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Effect of DHLA on response of isolated rat urinary bladder to repetitive field stimulation.

Lipoic acid is an essential coenzyme in the oxidation of pyruvate and alpha-ketoglutarate. It is easily converted to its reduced form, dihydrolipoic acid (DHLA), in vivo thereby forming a redox pair. DHLA is important in the maintenance and integrity of specific neuronal and subcellular membranes. In the present study we investigated the effect of DHLA on the response of isolated rat bladder strips to repetitive field stimulation (FS), a method used to exhaust synaptic stores of acetylcholine resulting in nerve and synaptic damage. Isolated strips of rat urinary bladders were separated into 4 groups. Group 1 strips were incubated with choline + acetyl-CoA; Group 2 strips with choline, acetyl-CoA + DHLA; and Group 3 with DHLA. Group 4 strips were controls. All strips in Groups 1-3 were subjected to 2 h of repetitive FS followed by 2 h of recovery. DHLA had no effect on the progressive decrease in contractile response observed during repetitive stimulation. However, strips incubated in the presence of DHLA showed a significantly greater degree of recovery than strips incubated in the absence of DHLA. We believe that the protection of the contractile response is related to DHLA's ability to protect nerve and/or muscle membranes from oxidative damage.

8,11,14-Eicosatrienoic Acid↗

[A glutathione deficiency in open-angle glaucoma and the approaches to its correction].

A total of 151 patients with open-angle glaucoma, 23 ones with closed angle glaucoma, and 57 ones with age-associated cataracts were examined. The reference group consisted of 21 subjects with posttraumatic cataracts (1.5 years after the injury) and normal subjects. Nonprotein sulfhydryl groups (glutathione) were measured in the peripheral blood, aqueous humor, and in tissue samples from the scleral drainage sites, obtained in antiglaucoma surgery and in surgery for cataract extraction. Aqueous humor of patients with posttraumatic cataracts, blood samples of these patients and normal subjects were examined for control. The level of sulfhydryl groups was found significantly lowered in the anterior chamber humor of patients with open-angle glaucoma, particularly in those with disease Stages II and III as against the controls. The content of sulfhydryl groups was lowered in the tissue samples from the scleral drainage area of patients with open-angle glaucoma Stages II and III vs. that in the patients with Stage I condition. Similar changes were found in the red cells of patients with Stages II and III open-angle glaucoma. Glutathione is an important component of the cellular antioxidant system. The findings point to a reduction of the processes of antioxidant defense of ocular tissues, developing as early as in the first stage of open-angle glaucoma. Lipoic acid administration for 2 months was associated with a rise of glutathione level in the red cells of patients with Stages II and III open-angle glaucoma.

Adult↗

[Thioctic acid].

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Humans↗

[Acute painful neuropathy at the initial period of effective insulin therapy].

We report on three patients (two men with recently discovered type 1 diabetes and one woman with type 2 diabetes and secondary failure of oral antidiabetic drugs) who developed acute painful neuropathy after the institution of effective insulintherapy and rapid drop of glycemia. The EMG disclosed in them traits of mixed lesions of motor-sensory neurons at the level of nerve fibres, more evident in sensory nerves of low extremities. In one patient (A) observed for 5 years, in spite of progressive partial remission of clinical symptoms and signs, no improvement in successive EMG was found. The evident therapeutic effect of alpha-lipoic acid in the presented cases needs to be confirmed in appropriate prospective studies.

Acute Disease↗

The role of chronic inflammation in cardiovascular disease and its regulation by nutrients.

Multiple risk markers for atherosclerosis and cardiovascular disease act in a synergistic way through inflammatory pathways. This article discusses some of the key inflammatory biochemical risk markers for cardiovascular disease; in particular, the role of three basic cell types affected by these risk markers (endothelial cells, smooth muscle cells, and immune cells), the crucial role of inflammatory mediators, nitric oxide balance in cardiovascular pathology, and the use of nutrients to circumvent several of these inflammatory pathways. Most risk markers for cardiovascular disease have a pro-inflammatory component, which stimulates the release of a number of active molecules such as inflammatory mediators, reactive oxygen species, nitric oxide, and peroxynitrite from endothelial, vascular smooth muscle, and immune cells in response to injury. Nitric oxide plays a pivotal role in preventing the progression of atherosclerosis through its ability to induce vasodilation, suppress vascular smooth muscle proliferation, and reduce vascular lesion formation. Nutrients such as arginine, antioxidants (vitamins C and E, lipoic acid, glutathione), and enzyme cofactors (vitamins B2 and B3, folate, and tetrahydrobiopterin) help to elevate nitric oxide levels and may play an important role in the management of cardiovascular disease. Other dietary components such as DHA/EPA from fish oil, tocotrienols, vitamins B6 and B12, and quercetin contribute further to mitigating the inflammatory process.

Arteriosclerosis↗

Enhancement of arsenic trioxide-induced apoptosis in renal cell carcinoma cells by L-buthionine sulfoximine.

Arsenic trioxide (As2O3) induces clinical remission in acute promyelocytic leukemic patients and apoptosis in various tumor cells in vitro. To develop As2O3-based combination chemotherapy for renal cell carcinoma (RCC), we investigated the cytotoxic effects of As2O3 in combination with chemotherapeutic agents or L-buthionine sulfoximine (BSO), a glutathione (GSH) synthesis inhibitor. Cytotoxicity and synergy were assessed by the MTT assay and isobolographic analysis, respectively. Apoptosis was monitored by Hoechst 33342 staining, flow cytometrical analysis, and DNA fragmentation assay. Treatment of ACHN cells with As2O3 in combination with adriamycin, vinblastine, or 5-fluorouracil induced an antagonistic effect. However, combination treatment with As2O3 and BSO resulted in a synergistic cytotoxic effect. Synergy was also obtained in Caki-1, Caki-2, NC65 cells and freshly derived RCC cells from 6 patients. Simultaneous treatment of ACHN cells with As2O3 and BSO caused significantly more cytotoxicity than the As2O3 first BSO second or the reverse treatment. We further explored the mechanisms underlying this synergistic effect and found that the synergistic cytotoxicity of As2O3 and BSO was realized by inducing apoptosis. This combination markedly decreased intracellular GSH content and GSH-S-transferase (GST) activity. However, neither the intracellular GSH nor GST was decreased by As2O3 with adriamycin, vinblastine, or 5-fluorouracil. Furthermore, the GSH-increasing agents N-acetylcysteine and lipoic acid significantly inhibited the combined cytotoxicity of As2O3 and BSO. These findings indicate that BSO sensitizes RCC cells to As2O3-induced apoptosis through the down-regulation of the intracellular GSH redox system, suggesting the potential application of a combination of As2O3 and BSO for the treatment of RCC.

Antineoplastic Combined Chemotherapy Protocols↗

[Vitamin sufficiency of young basketball players].

The investigation of vitamin sufficiency of young basket-ball players 14-16 years old (17 girls and 14 boys) has been carried out 59-77 per cent of the children had the deficiency of B group vitamins, 24-54 per cent--vitamin E insufficiency, most of them (82-100 per cent)--deficit of carotenoids while they were sufficiently vitamins C and A supplied. The girls were supplied with vitamins better than boys. There was no one adequately supplied with all vitamins among boys while 12 per cent of girls had adequately sufficiency. The girls had deficit of 1-2 vitamins more often whereas the combined insufficiency of 3-4 vitamins took place in 1.8-2.3 fold more frequently among boys. Daily intake of multivitamin containing 10 vitamins in daily recommended doses, lipoic acid, methionin and 9 minerals by boys lead to their blood plasma vitamin C, E, B-2 and beta-carotene level increase. Vitamin C insufficiency disappeared. Deficit of beta-carotene and vitamin B-6 became 1.5 fold rarely, vitamin B-2--2 fold, vitamin E--6 fold. Thus daily intake of recommended doses of vitamins eliminates biochemical signs of vitamin deficiency.

Adolescent↗

Effects of pirfenidone on the generation of reactive oxygen species in vitro.

Pirfenidone is a newly developed antifibrotic drug that has been reported to retard the progression of pulmonary fibrosis induced by bleomycin and cyclophosphamide in animal models of lung fibrosis. The present in vitro studies using noncellular and cellular systems evaluated the antioxidant and cytotoxic properties of this drug. The Fenton reaction [Fe(II) + H2O2 --> Fe(III) + *OH + OH-] and the xanthine/xanthine oxidase system were used as sources of hydroxyl (*OH) and superoxide anion (O2*-) radicals, respectively. Electron spin resonance spin trapping was used for free radical detection and measurement. The reaction rate of pirfenidone with *OH was found to be 1.63 x 10(10) M(-1) s(-1), which is comparable to several well-established antioxidants, such as ascorbate, glutathione, cysteine, azide, and lipoic acid. Compared to *OH radicals, the O2*- scavenging was less efficient 42.36 M(-1) s(-1) with pirfenidone. Pirfenidone was also effective in inhibiting zymosan-stimulated chemiluminescence. In a noncellular model of lipid peroxidation, pirfenidone inhibited crystalline silica-induced lipid peroxidation. The inhibition of crystalline silica-induced cytotoxic reactions and lipid peroxidation combined with the efficient antioxidant properties of pirfenidone indicate that this agent may express its antifibrotic effects partly through its ability to scavenge reactive oxygen species.

Animals↗

[Evidence-based pharmacotherapy of neuropathic pain syndromes].

Neuropathic pain can severely reduce quality of life. Double blind, placebo controlled studies confirm the efficacy of the treatment of painful neuropathy, postherpetic neuralgia and trigeminal neuralgia with tricyclic antidepressants, ion channel blockers, opioids and lipoic acid. The numbers-needed-to-treat (NNT) with monotherapy to achieve pain reduction of at least 50% are in the range of 2 to 4. Recent studies indicate that patients can benefit from combinations of opioids and tricyclic antidepressants or opioids and gabapentin.

Amines↗

[Regional anesthesia and timely treatment for neuropathy in patients with pyonecrotic forms of the diabetic foot].

Regional anesthesia was studied for its impact on the functional status of a peripheral nerve in 20 patients with purulent diseases of the lower extremities in the presence of diabetes mellitus. The impact of conservative therapy on the peripheral nerve was also studied in these patients. There was no negative impact of regional methods of anesthesia on the function of the nerve, its improvement due to treatment with alpha-lipoic acid and serotonin adipinate.

Adipates↗

[Recent changes in concepts of antioxidant treatment].

The promising theoretical possibilities of antioxidant prevention and protection against vascular diseases and neoplasms could not have been realized as yet. The author searches into the causes of this failure by analyzing data of recent literature. Previous preventive trials as well as newly discovered pharmacological and molecular biological effects of antioxidants are reviewed. Results of meta-analyses on prevention trials of vascular disease by vitamin-E and those of gastrointestinal cancers are also included. The lately recognized properties of antioxidants are surveyed with special regard to their capability of modulating apoptosis, inducing gene expressions and their transformation into pro-oxidants. The harmful consequence of high doses of a single antioxidant is emphasized. The retinoids, vitamins D and K possess both pro-apoptotic and antiproliferative activity, while N-acetylcysteine exerts mainly anti-apoptotic effects. Since the effects of the eight vitamin E homologues are different in many respects, alpha-tocopherol can not be regarded as vitamin E of full value. Antioxidant supply from natural sources does not seem to be sufficient for an adequate preventive effect. The author recommends such a combination in which physiological amounts of vitamins C, D, K and B-complex, N-acetylcysteine, vitamin E of natural origin might be complemented by allopurinol, co-enzyme Q-10 and alpha-lipoic acid. A diet rich in flavonoids and carotenoids is essential. Application of appropriate laboratory methods is of great value in the individualization, monitoring and control of antioxidant treatment.

Acetylcysteine↗

New and emerging treatment options for neuropathic pain.

A large number of neuroanatomical, neurophysiologic, and neurochemical mechanisms are thought to contribute to the development and maintenance of neuropathic pain (NP). As a result, a corresponding wide range of treatments have been employed to treat patients with NP, including antiepileptic drugs, opioid analgesics, tricyclic antidepressants, selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, N-methyl-D-aspartate receptor antagonists, cholecystokinin receptor antagonists, adenosine, lipoic acid, cannabinoids, isosorbide dinitrate, dronabinol, capsaicin, protein kinase C inhibitors, aldose reductase inhibitors, and VR-1 receptor modulators. Many of these compounds are limited by marginal efficacy and clinically significant adverse events; few have been evaluated in well-controlled, large-scale clinical trials. At present, the only agents approved for the treatment of painful diabetic peripheral neuropathy and postherpetic neuralgia are lidocaine patches 5%, duloxetine, gabapentin, and pregabalin. Of these, only pregabalin is indicated for both conditions.

Diabetic Neuropathies↗

Mutagenic and carcinogenic potential of menadione.

Menadione (2-methyl-l,4-naphthoquinone) or vitamin K3 is a lipid-soluble substance and promotes the hepatic biosynthesis of blood clotting factors. Carcinogenic potential of menadione was determined by a DC polarography method in strictly anhydrous N,N-dimethylformamide (DMF) in the presence of alpha-lipoic acid. Superoxide anion formation was measured after incubation of rat lung, liver and kidney microsomes with menadione. The genotoxic potential of menadione was investigated using the unscheduled DNA synthesis (UDS) and alkaline elution assays. The parameter of potential menadione carcinogenicity tg alpha was 0.0025 indicating no carcinogenic activity of menadione. Superoxide anion was generated in a concentration- and time-dependent manner when menadione was incubated with microsomes. In the mammalian cells (A 549) used for alkaline elution and UDS assays, menadione was cytotoxic at concentrations above 20 nmol/ml. The use of S9 mix (metabolic activation) fractions decreased the cytotoxicity of menadione. In the concentration range of above 20 nmol/ml menadione was genotoxic in the UDS test in absence of metabolic activation. In the presence of metabolic activation the menadione-induced DNA damage and repair was greatly reduced. Treatment of A 549 lung cells with 4-nitroquinoline-N-oxide (NQO) caused significant formation of DNA single-strand breaks both in the absence and presence of metabolic activation. Treatment of A 549 lung cells with menadione caused formation of DNA single-strand breaks in the absence of S9 mix. In the presence of metabolic activation menadione caused no significant formation of DNA strand breaks. Menadione-induced DNA repair in A 549 cells was concentration-, time-, and temperature- dependent. Measurement of unscheduled DNA (UDS) synthesis (repair) following treatment with NQO and menadione yielded strong UDS responses in the absence of S9 mix. Taken together the results of these studies suggest the mutagenic potential of NQO and menadione. These results indicate that menadione undergoes redox cycling with formation of reactive oxygen species which cause DNA damage and repair without having a carcinogenic potential.

Animals↗