Omeprazole and adenocarcinoma in the stomach of rats submitted to duodenogastric reflux. Is there a protective effect?

Abstract Purpose: To investigate the role of omeprazole and nitrites on the gastric mucosa of rats submitted to specific techniques to induce duodenogastric reflux. Methods: One hundred and twenty Wistar rats were divided into three groups: Group I (n=40) -gastrotomy; Group II (n=40) - duodenogastric reflux after gastrojejunoanastomosis latero-lateral (DGR); Group III (n=40) - retrograde duodenogastric reflux through the pylorus (DGR-P). The groups were divided into 4 subgroups of 10 animals, respectively treated for 16 weeks with water, omeprazole 1.6 mg / rat / day, nitrite 600 mg / kg / day and omeprazole plus nitrite simultaneously. Results: The proliferative lesions found were: squamous hyperplasia - 69.1%, adenomatous hyperplasia in the anastomosis - 29.1% and prepyloric adenomatous hyperplasia - 42.5%. Adenocarcinomas were registered in 7 animals (5.8%): one in Group I (omeprazole plus nitrite), two in Group II (omeprazole and nitrite plus omeprazole) and four in Group III (water, nitrite, omeprazole and omeprazole plus nitrite). Conclusions: The occurrence of squamous hyperplasia, adenomatous hyperplasia and adenocarcinoma increased after gastrojejunal anastomoses, which cause duodenogastric reflux. The association of omeprazole did not protect the development of proliferative lesions and cancer induced by duodenogastric reflux in rats.

Effects of ischemia and omeprazole preconditioning on functional recovery of isolated rat heart / Efeitos da isquemia e pré-condicionamento com omeprazol na recuperação funcional do coração isolado de rato

Abstract Objective: The aim of this study was to compare protective effects of ischemic and potential protective effects of pharmacological preconditioning with omeprazole on isolated rat heart subjected to ischemia/reperfusion. Methods: The hearts of male Wistar albino rats were excised and perfused on a Langendorff apparatus. In control group (CG) after stabilization period, hearts were subjected to global ischemia (perfusion was totally stopped) for 20 minutes and 30 minutes of reperfusion. Hearts of group II (IPC) were submitted to ischemic preconditioning lasting 5 minutes before 20 minutes of ischemia and 30 minutes of reperfusion. In third group (OPC) hearts first underwent preconditioning lasting 5 minutes with 100μM omeprazole, and then submitted 20 minutes of ischemia and 30 minutes of reperfusion. Results: Administration of omeprazole before ischemia induction had protective effect on myocardium function recovery especially regarding to values of systolic left ventricular pressure and dp/dt max. Also our findings are that values of coronary flow did not change between OPC and IPC groups in last point of reperfusion. Conclusion: Based on our results it seems that ischemic preconditioning could be used as first window of protection after ischemic injury especially because all investigated parameters showed continuous trend of recovery of myocardial function. On the other hand, preconditioning with omeprazole induced sudden trend of recovery with positive myocardium protection, although less effective than results obtained with ischemic preconditioning not withstand, we must consider that omeprazole may be used in many clinical circumstances where direct coronary clamping for ischemic preconditioning is not possible. .

Resumo Objetivo: O objetivo deste estudo foi comparar os efeitos protetores de efeitos protetores isquêmicos e potenciais de précondicionamento farmacológico com omeprazol no coração isolado de rato submetido à isquemia/reperfusão. Métodos: Os corações de ratos albinos Wistar machos foram excisados e perfundidos em um aparelho de Langendorff. No grupo controle (grupo I), após o período de estabilização, os corações foram submetidos à isquemia global (a perfusão foi totalmente interrompida) por 20 minutos e 30 minutos de reperfusão. Corações do grupo II (IPC) foram submetidos a précondicionamento isquêmico com duração de 5 minutos antes de 20 minutos de isquemia e 30 minutos de reperfusão. No terceiro grupo (OPC), corações foram submetidos a pré-condicionamento com duração de 5 minutos com 100 μM de omeprazol, e, então, submetidos a 20 minutos de isquemia e 30 minutos de reperfusão. Resultados: A administração de omeprazol antes da indução da isquemia teve efeito protetor sobre a recuperação funcional do miocárdio especialmente em relação aos valores de pressão sistólica ventricular esquerda e dp/dt max. Também os nossos achados são de que os valores de fluxo coronário não se alteraram entre os grupos OPC e IPC no último ponto de reperfusão. Conclusão: Com base nos nossos resultados, o pré-condicionamento isquêmico poderia ser usado como primeira janela de proteção após a lesão isquêmica, especialmente porque todos os parâmetros analisados apresentam tendência contínua de recuperação da função do miocárdio. Por outro lado, o pré-condicionamento induzido com omeprazol apresenta tendência repentina de recuperação com proteção miocárdio positiva, embora menos efetiva da obtida com o pré-condicionamento isquêmico. Devemos considerar que o omeprazol pode ser usado em muitas circunstâncias clínicas em que o pinçamento coronariano direto para pré-condicionamento isquêmico não é possível. .

A Proton Pump Inhibitor's Effect on Bone Metabolism Mediated by Osteoclast Action in Old Age: A Prospective Randomized Study

BACKGROUND/AIMS: Proton pump inhibitors (PPIs) act by irreversibly binding to the H+-K+-ATPase of the proton pump in parietal cells and may possibly affect the vacuolar H+-ATPase in osteoclasts. METHODS: We investigated the effect of 8 weeks of PPI treatment on the parameters of bone turnover and compared PPI with revaprazan, which acts by reversibly binding to H+-K+-ATPase in proton pumps. This study was a parallel randomized controlled trial. For 8 weeks, either a PPI or revaprazan was randomly assigned to patients with gastric ulcers. The parameters of bone turnover were measured at the beginning of and after the 8-week treatment period. RESULTS: Twenty-six patients (PPI, n=13; revaprazan, n=13) completed the intention-to-treat analysis. After the 8-week treatment period, serum calcium and urine deoxypyridinoline (DPD) were increased in the PPI group (serum calcium, p=0.046; urine DPD, p=0.046) but not in the revaprazan group. According to multivariate linear regression analysis, age > or =60 years was an independent predictor for the changes in serum calcium and urine DPD. CONCLUSIONS: In elderly patients, administering a PPI for 8 weeks altered bone parameters. Our study suggested that PPIs might directly alter bone metabolism via the vacuolar H+-ATPase in osteoclasts.

New Therapeutic Strategies against Helicobacter pylori / 대한소화기학회지

The standard therapy for Helicobacter pylori infection in Korea is a triple-drug regimen consisting of a proton pump inhibitor with two antibiotics such as clarithromycin, amoxicillin, and metronidazole. However, as the eradication rate of this regimen has declined over the past decade, this prompted the formulation of new therapeutic regimens. New therapeutic strategies against H. pylori infection that had been tried all over the world include sequential therapy, concomitant therapy, and tailored therapy This article will review the basic concepts and the results of previous clinical trials on the aforementioned new therapeutic regiments.

Análise qualitativa das alterações anatomopatológicas na mucosa gástrica decorrentes da terapêutica prolongada com inibidores da bomba de prótons: estudos experimentais x estudos clínicos / Qualitative analysis of anatomopathological changes of gastric mucosa due to long term therapy with proton pump inhibitors: experimental studies x clinical studies

INTRODUÇÃO: Há algumas décadas o uso prolongado de inibidores de bomba de prótons tem tido ampla aplicação no tratamento de doenças gastrointestinais. Desde então, entretanto, vários estudos têm alertado para o possível desenvolvimento de alterações anatomopatológicas da mucosa gástrica, decorrentes do uso prolongado desta modalidade terapêutica. Estudos clínicos e experimentais recentes sugerem que estas alterações teriam relação com o desenvolvimento não só de lesões pré-neoplásicas mas, também, de tumores gástricos. OBJETIVO: Apresentar uma análise qualitativa das alterações antomopatológicas da mucosa gástrica decorrentes do uso prolongado dos inibidores da bomba de prótons. MÉTODOS: Foram utilizados os descritores inibidores da bomba de prótons, lesões pré-neoplásicas e neoplasias gástricas para revisão não sistemática narrativa da literatura, com base nas plataformas Medline, Lillacs e Scielo. Foram selecionados 12 artigos, dentre estudos clínicos (9) e experimentais (3), para análise qualitativa dos resultados apresentados. RESULTADOS: A supressão ácida gástrica por altas doses de inibidores de bomba de prótons induz hipergastrinemia e o consequente aparecimento de tumores neuroendócrinos, em modelos animais. As alterações morfológicas encontradas nestes estudos experimentais foram: hiperplasia de células enterocromafins like, tumor neuroendócrino, atrofia, metaplasia e adenocarcinoma. Os estudos em humanos, entretanto, apesar de demostrarem hiperplasia de células enterocromafins like, tumores neuroendócrino e atrofia gástrica, não identificaram metaplasia gástrica ou adenocarcinoma. CONCLUSÃO: Apesar de não ser possível afirmar que o tratamento prolongado com inibidores de bomba de prótons induza ao aparecimento ou acelere o desenvolvimento do câncer gástrico, em humanos, vários autores sugeriram que a administração prolongada poderia promover o desenvolvimento do câncer gástrico. Dessa forma, as evidências demonstradas no modelo animal, bem como o grande número de pacientes que fazem ou que farão tratamento prolongado com esta classe de medicamentos, alertam para necessidade de seu uso mais criterioso, bem como, justificam a manutenção desta importante linha de pesquisa.

INTRODUCTION: For a few decades the long-term use of proton pump inhibitors has had wide application in the treatment of several gastrointestinal diseases. Since then, however, several studies have called attention to the possible development of anatomical and pathological changes of gastric mucosa, resulting from the long term use of this therapeutic modality. Recent experimental and clinical studies suggest that these changes have connection not only to the development of precancerous lesions, but also of gastric tumors. OBJECTIVE: To present a qualitative analysis of anatomical and pathological changes of gastric mucosa resulting from the long-term use of proton pump inhibitors. METHOD: The headings used were: proton pump inhibitors, precancerous lesions and gastric neoplasms for a non systematic review of the literature, based on Medline, Lillacs and Scielo. Twelve articles were selected from clinical (9) and experimental (3) studies, for qualitative analysis of the results. RESULTS: The gastric acid suppression by high doses of proton pump inhibitors induces hypergastrinemia and the consequent emergence of neuroendocrine tumors in animal models. Morphological changes most often found in these experimental studies were: enterochromaffin-like cell hyperplasia, neuroendocrine tumor, atrophy, metaplasia and adenocarcinoma. In the studies in humans, however, despite enterochromaffin-like cell hyperplasia, the other effects, neuroendocrine tumor and gastric atrophy, gastric metaplasia and or adenocarcinoma, were not identified. CONCLUSION: Although it is not possible to say that the long-term treatment with proton pump inhibitors induces the appearance or accelerates the development of gastric cancer in humans, several authors have suggested that prolonged administration of this drug could provoke the development of gastric cancer. Thus, the evidence demonstrated in the animal model as well as the large number of patients who do or will do a long-term treatment with proton pump inhibitors, justifies the maintenance of this important line of research.

Apical acidity decreases inhibitory effect of omeprazole on Mg2+ absorption and claudin-7 and -12 expression in Caco-2 monolayers

Clinical studies reported hypomagnesaemia in long-term omeprazole usage that was probably due to intestinal Mg2+ wasting. Our previous report demonstrated the inhibitory effect of omeprazole on passive Mg2+ transport across Caco-2 monolayers. The present study aimed to identify the underlying mechanism of omeprazole suppression of passive Mg2+ absorption. By using Caco-2 monolayers, we demonstrated a potent inhibitory effect of omeprazole on passive Mg2+, but not Ca2+, transport across Caco-2 monolayers. Omeprazole shifted the %maximum passive Mg2+ transport-Mg2+ concentration curves to the right, and increased the half maximal effective concentration of those dose-response curves, indicating a lower Mg2+ affinity of the paracellular channel. By continually monitoring the apical pH, we showed that omeprazole suppressed apical acid accumulation. Neomycin and spermine had no effect on passive Mg2+ transport of either control or omeprazole treated monolayers, indicating that omeprazole suppressed passive Mg2+ transport in a calcium sensing receptor (CaSR)-independent manner. The results of western blot analysis showed that omeprazole significantly suppressed claudin (Cldn)-7 and -12, but not Cldn-2, expression in Caco-2 cells. By using apical solution of pH 5.5, 6.0, 6.5, and 7.0, we found that apical acidity markedly increased passive Mg2+ transport, Mg2+ affinity of the paracellular channel, and Cldn-7 and -12 expression in Caco-2 monolayers. Apical acidity abolished the inhibitory effect of omeprazole on passive Mg2+ transport and Cldn-7 and -12 expression. Our results provided the evidence for the regulation of intestinal passive Mg2+ absorption by luminal acidity-induced increase in Cldn-7 and -12 expression.