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Surgery Today

, Volume 37, Issue 9, pp 768–777 | Cite as

Stable Gastric Pentadecapeptide BPC 157 in Trials for Inflammatory Bowel Disease (PL-10, PLD-116, PL14736, Pliva, Croatia) Heals Ileoileal Anastomosis in the Rat

  • Tihomir Vuksic
  • Ivan Zoricic
  • Luka Brcic
  • Marko Sever
  • Robert Klicek
  • Bozo Radic
  • Vedran Cesarec
  • Lidija Berkopic
  • Neike Keller
  • Alenka Boban Blagaic
  • Neven Kokic
  • Ivan Jelic
  • Juraj Geber
  • Tomislav Anic
  • Sven Seiwerth
  • Predrag Sikiric
Original Article

Abstract

Purpose

Gastric pentadecapeptide BPC 157 (BPC 157), which has been shown to be safe in clinical trials for inflammatory bowel disease (PL-10, PLD-116, PL14736, Pliva, Croatia), may be able to cure intestinal anastomosis dehiscence. This antiulcer peptide shows no toxicity, is limit test negative, and a lethal dose is not achieved. It is stable in human gastric juice. In comparison with other standard treatments it is more effective for ulcers and various wounds, and can be used without a carrier needed for other peptides, both locally and systemically (i.e., perorally, parenterally). We studied the effectiveness of BPC 157 for ileoileal anastomosis healing in rats.

Methods

We assessed ileoileal anastomosis dehiscence macroscopically, histologically, and biomechanically (volume [ml] infused through a syringe-perfusion pump system (1 ml/10 s), and pressure [mmHg] to leak induction [catheter connected to a chamber and a monitor, at 10 cm proximal to anastomosis]), at 1, 2, 3, 4, 5, 6, 7, and 14 days. BPC 157 (10 µg, 10 ng, 10 pg/kg i.p. (or saline [5 ml/kg]) was first administered after surgery, while it was last given 24 h before either assessment or sacrifice.

Results

Throughout the experiment, both higher doses of BPC 157 were shown to improve all parameters of anastomotic wound healing. The formation of adhesions remained slight, the blood vessels were filled with blood, and a mild intestinal passage obstruction was only temporarily observed. Anastomosis without leakage induces markedly higher volume and pressure values, with a continuous increase toward healthy values. From day 1, edema was markedly attenuated and the number of granulocytes decreased, while from days 4 or 5 necrosis decreased and granulation tissue, reticulin, and collagen formation substantially increased, thus resulting in increased epithelization.

Conclusion

This study showed BPC 157 to have a beneficial effect on ileoileal anastomosis healing in the rat.

Key words

Pentadecapeptide BPC 157 Ileoileal anastomosis healing Rat 

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References

  1. 1.
    Ilhan, YS, Bulbuller, N, Kirkil, C, Ozercan, R, Seckin, D 2005The effect of an angiotensin converting enzyme inhibitor of intestinal wound heakingJ Surg Res128615PubMedGoogle Scholar
  2. 2.
    Sikiric, P, Seiwerth, S, Grabarevic, Z, Petek, M, Rucman, R, Turkovic, B,  et al. 1994The 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 rates. A comparative study with H2 receptor antagonists, dopamine promoters and gut peptidesLife Sci54PL638PubMedCrossRefGoogle Scholar
  3. 3.
    Sikiric, P, Seiwerth, S, Grabarevic, Z, Rucman, R, Petek, M, Jagic, V,  et al. 1996Beneficial effect of novel pentadecapeptide BPC 157 on gastric lesions induced by restraint stress, ethanol, indomethacin, and capsaicin neurotoxicityDig Dis Sci41160414PubMedCrossRefGoogle Scholar
  4. 4.
    Sikiric, P, Seiwerth, S, Grabarevic, Z, Rucman, R, Petek, M, Jagic, V,  et al. 1997The influence of a novel pentadecapeptide BPC 157 on NG-nitro-L-arginine methylester and L-arginine effect on stomach mucosal integrity and blood pressureEur J Pharmacol3322333PubMedCrossRefGoogle Scholar
  5. 5.
    Bedekovic, V, Mise, S, Anic, T, Staresinic, M, Gjurasin, M, Kopljar, M,  et al. 2003Different effect of antiulcer agents on rat cysteamine-induced duodenal ulcer after sialoadenectomy, but not gastrectomyEuropean J Pharmacol4777380CrossRefGoogle Scholar
  6. 6.
    Mikus, D, Sikiric, P, Seiwerth, S, Petricevic, A, Aralica, G, Druzijanic, N,  et al. 2001Pentadecapeptide BPC 157 cream improves burn-wound healing and attenuates burn-gastric lesion in miceBurns12781727CrossRefGoogle Scholar
  7. 7.
    Sikiric, P, Seiwerth, S, Mise, S, Staresinic, M, Bedekovic, V, Zarkovic, N,  et al. 2003Corticosteroids-impairment healing and gastric pentadecapeptide BPC 157 creams in burned miceBurns2932334PubMedGoogle Scholar
  8. 8.
    Veljaca M, Krnic Z, Brajsa K, Mildner B, Pavic-Saladojev D, Seveljevic-Jaran D, et al. The development of PL 14736 for treatment of inflammatory bowel disease. IUPHAR-GI Section Symposium. Honolulu, Hawaii, 2002;13–15:0–32Google Scholar
  9. 9.
    Veljaca, M, Pavic Sladoljev, D, Mildner, B, Brajsa, K, Bubenik, M, Stipanicic, S,  et al. 2003Safety, tolerability and pharmacokinetics of PL 14736, a novel agent for treatment of ulcerative colitis, in healthy male volunteersGut51A309Google Scholar
  10. 10.
    Xue, XC, Wu, YJ, Gao, MT 2004Study of the protective effects of pentadecapeptide BPC 157 on wounds in small-type pigsChin New Drugs J126024Google Scholar
  11. 11.
    Staresinic, M, Sebecic, B, Jadrijevic, S, Suknaic, S, Perovic, D, Aralica, G,  et al. 2003Gastric pentadecapeptide BPC 157 accelerates healing of transected rat Achilles tendon and in vitro stimulates tendocytes growthJ Orthop Res2197683PubMedCrossRefGoogle Scholar
  12. 12.
    Bilic, M, Bumber, Z, Blagaic, AB, Batelja, L, Seiwerth, S, Sikiric, P 2005The stable gastric pentadecapeptide BPC 157, given locally, improves CO2 laser healing in miceBurns313105PubMedCrossRefGoogle Scholar
  13. 13.
    Sebecic, B, Nikolic, V, Sikiric, P, Seiwerth, S, Sosa, T, Patrlj, L,  et al. 1999Osteogenic effect of gastric pentadecapeptide BPC 157 on the healing of segmental bone defects in rabbits: a comparison with the bone marrow and autologous cortical bone implantationBone24195202PubMedCrossRefGoogle Scholar
  14. 14.
    Seiwerth, S, Sikiric, P, Grabarevic, Z, Grabarevic, Z, Zoricic, I, Hanzevacki, M,  et al. 1997BPC 157's effect on healingJ Physiol (Paris)911738CrossRefGoogle Scholar
  15. 15.
    Staresinic, M, Petrovic, I, Novinscak, T, Jukic, I, Pevec, D, Suknaic, S,  et al. 2006Effective therapy of transected quadriceps muscle in rat: gastric pentadecapeptide BPC 157J Orthop Res24110917PubMedCrossRefGoogle Scholar
  16. 16.
    Lazic, R, Gabric, N, Dekaris, I, Bosnar, D, Boban-Blagaic, A, Sikiric, P 2005Gastric pentadecapeptide BPC 157 promotes corneal epithelial defect healing in ratsColl Antropol293215PubMedGoogle Scholar
  17. 17.
    Veljaca, M, Chan, K, Guglietta, A 1995Digestion of h-EGF, h-TGF alpha and BPC-15 in human gastric juiceGastroenterology108761CrossRefGoogle Scholar
  18. 18.
    Urist, MR 1995The first three decades of bone morphogenetic proteinOsteologie420723Google Scholar
  19. 19.
    Mustoe, A, Pierce, GF, Thomason, A, Grmates, P, Sporn, MB, Deuel, TF 1987Accelarated healing of incisional wounds in rats induced by transforming growth factor-βScience23713336PubMedCrossRefGoogle Scholar
  20. 20.
    Xue, XC, Wu, YJ, Gao, MT, Li, WG, Zhao, N, Wang, ZL,  et al. 2004Protective effects of pentadecapeptide BPC 157 on gastric ulcer in ratsWorld J Gastroenterol1010326PubMedGoogle Scholar
  21. 21.
    Wood, JD 2004The first Noleb prize for integrated systems physiology: Ivan Petrovich Pavlov, 1904Physiology1932630PubMedCrossRefGoogle Scholar
  22. 22.
    Sikiric, P, Seiwerth, S, Grabarevic, Z, Rucman, R, Petek, M, Jagic, V,  et al. 1997Pentadecapeptide BPC 157 positively affects both non-steroidal anti-inflammatory agent-induced gastrointestinal lesions and adjuvant arthritis in ratsJ Physiol (Paris)9111322CrossRefGoogle Scholar
  23. 23.
    Veljaca, M, Lesch, CA, Pllana, R, Sanchez, B, Chan, K, Guglietta, A 1995BPC-15 reduces trinitrovenzene sulfonic acid-induced colonic damage in ratsJ Pharmacol Exp Ther27241722PubMedGoogle Scholar
  24. 24.
    Zoricic, I, Sikiric, P, Seiwerth, S 1997Pentadecapeptide BPC 157 beneficially influences the healing of colon-colon anastomoses in ratsMozsik, GNagy, LPar, ARainsford, KD eds. Cell injury and protection in the gastrointestinal trace. From basic sciences to clinical perspectives 1996Kluwer Academic PublishersDordrecht Boston London24958Google Scholar
  25. 25.
    Pajic, A, Fattorini, I, Gjurasin, M, Gogolja, D, Vlahovic, T, Vrtar, Z,  et al. 2003Gastric pentadecapeptide BPC 157 (PL-10, PL-116) reduces and reverses peritonitis intra-abdominal adhesion in normal and sialoadenectomized rat and abolished mortality in corticosteroid-ratDig Dis Sci481894Google Scholar
  26. 26.
    Thornton, FJ, Barbul, A 1997Healing in the gastrointestinal tractSurg Clin North Am7754973PubMedCrossRefGoogle Scholar
  27. 27.
    Hendriks, T, Mastboom, WJB 1990Healing of experimental intestinal anastomoses. Parameters for repairDis Colon Rectum33891901PubMedCrossRefGoogle Scholar
  28. 28.
    Ishimura, K, Tsubouchi, T, Okano, K, Maeba, T, Maeta, H 1998Wound healing of intestinal anastomosis after digestive surgery under septic condition: participation of local interleukin-6 expressionWorld J Surg22106975PubMedCrossRefGoogle Scholar
  29. 29.
    Veljaca, M, Lesch, CA, Sanchez, B, Low, J, Guglietta, A 1995Protection of BPC-15 on TNBS-induced colitis in rats: possible mechanisms of actionGastroenterology108936Google Scholar
  30. 30.
    Frank, S, Madlener, M, Pfeilschifter, J, Werner, S 1998Induction of inducible nitric oxide synthase and its corresponding retrahydrobiopterin-cofactor synthesizing enzyme GTP-cyclohydrolase I during cutaneous wound repairJ Invest Dermatol111105864PubMedCrossRefGoogle Scholar
  31. 31.
    Attard, JA, Raval, MJ, Martin, GR, Kolb, J, Afrouzian, M, Buie, WD,  et al. 2005The effects of systemic hypoxia on colon anastomotic healing: an animal modelDis Colon Rectum48146070PubMedCrossRefGoogle Scholar
  32. 32.
    Turkovic, B, Sikiric, P, Seiwerth, S, Mise, S, Anic, T, Petek, M,  et al. 2004Stable gastric pentadecapeptide BPC 157 studied for inflammatory bowel disease (PLD-116, PL14736, Pliva) induces nitric oxide synthesisGastroenterology126287Google Scholar
  33. 33.
    Sikiric, P, Separovic, J, Anic, T, Buljat, G, Mikus, D, Seiwerth, S,  et al. 1999The effect of pentadecapeptide BPC 157, H2-blockers, omeprazole and sucralfate on new vessels and new granulation tissue formationJ Physiol (Paris)9347985CrossRefGoogle Scholar
  34. 34.
    Lovric-Bencic, M, Sikiric, P, Separovic, J, Seiwerth, S, Rogic, D, Kusec, V,  et al. 2004Doxorubicin congestive heart failure-increased big-endothelin 1 plasma concentration. Reversal by amlodipine, losartan and gastric pentadecapeptide BPC 157 in rat and mouseJ Pharmacol Sci951926PubMedCrossRefGoogle Scholar
  35. 35.
    Ulland, AE, Shearer, JD, Coulter, C, Caldwell, MD 1997Altered wound arginine metabolism by corticosterone and retinoic acidJ Surg Res70848PubMedCrossRefGoogle Scholar
  36. 36.
    Camli, A, Barlas, M, Yagmurlu, A 2005Does L-arginine induce intestinal adaptation by epithelial growth factor?Aust NZ J Surg75735CrossRefGoogle Scholar
  37. 37.
    Kalogjera, L, Ries, M, Baudoin, T, Ferencic, Z, Trotic, R, Pegan, B 1997Dose-dependent protective effect of BPC 157 on capsaicin-induced rhinitis in ratsEur Arch Otorhyinolaryngol254S911CrossRefGoogle Scholar
  38. 38.
    Gjurasin, M, Miklic, P, Buljat, G, Perovic, D, Jukic, I, Sikiric, P,  et al. 2003Selective healing effect of the gastric pentadecapeptide BPC 157 on injured part of the nerve in subtotal sciatic nerve transectionDig Dis Sci481878Google Scholar
  39. 39.
    Seyer-Hansen, M, Andreassen, TT, Oxlund, H 1999Strength of colonic anastomoses and skin incisional wounds in old rates — influence by diabetes and growth hormoneGrowth Hormone IGF Res925461CrossRefGoogle Scholar
  40. 40.
    Schaffer, M, Fuchs, N, Volker, J, Kapischke, M, Viebach, R 2005Differential effect of tacrolimus on dermal and intestinal wound healingJ Invest Surg18719PubMedCrossRefGoogle Scholar
  41. 41.
    Petersen, TI, Kissmeyer-Nielsen, P, Flyvbjery, A, Laurbery, S, Christensen, H 1996Effect of insulin-like growth factor I (IGF-I) administration on the healing of colonic anastomoses in ratsInt J Colorectal Dis111924PubMedCrossRefGoogle Scholar
  42. 42.
    Gulcelik, MA, Dinc, S, Bir, F, Elitok, O, Alagol, H, Oz, M 2005Locally applied molgramostim improves wound healing at colonic anastomoses in rats after ligation of the common bile ductCan J Surg482138PubMedGoogle Scholar
  43. 43.
    Cetinkaya, K, Dinc, S, Gulcelik, MA, Renda, N, Ustun, H, Caydere, M,  et al. 2005Granulocyte macrophate-colony stimulating factor improves impaired anastomotic wound healing in rats treated with intraperitoneal mitomycin-CSurg Today352904PubMedCrossRefGoogle Scholar
  44. 44.
    Sakallioglu, AE, Yagmurlu, A, Dindar, H, Hasirci, N, Renda, N, Deveci, MS 2004Sustained local application of low-dose epidermal growth factor on steroid-inhibited colonic wound healingJ Pediatr Surg395915PubMedCrossRefGoogle Scholar
  45. 45.
    Papalambros, E, Filis, K, Angelopoulou, R, Diamantis, T, Tsigris, C, Bastounis, E 2004Does octreotide impair anastomotic healing after small bowel resection?Acta Chir Belg104198203PubMedGoogle Scholar
  46. 46.
    Migaly, J, Lieberman, J, Long, W, Fisher, C, Rolandelli, RH 2004Effect of adenoviral-mediated transfer of transforming growth factor-betal on colonic anastomotic healingDis Colon Rectum471699705PubMedCrossRefGoogle Scholar
  47. 47.
    Meddahi, A, Benoit, J, Ayoub, N, Sezeur, A, Barritault, D 1996Heparin-like polymers derived from dextran enhance colonic anastomosis resistance to leakageJ Biomed Mater Res312937PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Tokyo 2007

Authors and Affiliations

  • Tihomir Vuksic
    • 1
  • Ivan Zoricic
    • 1
  • Luka Brcic
    • 1
  • Marko Sever
    • 1
  • Robert Klicek
    • 1
  • Bozo Radic
    • 1
  • Vedran Cesarec
    • 1
  • Lidija Berkopic
    • 1
  • Neike Keller
    • 1
  • Alenka Boban Blagaic
    • 1
  • Neven Kokic
    • 1
  • Ivan Jelic
    • 1
  • Juraj Geber
    • 1
  • Tomislav Anic
    • 1
  • Sven Seiwerth
    • 1
  • Predrag Sikiric
    • 1
  1. 1.Departments of Pharmacology and Pathology, Medical FacultyUniversity of ZagrebZagrebCroatia

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