Spomenko Ilic

Revised Robert's 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 Roberts 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.

Stable gastric pentadecapeptide BPC 157-NO-system relation.

We reviewed stable gastric pentadecapeptide BPC 157-NO-system-relation, its close participation in Moncadas (maintained vascular integrity, platelets control) homeostatic healing response of NO-system to injury. Namely, BPC 157s particular healing effect also affects all events after vascular integrity loss (dependent on circumstances, it reduces either thrombosis (abdominal aorta anastomosis) or bleeding/thrombocytopenia (amputation, heparin, warfarin, aspirin)) and in a series of different injurious models, acute and chronic, BPC 157 consistently advances healing after severe injuries in various tissues spontaneously unable to heal; stimulates egr-1 and naB2 genes; exhibits high safety (LD1 not achieved)). Hypothesis, that BPC 157 (since formed constitutively in the gastric mucosa, stable in human gastric juice, along with significance of NO-synthase and the basal formation of NO in stomach mucosa, greater than that seen in other tissues) exhibits a general, effective competing both with L-arginine analogues (i. e., L-NAME) and L-arginine, and that this has some physiologic importance (NO-generation), later, practically supports its beneficial effects illustrating BPC 157 and NOsystem mutual (with L-NAME/L-arginine; alone and together) relations in (i) gastric mucosa and mucosal protection, following alcohol lesions, in cytoprotection course, NO-generation, and blood pressure regulation; (ii) alcohol acute/chronic intoxication, and withdrawal; (iii) cardiovascular disturbances, chronic heart failure, pulmonary hypertension, and arrhythmias; (iv) disturbances after hypokalemia and hyperkalemia, and potassium-cell membrane dysfunction; and finally, in (v) complex healing failure, proved by the fistulas healing, colocutaneous and esophagocutaneous. However, how this advantage of modulating NO-system (i. e., particular effect on eNOS gene), may be practically translated into an enhanced clinical performance remains to be determined.

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.

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 (12.5mg/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 3h 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.

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 Roberts 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.

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.

Celecoxib-induced gastrointestinal, liver and brain lesions in rats, counteraction by BPC 157 or L-arginine, aggravation by L-NAME

AIM To counteract/reveal celecoxib-induced toxicity and NO system involvement. METHODS Celecoxib (1 g/kg b.w. ip) was combined with therapy with stable gastric pentadecapeptide BPC 157 (known to inhibit these lesions, 10 μg/kg, 10 ng/kg, or 1 ng/kg ip) and L-arginine (100 mg/kg ip), as well as NOS blockade [N(G)-nitro-L-arginine methyl ester (L-NAME)] (5 mg/kg ip) given alone and/or combined immediately after celecoxib. Gastrointestinal, liver, and brain lesions and liver enzyme serum values in rats were assessed at 24 h and 48 h thereafter. RESULTS This high-dose celecoxib administration, as a result of NO system dysfunction, led to gastric, liver, and brain lesions and increased liver enzyme serum values. The L-NAME-induced aggravation of the lesions was notable for gastric lesions, while in liver and brain lesions the beneficial effect of L-arginine was blunted. L-arginine counteracted gastric, liver and brain lesions. These findings support the NO system mechanism(s), both NO system agonization (L-arginine) and NO system antagonization (L-NAME), that on the whole are behind all of these COX phenomena. An even more complete antagonization was identified with BPC 157 (at both 24 h and 48 h). A beneficial effect was evident on all the increasingly negative effects of celecoxib and L-NAME application and in all the BPC 157 groups (L-arginine + BPC 157; L-NAME + BPC 157; L-NAME + L-arginine + BPC 157). Thus, these findings demonstrated that BPC 157 may equally counteract both COX-2 inhibition (counteracting the noxious effects of celecoxib on all lesions) and additional NOS blockade (equally counteracting the noxious effects of celecoxib + L-NAME). CONCLUSION BPC 157 and L-arginine alleviate gastrointestinal, liver and brain lesions, redressing NSAIDs’ post-surgery application and NO system involvement.

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.

Sa1955 Ulcerogenic Effect of Clozapine, Olanzapine, Risperidone, Sertaline and Venlafaxine in Rats. Beneficial Effect of Stable Gastric Pentadecapeptide BPC 157

Aim. We focused on poorly studied effect of haloperidol (H) on lower esophageal and pyloric sphincter pressure, NO-synthase (NOS) blockade by L-NAME, and counteracting effect of stable gastric pentadecapeptide BPC 157 (GEPPPGKPADDAGLV, M.W. 1419), already successfully tested in patients with inflammatory bowel disease. Haloperidol, useful for severe nausea/emesis by acting at the chemoreceptor trigger zone (CTZ), is also ulcerogen, both producing and aggravating gastric lesions (Life Sci, 2001;68:1905-12). BPC 157 antagonizes haloperidol catalepsy and gastric lesions (Eur J Pharmacol, 1999;379:19-31), and has a particular anti-reflux effect on sphincters in health and diseased animals (J Pharm Sci, 2006; 102:269-77; 2007; 104:7-18). Methods. In all rats LES and PS pressure manometrical evaluation (cmH2O) was as described (J Pharm Sci, 2006; 102:269-77; 2007; 104:7-18) (the values of 68-76 cmH2O for LES and 68-74 cmH2O for PS as normal as determined before). Medication was haloperidol (6.25, 12.5, 25mg/kg/day ip) (given in ulcerogenic doses), BPC 157 (10ug, 10ng/kg/day ip) for 7 days, last application 30 min before assessment, L-NAME (5mg/kg ip) at 30min before assessment. Results. Haloperidol consistently produced a fall in LES (65±1 (H 6.25); 66±1 (H 12.5), 64±1 (H 25) and an even more prominent drop in PS (55±2;56±1;54±2 (H 6.25; 12.5; 25)); L-NAME co-administration induced an aggravation (LES below 60; PS below 50 cmH2O). Contrary, BPC 157 both doses counteracted haloperidol-induced fall in sphincters pressure, with a marked increase (PS) or even a rise till the normal values (LES). Likewise, BPC 157, given with L-NAME, counteracted L-NAME-aggravation of haloperidol-induced fall in sphincters pressure. Conclusions. Haloperidol-induced fall in sphincters pressure that contributes to its ulcerogenic effect is NOsystem related, while BPC 157 maintains and rescues LES and PS-function.

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

Stable gastric pentadecapeptide BPC 157 recovered short bowel sydrome in rats after massive small bowel resection, improved intestinal adaptation, villus height, crypt depth, and muscle thickness (and inner (circular) and/or outer (longitudinal) muscular layer)), induced weight gain in weight of normal healthy rats (Dig Dis Sci, 2008 in press). BPC 157 is a safe anti-ulcer peptide (PL-14736, Pliva) in trial for IBD, and wound therapy, no toxicology reported (Gastroenterology, 2005) that healed intestinal anastomosis and fistulas (Dig Dis Sci, 2008, J Pharm Sci, 2008). BPC 157 also prevented and reversed ulcerative colitis induced by cysteamine enema (J Physiol, 1999). However, BPC 157 was not tested after small bowel massive resection in rats with ulcerative colitis. Small bowel resection. Throughtout a 4 week period we tested rats with escalating bowel syndrome and progressive weight loss that had only 20% of small bowel (Dig Dis Sci, 2008, in press). Ulcerative colitis. Cysteamine enema 400 mg/kg i.r., 1ml/rat. Ulcerative colitis+small bowel resection. Enema was applied at 10 min before surgery. BPC 157 medication. BPC 157 (10 μg, 10ng/kg i.p. or in drinking water) first application 30 min following surgery, last 24 h before sacrifice (7, 14, 21, 28 days). Small bowel resection. The rats had an escalating bowel syndrome and progressive weight loss despite the fourfold muscle thickness increase and twofold villus height and crypt depth increase during the first week. BPC 157 groups recovery showed improved intestinal adaptation, villus height, crypt depth, and muscle thickness (and inner (circular) and/or outer (longitudinal) muscular layer))additionally increased. The rats immediately gained weight, ultimately to the weight of normal healthy rats. Ulcerative colitis. Controls exhibited pertinent ulceration, initial weight loss, and then decreased weight gain. BPC 157 rats immediately gained weight, ultimately to the weight of normal healthy rats, and had consistently less ulcerations. Ulcerative colitis+small bowel resection. Ulcerative colitis significantly aggravated all these parameters. BPC 157 retained the same beneficial effects, decreased ulcerative colitis, improved intestinal adaptation, villus height, crypt depth, and muscle thickness (and inner (circular) and/or outer (longitudinal) muscular layer)) additionally increased, early weight gain, ultimately to the weight of normal healthy rats. In addition to the recovery of the rats with short bowel syndrome or ulcerative colitis, BPC 157 can cure rats with short bowel syndrome complicated with ulcerative colitis.