Zinc

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References

[No authors listed] Drug Evaluation Subscription. Chicago, American Medical Association, Vol II, Section 13, Chapter 5, Winter 1993.

Abu-Hamdan DK, Desai H, Sondheimer J, Felicetta J, Mahajan S, McDonald F. Taste acuity and zinc metabolism in captopril-treated hypertensive male patients. Am J Hypertens 1988 Jul;1(3 Pt 3):303S-308S.
Abstract: Reduced taste acuity is a commonly reported side effect of captopril associated with zinc deficiency. This study assessed taste acuity using Henkin's three-drop stimulus technique and measured plasma zinc (PZn) level and urinary zinc excretion in 31 hypertensive patients. Of these, 11 were long-term, high-dose captopril recipients, six were short-term captopril recipients, and the remaining 14 served as noncaptopril controls. Compared to controls, the long-term captopril group had significantly higher taste detection and recognition thresholds, lower PZn and higher urinary zinc excretion. The short-term captopril group did not differ significantly from the noncaptopril group except for higher taste-recognition thresholds for NaCl and sucrose. Discontinuing captopril improved and almost normalized zinc parameters in two patients on long-term captopril. These results suggest that abnormalities of taste are commonly associated with captopril therapy and may be related to changes in zinc metabolism. This is especially true in patients on long-term, high-dose captopril therapy.

Anderson LA, Hakojarvi SL, Boudreaux SK. Zinc acetate treatment in Wilson's disease. Ann Pharmacother 1998 Jan;32(1):78-87. (Review)
Abstract: OBJECTIVE: To briefly review the pathophysiology and diagnosis of Wilson's disease, and to evaluate the pharmacology, pharmacokinetics, clinical utility, adverse effects, dosing regimens, and pharmacoeconomics of zinc acetate therapy in Wilson's disease. DATA SOURCES: A MEDLINE search (December 1966-December 1996) of the English-language literature using the terms zinc and Wilson's disease was conducted to identify pertinent clinical trials, review articles, and case reports. Additional articles were selected from bibliographies of the reviewed literature. STUDY SELECTION AND DATA EXTRACTION: Due to the rarity of the disease, all articles were considered for possible inclusion in this review. Single case reports are referenced, but were not selected for evaluation. DATA SYNTHESIS: Wilson's disease, an inherited disorder of copper metabolism, is fatal if untreated. The chelating drugs penicillamine and trientine have been the mainstay of therapy; however, adverse reactions of chelators often interfere with successful treatment. Recently, zinc acetate was approved in the US for maintenance therapy in patients initially treated with a chelating agent. Although studies evaluating large populations are lacking zinc therapy has demonstrated exceptional safety and efficacy over a period of 40 years. Zinc acetate can be used during pregnancy and for the treatment of presymptomatic patients, although data do not support its use as monotherapy in patients with acute neurologic or hepatic disease. CONCLUSIONS: Zinc acetate is an effective maintenance therapy for patients with Wilson's disease. Negligible toxicity, compared with that of previously approved treatments, is a major advantage.

Anonymous. Zinc lozenges reduce the duration of common cold symptoms. Nutr Rev 1997;55:82-88. (Review)

Argiratos V, Samman S. The effect of calcium carbonate and calcium citrate on the absorption of zinc in healthy female subjects. Eur J Clin Nutr 1994;48:198-204.

Baum M, Cassetti L, Bonvehi P, Shor-Posner G, Lu Y, Sauberlich H. Inadequate dietary intake and altered nutrition status in early HIV-1 infection. Nutrition 1994 Jan-Feb;10(1):16-20.
Abstract: Recent studies indicate that multiple nutritional abnormalities occur relatively early in the course of human immunodeficiency virus (HIV-1) infection. Decreased plasma levels of vitamins B6, B12, A, and E and zinc have been correlated with dietary intake and associated with significant alterations in immune response and cognitive function. To determine the level of intake consistent with normal plasma nutrient levels, we examined nutrition status in relation to food consumption and nutrient supplementation in HIV-1-seropositive (HIV+) and -seronegative (HIV-) homosexual men. The mean level of total intake (diet plus supplements) for all nutrients was significantly higher in HIV+ men. To achieve normal plasma nutrient values, the HIV+ men appeared to require intake in multiples of the recommended dietary allowance (RDA) for vitamins A, E, B6, and B12 and zinc. For the HIV+ men, a relatively high proportion of biochemical deficiency was associated with consumption of vitamin B6 and zinc at the RDA level. Because little evidence of deficiency was observed with elevated intake in both groups, an effective program of nutritional supplementation may be beneficial in maintaining adequate plasma nutrient levels.

Baum MK, Shor-Posner G, Lu Y, Rosner B, Sauberlich HE, Fletcher MA, Szapocznik J, Eisdorfer C, Buring JE, Hennekens CH. Micronutrients and HIV-1 disease progression. AIDS. 1995 Sep;9(9):1051-1056.
Abstract: OBJECTIVE: To determine whether nutritional status affects immunological markers of HIV-1 disease progression. DESIGN: A longitudinal study, to evaluate the relationship between plasma levels of nutrients and CD4 cell counts, along and in combination with beta 2-microglobulin (beta 2M; AIDS index) over an 18-month follow-up. METHODS: Biochemical measurements of nutritional status including plasma proteins, zinc, iron and vitamins B1, B2, B6, B12 (cobalamin), A, E, C and folate and immunological markers [lymphocyte subpopulations (CD4) and beta 2M] were obtained in 108 HIV-1-seropositive homosexual men at baseline and over three 6-month time periods. Changes in nutrient status (e.g., normal to deficient, deficient to normal), were compared with immunological parameters in the same time periods using an autoregressive model. RESULTS: Development of deficiency of vitamin A or vitamin B12 was associated with a decline in CD4 cell count (P = 0.0255 and 0.0377, respectively), while normalization of vitamin A, vitamin B12 and zinc was associated with higher CD4 cell counts (P = 0.0492, 0.0061 and 0.0112, respectively). These findings were largely unaffected by zidovudine use. For vitamin B12, low baseline status significantly predicted accelerated HIV-1 disease progression determined by CD4 cell count (P = 0.041) and the AIDS index (P = 0.005). CONCLUSIONS: These data suggest that micronutrient deficiencies are associated with HIV-1 disease progression and raise the possibility that normalization might increase symptom-free survival.

Brewer GJ, Dick RD, Johnson VD, Brunberg JA, Kluin KJ, Fink JT. Treatment of Wilson's disease with zinc: XV long-term follow-up studies. J Lab Clin Med 1998 Oct;132(4):264-278.
Abstract: Wilson's disease is an inherited disease of copper accumulation caused by a failure of biliary excretion of excess copper. Accumulated copper causes liver disease in these patients, and in perhaps two thirds of patients, it causes brain damage leading to clinical neurologic or psychiatric dysfunction. Maintenance treatment involves reversing the positive copper balance. The earliest approaches have used chelators, such as penicillamine or trientine, which increase the urinary excretion of copper. A more recent approach has used zinc, which blocks the absorption of copper and increases copper excretion in the stool. Because of the high level of endogenously secreted copper in alimentary secretions, the reabsorption of which is partially blocked by zinc therapy, zinc acts to remove accumulated copper from the body as well as prevent its reaccumulation. In the present article we present data on the long-term follow-up (up to 10 years) of maintenance zinc treatment of 141 patients with Wilson's disease. The data presented document that zinc is effective as a sole therapy in the long-term maintenance treatment of Wilson's disease and that it has a low toxicity. The results demonstrate the efficacy of zinc therapy in treating the presymptomatic patient from the beginning of therapy. We also present limited data on the use of zinc in the treatment of pregnant patients and children who have Wilson's disease; these data also indicate efficacy and low toxicity. The median follow-up period for the group as a whole is 4.8 years; for the presymptomatic patients it is 6.5 years; for the children it is 3.6 years.

Broun ER, Greist A, Tricot G, Hoffman R. Excessive zinc ingestion-a reversible cause of sideroblastic anemia and bone marrow depression. JAMA 1990;264:1441-1443.

Brouwers JR. Drug interactions with quinolone antibacterials. Drug Saf 1992 Jul-Aug;7(4):268-281. (Review)
Abstract: The quinolone antibacterials are prone to many interactions with other drugs. Quinolone absorption is markedly reduced with antacids containing aluminium, magnesium and/or calcium and therapeutic failure may result. Other metallic ion-containing drugs, such as sucralfate, iron salts, and zinc salts, can also reduce absorption. Some of the newer quinolones inhibit the cytochrome P450 system, e.g. enoxacin, pefloxacin and ciprofloxacin. The toxicity of drugs that are metabolised by the cytochrome P450 system is enhanced by concomitant use of some quinolones. Ciprofloxacin, enoxacin and pefloxacin can increase theophylline concentrations to toxic values. The pharmacokinetics of warfarin and cyclosporin are unaffected. Ofloxacin, fleroxacin and temafloxacin have a low inhibitory effect on the cytochrome P450 system and a low interaction potential may result. The affinity of quinolones for the gamma-aminobutyric acid (GABA) receptor may induce CNS adverse effects; these effects are enhanced by some nonsteroidal anti-inflammatory drugs (NSAIDs).

Brumas V, Hacht B, Filella M, Berthon G. Can N-acetyl-L-cysteine affect zinc metabolisms when used as a paracetamol antidote? Agents Actions 1992;36:278-288.

Buist RA. Drug-nutrient interactions - an overview. Intl Clin Nutr Rev 1984;4(3):114. (Review)

Bush AI, Pettingell WH, Multhaup G, et al. Rapid induction of Alzheimer A8 amyloid formation by zinc. Science 1994;265:1464-1465.

Bush, Irving and Assoc. Cook County Hospital, Chicago. Zinc and the prostate. Presented at the Annual Meeting of the AMA, Chicago, 1974.
Abstract: 19 patients took zinc sulfate150mg (34mg elemental zinc) daily. All patients reported symptomatic improvement and 14/19 had shrinkage of the prostate, as determined by rectal palpation, X-ray and endoscopy. The supplemented group had higher levels of zinc in the semen.

Chandra RK. Excessive intake of zinc impairs immune responses. JAMA 1984;252(11):1443.

Cherry FF, Sandstead HH, Rojas P, Johnson LK, Batson HK, Wang XB. Adolescent pregnancy: associations among body weight, zinc nutriture, and pregnancy outcome. Am J Clin Nutr 1989;Nov;50(5):945-954.

Clemmensen OJ, Siggaard-Andersen J, Worm AM, Stahl D, Frost F, Bloch I. Psoriatic arthritis treated with oral zinc suphate. Br J Dermatol. 1980 Oct;103(4):411-415.
Abstract: Twenty-four patients suffering from psoriatic arthritis participated in a double blind cross-over trial of peroral zinc sulphate versus placebo (Trial I). Eleven patients continued an open trial of peroral zinc sulphate for an additional 24 weeks (Trial II). Remission was assessed by the disappearance of symptoms (overall condition, morning stiffness, functional capacity of the joints and joint pains), and signs (mobility and swelling of the joints). Reduction of joint pains as well as increase of mobility and decrease of swelling of several joints were observed. the clinical signs of reduced inflammation were accompanied biochemically by reduction of serum immunoglobulins and an increase of serum albumin. The need for analgesics was diminished. Severe side-effects and changes in the psoriatic skin involvement were not seen. Oral zinc sulphate seems to be valuable in the treatment of psoriatic arthritis.

Cordova A, Navas FJ. Effect of training on zinc metabolism: changes in serum and sweat zinc concentrations in sportsmen. Ann Nutr Metab 1998;42(5):274-282.
Abstract: The purpose of this research was to determine the effects of daily physical training on serum and sweat zinc concentrations in professional sportsmen between October and December, during the competing season. Twelve volleyball players and another 12 control subjects have participated in this study. Tests were made in October and December which consisted of a progressive bicycle ergometer test (increasing 30 W every 3 min to reach maximum tolerated power). Blood samples were obtained at rest and immediately after exercise. Total serum zinc increased significantly after maximal exercise in both sportsmen and control subjects. In athletes, the change after exercise was significantly higher in December than in October. The percentage of ultrafiltrable zinc (ZnUf) in October was similar in sportsmen and in controls. In December, however, after exercise, the percentage of ZnUf was higher in athletes. With respect to sweat zinc, it was in the same range both in controls and in sportsmen in October. In December, however, sweat zinc was significantly higher in athletes as compared with the situation in October and with respect to the control group. In October, the zinc concentration of urine was similar for sportsmen and controls. In December, the sportsmen showed an increase in urinary zinc excretion with respect to control subjects. Cortisol in athletes increased significantly after exercise in December. In conclusion, a daily and maintained practice of exercise is probably responsible for an alteration of zinc metabolism. The results suggest that ZnUf control, zinc supplementation and/or stress control appear to be indicated in athletes to prevent the diminution of active ZnUf. In our practical opinion we think that alterations in zinc metabolism with increases in zinc excretion and stress levels lead to a situation of latent fatigue with a decreased endurance.

Crofton RW, Gvozdanovic D, Gvozdanovic S, Khin CC, Brunt PW, Mowat NA, Aggett PJ. Inorganic zinc and the intestinal absorption of ferrous iron. Am J Clin Nutr 1989;Jul;50(1):141-144.
Abstract: The effect of inorganic zinc on the absorption of inorganic iron (Fe+2) from a solution was assessed in two studies on healthy male volunteers. In the first study coadministration of 344 mumol of zinc had no effect (p less than 0.5) on the absorption of 842 mumol of radiolabeled Fe, assessed by the area under plasma Fe increment time curve during the 3 (AUC3) and 6 (AUC6) h postadministration (Fe alone AUC3 = 176.4 +/- 39.3; AUC6 = 387 +/- 101; Fe + Zn AUC3 = 180 +/- 33.1; AUC6 = 396 +/- 73.1 mumol.h-1.L-1), total plasma content of 59Fe, and whole-body retention of 59Fe. In the second study only the plasma appearance of Fe was monitored. After administration of 421 mumol of Fe alone, the AUC3 and AUC6 were 167 +/- 21.2 and 429.4 +/- 57 mumol.h-1.L-1, respectively; these were reduced to 56.4 +/- 17 and 119 +/- 34 (p less than 0.002) by 421 mumol Zn and further reduced by 1048 mumol Zn to 33 +/- 15 and 43.4 +/- 23.8 mumol.h-1.L-1 (p less than 0.001), respectively. It is concluded that Zn can impair the intestinal absorption of Fe.

Dawson EB, Albers J, McGanity WJ. Serum zinc changes due to iron supplementation in teen-age pregnancy. Am J Clin Nutr 1990;50:848-852.

Eby GA, Davis DR, Halcomb WW. Reduction in duration of common colds by zinc gluconate lozenges in a double blind study. Antimicrob Agents Chemother 1984 Jan;25(1):20-24.
Abstract: As a possible treatment for common colds, we tested zinc gluconate lozenges in a double-blind, placebo-controlled, clinical trial. One 23-mg zinc lozenge or matched placebo was dissolved in the mouth every 2 wakeful h after an initial double dose. After 7 days, 86% of 37 zinc-treated subjects were asymptomatic, compared with only 46% of 28 placebo-treated subjects (P = 0.0005). Side effects or complaints were usually minor and consisted mainly of objectionable taste and mouth irritation. Zinc lozenges shortened the average duration of common colds by about 7 days.

Eby GA. Zinc ion availability--the determinant of efficacy in zinc lozenge treatment of
common colds. J Antimicrob Chemother 1997 Oct;40(4):483-493.
Abstract: This is a re-analysis of reports from 1984 to 1992 of double-blind, placebo-controlled, clinical trials of zinc lozenges in thetreatment of common colds. This re-analysis was performed to test the hypothesis that major variations in daily zinc ion availability (ZIA) between chemically different lozenge formulations caused differing results in these clinical trials. Solution chemistry computations determined the bioavailability of Zn2+ ions at physiological pH from the lozenges used in these clinical trails. ZIA was derived from Fick's laws of diffusion in a bio-electric field. Lozenges that released Zn2+ ions at physiological pH (positive ZIAs) shortened colds. Lozenges that released negatively charged zinc species at physiological pH (negative ZIAs) lengthened colds. Lozenges having a zero ZIA had no effect on common colds. Lozenges with ZIA = 100 shortened colds by 7 days while ZIA = -55 lozenges lengthened colds by 4.4 days. A linear dose-response relationship exists between ZIAs of zinc lozenges and changes in duration of common colds. It is concluded that: prospective efficacy of zinc lozenges can be predicted based upon readily determined ZIA factors and ZIAs; chemically different zinc lozenge formulations having greatly different ZIAs resulted in greatly differing results in clinical trials; mast cell granule-derived Zn2+ ions are the foundation of the primary immune system; and high ZIA zinc acetate lozenges are beneficial for common colds.

Fahim MS, Ibrahim HH, Girgis SM, Essa HA, Hanafi S. Value of intraprostatic injection of zinc and vitamin C and of ultrasound application in infertile men with chronic prostatitis. Arch Androl. 1985;14(1):81-87.
Abstract: Seventy infertile men with chronic prostatitis were treated by prostatic massage and wide-spectrum chemotherapy as basic treatment to which intraprostatic injection of zinc or vitamin C with or without ultrasound application was added as a new line of treatment. Comparison showed no significant improvement of the additive treatment over the conventional treatment used alone. Pus cells in the expressed prostatic smear diminished significantly after treatment, which was associated with significant increase of percentage of motile spermatozoa and significant decrease of abnormal forms. Bacterial flora was studied in comparison with findings in 20 cases of infertile males without prostatitis; staphylococci predominated in both patient and control groups.

Fahim MS, Wang M, Sutcu MF, Fahim Z. Zinc arginine, a 5 alpha-reductase inhibitor, reduces rat ventral prostate weight and DNA without affecting testicular function. Andrologia. 1993 Nov-Dec;25(6):369-375.

Fahim MS, et al. Zinc treatment for the reduction of hyperplasia of the prostate. Fed Proc 1976; 35:361.
Abstract: Zinc has been implicated in steroid endocrinology of the prostate gland; and 5 alpha-dihydrotestosterone (DHT) is believed to express androgenic responses in the prostate. To note the effect of neutralized zinc (zinc gluconate + arginine) on the prostate, 50 sexually mature rats, weighing 325 +/- 20 g, were divided into five groups as follows: (1) control, (2) sham, (3) castrated, and injected intraprostatically with (4) 10 mg neutralized zinc, and (5) 20 mg neutralized zinc. Results indicated significant reduction (P < 0.05) of prostate weight, 5 alpha-reductase activity, and total protein and DNA concentrations in treated prostate tissue; no significant change in weight and histological structure of testes, epididymides, and seminal vesicles; and no significant effect on progeny and blood testosterone level of treated animals. These results suggest that direct application of neutralized zinc to the prostate offers a new modality for treatment of prostatitis without affecting spermatogenesis.

Fischer PWF, Giroux A, Labbe MR. Effect of zinc supplementation on copper status in adult man. Am J Clin Nutr 1984;40(4):743-746.

Garland ML, Hagmeyer KO. The role of zinc lozenges in treatment of the common cold. Ann Pharmacother 1998;32:93-69 . (Review)

Goldenberg RL, Tamura T, Neggers Y, Copper RL, Johnston KE, DuBard MB, Hauth JC . The effect of zinc supplementation on pregnancy outcome. JAMA 1995; Aug 9;274(6):463-468.
Abstract: OBJECTIVE--To evaluate whether zinc supplementation during pregnancy is associated with an increase in birth weight. DESIGN--A randomized double-blind placebo-controlled trial. SETTING--Outpatient clinic and delivery service at the University of Alabama at Birmingham. PATIENTS--Five hundred eighty medically indigent but otherwise healthy African-American pregnant women with plasma zinc levels below the median at enrollment in prenatal care, randomized at 19 weeks' gestational age. Women were subdivided by the population median body mass index of 26 kg/m2 into two groups for additional analyses. INTERVENTION--Women who were taking a non-zinc-containing prenatal multivitamin/mineral tablet were randomized to receive either a daily dose of 25 mg of zinc or a placebo until delivery. MAIN OUTCOME MEASURES--Birth weight, gestational age at birth, and head circumference at birth. RESULTS--In all women, infants in the zinc supplement group had a significantly greater birth weight (126 g, P = .03) and head circumference (0.4 cm, P = .02) than infants in the placebo group. In women with a body mass index less than 26 kg/m2, zinc supplementation was associated with a 248-g higher infant birth weight (P = .005) and a 0.7-cm larger infant head circumference (P = .007). Plasma zinc concentrations were significantly higher in the zinc supplement group. CONCLUSIONS--Daily zinc supplementation in women with relatively low plasma zinc concentrations in early pregnancy is associated with greater infant birth weights and head circumferences, with the effect occurring predominantly in women with a body mass index less than 26 kg/m2.

Golik A, Cohen N, Ramot Y, Maor J, Moses R, Weissgarten J, Leonov Y, Modai D. Type II diabetes mellitus, congestive heart failure, and zinc metabolism. Biol Trace Elem Res 1993 Nov;39(2-3):171-175.

Golik A, Zaidenstein R, Dishi V, Blatt A, Cohen N, Cotter G, Berman S, Weissgarten J. Effects of captopril and enalapril on zinc metabolism in hypertensive patients. J Am Coll Nutr 1998 Feb;17(1):75-78.

Graf WD, Oleinik OE, Glauser TA, Maertens P, Eder DN, Pippenger CE. Altered antioxidant enzyme activities in children with a serious adverse experience related to valproic acid therapy. Neuropediatrics 1998 Aug;29(4):195-201.
Abstract: Specific oxidative metabolites of valproic acid (VPA) have been associated with the clinically defined toxicity of the drug. To investigate the role of enzymatic detoxification in clinical toxicity, we compared activities of five antioxidant enzymes in 15 patients with a serious adverse experience (SAE) related to VPA therapy, to enzyme activities measured in 35 patients with good clinical tolerance of VPA, and 50 healthy, age-matched subjects. These enzymes included glutathione peroxidase (GSH-Px), glutathione reductase (GSSG-R), glutathione transferase, superoxide dismutase, and catalase in erythrocytes; and GSH-Px in plasma. We also determined levels of Se, Cu, and Zn, trace elemental cofactors for these enzymes, in plasma from each individual. In patients with a VPA-associated SAE, GSH-Px was significantly depressed and GSSG-R was significantly elevated relative to values for the other groups. Selenium and zinc concentrations were lower in SAE patients than in controls. These findings may indicate a role for selenium dependent antioxidant activity in individual susceptibility to an SAE related to VPA therapy.

Heinity M, et al. Clinical and biochemical aspects of the prophylaxis and therapy of senile cataract with zinc aspartate. Klin Monatsbl Augenheilkd 172 (5):778-83, 1978.
Abstract: Senile cataract glucose utilization is disturbed due to loss of activity of some key zinc dependent enzymes in the lens. Zinc supplementation improves the impaired glucose metabolism occurring in old age and prolonged administration of zinc aspartate is indicated for the prevention and treatment of senile cataracts. In the presence of magnesium deficiency magnesium should also be given.

Hurd RW, Van Rinsvelt HA, Wilder BJ, Karas B, Maenhaut W, De Reu L. Selenium, zinc, and copper changes with valproic acid: possible relation to drug side effects. Neurology 1984 Oct;34(10):1393-1395.
Abstract: Side effects of treatment with the anticonvulsant valproic acid (VPA) suggested the possibility of alteration of trace metal status. Administration of VPA for 1 week produced significant depletion of zinc and selenium in plasma of rats and a one-third reduction of hepatic selenium. Patients who were treated chronically, with VPA as the sole anticonvulsant medication, had decreased plasma selenium levels. Most cases of VPA-associated hepatotoxicity occur in children. This could be due to decreased selenium concentrations when mechanisms for protection against peroxidative damage are not fully developed.

Kaji M, Ito M, Okuno T, Momoi T, Sasaki H, Yamanaka C, Yorifuji T, Mikawa H. Serum copper and zinc levels in epileptic children with valproate treatment. Epilepsia 1992 May-Jun;33(3):555-557.
Abstract: Valproate (VPA) induces zinc (Zn) deficiency in experimental animals, but whether VPA treatment induces deterioration of serum trace metal homeostasis in humans is uncertain. We measured serum copper (Cu) and Zn levels in epileptic children treated with VPA and/or other antiepileptic drugs (AEDs). Patients treated with VPA monotherapy had significantly lower levels of serum Cu (82.2 +/- 16.6 micrograms/dl) than normal controls (97.3 +/- 23.0 micrograms/dl). Patients treated with VPA in addition to some other AED also had significantly lower levels of serum Cu (84.8 +/- 20.0 micrograms/dl). Serum Cu concentrations in patients treated with AEDs except for VPA (87.7 +/- 19.1 micrograms/dl) were not statistically different from those of control subjects. In contrast to the reported results of animal experiments, serum Zn levels were not altered in patients with VPA treatment. Although none of our patients showed any symptoms of Cu deficiency, we should pay attention to potential Cu deficiency in patients with VPA treatment.

King JC. Do women using oral contraceptive agents require extra zinc? J Nutr 1987 Jan;117(1):217-219.

Kotsaki-Kovatsi VP, Koehler-Samouilidis G, Kovatsis A, Rozos G. Fluctuation of zinc, copper, magnesium and calcium concentrations in guinea pig tissues after administration of captopril (SQ 14225). J Trace Elem Med Biol 1997 Apr;11(1):32-36.
Abstract: The effect of the administration of captopril on Zn (zinc), Cu (copper), Ca (calcium) and Mg (magnesium) concentrations in guinea pig tissues was studied. For nine weeks 2 mg captopril per kg b.w. were administered daily to adult male guinea pigs intraperitoneally. The concentrations of the studied metals were determined in several tissues. Captopril significantly decreased Zn concentration in liver, Cu concentration in liver, adrenals, jejunum, urine and hair and Mg concentrations in blood and urine. A significant increase was observed in testicular and epididymal Zn, in heart, epididymal and fecal Cu, in Mg concentration of lung, kidney, adrenals, jejunum, epididymis and hair and in Ca concentrations in brain, heart, lung, kidney, spleen and stomach. No significant changes were observed in the colon and the thigh bone concentrations of the various elements tested. In conclusion Captopril treatment can produce translocation and/or elimination of Zn, Cu, Mg and Ca ions in various tissues of guinea pigs.

Lerman-Sagie T, Statter M, Szabo G, Lerman P. Effect of valproic acid therapy on zinc metabolism in children with primary epilepsy. Clin Neuropharmacol 1987;10(1):80-86.
Abstract: The effect of long-term treatment with valproic acid (VPA) on zinc (Zn) metabolism was studied in 15 children with absence seizures. During treatment with VPA the erythrocyte Zn content was significantly lower than that found in controls matched for sex and age. Plasma and urine values of Zn and of copper were within normal limits. It is suggested that the anticonvulsive action of VPA may be mediated through its effect on the metabolism of Zn in the brain and the concomitant changes in the activity of the enzymes glutamic acid decarboxylase and carbonic anhydrase.

Li T, Lin R, Du S, Qu Z. [Long-term follow-up of combined therapy with large-dose zinc sulfate and low-dose penicillamine in children with hepatolenticular degeneration]. Chung Hua I Hsueh I Chuan Hsueh Tsa Chih 1999 Feb 10;16(1):19-21. [Article in Chinese]
Abstract: OBJECTIVE: To summarize the long-term effect of combined treatment with large-dose zinc sulfate and low-dose penicillamine in children with hepatolenticular degeneration (HLD). METHODS: The patients who had symptoms were treated with large-dose zinc sulfate (100-150mg, <6yr; 150-200mg, 6-8yr; 200-300mg, 9-10yr; 300mg,>10yr; 3 times a day) in addition to low-dose penicillamine(8-10mg/kg/d) at the beginning of treatment. Zinc sulfate alone was given to the presymptomatic patients and it was used as maintenance therapy when clinical improvement was obtained. 31 children were followed up for 4-11 years. RESULTS: In 3 presymptomatic patients, no clinical abnormalities were found. Among 28 patients with symptoms, 23 patients (82%) had their symptoms and signs subsided or much improved, 2 patients(7%) remained unchanged, and 3(11%) died. Blood concentrations of copper were persistently lower than normal. Urine copper excretion of 24 hours was significantly lower than that before the combined therapy in all patients, and it became normal in 5 cases(16%) after 6 months of treatment, and in 26 cases(84%) after 1-2 years of treatment. Higher blood concentrations of zinc were found in 20 cases(65%), and higher urine zinc excretion was noted in 25 cases(81%) once or more times during the therapy. CONCLUSION: Combined therapy of large-dose zinc sulfate and low-dose penicillamine is an effective, safe and cheap treatment for children with HLD.

Lim D, McKay M. Food-drug interactions. Drug Information Bull UCLA Department of Pharmaceutical Services. 1995;15(2). (Review).

Macknin ML, Piedmonte M, Calendine C, Janosky J, Wald E. Zinc gluconate lozenges for treating the common cold in children. A randomized controlled trial. JAMA 1998;Jun 24;279(24):1962-1967.
Abstract: CONTEXT: The common cold is one of the most frequently occurring illnesses and is responsible for substantial morbidity and economic loss. Biochemical evidence suggests that zinc may be an effective treatment, and zinc gluconate glycine (ZGG) lozenges have been shown to reduce the duration of cold symptoms in adults. OBJECTIVE: To determine the efficacy of ZGG treatment of colds in children and adolescents. DESIGN: A randomized, double-masked, placebo-controlled study. SETTING: Two suburban school districts in Cleveland, Ohio. PATIENTS: A total of 249 students in grades 1 through 12 were enrolled within the first 24 hours of experiencing at least 2 of 9 symptoms of the common cold. INTERVENTION: Zinc lozenges, 10 mg, orally dissolved, 5 times a day (in grades 1-6) or 6 times a day (in grades 7-12). MAIN OUTCOME MEASURES: Time to resolution of cold symptoms based on subjective daily symptom scores for cough, headache, hoarseness, muscle ache, nasal congestion, nasal drainage, scratchy throat, sore throat, and sneezing. RESULTS: Time to resolution of all cold symptoms did not differ significantly between students receiving zinc (n = 124) and those receiving placebo (n = 125) (median, 9 days; 95% confidence interval [CI], 8-9 days; median, 9 days, 95% CI, 7-10 days, respectively; P=.71). There were no significant differences in the time to resolution of any of the 9 symptoms studied. Compared with controls, more students in the zinc group reported adverse effects (88.6% vs 79.8%; P=.06); bad taste (60.2% vs 37.9%; P=.001); nausea (29.3% vs 16.1%; P=.01); mouth, tongue, or throat discomfort (36.6% vs 24.2%; P=.03); and diarrhea (10.6% vs 4.0%; P=.05). CONCLUSIONS: In this community-based, randomized controlled trial, ZGG lozenges were not effective in treating cold symptoms in children and adolescents. Further studies with virologic testing are needed to clarify what role, if any, zinc may play in treating cold symptoms.

Marz R. Medical Nutrition From Marz. Second Edition. Portland, OR. 1997.

Mossad SB, Macknin ML, Medendorp SV, Mason P. Zinc gluconate lozenges for treating the common cold. Ann Int Med. 1996 Jul 15;125(2):81-88.
Abstract: BACKGROUND. The common cold is one of the most frequent human illnesses and is responsible for substantial morbidity and economic loss. No consistently effective therapy for the common cold has been well documented, but evidence suggests that several possible mechanisms may make zinc an effective treatment. OBJECTIVE. To test the efficacy of zinc gluconate lozenges in reducing the duration of symptoms caused by the common cold. DESIGN. Randomized, double-blind, placebo-controlled study. SETTING. Outpatient department of a large tertiary care center. PATIENTS. 100 employees of the Cleveland Clinic who developed symptoms of the common cold within 24 hours before enrollment. INTERVENTION. Patients in the zinc group (n = 50) received lozenges (one lozenge every 2 hours while awake) containing 13.3 mg of zinc from zinc gluconate as long as they had cold symptoms. Patients in the placebo group (n = 50) received similarly administered lozenges that contained 5% calcium lactate pentahydrate instead of zinc gluconate. MAIN OUTCOME MEASURES. Subjective daily symptom scores for cough, headache, hoarseness, muscle ache, nasal drainage, nasal congestion, scratchy throat, sore throat, sneezing, and fever (assessed by oral temperature). RESULTS. The time to complete resolution of symptoms was significantly shorter in the zinc group than in the placebo group (median, 4.4 days compared with 7.6 days; P < 0.001). The zinc group had significantly fewer days with coughing (median, 2.0 days compared with 4.5 days; P = 0.04), headache (2.0 days and 3.0 days; P = 0.02), hoarseness (2.0 days and 3.0 days; P = 0.02), nasal congestion (4.0 days and 6.0 days; P = 0.002), nasal drainage (4.0 days and 7.0 days; P < 0.001), and sore throat (1.0 day and 3.0 days; P < 0.001). The groups did not differ significantly in the resolution of fever, muscle ache, scratchy throat, or sneezing. More patients in the zinc group than in the placebo group had side effects (90% compared with 62%; P < 0.001), nausea (20% compared with 4%; P = 0.02), and bad-taste reactions (80% compared with 30%; P < 0.001), CONCLUSION. Zinc gluconate in the form and dosage studied significantly reduced the duration of symptoms of the common cold. The mechanism of action of this substance in treating the common cold remains unknown. Individual patients must decide whether the possible beneficial effects of zinc gluconate on cold symptoms outweigh the possible adverse effects.

Netter A, Hartoma R, Nahoul K. Effect of zinc administration on plasma testosterone, dihydrotestosterone, and sperm count. Arch Androl. 1981 Aug;7(1):69-73.
Abstract: The effects of zinc therapy on plasma testosterone (T), dihydrotestosterone (DHT), and sperm count were studied in 37 patients with idiopathic infertility of more than five years duration. In the first group (T less than 4.8 ng/ml; 22 patients), T and DHT rose significantly after oral administration of zinc, as did the sperm count. Nine wives became pregnant, six within 3 months and three within 2 months of a second trial. In the second group (T greater than or equal to 4.8 ng/ml; 15 patients), T and sperm count were unaffected by zinc, while DHT increased significantly. There was no conception observed. The rationale of this treatment and the significance of the results are discussed.

Newsome DA, Swartz M, Leone NC, Elston RC, Miller E. Oral zinc in macular degeneration. Arch Ophthalmol. 1988 Feb;106(2):192-198.
Abstract: Macular degeneration associated with age and drusen, an important cause of severe visual loss in older persons, is of unknown cause. The sensory retina and retinal pigment epithelium, which are cell layers in zinc, appear to be prominently involved in the disease process. Because zinc plays a role in the metabolic function of several important enzymes in the chorioretinal complex, we undertook a prospective, randomized, double-masked, placebo-controlled investigation of the effects of oral zinc administration on the visual acuity outcome in 151 subjects with drusen or macular degeneration. Although some eyes in the zinc-treated group lost vision, this group had significantly less visual loss than the placebo group after a follow-up of 12 to 24 months. This is the first controlled oral intervention study to show a positive, if limited, treatment effect in macular degeneration, a major public health problem. Because of the pilot nature of the study and the possible toxic effects and complications of oral zinc administration, widespread use of zinc in macular degeneration is not now warranted.

Petrus EJ, Lawson KA, Bucci LR, Blum K. Randomized, double-masked, placebo-controlled clinical study of the effectiveness of zinc acetate lozenges on common cold symptoms in allergy-tested subjects. Curr Ther Res 1998;59:595-607.

Polk RE, Healy DP, Sahai J, Drwal L, Racht E. Effect of ferrous sulfate and multivitamins with zinc on absorption of ciprofloxacin in normal volunteers. Antimicrob Agents Chemother 1989 Nov;33(11):1841-1844.
Abstract: Cations such as magnesium and aluminum significantly impair the absorption of ciprofloxacin. Twelve healthy adult male volunteers participated in this four-way crossover study to investigate the effects of ferrous sulfate and multivitamins with zinc on the absorption of ciprofloxacin. Doses of ciprofloxacin (500 mg) were given 7 days apart and after an overnight fast. Dose 1 was administered alone (regimen A). The subjects then received either a ferrous sulfate tablet (325 mg three times a day; regimen B) or a once-daily multivitamin with zinc (regimen C) for 7 days; dose 2 of ciprofloxacin was then given with the last dose of regimen B or C. Subjects were crossed over to the alternate regimen for 7 days, and dose 3 of ciprofloxacin was again administered with the last dose of regimen B or C. After a 7-day washout, dose 4 of ciprofloxacin was given (regimen D). Ciprofloxacin concentrations were determined by high-pressure liquid chromatography. The areas under the concentration-time curve (AUCs) of ciprofloxacin for regimens A and D were not significantly different (14.5 +/- 2.3 versus 15.7 +/- 2.8 micrograms.h/ml, mean +/- standard deviation). The AUCs for regimen B (5.4 +/- 1.7 micrograms.h/ml) and regimen C (11.3 +/- 2.4 micrograms.h/ml) were significantly different from the AUCs for regimens A and D. Peak concentrations of ciprofloxacin with regimen B were below the MIC for 90% of strains of many organisms normally considered susceptible. Ferrous sulfate and multivitamins with zinc significantly impaired the absorption of ciprofloxacin. The effect of ferrous sulfate is likely to be clinically significant; the responsible component of multivitamins with zinc requires additional study.

Potocnik FC, van Rensburg SJ, Park C, Taljaard JJ, Emsley RA. Zinc and platelet membrane microviscosity in Alzheimer’s disease. S Afr Med J 1997 Sep;87(9):1116-1119.
Abstract: OBJECTIVES: To investigate the effects of oral zinc supplementation on: (i) plasma zinc concentrations; (ii) platelet membrane microviscosity in vivo; and (iii) cognitive function of Alzheimer's disease (AD) patients. DESIGN: An open-labelled pilot study. SETTING: University of Stellenbosch Medical School and Stikland Hospital. SUBJECTS: Six volunteer AD patients. OUTCOME MEASURES: Plasma zinc levels, platelet membrane microviscosity and cognition (MMSE and ADAS-cog tests). RESULTS: Oral zinc supplementation (30 mg/day) did not increase plasma zinc levels significantly, but significantly increased platelet membrane microviscosity (P = 0.02; 6 patients). Four patients, who underwent 12 months of evaluation, showed modest cognitive improvement on psychometric testing (Mini-Mental State Examination and the cognitive portion of the Alzheimer's Disease Assessment scale scores). CONCLUSIONS: While earlier literature promoted the use of zinc in AD patients, a recent study has contradicted this and implicated zinc in the aetiology of Alzheimer's disease. On the basis of the above results, it may be premature to single out zinc as a causal agent in AD.

Powanda MC, Blackburn BS, Bostian KA, Fowler JP, Hauer EC, Pekarek RS. Clofibrate-induced alterations in zinc, iron and copper metabolism. Biochem Pharmacol 1978 Jan 1;27(1):125-127.

Prasad A. Discovery of human zinc deficiency and studies in an experimental human model. Am J Clin Nutr 1991;53:403-412. (Review)

Prasad AS. Zinc in human health: an update. J Trace Elements Exper Med 1998;11:63-87.

Resiser S, et al. Effect of copper intake on blood cholesterol and its lipoprotein distribution in men. Nutr Rep Internat 1987;36(3):641-649.

Robinson C, Weigly E. Basic Nutrition and Diet Therapy. New York: Macmillan, 1984.

Roe DA. Drug-induced Nutritional Deficiencies. 2nd ed. Westport, CT: Avi Publishing, 1985.

Roe DA. Essential hyperlipemia with xanthomatosis: effects of cholestyramine and clofibrate. Arch Dermatol 1968 Apr;97(4):436-445.

Roe DA. Risk factors in drug-induced nutritional deficiencies. In: Roe DA, Campbell T, eds. Drugs and Nutrients: The Interactive Effects. New York: Marcel Decker, 1984: 505-523.

Sandstead HH. Requirements and toxicity of essential trace elements, illustrated by zinc and copper. Am J Clin Nutr 1995;61(suppl):621S-24S. (Review)

Schauss AG. Diet, Crime, and Delinquency. Berkeley: Parker House, 1980.

Simkin PA. Oral zinc sulphate in rheumatoid arthritis.Lancet. 1976 Sep 11;2(7985):539-542.

Sozuer DT, Barutcu UB, Karakoc Y, Yalcin E, Onen S. The effects of antiepileptic drugs on serum zinc and copper levels in children. J Basic Clin Physiol Pharmacol 1995;6(3-4):265-269.
Abstract: The results of previous studies that examined serum trace metal status of epileptic patients receiving antiepileptic drug (AED) therapy were variable. We measured serum zinc (Zn) and copper (Cu) levels in 52 epileptic children who were treated with either carbamazepine (CBZ) or valproic acid (VPA) or with a combination of CBZ and VPA. Serum Zn levels were significantly lower in the epileptics than in the two control groups which consisted of 7 untreated epileptics and 12 normal children (p < 0.05). Combination therapy and monotherapy with CBZ increased serum Cu levels (p < 0.05). No significant alteration in serum Cu levels was observed with VPA monotherapy. Serum Zn and serum Cu concentrations of the untreated epileptics were not significantly different from those of normal controls. Our results indicate that serum trace metal homeostasis may be affected by AED therapy, but not by the convulsive disorder itself.

Spencer H, Norris C, Williams D. Inhibitory effects of zinc on magnesium balance and magnesium absorption in man. J Am Coll Nutr 1994;13:479-484.

Sturniolo GC, Montino MC, Rossetto L, Martin A, D'Inca R, D'Odorico A, Naccarato R. Inhibition of gastric acid secretion reduces zinc absorption in man. J Am Coll Nutr 1991 Aug;10(4):372-375.
Abstract: Numerous factors seem to affect zinc absorption. Gastric acid secretion has been demonstrated to facilitate iron absorption. The zinc tolerance test (ZTT with ZnSO4 220 mg p.o.) was performed in 11 healthy volunteers to study the effects of administering the acid secretion inhibitor cimetidine (1 g/day p.o. for 3 days) and to evaluate the influence of HCl gastric secretion on zinc absorption in physiological conditions. Zinc absorption was reduced after cimetidine administration (p less than 0.005), suggesting that gastric pH influences zinc absorption. To rule out any direct effect of the drug on zinc absorption in five other healthy adults we further evaluated zinc absorption by using a different H2 antagonist (ranitidine 300 mg/day for 3 days and 300 mg before the test). Cimetidine was also tested in these subjects at half the dosage administered to the first group of subjects. Gastric acidity was monitored at 60-min intervals throughout the test via a nasogastric tube. The areas under the plasma concentration curves for zinc were significantly reduced after ranitidine (p less than 0.01), but not after cimetidine administration. Gastric acid was also reduced after ranitidine, but not after cimetidine (500 mg) administration, suggesting that gastric acid secretion plays a role in the regulation of zinc absorption in man.

Suzuki T, Koizumi J, Moroji T, Shiraishi H, Hori T, Baba A, Kawai N, Tada K. Effects of long-term anticonvulsant therapy on copper, zinc, and magnesium in hair and serum of epileptics. Biol Psychiatry 1992 Mar 15;31(6):571-581.

Trovato A, Nuhlicek DN, Midtling JE. Drug-nutrient interactions. Am Fam Physician 1991 Nov;44(5):1651-1658.(Review)

USDA: Composition of Foods. USDA Handbook #8. Washington DC, ARS, USDA, 1976-1986.

Watkins DW, Khalafi R, Cassidy MM, Vahouny GV. Alterations in calcium, magnesium, iron, and zinc metabolism by dietary cholestyramine. Dig Dis Sci 1985 May;30(5):477-482.
Abstract: Cholestyramine is an effective drug for the reduction of plasma cholesterol because of its ability to sequester intestinal bile acids. Since metabolic alterations, including diminished intestinal absorption of vitamin D and osteomalacia have been reported with long-term use of this resin, the influence of cholestyramine on dietary balance of four mineral elements has been investigated. Wistar-strain rats were fed either a 2% cholestyramine or control diet for one month. Dietary intakes and fecal and urinary excretions of calcium, magnesium, iron, and zinc were determined using atomic absorption spectrophotometry during three, 3-day balance periods. Cholestyramine-fed rats had a net negative balance for calcium and a lower net positive balance for magnesium, iron, and zinc than the controls. Other effects of cholestyramine were an increased urinary excretion of calcium and magnesium, a decreased urinary zinc, and an alkalinization of urine. Blood and tissue cation content was unchanged except for a reduction in serum magnesium with resin feeding. Alterations in calcium, magnesium, and zinc metabolism might be explained by inadequate vitamin D absorption from the intestine followed by an increased secretion of parathyroid hormone. A diminished iron absorption due to resin binding could account for the reported disturbance in iron balance.

Weismann K. Chelating drugs and zinc. Dan Med Bull 1986 Aug;33(4):208-211.

Weismann K, Jakobsen JP, Weismann JE, Hammer UM, Nyholm SM, Hansen B, Lomholt KE, Schmidt K. Zinc gluconate lozenges for common cold. A double-blind clinical trial. Dan Med Bull 1990 Jun;37(3):279-281.
Abstract: In a double-blind clinical trial, a total of 463 volunteers were enrolled in a study designed to compare the effects of zinc gluconate lozenges (4.5 mg zinc) and a placebo for common cold. The tablets were to be taken every 1-1 1/2 waking hours at the first symptoms and for the following days until the common cold was over, but for no longer than 10 days. During the winter months of 1987 and 1988, 145 experienced a common cold and 130 completed the study. For final analysis, 61 patients in the zinc lozenge group and 69 patients in the placebo lozenge group were evaluated. Based on the patients' records the duration and severity of the common cold were compared. No statistically significant differences were found between the patient groups. Two recent studies using a five-time higher zinc dose per lozenge for common cold showed a significant, positive effect, but associated with frequent side-effects, first of all taste distortion. In the present study there was a weak tendency (not statistically significant, p = 0.12) towards more patients in the zinc lozenge group than in the placebo lozenge group reporting side-effects.

Werbach MR. Foundations of Nutritional Medicine. Tarzana, CA: Third Line Press, 1997. (Review).

Wynn V. Vitamins and oral contraceptive use. Lancet 1975 Mar 8;1(7906):561-564.
Abstract: Reports concerning the interaction between steroidal contraceptives (the combined pill) and vitamins indicate that in users the mean serum-vitamin-A level is raised and the mean serum-vitamin-B2 (riboflavine), vitamin-B6 (pyridoxine), vitamine-C, folic-acid, and vitamin-B12 levels are reduced. Other vitamins have been insufficiently studied for comment. Biochemical evidence of co-enzyme deficiency has been reported for vitamin B2, vitamin B6, and folic acid. Clinical effects due to vitamin deficiency have been described for vitamin B6--namely, depression and impaired glucose tolerance. Folic-acid deficiency with megaloblastic anaemia has been reported in only 21 cases.