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LE Magazine September 2000

Continued from Medical Abstracts, September 2000

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Long-term ascorbic acid administration reverses endothelial vasomotor dysfunction in patients with coronary artery disease

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.

Circulation 1999 Jun 29;99(25):3234-40

Risk factors for Ki-ras protooncogene mutation in sporadic colorectal adenomas

The Ki-ras protooncogene frequently is mutated in colorectal adenocarcinomas, but the etiology of this molecular event is uncertain. We investigated the association between variables known or suspected to be related to risk for colorectal cancer and the occurrence of Ki-ras mutations in colorectal adenomas. This study was conducted among 678 male and female participants, 40-80 years of age, enrolled in a phase III trial testing the effects of a wheat bran fiber supplement on adenoma recurrence. Exposure information on the risk factors of interest was assessed through self-administered questionnaires. Mutations in codons 12 and 13 of the Ki-ras protooncogene were analyzed in baseline adenomas 0.5 cm or larger by PCR amplification followed by direct sequencing. Eighteen percent (120 of 678) of the participants had one or more adenoma(s) with Ki-ras mutations. A higher risk of Ki-ras mutations was associated with increasing age and a lower intake of total folate. The odds ratio (OR) for Ki-ras mutations for individuals >72 years of age was 1.98 [95% confidence interval (CI) = 1.19-3.27; P for trend = 0.008] compared with those less than 65 years of age. Compared with individuals in the lower tertile of total folate, those in the upper tertile had an approximately 50% lower risk of having Ki-ras mutation-positive adenomas (OR = 0.52; 95% CI = 0.30-0.88; P for trend = 0.02). There was a suggestion of a stronger inverse association of total folate with G-->T transversions (OR = 0.41; 95% CI = 0.20-0.87) than G-->A transitions (OR = 0.61; 95% CI = 0.31-1.21), although the CIs for the associations overlap. The results of these analyses suggest that the protective effect of folate in colon cancer observed in published studies may be mediated through folate's effect on Ki-ras mutations.

Cancer Res 1999 Oct 15;59(20):5181-5

Double-blind intervention trial on modulation of ozone effects on pulmonary function by antioxidant supplements

The aim of this study was to investigate whether the acute effects of ozone on lung function could be modulated by antioxidant vitamin supplementation in a placebo-controlled study. Lung function was measured in Dutch bicyclists (n = 38) before and after each training session on a number of occasions (n = 380) during the summer of 1996. The vitamin group (n = 20) received 100 mg of vitamin E and 500 mg of vitamin C daily for 15 weeks. The average ozone concentration during exercise was 77 microg/m3 (range, 14-186 microg/m3). After exclusion of subjects with insufficient compliance from the analysis, a difference in ozone exposure of 100 microg/m3 decreased forced expiratory volume in 1 second (FEV1) 95 ml (95% confidence interval (CI) -265 to -53) in the placebo group and 1 ml (95% CI -94 to 132) in the vitamin group; for forced vital capacity, the change was -125 ml (95% CI -384 to -36) in the placebo group and -42 ml (95% CI -130 to 35) in the vitamin group. The differences in ozone effect on lung function between the groups were statistically significant. The results suggest that supplementation with the antioxidant vitamins C and E confers partial protection against the acute effects of ozone on FEV1 and forced vital capacity in cyclists.

Am J Epidemiol 1999 Feb 15;149(4):306-14

Use of topical ascorbic acid and its effects on photodamaged skin topography

OBJECTIVE: To determine the efficacy of topical ascorbic acid application in treating mild to moderate photodamage of facial skin using an objective, computer-assisted image analysis of skin surface topography and subjective clinical, photographic, and patient self-appraisal questionnaires. DESIGN: A 3-month, randomized, double-blind, vehicle-controlled study. SETTING: Facial plastic surgery private practice. PATIENTS: Nineteen evaluable volunteer sample patients aged between 36 and 72 years with Fitzpatrick skin types I, II, and III who were in good physical and mental health with mild to moderately photodamaged facial skin were considered for analysis. INTERVENTION: Coded, unmarked medications were randomly assigned to the left and right sides of each subject's face, one containing the active agent, topical ascorbic acid (Cellex-C high-potency serum; Cellex-C International, Toronto, Ontario), the other, the vehicle serum (Cellex-C International). Three drops (0.5 mL) of each formulation were applied daily to the randomly assigned hemifaces over the 3-month study period. Treatment assignments were not disclosed to subjects, clinicians, or personnel involved in analyzing skin replicas. MAIN OUTCOME MEASURES: Specific clinical parameters were evaluated and graded on a 0- to 9-point scale (0, none; 1-3, mild; 4-6, moderate; and 7-9, severe). Reference photographs were used to standardize grading criteria. Overall investigator scores were compared with baseline and graded as excellent (much improved), good (improved), fair (slightly improved), no change, or worse. Patient self-appraisal questionnaires rated the degree of improvement (much improved, improved, slightly improved, no change, or worse) and reported adverse effects (burning, stinging, redness, peeling, dryness, discoloration, itching, and rash). Standard photographs were taken at baseline, including anteroposterior and left and right oblique views to facilitate subsequent clinical evaluations, and at the end of therapy for comparison. Optical profilometry analysis was performed on the skin surface replicas of the lateral canthal (crow's feet) region, comparing baseline to end-of-study specimens. Using this computer-based system, the resulting image was digitally analyzed, and numeric values were assigned to reflect surface features. The parameters obtained included Rz, Ra, and shadows. These values provided objective data that document pretreatment and posttreatment texture changes proportional to the degree of wrinkling, roughness, and other surface irregularities. RESULTS: Optical profilometry image analysis demonstrated a statistically significant 73.7% improvement in the Ra and shadows north-south facial axis values with active treatment greater than vehicle control, as well as a trend for improvement in the Rz north-south facial axis parameter, showing a 68.4% greater improvement of active treatment vs vehicle control. Clinical assessment demonstrated significant improvement with active treatment greater than control for fine wrinkling, tactile roughness, coarse rhytids, skin laxity/tone, sallowness/yellowing, and overall features. Patient questionnaire results demonstrated statistically significant improvement overall, active treatment 84.2% greater than control. Photographic assessment demonstrated significant improvement, active treatment 57.9% greater than control. CONCLUSIONS: A 3-month daily regimen of topical ascorbic acid provided objective and subjective improvement in photodamaged facial skin. Skin replica optical profilometry is an objective method for quantification of the skin surface texture changes.

Arch Otolaryngol Head Neck Surg 1999 Oct;125(10):1091-8

Plasma antioxidant defense in actinic keratosis and basal cell carcinoma

BACKGROUND: Reactive oxygen species and lipid peroxides have been implicated in the pathogenesis of a variety of diseases, particularly cancer. There may be an inverse correlation between lipid peroxidation and antioxidant defense mechanisms. The aim of this study was to investigate whether certain plasma antioxidants (ascorbic acid, alpha-tocopherol, total thiol groups, ceruloplasmin, urate, albumin and erythrocyte glutathione) are altered in actinic keratosis (AK) and basal cell carcinoma (BCC). METHODS: Plasma samples and red blood cells (RBC) of 13 patients with AK, 12 with BCC and 16 healthy controls were investigated. RESULTS: Data analysis indicates significant decrease of ascorbic acid (P < 0.001), alpha-tocopherol (P < 0.05 and P < 0.001), total thiol groups (P < 0.001), ceruloplasmin (P < 0.001 and P < 0.05), and RBC glutathione (P < 0.05) values in both AK and BCC groups compared to controls. Comparison of AK and BCC groups evidenced a significant decrease of alpha-tocopherol and RBC glutathione (P < 0.05) in BCC patient. CONCLUSION: Plasma antioxidants are decreased in the AK and BCC, probably due to the long exposure to UV irradiation which is one of the most important factors in the etiology of AK and BCC and alpha-tocopherol and RBC glutathione (P < 0.05) are most altered in BCC. J Eur Acad Dermatol Venereol 1999 Sep;13(2):96-101 Serum ascorbic acid and other correlates of self-reported cataract among older Americans The purpose of this study was to examine the correlates of self-reported cataract among older Americans, and specifically, to determine whether serum ascorbic acid levels are associated with a decreased prevalence of cataract. A national probability survey of Americans, the Second National Health and Nutrition Examination Survey (NHANES II), was conducted between 1976 and 1980. A total of 4001 participants were included between the ages of 60 and 74 years with data on serum ascorbic acid level and other variables of interest. A total of 252 women (12%) and 164 men (9%) reported a history of cataract. Serum ascorbic acid level was inversely associated with prevalence of cataract in multiple logistic regression analyses; each 1 mg/dl increase was independently associated with a 26% decrease in cataract (P = 0.03). Other independent correlates of cataract included increasing age, female sex, smoking, and diabetes mellitus (all P<0.01). We identified four correlates of cataract among older Americans: serum ascorbic acid level, increasing age, smoking, and diabetes mellitus. Ascorbic acid, a water-soluble antioxidant found in high concentrations in the lens, may be of importance for the prevention of cataract among older Americans.

J Clin Epidemiol 1999 Dec;52(12):1207-11

Role of oxidant stress in endothelial dysfunction produced by experimental hyperhomocyst(e)inemia in humans

BACKGROUND: Moderate elevations in plasma homocyst(e)ine concentrations are associated with atherosclerosis and hypertension. We tested the hypothesis that experimental perturbation of homocysteine levels produces resistance and conduit vessel endothelial dysfunction and that this occurs through increased oxidant stress. METHODS AND RESULTS: Oral administration of L-methionine (100 mg/kg) was used to induce moderate hyperhomocyst(e)inemia ( approximately 25 micromol/L) in healthy human subjects. Endothelial function of forearm resistance vessels was assessed by use of forearm vasodilatation to brachial artery administration of the endothelium-dependent dilator acetylcholine. Conduit vessel endothelial function was assessed with flow-mediated dilatation of the brachial artery. Forearm resistance vessel dilatation to acetylcholine was significantly impaired 7 hours after methionine (methionine, 477+/-82%; placebo, 673+/-110%; P=0.016). Methionine did not alter vasodilatation to nitroprusside and verapamil. Flow-mediated dilatation was significantly impaired 8 hours after methionine loading (0.3+/-2.7%) compared with placebo (8. 2+/-1.6%, P=0.01). Oral administration of the antioxidant ascorbic acid (2 g) prevented methionine-induced endothelial dysfunction in both conduit and resistance vessels (P=0.03). CONCLUSIONS: Experimentally increasing plasma homocyst(e)ine concentrations by methionine loading rapidly impairs both conduit and resistance vessel endothelial function in healthy humans. Endothelial dysfunction in conduit and resistance vessels may underlie the reported associations between homocysteine and atherosclerosis and hypertension. Increased oxidant stress appears to play a pathophysiological role in the deleterious endothelial effects of homocysteine.

Circulation 1999 Sep 14;100(11):1161-8

Folic acid inhibits homocysteine-induced proliferation of human arterial smooth muscle cells

PURPOSE: An elevated plasma homocysteine level has been identified as an independent risk factor for atherosclerosis. Whether this represents a marker for vascular disease or a direct effect on the vasculature remains unclear. Because vascular smooth muscle cells (VSMCs) play an integral role in the atherosclerotic process, we studied the effect of homocysteine on human infragenicular VSMC proliferation and the role of folic acid in reversing the homocysteine effect. METHODS: Human infragenicular VSMCs harvested from amputation specimens were studied. Various cell groups were exposed to physiologic (6.25 micromol/L and 12.5 micromol/L) and pathologic (25 micromol/L to 500 micromol/L) concentrations of homocysteine. Similar groups were simultaneously exposed to 20 nmol/L of folic acid. Cell counts and DNA synthesis, as reflected by [methyl-(3)H]-thymidine incorporation, were performed at 6 days and 24 hours, respectively. Additional groups were exposed to various combinations of folic acid (20 nmol/L), vitamin B(6) (145 nmol/L), and vitamin B(12) (0.45 nmol/L) in the presence of homocysteine (25, 50, and 250 micromol/L). RESULTS: Homocysteine resulted in a dose-dependent increase in DNA synthesis and cell proliferation. Cell counts increased significantly at homocysteine concentrations ranging from 25 micromol/L to 500 micromol/L (P <.05), with a maximal increase of 98% at 500 micromol/L of homocysteine. The addition of 20 nmol/L folic acid resulted in significant inhibition of cell proliferation at all homocysteine concentrations studied (P <.001). Maximal inhibition of 70% occurred in the cells exposed to 50 micromol/L of homocysteine. The increases in [methyl-(3)H]-thymidine incorporation ranged from 36% at 6 micromol/L homocysteine to a maximum of 247% at 500 micromol/L homocysteine. All increases were statistically significant (P <.05). The addition of 20 nmol/L folic acid resulted in significant inhibition of DNA synthesis (P <.002). Vitamins B(6) and B(12) did not demonstrate significant antiproliferative properties. CONCLUSION: A possible role of homocysteine in the formation of atherosclerotic lesions is through a direct proliferative effect on VSMCs in a dose-dependent fashion. Folic acid intake at levels available in dietary supplements may prove protective in hyperhomocysteinemia-induced atherosclerosis. Vitamins B(6) and B(12) alone do not appear to exhibit a substantial inhibitory effect in the setting of elevated homocysteine levels.

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