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May 9, 2000

National Academy of Sciences References

91. Lancet 1999 Dec 11;354(9195):2025-8Effect of vitamin C on frequency of reflex sympathetic dystrophy in wrist fractures: a randomised trial.

Zollinger PE, Tuinebreijer WE, Kreis RW, Breederveld RSDepartment of Orthopaedics, Leyenburg Hospital, The Hague, The Netherlands.

BACKGROUND: The pathogenesis of reflex sympathetic dystrophy (RSD) is not clear, nor is there a definitive treatment for this syndrome. The morbidity, costs in health care, and loss of work time justify the search for a means to prevent post-traumatic dystrophy. Although the role of toxic oxygen radicals has not yet been clarified, we investigated vitamin C (ascorbic acid) as a prophylactic antioxidant drug. METHODS: 123 adults with 127 conservatively treated wrist fractures were randomly allocated in a double-blind trial to take a capsule of 500 mg vitamin C or placebo daily for 50 days. Each participant's sex, age, side of fracture, dominance, fracture type, dislocation, reduction, and complaints with the plaster cast were recorded, and they were clinically scored for RSD. The follow-up lasted 1 year. FINDINGS: Eight patients were withdrawn after randomisation. 52 patients with 54 fractures (male 22%, female 78%; mean age 57 years) received vitamin C and 63 patients with 65 fractures (male 20%, female 80%; mean age 60 years) received placebo. RSD occurred in four (7%) wrists in the vitamin C group and 14 (22%) in the placebo group 15% (95% CI for differences 2-26). Other significant prognostic variables for the occurrence of RSD were complaints while wearing the cast (relative risk 0.17 [0.07-0.41]) and fracture type (0.37 [0.16-0.89]). INTERPRETATION: This prospective, double-blind study shows that vitamin C was associated with a lower risk of RSD after wrist fractures. Our hypothesis is that this beneficial effect of prophylaxis would be useful in other forms of trauma.

92. J Manipulative Physiol Ther 1999 Oct;22(8):530-3The effectiveness of vitamin C in preventing and relieving the symptoms of virus-induced respiratory infections.Gorton HC, Jarvis K

BACKGROUND: An ever increasing demand to evaluate the effect of dietary supplements on specific health conditions by use of a "significant scientific" standard has prompted the publication of this study. OBJECTIVE: To study the effect of megadose Vitamin C in preventing and relieving cold and flu symptoms in a test group compared with a control group. DESIGN: Prospective, controlled study of students in a technical training facility. SUBJECTS: A total of 463 students ranging in age from 18 to 32 years made up the control group. A total of 252 students ranging in age from 18 to 30 years made up the experimental or test group. METHOD: Investigators tracked the number of reports of cold and flu symptoms among the 1991 test population of the facility compared with the reports of like symptoms among the 1990 control population. Those in the control population reporting symptoms were treated with pain relievers and decongestants, whereas those in the test population reporting symptoms were treated with hourly doses of 1000 mg of Vitamin C for the first 6 hours and then 3 times daily thereafter. Those not reporting symptoms in the test group were also administered 1000-mg doses 3 times daily. RESULTS: Overall, reported flu and cold symptoms in the test group decreased 85% compared with the control group after the administration of megadose Vitamin C. CONCLUSION: Vitamin C in megadoses administered before or after the appearance of cold and flu symptoms relieved and prevented the symptoms in the test population compared with the control group.

93. Mutat Res 1999 Jul 16;428(1-2):353-61Effect of ascorbic acid and green tea on endogenous formation of N-nitrosodimethylamine and N-nitrosopiperidine in humans.Vermeer IT, Moonen EJ, Dallinga JW, Kleinjans JC, van Maanen JMDepartment of Health Risk Analysis and Toxicology, Maastricht University, P.O. Box 616, 6200 MD, Maastricht, Netherlands.

Many constituents present in the human diet may inhibit endogenous formation of N-nitroso compounds (NOC). Studies with human volunteers showed inhibiting effects of intake of ascorbic acid and green tea consumption on nitrosation using the N-nitrosoproline test. The aim of the present study was to evaluate the effects of ascorbic acid and green tea on urinary excretion of carcinogenic N-nitrosodimethylamine (NDMA) and N-nitrosopiperidine (NPIP) in humans. Twenty-five healthy female volunteers consumed a fish meal rich in amines as nitrosatable precursors in combination with intake of nitrate-containing drinking water at the Acceptable Daily Intake level during 7 consecutive days. During 1 week before and after nitrate intake a diet low in nitrate was consumed. Using the same protocol, the effect of two different doses of ascorbic acid (250 mg and 1 g/day) and two different doses of green tea (2 g and 4 g/day) on formation of NDMA and NPIP was studied. Mean nitrate excretion in urine significantly increased from control (76+/-24) to 167+/-25 mg/24 h. Intake of nitrate and fish resulted in a significant increase in mean urinary excretion of NDMA compared with the control weeks: 871+/-430 and 640+/-277 ng/24 h during days 1-3 and 4-7, respectively, compared with 385+/-196 ng/24 h (p<0.0002). Excretion of NPIP in urine was not related to nitrate intake and composition of the diet. Intake of 250 mg and 1 g of ascorbic acid per day resulted in a significant decrease in urinary NDMA excretion during days 4-7 (p=0.0001), but not during days 1-3. Also, consumption of four cups of green tea per day (2 g) significantly decreased excretion of NDMA during days 4-7 (p=0.0035), but not during days 1-3. Surprisingly, consumption of eight cups of green tea per day (4 g) significantly increased NDMA excretion during days 4-7 (p=0.0001), again not during days 1-3. This increase is probably a result of catalytic effects of tea polyphenols on nitrosation, or of another, yet unknown, mechanism. These results suggest that intake of ascorbic acid and moderate consumption of green tea can reduce endogenous NDMA formation.

94. J Am Acad Dermatol 1999 Aug;41(2 Pt 1):207-8Treatment of progressive pigmented purpura with oral bioflavonoids and ascorbic acid: an open pilot study in 3 patients.Reinhold U, Seiter S, Ugurel S, Tilgen WDepartment of Dermatology, The Saarland University Hospital, Homburg/Saar, Germany.

BACKGROUND: Bioflavonoids and ascorbic acid have been shown to increase capillary resistance and to mediate potent antioxidative radical scavenging activities. OBJECTIVE: We evaluated the clinical effect of oral bioflavonoids and ascorbic acid in patients with chronic progressive pigmented purpura (PPP). METHODS: In an open pilot study, oral rutoside (50 mg twice a day) and ascorbic acid (500 mg twice a day) were administered to 3 patients with chronic PPP. RESULTS: At the end of the 4-week treatment period, complete clearance of the skin lesions was achieved in all 3 patients. No adverse reactions were noted. All patients remained free of lesions at the end of 3 months after treatment. CONCLUSION: Our results suggest a beneficial effect of bioflavonoids in combination with ascorbic acid on PPP. Because the disease is mostly resistant to other treatment modalities, placebo-controlled studies are necessary to determine the usefulness of this therapy in PPP.

95. Med Hypotheses 1999 Feb;52(2):171-8Vitamin C supplementation and common cold symptoms: factors affecting the magnitude of the benefit.Hemila HDepartment of Public Health, University of Helsinki, Finland.

Placebo-controlled trials have shown that vitamin C supplementation decreases the duration and severity of common cold infections. However, the magnitude of the benefit has substantially varied, hampering conclusions about the clinical significance of the vitamin. In this paper, 23 studies with regular vitamin C supplementation (> or = 1 g/day) were analyzed to find out factors that may explain some part of the variation in the results. It was found that on average, vitamin C produces greater benefit for children than for adults. The dose may also affect the magnitude of the benefit, there being on average greater benefit from > or = 2 g/day compared to 1 g/day of the vitamin. In five studies with adults administered 1 g/day of vitamin C, the median decrease in cold duration was only 6%, whereas in two studies with children administered 2 g/day the median decrease was four times higher, 26%. The trials analyzed in this work used regular vitamin C supplementation, but it is conceivable that therapeutic supplementation starting early at the onset of the cold episode could produce comparable benefits. Since few trials have examined the effects of therapeutic supplementation and their results have been variable, further therapeutic trials are required to examine the role of vitamin C in the treatment of colds.

96. Nephron 1998 Nov;80(3):277-84

Administration of ascorbic acid and an aldose reductase inhibitor (tolrestat) in diabetes: effect on urinary albumin excretion.

McAuliffe AV, Brooks BA, Fisher EJ, Molyneaux LM, Yue DK

Department of Life Sciences in Nursing, University of Sydney, Sydney, Australia.

The important role of ascorbic acid (AA) as an anti-oxidant is particularly relevant in diabetes mellitus where plasma concentrations of AA are reduced. This study was conducted to evaluate the effects of treatment with AA or an aldose reductase inhibitor, tolrestat, on AA metabolism and urinary albumin excretion in diabetes. Blood and urine samples were collected at 0, 3, 6, 9, and 12 months from 20 diabetic subjects who were randomized into two groups to receive either oral AA 500 mg twice daily or placebo. Systolic and diastolic blood pressures, HbA1c, plasma lipids, urinary albumin, and total glycosaminoglycan excretion were measured at all time points, and heparan sulphate (glycosaminoglycan) was measured at 0 and 12 months. The same parameters, as well as urinary AA excretion, were determined at 0 and 3 months for 16 diabetes subjects receiving 200 mg tolrestat/day. AA treatment increased plasma AA (ANOVA, F ratio = 12.1, p = 0.004) and reduced albumin excretion rate (AER) after 9 months (ANOVA, F ratio = 3.2, p = 0.03), but did not change the other parameters measured. Tolrestat lowered plasma AA (Wilcoxon's signed-rank test, p < 0.05), but did not change AER or the other parameters measured. The ability of AA treatment to decrease AER may be related to changes in extracellular matrix or improvement in oxidative defence mechanism. Unlike the rat model of diabetes, inhibition of aldose reductase did not normalize plasma AA or AER in humans. In fact, tolrestat reduced the plasma AA concentration, a phenomenon which may be due to increased utilization of AA. Dietary supplementation of AA in diabetic subjects may have long-term benefits in attenuating the progression of diabetic complications.

97. Can J Physiol Pharmacol 1998 Apr;76(4):373-80Immune function in aged women is improved by ingestion of vitamins C and la Fuente M, Ferrandez MD, Burgos MS, Soler A, Prieto A, Miquel JDepartamento de Biologia Animal II (Fisiologia Animal), Facultad de Ciencias Biologicas, Universidad Complutense, Madrid, Spain.

We have investigated the effects of supplementation of the diet with the antioxidant vitamins C and E on several functions of the immune response of aged women. Ten healthy women and 20 women (72 +/- 6 years old) suffering two diseases often associated with age (10 with major depression disorders, MDD, and 10 with coronary heart disease, CHD) were administered 1 g of vitamin C and 200 mg of vitamin E daily for 16 weeks. Blood samples were collected before and after treatment for measurement of several immunological functions, namely proliferative response of lymphocytes to the mitogen phytohemagglutinin (20 mg/L) and phagocytic functions of polymorphonuclear (PMN) neutrophils, i.e., adherence to vascular endothelium, chemotaxis, phagocytosis of latex beads, and superoxide anion production. In addition, we also determined the levels of serum cortisol and lipid peroxides. Intake of vitamins resulted in a significant increase in the lymphoproliferative capacity and in the phagocytic functions of PMN neutrophils as well as in a significant decrease of serum levels of lipid peroxides and cortisol, both in the healthy aged women and in the aged women with MDD or CHD. These findings suggest an important role of antioxidant supplementation in the improvement of immune function in aged females as well as in the prevention and treatment of specific diseases associated with age that are quite prevalent in the developed countries.

98. AIDS 1998 Sep 10;12(13):1653-9Effects of vitamin E and C supplementation on oxidative stress and viral load in HIV-infected subjects.Allard JP, Aghdassi E, Chau J, Tam C, Kovacs CM, Salit IE, Walmsley SLDepartment of Medicine, University of Toronto, Ontario, Canada.

OBJECTIVES: The HIV-infected population is known to be oxidatively stressed and deficient in antioxidant micronutrients. Since in vitro replication of HIV is increased with oxidative stress, this study assessed the effect of antioxidant vitamin supplementation on lipid peroxidation, a measure of oxidative stress, and viral load in humans. DESIGN: A randomized placebo-controlled, double-blind study. METHODS: Forty-nine HIV-positive patients were randomized to receive supplements of both DL-alpha-tocopherol acetate (800 IU daily) and vitamin C (1000 mg daily), or matched placebo, for 3 months. Plasma antioxidant micronutrient status, breath pentane output, plasma lipid peroxides, malondialdehyde and viral load were measured at baseline and at 3 months. New or recurrent infections for the 6-month period after study entry were also recorded. RESULTS: The vitamin group (n = 26) had an increase in plasma concentrations of alpha-tocopherol (P < 0.0005) and vitamin C (P < 0.005) and a reduction in lipid peroxidation measured by breath pentane (P < 0.025), plasma lipid peroxides (P < 0.01) and malondialdehyde (P < 0.0005) when compared with controls (n = 23). There was also a trend towards a reduction in viral load (mean +/- SD changes over 3 months, -0.45 +/- 0.39 versus +0.50 +/- 0.40 log10 copies/ml; P = 0.1; 95% confidence interval, -0.21 to -2.14). The number of infections reported was nine in the vitamin group and seven in the placebo group. CONCLUSION: Supplements of vitamin E and C reduce oxidative stress in HIV and produce a trend towards a reduction in viral load. This is worthy of larger clinical trials, especially in HIV-infected persons who cannot afford new combination therapies.

99. Photodermatol Photoimmunol Photomed 1997 Oct-Dec;13(5-6):173-7Phototoxic lysis of erythrocytes from humans is reduced after oral intake of Ascorbic acid and d-alpha-tocopherol.Eberlein-Konig B, Placzek M, Przybilla BDermatologische Klinik und Poliklinik, Ludwig-Maximilians-Universitat Munchen,Germany.

Ultraviolet (UV) radiation causes hemolysis of human erythrocytes in the presence of photosensitizers. This can be used as an in vitro model for evaluating photosensitizing properties of substances. Antioxidants such as Ascorbic acid (VITAMIN C) and d-alpha-tocopherol (vitamin E) have been found to be photoprotective in such test systems. We assessed the effect of combined systemic intake of both Ascorbic acid and d-alpha-tocopherol by human volunteers on phototoxic in vitro lysis of their erythrocytes. In a double-blind placebo-controlled study, 10 subjects took daily 2 g Ascorbic acid combined with 1000 IU d-alpha-tocopherol, and 10 took a placebo. Blood was taken before and after 7 days of treatment, erythrocytes were prepared and then incubated with10(-3) mol/l fenofibrate, a photosensitizer acting in the UVA and UVB region. The suspensions were exposed to radiation rich in UVA (up to 40 J/cm2 UVA) or to radiation rich in UVB (up to 1.6 J/cm2). Photohemolysis of the samples was calculated as a percentage of complete hemolysis. At the end of the treatment phase, in the placebo group photohemolysis was not significantly reduced compared with the initial values at all irradiation doses except for 1.6 J/cm2 UVB (96% vs 79%; P < 0.01). In the group taking vitamins, photohemolysis was significantly reduced at nearly all UV doses, most impressively after moderate UVA irradiation (20 J/cm2 UVA: 86.5% vs 14.5%; P < 0.01). It is concluded that the results of the photohemolysis test are influenced by the antioxidative status of the cell donor and that Ascorbic acid and d-alpha-tocopherol also may protect against phototoxic damage in vivo.

100. Int J Sport Nutr 1997 Mar;7(1):1-9Exercise-induced oxidative stress before and after VITAMIN C supplementation.Alessio HM, Goldfarb AH, Cao G PHS Department, Miami University, Oxford, OH 45056, USA.

VITAMIN C (Ascorbic acid) was supplemented (1 g/day) for 1 day and 2 weeks in the same subjects. Plasma thiobarbituric acid reacting substances (TBARS) and oxygen radical absorbance capacity (ORAC) before and after 30 min submaximal exercise were measured. Different VITAMIN C supplementations did not affect resting TBARS or ORAC. Following 30 min exercise, values for TBARS were 12.6 and 33% above rest with 1 day and 2 weeks of VITAMIN C supplementation, respectively, compared to 46% higher with placebo. ORAC did not significantly change (11%) after exercise with a placebo, nor when subjects were given VITAMIN C supplements for 1 day or 2 days (4.9% and 5.73%, respectively). TBARS:ORAC, a ratio representing oxidative stress, increased 32% (p < .05) with placebo compared to 5.8 and 25.8% with VITAMIN C supplements for 1 day and 2 weeks, respectively. It was concluded that exercise-induced oxidative stress was highest when subjects did not supplement with VITAMIN C compared to either 1 day or 2 weeks of VITAMIN C supplementation.