Antioxidant Alpha Lipoic Acid (ALA) Significantly
Improves Symptoms of Diabetic Neuropathy
Mayo Clinic in Rochester Monday, April 07, 2003
ROCHESTER, Minn. -- A collaborative study between Mayo Clinic and a medical center in Russia found that alpha lipoic acid (ALA) significantly and rapidly reduces the frequency and severity of symptoms of the most common kind of diabetic neuropathy. Symptoms decreased include burning and sharply cutting pain, prickling sensations and numbness.
The findings appear in the March 2003 issue of Diabetes Care, http://care.diabetesjournals.org/.
"There appears to be a rather large effect on the pain of diabetic neuropathy with ALA," says Peter Dyck, M.D., Mayo Clinic neurologist and peripheral nerve specialist. "The magnitude of the change is considerable. We also found some improvement in neurologic signs and nerve conduction. We were surprised by the magnitude and the rapidity of the response."
When patients were given ALA, also known as thioctic acid, the researchers found statistically significant improvement in the symptoms of diabetic sensorimotor polyneuropathy (DSPN) damage to multiple nerves caused by diabetes. The researchers measured improvement by a total symptom score, a summation of the presence, severity and duration of burning and sharply cutting pain, prickling sensations and numbness. The patients who took ALA saw a 5.7-point total symptom score improvement from the start of the trial, while those who took placebo, an inactive substance, only improved 1.8 points. ALA produced no unfavorable side effects in the patients taking this substance.
"It’s very safe," says Dr. Dyck. "There have been no known complications."
The alternatives for managing the symptoms of DSPN -- narcotics, analgesics or antiepileptic drugs -- are less than ideal, according to Dr. Dyck.
"Most people can’t work while on narcotics, and there’s the concern about habituation," says Dr. Dyck. "If you take analgesics, you can get kind of dopey."
Dr. Dyck says that the intravenous ALA preparation at the dosage he studied is not available to U.S. physicians. It is available in oral form and in smaller doses in drug stores.
"I think it’s a promising lead for the future, in that antioxidants may be implicated in the cause of diabetic neuropathy, and ALA might conceivably be a preventative or interventative," says Dr. Dyck. "It may well be worthwhile for treatment, but I’d rather patients with diabetic neuropathy not go out swallowing large amounts of this drug yet. It isn’t Food and Drug Administration-approved for this purpose."
Dr. Dyck adds that a large, multi-center trial of oral ALA is under way. "We should see what the further data show before we give this widely to patients with diabetic neuropathy," says Dr. Dyck.
Mayo Clinic physicians Dr. Dyck, Phillip Low, M.D., and William Litchy, M.D., were involved in the design and helped oversee the phase 3 study, which included 120 type 1 or 2 diabetic patients, ages 18-74, with DSPN. The study was conducted at the Russian Medical Academy for Advanced Studies in Moscow. After hospital admission, patients were randomized, or selected by chance, to receive either ALA or a placebo in 14 intravenous doses over three weeks, following one week in which all participants received placebo. The study was double-blinded, thus neither patients nor investigators knew which patients received each substance. The researchers then measured the severity and constancy of each patient’s symptoms of burning and sharply cutting pain, prickling sensations and numbness. Trial participants’ progress was measured by written surveys in addition to testing nerve conduction, function of the autonomic nervous system function and sensation.
If the drug proved effective in this trial, the researchers also wanted to find out why it worked. They found that ALA improves the nerve function damaged by chronic hyperglycemia, or the condition when patients’ blood sugars consistently are not under proper control.
"It is known that ALA is a very strong antioxidant," says Dr. Dyck. "High glucose in diabetes leaves trace chemicals harmful to cells -- that process is called oxidative stress. If you burn something in the oven, it leaves soot. Similarly, in disease, there is ‘soot,’ and there are mechanisms that relieve ‘soot.’ Antioxidants promote getting rid of oxidative stress products.
"Oxidative stress is known to be implicated in many disease processes, including diabetic neuropathy," he adds. "If nerve fibers partially degenerate, you get pain and prickling and other symptoms of diabetic neuropathy."
Since 1959, physicians in Germany have treated diabetic neuropathy with ALA. However, there was insufficient research evidence to warrant its use, Dr. Dyck says. The manufacturer of ALA, a German company called Viatris Inc. (formerly ASTA Medica, Inc.), approached Dr. Dyck and other physicians about conducting clinical trials with this supplement to test its effectiveness in alleviating diabetic neuropathy.
Diabetic neuropathy may compromise a person’s quality of life. Previous studies have shown that patients with this syndrome may become depressed or anxious and may have trouble with work, social obligations, sleep and other daily activities.
Although regulating patients’ blood-sugar levels is the ideal way to prevent diabetic neuropathy, physicians have recognized that not all patients can or will control their blood sugars to the needed degree, according to Dr. Dyck. Some patients do not monitor their glucose levels or use their insulin injections or pumps often enough. For other patients, such as type 1 diabetics, blood sugars may fluctuate wildly and prove difficult to control tightly.
According to the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), 11.1 million people in the United States have been diagnosed with diabetes, while an estimated 5.9 million more remain undiagnosed. NIDDK estimates that of these, 50 percent experience some type of neuropathy.
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Efficacy of acetyl-l-carnitine for antiretroviral toxic neuropathy
Leighton Davies MD, for HIV i-Base
The results of a recently published trial by Andrew Hart and colleagues from Blond McIndoe Centre, Manchester, and the Royal Free Hospital in London, provide confirmatory evidence for the use of acetyl-l-carnitine as a pathogenesis-based treatment for antiretroviral-associated toxic neuropathy (ATN).  ATN is the commonest cause of distal symmetrical neuropathy affecting between 11% and 66 % of individuals on antiretroviral therapy and is usually associated with the dideoxynucleoside analogue drugs ddC, d4Tand ddI (the ‘d-drugs’).
Currently available therapies - analgesics +/- adjuvant therapies (tricyclic antidepressants, anticonvulsants, mexiletine and peptide T) offer little in the way of symptom amelioration.
The proposed mechanism of ATN is impairment of neuronal mitochondrial oxidative metabolism (mediated by RTI inhibition of DNA-gamma-polymerase, upon which mitochondrial DNA replication is dependent). This results in reduced metabolic function in the long peripheral axons, producing a dieback effect that is responsible for the glove and stocking distribution of symptoms. Abnormal sweating patterns (night sweats) have also been described, suggestive of an autonomic neuropathy.
Acetyl L-Carnitine (LAC), which is crucial for normal mitochondrial function, is also thought to potentiate nerve growth factor actions, promote peripheral nerve regeneration and is thought to be generally neuroprotective, based on animal studies of diabetic neuropathy.
This elegant study provides 33-month data on the efficacy of LAC at 1500mg twice daily in a cohort of 21 HIV-positive individuals with established stable dysaesthetic neuropathic symptoms (of grade 2-4 severity). Skin biopsies were taken from the legs of patients before LAC treatment and at 6-12 month intervals thereafter alongside five HIV-negative non-neuropathic control volunteers. The degree of neuronal re-growth was then assessed by means of immunohistochemical staining of the biopsies with nerve-fibre specific antibodies directed towards PGP (protein gene product 9.5) as a non-specific indicator of re-growth, CGRP (calcitonin gene-related product) as specific for C and A-delta (small sensory) fibres. Sections were then examined by fluorescence microscopy and a fractional area of immunostaining calculated as a representation of neuronal re-growth, which was then used for statistical comparisons. The results of the study showed that immunological parameters remained stable throughout the study. Median baseline CD4 count and viral load were 286 cells/mm3 and <400 copies/mL respectively and median neuropathy duration prior to the study was 11 months (range 2-41 months).
Morphologically, patients with established ATN exhibited reduced total innervation of epidermis, dermis and most markedly, sweat glands prior to commencing treatment. There was a statistically significant increase in neuronal regeneration during the course of LAC treatment. The increase in small sensory fibres (epidermis 100%, p=0.006; dermis 133%, p<0.05) was more than that for all fibre types (epidermis 16%, p= 0.04; dermis 49%, p<0.05; sweat glands 60%, p< 0.001) or for sympathetic sudomotor fibres (sweat glands 41%, p<0.0003). The benefits continued to improve after 24 months treatment while re-innervation of sweat glands stabilised. This correlated with an improvement in grade of neuropathic symptoms in 15 of 21 patients (76%). The temporal pattern of improvement accounts for the slow resolution of symptoms on starting LAC therapy.
This study reported that LAC treatment is associated with an improvement in neurological symptoms in 76% patients and remained unchanged in 19%. A randomised controlled clinical trial is now underway which will use a validated visual analogue pain scale to establish symptomatic benefit conclusively. Traditionally peripheral neuropathy has been the principal complication limiting the use of certain NRTIs, for which LAC many now offer an effective management approach.
First results from this study in six patients from 2000 were reported over four years ago in HTB Vol 1 No 2. (May 2000).
These results should in a larger number of patients should now make LAC easier to prescribe in the UK.
Ref: Hart AM, Wilson ADH, Youle M et al. Acetyl-l-carnitine: a pathogenesis based treatment for HIV-associated antiretroviral toxic neuropathy. AIDS. 18(11):1549-1560, July 23, 2004.
Common Nutrient May Ease Diabetic Pain
Monday September 19, 2005 (1609 PST)
ISLAMABAD: A common nutrient sold as a dietary supplement may help ease the pain caused by diabetic neuropathy, according to two new studies.
An analysis of the studies shows that a 1,000 milligrams three times a day of acetyl-L-carnitine was effective in relieving pain caused by nerve damage associated with the condition.
Diabetic neuropathy is a common long-term complication of diabetes and results in damage to nerve fibers, which can cause pain or a tingling sensation. People with this condition also suffer from a loss of sensory perception in the affected areas.
Acetyl-L-carnitine (ALC) is a naturally occurring chemical and is often sold as a dietary supplement.
In the analysis, which appears in the January issue of Diabetes Care, researchers evaluated the results of two studies testing two doses of acetyl-L-carnitine -- 500 milligrams and 1,000 milligrams three times a day.
The two studies involved 1,257 people with diabetic neuropathy in the U.S., Canada, and Europe and lasted for one year.
The analysis shows that people treated with the 1,000-milligram dose of acetyl-L-carnitine showed significant improvement after both six months and one year of treatment. Those who experienced the greatest pain reduction after one year with the 1,000-milligram dose were those with type 2 diabetes, those who took their medications as directed, and those who had their diabetes less than optimally controlled (HgA1c was greater than 8.5%).
In addition, the degree of pain relief was greatest among those who had diabetes for the shortest time period. Those with the shortest duration of diabetes also showed improvements in nerve structure and perception of vibration.