Thiogamma 600 Oral Mechanism of Action

Pharmacotherapeutic group: Neuropathy preparation. ATC Code: N07XB01.
Pharmacology: Pharmacodynamics: Mechanism of action: Thioctic acid is a vitamin-like, but endogenously formed substance with a coenzyme function in the oxidative decarboxylation of alpha-keto acids and a powerful antioxidant. Both thioctic acid and its reduced form dihydro-Lipoic acid (DHLA) are capable of scavenging a variety of reactive oxygen species. DHLA is capable of directly regenerating ascorbic acid from dehydroascorbic acid and indirectly regenerating vitamin E.
Pharmacodynamic effects: As a result of the hyperglycaemia caused by diabetes mellitus there is an accumulation of the glucose on the matrix proteins of the blood vessels and the formation of so-called "advanced glycosylation end products". This process results in a reduction in endoneural blood flow and endoneural hypoxia/ischaemia, which is associated with the increased production of free oxygen radicals which damage the peripheral nerve. A depletion of antioxidants such as glutathione has also been found in the peripheral nerve.
In experiments performed on rats, thioctic acid interacted with these biochemical processes by reducing the formation of advanced glycosylation end products, improving endoneural blood flow, raising physiological antioxidant levels of glutathione and acting as an antioxidant for free oxygen radicals in the diabetic nerve.
These effects observed in the experimental situation indicate that the functionality of the peripheral nerves can be improved by thioctic acid. This applies to sensory disturbances in diabetic polyneuropathy, which may manifest themselves as dysaesthesias and paraesthesias, such as a sensation of burning, pain, numbness and pins and needles.
Furthermore, patients who received ALA (alpha-lipoic acid) experienced significant improvement in insulin sensitivity.
Clinical efficacy and safety: ALA has been studied extensively for the treatment of diabetic polyneuropathy (DN). Eleven, prospective, randomized, double-blind, placebo-controlled trials with more than 1500 patients have been conducted on the effect of ALA for DN. The studies were performed with both oral and intravenous administration of ALA. In four studies, the effectiveness was investigated when administered orally, in four studies after intravenous administration and in three trials, ALA was applicated initial intravenously and then orally. Thioctic acid was found to have favourable effects on the investigated symptoms of burning, paraesthesia, numbness and pain. Moreover, the results from 14 uncontrolled studies with ALA in patients with DN are available.
ALA appears to be safe in dosages generally prescribed clinically. The adverse reaction profile is comparable to placebo, except of the high doses (≥ 1200 mg), and does not show certain, undesirable effects, which might restrict its use in certain patients. To date, ALA in doses up to 600 mg daily has been well tolerated. Minor side effects include skin reactions and gastrointestinal effects, such as nausea and vomiting, and allergic reactions. However, these effects have only been observed in a small percentage of subjects. At start of the therapy, a temporary worsening of neuropathy may occur.
Pharmacokinetics: Absorption: Thioctic acid is rapidly and almost completely absorbed from the gastrointestinal tract in humans. Following oral administration approximately 87% of a dose of ALA is absorbed. The bioavailability is about 20-30% that of an intravenous dose. Peak serum ALA concentration of 4.44±3.65 μg/ml occur within 0.31 ± 0.1 hours following oral administration of a single 600 mg dose. Food intake significantly reduced the bioavailability of ALA. Dose proportionality for both enantiomers of ALA was demonstrated after p.o doses of 50-600 mg.
Distribution: ALA is well distributed in tissue. Studies with 14C-labeled lipoate in rat, administered either i.p. or oral, the highest concentrations are found in the urine, as respiratory 14CO2, and in the tissues, of which highest concentrations were detected in the liver, muscle, intestine and nerves.
Biotransformation: ALA was shown to be metabolized largely through β-oxidation of the valeric acid side chain.
Major metabolites identified were bisnorlipoic acid, tetranorlipoic acid, and β-hydroxybisnorlipoic acid. Reduction of exogenous lipoic acid to dihydrolipoate occur in several mammalian cells and tissues. The serum elimination half-life after oral administration of 600 mg is rapid with a value of 34.79 ± 8.74 min on day one and 31.90 ± 7.47 min on day 4.
Excretion: ALA is excreted mainly in the urine within 24 hours of a single oral or parenteral dose. But the kinetic results revealed that urinary excretion of ALA and five of its main metabolites does not play a significant role in the elimination of ALA. Therefore, biliary excretion, further electrochemically inactive degradation products, and complete utilization of ALA as a primary substrate in the endogenous metabolism should be considered.
Toxicology: Preclinical Safety Data: Toxicological Properties: Acute and chronic toxicity: The toxicity profile is characterised by symptoms which affect both the vegetative nervous system and the central nervous system.
After repeated application the other target organs of toxic doses are mainly the liver and kidney.
Mutagenic and Tumour-Producing Potential: Investigations into mutagenic potential have not provided any indications of gene or chromosome mutations. A cancerogenicity study after the oral application of thioctic acid to rats did not bring to light any indications of a tumour-producing potential. A study on a tumour-promoting effect of thioctic acid in conjunction with the cancerogenic substance N-nitroso-dimethyl amine (NDEA) proved negative.
Reproduction Toxicity: Thioctic acid does not have any effect on fertility or early embryo development in rats up to the maximum investigated oral dose of 68.1 mg/kg. After intravenous injections to rabbits no deformation-producing properties are found up to the maternal-toxic dose range.