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Dietary Supplement Information for Physicians with Naturokinetics® GI Guard™ PM Product Code P2997 Category: GI Tract Support TECHNICAL SUMMARY GI Guard™ PM is a specialized, clinically supported combination of dietary zinc and melatonin formulated to be taken 30 to 60 minutes before bedtime for targeted GI tract epithelium repair. Zinc in GI Guard™ PM is in the form of Zinc-L-Carnosine (PepZin GI®), which is a stable complex of Zinc and L-Carnosine, a di-peptide formed by the amino acids β-alanine and L-histidine. Vitamins B, C and selected amino acids are included for additional restorative effect. Common Name: Chemical Name: Zinc-L-Carnosine, Polaprezinc Zinc N-(3aminopropionyl)histidine Melatonin N-Acetyl-5methoxytryptamine C9H12N4O3Zn C13H16N2O2 289.63 g/mol 232.28 g/mol Chemical Structure: Molecular Formula: Molecular Weight: Product Composition: Folic Acid, L-Tryptophan, L-Methionine, Betaine, Taurine, Zinc-L-Carnosine, Cyanocobalamin, Pyridoxine HCl, Ascorbyl Palmitate, Melatonin, Cellulose, Stearic Acid (vegetable source), Croscarmellose Sodium and Silica. Vegetarian/vegan. Delivery Form: Tablets. ROLE AS A NUTRIENT Essentiality and Dietary Sources: 1 Zinc is an essential mineral. Recommended daily intake for zinc is 15 mg/day. Zinc is found in a variety of plant foods. Carnosine, which is present in large quantities in muscle tissue, is a di-peptide composed of β-alanine (non-essential 2 amino acid) and L-histidine (essential amino acid). Carnosine is abundant in meat products and eggs. 3 Melatonin is synthesized in the body from L-tryptophan and is ubiquitously present in all animals. Methods of Evaluating Nutritional Status: In adults, normal plasma zinc level is 60-130 µg/dL. 4 Melatonin can be detected in plasma or saliva; its concentration strongly correlates with the circadian rhythm. Structural and Functional Role: Zinc is known for its stabilizing and anti-inflammatory effect on gastric mucosa. This effect is enhanced by slow dissociation of Zinc-L-Carnosine which causes zinc to stay within the GI tract long enough to bind to the injured 5 epithelium, while L-Carnosine simultaneously helps to neutralize free-radicals in and around the damaged mucosa. Melatonin was initially considered to be a systemic hormone exclusively derived from the pineal gland. It influences a variety of biological processes including neuroendocrine, immune and cardiovascular functions, as well as circadian rhythms. Melatonin has also been shown to be generated locally by neuroendocrine cells in many tissues, including those of the GI tract. In the gastric mucosa, melatonin acts via specific membrane receptors and also as a free-radical scavenger. It exerts a protective, anti-inflammatory effect on the gastric lining, helps support healthy pH levels, and 6 supports normal pepsin and gastrin production. Additionally, taken at bedtime, melatonin reduces difficulties 7 associated with falling asleep and improves symptoms associated with poorly coupled circadian rhythms. PepZin GI® is a registered trademark of Hamari Chemicals, Ltd. Page 1 of 4 Dietary Supplement Information for Physicians with Naturokinetics® RECOMMENDED USE NATUROKINETICS® Liberation: Dissolution data is not available. GI Guard™ PM P2997 tablets pass the standard disintegration test (< 60 minutes). Absorption: Due to slow dissociation, absorption of zinc from Zinc-L-Carnosine is significantly delayed, which allows for adhesion of zinc ions to gastric epithelium. Elevated gastric Zn concentration is maintained for a significantly longer period of time after Zinc-L-Carnosine compared to zinc sulfate administration (Figure 1). Peak plasma Zn 10 concentration is reached in ~ 4 hours (Tmax). The amount of Zn 11 absorbed from Zinc-L-Carnosine is estimated to be 11%. In healthy volunteers with normal sleep-awake cycle, single administration of 2 or 4 mg melatonin tablets results in maximum plasma concentrations in ~ 1 hour (Tmax) with absolute bioavailability of about 15% due to significant first-pass hepatic 12 metabolism (Figure 2). Distribution: Absorbed zinc and L-carnosine are distributed to the liver, kidney, prostate; and to a lesser extent to the testes and brain where zinc 13 uptake is tightly regulated by the blood-brain barrier. Melatonin is subject to systemic distribution and easily crosses the 14 blood-brain barrier. Metabolism: Metabolism of exogenous L-carnosine is similar to that of endogenous carnosine, which is hydrolyzed to β-alanine and L13 histidine by carnosinase in the blood, liver, and kidneys. 15 Melatonin is metabolized in the liver into 6-sulfatoxymelatonin. PepZin GI® is a registered trademark of Hamari Chemicals, Ltd. Radioactivity (µmol • eq/content) Support of Normal Gut Permeability: In a double-blind, placebo-controlled, crossover clinical trial with ten healthy volunteers (24–40 years old), five days of consecutive indomethacin administration (50 mg three times a day, days 3-7) plus placebo (days 1-7) caused a threefold increase in gut permeability (assessed as lactulose/rhamnose ratio) whereas no significant increase in permeability was detected when indomethacin was co-administered with Zinc-L-Carnosine (37.5 5 mg/twice a day, days 1-7). Support of Gastric Mucosa: In a randomized, placebo-controlled, clinical trial with 20 adult volunteers, supplementation with melatonin in the dose of 5 mg 30 minutes prior to administration of aspirin (1 gram twice a day for 11 days) resulted in significant protection of gastric mucosa as compared to aspirin plus placebo. The evaluation was conducted endoscopically using standardized Lonza score, which demonstrated 90% attenuation of lesions and 50% reduction in microbleeding when 6 melatonin was co-administered. Support of Esophageal Mucosa: In a prospective clinical trial with 36 volunteers with Gastro-Esophageal Reflux Disease (GERD) and healthy individuals as control, baseline plasma melatonin level was found to be significantly lower (~ 50%) in patients with GERD. Supplementation with melatonin (3 mg at bedtime) resulted in significant improvement in heartburn and epigastric pain symptoms, lowered esophageal sphincter pressure, and raised serum gastrin and melatonin levels following 4 and 8 weeks of therapy. The outcomes were comparable 8 with omeprazole treatment. 100 Support of Intestinal Mucosa: In a randomized, double-blind, placebo controlled clinical trial with 40 female IBS patients with sleep * 10 disturbances, supplementation with melatonin (3 mg at bed time for 2 weeks) significantly decreased mean abdominal pain score (p < 0.001) 1 9 as compared to placebo. 0.1 0.01 0.001 0 2 4 6 8 Time (hr) Figure 1: Time course of total mean radioactivity in gastric contents after oral administration of Zinc in the form of polapresinc or zinc sulfate ( 65Zn polaprezinc; 65ZnSO4; *P < 0.05). Figure 2: Mean serum concentration versus time profile following single oral administration of 2 and 4 mg of melatonin tablets in healthy volunteers. Page 2 of 4 Dietary Supplement Information for Physicians with Naturokinetics® Elimination: 65 Following a single administration of radiolabeled Zinc-L-Carnosine, 85% of Zn was eliminated with feces and 0.3% 11 with urine. 14 Predominant route of elimination of melatonin and its metabolite 6-sulfatoxymelatonin is via urine. SAFETY INFORMATION Tolerability: Upper limit for zinc is 40 mg/day. In clinical trials with typical daily dose of 75 mg, Zinc-L-Carnitine (containing 16 mg 16 elemental zinc) was well tolerated for up to 12 weeks, with a negligible amount of gastrointestinal complaints. 17 Doses of melatonin as high as 50 mg/kg of body weight have been used in humans without reported adverse effects. Cautions: Do not drive or use machinery for 4 to 5 hours after taking melatonin. INTERACTIONS Drug Interactions: Zinc has been shown to decrease the absorption of cisplatin, penicillamine, quinolone, and tetracycline antibiotics due to forming insoluble complexes with these medications in the gastrointestinal tract and thus reducing their systemic availability. Patients should be advised to take these drugs at least 2 hours before or 4-6 hours after zinc 18 supplements. Concomitant use of melatonin with alcohol, benzodiazepines, or other similar drugs might cause increased sedation. Melatonin may exhibit interaction with anti-coagulant/anti-platelet medications, antidepressants, anti-hypertensive, 18 and anti-diabetes drugs. Supplement Interactions: Zinc may inhibit function of supplemental enzymes, including bromelain. Large amounts of supplemental zinc can 19 competitively inhibit copper, magnesium and iron absorption. Zinc may increase manganese absorption when taken 20 together. 21 Melatonin may potentiate effect of the supplements with sedative component (5-HTP, kava, valerian root). Interactions with Lab Tests: 22 Supplementation with elemental zinc 50 mg/day has been shown to raise HgbA1C in type I diabetics. 23 Melatonin supplementation can increase human growth hormone serum levels and decrease serum luteinizing 24 hormone levels. Stability & Storage: Effective through the expiration date when stored in a cool, dry place. References: 1. 2. 3. 4. 5. 6. 7. 8. Lonnerdal B. Dietary factors influencing zinc absorption. J Nutr. May 2000; 130 (5S Suppl): 1378S-1383S. Everaert I, Mooyaart A, Baguet A, et al. Vegetarianism, female gender and increasing age, but not CNDP1 genotype, are associated with reduced muscle carnosine levels in humans. Amino Acids. Apr 2011; 40 (4): 12211229. Mercolini L, Mandrioli R, Raggi MA. Content of melatonin and other antioxidants in grape-related foodstuffs: measurement using a MEPS-HPLC-F method. J Pineal Res. Aug 2012; 53 (1): 21-28. Benloucif S, Burgess HJ, Klerman EB, et al. Measuring melatonin in humans. Journal of clinical sleep medicine : JCSM : official publication of the American Academy of Sleep Medicine. Feb 15 2008; 4 (1): 66-69. Mahmood A, FitzGerald AJ, Marchbank T, et al. Zinc carnosine, a health food supplement that stabilises small bowel integrity and stimulates gut repair processes. Gut. Feb 2007; 56 (2): 168-175. Konturek PC, Konturek SJ, Celinski K, et al. Role of melatonin in mucosal gastroprotection against aspirin-induced gastric lesions in humans. J Pineal Res. May 2010; 48 (4): 318-323. Hardeland R. Neurobiology, pathophysiology, and treatment of melatonin deficiency and dysfunction. TheScientificWorldJournal. 2012; 2012: 640389. Kandil TS, Mousa AA, El-Gendy AA, Abbas AM. The potential therapeutic effect of melatonin in Gastro-Esophageal Reflux Disease. BMC gastroenterology. 2010; 10: 7. PepZin GI® is a registered trademark of Hamari Chemicals, Ltd. Page 3 of 4 Dietary Supplement Information for Physicians with Naturokinetics® 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. Song GH, Leng PH, Gwee KA, Moochhala SM, Ho KY. Melatonin improves abdominal pain in irritable bowel syndrome patients who have sleep disturbances: a randomised, double blind, placebo controlled study. Gut. Oct 2005; 54 (10): 1402-1407. Furuta S, Toyama S, Miwa M, Itabashi T, Sano H, Yoneta T. Residence time of polaprezinc (zinc L-carnosine complex) in the rat stomach and adhesiveness to ulcerous sites. Japanese journal of pharmacology. Apr 1995; 67 (4): 271-278. Matsukura T, Tanaka H. Applicability of zinc complex of L-carnosine for medical use. Biochemistry (Mosc). Jul 2000; 65 (7): 817-823. DeMuro RL, Nafziger AN, Blask DE, Menhinick AM, Bertino JS, Jr. The absolute bioavailability of oral melatonin. J Clin Pharmacol. Jul 2000; 40 (7): 781-784. Furuta S, Suzuki M, Toyama S, Miwa M, Sano H. Tissue distribution of polaprezinc in rats determined by the double tracer method. J Pharm Biomed Anal. Mar 1999; 19 (3-4): 453-461. Bubenik GA, Blask DE, Brown GM, et al. Prospects of the clinical utilization of melatonin. Biological signals and receptors. Jul-Aug 1998; 7 (4): 195-219. Di WL, Kadva A, Johnston A, Silman R. Variable bioavailability of oral melatonin. N Engl J Med. Apr 3 1997; 336 (14): 1028-1029. Age-Related Eye Disease Study Research G. A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E, beta carotene, and zinc for age-related macular degeneration and vision loss: AREDS report no. 8. Arch Ophthalmol. Oct 2001; 119 (10): 1417-1436. Nickkholgh A, Schneider H, Sobirey M, et al. The use of high-dose melatonin in liver resection is safe: first clinical experience. J Pineal Res. May 2011; 50 (4): 381-388. Drug Interactions. http://www.drugs.com/drug_interactions.html. Accessed June 28, 2012. Olivares M, Pizarro F, Ruz M, Lopez de Romana D. Acute inhibition of iron bioavailability by zinc: studies in humans. Biometals : an international journal on the role of metal ions in biology, biochemistry, and medicine. Feb 2 2012. Freeland-Graves JH, Lin PH. Plasma uptake of manganese as affected by oral loads of manganese, calcium, milk, phosphorus, copper, and zinc. J Am Coll Nutr. Feb 1991; 10 (1): 38-43. Avery D, Lenz M, Landis C. Guidelines for prescribing melatonin. Annals of medicine. Feb 1998; 30 (1): 122-130. Cunningham JJ, Fu A, Mearkle PL, Brown RG. Hyperzincuria in individuals with insulin-dependent diabetes mellitus: concurrent zinc status and the effect of high-dose zinc supplementation. Metabolism. Dec 1994; 43 (12): 15581562. Forsling ML, Wheeler MJ, Williams AJ. The effect of melatonin administration on pituitary hormone secretion in man. Clin Endocrinol (Oxf). Nov 1999; 51 (5): 637-642. Nordlund JJ, Lerner AB. The effects of oral melatonin on skin color and on the release of pituitary hormones. J Clin Endocrinol Metab. Oct 1977; 45 (4): 768-774. PepZin GI® is a registered trademark of Hamari Chemicals, Ltd. Page 4 of 4