ALPHA LIPOIC ACID
(THIOCTIC ACID)

The Universal Action of Alpha Lipoic Acid

There is now evidence of another universal antioxidant called alpha lipoic acid, which not only has potent antioxidant action in virtually all the tissues of the body, but also is a co-factor for some of the key enzymes (alpha keto acid dehydrogenases) involved in generating energy from food and oxygen in mitochondria. Alpha Lipoic Acid is known by a variety of names including thioctic acid, 1,2-dithiolane-3-pentanoic acid, 1,2-dithiolane-3- valeric acid, and 6,8-thioctic acid. Alpha lipoic acid functions as a co-factor for energy production as lipomide and is also called lipoate when functioning in this manner. When alpha lipoic acid was first isolated in the early 1950's, it was tentatively classified as a Vitamin- Because of its vitamin-like properties, but was later found (unlike vitamins) to be synthesized in both animals and humans. The method by which alpha lipoic acid is synthesized within the body has not yet been fully characterized, but it appears as if two of its precursors are octanoate and the sulphur amino acid cysteine. Recent findings show that both alpha lipoic acid and its reduced form dihydrolipoic acid (DHLA) function as potent antioxidants within the body, and that both these compounds may be effective in preventing and treating the complications of diabetes and, perhaps, aging itself. Before we delve into the potential therapeutic benefits of alpha lipoic acid and DHLA, let's take a look at the findings showing their antioxidant properties.

Alpha lipoic acid (ALA) is a vitamin-like antioxidant, sometimes referred to as the universal antioxidant, because it is soluble in both fat and water.¹ ALA is capable of regenerating several other antioxidants back to their active states, including vitamin C,² vitamin E,³ glutathione,⁴ and coenzyme Q10.⁵

Alpha lipoic acid has several potential benefits for people with diabetes. It enhances glucose uptake in type 2 (non-insulin-dependent) diabetes, inhibits glycosylation (the abnormal attachment of sugar to protein), and has been used to improve diabetic nerve damage and reduce pain associated with that nerve damage.⁶ Most studies have used intravenous alpha lipoic acid, but oral supplementation has nonetheless proved partially helpful in treating at least one form of diabetic neuropathy, using 800 mg per day.⁷

Preliminary evidence indicates that 150 mg of alpha lipoic acid, taken daily for one month, improves visual function in people with glaucoma.⁸

Alpha lipoic acid has been shown to inhibit the replication of the HIV virus in the test tube. However, it is not known whether supplementing with alpha lipoic acid would benefit HIV-infected people.⁹

Intravenous administration of alpha lipoic acid has significantly increased the survival rate of people who have eaten poisonous mushrooms.¹⁰ Such a treatment should be prescribed by a doctor and should not be attempted on one�s own.

Alpha lipoic acid has been used in connection with the following conditions (refer to the individual health concern for complete information):

Rating	Health Concerns
	Diabetes
	Glaucoma Hepatitis
Reliable and relatively consistent scientific data showing a substantial health benefit. Contradictory, insufficient, or preliminary studies suggesting a health benefit or minimal health benefit. An herb is primarily supported by traditional use, or the herb or supplement has little scientific support and/or minimal health benefit.

Effect of lipoic acid (thioctic acid) on peripheral nerve of experimental diabetic neuropathy

Diabetes und Stoffwechsel (Germany), 1996, 5/3 SUPPL. (94- 97)

Oxidative stress is present in the diabetic state. Our work in streptozotocin-diabetic rats has focussed on its presence in peripheral nerve. Antioxidant enzymes are reduced in peripheral nerve and are further reduced in diabetic nerves. That lipid peroxidation will cause neuropathy is supported by evidence of the development of neuropathy de novo when normal rat nerve is rendered alpha- tocopherol deficient and augmentation of the conduction deficit in diabetic nerves subjected to this insult. The mechanism of oxidative stress appears to be primarily due to the processes of nerve ischemia and hyperglycemia auto- oxidation. The indices of oxidative stress include an increase in nerve, dorsal root and sympathetic ganglia lipid hydroperoxides and conjugated dienes. However the most reliable and sensitive index is a reduction in reduced glutathione. Experimental diabetic neuropathy results in myelinopathy of dorsal roots and a vacuolar neuropathy of dorsal root ganglion. The vacuoles are mitochondrial; we posit that lipid peroxidation causes mitochondrial DNA mutations that increase reduced oxygen species, causing further damage to mitochondrial chain and function, resulting in a sensory neuropathy. Alpha-lipoic acid is a potent antioxidant that prevents lipid peroxidation in vitro and in vivo. We evaluated the efficacy of the drug in doses of 20, 50 and 100 mg/kg, administered intraperitoneally to streptozotocin diabetic rats in preventing the biochemical, electrophysiologic and nerve blood flow deficits in peripheral nerve of experimental diabetic neuropathy. Alpha-lipoic acid dose- and time-dependently prevented the deficits in nerve conduction, nerve blood flow and biochemical abnormalities of a reduction in reduced glutathione and lipid peroxidation. The nerve blood flow deficit was 50% (p < 0.001). Supplementation dose-dependently prevented the deficit; at the highest concentration, nerve blood flow was not different to control nerves. Digital nerve conduction underwent a dose-dependent improvement at 1 month (p < 0.05). By 3 months, all treated groups had lost their deficit. The antioxidant drug is potentially efficacious for human diabetic sensory neuropathy.


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

Diabetes und Stoffwechsel (Germany), 1996, 5/3 SUPPL. (102- 110)

Treatment with anti-oxidants reduces oxidative stress and prevents neuropathy in experimental diabetes. Such a therapeutic approach based on pathogenetic mechanisms may have potential in diabetic patients with neuropathy. The efficacy and safety 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 Type 2 diabetic patients with symptomatic peripheral neuropathy who were randomly assigned to treatment with intravenous infusion of alpha-lipoic acid using three doses (ALA 1200 mg/600 mg/100 mg) or placebo (PLAC). Neuropathic symptoms (pain, burning, paraesthesiae, and numbness) were scored at baseline and each visit (days 2-5, 8-12, and 15-19) prior to infusion. In addition, the Hamburg Pain Adjective List (HPAL), a multidimensional specific pain questionnaire, as well as the Neuropathy Symptom Score (NSS) and Neuropathy Disability Score (NDS) were assessed at baseline and day 19. According to the protocol 260 (65/63/66/66) patients completed the study. The total symptom score (TSS) in the feet decreased from baseline to day 19 (mean plus or minus SD; %) by -4.5 plus or minus 3.7 (-58.6%) points in ALA 1200, -5.0 plus or minus 4.1 (-63.5%) points in ALA 600, -3.3 plus or minus 2.8 (-43.2%) points in ALA 100, and -2.6 plus or minus 3.2 (-38.4%) points in PLAC (ALA 1200 vs PLAC: p = 0.003; ALA 600 vs PLAC: p < 0.001). The response rates, defined as an improvement in the TSS of at least 30% after 19 days, 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 HPAL 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 the efficacy of intravenous treatment with alpha-lipoic acid using a dose of 600 mg/day over 3 weeks that is superior to placebo in reducing symptoms of diabetic peripheral neuropathy, without causing significant adverse reactions.


Effect of lipoic acid (thioctic acid) on glucose homeostasis and muscle glucose transporters in diabetic rats

Diabetes und Stoffwechsel (Germany), 1996, 5/3 SUPPL. (50- 54)

Background: alpha-Lipoic acid (LA), a cofactor of alpha- ketodehydrogenase, is a natural antioxidant. Though clinically used in treating peripheral diabetic polyneuropathy, its mode of action is not clear. In this study we tested whether LA affects glucose homeostasis and muscle glucose transporters.

Methods: LA was administrated to fasting control and streptozotocin diabetic rats either acutely (100 mg/kg, i.v.) or chronically (30 mg/kg, i.p. for 10 days).

Results: Acute administration reduced blood glucose, 76 plus or minus 16 vs. 38 plus or minus 9 mg% (p < 0.01) by 1 hour in control, and 255 plus or minus 22 vs. 185 plus or minus 41 mg% (p < 0.05) by 2 hours in diabetic rats. Chronic treatment reduced blood glucose concentration in diabetic, 341 plus or minus 36 vs. 189 plus or minus 48 mg% (p = 0.001), but not in control rats. Gastrocnemius GLUT4-protein content was increased by LA approximately 2-fold in both control and diabetic rats, resulting in normalization of muscle GLUT4 content in diabetic rats. Muscle lactate was increased in diabetic rats (19.9 plus or minus 5.5 vs. 10.4 plus or minus 2.8 in control p < 0.05, respectively), and normalized by chronic LA treatment.

Conclusions: Chronic LA treatment improves glycemia of streptozotocin diabetic rats by increasing muscle GLUT4- protein content. This may improve diabetes related muscle glucose metabolism abnormalities.


Altered 14C-deoxyglucose incorporation in rat brain following treatment with alpha-lipoic acid (thioctic acid). Clinical implications for diabetic neuropathy and neurodegenerative disorders

Diabetes und Stoffwechsel (Germany), 1996, 5/3 SUPPL. (31- 35)

The incorporation of 14C-2-deoxyglucose (2DG) into areas of basal ganglia was investigated in rats treated acutely or for 5 days with R- or S-thioctic acid (alpha-lipoic acid). In addition, the effect of animal source and age (up to 30 months) on the ability of R- and S-thioctic acid to alter 14C-2DG incorporation was studied. Following acute administration, R-thioctic acid was more effective than S-thioctic acid in altering 14C-2DG incorporation. For example, in substantia nigra of acute administration R- thioctic acid caused an approximately 40% increase in 14C- 2DG incorporation while S-thioctic acid was without effect. However, the effects observed were dependent on basal 14C-DG incorporation in different rat strains. Following subacute administration, the pattern of change in 14C-2DG incorporation was altered and now both isomers were equally effective. The effects of R-thioctic acid were largely maintained with increasing animal age but the ability of the S-isomer to alter 14C-2DG incorporation was lost by 30 months. The data indicate an ability of thioctic acid to alter glucose utilisation in vivo which may be relevant to the treatment of diabetic neuropathy and neurodegenerative disorders, such as Parkinson's disease.


Studies on the bioavailability of alpha lipoic acid in type I and type II diabetics with diabetic neuropathy

Diabetes und Stoffwechsel (Germany), 1996, 5/3 SUPPL. (23- 26)

In a controlled randomized cross-over study with two parallel groups 24 type I and type II diabetics with diabetes-induced polyneuropathy were given alpha lipoic acid in two different dosages and methods of administration. Group A (12 patients) was given 600 mg of alpha lipoic acid administered intravenously as a defined short infusion and orally in tablet form. Group B (12 patients) was given 200 mg of alpha lipoic acid administered intravenously as a defined short infusion and orally in tablet form. The extent of the bioavailability (AUC) of free alpha lipoic acid in plasma after intravenously administering 600 mg of alpha lipoic acid was 13.1 microg/ml.h and after 200 mg was 2.2 microg/ml.h. After 600 mg of orally administered alpha lipoic acid the AUC was 2.1 microg/ml.h and after 200 mg it was 0.4 microg/ml.h. The AUC of the single dose of 600 mg administered intravenously and orally was thus about twice as high as the adjusted dosage AUC of 200 mg. This difference was statistically significant. These results support the recommended therapy plan of 600 mg intravenously followed by an oral maintenance therapy of 1 x 600 mg daily.


On the pharmacokinetics of alpha-lipoic acid in patients with diabetic polyneuropathy

Diabetes und Stoffwechsel (Germany), 1996, 5/3 SUPPL. (17- 22)

After the administration von 600 mg alpha lipoic acid (alpha-L) per oral (Thioctacid(R) 200 film tablets) or as an intravenous infusion over 20 minutes (Thioctacid(R) T ampules) the kinetics of alpha-L in plasma were investigated in 12 diabetes type II-patients with normal liver and renal function and symptoms of diabetic neuropathy. alpha-L was electrochemically detected as a total fraction of lipoic and dihydrolipoic acid. alpha-L is quickly absorbed. Maximum plasma concentrations were found after 42.9 plus or minus 45.6 minutes. In seven of the 12 patients alpha-L showed alpha second peak behaviour with a mean difference of 89,1 minutes between the first and the second plasma peak. a-L was quickly eliminated from plasma with a mean terminal half-life time of 32.8 plus or minus 9.4 minutes. 7-10 hours after the start of the application of alpha-L its endogenous basic levels in plasma are reached, which are measured in a magnitude of 10 ng/ml. With respect to Thioctacid(R) 200 film tablets a mean absolute oral bioavailability of 20.2% (13.1-26.8%) for alpha-L was estimated. After a dose of 200 mg alpha-L healthy volunteers showed with 29.1% a 44% significantly higher bioavailability of a-L. The reduced bioavailability of alpha-L in patients with diabetic neuropathy is caused by a dose-inadequate, stronger elevation of the plasma levels of alpha-L after its intravenous administration. In patients with diabetic neuropathy the oral absorption behaviour of alpha-L is not different from that of normal persons.


Effects of treatment with the antioxidant alpha-lipoic acid on cardiac autonomic neuropathy in NIDDM patients: A 4-month randomized controlled multicenter trial (DEKAN study)

Diabetes Care (USA), 1997, 20/3 (369-373)

OBJECTIVE - To evaluate the efficacy and safety of oral treatment with the antioxidant alpha-lipoic acid (ALA) in NIDDM patients with cardiac autonomic neuropathy (CAN), assessed by heart rate variability (HRV).

RESEARCH DESIGN AND METHODS - In a randomized, double- blind placebo-controlled multicenter trial (Deutsche Kardiale Autonome Neurophatic (DEKAN) Study), NIDDM patients with reduced HRV were randomly assigned to treatment with a daily oral dose of 800 mg ALA (n = 39) or placebo (n = 34) for 4 months. Parameters of HRV at rest included the coeficient of variation (CV), root mean square successive difference (RMSSD), and spectral power in the low-frequency (LF; 0.5-0.15 Hz) and high-frequency (HF; 0.15-0.5 Hz) bands. In addition, cardiovascular autonomic symptoms were assessed.

RESULTS � Seventeen patients dropped out of the study (ALA n= 10; placebo n = 7). Mean blood pressure and HbA1 levels did not differ between the groups at baseline and during the study, but heart rate at baseline was higher in the group treated with ALA (P < 0.05). RMSSD increased from baseline to 4 months by 1.5 ms (-37.6 to 77.1) (median (minimum-maximum)) in the group given ALA and decreased by -0.1 ms (-19.2 to 32.8) in the placebo group (P < 0.05 for ALA vs. placebo). Power spectrum in the LF band incresed by 0.06 bpm2 (-0.09 to 0.62) in ALA, whereas it declined by -0.01 bpm2 (-0.48 to 1.86) in placebo (P < 0.05 for ALA vs. placebo). Furthermore, there was a trend toward a favorable effect of ALA versus placebo for the CV and HF band power spectrum (P = 0.097 and P = 0.094 for ALA vs. placebo. The charges in cardiovascular autonomic symptoms did not differ significantly between the groups during the period studied. No differences between the groups were noted regarding the rates of adverse events.

CONCLUSIONS - These findings suggest that treatment with AlA using a well-tolerated oral dose of 800 mg/day for months may slightly improve CAN in NIDDM patients.


Neuroprotection by the metabolic antioxidant alpha- lipoic acid

Free Radical Biology and Medicine (USA), 1996, 22/1-2 (359- 378)

Reactive oxygen species are thought to be involved in a number of types of acute and chronic pathologic conditions in the brain and neural tissue. The metabolic antioxidant alpha-lipoate (thioctic acid, 1, 2-dithiolane-3- pentanoic acid; 1, 2-dithiolane-3 valeric acid; and 6,8- dithiooctanoic acid) is a low molecular weight substance that is absorbed from the diet and crosses the blood-brain barrier. alpha-Lipoate is taken up and reduced in cells and tissues to dihydrolipoate, which is also exported to the extracellular medium; hence, protection is afforded to both intracellular and extracellular environments. Both alpha-lipoate and especially dihydrolipoate have been shown to be potent antioxidants, to regenerate through redox cycling other antioxidants like vitamin C and vitamin E, and to raise intracellular glutathione levels. Thus, it would seem an ideal substance in the treatment of oxidative brain and neural disorders involving free radical processes. Examination of current research reveals protective effects of these compounds in cerebral ischemia- reperfusion, excitotoxic amino acid brain injury, mitochondrial dysfunction, diabetes and diabetic neuropathy, inborn errors of metabolism, and other causes of acute or chronic damage to brain or neural tissue. Very few neuropharmacological intervention strategies are currently available for the treatment of stroke and numerous other brain disorders involving free radical injury. We propose that the various metabolic antioxidant properties of alpha-lipoate relate to its possible therapeutic roles in a variety of brain and neuronal tissue pathologies: thiols are central to antioxidant defense in brain and other tissues. The most important thiol antioxidant, glutathione, cannot be directly administered, whereas alpha-lipoic acid can. In vitro, animal, and preliminary human studies indicate that alpha- lipoate may be effective in numerous neurodegenerative disorders.


Stimulation of glucose uptake by the natural coenzyme alpha-lipoic acid/thioctic acid: Participation of elements of the insulin signaling pathway

Diabetes (USA), 1996, 45/12 (1798-1804)

Thioctic acid (alpha-lipoic acid), a natural cofactor in dehydrogenase complexes, is used in Germany in the treatment of symptoms of diabetic neuropathy. Thioctic acid improves insulin-responsive glucose utilization in rat muscle preparations and during insulin clamp studies performed in diabetic individuals. The aim of this study was to determine the direct effect of thioctic acid on glucose uptake and glucose transporters. In L6 muscle cells and 3T3-L1 adipocytes in culture, glucose uptake was rapidly increased by (R)-thioctic acid. The increment was higher than that elicited by the (S)-isomer or the racemic mixture and was comparable with that caused by insulin. In parallel to insulin action, the stimulation of glucose uptake by thioctic acid was abolished by wortmannin, an inhibitor of phosphatidylinositol 3-kinase, in both cell lines. Thioctic acid provoked an upward shift of the glucose-uptake insulin dose-response curve. The molar content of GLUT1 and GLUT4 transporters was measured in both cell lines. 3T3- L1 adipocytes were shown to have 10 times more glucose transporters but similar ratios of GLUT4: GLUT1 than L6 myotubes. The effect of (R)-thioctic acid on glucose transporters was studied in the L6 myotubes. Its stimulatory effect on glucose uptake was associated with an intracellular redistribution of GLUT1 and GLUT4 glucose transporters, similar to that caused by insulin, with minimal effects on GLUT3 transporters. In conclusion, thioctic acid stimulates basal glucose transport and has a positive effect on insulin- stimulated glucose uptake. The stimulatory effect is dependent on phosphatidylinositol 3-kinase activity and may be explained by a redistribution of glucose transporters. This is evidence that a physiologically relevant compound can stimulate glucose transport via the insulin signaling pathway.


Alpha-lipoic acid: Antioxidant potency against lipid peroxidation of neural tissues in vitro and implications for diabetic neuropathy

Free Radical Biology and Medicine (USA), 1996, 21/5 (631- 639)

Nerve lipid peroxidation is increased in experimental diabetic neuropathy, and alpha-lipoic acid will prevent the deficits in nerve blood flow, oxidative stress, and distal sensory conduction. Because these alterations can occur by mechanisms other than augmenting lipid peroxidation in vivo, and because both pro-oxidant and antioxidant effects of the agent have been reported, we undertook studies of in vitro lipid peroxidation of brain and sciatic nerve using an in vitro lipid peroxidation model with an ascorbate- iron-EDTA system. We evaluated the effectiveness of the R(+)-, S(-)- enantiomers, and racemate of alpha-lipoic acid in reducing thiobarbituric acid reactive substances (TEARS) generation in rat brain and sciatic nerve. Studies were also done in an incubation medium containing 20 mM glucose, which increased lipid peroxidation up to fourfold. A dose-dependent and statistically significant reduction in lipid peroxidation was seen with both tissues with similar potencies for both enantiomers. This effect was unassociated with any reduction in the loss of alpha-tocopherol.


Oral alpha lipoic acid preparation proves good bioavailability in diabetic polyneuropathy

Frankfurt am Main Germany Therapiewoche (Germany), 1995, 45/23 (1367-1370)

Causal therapy with alpha lipoic acid is capable of getting polyneuropathy, the most frequent concomitant disease of diabetes mellitus, under control or to influence its progression favourably: about half of all German diabetics, hence no less than 2 million people, suffer from that life-threatening disease. Yet a basic condition for the effectiveness of an oral dose of alpha lipoic acid, the per diem doses of which have been raised to 300 to 600 mg in recent years, is its absolute bioavailability. This has been shown to be 71% (arith. Mean) resp. 58% (geom. Mean) in case of Thiogamma 399 oral capsules by an open monocentric study covering 12 probands. Thus, a rational treatment with this preparation is guaranteed


Alternative therapeutic principles in the prevention of microvascular and neuropathic complications.

Diabetes Res Clin Pract (IRELAND) Aug 1995, 28 Suppl pS201- 7

Since the prevention of chronic diabetic complications by near normal metabolic control is not always achievable, alternative therapeutic principles have been developed. The specific intervention at metabolic abnormalities which seem to play a key role in the pathogenesis of complications has been shown to prevent the development of microangiopathy and neuropathy in experimental diabetes, e.g. inhibition of non-enzymatic glycation by aminoguanidine, inhibition of polyol pathway activity by aldose reductase inhibitors, prevention of hypoxia and oxidative stress by vasodilators and radical scavengers such as alpha-lipoic acid. Some of these drugs should soon be available for common clinical use.


[Treatment of diabetic neuropathy with oral alpha- lipoic acid]

MMW Munch Med Wochenschr (GERMANY, WEST) May 30 1975

100 patients were treated with Thioctacid orally for diabetic neuropathy. A successful assessment was possible with sufficient certainty in 89 patients. Of these, 29 received 2 X 50 mg and 60 patients 2 X 100 mg Thioctacid daily. In the first group the treatment was successful in 23 patients, and in 51 of the second group. According to these findings, administration of thiotic acid is effective in diabetic neuropathy just as frequently orally as intravenously.


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

Diabetologia (Germany), 1995, 38/12 (1425-1433)

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 plus or minus 3.7 (-58.6%) points (mean plus or minus SD) in ALA 1200, -5.0 plus or minus 4.1 (-63.5%) points in ALA 600, -3.3 plus or minus 2.8 (-43.2%) points in ALA 100, and -2.6 plus or minus 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.


Lipoic acid (thioctic acid): Antioxidant properties and their clinical implications

Diabetes und Stoffwechsel (Germany), 1996, 5/3 SUPPL. (98- 101)

The following article describes the protective effects of alpha-lipoic acid and the enantiomers of alpha-lipoic acid and dihydrolipoic acid on the in vitro cataractogenesis in rat lenses incubated with glucose (55.6 mM). Glucose also leads to a leakage of lactate dehydrogenase into the medium (32 plus or minus 3 units/g lens fresh weight/day). R-lipoic acid inhibited the leakage of LDH (4.34 plus or minus 3.23 units/g lens fresh weight/day, p < 0.001) and lens opacity. In addition, lipoic acid inhibited cataract formation in newborn rats under buthionine sulfoxide (BSO). While 100% of the rats given BSO showed cataract formation, this was observed only in 40 plus or minus 8% of the animals receiving BSO and alpha-lipoic acid (p < 0.005). Further influences of lipoic acid and dihydrolipoic acid on the cataract model are under discussion. The established interactions between dihydrolipoic acid and other antioxidants certainly have implications for both cataractogenesis and the clinical use of alpha-lipoic acid.


Lipoic acid alpha-potential modulator of insulin sensitivity in patients with non-insulin-dependent diabetes mellitus

Diabetes und Stoffwechsel (Germany), 1996, 5/3 SUPPL. (64- 70)

Thioctic acid, also known as alpha lipoic acid (ALA), a naturally occuring compound, is frequently used for the treatment of diabetic polyneuropathy and was shown to be a safe and reliable drug. Experimental studies revealed enhanced glucose transport and utilization in different animal models. Therefore, it was of interest to investigate whether ALA is also capable to stimulate glucose disposal in clinical conditions of reduced insulin sensitivity, such as NIDDM. A case report supported the hypothesis, and pilot studies were initiated, in which well controlled Type 2 diabetics received ALA (1.000 mg/500 ml NaCl; or vehicle only) during a hyperinsulinemic glucose-clamp (placebo controlled study) or 500 ml ALA/d over 10 d in an open uncontrolled study. While the acute administration of vehicle had no significant effect on insulin sensitivity (MCR1 3,6 plus or minus 0,21 vs. MCR2 4,01 plus or minus 0,19 ml/kg/min), the infusion of ALA resulted in a marked increase of glucose disposal by about 50% (MCR1 3,91 plus or minus 0,6 vs. MCR2 5,89 plus or minus 0,8 ml/kg/min, p less than or equal to 0,05, Wilcoxon-Rank-Sumtest). The ten-day treatment of type II diabetics with ALA enhanced insulin-stimulated whole body glucose disposal by about 30% (MCR1 2,47 plus or minus 0,28 vs. MCR2 3,15 plus or minus 0,35 ml/kg/min, p less than or equal to 0,05, Wilcoxon-Rank-Sumtest). Meanwhile other groups have confirmed these observations. In conclusion, the present data indicate that parenteral administration of thioctic acid enhances insulin-stimulated glucose disposal in NIDDM. Animal studies suggest that the compound increases insulin-stimulated glucose transport activity, non- oxidative glucose disposal and glucose oxidation in peripheral tissues, such as skeletal muscle.


Lipoic acid acutely ameliorates insulin sensitivity in obese subjects with type 2 diabetes

Diabetes und Stoffwechsel (Germany), 1996, 5/3 SUPPL. (59- 63)

Background: Alpha-lipoic acid, a natural cofactor of pyruvate-dehydrogenase, has long been suggested to improve glucose oxidation. Recent data from insulin resistant muscle models demonstrate, that glucose transport and hence non-oxidative glucose metabolism are ameliorated with this substance. Corresponding data in man are lacking.

Methods: The effect of an acute infusion of 600 mg alpha- lipoic acid on insulin sensitivity was investigated in a double blind randomised placebo controlled cross-over study using the isoglycemic glucose clamp technique in 12 obese, insulin resistant subjects (4 postmenopausal women, 8 men) aged between 48 and 69 years with poorly controlled type 2 diabetes.

Results: The infusion was well tolerated, only one subject complained of headache. Of the 12 multimorbid subjects, Z (58,3%) responded to the acute infusion of 600 mg alpha- lipoic acid with a clinically relevant increase (20%) in insulin sensitivity (metabolic clearance rate MCR<). The mean relative increase of MCR of all participants (including nonresponders) was 27% (p = 0.002). Conclusion: For the first time, a single infusion of 600- mg alpha-lipoic acid is shown to improve attenuated insulin sensitivity in a controlled study in a defined insulin resistant group of subjects with type 2 diabetes. The high number of nonresponders gives rise to further studies.


Studies on the bioavailability of alpha lipoic acid in type I and type II diabetics with diabetic neuropathy

Diabetes und Stoffwechsel (Germany), 1996, 5/3 SUPPL. (23- 26)

In a controlled randomized cross-over study with two parallel groups 24 type I and type II diabetics with diabetes-induced polyneuropathy were given alpha lipoic acid in two different dosages and methods of administration. Group A (12 patients) was given 600 mg of alpha lipoic acid administered intravenously as a defined short infusion and orally in tablet form. Group B (12 patients) was given 200 mg of alpha lipoic acid administered intravenously as a defined short infusion and orally in tablet form. The extent of the bioavailability (AUC) of free alpha lipoic acid in plasma after intravenously administering 600 mg of alpha lipoic acid was 13.1 microg/ml.h and after 200 mg was 2.2 microg/ml.h. After 600 mg of orally administered alpha lipoic acid the AUC was 2.1 microg/ml.h and after 200 mg it was 0.4 microg/ml.h. The AUC of the single dose of 600 mg administered intravenously and orally was thus about twice as high as the adjusted dosage AUC of 200 mg. This difference was statistically significant. These results support the recommended therapy plan of 600 mg intravenously followed by an oral maintenance therapy of 1 x 600 mg daily.


Modulation of cellular reducing equivalent homeostasis by alpha-lipoic acid. Mechanisms and implications for diabetes and ischemic injury

Biochemical Pharmacology (USA), 1997, 53/3 (393-399)

The therapeutic potential of alpha-lipoic acid (thioctic acid) was evaluated with respect to its influence on cellular reducing equivalent homeostasis. The requirement of NADH and NADPH as cofactors in the cellular reduction of alpha-lipoic acid to dihydrolipoate has been reported in various cells and tissues. However, there is no direct evidence describing the influence of such reduction of alpha-lipoate on the levels of cellular reducing equivalents and homeostasis of the NAD (P) H/NAD (P) ratio. Treatment of the human Wurzburg T-cell line with 0.5 mM alpha-lipoate for 24 hr resulted in a 30% decrease in cellular NADH levels. alpha-Lipoate treatment also decreased cellular NADPH, but this effect was relatively less and slower compared with that of NADH. A concentration-dependent increase in glucose uptake was observed in Wurzburg cells treated with alpha-lipoate. Parallel decreases (30%) in cellular NADH/NAD+ and in lactate/pyruvate -*--ratios were observed in alpha-lipoate- treated cells. Such a decrease in the NADH/NAD+ ratio following treatment with alpha-lipoate may have direct implications in diabetes, ischemia-reperfusion injury, and other pathologies where reductive (high NADH/NAD+ ratio) and oxidant (excess reactive oxygen species) imbalances are considered as major factors contributing to metabolic disorders. Under conditions of reductive stress, alpha- lipoate decreases high NADH levels in the cell by utilizing it as a co-factor for its own reduction process, whereas in oxidative stress both alpha-lipoate and its reduced form, dihydrolipoate, may protect by direct scavenging of free radicals and recycling other antioxidants from their oxidized forms.


Alpha-Lipoic acid corrects neuropeptide deficits in diabetic rats via induction of trophic support

Neuroscience Letters (Ireland), 1997, 222/3 (191-194)

This study compared the effects of treatment of diabetic rats with either alpha-lipoic acid (100 mg/kg/day i.p. 5 days/week) or with recombinant human nerve growth factor (rhNGF; 0.2 mg/kg s.c. 3 days/week) on NGF-like immunoreactivity (NGFLI) and neuropeptide Y-like immunoreactivity (NPYLI) levels in the sciatic nerve and on the release of substance P-like immunoreactivity (SPLI) from the spinal cord in response to electrical stimulation of the dorsal roots In vitro. Diabetic rats showed depletion of NGFLI and NPYLI, together with reduced release of SPLI. Treatment with NGF increased the sciatic nerve NGFLI (to four times that seen in untreated diabetic rats) and normalised stimulus-evoked release of SPLI, but did not affect the sciatic nerve NPYLI. Treatment with alpha-lipoic acid caused a small non-significant increase in sciatic nerve NGFLI, but normalised both NPYLI levels and stimulus; evoked release of SPLI. These findings indicate that alpha-lipoic acid can boost neurotrophic support in diabetic rats, with effects beyond those related to NGF.


Enhancement of glucose disposal in patients with type 2 diabetes by alpha-lipoic acid.

Arzneimittelforschung (GERMANY) Aug 1995, 45 (8) p872-4

Insulin resistance of skeletal muscle glucose uptake is a prominent feature of Type II diabetes (NIDDM); therefore pharmacological interventions should aim to improve insulin sensitivity. Alpha-lipoic acid (CAS 62-46-4, thioctic acid, ALA), a natural occurring compound frequently used for treatment of diabetic polyneuropathy, enhances glucose utilization in various experimental models. To see whether this compound also augments insulin mediated glucose disposal in NIDDM, 13 patients received either ALA (1000 mg/Thioctacid/500 ml NaCl, n = 7) or vehicle only (500 ml NaCl, n = 6) during a glucose-clamp study. Both groups were comparable in age, body-mass index and duration of diabetes and had a similar degree of insulin resistance at baseline. Acute parenteral administration of ALA resulted in a significant increase of insulin-stimulated glucose disposal; metabolic clearance rate (MCR) for glucose rose by about 50% (3.76 ml/kg/min = pre vs. 5.82 ml/kg/min = post, p < 0.05), whereas the control group did not show any significant change (3.57 ml/kg/min = pre vs. 3.91 ml/kg/min = post). This is the first clinical study to show that alpha-lipoic acid increases insulin stimulated glucose disposal in NIDDM. The mode of action of ALA and its potential use as an antihyperglycemic agent require further investigation.


Interaction of alpha-lipoic acid enantiomers and homologues with the enzyme components of the mammalian pyruvate dehydrogenase complex.

Biochem Pharmacol (ENGLAND) Aug 25 1995, 50 (5) p637-46

Lipoic acid (alpha-lipoic acid, thioctic acid) is applied as a therapeutic agent in various diseases accompanied by polyneuropathia such as diabetes mellitus. The stereoselectivity and specificity of lipoic acid for the pyruvate dehydrogenase complex and its component enzymes from different sources has been studied. The dihydrolipoamide dehydrogenase component from pig heart has a clear preference for R-lipoic acid, a substrate that reacts 24 times faster than the S-enantiomer. Selectivity is more at the stage of the catalytic reaction than of binding. The Michaelis constants of both enantiomers are comparable (Km = 3.7 and 5.5 mMfor R- and S-lipoic acid, respectively) and the S-enantiomer inhibits the R-lipoic acid dependent reaction with an inhibition constant similar to its Michaelis constant. When three lipoic acid homologues were tested, RS-1, 2-dithiolane-3-caproic acid was one carbon atom longer than lipoic acid, while RS- bisnorlipoic acid and RS-tetranorlipoic acid were two and four carbon atoms shorter, respectively. All are poor substrates but bind to and inhibit the enzyme with an affinity similar to that of S-lipoic acid. No essential differences with respect to its reaction with lipoicacid enantiomers and homologues exist between free and complex- bound dihydrolipoamide dehydrogenase. Dihydrolipoamide dehydrogenase from human renal carcinoma has a higher Michaelis constant for R-lipoic acid (Km = 18mM) and does not accept the S-enantiomer as a substrate. Both enantiomers of lipoic acid are inhibitors of the overall reaction of the bovine pyruvate dehydrogenase complex, but stimulate the respective enzyme complexes from rat as well as from Escherichia coli. The S-enantiomer is the stronger inhibitor, the R-enantiomer the better activator. The two enantiomers have no influence on the partial reaction of the bovine pyruvate dehydrogenase component, but do inhibit this enzyme component from rat kidney. The implications of these results are discussed.


Alpha-Lipoic acid as a biological antioxidant.

Free Radic Biol Med (UNITED STATES) Aug 1995, 19 (2) p227- 50

alpha-Lipoic acid, which plays an essential role in mitochondrial dehydrogenase reactions, has recently gained considerable attention as an antioxidant. Lipoate, or its reduced form, dihydrolipoate, reacts with reactive oxygen species such as superoxide radicals, hydroxyl radicals, hypochlorous acid, peroxyl radicals, and singlet oxygen. It also protects membranes by interacting with vitamin C and glutathione, which may in turn recycle vitamin E. In addition to its antioxidant activities, dihydrolipoate may exert prooxidant actions through reduction of iron. alpha- Lipoic acid administration has been shown to be beneficial in a number of oxidative stress models such as ischemia- reperfusion injury, diabetes (both alpha-lipoic acid and dihydrolipoic acid exhibit hydrophobic binding to proteins such as albumin, which can prevent glycation reactions), cataract formation, HIV activation, neurodegeneration, and radiation injury. Furthermore, lipoate can function as a redox regulator of proteins such as myoglobin, prolactin, thioredoxin and NF-kappa B transcription factor. We review the properties of lipoate in terms of (1) reactions with reactive oxygen species; (2) interactions with other antioxidants; (3) beneficial effects in oxidative stress models or clinical conditions. (153 Refs.)


Lipoate prevents glucose-induced protein modifications.

Free Radic Res Commun (SWITZERLAND) 1992, 17 (3) p211-7

Nonenzymatic glycation has been found to increase in a variety of proteins in diabetic patients. The present study examined a possibility of preventing glycation and subsequent structural modifications of proteins by alpha- lipoic acid (thioctic acid) as lipoate, a substance which has gained attention as a potential therapeutic agent for diabetes-induced complications. Incubation of bovine serum albumin (BSA) at 2 mg/ml with glucose (500 mM) in a sterile condition at 37 degrees C for seven days caused glycation and structural modifications of BSA observed by SDS-PAGE, near UV absorption, tryptophan and nontryptophan fluorescence, and fluorescence of an extrinsic probe, TNS (6-(p-toluidinyl) naphthalene-2-sulfonate). When BSA and glucose were incubated in the presence of lipoate (20mM), glycation and structural modifications of BSA were significantly prevented. Glycation and inactivation of lysozyme were also prevented by lipoate. These results suggest a potential for the therapeutic use of lipoic acid against diabetes-induced complications.


Stereospecific effects of R-lipoic acid on buthionine sulfoximine-induced cataract formation in newborn rats.

Biochem Biophys Res Commun (UNITED STATES) Apr 16 1996, 221 (2) p422-9

This study revealed a marked stereospecificity in the prevention of buthionine sulfoximine-induced cataract, and in the protection of lens antioxidants, in newborn rats by alpha-lipoate, R- and racemic alpha-lipoate decreased cataract formation from 100% (buthionine sulfoximine only) to 55% (buthionine sulfoximine + R-alpha-lipoic acid) and 40% (buthionine sulfoximine + rac-alpha-lipoic acid) (p<0.05 compared to buthionine sulfoximine only). S- alpha-lipoic acid had no effect on cataract formation induced by buthionine sulfoximine. The lens antioxidants glutathione, ascorbate, and vitamin E were depleted to 45, 62, and 23% of control levels, respectively, by buthionine sulfoximine treatment, but were maintained at 84-97% of control levels when R-alpha-lipoic acid or rac-alpha- lipoic acid were administered with buthionine sulfoximine; S-alpha-lipoic acid administration had no protective effect on lens antioxidants. When enantiomers of alpha- lipoic acid were administered to animals, R-alpha-lipoic acid was taken up by lens and reached concentrations 2- to 7-fold greater than those of S-alpha-lipoic acid, with rac- alpha-lipoic acid reaching levels midway between the R- isomer and racemic form. Reduced lipoic acid, dihydrolipoic acid, reached the highest levels in lens of the rac-alpha-lipoic acid-treated animals and the lowest levels in S-alpha-lipoic acid-treated animals. These results indicate that the protective effects of alpha- lipoic acid against buthionine sulfoximine-induced cataract are probably due to its protective effects on lens antioxidants, and that the stereospecificity exhibited is due to selective uptake and reduction of R- alpha-lipoic acid by lens cells.


Alpha-Lipoic acid as a biological antioxidant.

Free Radic Biol Med (UNITED STATES) Aug 1995, 19 (2) p 227- 50

alpha-Lipoic acid, which plays an essential role in mitochondrial dehydrogenase reactions, has recently gained considerable attention as an antioxidant. Lipoate, or its reduced form, dihydrolipoate, reacts with reactive oxygen species such as superoxide radicals, hydroxyl radicals, hypochlorous acid, peroxyl radicals, and singlet oxygen. It also protects membranes by interacting with vitamin C and glutathione, which may in turn recycle vitamin E. In addition to its antioxidant activities, dihydrolipoate may exert prooxidant actions through reduction of iron. alpha- Lipoic acid administration has been shown to be beneficial in a number of oxidative stress models such as ischemia- reperfusion injury, diabetes (both alpha-lipoic acid and dihydrolipoic acid exhibit hydrophobic binding to proteins such as albumin, which can prevent glycation reactions), cataract formation, HIV activation, neurodegeneration, and radiation injury. Furthermore, lipoate can function as a redox regulator of proteins such as myoglobin, prolactin, thioredoxin and NF-kappa B transcription factor. We review the properties of lipoate in terms of (1) reactions with reactive oxygen species; (2) interactions with other antioxidants; (3) beneficial effects in oxidative stress models or clinical conditions.


Alpha-lipoic acid supplementation prevents symptoms of vitamin E deficiency.

Biochem Biophys Res Commun (UNITED STATES) Oct 14 1994

alpha-Lipoic acid, an essential cofactor in mitochondrial dehydrogenases, has recently been shown to be a potent antioxidant in vitro, as well as being capable of regenerating vitamin E in vitro. In this study, using a new animal model for rapid vitamin E deficiency in adult animals and a new technique for tissue extraction of oxidized and reduced alpha-lipoic acid, we examined the antioxidant action of alpha-lipoic acid in vivo. Vitamin E- deficient adult hairless mice displayed obvious symptoms of deficiency within five weeks, but if the diet was supplemented with alpha-lipoic acid the animals were completely protected. At five weeks on a vitamin E- deficient diet animals exhibited similar decreases in tissue vitamin E levels, whether supplemented or unsupplemented with alpha-lipoic acid: vitamin E levels in liver, kidney, heart, and skin decreased 70 to 85%; levels in brain decreased only 25%. These data show that there was no effect of alpha-lipoic acid supplementation on vitamin E tissue concentrations, arguing against a role for alpha-lipoic acid in regenerating vitamin E in vivo.


Alpha-lipoic acid prevents buthionine sulfoximine- induced cataract formation in newborn rats.

Free Radic Biol Med (UNITED STATES) Apr 1995, 18 (4) p823-9

We investigated the effect of alpha-lipoic acid, a powerful antioxidant, on cataract formation in L- buthionine (S, R)-sulfoximine (BSO)-treated newborn rats and found that a dose of 25 mg/kg b.w. protected 60% of animals from cataract formation. L-buthionine (S, R)- sulfoximine is an inhibitor of glutathione synthesis, whose administration to newborn animals leads to the development of cataracts; this is a potential model for studying the role of therapeutic antioxidants in protecting animals from cataract formation. Major biochemical changes in the lens associated with the protective effect of alpha-lipoic acid were increases in glutathione, ascorbate, and vitamin E levels, loss of which are effects of BSO administration. Treatment with alpha-lipoic acid also restored the activities of glutathione peroxidase, catalase, and ascorbate free radical reductase in lenses of L-buthionine (S, R)- sulfoximine-treated animals but did not affect glutathione reductase or superoxide dismutase activity. We conclude that alpha-lipoic acid may take over some of the functions of glutathione (e.g., maintaining the higher level of ascorbate, indirect participation in vitamin E recycling); the increase of glutathione level in lens tissue mediated by lipoate could be also due to a direct protection of protein thiols. Thus, alpha-lipoic acid could be of potential therapeutic use in preventing cataracts and their complications.


An expanded concept of insurance supplementation-- broad-spectrum protection from cardiovascular disease.

Med Hypotheses (ENGLAND) Oct 1981, 7 (10) p1287-1302

The preventive merits of nutritional insurance supplementation can be considerably broadened if meaningful doses of nutrients such as mitochondrial metavitamins (coenzyme Q, lipoic acid, carnitine), lipotropes, and key essential fatty acids, are included in insurance supplements. From the standpoint of cardiovascular protection, these nutrients, as well as magnesium, selenium, and GTF-chromium, appear to have particular value. Sophisticated insurance supplementation would likely have a favorable impact on many parameters which govern cardiovascular risk--serum lipid profiles, blood pressure, platelet stability, glucose tolerance, bioenergetics, action potential regulation--and as a life- long preventive health strategy might confer substantial benefit. (111 Refs.)


Pharmacological prevention of diabetic microangiopathy

DIABETE METABOL. (France), 1994, 20/2 BIS (219-228)

The development of drugs in order to block metabolic pathways of glucose responsible for diabetic vascular dysfunction is in progress. Aldose reductase inhibitors prevent or reduce the different components of vascular dysfunction, cataract, neuropathy and nephropathy in animal models of diabetes. Promising results have been observed in diabetic patients concerning the prevention of neuropathy and of retinopathy. Larger scale studies with the second generation compounds are in progress. Glycation inhibitors, mainly aminoguanidine, have been shown to prevent or reduce vascular dysfunction and microvascular complications in animal models. Trials in diabetic patients with aminoguanidine are just beginning. Anti- oxidant therapy is also at its early stage of development (vitamine E, vitamine C, alpha lipoic acid). Antiplatelet agents (aspirin, ticlopidine) have been demonstrated to reduce the progression of non proliferative diabetic retinopathy. Angiotensin converting enzyme inhibitors are of particular interest in preventing diabetic glomerulopathy.