| Product Brand Name:
Lipoic Acid
Alpha-lipoic acid is available generically from numerous
manufacturers. Branded products include Ultra-Lipoic Forte (Westlake Labs).
1. Description: Alpha-lipoic acid, also
known as thioctic acid, is a disulfide compound that is a cofactor in
vital energy-producing reactions in the body. It is also a potent biological
antioxidant. Alpha-lipoic acid was once thought to be a vitamin for animals
and humans. It is made endogenously in humans—the details of its
synthesis are still not fully understood—and so it is not an essential
nutrient. There are, however, certain situations, for example, diabetic
polyneuropathy, where alpha-lipoic acid might have conditional essentiality.
And recent research indicates that the antioxidant roles of alpha-lipoic
acid may confer several health benefits. Alpha-lipoic acid is found widely
in plant and animal sources.
Most of the metabolic reactions in which alpha-lipoic acid participates
occur in mitochondria. These include the oxidation of pyruvic acid (as
pyruvate) by the pyruvate dehydrogenase enzyme complex and the oxidation
of alpha-ketoglutarate by the alpha-ketoglutarate dehydrogenase enzyme
complex. It is also a cofactor for the oxidation of branched-chain amino
acids (leucine, isoleucine and valine) via the branched-chain alpha-keto
acid dehydrogenase enzyme complex.
Alpha-lipoic acid is approved in Germany as a drug for the treatment of
polyneuropathies, such as diabetic and alcoholic polyneuropathies, and
liver disease.
Alpha-lipoic acid contains a chiral center and consists of two entantiomers,
the natural R- or D- entantiomer and the S- or L- entantiomer. Commercial
preparations of alpha-lipoic acid consist of the racemic mixture, i.e.
a 50/50 mixture of the R- and E-entantiomers. Alpha-lipoic acid has a
variety of names. In addition to being known as alpha-lipoic acid and
thioctic acid, it is also known as lipoic acid, 1,2-dithiolane-3-pentanoic
acid; 1,2-ditholane-3-valeric acid; 6,8-thiotic acid; 5-[3-C1,2-dithiolanyl)]-pentanoic
acid; delta-[3-(1,2-dithiacyclopentyl)] pentanoic acid; acetate replacing
factor and pyruvate oxidation factor. Alpha-lipoic acid is water-insoluble.
Although the details of its synthesis have yet to be worked out, alpha-lipoic
acid is synthesized in mitochondria; octanoic acid and L-cysteine (for
its sulfur) are precursors in its synthesis.
2. Action and pharmacology: Alpha-lipoic
acid has biological antioxidant activity, antioxidant recycling activity
and activity in enhancing biological energy production.
3. Mechanism of action: Alpha-lipoic
acid and its reduced metabolite, dihydrolipoic acid (DHLA), form a redox
couple and may scavenge a wide range of reactive oxygen species. Both
alpha-lipoic acid and DHLA can scavenge hydroxyl radicals, the nitric
oxide radical, peroxynitrite, hydrogen peroxide and hypochlorite. Alpha-lipoic
acid, but not DHLA, may scavenge singlet oxygen, and DHLA, but not alpha-lipoic
acid, may scavenge superoxide and peroxyl reactive oxygen species. Alpha-lipoic
acid has been found to decrease urinary isoprostanes, O-LDL and plasma
protein carbonyls, markers of oxidative stress. Further, alpha-lipoic
acid and its redox couple DHLA have been found to have antioxidant activity
in aqueous, as well as in lipophilic regions, and in extracellular and
intracellular environments. Finally, with regard to alpha-lipoic acid's
antioxidant activity, alpha-lipoic acid appears to participate in the
recycling of other important biologic antioxidants, such as vitamins E
and C, ubiquinone and glutathione. Exogenous alpha-lipoic acid has been
shown to increase ATP production and aortic blood flow during reoxygenation
after hypoxia in a working heart model. It is thought that this is due
to its role in the oxidation of pyruvate and alpha-ketoglutarate in the
mitochondria, ultimately enhancing energy production. This activity, and
possibly its antioxidant activity, may account for its possible benefit
in diabetic polyneuropathy.
4. Pharmacokinetics: Most pharmacokinetic
studies have been performed in animals. Alpha-lipoic acid is absorbed
from the small intestine and distributed to the liver via the portal circulation
and to various tissues in the body via the systemic circulation. The natural
R-entantiomer is more readily absorbed than the L-entantiomer and is the
more active form. Alpha-lipoic acid readily crosses the blood-brain barrier.
It is found, after its distribution to the various body tissues, intracellularly,
intramitochondrialy and extracellularly. Alpha-lipoic acid is metabolized
to its reduced form, dihydrolipoic acid (DHLA), by mitochondrial lipoamide
dehydrogenase. DHLA, together with lipoic acid, form a redox couple. It
is also metabolized to lipoamide, which functions as the lipoic acid cofactor
in the multienzyme complexes that catalyze the oxidative decarboxylations
of pyruvate and alpha-ketoglutarate. Alpha-lipoic acid may be metabolized
to dithiol octanoic acid, which can undergo catabolism.
5. Indications and usage: Lipoic acid
shows evidence of being effective in the treatment of diabetic neuropathy
and may be useful in treating some other aspects of diabetes. It may help
prevent the oxidation of LDL cholesterol and may be protective, generally,
against oxidative stress and, specifically, against atherosclerosis, ischemia-reperfusion
injury and various radiologic and chemical toxins. It may also be useful
in some inborn metabolic disorders. There is less evidence that it might
be helpful in some neurodegenerative conditions. There is preliminary
evidence that it might have some immune-modulating effects. It has been
suggested that lipoic acid may slow aging of the brain and that it may
be an anti-aging substance, in general.
6. Research summary: Lipoic acid is
an approved treatment for diabetic neuropathy in Germany. Numerous studies
in both animals and humans have produced promising results with lipoic
acid in this neuropathy. In animal models and culture studies, lipoic
acid has demonstrated antioxidant properties that help reduce or eliminate
a sequence of events that include reduced endoneural blood flow and oxygen
tension, which are pre-requisites of neuropathy. In addition, some of
these studies have revealed favorable lipoic acid effects that appear
to be independent of its antioxidant properties, including increased glucose
uptake, promotion of new neurite growth and chelation of transition metals
thought to play a role in diabetic neuropathy. In some animal experiments,
lipoic acid, administered for up to three months, significantly reversed
the increase in nerve vascular resistance and the decrease in nerve blood
flow in diabetic rats. Nerve conduction velocity was entirely restored
in some nerve groups after three months of treatment. Human clinical trials
have been similarly encouraging. In one of these studies, subjects received
200 milligrams of intravenous lipoic acid daily. After 21 days, significant
pain reduction was achieved in most subjects. In a larger, multi-center,
double-blind, randomized, placebo-controlled study of 328 patients with
type 2 diabetes, significant improvements were recorded in several clinical
measures of diabetic polyneuropathy, including pain, numbness, paresthesia
and burning sensations. These results were evident after three weeks of
intravenous lipoic acid given five times weekly in doses of 600 and 1200
milligrams. Nerve conduction velocity has not been shown to improve in
the short-term human studies conducted so far. One group of researchers
has suggested that proof of neurophysiological improvement in these neuropathies
may emerge from long-term lipoic acid supplementation studies, as has
been the case in some animal model studies. "A period of several
years," they have observed, "is required to slow progress of
diabetic neuropathy due to normalization of blood glucose levels."
There is evidence, too, that lipoic acid may help prevent or slow the
development of the atherosclerosis for which diabetics are at higher risk.
It may do this, in part, through a gene-regulatory mechanism that helps
prevent endothelial cell activity that has been implicated in the progression
of atherosclerosis. With respect to atherosclerosis, in general, lipoic
acid's antioxidant and metabolic effects appear to offer some protection,
as demonstrated in various animal models. Recently, researchers demonstrated,
in a 16-week randomized trial, that lipoic acid, in oral doses of 600
milligrams daily for eight weeks, significantly inhibits the oxidation
of LDL-cholesterol in healthy human subjects. The supplements also significantly
reduced levels of F-2 isoprostanes, markers of oxidative stress. In this
study, lipoic acid proved to be superior to vitamin E in decreasing levels
of plasma protein carbonyls. Protein oxidation and LDL-cholesterol oxidation
are implicated in heart disease. Various animal studies have suggested
that lipoic acid can prevent or reduce cell and tissue damage in heart
attacks and stroke. There is extensive animal work showing that lipoic
acid can exert significant protective effects against ischemia-reperfusion
injury. Lipoic acid is believed to work in this context, at least in part,
through its antioxidant properties and its reported ability to increase
cellular levels of glutathione that are typically depleted by the reactive
oxygen species formation that characterizes ischemia-reperfusion. More
research is needed to further elucidate these mechanisms and determine
whether these results will apply in humans. Animal work is also suggestive
of some modest benefit from lipoic acid in the treatment of various neurodegenerative
disorders, including Parkinson's disease, Alzheimer's disease, amyotrophic
lateral sclerosis and Huntington's disease. Results to date, however,
remain inconclusive. Clinical studies are needed. There is some evidence
that children afflicted with inborn errors of pyrurate metabolism may
derive some benefit from lipoic acid treatment. Those with Wilson's disease,
a genetic disorder characterized by disturbed copper metabolism, may be
helped by lipoic acid as well. The supplement has also proved useful in
conferring some protection against cadmium poisoning and hexane inhalation.
It has also been used in some liver toxicities, such as Amanita phalloides
mushroom poisoning. Lipoic acid's role in immunity is not well understood.
There are reports that it can augment antibody response in some animal
models of immunosuppression. This research warrants followup. Claims that
lipoic acid slows aging of the brain and is an anti-aging substance generally
seem to be related to its potent antioxidant properties. Direct proof
of anti-aging is lacking, but there is some animal work suggestive of
some possible anti-aging effects. Rats were fed a lipoic-acid supplemented
diet to see whether the substance can reverse age-related declines in
metabolism and mitochondrial function. Unsupplemented aged rats (24 to
26 months) exhibited ambulatory activity, said to be a general measure
of metabolic activity, that was threefold lower than that of young controls.
But this decline was significantly reversed in similarly aged rats supplemented
with lipoic acid for two weeks. Hepatocytes from untreated aged rats,
compared with hepatocytes of young controls (three to five months), had
significantly lower oxygen consumption and mitochondrial membrane potential.
But in supplemented aged rats, hepatocytes, by the same measures, were
comparable to those of the young controls. Lipoic acid supplementation
was reported to completely reverse age-related declines in hepatocyte
ascorbic acid and glutathione levels. There was additional evidence of
decreased oxidative damage in the lipoic-acid supplemented aged rats.
The researchers concluded: "Little is known about whether lipoic
acid may be an effective anti-aging supplement...in humans. Our present
findings using rats would suggest that lipoic acid supplementation may
be a safe and effective means to improve general metabolic activity and
increase antioxidant status, affording increased protection against external
oxidative and xenobiotic insults with age." Again, further study
is needed.
7.Contraindications: None known.
8. Pracautions: Because of lack of long-term safety data,
alpha-lipoic acid should be avoided by pregnant women and nursing mothers.
Those with diabetes and problems with glucose intolerance are cautioned
that supplemental alpha-lipoic acid may lower blood glucose levels. Blood
glucose should be monitored and antidiabetic drug dose adjusted, if necessary,
to avoide possible hypoglycemia.
9. Adverse reactions: To date, alpha-lipoic
acid in doses up to 600 milligrams daily has been well tolerated.
10. Interactions: Supplemental alpha-lipoic
acid may lower blood glucose levels. Those with diabetes on antidiabetic
medication should have their blood glucose monitored and antidiabetic
drug dose appropriately adjusted, if necessary, to avoid possible hypoglycemia.
11. Overdosage: There are no reports
of alpha-lipoic acid overdosage.
12. Dosage and administration: Alpha-lipoic
acid is available as a racemic mixture of D- and L- entantiomers. Some
studies showing significant antioxidant effects have used doses of the
racemic mixture of 600 milligrams daily. Alpha-lipoic acid is available
in Germany as a drug to treat polyneuropathy, such as diabetic polyneuropathy,
and liver disorders. It is available for oral and parenteral use. Those
with diabetic neuropathy use 300 milligrams daily of the oral preparation,
taken in divided doses. |
