D.M.D., M.Sc., Ph.D.
Ordinacija dentalne medicine dr. sc. Neven Kokić, dr. med. dent. specijalist oralne kirurgije, Zagreb, Nova Ves 7
Zagreb | Croatia
Main Specialties: Oral Medicine
Additional Specialties: Oral Surgeon, Oral Implantologist
Primary Affiliation: Ordinacija dentalne medicine dr. sc. Neven Kokić, dr. med. dent. specijalist oralne kirurgije, Zagreb, Nova Ves 7 - Zagreb , Croatia
14PubMed Central Citations
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.
J Pharmacol Sci 2007 May 24;104(1):7-18. Epub 2007 Apr 24.
Department of Pharmacology, Medical School, University of Zagreb, Croatia.
Inflammopharmacology 01/2007; 14(5-6):214-21.
Gastric pentadecapeptide BPC 157 (GEPPPGKPADDAGLV, M.W. 1419, safe in clinical trials for inflammatory bowel disease (PL 10, PLD 116, PLD 14736, Pliva, Croatia)) has a particular cytoprotective/adaptive cytoprotective activity. The cytoprotective/adaptive cytoprotection researches largely neglect that stomach distension could per se jeopardize the mucosal integrity, with constantly stretched mucosa and blood vessels, and sphincters more prone for reflux induction. After absolute alcohol instillation in fully distended rat stomach, gastric, esophageal and duodenal lesions occur. Throughout next 3 min, left gastric artery blood vessels clearly disappear at the serosal site, indicative for loss of vessels both integrity and function. Contrary, constant vessels presentation could predict the beneficial effect of applied agent. After pentadecapeptide BPC 157 instillation into the stomach the vessels presentation remains constant, and lesions of stomach, esophagus, and duodenum are inhibited. Standards (atropine, ranitidine, omeprazole) could only slightly improve the vessels presentation compared to control values, and they have only a partial effect on the lesions. In this review we emphasize BPC 157 unusual stability, and some of its important effects: effectiveness against various lesions in gastrointestinal tract, on nitric oxide (NO)-system, and NO-agents effects, on somatosensory neurons, salivary glands function, recovery of AMP-ADP-ATP system, endothelium protection, effect on endothelin, and on angiogenesis promotion. It also antagonizes other alcohol effects, including acute and chronic intoxication. Given peripherally, it counteracts the consequence of central dopamine system disturbances (receptor blockade), and induces serotonin release in substantia nigra. Therapeutic potential of BPC 157 as a cytoprotective agent is also seen in its capability to heal various wounds. Given directly into the stomach, BPC 157 instantly recovers disturbed lower esophageal and pyloric sphincter pressure in rats after 12-20 months of untreated esophagitis. All these could be suggestive for its role as a natural protectant in gastric juice with particular function throughout stomach distension.
J Pharmacol Sci 2006 Nov;102(3):269-77
Department of Pharmacology, Medical Faculty, University of Zagreb, Zagreb, Croatia.
Digestion 73 (2006) (S2) 1-74 / Arakawa, Tetsuo (ed.). - Basel : Karger AG, 2006. 48.
We focus whether the critical period for threatening outcome in prolonged esophagitis and relation with prolonged failure of lower esophageal sphincter (LES) and pyloric sphincter (PS) could be modified with a stable gastric pentadecapeptide BPC 157 , promising in inflammatory bowel disease (PLD116, PL14736, Pliva). It attenuates esophago-jejunal anastomosis-esophagitis (J Phys, 1999) (1 month), and recovers and maintains esophageal mucosal integrity and sphincters pressure for 1 year (Gastroenterology, 2004) in rats that had grossly intact GI tract with the essential function failure mimicked by tubes into LES and PS. Methods. This procedure induces prominent esophagitis, LES- and PS-malfunction (one tube inserted into LES, and the other tube into PS, for 1 week, then both artlessly removed), gastroduodenal contents reflux. Now, considerably extending esophagitis period, BPC 157 effect was compared in these esophagitis rats with grossly intact GI-tract with essential function failure, after 12 and 20 months, with respect to normal-healthy rats and (i) sphincters pressure (LES, PS) and (ii) esophagitis attenuation. Assessed at 12 or 18 months of esophagitis: (i) LES-, PS- pressure (cm H2O). Water manometer connected with drainage port of Foley catheter was implanted into the stomach either through esophageal or duodenal incision before BPC 157 or saline (1 ml/rat ; 5ml/kg) were given directly into the stomach ; assessment was at 5 min thereafter. (ii) Reflux esophagitis. Macro- (scored 0 (normal) to 4 (the worst)) as well as micro-scopically (program SFORM, VAMSTECH-Software Company, Croatia) ; BPC 157 (10 µ ; g /kg) i.p. once daily or in drinking water. Results. (i) Sphincter pressure. Esophagitis-rats present a marked sphincter dysfunction, constantly lessened LES- and PS-pressure. For both LES and PS, BPC 157 (a) promptly increases the decreased values till the level in healthy, then, (b) maintains pressure preserved at the healthy level during 12-18 months period, while (c) in normal rats, it increases LES- , but decreases PS- pressure (Fig. 1). (ii) Esophagitis-attenuation. BPC 157 attenuates esophageal lesion at either region, and either interval. Thinner epithelium and superficial corneal layer in controls (12-18 months) than in naive healthy and BPC 157 treated animals. Controls (12 months) present a stratification derangement in contrast to healthy controls and BPC treated animals.
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.
Med Sci Monit 2006 Apr 28;12(4):BR146-53. Epub 2006 Mar 28.
Department of Pharmacology, Medical Faculty University of Zagreb, Zagreb, Croatia.
Arthritis Rheum 2004;50(9):120
Arthritis and Rheumatism
PURPOSE: To investigate the effect of stable gastric pentadecapeptide BPC 157 (currently in clinical phase II for inflammatory bowel disease, PLD-14736,Pliva, recently shown to improve bone and tendon healing in animal studies) on myofibrotic contracture induced by multiple contusion leg injuries in the rat. METHODS: 360 Wistar rats were subjected to 6 consecutive blunt traumas, once daily. An instrumented drop-mass technique delivered a single impact to the posterior surface of the gastrocnemius muscle complex in right limb. BPC 157 (dissolved in saline, with no carrier addition), 10 μg/kg b.w., or an equivolume of saline were given intraperitoneally (i.p.), intragastrically (i.g.), and BPC 157, 1μg/g or saline of neutral cream locally at the site of injury. Agents were applied at 24hrs after the last injury, once daily with final application 24hrs before sacrifice at 2nd , 3rd, 4th, 7th, 14th, and 21st post-injury day. Functional recovery evaluation (assessed daily) included Tibial Function Index (TFI), and a newer, "Extensor Postural Thrust" (EPT) test. All animals were scanned on daily basis for gross measurements of hematoma and leg contracture. Maximum circumference of injured limb was measured before each drug administration. Histopathology was also performed. Kruskal-Wallis and Mann-Whitney U tests were used for statistical analysis and differences of P < 0.005 were considered statistically significant. RESULTS: Poorly reversible course of decreased EPT and TFI values, fully established, fully established severe posttraumatic edema, hematoma and leg contracture was apparently improved already after a short period upon BPC 157 regiments were started. In all control rats leg contracture persisted till the end of the experiment. Histology confirmed functional studies. There was statistically significant difference in all above mentioned results between BPC 157 treated and control groups (P < 0.005). CONCLUSIONS: These results suggest that stable gastric pentadecapeptide BPC 157 repairs already established fibrous development, promotes almost complete structural and functional muscle recovery, and completely reverses otherwise irreversible myofibrotic contracture even in the severe multiple contusion muscle injury. Further studies will be requiered to investigate the lowest BPC 157 therapeutic dose, possible sequels of this injury on surrounding tissues (nerve, bone), and in vitro studies.
Periodicum Biologorum 106 (2004), Supp 1;134
Arthritis Rheum 2003;48(9):1244
Arthritis & Rheumatology
Arthritis Rheum 2003;48(9):163
Arthritis & Rheumatology
J Dent Child (Chic) 2003 Jan-Apr;70(1):77-81
Department of Dental Anthropology, School of Dental Medicine, University of Zagreb, Croatia.
Burns. 2001 Dec;27(8):817-27.
The effects of the gastric pentadecapeptide BPC 157 were investigated when administered topically or systemically in burned mice. This agent is known to have a beneficial effect in a variety of models of gastrointestinal lesions, as well as on wound or fracture healing. Deep partial skin thickness burns (1.5x1.5 cm) covering 20% of total body area, were induced under anesthesia on the back of mice by controlled burning and gastric lesions were assessed 1, 2, 3, 7, 14 and 21 days following injury. The first application of BPC 157 was immediately following burning, and thereafter, once daily, until 24 h before sacrifice. In the initial experiments, exposure to direct flame for 5 s, the BPC 157 was applied at 10 microg or 10 ng/kg b.w. intraperitoneally (i.p.) by injection or alternatively, topically, at the burn, as a thin layer of cream (50 microg of BPC 157 dissolved in 2 ml of distilled water was mixed with 50 g of commercial neutral cream (also used as local vehicle-control)), while silver sulfadiazine 1% cream was a standard agent acting locally. Others received no local medication: they were treated i.p. by injection of distilled water (distilled water-control) or left without any medication (control). In subsequent experiments involving deeper burns (direct flame for 7 s), BPC 157 creams (50 microg, 5 microg, 500 ng, 50 ng or 5 ng of BPC 157 dissolved in 2 ml of distilled water was mixed with 50 g of commercial neutral cream), or vehicle as a thin layer of cream, were applied topically, at the burn. Compared with untreated controls, in both experiments, in the BPC 157 cream-treated mice all parameters of burn healing were improved throughout the experiment: less edema was observed and inflammatory cell numbers decreased. Less necrosis was seen with an increased number of capillaries along with an advanced formation of dermal reticulin and collagen fibers. An increased number of preserved follicles were observed. Two weeks after injury, BPC 157 cream-treated mice completely reversed the otherwise poor re-epithelization ratio noted in the untreated control or mice treated with vehicle only. Tensiometry investigation showed an increased breaking strength and relative elongation of burned skin, while water content in burned skin decreased. This was, however, not the case with the vehicle or silver sulfadiazine. Relative to the control values, in silver sulfadiazine cream-treated mice, only collagen fiber formation was increased, in addition to a decreased inflammatory cell number. Relative to control values, BPC 157 given i.p. decreased the number of inflammatory cells, lowered water content in burned skin, and raised breaking strength and relative elongation of burned skin during tensiometry. Through the experimental period, gastric lesions were continuously noted in all thermally injured mice left without local medication and they were consistently attenuated only by BPC 157 treatments: either given i.p. (at either dose), or given locally (at either concentration). Other treatments (i.e. local treatment with silver sulfadiazine cream or neutral cream in mice subjected for 5 s to direct flame), led to only poor, if any attenuation. This stable gastric pentadecapeptide appears to be active and gives a stimulation to burn healing at the defect site. The agent may act by causing an upregulation of the growth factors, as well as influencing other local factors.
Achilles tendon unilateral transection (ATT) in the rat was attenuated by a beneficial effect of a stable gastric pentadecapeptide, shown to heal a non-union fracture and deep thickness skin burns, and to reduce adjuvant arthritis, without special carrier, named BPC 157 (GEPPPGKPADDAGLV, M.W.1419). Assessed 4,7,10,14 days after surgery, tensiometry and microscopical investigation showed a steady healing improvement in saline treated controls, i.e. failure load (N) (1.71, 5.14, 10.42, 9.97), Yang elasticity module (2.14, 4.66, 6.46, 6.68), fibroblast number (1303, 1763, 1978, 1873) and collagen proportion per visual fields (0.32, 0.40). BPC 157 10 microg, 10 ng or 10 pg /kg b.w. dissolved in saline were given intraperitoneally immediately after the surgery, and thereafter once daily, last application 24 h before sacrifice. With respect to control values (P<0.05 / P<0.017) in pentadecapeptide BPC 157 rats we noted the increased failure load (13.4 (ng), 13.0 (microg), 14 day), Yang elasticity module (9.43 (microg), 10 day; 10.51 (microg), 14 day), fibroblast number (2019 (ng), 2023 (microg), 7 day; 2364 (ng), 2245 (microg), 10 day), collagen proportion per visual fields (0.49 (ng), 0.50 (microg), 10 day; 0.54 (ng), 0.52 (microg), 14 day). Therefore, pentadecapeptide BPC 157 may positively influence formation and differentiation (maturation), and strength of tissues during Achilles tendon healing after surgical transection. The significance of this advanced healing was especially supported by structural characteristics of pentadecapeptide BPC 157 shown by a computational investigation. Numerous BPC 157 motifs are clustered in collagens and proteoglycans, essential for the healing process, such as collagen a-1 (I), collagen a-1 (IX), aggrecan, fibromodulin precursor, chondroitin sulfate proteoglycan NG2 precursor and cartilage oligomeric matrix protein precursor. Likewise, a special relation over BMP-6 molecule is postulated.
Osteoarthrosis (OA) of the temporomandibular joint (TMJ) in the rat was attenuated by a beneficial effect of a stable gastric pentadecapeptide, shown to heal a non-union fracture and deep thickness skin burns, and to reduce adjuvant arthritis, without special carrier, named BPC 157 (GEPPPGKPADDAGLV, M.W.1419). OA-induction included: (i) unilateral condylar articular surface damage (i.e., partial removal), (ii) horizontal incision of both, the collateral ligament at the lateral border of the disk, and the posterior discal attachment, (iii) consequent aggravation by an instability of articular disc and disruption of its vascularization. BPC 157 10 mg or 10 ng/kg b.w. or an equivolume of saline (5.0 ml/kg b.w. (control)) were given intraperitoneally immediately after the surgery. Assessment was at 6 months after surgery. In all directly injured TMJs of controls, relative to the control contralateral undamaged TMJs (P<0.05 / P<0.025, median values (Md)) vertical cartilage fissures, loss of normal cartilage stratification appeared, and relative to the contralateral undamaged TMJs, chondrocyte clustering (number of clusters) was increased (5.5 (Md, undamaged) vs. 14.5 (Md, damaged) while decreased thickness of articular zone (26.3 (undamaged) vs. 13.5 (damaged). In directly injuried TMJs of pentadecapeptide BPC 157 treated rats, with respect to the control, the overall thickness of cartilage was specifically increased, since increased were thickness of cartilage zone (89.3 m (g) vs. 66.9 m (control)) and articular zone (43.3 m (g) vs. 13.5 m (contol)), while decreased were chondrocyte clustering (3.0 (g), 6.0 (ng) vs. 14.5 (control), and vertical cartilage fissures absent, normal cartilage stratification preserved. In non-surgically altered TMJs the chondrocyte clustering also decreased in pentadecapeptide BPC 157 treated rats relative to control (2.5 (g) vs. 5.5 (undamaged control)). The significance of this attenuation was especially supported by structural characteristics of pentadecapeptide BPC 157 shown by a computational investigation. Numerous BPC 157 motifs are clustered in collagens and proteoglycans, essential for the cartilage, bone and tooth development, such as collagen a-1 (I), collagen a-1 (IX), aggrecan, fibromodulin precursor, chondroitin sulfate proteoglycan NG2 precursor and cartilage oligomeric matrix protein precursor. Likewise, a special relation over BMP-6 molecule is postulated.
J Physiol Paris. 2001 Jan-Dec;95(1-6):303-8.
Journal of Physiology - Paris
Anti-ulcer agents may likely attenuate lesions outside the gastrointestinal tract, since they had protected gastrectomized rats (a "direct cytoprotective effect"). Therefore, their therapeutic potential in lung/stomach lesions were shown. Rats received an intratracheal (i.t.) HCl instillation [1.5 ml/kg HCl (pH 1.75)] (lung lesion), and an intragastric (i.g.) instillation of 96% ethanol (gastric lesion; 1 ml/rat, 24 h after i.t. HCl instillation), then sacrificed 1 h after ethanol. Basically, in lung-injured rats, the subsequent ethanol-gastric lesion was markedly aggravated. This aggravation, however, in turn, did not affect the severity of the lung lesions in the further period, at least for 1 h of observation. Taking intratracheal HCl-instillation as time 0, a gastric pentadecapeptide, GEPPPGKPADDAGLV, M.W.1419, coded BPC 157 (10 microg, 10 ng, 10 pg), ranitidine (10 mg), atropine (10 mg), omeprazole (10 mg), were given [/kg, intraperitoneally (i.p.)] (i) once, only prophylactically [as a pre-treatment (at -1h)], or as a co-treatment [at 0)], or only therapeutically (at +18h or +24 h); (ii) repeatedly, combining prophylactic/therapeutic regimens [(-1 h)+(+24 h)] or [(0)+(+24 h)], or therapeutic/therapeutic regimens [(+18 h)+(+24 h)]. For all agents, combining their prophylactic and salutary regimens (at -1 h/+24 h, or at 0/+24 h) attenuated lung lesions; even if effect had been not seen already with a single application, it became prominent after repeated treatment. In single application studies, relative to controls, a co-treatment (except to omeprazole), a pre-treatment (at -1 h) (pentadecapeptide BPC 157 and atropine, but not ranitidine and omeprazole) regularly attenuated, while therapeutically, atropine (at +18 h), pentadecapeptide BPC 157 highest dose and omeprazole (at +24 h), reversed the otherwise more severe lung lesions.
J Physiol Paris. 2001 Jan-Dec;95(1-6):315-24.
Journal of Physiology-Paris
Liver lesions and portal hypertension in rats, following chronic alcohol administration, are a particular target for therapy. Portal hypertension (mm Hg) assessed directly into the portal vein, and liver lesions induced by 7.28 g/kg b.w. of alcohol given in drinking water for 3 months, were counteracted by a stable gastric pentadecapeptide BPC 157, GEPPPGKPADDAGLV, M.W. 1419, known to have a beneficial effect in a variety of models of gastrointestinal or liver lesions (10 microg or 10 ng/kg b.w. i.p. or i.g.) and propranolol (10 mg/kg b.w. i.g.), but not ranitidine (10 mg/kg b.w. i.g.) or saline (5 ml/kg b.w. i.p./i.g.; control). The medication (once daily) was throughout either the whole 3 months period (1) or the last month only (2) (last application 24 h before sacrifice). In the background of 7.28 g/kg/daily alcohol regimen similar lesions values were assessed in control rats following alcohol consumption, after 2 or 3 months of drinking. Both prophylactic and therapeutic effects were shown. After a period of 2 or 3 months, in all control saline [intragastrically (i.g.) or intraperitoneally (i.p.)] treated rats, the applied alcohol regimen consistently induced a significant rise of portal blood pressure values over values noted in healthy rats. In rats that received gastric pentadecapeptide BPC 157 or propranolol the otherwise raised portal pressure was reduced to the values noted in healthy rats. Besides, a raised surface area (microm(2)) and increased circumference (microm) of hepatocyte or hepatocyte nucleus [HE staining, measured using PC-compatible program ISSA (VAMS, Zagreb, Croatia)] and an advanced steatosis [scored (0-4), Oil Red staining] (on 100 randomly assigned hepatocytes per each liver), an increased liver weight, all together parallel a raised portal pressure in controls. Some of them were completely eliminated (not different from healthy rats, i.e. portal pressure, the circumference and area of hepatocytes, liver weight), while others were markedly attenuated (values less than in drinking controls, still higher than in healthy rats, i.e. circumference and area of hepatocytes nucleus). On the other hand, ranitidine application attenuated only steatosis development. In summary, despite continuous chronic alcohol drinking, pentadecapeptide BPC 157, and propranolol may prevent portal hypertension as well as reverse already established portal hypertension along with related liver disturbances.
Acta Stomatol Croat. 1998;32(3):499-507.
Acta Stomatologica Croatica
Replantation of permanent central incisors with avital periodontal ligaments following exarticulation due to trauma is presented. The avulsed teeth were fluoridated before replantation for the purpose of deferring resorption. Following usual procedures for root canal preparation, the avulsed teeth were teated with an acidic fluoride solution for 4 minutes followed by replantation and immobilization with a wire-composite splint for a period of ten days. Based upon clinical follow-up parameters (radiographs, mobility test; gingival index) there are no signs of replacement root resorption thirty months following replantation. This case confirms that active fluoride penetrates into the cementum tubules impregnating the surface of the root and slowing down replacement root resorption. This prolongs the survival time of the avulsed tooth in the mouth which presents an advancement in the treatment of this type of avulsion.