Thiogamma I.V. Mechanism of Action

Pharmacotherapeutic group: Other medicines for the alimentary tract and metabolism. ATC Code: A16AX01.
Pharmacology: Pharmacodynamics: Thioctic acid, along with its major metabolite dihydro-lipoic acid (DHLA), is a potent antioxidant that is capable of scavenging oxygen free radicals, redox interaction with other antioxidants, and inhibition of lipid peroxidation. Thioctic acid is characterized by high reactivity to free radicals; it is capable of regenerating vitamins C and E, as well as glutathione.
Four main molecular mechanisms have been implicated in glucose-mediated microvascular damage (retinopathy, nephropathy, neuropathy). All seem to reflect a single hyperglycemia-induced initial process of overproduction of superoxide anion by the mitochondrial electron-transport chain. Thus, oxidative stress represents the primary cause of hyperglycaemia-induced microvascular complications, which provides the rationale for the treatment of diabetic neuropathy by antioxidants such as alpha-lipoic acid.
Experimental diabetic neuropathy is characterized by impaired nerve conduction velocity, reduced nerve blood flow, and a variety of metabolic abnormalities in peripheral nerve that have been ascribed to hyperglycemia, abnormal fatty acid metabolism, ischaemic hypoxia, and/or oxidative stress. Alpha-lipoic acid improves nerve blood flow, reduces oxidative stress, and also ameliorates nerve conduction, intraepidermal nerve fiber density, and nocifensive behavior in experimental diabetic neuropathy.
This means that alpha-lipoic acid also improves the criteria for establishing the presence of somatic diabetic neuropathy in rodent models. These criteria parallel those used to diagnose diabetic neuropathy in patients. In general, the experimental evidence supports the concept that the observed favorable effects of Thioctic acid have clinical relevance.
Pharmacokinetics: Biotransformation: Thioctic acid is subject to a first-pass effect in the liver.
There is considerable interindividual variation in the systemic availability of thioctic acid. By oxidation of the side chain and conjugation, alpha-lipoic acid is biotransformed and eliminated predominantly via the kidneys.
Elimination: The plasma half-life of thioctic acid in humans is approximately 25 minutes, while total plasma clearance is 10-15 ml/min/kg. At the end of a 30 minute infusion of 600 mg, the plasma levels are approximately 20 μg/ml. The use of radioactive markers in animal experiments (rats, dogs) has shown that the excretion path is mainly renal, at 80-90 % in the form of metabolites. Also, in humans there are only small quantities of intact substance excreted in the urine. Biotransformation occurs mainly by oxidative side chain shortening (β oxidation) and/or S-methylation of the corresponding thiols.
Thioctic acid reacts in vitro with metal ion complexes (e.g. with cisplatin). Thioctic acid forms difficult-to-dissolve complex compounds with sugar molecules.
Toxicology: Preclinical safety data: Acute toxicity: Acute toxicity in test animals is rare. The lethal intravenous dose in rats is about 400 mg/kg body weight, the lethal oral dose in dogs 400-500 mg/kg body weight. In dogs after administration of high doses vomiting, drooling and sedation were observed. In end-stage, tonic-clonic seizures occur.
Chronic toxicity: There are no data for chronic animal toxicity studies.
Mutagenicity and carcinogenicity: Studies of mutagenic potential did not provide evidence of gene or chromosomal mutations.
There was no evidence of a tumorigenic potential of thioctic acid when it was orally administrated to rats in a carcinogenicity study. Co-administration of thioctic acid and cancerogenic N-nitroso-dimethylamine (NDEA) does not increase its tumour-promoting effect.
Reproduction toxicity: Thioctic acid has no influence on fertility and early development of the embryo in rats, up to a maximum tested oral dose of 68.1 mg/kg body weight. No malformation producing properties were found after intravenous infusion in rabbits up to the maternal toxic dose range.