RESUMO
BACKGROUND: Rabeprazole sodium is the newest member of a class of substituted benzimidazole molecules known as proton pump inhibitors. Other proton pump inhibitors have been shown to be effective in healing active duodenal ulcer. METHOD: This randomized, double-blind, multicentre study, conducted at 25 European sites, compared the efficacy and tolerability of rabeprazole and omeprazole in patients with active duodenal ulcers. One hundred and two patients with active duodenal ulcer received rabeprazole 20 mg and 103 patients omeprazole 20 mg once daily for 2 or 4 weeks, with ulcer healing monitored by endoscopy. RESULTS: After 2 weeks, complete ulcer healing was documented in 69% of patients given rabeprazole 20 mg and in 62% of patients given omeprazole 20 mg (N.S.). After 4 weeks, healing rates were 98% in the rabeprazole group and 93% in the omeprazole group (P = 0.083). Rabeprazole-treated patients had significantly greater improvement in daytime pain symptom relief than those treated with omeprazole at the conclusion of the study (P = 0.038). Both drugs were well tolerated over the 4-week treatment period. Mean changes from baseline to end-point in fasting serum gastrin were significantly greater in the rabeprazole group, but at end-point mean values were well within normal limits for both groups. No clinically meaningful changes or other between-group differences were observed in laboratory parameters. CONCLUSION: In this study, rabeprazole produced healing rates equivalent to omeprazole at weeks 2 and 4, and provided significantly greater improvement in daytime pain. Both treatments were well tolerated.
Assuntos
Antiulcerosos/uso terapêutico , Benzimidazóis/uso terapêutico , Úlcera Duodenal/tratamento farmacológico , Omeprazol/uso terapêutico , 2-Piridinilmetilsulfinilbenzimidazóis , Adulto , Idoso , Benzimidazóis/efeitos adversos , Método Duplo-Cego , Feminino , Gastrinas/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Omeprazol/efeitos adversos , RabeprazolRESUMO
BACKGROUND: Rabeprazole sodium is the newest member of a class of substituted benzimidazole molecules known as proton pump inhibitors. Other proton pump inhibitors have been shown to be effective in healing active, benign gastric ulcers. METHODS: In this randomized, double-blind, multicentre study, conducted at 25 European sites, rabeprazole and omeprazole were compared in patients with active gastric ulcers. Two hundred and twenty-seven patients with active benign gastric ulcer were randomized to receive either rabeprazole 20 mg (n = 113) or omeprazole 20 mg (n = 114) once daily for 3 or 6 weeks, with healing monitored by endoscopy. RESULTS: After 3 weeks, complete healing (ITT analysis) was documented in 58% of patients given rabeprazole and 61% in patients given omeprazole (N.S.). After 6 weeks the healing rates were identical in both groups at 91%. Rabeprazole-treated patients had numerically greater symptom relief at all 12 points of comparison. The differences significantly favoured rabeprazole at week 3 for daytime pain improvement (P = 0.023) and at week 6 for pain frequency (P = 0.006) and complete resolution of night pain (P = 0.022). Both drugs were well-tolerated over the 6-week treatment course. Mean changes from baseline to end-point in fasting serum gastrin were comparable. No significant differences in laboratory parameters were seen. CONCLUSION: In this study, rabeprazole produced healing rates comparable to omeprazole at weeks 3 and 6, but provided more consistent and occasionally significantly superior symptom improvement. Both treatments were well-tolerated.
Assuntos
Antiulcerosos/administração & dosagem , Benzimidazóis/administração & dosagem , Omeprazol/administração & dosagem , Úlcera Gástrica/tratamento farmacológico , 2-Piridinilmetilsulfinilbenzimidazóis , Adolescente , Adulto , Idoso , Método Duplo-Cego , Feminino , Gastroscopia , Humanos , Masculino , Pessoa de Meia-Idade , Dor/tratamento farmacológico , Rabeprazol , Úlcera Gástrica/patologia , Resultado do TratamentoRESUMO
BACKGROUND: Rabeprazole sodium is the most recent member of a class of substituted benzimidazole molecules known as proton pump inhibitors. Other proton pump inhibitors have been shown to be effective in healing oesophagitis. METHODS: In this randomised, double-blind, multicentre study, conducted at 27 European sites, the efficacy and safety of rabeprazole and omeprazole were compared in patients with erosive or ulcerative gastro-oesophageal reflux disease (GERD).100 patients received rabeprazole 20 mg, and 102 patients omeprazole 20 mg once daily for 4 or 8 weeks, with healing monitored by endoscopy. RESULTS: Overall GERD healing rates observed and evaluated at weeks 4 and 8 were equivalent. Four-week healing rates for rabeprazole and omeprazole were 81%-81% and 92%-94% for 8-week healing. Rabeprazole-treated patients had similar relief of the frequency and intensity of heartburn to those treated with omeprazole. Both drugs were well tolerated over the 8-week treatment period. Mean changes in fasting serum gastrin were comparable. No significant differences in laboratory parameters were seen. Biopsies for argyrophil ECL cell histology at the end-point revealed a similar distributions of hyperplasia grades to those at baseline in both groups. Biopsies of body and antral mucosa for other parameters were similar between treatments for Helicobacter pylori colonization, presence or degree of inflammation, atrophy or intestinal metaplasia at the end-point. CONCLUSION: In this study, GERD healing rates following rabeprazole 20 mg once daily were equivalent to those obtained with omeprazole 20 mg once daily. Both treatments resulted in a comparable relief of the frequency and intensity of heartburn associated with this disease, and both were well tolerated.
Assuntos
Antiulcerosos/uso terapêutico , Benzimidazóis/uso terapêutico , Refluxo Gastroesofágico/tratamento farmacológico , Omeprazol/uso terapêutico , Úlcera Péptica/complicações , Inibidores da Bomba de Prótons , 2-Piridinilmetilsulfinilbenzimidazóis , Adulto , Idoso , Idoso de 80 Anos ou mais , Método Duplo-Cego , Endoscopia Gastrointestinal , Europa (Continente) , Feminino , Refluxo Gastroesofágico/complicações , Humanos , Masculino , Pessoa de Meia-Idade , Rabeprazol , Resultado do TratamentoRESUMO
The role of oxidative stress as an important pathogenetic factor in experimental AP is commonly accepted, but its role in human AP has still not been evaluated satisfactorily. In the present study we compared the parameters of oxidative stress to the level of PLA2 and PMN-E in patients with AP. The study was performed in 77 patients with mild (n = 31), moderate (n = 20), and severe (n = 26) AP (alcoholic and biliary) as assessed according to Ranson's and Balthazar's criteria. Serum and urine malondialdehyde (MDA) concentrations, as an index of oxidant-mediated lipid peroxidation, and sulfhydryl (SH) groups, a major nonenzymatic antioxidant, were measured along with serum PLA2 and plasma PMN-E at admission (day 0) and on days 2, 5, and 10 of the disease. The Serum MDA level in severe AP was elevated by 267% on day 0 and 230% after 10 days, in comparison to the control, by 104 and 105% in comparison to mild AP, and by 50 and 76% in comparison to moderate AP, respectively. This was accompanied by a decrease in serum SH groups by 23% on day 0 and 36% after 10 days, in comparison to the control, by 31 and 32% in comparison to mild AP, and by 20 and 11% (ns) in comparison to moderate AP, respectively. In all severity forms of AP, oxidative stress was proportionally accompanied by increased levels of PLA2 and plasma PMN-E. In conclusion, oxidative stress is an early phenomenon in patients with AP, and at the time of admission it is detectable in the serum and urine. The intensity of oxidative stress correlates with the severity of AP. Because of the significant correlation between MDA and PLA2 or PMN-E, we suppose that the parameters of oxidative stress may be useful as another early prognostic factor in human AP.
Assuntos
Ensaios Enzimáticos Clínicos , Elastase de Leucócito/sangue , Estresse Oxidativo , Pancreatite/diagnóstico , Fosfolipases A/sangue , Doença Aguda , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Avaliação como Assunto , Feminino , Glutationa/sangue , Glutationa/urina , Humanos , Peroxidação de Lipídeos , Masculino , Malondialdeído/sangue , Malondialdeído/urina , Pessoa de Meia-Idade , Pancreatite/sangue , Fosfolipases A2 , PrognósticoRESUMO
It has been recently reported that kinases that belong to the mitogen-activated protein kinase (MAPK) family are rapidly activated by cholecystokinin (CCK) in rat pancreas both in vitro and in vivo. It is known that reactive oxygen species (ROS) play an important role in the pathogenesis of acute pancreatitis induced by supraphysiologic stimulation with CCK analogue, cerulein. The aim of our study was to evaluate whether MAPKs are activated by ROS in pancreatic acini. The activity of MAPK, c-Jun amino-terminal kinase (JNK), and p38 MAPK was determined in isolated rat pancreatic acinar cells by means of Western blotting, with the use of specific antibody that recognizes active, dually phosphorylated kinases. Incubation of acini with ROS donors, hydrogen peroxide (H2O2) and/or menadione (MND), strongly activated all three kinases. Activation of these kinases by ROS, but not by CCK, was substantially inhibited by pretreatment of acini with antioxidant N-acetylo-L-cysteine (NAC). Whereas CCK-induced activation of MAPK or JNK was totally or partially blocked by protein kinase C (PKC) inhibitor GF-109203X, ROS-induced activation of MAPK, JNK, and p38 MAPK was PKC independent. In conclusion, ROS strongly activate MAPK, JNK, and p38 MAPK in pancreatic acinar cells. It may be of importance in acute pancreatitis, because ROS are involved in the pathogenesis of this disease.
Assuntos
Proteínas Quinases JNK Ativadas por Mitógeno , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Pâncreas/enzimologia , Espécies Reativas de Oxigênio , Acetilcisteína/farmacologia , Animais , Colecistocinina/farmacologia , Ativação Enzimática , Peróxido de Hidrogênio/farmacologia , Indóis/farmacologia , MAP Quinase Quinase 4 , Masculino , Maleimidas/farmacologia , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Proteína Quinase C/fisiologia , Ratos , Ratos Wistar , Vitamina K/farmacologia , Proteínas Quinases p38 Ativadas por MitógenoRESUMO
The promoting effect of acute ethanol (E) abuse and protective effect of prostaglandin derivatives in acute pancreatitis (AP) remain obscure. The aim of this study was to assess the effect of previous intake of high-dose E on trypsinogen (Tn) activation and labilization of pancreatic lysosomal membranes (PLM), in taurocholate AP in rats, considering treatment with stable beta-thia-iminoprostacyclin (T). In 60 male Wistar rats taurocholate AP was induced or a sham operation was performed. Half of them received 40% E (5 g/kg body weight), 6 h earlier. T (0.3 mg/kg body weight i.g.) was applied before E or before the induction of AP. Free active (FAT) and total potential (TPT) trypsin, free (F) and total (T) cathepsin B, phospholipase A2 (PLA2), and lipase (L) activities were assayed. Percentage FAT/TPT was an index of Tn activation and fractional free (% F/T) activity of cathepsin B was an index of PLM fragility. FAT increased after 12 h of AP, and in E rats this increase was even more evident. Pretreatment and treatment with T partly prevented this increase, however, this effect was abolished or limited in rats previously given E-the changes were not effected by T. PLA2 and L activities in AP were not diminished after T. The promoting effect of acute E abuse prior to AP could be dependent on augmented activation of Tn and labilization of PLM. The protective effect of T seems to be dependent on the decrease in Tn activation in pancreatitic tissue. The potential therapeutic effect of this drug in AP could be limited by previous acute E intake, as evidenced by differences in histopathological changes.
Assuntos
Consumo de Bebidas Alcoólicas/metabolismo , Depressores do Sistema Nervoso Central/farmacologia , Epoprostenol/análogos & derivados , Etanol/farmacologia , Pancreatite/metabolismo , Inibidores da Agregação Plaquetária/farmacologia , Animais , Catepsina B/metabolismo , Colagogos e Coleréticos , Epoprostenol/farmacologia , Lipase/metabolismo , Masculino , Pâncreas/efeitos dos fármacos , Pâncreas/metabolismo , Pancreatite/induzido quimicamente , Pancreatite/patologia , Fosfolipases A/metabolismo , Fosfolipases A2 , Ratos , Ratos Wistar , Ácido Taurocólico , Tripsina/metabolismo , Tripsinogênio/metabolismoRESUMO
In the last decade, the role of oxidative stress has been extensively evaluated in different experimental models of acute pancreatitis. This review shows that there is strong evidence that this stress occurs as an early phenomenon in pancreatic tissue in the course of caerulein-induced acute pancreatitis. Oxidative stress was documented in pancreatic tissue by means of methods showing generation of reactive oxygen species (e.g., chemiluminescence) and accumulation of products of reactive oxygen species-mediated lipid peroxidation. with concomitant depletion of enzymatic and low molecular weight antioxidants. Features of acinar cell injury and inflammation, especially pancreatic edema, show a marked improvement following treatment with a broad spectrum of antioxidants, platelet activating factor antagonists, or donors of nitric oxide (NO). Unfortunately, in most cases these beneficial effects are temporary and generally restricted to an early phase of the disease. However, results of well-designed clinical trials should finally evaluate the importance of oxidative stress-oriented treatment in acute pancreatitis in humans.
Assuntos
Ceruletídeo/efeitos adversos , Fármacos Gastrointestinais/efeitos adversos , Estresse Oxidativo/fisiologia , Pancreatite/metabolismo , Doença Aguda , Animais , Humanos , Pancreatite/etiologiaRESUMO
The aim of this study was to investigate the effect of Nafamostat mesilate (FUT-175) on some blood platelet properties during the first hours of acute experimental pancreatitis (AEP) in dogs. A significant decrease in platelet count, hyperaggregability of platelets by ADP and PAF as well as an increased level of TXB2, were found in the early stage of AEP. No changes in platelet aggregation induced with AA were demonstrated. FUT-175 prevented a decrease in platelet number and inhibited platelet aggregation induced with ADP, PAF and AA when it was given immediately after induction of AEP. No evident changes in TXB2 levels in dogs treated with FUT-175 were found. Our results indicate that the positive effect of FUT-175 in AEP in part depends on its antiaggregatory action.
Assuntos
Plaquetas/efeitos dos fármacos , Guanidinas/farmacologia , Pancreatite/sangue , Inibidores de Proteases/farmacologia , Doença Aguda , Animais , Benzamidinas , Cães , Masculino , Pancreatite/tratamento farmacológico , Inibidores da Agregação Plaquetária/farmacologia , Contagem de Plaquetas/efeitos dos fármacos , Tromboxano B2/sangueRESUMO
The role of blood platelets in the disturbed haemostasis in acute pancreatitis is not fully elucidated. The aim of this study was to evaluate the blood platelet function during the first hours of acute experimental pancreatitis (AEP) in dogs. AEP was induced by the retrograde injection of bile and trypsin into the main pancreatic duct. Platelet count, platelet aggregation induced with ADP, PAF, AA as well as plasma Beta-TG and TXB2 levels were determined. At 30 min after induction of AEP a significant decrease of platelet count was noted; these changes were observed until 4 th hr. At 30 min as well as at 60 min of AEP increased sensitivity of platelet aggregation to ADP was found. After that time evident decrease of platelet aggregation to ADP was shown. Platelets sensitivity to PAF was higher at 30 min of AEP whereas 60 min, 2 and 4 hrs after AEP normalization of platelet aggregation by PAF was observed. The significant increase of plasma Beta-TG and TXB2 concentrations corresponded well to changes of platelet aggregation. These results indicate that AEP affects blood platelet function with the drop of their count.
Assuntos
Plaquetas/fisiologia , Pancreatite/sangue , Doença Aguda , Difosfato de Adenosina/farmacologia , Animais , Ácido Araquidônico , Ácidos Araquidônicos/farmacologia , Plaquetas/efeitos dos fármacos , Cães , Hemostasia , Técnicas In Vitro , Pancreatite/etiologia , Fator de Ativação de Plaquetas/farmacologia , Agregação Plaquetária/efeitos dos fármacos , Contagem de Plaquetas , Tromboxano B2/sangue , beta-Tromboglobulina/metabolismoRESUMO
The damage to the liver appears to be an important aspect of multisystem organ failure in acute pancreatitis with poor prognosis. The objective of this study was to evaluate the protective effect of stable prostacyclin analogue--tilsuprost on the liver energy metabolism in taurocholate pancreatitis in rats preceded by acute ethanol intake. The respiratory control ratio (RCR) and ADP/O ratio of liver mitochondria with glutamate+malate as substrates and mitochondrial DNP (uncoupler)-dependent ATPase activity were significantly depressed after 12 h of taurocholate pancreatitis-the effects that were not significantly aggravated by antecedent acute ethanol intake. Tilsuprost (0.3 mg/kg i.g.) given just before induction of pancreatitis partly prevented the impairment of mitochondrial oxidative and phosphorylative functions, however these positive effects were limited in acute pancreatitis preceded by acute ethanol intake. These results suggest that prostacyclin analogues could be effective in the treatment of hepatic complications in acute pancreatitis, however their effectiveness could be limited in the case of acute ethanol antecedent abuse.
Assuntos
Alcoolismo/complicações , Epoprostenol/análogos & derivados , Mitocôndrias Hepáticas/efeitos dos fármacos , Pancreatite/patologia , Ácido Taurocólico/toxicidade , Adenosina Trifosfatases/metabolismo , Animais , Epoprostenol/farmacologia , Ácido Glutâmico/metabolismo , Malatos/metabolismo , Masculino , Mitocôndrias Hepáticas/enzimologia , Mitocôndrias Hepáticas/metabolismo , Fosforilação Oxidativa , Oxigênio/metabolismo , Pancreatite/induzido quimicamente , Pancreatite/complicações , Ratos , Ratos WistarRESUMO
OBJECTIVES: Nitric oxide (NO) is involved in the control of pancreatic blood flow and secretion, and its role in the maintenance of pancreatic tissue has been suggested. The aim of our study was to evaluate the influence of NO on pancreatic trophic parameters during acute pancreatitis induction and the pancreas recovery process. DESIGN/METHODS: Acute pancreatitis was induced in rats by a supramaximal dose of caerulein. During acute pancreatitis induction, rats were treated with L-arginine (a substrate for NO synthesis), glyceryl trinitrate (NTG, NO donor), glycine, N(G)-nitro-L-arginine (L-NNA, NO synthase inhibitor), L-arginine + L-NNA, or saline. Pancreatic weight, total contents of RNA, DNA, protein, amylase and chymotrypsin as well as pancreas histology and the number of proliferating acinar cells were evaluated after pancreatitis induction in all groups and additionally after 7 and 14 days of recovery in untreated acute pancreatitis rats or those injected with L-NNA and/or L-arginine. RESULTS: Pancreas destruction after acute pancreatitis was evidenced by similar decreases of all parameters in untreated acute pancreatitis rats or those treated with L-NNA or glycine when compared to control healthy animals. The recovery process after acute pancreatitis was not affected by L-NNA injections; however, the increased cell proliferation occurred later than in untreated rats. NTG and especially L-arginine treatment resulted in significant attenuation of pancreas damage (partially prevented by L-NNA treatment) as evidenced by biochemical data with a slight improvement in morphology. Treatment with L-arginine alone or in combination with L-NNA resulted in augmented cell proliferation after acute pancreatitis induction followed by earlier recovery in comparison to untreated acute pancreatitis rats or the L-NNA-injected group. CONCLUSION: The present study suggests the involvement of NO in mild acute pancreatitis and in the recovery process after inflammatory damage.
Assuntos
Arginina/uso terapêutico , Óxido Nítrico Sintase/antagonistas & inibidores , Óxido Nítrico/fisiologia , Pancreatite/fisiopatologia , Doença Aguda , Animais , Arginina/farmacologia , Ceruletídeo , Masculino , Nitroglicerina/farmacologia , Nitroglicerina/uso terapêutico , Pâncreas/patologia , Pancreatite/induzido quimicamente , Pancreatite/tratamento farmacológico , Pancreatite/patologia , Ratos , Ratos WistarRESUMO
OBJECTIVE: To compare the efficacy and safety of ebrotidine and ranitidine administered once daily in equimolar doses of 800 and 300 mg, respectively. PATIENTS: A total of 298 duodenal ulcer patients were studied. DESIGN: A multicentre, parallel, randomized clinical trial. METHODS: Of the 298 patients studied, 150 were randomly assigned to ebrotidine and 148 to ranitidine treatment. Digestive endoscopy was performed at enrolment and at weeks 4, 6 and 8 unless the ulcer had healed before. Endoscopic findings were the main parameter for the assessment of treatment efficacy. Plasma gastrin and pancreatic polypeptide concentrations were also measured before and after termination of the therapy. RESULTS: Ebrotidine achieved a duodenal ulcer healing rate comparable to that of ranitidine, and no statistically significant difference was found between the two drugs. The drugs were equally effective in improving ulcerous dyspeptic symptoms and in relieving gastric pain. Both tobacco and ethanol consumption influenced ulcer healing adversely, but healing in smokers was more pronounced in patients treated with ebrotidine, possibly because of its cytoprotective activity. CONCLUSIONS: Ebrotidine 800 mg is as effective and safe as ranitidine 300 mg in healing duodenal ulcer, but ebrotidine appears to be superior in promoting the healing of duodenal ulceration in smokers.
Assuntos
Antiulcerosos/uso terapêutico , Benzenossulfonatos/uso terapêutico , Úlcera Duodenal/tratamento farmacológico , Ranitidina/uso terapêutico , Tiazóis/uso terapêutico , Adulto , Antiulcerosos/efeitos adversos , Benzenossulfonatos/efeitos adversos , Método Duplo-Cego , Feminino , Gastrinas/sangue , Humanos , Masculino , Polipeptídeo Pancreático/sangue , Ranitidina/efeitos adversos , Tiazóis/efeitos adversosRESUMO
The pathophysiological mechanisms of peptic ulcer and reflux oesophagitis are described. Special attention has been paid to the gastric mucosal defence factors, e.g. epidermal growth factor, mucosal blood flow and gastric mucus. The possible effects of neutrophils activation on nitric oxide generation and gastric mucosal capillary blood flow are discussed. Most useful diagnostic tests of gastro-oesophageal reflux are presented. The role of antacids in the treatment of reflux oesophagitis and reflux without oesophagitis is underlined.
Assuntos
Esofagite Péptica/fisiopatologia , Úlcera Péptica/fisiopatologia , Animais , Esofagite Péptica/diagnóstico , Esofagite Péptica/terapia , Humanos , Úlcera Péptica/tratamento farmacológico , Úlcera Péptica/etiologiaRESUMO
Current view on the role of Helicobacter pylori (Hp) infection in the pathogenesis of peptic ulcer disease is presented. It was shown that Hp is an important risk factor for the development of the disease for which other cofactors are necessary. Different drug regiments for Hp eradication are discussed. The eradication rates of 80 to 90 percent are achievable--most often including 7-10 days triple therapy (drugs increasing intragastric pH, antibiotics and antimicrobial agents). Resistance of Hp to used antibiotics and antimicrobial drugs is underlined.
Assuntos
Antiulcerosos/uso terapêutico , Infecções por Helicobacter/tratamento farmacológico , Helicobacter pylori , Úlcera Péptica/tratamento farmacológico , Amoxicilina/administração & dosagem , Antibacterianos/uso terapêutico , Bismuto/administração & dosagem , Claritromicina/administração & dosagem , Quimioterapia Combinada , Humanos , Metronidazol/administração & dosagem , Tetraciclinas/administração & dosagem , Tinidazol/administração & dosagemRESUMO
This study was undertaken to determine whether synthetic proteinase inhibitors--nafamostat mesilate (FUT-175) and gabexate mesilate (FOY) have any influence on multiorgan oxidant-antioxidant balance in acute haemorrhagic pancreatitis induced in Wistar rats using a retrograde intraductal injection of 5% Na-taurocholate. Rats were treated with FUT-175 25 x 10(-3) g.kg-1.h-1) or FOY (2.5 x 10(-3) g.kg-1.h-1) and sacrificed at 3 h. Malondialdehyde and sulfhydryl groups concentration, as an index of oxidative stress, we measured in pancreatic, lung and liver tissue. In rats with acute pancreatitis treated with these proteinase inhibitors, oxidative stress expressed by malondialdehyde elevation and sulfhydryl groups depletion, was markedly diminished. It was observed in the pancreas and lung, and to a lesser extent in the liver. These effects of FUT-175 or FOY treatment, at least in part, may account for recently postulated favorable systemic effects of such a medication.
Assuntos
Gabexato/uso terapêutico , Guanidinas/uso terapêutico , Pulmão/metabolismo , Malondialdeído/metabolismo , Pâncreas/metabolismo , Pancreatite/tratamento farmacológico , Doença Aguda , Animais , Benzamidinas , Pulmão/efeitos dos fármacos , Masculino , Estresse Oxidativo/efeitos dos fármacos , Pâncreas/efeitos dos fármacos , Pancreatite/induzido quimicamente , Pancreatite/metabolismo , Ratos , Ratos Wistar , Compostos de Sulfidrila/metabolismo , Ácido TaurocólicoRESUMO
Activation of pancreatic phospholipase D (PLD) has been previously observed in response to caerulein (Cae), phorbol myristate acetate and growth factors. Although PLD involvement has been postulated in pancreatic cell proliferation and differentiation, the physiological role of this enzyme in pancreatic cells still remains unclear. In the presence of ethanol, PLD catalysed transphosphatidylation reaction, forming phosphatidylethanol (PEt). This study was thus undertaken to determine the involvement of PLD in ethanol metabolism in isolated pancreatic acini and to show the potential physiological consequences of transphosphatidylation. Dispersed pancreatic acini prelabelled with 3H myristic acid were incubated with 500 pM Cae in the presence or absence of different concentrations of ethanol, and labelled phosphatidylethanol (3H PEt) production or phosphatidic acid (3H PA) accumulation were measured. The production of PEt after Cae stimulation in pancreatic acini was significant from 0.5% up to 4% of ethanol in the medium and was not dependent on increasing concentration of ethanol. Prolonged up to 2 h stimulation with Cae in the presence of 1% ethanol did not increase PEt production which was almost stable since 5 min of stimulation. In the presence of different concentrations of ethanol (1-4%), the significant inhibition of PA accumulation was obtained after Cae stimulation, similar to inhibition with a specific PLD inhibitor--wortmannin. These data indicate that Cae activated PLD in the presence of ethanol caused PEt production in pancreatic acini. During formation of PEt in pancreatic acinar cells significant and parallel inhibition of PA accumulation was observed. This indicates the relation of PLD activation in isolated pancreatic acini to ethanol metabolism. Ethanol can act as an inhibitor of PLD activity. Since PA, a product of PLD, is known as a second messenger probably involved in cell proliferation and differentiation, this may suggest a potentially new mechanism for pancreatic tissue injury after ethanol ingestion.
Assuntos
Etanol/metabolismo , Glicerofosfolipídeos , Pâncreas/metabolismo , Ácidos Fosfatídicos/metabolismo , Fosfolipase D/metabolismo , Animais , Bovinos , Ceruletídeo/farmacologia , Ativação Enzimática , Etanol/farmacologia , Fármacos Gastrointestinais/farmacologia , Técnicas In Vitro , Masculino , Pâncreas/citologia , Pâncreas/efeitos dos fármacos , Fosfolipase D/antagonistas & inibidores , Fosfotransferases/metabolismo , Ratos , Ratos WistarRESUMO
The mechanism by which Helicobacter pylori (Hp) predisposes to duodenal and gastric ulcers remains still unclear. It is possible that Hp infection impaires gastric secretion. Evaluation of gastric acid and mucus secretion before and after Hp eradication would let to estimate the influence of Hp infection on gastric secretion. To evaluate the effect of Hp infection on gastric acid and gastric mucous secretion before and one year after Hp eradication. We examined 28 Hp positive peptic ulcer disease patients (10-gastric ulcer GU, 18-duodenal ulcer DU) before and one year after antibacterial treatment. Gastric acid output was examined basely (BAO) and in response to pentagastrin (6 micrograms/kg) (MAO) using Kay's standard method. Some components of gastric mucus as fucose, galactose, hexosamines and sialic acid were measured using calorimetric methods basaly and after pentagastrin stimulation. Plasma gastrin concentration was measured in 20 patients (6-GU, 14-DU) by radioimmunoassay before and one year after eradication. Hp status was determined by rapid urease test (CLO) and histology (Giemsa stain). One year after Hp successful eradication gastric acid secretion was significantly reduced-BAO: 3,31 vs 1,474 mmol/h; MAO: 19,63 vs 14,85 mmol/h, p < 0.05. Plasma gastrin concentration decreased significantly from 9,783 to 6,017 pmol/I, p < 0.05. In patients with ineffective eradication we did not observe any significant changes in gastric acid secretion. An evident, but not statistically significant, decrease of sialic acid output in eradicated patients was noted. The study has shown the significant influence of Hp infection on gastric acid secretion. Those results support the hypothesis that increased gastric acid secretion may be one of the pathogenic mechanism of Hp infection inducing mucosal damage.
Assuntos
Úlcera Duodenal/metabolismo , Mucosa Gástrica/metabolismo , Infecções por Helicobacter/fisiopatologia , Helicobacter pylori , Úlcera Gástrica/metabolismo , Adolescente , Adulto , Úlcera Duodenal/sangue , Feminino , Fucose/análise , Ácido Gástrico/metabolismo , Gastrinas/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Muco/química , Ácido N-Acetilneuramínico/análise , Úlcera Gástrica/sangue , Fatores de TempoRESUMO
UNLABELLED: Increase of phosphatidic acid (PA) accumulation in response to caerulein (Cae) and after subtotal pancreatectomy (SP) has been previously described and phospholipase D (PLD) derived PA involvement in pancreatic regeneration was suggested. We also described decrease of Cae stimulated PA accumulation after a single dose of ethanol (both in vitro and in vivo). The present study was undertaken in order to determine the influence of chronic ethanol feeding on basal and Cae stimulated PA accumulation and other parameters of pancreatic regeneration in control and ethanol feed rats. Male rats were pair fed ad libitum with an isocaloric liquid diet (Lieber De Carli) with or without ethanol. In vitro study: pair fed rats were killed after 2 or 6 weeks of feeding, pancreata were dissected out and weighted, dispersed pancreatic acini were then prepared and loaded with 3H myristic acid in order to label the phosphatidylcholine pool. Phosphatidic acid (3H PA) accumulation, in the presence of propranolol, was measured after stimulation with increasing doses of Cae. In vivo study: PA was measured 3 days after SP or sham operation in both groups of rats, and also after 1 h of Cae infusion (0.25 microg/kg/h). Pancreatic weight, amylase, protein, RNA and DNA content were established. RESULTS: In vitro study 1) Basal PLD activity expressed as PA accumulation was significantly elevated after 6 weeks of ethanol feeding in comparison to the control values (28%). 2) Cae in doses ranging from 100 pM to 5 nM was not able to stimulate PA accumulation in isolated pancreatic acini prepared from ethanol fed rats. In vivo study: 1) Body weight and pancreatic weight were similar in, both the ethanol fed and the control groups, after 2 and 6 weeks. 2) Ethanol feeding significantly decreased total amylase content in the pancreas, but did not change protein, RNA and DNA content. 3) in contrast to the control animals in which SP caused a 71.1% increase of PA accumulation over the sham operation, subtotal pancreatectomy was not able to stimulate PA in rats fed with ethanol. 4) Also Cae infusion did not stimulate PA accumulation in the ethanol fed animals in comparison to the controls. Since the involvement of PLD activation in the early stages of pancreatic regeneration was postulated, our results suggest that chronic ethanol feeding can influence this process by decrease of PA production, probably because of the inhibition of hydrolytic PLD activity in the presence of ethanol. This could be one of the mechanisms responsible for pancreatic injury after chronic ethanol consumption.
Assuntos
Ceruletídeo/farmacologia , Etanol/administração & dosagem , Fármacos Gastrointestinais/farmacologia , Pâncreas/efeitos dos fármacos , Ácidos Fosfatídicos/biossíntese , Regeneração/fisiologia , Solventes/administração & dosagem , Amilases/análise , Animais , Peso Corporal/efeitos dos fármacos , Quimotripsina/análise , DNA/análise , Masculino , Tamanho do Órgão/efeitos dos fármacos , Pâncreas/metabolismo , Pâncreas/fisiologia , Pancreatectomia , Ácidos Fosfatídicos/metabolismo , Proteínas/análise , RNA/análise , Ratos , Ratos WistarRESUMO
UNLABELLED: This study was undertaken in order to determine the influence of chronic ethanol administration on pancreatic regeneration during acute pancreatitis (AP). Rats were pair fed with isocaloric diet containing or not ethanol. After 8 weeks of such feeding AP was induced by s.c. injection of caerulein (Cae). 6 h, 24 h and 5 days after first Cae dose pancreatic weight, amylase, chymotrypsin, protein, RNA, DNA contents were determined and phosphatidic acid (PA) production in isolated pancreatic acini was measured. Proliferating cells were quantified by immunochemical staining of cells incorporating bromodeoxyuridine (BrdU). RESULTS: Pancreatic weight was significantly higher at 6 h after first Cae injection in both, ethanol fed (EF) and control groups (C), however at 24 h pancreatic weight did not differ from prior to AP induction in EF rats. Ethanol feeding (EF) did not influence significantly protein, chymotrypsin and amylase content in pancreatic tissue in groups with AP. In EF rats RNA content after 5 days of AP was higher than in control animals. Total DNA content in EF rats with AP was lower 6 h after AP induction, earlier than in control animals with AP. Immunochemistry showed higher labelling index for BrdU after 6 h, 24 h and 5 days of AP in EF rats. In contrast to this findings, in EF animals, AP induction was not able to stimulate further PA accumulation. CONCLUSION: We conclude that chronic ethanol feeding, while inhibiting PA accumulation in comparison to control group, does not impair pancreatic tissue regeneration during the early phase of Cae-induced AP. Stimulation of regenerative/reparative processes in EF rats during Cae-induced AP seems to be even more pronounced than in the control group.
Assuntos
Etanol/toxicidade , Pâncreas/fisiopatologia , Pancreatite/fisiopatologia , Regeneração/efeitos dos fármacos , Doença Aguda , Amilases/metabolismo , Animais , Peso Corporal/efeitos dos fármacos , Quimotripsina/metabolismo , Masculino , Ácidos Nucleicos/análise , Tamanho do Órgão/efeitos dos fármacos , Ácidos Fosfatídicos/metabolismo , Ratos , Ratos WistarRESUMO
Recent animal studies have suggested that nitric oxide (NO) plays an important role in the regulation of esophageal motility, being partly responsible for latency period and latency gradient between the onset of a swallow and contractions of esophageal circular smooth muscles. The aim of this study was to evaluate whether endogenous NO is responsible for physiological timing of forthcoming contractions in the human esophageal body after swallowing. Eight male volunteers (age 21-25 years, weight 67-82 kg) were involved in this placebo controlled study on the effects of increasing doses of the NO synthase blocker, NG-monomethyl-L-arginine (L-NMMA 1.0-4.0 mumol/min i.v.), and/or L-arginine (L-arg) (30 mumol/kg-min i.v.) on the peristalsis of esophageal body in response to wet swallows (5 ml of water) and lower esophageal sphincter (LES) resting pressure. The esophageal motor activity was determined manometrically using 3-channel electronic catheter. Additionally, during all examinations arterial blood pressure (BP) was measured every 5 min. L-NMMA resulted in a significant and dose-dependent reduction in the latency period between swallows and the onset of contractions which was most pronounced in the distal esophagus (control: 7.07 +/- 0.74 s vs. L-NMMA 4.0 mumol/min: 5.87 +/- 0.57 s), and this effect was partially reversed after addition of L-arg to the L-NMMA infusion (6.91 +/- 0.62 s). L-NMMA infusion significantly reduced the duration of contractions and increased the velocity of onset propagation but did not change the amplitude of contractions and again, these effects were reversed during simultaneous infusion of L-arg. The resting tone of LES increased significantly during infusion of L-NMMA and these effects were reversed by addition of L-arg. The mean BP significantly increased during infusion of L-NMMA (control 97.0 +/- 5.7 vs. L-NMMA 4.0 mumol/min: 116.4 +/- 3.1 mm Hg) and this was also reversed by L-arg. We conclude that in humans endogenous NO is involved, at least in part, in the physiological regulation of motility patterns of the distal esophageal body and LES.