: This review is focused on the healing of fistulas and stable gastric pentadecapeptide BPC 157. Assuming that the healing of the various wounds is essential also for the gastrointestinal fistulas healing, the healing effect on fistulas in rats, consistently noted with the stable gastric pentadecapeptide BPC 157, may raise several interesting possibilities. BPC 157 is originally an anti-ulcer agent, native to and stable in human gastric juice (for more than 24 h). Likely, it is a novel mediator of Robert’s cytoprotection maintaining gastrointestinal mucosal integrity. Namely, it is effective in the whole gastrointestinal tract, and heals various wounds (i.e., skin, muscle, tendon, ligament, bone; ulcers in the entire gastrointestinal tract; corneal ulcer); LD1 is not achieved. It is used in ulcerative colitis clinical trials, and now in multiple sclerosis, and addressed in several reviews. Therefore, it is not surprising that BPC 157 has documented consistent healing of the various gastrointestinal fistulas, external (esophagocutaneous, gastrocutaneous, duodenocutaneous, colocutaneous) and internal (colovesical, rectovaginal). Taking fistulas as a pathological connection, this rescue is verified with the beneficial effects in rats with the various gastrointestinal anastomoses, esophagogastric, jejunoileal, colo-colonic, ileoileal, esophagojejunal, esophagoduodenal, and gastrojejunal. This beneficial effect occurs equally when the gastrointestinal anastomoses are impaired with the application of NSAIDs, cysteamine, large bowel resection, as well as concomitant esophageal, gastric, and duodenal lesions and/or ulcerative colitis presentation, short bowel syndrome progression, liver and brain disturbances presentation. Particular aspects of the BPC 157 healing of the fistulas are especially emphasized.

With the stable gastric pentadecapeptide BPC 157 therapy known to heal various both external and internal rat fistulas, we attempt to approach vesicovaginal fistula, continuous urine leaking through vagina, bladder stones, and a possible therapy solution among rats with well-formed 2 week-fistulas (vaginal/vesical 4 mm large defects) started with delayed therapy. Subsequent control fistula course (the subsequent 1, 2, 4, and 6 weeks) since beginning revealed the failed healing, fistula leaking, adhesions, urinary leaking through vagina, failed epithelization, collagenization, granulation tissue and neovascularization, increased inflammation, and necrosis. Thereby, the later intervals revealed the persistent inability to sustain even minimal volume, vesical, and vaginal defects and stone formation at the end of the experiment (fistula-time day 56). BPC 157 therapy (10 µg/kg, 10 ng/kg, intraperitoneally once time daily or perorally in drinking water until sacrifice) was initiated with a considerable delay (at 2 weeks after fistula formation). Already within 1 week therapy, all BPC 157 regimens stopped urinary leaking through vagina, reversed the otherwise resistant poor healing course to the increased epithelization, collagenization, granulation tissue and neovascularization, decreased inflammation, and decreased necrosis. Thereby, at later intervals, all BPC 157 rats exhibited a five times larger volume that can be sustained before leaking as in healthy, vesical, and vaginal defects completely closed and no stone formation. Thus, macro/microscopic and functional recovery, and counteracted stone formation. Concluding, BPC 157 therapy’s beneficial effects resulted in healing and no stone formation, with µg- and ng-regimens, either given daily perorally in drinking water or intraperitoneally.

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AimFrequently, large vesicovaginal fistulas need operation treatment. Stable gastric pentadecapeptide BPC 157, tested in clinical trials for ulcerative colitis therapy and now multiple sclerosis (Curr Pharm Des. 2017;23(27):4012–4028; Curr Pharm Des. 2014;20(7):1126–35; Curr Pharm Des. 2010;16(10):1224–34), already resolved the healing of various fistulas (Eur J Pharmacol. 2016 Jun 5;780:1–7; Life Sci. 2016 Mar 1;148:63–70; J Physiol Pharmacol. 2015 Aug;66(4):581–90; Eur J Pharmacol. 2013 Feb 15;701(1–3):203–12; J Pharmacol Sci. 2008 Sep;108(1):7–17; Dig Dis Sci. 2009 Jan;54(1):46–56). Thus, BPC 157 may be a successful therapy of vesicovaginal fistulas in rats.MethodsVesicovaginal fistulas were created in Wistar rats. The vesicovaginal fistula was surgically created (4mm length between posterior wall of the urinary bladder and anterior vaginal wall ). Medication. Pentadecapaptide BPC 157 (10 μg/kg/day, 10ng/kg/day) was given intraperitoneally (5 ml/kg) or in drinking water (0.16 μg/ml, 0.16 ng/ml, 12 ml/rat/day) while controls received equivolume of saline or drinking water only. Assessment (the pressure required for leakage of fluid through fistula (mLH2O), diameter of the fistula defects (mm) (bladder, vaginal side), macro/microscopical evaluation, urinary stone presentation) was 1, 2, 3, 4, and 6 weeks. Prophylactic regimen. Medication was started immediately after fistulas creation. Therapy regimen. Medication was initiated with already advanced fistula formation, after 2 weeks.ResultsUnlike poor healing in controls, BPC 157 reduced fistulas diameters (7th day) leading to the complete closure at 46th day and considerable volume needed to leakage of fluid through fistula (V: 5.3+/−0.3 mL). Finally, the fistula was successfully healed and microscopically confirmed in BPC 157 rats (day 46, 0+/−0 mm (diameter, bladder/vagina), unlike open defects in controls: 3.1+/−0.6 (mm, bladder), 3.3+/−0.8 (mm, vagina)) diameter and small volume sustained before leakage (V: 1.2+/−0.4 mL, day 14). In posttreatment BPC 157 group we noticed reducing of fistula diameter since a first posttreatment week ( con 3.8 +/−0.2 mm, BPC 157 3.1 +/−0.1 mm) leading to fistula closing during the 4th posttreatment week. In all control animals, we noticed urinary bladder stone creation which was absent in BPC 157 animals. In posttreatment animals, BPC 157 (therapy regimen) stopped further urinary stone creation.ConclusionPentadecapeptide BPC 157 improved vesicovaginal fistula healing, and it could be the pharmacological solution for the complex clinical problem of vesicovaginal fistulas healing. Vesicovaginal fistula could be used as a urinary stone animal model. BPC157 reduces urinary stone creation.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

AimAs a novel approach in therapy of various fistulas, we hypothesize the stable gastric pentadecapeptide BPC 157 in therapy of internal fistulas, in particular vesicovaginal fistulas in rats. BPC 157 was originally an anti‐ulcer peptide used in trials for ulcerative colitis and now is in trials for the treatment of multiple sclerosis that largely interacts with NO‐system (Curr Pharm Des 2014;20(7):1126–35) and thought to be novel mediator of Robert's cytoprotection in rat studies, known to exert an immediate endothelium protection alongside with mucosal protection in stomach, known to counteract variously induced gastrointestinal lesions in various species, and in particular, various fistulas healing, external fistulas (esophagocutaneous (Eur J Pharmacol 2013;701(1–3):203–12), gastrocutaneous (Dig Dis Sci 2009;54(1):46–56), duodenocutaneous (J Physiol Pharmacol. 2015;66(4):581–90), colocutaneous (J Pharmacol Sci 2008;108(1):7–17)), and internal fistulas (colovesical (Eur J Pharmacol 2016;780:1–7) and rectovaginal (Life Sci 2016;148:63–70)). Thereby, providing simultaneous healing of different tissues, and likely correlation with human fistulas disturbances, it seems to be suited for the necessary generalization of the fistulas concept healing. Thus, BPC 157 was used in further therapy of internal fistulas, in particular vesicovaginal fistulas in rats.Materials and methodsIn female Wistar Albino rats, 200g vesicovaginal fistulas were created by longitudinal incision on the posterior wall of the urinary bladder and anterior vaginal wall (4mm) were performed. Fistula was created using single‐layer suture technique. Medication includes pentadecapeptide BPC 157 (10μg/kg/day, 10ng/kg/day) dissolved in saline, applied (a) intraperitoneally (first application 30min after surgery, last 24h before sacrifice, 5ml/kg) or (b) in drinking water (0.16μg/ml, 0.16ng/ml, 12ml/rat/day) or an equivolume of saline i.p. or drinking water only (controls) for 7, 14, 21, 28 and 42 days. As described before in our fistulas studies, assessed were the pressure required for leakage of fluid through fistula (mLH2O), diameter of the fistula defects (mm) (bladder, vaginal side).ResultsIn general, unlike poor healing in controls, BPC 157 reduced fistulas diameters (7th day) leading to the complete closure. Finally, the fistula was successfully healed in all rats underwent BPC 157 therapy (i.e., day 46, 0+/−0mm (diameter, bladder/vagina), considerable volume needed to leakage of fluid through fistula (V: 5.3+/−0.3 mL), in rats treated intraperitoneally), unlike open defects in controls: 3.1+/−0.6 (mm, bladder), 3.3+/−0.8 (mm, vagina)) diameter and small volumen sustained before leakage (V: 1.2+/−0.4 mL).ConclusionEffectiveness of BPC 157 in therapy of fistulas in rats, internal fistulas in particular, and especially in vesicovaginal fistulas, may be a particular indication for further clinical studies.Support or Funding InformationUniversity of Zagreb, Croatia (Grant number BM099)