DE4343592C2 - Use of R - (+) - alpha-lipoic acid and its metabolites in the form of the free acid or as salts or esters or amides for the treatment of glucose metabolic disorders in the central nervous system - Google Patents

Description

The invention relates to the new use of a drug known per se for the treatment of Central nervous system disorders and their glucose metabolism disorders Manufacturing.

R - (+) - α-lipoic acid is the physiologically occurring enantiomer of 1,2- Dithio-cyclopentane-3-valeric acid.

R - (+) - α-lipoic acid is a coenzyme of ubiquitous in the plant and animal kingdom alpha-keto acid dehydrogenases (pyruvate dehydrogenase, alpha-ketoglutarate dehydrogenase u. a. m) and thus acts at a key point in the sugar and Cell energy metabolism. It functions as an intramolecular The redox system is oxidized (α-lipoic acid) and reduced (dihydrolipoic acid).

As a 50/50 mixture of the R - (+) - α-lipoic acid and the S - (-) - α-lipoic acid, this is Racemat used for the treatment of diabetic and alcoholic Polyneuropathy, for the treatment of tuberous leaf poisoning and chronic and alcoholic liver disease.

Medicines that contain R - (+) - α-lipoic acid or S - (-) - α-lipoic acid as the active ingredient and the one antiviral, cytoprotective, anti-inflammatory and analgesic Developing effects are known, the enantiomers differing in terms of their Distinguish pharmacological effect (patent specification EP-A 427 247).

Older case reports indicate that R, S- (±) -α-lipoic acid in patients with arteriosclerotic and dementia symptoms lead to an improvement may (Boysen K.-H., Med Welt 1967, 395-400). Parkinsonism, however, seemed not to address. Confirmation of these results within thirty Years of therapeutic use of R, S- (±) -α-lipoic acid in Germany did not happen.

The object of the invention is the provision of drugs by Improvement in glucose uptake in the brain contributes to the loss of performance  chronic degenerative diseases of the central nervous system compensate for or reduce the process of chronic degeneration of Can slow down, stop or reverse nerve or auxiliary cells.

It has now surprisingly been found that the R - (+) - α, -liponic acid as proves suitable for the treatment of glucose metabolic disorders of the central Nervous system.

The R enantiomer increases glucose uptake very significantly in most Areas of the central nervous system. The S enantiomer is less or not effective and even inhibits several brain regions. An exclusive one Use of R - (+) - α-lipoic acid in drugs without the partially inhibiting S- Enantiomer therefore offers a decisive advantage.

Both with increasing age and especially with numerous chronic degenerative diseases of the central nervous system is one Deterioration of energy metabolism in the central nervous system (Hoyer S. et al. J. Neural. Transm. (Parkinson's disease and Dementia section), 3, 1-14, (1991)).

By treating glucose uptake disorders with R - (+) - α-lipoic acid are both acute nerve performances and thus cerebral performance improves as well as delays or delays chronic nerve degeneration processes stopped as in chronic degenerative CNS diseases as well Performance disorders of old age occur.

Pharmacological examples

• 1. Animal experiments have found that the radiolabeled active ingredient brain barrier permeable.
• 2. In experiments on the uptake of glucose in the CNS it was surprising shown that R - (+) - α-lipoic acid leads to a stronger and more pronounced uptake of glucose (measured with radioactively labeled deoxyglucose) into various Brain areas lead as with the S (-) - enantiomer, which partially inhibits.

Male Wistar rats (280-320 g body weight) were treated with R- or S-α- Lipoic acid (50 mg / kg body weight) i. v. treated. Two hours after giving the Active ingredients were 14C-deoxyglucose (25 µCi) i. v. applied. The Plasma radioactivity was followed over 45 minutes. Then the Animals decapitated. The frozen brain was cryosectioned and autoradiographed. The autoradiographs were computerized Image analyzer evaluated. The results are in µmol / 100 g × min Glucose uptake expressed as the rate of local cerebral glucose uptake. Here the glucose uptake was according to Sokoloff (Sokoloff et al. J. Neurochem., 28, 897-916, (1977)) from the concentration of radioactivity in the CNS and calculated in the plasma as well as the glucose concentration.

percentage change in glucose uptake

It was unexpectedly found that the observed changes occurred according to age. While young animals have a slight improvement in The glucose uptake by the drug showed improvement age-dependent. The effect was again weaker in very old animals pronounced.

Statistically significant improvements in glucose uptake in different brain areas by R - (+) - α-lipoic acid in animal groups of different ages (+: p <0.05, ++: P <0.01)

R - (+) - α, -liponic acid can thus be used as a highly specific, effective drug Treatment of glucose metabolism disorders in chronic degenerative diseases Central nervous system disorders as well as central age-related disorders Performance losses apply. Similarly, the metabolites z. B. R - (-) - Dihydroliponic acid, bisnorliponic acid or tetranorliponic acid, and the salts, Esters or amides can be used.  

As indications for the use of drugs containing the substances mentioned include, for example:

• - Parkinson's disease
• - Alzheimer's disease
• - Multi-infarct dementia
• - Age-related cerebral loss of performance
• - Encephalopathies of different origins
• - Down syndrom
• - progeria
• - Tardive dyskinesia
• - inflammatory diseases of the CNS
• - Myatrophic lateral sclerosis (ALS)
• - Senile dementia

The invention relates to the use of R - (+) - α-lipoic acid or its Metabolites (e.g. R - (-) - dihydroliponic acid, bisnorliponic acid or Tetranorliponic acid) and its salts, esters or amides for treatment of central nervous system glucose metabolism disorders.

These compounds are prepared in a known manner (see for example also DE-OS 41 37 773, EP 0197 407).

Examples of individual doses of the active ingredients are:

• a. oral forms: 10 mg-3 g
• b. Parenteral forms (intravenous or intramuscular): 10 mg-12 g
• c. Inhalation agent: 10 mg-2 g

The doses a) to c) can, for example, 1 to 6 times a day or as Continuous infusion can be given.

Galenic examples

The stated weight amounts relate to the pure optical Isomer, not on the salts. When using salts, esters or amides adjust the weight information according to the changed molecular weights. The salts are prepared in a known manner (see also patent EP-A 427 247).  

The pharmaceutical preparations generally contain 5 mg to 3 g of the Compounds used according to the invention mentioned above as a single dose. The Effective levels in the body should be between 0.1 and 100 after multiple doses mg / kg body weight. It is administered in the form of tablets, Chewable tablets, lozenges, pills, coated tablets, capsules, granules Effervescent tablets, effervescent powder, ready-to-drink solutions, liquid forms for parenteral application and aerosols. Ready-to-drink solutions and liquid forms for parenteral administration, alcoholic and aqueous solutions, Suspensions and emulsions.

The respective pharmaceutical forms can be used as additives, stabilizers or auxiliary substances at least one substance from the group vitamin E, vitamin C, NADH, NADPH, and ubiquinone included.

Preferred forms of use are, for example, tablets which are between 10 mg and 2 g as well as solutions that are active between 1 mg and 200 mg / ml liquid Contain substance.

Examples: Example 1: Tablets with 100 mg R - (+) - α-lipoic acid

250 g of R - (+) - α-lipoic acid become uniform with 750 g of microcrystalline cellulose rubbed. After sieving the mixture, 250 g of starch (Starch 1500 / Colorcon), 732.5 g lactose, 15 g magnesium stearate and 2.5 g highly disperse Silicon dioxide was added and the mixture to tablets weighing 800.0 mg pressed.

One tablet contains 100 mg R - (+) - α-lipoic acid. If necessary, the Tablets using a gastric juice-soluble or gastric juice-permeable film coating.

Example 2: Ampoules with 250 mg R - (+) - α, -liponic acid as trometamol salt in 10 ml

250 g of R - (+) - α-lipoic acid are combined with 352.3 g of trometamol (2-amino-2- (hydroxymethyl) -1,3-propanediol) in a mixture of 9 liters of water for Injections and 200 g of 1,2-propylene glycol dissolved with stirring. The solution is made up to 10 liters with water for injections and then by a membrane filter with a pore size of 0.2 µm is filtered with a glass fiber pre-filter. The filtrate becomes 10 ml in sterilized 10 ml ampoules under aseptic conditions bottled.

One ampoule contains 250 mg R - (+) - α-lipoic acid in 10 ml solution for injection Trometamol salt.

Example 3: Ampoules with 250 mg R - (-) - dihydrolipoic acid in 10 ml solution for injection

60 mg trometamol and 1 g ethylenediaminetetraacetic acid, disodium salt are in 1.8 liters of water dissolved for injections. The solution is with for 30 minutes Nitrogen fumigated. With further gassing with nitrogen, 2 g Sodium disulfite and then 50 g of R - (-) - dihydrolipoic acid dissolved. The solution with water for injections that has been gassed with nitrogen Replenished volume of 2 liters. After careful mixing, the solution is over filtered a membrane filter with a pore size of 0.2 µm and the filtrate under aseptic Conditions and with pre- and post-gassing with nitrogen in ampoules of 10 ml Filled volume.

One ampoule contains 250 mg R - (-) - dihydrolipoic acid in 10 ml solution Trometamol salt

Claims (2)

1. Use of R - (+) - α-lipoic acid or its metabolites and its Salts, esters or amides for the treatment of glucose metabolism disorders of the central nervous system. 2. Use of at least one substance from the group vitamin E, vitamin C, NADH, NADPH and ubiquinone as additives, stabilizers or auxiliaries according to claim 1.