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Copper

Nutrient Name: Copper.
Synonyms: Copper carbonate, copper citrate, copper gluconate, copper glyconate, copper lysinate, copper sebacate, copper sulfate, cupric acetate, cupric oxide; cuprum.
Elemental Symbol: Cu.
Related Substance: Chlorophyllin.

Summary Table

Drug/Class Interaction Type	Mechanism and Significance	Management
Allopurinol /	Allopurinol, a potent inhibitor of xanthine oxidase, forms a complex with copper that can reduce cardiac damage, which appears to be due to copper- and ascorbate-mediated DNA breakage, in patients undergoing cardiac bypass surgery. The mechanisms involved are not fully understood, but the resulting complex exhibits low redox activity.	Chelation of copper by allopurinol may help protect against cardiac damage during reperfusion of the heart. Avoid copper before bypass surgery.
Antacids	Antacids can inhibit copper absorption and induce intestinal alkaline pH, which can precipitate dietary copper. Copper depletion and deficiency may result from excessive or extended use of antacids, especially with pyloric stenosis. Mechanism reasonable, but clinically significant adverse effects probably infrequent.	Coadminister with extended antacid use.
Cimetidine /	Animal studies indicate cimetidine complexes with Cu(II) [and Fe(III)] ions and may elevate tissue copper concentrations, particularly in the liver. By binding copper (and iron), cimetidine may also act as a free-radical scavenger. Although the proposed mechanisms are plausible, evidence remains preliminary.	Coadminister if indicated. Separate intake by at least 2 hours.
Ciprofloxacin	Copper and other minerals can bind to ciprofloxacin and reduce its absorption. Copper evidence preliminary, but parallel phenomenon with iron generally recognized. Drug efficacy could be impaired.	Separate intake by at least 2 hours.
Clofibrate fibrates / / /	Clofibrate may enhance copper metabolism and elevate hepatic copper levels, and may reduce hypercholesterolemia, particularly with compromised copper status. Research is limited, with mixed findings and conclusions.	Coadminister, as appropriate; monitor.
Ethambutol / /	Ethambutol forms chelate complexes with copper (and zinc), which may contribute to drug-induced optic neuropathy.	Coadminister and monitor visual function. Separate intake by at least 2 hours
Famotidine H²receptor antagonists (H²RAs)	Famotidine and H²RAs interfere with the acidic gastric environment optimal for copper absorption. Such drug-induced changes can inhibit copper absorption and induce alkaline intestinal pH, which can precipitate dietary copper. Subsequent copper depletion and deficiency may result from excessive or extended gastric acid–suppressive therapy. Mechanism reasonable but frequency of clinically significant adverse effects unknown.	Coadminister with extended H²RA use. Separate intake by at least 2 hours.
Nonsteroidal anti-inflammatory drugs (NSAIDs) /	Copper tends to complex with NSAIDs and might enhance their anti-inflammatory effects while reducing their ulcerogenic effects. Evidence preliminary and promising, but mixed; clinical implications likely significant.	Consider coadministration.
Oral contraceptives (OCs) Estrogens/progestins Hormone replacement therapy (HRT)	Exogenous female hormones, especially progestins, may enhance copper absorption and elevate copper levels. Clinical significance may vary with age, specific medication, and other factors and could contribute to increased adverse drug effects, e.g., cardiovascular risk.	Avoid concomitant copper supplementation unless risk of depletion or other prevailing benefits.
Penicillamine, trientine, and tetrathiomolybdate Chelating agents /	These chelating agents are designed to bind copper and limit its absorption and accumulation, particularly in treatment of mineral deposition disorders such as Wilson's disease and increasingly in antiangiogenic cancer therapy. Interaction is purposeful, and its clinical significance is generally recognized.	Limit dietary and avoid supplemental copper intake. Monitor for adverse drug effects.
Valproic acid Anticonvulsant medications /	Valproic acid and related antiepileptics may induce copper deficiency and disrupt copper homeostasis by increasing excretion into bile. Preliminary evidence of depletion pattern; prevalence uncertain. Possible risk of clinical significance primarily with long-term anticonvulsant therapy.	Monitor copper (and zinc) status. Copper administrator warranted with deficiency indications or other risk factors.
Zidovudine (AZT) Reverse-transcriptase inhibitor (nucleoside) antiretroviral agents / / /	Coadministration of zinc with AZT can reduce adverse effects and enhance efficacy but extended therapy requires complement of copper to prevent adverse effects from zinc, thus providing a more comprehensive approach to supporting patients on AZT. Evidence preliminary, clinical significance unconfirmed.	Coadminister copper with extended zinc use.

nutrient description

Chemistry and Forms

Copper carbonate, copper citrate, copper gluconate, copper glycinate, copper lysinate, copper sebacate, copper sulfate; copper amino acid chelates; cupric acetate, cupric oxide.

Physiology and Function

Copper is an essential trace mineral that is present in all tissues and acts as a cofactor in several key enzyme systems. The average adult body contains about 80 to 120 milligrams of copper, most of which is stored in the liver. Copper stimulates iron absorption and is an important catalyst in hemoglobin synthesis and function. Copper is necessary to make adenosine triphosphate (ATP) and acts as an essential component of cytochrome oxidase, which is necessary for energy metabolism, cellular respiration, and myelin formation.

Copper is involved in the synthesis and breakdown of several hormones. Copper serves as a cofactor in dopamine–β-hydroxylase, which oxidizes ascorbic acid and synthesizes norepinephrine. It is also involved in the catabolism of estrogenic hormones. Copper may play a role in emotional regulation and cognitive function.

Copper is absorbed in the small intestine, where it is transferred across the gut wall by albumin, and carried on transcuprein and albumin to the liver, where it is incorporated into liver enzymes and secreted into the blood on the protein ceruloplasmin. Copper absorption has been found to be greater in women (71%) than in men (64%), age 20 to 59 years, but did not differ in men and women 60 to 83 years old. Copper elimination is primarily via bile, with small amounts eliminated in urine, sweat, and epidermal shedding.

Copper plays a central role in decreasing inflammation through both ceruloplasmin and the copper-containing form of superoxide dismutase (SOD). Ceruloplasmin is a weak, broad-specificity oxidase whose main functions include copper transport and extracellular scavenging of superoxide and other oxygen radicals. Adequate ceruloplasmin levels also minimize copper toxicity by limiting absorption of copper. Copper, along with zinc, as well as manganese, is found in cytostolic SOD. SOD is a primary quencher of superoxide radical, a prevalent and highly reactive free-radical form of oxygen produced during oxidative phosphorylation, which can be quite destructive if not rapidly quenched. SOD slows age-related deterioration, protects against chemical sensitivities (along with polyphenol oxidase), and enables the normal humoral immune response. There are also copper-containing amino acid chelates that have SOD activity. During inflammatory conditions, such as acute infections, serum copper levels, as ceruloplasmin, generally increase by 20% to 30%, whereas serum iron levels decline. Plasma copper, enzymatic ceruloplasmin, and immunoreactive (RID) ceruloplasmin have been observed to be significantly higher in women than in men, but SOD and in vitro ⁶⁷ Cu uptake by red blood cells does not appear to differ between the genders.

Histaminase, which breaks down histamine to control allergies and inflammation, is another copper-dependent enzyme involved in regulating inflammatory processes. Tyrosinase, an enzyme that requires copper, plays a role in melanin synthesis, enabling skin pigmentation and hair coloration, as well as keratinization of hair.

Some researchers have proposed that copper deficiency is associated with elevated cholesterol and triglycerides, the development of atherosclerosis, and increased risk of cardiovascular disease.

Copper functions in the synthesis of collagen and repair of connective tissue, providing structural elasticity not only throughout the musculoskeletal system, but also in tissues of the lungs, blood vessels, and skin. Lysil oxidase, a copper-containing enzyme secreted by connective tissue cells, is necessary for the formation of the cross-links of collagen and elastin.

Copper is an essential element and its level in the body is strictly controlled. Under most conditions, excess copper is excreted in the urine and feces (via the bile). In cases of elevated copper, the adverse effects that develop are often caused less directly by copper toxicity than by its interference with the absorption and distribution of other mineral nutrients, such as iron and zinc.

Copper sulfate, cupric acetate, and alkaline copper carbonate are among the forms of copper best absorbed in the gut. Nevertheless, even though animal studies have demonstrated that it is poorly absorbed in the gut, cupric oxide (CuO) is the form of copper most often used in over-the-counter (OTC) preparations. Chlorophyllin is a relatively new, water-soluble copper complex of chlorophyll.

nutrient in clinical practice

Known or Potential Therapeutic Uses

Copper has been proposed as offering therapeutic benefit in a wide range of conditions. Such therapeutic action has largely been premised on the hypothesis that administration will enhance or restore healthy function in the numerous enzyme systems where copper plays a critical role. Nevertheless, direct evidence confirming copper's efficacy in treating most of the diseases proposed is largely lacking, other than to prevent or treat those directly attributable to, or exacerbated by, copper deficiency or depletion.

Historical/Ethnomedicine Precedent: As the classical metal of Venus, copper was associated with the female reproductive system in ancient times.

Possible Uses

Anemia, aneurysms, atherosclerosis, athletic performance, benign prostatic hyperplasia, burns, cardiac arrhythmia, cardiovascular disease, decubitus ulcers, hypercholesterolemia, hypoglycemia, immune enhancement, Menkes’ syndrome, muscle spasms, osteoporosis, peptic ulcer, peripheral vascular disease, rheumatoid arthritis, skin cancer (prevention), sprains and strains, stomach cancer (prevention), vitiligo, wound healing.

Deficiency Symptoms

Most research into copper deficiency has focused on acute, severe deficiency. Such frank clinical copper deficiency is relatively rare in humans and animals on typical, varied diets. However, marginal, chronic deficiency is not uncommon. Dietary surveys indicate that the average dietary intake of copper in the U.S. population is only half of the recently established recommended dietary allowance (RDA). Most cases of copper deficiency involve premature infants, infants suffering from malnutrition, or children with iron deficiency anemia, severe protein malnutrition, chronic diarrhea, or other malabsorption difficulties. Overt symptoms in adults are rare but may occur with inadequate or unbalanced dietary intake over an extended time or in those who consume zinc supplements chronically without counterbalancing copper. The determination of copper needs and marginal deficiency is obscured because copper deficiency may not manifest as decreased levels of copper-dependent enzymes, but it may still significantly lower their activity.

Because copper is required for a wide range of enzyme systems and metabolic processes, a deficiency can cause a variety of disorders. Laboratory animals fed copper-deficient diets tend to develop anemia, cardiac abnormalities and abnormal electrocardiograms, and elevated levels of serum cholesterol, triglycerides, and glucose. Symptoms of copper deficiency in humans include fatigue, hypotonia, hypothermia, growth retardation, reduced resistance to infection, various nervous system disorders, anemia, neutropenia, degeneration of vasculature, cardiac damage, hemolysis with potential liver and brain damage, various cardiovascular problems, impaired respiration, emphysema, elevated low-density lipoprotein (LDL) cholesterol and reduced high-density lipoprotein (HDL) cholesterol, impaired collagen formation, breakdown of connective tissue, bone demineralization, osteoporosis, depigmentation of skin, and changes in structure and appearance of hair.

Genetic Conditions Relating to Copper

Two primary genetic diseases involve copper metabolism: Menkes’ syndrome and Wilson's disease.

Menkes’ syndrome results from an X-linked mutation of genes encoding Cu-binding P-type adenosinetriphosphatase (ATPase) for the efflux of Cu, ATP7A. Apart from the distinctive kinky or steely hair, this syndrome is also characterized by stunted growth, abnormalities in cardiovascular and skeletal development, progressive cognitive decline, and premature death. This inborn error in metabolism limits absorption of copper in the intestines and uptake in the liver. Copper subsequently accumulates in the intestinal cells and produces symptoms resembling copper deficiency.

Wilson's disease, caused by the mutation of genes encoding Cu-binding ATPase for the efflux of Cu, ATP7B, is characterized by accumulation of copper in the liver, leading to severe hepatic damage; elevated copper levels subsequently affect the brain and result in neurological problems.

Dietary Sources

Oysters are the most abundant food source of copper. Other copper-containing foods include soy, peas, and other dried legumes; dark-green leafy vegetables; whole-grain breads and cereals; seafood, including crab and lobster; lamb, pork, and other meats, especially organ meats such as liver; nuts (almonds, pecans, walnuts); raisins, prunes, and pomegranates; and tea, coffee, and chocolate.

Foods rich in copper are generally also rich in iron.

Nutrient Preparations Available

Copper sulfate, cupric acetate, cupric oxide, and alkaline copper carbonate. As previously noted, CuO is the form most often used in OTC preparations, primarily because of its low cost. Chlorophyllin is a copper complex of chlorophyll.

Copper is usually found in multimineral or multivitamin/multimineral formulations.

Copper is often taken with, although preferably ingested apart from, long-term zinc administration to counteract the tendency to copper depletion associated with zinc intake without copper. Recommended Zn/Cu ratio in formulations is 10:1 to 15:1.

Dosage Forms Available

Capsule, tablet; cupric sulfate: injection (U.S.).

Dosage Range

Adult

Dietary: 1.0 to 1.5 mg/day

Supplemental/Maintenance: 1 to 2 mg/day

Pharmacological/Therapeutic: 2+ mg/day

Pharmacological doses of copper in scientific studies usually range from 2 to 4 mg per day. Copper dose is usually based on zinc intake. Many experts consider the optimal zinc/copper ratio as 10:1. Some practitioners of nutritional therapeutics use zinc at dosages up to 45 mg/day as part of therapeutic protocols. In such cases, LDL and HDL cholesterol levels need to be monitored. Zinc may need to be reduced or copper increased; even so, doses of copper greater than 3 mg/day are usually avoided.

Pediatric (<18 Years)

Supplemental/Maintenance: 0.5 to 1.0 mg/day

Pharmacological/Therapeutic: 1 to 2 mg/day

Laboratory Values

Serum ceruloplasmin concentrations and white blood cell (WBC) levels have been considered the most reliable methods of evaluation but often are insensitive to subtle changes in copper status. Copper-containing enzymes, such as Cu-Zn SOD, cytochrome- c oxidase, and diamine oxidase, may be more reliable, but evidence to date is not conclusive. ¹ LDL and HDL cholesterol levels are sometimes used.

Serum, plasma, urinary, or hair copper concentrations are not considered particularly reliable because these monitoring parameters are subject to many variables and may not accurately demonstrate actual copper load; when used, such determinations are recommended monthly.

safety profile

Overview

Copper is generally considered safe when taken at customary dietary or typical supplemental dosage levels. Chronic copper toxicity from intentional intake in adults is rare. Long-term doses of 10 to 35 mg per day are considered safe. The tolerable upper limit (UL) of copper intake established by the U.S. National Institute of Medicine for adults is 10 mg per day, combining dietary and supplemental sources. However, research has suggested that the body cannot eliminate more than 3 mg/day, so in individuals who are copper replete or overloaded, greater than 3 mg/day dietary copper may contribute to further accumulation.

Nutrient Adverse Effects

General Adverse Effects

In adults, 10 mg of copper daily can induce nausea, and 60 mg may cause vomiting. Tissue elevations usually occur only when intake is 300 to 500 times above normal. The adverse effects on zinc metabolism represent the primary adverse effect of excessive copper levels.

Mutagenicity

No human data are available. Results from short-term tests on mutagenicity have been negative or inconclusive.

Adverse Effects Among Specific Populations

Copper intake exerts particular risk for individuals with Wilson's disease, a genetic disorder that causes a toxic accumulation of copper in the liver, kidneys, central nervous system (CNS), and cornea. Maximum safe daily dosages of copper intake for individuals with severe liver or kidney disease are of concern but have not been determined. Copper toxicity has occasionally been reported in individuals living in houses where copper from water pipes has leached into the drinking water.

Pregnancy and Nursing

Maximum safe daily dosages of copper intake for pregnant or nursing women have not been determined. There are no reports in the literature reviewed of teratogenicity or embryotoxicity in humans induced by excess copper intake. However, animal studies indicate that a deficiency or excess of copper in the body can cause significant harm to developing embryos.

Infants and Children

Maximum safe daily dosages of copper intake for infants and young children have not been determined. Copper can exert a lethal dose in children at levels as low as 3.5 g. The copper (and zinc) status of epileptic children taking valproate derivatives should be monitored.

Toxicity Signs and Symptoms

Symptoms of moderate copper toxicity include weakness, dizziness, fainting, headache (severe or continuing), burning sensation in the throat, gastrointestinal disturbances, loss of appetite, vomiting, excess salivation, metallic taste in mouth, dyspepsia, epigastric pain, painful urination, and low back pain. Severe cases can result in hemolytic anemia, hypertension, liver damage, jaundice, hemochromatosis, hemoglobinuria, hematuria, kidney failure, coma, and death. O’Donohue et al. ² reported a case of adult chronic copper self-intoxication, after daily doses of 30 to 60 mg for 3 years, which resulted in severe liver cirrhosis necessitating orthotopic liver transplantation.

Contraindications

Biliary disease, cancer, heart bypass patients, liver disease, migraines, Wilson's disease. Copper is also contraindicated during the course of anticopper therapies. Some individuals may have a total body excess of copper resulting from a lifetime of drinking water from copper plumbing, and copper supplementation may not be desirable in such people.

Precautions and Warnings

Some individuals may become sensitized to copper sulfate and develop allergic contact dermatitis.

interactions review

Strategic Considerations

Many medications may deplete copper or interfere with its metabolic functions, sometimes incidentally, but often intentionally. Copper supplementation may be appropriate to correct drug-induced depletion patterns. In certain cases, however, such action is central to the therapeutic strategy, and supplementation is contraindicated, except in response to specific episodes of adverse effects of excessive copper deficiency caused by depletion. Conversely, in some situations, drugs such as allopurinol may provide benefit by reducing copper levels.

nutrient-drug interactions

Allopurinol

Allopurinol (Oxypurinol; Aloprim, Apo-Allopurinol, Lopurin, Purinol, Zyloprim).

	Drug-Induced Nutrient Depletion, Supplementation Contraindicated, Professional Management Appropriate
	Prevention or Reduction of Nutrient Adverse Effect

Probability: 2. Probable
Evidence Base:

Preliminary

Effect and Mechanism of Action

Allopurinol, a potent inhibitor of xanthine oxidase, is known to protect the heart effectively against damage in patients undergoing cardiac bypass surgery. Nevertheless, the mechanism underlying the protective effect of allopurinol is unclear because of ambiguity concerning the presence of xanthine oxidase in the human heart. Allopurinol apparently chelates copper and reduces DNA breakage (see next).

Research

In 1993, Malkiel et al. ³ published a paper examining the possible role of the interaction between allopurinol and copper in myocardial protection. They found that allopurinol forms a one-to-one complex with Cu(II) ions in vitro, yielding a complex with low oxidation-reduction (redox) activity, and concluded that allopurinol substantially reduced copper-mediated and ascorbate-driven DNA breakage. Later research by Lapenna et al. ⁴ found that allopurinol, at therapeutically relevant concentrations (9-58 µM), significantly counteracted copper-catalyzed human non–HDL lipoprotein oxidation through metal complexation.

Nutritional Therapeutics, Clinical Concerns, and Adaptations

The ability of allopurinol to chelate copper may impart the protective effects against cardiac damage in bypass patients during reperfusion of the heart. These findings suggest that patients undergoing bypass surgery should avoid copper supplementation.

Antacids

Aluminum carbonate gel (Basajel), aluminum hydroxide (Alternagel, Amphojel); combination drugs: aluminum hydroxide, magnesium carbonate, alginic acid, and sodium bicarbonate (Gaviscon Extra Strength Tablets, Gaviscon Regular Strength Liquid, Gaviscon Extra Strength Liquid); aluminum hydroxide and magnesium hydroxide (Advanced Formula Di-Gel Tablets, co-magaldrox, Di-Gel, Gelusil, Maalox, Maalox Plus, Mylanta, Wingel); aluminum hydroxide, magnesium trisilicate, alginic acid, and sodium bicarbonate (Alenic Alka, Gaviscon Regular Strength Tablets); calcium carbonate (Titralac, Tums), magnesium hydroxide (Phillips’ Milk of Magnesia MOM); combination drugs: magnesium hydroxide and calcium carbonate (Calcium Rich Rolaids); magnesium hydroxide, aluminum hydroxide, calcium carbonate, and simethicone (Tempo Tablets); magnesium trisilicate and aluminum hydroxide (Adcomag trisil, Foamicon); magnesium trisilicate, alginic acid, and sodium bicarbonate (Alenic Alka, Gaviscon Regular Strength Tablets); combination drug: sodium bicarbonate, aspirin, and citric acid (Alka-Seltzer). See also Cimetidine and Famotidine.

Drug-Induced Nutrient Depletion, Supplementation Therapeutic, Not Requiring Professional Management

Probability: 3. Possible:
Evidence Base:

Preliminary

Effect and Mechanism of Action

The normally acidic environment of the stomach facilitates optimal absorption of copper and other nutrients. Antacids may induce a copper deficiency by inhibiting copper absorption and precipitating dietary copper through drug-induced alkaline pH in the intestines.

Reports

Roe, van Kalmthout, and other authors have reported cases where individuals have demonstrated the effects of copper deficiency subsequent to excessive use of antacids. ^5-9 Such outcomes may appear to be more likely with extended use of antacids and the occurrence of pyloric stenosis.

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Clinically significant adverse effects from antacids reducing copper absorption appear to occur infrequently. Nevertheless, individuals who take antacids for an extended period may benefit from 1 to 2 mg of copper supplementation daily, possibly in the form of a multivitamin/mineral formula.

Cimetidine

Cimetidine (Tagamet; Tagemet HB)

	Minimal to Mild Adverse Interaction—Vigilance Necessary
	Adverse Drug Effect on Nutritional Therapeutics, Strategic Concern

Probability: 4. Plausible
Evidence Base:

Preliminary

Effect and Mechanism of Action

Cimetidine complexes with Cu(II) and Fe(III) ions and may elevate tissue copper concentrations.

Research

The considerations regarding this interaction derive from research involving rats. Naveh et al. ¹⁰ published a paper in 1987 that described elevated hepatic and plasma copper concentrations, mineral redistribution, and pathological changes in some tissues after intermediate to high doses of cimetidine (875-1750 mg/kg/day) administered intragastrically to young rats four times weekly for 5 weeks. More recent research by Lambat et al. ¹¹ and others has focused on the action of cimetidine as a free-radical scavenger and neuroprotective agent through its ability to bind to iron and copper, thus making them unavailable for free-radical production.

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Given the consistent evidence of cimetidine's mineral-binding properties, individuals taking copper supplements are advised to allow at least a 2-hour interval after taking cimetidine to avoid diminished therapeutic effect from the nutrient. The therapeutically appropriate level copper supplementation would be in the range of 1 to 2 mg/day.

Ciprofloxacin

Ciprofloxacin (Ciloxan, Cipro)

Impaired Drug Absorption and Bioavailability, Precautions Appropriate

Probability: 2. Probable
Evidence Base:

Emerging

Effect and Mechanism of Action

Minerals, including copper, can bind to ciprofloxacin, greatly reducing the absorption of the medication.

Research

The formation of a ferric ion–ciprofloxacin complex is a well-documented cause of the reduction in ciprofloxacin bioavailability in the presence of iron. ^12-14 Complexation between Cu(II) and 4-quinolone antibacterials, including ciprofloxacin, has been studied in an aqueous medium.

Clinical Implications and Adaptations

Even though not as severe as with iron supplements, the tendency for copper and other minerals to bind ciprofloxacin suggests that individuals taking this and related antibacterial medications can reduce the risk of interfering with the drug's therapeutic effect by allowing at least a 2-hour interval after ingesting any copper or multimineral supplement.

Clofibrate and Related Fibrates

Evidence: Clofibrate (Atromid-S). Extrapolated, based on similar properties: Bezafibrate (Bezalip), ciprofibrate (Modalim), fenofibrate (Lofibra, Tricor, Triglide), gemfibrozil (Apo-Gemfibrozil, Lopid, Novo-Gemfibrozil).

	Drug-Induced Nutrient Depletion, Supplementation Therapeutic, with Professional Management
	Bimodal or Variable Interaction, with Professional Management
	Drug-Induced Effect on Nutrient Function, Supplementation Contraindicated, Professional Management Appropriate
	Interaction Possible but Uncertain Occurrence and Unclear Implications

Probability: 2. Probable
Evidence Base:

Mixed

Effect and Mechanism of Action

Even as it binds other nutrients, such as iron, and tends to produce malabsorption, clofibrate is hypothesized to improve copper nutriture. Leslie M. Klevay, a researcher who has studied copper metabolism extensively, described clofibrate as a “cholesterotropic and cuprotropic” substance. He has observed that clofibrate lowers plasma cholesterol and enhances copper metabolism. Thus, Klevay and others have proposed that clofibrate reduces hypercholesterolemia, at least in part, through its effect on copper deficiency. ^15,16 This effect is mediated by an increase in hepatic copper. Possibly as a result of such actions, however, clofibrate has a poor safety profile with significant risk of liver damage, as well as other adverse effects, including increased risk of cancer and pancreatitis. In research involving rats, Fields et al. ¹⁷ and others have reported that administration of clofibrate reduces the activity of the lipogenic enzyme glucose-6-phosphate dehydrogenase (G6PD), even though total hepatic lipid was not reduced. Further, clofibrate did not affect hepatic lipid concentration, and the pathology associated with copper deficiency when fructose was fed was not prevented by the consumption of clofibrate. Also, the tendency for hypercholesterolemic people to be more likely to be malnourished in copper than normocholesterolemic people may influence differential responses among various populations and manifest as a change in copper metabolism in response to the drug.

Research

Clofibrate is consistently recognized as altering copper metabolism. However, various researchers have arrived at differing conclusions as to whether the net effect of clofibrate therapy is to enhance or deplete copper status, whether observed changes reflect the drug's action or the metabolic alterations associated with pathology, and the degree to which the interaction is clinically significant. ^16,18 Clofibrate may bind copper and reduce absorption, but it also tends to elevate tissue levels, particularly in the liver. In particular, although research consistently indicates that clofibrate is active in animals malnourished in copper, it is still uncertain whether observed changes reflect changes in cholesterol metabolism induced by clofibrate because of a change in copper metabolism or other processes, and how such laboratory findings illuminate clinical practice involving humans.

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Copper supplementation may be appropriate. Periodic monitoring is advised.

ESTROGENS, PROGESTINS, AND ESTROGEN-PROGESTIN COMBINATIONS:
Oral Contraceptives: Monophasic, Biphasic, and Triphasic Estrogen Preparations (Synthetic Estrogen and Progesterone Analogs)
Hormone Replacement Therapy (HRT): Estrogen-Containing and Synthetic Estrogen and Progesterone Analog Medications

OC:Ethinyl estradiol and desogestrel (Desogen, Ortho-TriCyclen).Ethinyl estradiol and ethynodiol (Demulen 1/35, Demulen 1/50, Nelulen 1/25, Nelulen 1/50, Zovia).Ethinyl estradiol and levonorgestrel (Alesse, Levlen, Levlite, Levora 0.15/30, Nordette, Tri-Levlen, Triphasil, Trivora).Ethinyl estradiol and norethindrone/norethisterone (Brevicon, Estrostep, Genora 1/35, GenCept 1/35, Jenest-28, Loestrin 1.5/30, Loestrin1/20, Modicon, Necon 1/25, Necon 10/11, Necon 0.5/30, Necon 1/50, Nelova 1/35, Nelova 10/11, Norinyl 1/35, Norlestin 1/50, Ortho Novum 1/35, Ortho Novum 10/11, Ortho Novum 7/7/7, Ovcon-35, Ovcon-50, Tri-Norinyl, Trinovum).Ethinyl estradiol and norgestrel (Lo/Ovral, Ovral).Mestranol and norethindrone (Genora 1/50, Nelova 1/50, Norethin 1/50, Ortho-Novum 1/50).Related, internal application: Etonogestrel/ethinyl estradiol vaginal ring (Nuvaring).HRT, estrogens:Chlorotrianisene (Tace); conjugated equine estrogens (Premarin); conjugated synthetic estrogens (Cenestin); dienestrol (Ortho Dienestrol); esterified estrogens (Estratab, Menest, Neo-Estrone); estradiol, topical/transdermal/ring (Alora Transdermal, Climara Transdermal, Estrace, Estradot, Estring FemPatch, Vivelle-Dot, Vivelle Transdermal); estradiol cypionate (Dep-Gynogen, Depo-Estradiol, Depogen, Dura-Estrin, Estra-D, Estro-Cyp, Estroject-LA, Estronol-LA); estradiol hemihydrate (Estreva, Vagifem); estradiol valerate (Delestrogen, Estra-L 40, Gynogen L.A. 20, Progynova, Valergen 20); estrone (Aquest, Estragyn 5, Estro-A, Estrone ‘5’, Kestrone-5); estropipate (Ogen, Ortho-Est); ethinyl estradiol (Estinyl, Gynodiol, Lynoral).HRT, estrogen/progestin combinations:Conjugated equine estrogens and medroxyprogesterone (Premelle cycle 5, Prempro); conjugated equine estrogens and norgestrel (Prempak-C); estradiol and dydrogesterone (Femoston); estradiol and norethindrone, patch (CombiPatch); estradiol and norethindrone/norethisterone, oral (Activella, Climagest, Climesse, FemHRT, Trisequens); estradiol valerate and cyproterone acetate (Climens); estradiol valerate and norgestrel (Progyluton); estradiol and norgestimate (Ortho-Prefest).HRT, estrogen/testosterone combinations:Esterified estrogens and methyltestosterone (Estratest, Estratest HS).See also Medroxyprogesterone.

Drug-Induced Effect on Nutrient Function, Supplementation Contraindicated, Professional Management Appropriate

Probability: XXX
Evidence Base: XXX

Effect and Mechanism of Action

Oral contraceptives (OCs) and other exogenous female hormone medications have been shown to elevate intracellular copper and serum copper levels in humans and thereby potentially contribute to alterations in glucose metabolism, oxygen metabolism, and a woman's mental and emotional well-being. Although estrogens are known to affect copper absorption and metabolism, progestins in OCs are believed to be the primary determinant of elevated copper levels.

With regard to hormone replacement therapy (HRT), knowledge continues to evolve as to the respective roles of estrogen, in its various forms, and progestins. The issues and evidence concerning OCs inherently influences and sets the stage for an emerging understanding of interactions between combined HRTs and copper and their clinical implications.

Research

Studies have consistently found OC use positively associated with increased absorption of copper and increased serum copper and ceruloplasmin levels. ^19-22 Even though higher serum copper concentration in women using OCs is well known, uncertainty still surrounds the influence of newer progestin compounds in OCs on serum copper concentration. In a study involving low-estrogen preparations, Liukko et al. ²³ noted that copper levels rose significantly in women while using OCs over a 2-year period, but returned to initial levels after the OCs were discontinued. Johnson et al. ²⁴ observed that OCs elevated plasma copper, enzymatic ceruloplasmin, and SOD activity, but not copper absorption and biological half-life, in women age 20 to 39. In a more recent epidemiological study (1998) of 610 nonpregnant and nonlactating women (18-44 years old), Berg et al. ²⁵ reported that although elevated serum copper concentration was found in users of all OC types, elevation was more pronounced among women taking OCs with antiandrogen progestins (56% elevation) than with desogestrel (46%), norethisterone/lynestrenol (42%), or levonorgestrel (34%), after adjusting for multiple covariaters/variables (e.g., age, smoking, alcohol intake).

The effects of hormonal interventions on copper absorption and metabolism occur within a context influenced by gender and life stage. In their study of 44 healthy postmenopausal women, 50 to 60 years old, 18 of whom were treated by oral combined HRT for at least 2 years, and 26 of whom were untreated, Bureau et al. ²⁶ examined plasma trace-mineral levels (Zn, Se, Cr, Mn, Cu), red blood cell antioxidant enzymes (Cu-Zn SOD, Se-GPX, Cu), and urinary excretion (Zn, Cr, Mg, Ca). Plasma copper concentrations were higher in women treated by HRT, whereas erythrocyte copper levels were not modified. Zinc, selenium, and manganese plasma levels; activities of Cu-Zn-SOD; and GSH-PX in erythrocytes were not statistically different between the two groups. The authors interpreted this as suggesting that HRT provides beneficial effects on trace-mineral status related to menopause. In their study of the effects of age and gender on copper absorption, biological half-life, and status, Johnson et al. ²⁴ observed that among younger individuals, 20 to 59 years old, absorption was greater in women (71%) than in men (64%), but that the difference between men and women was negligible among those age 60 to 83. Likewise, biological half-life of ⁶⁷ Cu ranged from 13 to 33 days and differed between men and women age 20 to 59, but not between men and women age 60 to 83. Such findings illuminate the changes in women's metabolism as they age and pass through their reproductive years and into menopause.

Although a causal relationship has not been demonstrated, recent epidemiological studies have shown an increased mortality from cardiovascular diseases in individuals with higher serum copper levels. In 1991, in an epidemiological study of Finnish men, Salonen et al. ²⁷ concluded that high copper status, reflected by elevated serum copper concentration, is an independent risk factor for ischemic heart disease. This issue is of particular interest in the light of recent findings of an increased risk of venous thromboembolism in users of OCs containing newer progestins such as desogestrel, compared with users of other OCs. Further, Reunanen et al., ²⁸ in a nested case-control study (1996) within a prospective population study, found high serum copper and low serum zinc levels significantly associated with increased mortality from all cardiovascular diseases, particularly coronary heart disease.

Given the recent upheavals in medical consensus and practice guidelines, the emerging research picture, and the as-yet unclear clinical implications of HRT in relation to cardiovascular health and risk, the issues of copper status deserve further attention as part of the continued research.

Nutritional Therapeutics, Clinical Concerns, and Adaptations

At this time, evidence is inadequate to warrant routine monitoring of copper concentrations in female patients using estrogen and progestin medications in the absence of other specific cardiovascular risk factors. OCs can raise serum copper levels, but it is not clear whether or to what degree this occurs at the tissue level. Women using OCs may have increased needs for zinc based on potential depletion, as well as greater needs for folate and vitamins B ¹² and B ⁶ . Individual evaluation of safe and effective hormone dosage levels is necessary. Pending such individualized assessment, patients requesting advice on copper intake might be well advised to refrain from additional supplementation in the absence of therapeutic imperatives involving depletion or deficiency status; zinc coadministration may be appropriate in some cases.

Ethambutol

Evidence: Ethambutol (Myambutol).Extrapolated, based on similar properties: Isoniazid (isonicotinic acid hydrazide, INH; Laniazid, Nydrazid); combination drugs: isoniazid and rifampicin (Rifamate, Rimactane); isoniazid, pyrazinamide, and rifampicin (Rifater).

	Prevention or Reduction of Drug Adverse Effect
	Drug-Induced Adverse Effect on Nutrient Function, Coadministration Therapeutic, with Professional Management
	Beneficial or Supportive Interaction, with Professional Management

Probability: XXX
Evidence Base: XXX

Effect and Mechanism of Action

The antimycobacterial agent ethambutol (EMB) forms chelate complexes with the bivalent metal ions (copper and zinc) participating in RNA biosynthesis or stabilization. Clinical research and case reports have consistently found that the optic neuropathy associated with ethambutol results from its effect on copper metabolism. Both ethambutol and its fellow antituberculosis agent isoniazid have been implicated as causes of reduced visual acuity, visual field defects, and disturbances of color vision.

Research

Findings from animal studies indicate that ethambutol alters trace-mineral metabolism through its chelating action. Binding of copper(II) and zinc(II) by 2,2′-(ethylenediimino)-dibutyric acid (EDBA), the metabolic oxidation product of dextro-2,2′-(ethylenediimino)-di- 1-butanol (ethambutol), may account for many of the adverse effects of EMB treatment. In particular, ethambutol produced significant decreases in heart copper, kidney zinc, plasma zinc, and liver copper and zinc, not attributable to changes in dietary intake. ^9,29

The principal adverse effect of ethambutol is an optic neuropathy with clinical features closely paralleling a mitochondrial hereditary optic neuropathy (Leber's). As noted, EMB and isoniazid have been implicated in reduced visual acuity, visual field defects, and color vision disturbances. Research consistently indicates that chelation of copper causes EMB-induced optic neuropathy by precluding normal cytochrome- coxidase activity and mitochondrial metabolism in the optic nerve. An in vitro study by Kozak et al. ³⁰ (1998) suggests that if copper were given to patients to prevent EMB-induced optic neuropathy, such supportive supplementation would not compromise EMB's bacteriostatic properties against Mycobacterium tuberculosisand Mycobacterium avium. In concluding their study of 42 Congolese patients with tuberculosis receiving ethambutol treatment, Kaimbo et al. ³¹ emphasized the importance of color vision examinations in the detection of the complications of EMB treatment.

Nutritional Therapeutics, Clinical Concerns and Adaptations

Coadministration of copper with ethambutol may reduce adverse effects, particularly on the optic nerve and related functions, typically associated with EMB use. Monitoring of visual function is generally appropriate during ethambutol therapy. Supervision is advisable but may not be necessary because no known adverse effects are associated with concomitant copper intake. However, given the consistent evidence of EMB's copper-binding properties, individuals taking concomitant copper are advised to allow at least a 2-hour interval after taking ethambutol to avoid diminished therapeutic effect from the nutrient. The therapeutically appropriate level of copper would be 1 to 2 mg per day.

Famotidine and Related Histamine (H ² ) Receptor Antagonists

Evidence: Famotidine (Pepcid, Pepcid AC, Pepcid RPD).Extrapolated, based on similar properties: Cimetidine (Tagamet, Tagamet HB), nizatidine (Axid, Axid AR), ranitidine (Zantac); combination drug: ranitidine, bismuth, and citrate (Tritec).See also Antacids and Cimetidine.

Drug-Induced Nutrient Depletion, Supplementation Therapeutic, Not Requiring Professional Management

Probability: XXX
Evidence Base: XXX

Effect and Mechanism of Action

The normally acidic environment of the stomach facilitates optimal absorption of copper and other nutrients. Famotidine may induce a copper deficiency by inhibiting copper absorption and precipitating dietary copper.

Research

Famotidine may reduce absorption of copper by interfering with normal gastrointestinal (GI) physiology and function. ^5,32

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Repeated use of famotidine, or other H ² receptor antagonists (H ² RAs), over an extended period may tend to promote a deficiency of affected nutrients, such as copper. Nevertheless, evidence is lacking to support the conclusion that clinically significant adverse effects of copper deficiency due to famotidine are common. Nevertheless, individuals who regularly use famotidine, or another H ² RA medication, for an extended time may benefit from 1 to 2 mg of copper daily, possibly in the form of a multivitamin/mineral formula, taken at least 2 hours away from the drug.

Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)

COX-1 inhibitors:Diclofenac (Cataflam, Voltaren); combination drug: diclofenac and misoprostol (Arthrotec); diflunisal (Dolobid), etodolac (Lodine), fenoprofen (Dalfon), furbiprofen (Ansaid), ibuprofen (Advil, Excedrin IB, Motrin, Motrin IB, Nuprin, Pedia Care Fever Drops, Provel, Rufen); combination drug: hydrocodone and ibuprofen (Reprexain, Vicoprofen); indomethacin (indometacin; Indocin, Indocin-SR), ketoprofen (Orudis, Oruvail), ketorolac (Acular ophthalmic, Toradol), meclofenamate (Meclomen), mefenamic acid (Ponstel), meloxicam (Mobic), nabumetone (Relafen), naproxen (Anaprox, Naprosyn), oxaprozin (Daypro), piroxicam (Feldene), salsalate (salicylic acid; Amigesic, Disalcid, Marthritic, Mono Gesic, Salflex, Salsitab), sulindac (Clinoril), tolmetin (Tolectin).COX-2 inhibitor:Celecoxib (Celebrex).

	Prevention or Reduction of Drug Adverse Effect
	Potential or Theoretical Beneficial or Supportive Interaction, with Professional Management

Probability: XXX
Evidence Base: XXX

Effect and Mechanism of Action

Copper complexes of NSAIDs are more effective in their anti-inflammatory effect and less toxic than the parent NSAID substances. Based on these observations, Sorenson ³³ proposed that copper complexes of NSAIDs are their active metabolites. However, continuing research by Berthon, Brumas, Miche, and associates indicates that the extra anti-inflammatory activity induced by copper on NSAIDs appears to be independent of any Cu(II)-NSAID association in vivo. On the contrary, the binding of inactive substances with copper(II) at inflammatory sites seems to be essential to their activation by copper. Parallel investigations suggest that the apparent copper potentiation of NSAIDS may be caused by copper interactions with endogenous histidine. ^34-36

Research

Kishore ³⁷ reported that administration of copper aspirinate to arthritic rats for 20 days increased hepatic copper concentrations. Such animal models of inflammation have also shown that the copper chelate of aspirin is active at one-eighth the effective amount of aspirin. These copper complexes are less toxic than the parent compounds as well. Based on such findings, speculation has been raised that copper supplementation might enhance the anti-inflammatory effects of NSAIDs while reducing their ulcerogenic effects. However, the ability of NSAIDs to influence copper metabolism is still poorly understood, and apart from the proposed SOD-like activity of copper salts in vivo, knowledge is limited as to how copper-NSAID interactions participate in the regulation of the inflammatory process. Interactions between copper and anti-inflammatory medications deserve continued research, especially within the context of deepening our understanding of copper absorption and metabolism and the inflammatory responses of the immune system.

Clinical Implications and Adaptations

Copper complexes may be more active than parent NSAIDs, but concomitant copper will not necessarily result in or amplify such effects. Coadministration of 1 to 2 mg/day of copper might enhance the anti-inflammatory activity of NSAIDs while reducing potential adverse effects caused by such medications. However, such action is not based on a clear, consistent, and substantive pattern of evidence; some research questions such a conclusion. Nevertheless, the risk of adverse effects from low levels of copper intake would be negligible and probably less than the potential risk of adverse effects typically associated with use of NSAIDs.

Penicillamine and Related Chelating Agents

Deferasirox (Exjade), desferoxamine (desferrioxamine mesilate, desferoxamine mesylate; Desferal), EDTA (ethylenediaminetetraacetic acid), penicillamine (Cuprimine, Depen), tetrathiomolybdate (TM), trientine (trien, trienthylene tetramine; Syprine).

	Drug-Induced Effect on Nutrient Function, Supplementation Contraindicated, Professional Management Appropriate
	Drug-Induced Nutrient Depletion, Supplementation Contraindicated, Professional Management Appropriate

Probability: XXX
Evidence Base: XXX

Effect and Mechanism of Action

Penicillamine, trientine (trienthylene tetramine), and tetrathiomolybdate are chelating agents that bind metals and carry them out of the body. Tetrathiomolybdate was initially developed as a less toxic copper chelator than penicillamine and is now considered the treatment of choice for Wilson's disease, with zinc acetate maintenance after the copper levels are sufficiently low. Oral administration of copper, as well as aluminum, iron, and magnesium salts, and possibly other minerals (e.g., calcium, zinc), may decrease the GI absorption and bioavailability of these chelating agents, and vice versa. The medication's chelation of polyvalent metal ions resulting in a nonabsorbable complex constitutes the operative mechanism.

Research

Penicillamine is used to treat people with Wilson's disease, cystinuria, and severe rheumatoid arthritis. Wilson's disease (WD) is an autosomal recessive disease that causes excessive copper deposition in the liver, basal ganglia, kidney, cornea, and other tissues, with resultant hepatic, neurological, and visual sequelae. Medical research continues to clarify the pathophysiology of WD, with major advances in recent years. The key strategy of current conventional medical treatment focuses on reducing the amount of copper in the liver and other tissues by administering both copper-chelating agents and a low-copper diet. Although major progress has been achieved in the treatment of WD, significant controversy remains as to the optimal treatment of individuals in the various stages of the disease. Specifically, the relative roles of penicillamine, trientene, and tetrathiomolybdate in the initial treatment of the symptomatic patient with WD continue to be researched, debated, and emergent. ^9,38,39 Copper control using these agents has also emerged as an antiangiogenic anticancer therapy. ^40,41

Penicillamine prevents the formation or promotes the solubilization of copper-rich particles occurring in lysosomes of hepatocytes and Kupffer cells in the livers of individuals with WD. Once chelated with D-penicillamine, copper can then be excreted into urine. However, research indicates that the mobilization of copper by D-penicillamine is limited because of the binding of the metal to metallothionein in liver cytosol. This form of copper, even at relatively high concentrations, appears to be well tolerated. ^42,43

Penicillamine use is associated with numerous adverse effects, often severe, such as systemic lupus erythematosus (SLE) and nephrotic syndrome, which occur in 20% to 25% of all patients. In cases where D-penicillamine has to be withdrawn, trientine becomes the drug of choice and is generally considered to be as effective as penicillamine. Trientine is sometimes administered as a first-choice drug to individuals with neurological symptoms. ^42,44

Again, among the primary therapeutic uses of chelating agents such as penicillamine and trientine is the treatment of WD, in which toxic deposits of copper accumulate. Penicillamine is also used to treat individuals with cystinuria and severe rheumatoid arthritis. ^33,38,45

Copper also plays an essential role in promoting angiogenesis. Tumors that become angiogenic acquire the ability to enter a phase of rapid growth and exhibit increased metastatic potential, the major cause of morbidity and mortality in cancer patients. Human and animal research on breast, lung, and other cancers indicates that copper deficiency induced by chelating agents, such as tetrathiomolybdate, significantly impairs tumor growth and angiogenesis through suppression of nuclear factor kappa B (NF-κB), contributing to a global inhibition of NF-κB–mediated transcription of proangiogenic factors. ^46,47 NF-κB expression is also associated with the development of both chemotherapy and radiation resistance in cancer cells.

Note:
Given the high risk of teratogenicity, based on animal studies, and the known adverse effects associated with many chelating agents, Brewer et al. ⁴⁸ and other researchers have investigated the treatment of WD using tetrathiomolybdate, followed by zinc monotherapy or complementary use of zinc salts, using zinc in particular during pregnancy and with children.

Clinical Implications and Adaptations

Given the therapeutic objective of reducing toxic levels of copper in the body by increasing urinary excretion of the mineral, individuals with WD should minimize dietary intake of copper and avoid consuming copper supplements of any kind, even in the small doses found in most multivitamin/mineral formulas. In individuals taking any of these chelating agents to reduce copper levels, the consumption of any supplemental copper would obviously have an adverse effect on the drug's performance.

If copper (or iron) supplementation is incidental to the consumption of other medications or supplements or therapeutically indicated in some extraordinary circumstance, substances containing such minerals should be taken 2 hours before or after penicillamine, trientine, or tetrathiomolybdate to minimize interference with the medication's effects.

Note:
Clinicians should also be aware of chlorophyllin, a water-soluble copper complex of chlorophyll that is becoming increasingly popular as a nutritional supplement. Chlorophyllin has antimutagenic and anticarcinogenic properties, but it is also a source of copper and needs to be considered as part of the standard supplement inventory inquiry.

Valproic Acid and Related Anticonvulsant Medications (AEDs)

Evidence: Divalproex semisodium, divalproex sodium (Depakote), sodium valproate (Depacon), valproate semisodium, valproic acid (Depakene, Depakene Syrup).Similar properties but evidence lacking for extrapolation: Carbamazepine (Carbatrol, Tegretol), clonazepam (Klonopin), clorazepate (Tranxene), ethosuximide (Zarontin), ethotoin (Peganone), felbamate (Felbatol), fosphenytoin (Cerebyx, Mesantoin), levetiracetam (Keppra), mephenytoin, mephobarbital (Mebaral), methsuximide (Celontin), oxcarbazepine (GP 47680, oxycarbamazepine; Trileptal), phenobarbital (phenobarbitone; Luminal, Solfoton), phenytoin (diphenylhydantoin; Dilantin, Phenytek), piracetam (Nootropyl), primidone (Mysoline), topiramate (Topamax), trimethadione (Tridione), vigabatrin (Sabril), zonisamide (Zonegran).

	Drug-Induced Nutrient Depletion, Supplementation Therapeutic, with Professional Management
	Drug-Induced Adverse Effect on Nutrient Function, Coadministration Therapeutic, with Professional Management

Probability: XXX
Evidence Base: XXX

Effect and Mechanism of Action

Valproic acid (VPA) may induce increased excretion of copper into the bile, thereby disrupting the homeostatic balance of copper and causing abnormalities in serum copper concentration.

Research

In several studies of children with epilepsy being treated with VPA, serum copper levels remained unchanged relative to control groups. ^49-53 Subsequently, however, Kaji et al. ⁵⁴ investigated serum zinc and copper levels in epileptic children treated with VPA and/or other antiepileptic drugs (AEDs). They found that patients “treated with VPA monotherapy had significantly lower levels of serum Cu” than normal controls, as did those “treated with VPA in addition to some other AED,” whereas those “treated with AEDs except for VPA” exhibited serum copper concentrations “not statistically different from those of control subjects.” These researchers suggested that physicians should watch for potential symptoms of copper deficiency, even though none of their patients showed any symptoms of copper deficiency at the time of the study. ⁵⁴ Suzuki et al. ⁵⁵ reported that long-term anticonvulsant therapy could induce alterations in both the metabolism and the distribution of copper, zinc, and magnesium, and that gender was a significant factor in the resultant effects.

Clinical Implications and Adaptations

No definitive evidence has emerged as to the prevalence or clinical significance of copper depletion or deficiency resulting from valproic acid. Physicians prescribing VPA, especially in children, should consider coadministration of copper to restore proper trace-mineral balance and avoid possible deficiency. Inadequate consumption of copper through dietary sources is common. Copper (and zinc) status should be monitored, particularly in epileptic children taking valproate derivatives. Coadministration of copper at 1 to 3 mg daily may be beneficial, especially for individuals taking zinc supplements.

Zidovudine (AZT) and Related Reverse-Transcriptase Inhibitor (Nucleoside) Antiretroviral Agents

Evidence: Zidovudine (azidothymidine, AZT, ZDV, zidothymidine; Retrovir).Extrapolated, based on similar properties: Abacavir (Ziagen), didanosine (ddI, dideoxyinosine; Videx), dideoxycytidine (ddC, zalcitabine; Hivid), lamivudine (3TC, Epivir), stavudine (D4T, Zerit), tenofovir (Viread); zidovudine combination drugs: zidovudine and lamivudine (Combivir); abacavir, lamivudine, and zidovudine (Trizivir).Protease inhibitors: Amprenavir (Agenerase), atazanavir (Reyataz), brecanavir, darunavir (Prezista), fosamprenavir (Lexiva), indinavir (Crixivan), nelfinavir (Viracept), ritonavir (Norvir), saquinavir (Fortovase, Invirase), tipranavir (Aptivus); combination drugs: lopinavir and ritonavir (Aluvia, Kaletra); saquinavir and ritonavir (SQV/RTV).

	Drug-Induced Nutrient Depletion, Supplementation Therapeutic, with Professional Management
	Potential or Theoretical Beneficial or Supportive Interaction, with Professional Management
	Prevention or Reduction of Nutrient Adverse Effect
	Adverse Drug Effect on Nutritional Therapeutics, Strategic Concern

Probability: XXX
Evidence Base: XXX

Effect and Mechanism of Action

Coadministration of zinc during AZT therapy will tend to deplete copper during extended therapy. The antagonistic relationship between copper and zinc might be a concern, given the importance of zinc for immune status.

Research

Preliminary human research by Baum et al. ⁵⁶ published in 1991 suggested AZT therapy might cause decreased levels of zinc and copper along with a significant increase in red cell folate. The level of plasma zinc appeared to be particularly important in maintaining immune function in the zidovudine-treated group. Also in 1991, Graham et al. ⁵⁷ reported that higher serum copper and lower serum zinc levels predicted progression to acquired immunodeficiency syndrome (AIDS) independently of baseline CD4+ lymphocyte level, age, and calorie-adjusted dietary intakes of both nutrients. Allavena et al. ⁵⁸ observed alterations in parameters of several trace minerals during AZT treatment but reported that copper values were within normal limits. More recently, however, in a 2001 paper on survival in a cohort of HIV-1–infected homosexual men, Lai et al. ⁵⁹ reported that although plasma zinc inadequacy or the plasma copper/zinc ratio may be useful predictors of survival in human immunodeficiency virus type 1 (HIV-1) infection, plasma levels of copper were not significantly associated with mortality. In a study involving 86 subjects with known HIV infection, Jimenez-Exposito et al. ⁶⁰ found that AIDS patients with active opportunistic infection showed significantly lower serum concentrations of vitamin A and significantly higher serum concentrations of copper. They concluded that these findings were correlated with various inflammatory parameters more than with nutritional status.

Nutritional Therapeutics, Clinical Concerns, and Adaptations

The clinical significance of these findings remains unclear with regard to dietary intake of copper and potential therapeutic effects of an interaction between copper and zidovudine. Copper appears to play an important role in the immune system's inflammatory response, but no conclusive evidence has emerged indicating that copper coadministration would be therapeutically beneficial. However, any extended supplementation of zinc might induce a copper deficiency and would suggest a need for countervailing copper, 1 to 2 mg/day. Ultimately, the evidence at this point indicates the importance of monitoring nutritional status of individuals with HIV infection, whether or not they are undergoing retroviral therapy such as with zidovudine.

nutrient-nutrient interactions

Iron

The metabolic pathways and functions of copper and iron are intertwined, and the minerals have many similarities and some significant interactions. Copper stimulates intestinal absorption and improves utilization of iron, whereas iron can inhibit copper absorption. Both are transition elements that can participate in redox reactions; both can also be sequestered by proteins and thus prevent undesirable redox reactions. Iron deficiency can contribute to increased concentrations of copper in tissues, and copper deposition can be a significant risk in some anticancer therapies aimed at altering iron status.

Molybdenum

Within integrative chemotherapy regimens, as well as the treatment of Wilson's disease, administration of tetrathiomolybdate, which contains molybdenum at the center of four chelating sulfhydryl groups, can serve as an effective copper-chelating agent with significantly fewer adverse effects than most conventional copper chelators.

Vitamin C

Vitamin C intake at pharmacological doses for extended periods can lead to a depletion of copper, in the absence of compensatory copper intake supplementation.

Zinc

Zinc significantly interferes with copper absorption. ⁶¹ Zinc induces intestinal cell metallothionein, which binds copper and prevents its transfer into blood. eventually the intestinal cells die and slough, taking the trapped copper with them in the stool, thus preventing intestinal absorption of copper. Prolonged intake of supplemental zinc, particularly longer than 1 month, warrants compensatory copper, except for individuals with Wilson's disease and those whose therapeutic strategy employs zinc as an anticopper agent. Copper supplements should be taken at least 2 hours after zinc supplements.

Citations and Reference Literature

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