Publications by authors named "Neven Kokic"

6 Publications

  • Page 1 of 1

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

Surg Today 2007 27;37(9):768-77. Epub 2007 Aug 27.

Department of Pharmacology, Medical Faculty, University of Zagreb, Salata 11, POB 916, 10000 Zagreb, Croatia.

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.
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http://dx.doi.org/10.1007/s00595-006-3498-9DOI Listing
December 2007

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

J Pharmacol Sci 2007 May 24;104(1):7-18. Epub 2007 Apr 24.

Department of Pharmacology, Medical School, University of Zagreb, Croatia.

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.
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http://dx.doi.org/10.1254/jphs.fp0061322DOI Listing
May 2007

An experimental model of prolonged esophagitis with sphincter failure in the rat and the therapeutic potential of gastric pentadecapeptide BPC 157.

J Pharmacol Sci 2006 Nov;102(3):269-77

Department of Pharmacology, Medical Faculty, University of Zagreb, Zagreb, Croatia.

We report a simple novel rat model that combines prolonged esophagitis and parallel sphincters failure. The anti-ulcer gastric pentadecapeptide BPC 157, which was found to be stable in gastric juice, and is being evaluated in inflammatory bowel disease trials, is an anti-esophagitis therapy that recovers failed sphincters. Twelve or twenty months after the initial challenge (tubes sutured into sphincters for one week and then spontaneously removed by peristalsis), rats exhibit prolonged esophagitis (confluent hemorrhagic and yellowish lesions, thinner epithelium and superficial corneal layer, with stratification derangement); constantly lowered pressure of both sphincters (assessed by using a water manometer connected to the drainage port of a Foley catheter implanted into the stomach either through esophageal or duodenal incision); and both lower esophageal and pyloric sphincter failure. Throughout the esophagitis experiment, BPC 157 was given at either 10 micro g/kg, i.p., once a day (last application 24 h before assessment) or alternatively, it was given continuously in drinking water at 0.16 micro g/ml (12 ml/rat). This treatment recovers i) esophagitis (macroscopically and microscopically, at either region or investigated time period) and ii) pressure in both sphincters (cmH2O). In addition, BPC 157 (10 micro g/kg) or saline (1 ml/rat, 5 ml/kg) was specifically given directly into the stomach; pressure assessment was performed at 5 min thereafter. The effect of BPC 157 is specific because in normal rats, it increases lower esophageal sphincter-pressure, but decreases pyloric sphincter-pressure. Ranitidine, given as the standard drug using the same protocol (50 mg/kg, i.p., once daily; 0.83 mg/ml in drinking water; or 50 mg/kg directly into the stomach) had no effect.
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http://dx.doi.org/10.1254/jphs.fp0060070DOI Listing
November 2006

Effective therapy of transected quadriceps muscle in rat: Gastric pentadecapeptide BPC 157.

J Orthop Res 2006 May;24(5):1109-17

Department of Pharmacology, School of Medicine, University of Zagreb, Salata 11, P.O.B. 916, 10000 Zagreb, Croatia.

We report complete transection of major muscle and the systemic peptide treatment that induces healing of quadriceps muscle promptly and then maintains the healing with functional restoration. Initially, stable gastric pentadecapeptide BPC 157 (GEPPPGKPADDAGLV, M.W. 1419, PL-10, PLD-116, PL 14736 Pliva, Croatia; in trials for inflammatory bowel disease; wound treatment; no toxicity reported; effective alone without carrier) also superiorly accelerates the healing of transected Achilles tendon. Regularly, quadriceps muscle completely transected transversely 1.0 cm proximal to patella presents a definitive defect that cannot be compensated in rat. BPC 157 (10 microg, 10 ng, 10 pg/kg) is given intraperitoneally, once daily; the first application 30 min posttransection, the final 24 h before sacrifice. It consistently improves muscle healing throughout the whole 72-day period. Improved are: (i) biomechanic (load of failure increased); (ii) function (walking recovery and extensor postural thrust/motor function index returned toward normal healthy values); (iii) microscopy/immunochemistry [i.e., mostly muscle fibers connect muscle segments; absent gap; significant desmin positivity for ongoing regeneration of muscle; larger myofibril diameters on both sides, distal and proximal (normal healthy rat-values reached)]; (iv) macroscopic presentation (stumps connected; subsequently, atrophy markedly attenuated; finally, presentation close to normal noninjured muscle, no postsurgery leg contracture). Thus, posttransection healing-consistently improved-may suggest this peptide therapeutic application in muscle disorders.
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http://dx.doi.org/10.1002/jor.20089DOI Listing
May 2006

The presentation and organization of adaptive cytoprotection in the rat stomach, duodenum, and colon. Dedicated to André Robert the founder of the concept of cytoprotection and adaptive cytoprotection.

Med Sci Monit 2006 Apr 28;12(4):BR146-53. Epub 2006 Mar 28.

Department of Pharmacology, Medical Faculty University of Zagreb, Zagreb, Croatia.

Background: Adaptive cytoprotection could be demonstrated in lesion attenuation within the whole gastrointestinal tract, in particular sequences, with onset and duration longer than the initial short-lasting period (i.e. one hour) defined by Robert in the stomach only.

Material/methods: Adaptive cytoprotection possibly appeared and lesions were attenuated when the stomach, duodenum or colon, in various combinations and sequences, were challenged with initial (mild) and/or final (strong) irritants over a two-week period. Rats were challenged with the mild or strong irritants 25% or 96% ethanol intragastrically 1 ml/rat (stomach) and cysteamine 40 mg or 400 mg/kg subcutaneously (duodenum), or intrarectally (colon). To postulate the prostaglandin relationship known in Robert's cytoprotection and adaptive cytoprotection, indomethacin (1 mg/kg subcutaneously) was given simultaneously with the second challenge.

Results: Administering the mild and strong irritant protocols within the same part of the gastrointestinal tract, adaptive cytoprotection presents in the stomach (1 h to 14 days), duodenum (2 h to 14 days), but not in the colon. With these protocols applied to different parts of the gastrointestinal tract, adaptive cytoprotection cross-reaction was evident in the stomach-duodenum, duodenum-stomach (1 h-14 days and 2 h-14 days), stomach-colon, and duodenum-colon (both 2-24 hours), but not in the colon-stomach or colon-duodenum. This protection was fully antagonized with indomethacin.

Conclusions: As observed for a day and even weeks, stomach-duodenum-colon adaptive cytoprotection is an important new defensive phenomenon.
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April 2006

The treatment options of dens invaginatus complications in children: report of 3 cases.

J Dent Child (Chic) 2003 Jan-Apr;70(1):77-81

Department of Dental Anthropology, School of Dental Medicine, University of Zagreb, Croatia.

Purpose: The authors described 3 cases of dens invaginatus accompanied by different periapical complications in children, as well as the therapy methods they used.

Methods: The 3 children were between the ages of 12 and 16 years. The type of dens invaginatus was classified according to Schulze and Brand.

Results: All 3 cases had dens invaginatus on their permanent teeth in the maxilla. The complications occurred while the teeth were growing, and they were accompanied by swelling in the region of the dens invaginatus.

Conclusions: The periapical complications required early diagnostic and endodontic treatment to prevent further difficulties at a later stage.
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September 2003
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