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May 9, 2000

National Academy of Sciences References

61. Schweiz Med Wochenschr 1994 Aug 9;124(31-32):1373-80[Scurvy--a mistakenly forgotten disease].[Article in German]Hurlimann R, Salomon FDepartement fur Innere Medizin, Universitatsspital Zurich.

Four cases of scurvy diagnosed within a period of two years are reported. Theycomprised 2 male patients with heavy nicotine and alcohol abuse, a 35-year-oldwoman with malnutrition due to food supplements phobia, and a 69-year-old womanwith malnutrition due to dementia and social isolation. All four patients wereadynamic and anemic. Three patients showed typical dermatologic signs withhemorrhagic hyperceratosis, suffusions or cork-screw hair. Two patientscomplained of parodontol disorders. Other symptoms were gastrointestinalbleeding, sicca syndrome, retinal bleeding, subdural hematoma, edema andarthralgia. Associated disorders were folic acid and vitamin B12 depletion intwo cases, and nephropathy and pneumonia with pneumothorax in one case each. Inall cases the serum asorbic acid concentration was below the scorbutic level of11 mumol/l. Historical data, pathogenesis, incidence, clinical presentation,diagnosis and therapy of scurvy are discussed. We conclude that scurvy can beobserved even in a developed country such as Switzerland at the end of the 20thcentury. The real incidence may be underestimated because symptoms are not wellknown and disappear rapidly after admission because of sufficient vitamin Ccontent in normal diet. Patients at risk are socially isolated alcoholics, oldpeople, psychiatric patients and diet enthusiasts. Usually scurvy occurs inconjunction with other deficiencies. Smoking and acute illness enhance ascorbicacid depletion. With a knowledge of the symptomatology of scurvy, it is easy todiagnose and treatment is simple and effective.

62. J Am Acad Dermatol 1994 May;30(5 Pt 2):881-3Scurvy.Ghorbani AJ, Eichler CAlbany Medical College, New York.

Scurvy is caused by a deficiency of ascorbic acid. We describe a 31-year-oldHispanic man who had perifollicular hemorrhages, follicular hyperkeratosis,corkscrew hairs, and gingival hemorrhage after consuming a peculiar andrestricted diet for 1 year. A diagnosis of scurvy was made and the patient'sdisease resolved after treatment with vitamin C.

63. Free Radic Biol Med 2000 Feb 1;28(3):428-36Vitamin C prevents the acute atherogenic effects of passive smoking.Valkonen MM, Kuusi TDepartment of Medicine, University of Helsinki, Helsinki, Finland.

During passive smoking the body is attacked by an excess of free radicalsinducing oxidative stress. In nonsmoking subjects even a short period of passivesmoking breaks down serum antioxidant defense (TRAP) and accelerates lipidperoxidation leading to accumulation of their low-density lipoprotein (LDL)cholesterol in cultured human macrophages. We now studied whether these acuteproatherogenic effects of secondhand smoke could be prevented by an effectivefree radical scavenger, vitamin C. Blood samples were collected from nonsmokingsubjects (n = 10) as they were consecutively exposed to normal air or cigarettesmoke during four separate days. During the last 2 d, a single dose of vitamin C(3 g) was given, which doubled its plasma concentration. Vitamin C did notinfluence the plasma antioxidant defense or the resistance of LDL to oxidationin normal air, but prevented the smoke-induced decrease in plasma TRAP (p<.001), the decrease in the resistance of LDL to oxidation (p <.05), and theaccelerated formation of serum thiobarbituric acid reactive substances (TBARS)(p <.05) otherwise observed 1.5 h after the beginning of passive smoking.Vitamin C protected nonsmoking subjects against the harmful effects of freeradicals during exposure to secondhand smoke.

64. Clin Sci (Colch) 1997 Apr;92(4):361-5Combination oral antioxidant supplementation reduces blood pressure.Galley HF, Thornton J, Howdle PD, Walker BE, Webster NRClinical Oxidant Research Group, St James's University Hospital, Leeds, UK.

1. Hypertension affects 30% of adults and low intakes of antioxidants have beenassociated with increased risk of hypertension and cardiovascular disease. Toinvestigate the effect of short-term high-dose antioxidant supplementation onblood pressure in hypertensive and normotensive outpatients, we undertook arandomized, double-blind, crossover design placebo-controlled study. 2. Fortysubjects were recruited from medical outpatient clinics, of whom 38 completedthe study. Twenty-one were attending for treatment of hypertension and 17 werenormotensive, attending for minor gastrointestinal complaints. Subjects wererandomly assigned to receive either 8 weeks placebo followed by 2 weeks washoutthen 8 weeks antioxidants or vice versa. The combination of antioxidantsconsisted of 200 mg of zinc sulphate, 500 mg of ascorbic acid, 600 mg ofalpha-tocopherol (sodium succinate salt) and 30 mg of beta-carotene daily. 3.Systolic blood pressure fell at the end of the antioxidant phase compared withthe placebo phase both in subjects receiving anti-hypertensive therapy (P <0.01) and those who were normotensive (P = 0.067). Circulating levels ofbeta-carotene and alpha-tocopherol increased in all subjects duringsupplementation (P < 0.01) and urine nitrite increased in hypertensive patients(P < 0.05). 4. Short-term oral high-dose combination antioxidant therapy reducesblood pressure, possibly via increased availability of nitric oxide. This studymay have implications for the innovative use of antioxidants as an adjunct toanti-hypertensive therapy.

65. Circulation 1999 Jun 29;99(25):3234-40Long-term ascorbic acid administration reverses endothelial vasomotordysfunction in patients with coronary artery disease.Gokce N, Keaney JF Jr, Frei B, Holbrook M, Olesiak M, Zachariah BJ, LeeuwenburghC, Heinecke JW, Vita JA

Evans Memorial Department of Medicine, Cardiology Section, and WhitakerCardiovascular Institute, Boston University School of Medicine, Boston, MA, USA.

BACKGROUND: Loss of endothelium-derived nitric oxide (EDNO) contributes to the clinical expression of coronary artery disease (CAD). Increased oxidative stress has been linked to impaired endothelial vasomotor function in atherosclerosis, and recent studies demonstrated that short-term ascorbic acid treatment improves endothelial function. METHODS AND RESULTS: In a randomized, double-blind, placebo-controlled study, we examined the effects of single-dose (2 g PO) and long-term (500 mg/d) ascorbic acid treatment on EDNO-dependent flow-mediated dilation of the brachial artery in patients with angiographically established CAD. Flow-mediated dilation was examined by high-resolution vascular ultrasound at baseline, 2 hours after the single dose, and 30 days after long-term treatment in 46 patients with CAD. Flow-mediated dilation improved from 6.6+/-3.5% to 10.1+/-5.2% after single-dose treatment, and the effect was sustained after long-term treatment (9. 0+/-3.7%), whereas flow-mediated dilation was 8.6+/-4.7% at baseline and remained unchanged after single-dose (7.8+/-4.4%) and long-term (7.9+/-4.5%) treatment with placebo (P=0.005 by repeated-measures ANOVA). Plasma ascorbic acid concentrations increased from 41.4+/-12. 9 to 115.9+/-34.2 micromol/L after single-dose treatment and to 95. 0+/-36.1 micromol/L after long-term treatment (P<0.001). CONCLUSIONS: In patients with CAD, long-term ascorbic acid treatment has a sustained beneficial effect on EDNO action. Because endothelial dysfunction may contribute to the pathogenesis of cardiovascular events, this study indicates that ascorbic acid treatment may benefit patients with CAD.

66.Circulation 1999 Mar 9;99(9):1156-60Demonstration of rapid onset vascular endothelial dysfunction afterhyperhomocysteinemia: an effect reversible with vitamin c therapy.Chambers JC, McGregor A, Jean-Marie J, Obeid OA, Kooner JS

National Heart and Lung Institute, Imperial College School of Medicine,Hammersmith Hospital, London, UK.

BACKGROUND: Hyperhomocysteinemia is a major and independent risk factor forvascular disease. The mechanisms by which homocysteine promotes atherosclerosis are not well understood. We hypothesized that elevated homocysteine concentrations are associated with rapid onset endothelial dysfunction, which is mediated through oxidant stress mechanisms and can be inhibited by the antioxidant vitamin c. Methods and RESULTS: We studied 17 healthy volunteers (10 male and 7 female) aged 33 (range 21 to 59) years. Brachial artery diameter responses to hyperemic flow (endothelium dependent), and glyceryltrinitrate (GTN, endothelium independent) were measured with high resolution ultrasound at 0 hours (fasting), 2 hours, and 4 hours after (1) oral methionine (L-methionine 100 mg/kg), (2) oral methionine preceded by vitamin c (1g/day, for 1 week), and (3) placebo, on separate days and in random order. Plasma homocysteine increased (0 hours, 12.8+/-1.4; 2 hours, 25.4+/-2.5; and 4 hours, 31. 2+/-3.1 micromol/l, P<0.001), and flow-mediated dilatation fell (0 hours, 4.3+/-0.7; 2 hours, 1.1+/-0.9; and 4 hours, -0.7+/-0.8%) after oral L-methionine. There was an inverse linear relationship between homocysteine concentration and flow-mediated dilatation (P<0. 001). Pretreatment with vitamin c did not affect the rise in homocysteine concentrations after methionine (0 hours, 13.6+/-1.6; 2 hours, 28.3+/-2.9; and 4 hours, 33.8+/-3.7 micromol/l, P=0.27), but did ameliorate the reduction in flow-mediated dilatation (0 hours, 4. 0+/-1.0; 2 hours, 3.5+/-1.2 and 4 hours, 2.8+/-0.7%, P=0.02). GTN-induced endothelium independent brachial artery dilatation was not affected after methionine or methionine preceded by vitamin c. CONCLUSIONS: We conclude that an elevation in homocysteine concentration is associated with an acute impairment of vascular endothelial function that can be prevented by pretreatment with vitamin c in healthy subjects. Our results support the hypothesis that the adverse effects of homocysteine on vascular endothelial cells are mediated through oxidative stress mechanisms.

67.J Cardiovasc Pharmacol 1999 Nov;34(5):690-3Oral vitamin C reduces arterial stiffness and platelet aggregation in humans. Wilkinson IB, Megson IL, MacCallum H, Sogo N, Cockcroft JR, Webb DJClinical Pharmacology Unit & Research Centre, University of Edinburgh, Western General Hospital, Scotland.

Atherosclerosis is associated with stiffening of conduit arteries and increased platelet activation, partly as a result of reduced bioavailability of nitric oxide (NO), a mediator that normally has a variety of protective effects on blood vessels and platelets. Increased levels of oxygen free radicals are a feature of atherosclerosis that contributes to reduced NO bioavailability and might lead to increased arterial stiffness and platelet activation. Vitamin C is a dietary antioxidant that inactivates oxygen free radicals. This placebo-controlled, double-blind, randomized study was designed to establish whether acute oral administration of vitamin C (2 g), would reduce arterial stiffness and in vitro platelet aggregation in healthy male volunteers. Plasma vitamin C concentrations increased from 42+/-8 to 104+/-8 microM at 6 h after oral administration, and were associated with a significant reduction in augmentation index, a measure of arterial stiffness (by 9.6+/-3.0%; p = 0.016), and ADP-induced platelet aggregation (by 35+/-13%; p = 0.046). There was no change in these parameters after placebo. Vitamin C, therefore, appears to have beneficial effects, even in healthy subjects. The mechanism responsible is likely to involve protection of NO from inactivation by oxygen free radicals, but this requires confirmation. If similar effects are observed in patients with atherosclerosis or risk factors, vitamin C supplementation might prove an effective therapy in cardiovascular disease.68. Eur Heart J 1999 Nov;20(22):1676-80Vitamin C improves endothelial function of epicardial coronary arteries in patients with hypercholesterolaemia or essential hypertension--assessed by cold pressor testing.Jeserich M, Schindler T, Olschewski M, Unmussig M, Just H, Solzbach UMedizinische Klinik III, Universitat Freiburg, Freiburg, Germany.

AIMS: There is evidence that formation of free radicals increases in patients with hypertension or hypercholesterolaemia, which may contribute to endothelial dysfunction of epicardial coronary arteries due to inactivation of the vasodilator NO. The present study was designed to test whether the abnormal constriction of epicardial coronary arteries due to sympathetic stimulation by the cold pressor test in patients with essential hypertension or hypercholesterolaemia could be reversed by administration of the antioxidant vitamin C. METHODS and RESULTS: In 28 patients without relevant coronary artery stenosis the cold pressor test was performed before and after a 3 g infusion of vitamin C. In five normal controls the cold pressor test led to a similar increase in luminal area before and after vitamin C (3.7+/-1.3% and 1.9+/-0.8%, ns vs before vitamin C). In nine hypercholesterolaemic patients the cold pressor test led to a -14.1+/-2.8% reduction in cross-sectional area before vitamin C. This constriction was significantly improved after vitamin C to -7.6%+/-2.0, P=0.027 vs before vitamin C. In nine hypertensive patients, the cold pressor test led to a -17.1+/-3.2% decrease in cross-sectional area before vitamin C, which was improved to -7.1+/-3.1 after vitamin C, P=0.004 vs before vitamin C. This increase in luminal area was significant in each group in comparison with normal controls (each P<0.05). Administration of saline (placebo group, five patients) had no significant effect on cold pressor test-induced constriction (-6.9+/-3.9% before and -6. 8+/-3.7% after saline). CONCLUSION: The antioxidant vitamin C reverses cold pressor test-induced vasoconstriction of epicardial coronary arteries in patients with hypertension or hypercholesterolaemia. Our data suggest that enhanced oxidative stress contributes to impaired endothelial function in this patient population.

69. Proc Soc Exp Biol Med 1999 Dec;222(3):196-204On the role of vitamin C and other antioxidants in atherogenesis and vascular dysfunction.Frei BLinus Pauling Institute, Oregon State University, Corvallis, OR 97331-6512, USA.

Oxidative stress has been implicated as an important etiologic factor in atherosclerosis and vascular dysfunction. Antioxidants may inhibit atherogenesis and improve vascular function by two different mechanisms. First, lipid-soluble antioxidants present in low-density lipoprotein (LDL), including alpha-tocopherol, and water-soluble antioxidants present in the extracellular fluid of the arterial wall, including ascorbic acid (vitamin C), inhibit LDL oxidation through an LDL-specific antioxidant action. Second, antioxidants present in the cells of the vascular wall decrease cellular production and release of reactive oxygen species (ROS), inhibit endothelial activation (i.e., expression of adhesion molecules and monocyte chemoattractants), and improve the biologic activity of endothelium-derived nitric oxide (EDNO) through a cell- or tissue-specific antioxidant action. alpha-Tocopherol and a number of thiol antioxidants have been shown to decrease adhesion molecule expression and monocyte-endothelial interactions. Vitamin C has been demonstrated to potentiate EDNO activity and normalize vascular function in patients with coronary artery disease and associated risk factors, including hypercholesterolemia, hyperhomocysteinemia, hypertension, diabetes, and smoking.

70. Atherosclerosis 1996 Jan 26;119(2):139-50Effect of ascorbate supplementation on low density lipoprotein oxidation in smokers.Fuller CJ, Grundy SM, Norkus EP, Jialal IDepartment of Clinical Nutrition, University of Texas-Southwestern Medical Center, Dallas, USA.

The oxidative modification of low density lipoprotein (LDL) may play a role in the pathogenesis of atherosclerosis. Furthermore, evidence of oxidized LDL (ox-LDL) has been found in vivo. Supplementation of some animal models with antioxidants has been shown to retard the formation of aortic atherosclerosis. Ascorbate (vitamin c) is a highly potent aqueous-phase antioxidant in plasma, which has been shown in vitro to retard LDL oxidation. Cigarette smokers have reduced concentrations of ascorbate in their plasma, and their LDL may be more prone to xidation. Hence, the objective of the present study was to examine the effect of ascorbate depletion and supplementation on the propensity of LDL to oxidize in smokers in a 6-week study. Nineteen healthy smokers followed a low ascorbate diet (< or = 30 mg/day) for 2 weeks, then were randomly assigned to receive placebo or 1000 mg ascorbate per day for 4 weeks. Blood was taken at 0 and 4 weeks of supplementation for study of LDL oxidative susceptibility. LDL was oxidized with 5 mumol/l copper. The ascorbate-supplemented group had significant increases in plasma ascorbate. The placebo group showed no change in the time course of LDL oxidation between 0 and 4 weeks. However, the ascorbate-supplemented group has a significant reduction in LDL oxidative susceptibility as measured by thiobarbituric acid-reactive substances (TBARS) and the formation of conjugated dienes. The ascorbate-supplemented group demonstrated significantly increased lag phase and decreased oxidation rate at 4 weeks compared to 0 weeks. No changes were found in the placebo group. The ascorbate-supplemented group showed no biochemical signs consistent with increased body iron stores. Supplementation of otherwise healthy smokers for 4 weeks with 1000 mg ascorbate per day resulted in increased plasma ascorbate and reduced LDL oxidative susceptibility.