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The Role of Zinc in Human Physiology and its Pharmaceutical Importance Zinc (1)

Zinc is an essential trace element for all forms of life. The significance of zinc in human nutrition and public health was recognized relatively recently. Clinical zinc deficiency in humans was first described in 1961, when the consumption of diets with low zinc bioavailability due to high phytic acid content was associated with "adolescent nutritional dwarfism" in the Middle East. Since then, zinc insufficiency has been recognized by a number of experts as an important public health issue, especially in developing countries. Occurrence in human body: (2, 3) Storage: - The human body stores between 2g and 3g of zinc. Around 60% of this is stored in the muscles, 30% in the bones and 5% in the skin. The highest concentrations of zinc are found in tissues such as the cochlea of the middle ear (hearing and balance), the eyes (vision), the male prostate (production of sperm), and all epithelial tissue, namely, our skin, which includes the entire lining of our digestive tract, from the mouth to the anal canal. Without zinc, we would not be able to survive or protect ourselves from the many potentially lethal pathogens found in our environment. Food sources: (2, 3) Food Sources: - Protein rich foods are the best source of zinc. The list below contains five of the richest food sources: - Cheddar Cheese = 3.1mg per 100g. - Peanuts = 6.6mg per 100g. - Pumpkin Seeds = 10mg per 100g. - Roast Beef = 10mg per 100g. - Roast Lamb = 4.1mg per 100g Characteristic manifestations of the Deficiency of Zinc: (1) Since zinc is found throughout the human body, evidence of zinc deficiency can cause a wide range of signs and symptoms that affect virtually every organ or tissue in the human body. Clinical manifestations of human zinc deficiency include: alopecia, skin lesions, immune deficiencies, behavioural disturbances, night blindness, impaired taste (hypoheusia), wound healing, eating disorders, and in children and adolescents, growth retardation and delayed sexual maturation, respectively. Zinc is also important in arthroses (rheumatoid and osteoarthritis) and connective tissue disorders because of its role in collagen synthesis. And zinc deficiency can

cause a decrease in insulin response and impaired glucose metabolism and regulation, both factors important to diabetics or in the prevention of adult-onset diabetes (Type II). Role of Zinc in human metabolism: (1) The mineral zinc is present in every part of the body and has a wide range of functions. It helps with the healing of wounds and is a vital component of many enzyme reactions. Zinc is vital for the healthy working of many of the body's systems. It is particularly important for healthy skin and is essential for a healthy immune system and resistance to infection. Zinc is one of the minerals men should never be without and has such a wide application in human health that everybody should ensure that they obtain enough of this humble trace element. A vital enzyme, carbonic anhydrase, contains zinc. It is also essential for the activity of some enzymes and hence essential foe the life of the organism. Other enzymes viz. several dehydrogenases (alcohol, glutamic, certain pyridine nucleotide) and pancreatic carboxypeptidase contain zinc. It is chiefly excreted in urine. Our body contains about 2-3g of zinc. There are no specific storage sites known for zinc and so a regular supply in the diet is required. Zinc is found in all parts of our body, 60% is found in muscle, 30% in bone and about 5% in our skin. Particularly high concentrations are in the prostate gland and semen. Men need more zinc than women because male semen contains 100 times more zinc than is found in the blood. The more sexually active a man the more zinc he will require. The recommended amounts of zinc for adult men are 1/3 higher than those for women. It is thought that zinc supplementation can help skin conditions such as acne and eczema, prostate problems, anorexia nervosa, alcoholics and those suffering from trauma or post-surgery. It is always better to seek the advice of an expert before taking any supplements. If you choose to take a zinc supplement you should not need more than the daily recommended amount unless medical advice says otherwise. Only 20% of the zinc present in the diet is actually absorbed by the body. Dietary fibre and phytic acid, found in brain, wholegrain cereals, pulses and nuts, inhibit zinc absorption. Phytic acid forms a highly insoluble complex with zinc, which the body cannot absorb. Cooking processes can reduce the adverse effects of both phytic acid and dietary fibre on zinc absorption. Baking can destroy over half the phytic acid in whole meal bread.

Numerous aspects of cellular metabolism are zinc-dependent. Zinc plays important roles in growth and development, the immune response, neurological function, and reproduction. On the cellular level, the function of zinc can be divided into three categories:

1. Catalytic, 2. Structural, and 3. Regulatory. Catalytic role Zinc-dependent enzymes can be found in all known classes of enzymes. Zinc is a component in over 200 enzyme reactions which are vital and also including enzymes that metabolise alcohol (alcohol dehydrogenase) or reduce lactic acid build up during or following exercise (lactic dehydrogenase). Structural role Zinc plays an important role in the structure of proteins and cell membranes. A fingerlike structure, known as a zinc finger motif, stabilizes the structure of a number of proteins. For example, copper provides the catalytic activity for the antioxidant enzyme copper-zinc superoxide dismutase (CuZnSOD), while zinc plays a critical structural role. The structure and function of cell membranes are also affected by zinc. Loss of zinc from biological membranes increases their susceptibility to oxidative damage and impairs their function. Regulatory role Zinc finger proteins have been found to regulate gene expression by acting as transcription factors (binding to DNA and influencing the transcription of specific genes). Zinc also plays a role in cell signaling and has been found to influence hormone release and nerve impulse transmission. Recently, zinc has been found to play a role in apoptosis (gene-directed cell death), a critical cellular regulatory process with implications for growth and development, as well as a number of chronic diseases. Primary role of zinc ions Most serum Zn2+ ions are used by the body to stabilize cell membranes and close pores in cell membranes. In vitro, it was found that increasing Zn2+ ion concentrations to be a novel and newly recognized form of host defense, because they strengthen cell membranes and protect them from damage from many cytotoxins, including viruses, and venoms. Similarly, there is evidence that oral intake of extremely large doses of ionizable zinc compounds can prevent injury and possibly death from potentially lethal cytolytic agents.

Three grams of zinc (from zinc gluconate) taken in four 750-mg doses per day with meals for a week has been successfully used to prevent severe tissue necrosis and possible death from a brown recluse spider bite in the navel of a 100-pound female adult. This treatment produced no observable side effects (neither nausea nor vomiting), rapidly eliminated systemic bloating and generalized pain, and resulted in rapid wound healing without scarring. However, if such extreme dosage is given in health, zinc toxicity must always be expected. Excessive consumption of zinc over a long period can interfere with copper absorption and has reversible side effects, the most noticeable being anemia and neutropenia. Like overdoses of any nutrient, stopping or reducing dietary zinc supplementation has been reported to be corrective. On the other hand, many people carrying a burden of excess -- and potentially toxic copper may be beneficially adjusted by supplemental zinc. Anti oxidant effects: Zn2+ ions are natures strongest antioxidants, far more so than vitamins C and E, and much safer than selenium. Generally, therapeutic doses of zinc in highly ionic forms to treat diseases, wounds, burns, and venomous bites are a fresh and promising area demanding further research. The Recommended Dietary Allowance (RDA) The U.S. recommended dietary allowance (RDA) for zinc is listed by gender and age group in the table below. Infants, children, and pregnant and lactating women are at increased risk of zinc deficiency. Since a sensitive indicator of zinc nutritional status is not readily available, the RDA for zinc is based on a number of different indicators of zinc nutritional status and represents the daily intake likely to prevent deficiency in nearly all individuals in a specific age and gender group

The Recommended Dietary Allowance (RDA) for Zinc Life Stage Infants Infants Children Children Children Adolescents Adults Age 0-6 months 7-12 months 1-3 years 4-8 years 9-13 years 14-18 years 19 years and older Males (mg/day) 2 (AI) 3 3 5 8 11 11 Females (mg/day) 2 (AI) 3 3 5 8 9 8

Pregnancy Pregnancy Breast-feeding Breast-feeding

18 years and younger 19 years and older 18 years and younger 19 years and older

12 11 13 12

Zinc and its Pharmaceutical importance: The use of Zinc in the pharmaceutical industry can be in the following types: 1. Zinc Sulphate (ZnSO4): Zinc sulfate is the inorganic compound with the formula ZnSO4 as well as any of three hydrates. It was historically known as "white vitriol". It is a colorless solid that is a common source of soluble zinc ions. (4)

This medication is a mineral used to treat or prevent low levels of zinc. 2. Zinc Stearate: Zinc stearate (Zn(C18H35O2)2) is a zinc soap that repels water. It is insoluble in polar solvents such as alcohol and ether but soluble in aromatic hydrocarbons (e.g., benzene and chlorinated hydrocarbons) when heated. It is the most powerful mold release agent among all metal soaps. (4)

It can be used as a lubricant in cosmetics to improve texture. 3. Zinc gluconate (also called zincum gluconicum) is the zinc salt of gluconic acid. It is an ionic compound consisting of two moles of gluconate for each mole of zinc. Zinc gluconate is a popular form for the delivery of zinc as a dietary supplement. (4)

Zinc gluconate may interfere with the absorption of antibiotics, so combinations may be unsafe.

It is the most common form used in the preparation of Zinc lozenges which can be an ailment to common cold. 4. Zinc Picolinate: 20 to 30 mg a day * Antioxidant. A component of insulin. The picolinate form of zinc is most easily absorbed. Next are the citrate, gluconate, and acetate forms while the sulfate form is the most poorly absorbed.

The above forms of Zinc can be administered through various types of dosage forms for the treatment or cure of following some disease conditions: Common cold Zinc lozenges (5, 6) The use of zinc lozenges within 24 hours of the onset of cold symptoms, and continued every 2-3 hours while awake until symptoms resolve, has been advocated for reducing the duration of the common cold. At least ten controlled trials of zinc gluconate lozenges for the treatment of common colds in adults have been published. Five studies found that zinc lozenges reduced the duration of cold symptoms, whereas five studies found no difference between zinc lozenges and placebo lozenges with respect to the duration or severity of cold symptoms. A recent metaanalysis of published randomized controlled trials on the use of zinc gluconate lozenges in colds found that evidence for their effectiveness in reducing the duration of common colds was still lacking. Two clinical trials examined the effect of zinc acetate lozenges on cold symptoms. While one of the trials found that zinc acetate lozenges (12.8 mg of zinc per lozenge) taken every 2-3 hours while awake reduced the duration of overall cold symptoms (4.5 vs. 8.1 days) compared to placebo. Short-term use of zinc lozenges (e.g., less than five days) has not resulted in serious side effects, though some individuals experienced gastrointestinal disturbances and mouth irritation. Use of zinc lozenges for prolonged periods (e.g., 6-8 weeks) is likely to result in copper deficiency. For this reason, some experts have recommended that a person who does not show clear evidence of improvement of cold symptoms after 3-5 days of zinc lozenge treatment seek medical evaluation. Intranasal zinc (zinc nasal gels and nasal sprays) (7, 8, 9) Intranasal zinc preparations, designed to be applied directly to the nasal epithelium (cells lining the nasal passages), are also marketed as over-the-counter cold remedies. While two placebocontrolled trials found that intranasal zinc gluconate modestly shortened the duration of cold symptoms, three other placebo-controlled studies found intranasal zinc to be of no benefit.

Of serious concern are several case reports of individuals experiencing loss of the sense of smell (anosmia) after using intranasal zinc as a cold remedy. Since zinc-associated anosmia may be irreversible, intranasal zinc preparations should be avoided. Age-related macular degeneration (10): A leading cause of blindness in people over the age of 65 in the U.S. is a degenerative disease of the macula, known as age-related macular degeneration (AMD). The macula is the portion of the retina in the back of the eye involved with central vision. A large randomized controlled trial of daily supplementation with antioxidants (500 mg of vitamin C, 400 IU of vitamin E, and 15 mg of beta carotene) and high-dose zinc (80 mg of zinc and 2 mg of copper) found that the antioxidant combination plus high-dose zinc, and high-dose zinc alone, both significantly reduced the risk of advanced macular degeneration compared to placebo in individuals with signs of moderate to severe macular degeneration in at least one eye. Diabetes mellitus: (11) Zinc supplementation reportedly improves immune function in diabetics. Supplementation of type 2 diabetics with 30 mg/day of zinc for six months reduced a non-specific measure of oxidative stress without significantly affecting blood glucose control. Presently, the influence of zinc on glucose metabolism requires further study before high-dose zinc supplementation can be advocated for diabetics. HIV/AIDS: (12) Sufficient zinc is essential in maintaining immune system function and HIV-infected individuals are particularly susceptible to zinc deficiency. In HIV-infected patients, low serum levels of zinc have been associated with a more advanced stage of the disease and also with increased mortality. In one of the few zinc supplementation studies conducted in AIDS patients, 45 mg/day of zinc for one month resulted in a decreased incidence in opportunistic infections compared to placebo.

Formulations of Apex containing Zinc as one of the ingredient: (13) 1. Actilife Tablets: Nutritional complement for a Healthy Heart and an active life. Offers more number of micronutrients that complement the role of Chromium, Zinc and Selenium and prevent the risk of Diabetes.

2. Folinz Tablets: FOLINZ is the brand with combination of Zinc and Folic acid, introduced by apex for the first time in India. Zinc is combined with folic acid for the prevention of Neural tube defects (NTDs). If folic acid supplementation is given, additional Zinc supplementation should be considered for the further decrease in recurrence and occurrence of Neural tube defects (NTDs).

3. Zincofer Tablets: Zincofer is the first bimetallic Haematinic - Ferrous fumarate with zinc. Zinc in Zincofer initiates DNA and RNA synthesis and ensures proper fetus formation.

4. Zincovit Tablets: Zincovit is an advanced formula of high concentration of vitamins, essential minerals and Zinc. Zinc has been found to be very important for boosting up immunity. T-cell producing thymus gland depends on regular supply of zinc for its normal phagocytic functions including maturation of T-cells.

5. Cofstop-Z Syrup: It contains Zinc Gluconate 7.5mg along with other ingredients. In this Zinc reduces the severity, and duration of common cold symptoms.

6. Soyamin 22 Liquid: Soyamin 22 - a protein tonic is a combination of soyproteins, Vitamins, Iron and Zinc. Zinc in Soyamin-22 enhances protein absorption.

7. Zincofer Liquid: Zincofer is the first bimetal haematinic offering Zinc with along iron and other important haemopoietic factors. Zinc and Iron in Zincofer Liquid corrects anemia and improves cognition in school going children.

8. Zincovit Drops: Zincovit drops is the only pediatric drops in India offering all these 4 essential factors together., Zinc, Lysine Vitamin C and Vitamin E. Zinc is essential for the proper brain development.

9. Zincovit Syrup: It is a delicious fruity flavoured multivitamin mineral supplement, for growth immunity and intellegenence in children. Zinc in Growth: The inhibition of growth is a cardinal symptom of zinc deficiency. Zinc is needed for the regulation of cell proliferation and is essential for the activity of enzyme systems. Zinc may directly regulate DNA and RNA synthesis which ensures proper growth and development in children. Zinc in Immunity: Zinc supplementation in children has been proved to boost up Immunity. Zinc in Intelligence: Zinc supplementation improves mental development and behavior in children.

10. Zincoderm: Topical Zinc concept by the introduction of Zincoderm group of creams which brings in a breakthrough in dermato-therapy. Topical Zinc enhances anti-inflammatory effect, prevents super infection, reduces the adverse effects of potent steroids and also reduces the recurrence of dermatoses.

11. Ascazin Capsules: Ascazin capsules are specially indicated for Zinc deficiency disorders. Ascazin capsules contain plain Zinc sulphate monohydrate. Zinc has got inverse relationship with copper. Based on this principle, Ascazin has been successfully employed in the treatment of Wilson's disease and Indian childhood cirrhosis - the condition due to excessive accumulation of copper in the body.

12. Happynap Cream: It contains Benzalkonium chloride and Zinc oxide. Zinc oxide exhibits anti inflammatory, anti infective and anti seborrheic properties and also it can provide an important and helpful antioxidant defence for skin.

Along with these products, Zinc is also used in topical creams like Betzee and Lozee group which are intended topically for the treatment of psoriasis and atopic dermatitis respectively.

References: 1. Jane Higdon, Ph.D; Linus Pauling Institute; Zinc and its importance in human metabolism; 2003; page no. 1-8. 2. 3. 4. 5. Jackson JL, Lesho E, Peterson C. Zinc and the common cold: a meta-analysis revisited. J Nutr. 2000;130(5S Suppl):1512S-1515S. (PubMed) 6. Prasad AS, Fitzgerald JT, Bao B, Beck FW, Chandrasekar PH. Duration of symptoms and plasma cytokine levels in patients with the common cold treated with zinc acetate. A randomized, double-blind, placebo-controlled trial. Ann Intern Med. 2000;133(4):245252. (PubMed) 7. Mossad SB. Effect of zincum gluconicum nasal gel on the duration and symptom severity of the common cold in otherwise healthy adults. QJM. 2003;96(1):35-43. (PubMed) 8. Turner RB. Ineffectiveness of intranasal zinc gluconate for prevention of experimental rhinovirus colds. Clin Infect Dis. 2001;33(11):1865-1870. (PubMed) 9. DeCook CA, Hirsch AR. Anosmia due to inhalational zinc: a case report. Chem Senses. 2000;25(5):659. 10. A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E, beta carotene, and zinc for age-related macular degeneration and vision loss: AREDS report no. 8. Arch Ophthalmol. 2001;119(10):1417-1436. (PubMed). 11. Anderson RA, Roussel AM, Zouari N, Mahjoub S, Matheau JM, Kerkeni A. Potential antioxidant effects of zinc and chromium supplementation in people with type 2 diabetes mellitus. J Am Coll Nutr. 2001;20(3):212-218. (PubMed) 12. Mocchegiani E, Muzzioli M. Therapeutic application of zinc in human immunodeficiency virus against opportunistic infections. J Nutr. 2000;130(5S Suppl):1424S-1431S. (PubMed) 13.