Therapy of the rat hemorrhagic cystitis induced by cyclophosphamide. Stable gastric pentadecapeptide BPC 157, L-arginine, L-NAME.

We focused on the cyclophosphamide-induced hemorrhagic cystitis (100 mg/kg/day intraperitoneally throughout three days) as a particular NO-system disturbance, and therapy possibilities. We demonstrated that it may be attenuated by subsequent administration of the NOS substrate L-arginine (100 mg/kg/day intraperitoneally), aggravated by NOS-blocker L-NAME (5 mg/kg/day intraperitoneally), all influenced by the stable gastric pentadecapeptide BPC 157 (10 µg/kg/day, 10 ng/kg/day, intraperitoneally or perorally, in drinking water). Regularly, cyclophosphamide dose- and time-dependently induced severe hemorrhagic cystitis lesions, gross lesions, and corresponding urothelial necrosis, vesical edema, erosion, hemorrhage, inflammation, and ulceration, microscopically. The bladder wet weight dramatically increased. Functionally, already after first cyclophosphamide administration, there is an increased leak point pressure. Until the second cyclophosphamide administration, L-arginine consistently attenuated regular cyclophosphamide-induced severe hemorrhagic cystitis lesions, grossly and microscopically, but not functionally. L-NAME aggravated these lesions and eradicated beneficial effect of L-arginine when combined. BPC 157 administration after cyclophosphamide, given in either dose or in either regimen markedly attenuated all cyclophosphamide lesions, grossly, microscopically. The increase of the bladder wet weight was consistently attenuated. Functionally, increased leak point pressure was reversed to the values noted in normal rats. The similar findings were noted in rats that received BPC 157 together with L-NAME or L-arginine, given alone or combined. Thus, the lesions are NO-related based on the administration of L-NAME as well as administration of L-arginine, and their mutual interaction, and counteraction by BPC 157 application. Likewise, we reveal new therapeutic possibilities, emphasizing stable gastric pentadecapeptide BPC 157 and L-arginine, versus L-NAME in rats underwent cyclophosphamide-induced cystitis.

Stable gastric pentadecapeptide BPC 157 in the therapy of the rats with bile duct ligation.

Recently, stable gastric pentadecapeptide BPC 157 reversed the high MDA- and NO-tissue values to the healthy levels. Thereby, BPC 157 therapy cured rats with bile duct ligation (BDL) (sacrifice at 2, 4, 6, 8 week). BPC 157-medication (10 µg/kg, 10 ng/kg) was continuously in drinking water (0.16 µg/ml, 0.16 ng/ml, 12 ml/rat/day) since awakening from surgery, or since week 4. Intraperitoneal administration was first at 30 min post-ligation, last at 24 h before sacrifice. Local bath BPC 157 (10 µg/kg) with assessed immediate normalization of portal hypertension was given immediately after establishing portal hypertension values at 4, 6, 8 week. BPC 157 therapy markedly abated jaundice, snout, ears, paws, and yellow abdominal tegmentum in controls since 4th week, ascites, nodular, steatotic liver with large dilatation of main bile duct, increased liver and/or cyst weight, decreased body weight. BPC 157 counteracts the piecemeal necrosis, focal lytic necrosis, apoptosis and focal inflammation, disturbed cell proliferation (Ki-67-staining), cytoskeletal structure in the hepatic stellate cell (α-SMA staining), collagen presentation (Mallory staining). Likewise, counteraction includes increased AST, ALT, GGT, ALP, total bilirubin, direct and indirect and decreased albumin serum levels. As the end-result appear normalized MDA- and NO-tissue values, next to Western blot of NOS2 and NOS3 in the liver tissue, and decreased IL-6, TNF-α, IL-1ß levels in liver tissue. Finally, although portal hypertension is sustained in BDL-rats, with BPC 157 therapy, portal hypertension in BDL-rats is either not even developed or rapidly abated, depending on the given BPC 157's regimen. Thus, BPC 157 may counteract liver fibrosis and portal hypertension.

Common Bile Duct Stricture After Laparoscopic Cholecystectomy: Case Report

Despite progress in laparoscopic surgery and increasing surgical experience, the incidence of bile duct injury during laparoscopic cholecystectomy fails to fall below 0.3%-0.6% and it is still higher than those recorded in the era of open cholecystectomy. Bile duct injuries belong to the most serious complications of abdominal surgery in general and often end up with liver transplantation as the only hope for cure. We present a case of a 78-year-old jaundiced male patient who sustained common hepatic duct injury during laparoscopic cholecystectomy eight months earlier. Exploratory laparotomy, ERCP and MRCP revealed a metal clip placed just below hepatic duct confluence and causing stricture of bile duct with dilatation of bile ducts proximal to the level of stenosis (Strasberg classification type E3 injury). Repair of the injury was performed by creating termino-lateral hepaticojejunostomy between the right and left hepatic ducts and retrocolic Roux en-Y jejunal limb. By presenting this case, we wish to emphasize the importance of timely conversion and execution of intraoperative cholangiography in all cases when identification of the structures of Calot's triangle is not clear enough. Successful treatment of bile duct injury is only possible with joint approach of radiologist, gastroenterologist and experienced hepatobiliary surgeon.

Stress in Gastrointestinal Tract and Stable Gastric Pentadecapeptide BPC 157. Finally, do we have a Solution?

Selye's syndrome produced by diverse nocuous agents and "response to damage as such" means Selye's stress triad in stress coping response to reestablish homeostasis. Logically, from the gastrointestinal tract viewpoint, such organoprotective/healing response implies the angiogenic growth factors that commonly signify the healing. Thereby, the gastric pentadecapeptide BPC 157-organoprotection (huge range of beneficial effects) signifies the Selye's stress concept/stress coping response implemented in and from gastrointestinal tract, and BPC 157 as an integrative mediator that integrates the adaptive bodily response to stress. In clinical trials without side effects, LD1 not achieved, BPC 157 healing in gastrointestinal tract, and particularly the healing of the extragastrointestinal tissues (i.e., skin/tendon/ligament/muscle/bone; nerve; cornea/ brain) were referred throughout its integrative capabilities (i.e., ulcerative colitis/multiple sclerosis model equally counteracted), native in gastrointestinal tract, stability in human gastric juice (and thereby, strong efficacy and applicability), its relevance for dopamine-system function (and thereby, counteracting effects of dopamine-system dysfunction and overfunction, centrally and peripherally (mucosa maintenance); interaction with serotonin- and GABA-system)), afforded cytoprotection/adaptive cytoprotection/organoprotection (and thereby, beneficial effects on gastric and whole intestinal tract lesions and adaptation, wounds and fistulas healing, blood vessels, somatosensory neurons, NSAIDs-side effects (including also pancreas, liver, brain lesions, and blood disturbances, prolonged bleeding, thrombocytopenia, thrombosis)). Further, we combine such gut-brain axis and the NO-system where BPC 157 counteracts complications of either L-NAME application (i.e., various lesions aggravation, hypertension) or Larginine application (i.e., hypotension, prolonged bleeding, thrombocytopenia). Also, BPC 157 particularly affects genes functions (i.e., Fos, c-Jun, Egr-1), all together suggestive for an indicative generalization. Thus, we could suggest gastric pentadecapeptide BPC 157 and BPC 157 induced-organoprotection as integrative mediator that integrates the adaptive bodily response to stress, and thereby practically applied in further therapy and in effective realization of Selye's stress response.

Laparoscopic Treatment of Morgagni Hernia: Report of Three Cases.

We report on three cases of diaphragmatic (Morgagni) hernia with different clinical presentation. It is important to consider the possibility of this rare but potentially very dangerous condition in patients with respiratory problems and pain in the upper abdomen. Before laparoscopy, two different approaches were used in diaphragmatic hernia operations (abdominal and thoracic approach). Laparoscopy has brought significant changes in the treatment of diaphragmatic hernia. It is important to stress that laparoscopic diaphragmatic surgical therapy uses stronger mesh than the mesh used to repair an inguinal hernia.

What is the Right Therapeutic Approach to Biliary Choledochal Cyst?

We report a case of biliary cyst type II which, independently of its a priori benign nature, caused numerous complications such as recurrent cholangitis and pancreatitis, as well as subsequent hepatic fibrosis and the potential danger of choledochocele perforation. Although they are benign, biliary/choledochal cysts can cause numerous disorders such as cholestasis, leading to cholangitis and pancreatitis and biliary sepsis, and due to chronic inflammation of the biliary system even cholangiocarcinogenesis. Our findings showed that sometimes this type of biliary cyst (according to the available literature the rarest and most benign type), as well as type I cyst, should undergo timely radical excision. In our patient, timely choledochocele resection would have certainly contributed to the reduction of subsequent complications, as well as to obviating repeated invasive diagnostic and surgical procedures.

Effects of Diclofenac, L-NAME, L-Arginine, and Pentadecapeptide BPC 157 on Gastrointestinal, Liver, and Brain Lesions, Failed Anastomosis, and Intestinal Adaptation Deterioration in 24 Hour-Short-Bowel Rats.

Stable gastric pentadecapeptide BPC 157 was previously used to ameliorate wound healing following major surgery and counteract diclofenac toxicity. To resolve the increasing early risks following major massive small bowel resectioning surgery, diclofenac combined with nitric oxide (NO) system blockade was used, suggesting therapy with BPC 157 and the nitric oxide synthase (NOS substrate) L-arginine, is efficacious. Immediately after anastomosis creation, short-bowel rats were untreated or administered intraperitoneal diclofenac (12 mg/kg), BPC 157 (10 µg/kg or 10 ng/kg), L-NG-nitroarginine methyl ester (L-NAME, 5 mg/kg), L-arginine (100 mg/kg) alone or combined, and assessed 24 h later. Short-bowel rats exhibited poor anastomosis healing, failed intestine adaptation, and gastrointestinal, liver, and brain lesions, which worsened with diclofenac. This was gradually ameliorated by immediate therapy with BPC 157 and L-arginine. Contrastingly, NOS-blocker L-NAME induced further aggravation and lesions gradually worsened. Specifically, rats with surgery alone exhibited mild stomach/duodenum lesions, considerable liver lesions, and severe cerebral/hippocampal lesions while those also administered diclofenac showed widespread severe lesions in the gastrointestinal tract, liver, cerebellar nuclear/Purkinje cells, and cerebrum/hippocampus. Rats subjected to surgery, diclofenac, and L-NAME exhibited the mentioned lesions, worsening anastomosis, and macro/microscopical necrosis. Thus, rats subjected to surgery alone showed evidence of deterioration. Furtheremore, rats subjected to surgery and administered diclofenac showed worse symptoms, than the rats subjected to surgery alone did. Rats subjected to surgery combined with diclofenac and L-NAME showed the worst deterioration. Rats subjected to surgery exhibited habitual adaptation of the remaining small intestine, which was markedly reversed in rats subjected to surgery and diclofenac, and those with surgery, diclofenac, and L-NAME. BPC 157 completely ameliorated symptoms in massive intestinal resection-, massive intestinal resection plus diclofenac-, and massive intestinal resection plus diclofenac plus L-NAME-treated short bowel rats that presented with cyclooxygenase (COX)-NO-system inhibition. L-arginine ameliorated only L-NAME-induced aggravation of symptoms in rats subjected to massive intestinal resection and administered diclofenac plus L-NAME.

Therapy of umbilical hernia during laparoscopic cholecystectomy.

The aim of this study is to show our experience with umbilical hernia herniorrhaphy and laparoscopic cholecystectomy, both in the same act. During last 10 years we operated 89 patients with cholecystitis and pre-existing umbilical hernia. In 61 of them we performed standard laparoscopic cholecystectomy and additional sutures of abdominal wall, and in 28 patients we performed in the same act laparoscopic cholecystectomy and herniorrhaphy of umbilical hernia. We observed incidence of postoperative herniation, and compared patients recovery after herniorrhaphy combined with laparoscopic cholecystectomy in the same act, and patients after standard laparoscopic cholecystectomy and additional sutures of abdominal wall. Patients, who had in the same time umbilical hernia herniorrhaphy and laparoscopic cholecystectomy, shown better postoperative recovery and lower incidence of postoperative umbilical hernias then patients with standard laparoscopic cholecystectomy and additional abdominal wall sutures.

[Pyogenic liver abscess caused by Klebsiella pneumoniae]. / Piogeni jetreni apsces uzrokovan bakterijom Klebsiella pneumoniae.

Pyogenic liver abscess caused by Klebsiella pneumoniae is usually found in Southeast Asia, while in Europe Escherichia coli, Streptococcus or Staphylococcus are most common. In case of a failed ultrasound controlled abscess, aspiration surgical treatment is indicated. This paper reports the clinical case of pyogenic liver abscess caused by Klebsiella pneumoniae, which was treated by operative drainage. A 60-year-old patient was transferred to our institution from the University Hospital for Infectious Diseases with septic temperature, abdominal pain and finding of Klebsiella pneumoniae liver abscess (resistant to antibiotic therapy). Additional laboratory tests and abdominal MSCT scan confirmed the initial diagnosis. The localization of abscesses technically prevented ultrasound-controlled abscess aspiration and drainage; after appropriate preparation, operative liver abscess incision and drainage were performed. Microbiological examination of the abscess sample revealed Klebsiella pneumoniae as the cause of liver abscess.

[Bile stone ileus with cholecystoduodenal fistula--Bouveret's syndrome]. / Visoki ileus uzrokovan uglavljenim zucnim kamenom u silaznom dvanaesniku kao posljedica kolecistoduodenalne fistule--Bouveretov sindrom.

This is a case report of a 71-year-old man, who presented to emergency department with elevated temperature, vomiting and epigastric pain. Computed tomography of the abdomen revealed a large fistulous tract extending from the gallbladder to the duodenal bulb, as well as a large calculus obstructing the second part of the duodenum. The patient subsequently underwent successful surgical 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.

Single incision laparoscopic cholecystectomy--a new advantage of gallbladder surgery.

In this study is demonstrated our experience in single incision laparoscopic cholecystectomy (SILS), compared to standard laparoscopic cholecystectomy. There were 48 single incision laparoscopic cholecystectomies (SILS) performed during one-year period (A group) and results have been compared with a group of 50 patients who underwent standard laparoscopic cholecystectomy (B group). Outcome measures included operative time, need for conversion, complications, additional analgesia for pain control after procedure, hospital stay and cosmetic outcome. The mean operative time was 46 +/- 3.5 min in A group, and 43 +/- 4 min in B patients group. Early postoperative complications were not detected. The mean hospitalization period was 2 days in both groups. Our experience suggests that SILS cholecystectomy can be performed with outcome similar to standard laparoscopic surgery while affording better cosmesis.

[A contribution to surgical treatment of gastric and duodenal ulcer hemorrhage in critically unstable patients]. / Prilog operacijskom lijecenju krvareceg ulkusa zeluca i dvanaesnika u vitalno ugrozenih bolesnika.

UNLABELLED: One of the complications of gastroduodenal ulcer disease is gastrointestinal hemorrhage; it is a cause of a substantial mortality. Standard therapy of gastroduodenal hemorrhage consists of endoscope sclerosation, over sewing or resection. The aim of this study is to analyze our results and methods in treatment of life threatening patients with gastroduodenal hemorrhage. PATIENTS AND METHODS: A series of 47 life treating patients was surgically treated in General Hospital Sveti Duh in Zagreb for gastroduodenal hemorrhage during the period of 10 years and were retrospectively analyzed. Massive gastroduodenal hemorrhage was endoscopically confirmed, and after insufficient endoscopic therapy, surgically treated. For a treatment in 47 patients (which could not survive gastric resection) we used ulcer over sewing in 20 of them combined with gastroduodenal artery (GDA) or left gastric artery (LGA) ligation. RESULTS: Patients which were treated with combination of artery ligation and ulcer oversewing, had better results in stopping gastroduodenal hemorrhage, lower mortality and recidivism when they were compared with group which was treated only with standard ulcer oversewing, without artery ligations. CONCLUSIONS: Combination of artery ligation (LGA or GDA) and ulcer oversewing shows better results in stopping gastroduodenal hemorrhage than standard ulcer suture itself.

Impact of pentadecapeptide BPC 157 on muscle healing impaired by systemic corticosteroid application.

BACKGROUND: The effect of systemic and local peptide treatment effective in muscle contusion and then on counteraction of corticosteroid-induced impairment was tested. The pentadecapeptide BPC 157, given without a carrier, improved the healing of transected quadriceps muscle. It also improved muscle healing in rats with muscle crush injury when applied systemically or locally. Importantly, it counteracted corticosteroid-impairment in tendon to bone healing. Thus BPC 157 is proposed as an effective treatment that can improve muscle healing in spite of corticosteroid treatment. MATERIAL/METHODS: After the gastrocnemius muscle complex had been injured, rats received BPC 157 (intraperitoneally or locally as a cream) and/or 6alpha-methylprednisolone (intraperitoneally) only once (immediately after injury, sacrifice at 2 h) or once daily (final dose 24 hours before sacrifice and/or assessment procedure at days 1, 2, 4, 7, and 14). Muscle healing was evaluated functionally, macroscopically, and histologically. RESULTS: Without therapy, crushed gastrocnemius muscle complex controls showed limited improvement. 6alpha-methylprednisolone markedly aggravated healing. In contrast, BPC 157 induced faster muscle healing and full function restoration and improved muscle healing despite systemic corticosteroid treatment when given intraperitoneally or locally and demonstrated functionally, macroscopically, and histologically at all investigated intervals. CONCLUSIONS: BPC 157 completely reversed systemic corticosteroid-impaired muscle healing.

Gastric pentadecapeptide BPC 157 and short bowel syndrome in rats.

The gastric pentadecapeptide BPC 157, which was shown to be safe as an antiulcer peptide in trials for inflammatory bowel disease (PL14736, Pliva), successfully healed intestinal anastomosis and fistula in rat. Therefore, we studied for 4 weeks rats with escalating short bowel syndrome and progressive weight loss after small bowel resection from fourth ileal artery cranially of ileocecal valve to 5 cm beneath pylorus. BPC 157 (10 microg/kg or 10 ng/kg) was given perorally, in drinking water (12 ml/rat/day) or intraperitoneally (once daily, first application 30 min following surgery, last 24 h before sacrifice). Postoperatively, features of increasingly exhausted presentation were: weight loss appearing immediately regardless of villus height, twofold increase in crypt depth and fourfold increase in muscle thickness within the first week, jejunal and ileal overdilation, and disturbed jejunum/ileum relation. In contrast, constant weight gain above preoperative values was observed immediately with BPC 157 therapy, both perorally and parenterally, and villus height, crypt depth, and muscle thickness [inner (circular) muscular layer] also increased, at 7, 14, 21, and 28 days. Moreover, rats treated with pentadecapeptide BPC 157 showed not different jejunal and ileal diameters, constant jejunum-to-ileum ratio, and increased anastomosis breaking strength. In conclusion, pentadecapeptide BPC 157 could be helpful to cure short bowel syndrome.

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.

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 microg/kg) (12 ml/rat/day) or intraperitoneally (10 microg/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.

Pentadecapeptide BPC 157, in clinical trials as a therapy for inflammatory bowel disease (PL14736), is effective in the healing of colocutaneous fistulas in rats: role of the nitric oxide-system.

We focused on the therapeutic effect of the stable gastric pentadecapeptide BPC 157 and how its action is related to nitric oxide (NO) in persistent colocutaneous fistula in rats (at 5 cm from anus, colon defect of 5 mm, skin defect of 5 mm); this peptide has been shown to be safe in clinical trials for inflammatory bowel disease (PL14736) and safe for intestinal anstomosis therapy. BPC 157 (10 microg/kg, 10 ng/kg) was applied i) in drinking water until the animals were sacrificed at post-operative day 1, 3, 5, 7, 14, 21, and 28; or ii) once daily intraperitoneally (first application 30 min following surgery, last 24 h before sacrifice) alone or with N(G)-nitro-L-arginine methyl ester (L-NAME) (5 mg/kg), L-arginine (200 mg/kg), and their combinations. Sulphasalazine (50 mg/kg) and 6-alpha-methylprednisolone (1 mg/kg) were given once daily intraperitoneally. BPC 157 accelerated parenterally or perorally the healing of colonic and skin defect, leading to the suitable closure of the fistula, macro/microscopically, biomechanically, and functionally (larger water volume sustained without fistula leaking). L-NAME aggravated the healing failure of colocutaneous fistulas, skin, and colon wounds (L-NAME groups). L-Arginine was effective only with blunted NO generation (L-NAME + L-arginine groups) but not without (L-arginine groups). All of the BPC 157 beneficial effects remained unchanged with blunted NO-generation (L-NAME + BPC 157 groups) and with NO substrate (L-arginine + BPC 157 groups) as well as L-NAME and L-arginine co-administration (L-NAME + L-arginine + BPC 157 groups). Sulphasalazine was only moderately effective, and corticosteroid even had an aggravating effect.

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

PURPOSE: 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. METHODS: 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. RESULTS: 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). CONCLUSION: BPC 157, at all investigated intervals, given locally or intraperitoneally, accelerated post-injury muscle healing and also helped to restore the full function.

Stable gastric pentadecapeptide BPC 157 in trials for inflammatory bowel disease (PL-10, PLD-116, PL14736, Pliva, Croatia) heals ileoileal anastomosis in the rat.

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 microg, 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.

Prolonged esophagitis after primary dysfunction of the pyloric sphincter in the rat and therapeutic potential of the gastric pentadecapeptide BPC 157.

Seven or fourteen days or twelve months after suturing one tube into the pyloric sphincter (removed by peristalsis by the seventh day), rats exhibit prolonged esophagitis with a constantly lowered pressure not only in the pyloric, but also in the lower esophageal sphincter and a failure of both sphincters. Throughout the esophagitis experiment, gastric pentadecapeptide BPC 157 (PL 14736) is given intraperitoneally once a day (10 microg/kg, 10 ng/kg, last application 24 h before assessment), or continuously in drinking water at 0.16 microg/ml, 0.16 ng/ml (12 ml/rat per day), or directly into the stomach 5 min before pressure assessment (a water manometer connected to the drainage port of a Foley catheter implanted into the stomach either through an esophageal or duodenal incision). This treatment alleviates i) the esophagitis (macroscopically and microscopically, at either region or interval), ii) the pressure in the pyloric sphincter, and iii) the pressure in the lower esophageal sphincter (cmH2O). In the normal rats it increases lower esophageal sphincter pressure, but decreases the pyloric sphincter pressure. Ranitidine, given using the same protocol (50 mg/kg, intraperitoneally, once daily; 0.83 mg/ml in drinking water; 50 mg/kg directly into the stomach) does not have an effect in either rats with esophagitis or in normal rats.