Role of non-steroidal anti-inflammatory drugs on intestinal permeability and nonalcoholic fatty liver disease

The use of non-steroidal anti-inflammatory drugs(NSAIDs) is widespread worldwide thanks to their analgesic, anti-inflammatory and antipyretic effects. However, even more attention is placed upon the recurrence of digestive system complications in the course of their use. Recent data suggests that the complications of the lower gastro-intestinal tract may be as frequent and severe as those of the upper tract. NSAIDs enteropathy is due to enterohepatic recycling of the drugs resulting in a prolonged and repeated exposure of the intestinal mucosa to the compound and its metabolites. Thus leading to so-called topical effects, which, in turn, lead to an impairment of the intestinal barrier. This process determines bacterial translocation and toxic substances of intestinal origin in the portal circulation, leading to an endotoxaemia. This condition could determine a liver inflammatory response and might promote the development of nonalcoholic steatohepatitis, mostly in patients with risk factors such as obesity, metabolic syndrome and a high fat diet, which may induce a small intestinal bacterial overgrowth and dysbiosis. This alteration of gut microbiota may contribute to nonalcoholic fatty liver disease and its related disorders in two ways: firstly causing a malfunction of the tight junctions that play a critical role in the increase of intestinal permeability, and then secondly leading to the development of insulin resistance, body weight gain, lipogenesis, fibrogenesis and hepatic oxidative stress.

Lansoprazole prevents experimental gastric injury induced by non-steroidal anti-inflammatory drugs through a reduction of mucosal oxidative damage

AIM:This study investigated the mechanisms of protection afforded by the proton pump inhibitor lansoprazole against gastric injury induced by different non-steroidal anti-inflammatory drugs (NSAIDs) in rats. METHODS: Male Sprague-Dawley rats were orally treated with indomethacin (100 μmol/kg), diclofenac (60 μmol/kg), piroxicam (150 μmol/kg) or ketoprofen (150 μmol/kg). Thirty minutes before NSAIDs, animals were orally treated with lansoprazole 18 or 90 umol/kg. Four hours after the end of treatments, the following parameters were assessed: gastric mucosal PGE2, malondialdehyde (MDA), myeloperoxidase (MPO) or non-proteic sulfhydryl compounds (GSH) levels; reverse transcription-polymerase chain reaction (RT-PCR) of mucosal COX-2 mRNA; gastric acid secretion in pylorus-ligated animals; in vitro effects of lansoprazole (1-300 μmol/L) on the oxidation of low density lipoproteins (LDLs) induced by copper sulphate. RESULTS: All NSAIDs elicited mucosal necrotic lesions which were associated with neutrophil infiltration and reduction of PGE2 levels. Increments of MPO and MDA contents, as well as a decrease in GSH levels were detected in the gastric mucosa of indomethacin- or piroxicam-treated animals. Indomethacin enhanced mucosal cyclooxygenase-2 expression, while not affecting cyclooxygenase-1. At the oral dose of 18 μmol/kg lansoprazole partly counteracted diclofenac-induced mucosal damage, whereas at 90 μmol/kg it markedly prevented injuries evoked by all test NSAIDs. Lansoprazole at 90 μmol/kg reversed also the effects of NSAIDs on MPO, MDA and GSH mucosal contents, without interfering with the decrease in PGE2 levels or indomethacin-induced cyclooxygenase-2 expression. However, both lansoprazole doses markedly inhibited acid secretion in pylorus-ligated rats. Lansoprazole concentration-dependently reduced the oxidation of LDLs in vitro. CONCLUSION: These results suggest that, besides the inhibition of acid secretion, lansoprazole protection against NSAID-induced gastric damage depends on a reduction in mucosal oxidative injury, which is also responsible for an increment of sulfhydryl radical bioavailability. It is also suggested that lansoprazole does not influence the down-regulation of gastric prostaglandin production associated with NSAID treatment.

Exacerbation of inflammatory bowel disease by nonsteroidal anti-inflammatory drugs and cyclooxygenase-2 inhibitors:Fact or fiction?

The existence of a possible link between inflammatory bowel disease （IBD） and nonsteroidal anti-inflammatory drugs （NSAIDs） has been repeatedly suggested. Recently, a few studies have addressed the issue of a possible, similar effect by selective cyclooxygenase-2 inhibitors （COXIBs）. The present article reviews the available scientific evidence for this controversial subject.

Pharmacology of tetrandrine and its therapeutic use in digestive diseases

INTRODUCTIONTetrandrine (Tet) is a dibenzylisoquinoline alkaloid isolatedfrom Stephania tetrandra S. Moore, a Chinese herbalmedicine. In the past decade, lots of studies demonstrated that Tet has multiple bioactivities, It is promising to use Tet as an antifibrogenetic in liver or lung fibrosis with or without portal or pulmonary hypertension, as well as an immunomodulating and anticarcinoma drug.

Pathogenesis of NSAID-induced gastric damage:Importance of cyclooxygenase inhibition and gastric hypermotility

This article reviews the pathogenic mechanism of nonsteroidal anti-inflammatory drug(NSAID)-induced gastric damage,focusing on the relation between cyclooxygenase(COX) inhibition and various functional events.NSAIDs,such as indomethacin,at a dose that inhibits prostaglandin(PG) production,enhance gastric motility,resulting in an increase in mucosal permeability,neutrophil infiltration and oxyradical production,and eventually producing gastric lesions.These lesions are prevented by pretreatment with PGE 2 and antisecretory drugs,and also via an atropine-sensitive mechanism,not related to antisecretory action.Although neither rofecoxib(a selective COX-2 inhibitor) nor SC-560(a selective COX-1 inhibitor) alone damages the stomach,the combined administration of these drugs provokes gastric lesions.SC-560,but not rofecoxib,decreases prostaglandin E 2(PGE 2) production and causes gastric hypermotility and an increase in mucosal permeability.COX-2 mRNA is expressed in the stomach after administration of indomethacin and SC-560 but not rofecoxib.The up-regulation of indomethacin-induced COX-2 expression is prevented by atropine at a dose that inhibits gastric hypermotility.In addition,selective COX-2 inhibitors have deleterious influences on the stomach when COX-2 is overexpressed under various conditions,including adrenalectomy,arthritis,and Helicobacter pylori-infection.In summary,gastric hypermotility plays a primary role in the pathogenesis of NSAID-induced gastric damage,and the response,causally related with PG deficiency due to COX-1 inhibition,occurs prior to other pathogenic events such as increased mucosal permeability;and the ulcerogenic properties of NSAIDs require the inhibition of both COX-1 and COX-2,the inhibition of COX-1 upregulates COX-2 expression in association with gastric hypermotility,and PGs produced by COX-2 counteract the deleterious effect of COX-1 inhibition.

Ischemic heart disease,factor predisposing to Barrett's adenocarcinoma: A case control study

AIM:To define the significance of ischemic heart disease(IHD)(stable angina to infarction) co-existance in Barrett esophagus(BE) patients and patients with esophageal adenocarcinoma(AdE).METHODS: All BE/AdE patients in Blackpool-Wyre-Fylde area and Trikala prefecture identified from medical records. Patient clinical details were obtained from hospital and General Practitioner records. Additional information was gathered from validated questionnaire.RESULTS: Forty(33%) AdE and 83(19%) BE patients had IHD(P = 0.002). Eighteen(15%) AdE and 34(8%) BE patients had suffered a myocardial infarction(P = 0.03). Three(3%) AdE and 7(2%) BE patients had severe heart failure(P = 0.82). Thirty-nine(47%) BE with IHD and 8(20%) AdE patients with IHD consumed aspirin daily(P = 0.004). Seventh-seven(93%) BE patients with IHD and 36(90%) AdE patients with IHD were on statins(P = 0.86). Logistic regression analysis: AdE was more frequent in the elderly,with long termreflux,long BE and concurrent IHD(odds ratio: 2.086,P = 0.001) not consuming statins. Eighteen(22%) BE patients with IHD [16(84%) with myocardial infarction] vs 33(10%) without IHD died from non-neoplastic causes within 24 mo from BE diagnosis(P = 0.005). CONCLUSION: IHD is more prevalent in AdE than BE patients. Increased prevalence of AdE is related with the presence of myocardial infarction but not severe heart failure,possibly because patients with BE and se-vere IHD have low life expectancy.

Trends in upper gastrointestinal bleeding management

Upper gastrointestinal bleeding(UGIB)can be attributed to either non-variceal or variceal causes.The latter is more aggressive with hemodynamic instability secondary to decompensated cirrhosis and portal hypertension.Non-variceal UGIB(NVUGIB)occurs due to impaired gastroprotective mechanisms attributed to several drugs such as anticoagulants and nonsteroidal anti-inflammatory drugs.Helicobacter pylori infection contributes to the development of peptic ulcer bleeding as well.NVUGIB presentation can be either hemodynamically stable or unstable.During the initial assessment a scoring system including patient-related factors(current cardiac,renal,and liver diseases and hemodynamic and labo-ratory parameters)is used to determine the patient’s prognosis.The Glasgow Blatchford score has been shown to be the most useful and precise.Those with high-risk NVUGIB require urgent assessment and upper endoscopy to achieve better short-term and long-term outcomes such as less hospitalization,blood transfusion,and surgery.

朱生樑辨治非甾体类抗炎药相关性胃病经验

非甾体类抗炎药相关性胃病是由于服用非甾体抗炎药导致胃黏膜损伤而引起的一类疾病,临床日趋多见,西医目前缺乏较好的治疗方法。朱生樑教授通过长期的临床实践,积累了丰富的辨治非甾体类抗炎药相关性胃病的经验。朱教授认为服用非甾体抗炎药是本病的病因,病机以脾胃虚弱为本,湿热、气滞、瘀血为标,临床常为本虚标实之证。治疗以健脾养胃、清化湿热、活血祛瘀、燮理气机、协调升降为大法来指导遣方用药,发挥中医药的优势,取得了较好的临床疗效。本文对上述辨治经验进行阐述,并举验案一则。

胃黏膜损伤相关疾病中药的研究现状及其开发思路

胃黏膜损伤相关疾病都是一些常见病、多发病,属中医"胃痞"、"胃脘痛"的范畴。为了发挥中医药在治疗胃黏膜损伤相关疾病的作用,提高研发水平,从流行病学、发病机制、药物干预途径和治疗胃黏膜损伤相关疾病的中药新药开发思路4个方面进行综述。