Search

Acute pancreatitis is a still a medical emergency. unfourtanetley, the medical treatment of acute pancreatitis still remains unsatisfactory and mortality is still high. Therefore, in terms of the suggested organoprotective effect, our newly isolated human gastric juice peptide (M.P), witch we call Body Protection Compound (BPC9 partialy sequenced H2N--Gly-Glu-Pro-Pro-Pro-Gly-Lys-Pro-Ala-Asp-Asp-Ala-Gly-Leu-Val-COOH ; MW 40, 000) was investigated on models of acute pancreatitis.

Hypothesis: stomach stress response, diagnostic and therapeutical value - a new approach in organoprotection.

To elucidate any mechanism, the observed events should be investigated also by the way of their modulations induced by particular organ ablation. For body protection compound (BPC), a novel partially characterized gastric juice peptide (1), the gastroprotection has been largely studied in normal and modified conditions. Between a huge range of organoprotective effects (intestinium, kidney, liver, pancreas, inflammation, diabetes mellitus), the gastroprotection has been supposed by us (1) to be firstly a crucial pattern in general concept of organoprotection, and secondly for BPC beneficial action, as the mediator of the sugested "stomach-stress organoprotective response". Therefore, the obtained modulations: (1) abolition: ovariectomy, demedullation ; (2) decrease: thyroparathyroidoectomy ; (3) no change: orchidectomy, vagotomy, spleenectomy - could probably be complex as well as specific way of BPC beneficial action. 1. Sikirić, P. et al. Exp. Clin, Gastroenterol. 1: 15-16, 1991.

The protection against different experimental gastric and/ or duodenal lesions is a very important point in the concept of organoprotection. Likewise, it is a remarkable property of many known gastrointestinal peptides. In this report, the powerfoul antiulcerogenic effect of a new human gastric juice peptide, MW 40, 000, which we call Body Protection Compound (BPC) is described. It has been isolated very recently by us (M.P.) and partialy sequenced (H2N-Gly-Glu-Pro-Pro-Pro-Gly-Lys-Pro-Ala-Asp-Asp-Ala-Gly-Leu-Val-COOH). In addition, supporting its organoprotective action, its beneficial effects on the generally employed models of inflammatory diseases is also presented. Noteworthy, these investigation were also encouraged with our acute toxicology, and surprisingly high TI.

The present study investigated both the healing rate (after four weeks) and relapse rate (during six months) following treatment with the dopamine- like drugs bromocriptine (2.5 mg twice daily), amantadine (100 mg nocte), or with H2 blockers cimetidine (800 mg nocte), and famotidine (40 mg nocte) in 124 patients with endoscopically proven duodenal ulcer (DU). The ulcer was completly healed in 27 (amatidine), 26 (bromosriptine), 23 (cimetidine), and 24 (famotidine) patients. Relapse was noted 34.7 % (cimetidine) and 25 % (famotidine) versus 11.7 % (amatidine) and 7.7 % (bromocriptine) DU patients. No significant difference was found in initial healing rates. However, the relapse rate in the cimetidine- treated group was significantly higher than in all the other test groups. Additional comparisons between all the treatment categories showed a signifcantly lower relaps rate with the dopamine- like agents. These important new results indicate that dopamine- like compounds are equally effective as H2 blockers in inducing DU healing and may offer a promising advantage over H2 blockers concerning their efficacy in preventing ulcer relapse in DU patients.

It could be argued that many experimental "stress-ulcersinducing methods are not completely related to the naturally occuring circumstances (e.g.restraint stress). Therefore, the influence of dopamine agents bromocriptine (10.o mg/kg b.w.) and amantadine (20.0 mg/kg b.w.) on fracture (metatarsus)-induced gastric lesions was invastigated in rats (Wistar strain, both sexes, 200 g b.w.) Each drug was given i.p. 1 h before injury induction and subsequently once a day. The control animals received an equivolume of saline. The animals were sacrificed 1, 2, 3, 5, 8, 12 and 33 days after injury induction (15 rats for each experimental group) and the stomach examined for presence of lesions as discrabed before (Sikirić et al. , Eur. J. Pharmacol. 1985, 1986, 1987, 1988). Marked gastric lesions were found in the control rats sacrificed 5 (number of lesions per rat 3.7.+0.3, sum of their longest diameters per rat 4.2+-o.1 mm) and 8 (4.0.+-0.2, 4.3+-0.3 mm) days post fracture. No lesionswere noted in treated groups (Student´s t-test vs controls

The beneficial effect of dopamine (D) on gastroduodenal as well as liver lesion is well known. Noteworthy, their relationship has not been simultaneously studied in the same experimental model, Therefore, we applied in rats D agonists (DAG) bromocriptine (B) (10) and amantadine (AM) (20) or D antagonists (DAN) haloperidol (H) and and domperidone (DOMP) (both 5 mg/kg b.w.i.p.) 1 h before 6 hr- restraint stress (exp 1) or 48 h-restraint stress (exp.2) (gastric/liver lesions)as wellas 24 h-bile duct+hepatic artery ligation (exp.III) (duodenal/liver lesions)Gastrointestinal lesions were assessed as before (Eur. J. Pharmacol. e.g. 1988). Liver lesion were recorded semiquantitativly macro/microscopically concerning their their extent and severity (score 0-4. Exp.I Stomach: A strong protection was noted for both DAG, and significant aggravitation for both DAN, which could be inhibited by simultaneous coadministration of DAG. Liver: DAN strongly aggravated otherwise small lesion (vascular degeneratio and fatty accumulation in hepatocytes), an effect counteracted by simultaneus administration of DAG (exceptions DOMP and AM).Exp II: Stomach: No influence of D-drugs (both DAG and DAN) was noted. Liver: A strong protection was noted for both DAG, significantly inhibited by both DAN. Exp.III: Duodenum: A significant protection was found only for AM, but no further influence was demonstrated for any invastigated agent. Liver: B but not AM, strongly protected liver from severe ischaemic necrosis. This effect was inhibited by either H or DOMP. From these results we conclude that both beneficial effects of DAG, either stomach protection (exp.I. or liver protection (exp.III.) could be inhibited by DAN. Hence, the involment of D_mechanisms in both organs lesions seems likely. On the other hend, the effect of D-drugs were observed in gastrointestinal tract particulary in earlier period (6h), unlike their effects on liver noted after delayed (24 and 48 H). Likewise, some other effects of D-drugs, either DAG (lack of protection: liver:exp.1, stomach: exp.II or DAN (lack of aggravation: duodenum, liver:exp.III) point to the particular difference between them.

A simultaneous comparison between the effects of dopamine (D) drugs on gastric and myocardial lesions (as yet known only from sepatate data) was carried out in Wistar rats (200 g) subjected to 6 h or 48 h restraint stress (RS). Investigatet agents (mg/kg b.w.) (D-agonists (AG) bromocriptine 10, amantadine 20, D-antagonists (AN) haloperidol 5, domperidone 5) were administred i.p. 1 h before RS. Unstressed rats (hellty control) were also used for comparison. Previously described metods (Sikiric et al., EJP 158, 61, 1988) as well as simple microscopical scoring system (score 0-4) were used for stomach/hart lession assassment. Results. Time-dependent worseing of stomach and hart lessions was noted in RS. 6 h. We demonstrated a strong protection for DAG, and for DAN an aggravation inhibited by cooadministration of DAG. Heart. No significant influence of any studied agent. Conclusion. Therfore based on parallel and simultaneus comparison as well as know actions of used grugs DAG or DAN, these data do not provide the clear evidence for a concurrent involment of D-mechanisms in gastric and myocardial lesions in RS in any studied period. However, in wiew of D influence on gastric RS-lesion, additional investigations are certainly needed to clarify this problem.

Spontani bakterijski peritonitis u bolesnika s dekompenziranom cirozom jetre i ˝napetim˝ ascitesom.

A simultaneous comparison between the effects of dopamine (D) drugs on gastric and pancreatic lesions (as yet known only from separate data) was carried out in Wistar rats (200 g) subjected to 6 h or 48 h restraint stress (RS). Investigated agents (mg/kg b.w.) (D-agonists (AG) bromocriptine 10, amantadine 20, D-antagonists (AN) haloperidol 5, domperidone 5) were given i.p. 1 h before RS. Unstressed (healthy control) and saline preatreated RS-rats were used for comparison. Previously described methods (Sikiric et al., EJP 147, 321, 1988 ; Sikiric et al., EJP 158, 61, 1988) were used for gastric/pancreatic lesions assesment. Results. Time-dependent worseing of stomach and pancreas lesions were noted in RS. 6 h. Stomach. We demonstrated a strong protection for DAG, and for DAN an aggravation inhibited by coadministration of DAG. Pancreas. Domperidone did aggravate the present lesions. No aditional influence of any investigated agent was observed. 48 h. Stomach. Pancreas. No influence of D-drugs was noted. Conclusion. Therefore, based on this parallel and simoultaneous comparison as well known actions of investigated agents as DAG or DAN, these data do not provide the clear evidence for general involvement of D-mechanism in both gastric and pancreatic lesions development in RS. However, the harmful effect of domperidone (6 h-RS), as rather specific peripheral DAN, consistently with our results on bille duct-ligated rats Sikiric et al., EJP 147, 321, 1988), suggests the need for further investigation in RS.

Dopamine agents (saline in control groups) were coadministered with indomethacin by either single or repeated application. The ulcerogenic effect (erosions and/or ulcers) of repeated given indomethacin on gastric mucosa differed clearly from that on intestinal mucosa. The effect on intestinal mucosa was markedly greater than after a single dose. The effects of dopamine agents appeared to be more consistent. Domperidone and haloperidol, given as single or repeated doses, strongly aggravated both the gastric and intestinal lesions. Bromocriptine and amantadine had a protective effect. The adverse effects of both dopamine antagonists (increased after repeated administration) were strongly inhibited by the simultaneous administration of either bromocriptine or amantadine. The involvement of the dopamine system (central or peripheral) in the mechanisms that maintain gastric (probably related to cytoprotection also) and intestinal mucosa integrity is therefore suggested.