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131. Experimental and clinical studies on the reduction of erythrocyte sorbitol-glucose ratios by Ascorbic acid in diabetes mellitus.

Diabetes Res Clin Pract 1995 Apr;28(1):1-8
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). Publication Types: Clinical trial PMID: 7587907, UI: 96037098

132. Correction of anemia and iron deficiency in vegetarians by administration of Ascorbic acid.

Indian J Physiol Pharmacol 1995 Oct;39(4):403-6
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. Publication Types: Clinical trial PMID: 8582755, UI: 96157602

133. Metabolic benefits deriving from chronic VITAMIN C supplementation in aged non-insulin dependent diabetics.

J Am Coll Nutr 1995 Aug;14(4):387-92
Paolisso G, Balbi V, Volpe C, Varricchio G, Gambardella A, Saccomanno F, Ammendola S, Varricchio M, D'Onofrio F Department of Geriatric Medicine and Metabolic Diseases, II University of Naples, Italy.

OBJECTIVE: Our study investigated the metabolic benefits deriving from chronic pharmacological VITAMIN C administration in aged non-insulin dependent (Type II) diabetic patients. METHODS: Forty type II diabetic patients (age: 72 +/- 0.5 years) underwent placebo and VITAMIN C (0.5 g twice daily) administration in double-blind, randomized, cross-over fashion. All patients were treated by oral hypoglycaemic agents which continued throughout the study. After baseline observations, treatment periods lasted 4 months and were separated by a 30-day wash-out period. RESULTS: Patients' antropometric data were unchanged throughout the study. Chronic VITAMIN C administration vs placebo was associated with a significant decline in fasting plasma free radicals (0.26 +/- 0.06 vs 0.49 +/- 0.07 p < 0.03) and insulin (90 +/- 4 vs 73 +/- 6 pmol/L p < 0.04), total- (7.3 +/- 0.5 vs 5.8 +/- 0.4 mmol/L p < 0.03), LDL-cholesterol (5.6 +/- 0.6 vs 4.1 +/- 0.3 mmol/L p < 0.05) and triglycerides (2.58 +/- 0.07 vs 2.08 +/- 0.04 mmol/L p < 0.04) levels. In 20 patients, chronic VITAMIN C administration improved whole body glucose disposal and nonoxidative glucose metabolism. Percent increase in plasma VITAMIN C levels correlated with the percent decline in plasma LDL-cholesterol (r = 0.44; p < 0.007) and insulin levels (r = 0.42; p < 0.006). Finally percent increase in plasma VITAMIN C levels was correlated with the percent decline in plasma free radicals and increase in GSH levels. CONCLUSIONS: Chronic VITAMIN C administration has beneficial effects upon glucose and lipid metabolism in aged non-insulin dependent (type II) diabetic patients. Publication Types: Clinical trial Randomized controlled trial PMID: 8568117, UI: 96025408

134. Resistance to erythropoietin in iron-overloaded haemodialysis patients can be overcome by Ascorbic acid administration.

Nephrol Dial Transplant 1995;10 Suppl 6:44-7
Gastaldello K, Vereerstraeten A, Nzame-Nze T, Vanherweghem JL, Tielemans C Department of Nephrology, Dialysis, and Transplantation, Cliniques Universitaires de Bruxelles, Hopital Erasme, Universite Libre de Bruxelles, Belgium.

Haemodialysis patients with iron overload sometimes develop resistance to erythropoietin therapy due to 'functional iron deficiency'. It is known that this resistance may be overcome by iron supplementation; however, the latter could worsen haemosiderosis. Therefore, we treated four iron-overloaded haemodialysis patients who had developed relative resistance to erythropoietin (among whom three had features of 'functional iron deficiency') with Ascorbic acid (500 mg intravenously after haemodialysis, 1-3 times a week). The erythropoietin doses were voluntarily kept unchanged during the study. After a latency of 2-4 weeks, haematocrit and haemoglobin had increased respectively from 26.5 +/- 0.7 to 32.7 +/- 0.4 vol% and from 8.8 +/- 0.3 to 10.8 +/- 0.2 g/dl (means +/- SEM, P < 0.001). While serum ferritin remained unchanged, transferrin saturation increased from 27 +/- 7 to 54 +/- 12% (P < 0.05), suggesting that Ascorbic acid supplementation had allowed mobilization of iron from tissue burdens. In one patient, haematocrit declined after withdrawal of VITAMIN C and increased again after rechallenge. Also, ascorbate supplementation was continued after the study in two patients and allowed the erythropoietin doses to be decreased, 8 and 11 weeks, respectively, after the start of the trial. When a control group of seven patients with normal iron status and without resistance to erythropoietin were challenged in the same manner with ascorbate, no elevation of haematocrit or transferrin saturation was noted. We conclude that ascorbate supplementation may circumvent resistance to erythropoietin that sometimes occurs in iron-overloaded patients, in particular, in the setting of 'functional iron deficiency'. Publication Types: Clinical trial Controlled clinical trial PMID: 8524494, UI: 96052981

135. Effect of pantothenic acid and Ascorbic acid supplementation on human skin wound healing process. A double-blind, prospective and randomized trial.

Eur Surg Res 1995;27(3):158-66
Vaxman F, Olender S, Lambert A, Nisand G, Aprahamian M, Bruch JF, Didier E, Volkmar P, Grenier JF INSERM U 61, Hospices Civils, Strasbourg, France.

This study aimed at testing human skin wound healing improvement by a 21-day supplementation of 1.0 g Ascorbic acid (AA) and 0.2 g pantothenic acid (PA). 49 patients undergoing surgery for tattoos, by the successive resections procedure, entered a double-blind, prospective and randomized study. Tests performed on both skin and scars determined: hydroxyproline concentrations, number of fibroblasts, trace element contents and mechanical properties. In the 18 supplemented patients, it was shown that in skin (day 8) Fe increased (p < 0.05) and Mn decreased (p < 0.05); in scars (day 21), Cu (p = 0.07) and Mn (p < 0.01) decreased, and Mg (p < 0.05) increased; the mechanical properties of scars in group A were significantly correlated to their contents in Fe, Cu and Zn, whereas no correlation was shown in group B. In blood, AA increased after surgery with supplementation, whereas it decreased in controls. Although no major improvement of the would healing process could be documented in this study, our results suggest that the benefit of AA and PA supplementation could be due to the variations of the trace elements, as they are correlated to mechanical properties of the scars. Publication Types: Clinical trial Randomized controlled trial PMID: 7781653, UI: 95300835

136. [Reduction of erythrocyte sorbitol by Ascorbic acid in patients with diabetes mellitus].

Chung Hua I Hsueh Tsa Chih 1994 Sep;74(9):548-51, 583
Wang H, Zhang ZB, Wen RR Department of Endocrinology, First Affiliated Hospital, Nanjing Medical University.

The content of erythrocyte sorbitol could be reduced by Ascorbic acid (AA). To confirm the effect of AA on human erythrocyte sorbitol accumulation and explore its mechanism of the action, we studied in vitro the effects of Ascorbic acid on the contents of both sorbitol and glucose in human erythrocytes. The effect of AA on the ratio of sorbitol to glucose in erythrocyte (S/EG) which was referred to as a marker of aldose reductase (AR) activity was observed. Both the accumulation of erythrocyte sorbitol and S/EG were reduced by the addition of Ascorbic acid (AA) during in vitro incubations. The sorbitol content in the erythrocyte and S/EG were reduced by a maximum of 87.3%, 83.4% and 93.8%, 63.9% when the medium's AA concentration was at its peak in the 5.6 mmol/L and 28 mmol/L glucose concentration of medium respectively. These suggested that the activity of polyol pathway could be inhibited effectively by AA which might directly act on the activity of AR. The results of a double-blind cross-over trial using AA tablets or inert inositol tablets in 8 diabetic patients showed that the supplementation of 1,000 mg AA/day continued for 2 weeks resulted in reductions of 12.2% and 21.8% in both erythrocyte sorbitol and red cell sorbitol: plasma glucose (S/PG) ratio, respectively (P < 0.05). The fasting plasma glucose levels measured coincidently revealed no changes (P > 0.05). This suggests that the supplementation of moderate AA (1,000 mg/day) might provide a simple, safe and effective means of preventing and ameliorating chronic complications of diabetes.

137. Inhibitory effect of vitamins C and E on the oxygen free radical production in human polymorphonuclear leucocytes.

Eur J Clin Invest 1994 May;24(5):316-9
Herbaczynska-Cedro K, Wartanowicz M, Panczenko-Kresowska B, Cedro K, Klosiewicz-Wasek B, Wasek W Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland.

Beneficial effects of dietary supplementation with antioxidant vitamins are attributed mainly to the influence upon lipid metabolism, endothelial and vascular functions. Their effect upon leucocyte oxygen free radical producing capacity has not been investigated. In 13 healthy volunteers we examined the influence of oral supplementation with vitamins C and E (AA 600 mg per day for 14 days) upon leucocyte oxygen free radical production estimated by lucigenin-amplified chemiluminescence in isolated leucocytes stimulated with arachidonic acid. After supplementation with vitamins, significant increase in serum content of Ascorbic acid and tocopherol was concomitant with significant (P < 0.001) decrease of leucocyte chemiluminescent response (mean 63.2 + 23.0 SD, % of initial values) and lowering of serum lipid peroxides (P < 0.05). These findings suggest that suppression of leucocyte capacity to produce oxygen free radicals as shown in this study, may contribute to vasoprotective action of vitamins C and E. PMID: 8088307, UI: 94374385

138. Megadose vitamins in bladder cancer: a double-blind clinical trial.

J Urol 1994 Jan;151(1):21-6
Lamm DL, Riggs DR, Shriver JS, vanGilder PF, Rach JF, DeHaven JI Department of Urology, West Virginia University School of Medicine, Morgantown.

Epidemiological and laboratory studies suggest that vitamin supplements may be helpful in the prevention of some cancers but clinical trials to date have failed to demonstrate protection with naturally occurring vitamins. Without substantiation of the highly touted benefits of vitamins, few physicians who care for cancer patients have recommended their use. A total of 65 patients with biopsy confirmed transitional cell carcinoma of the bladder enrolled in a randomized comparison of intravesical bacillus Calmette-Guerin (BCG) with or without percutaneous administration was also randomized by closed envelope to therapy with multiple vitamins in the recommended daily allowance (RDA) versus RDA multivitamins plus 40,000 units vitamin A, 100 mg. vitamin B6, 2,000 mg. VITAMIN C, 400 units vitamin E and 90 mg. zinc. The addition of percutaneous BCG did not significantly lessen tumor recurrence but recurrence after 10 months was markedly reduced in patients receiving megadose vitamins. The 5-year estimates of tumor recurrence are 91% in the RDA arm and 41% in the megadose arm (p = 0.0014, Mantel-Cox). Overall recurrence was 24 of 30 patients (80%) in the RDA arm and 14 of 35 (40%) in the high dose arm (p = 0.0011, 2-tailed Fisher's exact test). Megadose vitamins A, B6, C and E plus zinc decrease bladder tumor recurrence in patients receiving BCG immunotherapy. Further research will be required to identify which ingredient(s) provide this protection. Publication Types: Clinical trial Randomized controlled trial

139. Apparent partial remission of breast cancer in 'high risk' patients supplemented with nutritional antioxidants, essential fatty acids and coenzyme Q10.

Mol Aspects Med 1994;15 Suppl:s231-40
Lockwood K, MoesgAArd S, Hanioka T, Folkers K Private Outpatient Clinic, Copenhagen, Denmark.

Thirty-two typical patients with breast cancer, aged 32-81 years and classified 'high risk' because of tumor spread to the lymph nodes in the axilla, were studied for 18 months following an Adjuvant Nutritional Intervention in Cancer protocol (ANICA protocol). The nutritional protocol was added to the surgical and therapeutic treatment of breast cancer, as required by regulations in Denmark. The added treatment was a combination of nutritional antioxidants (VITAMIN C: 2850 mg, Vitamin E: 2500 iu, beta-carotene 32.5 iu, selenium 387 micrograms plus secondary vitamins and minerals), essential fatty acids (1.2 g gamma linolenic acid and 3.5 g n-3 fatty acids) and Coenzyme Q10 (90 mg per day). The ANICA protocol is based on the concept of testing the synergistic effect of those categories of nutritional supplements, including vitamin Q10, previously having shown deficiency and/or therapeutic value as single elements in diverse forms of cancer, as cancer may be synergistically related to diverse biochemical dysfunctions and vitamin deficiencies. Biochemical markers, clinical condition, tumor spread, quality of life parameters and survival were followed during the trial. Compliance was excellent. The main observations were: (1) none of the patients died during the study period. (the expected number was four.) (2) none of the patients showed signs of further distant metastases. (3) quality of life was improved (no weight loss, reduced use of pain killers). (4) six patients showed apparent partial remission. Publication Types: Clinical trial PMID: 7752835, UI: 95272328

140. VITAMIN C: an aldose reductase inhibitor that normalizes erythrocyte sorbitol in insulin-dependent diabetes mellitus.

J Am Coll Nutr 1994 Aug;13(4):344-50
Cunningham JJ, Mearkle PL, Brown RG Department of Nutrition, University of Massachusetts, Amherst 01003-1420.

OBJECTIVE: Diabetic hyperglycemia promotes sorbitol production from glucose via aldose reductase. Since the intracellular accumulation of sorbitol, or its sequelae, are postulated to contribute to the progression of chronic diabetic complications, aldose reductase inhibitors (ARI) offer therapeutic promise. Others have shown that VITAMIN C at pharmacologic doses decreases erythrocyte (RBC) sorbitol. We examined whether smaller, physiologic doses of VITAMIN C were also effective in individuals with insulin-dependent diabetes mellitus (IDDM) and whether VITAMIN C was an ARI in vitro. METHODS: VITAMIN C supplements (100 or 600 mg) were taken daily for 58 days by young adults with IDDM and nondiabetic adults in an otherwise free-living design. Diabetic control was monitored by fasting plasma glucose, glycosylated hemoglobin, and glycosuria and was moderate to poor throughout the study. RBC sorbitol was measured at baseline and again at 30 and 58 days. Three-day dietary records and 24-hour urine collections were performed for each sampling day. RESULTS: RBC sorbitol levels were significantly elevated in IDDMs, on average doubled, despite their more than adequate dietary intakes of VITAMIN C and normal plasma concentrations. VITAMIN C supplementation at either dose normalized the RBC sorbitol in IDDMs within 30 days. This correction of sorbitol accumulation was independent of changes in diabetic control. Furthermore, our in vitro studies show that Ascorbic acid inhibited aldose reductase activity. CONCLUSIONS: VITAMIN C supplementation is effective in reducing sorbitol accumulation in the erythrocytes of diabetics. Given its tissue distribution and low toxicity, we suggest a superiority for VITAMIN C over pharmaceutic ARIs. Publication Types: Clinical trial Controlled clinical trial PMID: 7963139, UI: 95052182.