Chemie und Biochemie der α‐Liponsäure

Schmidt, Ulrich; Grafen, Paul; Goedde, H. W.

doi:10.1002/ange.19650772004

Cited by 14 publications

(4 citation statements)

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“…With prolonged use they might also be expected to prevent or improve neuropathy (20). Here we test whether positive neuropathic sensory symptoms can be ameliorated by the potent antioxidant ALA that has additional favorable metabolic actions (21)(22)(23)(24)(25). Racemic ALA, 6,8-dithioctane (the active ingredient studied here) is widely distributed in biological tissues and has a low toxicity profile (26 -30).…”

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confidence: 99%

The Sensory Symptoms of Diabetic Polyneuropathy Are Improved With α-Lipoic Acid

Аметов¹,

Barinov²,

Dyck³

et al. 2003

Diabetes Care

341

199

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OBJECTIVE -Because ␣-lipoic acid (ALA), a potent antioxidant, prevents or improves nerve conduction attributes, endoneurial blood flow, and nerve (Na(ϩ) K(ϩ) ATPase activity in experimental diabetes and in humans and may improve positive neuropathic sensory symptoms, in this report we further assess the safety and efficacy of ALA on the Total Symptom Score (TSS), a measure of positive neuropathic sensory symptoms.RESEARCH DESIGN AND METHODS -Metabolically stable diabetic patients with symptomatic (stage 2) diabetic sensorimotor polyneuropathy (DSPN) were randomized to a parallel, double-blind study of ALA (600 mg) (n ϭ 60) or placebo (n ϭ 60) infused daily intravenously for 5 days/week for 14 treatments. The primary end point was change of the sum score of daily assessments of severity and duration of TSS. Secondary end points were sum scores of neuropathy signs (NIS), symptoms (NSC), attributes of nerve conduction, quantitative sensation tests (QSTs), and an autonomic test.RESULTS -At randomization, the groups were not significantly different by the criteria of metabolic control or neuropathic end points. After 14 treatments, the TSS of the ALA group had improved from baseline by an average of 5.7 points and the placebo group by an average of 1.8 points (P Ͻ 0.001). Statistically significant improvement from baseline of the ALA, as compared with the placebo group, was also found for each item of the TSS (lancinating and burning pain, asleep numbness and prickling), NIS, one attribute of nerve conduction, and global assessment of efficacy.CONCLUSIONS -Intravenous racemic ALA, a potent antioxidant, rapidly and to a significant and meaningful degree, improved such positive neuropathic sensory symptoms as pain and several other neuropathic end points. This improvement of symptoms was attributed to improved nerve pathophysiology, not to increased nerve fiber degeneration. Because of its safety profile and its effect on positive neuropathic sensory symptoms and other neuropathic end points, this drug appears to be a useful ancillary treatment for the symptoms of diabetic polyneuropathy. Diabetes Care 26:770 -776, 2003T he neuropathies associated with diabetes are heterogeneous (1). Perhaps the most common variety is diabetic sensorimotor polyneuropathy (DSPN), the disorder studied here. This variety appears to be caused by chronic hyperglycemia and associated metabolic derangements, damaging neurons (axons) or Schwann cells (or myelin) directly or indirectly by functional and structural alterations of microvessels or the blood nerve barrier. Inflammation, perhaps from immune mechanisms, may also be implicated in some cases (2).Recognizing that total hyperglycemic exposure may be the most important modifiable risk covariate for diabetic complications such as DSPN (3-8), why search for ancillary treatments in addition to rigorous glucose control? First, despite considerable effort to achieve near euglycemia (by frequent monitoring of plasma glucose, use of multiple injections of insulin, or use of insulin pumps), many ...

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confidence: 99%

The Sensory Symptoms of Diabetic Polyneuropathy Are Improved With α-Lipoic Acid

Аметов¹,

Barinov²,

Dyck³

et al. 2003

Diabetes Care

341

199

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“…a-Lipoic acid is an essential cofactor in the multienzyme complexes of a-ketoacid-dehydrogenases such as pyruvate-, a-keto-glutarate-and branched chain aketo-acid-dehydrogenases (Schmidt et al, 1965). a-Lipoic acid is a strong antioxidant (Packer et al, 1995) and interacts with reactive oxygen species (ROS), such as superoxide radicals, hydroxyl radicals, hypochloric acid, peroxyl radicals, and singlet oxygen (Biewanga et al, 1997).…”

Section: Discussionmentioning

confidence: 99%

Alpha-lipoic acid as a new treatment option for Azheimer type dementia

Häger¹,

Marahrens²,

Kenklies³

et al. 2001

Archives of Gerontology and Geriatrics

167

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Oxidative stress and energy depletion are characteristic biochemical hallmarks of Alzheimer's disease (AD), thus antioxidants with positive effects on glucose metabolism such as thioctic (a-lipoic) acid should exert positive effects in these patients. Therefore, 600 mg a-lipoic acid was given daily to nine patients with AD and related dementias (receiving a standard treatment with acetylcholinesterase inhibitors) in an open study over an observation period of, on avarage, 337 980 days. The treatment led to a stabilization of cognitive functions in the study group, demonstrated by constant scores in two neuropsychological tests (mini-mental state examination: MMSE and AD assessment scale, cognitive subscale: ADAScog). Despite the fact that this study was small and not randomized, this is the first indication that treatment with a-lipoic acid might be a successful 'neuroprotective' therapy option for AD and related dementias.

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“…Biochemistry a-Lipoic acid is involved in central biochemical processes as a protein-bound coenzyme [1]. It oc curs, for example, as a cofactor of multienzyme complexes which control energy-producing pro cesses such as aerobic glycolysis and photosynthe sis.…”

Section: Resultsmentioning

confidence: 99%

“…hydrochlorid acid. (1): 1700 ml of water and 52 g (about 0.2 mol) of crude dihydrolipoic acid (7) are introduced into a 3 1 glass reactor (aerating stirrer, pH probe, dropping funnel, waste gas tube) and treated with 2 N sodium hydroxide solution at room tem peratur to pH 8 .8 (about 130 ml = 0.24 mol). 1.2 ml of 10 percent iron (III) chloride solu tion is added and the m ixture is gassed with air until the color changes from black-gray to yellow (about 2 1/min, 2.5 h).…”

Section: Rs-d Ihydrolipoic Acidmentioning

confidence: 99%

A Short and Productive Synthesis of Racemic α-Lipoic Acid

Balkenhohl

Paust

1999

Zeitschrift Für Naturforschung B

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Lipoic A cid, Radical Induced C-C-Bond Formation, Baeyer-Villiger Oxidation, Ether Cleavage, Isothiuronium SaltsRacemic a-lipoic acid is synthesized in four steps from the base chemicals vinyl ethyl ether and cyclohexanone. The total yield is 40%. Results and DiscussionBiochemistry a-Lipoic acid is involved in central biochemical processes as a protein-bound coenzyme [1]. It oc curs, for example, as a cofactor of multienzyme complexes which control energy-producing pro cesses such as aerobic glycolysis and photosynthe sis. Scheme 1 shows the biochemical role of lipoic acid in the oxidative decarboxylation of pyruvic acid. UsePatients who suffer form diabetes mellitus or the consequences of alcohol abuse have reduced lipoic acid levels. Thus, the supply of the nerve cells with ATP is no longer guaranteed and neuro logical complications generally occur. The admin istration of lipoic acid has therefore proven suit able, in particular as a therapy in diabetic and alcoholic polyneuropathy [2 ], Together with other biological antioxidants, dihydrolipoic acid has a membrane-stabilizing action and can prevent, for example, oxidative damage in the case of reperfusion after by-pass operations [3]- SynthesisA fter the isolation and structural elucidation [4] of a-lipoic acid, num erous syntheses were pub lished in patent specifications and the scientific lit erature. They can be divided into three categories with respect to the preparation of C8 precursors * Reprint requests to Dr. J. Paust.which carry functional groups in positions 1 , 6 and 8 , Scheme 2 [5].(I) Friedel-Crafts addition of adipic acid m onoester chloride to ethylene yields the unsatu rated keto ester 2 after spontaneous elimination of hydrogen chloride.(II) Prins reaction of term inal C7-olefins affords 1,3-dioxane derivatives 3.(III) Baeyer-Villiger oxidation of 2-substituted cyclohexanones 4 leads to the caprolactones 5.In addition to the routes (I)-(I II), specific pro cesses have also been developed for the prepara tion of 1, 6 , 8 -functional interm ediates [5],The introduction of sulfur groups into the inter mediates 2, 3 and 5 is carried out either directly by heating with hydrohalic acids and thiourae [6 ] or in two steps via 6 ,8 -dihalides or -disulfonates and reaction with sulfur nucleophiles [7], Industrial syntheses of racemic a-lipoic acid are based mainly on the Friedel-Crafts route (I). Our process follows the Baeyer-Villiger strategy (III), however. It is different from the variants known from the literature [5,8 ], in particular in the first two steps, Scheme 3 [9].2-(2'-Ethoxyethyl)cyclohexanone (4, Rj = Et) is synthesized in one stage from the base chemicals vinyl ethyl ether and cyclohexanone. Di-terf-butyl peroxide is particularly suitable as a catalyst. The reaction is carried out in excess cyclohexanone as a solvent, which can be recovered and recycled during the distillative isolation of 4. 2-(2'-Acetoxyethyl)cyclohexanone (4 , R.! = AC) is analogously formed from vinyl acetate and cyclohexanone in 35% yield.The subsequent Baeyer-Vi...

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Chemie und Biochemie der α‐Liponsäure

Cited by 14 publications

References 148 publications

The Sensory Symptoms of Diabetic Polyneuropathy Are Improved With α-Lipoic Acid

The Sensory Symptoms of Diabetic Polyneuropathy Are Improved With α-Lipoic Acid

Alpha-lipoic acid as a new treatment option for Azheimer type dementia

A Short and Productive Synthesis of Racemic α-Lipoic Acid

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