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Zinc

Nutrient Name: Zinc.
Elemental Symbol: Zn.
Forms: Zinc acetate, zinc arginate, zinc ascorbate, zinc aspartate, zinc carbonate, zinc citrate, zinc gluconate, zinc glycerate, zinc glycinate, zinc histidinate, zinc lactate, zinc methionate, zinc monomethionine, zinc oxide, zinc picolinate, zinc selenate, zinc sulfate, zinc undecylenate.

Summary Table
nutrient description

Chemistry and Forms

Zinc acetate, zinc arginate, zinc ascorbate, zinc aspartate, zinc carbonate, zinc citrate, zinc gluconate, zinc glycerate, zinc glycinate, zinc histidinate, zinc lactate, zinc methionate, zinc monomethionine, zinc oxide, zinc picolinate, zinc selenate, zinc sulfate, zinc undecylenate.

Physiology and Function

Zinc is required throughout the human body for protein synthesis, DNA synthesis, cell division, hormonal activity, neurotransmitter signaling, and other critical functions. Zinc's essential role in many biological processes is illustrated by its participation in the activity of up to 300 enzymes, in all known classes. Although its activity in immune function has often received the greatest attention, zinc is required for normal physiological functioning of most body systems, particularly growth and development, neurological function, and reproduction, as well as numerous catalytic, structural, and regulatory functions at the cellular level.

Absorption of zinc occurs both by carrier-mediated and energy-dependent saturable processes and by simple (nonsaturable) diffusion throughout the length of the small intestine, primarily in the jejunum. Absorption is regulated homeostatically, in a range of 2% to 70%, depending on concomitant intake and zinc status in healthy individuals, and is optimal at an intragastric pH of 3 or less because solubility of zinc salts is affected by pH. 1 Zinc is actively transported with albumin, amino acids, and an α2-macroglobulin; transport is regulated, in part, by sulfur-containing amino acids. Bioavailability is mainly influenced by zinc status and form; however, red wine, soy protein, and glucose can enhance zinc absorption, and iron, copper, calcium, fiber, and phytates (a component of cereal grain fiber) can inhibit absorption. Elimination of zinc is primarily through the feces, with minor amounts excreted through the urine and perspiration.

The average adult human body contains a total of 1.4 to 2.5 grams of zinc, with 60% to 65% stored in skeletal muscle, 30% in bone, particularly marrow, and 4% to 6% in the skin. The brain (especially the hippocampus and cerebral cortex) is the organ with the highest zinc concentrations, with enzymatic zinc (85%-95%) and synaptic zinc constituting two separate pools of brain zinc. Zinc is also found in relatively high concentrations in the eye (particularly iris, macula of retina, and choroid), liver, spleen, pancreas, kidney, prostatic fluid, and spermatozoa. Both red blood cells (RBCs) and white blood cells (WBCs) contain relatively high concentrations of zinc.

Zinc is a cofactor in the synthesis of proteins, fats, and cholesterol, and as a metalloenzyme activator, zinc is associated with the activity of more enzymes than any other mineral. Carboxypeptidase is necessary for the digestion of dietary proteins. Several dehydrogenases require zinc, including alcohol, retinol, and sorbitol dehydrogenase. Carbonic anhydrase, a zinc enzyme, catalyzes the interconversion of carbon dioxide (CO2) and bicarbonate (HCO3) and thereby contributes to acid-base balance in RBCs. Cytochrome c is essential to electron transport and energy production. Superoxide dismutase (SOD), which contains both zinc and copper, inactivates free radicals in cytosol. Alkaline phosphatase (ALP) liberates inorganic phosphates for use in bone metabolism. The activity of these enzymes may be hampered by disruptions in zinc availability that are subclinical in degree (far short of frank deficiency) and conversely, are enhanced by increased zinc nutriture.

The immune, antioxidant, and detoxification systems require zinc, in ready availability and broad distribution, to maintain their functions at healthy levels. Immune function depends directly on zinc status in many ways through its central role in the production, regulation, activity, and equilibrium of both cellular and humoral immune responses, particularly as mediated by the thymus gland. Zinc participates in the regulation of a wide range of immune functions, including T lymphocytes, CD4 cells, natural killer (NK) T cells, interleukin-2 (IL-2), and SOD. As early manifestations of zinc deficiency, lymphopenia and thymic atrophy follow quickly on decreases in precursor T and B cells in the bone marrow, and IL-2 production by helper T (Th) lymphocytes will drop as lymphocyte proliferation decreases and cell-mediated immune function declines. Thus, decreases in available zinc may contribute to a premature transition from efficient Th1-dependent cellular immune activity to Th2-dependent humoral immune functions. The presence of adequate Zn2+and nitrogen oxide tilt the thymic balance toward Th1 and IL-2 as nitrogen oxide releases Zn2+from metallothionein, an intracellular storage molecule, and together they cooperate with glutathione (GSH) and GSSG, its oxidized form, to regulate immune responses to antigens. Conversely, a shift toward Th2 will be characterized by elevations in levels of IL-4, IL-6, IL-10, leukotriene-B4(LTB4), and prostaglandin E2(PGE2). Zinc is well known as a cofactor for SOD, a key antioxidant enzyme, but it also functions as a cofactor for alcohol metabolism and delta-6-desaturase (involved in PGE1synthesis). Among its activities in protecting against heavy metal toxicity, such as cadmium and lead, zinc's unique relationship with copper gives it a special capacity in countering toxic accumulation in Wilson's disease. Vitamin A levels are also regulated by a zinc-controlled release of hepatic stores.

Zinc plays diverse regulatory and support roles throughout the endocrine and reproductive systems as well as cell growth and differentiation processes. Proper functioning of genetic activities at many levels requires zinc, including the synthesis of DNA and RNA, protein synthesis, cellular division, and gene expression. Moreover, in its antioxidant capacity, zinc protects DNA from damage caused by oxidative stress. Zinc is necessary for the maturation of sperm, for ovulation, and for fertilization and normal fetal development. Zinc inhibits the activity of 5-alpha-reductase, the enzyme that irreversibly converts testosterone to dihydrotestosterone, a form that strongly binds to prostate tissue and thus contributes to hypertrophy. The hypogonadism observed in zinc deficiency may be related to impaired leptin secretion, which is also associated with zinc deficiency. Zinc promotes the conversion of thyroxine (T4) to triiodothyronine (T3) and enhances vitamin D activity. Thus, zinc plays a central role in normal growth and maturation, at cellular and systemic levels.

Synaptic zinc plays a modulatory role in synaptic neurotransmission. In the brain, zinc-containing neurons are found primarily in limbic and cerebrocortical systems. All neurons bearing synaptic zinc are glutamatergic. Synaptically released zinc plays a central role in brain excitability through modulation of ionic channels and amino acid receptors, including alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA), N-methyl-D-aspartate (NMDA), and gamma-aminobutyric acid (GABA) receptors. In particular, zinc acts as a potent antagonist of the glutamate-NMDA receptor. Zinc also induces brain-derived neurotrophic factor (BDNF) gene expression in the hippocampal/cortical neurons. 2 Anorexia, dysphoria, impaired learning, diminished cognitive function, and other behavioral disturbances and mood disorders, as well as some neurological disorders (e.g., epilepsy, Alzheimer's disease), can be associated with zinc depletion and alterations of brain zinc homeostasis. 3,4

Zinc participates in the somatic interface with the environment through both the superficial tissues and the sensory organs. In addition to its presence in the skin and release through perspiration, the presence of zinc in the nails and hair is also notable (with deficiency indicated by leukonychia). Zinc's crucial role in skin health and wound healing is inherently related to its physiological and therapeutic activity in epithelial tissue. As mentioned, zinc is particularly concentrated in various components of the eye, where it is essential to dark adaptation and night vision. It also participates in the regulation of sensory perception through taste and smell. Not only is zinc crucial for taste perception, especially of salt, but taste response (or lack thereof) to zinc itself is predictive of deficiency status.

nutrient in clinical practice

Known or Potential Therapeutic Uses

Proposed therapeutic and preventive uses of zinc range from the more common, and often self-prescribed, administration for prevention and mitigation of the common cold, treatment of acne and other dermatological conditions, enhancement of wound healing and immune response, to more clinical applications for high-risk mothers and malnourished infants, HIV and other viral infections, diminished fertility and reproductive gland function, gastric and bowel conditions, macular degeneration and other ophthalmologic diseases, and inflammatory processes such as rheumatoid arthritis. Notably, zinc administration can enhance muscular strength and endurance in healthy individuals, even in the absence of zinc deficiency. 5 Pharmacological doses of zinc are administered for the treatment of acrodermatitis enteropathica (clinical zinc deficiency caused by congenital zinc malabsorption), to ascertain level of zinc absorption, and Wilson's disease, to prevent the copper accumulation in tissues. Effective treatment of mild or moderate zinc depletion typically requires months of zinc administration to reverse, and severe zinc depletion can require a year or more to resolve in some cases.

Historical/Ethnomedicine Precedent

Recorded use of zinc dates back to Egypt, circa 2000BCE, in the Western medical tradition. Known primarily for its use in skin lotions in both classical and folk traditions, its presence as zinc ore in calamine lotion is perhaps its most familiar form in recent popular memory and usage. Zincum metallicum and other forms of zinc were introduced into homeopathic medicine by Franz (1827), provings were conducted by Hahnemann (1839), and a large and systematic catalog of toxicology was assembled in the materia medica texts of Allen and others throughout the 1800s; these agents have been included in the official Homeopathic Pharmacopeia of the United States for more than 100 years. In the 1870s, W.H. Burt, 6 a highly respected homeopathic physician, wrote: “Zinc corresponds to diseases of the nervous system, the same as Iron does to diseases of the blood.”

Although often selected because of their morphological similarity to male sexual organs (or “signature”), the recommendation of mussels (especially oysters and geoducks), seeds, and nuts as male tonics in many traditional systems of nutritional therapy may derive, at least in good part, from relatively high concentrations of zinc (and essential fatty acids). In pharmacognosy, the standard term for seed is semen, with both meanings related to substances rich in zinc.

Possible Uses

Acne vulgaris, acrodermatitis enteropathica, ageusia or hypogeusia (loss or diminishment of taste sensation), amenorrhea, anorexia nervosa, anosmia (lack of ability to smell), aphthous stomatitis (topical), athletic performance, attention deficit–hyperactivity disorder (ADHD), benign prostatic hyperplasia, birth defects (risk reduction), cataracts, celiac disease, cervical dysplasia, childhood intelligence (deficiency), cirrhosis (deficiency), common cold, contact dermatitis, Crohn's disease, cystic fibrosis, dermatitis herpetiformis (deficiency), diaper rash, diabetes mellitus (types 1 and 2), diarrhea (including with HIV), diverticulitis, Down syndrome, eczema, gastric ulcer healing, gastritis, halitosis, hepatitis, herpes simplex infection, HIV support, hypoglycemia, hypothyroidism, immune support/enhancement, infection, insulin resistance syndrome, lead and cadmium toxicity, macular degeneration, male infertility, male sexual function, minor injuries, night blindness, Osgood-Schlatter disease (with selenium), osteoarthritis, otitis media (recurrent), peptic ulcer, periodontal disease, pharyngitis, psoriasis, radiation therapy support, rheumatoid arthritis, sickle cell anemia, skin ulcers, thalassemia (deficiency), ulcerative colitis, warts, Wilson's disease, wound healing (oral and topical).

Deficiency Symptoms

Primary (dietary) zinc deficiency in humans was first described in patients with alcoholic cirrhosis (in 1956) and then in rural Iranian children and Iranian and Egyptian farmers with inadequate nutritional intake in the early 1960s. Primary deficiency has largely been considered a significant risk in individuals and populations with malnourishment or compromised physiology. However, awareness continues to grow as to the full extent of at-risk populations from a broad range of age groups, socioeconomic conditions, and living situations. Foods grown in nutrient-depleted soil and processed foods are often low in zinc. In addition to protein/calorie-restricted diets, potential deficiencies from diets replete with zinc-poor foods but limited in foods rich in highly bioavailable zinc are often aggravated by foods that are rich in inhibitors of zinc absorption. Infants, impoverished and elderly persons with poor nutritional status, and those consuming excessive alcohol or with renal and hepatic disease are clearly susceptible, but seemingly healthy individuals with unbalanced nutritional intakes, elevated demands, or adverse genetic characteristics may be equally at risk. Survey data indicate that more than 60% of adults (≥20 years) in the United States do not consume dietary zinc at the level of the recommended dietary allowance (RDA). Even by following the U.S. Department of Agriculture (USDA) food pyramid recommendations of the past several decades, an individual will not obtain adequate zinc intake on a daily basis. Moreover, some young women who avoid red meat contribute, at least in part, to their being both zinc and iron deficient. Thus, the typical diet in developed countries usually provides insufficient zinc for healthy function, with infants, adolescents, women, and the elderly at greater risk. 7-10The prevalence of primary zinc deficiency is estimated at 25% to 49% of the world's population. 11,12

Mild zinc deficiency is fairly common and can have a significant and pervasive impact within a short time. The supply of zinc within the human body operates with a small margin of error relative to metabolic needs. The very small amount of zinc that functions as the “exchangeable zinc pool” in the human body is sufficient for only a few days without intake. Even with the relative inaccessibility of zinc deposits in bone or muscle tissue, excess zinc intake in the short-term is not usually retained (because of decreased absorption or rapid excretion). Consequently, consistent zinc intake is essential to maintain zinc metabolism within the narrow parameters between healthy function and systemic repercussions of insufficiency. Thus, a zinc-poor diet, poor assimilation, interfering agents, and an increase in physiologic demands can result in adverse effects within a short period. Nevertheless, scientific knowledge of the pathogenic mechanisms and complete characteristics of zinc deficiency remain incomplete.

A wide range of conditions can contribute to compromised zinc nutriture, insufficiency, and conditioned (secondary) deficiency. Acrodermatitis enteropathica is an inherited (autosomal recessive) disease characterized by zinc malabsorption and resulting in eczematoid skin lesions, alopecia, diarrhea, and concurrent bacterial and yeast infections. The life stages characterized by rapid growth, particularly pregnancy and lactation, childhood, and adolescence, are potentially as vulnerable as the hospitalized or institutionalized elderly person. Multiple pregnancies or shifts in growth rate, as well as infection or malignancy, can further aggravate disequilibrium in zinc metabolism. Likewise, deficient zinc intake can occur with chronic dieting, as well as poorly planned vegan, vegetarian, and semivegetarian diets. Excessive iron, calcium, or grain intake, particularly with simultaneous ingestion, may also interfere with zinc absorption, particularly because of phytic acid content of cereal grains. Impaired zinc absorption also occurs in individuals with gastrointestinal (GI) disorders, including diarrhea, pancreatic insufficiency, celiac sprue or other malabsorption syndromes, inflammatory bowel disease, Crohn's disease, and ulcerative colitis. Likewise, injuries or inflammatory conditions, such as burns, wound healing, dermatitis, rheumatoid arthritis, and chronic inflammatory diseases, that increase interleukin-1 (IL-1) can rapidly deplete available zinc due to increased utilization, thus producing short-term adverse effects. Hemorrhage, hemolytic anemias (e.g., sickle cell disease, thalassemia), superficial losses, excessive diuresis, or GI tract wastage into stool can also produce rapid zinc loss sufficient to cause systemic problems. Renal insufficiency predisposes to excess zinc excretion. Macular degeneration, type 2 diabetes mellitus, malignant melanoma, congestive heart failure, and other degenerative conditions are also associated with zinc deficiency. The variety of conditions that can adversely affect zinc status, together with the delicate balance of zinc available within the human organism, render zinc nutriture critical and the consequences of deficiencies pervasive and potentially significant.

The classic clinical presentation of severe zinc deficiency is characterized by diarrhea, poor wound or ulcer healing, dermatitis, psychiatric disturbances, weight loss, intercurrent or recurrent infection, alopecia, and hypogonadism (in males). Immunodepression, muscle pain, and fatigue are also among the first and most important signs and symptoms of zinc deficiency, and immune function can be depressed in humans with even mild zinc deficiency. In general, any rapidly growing cells can be affected in initial stages. Thus, compromised health of epithelial tissues, manifesting as impaired wound healing, dermatitis, rough skin, inflammatory acne, poor nail health, increased incidence of infections, diminished immune response, and elevated intolerance to environmental toxins may also indicate impaired zinc status. Anosmia and reduced taste acuity can also suggest zinc deficiency and may manifest only through poor appetite. Photophobia, night blindness, nystagmus, or decline in visual acuity may signal diminished zinc availability affecting the eyes, resulting, at least in part, from decreased ability to mobilize retinol from the liver. Diminished fertility, particularly with impaired spermatogenesis or ovulation, menstrual irregularities, weight loss, impaired glucose tolerance, and increased lipid peroxidation are among the predictable but often-unrecognized consequences of deficiencies in physiological functions dependent on zinc nutriture. Also less obvious, but more insidious in outcomes, are longer-term changes that can result from poor zinc status, such as slow or stunted growth and delayed puberty or other sexual development, as well as irritability, anxiety, depression, difficulty with concentration and cognitive function, impaired learning, or other psychoneurological conditions. Zinc deficiency before and during pregnancy may contribute to intrauterine growth retardation and congenital fetal abnormalities. In rat studies, zinc deficiency during pregnancy results in lifelong immune abnormalities in the offspring despite adequate zinc intake from birth, which requires three generations of normal zinc nutriture to reverse. 13

Dietary Sources

Seafood and red meat (especially liver and other organ meats) are the richest dietary sources of zinc, with a single oyster providing about 8 to 15 mg zinc. Poultry and eggs provide moderate amounts of dietary sources of zinc. Whole grains, nuts, and seeds provide smaller amounts of zinc, ranging from 0.2 to about 3 mg per serving, with notable sources being sunflower and squash seeds, wheat germ, hard-wheat berries, wheat bran, buckwheat, rice bran, millet, whole-wheat flour, oatmeal, brown rice, cornmeal, and sprouted grains. However, the zinc in plant foods, particularly whole-grain cereals and soy protein, can bind to phytic acid to form an insoluble zinc-phytate complex and thus is usually less bioavailable. Breads, breakfast cereals, and nutrition bars are often fortified with substantial amounts of zinc. Other food sources of zinc include hard cheese, peanuts, soy meal, black-eyed peas, green beans, chickpeas, lima beans, spinach, green onion, and green leafy vegetables. In general, food processing removes or destroys a high proportion of zinc, as well as other trace elements. The presence of certain amino acids, such as cysteine and histidine, may enhance absorption of zinc from foods.

Nutrient Preparations Available

Numerous forms of zinc are available, as previously listed. Zinc sulfate is an inexpensive form most often used in clinical trials. Many experienced practitioners of nutritional therapeutics, however, prefer to administer organically bound or chelated forms (e.g., zinc acetate, zinc citrate, gluconate, zinc glycerate, zinc monomethionine, zinc orotate, zinc picolinate, zinc-protein hydrolysate), based on a lower incidence of gastric irritation and (presumed) superior bioavailability and utilization. In general, zinc acetate provides the most bioavailable form of zinc, across a broad range of gastric pH.

Lozenges generally contain zinc gluconate, zinc gluconate-glycinate, or zinc acetate. The efficacy of various lozenges correlates with their relative iZn dosage, the sum of all positively charged (ionized) zinc species for zinc compounds at physiologic pH of 7.4. 14 Although all others forms are available over the counter (OTC) as nutritional supplements, zinc acetate is considered a prescription item because of its use in the treatment of Wilson's disease, although zinc acetate lozenges are available as an OTC drug for upper respiratory infection (URI) treatment.

The various forms of oral zinc are salts with differing zinc content. For example, zinc sulfate contains 23% elemental zinc and zinc gluconate 14.3% elemental zinc. Thus, the amount of zinc in some typical supplemental forms is as follows: zinc amino acid chelate, 100 mg/g; zinc gluconate, 130 mg/g; zinc orotate, 170 mg/g; and zinc sulfate, 227 mg/g. A typical zinc sulfate dose of 220 mg provides approximately 55 mg of elemental zinc. However, solubility and ionizability of the various salts of can have major impact on bioavailability.

Dosage Forms Available

Capsule, injectable, intranasal gel, intranasal spray, liquid, lozenge, tablet, topical. Parenterally, zinc is usually included as a component of total parenteral nutrition (TPN).

For optimal absorption, oral zinc should usually be ingested between meals. However, if adverse GI effects occur, consumption with meals may be adequate and effective. In general, oral zinc intake should be separated from ingestion of high-fiber foods to minimize impairment of absorption, as well as high-dose calcium or iron supplements. Likewise, the antiviral activity of zinc lozenges may be impaired by certain flavorings, sweeteners, or other additives.

Source Materials for Nutrient Preparations

Zinc acetate and zinc chloride are derived from mineral salts consisting of zinc and chloride or zinc nitrate and acetic anhydride, respectively. Zinc carbonate is derived from smithsonite or zincspar. Chelates such as zinc citrate, zinc gluconate, zinc lactate, zinc orotate, zinc picolinate, and zinc selenate are derived from smithsonite or other rock processed with citric acid, gluconic acid, lactic acid, orotic acid, picolinic acid, or selenic acid, respectively. Zinc oxide is derived from zincite and zinc phosphate from hopeite.

Dosage Range

The issue of zinc dosage is unclear and eludes scientific knowledge necessary to establish a basis for widely agreed conclusions. Dietary supplements typically contain 5 to 50 mg (elemental zinc) per daily dose. Moderate intake of 15 to 50 mg daily can be used safely to provide for physiological requirements and prevent deficiency. Short-term, repeated use of zinc lozenges containing higher doses (e.g., 13-25 mg each), with up to 10 lozenges daily, is generally well tolerated for several-day periods. Therapeutic application of zinc at 50 mg, one to three times daily, may be appropriate for certain conditions, such as copper overload in Wilson's disease, under the supervision of a health care professional. The presence of zinc in some fortified foods may alter the equation for any given individual based on consumption, but is often offset by impaired bioavailability resulting from certain dietary constituents and how they affect certain forms of zinc.

Adult

  • Dietary:   The U.S. RDA for zinc is 15 mg per day for adult men and 12 mg per day for adult women, but average daily intake in developed societies is typically only 60% to 70% of that amount, with the average adult daily diet in the United Kingdom providing 11.7 mg for men and 8.7 mg for women. The official U.S. recommendations for daily intake in pregnant women is 11 mg (13 mg if ≤18 years old) and 12 mg for nursing women (14 mg if ≤18 years old).

  • Supplemental/Maintenance:   15 to 50 mg per day, preferably with copper.

In some respects, however, zinc intake beyond adequate dietary intake is sometimes considered inappropriate unless indicated, given “almost no gap for supplementation” above the RDA and the reference dose (RfD) for safe intake of zinc, although, as noted, usually a gap exists between average daily dietary intake and the recommended daily intake. 12 Few data are available on optimal zinc intakes (as assessed by function of zinc-dependent enzymes in free-living human subjects), and it is likely that optimal intakes vary considerably depending on age, lifestyle, and various states of health and disease.

Pharmacological/Therapeutic: 50 to 350 mg (elemental zinc) per day.

Oral doses as high as 220 mg zinc sulfate three times daily have been used in trials of zinc for the prevention of crisis in sickle cell anemia, and twice daily for 12 weeks to correct zinc deficiency in cirrhotic patients with symptoms of deficiency (e.g., blunted taste/smell). 15,16In a trial involving patients with chronic fatigue syndrome, 135 mg/day was administered for 15 days (along with 2 mg copper daily) to correct zinc deficiency. 17

  • Toxic:   Toxicity can occur at levels as low as 60 mg/day (with prolonged intake) but is more frequently associated with doses higher than 300 mg/day. Prolonged intake at doses higher than 150 mg/day may be associated with adverse effects. The official U.S. tolerable upper limit (UL) for adults (≥19 years) is 40 mg, including pregnant or nursing women, although it is 34 mg/day if such women are 18 years old or younger. 18 This amount includes dietary intake and thus may vary considerably with high consumption of fortified foods or foods naturally rich in zinc.

Pediatric (<18 Years)

Dietary: Zinc concentrations in breast milk are relatively low, but such zinc is highly absorbable. Official U.S. recommendations for daily intake follow 18 :

  • Infants, birth to 6 months: 2 mg/day
  • Infants, 7 to 12 months: 3 mg/day
  • Children, 1 to 3 years: 3 mg/day
  • Children, 4 to 8 years: 5 mg/day
  • Children, 9 to 13 years: 8 mg/day
  • Adolescents, 14 to 18 years: 9 mg/day for females; 11 mg/day for males

Clinical experience with adolescents suggests that much larger amounts may be required during growth spurts (up to 40 mg/day).

  • Supplemental/Maintenance:   Usually not recommended for children under 12 years of age with healthy, balanced diet, without excessive dietary phytates.

  • Pharmacological/Therapeutic:   5 to 40 mg per day, for specified periods.

Trials investigating zinc supplementation in infants born small for gestational age (SGA) typically use 5 mg zinc sulfate daily, often combined with other nutrients. 19 Zinc acetate (10 mg twice daily for 5 days) has been used successfully in infants and young children with severe acute lower respiratory infection. 20 Several prominent trials have found efficacy of low-dose oral zinc in acute and persistent diarrhea in children under 5 years of age in developing countries.

  • Toxic:   150 mg/day on a chronic basis, or acutely with doses greater than 200 mg daily. However, the toxic dose of zinc depends primarily on dose and duration, and also varies with status and absorption, weight, and concomitant intake. Single intravenous (IV) doses of 1 to 2 mg zinc/kg body weight have been given to adult leukemia patients without toxic manifestations. Consensus as to toxic dose in clinical applications has not been established, and plasma levels sufficient to produce symptoms of toxic manifestations are not known.

Tolerable upper intake levels (UL) for zinc follow 18 :

  • Infants, 0 to 6 months: 4 mg/day
  • Infants, 7 to 12 months: 5 mg/day
  • Children, 1 to 3 years: 7 mg/day
  • Children, 4 to 8 years: 12 mg/day
  • Children, 9 to 13 years: 23 mg/day
  • Adolescents, 14 to 18 years: 34 mg/day

Laboratory Values

Overview

Clinicians and researchers broadly agree that clinical presentation and response to zinc administration provide the most accurate means of assessing zinc status and confirming deficiency status. Thereafter, retesting (e.g., plasma zinc) and reevaluation of symptoms after 4 to 6 months of treatment are usually effective for determining if dosages need adjustment. In a review, Hambridge 21 (2003) concluded that there is a “compelling demand for improved zinc biomarkers” based on numerous characteristics peculiar to the physiology of zinc in the human organism. “More specific markers of zinc status are needed, and their relationships to zinc-dependent cellular functions and the distribution and allocation of zinc to the different organ systems need to be clarified.” Some physicians experienced in nutritional therapeutics consider measuring the leukocyte zinc level as the best laboratory method for determining zinc status. 22 Most clinicians and researchers do not consider hair a reliable form of analysis for measuring tissue levels of zinc. 23 Moreover, some clinicians observe that urine and hair tissue levels are often elevated in patients with zinc deficiency because of dysfunction in zinc metabolism and high rates of excretion.

Erythrocyte Zinc

Most of the zinc measured as erythrocyte zinc is incorporated in carbonic anhydrase. Although some studies report detection of depletion through low levels, erythrocyte zinc has been generally regarded as not readily depleted and therefore not accurately indicative of zinc status. 24

Hair Zinc

Some clinicians have suggested that analysis of hair zinc concentrations might reveal associations between low hair zinc levels and zinc depletion status. However, numerous factors, such as age, growth rate, and dietary intake of phytates and meat, can confound analysis and decrease this test's ability to consistently determine impaired zinc status or inadequate intake. 23,25-29Antidandruff shampoos often incorporate zinc as well, which can greatly elevate hair zinc levels.

Plasma Zinc

The range for normal plasma levels for zinc is 58 to 106 µg/dL. In blood plasma, zinc is bound to albumin (80%) and to α2-macroglobulin (20%). Plasma zinc levels appear to follow a circadian rhythm, with the highest values occurring late morning, at approximately 10AM. Plasma zinc can be normal even when plasma albumin is low, because albumin normally contains many unsaturated binding sites.

Plasma zinc and serum zinc are often used in clinical and research settings but are physiologically insensitive and of limited diagnostic value. Hambridge 21 observed: “Plasma zinc is currently the most widely used and accepted biomarker of zinc status despite poor sensitivity and imperfect specificity…. One reason that plasma zinc does not accurately reflect the volatile relationship between zinc intake and absorption is that homeostatic control of plasma zinc concentrations can occur while moderate changes are occurring in the zinc content of one or more of the pools of zinc that exchange rapidly with zinc in plasma.” Furthermore, the decline that occurs as a recognized component of the acute-phase response in infections represents at least one important limitation affecting the specificity of plasma zinc as an index of zinc status. 30,31Severe acute zinc deficiency states, such as untreated acrodermatitis enteropathica, may reveal profoundly depressed plasma zinc levels. However, mild zinc deficiencies that can adversely affect physiological function may appear as plasma zinc concentrations within the normal range, as with growth-limiting zinc deficiency states in young children. 26 Various studies have conflicting findings and mixed conclusions regarding an association between zinc intake and plasma zinc. Nevertheless, concentrations less than 70 µg zinc/dL plasma can serve as a useful predictor of growth response to zinc supplementation, and beneficial effects of zinc administration in the prevention and management of diarrhea can be predicted using lower cutoff values. Plasma levels less than 70 µg/dL might constitute a better definition of deficiency state.

Red Cell Membrane Zinc

Metallothionein levels in erythrocytes respond to administration of zinc as well as restricted dietary intake. 32 Thus, RBC membrane zinc may be a sensitive indicator of zinc depletion, but its practical implementation on a widespread basis is considered unlikely given the complexity of sample preparation. A parallel situation appears with monocyte, neutrophil, or platelet zinc. 33-36

Serum Zinc

Serum zinc concentration less than 33 µg/dL indicates zinc deficiency. Serum levels 33 to 50 µg/dL indicate marginal zinc status. The normal range for serum zinc is 67 to 124 µg/dL, although this varies between clinical laboratories.

Serum zinc is considered an insensitive marker of physiological zinc status, for the same reasons previously stated in relationship to plasma zinc.

White Blood Cell Zinc

The levels of zinc in leukocytes or lymphocytes appears to reflect zinc status accurately, particularly in relation to key zinc-related functions such as immune function, life stage, and growth processes. For example, leukocyte (WBC) zinc is reflective of fetal growth and associated with maternal muscle zinc concentration. Likewise, activity of lymphocyte ecto-5′-nucleotidase is a sensitive indicator of zinc status. 12,37-41

Assessment of gene expression of zinc-dependent genes in lymphocytes (specifically cellular zinc transporter hZip1) offers promise as a biomarker of expression of the cellular zinc response to zinc intake and bioassay for zinc status. 42

Zinc Tally

In this quick and simple screening method for evaluating zinc status, the absence of the typical metallic taste of zinc, after placing 2 teaspoons of a 0.1% solution of zinc sulfate heptahydrate in the patient's mouth and holding it there for 10 seconds, suggests deficiency. An immediate taste perception indicates that zinc status may be adequate; conversely, lack of zinc taste suggests deficiency.

Zinc Tolerance Test

In this test an oral load of 50 mg elemental zinc is administered, after a baseline plasma zinc measurement, and plasma zinc is remeasured 120 minutes later. A twofold to threefold increase in plasma zinc indicates zinc deficiency. Zinc supplements need to be avoided for 24 hours before sampling of plasma.

CD4+/CD8+ T-Lymphocyte Ratio and Thymulin Activity

The CD4+/CD8+ T-lymphocyte ratio and thymulin activity have been advanced as potential immunological tests for zinc deficiency, but evidence confirming their accuracy is lacking.

Other findings possibly consistent with zinc insufficiency, but also resulting from other causes, include the following 43 :

  • Elevated anserine and carnosine peptides, with low levels of essential amino acids, in urine or plasma amino acid analysis.
  • Elevated phosphoserine and phosphoethanolamine in urine amino acid analysis.
  • Elevated lactic acid in plasma or urine (lactic acid dehydrogenase also is zinc dependent).
  • Elevated or normal linolenic acid, but low gamma-linolenic acid, consistent with weak delta-6-desaturase activity (zinc dependent).

safety profile

Overview

Zinc dosage beyond the RDA is not established, and the perpetually marginal nature of zinc nutriture leaves a relatively small dosage range and tight time frame for safe and effective use of zinc between suboptimal and potentially toxic intake levels, particularly with extended use outside a balanced nutrient regimen. The affinity of zinc for certain tissues appears to result in a pattern of benefit and toxicity converging (e.g., immune system, possibly prostate). The dose typically used for short-term immune stimulation as a lozenge (13-25 mg each) would be excessive for continued use with oral intake and could impair immune function (at >150-300 mg/day). Likewise, 25 to 30 mg daily has been used to improve pregnancy outcomes in low-income pregnant women and pregnant teenagers, but a significantly higher dose could have potentially adverse effects during pregnancy, especially on embryogenesis.

Zinc is perhaps the least toxic mineral nutrient at usual doses but can be strikingly toxic at very high doses associated with industrial exposure. Notably, major authorities on zinc physiology, requirements, and safety acknowledge the limited scope of scientific knowledge as to its physiological functions, the multiple variables affecting bioavailability, dynamic relationships between zinc and other minerals, parameters governing insufficiency and toxicity, and methods of assessing functional zinc levels.

Nutrient Adverse Effects

General Adverse Effects

Zinc is generally considered relatively nontoxic at low to moderate levels typical of supplemental use: less than 50 mg elemental per day. Given the narrow gap between potentially insufficient and excessive levels, both deficiency and toxicity can vary significantly among individuals based on tissue and circulating levels, historic intake, zinc pool status, recent or active infection, blood loss or other depletion factors, dietary interactions, and other variables. Gastrointestinal upset and nausea are quite common when zinc supplements, especially zinc sulfate, are taken on an empty stomach. More importantly, zinc administration, especially lacking in compensatory copper support, can produce adverse effects rapidly (as with deficiency), which grow in intensity based on dose and duration and influenced by other variables. The primary toxic effects of zinc, typically associated with prolonged intake at levels greater than 150 mg daily, include copper deficiency anemia, depressed immune function, and reduced high-density lipoprotein (HDL) cholesterol levels.

Topical zinc preparations are generally considered safe and unlikely to produce any adverse effects. However, anosmia has been reported with zinc nasal spray and in rare cases has been reported to be severe or permanent. 44

The primary effects of zinc toxicity can occur with doses higher than 150 mg/day on a chronic basis or acutely with doses greater than 200 mg daily. They include diarrhea, nausea, vomiting, metallic taste in the mouth, dizziness, drowsiness, incoordination, and lethargy. Gastric erosion and hematuria with chronic high-dose use have been reported but not confirmed. Ingestion of 10 to 30 g of zinc sulfate can be lethal in adults. However, acute zinc toxicity is extremely rare because ingestion of the amounts required for toxicity symptoms (2 g/kg) will usually provoke vomiting before toxic dose levels are attained. Impairment of copper absorption can begin at daily doses as low as 50 mg elemental zinc, with copper depletion accruing over time and manifesting as low serum copper and ceruloplasmin levels, microcytic anemia, and neutropenia; iron deficiency is also possible. Immune function can become impaired, HDL cholesterol levels decrease, and total cholesterol levels increase with daily doses over 300 mg/day for extended periods, but possibly as low as 150 mg/day, perhaps as a result of induced copper deficiency. 45-49Subsequently, zinc-induced copper deficiency has been associated with cases of reversible acquired sideroblastic anemia, cardiac arrhythmias, and bone marrow depression. Such reports have involved chronic intake of 450 to 1600 mg daily, and many such cases are properly characterized as zinc abuse, with ingestion of coins being the source of zinc in one individual. 50-55Inhalation of zinc oxide in certain industrial settings and the use of galvanized pipes for drinking water are also known causes of excess zinc exposure.

Short-term frequent use of zinc lozenges can occasionally produce digestive upset, local oral irritation, and unpleasant taste; typically reversible with cessation. 49,56

Adverse Effects Among Specific Populations

One study from India suggests that the concomitant use of zinc and oral antibiotics in the acute management of pneumonia of infants or children may delay recovery during the hot season, particularly in the absence of zinc deficiency. 57

Two preliminary papers by Bush et al. 58,59discussed the possibility of zinc aggravating amyloid formation in individuals with Alzheimer's disease. However, subsequent research articles and reviews have concluded that zinc does not cause or exacerbate Alzheimer's disease symptoms, and may enhance mental function by improving platelet membrane microviscosity. 60,61

Genotoxicity

“Zinc is apparently neither a mutagen nor a carcinogen.” 12,62However, in one study analyzing data from a larger trial, researchers reported a slight increase in the relative risk of prostate cancer among men who used zinc supplements for more than 10 years, particularly at doses greater than 100 mg elemental zinc daily. 63

Pregnancy and Nursing

Maternal nutritional zinc deficit “can have permanent negative effects on the growth of offspring,” and zinc administration at typical dose levels may be beneficial during pregnancy. However, excess zinc intake “during embryogenesis can be teratogenic or lethal,” and premature birth and stillbirth have been reported when women consumed 100 mg three times daily during the third trimester. 12,62,64The use of supplemental zinc by nursing mothers over an extended period, without compensatory copper support, could contribute to zinc-induced copper deficiency in breastfed infants. Nevertheless, no reports or studies in the scientific literature show any adverse effects on fetal development from supplemental zinc, at typical doses, in well-nourished mothers or in infants who are breastfed.

Contraindications

No contraindications have been established for zinc.

Precautions and Warnings

Extended use of zinc without copper carries a warning. The recommended ratio of zinc to copper is 15:1 to 20:1. This ratio is higher in elderly persons, who, in the United States, tend to have high copper levels and low zinc levels because of a history of chronic ingestion of water carried through copper pipes.

interactions review

Strategic Considerations

Three simple and consistent themes are recurrent among the various interactions between zinc and pharmacological agents. First, as a mineral/metal, zinc tends to chelate with many substances when ingested simultaneously or in temporal proximity. This potential problem is easily avoided through patient education and clinical management; individuals should separate intake, preferably taking zinc at least 2 hours before or 4 hours after such medications. Second, in all situations except the treatment of individuals with Wilson's disease, the default prudent measure with any long-term application of zinc is to avoid zinc-induced copper deficiency by periodically monitoring serum copper levels and coadministering low-dose copper (1-3 mg/day). Third, within the human organism, zinc is volatile with an ever-shifting distribution between pools. Thus, establishing zinc deficiency or monitoring the impact of any agent on functional zinc status is difficult and unreliable. Consequently, at usual dosage levels and with attentiveness to clinical manifestations of zinc deficiency (or excess), coadministration of zinc within a therapeutic strategy carries minimal risk of adverse interactions, other than copper depletion and the predictable chelation phenomena common to most minerals when ingested with other substances.

Numerous pharmaceutical agents are associated with adverse effects, both subtle and overt, of zinc depletion. Consequently, numerous clinical situations occur in which coadministration of zinc may improve zinc nutriture, related physiological functions, and clinical manifestations, even when prior conventional laboratory assessment had revealed no measurable signs of depletion, insufficiency, or deficiency. These recurrent patterns indicate two probable phenomena: zinc can provide benefit in the absence of depletion, detected or not, and conventional laboratory methods currently applied for assessing zinc status are insensitive and inadequate to clinical demands. Our limited knowledge of the many functions of zinc is repeatedly revealed in the sparsity and limited depth of both the observations of zinc-related benefits and interactions and the mechanisms involved.

Many widely used pharmaceutical agents contribute to zinc depletion, usually through binding and increased urinary zinc excretion. Thus, coadministration of zinc may reduce depletion effects or prevent other adverse effects associated with a wide range of medications used to treat hypertension, inflammation, and other conditions. Particularly with chronic use, thiazide diuretics increase urinary zinc excretion, as do loop diuretics, although probably to a lesser degree. Although patients treated with angiotensin-converting enzyme (ACE) inhibitors (especially captopril) at clearly are risk for zinc depletion, the effects of potassium-sparing diuretics on zinc are diverse and complicated. Furthermore, amiloride is often combined with a thiazide diuretic to reduce mineral loss, but amiloride may cause zinc accumulation by reducing urinary excretion. In contrast, triamterene can increase urinary zinc excretion in the short-term and cause depletion with extended use. In patients treated with antacids and gastric acid–suppressive medications, long-term drug therapy can impair zinc absorption and reduce availability by interfering with the normal acid environment of the stomach; although cimetidine appears to be an exception among H2blockers. With these drugs, administration of zinc can prevent or reverse depletion and enhance healing of gastric tissue damaged by ulceration. When coadministered with nonsteroidal anti-inflammatory drugs (NSAIDs), zinc may reduce risk of adverse effects on zinc status while providing protective effects and contributing to enhanced therapeutic outcomes.

Oral corticosteroids and valproic acid, alone or in combination with other anticonvulsant agents, represent examples of medications that can deplete zinc, but for which evidence of benefit from concomitant zinc is limited or lacking.

Evidence of variable strength suggests a probable synergy or other benefit from concomitant zinc administration with a wide range of conventional interventions, including mixed amphetamines, androgens, clobetasol (and potentially other topical corticosteroids), metronidazole (in treating trichomoniasis), and chlorhexidine-zinc oral rinse. In the treatment of individuals with Wilson's disease, concomitant zinc may enhance the therapeutic activity of penicillamine in reducing copper levels, although intake needs to be separated. Zinc therapy can be applied to reduce adverse effects to taste sensation in patients receiving radiation therapy, particularly to the head and neck.

In several areas the coadministration of zinc with conventional therapies appears to produce mixed effects, depending on patient characteristics, with full implications as yet unclear. For example, in women of reproductive age, oral contraceptives may decrease serum levels of zinc; conversely, osteoporotic postmenopausal women taking conjugated estrogens and medroxyprogesterone may exhibit reductions in previously elevated urinary zinc excretion. Zidovudine (AZT) and related antiretroviral agents present another complicated situation where divergent responses are common. In a patient population often characterized by zinc insufficiency, zinc coadministration may reduce drug-related adverse effects, add protective benefits (particularly in patients with diarrhea and opportunistic infections), provide no significant benefit, or even potentially elevate the risk of complications.

Numerous clinical situations allow for possible synergy, particularly in individuals or populations at greater risk for compromised zinc or broader nutritional status. The areas of antibiotic therapy, oral or topical, and antidepressant medications, particularly tricyclic and selective serotonin reuptake inhibitor (SSRI) antidepressants, offer significant potential for continued research into integrative therapeutic applications.

In many situations, zinc (as well as most other minerals) tends to bind with other substances and thereby decrease bioavailability and therapeutic action or nutritive value of both agents. Separation of intake remediates this problem. Antibiotics from the tetracycline class (other than doxycycline) or fluoroquinolone class (particularly ciprofloxacin) and warfarin or related oral vitamin K antagonist anticoagulants stand as primary examples of situations commonly accepted as involving a significant risk of pharmacokinetic interference.

Zinc may play a central role in the intimate relationships between the immune system and the mental-emotional states traditionally ascribed to the central nervous system (CNS). The body of scientific knowledge emerging within the field of psychoneuroimmunology may render obsolete conventional parsing of academic disciplines, which often are inadequate in conveying the totality of complex physiological functioning inherent in clinical medicine. A more comprehensive model can provide a forum for further research into the broader functions of zinc that transcend narrow categorization and defy reductionist analysis.

nutrient-drug interactions
Amphetamines and Related Stimulant Medications
Androgens
Antibiotics and Antimicrobial Agents (Systemic)
Antibiotics, Topical
Antidepressants, Including Tricyclic Antidepressants and Selective Serotonin Reuptake Inhibitor (SSRI) Antidepressants
Calcium-Based Antacids
Captopril, Enalapril, and Related Angiotensin-Converting Enzyme (ACE) Inhibitors
Chlorhexidine
Ciprofloxacin and Related Fluoroquinolone (4-Quinolone) Antibiotics
Clobetasol and Related Topical Corticosteroids
Cisplatin
Corticosteroids, Oral, Including Prednisone
Oral Contraceptives: Monophasic, Biphasic, and Triphasic Estrogen Preparations (Synthetic Estrogen and Progesterone Analogs)
Hormone Replacement Therapy (HRT), Estrogens
Progestin/Progestogen-Only Oral Contraceptives, Implants, and Postcoital Contraceptives
Hormone Replacement Therapy
Histamine (H 2 ) Receptor Antagonists and Related Antacids and Gastric Acid–Suppressive Medications
Loop Diuretics
Metronidazole, Vaginal
Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)
Penicillamine
Potassium-Sparing Diuretics
Radiotherapy
Tetracycline Antibiotics
Thiazide Diuretics
Valproic Acid and Related Anticonvulsant Medications (AEDs)
Warfarin and Related Oral Vitamin K Antagonist Anticoagulants
Zidovudine (AZT) and Related Nucleoside or Nonnucleoside (Analog) Reverse-Transcriptase Inhibitors (NRTIS or NNRTIS) Antiretroviral Agents
Evidence: Zidovudine (azidothymidine, AZT, ZDV, zidothymidine; Retrovir).Extrapolated, based on similar properties: Azidothymidine combination drugs: abacavir, lamivudine, and zidovudine (Trizivir); zidovudine and lamivudine (Combivir); didanosine (ddI, dideoxyinosine; Videx), dideoxycytidine (ddC, zalcitabine; Hivid), lamivudine (3TC, Epivir), stavudine (D4T, Zerit), tenofovir (Viread).
Drug-Induced Nutrient Depletion, Supplementation Therapeutic, with Professional Management
Beneficial or Supportive Interaction, with Professional Management
Bimodal or Variable Interaction, with Professional Management
Potential or Theoretical Adverse Interaction of Uncertain Severity

Probability: XXX
Evidence Base: XXX

Effect and Mechanism of Action

Zinc plays a central role in many immune functions, including T-cell division, maturation, differentiation, and function; lymphocyte response to mitogens; programmed cell death of lymphoid and myeloid origins; gene transcription; and biomembrane function. Thymulin, a zinc-bound hormone, and Cu/Zn superoxide dismutase, as well as congenital or acquired zinc deficiencies, are associated with immune abnormalities and increased susceptibility to infectious diseases. 169 AZT may deplete zinc (and other nutrients). Populations likely to have a high incidence of HIV infection may also be more likely to exhibit compromised zinc status, possibly due to malnutrition, progression of the pathology, or excessive ejaculation. 170-173 “AIDS subjects suffer from reduced zinc bioavailability, more severe in stage IV than in stage III.” 174

Zidovudine may deplete plasma zinc levels; conversely, adequate zinc levels may enhance therapeutic response to AZT treatment. 175 Zinc deficiency may diminish drug effectiveness because zidovudine requires thymidine kinase, a zinc-dependent enzyme, for conversion to its active triphosphate form. 170,175 Notably, individuals with HIV infection, particularly later stages of AIDS, tend to exhibit elevated cooper levels. 176

Research

In a 1991 longitudinal study involving 37 HIV-positive participants, 15 treated with ZDV (AZT, 500-1200 mg/day) and 22 serving as untreated, CD4 level–matched controls, Baum et al. 175 found significantly decreased mean plasma levels of zinc (and copper) in a “large proportion” of AZT-treated subjects after 12 months of antiviral therapy. Hematological and plasma nutrient levels were similar in both groups before treatment, but after therapy, “drug-treated subjects demonstrated alterations in hematological and nutritional parameters.” The authors noted that the “level of plasma zinc appeared to be particularly important in maintaining immune function in the ZDV-treated group. Whereas ZDV-treated subjects with adequate zinc levels displayed a significant increase in the response of peripheral blood lymphocytes to mitogens, this enhancement was not demonstrated in zinc-deficient, ZDV-treated participants or in untreated individuals whose lymphocyte response significantly declined over time, despite adequate zinc status.” The authors concluded that their findings “reveal a zidovudine-induced effect on nutritional parameters, indicating the importance of monitoring nutritional status with drug therapeutic regimens.” 175 Subsequent papers by Baum et al. 169 and Bogden et al. 176 have emphasized the key physiological roles of zinc and the importance of zinc status in HIV infection, providing evidence that compromised nutritional and antioxidant status begins early in HIV-1 infection and may contribute to disease progression.

Although some survey data indicate that higher zinc intake may be associated with worse outcomes in HIV-positive individuals (regardless of AZT therapy), other trials suggest a potential synergistic benefit from coadministration in patients treated with AZT. In a survey of 281 HIV-positive homosexual/bisexual men, Tang et al. 177 reported that increased intake (from food and supplements) of “zinc was monotonically and significantly associated with an increased risk of progression to AIDS.” In a follow-up paper the authors reported that “any intake of zinc supplements, however, was associated with poorer survival” and suggested that further “studies are needed to determine the optimal level of zinc intake in HIV-1-infected individuals.” 178 Conversely, in a study investigating the relationship between zinc deficiency and survival in HIV-positive homosexual men, Campa et al. 179 found that higher zinc levels were associated with better immune function and higher CD4+ cell counts, while zinc deficiency was associated with greater incidence of HIV-related mortality. Subsequently, Mocchegiani et al. 174 conducted a clinical trial involving 17 AZT-treated stage III subjects with generalized lymphadenopathy and 12 stage IV/subgroup C1 AIDS patients, with 18 stage III subjects with generalized lymphadenopathy and 10 stage IV/subgroup C1 subjects treated only with AZT serving as controls. Stage III and stage IV/C1 patients administered zinc sulfate (200 mg daily for 30 days) exhibited an “increase or a stabilization in the body weight and an increase of the number of CD4+ cells and the plasma level of active zinc-bound thymulin,” and the “frequency of opportunistic infectious episodes in the 24 months following entry into the study was reduced after zinc supplementation in stage IV C1 subjects (11 infections versus 25 in controls) and delayed in stage III zinc-treated subjects (1 infection/24 months versus 13 infections/24 months in controls).” Notably, the beneficial effect of zinc on opportunistic infections was “restricted to infections due to Pneumocystis cariniiand Candida,whereas no variations have been observed in the frequencies of cytomegalovirusand toxoplasmainfections.” The authors concluded that these data “may support the benefit of zinc as an adjunct to AZT therapy in AIDS pathology.” 174

In a randomized, double-blind, placebo-controlled trial involving 96 children with HIV-1 infection in South Africa, Bobat et al. 180 found that administering 10 mg daily of elemental zinc, as sulfate, reduced watery diarrhea significantly and lowered the incidence of pneumonia (compared to placebo), without adversely affecting (i.e., increasing) plasma HIV-1 viral load. In a randomized controlled trial involving 159 HIV-infected adults in Peru, with at least a 7-day history of diarrhea, Carcamo et al. 181 found that 2 weeks of treatment with 50 mg zinc twice daily does not reduce or eliminate persistent diarrhea in adults infected with HIV. The authors added: “Longer treatment or follow-up beyond 2 weeks might have revealed treatment benefit…. Among children, however, benefits of zinc supplementation on diarrhea have been evident after the fourth day of supplementation.”

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Physicians treating HIV-infected individuals with AZT or related antiretroviral regimens should always assess nutritional status, particularly dietary intake and use of antioxidant and other supplements, and consider coadministration of zinc, selenium, glutathione/ N-acetylcysteine, and other nutrients that may be beneficial. Multiple factors, including the underlying pathology, concomitant health and lifestyle factors, comorbid conditions, and the multiple medications often used, strongly suggest high susceptibility to compromised nutritional status, which may be further exacerbated by drug-induced nutrient depletion patterns.

Moderate-dose to high-dose zinc, 50 to 100 mg elemental zinc daily, may counter preexisting deficiency, reduce effects of drug-induced depletion, and facilitate the activity of AZT. Coadministration of 1 to 2 mg of copper may be appropriate (but may be contraindicated if serum/plasma levels are already high) to neutralize the potential risk of adverse effects on the immune system from the long-term zinc. Laboratory assessment of zinc status may be less than ideal, but regular monitoring of the nutritional and metabolic status of such patients is essential, including instructing the patient to be attentive to signs of possible zinc deficiency. Clinical management of HIV-positive patients using multiple treatment modalities in an individualized and evolving integrative strategy requires close collaboration and regular coordination among health care professionals trained and experienced in conventional pharmacology and nutritional therapeutics.

theoretical, speculative, and preliminary interactions research, including overstated interactions claims
Acetylsalicylic Acid (Aspirin) and Related Anti-Inflammatory Analgesic Medications
Bile Acid Sequestrants
Bisphosphonates
Clofibrate and Related Fibrates
Cyclosporine
Dopamine Receptor Antagonists
EDTA
Ethambutol
Folic Acid
Hydralazine
Interferon Alfa (Interferon Alpha)
Nystatin
nutrient-nutrient interactions
Antioxidant Nutrients
Calcium and Calcium-Based Antacids
Copper
SMALLCAPS L END_SMALLCAPS -Cysteine
Folic Acid
Glutamine and Probiotic Bacterial Flora
SMALLCAPS L END_SMALLCAPS -Histidine
Iron
Magnesium
Manganese
N -Acetylcysteine (NAC)
Vitamin B 2 (Riboflavin)
herb-nutrient interactions
Ashwagandha
Bloodroot
Evening Primrose Oil
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