Alpha-2 adrenoceptor subtype causing nitric oxide-mediated vascular relaxation in rats.
Bockman C.S.; Gonzalez-Cabrera I.; Abel P.W.
Dr. P.W. Abel, Department of Pharmacology, Crisa III, Creighton Univ. School of Medicine, 2500 California Plaza, Omaha, NE 68178 USA
Journal of Pharmacology and Experimental Therapeutics (USA), 1996, 278/3 (1235-1243)
The alpha-2 adrenoceptor subtype and its signal transduction pathway mediating vascular relaxation in rats were studied in vitro using rings of superior mesenteric arteries. Removal of endothelium or incubation with N(G)- nitro-L-arginine completely blocked relaxant responses to UK14,304, suggesting endothelium-derived nitric oxide mediates relaxation. The order of potency for full (F) or partial (P) agonists causing relaxation was guanabenz (P) > UK14,304 (F) > clonidine (P) > epinephrine (F) > norepinephrine (F). Affinities (K(B)) of alpha-2 adrenoceptor subtype-selective drugs for blocking relaxation were obtained in side-by-side experiments comparing rat mesenteric arteries with pig coronary arteries. Relaxation of pig coronary arteries is known to be mediated by the alpha-2A adrenoceptor subtype. K(B) values in nM for rauwolscine (19), WB-4101 (265), SKF-104078 (197), spiroxatrine (128), and prazosin (1531) for blocking relaxation in rat arteries were consistent with their affinities for binding at the alpha-2D adrenoceptor subtype. K(B) values for rauwolscine and WB-4101, drugs distinguishing the alpha-2D from the alpha-2A adrenoceptor subtype, were significantly higher in blocking relaxation of rat arteries compared with pig arteries, suggesting the alpha-2D adrenoceptor subtype mediates NO-induced relaxation in rat arteries. We used forskolin to oppose alpha-2 adrenoceptor- mediated inhibition of cAMP formation by directly stimulating cAMP formation in endothelium. Forskolin did not affect the relaxant response to UK14,304, suggesting that cAMP is not involved in the coupling of alpha-2 adrenoceptors to nitric oxide-induced vascular relaxation.
Endothelial dysfunction: Clinical implications.
Drexler H.
Germany
Progress in Cardiovascular Diseases (USA), 1997, 39/4 (287-324)
The endothelium is involved in the control of vascular tone and homeostasis. Risk factors for arteriosclerosis, as well as other conditions have been shown to be associated with a dysfunctional endothelium. Clinically, endothelial function and dysfunction have been mostly evaluated by the assessment of endothelial dependent relaxation, for example in response to acetylcholine or increase inflow. The functional implications of endothelial dysfunction in cardiovascular disease are not well defined, but recent clinical trials have suggested that endothelial dysfunction may affect vascular tone and organ perfusion particularly during stress situations such as exercise. Moreover, endothelial dysfunction may represent an early event in the development of arteriosclerosis. Therefore, recent clinical studies have been performed to restore normal endothelial function in patients, using interventions such as L-arginine, lipid lowering drugs, vitamin C, other antioxidants, or exercise.
Plasma ascorbic acid concentrations in the Republic of Karelia, Russia and in North Karelia, Finland.
Matilainen T.; Vartiainen E.; Puska P.; Alfthan G.; Pokusajeva S.; Moisejeva N.; Uhanov M.
National Public Health Institute, Dept. Epidemiology Health Promotion, Mannerheimintie 166, 00300 Helsinki Finland
European Journal of Clinical Nutrition (United Kingdom), 1996, 50/2 (115-120)
Objectives: To determine the plasma ascorbic acid concentrations among men in North Karelia (Finland) and in Pitkaranta (Republic of Karelia) and to test how a short intervention would affect the plasma concentrations. Design: The baseline survey was done as a cross-sectional population survey. A subsample was selected to the intervention study and randomised to treatment and control groups. Setting: North Karelia province in Finland and the Pitkaranta area in the Republic of Karelia. Subjects: In the cross-sectional population survey the stratified random sample of men between 25 and 64 years of age was 1000 in North Karelia and 500 in Pitkaranta. Participation rates were 68% and 77%, respectively. Plasma ascorbic acid measurements were made in one-third of the sample. In Pitkaranta 60 men, having very low plasma ascorbic acid concentrations, were invited to the intervention study. Interventions: A controlled intervention study was made with blackcurrant-strawberry nectar in which vitamin C content was approximately 70mg/100g. The treatment group drank two times daily 200ml nectar for 4-5 weeks. After intervention plasma ascorbic acid concentration was measured from both treatment and control groups. Results: Plasma ascorbic acid concentrations were very different in the two areas. In Pitkaranta 93% of the men and in North Karelia only 2% of the men had plasma levels suggesting severe vitamin C deficiency. After intervention 46% of the men in the experimental group compared with 5% in the control group had plasma ascorbic acid concentrations exceeding 23 micromol/l (4.0 mg/l). Conclusions: In addition to a high smoking prevalence the very low ascorbic acid concentration among men in the Republic of Karelia can have an effect on the high cardiovascular disease mortality.
[The role of platelets in the protective effect of a combination of vitamins A, E, C and P in thrombinemia]
Gematol Transfuziol (RUSSIA) Sep-Oct 1995, 40 (5) p9-11
White rat experiments have shown that combination of vitamins A, E, C and P diminishes thrombin-induced thrombocytopenia and low platelet aggregation. This is explained by limited activation of free radical processes initiated by thrombin in plasma, red cells and platelets. It was found that thrombin ability to activate lipid peroxidation is not related to coagulatory transformation of fibrinogen, but is rather due to a direct contact of the enzyme with platelets. A protective effect of vitamins-antioxidants in thrombinemia is likely to rest on their ability to restrict activation of free radical oxidation in platelets
Investigation of the protective effects of the antioxidants ascorbate, cysteine, and dapsone on the phagocyte-mediated oxidative inactivation of human alpha-1-protease inhibitor in vitro.
Am Rev Respir Dis (UNITED STATES) Nov 1985, 132 (5) p1049-54
Oxidants derived from the atmosphere or from activated pulmonary phagocytes mediate functional inactivation of alpha-1-protease inhibitor (alpha-1-PI). Chronic exposure to these oxidants may cause emphysema. In this study we have investigated the effects of the antioxidants ascorbate, cysteine (10(-4) M to 10(-1) M), and dapsone (10(-6) M to 10(-3) M) on the oxidative inactivation of human alpha-1-PI by leukoattractant-activated polymorphonuclear leukocytes (PMNL) in vitro. During exposure of alpha-1-PI to stimulated PMNL in the presence of ascorbate and cysteine at concentrations of greater than 10(-4) M and dapsone at greater than 10(-6) M, the elastase inhibitory activity of alpha-1-PI was preserved. However, exposure of the alpha-1-PI to the antioxidants subsequent to PMNL-mediated oxidative inactivation was not associated with reactivation of elastase inhibitory capacity. Ascorbate, cysteine, and dapsone at concentrations that caused 50% protection of alpha-1-PI did not affect degranulation or the binding of radiolabeled leukoattractant to PMNL. It is suggested that the protective effects of the antioxidants are related to their ability to scavenge superoxide and oxidants generated by the PMNL-myeloperoxidase/H2O2/halide system. Because the effects of ascorbate and especially those of dapsone were observed at concentrations of these agents that are attainable in vivo, our results may have clinical significance
Nutrient intake and food use in an Ojibwa-Cree community in Northern Ontario assessed by 24h dietary recall
Nutrition Research (USA), 1997, 17/4 (603-618)
As part of a diabetes prevention program in a remote Ojibwa-Cree community in Northern Ontario, 72% of residents >9y of age (729/1019) underwent an oral glucose tolerance test; >98% (718/729) of participants provided a complete 24h dietary recall. Their diet was typical of that for aboriginal North American populations undergoing rapid cultural change, being high in saturated fat (similar13% energy), cholesterol and simple sugars (similar22% energy), low in dietary fibre (11g/d) and nigh in glycaemic index (similar90). There were high prevalences of inadequate intakes of vitamin A (77%), calcium (58%), vitamin C (40%) and folate (37%). Adolescents aged 10-19y consumed more simple sugars and less protein than adults aged >49y and ate more potato chips, flied potatoes, hamburger, pizza, soft drinks and table sugar. Adults >49y retained more traditional eating habits, using more bannock (fried bread) and wild meats than younger individuals. Interventions to prevent diabetes in the community should include culturally appropriate and effective ways to improve the nutritional adequacy of the diet, reduce fat intake and increase the use of less refined carbohydrate foods.
Effect of vitamin C supplementation on hepatic cytochrome P450 mixed-function oxidase activity in streptozotocin-diabetic rats
Toxicology Letters (Ireland), 1996, 89/3 (249-256)
The effect of vitamin C supplementation on hepatic cytochrome P450 expression was investigated in streptozotocin (STZ) diabetic male Wistar Albino rats. STZ-treated rats displayed the usual characteristics of diabetes including; hyperphagia, polydipsia, decreased body weight gain and also the increased expression and activity of hepatic CYP1A, 2B, 2E and 4A proteins. Vitamin C administration in drinking water (2% w/v) was associated with significant decreases in the levels of hyperglycaemia (P < 0.05), glycosylated haemoglobin (P < 0.05), hyperlipidaemia (P < 0.001), and hyperketonaemia (P < 0.001) associated with STZ-diabetes. Vitamin C-treatment selectively reduced the activity and expression of CYP2E proteins (P < 0.001). These effects on CYP2E expression may be mediated by the reduced levels of circulating ketone bodies, however, a direct effect on CYP2E expression in diabetes cannot be discounted.
Total vitamin C, ascorbic acid, and dehydroascorbic acid concentrations in plasma of critically ill patients
American Journal of Clinical Nutrition (USA), 1996, 63/5 (760-765)
Plasma concentrations of the antioxidant vitamin ascorbic acid were measured by high-performance liquid chromatography in critically ill patients in whom the excessive generation of reactive oxygen species could compromise antioxidant defense mechanisms. Median concentrations of both total vitamin C (ascorbic acid and dehydroascorbic acid) and ascorbic acid in these patients were < 25% (P < 0.001) of the values found in healthy control subjects and in subjects in two other disease groups (diabetes, gastritis) in which reactive oxygen species are reported to be increased. The low values could not be explained by age, sex, intake, or treatment differences, but were associated with the severity of the illness and were not prevented by the use of parenteral nutrition containing ascorbic acid. In addition, the vitamin was less stable in blood samples taken from critically ill patients than in similar samples from subjects in the other groups. The findings indicate that antioxidant defenses could be considerably compromised in these very sick patients. If this reduces the patient's capacity to scavenge reactive species, then the potential of these species to damage DNA and lipid membranes could be increased and compromise recovery.
Leukocyte lipid peroxidation, superoxide dismutase, glutathione peroxidase and serum and leukocyte vitamin C levels of patients with type II diabetes mellitus
Clinica Chimica Acta (Netherlands), 1996, 244/2 (221-227)
In the present study, leukocyte lipid peroxidation, superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and serum and leukocyte vitamin C levels of patients with type II diabetes mellitus and healthy controls were investigated. Patients consisted of 53 cases (23 male, 30 female) aged 35-75 years and controls of 34 subjects (15 male, 19 female) aged 34-66 years. Leukocyte lipid peroxidation of diabetics was significantly increased (P < 0.05) whereas vitamin C level was decreased (P < 0.05) compared to those of controls. There was no significant difference in the other parameters. Also, there was no correlation between the above parameters and HbA1c and glucose levels. Our results show that leukocytes of diabetics are affected by oxidative stress which might be a reason for decreased microbicidal activity.
Erythrocyte and plasma antioxidant activity in type I diabetes mellitus
Presse Medicale (France), 1996, 25/5 (188-192)
Objectives: Some biologic parameters involved in cell defence against oxygen radicals (plasmatic vitamins C and E, erythrocyte glutathione peroxidase, glutathione reductase and superoxide dismutase) were measured in single blood samples from 119 diabetic infants, adolescents and young adults. Methods: Data were studied in relation to residual insulin secretion determined by C peptide, level of metabolic control appreciated by glycosylated haemoglobin, lipid abnormalities and subclinical complications (retinopathy, neuropathy and nephropathy). Results: There was no change in antioxidant parameters with insulin secretion. Patients with poor glycaemic control and high plasma lipids had higher levels of plasma vitamin E. Patients with nephropathy had lower plasma vitamin C levels and those with neuropathy showed lower erythrocyte glutathione peroxidase activity. Plasma vitamin C concentrations and erythrocyte glutathione reductase activities were negatively correlated with the age of the patients and the duration of the disease. Conclusion: Higher transport capacity of vitamin E probably explains the elevated levels of vitamin E observed in patients with high lipid levels and long lasting illness. The lower levels of vitamin C in the presence of nephropathy may be due to an increased renal excretion of this vitamin. The reduction of glutathione peroxidase, glutathione reductase activities and vitamin C levels confirms the existence of an oxidative stress in type 1 diabetes.
Vitamin C improves endothelium-dependent vasodilation in patients with non-insulin-dependent diabetes mellitus
Journal of Clinical Investigation (USA), 1996, 97/1 (22-28)
Endothelium-dependent vasodilation is impaired in humans with diabetes mellitus. Inactivation of endothelium-derived nitric oxide by oxygen-derived free radicals contributes to abnormal vascular reactivity in experimental models of diabetes. To determine whether this observation is relevant to humans, we tested the hypothesis that the antioxidant, vitamin C, could improve endothelium-dependent vasodilation in forearm resistance vessels of patients with non-insulin-dependent diabetes mellitus. We studied 10 diabetic subjects and 10 age-matched, nondiabetic control subjects. Forearm blood flow was determined by venous occlusion plethysmography. Endothelium-dependent vasodilation was assessed by intraarterial infusion of methacholine (0.3-10 microg/min). Endothelium-independent vasodilation was measured by intraarterial infusion of nitroprusside (0.3-10 microg/min) and verapamil (10-300 microg/min). Forearm blood flow dose-response curves were determined for each drug before and during concomitant intraarterial administration of vitamin C (24 mg/min). In diabetic subjects, endothelium-dependent vasodilation to methacholine was augmented by simultaneous infusion of vitamin C (P = 0.002); in contrast, endothelium-independent vasodilation to nitroprusside and to verapamil were not affected by concomitant infusion of vitamin C (P = 0.9 and P = 0.4, respectively). In nondiabetic subjects, vitamin C administration did not alter endothelium-dependent vasodilation (P = 0.8). We conclude that endothelial dysfunction in forearm resistance vessels of patients with non- insulin-dependent diabetes mellitus can be improved by administration of the antioxidant, vitamin C. These findings support the hypothesis that nitric oxide inactivation by oxygen-derived free radicals contributes to abnormal vascular reactivity in diabetes.
[Comparison of metabolism of water-soluble vitamins in healthy children and in children with insulin-dependent diabetes mellitus depending upon the level of vitamins in the diet]
Vopr Med Khim (RUSSIA) Apr-Jun 1996, 42 (2) p153-8
Metabolism of vitamins C, B2, B6 and niacin in children with insulin-dependent diabetes mellitus was distinctly different from that of healthy persons of the same age as shown by studies of the correlation between content of vitamins or their coenzyme forms in blood, excretion of the vitamins with urine and content of the vitamins in a diet. These data corroborated once again that in estimation of the vitamins consumption suitable for ill children, the criteria of healthy children requirements for vitamins should not be taken into consideration. Dissimilar metabolism in healthy and impaired persons may also demonstrate some differences in consumption of these vitamins. Preliminary data showed that requirements of the impaired children for vitamin C were slightly increased, for vitamin B2--similar or slightly decreased as compared with healthy children. These results suggest that additional investigations are required for evaluation of vitamins consumption in children with diabetes mellitus of the I type.
[Erythrocyte and plasma antioxidant activity in diabetes mellitus type I] Activite anti-oxydante erythrocytaire et plasmatique dans le diabete de type I.
Presse Med (FRANCE) Feb 10 1996, 25 (5) p188-92
OBJECTIVES: Some biologic parameters involved in cell defence against oxygen radicals (plasmatic vitamins C and E, erythrocyte glutathione peroxidase, glutathione reductase and superoxide dismutase) were measured in single blood samples from 119 diabetic infants, adolescents and young adults. METHODS: Data were studied in relation to residual insulin secretion determined by C peptide, level of metabolic control appreciated by glycosylated haemoglobin, lipid abnormalities and subclinical complications (retinopathy, neuropathy and nephropathy). RESULTS: There was no change in antioxidant parameters with insulin secretion. Patients with poor glycaemic control and high plasma lipids had higher levels of plasma vitamin E. Patients with nephropathy had lower plasma vitamin C levels and those with neuropathy showed lower erythrocyte glutathione peroxidase activity. Plasma vitamin C concentrations and erythrocyte glutathione reductase activities were negatively correlated with the age of the patients and the duration of the disease. CONCLUSION: Higher transport capacity of vitamin E probably explains the elevated levels of vitamin E observed in patients with high lipid levels and long lasting illness. The lower levels of vitamin C in the presence of nephropathy may be due to an increased renal excretion of this vitamin. The reduction of glutathione peroxidase, glutathione reductase activities and vitamin C levels confirms the existence of an oxidative stress in type I diabetes.
Hyperglycemia-induced latent scurvy and atherosclerosis: the scorbutic-metaplasia hypothesis.
Med Hypotheses (ENGLAND) Feb 1996, 46 (2) p119-29
Latent scurvy is characterized by a reversible atherosclerosis that closely resembles the clinical form of this disease. Acute scurvy is characterized by microvascular complications such as widespread capillary hemorrhaging. Vitamin C (ascorbate) is required for the synthesis of collagen, the protein most critical in the maintenance of vascular integrity. We suggest that in latent scurvy, large blood vessels use modified LDL--in particular lipoprotein(a)--in addition to collagen to maintain macrovascular integrity. By this mechanism, collagen is spared for the maintenance of capillaries, the sites of gas and nutrient exchange. The foam-cell phenotype of atherosclerosis is identified as a mesenchymal genetic program, regulated by the availability of ascorbate. When vitamin C is limited, foam cells develop and induce oxidative modification of LDL, thereby stabilizing large blood vessels via the deposition of LDL. The structural similarity between vitamin C and glucose suggests that hyperglycemia will inhibit cellular uptake of ascorbate, inducing local vitamin C deficiency. (136 Refs.)
[Vitamin metabolism in children with insulin-dependent diabetes mellitus. Effect of length of illness, severity, and degree of disruption of substance metabolism]
Vopr Med Khim (RUSSIA) Jul-Aug 1994, 40 (4) p33-8
Correlation between the state of vitamin metabolism and the impairments in carbohydrate, lipid and protein metabolism was studied in 35 children of 9-13 years of age with diabetes mellitus of various severity standing for up to 7 years. Deterioration of riboflavin metabolism in insulin-dependent diabetes mellitus, expressed as an increase of the vitamin excretion with urine, was augmented with prolongation of the disease duration; the deterioration was sometimes related to the value of glycemia and glucosuria, being the indicative symptom of the disease. In spite of some limitations in validity of experiments related to insufficient number of children in some groups, a decrease in excretion of 1-methyl nicotinamide with urine was detected in all the children with the comatose state, in acidoketosis and glucosuria (above 20 g/day), whereas normal content of nicotinamide coenzymes was found in erythrocytes. Deficiency in vitamins B1, B6 and C was observed more often (5-100%) in children with elevated content of cholesterol as compared with 7-67% of children exhibiting normal level of cholesterol. Optimization of vitamins B and C consumption in children as well as use of any means for correction of these vitamins deficiency are discussed.
Malnutrition in geriatric patients: diagnostic and prognostic significance of nutritional parameters.
Ann Nutr Metab (SWITZERLAND) 1992, 36 (2) p97-112
Nutritional status was assessed in 300 geriatric patients aged 75 years or more using clinical, anthropometric, biochemical and immunologic methods. Relations between different assessment methods and their prognostic significance with regard to 18-month mortality were examined. For biochemical variables 10% (prealbumin, vitamin B6) to 37% (vitamins A and C) were below conventional limits. In 44% of the patients lymphocytes were diminished. 44% were anergic. Judgement of nutritional status by clinical impression resulted in 22% being deemed undernourished. Clinical diagnosis of undernutrition was associated with low anthropometric measurements (p less than 0.05 for all parameters) and a high prevalence of low biochemical values (p less than 0.05 for albumin, prealbumin, transferrin, vitamin A, vitamin B1). The mean values of all anthropometric variables, plasma proteins, vitamins A and C were significantly lower in patients who died within the following 18 months compared to survivors. The greatest prognostic significance was related to the clinical diagnosis of malnutrition. We conclude that clinical assessment is useful for the evaluation of nutritional status in geriatric patients and the best of numerous nutritional parameters to estimate risk of long-term mortality.
Effects of oral contraceptives on nutritional status.
Am Fam Physician (UNITED STATES) Jan 1979, 19 (1) p119-23
Major effects of oral contraceptives on nutritional status are elevation of triglycerides, decline in glucose tolerance, an apparent increase in the need for folate and vitamins C, B2 and B6, and a decrease in iron loss. Women at greater risk of nutritional deficits due to oral contraceptives include those who have just had a baby, are planning to have a baby later, already show nutritional deficiencies, have had recent illness or surgery, have poor dietary habits, are still growing or have a family history of diabetes or heart disease.
Ascorbate administration to normal and cholesterol-fed rats inhibits in vitro TBARS formation in serum and liver homogenates.
Life Sci (ENGLAND) 1996, 58 (14) p1101-8
We have recently shown that ascorbate has a hypocholesterolemic and hypotriglyceridemic effect on rats fed a diet enriched with 1.5% cholesterol and 25% hydrogenated coconut oil (Nath diet). In this study we evaluated the effect of intraperitoneal ascorbate administration on susceptibility to lipoperoxidation either in rats fed standard or Nath diet. In normal rats ascorbate treatment decreased (p<0.05) the susceptibility to lipoperoxidation induced by incubation of serum for 24 hours with 2.2 mM Cu++, without altering the normal serum fatty acid profile. In rats fed Nath diet we observed a reduced susceptibility of serum to CU++-induced lipoperoxidation (36%), according with their low levels of serum unsaturated fatty acids (40% less than rats fed standard diet). In these animals ascorbate administration affects serum fatty acid profile leading to a decrease of S/U ratio from 1.6 to 1.2 without significantly modifying the susceptibility of serum to lipoperoxidation. Moreover, the production of spontaneous lipid peroxides in liver homogenates, measured as TBARS levels, was strongly inhibited by ascorbate (p<0.01) in rats fed either standard or Nath diet. These data indicate that ascorbate administration exerts an antioxidant effect and that in hypercholesterolemic rats, in addition to a lipid lowering effect, ascorbate exerts a protective role against the peroxidative damage of lipids.
Vitamin C supplementation and common cold symptoms: Problems with inaccurate reviews
Nutrition (USA), 1996, 12/11-12 (804-809):
In 1971, Linus Pauling carried out a meta-analysis of four placebo- controlled trials and concluded that it was highly unlikely that the decrease in the 'integrated morbidity of the common cold' in vitamin C groups was caused by chance alone (P < 0.00003). Studies carried out since then have consistently found that vitamin C (less than or equal to 1 g/d) alleviates common cold symptoms, indicating that the vitamin does indeed have physiologic effects on colds. However, widespread conviction that the vitamin has no proven effects on the common cold still remains. Three of the most influential reviews drawing this conclusion are considered in the present article. Two of them are cited in the current edition of the RDA nutritional recommendations as evidence that vitamin C is ineffective against colds. In this article, these three reviews are shown to contain serious inaccuracies and shortcomings, making them unreliable sources on the topic. The second purpose is to suggest possible conceptual reasons for the persistent resistance to the notion that vitamin C might have effects on colds. Although placebo-controlled trials have shown that vitamin C does alleviate common cold symptoms, important questions still remain.
Vitamin C, the placebo effect, and the common cold: A case study of how preconceptions influence the analysis of results
Journal of Clinical Epidemiology (USA), 1996, 49/10 (1079-1085,1087)
A large number of placebo controlled studies have shown that vitamin C supplementation alleviates the symptoms of the common cold, but widespread skepticism that vitamin C could have any significant effect remains. One of the most influential common cold studies, published in 1975, was carried out by Thomas Karlowski et al. at the National Institutes of Health. Their placebo consisted of lactose, which can easily be distinguished from ascorbic acid by taste. Karlowski et al. found a 17% decrease in the duration of cold episodes in the group administered vitamin C (6 g/day); however, they suggested that the decrease was entirely due to the placebo effect. In this article it will be shown that the placebo effect is not a valid explanation for the results of the Karlowski study, as it is inconsistent with their results. This is an important conclusion for two reasons. First, the placebo explanation becomes even more unreasonable as regards the reported benefits found in several other studies with valid placebo tablets. Second, as the results from the Karlowski study are not due to the placebo effect, their results can be used to assess the quantitative effects of vitamin C supplementation. The most important conclusions from Karlowski's study are that therapeutic vitamin C supplementation during a common cold episode appears to be as effective as regular supplementation, and that there appears to be linear dose dependency at least up to 6 g/day. These findings suggest that large therapeutic vitamin C doses might alleviate the symptoms of the common cold substantially.
Vitamin C and common cold incidence: A review of studies with subjects under heavy physical stress
International Journal of Sports Medicine (Germany), 1996, 17/5 (379-383)
Several studies have observed an increased risk of respiratory infections in subjects doing heavy physical exercise. Vitamin C has been shown to affect some parts of the immune system, and accordingly it seems biologically conceivable that it could have effects on the increased incidence of respiratory infections caused by heavy physical stress. In this report the results of three placebo-controlled studies that have examined the effect of vitamin C supplementation on common cold incidence in subjects under acute physical stress are analyzed. In one study the subjects were school-children at a skiing camp in the Swiss Alps, in another they were military troops training in Northern Canada, and in the third they were participants in a 90 km running race. In each of the three studies a considerable reduction in common cold incidence in the group supplemented with vitamin C (0.6-1.0 g/day) was found. The pooled rate ratio (RR) of common cold infections in the studies was 0.50 (95% CI: 0.35-0.69) in favour of vitamin C groups. Accordingly, the results of the three studies suggest that vitamin C supplementation may be beneficial for some of the subjects doing heavy exercise who have problems with frequent upper respiratory infections.
Social ties and susceptibility to the common cold.
JAMA (UNITED STATES) Jun 25 1997, 277 (24) p1940-4
OBJECTIVE: To examine the hypothesis that diverse ties to friends, family, work, and community are associated with increased host resistance to infection. DESIGN: After reporting the extent of participation in 12 types of social ties (eg, spouse, parent, friend, workmate, member of social group), subjects were given nasal drops containing 1 of 2 rhinoviruses and monitored for the development of a common cold. SETTING: Quarantine. PARTICIPANTS: A total of 276 healthy volunteers, aged 18 to 55 years, neither seropositive for human immunodeficiency virus nor pregnant. OUTCOME MEASURES: Colds (illness in the presence of a verified infection), mucus production, mucociliary clearance function, and amount of viral replication. RESULTS: In response to both viruses, those with more types of social ties were less susceptible to common colds, produced less mucus, were more effective in ciliary clearance of their nasal passages, and shed less virus. These relationships were unaltered by statistical controls for prechallenge virus-specific antibody, virus type, age, sex, season, body mass index, education, and race. Susceptibility to colds decreased in a dose-response manner with increased diversity of the social network. There was an adjusted relative risk of 4.2 comparing persons with fewest (1 to 3) to those with most (6 or more) types of social ties. Although smoking, poor sleep quality, alcohol abstinence, low dietary intake of vitamin C, elevated catecholamine levels, and being introverted were all associated with greater susceptibility to colds, they could only partially account for the relation between social network diversity and incidence of colds. CONCLUSIONS: More diverse social networks were associated with greater resistance to upper respiratory illness.
Vitamin C and the common cold: a retrospective analysis of Chalmers' review
J Am Coll Nutr (UNITED STATES) Apr 1995
In 1975 Thomas Chalmers analyzed the possible effect of vitamin C on the common cold by calculating the average difference in the duration of cold episodes in vitamin C and control groups in seven placebo-controlled studies. He found that episodes were 0.11 +/- 0.24 (SE) days shorter in the vitamin C groups and concluded that there was no valid evidence to indicate that vitamin C is beneficial in the treatment of the common cold. Chalmers' review has been extensively cited in scientific articles and monographs. However, other reviewers have concluded that vitamin C significantly alleviates the symptoms of the common cold. A careful analysis of Chalmers' review reveals serious shortcomings. For example, Chalmers did not consider the amount of vitamin C used in the studies and included in his meta-analysis was a study in which only 0.025-0.05 g/day of vitamin C was administered to the test subjects. For some studies Chalmers used values that are inconsistent with the original published results. Using data from the same studies, we calculated that vitamin C (1-6 g/day) decreased the duration of the cold episodes by 0.93 +/- 0.22 (SE) days; the relative decrease in the episode duration was 21%. The current notion that vitamin C has no effect on the common cold seems to be based in large part on a faulty review written two decades ago.
Interrelation of vitamin C, infection, haemostatic factors, and cardiovascular disease
BMJ (ENGLAND) Jun 17 1995, 310 (6994) p1559-63
OBJECTIVE--To examine the hypothesis that the increase in fibrinogen concentration and respiratory infections in winter is related to seasonal variations in vitamin C status (assessed with serum ascorbate concentration). DESIGN--Longitudinal study of individuals seen at intervals of two months over one year. SETTING--Cambridge. SUBJECTS--96 men and women aged 65-74 years living in their own homes. MAIN OUTCOME MEASURES--Haemostatic factors fibrinogen and factor VIIC; acute phase protein; respiratory symptoms; respiratory function. RESULTS--Mean dietary intake of vitamin C varied from about 65 mg/24 h in winter to 90 mg/24 h in summer; mean serum ascorbate concentration ranged from 50 mumol/l in winter to 60 mumol/l in summer. Serum ascorbate concentration was strongly inversely related to haemostatic factors fibrinogen and factor VIIC as well as to acute phase proteins but not to self reported respiratory symptoms or neutrophil count. Serum ascorbate concentration was also related positively to forced expiratory volume in one second. An increase in dietary vitamin C of 60 mg daily (about one orange) was associated with a decrease in fibrinogen concentrations of 0.15 g/l, equivalent (according to prospective studies) to a decline of approximately 10% in risk of ischaemic heart disease. CONCLUSION--High intake of vitamin C has been suggested as being protective both for respiratory infection and for cardiovascular disease. These findings support the hypothesis that vitamin C may protect against cardiovascular disease through an effect on haemostatic factors at least partly through the response to infection; this may have implications both for our understanding of the pathogenetic mechanisms in respiratory and cardiovascular disease and for the prevention of such conditions.
Does vitamin C alleviate the symptoms of the common cold?--a review of current evidence.
Scand J Infect Dis (SWEDEN) 1994, 26 (1) p1-6
Since 1971, 21 placebo-controlled studies have been made to establish whether vitamin C at a dosage of > or = 1 g/day affects the common cold. These studies have not found any consistent evidence that vitamin C supplementation reduces the incidence of the common cold in the general population. Nevertheless, in each of the 21 studies, vitamin C reduced the duration of episodes and the severity of the symptoms of the common cold by an average of 23%. However, there have been large variations in the benefits observed, and clinical significance cannot be clearly inferred from the results. Still, the consistency of the results indicates that the role of vitamin C in the treatment of the common cold should be reconsidered.
Recommended dietary allowance: support from recent research.
J Nutr Sci Vitaminol (Tokyo) (JAPAN) 1992, Spec No p173-6
Increasing evidence is accumulating that a synergistic role of the so-called antioxidant vitamins (C, E, beta-carotene) may have a dominant role in the prevention of cancer, cardiovascular diseases and cataract formation. Controversy still exists regarding the optimum intake of vitamin C. This is partly due to lack of accurate and easily accessible health-relevant end-points, and lack of knowledge of the role of vitamin C in biochemical functions. Today, it is clearly recognized and broadly accepted that optimal health is a consequence of dietary optimization. Attainment of optimal health rather than prevention of deficiency symptoms is the goal. There can be little doubt that in this respect the requirements for vitamin C are greater than the amount required for the mere prevention of overt or classical scurvy. The recommendation of varying levels of requirement could overcome the controversy. The following is therefore proposed: The lowest level is that value which prevents deficiency symptoms. The second level is valid for healthy populations (< 200 mg/d). This level would take into account needs which differ according to age, sex, physical activity, physiological status (e.g. pregnancy or lactation) and environmental factors such as smoking, pollution and alcohol intake. Finally, a third level should be determined for the prevention of the above-mentioned non-communicable diseases. These diseases are an important cause of disability, resulting in costs of billions of dollars annually in medical costs. Many of the above-mentioned diseases can be prevented by supplementation with vitamin C. Medical costs could thereby also be dramatically reduced.
Vitamin C and the common cold.
Br J Nutr (ENGLAND) Jan 1992, 67 (1) p3-16
The effect of vitamin C on the common cold has been the subject of several studies. These studies do not support a considerable decrease in the incidence of the common cold with supplemental vitamin C. However, vitamin C has consistently decreased the duration of cold episodes and the severity of symptoms. The benefits that have been observed in different studies show a large variation and, therefore, the clinical significance may not be clearly inferred from them. The biochemical explanation for the benefits may be based on the antioxidant property of vitamin C. In an infection, phagocytic leucocytes become activated and they produce oxidizing compounds which are released from the cell. By reacting with these oxidants, vitamin C may decrease the inflammatory effects caused by them. Scurvy, which is caused by a deficiency in vitamin C, is mostly attributed to the decreased synthesis of collagen. However, vitamin C also participates in several other reactions, such as the destruction of oxidizing substances. The common cold studies indicate that the amounts of vitamin C which safely protect from scurvy may still be too low to provide an efficient rate for other reactions, possibly antioxidant in nature, in infected people.
Vitamin C and the common cold: using identical twins as controls.
Med J Aust (AUSTRALIA) Oct 17 1981, 2 (8) p411-2
We analysed self-reported cold data for 95 pairs of identical twins who took part in a double-blind trial of vitamin C tablets. One member of each twin pair took vitamin C and the other took a well matched placebo each day for 100 days. Vitamin C had no significant effect except for shortening the average duration of cold episodes by 19%.
The effects of ascorbic acid and flavonoids on the occurrence of symptoms normally associated with the common cold.
Am J Clin Nutr (UNITED STATES) Aug 1979, 32 (8) p1686-90
A controlled study was made of the effects of natural orange juice, synthetic orange juice, and placebo in the prevention of the common cold; both natural and synthetic orange juices contained 80 mg of ascorbic acid daily. Three-hundred sixty-two healthy normal young adult volunteers, ages 17 to 25 years, were studied for 72 days with 97% of participants completing the trial. There was a 14 to 21% reduction in total symptoms due to the common cold in the supplemented groups that was statistically significant (P less than 0.05). Ascorbic acid supplementation also increased the number of "episode-free" subjects. However, the clinical usefulness of the results does not support prophylactic ascorbic acid supplements in the well-nourished adult. The results in this study with both natural and synthetic orange juice of physiological content of ascorbic acid, are similar to those obtained using a "megadose" of ascorbic acid.
Winter illness and vitamin C: the effect of relatively low doses.
Can Med Assoc J (CANADA) Apr 5 1975, 112 (7) p823-6
After their random -llocation to one of three treatment aroups, 622 volunteers received either vitamin C or placebo in a maintenance dose of 500 mg once weekly and a therapeutic dose of 1500 mg daily on the 1st day and 1000 mg on the next 4 days of any illness. Two forms of vitamin C were employed: a sustained-release capsule containing ascorbic acid and a regular tabet containing a mixture of sodium and calcium ascorbate. In the 448 subjects who completed an average of 15 weeks in the study of total of 635 episodes of illness were recroded. Respiratory symptoms were recorded on at least 1 day in 92 per cent of these episodes. There were no consistent or significant differences in the sickness experience of the subjects receiving the sustained-release vitamin capsules compared to those receiving the vitamin tablets, but subjects in both vitamin groups experienced less severe illness than subjects in the placebo group, with approximately 25 per cent fewer days spent indoors because of the illness (P smaller than 0.05). These results are compatible with the belief that supplementary vitamin C can reduce the burden of winter illness, but the intake need not be as high as has sometimes been claimed.
51Cr release and oxidative stress in the lens.
Lens Eye Toxic Res (UNITED STATES) 1989, 6 (1-2) p183-202
Examination of the opaque areas of human cortical cataracts has shown that a large portion of the opacity could be attributed to the globules found there. We tested models involving globule formation as a result of oxidative damage to rat lens cells in culture and whole chick embryo lenses. When cell monolayers from a lens cell line were exposed to oxidizing conditions they developed globules on the cell surface. The cells were protected from damage by the addition of glutathione and vitamin C. Thirteen-day chick embryo lenses were also incubated in oxidizing conditions and the amount of cellular damage was assessed using a chromium-51 release assay we have developed. After 24 hr the percent 51Cr in the medium increased by an average of 20% as a result of 10 mM hydrogen peroxide treatment. The addition of the 10 mM vitamin C to the hydrogen peroxide significantly reduced the 51Cr leakage to the control level. Light microscopy of sections of the lens showed a breakdown of the equatorial fibre arrangement in the presence of H2O2, while addition of vitamin C restored the fibre organization to almost normal. The findings suggest that oxidative stress is an important step in cataractogenesis and point towards the use of water soluble antioxidants as protective agents.
Enhancement of the antineoplastic effect of anticarcinogens on benzo[a]pyrene-treated Wistar rats, in relation to their number and biological activity.
Cancer Lett. 1994 Jul 29. 82(2). P 153-65
Naturally occurring anticarcinogens, such as vitamins C and E, and the microelement selenium were found to inhibit the induction of benzo[a]pyrene-induced malignant tumors in Wistar rats to various extends. The antineoplastic effect of the tested anticarcinogens is gradually increased according to the number of inhibitors selected. To date the maximum action against malignancy is manifested by use of the above three inhibitors. In the group of rats receiving vitamins C, E and selenium, the prolongation of life induced by adding more than one anticarcinogen to the treatment regime reached, and in some cases surpassed, the normal life expectancy of the rats. It is expected that by adding even more anticarcinogens, the antineoplastic potency (Ap) of the inhibitors will be further improved. These results encouraged us to conduct a clinical trial in terminal human cancer cases, in conjunction with the usual treatments of surgery or chemotherapy and irradiation.
Critical reappraisal of vitamins and trace minerals in nutritional support of cancer patients.
Support Care Cancer. 1993 Nov. 1(6). P 295-7
The potential of a high intake of fresh fruits and vegetables in cancer prevention is well established. Epidemiological studies support carotene, vitamins A, C, E and selenium as the active compounds. Antioxidant properties and direct effects (e.g. inhibition of N-nitrosamine formation or cell-to-cell interactions) are invoked. The role of other trace elements is less clear. The modulation of immune function by vitamins and trace elements remains important and affects survival. In established cancers, the site-specific differences in the diet/cancer relation require appropriate dietary changes, e.g. low fat (20% by energy) in breast cancer, or high vegetable or fruit intake in lung cancer. Single high-dose supplements (e.g. vitamin C) have proved to have no curative or life-prolonging effect. Chemotherapy and radiation increase the requirements for antioxidant compounds. Supplementation can diminish the damage induced by peroxidation. Carefully planned and monitored trials that establish the optimal intake of micronutrients as adjuvants in cancer patients are required.
