Pharmacological Data of Multi- Vitamins Plus minerals(Trace Elements)

Trace Elements

Trace elements are inorganic substance found in small amounts in the tissue and required for various metabolic processes; together with the vitamins (see below) they are sometimes referred to as micronutrients. The elements considered essential are chromium, copper, fluorine, iodine, iron, manganese, molybdenum, selenium, and zinc. Iron, in the form of haem, plays an essential role in oxygen transport while iodine is required by the thyroid for the formation of thyroid hormones; most of the other essential trace elements are cofactors for various enzymes. Boron, nickel, silicon, and vanadium may also be essential, and it has been suggested on the basis of animal studies that there might be a requirement for tin.

Well-defined deficiency syndromes exist for copper, iodine, iron, selenium, and zinc; although deficiency of other trace elements is possible, their deficiency syndromes are not well defined because of their ubiquity in the diet. Guidance concerning the intake of various trace elements has been published—see also Human Requirements under Vitamins, below.

Vitamins

Vitamins are organic substance required by the body in small amounts for various metabolic processes. Most are not synthesized in the body, or are synthesised in small or insufficient quantities. Vitamins are sometimes classified as fat soluble or water soluble. Substances in the vitamin A, D, E, and K groups are generally fat soluble, and biotin, folic acid, niacin, pantothenic acid, vitamins B₁, B₂, B₆, and B₁₂, and vitamin C substances are generally water soluble.

Vitamin deficiency may result from an inadequate diet, perhaps due to increased requirements such as during pregnancy, or may be induced by disease or drugs. Vitamin may be used clinically for the prevention and treatment of specific vitamin deficiency states and details of these uses are provided under the individual drug monographs.

Large doses of vitamins (megavitamin therapy) have been proposed for a variety of disorders, but adequate evidence of their value is lacking. Excessive intakes of most water-soluble vitamins have little effect due to their rapid excretion in urine, but excessive intakes of fat-soluble vitamins accumulate in the body and are potentially dangerous.

Stability.

Water-soluble vitamins are liable to degrade in solution especially if exposed to light. Addition of vitamin mixtures to infusion solutions for parenteral nutrition should therefore be carried out as possible before infusion. Solutions should be used within 24 hours of preparation and be protected from light.

Human requirements.

Vitamin and trace elements are essential nutrients and in many countries guidance has been published concerning their intake.

In the UK various terms are used to define intake:

· Estimated average requirement (EAR) is used for the requirements of energy, proteins, vitamins, or minerals of a group of people and usually about half will need more and half less than the specified figure.

· Lower reference nutrient (LRN) is applied to proteins, vitamins, or minerals and is that amount that is enough for only a few people who have low needs.

· Reference nutrient intake (RNI) is also applied to proteins, vitamins, or minerals and is an amount that is enough, or more than enough, for about 97% of people in a group.

· A safe intake is used to indicate an intake or range of intakes where there is not enough information to estimate EAR, LRNI, or RNI, but rather it is an amounts enough for almost everyone but is not so large as to cause undesirable effects.

· Dietary reference value (DRV) is used to cover EAR, LRNI, RNI, and safe intake.

It is emphasised in the report that these intakes are not meant to be recommendation for any individual or group; they do not reflect either a recommendation that such an amount should be taken daily in the diet or as a supplement. They are intended rather as yardsticks for the assessment of dietary surveys and food supply statistics; to provide guidance on appropriate dietary composition and meal provision; or for food labeling purposes in which case it is envisaged that an ERA will be used.

In the USA the National Academy of Science has traditionally set recommended dietary allowances (RDAs), defined as the levels of intake of essential nutrients that, on the basis of scientific knowledge, are judged to be adequate to meet the known nutrient needs of practically all healthy persons. The allowances are amounts that are intended to be consumed as part of a normal diet. However, new dietary reference intakes (DRIs) are being developed, which will include 3 reference values in addition to the traditional RDA as follows:

• The estimated average requirement is the intake that meets the needs of half the individuals in a group
• The adequate intake is the mean intake level that appears to sustain a desired marker of health, and will be set when there is insufficient evidence to establish an RDA
• The tolerable upper intake level is the maximum intake that is not likely to adversely affect health.

Information pertaining to the requirements of specific vitamins and minerals is provided under the individual monographs.

Supplement

An adequate dietary intake of vitamins is necessary for good health but whether vitamin supplementation in the absence of any demonstrable deficiency is beneficial or even worthwhile remains debatable.

It is generally considered that healthy persons eating a normal balanced diet should have no need for vitamin supplementation. A review of the topic pointed out that the vitamins that people chose foe self medication are often not the ones that are actually present in inadequate amounts in their diets and that the commercial preparations available often do not make it clear whether the amounts or many times greater. Supplementation should concentrate on groups of people at risk of deficiency such as neonate, who need vitamin K; pregnant and lactating women, who need calcium, folic acid, and iron; and certain groups, who need vitamin D; vegans and their infants may require vitamin B₁₂ supplements. A multivitamin supplement might be considered for some groups such as the elderly and those with reduced calorie intake. However, one might have difficulty in finding a good multivitamin preparation containing all 13 vitamins bit no non-vitamins. Also with many of the multivitamin preparation the doses and ratios varied inexplicably.

A review of supplementation specifically in children concluded that, provided school children and adolescents eat a wide variety of foods, there was no need for vitamin supplementation. However, it was recommended that supplementation with vitamins A, C, and D should be given to those between the ages of 6 month and 2 years and preferably up to the age of 5 years.

A subsequent study supports the suggestion that supplementation may be of some benefit in the elderly. Supplementation ments resulted in an improvement in immune response and a decreased frequency of infection in elderly subjects. It was suggested that dosage might be crucial and that excessive doses of micronutrients could impair rather than improve immune response.

MENTAL FUNCTION. Administration of vitamin and mineral supplement to children was reported in 1988 to increase non-verbal intelligence and the topic has science remained highly controversial. In the following two years more studies were published but these failed to substantiate the earlier possible effect and concluded that vitamin supplementation did not improve mental functioning or reasoning in children. Suggestions were made shortly after these publications that there might be a subset of children with poor nutritional status who would receive some benefit but this again was disputed.

In 1991 another study was published, this time coinciding with the lunch of the proprietary product used in the study, with the publication of a book on the subject, and with the showing on British television of a documentary concerning the study. This study purported to demonstrate that supplementation with exactly the recommended dietary allowance of vitamin improved the IQ of children, a finding that was said not to occur significantly with other quantities of vitamin supplementation. This view attracted extremely harsh criticism from physicians, nutritionists, psychologists, and epidemiologists.

PROPHYLAXIS OF ISCHAEMIC HEART DISEASE. Hypercholesterolaemia is a major risk factor for the development of atherosclerosis and consequently ischemic heart disease. Since oxidation of lipids, particularly low-density-lipoprotein (LDL) cholesterol has been proposed as a factor in atherogenesis, the possibility of preventing atherosclerosis by the use of dietary antoxidants such as vitamin E and C and betacarotene has been investigated. Prospective epidemiological studies have revealed a reduced risk of ischaemic heart disease in individuals taking vitamin E supplement, and those with a high carotene intake (particular smoker). In a further prospective cohort study, dietary vitamin E consumption, but not vitamin E supplementation, was associated with decreased risk of death from ischaemic heart disease. Conversely, in these studies, intake of vitamin C did not appear to be associated with a decreased risk of ischaemic heart disease. Data from some studies assessing serum or fat concentrations also provide evidence that high betacarotene concentrations are associated with decreased cardiovascular disease.

However, despite these promising epidemiological data, results from randomised placebo-controlled trials have failed to find any befit for betacarotene supplements in the primary or secondary prevention of inconclusive, in the Alpha Tocopherol, Beta Carotene Cancer Prevention (ATBC) study, which monitored cardiovascular disease as a secondary end-point, vitamin E was not associated with a decreased incidence of ischaemic heart disease, and betacarotene was associated with a small increased risk. In further analyses, neither supplement appreciably altered the incidence of angina pectoris, nor showed any beneficial effects on cardiovascular deaths in the subset of men with previous myocardial infractions. In has been suggested that the lack of effects of vitamin E in this study may be due to an insufficiently high dose of tocopherol. Similarly, neither the Betacarotene and Retinol Efficacy Trial (CARET) nor the Skin Cancer Prevention Study found on effects for betacartene supplementation on the risk of death from cardiovascular disease. In studies specifically on cardiovascular end-points, no benefit from betacarotene supplements was seen in a large, randomised, placebo-controlled study in healthy men, and an initial study of supplementation with high-dose vitamin E in patients with evidence of ischaemic heart disease failed to show any beneficial effects on cardiovascular deaths. However, there was a reduction in non-fatal myocardial infraction and major cardiovascular events. The Heart Outcomes Prevention Evaluation (HOPE) study also showed that vitamin E treatment for 4 to 6 years had no effect on cardiovascular events in high-risk patients. Another large-scale study is underway; the Heart Protection Study is assessing the effects of a ‘cocktail’ of vitamin E, vitamin C, and betacarotene on the development of ischaemic heart disease in high risk subjects. Until results from all studies are known, it has been recommended that the emphasis should be on consuming a balanced diet including anotoxidant-rich fruits, vegetables, and whole grains rather than vitamin supplements. For a discussion of the possibility that folic acid may reduce ischaemic heart disease through its homocysteine-lowering effects.

PROPHYLAXIS OF MALIGNANT NEOPLASMS. There is evidence that a diet rich in fruit and vegetables is associated with a lower incidence of malignant disease, particularly of the respiratory and digestive tracts. It has been hypothesised that some of the benefits of such a diet derive from the role of antoxidant vitamins such as the carotenoids and vitamins C and E in scavenging free radicals. However, it is by no means certain that these are the only, or necessary the most important, dietary components responsible for benefit, since components such as dietary fibre may also play a role. In addition, different antioxidants may vary in their properties and efficacy, and the appropriate dosage remains largely conjectural, and perhaps as a result the evidence of benefit is often conflicting.

Several clinical trials of the use of vitamin A or betacarotene in the secondary or primary prevention of malignancy have been reported. Prolongation of disease-free intervals in patients with various malignant neoplasms was reported in 1 study of betacaroten, and another reported remission of oral leukoplakia in patients treated with betacarotene and vitamin A. Vitamin A alone was reported to reduce the incidence of primary tobacco-related neoplasms in a study of patients treated surgically for lung cancer. However, other results have largely failed to substantiate any benefit for secondary prevention. No reduction in the incidence of new skin cancers, or in malignant transformation of cervical dysplasia, or in new colorectal adenomas was reported in 3 other studies. In a primary prevention study, a combination of betacarotene, vitamin E and selenium was associated with a reduction in stomach and oesophageal cancers in a population at high risk of these cancers and with a diet low in micronutrients in China. In contrast, other primary prevention studies have failed to show any benefit, and possibly some harm, from betacarotene supplements in will-nourished populations. A study in smokers showed an increase in lung cancer and associated mortality in those receiving bectacarotene (20 mg daily), but not these receiving vitamin E (50 mg daily). Similarly, an increased risk of lung cancer was noted in recipients of betacarotene (30 mg daily) with vitamin A (25 000 units daily) in another study in individual at high risk of lung cancer, and this study was stopped early as a result. A third study in healthy men found no benefit or harm for betacarotene supplements (50 mg on alternate days) in terms of incidence of malignant neoplasms, including those of the lung.

Vitamin C has also been proposed for this purpose but there is no real evidence to justify it. It certainly appears to be ineffective as adjuvant therapy in the treatment of advanced malignancy, and combination with betacarotene and vitamin E failed to show any effect in preventing colorectal adenoma. At physiological concentration vitamin C is an important antoxidant, but supplementation is unlikely to be justified in anyone eating a balanced diet.

Vitamin E substances are also known to play an important antoxidant role in the body. Animal studies have suggested that they should inhibit tumour production, and the Chinese study mentioned above found combined antoxidant therapy including vitamin E to be benefit in the primary prevention of stomach and osophageal cancers. Other studies in western populations have generally been disappointing; vitamin E had no effect on lung cancer incidence in those at risk, and did not prevent the development of new colorectal adenomas.

However, further analysis of the lung-cancer study suggests that vitamin E may have protected against prostate cancer.

Result from the Nurses’ Health study have indicated that prolonged use of multivitamins was associated with reduced risk of developing cancer of the colon. This effect was thought to be due to the folate component and could be demonstrated after 15 years of use, but not after shorter-term ingestion. Dietary folate was also associated with a modest reduction in risk for colon cancer.

At present, therefore, the only conclusion that appears uncontroversial is that a diet involving frequent consumption of fruit and vegetable is likely to be beneficial. However, given the present difficulties in treating many malignancies once they develop interest in the topic seems likely to continue.