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May 9, 2000

National Academy of Sciences References

101. Urol Res 1997;25(1):49-58Postprandial hyperinsulinaemia, insulin resistance and inappropriately high phosphaturia are features of younger males with idiopathic calcium urolithiasis: attenuation by Ascorbic acid supplementation of a test meal.Schwille PO, Schmiedl A, Herrmann U, Wipplinger J Department of Surgery, University of Erlangen, Germany.

In idiopathic recurrent calcium urolithiasis (RCU) the state of insulin and carbohydrate metabolism, and relationships to minerals such as phosphate, are insufficiently understood. Therefore, in two groups of males with RCU (n = 30) and healthy controls (n = 8) the response to an oral carbohydrate- and calcium-rich test meal was studied with respect to glucose, insulin, and C-peptide in peripheral venous blood (taken before and up to 180 min post-load), and phosphate and glucose in fasting and post-load urine. In one RCU group (n = 16) the meal was supplemented with Ascorbic acid (ASC; 5 mg/kg body weight). The mean age (RCU 29, RCU + ASC 30, controls 27 years) and mean body mass index [RCU 24.4, RCU + ASC 25.0, controls 24.0 kg/m2] were similar. Insulin resistance (synonymous sensitivity of peripheral organs to insulin) was calculated from insulin serum concentration, as was also integrated insulin, C-peptide, and glucose. Untreated stone patients (RCU) developed hyperinsulinaemia between 60 and 120 min post-load, increased integrated insulin, and insulin resistance (P < or = 0.05 vs controls), whereas the rise of C-peptide and glycaemia (absolute and integrated values) was only of borderline significance. Fasting phosphaturia was low in both RCU subgroups vs controls; however, phosphaturia in untreated RCU rose in response to the meal, contrasting sharply with a decrease in controls. ASC supplementation of the meal (in the RCU + ASC subgroup) normalized insulin, failed to normalize post-load phosphaturia, but reduced post-load glucosuria and urinary pH significantly (mean pH values 5.55 vs 5.93 in untreated RCU, controls 5.50). Postprandial urinary oxalate, calcium, protein, and supersaturation products were not changed. The postprandial changes in phosphaturia and insulin sensitivity were inversely correlated (n = 38, r = -0.44, P = 0.007). It was concluded that in younger RCU males: (1) postprandial hyperinsulinaemia, the failure to reduce phosphaturia and - within limits - glucosuria, appropriately, as well as poor urine acidification are important features of the metabolism; (2) these phenomena are probably caused by insulin resistance of organs, the kidney included; and (3) the addition of a supraphysiological dose of ASC to a meal, the subsequent abolition of hyperinsulinaemia, and the restoration of normal urine acidification suggest that this antioxidant is capable of counteracting some pre-existing basic abnormality of cell metabolism in RCU.

102. Br J Nutr 1997 Jan;77(1):59-72VITAMIN C intake and susceptibility to the common cold.Hemila H Department of Public Health, University of Helsinki, Finland.

Although the role of VITAMIN C in common cold incidence had been studied extensively, the level of VITAMIN C intake has not been unequivocally shown to affect the incidence of colds. In the present study the six largest VITAMIN C supplementation (> or = 1 g/d) studies, including over 5000 episodes in all, have been analysed, and it is shown that common cold incidence is not reduced in the VITAMIN C-supplemented groups compared with the placebo groups (pooled rate ratio (RR) 0.99; 95% CI 0.93, 1.04). Consequently these six major studies give no evidence that high-dose VITAMIN C supplementation decreases common cold incidence in ordinary people. Nevertheless, the analysis was continued with the hypothesis that VITAMIN C intake may affect common cold susceptibility in specific groups of people. It was assumed that the potential effect of supplementation might be most conspicuous in subjects with low dietary VITAMIN C intake. The average VITAMIN C intake has been rather low in the UK and plasma VITAMIN C concentrations are in general lower in males than in females. In four studies with British females VITAMIN C supplementation had no marked effect on common cold incidence (pooled RR 0.95; 95% CI 0.86, 1.04). However, in four studies with British male schoolchildren and students a statistically highly significant reduction in common cold incidence was found in groups supplemented with VITAMIN C (pooled RR 0.70; 95% CI 0.60, 0.81). Thus, these studies with British males indicate that VITAMIN C intake has physiological effects on susceptibility to common cold infections, although the effect seems quantitatively meaningful only in limited groups of people and is not very large. Publication Types: Meta-analysis Comments: Comment in: Br J Nutr 1997 Nov;78(5):857-9; discussion 861-6 Comment in: Br J Nutr 1997 Nov;78(5):859-61; discussion 861-6

103. Eur J Clin Invest 1997 May;27(5):387-91The effect of VITAMIN C in high doses on plasma and biliary lipid composition in patients with cholesterol gallstones: prolongation of the nucleation time.Gustafsson U, Wang FH, Axelson M, Kallner A, Sahlin S, Einarsson K Department of Surgery, Danderyd Hospital, Sweden.

VITAMIN C deficiency in guinea pigs leads to cholesterol supersaturation of bile and formation of cholesterol gallstones. It has been suggested that there may also exist an association between VITAMIN C and cholesterol gallstones in man, but such a relationship has not been studied in gallstone patients. In order to study the possible effects of VITAMIN C on gallstone disease in humans, plasma lipid levels, hepatic cholesterol metabolism, biliary lipid composition, cholesterol saturation and nucleation time of gallbladder bile were analysed in 16 consecutive gallstone patients, who were planned for laparoscopic cholecystectomy and were treated with VITAMIN C (500 mg, four times a day) for 2 weeks before surgery. The plasma concentration of VITAMIN C increased by 42% in the treatment group. The concentrations of plasma lipids did not differ before and after VITAMIN C treatment; nor did the plasma levels of lathosterol and 7 alpha-hydroxy-4-cholesten-3-one, reflecting cholesterol and bile acid synthesis respectively. The relative concentrations of cholesterol, bile acids and cholesterol concentration of bile did not differ significantly between the two groups, but the relative concentration of phospholipids was slightly higher in the treated group. The bile acid composition was changed; the percentage of cholic acid being lower and those of deoxycholic acid, ursodeoxycholic acid and lithocholic acid higher in the VITAMIN C-treated patients compared with the untreated group. The nucleation time was significantly longer in the treatment group (7 days) compared with the untreated group (2 days). Our findings indicate that VITAMIN C supplementation may also influence the conditions for cholesterol gallstone formation in humans. PMID: 9179545, UI: 97323055

104. Am J Clin Nutr 1996 Dec;64(6):960-5Supplementation with vitamins C and E enhances cytokine production by peripheral blood mononuclear cells in healthy adults.Jeng KC, Yang CS, Siu WY, Tsai YS, Liao WJ, Kuo JS Department of Medical Research, Taichung Veteran's General Hospital, Taiwan, Republic of China.

The effect of supplementation with vitamins C and E on cytokine production of healthy adult volunteers was studied in a single-blind trial. Ten subjects in each group received daily VITAMIN C (1 g Ascorbic acid), vitamin E (400 mg dl-alpha-tocopheryl acetate), or vitamins C and E for 28 d. Plasma concentrations of alpha-tocopherol, ascorbate, and lipid peroxides as well as the production of cytokines by peripheral blood mononuclear cells (PBMCs) were measured before, during, and at the end of the supplementation and 1 wk later. PBMCs were cultured in the presence of absence of lipopolysaccharide for 24 h. The interleukin 1 (IL-1), interleukin 6 (IL-6), and tumor necrosis factor alpha (TNF-alpha) in the culture supernates were assayed by enzyme-linked immunosorbent assay methods. Production of IL-1 beta and TNF-alpha in the group supplemented with vitamins C and E was significantly higher (P < 0.05) than that of the groups given vitamin E or VITAMIN C alone. The enhancing effect of supplementation with a combination of vitamins E and C coincided with peak plasma alpha-tocopherol and ascorbate concentrations and the lowest plasma lipid peroxide concentrations (P < 0.05) on day 14. In addition, an in vitro experiment with PBMCs showed that vitamins E and C reduced lipopolysaccharide-induced prostaglandin E2 production and enhanced TNF-alpha production. These results indicate that combined supplementation with vitamins C and E is more immunopotentiating than supplementation with either vitamin alone in healthy adults

105. Gut 1996 Apr;38(4):518-24Effect of allopurinol, sulphasalazine, and VITAMIN C on aspirin induced gastroduodenal injury in human volunteers.McAlindon ME, Muller AF, Filipowicz B, Hawkey CJ Division of Gastroenterology, University Hospital, Nottingham.

BACKGROUND--The mechanisms of aspirin induced gastroduodenal injury are not fully understood. Aspirin induces the release of reactive oxygen metabolites in animal models, which may contribute to mucosal injury. AIMS--To investigate the effects of aspirin administered with placebo or antioxidants on gastric mucosal reactive oxygen metabolite release and gastroduodenal injury in human volunteers. SUBJECTS--Fourteen healthy volunteers participated in the study (seven male; mean age 27 years, range 20-40). METHODS--In a double blind, randomised, crossover study, volunteers received aspirin 900 mg twice daily and either placebo, allopurinol 100 mg twice daily, sulphasalazine 1 g twice daily or VITAMIN C 1 g twice daily for three days. Injury was assessed endoscopically and by quantifying mucosal reactive oxygen metabolite release by measuring chemiluminescence before and after each treatment. The effect on prostanoids was determined by measuring ex vivo antral prostaglandin E2 (PGE2) synthesis and serum thromboxane B2 (TXB2). RESULTS--No drug reduced any parameter of gastric injury but VITAMIN C reduced duodenal injury assessed by Lanza score (p < 0.005). Chemiluminescence increased after aspirin both with placebo (p < 0.05) and VITAMIN C (p < 0.05). Post-treatment chemiluminescence was lower in subjects taking allopurinol (p < 0.05) or sulphasalazine (p < 0.005) than in those taking placebo with aspirin. CONCLUSIONS--In this study, aspirin induced gastric injury was associated with reactive oxygen metabolite release. This was reduced by sulphasalazine and allopurinol, although macroscopic injury was not affected. VITAMIN C, however, was shown to have a previously unrecognised protective effect against aspirin induced duodenal injury.

106. Photodermatol Photoimmunol Photomed 1996 Feb;12(1):27-30A double-blind, placebo-controlled, crossover trial of oral VITAMIN C in erythropoietic protoporphyria.Boffa MJ, Ead RD, Reed P, Weinkove C Dermatology Centre, University of Manchester School of Medicine, United Kingdom.

There is evidence that reactive oxygen species and free radicals may be involved in the pathogenesis of photosensitivity in erythropoietic protoporphyria (EPP). Considering the well-known antioxidant properties of VITAMIN C, we investigated whether oral supplementation with this vitamin was photoprotective in patients with EPP. Twelve patients with EPP received either oral VITAMIN C 1 g daily or placebo, for 4 weeks, followed by a crossover period of another 4 weeks. Nine patients were already receiving beta carotene at entry and continued this at the same dose throughout the study. Patients compared their sunlight tolerance throughout each of the treatment periods with sunlight tolerance at entry on a 10 cm visual analogue scale; at the end of the study, they were asked to choose which treatment period they felt had been associated with least photosensitivity. Eight patients stated that they were able to tolerate sunshine better during the VITAMIN C period, 2 during the placebo period and 2 noticed no difference between the two periods. This distribution of preferences approached but did not reach statistical significance in favour of VITAMIN C. Visual analogue scores improved by a median of 1.2 cm in the VITAMIN C period. This change too approached but did not reach statistical significance. Although these results do not reach statistical significance, it appears possible that oral VITAMIN C may reduce photosensitivity in some patients with EPP. A larger study is necessary to confirm this impression.

107. Free Radic Biol Med 1996;21(2):211-7The effect of ascorbate and ubiquinone supplementation on plasma and CSF total antioxidant capacity.Lonnrot K, Metsa-Ketela T, Molnar G, Ahonen JP, Latvala M, Peltola J, Pietila T, Alho H Department of Biomedical Sciences, University of Tampere, Finland.

Free radicals are thought to be involved in the onset of neuronal disturbances such as Alzheimer's disease, Parkinson's disease, and neuronal ceroid lipofuscinosis. It is also assumed that they play a role in cerebral injury caused by ischemia or trauma. Plasma and cerebrospinal fluid (CSF), Total (peroxyl) Radical-trapping Antioxidant Parameter (TRAP), and the known antioxidant components of TRAP, for instance, Ascorbic acid, uric acid, protein sulfhydryl groups, tocopherol, and ubiquinol were analyzed and the remaining unidentified fragment was calculated in five healthy volunteers before and after 4 weeks of ascorbate and ubiquinone (Q-10) supplementation. In CSF, TRAP was significantly lower than in plasma. The major contributor to plasma's antioxidant capacity was uric acid (UA), whereas in CSF it was Ascorbic acid (AA). In CSF, AA concentrations were four times higher than in plasma. Oral supplementation of AA (500 mg/d first 2 weeks, 1,000 mg/d following 2 weeks) and Q-10 (100 mg/d first 2 weeks, 300 mg/d following 2 weeks) induced a significant increase in plasma AA and Q-10. Surprisingly, in spite of the high lipophilicity of Q-10, its concentration did not change in CSF. The supplementation of AA increased its concentration in CSF by 28% (p < .05). However, the increase in AA did not result in an increase in CSF TRAP. This indicates that AA had lost one-third of its radical trapping capacity as compared to that in plasma. The facts that AA is the highest contributor to CSF TRAP and its effect on TRAP is concentration dependent could indicate that the peroxyl radical-trapping capacity of CSF is buffered by AA

108. Neurol Neurochir Pol 1996 Jan-Feb;30(1):49-56[The effect of intravenous Ascorbic acid on urinary 17-hydroxysteroid excretion at an early stage of cerebral stroke].Nadgrodkiewicz K Oddzialu Neurologii Wojewodzkiego Szpitala Zespolonego w Radomiu.

The main symptoms of stroke such as a displacement of intracranial structures, changes in spatial relations, secondary hemorrhagic and ischemic foci, oedema and metabolic disturbances are the cause of the disorders of hypothalamus-hypophysis system leading to increased secretion of corticosteroids including 17-hydroxyketosteroids (17-OHKS). Steroidogenesis in inhibited by high concentrations of Ascorbic acid. Intravenous injections of Ascorbic acid 0.5 g were given to the patients with stroke and their urine was analysed daily to examine the secretion of 17-OHKS. A slight increase in 17-OHKS secretion was found on 1 and 2 days of the disease in patients suffering from TIA and a significant increase in 17-OHKS secretion was detected in patients with cerebral ischaemia (ischemic stroke) and cerebral hemorrhage and persisted for 3-4 days of the illness. One can presume that the disorders of hypothalamus-hypophysis-adrenal system contributes much more to the decrease in 17 OHKS secretion on successive days of stroke than the administration of Ascorbic acid. PMID: 8657350, UI: 96249747

109. Diabetes Res Clin Pract 1995 Apr;28(1):1-8Experimental and clinical studies on the reduction of erythrocyte sorbitol-glucose ratios by Ascorbic acid in diabetes mellitus.Wang H, Zhang ZB, Wen RR, Chen JW Department of Endocrinology, First Affiliated Hospital, Nanjing Medical University, Jiangsu, People's Republic of China.

In order to confirm the effect of Ascorbic acid (AA) on human erythrocyte sorbitol accumulation and explore its mechanism of action, the effects of Ascorbic acid in vitro on the sorbitol (S) and glucose (EG) content of human erythrocytes and in particular on the S/EG ratio as a marker of aldose reductase (AR) activity were carefully observed. The results showed that both the accumulation of erythrocyte sorbitol and the S/EG ratio were strongly reduced by the addition of AA. The sorbitol content in the erythrocyte and the S/EG ratio were reduced by a maximum of 87.3% and 83.4% and 93.8% and 63.9% when the medium's AA concentration was at its peak with 5.6 mmol/l and 28 mmol/l glucose in the medium, respectively. The contents of erythrocyte glucose measured coincidentally revealed a positive correlation with the Ascorbic acid concentration in the medium during incubation in 5.6 mmol/l glucose while at a higher glucose level (28 mmol/l) in the medium the correlation became negative. These results suggested that the polyol pathway could be inhibited effectively by AA through its direct action on AR. The results of a double-blind cross-over trial using AA tablets or inositol tablets in eight diabetic patients showed that the supplementation of 1000 mg AA/day for 2 weeks resulted in reductions of 12.2% and 21.8% in erythrocyte sorbitol and red cell sorbitol/plasma glucose (S/PG) ratio, respectively (P < 0.05), whereas the fasting plasma glucose levels measured coincidentally revealed no changes (P > 0.05).

110. Indian J Physiol Pharmacol 1995 Oct;39(4):403-6Correction of anemia and iron deficiency in vegetarians by administration of Ascorbic acid.Sharma DC, Mathur R Department of Biochemistry, S M S Medical College, Jaipur.

Twenty-eight strict vegetarians were given 500 mg Ascorbic acid twice daily after lunch and dinner for two months. Hemoglobin and certain iron status parameters were measured before and after the treatment. Ascorbate treatment increased mean hemoglobin by 8%, serum iron by 17% and transferrin saturation by 23% and decreased total iron binding capacity by 7%. All these changes were statistically significant. The rise in serum ferritin was 12%. The serum protein or copper level did not indicate their dietary deficiency, while initial serum ascorbate level were low which rose by 60% on therapy. It is concluded that ascorbate supplementation is a better method of improving hematologic and iron status than iron salt administration.