Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022104 (irritable bowel syndrome)
 8,033 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Motilin, normally present in a specific cell type in the upper small intestine, is believed to have a physiologic role in initiating the interdigestive migrating motor complex. Motilin may play a pathophysiologic role in the diarrhea in the irritable bowel syndrome, the dumping syndrome, chronic liver disease, and chronic renal failure. Furthermore, increased frequency of bowel movements is an important symptom in patients with the carcinoid syndrome. We have studied 73 patients with metastatic carcinoid tumors with regard to stool frequency and plasma concentration of motilin and neuropeptide K (NPK) and diurnal urinary excretion of 5-hydroxyindoleacetic acid (5-HIAA). Thirty-eight (52%) of the 73 patients had elevated (greater than 126 pmol/l) plasma concentrations of motilin, whereas 59 (81%) of the patients had diarrhea. The increased frequency of bowel motions correlated significantly (p less than 0.01) with the plasma concentrations of motilin, whereas no significant correlation with 5-HIAA and NPK was found. High-performance liquid chromatography of plasma extracts showed a single component eluting in the position of synthetic porcine motilin. However, extracts from five carcinoid tumors did not contain any significant levels of motilin. Carcinoid tumors are known to contain and secrete several biologically active substances such as serotonin, histamine, prostaglandins, and tachykinins, which are likely to cause disturbances of intestinal secretion and motility, which in turn might release motilin from the motilin-containing cells of the small intestine. The increased motilin levels might then participate in a vicious diarrhea circle together with the other agents.
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PMID:Motilin in plasma and tumor tissues from patients with the carcinoid syndrome. Possible involvement in the increased frequency of bowel movements. 244 32

Insulin-like growth factor II is secreted primarily by the liver and is reported to be transcribed in many primary hepatocellular carcinoma (PHC) cell lines. We have studied diagnostic significance of serum IGF-II in chronic liver diseases using specific enzyme immunoassay. Serum IGF-II levels (mean +/- SE) were decreased in chronic hepatitis (538 +/- 51 ng/ml; N = 29), liver cirrhosis (427 +/- 45; 50) and PHC (260 +/- 41; 17) compared to controls (830 +/- 49; 57). Serum IGF-II was not different from controls in any of nonhepatic diseases such as diabetes (1032 +/- 97; 19) pancreatic cancer (1413 +/- 282; 8), chronic pancreatitis (999 +/- 126; 17), peptic ulcer (1186 +/- 43; 11), irritable bowel syndrome (1002 +/- 109; 12), gastrointestinal tract cancer (1250 +/- 216; 21) and chronic renal failure (733 +/- 135; 14). In liver diseases serum IGF-II showed a significant correlation with liver function test (negative with retention of indocyanine green and total bile acids; positive with albumin, thrombo-test, and cholinesterase). These results suggest that serum IGF-II reflects a reduced production of IGF-II in the liver and that it can be an index for the residual capacity of liver function.
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PMID:Serum insulin-like growth factor II in chronic liver disease. 253 15

Diagnostic significance of a simple and rapid screening procedure for determining the relative amounts of pancreatic and salivary isoamylase using an amylase inhibitor was evaluated in 242 subjects (controls 84, acute pancreatitis nine, chronic pancreatitis 28, pancreatic cancer 14, peptic ulcer 25, liver cirrhosis 15, cholelithiasis 24, irritable colon syndrome 13, diabetes mellitus 13, mumps seven, and chronic renal failure 10). Electrophoretically separated isoamylases of saliva and pure pancreatic juice were all inhibited at similar degrees to the corresponding unfractionated amylases. Total amylase and pancreatic isoamylase were elevated in all nine patients with acute pancreatitis. Pancreatic isoamylase was decreased in 12 of 28 patients (43%) with chronic pancreatitis and increased in nine of 14 patients (64%) with pancreatic cancer. The mean pancreatic isoamylase activity in the patients with acute pancreatitis was significantly higher (p less than 0.01), while that of chronic pancreatitis was significantly lower (p less than 0.05) when compared with controls. The inhibition method offers simple, rapid, and specific analysis of serum isoamylase for the differential diagnosis of hyperamylasemia in cases of emergency.
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PMID:Differential determination of serum isoamylase using an amylase inhibitor and its clinical application. 396 56

Major advances have been made in the understanding of the pathophysiology of stress-related alteration of gut function. A wealth of information indicates that CRF is involved in the central mechanisms by which stress inhibits gastric emptying while stimulating colonic motor function. CRF acts in the PVN to trigger both the inhibition of gastric emptying and the stimulation of colonic motor function in response to stress, in addition to previously established endocrine and behavioral responses. Preliminary evidence exists that CRF acts in the locus coeruleus to induce a selective stimulation of colonic transit without influencing gastric emptying. The central actions of CRF to alter gastric and colonic motor function are conveyed by autonomic pathways and are unrelated to the associated stimulation of pituitary hormone secretion. The demonstration that central CRF plays a role in mediating gastric stasis resulting from surgery, peritonitis or high levels of central interleukin-1 provides new insight into the mechanisms involved in gastric ileus induced postoperatively or by infectious disease. Likewise, the demonstration that CRF in the PVN and locus coeruleus induce the anxiogenic and colonic motor responses to stress and that colonic distention activates neurons in the locus coeruleus opens new avenues for the understanding of the pathogenesis of a subset of IBS patients with colonic hypersensitivity associated with psychopathological disturbance and diarrhea-predominant symptoms.
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PMID:Role of CRF in stress-related alterations of gastric and colonic motor function. 825 13

The function of serotonin (5-HT)3 receptors on colonic transit was investigated in unanesthetized rats. The colonic transit was accelerated by 5-HT (10 mg/kg, s.c.), 2-methyl-5-HT (30 mg/kg, s.c.), neostigmine (0.03-0.1 mg/kg, s.c.), corticotropin releasing factor (CRF; 1 microgram intracerebroventricular administration) and restraint stress (for 45 minutes). A potent and selective 5-HT3 receptor antagonist, azasetron (+/-)-N-(1-azabicyclo[2.2.2]oct-3-yl)-6-chloro- 4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-8-carboxamide monohydrochloride ; 0.01-10 mg/kg, p.o. inhibited the 5-HT-, CRF- and stress-accelerated colonic transit in a dose-dependent manner. Ondansetron (10 mg/kg, p.o.) and granisetron (1 mg/kg, p.o) also inhibited the stress-accelerated colonic transit, but azasetron was more effective than these two drugs. Atropine methylbromide (0.1 mg/kg, s.c.) and tetrodotoxin (0.01 mg/kg, s.c.) inhibited the accelerated colonic transit under stress conditions, but methysergide (10 mg/kg, s.c.), SDZ205-557 (10 mg/kg, s.c.), domperidone (30 mg/kg, p.o.), trimebutine (300 mg/kg, p.o.), did not. Azasetron (10 micrograms) administered intracerebroventricularly did not inhibit the stress-induced acceleration. These results suggest that endogenous 5-HT which is released through stress accelerates the colonic transit via the 5-HT3 receptors and finally a cholinergic mechanism. It is considered that azasetron inhibits colonic transit particularly under stress conditions through the blockade of the peripheral 5-HT3 receptors. Azasetron may improve bowel function in stress-related colonic dysfunction like irritable bowel syndrome.
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PMID:The function of 5-HT3 receptors on colonic transit in rats. 865 66

The present review focuses on the corticotropin releasing factor type 1 (CRF(1)) receptor as a novel target for treating depression, anxiety and other stress-related disorders. An organism's stress response system is a complex network of neuronal, endocrine and autonomic pathways which has evolved to provide adaptive reactions to severe environmental and physiological stressors. The peptide CRF plays a critical role in the proper functioning of the stress response system through its actions on CRF(1) receptors located at multiple anatomical sites. Clinical data indicate that dysfunctions of the stress response system, expressed as excessive CRF activity and possible hyperstimulation of CRF(1) receptors, are present in a range of stress-related disorders, including depression, anxiety, and irritable bowel syndrome. CRF(1) dysfunction may be particularly prominent in severe forms of these disorders (e.g. melancholic or psychotic depression, comorbid conditions, chronic posttraumatic stress disorder) and/or when these disorders are accompanied by a history of exposure to early life trauma. Available clinical data support the potential therapeutic efficacy of pharmacological agents which block the CRF(1) receptor. Preclinical studies demonstrate that CRF(1) receptor antagonists are efficacious in animal models in which CRF pathways and CRF(1) receptors are hyperactivated, whereas they tend to be quiescent in states of low basal CRF activity, indicative of potentially reduced side effects in humans. Symptom diversity in animal models of stress and in human stress disorders may result from dysfunctions in different CRF(1) receptor populations and/or different functional states of the CRF(1) receptor. Small molecule, orally-active CRF(1) receptor antagonists may be a broadly useful approach for treating a range of stress-related disorders that are associated with excessive CRF(1) receptor stimulation.
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PMID:The CRF1 receptor, a novel target for the treatment of depression, anxiety, and stress-related disorders. 1751 14

Only a small number of new drugs have recently become available for gastrointestinal (GI) disorders. This is partly because we await outcomes of research into functional bowel disorder aetiology (e.g., role of microbiota) and of trials to control stress- related or painful GI symptoms (e.g., via CRF(1) receptors or beta(3) adrenoceptors). Nevertheless, only the ClC-2 channel activator lubiprostone has recently reached the clinic, joining the 5-HT(3) antagonist alosetron and the long-established 5-HT(4) agonist and D(2) antagonist metoclopramide; tegaserod, a non-selective ligand, was withdrawn. Interestingly, each has shortcomings, providing opportunities for molecules with 5-HT(4) or motilin receptor selectivity, and for new biology via guanylate cyclase C or ghrelin receptor activation. For translation into new drugs, the molecule must have appropriate efficacy, selectivity and pharmacodynamic properties. It is argued that the compound must then be evaluated in conditions where changes in motility are known to exist, before considering more difficult symptomatic conditions such as irritable bowel syndrome (IBS) or functional dyspepsia (FD), where relationships with disordered motility are unclear. Thus, it may be better to begin studying a gastric prokinetic in diabetics requiring improved glucose control, rather than in FD. Notably, new 5-HT(4) receptor agonists are being evaluated firstly as treatments of constipation, not IBS. New antidiarrhoeal agents should be developed similarly. Thus, progression of new drugs may require initial studies in smaller patient populations where clinical outcome is better defined. Only then can disease-related ideas be properly tested and drugs brought forward for these disorders (with high clinical need) and then, if successful for IBS and FD.
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PMID:Development of drugs for gastrointestinal motor disorders: translating science to clinical need. 1825 67

Antagonists of the corticotropin releasing factor (CRF or CRH) receptor have shown promise for the treatment of anxiety, depression, and irritable bowel syndrome. In the present article, medicinal chemistry developments surrounding small molecule CRF receptor antagonists are reviewed, focusing on publications and patents from mid-2004 through the first quarter of 2006. While the CRF type 2 receptor remains an intractable target, incremental progress has been made in the search for drug-like antagonists of the CRF type 1 receptor. Most recent work has not ventured far from previously-established pharmacophoric topologies. A common theme in recent patent disclosures is the addition of novel polar substituents to known heterocyclic core structures to reduce overall lipophilicity. New disclosures of pharmacokinetic (PK) data for several series of antagonists reveal that achieving appropriate PK remains a challenge for the field. The recent publication of selection patents and patents relating to salt and crystal forms of particular compounds suggests that several second generation compounds are nearing or have entered clinical development.
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PMID:Small molecule antagonists of the corticotropin releasing factor (CRF) receptor: recent medicinal chemistry developments. 1839 72

Irritable bowel syndrome (IBS) supports the concept of a dysregulated hypothalamic-pituitary-adrenal (HPA) axis. This study investigates the neuroendocrine and psychological responses to the acute physical stress of a lumbar puncture (LP) in women with diarrhea-predominant IBS by assessing central and peripheral HPA activity and affective measures. Blood samples have been collected at baseline and immediately post- and 1 hr following LP from 13 women with IBS and 13 controls. Plasma adrenocorticotropic hormone (ACTH), cortisol, epinephrine, and norepinephrine levels are analyzed. A single measure of cerebrospinal fluid (CSF) concentrations of corticotropin-releasing factor (CRF(CSF)) and norepinephrine(CSF) is noted. Affective assessments are used to rate anxiety and depression with the Hospital Anxiety and Depression Scale (HADS) and acute mood state is rated using the Stress Symptom Rating questionnaire (stress, anxiety, anger, arousal). The women with IBS display blunted ACTH and cortisol responses to the LP along with a profile of affective responsiveness suggestive of chronic psychosocial stress, although no CRF(CSF) differences between groups are observed.
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PMID:Hypothalamic--pituitary-- adrenal axis dysregulation in women with irritable bowel syndrome in response to acute physical stress. 1985 23

Adaptive responding to threatening stressors is of fundamental importance for survival. Dysfunctional hyperactivation of corticotropin releasing factor type-1 (CRF(1)) receptors in stress response system pathways is linked to stress-related psychopathology and CRF(1) receptor antagonists (CRAs) have been proposed as novel therapeutic agents. CRA effects in diverse animal models of stress that detect anxiolytics and/or antidepressants are reviewed, with the goal of evaluating their potential therapeutic utility in depression, anxiety, and other stress-related disorders. CRAs have a distinct phenotype in animals that has similarities to, and differences from, those of classic antidepressants and anxiolytics. CRAs are generally behaviorally silent, indicating that CRF(1) receptors are normally in a state of low basal activation. CRAs reduce stressor-induced HPA axis activation by blocking pituitary and possibly brain CRF(1) receptors which may ameliorate chronic stress-induced pathology. In animal models sensitive to anxiolytics and/or antidepressants, CRAs are generally more active in those with high stress levels, conditions which may maximize CRF(1) receptor hyperactivation. Clinically, CRAs have demonstrated good tolerability and safety, but have thus far lacked compelling efficacy in major depressive disorder, generalized anxiety disorder, or irritable bowel syndrome. CRAs may be best suited for disorders in which stressors clearly contribute to the underlying pathology (e.g. posttraumatic stress disorder, early life trauma, withdrawal/abstinence from addictive substances), though much work is needed to explore these possibilities. An evolving literature exploring the genetic, developmental and environmental factors linking CRF(1) receptor dysfunction to stress-related psychopathology is discussed in the context of improving the translational value of current animal models.
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PMID:Therapeutic utility of non-peptidic CRF1 receptor antagonists in anxiety, depression, and stress-related disorders: evidence from animal models. 2082 81


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