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May 9, 2000

National Academy of Sciences References

81. Cor Vasa 1992;34(3):246-54Plasma lipids, lipoproteins and atherogenic index in men and women administered vitamin c.Cerna O, Ramacsay L, Ginter EResearch Institute of Human Nutrition, Comenius University College of Physical Education, Bratislava, Czechoslovakia.

The aim of the study was to establish whether it is possible, in a group of deliberately selected subjects with hyperlipidaemia, to modulate cholesterol levels by ascorbic acid administered at a dose of 500 mg/day. The authors assessed the levels of vitamin c, total and HDL cholesterol, triacylglycerols in the blood serum of 140 probands assigned to an 83-member experimental group, and to a 57-member control group. The experimental group was provided Celaskon effervescens Spofa at a dose of 500 mg/day/person. The experiment lasted for 18 months. Blood collections were made in the whole cohort at six-month intervals.Administration of L-ascorbic acid led to a highly significant decrease in the levels of total and LDL cholesterol. After 12 months of study, a highly significant decrease in atherogenic index and an increase in HDL cholesterol levels were found persisting until the end of the experiment.

82. Bratisl Lek Listy 1991 Mar-Apr;92(3-4):174-83Protective effect of alpha-tocopherol and L-ascorbic acid against theischemic-reperfusion injury in patients during open-heart surgery.Barta E, Pechan I, Cornak V, Luknarova O, Rendekova V, Verchovodko PInstitute for Cardiovascular Diseases, Medical Faculty, Comenius University, Bratislava, CSFR.

The purpose of the investigation was: 1. to examine the effect ofcardiopulmonary bypass (CPB) on the generation of cytotoxic oxygen-derived radicals and 2. to determine if the pretreatment of patients with vitamins E and C will combat generation of such radicals. Twenty patients undergoing CPB for treatment of cardiac disease were entered into the study and randomized to one of two groups. Group 1 (n = 9) served as control. Group 2 (n = 11) consisted of patients pretreated with 2000 IU of vitamin E 12 h prior to surgical intervention and 2 g of vitamin c given in the morning on the day of operation. Blood samples from arterial and mixed venous blood for analysis were obtained at the following intervals: 1. before anesthesia, 2. before sternotomy, 3. at the start of CPB, 4. at the end of CPB, 5. at the time of skin closure, 6. in the morning of the following day. Blood specimens from the coronary sinus were withdrawn A--before aortic cross-clamping, B--immediately after aortic declamping, C--in the 5th min, and D--in the 15th min of reperfusion. The concentration of inorganic phosphate as well as of uric acid was significantly higher in the control group what might indicate that vitamins E and C attenuate the degradation of adenine nucleotides. The most important difference between treated and control groups was observed in plasma concentration of malondialdehyde--a marker of lipid peroxidation--which was significantly lower in pretreated patients. A similar pattern of changes was found in the level of the lysosomal enzyme N-acetyl-glucosaminidase. Finally, pretreatment with vitamins E and C inhibited the decrease of catalase, observed in controls.

83. Am J Clin Nutr 1991 May;53(5):1222-9Effects of antioxidant supplementation on platelet function: a randomized pair-matched, placebo-controlled, double-blind trial in men with low antioxidant status.Salonen JT, Salonen R, Seppanen K, Rinta-Kiikka S, Kuukka M, Korpela H, Alfthan G, Kantola M, Schalch W Department of Community Health and General Practice, University of Kuopio, Finland.

We investigated the effect on platelet function of supplementing men with low antioxidant status with 600 mg Ascorbic acid, 300 mg alpha-tocopherol, 27 mg beta-carotene, and 75 micrograms selenium in yeast daily. Eighty men were randomly assigned in pairs (matched for smoking, baseline antioxidant status, and time and day of entry) by use of a double-blind design to receive supplement or placebo for 5 mo. Compared with 39 control subjects, 39 antioxidant-supplemented men experienced the following net reductions during the double-blind period: 20% (P = 0.012) in serum lipid peroxides, 24% (P = 0.035) in ADP-induced platelet aggregation, 42% (P = 0.040) in the rate of ATP release during aggregation, 51% (P = 0.018) in serum (platelet-produced) thromboxane B2, and 29% (P = 0.024) in plasma beta-thromboglobulin concentration. The data support our hypothesis that antioxidant supplementation of men with low antioxidant status and high fat intake reduces lipid peroxidation, the capacity of platelets to aggregate and to produce thromboxane A2, and in vivo platelet activation.

84. Prev Med 1997 May-Jun;26(3):277-83Vitamin c intake and cardiovascular disease risk factors in persons with non-insulin-dependent diabetes mellitus. From the Insulin Resistanc Atherosclerosis Study and the San Luis Valley Diabetes Study.Mayer-Davis EJ, Monaco JH, Marshall JA, Rushing J, JuhaeriDepartment of Public Health Sciences, Bowman Gray School of Medicine, WakeForest University, Winston-Salem, North Carolina 27157-1063,

BACKGROUND: Persons with non-insulin-dependent diabetes mellitus (NIDDM) are at increased risk for cardiovascular disease, partly due to concomitant worsening of traditional risk factors including dyslipidemia and hypertension. Based on evidence from small, controlled clinical trials, we hypothesized that increased intake of vitamin c would be associated with improved cardiovascular disease (CVD) risk factor status among community-dwelling persons with NIDDM. METHODS:In separate but parallel statistical analyses, hypotheses were evaluated among persons with NIDDM confirmed by WHO criteria from the Insulin Resistance Atherosclerosis Study (IRAS, n = 520) and from the San Luis Valley Diabetes Study (SLVDS, n = 422). For IRAS, diet and vitamin supplement use was assessed by food frequency interview and for SLVDS, by 24-hr dietary recall interview. RESULTS: Mean vitamin c intake (mg/day) was 275 for IRAS and 133 for SLVDS, including supplements. In cross-sectional regression models from each data set, vitamin c intake was not associated with systolic or diastolic blood pressure nor with HDL-C, LDL-C, or triglycerides (P values > 0.10; adjusted for calories, demographic and lifestyle variables, obesity, diabetes duration, and medications). In prospective analyses including 285 SLVDS participants, baseline vitamin c intake was not related to any of these CVD risk factors measured an average of 4 years later nor to change in CVD risk factor status during the follow-up period. CONCLUSIONS: We conclude that, across a wide range of intake, vitamin c does not appear to be associated with improved CVD risk factor status among community-dwelling persons with diabetes.

85. Pharmacotherapy 1995 Jul-Aug;15(4):458-64The effect of high-dose ascorbate supplementation on plasma lipoprotein(a) levels in patients with premature coronary heart disease.Bostom AG, Hume AL, Eaton CB, Laurino JP, Yanek LR, Regan MS, McQuade WH, Craig WY, Perrone G, Jacques PFDepartment of General Internal Medicine, Rhode Island Hospital, Providence, USA.

STUDY OBJECTIVE. To determine the efficacy of high-dose ascorbatesupplementation in lowering lipoprotein(a) [Lp(a)] levels in patients with premature coronary heart disease (CHD). DESIGN. Randomized, double-blind, placebo-controlled trial. SETTING. Outpatient clinic. PATIENTS. Forty-four patients with documented premature CHD, defined as confirmed myocardial infarction and/or angiographically determined stenosis of 50% or greater in at least one major coronary artery before age 60 years. INTERVENTIONS. Patients were block randomized on the basis of age, gender, and screening Lp(a) concentrations to receive ascorbate 4.5 g/day or placebo for 12 weeks. MEASUREMENTS AND MAIN RESULTS. High-dose ascorbate was well tolerated and produced a marked elevation in mean plasma ascorbate levels (+1.2 mg/dl; p < 0.001). Multiple linear regression analysis revealed no significant effect ofsupplementation on postintervention Lp(a) levels (p = 0.39) in a model that included treatment group assignment, and baseline Lp(a) levels. CONCLUSIONS. Our findings do not support a clinically important lowering effect of high-dose ascorbate on plasma Lp(a) in patients with premature CHD.

86. J Thorac Cardiovasc Surg 1997 May;113(5):942-8Effect of preoperative supplementation with alpha-tocopherol and ascorbic acid on myocardial injury in patients undergoing cardiac operations.Westhuyzen J, Cochrane AD, Tesar PJ, Mau T, Cross DB, Frenneaux MP, Khafagi FA,Fleming SJDepartment of Cardiology, Royal Brisbane Hospital, Australia.

Augmentation of antioxidant defenses may help protect tissues againstischemia-reperfusion injury associated with operations involving cardiopulmonary bypass. In this study we examined the effect of pretreating patients with alpha-tocopherol (vitamin E) and ascorbic acid (vitamin c) or placebo on injury to the myocardium. Seventy-six subjects undergoing elective coronary artery bypass grafting participated in a prospective, double-blind, placebo-controlled randomized trial, receiving either placebo or both 750 IU dl-alpha-tocopherol per day for 7 to 10 days and 1 gm ascorbic acid 12 hours before the operation. Plasma alpha-tocopherol concentrations, raised fourfold by supplementation, fell by 70% after the operation in the supplemented group and to negligible levels in the placebo group. There were no significant differences between the groups with respect to release of creatine kinase MB isoenzyme over 72 hours, nor in the reduction of the myocardial perfusion defect determined by thallium 201 uptake. Electrocardiography provided no evidence of a benefit from antioxidant supplementation. Thus the supplementation regimen prevented the depletion of the primary lipid soluble antioxidant in plasma, but provided no measurable reduction in myocardial injury after the operation

87. Arch Surg 2000 Mar;135(3):326-31Reduction of resuscitation fluid volumes in severely burned patients using ascorbic acid administration: a randomized, prospective study.Tanaka H, Matsuda T, Miyagantani Y, Yukioka T, Matsuda H, Shimazaki SDepartment of Traumatology, Kyorin University, Tokyo, Japan.

HYPOTHESIS: High-dose ascorbic acid (vitamin C) therapy (66 mg/kg per hour) attenuates postburn lipid peroxidation, resuscitation fluid volume requirements, and edema generation in severely burned patients. STUDY DESIGN AND SETTING: A prospective, randomized study at a university trauma and critical care center in Japan. SUBJECTS AND METHODS: Thirty-seven patients with burns over more than 30% of their total body surface area (TBSA) hospitalized within 2 hours after injury were randomly divided into ascorbic acid and control groups. Fluid resuscitation was performed using Ringer lactate solution to maintain stable hemodynamic measurements and adequate urine output (0.5-1.0 ml/kg per hour). In the ascorbic acid group (n = 19; mean burn size, 63% +/- 26% TBSA; mean burn index, 57 +/- 26; inhalation injury, 15/ 19), ascorbic acid was infused during the initial 24-hour study period. In the control group (n = 18; mean burn size, 53% +/- 17% TBSA; mean burn index, 47 +/- 13; inhalation injury, 12/18), no ascorbic acid was infused. We compared hemodynamic and respiratory measurements, lipid peroxidation, and fluid balance for 96 hours after injury. Two-way analysis of variance and Tukey test were used to analyze the data. RESULTS: Heart rate, mean arterial pressure, central venous pressure, arterial pH, base deficit, and urine outputs were equivalent in both groups. The 24-hour total fluid infusion volumes in the control and ascorbic acid groups were 5.5 +/- 3.1 and 3.0 +/- 1.7 mL/kg per percentage of burn area, respectively (P<.01). In the first 24 hours, the ascorbic acid group gained 9.2% +/- 8.2% of pretreatment weight; controls, 17.8% +/- 6.9%. Burned tissue water content was 6.1 +/- 1.8 vs 2.6 +/- 1.7 mL/g of dry weight in the control and ascorbic acid groups, respectively (P<.01). Fluid retention in the second 24 hours was also significantly reduced in the ascorbic acid group. In the control group, the ratio of PaO2 to fraction of inspired oxygen at 18, 24, 36, 48, and 72 hours after injury was less than that of the ascorbic acid group (P<.01). The length of mechanical ventilation in the control and ascorbic acid groups was 21.3 +/- 15.6 and 12.1 +/- 8.8 days, respectively (P<.05). Serum malondialdehyde levels were lower in the ascorbic acid group at 18, 24, and 36 hours after injury (P<.05). CONCLUSIONS: Adjuvant administration of high-dose ascorbic acid during the first 24 hours after thermal injury significantly reduces resuscitation fluid volume requirements, body weight gain, and wound edema. A reduction in the severity of respiratory dysfunction was also apparent in these patients.

88. Surg Neurol 2000 Feb;53(2):110-7; discussion 117-8Cisternal irrigation therapy with urokinase and ascorbic acid for prevention of vasospasm after aneurysmal subarachnoid hemorrhage. Outcome in 217 patients.Kodama N, Sasaki T, Kawakami M, Sato M, Asari JDepartment of Neurosurgery, Fukushima Medical School, Japan.

BACKGROUND: Cisternal irrigation therapy with urokinase and ascorbic acid was introduced to prevent symptomatic vasospasm after aneurysmal subarachnoid hemorrhage (SAH). To dissolve and wash out the subarachnoid clot, cisternal irrigation with urokinase is used. Ascorbic acid is added to degenerate oxy-hemoglobin, one of the strongest spasmogenic substances, into verdohemelike products, which are nonspasmogenic. The efficacy and safety of this therapy were evaluated. METHODS: This therapy was performed consecutively in 217 patients. The degree of SAH of the patients was classified as Fisher CT Group 3, and the highest CT number (Hounsfield number) exceeded 60 in the SAH, which suggested a significant risk for symptomatic vasospasm. All patients underwent surgery within 72 hours from the onset of SAH. After clipping the aneurysm, irrigation tubes were placed in the Sylvian fissure (inlet) unilaterally or bilaterally and in the prepontine or chiasmal cistern (outlet). Lactated Ringer's solution with urokinase (120 IU/mL) and ascorbic acid (4 mg/mL) was infused at a rate of 30 mL/hour/side for approximately 10 days. RESULTS: Of the 217 patients studied, symptomatic vasospasm was observed in 6 cases (2.8%), and two of these six cases (0.9%) demonstrated sequelae. The average total blood volume calculated from the drainage fluid was approximately 114 mL. Analysis of the absorption spectrum of the drainage fluid revealed disappearance of the oxy-hemoglobin-specific 576-nm peak. Complications occurred in eight patients during irrigation therapy; two patients experienced seizures, two patients developed meningitis, and four patients had an intracranial hemorrhage. However, all of these patients recovered without neurological deficits. CONCLUSIONS: These results suggest that cisternal irrigation therapy with urokinase and ascorbic acid is effective in preventing symptomatic vasospasm after aneurysmal SAH.

89. Altern Med Rev 2000 Feb;5(1):28-38Male infertility: nutritional and environmental considerations.Sinclair SGreen Valley Health, Hagerstown, MD 21742, USA.

Studies confirm that male sperm counts are declining, and environmental factors, such as pesticides, exogenous estrogens, and heavy metals may negatively impact spermatogenesis. A number of nutritional therapies have been shown to improve sperm counts and sperm motility, including carnitine, arginine, zinc, selenium, and vitamin B-12. Numerous antioxidants have also proven beneficial in treating male infertility, such as vitamin C, vitamin E, glutathione, and coenzyme Q10. Acupuncture, as well as specific botanical medicines, have been documented in several studies as having a positive effect on sperm parameters. A multi-faceted therapeutic approach to improving male fertility involves identifying harmful environmental and occupational risk factors, while correcting underlying nutritional imbalances to encourage optimal sperm production and function. (The following are excepts from this study:)"Studies have shown the concentration of ascorbic acid in seminal plasma directly reflects dietary intake, and lower levels of vitamin C may lead to infertility and increased damage to the sperm's genetic material.36 Fraga et al demonstrated this by reducing ascorbic acid intake in healthy men from 250 mg to 5 mg per day. Seminal plasma levels of vitamin C decreased by 50 percent, with a concomitant 91-percent increase in sperm with DNA damage.37Cigarette smoking has been documented as having deleterious effects on sperm quality. In a University of Texas study on vitamin C and sperm quality in heavy smokers, 75 men were divided into three supplementation groups; one was given placebo, the other groups received 200 mg or 1000 mg ascorbic acid. While the placebo group showed no improvement, the ascorbic acid groups showed significant improvement in sperm quality, with the greatest improvement occurring in the 1000 mg group.38In perhaps one of the best studies on vitamin C and male infertility, 30 infertile but otherwise healthy men were given a placebo, 200 mg, or 1000 mg vitamin C daily. After one week, the group receiving 1000 mg/day had a 140-percent increase in sperm count, while there was no change in the placebo group. The 200 mg/day group had a 112-percent increase in sperm count, while both groups demonstrated significant reductions in the number of agglutinated sperm. Most importantly, by the end of the 60-day study every participant in the vitamin C group had impregnated their partner, while no pregnancies occurred in the placebo group"

90. Br J Ophthalmol 1999 Nov;83(11):1277-82Oral vitamins C and E as additional treatment in patients with acute anterior uveitis: a randomised double masked study in 145 patients.van Rooij J, Schwartzenberg SG, Mulder PG, Baarsma SGEye Hospital Rotterdam, Rotterdam, Netherlands.

AIM: To investigate the effect of additional oral vitamins C and E on acute anterior uveitis. METHODS: A placebo controlled double masked study on the effect of vitamin C 500 mg in combination with vitamin E 100 mg twice daily in 145 patients with acute anterior uveitis. As a primary end point variable, laser cell/flare measurements were performed. Best corrected and stenopeic visual acuity (VA) testing and clinical variable scores were measured. RESULTS: Laser flare measurements (ph/s) before treatment were 207.1 (SD 258) in the vitamin group and 143.6 (156) in the placebo group. After 3 days corresponding values were 80.2 (129) and 54.7 (82), after 7 days 89.2 (187) (12.5) and 85.8 (208), after 14 days 47.1 (109.5) and 40.5 (116) after 28 days 23.1 (53.6) and 23.1 (48), and after 56 days 15.6 (26) and 15.3 (17). There was no significant difference in time trend between the two treatment groups (RMANOVA; p = 0.53). Baseline VA (logMAR) was 0.106 (0.241) in the vitamin group and 0.128 (0.456) in the placebo group. VA after 3 days was 0. 236 (0.293) and 0.344 ( 0.489), after 7 days 0.204 (0.292) and 0.292 (0.479), after 14 days 0.162 (0.274) and 0.193 (0.454), after 28 days 0.096 (0.232) and 0.158 (0.436), and 0.026 (0.213) and 0.106 (0. 437) after 56 days. Although no significant difference in time trend was detected, evaluation of the VA data of the last time point (56 days) by means of the Mann-Whitney test showed a significantly better VA in the vitamin group (p = 0.01). CONCLUSIONS: There was no significant effect of vitamins C and E on laser flare measurements. The significant effect of the oral vitamins on visual acuity at 8 weeks after start of the oral vitamins C and E may indicate a protective effect in patients with acute anterior uveitis.