Zinc is an essential trace element. Zinc salts are used for supplementation to correct zinc-deficiency conditions such as acrodermatitis enteropathica, as an astringent to relieve minor eye irritations, and for therapy with penicillamine (e.g., such as that used for Wilson's disease). Other disease entities associated with zinc-depletion are anorexia nervosa, arthritis, diarrhea, eczema, recurrent infections, and recalcitrant skin problems. Other illnesses where efficacy, safety, and standardized dose of zinc have yet to be established include sickle cell disease, thalassemia, senile dementia, the common cold, diabetes mellitus, virile potency disturbances, acne vulgaris, neoplasia, and infertility. However, the mechanisms of action of zinc have to be further clarified and more studies are needed to determine its specific place in therapy.
Zinc can be administered as zinc sulfate, zinc acetate, zinc chloride, zinc-D-gluconate, zinc carbonate, zinc oxide, zinc aspartate, bis(L-histidinato)zinc or zinc orotate. A 220-mg dose of zinc sulfate is equivalent to 50 mg of elemental Zinc (Alpers et al, 1995).
Actions & Pharmacology
Zinc is thought to have antimicrobial, anti-sickling, cell-protective, copper-absorbing, enzyme-regulating, and growth-stimulating effects.
Zinc may reduce the growth rate of plaque bacteria and thus decrease oral plaque growth (Cohen et al, 1986; Harrap et al, 1984).
Zinc increases the filterability of partially deoxygenated cells in vitro. It decreases calcium-induced hemoglobin binding to red cell membranes and antagonizes the echinocyte-promoting effect of calcium. Thus, it can be used as an anti-sickling agent (Gupta & Choubey, 1987).
Zinc exerts a protective effect in maintaining the integrity of both cellular and organelle membranes. Zinc deficiency can cause increased membrane peroxidation and subsequent membrane damage and abnormalities of cellular transport with decreased enzyme activity (Gupta & Choubey, 1987).
Zinc inhibits copper absorption and induces a negative copper balance, which is the primary goal in the treatment of Wilson's disease (Hoogenraad & Van Hattum, 1988). It is thought that zinc causes copper malabsorption by preventing serosal transfer of copper secondary to induction of the intestinal copper-binding protein metallothionein and the copper is thus excreted in the feces (Friedman, 1993; Brewer et al, 1987).
Zinc is an integral part of several enzymes necessary for protein and carbohydrate metabolism. It is required for synthesis and mobilization of retinol-binding protein.
Zinc supplementation may increase hepatic synthesis of somatomedin-C; it may accelerate growth response to growth hormone, or it can be involved directly in promoting growth. Studies are needed to establish the relationship of growth hormone, somatomedin, and zinc in beta thalasemia major (Arcasoy et al, 1987).
Results of a prospective study in children suggest a prophylactic role for zinc sulphate in decreasing the occurrence and severity of common cold and in shortening its mean duration. This randomized, double-blind, placebo-controlled study enrolled 200 healthy children, who were evenly assigned to treatment with either oral zinc sulphate syrup (providing 15 mg of zinc) or placebo syrup. Treatment was administered once daily for 7 months; this dosage was increased to twice daily at the onset of cold, until a reduction in symptoms was observed. Results showed that the mean number of colds was significantly reduced in the zinc group compared to the placebo group (mean 1.2 vs 1.7 cold per child; p=0.003), as was the mean duration of cold symptoms (4.7 days in the zinc group, compared to 5.3 days in the placebo group; p<0.0001). Total severity scores for cold symptoms were also decreased with supplementation vs placebo (p<0.0001) (Kurugol et al 2006).
Zinc lozenges have been reported to be effective in some studies and ineffective in others. Efficacy may depend on whether the zinc is provided in a molecular form, as demonstrated by a re-analysis of findings from 10 double-blind, placebo-controlled trials published between 1984 and 2004. Taking a fresh look at the data, the investigator found a statistically significant correlation between total daily dosages of positively charged zinc species and reductions in median (p=0.005) and mean (p<0.02) duration of common colds in the trials studied (Eby 2004). Similar outcomes were noted in a 2004 review on the medicinal value of zinc for the treatment of the common cold. That review found that zinc effectively reduced the duration and severity of common cold when administered within 24 hours following onset of symptoms (Husliz 2004).
A prospective phase IV study examined the prophylactic and therapeutic effects of a specific brand of zinc lozenges (Cold-Eeze®) on common cold in 134 children aged 12 to 18 years. Therapeutic use (4 lozenges per day) resulted in a significant reduction in average cold duration vs placebo (mean, 6.9 days vs 9.0 days; p<0.001). Prophylactic use during the cold season (once daily) resulted in a 25% reduction in cold incidence and overall, two-thirds of treated subjects had only one cold or none at all (McElroy and Miller 2003). A randomized, controlled study conducted in geriatric subjects (aged 60 to 91 years) found similar benefits, and concluded that use of zinc gluconate glycine lozenges is safe and well tolerated in this population (Silk and LeFante 2005).
An earlier meta-analysis of 6 clinical trials evaluated the effectiveness of zinc salts lozenges in the common cold; all studies included had consistent moderate quality scores. The summary odds ratio for the incidence of any cold symptom was reported to be 0.50, but this did not reach statistical significance (Jackson et al, 1997).
Positive results were reported in a double-blind, placebo-controlled study of 100 patients. Zinc gluconate therapy was initiated within 24 hours of symptom onset. One zinc gluconate lozenge containing 13.3 mg of zinc was administered every 2 hours while awake for the duration of cold symptoms in 50 patients. The zinc-treated group had a significantly shorter time to symptom resolution than the placebo group (4.4 versus 7.6 days, p<0.001). Coughing, headache, hoarseness, nasal congestion and drainage, and sore throat were the symptoms that responded to zinc treatment. Nausea (10 vs 2 patients) and bad-taste reactions (39 vs 15 patients) were significantly more common in the zinc-treated group than the placebo group; one zinc-treated patient withdrew because of intolerance to the lozenge (Mossad et al, 1996).
Herpes Simplex Virus/Oral Herpes (Cold Sores)
Treatment with systemic zinc sulphate led to a reduction in the number of episodes and time to recovery associated with herpes labialis in one pilot study. Twenty patients with a history of the disease (>6 episodes per year) were treated with 22.5 mg zinc sulphate twice daily for 2 consecutive months, followed by a 5-month break, and then treated again for 2 consecutive months. After 1 year, investigators noted a reduction in flare-ups among subjects, with episodes declining to <4 episodes (average, 3). In addition, each episode lasted less than 7 days (Femiano et al 2005).
A randomized, double-blind, placebo-controlled trial involving 46 subjects examined the effect of a topical formulation of zinc oxide/glycine cream on facial and circumoral herpes infection (cold sores). Subjects were instructed to apply the cream within 24 hours after symptoms manifested, and to continue treatment every 2 hours until the lesion resolved, for up to 3 weeks; the control group was treated with a placebo cream. Cold sores occurring in the zinc treatment arm were of a significantly shorter duration following treatment (mean, 5 days) compared with the placebo arm (mean, 6.5 days). Application of the cream was also associated with a reduction in the severity of signs and symptoms of oral herpes, including blistering, soreness, itching, and tingling (Godfrey et al 2001).
A solution of 0.25% zinc sulfate can cause clearing of herpes simplex lesions, but solutions of 0.025% to 0.05% were ineffective as treatment for acute attacks or as prophylaxis for recurrent infections. Zinc sulfate gel 103 mg/g applied topically every 2 hours was more effective than placebo in clearing herpes simplex labialis infections in a controlled double-blind trial with 80 patients. Symptoms were milder and lesions healed more rapidly with zinc sulfate gel than with placebo gel. (Kneist et al, 1995)
In another study, 200 patients with herpes simplex showed clearing of lesions within 3 to 6 days of treatment with 0.25% zinc sulfate in camphor water USP applied 8 to 10 times per day beginning within 24 hours after the appearance of the lesions (Finnerty, 1986).
Zinc supplementation in a population of elderly subjects significantly decreased the incidence of infection in one randomized, double-blind, placebo-controlled trial. Study participants (age range, 55-87 years) were assigned to daily treatment with either 45 mg oral zinc gluconate (n=24) or placebo (n=25). Following 1 year of treatment, the group receiving zinc supplementation had significantly fewer infections than their unsupplemented counterparts (0.29±0.46 vs 1.4±0.95, respectively; p<0.01). The generation of tumor necrosis factor alpha and oxidative stress markers was significantly lowered by zinc supplementation in this study compared to placebo, and plasma levels of zinc were significantly increased from baseline with supplementation (Prasad et al 2007).
Zinc supplementation may improve cell-mediated immunity and leukocyte chemotaxis independently of zinc depletion. The cell-mediated immune response determined by CD4, DR, T-cells and cytotoxic T-lymphocytes was improved after zinc supplementation in a randomized, double-blind, placebo-controlled study of 118 patients older than 65 years. Patients received 25 mg of zinc sulfate per day; 800 mcg of retinol palmitate; 25 mg of zinc per day plus 800 mcg of retinol palmitate; or placebo. Significant increases in the zinc group were observed for CD4 + DR + T-cells (P=0.016) and cytotoxic t-lymphocytes (P=0.005). For vitamin A, reductions in the counts of CD3 + T-cells (P=0.012) and CD4 + T-cells (P=0.0129) were reported (Fortes et al, 1998).
The rate of infection was significantly reduced by zinc and selenium supplementation in a 2-year randomized, placebo-controlled study of 81 institutionalized elderly patients. Daily doses of 20 mg of zinc plus 100 mcg of selenium or the same doses of trace elements plus daily doses of 120 mg of vitamin C, 6 mg of beta-carotene, and 15 mg of alpha-tocopherol were equally effective in correcting deficiencies after 6 months and in preventing infectious events (Girodon et al, 1997).
Zinc supplementation has yet to be proven useful in age-related macular degeneration (ARMD). Prospective, randomized, controlled trials have been conducted investigating the role of zinc in ARMD using doses 5.3 times the RDA of zinc for men and 6.7 times the RDA of zinc for women. Beneficial results from one small trial could not be confirmed in the much larger AREDS trial (see below), which failed to find a significant reduction in visual acuity loss after zinc therapy.
The Age-Related Eye Disease Study report 8 (AREDS) was an 11-center, double-blind, prospective trial designed to evaluate the effect of high-dose vitamins C and E, beta-carotene, and zinc supplementation on ARMD progression and visual acuity. Three thousand six hundred forty (3,640) participants aged 55 to 80 years were enrolled. All subjects had extensive small drusen, intermediate drusen, large drusen, noncentral geographic atrophy, or pigment abnormalities in one or both eyes, or advanced ARMD or vision loss due to ARMD in one eye. At least one eye had best corrected visual acuity of 20/32 or better. Participants were randomized to 1 of 4 treatment groups: antioxidants (500 mg vitamin C, 400 IU vitamin E, and 15 mg beta-carotene daily); zinc oxide and cupric oxide (80 mg elemental zinc and 2 mg elemental copper daily); antioxidants plus zinc; or placebo. The total daily dosage of each supplement was taken orally by each participant in 2 divided doses with food to avoid potential gastrointestinal irritation by zinc. The main outcome measures included photographic assessment of progression to or treatment for advanced ARMD and at least moderate visual acuity loss from baseline (15 or more letters from the Snellen eye chart). Comparison with placebo demonstrated a statistically significant odds ratio (OR) reduction for the development of advanced AMD with antioxidants plus zinc (0.72, 99% confidence interval (CI) 0.52-0.98, p<0.007). The ORs for zinc alone (0.75, 99% CI 0.55-1.03, p<0.02) and antioxidants alone (0.80, 99% CI 0.59-1.09, p less than 0.07) were not found to be statistically significant (Anon, 2001b).
Indications & Usage
Approved by the FDA for:
- Zinc deficiency
Zinc supplements are used for numerous conditions, including the following: acne vulgaris, acrodermatitis enteropathica, Alzheimer's disease, common cold, dental hygiene, diabetes mellitus, diarrhea, eczema, eye irritation, growth, Hansen's disease, herpes simplex infection, hypertension, hypogeusia (decreased sense of taste), immunodeficiency, impotence, infertility, leg ulcers, lipid peroxidation, macular degeneration, necrolytic migratory erythema, parasites, peptic ulcer disease, psoriasis, scalp dermatoses, schistosomiasis, sepsis, sickle cell anemia, stomatitis, thalassemia major, trichomoniasis, Wilson's disease, and wound healing.
Precautions & Adverse Reactions
Zinc ophthalmic solution should be used cautiously in patients with glaucoma.
Side effects include gastrointestinal discomfort, nausea, vomiting, headaches, drowsiness, and metallic taste. Do not use zinc ophthalmic solutions that have changed color.
Zinc should not be used in doses greater than the RDA during lactation.
Caffeine: Concurrent administration with zinc reduces zinc absorption. Coffee reduces zinc absorption by up to 50%. Wait 1 to 2 hours before drinking coffee after zinc administration (Pecoud et al, 1975).
Foods containing high amounts of phosphorous, calcium (dairy), or phytates (e.g., bran, brown bread) may reduce absorption.
Concurrent use may result in decreased gatifloxacin effectiveness. Clinical Management: Gatifloxacin should be administered 4 hours before or 4 hours after zinc or any product containing zinc.
Concurrent use may result in decreased levofloxacin effectiveness. Clinical Management
Administer levofloxacin at least 2 hours before or 2 hours after zinc or a multiple ingredient product which contains zinc.
Concurrent use may result in decreased efficacy of grepafloxacin. Clinical Management: Zinc supplements or zinc-containing products should be administered 4 hours before or 4 hours after grepafloxacin.
Concurrent use may result in decreased efficacy of moxifloxacin. Clinical Management: Moxifloxacin should be administered at least 4 hours before or 8 hours after zinc.
Concurrent use may result in decreased efficacy of norfloxacin. Clinical Management: Avoid concurrent use. However, if used concurrently, the dose of the zinc salt should be given at least 6 hours before or 4 hours after the norfloxacin dose.
Concurrent use may result in decreased efficacy of ofloxacin. Clinical Management: Zinc supplements or zinc-containing products should be administered 2 hours before or 2 hours after ofloxacin.
Concurrent use may result in decreased efficacy of sparfloxacin. Clinical Management: If sparfloxacin and a product containing zinc must be taken concurrently, administer the zinc-containing preparation 4 hours after the sparfloxacin is given.
Concurrent use may result in decreased tetracycline effectiveness. Clinical Management: Administer tetracycline at least 2 hours before or 3 hours after zinc.
Concurrent use may result in decreased ciprofloxacin effectiveness. Clinical Management: Zinc salts or vitamins containing zinc should be given 2 hours after or 6 hours before oral ciprofloxacin.
Concurrent administration with zinc may inhibit the absorption of copper or zinc. Clinical Management: Optimal dosage separation time has not been determined. Space administration of zinc and copper as far apart as possible.
Concurrent administration with zinc reduces zinc absorption. Clinical Management: Optimal dosage separation time has not been determined. Space administration of zinc and penicillamine as far apart as possible.
Concurrent use may result in impaired tetracycline absorption.
Concurrent use may result in decreased gastrointestinal resorption.
Concurrent use may result in decreased absorption.
Concurrent use may result in decreased absorption of temafloxacin.
Intravenous overdose has been associated with thrombocytopenia, hypotension, cardiac arrhythmias, oliguria, hyperamylasemia, diarrhea, jaundice, and pulmonary edema, sideroblastic anemia, microcytic anemia secondary to zinc-induced copper deficiency anemia, copper deficiency, hemorrhagic gastric erosions, and lymphocytoma cutis.
Mode of Administration
oral, topical, intramuscular
tablet, cream, gel
Recommended Dietary Allowance (RDA): Men and adolescent boys 14 and older – 11 mg/day; adolescent girls 14 to 18 years – 9 mg/day; women 19 years and older – 8 mg/day; pregnancy (19 years and older) – 11 mg/day; lactation (19 years and older) – 12 mg/day. Infants and children: 7 months to 3 years – 3 mg/day; 4 to 8 years – 5 mg/day; 9 to 13 years – 8 mg/day.
- Dietary supplement: daily oral doses range from 9 to 25 mg
- Acne and dermatitis: a topical preparation (cream or gel) of 10 mg zinc sulfate per gram or 27 to 30 mg zinc oxide per gram used several times daily.
- Acne: 90 to 135 mg orally daily
- Zinc deficiency/acrodermatitis: maximum doses up to 40 mg orally daily
- Wilson's Disease, tablet: 300 mg to 1200 mg orally daily in divided doses
- Acne: 135 mg orally daily.
- Zinc deficiency: daily doses ranging from 1.5 to 12 mg, depending on age.
- Supplementation (intramuscular injection): 100 mcg per kg body weight per day for children up to 5 years old.
- Wilson's disease (intramuscular injection): 25 mg 3 times daily for children 10 years and older.
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