkling and inhibition of myelinated fibre
atrophy in NAC-treated diabetic rats. NAC treatment had no effect on blood
glucose levels or on the nerve glucose, sorbitol and cAMP contents, whereas
it corrected the decreased GSH levels in erythrocytes, the increased lipid
peroxide levels in plasma and the increased lipopolysaccharide-induced TNF
activity in sera of diabetic rats. Thus, NAC inhibited the development of
functional and structural abnormalities of the peripheral nerve in
streptozotocin-induced diabetic rats.

           Effect of acetyl-L-carnitine in the treatment of painful
peripheral neuropathies in HIV+ patients.

           Scarpini E, Sacilotto G, Baron P, Cusini M, Scarlato G.
Department of Clinical Neurology, IRCCS-Ospedale Maggiore Policlinico,
University of Milano, Italy.

           J Peripher Nerv Syst 1997;2(3):250-2

           We studied the effects of acetyl-L-carnitine on pain in 16 HIV+
patients affected by painful distal symmetrical neuropathy. Patients were
treated with 0.5-1 gr per day of acetyl-L-carnitine either i.m. or i.v. for
3 weeks. Pain intensity was measured before and after the treatment by the
Huskisson's analogic scale. Ten patients (62.5%) reported an improvement of
symptoms, five patients (31.25%) were unchanged, one patient worsened. The
results of this open study show that acetyl-L-carnitine can have a role in
the treatment of pain in distal symmetrical polyneuropathy related to HIV
infection. However, further double-blind, placebo-controlled studies are
needed to confirm these preliminary results.

           Molecular mechanisms of thiamine utilization.

           Singleton CK, Martin PR. Department of Biological Science,
Vanderbilt University, Nashville, TN 37235, USA.
Charles.K.Singleton@Vanderbilt.edu

           Curr Mol Med 2001 May;1(2):197-207

           Thiamine is required for all tissues and is found in high
concentrations in skeletal muscle, heart, liver, kidneys and brain. A state
of severe depletion is seen in patients on a strict thiamine-deficient diet
in 18 days, but the most common cause of thiamine deficiency in affluent
countries is alcoholism. Thiamine diphosphate is the active form of
thiamine, and it serves as a cofactor for several enzymes involved primarily
in carbohydrate catabolism. The enzymes are important in the biosynthesis of
a number of cell constituents, including neurotransmitters, and for the
production of reducing equivalents used in oxidant stress defenses and in
biosyntheses and for synthesis of pentoses used as nucleic acid precursors.
Because of the latter fact, thiamine utilization is increased in tumor
cells. Thiamine uptake by the small intestines and by cells within various
organs is mediated by a saturable, high affinity transport system. Alcohol
affects thiamine uptake and other aspects of thiamine utilization, and these
effects may contribute to the prevalence of thiamine deficiency in
alcoholics. The major manifestations of thiamine deficiency in humans
involve the cardiovascular (wet beriberi) and nervous (dry beriberi, or
neuropathy and/or Wernicke-Korsakoff syndrome) systems. A number of inborn
errors of metabolism have been described in which clinical improvements can
be documented following administration of pharmacological doses of thiamine,
such as thiamine-responsive megaloblastic anemia. Substantial efforts are
being made to understand the genetic and biochemical determinants of
inter-individual differences in susceptibility to development of thiamine
deficiency-related disorders and of the differential vulnerabilities of
tissues and cell types to thiamine deficiency.

           Biochemical pathogenesis of subacute combined degeneration of
the spinal cord and brain.

           Surtees R. Institute of Child Health, London, UK.

           J Inherit Metab Dis 1993;16(4):762-70

           In humans, subacute combined degeneration of the spinal cord and
brain, a primary demyelinating disease, is caused by cobalamin or
methyltetrahydrofolate deficiency. Experimental studies into its
pathogenesis suggest that dysfunction of the methyl-transfer pathway may be
the cause. Compelling evidence for this comes from the study of inborn
errors of cobalamin metabolism where deficiency of methylcobalamin, but not
deoxyadenosylcobalamin, is associated with demyelination. Recent studies
have focused upon inborn errors of the methyl-transfer pathway.
Cerebrospinal fluid concentrations of metabolites of the methyl-transfer
pathway have been measured in humans with sequential errors of the pathway
and correlated with demyelination demonstrated on magnetic resonance imaging
of the brain. This has provided new data suggesting that deficiency of
S-adenosylmethionine is critical to the development of demyelination in
cobalamin deficiency.

           Effects of propionyl-L-carnitine on cardiac dysfunction in
streptozotocin-diabetic rats.

           Terada R, Matsubara T, Koh N, Nakamura J, Hotta N. Third
Department of Internal Medicine, Nagoya University School of Medicine,
Japan.

           Eur J Pharmacol. 1998 Sep 18;357(2-3):185-91

           The effects of orally administered propionyl-L-carnitine on
cardiac dysfunction in rats with streptozotocin-induced diabetes were
investigated. Wistar male rats were divided into four groups: untreated
normal, propionyl-L-carnitine (daily for 4 weeks with 3 g/kg
orally) -treated normal, untreated diabetic, propionyl-L-carnitine-treated
diabetic. Four weeks after streptozotocin administration, plasma lipid
levels were increased and myocardial carnitine content was decreased in
untreated diabetic rats. These changes were significantly reversed by the
propionyl-L-carnitine treatment. Assessment of cardiac function with
isolated perfused working hearts revealed a depression of left ventricular
developed pressure as well as both maximum positive and negative dP/dt in
untreated diabetic as compared with that in normal hearts. Cardiac function
at the higher left atrial filling pressures in the
propionyl-L-carnitine-treated diabetic rats was improved significantly
compared to that in untreated hearts. The data thus suggest that oral
administration of propionyl-L-carnitine can reduce abnormalities of cardiac
function, correlated with a significant increase in myocardial carnitine
content and improved lipid metabolism in terms of lowered plasma lipids.

           A new mechanism of neurodegeneration: a proinflammatory cytokine
inhibits receptor signaling by a survival peptide.

           Venters HD, Tang Q, Liu Q, VanHoy RW, Dantzer R, Kelley KW.
Laboratory of Immunophysiology, Department of Animal Sciences, University of
Illinois, Urbana, IL 61801, USA.

           Proc Natl Acad Sci U S A 1999 Aug 17;96(17):9879-84

           Heightened expression of both a proinflammatory cytokine, tumor
necrosis factor alpha (TNF-alpha), and a survival peptide, insulin-like
growth factor I (IGF-I), occurs in diverse diseases of the central nervous
system, including Alzheimer's disease, multiple sclerosis, the AIDS-dementia
complex, and cerebral ischemia. Conventional roles for these two proteins
are neuroprotection by IGF-I and neurotoxicity by TNF-alpha. Although the
mechanisms of action for IGF-I and TNF-alpha in the central nervous system
originally were established as disparate and unrelated, we hypothesized that
the signaling pathways of these two cytokines may interact during
neurodegeneration. Here we show that concentrations of TNF-alpha as low as
10 pg/ml markedly reduce the capacity of IGF-I to promote survival of
primary murine cerebellar granule neurons. TNF-alpha suppresses
IGF-I-induced tyrosine phosphorylation of insulin receptor substrate 2
(IRS-2) and inhibits IRS-2-precipitable phosphatidylinositol 3'-kinase
activity. These experiments indicate that TNF-alpha promotes IGF-I receptor
resistance in neurons and inhibits the ability of the IGF-I receptor to
tyrosine-phosphorylate the IRS-2 docking molecule and to subsequently
activate the critical downstream enzyme phosphatidylinositol 3'-kinase. This
intracellular crosstalk between discrete cytokine receptors reveals a novel
pathway that leads to neuronal degeneration whereby a proinflammatory
cytokine inhibits receptor signaling by a survival peptide.

           [Pharmacological studies on degeneration and regeneration of the
peripheral nerves. (2) Effects of methylcobalamin on mitosis of Schwann
cells and incorporation of labeled amino acid into protein fractions of
crushed sciatic nerve in rats] [Article in Japanese]

           Yamatsu K, Yamanishi Y, Kaneko T, Ohkawa I.

           Nippon Yakurigaku Zasshi 1976 Mar;72(2):269-78

           Male Wistar rats (140 to 150 g) in which the unilateral sciatic
nerve had been crushed were treated consecutively with methylcobalamin (5,
50 and 500 mug/kg/day i.p.) or saline immediately after the nerve-crush.
Thereafter, they were periodically sacrificed for biochemical and
histological examinations. At different intervals after the nerve-crush,
L-leucine-4,5-T (20 mu Ci/100g, specific activity 15 mCi/m mole) or
L-leucine -14C(U) (15 muCi/100g, specific activity 270 mCi/m mole) was given
i.p. to some rats of each group and 3 hr later they were sacrificed to
determine the rate of leucine incorporation into protein fractions of the
crushed nerve and the denervated muscles. The nerve and muscles of the
contralateral side served as control. Longitudinal sections of proximal and
distal stumps of the sciatic nerve were prepared and stained with
hematoxylin and eosin. As compared with saline group, repeated injections of
5, 50 and 500 mug/kg/day of methyl-cobalamin caused a significant increase
of the in vivo incorporation of radioactive leucine into the protein
fraction of the crushed sciatic nerve 5 to 7 days after the crush. In
contrast, a recovery of the increased incorporation of leucine into the
crushed nerve was more rapid in methylcobalamin groups than in the saline
group. On the other hand, methylcobalamin (5 approximately 500 mug/kg/day
i.p.) had no significant effect on the leucine incorporation into the
denervated muscles (m. gastrocnemius, m. tibialis anterior and m. soleus).
In addition, consecutive injections of methylcobalamin (5 approximately 500
mug/kg/day) did not affect the mitosis of Schwann cells during the period of
Wallerian degeneration of the crushed sciatic nerve. These results suggest
that methylcobalamin possesses a stimulating effect on proteosynthesis in
Schwann cells at the initial stage of axon regeneration and it may
facilitate neural regeneration.

           Treatment of symptomatic diabetic peripheral neuropathy with the
anti-oxidant alpha-lipoic acid. A 3-week multicentre randomized controlled
trial (ALADIN Study).

           Ziegler D, Hanefeld M, Ruhnau KJ, Meissner HP, Lobisch M,
Schutte K, Gries FA. Diabetes-Forschungsinstitut an der
Heinrich-Heine-Universitat, Dusseldorf, Germany.

           Diabetologia. 1995 Dec;38(12):1425-33.

           Anti-oxidant treatment has been shown to prevent nerve
dysfunction in experimental diabetes mellitus, thus providing a rationale of
potential therapeutic value for diabetic patients. The effects of the
anti-oxidant alpha-lipoic acid (thioctic acid) were studied in a 3-week
multicentre, randomized, double-blind placebo-controlled trial (Alpha-Lipoic
Acid in Diabetic Neuropathy; ALADIN) in 328 non-insulin-dependent diabetic
patients with symptomatic peripheral neuropathy who were randomly assigned
to treatment with intravenous infusion of alpha-lipoic acid using three
doses (1200, 600, or 100 mg ALA) or placebo (PLAC). Neuropathic symptoms
(pain, burning, paraesthesiae, and numbness) were scored at baseline and at
each visit (days 2-5, 8-12, and 15-19) prior to infusion. In addition, the
Hamburg Pain Adjective List, a multidimensional specific pain questionnaire,
and the Neuropathy Symptom and Disability Scores were assessed at baseline
and day 19. According to the protocol 260 (65/63/66/66) patients completed
the study. The total symptom score in the feet decreased from baseline to
day 19 by -4.5 +/- 3.7 (-58.6%) points (mean +/- SD) in ALA 1200, -5.0 +/-
4.1 (-63.5%) points in ALA 600, -3.3 +/- 2.8 (-43.2%) points in ALA 100,
and -2.6 +/- 3.2 (-38.4%) points in PLAC (ALA 1200 vs PLAC: p = 0.003; ALA
600 vs PLAC: p < 0.001). The response rates after 19 days, defined as an
improvement in the total symptom score of at least 30%, were 70.8% in ALA
1200, 82.5% in ALA 600, 65.2% in ALA 100, and 57.6% in PLAC (ALA 600 vs
PLAC; p = 0.002). The total scale of the Pain Adjective List was
significantly reduced in ALA 1200 and ALA 600 as compared with PLAC after 19
days (both p < 0.01). The rates of adverse events were 32.6% in ALA 1200,
18.2% in ALA 600, 13.6% in ALA 100, and 20.7% in PLAC. These findings
substantiate that intravenous treatment with alpha-lipoic acid using a dose
of 600 mg/day over 3 weeks is superior to placebo in reducing symptoms of
diabetic peripheral neuropathy, without causing significant adverse
reactions.

           Treatment of symptomatic diabetic polyneuropathy with the
antioxidant alpha-lipoic acid: a 7-month multicenter randomized controlled
trial (ALADIN III Study). ALADIN III Study Group. Alpha-Lipoic Acid in
Diabetic Neuropathy.

           Ziegler D, Hanefeld M, Ruhnau KJ, Hasche H, Lobisch M, Schutte
K, Kerum G, Malessa R. Diabetes-Forschungsinstitut an der
Heinrich-Heine-Universitat, Dusseldorf, Germany.
dan.ziegler@dfi.uni-duesseldorf.de

           Diabetes Care. 1999 Aug;22(8):1296-301.

           OBJECTIVE: To evaluate the efficacy and safety of alpha-lipoic
acid given intravenously, followed by oral treatment in type 2 diabetic
patients with symptomatic polyneuropathy.

           RESEARCH DESIGN AND METHODS: In a multicenter randomized
double-blind placebo-controlled trial (Alpha-Lipoic Acid in Diabetic
Neuropathy [ALADIN] III Study), 509 outpatients were randomly assigned to
sequential treatment with 600 mg alpha-lipoic acid once daily intravenously
for 3 weeks, followed by 600 mg alpha-lipoic acid three times a day orally
for 6 months (A-A; n = 167); 600 mg alpha-lipoic acid once daily
intravenously for 3 weeks, followed by placebo three times a day orally for
6 months (A-P; n = 174); and placebo once daily intravenously for 3 weeks,
followed by placebo three times a day orally for 6 months (P-P; n = 168).
Outcome measures included the Total Symptom Score (TSS) for neuropathic
symptoms (pain, burning, paresthesias, and numbness) in the feet, and the
Neuropathy Impairment Score (NIS). Data analysis was based on the intention
to treat.

           RESULTS: No significant differences between the groups were
noted for the demographic variables and the nerve function parameters at
baseline. The TSS in the feet decreased from baseline to day 19 (median
[range]) by -3.7 (-12.6 to 5.0) points in the group given alpha-lipoic acid
intravenously and by -3.0 (-12.3 to 8.0) points in the placebo group (P =
0.447), but the area under curve on a daily basis was significantly smaller
in the active as compared with the placebo group (85.6 [0-219] vs. 95.9
[5.5-220]); P = 0.033). After 7 months, the changes in the TSS from baseline
were not significantly different between the three groups studied, which
could be due to increasing intercenter variability in the TSS during the
trial. The NIS decreased after 19 days by -4.34+/-0.35 points (mean +/- SEM)
in A-A and A-P and -3.49+/-0.58 points in P-P (P = 0.02 for alpha-lipoic
acid versus placebo) and after 7 months by -5.82+/-0.73 points in
A-A, -5.76+/-0.69 points in A-P, and -4.37+/-0.83 points in P-P (P = 0.09
for A-A vs. P-P). The rates of adverse events were not different between the
groups throughout the study.

           CONCLUSIONS: These findings indicate that a 3-week intravenous
treatment with alpha-lipoic acid, followed by a 6-month oral treatment, had
no effect on neuropathic symptoms distinguishable from placebo to a
clinically meaningful degree, possibly due to increasing intercenter
variability in symptom scoring during the study. However, this treatment was
associated with a favorable effect on neuropathic deficits without causing
significant adverse reactions. Long-term trials that focus on neuropathic
deficits rather than symptoms as the primary criterion of efficacy are
needed to see whether oral treatment with alpha-lipoic acid over several
years may slow or reverse the progression of diabetic neuropathy.

           Alpha-lipoic acid in the treatment of diabetic polyneuropathy in
Germany: current evidence from clinical trials.

           Ziegler D, Reljanovic M, Mehnert H, Gries FA.
Diabetes-Forschungsinstitut an der Heinrich-Heine-Universitat, Dusseldorf,
Germany. dan.ziegler@dfi.uni-duesseldorf.de

           Exp Clin Endocrinol Diabetes. 1999;107(7):421-30.

           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.