Stable Gastric Pentadecapeptide BPC Research Articles

Salutary effect of gastric pentadecapeptide BPC 157 in two different stress urinary incontinence models in female rats

BackgroundSince an originally anti-ulcer stable gastric pentadecapeptide BPC 157 (PL 14736) was shown to promote healing of injured striated muscle and smooth muscle in the gastrointestinal tract, we explored its therapeutic potentials for leak point pressure (LPP) recovery in rat stress urinary incontinence (SUI) after transabdominal urethrolysis (TU) and prolonged vaginal dilatation (VD).Material/MethodsDuring a 7-day period, TU-rats and VD-rats (or healthy rats) received BPC 157, either (i) intraperitoneally, 10 μg/kg or 10 ng/kg, once daily (first administration 30 min after surgery, last 24 h before LPP-testing and sacrifice), or (ii) per-orally, 10 μg/kg in drinking water (0.16 μg/mL, 12 mL/rat/day). Vesicourethral segments were harvested for immunohistochemical evaluation.ResultsAll BPC 157 regimens counteracted decrease of LPP values in TU-rats and VD-rats. Additionally, BPC 157-TU rats (μg-intraperitoneally or per-orally) and BPC 157-VD rats (μg intraperitoneally) reached LPP values originally noted in healthy rats. Conversely, in healthy rats, BPC 157 did not alter LPP. Immunohistochemical studies revealed higher desmin (delineates striated organization of skeletal muscle), smooth muscle actin, and CD34 (angiogenic marker) positivity within the urethral wall in BPC 157-treated rats vs. controls, as well as overall preserved muscle/connective tissue ratio assessed with Mallory’s trichrome staining.ConclusionsPentadecapeptide BPC 157, applied parenterally or per-orally, appears to ameliorate the SUI in rat models, improving the otherwise detrimental course of healing after VD and TU, which may be analogous to human injury. These beneficial effects may possibly be selectively used in future strategies for treatment of SUI.

Toxicity by NSAIDs. Counteraction by Stable Gastric Pentadecapeptide BPC 157

Stable gastric pentadecapeptide BPC 157 is an anti-ulcer peptidergic agent, proven in clinical trials to be both safe in inflammatory bowel disease (PL-10, PLD-116, PL 14736) and wound healing, stable in human gastric juice, with no toxicity being reported. Recently, we claim that BPC 157 may be used as an antidote against NSAIDs. We focused on BPC 157 beneficial effects on stomach, duodenum, intestine, liver and brain injuries, adjuvant arthritis, pain, hyper/hypothermia, obstructive thrombus formation and thrombolysis, blood vessel function, counteraction of prolonged bleeding and thrombocytopenia after application of various anticoagulants and antiplatelet agents and wound healing improvement. The arguments for BPC 157 antidote activity (i.e., the role of BPC 157 in cytoprotection, being a novel mediator of Robert’s cytoprotection and BPC 157 beneficial effects on NSAIDs mediated lesions in the gastrointestinal tract, liver and brain and finally, counteraction of aspirin-induced prolonged bleeding and thrombocytopenia) obviously have a counteracting effect on several established side-effects of NSAIDs use. The mentioned variety of the beneficial effects portrayed by BPC 157 may well be a foundation for establishing BPC 157 as a NSAIDs antidote since no other single agent has portrayed a similar array of effects. Unlike NSAIDs, a very high safety (no reported toxicity (LD1 could be not achieved)) profile is reported for BPC 157. Also, unlike the different dosage levels of aspirin, as a NSAIDs prototype, which differ by a factor of about ten, all these beneficial and counteracting effects of BPC 157 were obtained using the equipotent dosage (μg, ng/kg) in parenteral or peroral regimens. Keywords: NSAIDs-gastrointestinal tract lesions, NSAIDs-liver lesions, NSAIDs-brain lesions, aspirin-prolonged bleeding/ thrombocytopenia, stable gastric pentadecapeptide BPC 157, counteraction, antidote against NSAIDs, clinical trials, inflammatory bowel disease, anticoagulants

Toxicity by NSAIDs. Counteraction by Stable Gastric Pentadecapeptide BPC 157

Stable gastric pentadecapeptide BPC 157 is an anti-ulcer peptidergic agent, proven in clinical trials to be both safe in inflammatory bowel disease (PL-10, PLD-116, PL 14736) and wound healing, stable in human gastric juice, with no toxicity being reported. Recently, we claim that BPC 157 may be used as an antidote against NSAIDs. We focused on BPC 157 beneficial effects on stomach, duodenum, intestine, liver and brain injuries, adjuvant arthritis, pain, hyper/hypothermia, obstructive thrombus formation and thrombolysis, blood vessel function, counteraction of prolonged bleeding and thrombocytopenia after application of various anticoagulants and antiplatelet agents and wound healing improvement. The arguments for BPC 157 antidote activity (i.e., the role of BPC 157 in cytoprotection, being a novel mediator of Robert's cytoprotection and BPC 157 beneficial effects on NSAIDs mediated lesions in the gastrointestinal tract, liver and brain and finally, counteraction of aspirin-induced prolonged bleeding and thrombocytopenia) obviously have a counteracting effect on several established side-effects of NSAIDs use. The mentioned variety of the beneficial effects portrayed by BPC 157 may well be a foundation for establishing BPC 157 as a NSAIDs antidote since no other single agent has portrayed a similar array of effects. Unlike NSAIDs, a very high safety (no reported toxicity (LD1 could be not achieved)) profile is reported for BPC 157. Also, unlike the different dosage levels of aspirin, as a NSAIDs prototype, which differ by a factor of about ten, all these beneficial and counteracting effects of BPC 157 were obtained using the equipotent dosage (μg, ng/kg) in parenteral or peroral regimens.

Sa1480 Prolonged Severe Hypercalcemia Induces an Acute Pancreatitis in Rats, and Shortening of QTc Interval and Prolongation of Pq Interval. the Effect of the Therapy With Stable Gastric Pentadecapeptide BPC 157 (PL 14736)

Sa1480 Prolonged Severe Hypercalcemia Induces an Acute Pancreatitis in Rats, and Shortening of QTc Interval and Prolongation of Pq Interval. the Effect of the Therapy With Stable Gastric Pentadecapeptide BPC 157 (PL 14736)

Mortal Furosemide-Hypokalemia-Disturbances in Rats NO-System Related Shorten Survival by L-NAME. Therapy Benefit with BPC 157 Peptide More Than With L-Arginine

Background: We focused on NO-system-relations (worsening/amelioration) of furosemide (100 mg/kg intraperitoneally)-diuresis-hypokalemia mortal course in rats and beneficial effect of BPC 157 therapy. Methods: Electrocardiographically 90-150 min post-furosemide application duration of PR, RR, QRS, QT intervals, P, R, S, T waves and its amplitude as well were analysed along with appearance of AV block, ventricular premature beats, ventricular tachycardia. Clinically, skeletal muscle myoclonal activity and lethality at 150 min were also analysed. Results: All NO-system-related agents (alone and/or combined, before/after furosemide) not changed hypokalemia and all averted to some extent furosemide-forced diuresis. NOS-blocker, L-NAME (5 mg/kg intraperitoneally) accelerated mortality, aggravated cardiac and extra-cardiac manifestations, thereby, NO-systemrelated. Prevented hypokalemia-mortality was with NO-precursor L-arginine (100 mg/kg intraperitoneally) and stable gastric pentadecapeptide BPC 157 (10 ug, 10 ng/kg intraperitoneally/intragastrically). Specifically, BPC 157 showed most complete benefit. i. BPC 157 given 15 min before furosemide. All BPC 157 regimens maintained sinus rhythm, had no ventricular premature beats, ventricular tachycardia, AV block, no prolongation of intervals and waves without reduction of amplitude. ii. BPC 157 given 90 min after furosemide (with hypokalemia, 3rd grade AV block and/ or ventricular tachycardia being present). Within 5-10 minutes, BPC 157 regimens normalized P, R, S, T waves, PR, RR, QRS, QT interval duration, R, S, T wave amplitude, total AV block and terminated ventricular tachycardia. Likewise, BPC 157 eliminated skeletal muscle myoclonus. Conclusion: L-NAME/L-arginine was mutual counteraction while BPC 157 completely eliminated L-NAME (arrhythmias, myoclonus, mortality), without an additive benefit when combined with L-arginine. Thus, we showed potentially effective therapeutic interventions for acute hypokalemia.

Focus on Ulcerative Colitis: Stable Gastric Pentadecapeptide BPC 157

Stable gastric pentadecapeptide BPC 157 (GEPPPGKPADDAGLV, M.W. 1419) may be the new drug stable in human gastric juice, effective both in the upper and lower GI tract, and free of side effects. BPC 157, in addition to an antiulcer effect efficient in therapy of inflammatory bowel disease (IBD) (PL 14736) so far only tested in clinical phase II, has a very safe profile, and exhibited a particular wound healing effect. It also has shown to interact with the NO-system, providing endothelium protection and angiogenic effect, even in severely impaired conditions (i.e., it stimulated expression of early growth response 1 gene responsible for cytokine and growth factor generation and early extracellular matrix (collagen) formation (but also its repressor nerve growth factor 1-A binding protein-2)), important to counteract severe complications of advanced and poorly controlled IBD. Hopefully, the lessons from animal studies, particularly advanced intestinal anastomosis healing, reversed short bowel syndrome and fistula healing indicate BPC 157's high significance in further IBD therapy. Also, this supportive evidence (i.e., no toxic effect, limit test negative, LD1 not achieved, no side effect in trials) may counteract the problems commonly exercised in the use of peptidergic agents, particularly those used on a long-term basis.

Pentadecapeptide BPC 157 reduces bleeding time and thrombocytopenia after amputation in rats treated with heparin, warfarin or aspirin

Recently, in rat abdominal aorta terminoterminal-anastomosis the stable gastric pentadecapeptide BPC 157 prevents obstructive thrombus formation and rapidly destroys already formed obstructive thrombus. Also, BPC 157 wound healing may signify the clot as conductive matrix or “scaffold” to speed up wound healing process, and decrease bleeding. Here, in rats, BPC 157 (10μg/kg, 10ng/kg) improved always reduced bleeding time and amount of bleeding after (tail) amputation only, heparin (250mg/kg, 25mg/kg, 10mg/kg i.v.), warfarin (1.5mg/kg i.g. once daily for 3 consecutive days), aspirin (0.1g/kg i.g. (once daily/3 consecutive days) or 1.0g/kgi.p. once), and amputation associated with those agents application. BPC 157 counteracting regimens (i.v., i.p., i.g. (immediately after any challenge)) correspondingly follow the route of bleeding-agents application. All heparin-, warfarin-, and aspirin-rats and normal-rats that received BPC 157 exhibited lesser fall in platelets count. BPC 157 attenuated over-increased APTT-, TT-values in 10mg/kg heparin-rats, but did not influence heparin activity (anti-Xa test). Indicatively, unless counteracted in BPC 157 rats, excessive bleeding-acute thrombocytopenia (<20% of initial values in heparin-rats) approaches substantial fall in platelets count known in type II HIT. Also, BPC 157 markedly prolongs the survival time (heparin-rats, 25mg/kg, right foot amputation).

Stable Gastric Pentadecapeptide BPC 157: Novel Therapy in Gastrointestinal Tract

Stable gastric pentadecapeptide BPC 157 is an anti-ulcer peptidergic agent, safe in inflammatory bowel disease clinical trials (GEPPPGKPADDAGLV, M.W. 1419, PL 14736) and wound healing, stable in human gastric juice and has no reported toxicity. We focused on BPC 157 as a therapy in peridontitis, esophagus, stomach, duodenum, intestine, liver and pancreas lesions. Particularly, it has a prominent effect on alcohol-lesions (i.e., acute, chronic) and NSAIDs-lesions (interestingly, BPC 157 both prevents and reverses adjuvant arthritis). In rat esophagitis and failed function of both lower esophageal sphincter (LES) and pyloric sphincters (PS), BPC 157 increased pressure in both sphincters till normal and reduced esophagitis. However, in healthy rats, it may decrease (PS) or increase (LES) the pressure in sphincters. It has strong angiogenic potential, it acts protectively on endothelium, prevents and reverses thrombus formation after abdominal aorta anastomosis, affects many central disturbances (i.e., dopamine and 5-HT system), the NO-system (either L-arginine and L-NAME effects), endothelin, acts as a free radical scavenger (counteracting CCl4-, paracetamol-, diclofenac-injuries) and exhibits neuroprotective properties. BPC 157 successfully heals the intestinal anastomosis, gastrocutaneous, duodenocutaneous and colocutaneous fistulas in rats, as well as interacting with the NO-system. Interestingly, the fistula closure was achieved even when the BPC 157 therapy was postponed for one month. In short-bowel syndrome escalating throughout 4 weeks, the constant weight gain above preoperative values started immediately with peroral and parental BPC 157 therapy and the villus height, crypth depth and muscle thickness (inner (circular) muscular layer) additionally increased. Thus, BPC 157 may improve gastrointestinal tract therapy.

Ibuprofen hepatic encephalopathy, hepatomegaly, gastric lesion and gastric pentadecapeptide BPC 157 in rats

Chronic ibuprofen (0.4 g/kg intraperitoneally, once daily for 4 weeks) evidenced a series of pathologies, not previously reported in ibuprofen-dosed rats, namely hepatic encephalopathy, gastric lesions, hepatomegaly, increased AST and ALT serum values with prolonged sedation/unconsciousness, and weight loss. In particular, ibuprofen toxicity was brain edema, particularly in the cerebellum, with the white matter being more affected than in gray matter. In addition, damaged and red neurons, in the absence of anti-inflammatory reaction was observed, particularly in the cerebral cortex and cerebellar nuclei, but was also present although to a lesser extent in the hippocampus, dentate nucleus and Purkinje cells. An anti-ulcer peptide shown to have no toxicity, the stable gastric pentadecapeptide BPC 157 (GEPPPGKPADDAGLV, MW 1419, 10 μg, 10 ng/kg) inhibited the pathology seen with ibuprofen (i) when given intraperitoneally, immediately after ibuprofen daily or (ii) when given in drinking water (0.16 μg, 0.16 ng/ml). Counteracted were all adverse effects, such as hepatic encephalopathy, the gastric lesions, hepatomegaly, increased liver serum values. In addition, BPC 157 treated rats showed no behavioral disturbances and maintained normal weight gain. Thus, apart from efficacy in inflammatory bowel disease and various wound treatments, BPC 157 was also effective when given after ibuprofen.

The Effect of Pentadecapeptide BPC 157 and High Dose Diclofenac on Induced Short Bowel Syndrome

Stable gastric pentadecapeptide BPC 157 (an anti-ulcer peptide effective in IBD trials, LD1 not achieved) counteracted short bowel syndrome (Sever et al., Dig Dis Sci, 2009) and protected rats against diclofenac gastrointestinal injuries (Ilic et al., J Physiol Pharmacol, 2009). Aim: In this study we tested the effect of pentadecapeptide 157 on induced short bowel syndrome rats aggravated with high dose of diclofenac. Material and methods We used 80%-small intestine resection and then short bowel syndrome rats received diclofenac application (12.5 mg/kg i.p.). Medication (BPC 157 10 μg/kg or an equivolume of saline (5 ml/kg ip) was given immediately after diclofenac. Animals were sacrificed 24 h after the surgery. Assessment included bleeding period (sec), gastrointestinal lesions (sum of longest diameters of lesions stomach, small and large intestine), serum AST, ALT, bilirubine levels. Microscopic analysis was also performed. Results All BPC 157 treated animals had shorter bleeding period compared to control group animals (210 +/- 37s vrs. 480 +/- 43 s). Bilirubine levels were significantly increased in control group animals compared to BPC 157 treated animals ( 192.3 +/- 46.7 μmol/ L vrs 6.8+/- 3.1 μmol/L). AST, ALT, LDH were increased in both tested groups (AST: 308+/-14 u/L (BPC157) vrs 383+/-27 u/L (con.) ; ALT: 52+/-4 u/L (BPC157) vrs 63+/-6 u/L (con.)) Number of gastrointestinal lesions (gastric, duodenal, small and large intestinal ulcerations) was significantly larger in control animal group compared to BPC 157 treated animals (gastric: 5.6 +/- 2.7 lesions (con) vrs . 0.5+/-0.2 lesions (BPC) ; duodenal (1.3 +/-0.2 lesions(con) vrs 0 lesions (BPC) ; jejunum, ileum and rectum score (1- ulcerations, 2- erosions and erithema, 3- normal mucosal surface) ; Jejunum: 1.6+/- 0, 7(con) vrs 2.8+/-0.2 (BPC) ; Ileum: 1 +/- 0, 4 (con) vrs 2.8+/-2 (BPC) ; Rectum 1+/-0.3 (con) vrs 2.6 +/- 0, 4 (BPC)). Conclusion According to our results we could conclude that BPC 157 improves small bowel and liver lesions healing in malnutrition conditions even during high dose diclofenac exposure.

MLK3 Signaling Stimulates Intestinal Mucosal Healing

Stable gastric pentadecapeptide BPC 157 (an anti-ulcer peptide effective in IBD trials, LD1 not achieved) counteracted short bowel syndrome (Sever et al., Dig Dis Sci, 2009) and protected rats against diclofenac gastrointestinal injuries (Ilic et al., J Physiol Pharmacol, 2009). Aim: In this study we tested the effect of pentadecapeptide 157 on induced short bowel syndrome rats aggravated with high dose of diclofenac. Material and methodsWe used 80%-small intestine resection and then short bowel syndrome rats received diclofenac application (12.5 mg/kg i.p.). Medication (BPC 157 10 μg/kg or an equivolume of saline (5 ml/kg ip) was given immediately after diclofenac. Animals were sacrificed 24 h after the surgery. Assessment included bleeding period (sec), gastrointestinal lesions (sum of longest diameters of lesions stomach, small and large intestine), serumAST, ALT, bilirubine levels. Microscopic analysis was also performed. Results All BPC 157 treated animals had shorter bleeding period compared to control group animals (210 +/37s vrs. 480 +/43 s). Bilirubine levels were significantly increased in control group animals compared to BPC 157 treated animals ( 192.3 +/46.7 μmol/ L vrs 6.8+/3.1 μmol/L). AST, ALT, LDH were increased in both tested groups (AST: 308+/-14 u/L (BPC157) vrs 383+/-27 u/L (con.); ALT: 52+/-4 u/L (BPC157) vrs 63+/-6 u/L (con.)) Number of gastrointestinal lesions (gastric, duodenal, small and large intestinal ulcerations) was significantly larger in control animal group compared to BPC 157 treated animals (gastric: 5.6 +/2.7 lesions (con) vrs . 0.5+/0.2 lesions (BPC); duodenal (1.3 +/-0.2 lesions(con) vrs 0 lesions (BPC); jejunum, ileum and rectum score (1ulcerations, 2erosions and erithema, 3normal mucosal surface); Jejunum: 1.6+/0,7(con) vrs 2.8+/-0.2 (BPC); Ileum: 1 +/0,4 (con) vrs 2.8+/-2 (BPC); Rectum 1+/-0.3 (con) vrs 2.6 +/0,4 (BPC)). Conclusion According to our results we could conclude that BPC 157 improves small bowel and liver lesions healing in malnutrition conditions even during high dose diclofenac exposure.

Pentadecapeptide BPC 157 Counteracts Failure of Lower Esophageal and Pyloric Sphincter Induced by NSAIDs in Rats

The risks of aspirin/NSAIDs to induce esophageal and other GI tract lesions have been documented, whilst their effect on lower esophagea sphincter (LES) and pyloric sphincter (PS) pressure is far less studied. Thereby, we tested in rats various NSAIDs and a safe stable gastric pentadecapeptide BPC 157(GEPPPGKPADDAGLV, MW 1419), LD1 not achieved, since successful in inflammatory bowel disease trials, and counteracts esophagitis, sphincters failure, gastrointestinal ulcer and skin ulcer, gastro- or colo-cutaneous fistulas in rats, and particularly counteracts NSAIDs-lesions(1-6). Diclofenac (DI) (12.5 or 40 mg/kg ip, once daily, for 1, 2 or 3 days), ibuprofen (IB) (400 mg/day/kg for 4 weeks), paracetamol (PA) (150 mg/kg ip, 250 mg/kg ig, 5 g/kg ip once), aspirin (AS) (400 mg/kg i.p. or i.g.), BPC 157 immediately after NSAIDs (10 ug/kg i.p. or i.g.), LES and PS pressure (cm H2O), 10 rats at least per group, assessed as described before (3). NSAIDs (control). Regularly, fall of pressure occurred rapidly and persisted (i.e., DI, 12.5 mg: 30 mins: 45.0±2.5 PS, 55.0±2.5 LES - 3h: 43.8±2.5 PS, 56.0±2.5 LES -41.0±3.0 PS, 48.6±3.5 LES (3 days) ; PA 250 mg ig: 60.0±1.5 PS, 63.0±1.0 LES (15 mins) ; PA 5g ip: 35.0±5.5 PS, 40.0±3.5 LES (3h) ; IB, 4 weeks: 33.0±3.5 PS, 43.0±3.0 LES ; AS 400mg ip, 3h: 60.0±1.5 PS, 62.0±0.5 LES (3h) ; AS 400mg ig, 3h: 58.0±1.5 PS, 61.0±1.0 LES ; BPC 157. Regularly, initial fall of pressure was minimized and pressure values restored to normal values (i.e., DI, 12.5 mg: 30 mins: 66.0±2.5 PS, 70.0±2.5 LES - 3h: 62.8±2.5 PS, 69.0±3.5 LES – 62.2±3.0 PS, 72.6±5.5 LES (3 days) ; PA 250 mg ig: 70.0±1.5 PS, 73.0±1.0 LES (15 mins) ; PA 5g ip: 68.0±5.5 PS, 70.0±2.5 LES (3h) ; IB, 4 weeks: 70.0±5.5 PS, 73.0±6.0 LES ; AS 400mg ip, 3h: 65.0±0.5 PS, 70.0±0.8 LES (3h) ; AS 400mg ig, 3h: 68.0±1.5 PS, 71.0±0.9 LES ; ; (vs. control p<0.05). Finally, these BPC 157 effects correlate with attenuated injuries of liver (PA+BPC157 ; IB+BPC157), stomach (AS+BPC 157, IB+BPC 157, DI+BPC157), and small intestine (DI+BPC157). All tested NSAIDs decrease pressure in LES and PS, whilst BPC 157 counteracts their effects and restored LES and PS function. Literature. 1.Curr Pharm Des. 2010 ; 16:1224-34, 2. Dig Dis Sci. 2009 ; 54:2070-83, 3. J Pharmacol Sci. 2008 ; 108:7-17, 4. Dig Dis Sci. 2009 ; 54:46-56, 5. J Pharmacol Sci. 2007 ; 104:7-18. 6. J Physiol Pharmacol. 2010 ; 61:241-50.

Pentadecapeptide BPC 157 and its effects on a NSAID toxicity model: Diclofenac-induced gastrointestinal, liver, and encephalopathy lesions

Aims We attempted to fully antagonize the extensive toxicity caused by NSAIDs (using diclofenac as a prototype). Main methods Herein, we used the stable gastric pentadecapeptide BPC 157 (GEPPPGKPADDAGLV, MW 1419), an anti-ulcer peptide shown to be efficient in inflammatory bowel disease clinical trials (PL 14736) and various wound treatments with no toxicity reported. This peptide was given to antagonize combined gastrointestinal, liver, and brain toxicity induced by diclofenac (12.5 mg/kg intraperitoneally, once daily for 3 days) in rats. Key findings Already considered a drug that can reverse the toxic side effects of NSAIDs, BPC 157 (10 μg/kg, 10 ng/kg) was strongly effective throughout the entire experiment when given (i) intraperitoneally immediately after diclofenac or (ii) per-orally in drinking water (0.16 μg/mL, 0.16 ng/mL). Without BPC 157 treatment, at 3 h following the last diclofenac challenge, we encountered a complex deleterious circuit of diclofenac toxicity characterized by severe gastric, intestinal and liver lesions, increased bilirubin, aspartate transaminase (AST), alanine transaminase (ALT) serum values, increased liver weight, prolonged sedation/unconsciousness (after any diclofenac challenge) and finally hepatic encephalopathy (brain edema particularly located in the cerebral cortex and cerebellum, more in white than in gray matter, damaged red neurons, particularly in the cerebral cortex and cerebellar nuclei, Purkinje cells and less commonly in the hippocampal neurons). Significance The very extensive antagonization of diclofenac toxicity achieved with BPC 157 (μg-/ng-regimen, intraperitoneally, per-orally) may encourage its further use as a therapy to counteract diclofenac- and other NSAID-induced toxicity.

Pentadecapeptide BPC 157 (PL 14736) improves ligament healing in the rat

We improved medial collateral ligament (MCL) healing throughout 90 days after surgical transection. We introduced intraperitoneal, per-oral (in drinking water) and topical (thin cream layer) peptide therapy always given alone, without a carrier. Previously, as an effective peptide therapy, stable gastric pentadecapeptide BPC 157 (GEPPPGKPADDAGLV, an anti-ulcer peptide effective in inflammatory bowel disease therapy (PL 14736)) particularly improved healing of transected tendon and muscle and wound healing effect including the expression of the early growth response 1 (egr-1) gene. After MCL transection BPC 157 was effective in rats when given once daily intraperitoneally (10 microg or 10 ng/kg) or locally as a thin layer (1.0 microg dissolved in distilled water/g commercial neutral cream) at the site of injury, first application 30 min after surgery and the final application 24 h before sacrifice. Likewise, BPC 157 was effective given per-orally (0.16 microg/ml in the drinking water (12 ml/day/rat)) until sacrifice. Commonly, BPC 157 microg-ng-rats exhibited consistent functional, biomechanical, macroscopic and histological healing improvements. Thus, we suggest BPC 157 improved healing of acute ligament injuries in further ligament therapy.

S1823 Acute Pancreatitis Can Induce Esophagitis and Sphincter Failure as Well as Aggravate a Preexsisting Esophagitis and Sphincter Failure in Rats. Successful Effect of Stable Gastric Pentadecapeptide BPC 157 (PL 14736)

Recently, we showed the failed sphincter function in esophagitis-rats (J Pharm Sci, 200, 2007) and that pyloric sphincter (PS) failure induced lower esophageal sphincter (LES) failure. The next focus was on whether acute pancreatitis can aggravate or even induce esophagitis development and/or affect the pressure in lower esophageal and pyloric sphincters. As a solution, we proposed an orally active, stable gastric pentadecapeptide BPC 157 (GEPPPGKPADDAGLV, MW 1419, an anti-ulcer peptide efficient in trials for inflammatory bowel disease (PL 14736, Pliva) and various wound treatment, no toxicity reported). In esophagitis-rats with sphincter dysfunction (J Pharm Sci, 2006, 2007) BPC 157 attenuated esophagitis and recovered low pressure in LES and PS. Previously, it was concluded that it also attenuates acute pancreatitis (Dig Dis Sci, 1996). As we described before in rats (J Pharm Sci, 2007, Eur J Pharmacol, 1987, Dig Dis Sci, 1996), tube insertion into PS induced esophagitis and LES and PS failure while bile duct ligation induced acute pancreatitis, assessed at 24 hours after surgery. Fall or raise in sphincter pressure (cm H2O) was assessed as a percentage of initial values in normal rats. BPC 157 (10 µg, 10 ng/kg, i.p. or i.g.) was given immediately after surgery, and/or 5 min before sphincter pressure assessment. Acute pancreatitis+esophagitis vs. esophagitis-rats. Compared with esophagitis-rats (tube only into PS) (80% LES, 83% PS fall) acute pancreatitis in esophagitis-rats (bile duct ligation+tube into PS) additionally aggravated esophagitis and reduced LES- and PS-pressure to 71% (LES) and 70% (PS). Also, acute pancreatitis itself (bile duct ligation) induced esophagitis and reduced LES- and PS-pressure to 79% (LES) and 81% (PS). BPC 157 therapy macro/microscopically and biochemically attenuated esophagitis (tube into PS), acute pancreatitis +esophagitis (bile duct ligation+tube into PS) and acute pancreatitis (bile duct ligation) and generally induced an increase in pressure of LES and PS(110% LES, 105% PS raise in esophagitis-rats ; 105% LES, 102% PS raise in acute pancreatitis+esophagitis-rats ; 111% LES, 107% PS raise in acute pancreatitis-rats). Acute pancreatitis can induce esophagitis and sphincter failure as well as aggravate already existing esophagitis and sphincter failure in rats while BPC 157 can be a successful medication.

S1826 CpG DNA Activates Pancreatic Stellate Cell via Toll Like Receptor9

Acute Pancreatitis Can Induce Esophagitis and Sphincter Failure as Well as Aggravate a Preexsisting Esophagitis and Sphincter Failure in Rats. Successful Effect of Stable Gastric Pentadecapeptide BPC 157 (PL 14736) Ivan Dobric, Igor Petrovic, Robert Klicek, Spomenko Ilic, Marinko Filipovic, Marko Sever, Ivan Barisic, Bozo Radic, Vide Bilic, Lidija Berkopic, Luka Brcic, Iva Brcic, Danijela Kolenc, Tomislav Becejac, Dinko Stancic Rokotov, Sven Seiwerth, Predrag Sikiric

W1339 Safe Anti-Ulcer Peptide, in Trial for Inflammatory Bowel Desease, Stable Gastric Pentadecapeptide BPC 157 (PL14736) Can Cure Rats With Short Bowel Syndrome Complicated With Ulcerative Colitis

W1339 Safe Anti-Ulcer Peptide, in Trial for Inflammatory Bowel Desease, Stable Gastric Pentadecapeptide BPC 157 (PL14736) Can Cure Rats With Short Bowel Syndrome Complicated With Ulcerative Colitis

Revised Roberts Cytoprotection and Adaptive Cytoprotection and Stable Gastric Pentadecapeptide BPC 157. Possible Significance and Implications for Novel Mediator

The significance of cytoprotection and adaptive cytoprotection and the peptides importance remained to be not completely determined. BPC 157 is an anti-ulcer peptidergic agent, proven in clinical trials to be both safe in inflammatory bowel disease (PL-10, PLD-116, PL 14736) and wound healing, and stable in human gastric juice, with no toxicity being reported. It has a prominent effect on alcohol- lesions (i.e., induced acutely and chronically) and non-steroidal anti-inflammatory drugs-lesions (while interestingly BPC 157 may both prevent and reverse adjuvant arthritis). To review the importance of BPC 157, this review focused on Robert's cytoprotection concept described in rat stomach, reviewing our evidence that may resolve whether the cytoprotection and adaptive cytoprotection is an uniform phenomenon or not; whether the phenomenon or phenomena are endogenous or not, depending on nature of the irritants (mild or strong); whether this may contribute to stomach mucosa defense either when threaten by various ulcerogens or afforded by various antiulcer agents; whether these phenomena are uniform in whole gastrointestinal tract or not; whether they are interrelated or not. Finally, the importance of the cytoprotection phenomena and cytoprotection activity for skin wound healing, and wound healing in general was challenged. Thereby, this review focused on BPC 157 role in cytoprotection and adaptative cytoprotection suggesting that it may be the essential endogenous mediator able to mediate both cytoprotective and adaptive cytoprotective response in stomach and the whole gastrointestinal tract with significant importance in wound healing as well.

Peptide therapy with pentadecapeptide BPC 157 in traumatic nerve injury

We focused on the healing of rat transected sciatic nerve and improvement made by stable gastric pentadecapeptide BPC 157 (10 µg, 10 ng/kg) applied shortly after injury (i) intraperitoneally/intragastrically/locally, at the site of anastomosis, or after (ii) non-anastomozed nerve tubing (7 mm nerve segment resected) directly into the tube. Improvement was shown clinically (autotomy), microscopically/morphometrically and functionally (EMG, one or two months post-injury, walking recovery (sciatic functional index (SFI)) at weekly intervals). BPC 157-rats exhibited faster axonal regeneration: histomorphometrically (improved presentation of neural fascicles, homogeneous regeneration pattern, increased density and size of regenerative fibers, existence of epineural and perineural regeneration, uniform target orientation of regenerative fibers, and higher proportion of neural vs. connective tissue, all fascicles in each nerve showed increased diameter of myelinated fibers, thickness of myelin sheet, number of myelinated fibers per area and myelinated fibers as a percentage of the nerve transected area and the increased blood vessels presentation), electrophysiologically (increased motor action potentials), functionally (improved SFI), the autotomy absent. Thus, BPC 157 markedly improved rat sciatic nerve healing.

Gastric pentadecapeptide BPC 157 as an effective therapy for muscle crush injury in the rat

Stable gastric pentadecapeptide BPC 157 accelerates the healing of a transected Achilles tendon and a transected quadriceps muscle. It may also be of clinical relevance as a systemic and local peptide treatment for crush injury of a major muscle, such as gastrocnemius muscle complex. BPC 157 is effective without a carrier, and it is presently undergoing trials for inflammatory bowel disease, and no toxicity has so far been reported. In crushed rats (force delivered 0.727 Ns/cm2), BPC 157 was applied either intraperitoneally or locally, as a thin cream layer, immediately after injury (sacrifice at 2 h), and once a day for 14 days. BPC 157 improved muscle healing, macroscopically (less hematoma and edema, no post-injury leg contracture), microscopically, functionally, and also based on enzyme activity (creatine kinase, lactate dehydrogenase, aspartate aminotransferase, alanine aminotransferase). BPC 157, at all investigated intervals, given locally or intraperitoneally, accelerated post-injury muscle healing and also helped to restore the full function.