[L. D. 3300 by mouth. Therapeutic trial in dental practice].
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Charcot-Marie-Tooth disease (CMT) is the most common hereditary peripheral neuropathy, affecting 1 in 2,500 people. The only treatment currently available is rehabilitation or corrective surgery. The most frequent form of the disease, CMT-1A, involves abnormal myelination of the peripheral nerves. Here we used a mouse model of CMT-1A to test the ability of ascorbic acid, a known promoter of myelination, to correct the CMT-1A phenotype. Ascorbic acid treatment resulted in substantial amelioration of the CMT-1A phenotype, and reduced the expression of PMP22 to a level below what is necessary to induce the disease phenotype. As ascorbic acid has already been approved by the FDA for other clinical indications, it offers an immediate therapeutic possibility for patients with the disease.
In a search for plant products against cancer, the protective effect of two plant products, ursolic acid isolated from Ocimum sanctum and oleanolic acid from Eugenia jumbolana against free radical induced damage was studied. Three different standard systems viz., ascorbic acid, carbon tetrachloride, ADP/Iron were used to induce lipid peroxidation in isolated rat liver microsomes in vitro. Both oleanolic acid and ursolic acid offered remarkable protection of 90% and 60% respectively. Both the compounds did not induce lipid peroxidation by themselves that improved the therapeutic application.
Levodopa/inhibitor improves motor function in parkinsonian patients. In its usual tablet form, however, its efficacy is reduced after several years, partially due to absorption deficiencies and changes in plasma kinetics; thus, other therapeutic strategies to provide a stable, easy to prepare formula are being sought. One such approach could be to dissolve L-dopa/carbidopa in ascorbic acid. This report describes the preparation method and demonstrates the stability of the sample using High pressure liquid cromatography (HPLC) with electrochemical detection. Regardless of the number of tablets the patient takes, the concentration of L-dopa/carbidopa/ascorbic acid remains constant (1/0.25/2 mg/ml). Thus, a patient taking 5 tablets of Sinemet Plus a day, would pulverize them in a glass, ceramic or marble mortar and add them to a measuring cup containing a 1 gram tablet of vitamin C (Redoxon) dissolved in 500 cc of cold water. This would be shaken or stirred until the Sinemet powder had dissolved. A few particles remaining in suspension after this process would be of no concern. The liquid would be stored in the refrigerator in an opaque or aluminum foil-covered glass bottle or, if possible, in several small dose-size vials. Using a measuring cup, a test tube and a syringe, the correct volume can be drawn out of the bottle and shaken well before drinking. The solution would be taken at regular intervals throughout the day (which vary from one patient to another) to maintain stable plasma L-dopa levels.
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This candidate Reference Method for measuring total bilirubin in serum is based on the Jendrassik-Gróf principle (Clin Chem 29: 297-301, 1983). Standard Reference Material no. 916 bilirubin (National Bureau of Standards) is used as the standard. Bilirubin standard solutions may be prepared either in human serum or in 40 g/L albumin solution (human or bovine), because we found the molar absorptivity of the azopigment at 598 nm to be identical in these media. The absorptivities of the unconjugated and conjugated azopigments appear to be identical, but the conjugated azopigment is completely hydrolyzed in the final reaction mixture. Bilirubin added to serum from adults or neonates was quantitatively accounted for. Interference by hemoglobin (up to 2 g/L), ascorbic acid (up to 20 mg/L), or zinc (at physiological concentrations) is negligible. Of the therapeutic drugs we tested, only L-dopa and alpha-methyldopa interfere. We established normal adult reference values for total bilirubin and examined the intraindividual variation in 19 subjects.
A child with hypophosphatemic vitamin D-resistant rickets was treated for three years with the conventional vitamin D-inorganic phosphate supplementation followed by a new therapeutic regimen consisting of 1,25 dihydroxyvitamin D3 (1,25 (OH)2D3) and half of the previous phosphate supplementation. The effectiveness of the two treatment regimens was compared by calcium, phosphate, and magnesium balance techniques and by serial radiological examinations as well as careful height measurements. In addition, the lowering of the urinary pH with ascorbic acid supplementation seems to be associated with improvement in the renal tubular reabsorption of phosphate, but its distinct effect, separate from the rest of the treatment modalities, was not tested in this study. The conventional treatment did not correct the hypophosphatemia and alkaline phosphatase elevation, whereas the 1,25 (OH)2 D3-inorganic phosphate regimen is well tolerated and effective in achieving a sustained normalization of these variables. In addition, the improved growth and healing of rickets further attest to the efficacy of the new treatment.
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Since oxidative stress plays an important role in dysregulation of the microcirculation as well as the pathogenesis of atherosclerosis, therapeutic intervention with antioxidants has been speculated to prevent cardiovascular diseases. Ascorbic acid (AA) has been reported to improve endothelial function; however, its intracellular metabolic pathway has not been fully determined. Sodium-dependent vitamin C transporter (SVCT) types 1 and 2 were recently cloned. In the present study, we investigated whether SVCT-2 is functionally expressed in vascular endothelial cells and, if so, what factors modulate its activity. The uptake of AA into human umbilical vein endothelial cells (HUVECs) was examined by incubation with radiolabeled AA (14C-AA). AA was transported into HUVECs in a dose- and time-dependent manner. Replacement of sodium chloride with choline chloride in the medium suppressed the uptake of AA. RT-PCR revealed that HUVECs expressed SVCT-2 mRNA, but not SVCT-1. Transfection of HUVECs with the antisense oligonucleotide of SVCT-2 significantly suppressed the uptake of AA. Furthermore, tumor necrosis factor-alpha and interleukin-1beta inhibited the transport activity of AA. Thus, SVCT-2 is functionally expressed in human endothelial cells, and its activity is negatively regulated by inflammatory cytokines. Our findings might provide a new insight into understanding the treatment of cardiovascular diseases with AA.
Redox regulation has been shown to be an important component of malignant cell survival. Tipping the cellular redox balance through pharmacologic regulation in favor of increasing intracellular reactive oxygen species (ROS) and/or depleting protective reducing metabolites (such as glutathione and nicotinamide adenine dinucleotide phosphate) may lead to oxidative stress and resultant induction of apoptosis for the treatment of cancer. We review the biology and importance of ROS with regard to malignant and normal cells. Moreover, we discuss pre-clinical and clinical data regarding novel therapeutic agents that modulate the cellular redox system including buthionine sulfoximine, ascorbic acid, arsenic trioxide, imexon, and motexafin gadolinium as single-agents and in combination. Continued research is needed to better understand the mechanisms and specific apoptotic pathways involved in ROS-induced cell death, as well as, to determine the most rationale and effective combination of redox-active agents.
A naso-orbital injury is often associated with a craniocerebral injury due to the close anatomical localization of the facial and cerebral compartments of the skull. Patients with such injuries showed enhancement of free-radical lipid oxidation and microcirculation disorders. They were controlled by traditional therapeutic methods in combination with antioxidants of direct and indirect action (ascorbic acid, flacumin, alpha-tocopherol acetate, pentoxifylline ) that were given in standard doses. Improvement of microcirculation and decrease of free-radical oxidation of lipids were followed by faster normalization of bioelectric activity and hemodynamics of the brain and earlier clinical recovery. Microcirculation parameters recorded during biomicroscopy of vessels of the bulbar conjunctiva can be used for evaluating cerebral circulation because vessel responses of the eyeball and the brain are similar.
T-cell prolymphocytic leukaemia (T-PLL) is a rare form of mature T-cell leukaemia that is generally resistant to conventional chemotherapy. Mice transgenic for MTCP1 develop leukaemia similar to human T-PLL, providing a model useful for testing therapeutics. We here evaluated the potential effectiveness of arsenic trioxide (ATO) in murine T-PLL. In vitro, ATO consistently reduced the viability of murine T-PLL cells at a clinically achievable concentration (1 micromol/l). The percentage of viable cells after 24 h was 77 +/- 4%, 56 +/- 6%, 31 +/- 7% with 0 micromol/l, 0.5 micromol/l and 1 micromol/l ATO respectively. ATO cytotoxicity was enhanced by ascorbic acid (125 micromol/l). Mice were then treated with ATO (5 microg/g/d intra peritoneally, 5 d per week) or saline for 4 weeks, starting 14 d after tumoral engraftment. The appearance of lymphocytosis and splenomegaly was delayed in the group treated with ATO and survival was significantly prolonged (mean survival in days: 57.6 +/- 0.8 for ATO versus 45 +/- 0 for saline, P < 10-4). No additional effect was observed in vivo by combining ATO with ascorbic acid (500 microg/g/d, 5 d per week, intra peritoneally). These findings provide support for clinical trials to test therapeutic effects of ATO for human T-PLL.
We studied effect of exogenous ascorbic acid, alpha-tocopherol, lecithin and L-ornithine-L-aspartate on serum lipids and proteins in experimental hepatotoxic Wistar rats. Eleven groups (n = 6) of animals were used. Hepatotoxicity was induced by administering ethanol (1.6 g/kg/day) for 28 days. Both preventive and curative options were studied. Percentage increase in body weight was significantly lower in ethanol treated rats. Ethanol significantly (P<0.05) increased cholesterol, triglycerides and LDL, and decreased protein, albumin and A:G ratio in serum. Ascorbic acid, alpha-tocopherol, lecithin and L-ornithine-L-aspartate exhibited an ability to counteract the alcohol-induced changes in the body weight and biochemical parameters in preventive and therapeutic models in varying degree. Antioxidants showed better effect.
The present study shows that homocysteine depleted cystine from cystinotic fibroblasts in vitro. No toxic effects were noted as judged by morphology and growth patterns. Efflux of radioactivity from cystinotic cells prelabeled with [35S]cystine was greater in homocysteine-treated cystinotic cells than in untreated controls. This radioactivity was found, by high voltage electrophoresis separation of effluxed products, to consist mainly of [35S]cystine, along with smaller amounts of [35S]homocysteine-cysteine mixed disulfide. When homocysteine and cysteamine were presented together to cystinotic cells at dose levels individually ineffective in removing cystine from these cells, a marked synergistic effect was observed and cystine content fell to 10% of that seen in untreated cystinotic fibroblasts. Similarly, synergistic effects of cystine depletion from cystinotic cells were demonstrated when cells were treated with a combination of cysteamine and dithiothreitol or glutathione. Incubation of cystinotic cells with homocysteine, dithiothreitol, or cysteamine in combination with vitamin C did not yield synergistic effects. The above findings suggest a novel way to probe metabolic processes in these mutant cells. Exploration of these synergistic effects may lead to more efficacious therapeutic protocols for cystinosis.
Studies were carried out to assess the prospects of adapting an enzyme administration procedure developed with rat liver gulonolactone oxidase to other enzymes of therapeutic interest. The enzyme is administered intraperitoneally as the glutaraldehyde-reacted immunoprecipitate. A gulonolactone oxidase from a different source, chicken kidney, also shows catalytic capability following administration. This finding suggests that other enzymes modified by this procedure might also act in vivo. Four out of five enzymes tested (asparaginase, serum cholinesterase, rat and chicken gulonolactone oxidases) have significant catalytic activity and relatively minor changes in affinity for substrate after the modification, and only one (histidase) is inactivated by the modification. Analysis of immunoprecipitates by sodium dodecyl sulfate-polyacrylamide gel electrophoresis of these enzymes indicates that they consist largely of enzyme and immunoglobulin G. All five of these modified enzymes are not toxic even with repetitive administrations whereas unmodified asparaginase is allergenic to a majority of guinea pigs tested. The modification described is very simple and rapid and is, therefore, a practical means of preparing certain enzymes for therapeutic administration.
Be it ever so complex the natural antioxidant scavenger system of the organism, the protection provided by it seems to be inappropriate in certain diseases of the gastrointestinal mucus membrane, such as chronic inflammation, immune- and malignant diseases of the bowel. Despite the wide range of therapeutic attempts, the treatment of these diseases has not yet been solved, and the anti-inflammatory-, immunomodulatory-, cytostatic drugs currently used, have several side effects. Therefore, the so called natural- and synthetic antioxidants have been more widely employed for additional and adjuvant treatment. It also has become clear that the direct free radical scavenging effect and/or the membrane protection play an important role in the action mechanism of several old-established drugs. The recent report lists those natural and synthetic antioxidants which have been successfully employed in the clinical treatment of bowel diseases. Among the natural antioxidants, a protective effect of vitamins A, C and E have been demonstrated in the treatment of gastroduodenal ulcer and gastric cancer. Among the synthetic antioxidants, 5-amino-salicylic acid was the most effective drug in the treatment of chronic inflammations of the bowel. With getting the more precise knowledge about details of free radical reactions and with clearing up their role in pathological processes, it is possible to develop new and effective synthetic antioxidants, and widely employ them therapeutically.