Post-marketing surveillance of zinc acetate dihydrate for hypozincemia in Japan.

Zinc is an essential microelement, and its deficit causes various diseases and symptoms. In adults, especially in elderly individuals, zinc shortage can cause symptoms such as taste disorder, dermatitis, and susceptibility to infection. In children, zinc deficiency can lead to growth retardation. In 2017, the indication for zinc acetate dihydrate (NOBELZIN®) was expanded from Wilson's disease to include hypozincemia, leading to wider use of zinc acetate dihydrate. At five years after this broadening of use, we conducted a post-marketing study (PMS) to investigate the utilization, safety, and effectiveness of zinc acetate dihydrate. Over 52 weeks, the overall incidence of adverse drug reactions (ADRs) was 9.4% (87/928). The most common ADR was copper deficiency (2.4%), followed by nausea (1.4%). Among 928 patients, 19 (2%) developed serious ADRs. Of the patients with copper deficiency, 92% were >65 years of age, and all had comorbidities at baseline. Physicians evaluated the effectiveness of zinc acetate dihydrate using three categories: "effective", "not effective", and "indeterminate". The overall efficacy rate was 83.0%. The average serum zinc levels were elevated from 50-60 µg/dL to >90 µg/dL within 12 weeks, and were maintained up to 52 weeks after administration. Among the symptomatic sub-categories, the efficacy rate was highest in pressure ulcer (96.2%; 25/26), followed by in stomatitis (87.5%; 42/48), and taste disorder (87.4%; 181/207). Among pediatric patients with developmental symptoms, an efficacy rate of 66% was achieved. In conclusion, zinc acetate dihydrate has been safely used, and has produced beneficial effects on various diseases and symptoms.

Dietary Zinc Ameliorates TNBS-Induced Colitis in Mice Associated with Regulation of Th1/Th2/Th17 Balance and NF-κB/NLRP3 Signaling Pathway.

Inflammatory bowel diseases (IBDs), including Crohn's disease and ulcerative colitis, are chronic relapsing inflammatory gastrointestinal tract diseases of uncertain origin, which are frequently associated with zinc deficiency. Animal models have a considerable value in elucidating the process of IBD. In this study, 50 male C57BL/6 J mice were randomly assigned to five groups: control group (Con), 2,4,6-trinitrobenzenesulfonic acid (TNBS) group, and three zinc supplementation groups, namely 160 ppm group, 400 ppm group, and 1000 ppm group. The results showed that supplementation of dietary zinc with zinc oxide could effectively relieve the severity of ulcerative colitis induced by TNBS in mice. We demonstrate that the protective mechanism involves the immunomodulation of dietary zinc by increasing CD3+, CD3+CD8+, and Th2 cells, suppressing Th1 and Th17 cells, and decreasing the production of serum IL-1ß and IL-18. The dietary zinc oxide seems to be able to suppress the NF-κB/NLRP3 signaling pathway by downregulating the mRNA and protein expression of NIK, IKK, NF-κB, and NLRP3. The results suggest that dietary supplementation of zinc oxide may protect against colitis, and proper daily zinc supplementation may reduce the risk of IBD.

Habitual intake of iron, copper, and zinc and the risk of type 2 diabetes in a prospective cohort: The CAVAS (Cardiovascular Disease Association Study).

BACKGROUND AND AIMS: Unlike iron, evidence of the association between dietary copper and zinc intake and type 2 diabetes (T2D) risk is limited. This study aimed to examine the prospective associations of dietary intake of iron (total, plant-based, and animal-based), copper, and zinc with T2D risk among adults aged ≥40 years. METHODS AND RESULTS: For 16,666 participants, dietary intakes (baseline, cumulative average, and most recent) of iron, copper, and zinc were calculated from repeated food frequency questionnaires; a modified Poisson regression model with a robust error estimator was conducted. In men, positive associations between T2D and baseline dietary intake of Cu and Zn, cumulative average dietary intake of Fe (total and animal-based), Cu and Zn, and most recent dietary intake of Fe (total, plant-based, and animal-based), Cu, and Zn [most recent diet: for total Fe, IRR(95%CI) = 1.93 (1.41-2.64); for plant-based Fe, 1.56 (1.15-2.11); for animal-based Fe, 1.44 (1.09-1.90); for Cu, 3.17 (2.33-4.30); for Zn, 2.18 (1.64-2.89)] were observed, where as in women, there were positive associations of only cumulative average dietary Zn intake and most recent dietary intake of plant-based Fe, Cu, and Zn [most recent diet: for plant-based Fe, 1.30 (1.01-1.68); for Cu, 1.62 (1.27-2.08); for Zn, 2.07 (1.61-2.66)]. CONCLUSION: Dietary intakes of iron (total, plant-based, and animal-based), copper, and zinc may be positively associated with T2D risk. These positive associations are predominantly observed in most recent diet and appear to be stronger compared to baseline and cumulative average diet.

Severe copper deficiency anemia caused by zinc supplement use.

Copper deficiency is an uncommon condition primarily affecting the hematologic and neurologic systems. We report a unique case of severe anemia in a patient with copper deficiency caused by zinc supplement use.

Ionically bridged dexamethasone sodium phosphate-zinc-PLGA nanocomplex in alginate microgel for the local treatment of ulcerative colitis.

Colon-targeted oral drug delivery systems comprising nanoparticles and microparticles have emerged as promising tools for the treatment of ulcerative colitis (UC) because they minimize side effects and maximize the local drug concentration. Dexamethasone sodium phosphate (DSP) is a potent anti-inflammatory glucocorticoid used for the treatment of UC. However, it remains a rather short-term treatment option owing to its side effects. In the present study, we developed the alginate gel encapsulating ionically bridged DSP-zinc-poly(lactic-co-glycolic acid) (PLGA) nanocomplex (DZP-NCs-in-microgel) for the oral local treatment of UC. The successful encapsulation of DSP-zinc-PLGA nanocomplex (DZP-NCs) in alginate microgel was confirmed by SEM imaging. The prepared gel released DZP-NCs in the stimulated intestinal fluid and dampened the release of DSP in the upper gastrointestinal tract. Furthermore, DZP-NCs-in-microgel alleviated colonic inflammation in a mouse model of dextran sodium sulfate-induced colitis by relieving clinical symptoms and histological marks. Our results suggest a novel approach for the oral colon-targeted delivery of dexamethasone sodium phosphate for the treatment of UC.

Clinical study on the efficacy and tolerability of an oral supplement based on arginine, l-cystine, zinc and B6 vitamin (Cystiphane®) in patients with telogen effluvium.

BACKGROUND: Telogen effluvium (TE) is a common cause of non-cicatricial hair loss with no treatment-standardized protocol. The aim of our study was to evaluate the efficacy, tolerability, and patient compliance of a treatment with an oral supplement based on arginine, l-cystine, zinc and B6 vitamin (Cystiphane®, Laboratoires Bailleul, Geneva, Switzerland) with hair-growth properties, administered 4 times daily, in patients affected by TE. METHODS: We recruited 20 patients, aged between 18 and 70 years old, affected by TE. Patients were asked to take the oral supplement as a monotherapy, four tablets daily, in one or two administrations during meals. The study lasted 3 months. We evaluated the efficacy and tolerability of the treatment both qualitatively by collecting the clinician's opinion through a clinical evaluation and clinical-anamnestic form filled in by the researcher, and quantitatively through global photography and trichoscopy. We collected the patient's opinion through a self-assessment test, at the beginning of the recruitment and after 3 months of treatment. RESULTS: Eighteen patients were evaluated. After 3 months of taking the supplement, the researcher rated an average improvement of 2.89 at the clinical evaluation. For what concerns hair quantity, at the control trichoscopy, the mean trichoscopic value had risen to +2.055, whereas for hair diameter the mean trichoscopic diameter value had increased to +1.83. After 3 months of treatment, patients gave an average efficacy opinion of 3.61. CONCLUSIONS: The oral supplement has proved effective as an adjuvant in the treatment of TE in our cohort of patients.

Efficacy and safety of supramolecular active zinc in the treatment of scalp psoriasis: a multicentre, randomized, observed-blind, parallel-group, placebo- and active-controlled noninferiority trial.

BACKGROUND: Controlling the relapses of scalp psoriasis is a clinical issue. OBJECTIVES: To evaluate the efficacy and safety of a supramolecular active zinc antidandruff hair conditioner in managing scalp psoriasis (SP). METHODS: This multicentre randomized, observed-blind, parallel-group, placebo- and active-controlled noninferiority trial enrolled 211 patients with SP between October 2018 and June 2019. The participants were randomized 1 : 1 : 1 to the experimental (supramolecular active zinc antidandruff hair conditioner), placebo (supramolecular hydrogel) or positive control (calcipotriol ointment) group. The primary efficacy endpoint was the disease control rate at the end of the fourth week of treatment, measured using the Investigator's Global Assessment score. RESULTS: This study included 70, 70 and 71 participants in the experiment, control and placebo groups, respectively. The disease control rates of SP at the end of week 4 of treatment in the full-analysis set (FAS) were 39%, 25% and 37% in the experimental, placebo and control groups. The margin of superiority between the experimental and placebo groups was > 0 [96% confidence interval (CI) 13.22% (0.43% to ∞)] in the FAS. The experimental group was superior to the placebo group. The noninferiority margin between the experiment and control groups was > -15% [96% CI -1.43% (-14.91% to ∞)] in the FAS. The experimental group was not inferior to the control group. CONCLUSIONS: Supramolecular active zinc antidandruff hair conditioner was helpful for the treatment of SP, and it has good clinical efficacy in maintaining therapeutic effect and assisting in preventing the recurrence of psoriasis.

Metal Exposure and Risk of Parkinson Disease: A Systematic Review and Meta-Analysis.

Metal exposure has been suggested as a possible environmental risk factor for Parkinson disease (PD). We searched the PubMed, EMBASE, and Cochrane databases to systematically review the literature on the relationship between metal exposure and PD risk and to examine the overall quality of each study and the exposure assessment method. A total of 83 case-control studies and 5 cohort studies published during the period 1963-July 2021 were included, of which 73 were graded as being of low or moderate overall quality. Investigators in 69 studies adopted self-reported exposure and biomonitoring after disease diagnosis for exposure assessment approaches. The meta-analyses showed that concentrations of copper and iron in serum and concentrations of zinc in either serum or plasma were lower, while concentrations of magnesium in CSF and zinc in hair were higher, among PD cases as compared with controls. Cumulative lead levels in bone were found to be associated with increased risk of PD. We did not find associations between other metals and PD. The current level of evidence for associations between metals and PD risk is limited, as biases from methodological limitations cannot be ruled out. High-quality studies assessing metal levels before disease onset are needed to improve our understanding of the role of metals in the etiology of PD.

Iatrogenic copper deficiency: Risks and cautions with zinc prescribing.

AIMS: Copper deficiency resulting from prescribing zinc in high doses is a rare but life-changing diagnosis that is frequently overlooked. The aim of this study is to gauge how often zinc-induced copper deficiency is missed, to raise awareness of the condition and to stress the need for guidelines for prescribing zinc. METHODS: Suspected cases of zinc-induced copper deficiency were retrospectively obtained by selecting those patients with hyperzincaemia and hypocupraemia from the database of the Scottish Trace Element Laboratory. Case records were reviewed to determine the validity of the suspected diagnosis. RESULTS: After exclusions, 23 instances of high serum zinc and low serum copper concentrations were found. A positive diagnosis of zinc-induced copper deficiency was made in 14 patients, of which 7 (50%) were previously undiagnosed. CONCLUSION: Serum zinc and copper concentrations are rarely measured in patients prescribed zinc and so the vast majority of cases of zinc-induced copper deficiency are likely to be undiagnosed. We recommend the current official advice on the dose and frequency of zinc administration is revised in order to limit, and potentially eradicate, the condition.

Low Zinc Alleviates the Progression of Thoracic Aortic Dissection by Inhibiting Inflammation.

Vascular inflammation triggers the development of thoracic aortic dissection (TAD). Zinc deficiency could dampen tissue inflammation. However, the role of zinc as a nutritional intervention in the progression of TAD remains elusive. In this study, we employed a classical ß-aminopropionitrile monofumarate (BAPN)-induced TAD model in mice treated with low zinc and observed that the TAD progression was greatly ameliorated under low zinc conditions. Our results showed that low zinc could significantly improve aortic dissection and rupture (BAPN + low zinc vs. BAPN, 36% vs. 100%) and reduce mortality (BAPN + low zinc vs. BAPN, 22% vs. 57%). Mechanically, low zinc attenuated the infiltration of macrophages and inhibited the expression of inflammatory cytokines, suppressed the phenotype switch of vascular smooth muscle cells from contractile to synthetic types, and eventually alleviated the development of TAD. In conclusion, this study suggested that low zinc may serve as a potential nutritional intervention approach for TAD prevention.

Severe leukocytopenia due to copper deficiency induced by zinc supplementation in a patient on peritoneal dialysis: a case report.

Zinc deficiency is one cause of anemia. However, it has been reported that some patients who were treated with zinc supplementation to resolve this anemia subsequently experienced copper deficiency, which lead to continued anemia, as well as leukocytopenia and other symptoms. However, only two patients with copper deficiency induced by zinc supplementation undergoing peritoneal dialysis have been reported. Here, we report the case of a 59 year-old man with copper deficiency after zinc supplementation undergoing peritoneal dialysis (PD). He took meals only once a day and drank about 750 mL/day of wine every day. He had been receiving zinc supplementation for 4 months. He was diagnosed with severe leukocytopenia and worsening anemia at a planned outpatient visit; in addition, his copper levels had markedly decreased. Thus, zinc supplementation was discontinued, and the patient was instructed to take cocoa for copper supplementation. Because of severe leukocytopenia, he was admitted to our hospital, and granulocyte colony-stimulating factor was administered. Red blood cell transfusions were performed for anemia. After discontinuing zinc supplementation, his white blood cell count and hemoglobin levels improved.To avoid Cu deficiency, patients' dietary history should be checked in detail and Cu should be monitored carefully when Zn is supplemented in patients undergoing PD.

Assessment of the Antitumor Activity of Green Biosynthesized Zinc Nanoparticles as Therapeutic Agent Against Renal Cancer in Rats.

Zinc nanoparticles (Zn-NPs) have garnered a great deal of attention as potential cancer therapy. The use of microorganisms in the synthesis of nanoparticles emerges as an eco-friendly and exciting approach. This study was designed to assess biosynthesized Zn-NPs as therapeutic agent against kidney cancer induced by ferric-nitrilotriacetate (Fe-NTA) in rats.Zn-NPs were synthesized from edible mushroom then characterized by transmission electron microscopy analysis, dynamic light scattering, and Fourier transform infrared spectroscopy. Rats were divided into 4 different groups: group I (control), group II (Fe-NTA group), group III (Zn-NPs group), and group IV (Fe-NTA + Zn-NPs group). Animals were sacrificed then kidney and liver function tests, MDA level, glutathione, glutathione peroxidase, and superoxide dismutase activities were measured by using colorimetric methods. Caspase-3 level and carcinoembryonic antigen concentration were measured by using ELISA. Finally, DNA fragmentation was visualized by using agarose gel electrophoresis.Treatment with Zn-NPs significantly suppressed renal oxidative stress by restoring glutathione level, glutathione peroxidase, and superoxide dismutase activities and ameliorated oxidative damage parameters of lipid peroxidation as well as renal toxicity markers. Molecular and tumor markers showed significant improvement with respect to induction group, and this was well appreciated with the histopathological alteration findings in the treated groups.Microbial synthesized Zn-NPs possess antitumor-promoting activity against Fe-NTA-induced toxicity and carcinogenesis, which should be evaluated in a clinical study.

Zinc supplement use and risk of aggressive prostate cancer: a 30-year follow-up study.

BACKGROUND: Zinc supplementation was hypothesized to have therapeutic potential against prostate cancer, but its influence on prostate cancer incidence especially at high doses is controversial. METHODS: A total of 47,240 men from the Health Professionals Follow-up Study were followed from 1986 to 2016. Men reported their zinc supplement use at baseline and biennially thereafter. Clinical features of prostate cancer included stage, grade, lethal and aggressive (T4 or N1 or M1 or Gleason 8-10) outcome. Multivariable Cox proportional hazards models were used to evaluate the association between zinc supplement use and incidence of prostate cancer. RESULTS: During a median follow-up of 28.3 years, we documented 6,980 incident prostate cancer cases including 1,053 lethal and 1,143 aggressive. Zinc supplement use was not associated with overall, localized, low- and intermediate-grade prostate cancer. However, compared to never-users, men who used supplement zinc more than 75 mg/day were at higher risk for lethal (HR: 1.76, 95% CI: 1.16-2.66, Ptrend = 0.001) and aggressive prostate cancer (HR: 1.80, 95% CI: 1.19-2.73, Ptrend = 0.006). Similarly, men who took supplemental zinc for 15 or more years had a higher risk for lethal (HR: 1.91, 95% CI: 1.28-2.85, Ptrend <0.001) and aggressive prostate cancer (HR: 1.55, 95% CI: 1.03-2.33, Ptrend = 0.004). CONCLUSION: Zinc supplementation of more than 75 mg per day or over 15 years may substantially increase risk of lethal and aggressive prostate cancer. Caution is warranted regarding excessive usage of zinc supplements among adult men.

Adverse Effects of Excessive Zinc Intake in Infants and Children Aged 0-3 Years: A Systematic Review and Meta-Analysis.

Zinc supplementation reduces morbidity, but evidence suggests that excessive intakes can have negative health consequences. Current guidelines of upper limits (ULs) of zinc intake for young children are extrapolated from adult data. This systematic review (PROSPERO; registration no. CRD42020215187) aimed to determine the levels of zinc intake at which adverse effects are observed in young children. Studies reporting potential adverse effects of zinc intake in children aged 0-3 y were identified (from inception to August 2020) in MEDLINE, Embase, and the Cochrane Library, with no limits on study design. Adverse clinical and physical effects of zinc intake were synthesized narratively, and meta-analyses of biochemical outcomes were conducted. Random effects models were used to generate forest plots to examine the evidence by age category, dose, dose duration, chemical formula of zinc, and zinc compared with placebo. The Joanna Briggs Institute Critical Appraisal Checklist, Cochrane Risk of Bias 2, and Grading of Recommendations Assessment, Development, and Evaluation (GRADE) guideline were employed to assess risk of bias and to appraise the certainty of evidence. Fifty-eight studies assessed possible adverse effects of zinc doses ranging from 3 to 70 mg/d. Data from 39 studies contributed to meta-analyses. Zinc supplementation had an adverse effect on serum ferritin, plasma/serum copper concentration, serum transferrin receptor, hemoglobin, hematocrit, and the odds of anemia in ≥1 of the subgroups investigated. Lactulose:mannitol ratio was improved with zinc supplementation, and no significant effect was observed on C-reactive protein, erythrocyte superoxide dismutase, zinc protoporphyrin, blood cholesterol, and iron deficiency anemia. The certainty of the evidence, as assessed using GRADE, was very low to moderate. Although possible adverse effects of zinc supplementation were observed in some subgroups, it is unclear whether these findings are clinically important. The synthesized data can be used to undertake a dose-response analysis to update current guidelines of ULs of zinc intake for young children.

Long Noncoding RNA Zinc Finger Antisense 1 Affects Glucocorticoid-Induced Osteonecrosis of the Femoral Head by Performing as a ceRNA for MicroRNA-124-3p and Accelerating Transforming Growth Factor Type III Receptor.

In recent years, plentiful studies have uncovered the long noncoding RNA's (lncRNA's) momentous functions in osteonecrosis of the femoral head (ONFH), but the specific mechanism has not been fully illustrated. The study was to figure out lncRNA Zinc finger antisense 1 (LncZFAS1)'s biological function and its latent downstream molecular mechanism in glucocorticoid- (GC-) induced ONFH. The results manifested LncZFAS1 and transforming growth factor type III receptor (TGFBR3) were elevated, while microRNA- (miR-) 124-3p was reduced in ONFH tissues and cells. Knockdown LncZFA1 reduced rat femoral cell apoptosis, perfected bone microstructure and bone density, and accelerated osteogenic proteins bone morphogenetic protein- (BMP-) 9, BMP-3, and osteocalcin. In vitro studies manifested knockdown LncZFAS1 prevented GC-induced reduction in osteoblast advancement with facilitating osteoblast calcification capacity, ALP activity, and osteogenic proteins. Elevation of LncZFAS1 further aggravated GC-induced osteoblast injury, but this effect was turned around by enhancement of miR-124-3p or knockdown of TGFBR3. Mechanistically, LncZFAS1 performed as a sponge for miR-124-3p to mediate TGFBR3 expression to motivate GC-induced ONFH. All in all, the results of this study indicate the LncZFAS1/miR-124-3p/TGFBR3 axis is supposed to be a latent therapeutic molecular target for GC-induced ONFH.

Heavy Metals in Breast Implant Capsules and Breast Tissue: Findings from the Systemic Symptoms in Women-Biospecimen Analysis Study: Part 2.

BACKGROUND: Breast Implant Illness (BII), as described in recent medical literature and by social media, describes a range of symptoms in patients with breast implants for which there are no physical findings or laboratory results that explain their symptoms. OBJECTIVES: Part 2 of this study aims to determine whether heavy metals are present in the capsules around saline and silicone implants and if there are statistical differences in the type or level of these metals between women with or without symptoms. Demographic data was collected to investigate potential alternate sources of metals: inhaled, absorbed, or ingested. METHODS: A prospective, blinded study enrolled 150 consecutive subjects divided equally into in three cohorts: (A) women with systemic symptoms they attribute to their implants who requested implant removal, (B) women with breast implants requesting removal or exchange who do not have symptoms they attribute to their implants, and (C) women undergoing cosmetic mastopexy who have never had any implanted medical device. Capsule tissue was removed from Cohort A and B for analysis of 22 heavy metals. Additionally, breast tissue was obtained from a control group with no previous exposure to any implanted medical device. RESULTS: The study was performed between 2019-2021. Heavy metal content was compared between the capsule tissue from Cohort A and B. The only statistically significant differences identified in Cohort A were higher levels of arsenic and zinc, and lower levels of cobalt, manganese, silver, and tin. There were no elevated levels or statistically significant differences in the other metals tested between Cohorts A and B. CONCLUSIONS: This study analyzes the metal content in capsules surrounding both saline and silicone breast implants. Heavy metals were also detected in the non-implant control group breast tissue, with some metals at numerically higher levels than either breast implant cohort. Smoking, gluten free diets, dietary supplements, and the presence of tattoos were all identified as statistically significant sources of arsenic and zinc in Cohort A. The risk of heavy metal toxicity should not be used as an indication for total capsulectomy if patients elect to remove their breast implants.

U-shaped Association Between Dietary Zinc Intake and New-onset Diabetes: A Nationwide Cohort Study in China.

AIMS: We aimed to investigate the relationship of dietary zinc intake with new-onset diabetes among Chinese adults. MATERIALS AND METHODS: A total of 16 257 participants who were free of diabetes at baseline from the China Health and Nutrition Survey were included. Dietary intake was measured by 3 consecutive 24-hour dietary recalls combined with a household food inventory. Participants with self-reported physician-diagnosed diabetes, or fasting glucose ≥ 7.0 mmol/L, or glycated hemoglobin ≥ 6.5% during the follow-up were defined as having new-onset diabetes. RESULTS: A total of 1097 participants developed new-onset diabetes during a median follow-up duration of 9.0 years. Overall, the association between dietary zinc intake and new-onset diabetes followed a U-shape (P for nonlinearity < 0.001). The risk of new-onset diabetes was significantly lower in participants with zinc intake < 9.1 mg/day (per mg/day: hazard ratio [HR], 0.73; 95% CI, 0.60-0.88), and higher in those with zinc intake ≥ 9.1 mg/day (per mg/day: HR, 1.10; 95% CI, 1.07-1.13). Consistently, when dietary zinc intake was assessed as deciles, compared with those in deciles 2-8 (8.9 -<12.2 mg/day), the risk of new-onset diabetes was higher for decile 1 (<8.9 mg/day: HR, 1.29; 95% CI, 1.04-1.62), and deciles 9 to 10 (≥12.2 mg/day: HR, 1.62; 95% CI, 1.38-1.90). Similar U-shaped relations were found for plant-derived or animal-derived zinc intake with new-onset diabetes (all P for nonlinearity < 0.001). CONCLUSIONS: There was a U-shaped association between dietary zinc intake and new-onset diabetes in general Chinese adults, with an inflection point at about 9.1 mg/day.