Chemistry:Zinc L-carnosine

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Short description: Chelating agent containing zinc and carnosine

Zinc L-carnosine (beta-alanyl-L-histidinato zinc[1]) (N-(3-aminopropionyl)-L-histidinato zinc[2]), often simply called zinc carnosine, and also known as polaprezinc,[3] is a mucosal protective[4][5] chelate compound of zinc and L-carnosine invented by Hamari Chemicals, Ltd.[6][7] It is a quadridentate 1:1 complex of a polymeric nature.[6] Although it contains 23% zinc and 77% L-carnosine by mass,[8] zinc carnosine is a molecule and not a mixture of zinc and L-carnosine.

It is an approved drug requiring a medical prescription in Japan and South Korea where it is clinically used to treat gastric ulcers.[3][9] Clinical studies have also shown its efficacy for oral mucositis, esophagitis, proctitis, taste alteration and dermatitis during and after radiotherapy.[10][11] In the United States , zinc carnosine is regulated as a New Dietary Ingredient, where notification with the US-FDA is required.[12] In Australia , it is regulated as a complementary medicine.[13] In Canada , it is regulated as a Natural Health Product.[14]

Mechanisms of action

Gastrointestinal

Its mechanism of action is oxygen radical scavenging, anti-oxidation, and acceleration of gastrointestinal wound healing.[3] It exhibits ROS-quenching activities.[4] It can remain in the stomach without rapid dissociation and adhere specifically to ulcerous lesions, after which L-carnosine and zinc are released to heal the ulcer.[6] It has been shown to stimulate mucus production and to maintain the integrity of the gastric mucosal barrier.[5] It maintains homeostasis of the gastric mucosa by prostaglandin-independent cytoprotective effects due to anti-oxidative membrane stabilizing actions, and it promotes the repair of damaged tissues by wound healing action.[6]

It exerts cytoprotection through regulating heat shock proteins and chemokines, and by stabilizing mast cells.[10] It does so without affecting the secretion of gastric acid.[10] It has a potential to stimulate Hsp70 expression, with overexpression of Hsp70 being found to prevent the development of inflammatory process in the large intestinal mucosa provoked by various damaging factors.[15] It decreases p53, p21 and Bax expression and apoptosis in the intestine after irradiation.[10] It possesses antioxidant, anti-inflammatory, and genomic stability enhancement effects, thereby having potential in preventing gastrointestinal cancer development.[9]

It exhibits an inhibitory effect on H. pylori.[6]

Comparisons

Its healing efficacy against ulceration is significantly greater than that of other zinc complexes, free L-carnosine, and zinc D-carnosine[6] (which is not sold as a supplement to consumers). The pharmacological activity of zinc L-carnosine seems attributable mainly to zinc ion, presumably transported effectively into the ulcer by means of L-carnosine together with the action of L-carnosine itself.[6] In contrast, a simple mixture of L-carnosine and zinc had a lesser effect, presumably due to rapid diffusion of L-carnosine and zinc ion in the entire stomach.[6] Per preclinical data, zinc L-carnosine is superior to zinc sulfide for mucositis.[10]

Other

It has a stimulatory effect on bone formation and a restorative effect on bone loss under various pathophysiologic conditions.[16]

Usage

Zinc L-carnosine has been used orally[8][17] or as an oral rinse, lozenge or suppository.[10] The typical clinical oral dose is 150 mg/day, containing 34 mg zinc and 116 mg L-carnosine.[8][17] (The Tolerable Upper Intake Level (UL) for total zinc intake from all sources in adults is 40 mg/day.[18])

As an oral rinse, it has been used three to four times a day, with or without swallowing, providing a total amount of 150 mg/day.[10] A solution of 5% sodium alginate has been used.[10] Alternatively, it has been used as a lozenge containing 18.75 mg, four times a day.[10] It has also been used as a suppository of 75 mg with Witepsol as a base.[10]

Safety

Good clinical compliance was observed at the typical clinical oral dose of 150 mg/day, with no symptomatic side effect reported.[6] The adverse event rate was higher at high dose zinc L-carnosine (300 mg/day) without additional benefits, and therefore high dose is not recommended.[19] Side-effects are associated with the amount of zinc intake.[19]

According to the Japanese product monograph, safety in children below the age of 12, pregnant women and lactating women are not established (no experience in use); and the level of use in the elderly population is suggested and recommended at 100 mg zinc L-carnosine per day because of reduced digestive system function in the general elderly population; and those with poor liver functions should be under medical supervision.[20]

Those with copper deficiency should also be under medical supervision.[21] Although zinc L-carnosine caused an increase in serum zinc level, the serum copper level and copper:zinc ratio decreased, and a case of preexisting copper deficiency deteriorated.[8] As a mitigative, supplementation of 2 mg/day copper as glycinate chelate safely increases Cu-Zn superoxide dismutase activity.[22]

There is no evidence of a reduced tumor response to radiotherapy.[10]

See also

References

  1. ↑ "beta-Alanyl-L-histidinato zinc and bone resorption". General Pharmacology 26 (6): 1179–83. 1995. doi:10.1016/0306-3623(95)00008-o. PMID 7590105. "beta-Alanyl-L-histidinato zinc (AHZ), in which zinc is chelated to beta-alanyl-L-histidine, is a new zinc compound.". 
  2. ↑ "Antioxidant therapy in digestive diseases". Journal of Nutritional Science and Vitaminology 39 (Suppl): S35–41. 1993. doi:10.3177/jnsv.39.supplement_s35. PMID 8164065. "Zinc-carnosine (Z-103), N-(3-aminopropionyl)-L-histidinato zinc, is a chelate compound consisting of zinc ion and L-carnosine". 
  3. ↑ 3.0 3.1 3.2 "[Development of polaprezinc research]" (in ja). Yakugaku Zasshi 132 (3): 271–7. 2012. doi:10.1248/yakushi.132.271. PMID 22382829. "Polaprezinc (Promac(®), Zeria Pharmaceutical Co., Ltd.), a chelate compound consisting of zinc and L-carnosine, is a zinc-related medicine approved for the first time in Japan, which has been clinically used to treat gastric ulcers. Its mechanism of action is believed to oxygen radical scavenging, anti-oxidation, and acceleration of wound healing.". 
  4. ↑ 4.0 4.1 "Gastrointestinal defense mechanisms". Current Opinion in Gastroenterology 27 (6): 543–8. 2011. doi:10.1097/MOG.0b013e32834b3fcb. PMID 21897225. "The mucosal protective drug polaprezinc exhibits ROS-quenching activities.". 
  5. ↑ 5.0 5.1 "Novel therapeutic approaches to gastric and duodenal ulcers: an update". Expert Opinion on Investigational Drugs 9 (7): 1537–44. 2000. doi:10.1517/13543784.9.7.1537. PMID 11060758. "
    •Polaprezinc and nocloprost are also mucosal protective drugs, which are in clinical development.
    •Its mechanism of action is not totally known, but it has been shown to stimulate mucus production and to maintain the integrity of the gastric mucosal barrier [51].".     
  6. ↑ 6.0 6.1 6.2 6.3 6.4 6.5 6.6 6.7 6.8 "Applicability of zinc complex of L-carnosine for medical use". Biochemistry 65 (7): 817–23. 2000. PMID 10951100. http://protein.bio.msu.ru/biokhimiya/contents/v65/full/65070961.html. Retrieved 2016-06-20. 
  7. ↑ "Characterization of crystalline L-carnosine Zn(II) complex (Z-103), a novel anti-gastric ulcer agent: tautomeric change of imidazole moiety upon complexation". Chem Pharm Bull 38 (11): 3140–3146. November 1990. doi:10.1248/cpb.38.3140. PMID 2085900. 
  8. ↑ 8.0 8.1 8.2 8.3 "Oral treatment of pressure ulcers with polaprezinc (zinc L-carnosine complex): 8-week open-label trial". Biological Trace Element Research 158 (3): 280–8. 2014. doi:10.1007/s12011-014-9943-5. PMID 24691900. "
    •Patients with stage II-IV pressure ulcers for ≥ 8 weeks received 150 mg/day polaprezinc (containing 116 mg L-carnosine and 34 mg zinc) per os for a maximum of 8 weeks.
    •Serum zinc levels increased significantly (P < 0.001), whereas serum copper levels (P= 0.001) and copper/zinc ratios (P < 0.001) decreased significantly. In one patient, preexisting copper deficiency deteriorated.".     
  9. ↑ 9.0 9.1 "Antioxidant, Anti-inflammatory, and Genomic Stability Enhancement Effects of Zinc l-carnosine: A Potential Cancer Chemopreventive Agent?". Nutrition and Cancer 69 (2): 201–210. 2017. doi:10.1080/01635581.2017.1265132. PMID 28094570. "Zinc L-carnosine (ZnC), which is clinically used as gastric ulcer treatment in Japan, has been suggested to have the potential in preventing cancer development. Multiple studies have revealed that ZnC possesses potent antioxidant, antiinflammatory, and genomic stability enhancement effects.". 
  10. ↑ 10.00 10.01 10.02 10.03 10.04 10.05 10.06 10.07 10.08 10.09 10.10 "Utility of polaprezinc in reducing toxicities during radiotherapy: a literature review". Future Oncology (London, England) 14 (19): 1977–1988. August 2018. doi:10.2217/fon-2018-0021. PMID 30074413. 
  11. ↑ "Zeria Of Japan Obtains Korean Approval For Ulcer Drug Polaprezinc". https://pink.pharmaintelligence.informa.com/SC071745/Zeria-Of-Japan-Obtains-Korean-Approval-For-Ulcer-Drug-Polaprezinc.. 
  12. ↑ "Lonza Announces New Dietary Supplement Ingredient PepZin GI™". 18 September 2002. https://www.newhope.com/supply-news-amp-analysis/lonza-announces-new-dietary-supplement-ingredient-pepzin-gi. 
  13. ↑ "Therapeutic Goods (Permissible Ingredients) Determination (No.1) 2020 - Volume 5". Australian Government. https://www.legislation.gov.au/Details/F2020L00150/Html/Volume_5. 
  14. ↑ "Chemical Substance - Polaprezinc". Health Canada. 26 July 2004. http://webprod.hc-sc.gc.ca/nhpid-bdipsn/ingredReq.do?id=11575&lang=eng. 
  15. ↑ "The Role of HSP70 Heat Shock Proteins in the Pathogenesis and Treatment of Inflammatory Bowel Diseases". Advances in Clinical and Experimental Medicine 24 (3): 525–30. 2015. doi:10.17219/acem/44144. PMID 26467144. "
    •In experimental studies, overexpression of HSP70 was found to prevent the development of inflammatory process in the large intestinal mucosa provoked by various damaging factors.
    •There is also a potential for pharmacological stimulation of HSP70 expression, linked (for example) to geranylgeranylacetone, polaprezinc and mesalazine.".     
  16. ↑ "Role of nutritional zinc in the prevention of osteoporosis". Molecular and Cellular Biochemistry 338 (1–2): 241–54. 2010. doi:10.1007/s11010-009-0358-0. PMID 20035439. "beta-Alanyl-L: -histidinato zinc (AHZ) is a zinc compound, in which zinc is chelated to beta-alanyl-L: -histidine. The stimulatory effect of AHZ on bone formation is more intensive than that of zinc sulfate. Zinc acexamate has also been shown to have a potent-anabolic effect on bone. The oral administration of AHZ or zinc acexamate has the restorative effect on bone loss under various pathophysiologic conditions including aging, skeletal unloading, aluminum bone toxicity, calcium- and vitamin D-deficiency, adjuvant arthritis, estrogen deficiency, diabetes, and fracture healing.". 
  17. ↑ 17.0 17.1 "Effects of L-carnosine and its zinc complex (Polaprezinc) on pressure ulcer healing". Nutrition in Clinical Practice 28 (5): 609–16. 2013. doi:10.1177/0884533613493333. PMID 23835365. "Forty-two patients with stage II-IV pressure ulcers for 4 or more weeks were allocated to 1 of 3 groups in order of recruitment: the control group (n = 14) was untreated, the PLZ group (n = 10) orally received 150 mg/d PLZ (containing 116 mg CAR and 34 mg zinc), and the CAR group (n = 18) orally received 116 mg/d CAR.". 
  18. ↑ Institute of Medicine (US) Panel on Micronutrients (2001). Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc. ISBN 9780309072793. http://www.nap.edu/catalog.php?record_id=10026. Retrieved 2016-06-25. "A LOAEL of 60 mg/day was divided by a UF of 1.5 to derive a UL of 40 mg/day for total intake of zinc from food, water, and supplements." 
  19. ↑ 19.0 19.1 "Polaprezinc Combined With Clarithromycin-Based Triple Therapy for Helicobacter Pylori-Associated Gastritis: A Prospective, Multicenter, Randomized Clinical Trial". PLOS ONE 12 (4): e0175625. 2017. doi:10.1371/journal.pone.0175625. PMID 28407007. Bibcode: 2017PLoSO..1275625T. 
  20. ↑ "インタビューフォーム". Zeria Pharmaceutical Co., Ltd.. https://medical.zeria.co.jp/di/promac/. "Accessible only to health professionals. Text in Japanese." 
  21. ↑ "Pharmaceutical and Medical Devices Safety Information, No. 339, December 2016". PMDA, Government of Japan. https://www.pmda.go.jp/files/000215497.pdf. 
  22. ↑ "Opinion on certain bisglycinates as sources of copper, zinc, calcium, magnesium and glycinate nicotinate as source of chromium in foods intended for the general population (including food supplements) and foods for particular nutritional uses - Scientific Opinion of the Scientific Panel on Food Additives, Flavourings, Processing Aids and Materials in Contact with Food". EFSA Journal 6 (6): 718. 2008. doi:10.2903/j.efsa.2008.718. 



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