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Heart involvement in acromegaly is mostly recognized by the presence of LV hypertrophy (LVH), often accompanied by diastolic dysfunction (DD). Although it is known that patients (pts) with active disease have more pronounced LVH than pts in remission, the impact of pituitary adenoma size might also be important. We sought to analyze the degree of LVH and DD in acromegaly with regard to adenoma size. The diagnosis of acromegaly was based on clinical characteristics, failure to suppress serum GH level below 1 µ g/L after a glucose tolerance test and a high serum IGF1 level. 32 pts with acromegaly (49± 11 years) and normal systolic function were distributed in 2 groups by adenoma size (measured from MRI images of the hypothalamo-pituitary region). MACRO: 11 pts with macroadenoma (>10 mm in diameter) ; MICRO: 21 pts with microadenoma (

From isolated cells, it was suggested that chronic ischemia decreases but prolongs contraction. Additionally, severe aortic stenosis shows, higher but often prolonged outflow velocities. Outflow velocities represent the pressure gradient between LV and aorta and thus influenced by either of them. However, a dynamically increasing resistance in the vessel tree reduces late velocities while late increases should be related to prolonged contraction. We assumed a relationship between the morphology and duration of aortic outflow velocities and myocardial function in coronary artery disease (CAD). We studied 109 pts undergoing routine dobutamine stress echo (DSE). Pts were divided in 2 groups: group A: 61 pts without evidence of CAD and/or normal DSE, group B: 48 pts with angiographically proven CAD and/or positive DSE. Automated analysis using modelling was applied on digitally stored aortic CW traces and deceleration time (TF: from peak to end of spectrum) and symmetry measure (symm: ratio of area under the curve of left and right half of the spectrum). Figure 1 left shows a CW trace and curve analysis of a normal: triangular in shape, with an early peak, while right (CAD) shows typical broadening with a much more rounded shape and later peak. Group A: symm=0, 34± 0, 07 ; TF=79, 90± 11.58 ms. Group B: symm=0, 31± 0, 08* ; TF=73, 10± 12, 71 ms* (*p

To attenuate functional disarrangement subsequently to surgically induced temporomandibular joint osteoarthrosis, and transosseal mandibular defects in the rat, we used a stable gastric pentadecapeptide BPC 157. This study is based on previously reported beneficial effect on osteoarthrosis, non union fracture, deep thickness skin burns, and adjuvant athritis, without special carrier.

A gastric pentadecapeptide, GEPPPGKPADDAGLV, M.W. 1419, coded BPC-157, with mucosal protective, wound healing and anti-inflammatory effect, interacting with NO, and somatosensory neurones system, and a peculiar high stability in gastric juice, was recently shown to block stereotypy and heightened startle responses, produced by an application of dopamine agonist amphetamine. Therefore, the next focus was to see the effect on chronic exposure to amphetamine in rats (i.e., 10 mg/kg b.w. i.p.., once time daily for five subsequent days, and thereafter at the day 8, 16 and 46). Considering the prominent effect of single application of pentadecapeptide BPC 157 (10 ľg/kg or 10 ng/kg b.w. i.p.) or saline (5.0 ml/kg i.p.) on both development as well as reversal of amphetamine stereotypy and heightened startle response, pentadecapeptide BPC 157 (10 ľg/kg or 10 ng/kg b.w. i.p.) or saline (5.0 ml/kg i.p.) were given only at the beginning of the experiment, simultaneously with the initial dose of the amphetamine. In relation initial-single/repeated- intermittent application(s), the changes in stereotyped behavior and heightened startle response, increment or decrement, noted in control amphetamine rats are in line with the changes commonly referred in chronic amphetamine studies as tolerance (lesser grade of stereotyped behavior, without increased excitability) and reverse tolerance (i.e., prominent stereotyped behavior and heightened startle response upon late amphetamine challenges). After the initial application of the amphetamine, in rats receiving the higher BPC 157 dosage the stereotyped behavior was apparently attenuated, while in rats receiving the lower dosage of BPC 157 statistical significance was not found. These differences were present throughout the observation period (120 minutes after amphetamine application, and each animal was observed for 10 seconds in 5 minutes intervals) and were statistically significant at all the observed intervals. Considering the forthcoming amphetamine challenges, in the rats initially protected with pentadecapeptide BPC 157 at the time of the first application of amphetamine, the stereotyped behavior remains to be attenuated after all additional amphetamine challenges (at the day 2-5, 8, 16, and 46). Moreover, in these days, a significant attenuation appeared also in the rats that had been treated with the lower dose of the pentadecapeptide BPC 157 at the time of the fist amphetamine application. After the initial application of the amphetamine, in rats receiving the BPC 157 dosage, either higher or lower, the heightened startle response was apparently mitigated. These differences were present throughout the observation period and were statistically significant at all the observed intervals. Considering the forthcoming amphetamine challenges, in the rats initially protected with pentadecapeptide BPC 157 at the time of the first application of amphetamine, they showed apparently less abnormal excitability at all tested points. Like in the rats damaged with only first application of amphetamine, this mitigation was consistently evident in both ug- and ng-BPC 157 regimens. Thus, taking together these data, it seems that this pentadecapeptide has a modulatory effect on dopamine system, and it could be used in chronic amphetamine disturbances.

Liver lesions and portal hypertension in rats, following chronic alcohol administration, are particuiar 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, GEPPGKPADDAGLV, M.W.1419, known to have beneficial effect in a variety of models of gastrointestinal or liver lesions(10 ľg 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 a 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 werw 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 consistentently induced a sagnificant rise of portal blood pressure values over values noted in healthy rats.In rats that recived 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 (ľm2) and increased circumference (micrometr)of hepatocyte or hepatocyte nucleus(HE staining, measured using PC-compatibile 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, aii 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 ih 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.

We reported for gastric pentadecapeptide BPC 157 GEPPPGKPADDAGLV, M.W. 1419, a anxiolytic effect in shock probe/ burying test (no burying, lack of panic reaction) and in light/dark test (no effect in light areas, and particularly increased activity in dark zone). Possible anxiolytic effect is along with proposed pentadecapeptide BPC 157-regulation of dopamine mediated events within extrapyramidal system and behaviors dependent on striatal functions (as follows from antagonization of neuroleptic catalepsy, amphetamine stereotypes, antidepressant effect, haloperidol/amphetamine climbing behavior, MPTP and reserpine motor disturbances), and possible role of pentadecapeptide BPC 157 in stress reaction. In shock probe/burying test pentadecapeptide BPC 157 (10 ľg, 10 ng/kg b.w. i.p), diazepam (0.075, 0.0375 mg/kg b.w. i.p.), an equivolume of saline (5 ml/kg b.w. i.p.) were given at 30 min prior, rats were individually placed into the test box, observation for 15 min. Rats treated with either diazepam or pentadecapeptide BPC 157 were much less afraid after the shock: almost not burying and the total time spent in burying was clearly less than in controls. However, while in the diazepam treated rats the number of shocks received increased over control values, in pentadecapeptide BPC 157 treated groups the number of shocks remained not modified compared with the control values. In light/dark test, medication (pentadecapeptide BPC 157 (10 ľg, 10 ng/kg b.w. i.p), diazepam (0.1 mg/kg b.w. i.p.), an equivolume of saline (5 ml/kg b.w. i.p.)) was given at 45 min prior procedure, each mouse was tested by placing it in the centre of the white area and allowing it to explore the novel environment for 10 minutes. After exposure to the intense light, diazepam treated mice had longer latencies of crossing to the dark compartment, a greater number of crossing and a greater number of exploratory rearing, and spent longer time in the light compartment, as compared to the control mice, while BPC 157 mice had a similar behavior to that of the control mice. In contrast with the effect in light area, in dark zone diazepam produced no change with respect to controls, while BPC 157 (10 ľg) mice had a greater number of crossing and a greater number of exploratory rearing. Thus, both agents displayed a bidirectional antianxiety effect (measured by an increase of in specific activity in one paradigm (a light/dark test), and a decrease in a specific activity in the other paradigm (shock probe/burying)), thereby not related to nonspecific effects on general activity or arousal. However, at the same time, these indicate anxiolytic activity of pentadecapeptide BPC 157 to be particular, and different from diazepam. Therefore, in relation with its other behavioral effects, the particular anxiolytic activity of pentadecapeptide BPC 157 in anxiety models is fully compatible with a general statement that drugs acting at various target areas might be expected to provide selective actions on some but not all of the somatic symptoms associated with anxiety.

Changing of left ventricular diastolic function in hypertensive patients according to different antihypertensive treatment.

Besides a superior protection of the pentadecapeptide BPC 157 (an essential fragment of an organoprotective gastric juice peptide BPC) against different gastrointestinal and liver lesions, an acute anti-inflammatory and analgetic activity was also noted (1-8). For instance, pentadecapeptide BPC 157 administered either in ng or ug per kg range intraperitoneally, significantly reduced pain reaction in writhing (inflammatory and non-inflamatory, prostaglandin dependent and independent). consequently, its effect on chronic inflammation lesions, such as adjuvant arthritis, and non-steroidal anti-inflammatory agents (NSAIAs)-induced gastrointestinal lesion was simultaneously studied in rats. In gastrointestinal lesion (indomethacin 30mg/kg s.c.), aspirin (400 mg/kg i.g.) and diclofenac (125 mg/kg i.p.) studies, BPC 157 (10 ug or 10 ng/kg i.p.) was regularly given simultaneously and/or one hour prior to drug application (indomethacin). In the adjuvant arthritis (tail-application of 0, 2 ml of Freund's adjuvant) studies (14 days, 30 days, one year) BPC 157 (10 ug or 10 ng/kg i.p.) it was given as a single application (at 1 hour either before or following the application of Freund's adjuvant) or in a once daily regiment (0-14th day, 14-30th day, 14th day-one year). Given with the investigated NSAIAs, BPC 157 consistently reduced the otherwise prominent lesions in the stomach of the control rats, as well as the lesions in the small intestine in the indomethacin groups. In the adjuvant arthritis studies, the lesions development seems to be considerably reduced after single pentadecapeptide medication, and even more attenuated in rats daily treated with BP 157. As a therapy of already established adjuvant arthritis, its salutary effect consistently appeared already after two weeks of medication and it could be cleary seen also after one year of application. Taking togather all of these results, these data likely point to a special inflammatory and mucosa integrity protective effect.

A clear protection of G-I tract and an evident anti-inflammatory effect were shown for a novel stomach pentadecapeptide BPC(i.p./i.g.) in comparison with several reference standards in various ulcer models alog with a protection of endothelium. Thus, in the first experiments we evaluated whether this pentadecapeptide and other gastroprotective agents could affect the angiogenesis and healing process in vivo (using a slightly modified method of Szabo et al., AJM 9l, 1558, 1991). Number of new formed endothelial spacec inside new-formed granulation tissued in controls increased from 7, 94+/-1, 23 (day 3) to 14, 8+/-3, 12 (day 7) (P

Since definition of cytoprotection as an important phenomenon independent from gastric acid by A. Robert in Gastroenterology 1979, a direct evidence about the definitive role of gastric acid is not provided. In the first experiments (Sikiric et al., Dig.Dis.Sci, 1997) along with a widely proclaimed independency between Robert's cytoprotection and gastric acid secretion, a total gastrectomy was performed to further define this pentadecapeptide cytoprotective capacity, as a "direct" cytoprotective effect. Both theoretically and practically, gastrectomy could be taken as a new experimental improvement to create an acid-free environmental logically needed for cytoprotective studies. In this, a clear evidence about suggested non-acid (cytoprotective) phenomenology was based on at least two convincing experimental demonstrations. Firstly, like in the intact rats, cysteamine-duodenal lesions could be induced also in gastrectomized rats, with esophagoduodenal terminoterminal anastomosis (as emphasised, cysteamine in otherwise used commonly as a duodenal ulcerogen duo to its supposed effect on gastric acid hypersecretion). Secondly, the pentadecapeptide BPC 157 would antagonize the duodenal cysteamine lesions also in gastrectomized animals, an effect shared with standar antiulcer drugs (cimetidine, ranitidine, omeprazole, bromcriptine, atropine). Thus, a "direct cytoprotection" was evidenced for pentadecapeptide BPC 157 and standard antiulcer agents in totally gastrectomized rats' duodenum challanged with cysteamin (shown to have a damaging effect essentially independent from gastric acid). In the second experiments (Sikiric et al., Gastroenterology 1997), considering gastrectomized acid free rats as an ideal model for long-term cytoprotective studies, and expending these findings, pentadecapeptide BPC 157 qwas shown to markedly attenuate terminolateral esophagojejunal anastomosis-reflux esophagitis also over a quite prolonged period (1, 2, 4 weeks), having an effect (medication, per kg b.w., given in drinking water since 24 hours after surgery till sacrifice) superior then other reference agents. Relative to the control values, less damaged mucosa was noted in the rats drinking (12, 5 ml/rat daily) ranitidine (125 mg), sucralfate (725 mg) (dose per kg b.w.) after one week esophagitis, but not further oserved in later invervals (microscopical assessment). Compared with these results, pentadecapeptide BPC 157 (125 ug or 125 ng) attenuation of esophagitis were apparently more pronounced, and clearly appeared in all tested intervals, assessed either macroscopically or microscopically. Thus, despite limitation, a generalization supporting a direct importance of a common cytoprotective approach, and particularly the importance of the pentadecapeptide BPC, could be clearly provided. A useful, long-lasting cytoprotective activity (apparently more prominent in BPC 157-rats, than in referece agents) could be likely exemplified as a suitable therapy in various, otherwise resistant conditions, such as reflux esophagitis as well.

U ovoj disertaciji opisani su rezultati istraživanja djelovanja novog pentadekapeptida BPC-157 na eksperimentalne modele kardiotoksičnosti. Pokusi su izvedeni na albino štakorima soja Wistar i zamorčićima soja Hartley. Kardiotoksičnost smo izazivali primjenom otopine barijevog klorida (10mg/kg t.t.), dezipramina (10 mg/kg), digitalisa (ukupna doza 6.5 mg/kg) i izoprenalina (15 mg/kg) kroz vensku kanilu na jugularnoj poziciji. Višekratnom (3mg/kg subkutano, jednom tjedno 13 tjedana) i jednokratnom (7 mg/kg intravenski) primjenom doksorubicina izazivali smo kardiomiopatiju. Kardiotoksičnost smo izazvali i imobilizacijskim stresom, kao nefarmakološko oštećenje miokarda. Ispitivani pentadekapeptid primjenjen je ovisno o modelu: 1. barijev klorid- a) pretretman(jedan sat prije): BPC-157 50mg/kg 10mg/kg i 10 ng/kg intraperitonelano, b) posttretman(nakon 60 sekundi): BPC-157 10mg/kg i 10 ng/kg intravenski ; 2.dezipramin: BPC-157 50mg/kg i 50 ng/kg intraperitonealno sat vremena prije, 3. digitalis: BPC-157 50mg/kg i 50 ng/kg intravenski svakih 15 minuta, 4. izoprenalin: BPC-157 50mg/kg i 50 ng/kg intravenski 15 minuta prije, 5. imobilizacijski stres: BPC-157 10mg/kg i 10 ng/kg intraperitonealno sat vremena prije i neposredno prije vezivanja, te u 24-tom i 48- satu imobilizacije. 6. a) doksorubicin kronična toksičnost: BPC-157 10mg/kg i 10 ng/kg intraperitonealno istovremeno sa doksorubicinom, b) doksorubicin akutna toksičnost: BPC-157 10mg/kg i 10 ng/kg intraperitonealno sat vremena prije doksorubicina. U modelima aritmija, anesteziranoj životinji elektrokardiogram je bilježen kontinuirano brzinom 1 mm/s, a svakih 15 s ili kod poremećja ritma učinjeni su duži odsječci zapisa brzinom 25mm/s, 5o mm/s ili 100 mm/s. U ostalim modelima elektrokardiogram je bilježen jednokratno ili višektratno, na dužim odsječcima brzinom 5o mm/s, pri čemu je životinja kratkotrajno anestezirana, . Doksorubicinska kardiotoksičnost evaulirana je makroskopskom i mikroskopskom analizom srca i ostalih organa, te biokemijskim pretragama. Sličan postupak primjenjen je i kod imobilizacijskog stresa Rezultati našeg istraživanja pokazuju antiaritmički učinak ispitivanog pentadekapeptida u modelu izaziavnja aritmija barijevim kloridom. U pretretmanu ispitivani pentadekapeptid odgađa i prevenira pojavu aritmija, i skraćuje i prevenira nastajanje ishemije. U postretmanu dovodi do brže konverzije u sinus ritam i prevenira ponovno javljanje aritmija. U potpunosti prevenira naglo usporavanje frekvencije i smetnje provođenja izazvane dezipraminom (PQ prolongaciju i širenje QRS-kompleksa), kao i pojavu ventrikulske tahikardije u sklopu proaritmičkog učinka dezipramina i teže oblike atrioventrikulskog bloka. Učinak je zavisan o dozi. Ispitivani pentadekapeptid BPC-157 ima selektivan učinak na kardiotoksičnost izazvanu digitalisom. Pozitivan učinak pokazuje kod naglih usporavanja frekvencije i poremećaja ritma (ventrikulske ekstrasistolije, ventrikulsku tahikardiju i atrioventrikulski blok) koje prevenira ili umanjuje, dok nema značajnog djelovanja na usporavanje provođenja izazvanog toksičnom dozom digitalisa. Učinak je jače zražen kod primjene mikrogramske doze pentadekapeptida. Nismo registrirali sigurno pozitivno djelovanje na tahikardiju uzrokovanu izoprenalinom. Með utim, ispitivani pentadekapeptid BPC-157 pokazao je jasno preveniranje ishemije i razvoj infarkta miokarda. Učinak je izraženiji u mikrogramskoj dozi. Isto tako ishemija (utvrđena elektrokardiografski) kao i histološka oštećenja miokarda izazvana imobilizacijskim stresom, jasno se preveniraju jednokratnom intraperitonealnom primjenom pentadekapeptida BPC-157 u pretretmanu. Ishemija se gubi i primjenom pentadekapeptida u postretmanu kod već izraženih elektrokardiografskih promjena nakon 24 sata mobilizacije štakora. Primjena mikorgramske doze pentadekapeptida izaziva povećanje napetosti-potencijal QRS kompleksa, naročito u pretretmanu. Ispitivani pentadekapeptid BPC-157 značajno je umanjio i patomorfološki nalaz antraciklinske kardiomoipatije (teško oštećenje miocita i stijenki krvnih žila i vakuolizaciju) nakon jednokratne i još više nakon višekratne primjene doksorubicina. Aktivnost enzima LDH značajno je niža, iako su apsolutne vrijednosti vrlo visoke.

The effect of BPC 157, a novel pentadecapeptide, on chronic gastric ulcers and cysteamine duodenal ulcers rats were investigated. Ranitidine was given as reference agent. Intragstrical application of both BPC 157 and ranitidine markedly accelerated healing of gastric ulcers. Both of them also had a beneficial effect on rats' intact stomachs. A highly cytoprotective capacity, common for BPC 157 and ranitidine, could be clearly suggested.

U ovoj studiji ispitivali smo razlike u učincima gastrointestinalnih hormona: BPC-a, sekretina, glukagona, CKK-a i NPY-a na eksperimentalne gastroduodenalne lezije. Lezije želuca i duodenuma izazvane su različitim metodama, kao što su cisteaminske lezije duodenuma, etanolske lezije želuca i imobilizacijski stres, na kojima ovi peptidi-hormoni do sada nisu ispitivani. U pokusima su korištene eksperimentalne životinje, štakori oba spola. Substance su primjenjene intraperitonealno u slijedećim dozama, ovisno o metodi: BPC 10 ľg i 10 ng/kg t.t., sekretin 10 ľg i 10 ng/kg t.t., glukagon 10 i 20 ľg/kg t.t., CKK 10 i 20 ľg/kg t.t., NPY 10 i 20 ľg/kg t.t. Kontrolne životinje su dobivale 5.5 ml/kg t.t., 0.9 % NaCl i.p., istovremeno. Nakon žrtvovanja, uzeti materijal je morfološki analiziran uz dodatnu histološku ilustraciju lezija želuca i duodenuma. Protektivni učinak, koji se ogleda u značajnom smanjenju broja i velićine lezija, utvrđen je za: BPC ( fragment BPC 157) (10 ľg i 10 ng/kg t.t), sekretin (10 ľg/kg), glukagon (20 ľg/kg), i NPY ( 20 ľg/kg). Stupanj protekcije ovisan je o metodi izazivanja lezija i dozi, osim za BPC. CKK nije pokazao protektivan učinak u primjenjenim dozama. Antagoniziranje protektivnog učinka BPC-a, NPY-a i sekretina, ne postiže se predtretmanom (1 sat prije) sa inhibitorima dopaminskog sustava (haloperidol 5 mg/kg i domperidon 5 mg/kg), što upućuje na druge mehanizme djelovanja. Učinak BPC-a ne mijenja se ni primjenom inhibitora prostaglandinskog sustava (indometacin 1 mg/kg) jedan sat prije tretmana BPC-om 10 ľg/kg. Dakle protektivno djelovanje ispitivanih gastrointestinalnih hormona postoji, medusobno je različito i ovisno o dozi i metodi, a nije posredovano dopaminskim ni prostaglandinskim sustavom. U rasvjetljavanju njihovog protektivnog djelovanja potrebna su daljnja istraživanja.