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Therapy for Unhealed Gastrocutaneous Fistulas in Rats as a Model for Analogous Healing of Persistent Skin Wounds and Persistent Gastric Ulcers: Stable Gastric Pentadecapeptide BPC 157, Atropine, Ranitidine, and Omeprazole

  • Sandra Skorjanec
  • Zdravko Dolovski
  • Ivan Kocman
  • Luka Brcic
  • Alenka Blagaic Boban
  • Lovorka Batelja
  • Marjana Coric
  • Marko Sever
  • Robert Klicek
  • Lidija Berkopic
  • Bozo Radic
  • Domagoj Drmic
  • Danijela Kolenc
  • Spomenko Ilic
  • Vedran Cesarec
  • Ante Tonkic
  • Ivan Zoricic
  • Stjepan Mise
  • Mario Staresinic
  • Mihovil Ivica
  • Martina Lovric Bencic
  • Tomislav Anic
  • Sven Seiwerth
  • Predrag SikiricEmail author
Original Paper

Abstract

Objective This study focused on unhealed gastrocutaneous fistulas to resolve whether standard drugs that promote healing of gastric ulcers may simultaneously have the same effect on cutaneous wounds, and corticosteroid aggravation, and to demonstrate why peptides such as BPC 157 exhibit a greater healing effect. Therefore, with the fistulas therapy, we challenge the wound/growth factors theory of the analogous nonhealing of wounds and persistent gastric ulcers. Methods The healing rate of gastrocutaneous fistula in rat (2-mm-diameter stomach defect, 3-mm-diameter skin defect) validates macro/microscopically and biomechanically a direct skin wound/stomach ulcer relation, and identifies a potential therapy consisting of: (i) stable gastric pentadecapeptide BPC 157 [in drinking water (10 μg/kg) (12 ml/rat/day) or intraperitoneally (10 μg/kg, 10 ng/kg, 10 pg/kg)], (ii) atropine (10 mg/kg), ranitidine (50 mg/kg), and omeprazole (50 mg/kg), (iii) 6-alpha-methylprednisolone (1 mg/kg) [intraperitoneally, once daily, first application at 30 min following surgery; last 24 h before sacrifice (at postoperative days 1, 2, 3, 7, 14, and 21)]. Results Greater anti-ulcer potential and efficiency in wound healing compared with standard agents favor BPC 157, efficient in inflammatory bowel disease (PL-14736, Pliva), given in drinking water or intraperitoneally. Even after 6-alpha-methylprednisolone aggravation, BPC 157 promptly improves both skin and stomach mucosa healing, and closure of fistulas, with no leakage after up to 20 ml water intragastrically. Standard anti-ulcer agents, after a delay, improve firstly skin healing and then stomach mucosal healing, but not fistula leaking and bursting strength (except for atropine). Conclusion We conclude that BPC 157 may resolve analogous nonhealing of wounds and persistent gastric ulcers better than standard agents.

Keywords

Unhealed gastrocutaneous fistulas Stable gastric pentadecapeptide BPC 157 Atropine Ranitidine Omeprazole Analogous healing Persistent skin ulcer Persistent gastric ulcer Rat 

References

  1. 1.
    Papavramidis ST, Eleftheriadis EE, Papavramidis TS, Kotzampassi KE, Gamvros OG (2004) Endoscopic management of gastrocutaneous fistula after bariatric surgery by using a fibrin sealant. Gastrointest Endosc 59:296–300PubMedCrossRefGoogle Scholar
  2. 2.
    Deruyter L, Van Blerk M, Cadière GB, De Graef J, Willems G (1991) Treatment of high-output gastric fistulas with omeprazole. Hepatogastroenterology 38(Suppl 1):83–86PubMedGoogle Scholar
  3. 3.
    Paran H, Neufeld D, Kaplan O, Klausner J, Freund U (1995) Octreotide for treatment of postoperative alimentary tract fistulas. World J Surg 19:430–433PubMedCrossRefGoogle Scholar
  4. 4.
    di Costanzo J, Cano N, Martin J, Richieri JP, Mercier R, Lafille C, Lepeuch D (1987) Treatment of external gastrointestinal fistulas by a combination of total parenteral nutrition and somatostatin. J Parenter Enteral Nutr 11:465–470CrossRefGoogle Scholar
  5. 5.
    Misiewicz JJ (1985) Future trends in the management of peptic ulcer disease. Scand J Gastroenterol Suppl 146:175–184Google Scholar
  6. 6.
    Szabo S, Vincze A (2000) Growth factors in ulcer healing: lessons from recent studies. J Physiol (Paris) 94:77–81CrossRefGoogle Scholar
  7. 7.
    Christensen S, Riis A, Nørgaard M, Thomsen RW, Tønnesen EM, Larsson A, Sørensen HT (2006) Perforated peptic ulcer: use of pre-admission oral glucocorticoids and 30-day mortality. Aliment Pharmacol Ther 23:45–52PubMedCrossRefGoogle Scholar
  8. 8.
    Sikiric P, Petek M, Rucman R, Seiwerth S, Grabarevic Z, Rotkvic I et al (1993) A new gastric peptide BPC. An overview of stomach-organoprotection hypothesis and beneficial effect of BPC. J Physiol (Paris) 87:313–327CrossRefGoogle Scholar
  9. 9.
    Sikiric P, Seiwerth S, Brcic L, Blagaic AB, Zoricic I, Sever M, Klicek R, Radic B, Keller N, Sipos K, Jakir A, Udovicic M, Tonkic A, Kokic N, Turkovic B, Mise S, Anic T (2006) Stable gastric pentadecapeptide BPC 157 in trials for inflammatory bowel disease (PL-10, PLD-116, PL 14736, Pliva, Croatia). Full and distended stomach, and vascular response. Inflammopharmacology 14:214–221PubMedCrossRefGoogle Scholar
  10. 10.
    Wood JD (2004) The first Nobel prize for integrated systems physiology: Ivan Petrovich Pavlov, 1904. Physiology 19:326–330PubMedCrossRefGoogle Scholar
  11. 11.
    Sikiric P, Seiwerth S, Grabarevic Z, Petek M, Rucman R, Turkovic B et al (1994) The beneficial effect of BPC 157, a 15 amino acid peptide BPC fragment, on gastric and duodenal lesion induced by restraint stress, cysteamine and 96% ethanol in rats. A comparative study with H2 receptor antagonists, dopamine promoters and gut peptides. Life Sci 54:PL63–PL68Google Scholar
  12. 12.
    Sikiric P, Seiwerth S, Grabarevic Z, Rucman R, Petek M, Jagic V et al (1996) Beneficial effect of novel pentadecapeptide BPC 157 on gastric lesions induced by restraint stress, ethanol, indomethacin, and capsaicin neurotoxicity. Dig Dis Sci 41:1604–1614PubMedCrossRefGoogle Scholar
  13. 13.
    Sikiric P, Seiwerth S, Grabarevic Z, Rucman R, Petek M, Jagic V et al (1997) The influence of a novel pentadecapeptide BPC 157 on NG-nitro-L-arginine methylester and L-arginine effect on stomach mucosal integrity and blood pressure. Eur J Pharmacol 332:23–33PubMedCrossRefGoogle Scholar
  14. 14.
    Sikiric P, Mikus D, Seiwerth S, Grabarevic Z, Rucman R, Petek M et al (1997) Pentadecapeptide BPC 157, cimetidine, ranitidine, bromocriptine, and atropine effect in cysteamine lesions in totally gastrectromized rats: a model for cytoprotective studies. Dig Dis Sci 42:1029–1037PubMedCrossRefGoogle Scholar
  15. 15.
    Bedekovic V, Mise S, Anic T, Staresinic M, Gjurasin M, Kopljar M et al (2003) Different effect of antiulcer agents on rat cysteamine-induced duodenal ulcer after sialoadenectomy, but not gastrectomy. Eur J Pharmacol 477:73–80PubMedCrossRefGoogle Scholar
  16. 16.
    Xue XC, Wu YJ, Gao MT, Li WG, Zhao N, Wang ZL, Bao CJ, Yan Z, Zhang YO (2004) Protective effects of pentadecapeptide BPC 157 on gastric ulcer in rats. World J Gastroenterol 10:1032–1036PubMedGoogle Scholar
  17. 17.
    Sandor Z, Deng XM, Khomenko T, Tarnawski AS, Szabo S (2006) Altered angiogenic balance in ulcerative colitis: a key to impaired healing? Biochem Biophys Res Commun 350:147–150PubMedCrossRefGoogle Scholar
  18. 18.
    Veljaca M, Chan K, Guglietta A (1995) Digestion of h-EGF, h-TGF alpha and BPC-15 in human gastric juice. Gastroenterology 108:761CrossRefGoogle Scholar
  19. 19.
    Ruenzi M, Stolte M, Veljaca M, Oreskovic K, Peterson J, Ulcerative Colitis Study Group (2005) A multicenter, randomized, double blind, placebo-controlled phase II study of PL 14736 enema in the treatment of mild-to-moderate ulcerative colitis. Gastroenterology 128:A584Google Scholar
  20. 20.
    Veljaca M, Krnic Z, Brajsa K, Mildner B, Pavic-Saladojev D, Seveljevic-Jaran D et al (2002) The development of PL 14736 for treatment of inflammatory bowel disease. IUPHAR-GI section symposium, Honolulu, Hawaii, 2002, 13–15 July, O–32.Google Scholar
  21. 21.
    Veljaca M, Pavic Sladoljev D, Mildner B, Brajsa K, Bubenik M, Stipanicic S et al (2003) Safety, tolerability and pharmacokinetics of PL 14736, a novel agent for treatment of ulcerative colitis, in healthy male volunteers. Gut 51(Suppl III):A309Google Scholar
  22. 22.
    Mikus D, Sikiric P, Seiwerth S, Petricevic A, Aralica G, Druzijanic N et al (2001) Pentadecapeptide BPC 157 cream improves burn-wound healing and attenuates burn-gastric lesions in mice. Burns 127:817–827CrossRefGoogle Scholar
  23. 23.
    Sikiric P, Seiwerth S, Mise S, Staresinic M, Bedekovic V, Zarkovic N et al (2003) Corticosteroids-impairment healing and gastric pentadecapeptide BPC 157 creams in burned mice. Burns 29:323–334PubMedGoogle Scholar
  24. 24.
    Seiwerth S, Sikiric P, Grabarevic Z, Zoricic I, Hanzevacki M, Ljubanovic D et al (1997) BPC 157’s effect on healing. J Physiol (Paris) 91:173–178CrossRefGoogle Scholar
  25. 25.
    Seveljevic Jaran D, Cuzic S, Dominis Kramaric M, Glojnaric I, Ivetic V, Radosevic S et al (2006) Accelerated healing of excisional skin wound by PL 14736 in alloxan-hyperglycemic rats. Skin Pharmacol Physiol 19:266–274PubMedCrossRefGoogle Scholar
  26. 26.
    Xue XC, Wu YJ, Gao MT (2004) Study of the protective effects of pentadecapeptide BPC 157 on wounds in small type pigs. Chin New Drugs J 12:602–604Google Scholar
  27. 27.
    Ivetic Tkalcevic I, Cuzic S, Brajsa K, Mildner B, Bokulic A, Situm K et al (2007) Enhancement by PL 14736 of granulation and collagen organization in healing wounds and the potential role of egr-1 expression. Eur J Pharmacol 570:212–221CrossRefGoogle Scholar
  28. 28.
    Sebecic B, Nikolic V, Sikiric P, Seiwerth S, Sosa T, Patrlj L et al (1999) Osteogenic effect of a gastric pentadecapeptide, BPC-157, on the healing of segmental bone defect in rabbits: a comparison with bone marrow and autologous cortical bone implantation. Bone 24:195–202PubMedCrossRefGoogle Scholar
  29. 29.
    Rao KS, Patil PA, Malur PR (2007) Promotion of cutaneous wound healing by famotidine in Wistar rats. Indian J Med Res 125:149–154PubMedGoogle Scholar
  30. 30.
    Räntfors J, Cassuto J (2003) Role of histamine receptors in the regulation of edema and circulation postburn. Burns 29:769–777PubMedCrossRefGoogle Scholar
  31. 31.
    Numata Y, Terui T, Okuyama R, Hirasawa N, Sugiura Y, Miyoshi I et al (2006) The accelerating effect of histamine on the cutaneous wound-healing process through the action of basic fibroblast growth factor. J Invest Dermatol 126:1403–1409PubMedCrossRefGoogle Scholar
  32. 32.
    Yang YX, Lewis JD, Epstein S, Metz DC (2006) Long-term proton pump inhibitor therapy and risk of hip fracture. JAMA 296:2947–2953PubMedCrossRefGoogle Scholar
  33. 33.
    Frank S, Madlener M, Pfeilschifter J, Werner S (1998) Induction of inducible nitric oxide synthase and its corresponding tetrahydrobiopterin-cofactor-synthesizing enzyme GTP-cyclohydrolase I during cutaneous wound repair. J Invest Dermatol 111:1058–1064PubMedCrossRefGoogle Scholar
  34. 34.
    Eubanks TR, Greenberg JJ, Dobrin PB, Harford FJ, Gamelli RL (1997) The effects of different corticosteroids on the healing colon anastomosis and cecum in a rat model. Am Surg 63:266–269PubMedGoogle Scholar
  35. 35.
    Golan J, Mitelman S, Baruchin A, Ben-Hur N (1980) Vitamin A and corticosteroid interaction in wound healing in rats. Isr J Med Sci 16:572–575PubMedGoogle Scholar
  36. 36.
    Filaretova L, Podvigina T, Bagaeva T, Bobryshev P, Takeuchi K (2007) Gastroprotective role of glucocorticoid hormones. J Pharmacol Sci 104:195–201PubMedCrossRefGoogle Scholar
  37. 37.
    Sikiric P, Separovic J, Anic T, Buljat G, Mikus D, Seiwerth S et al (1999) The effect of pentadecapeptide BPC 157, H2 blockers and sucralfate on new vessels and new granulation tissue formation. J Physiol (Paris) 93:479–485CrossRefGoogle Scholar
  38. 38.
    Szabo S (1986) Experimental basis for a role for sulfhydryls and dopamine in ulcerogenesis: a primer for cytoprotection–organoprotection. Klin Wochenschr 64:116–122PubMedGoogle Scholar
  39. 39.
    Torres-García AJ, Argüello JM, Balibrea JL (1994) Gastrointestinal fistulas: pathology and prognosis. Scand J Gastroenterol 207(Suppl):39–41CrossRefGoogle Scholar
  40. 40.
    Krivic A, Anic T, Seiwerth S, Huljev D, Sikiric P (2006) Achilles detachment in rat and stable gastric pentadecapeptide BPC 157: promoted tendon to bone healing and opposed corticosteroid aggravation. J Orthopaed Res 24:982–989CrossRefGoogle Scholar
  41. 41.
    Staresinic M, Sebecic B, Jadrijevic S, Suknaic S, Perovic D, Aralica G et al (2003) Gastric pentadecapeptide BPC 157 accelerates healing of transected rat Achilles tendon and in vitro stimulates tendocytes growth. J Orthopaed Res 21:976–983CrossRefGoogle Scholar
  42. 42.
    Gjurasin M, Miklic P, Buljat G, Perovic D, Jukic I, Sikiric P et al (2003) Selective healing effect of the gastric pentadecapeptide BPC 157 on injured part of the nerve in subtotal sciatic nerve transection. Dig Dis Sci 48:1878Google Scholar
  43. 43.
    Staresinic M, Petrovic I, Novinscak T, Jukic I, Pevec D, Suknaic S et al (2006) Effective therapy of transected quadriceps muscle in rat: gastric pentadecapeptide BPC 157. J Orthopaed Res 24:1109–1117CrossRefGoogle Scholar
  44. 44.
    Lazic R, Gabric N, Dekaris I, Bosnar D, Boban-Blagaic A, Sikiric P (2005) Gastric pentadecapeptide BPC 157 promotes corneal epithelial defects healing in rats. Coll Antropol 29:321–325PubMedGoogle Scholar
  45. 45.
    Kalogjera L, Ries M, Baudoin T, Ferencic Z, Trotic R, Pegan B (1997) Dose-dependent protective effect of BPC 157 on capsaicin-induced rhinitis in rats. Eur Arch Otorhinolaryngol 254(Suppl 1):S9–S11PubMedCrossRefGoogle Scholar
  46. 46.
    Grabarevic Z, Tisljar M, Artukovic B, Bratulic M, Dzaja P, Seiwerth S et al (1997) The influence of BPC 157 on nitric oxide agonist and antagonist induced lesions in broiler chicks. J Physiol (Paris) 91:139–149CrossRefGoogle Scholar
  47. 47.
    Turkovic B, Sikiric P, Seiwerth S, Mise S, Anic T, Petek M et al (2004) Stable gastric pentadecapeptide BPC 157 studied for inflammatory bowel disease (PLD-116, PL14736, Pliva) induces nitric oxide synthesis. Gastroenterology 126:287Google Scholar
  48. 48.
    Lovric-Bencic M, Sikiric P, Separovic J, Seiwerth S, Rogic D, Kusec V et al (2004) Doxorubicine congestive heart failure-increased big-endothelin 1 plasma concentration. Reversal by amlodipine, losartan and gastric pentadecapeptide BPC 157 in rat and mouse. J Pharmacol Sci 95:19–26PubMedCrossRefGoogle Scholar
  49. 49.
    Petrovic I, Dobric I, Drvis P, Shejbal D, Brcic L, Boban Blagaic A et al (2006) An experimental model of prolonged esophagitis with sphincter failure in rat and therapeutic potential of gastric pentadecapeptide BPC 157. J Pharmacol Sci 102:269–277PubMedCrossRefGoogle Scholar
  50. 50.
    Dobric I, Drvis P, Petrovic I, Shejbal D, Brcic L, Boban Blagaic A et al (2007) Prolonged esophagitis after primary dysfunction of the pyloric sphincter in the rat and therapeutic potential of the gastric pentadecapeptide BPC 157. J Pharm Sci 104:7–18CrossRefGoogle Scholar
  51. 51.
    Pawlik WW, Sikiric P, Brzozowski T, Seiwerth S, Drozdowicz D, Pajdo R, Pawlik M, Konturek SJ (2004) Acceleration of ulcer healing by pentadecapeptide BPC 157 in rats. Involvement of endogenous prostaglandins and gastric secretion. Gastroenterology 126:541CrossRefGoogle Scholar
  52. 52.
    Robert A (1979) Cytoprotection by prostaglandins. Gastroenterology 77:761–767PubMedGoogle Scholar
  53. 53.
    Okabe S, Amagase K (2005) An overview of acetic acid ulcer models–the history and state of the art of peptic ulcer research. Biol Pharm Bull 28:1321–1341PubMedCrossRefGoogle Scholar
  54. 54.
    Selye H, Szabo S (1973) Experimental model for production of perforating duodenal ulcers by cysteamine in the rat. Nature 244:458–459PubMedCrossRefGoogle Scholar
  55. 55.
    Suzuki T, Tsukamoto Y, Goto H, Hase S, Arisawa T, Asai J (1992) Effects of histamine H2-receptor antagonists and a proton pump inhibitor on the mucosal hydroxyproline content of ethanol-HCl-induced gastric lesions in rats. Digestion 51:161–167PubMedGoogle Scholar
  56. 56.
    Houck JC (1964) Connective tissue. X. Dermal chemical response to atropine. Proc Soc Exp Biol Med 115:725–728PubMedGoogle Scholar
  57. 57.
    Arisawa T, Harata M, Kamiya Y, Shibata T, Nagasaka M, Nakamura M, Fujita H, Hasegawa S, Nakamura M, Mizuno T, Tahara T, Ohta Y, Nakano H (2006) Is omeprazole or misoprostol superior for improving indomethacin-induced delayed maturation of granulation tissue in rat gastric ulcers? Digestion 73:32–39PubMedCrossRefGoogle Scholar
  58. 58.
    Park PO, Alumets J, Arvidsson S, Grimelius L, Haglund U (1990) The influence of a histamine2-receptor antagonist on the healing of an experimentally induced gastric mucosal lesion. APMIS 98:305–312PubMedCrossRefGoogle Scholar
  59. 59.
    Bairy KL, Rao CM, Ramesh KV, Kulkarni DR (1991) Effects of antihistamines on wound healing. Indian J Exp Biol 29:398–399PubMedGoogle Scholar
  60. 60.
    Karádi O, Nagy Z, Bódis B, Mózsik G (2001) Atropine-induced gastrointestinal cytoprotection dependences to the intact of vagal nerve against indomethacin-induced gastrointestinal mucosal and microvascular damage in rats. J Physiol (Paris) 95:29–33CrossRefGoogle Scholar
  61. 61.
    Clissold SP, Campoli-Richards DM (1986) Omeprazole. An updated review. Drugs 32:15–47PubMedCrossRefGoogle Scholar
  62. 62.
    Veljaca M, Lesch CA, Sanchez B, Low J, Guglietta A (1995) Protection of BPC-15 on TNBS-induced colitis in rats: possible mechanisms of action. Gastroenterology 108:936Google Scholar
  63. 63.
    Veljaca M, Lesch CA, Pllana R, Sanchez B, Chan K, Guglietta A (1994) BPC-15 reduces trinitrobenzene sulfonic acid-induced colonic damage in rats. J Pharmacol Exp Ther 272:417–422Google Scholar
  64. 64.
    Gelbmann CM, Rogler G, Gross V, Gierend M, Bregenzer N, Andus T et al (2002) Prior bowel resections, perianal disease, and a high initial Crohn’s disease activity index are associated with corticosteroid resistance in active Crohn’s disease. Am J Gastroenterol 97:1438–1444PubMedCrossRefGoogle Scholar
  65. 65.
    Lamarque D, Whittle BJ (2001) Increase in gastric intramucosal hydrogen ion concentration following endotoxin challenge in the rat and the actions of nitric oxide synthase inhibitors. Clin Exp Pharmacol Physiol 28:164–168PubMedCrossRefGoogle Scholar
  66. 66.
    Bayir Y, Odabasoglu F, Cakir A, Aslan A, Suleyman H, Halici M et al (2006) The inhibition of gastric mucosal lesion, oxidative stress and neutrophil-infiltration in rats by the lichen constituent diffractaic acid. Phytomedicine 13:584–590PubMedCrossRefGoogle Scholar
  67. 67.
    Murakami I, Satoh H, Asano S, Maeda R (1996) Role of capsaicin-sensitive sensory neurons and nitric oxide in the protective effect of lansoprazole, a proton pump inhibitor, on the gastric mucosa in rats. Jpn J Pharmacol 72:137–147PubMedCrossRefGoogle Scholar
  68. 68.
    Whittle BJR, Boughton-Smith NK, Moncada S (1992) Biosynthesis and role of the endothelium-derived vasodilator, nitric oxide in gastric mucosa. Ann NY Acad Sci 664:126–139PubMedCrossRefGoogle Scholar
  69. 69.
    Tabrizi MN, Chams-Davatchi C, Esmaeeli N, Noormohammadpoor P, Safar F, Etemadzadeh H et al (2007) Accelerating effects of epidermal growth factor on skin lesions of pemphigus vulgaris: a double-blind, randomized, controlled trial. J Eur Acad Dermatol Venereol 21:79–84PubMedCrossRefGoogle Scholar
  70. 70.
    Obara K, Ishihara M, Fujita M, Kanatani Y, Hattori H, Matsui T et al (2005) Acceleration of wound healing in healing-impaired db/db mice with a photocrosslinkable chitosan hydrogel containing fibroblast growth factor-2. Wound Repair Regen 13:390–397PubMedCrossRefGoogle Scholar
  71. 71.
    Cheng B, Liu HW, Fu XB, Sun TZ, Sheng ZY (2007) Recombinant human platelet-derived growth factor enhanced dermal wound healing by a pathway involving ERK and c-fos in diabetic rats. J Dermatol Sci 45:193–201PubMedCrossRefGoogle Scholar
  72. 72.
    Urist MR (1996) The first three decades of bone morphogenetic protein. Osteologie 4:207–233Google Scholar
  73. 73.
    Mustoe TA, Pierce GF, Thomason A, Gramates P, Sporn MB, Duel TF (1987) Accelarated healing of incisional wounds in rats induced by transforming growth factor-β. Science 237:1333–1336PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • Sandra Skorjanec
    • 1
  • Zdravko Dolovski
    • 1
  • Ivan Kocman
    • 1
  • Luka Brcic
    • 2
  • Alenka Blagaic Boban
    • 1
  • Lovorka Batelja
    • 2
  • Marjana Coric
    • 2
  • Marko Sever
    • 1
  • Robert Klicek
    • 1
  • Lidija Berkopic
    • 1
  • Bozo Radic
    • 1
  • Domagoj Drmic
    • 1
  • Danijela Kolenc
    • 1
  • Spomenko Ilic
    • 1
  • Vedran Cesarec
    • 1
  • Ante Tonkic
    • 1
  • Ivan Zoricic
    • 1
  • Stjepan Mise
    • 1
  • Mario Staresinic
    • 1
  • Mihovil Ivica
    • 1
  • Martina Lovric Bencic
    • 1
  • Tomislav Anic
    • 1
  • Sven Seiwerth
    • 2
  • Predrag Sikiric
    • 1
    Email author
  1. 1.Department of Pharmacology, Medical SchoolUniversity of ZagrebZagrebCroatia
  2. 2.Institute of Pathology, Medical SchoolUniversity of ZagrebZagrebCroatia

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