Zinc L-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. It is a quadridentate 1:1 complex of a polymeric nature.[6] It contains 23% zinc and 77% L-carnosine by mass.[7]

It is an approved drug in Japan where it is clinically used to treat gastric ulcers.[3][8] Clinical studies have also shown its efficacy for oral mucositis, esophagitis, proctitis, taste alteration and dermatitis during and after radiotherapy.[9]

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.[9] It does so without affecting the secretion of gastric acid.[9] 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.[10] It decreases p53, p21 and Bax expression and apoptosis in the intestine after irradiation.[9] It possesses antioxidant, anti-inflammatory, and genomic stability enhancement effects, thereby having potential in preventing gastrointestinal cancer development.[8]

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] Note that D-carnosine 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.[9]

Other

It has a stimulatory effect on bone formation and a restorative effect on bone loss under various pathophysiologic conditions.[11]

Usage

Zinc L-carnosine has been used orally[7][12] or as an oral rinse, lozenge or suppository.[9] The typical clinical oral dose is 150 mg/day, containing 34 mg zinc and 116 mg L-carnosine.[7][12]

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.[9] A solution of 5% sodium alginate has been used.[9] Alternatively, it has been used as a lozenge containing 18.75 mg, four times a day.[9] It has also been used as a suppository of 75 mg with Witepsol as a base.[9]

Safety

Good clinical compliance was observed at the typical clinical oral dose of 150 mg/day, with no symptomatic side effect reported.[6] 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.[7] As a mitigative, supplementation of 2 mg/day copper as glycinate chelate safely increases Cu-Zn superoxide dismutase activity.[13]

Note that the Tolerable Upper Intake Level (UL) for total zinc intake from all sources in adults is 40 mg/day.[14]

As of 2018, there is no evidence of a reduced tumor response to radiotherapy.[9]

See also

References

  1. ↑ Yamaguchi M (1995). "beta-Alanyl-L-histidinato zinc and bone resorption". General Pharmacology. 26 (6): 1179–83. doi:10.1016/0306-3623(95)00008-o. PMID 7590105. Retrieved 2016-06-25. beta-Alanyl-L-histidinato zinc (AHZ), in which zinc is chelated to beta-alanyl-L-histidine, is a new zinc compound.
  2. ↑ Yoshikawa T, Naito Y, Kondo M (1993). "Antioxidant therapy in digestive diseases". Journal of Nutritional Science and Vitaminology. 39 Suppl: S35–41. doi:10.3177/jnsv.39.supplement_s35. PMID 8164065. Retrieved 2016-06-25. Zinc-carnosine (Z-103), N-(3-aminopropionyl)-L-histidinato zinc, is a chelate compound consisting of zinc ion and L-carnosine
  3. 1 2 3 Takei M (2012). "[Development of polaprezinc research]". Yakugaku Zasshi (in Japanese). 132 (3): 271–7. doi:10.1248/yakushi.132.271. PMID 22382829. Retrieved 2016-06-20. 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. 1 2 Palileo C, Kaunitz JD (2011). "Gastrointestinal defense mechanisms". Current Opinion in Gastroenterology. 27 (6): 543–8. doi:10.1097/MOG.0b013e32834b3fcb. PMID 21897225. Retrieved 2016-06-20. The mucosal protective drug polaprezinc exhibits ROS-quenching activities.
  5. 1 2 Dajani EZ, Klamut MJ (2000). "Novel therapeutic approaches to gastric and duodenal ulcers: an update". Expert Opinion on Investigational Drugs. 9 (7): 1537–44. doi:10.1517/13543784.9.7.1537. PMID 11060758. Retrieved 2016-06-20.
    •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. 1 2 3 4 5 6 7 8 Matsukura T, Tanaka H (2000). "Applicability of zinc complex of L-carnosine for medical use". Biochemistry. 65 (7): 817–23. PMID 10951100. Retrieved 2016-06-20.
    •Zinc ion coordinates with L-carnosine to form a quadridentate 1:1 complex of polymeric nature in order to maintain low strain of chelate rings. L-CAZ can remain in stomach juice without rapid dissociation and adhere to ulcerous lesion specifically, after which L-carnosine and zinc are released to heal the ulcer. L-CAZ exhibited high efficacy in clinical use without any serious side effect. L-CAZ exhibited an inhibitory effect on Helicobacter pylori.
    •Table 2 shows the healing efficacy of L-CAZ along with those of other zinc complexes against water-immersion stress ulceration in rats. The inhibitory effect was greater than that of cimetidine, which is renowned as an anti gastric ulcer drug all over the world. We have also investigated other metal salts (K, Na, Ca, Mg) of L-carnosine, but no significant effect was observed with those salts or with free L-carnosine. The comparison of the inhibitory effect of L-CAZ, D-CAZ, and cetraxate hydrochloride, which is an approved cytoprotective anti gastric ulcer drug in Japan was also investigated (Table 3). L-CAZ dose-dependently inhibited the formation of gastric ulcers, and the pharmacological activity 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. Interestingly, D-carnosine with zinc did not show significant anti-ulcer effect, suggesting that non-natural carnosine is not capable of acting as a carrier for the transportation of zinc.
    •A simple mixture of L-carnosine and zinc presented less anti-ulceration effect, especially on free-radical induced lesions [8], presumably due to rapid diffusion of L-carnosine and zinc ion in the whole stomach.
    •From these results, it was concluded that L-CAZ maintains homeostasis of the gastric mucosa by prostaglandin-independent cytoprotective effects due to anti-oxidative membrane stabilizing actions and promotes the repair of damaged tissues by wound healing action.
    •Excellent improvement with good compliance was proved in numerous clinical studies by the use of L-CAZ at 150 mg per day administration.
    •No symptomatic side effect was reported in 691 cases of clinical trials, indicating the toxicity of L-CAZ should be very low.
  7. 1 2 3 4 Sakae K, Yanagisawa H (2014). "Oral treatment of pressure ulcers with polaprezinc (zinc L-carnosine complex): 8-week open-label trial". Biological Trace Element Research. 158 (3): 280–8. doi:10.1007/s12011-014-9943-5. PMID 24691900. Retrieved 2016-06-25.
    •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.
  8. 1 2 Ooi TC, Chan KM, Sharif R (2017). "Antioxidant, Anti-inflammatory, and Genomic Stability Enhancement Effects of Zinc l-carnosine: A Potential Cancer Chemopreventive Agent?". Nutrition and Cancer. 69 (2): 201–210. doi:10.1080/01635581.2017.1265132. PMID 28094570. Retrieved 2017-02-26. 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.
  9. 1 2 3 4 5 6 7 8 9 10 11 Doi H, Kuribayashi K, Kijima T (August 2018). "Utility of polaprezinc in reducing toxicities during radiotherapy: a literature review". Future Oncology (London, England). doi:10.2217/fon-2018-0021. PMID 30074413.
    •An aliquot of the PZ oral rinse was used four-times a day without swallowing, to a total amount of PZ at 150 mg/day.
    •PZ (75 mg) was briefly suspended in 20 ml of 5% sodium alginate solution. A 5 ml portion of the suspension was orally rinsed and then swallowed four-times a day.
    •Hayashi et al. also showed PZ for mucositis in a lozenge form, wherein one lozenge containing 18.75 mg PZ was sucked and swallowed four-times a day.
    •They used a mixture of 60 ml sodium alginate solution and 150 mg PZ, which was administered orally in three divided doses per day before every meal during radiotherapy.
    •Moreover, Doi et al. have clinically developed a PZ suppository containing 75 mg PZ per suppository with Witepsol as a base, and administered the drug rectally in five patients with late radiation proctitis.
    •Matsuu-Matsuyama et al. reported that PZ decreased the p53, p21 and Bax expression in the intestine after irradiation
    •Reduction of apoptosis, protection of intestinal stem cells and acute inflammation following irradiation in the normal intestine have also been reported after PZ administration.
    •PZ exerts a direct cytoprotective action through regulating heat shock proteins and chemokines and stabilizing mast cells in different pathological states, without affecting the secretion of gastric acid. Particularly, PZ scavenges free radicals [12–14] . It has been reported that PZ suppresses mast cells from damaged mucosa.
    •Preclinical and clinical studies have shown the efficacy of PZ for oral mucositis, esophagitis, proctitis, taste alteration and dermatitis during and after radiotherapy, and preclinical data exist to support clinical data.
    •There are no preclinical and clinical data that directly compare between using zinc alone and using PZ in normal tissues after radiation exposure; however, preclinical data on chemical-induced mucositis indicate the superiority of PZ than zinc sulfide in terms of antioxidant effects.
    •To our knowledge, there is no current evidence that PZ use was associated with reduced tumor response to radiotherapy.
  10. ↑ Samborski P, Grzymisławski M (2015). "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. 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.
  11. ↑ Yamaguchi M (2010). "Role of nutritional zinc in the prevention of osteoporosis". Molecular and Cellular Biochemistry. 338 (1–2): 241–54. doi:10.1007/s11010-009-0358-0. PMID 20035439. Retrieved 2016-06-25. 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.
  12. 1 2 Sakae K, Agata T, Kamide R, Yanagisawa H (2013). "Effects of L-carnosine and its zinc complex (Polaprezinc) on pressure ulcer healing". Nutrition in Clinical Practice. 28 (5): 609–16. doi:10.1177/0884533613493333. PMID 23835365. Retrieved 2016-06-25. 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.
  13. ↑ F. Aguilar, H. Autrup, S. Barlow, L. Castle, R. Crebelli, W. Dekant, K.-H. Engel, N. Gontard, D. Gott, S. Grilli, R. Gürtler, J.-C. Larsen, C. Leclercq, J.-C. Leblanc, F. X. Malcata, W. Mennes, M.-R. Milana, I. Pratt, I. Rietjens, P. Tobback, F. Toldrá (2008). "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". European Food Safety Authority. doi:10.2903/j.efsa.2008.718. Retrieved 2017-12-31.
    •Participants were then given 2 mg of copper amino acid chelate per day for 4 weeks. After the treatment an analysis of Cu-Zn SOD activity was carried out in the blood.
    •The results showed that the copper amino acid chelate supplementation increased erythrocyte Cu-Zn SOD activity in 18 of 23 rheumatoid arthritis patients. The average increase was 21%, showing that the copper chelate was absorbed and was effective in increasing erythrocyte Cu-Zn SOD activity in the majority of rheumatoid arthritis patients (DiSilvestro et al., 1992).
    •The Panel concludes that the use of copper bisglycinate chelate as a source for copper added for nutritional purposes to food supplements, and of calcium bisglycinate chelate and magnesium bisglycinate chelate as sources for respectively calcium and magnesium added for nutritional purposes to foods for particular nutritional uses and food supplements, and of zinc bisglycinate chelate when used as a source for zinc in foods intended for the general population (including food supplements) and foods for particular nutritional uses, is not of safety concern.
  14. ↑ 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". PMID 25057538. 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.
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