Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0030305 (pancreatitis)
 16,014 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We examined the therapeutic effects of the inflammatory cell infiltration inhibitor IS-741 (N-(2-((ethylsulfonyl)amino)-5-(trifluoromethyl)-3-pyridinyl)-cyclohexanecarboxamide monosodium salt monohydrate) on a rat colitis model. As a result of its effects on leukocyte infiltration, IS-741 inhibits cell adhesion, alleviates symptoms and signs of pancreatitis and multiple organ failure and demonstrates a life-saving effect in a model of severe acute pancreatitis. A rat model was prepared by inducing colitis with 3% dextran sodium sulfate (DSS) and maintaining pathology with 1% DSS. Repeated oral administration of IS-741 at 1, 10 or 100 mg/kg per day was conducted for 2 weeks (during treatment with 1% DSS). IS-741 at each dose decreased the area of erosion in the large intestine, thickening of the wall of the large intestine and anemia caused by melena. Some effects of IS-741 were nearly equivalent to those of the control compound salazosulfapyridine. Furthermore, IS-741 markedly alleviated inflammatory cell infiltration into the intestinal wall. IS-741 improved lesions in a rat DSS model by inhibiting leukocyte infiltration, suggesting the possibility of clinical application of this drug for IBD.
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PMID:Efficacy of the inflammatory cell infiltration inhibitor IS-741 on colitis induced by dextran sulfate sodium in the rat. 1170 14

Eosinophilic gastroenteritis is a rare gastrointestinal (GI) disorder of undetermined cause characterized by infiltration of eosinophils in the GI tract. Eosinophils accumulate in tissues and may release highly cytotoxic granular proteins, which cause severe tissue damage characteristic of eosinophilic gastroenteritis. Eotaxin may play a role in the recruitment of eosinophils into tissue in combination with chemoattractants and cytokines, including interleukin 3 and 5 and granulocyte-macrophage colony-stimulating factor. Food allergy, especially in children, can be a triggering factor, and an amino acid-based diet may be helpful. Accumulation of eosinophils in the gut is a common feature in food-induced GI disorders that can be regulated through a complex molecular network involving Th2 cells, various cytokines, and chemokines. Eosinophilic gastroenteritis has a wide spectrum of clinical presentation depending on the site of involvement. It may be confused with irritable bowel syndrome or dyspepsia and, rarely, mimics pancreatitis or appendicitis. Diagnosis is important and is usually made by a pathologist. Eosinophilic gastroenteritis is a treatable disease; patients generally respond to steroid therapy, although relapse is common. Non-enteric-coated budesonide, a locally acting corticosteroid with little risk of adrenal suppression, may be substituted, although more experience is needed. Promising new drugs for eosinophilic gastroenteritis include montelukast, a selective leukotriene receptor antagonist, and suplaplast tosilate, a selective Th2 cytokine inhibitor with inhibitory effects on allergy-induced eosinophilic infiltration and IgE production. Although it is likely a separate disease, more experience has accumulated, and an elimination or specific amino acid-based diet appears to be helpful in treatment.
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PMID:Eosinophilic gastroenteritis. 1222 38

More than 10 years of intensive preclinical investigation of selective tachykinin (TK) receptor antagonists has provided a rationale to the speculation that peripheral neurokinin (NK)-1, -2 and -3 receptors may be involved in the pathophysiology of various human diseases at the visceral level. In the airways, despite promising effects in animal models of asthma, pilot clinical trials with selective NK-1 or -2 receptor antagonists in asthmatics have been ambiguous, whereas the potential antitussive effects of NK-1, -2 or -3 antagonists have not yet been verified in humans. In the gastrointestinal (GI) tract, irritable bowel syndrome (IBS) and pancreatitis are appealing targets for peripherally-acting NK-1 and -2 antagonists, respectively. In the genito-urinary tract, NK-1 receptor antagonists could offer some protection against nephrotoxicity and cytotoxicity induced by chemotherapeutic agents, whereas NK-2 receptor antagonists appear to be promising new agents for the treatment of neurogenic bladder hyperreflexia. Finally, there is preclinical evidence for hypothesising an effect of NK-3 receptor antagonists on the cardiovascular disturbance that characterises pre-eclampsia. Other more speculative applications are also mentioned.
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PMID:Peripheral tachykinin receptors as potential therapeutic targets in visceral diseases. 1278 71

Kappa (kappa)-opioid receptor agonists are particularly effective analgesics in experimental models of visceral pain. Their analgesic effects are mediated in the periphery. The molecular targets involved include peripherally located kappa-receptors and possibly, at least for some nonpeptidic kappa-agonists, additional nonopioid molecular targets such as sodium channels located on primary sensory afferents. Overall, these properties are expected to be of therapeutic interest in various visceral pain conditions, including abdominal surgery associated with postoperative pain and ileus, pancreatitis pain, dysmenorrhea, labor pain and functional disorders such as irritable bowel syndrome or dyspepsia. The first kappa-agonists to be developed were brain-penetrating organic small molecules. Their development was eventually discontinued due to central side effects such as sedation and dysphoria attributed to kappa-receptors located behind the blood-brain barrier. New drug discovery programs are now geared towards the design of peripherally-selective kappa-agonists. So far, most of the organic molecule-based peripheral kappa-agonists have achieved limited peripheral selectivity and a practically insufficient therapeutic window to justify full development. These compounds have been used in a small number of clinical pilot studies involving visceral pain. Although encouraging, the clinical data available so far with this class of compounds are too limited and fragmented to fully validate the therapeutic utility of kappa-agonists in visceral pain. Additional clinical studies with safer kappa-agonists (i.e. with higher peripheral selectivity) are still required. The most suitable tools to address this question in the future appear to be the newly discovered class of tetrapeptide-based kappa-agonists, which have shown unprecedented levels of peripheral selectivity.
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PMID:Peripheral kappa-opioid agonists for visceral pain. 1505 26

According to the literature data the modern concepts of the etiological factors, the pathomorphological features, the diagnosis, the clinical features and the treatment of the drug-induced and the idiopathic pancreatitis, accompanying the IBD are reviewed. The results of a retrospective review of the clinical data of 50 patients, operated on--16 with Crohn's disease and 34 with ulcerative colitis, are shown. Postoperative hyperamylasemia was found in 2 patients with Crohn's disease and in 3 patients with ulcerative colitis. One of them also had primary sclerosing cholangitis. All patients were treated with Metronidazole and Cortizone. Nine years after the operation one of the patients with ulcerative colitis had acute pancreatitis, treated conservatively.
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PMID:[Pancreatitis accompanying inflammatory bowel diseases, and our observations]. 1570 45

Cholecystokinin (CCK) is a peptide hormone which is found both in the gastrointestinal tract throughout the human small intestine and nerves in the myenteric plexus of the enteric nervous system and in the central nervous system. This dual location constitutes the anatomical basis for this in functions as a hormone and a neurotransmitter implicated in the regulation of both systems. CCK regulates not only motor functions in the gastrointestinal tract like lower oesophageal sphincter relaxation, gastric secretion and emptying, gall bladder contractility and bile secretion into the duodenum, intestinal and colonic motility, but also sensory functions and plays a role in the regulation of food intake. These effects are mediated through selective receptors CCK1 and CCK2. Over the last few years, research has focused on understanding the role of CCK, its receptors with antagonists at the biological, pharmacological, clinical and therapeutic level. As far as the CCK1 antagonists is concerned, important inroads have been made in the potential role of these antagonists in the treatment of GERD, IBS and pancreatitis. They have also shown encouraging results in sphincter of Oddi dysfunction and some gastrointestinal cancers. This review focuses on the recent ad vances of the biological role of CCK and their CCK1 antagonists: their current basic and clinical status in gastroenterology, with particular emphasis on the potential therapeutic role of the CCK1 antagonists and future research directions.
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PMID:CCK1 antagonists: are they ready for clinical use? 1669 65

Gastrin and cholecystokinin (CCK) are two of the oldest hormones and within the past 15 years there has been an exponential increase in knowledge of their pharmacology, cell biology, receptors (CCK1R and CCK2R), and roles in physiology and pathological conditions. Despite these advances there is no approved disease indication for CCK receptor antagonists and only a minor use of agonists. In this review, the important factors determining this slow therapeutic development are reviewed. To assess this it is necessary to briefly review what is known about the roles of CCK receptors (CCK1R and CCK2R) in normal human physiology, their role in pathologic conditions, the selectivity of available potent CCKR agonists/antagonists as well as to review their use in human conditions to date and the results. Despite extensive studies in animals and in humans, recent studies suggest that monotherapy with CCK1R agonists will not be effective in obesity, nor CCK2R antagonists in panic disorders or CCK2R antagonists to inhibit growth of pancreatic cancer. Areas that require more study include the use of CCK2R agonists for imaging tumors and radiotherapy, CCK2R antagonists in hypergastrinemic states especially with long-term PPI use and for potentiation of analgesia as well as use of CCK1R antagonists for a number of gastrointestinal disorders [motility disorders (irritable bowel syndrome, dyspepsia, and constipation) and pancreatitis (acute and chronic)].
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PMID:Progress in developing cholecystokinin (CCK)/gastrin receptor ligands that have therapeutic potential. 1799 37

Intestinal microflora can be considered as a ''dynamic system'' that actively interacts with the intestinal epithelium and the local immune system. It synthesizes antimicrobial substances (bacteriocins), vitamins (PP, B1, B6, B12), it produces a major intestinal nutrient (butyric acid) and interacts in a competitive fashion with the pathogens. Lactobacilli concentration (Gram+, Gram variable, facultative anaerobes) is generally decreased in irritable bowel syndrome (IBS) patients. This syndrome has, until recently been considered to be ''functional'', whereas, in fact, it may result from previous enteritis (in up to 31% of patients), featuring a persistent low-grade intestinal inflammation and a reduction in interleukin-10 (IL-10) concentration. Some Lactobacilli strains (e.g. L. paracasei subsp. paracasei) in vitro lead to normalisation of the hypercontractility of the smooth muscle cells. A growing body of clinical findings indicates that some ''genetically stable'' strains of Lactobacilli may be useful in the treatment, even long term, of IBS, and reduce the postoperative infection rate, especially in critically ill patients (orthotopic liver transplant, severe pancreatitis). However, some Lactobacilli, ''not genetically stable'', used in the treatment of neutropenic patients during chemotherapy and in pediatric patients submitted to gastrojejunostomy, have been reported to lead to bacteremia and endocarditis. These effects may be due to transfer of bacteria and genetic material. Therefore, the confirmed genetic stability and the fact that no antibiotic resistance occurs are fundamental requisites for the use of Lactobacilli in certain disorders of the gastrointestinal tract, such as, for instance, IBS. In conclusion, ''genetically stable'' Lactobacilli (L. paracasei subsp. Paracasei F19) have recently become available, representing an exiting new field in clinical studies and for treatment purposes, offering guarantees of safety also for long-term use. Careful personalized evaluation, as always in medical practice, is necessary in order to gain further insight into, and to validate with additional studies, the role of ''genetically stable'' Lactobacilli in the treatment of IBS.
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PMID:New insights into Lactobacillus and functional intestinal disorders. 1861 77

Of all the body systems, the gastrointestinal (GI) tract is the most exposed to proteinases. Proteolytic activity must thus be tightly regulated in the face of diverse environmental challenges, because unrestrained or excessive proteolysis leads to pathological GI conditions. The protease-activated receptor-2 (PAR-2) is expressed in numerous cell types within the GI tract, suggesting both multiple functions and numerous modes of receptor activation. Although best known as a pancreatic digestive enzyme, trypsin has also been found in other tissues and various cancers. Of interest, trypsin and PAR-2 act together in an autocrine loop that promotes proliferation, invasion and metastasis in neoplasia through various mechanisms. Trypsin and PAR-2 seem to act both directly and indirectly through activation of other proteinase cascades, including metalloproteinases. PAR-2 activation can participate in inflammatory reactions, be protective to mucosal surfaces, send or inhibit nociceptive messages, modify gut motility or secretory functions, and stimulate cell proliferation and motility. Several studies point to a role for the PARs in disease processes of the GI tract and pancreas ranging from inflammatory bowel disease, symptoms associated with irritable bowel syndrome, pain in pancreatitis, development of colon and other GI cancers, and even infectious colitis. Proteinases should not only be considered from the traditional view as digestive or degradative enzymes in the gut, but additionally as signalling molecules that actively participate in the spectrum of physiology and diseased states of the GI tract.
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PMID:Proteinase-activated receptor 2 (PAR-2) in gastrointestinal and pancreatic pathophysiology, inflammation and neoplasia. 1908 62

Visceral pain is the most common reason for doctor visits in the US. Like somatic pain, virtually all visceral pain sensations begin with the activation of primary sensory neurons innervating the viscera and/or the blood vessels associated with these structures. Visceral afferents also play a central role in tissue homeostasis. Recent studies show that in addition to monitoring the state of the viscera, they perform efferent functions through the release of small molecules (e.g. peptides like CGRP) that can drive inflammation, thereby contributing to the development of visceral pathologies (e.g. diabetes Razavi, R., Chan, Y., Afifiyan, F.N., Liu, X.J., Wan, X., Yantha, J., Tsui, H., Tang, L., Tsai, S., Santamaria, P., Driver, J.P., Serreze, D., Salter, M.W., Dosch, H.M., 2006. TRPV1+ sensory neurons control beta cell stress and islet inflammation in autoimmune diabetes, Cell 127 1123-1135). Visceral afferents are heterogeneous with respect to their anatomy, neurochemistry and function. They are also highly plastic in that their cellular environment continuously influences their response properties. This plasticity makes them susceptible to long-term changes that may contribute significantly to the development of persistent pain states such as those associated with irritable bowel syndrome, pancreatitis, and visceral cancers. This review examines recent insights into visceral afferent anatomy and neurochemistry and how neonatal insults can affect the function of these neurons in the adult. New approaches to the treatment of visceral pain, which focus on primary afferents, will also be discussed.
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PMID:Development, plasticity and modulation of visceral afferents. 1915 Mar 71


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