Harri Hemilä

Vitamin C for preventing and treating the common cold

Whether vitamin C has an effect on the common cold has been a subject of controversy for at least 60 years. What does the evidence show?

Hormone-sensitive lipase is closely related to several bacterial proteins, and distantly related to acetylcholinesterase and lipoprotein lipase: Identification of a superfamily of esterases and lipases

We have sequenced a gene from Bacillus acidocaldarius which encodes an open reading frame (ORF3) of 310 amino acids. The ORF3 was found to be related to the mammalian hormone-sensitive lipase (HSL). Searching the protein data base revealed five other bacterial proteins related to the HSL. Upon further sequence comparisons this HSL-group was found to be related to the family of carboxylesterases, and to a family of lipases (lipoprotein, hepatic and pancreatic lipases). The evolutionary relationship of these serine-dependent hydrolytic enzymes has not been studied previously, and it has not been known that these proteins belong to the same superfamily. Finally, the alignment of the HSL with the bacterial proteins allowed us to infer the location of the hormone-sensitive regulatory domain of the HSL-protein.

Vitamin C and the common cold

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.

Activated polymorphonuclear leucocytes consume vitamin C

Polymorphonuclear leucocytes (PMN) are known to produce Superoxide and other oxygen derivatives upon activation as part of their microbicidal armory. Here we report that extracellular ascorbate is effectively oxidised by activated but not by resting human PMN in vitro. The oxidation of ascorbate is mainly caused by the Superoxide that is generated by the activated cells, as shown by its effective inhibition by Superoxide dismutase. However, myeloperoxidase, which may generate hypochlorite, also contributes to a significant extent. Ascorbate reduces Superoxide to peroxide, as indicated by measurements of the stoichiometry of ascorbate and oxygen consumption. These results support the notion that extracellular ascorbate may serve as an important physiological protecting agent against oxygen radical damage in inflammation.

Vitamin C intake and susceptibility to the common cold

Although the role of vitamin C in common cold incidence had been studied extensively, the level of vitamin C intake has not been unequivocally shown to affect the incidence of colds. In the present study the six largest vitamin C supplementation (> or = 1 g/d) studies, including over 5000 episodes in all, have been analysed, and it is shown that common cold incidence is not reduced in the vitamin C-supplemented groups compared with the placebo groups (pooled rate ratio (RR) 0.99; 95% CI 0.93, 1.04). Consequently these six major studies give no evidence that high-dose vitamin C supplementation decreases common cold incidence in ordinary people. Nevertheless, the analysis was continued with the hypothesis that vitamin C intake may affect common cold susceptibility in specific groups of people. It was assumed that the potential effect of supplementation might be most conspicuous in subjects with low dietary vitamin C intake. The average vitamin C intake has been rather low in the UK and plasma vitamin C concentrations are in general lower in males than in females. In four studies with British females vitamin C supplementation had no marked effect on common cold incidence (pooled RR 0.95; 95% CI 0.86, 1.04). However, in four studies with British male schoolchildren and students a statistically highly significant reduction in common cold incidence was found in groups supplemented with vitamin C (pooled RR 0.70; 95% CI 0.60, 0.81). Thus, these studies with British males indicate that vitamin C intake has physiological effects on susceptibility to common cold infections, although the effect seems quantitatively meaningful only in limited groups of people and is not very large.

Does vitamin C alleviate the symptoms of the common cold?--a review of current evidence.

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.

Vitamin C, vitamin E, and beta-carotene in relation to common cold incidence in male smokers

We evaluated the role of dietary vitamin C, vitamin E, and beta-carotene, as well as long-term vitamin E and beta-carotene supplementation, on the incidence of common cold episodes. A cohort of 21,796 male smokers was drawn from the Alpha-Tocopherol Beta-Carotene Cancer Prevention Study, which examined the effects of 50 mg per day vitamin E and 20 mg per day beta-carotene on lung cancer. Diet and background characteristics were recorded at the study entry, and subjects were queried three times per year on common cold episodes. We modeled the total number of colds during a 4-year follow-up period with Poisson regression, adjusting for covariates of dietary intake. Dietary vitamins C and E and beta-carotene had no meaningful association with common cold incidence. Long-term vitamin E and beta-carotene supplementation had no overall effect. Among subjects 65 years of age or older, the incidence of colds was slightly lower in the vitamin E group (RR = 0.95; 95% CI = 0.90–1.00); this reduction was greatest among older city dwellers who smoked fewer than 15 cigarettes per day (RR = 0.72; 95% CI = 0.62–0.83). In this male smoking population, vitamins C and E and beta-carotene had no overall association with the incidence of common cold episodes.

Modification of the Effect of Vitamin E Supplementation on the Mortality of Male Smokers by Age and Dietary Vitamin C

The Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study (1985–1993) recruited 29,133 Finnish male cigarette smokers, finding that vitamin E supplementation had no overall effect on mortality. The authors of this paper found that the effect of vitamin E on respiratory infections in ATBC Study participants was modified by age, smoking, and dietary vitamin C intake; therefore, they examined whether the effect of vitamin E supplementation on mortality is modified by the same variables. During a median follow-up time of 6.1 years, 3,571 deaths occurred. Age and dietary vitamin C intake had a second-order interaction with vitamin E supplementation of 50 mg/day. Among participants with a dietary vitamin C intake above the median of 90 mg/day, vitamin E increased mortality among those aged 50–62 years by 19% (95% confidence interval: 5, 35), whereas vitamin E decreased mortality among those aged 66–69 years by 41% (95% CI: −56, −21). Vitamin E had no effect on participants who had a dietary vitamin C intake below the median. Smoking quantity did not modify the effect of vitamin E. This study provides strong evidence that the effect of vitamin E supplementation on mortality varies between different population groups. Further study is needed to confirm this heterogeneity.

Vitamin C, the placebo effect, and the common cold: A case study of how preconceptions influence the analysis of results☆

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 Karlowskis 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.

Zinc Lozenges May Shorten the Duration of Colds: A Systematic Review

Background: A number of controlled trials have examined the effect of zinc lozenges on the common cold but the findings have diverged. The purpose of this study was to examine whether the total daily dose of zinc might explain part of the variation in the results. Methods: The Medline, Scopus and Cochrane Central Register of Controlled Trials data bases were searched for placebocontrolled trials examining the effect of zinc lozenges on common cold duration. Two methods were used for analysis: the P-values of the trials were combined by using the Fisher method and the results of the trials were pooled by using the inverse-variance method. Both approaches were used for all the identified trials and separately for the low zinc dose and the high zinc dose trials. Results: Thirteen placebo-controlled comparisons have examined the therapeutic effect of zinc lozenges on common cold episodes of natural origin. Five of the trials used a total daily zinc dose of less than 75 mg and uniformly found no effect. Three trials used zinc acetate in daily doses of over 75 mg, the pooled result indicating a 42% reduction in the duration of colds (95% CI: 35% to 48%). Five trials used zinc salts other than acetate in daily doses of over 75 mg, the pooled result indicating a 20% reduction in the duration of colds (95% CI: 12% to 28%). Conclusions: This study shows strong evidence that the zinc lozenge effect on common cold duration is heterogeneous so that benefit is observed with high doses of zinc but not with low doses. The effects of zinc lozenges should be further studied to determine the optimal lozenge compositions and treatment strategies.