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)

Irritable bowel syndrome (IBS) is an extremely common cause of consultation, and at present is diagnosed on the basis of symptoms and a few simple exclusion tests. Exclusion diets can be successful, but many patients have already attempted and failed such treatments before consulting. Anxiety and somatization may be an important driver of consultation. Patients' concerns should be understood and addressed. Those with prominent psychiatric disease may benefit from psychotherapy. Hypnotherapy benefits symptoms in those without psychologic disturbance, but its availability is limited. Antidepressants are effective in improving both mood and IBS symptoms globally, and the evidence is particularly good for tricyclic antidepressants. Although antispasmodics are currently the most commonly prescribed drugs, most responses (75%) are due to the placebo effect and not specific to the drug. Bulk laxatives such as ispaghula can increase stool frequency and help pain, but bloating may be aggravated. Loperamide is effective treatment for urgency and loose stools, but less effective for bloating and pain. 5-HT(3) antagonists such as alosetron improve urgency, stool consistency, and pain in diarrhea-predominant-IBS. The 5-HT(4) agonist tegaserod shows modest benefit in constipation-predominant IBS, improving stool frequency, consistency, and bloating as well as global improvement. There are many new drugs, such as cholecystokinin, neurokinin, and corticotropin receptor antagonists, in development.
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PMID:Treatment of Irritable Bowel Syndrome. 1284 42

A complex relationship links biliary symptoms with the mechanisms of gallbladder emptying and the presence of gallstones. This relationship has been investigated by clinical studies of symptoms associated with gallstones, by investigation of gallbladder emptying and cholecystokinin (CCK) release in patients with gallstones, and after cholecystectomy, or truncal vagotomy, and in the irritable bowel syndrome (IBS). Laboratory studies examined receptor density on bovine gallbladder, and contractility of human gallbladder in response to a variety of stimuli was studied in vitro. A set of six symptoms associated with the presence of gallstones was identified; IBS appeared to be present in two-fifths of patients before cholecystectomy but only one-third of these patients had persistent IBS symptoms one year after operation. Gallbladder emptying studies confirmed the poor contraction of stone-bearing gallbladders; abnormal patterns of emptying were also found in patients with IBS. Gallbladder emptying and filling appear to be largely neurally regulated. CCK receptor density was very low in gallbladder tissue, suggesting that receptors on nerve cells might mediate the action of CCK. Relaxation of gallbladder muscle was mediated by adrenergic and nitrergic nerves. The inflammatory mediator bradykinin, however, had a strong direct action on muscle cells to cause gallbladder contraction. The work reported here gives an overview of the symptoms and mechanisms of disease associated with the presence of stones in the gallbladder.
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PMID:Arris & Gale lecture. Regulation and responses of gallbladder muscle activity in health and disease. 1459 32

Cholecystokinin (CCK) is a brain-gut peptide; it functions both as a neuropeptide and as a gut hormone. Although the pancreas and the gallbladder were long thought to be the principal peripheral targets of CCK, CCK receptors are found throughout the gut. It is likely that CCK has a physiological role not only in the stimulation of pancreatic and biliary secretions but also in the regulation of gastrointestinal motility. The motor effects of CCK include postprandial inhibition of gastric emptying and inhibition of colonic transit. It is now evident that at least two different receptors, CCK(1) and CCK(2) (formerly CCK-A and CCK-B, respectively), mediate the actions of CCK. Both localization and functional studies suggest that the motor effects of CCK are mediated by CCK(1) receptors in humans. Since CCK is involved in sensory and motor responses to distension in the intestinal tract, it may contribute to the symptoms of constipation, bloating and abdominal pain that are often characteristic of functional gastrointestinal disorders in general and irritable bowel syndrome (IBS), in particular. CCK(1) receptor antagonists are therefore currently under development for the treatment of constipation-predominant IBS. Clinical studies suggest that CCK(1) receptor antagonists are effective facilitators of gastric emptying and inhibitors of gallbladder contraction and can accelerate colonic transit time in healthy volunteers and patients with IBS. These drugs are therefore potentially of great value in the treatment of motility disorders such as constipation and constipation-predominant IBS.
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PMID:Involvement of endogenous CCK and CCK1 receptors in colonic motor function. 1510 Jan 63

Dexloxiglumide (DEX) is a cholecystokinin type-1 receptor antagonist under development for the treatment of constipation-predominant irritable bowel syndrome. Studies of the potential interaction of DEX with human cytochromes P450 (CYPs) were conducted in vitro. DEX (300 micro M), both with and without a 15-min pre-incubation, was incubated with pooled human liver microsomes and substrates selective for each of eight CYPs. This resulted in >30% inhibition of tolbutamide 4-methyl-hydroxylase (CYP2C9/10) and lauric acid 11-hydroxylase (CYP2E1) activities. Mean K(i) (SD) for CYP2C9/10 and CYP2E1 were 69.0 (24.3) and 426 (60) microM, respectively. Incubations of [(14)C]DEX with pooled human liver microsomes produced one major phase I metabolic fraction, with V(max)=131 pmol/min/mg protein and K(m)=23.7 microM. Further incubations with (i) liver microsomes from 16 individual donors (correlation analysis), (ii) Supersomes trade mark and (iii) selective chemical inhibitors, implicated CYP3A4/5, CYP2B6 and CYP2C9 in the formation of this component. Thus, DEX interacts with CYP2C9 both as inhibitor (K(i)=69.0 microM) and as substrate in vitro. However, based on the maximum concentration (27 microM) after repeated oral doses of 200 mg t.i.d. and the unbound fraction (0.03) of DEX in human plasma, no clinically relevant metabolic interactions with other CYP substrates are predicted.
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PMID:Interaction of dexloxiglumide, a cholecystokinin type-1 receptor antagonist, with human cytochromes P450. 1510 19

Irritable bowel syndrome (IBS) is the most common chronic gastrointestinal (GI) disorder, affecting about 20% of the world's population. Chronic abdominal pain or discomfort relieved by defecation and associated with altered bowel habits are the mainstay in diagnosis. The pathophysiology of IBS remains unknown. This biopsychosocial disorder involves dysregulation of the nervous system, altered intestinal motility, and increased visceral sensitivity. All of these result from dysregulation of the bidirectional communication between the gut with its enteric nervous system and the brain (the brain-gut axis), modulated by various psychosocial and environmental factors (e.g. infection, inflammation). Numerous neurotransmitters are found in the brain and gut that regulate GI activities, including 5-hydroxytryptamine (5-HT, serotonin) and its 5-HT3 and 5-HT4 receptors. The current approach to IBS patients is based on a positive diagnosis of the symptom complex, exclusion of underlying organic disease, and institution of a therapeutic trial. Traditional symptomatic treatment has included antidiarrheals, laxatives and bulking agents/fiber, low-dose tricyclic antidepressants, antispasmodics for pain, and "alternative" therapies (e.g. psychotherapy, hypnotherapy). The scientific evidence supporting this therapy is limited. Novel approaches include visceral analgesics and serotonin agonists and antagonists. In patients with severe diarrhea, 5-HT3 receptor antagonists (e.g. alosetron) and selective M3-type anticholinergics are indicated, in constipation 5-HT4 agonists (e.g. tegaserod), and in pain alfa2-adrenergics (e.g. clonidine), cholecystokinin antagonists, kappa-opioid agonists (e.g. fedotozine), and neurokinin antagonists; some of these agents are still being investigated. Understanding the brain-gut axis is crucial in the development of effective therapies for IBS.
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PMID:The brain-gut axis in irritable bowel syndrome--clinical aspects. 1517 82

The 5-HT3 receptor is a ligand-gated cation channel located in the central and peripheral nervous system; it has also been detected on a variety of other cells. In the periphery, it is found on autonomic neurons and on neurons of the sensory and enteric nervous system. In the CNS, the 5-HT3 receptor has been localized in the area postrema, nucleus tractus solitarii, nucleus vaudatus, nucleus accumbens, amygdala, hippocampus, entorhinal, frontal, cingulate cortex, and in the dorsal horn ganglia. Further extraneuronal locations include among others lymphocytes, monocytes, and foetal tissue. 5-HT3 receptors modulate the release of neurotransmitters and neuropeptides like dopamine, cholecystokinin, acetylcholine, GABA, substance P, and serotonin itself. They have been demonstrated to be involved in sensory transmission, regulation of autonomic functions, integration of the vomiting reflex, pain processing and control of anxiety. While the physiologic functions of the 5-HT3 receptor are discrete and difficult to detect, it plays a key role in certain pathologic situations related to increased serotonin release. Clinical development of 5-HT3 receptor antagonists revealed a remarkable range of activities. 5-HT3 receptor antagonists do not modify any aspect of normal behaviour in animals or induce pronounced changes of physiological functions in healthy subjects. Clinical efficacy was shown for various forms of emesis like chemotherapy-induced, radiotherapy-induced, and postoperative emesis, diarrhoea-predominant irritable bowel syndrome, anxiety, chronic fatigue syndrome, alcohol abuse, and in pain syndromes such as fibromyalgia and migraine. Most recent data also suggest that 5-HT3 receptor antagonists are effective for the treatment of other rheumatic diseases such as rheumatoid arthritis, tendinopathies, periarthropathies, and myofascial pain. Other possible indications under discussion are chronic heart pain and bulimia. Unfortunately, experimental findings do not yet provide a homogenous conception of the significance of 5-HT3 receptors in all investigated fields; in nociception, for example, contradictory observations are still inadequately explained and complicated by bell-shaped dose-response curves. Further elucidation and better understanding of the serotonergic neuronal network remains a task for the next decade.
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PMID:Physiology and pathophysiology of the 5-HT3 receptor. 1551 4

Recent research has provided new information about drugs that could be used to treat functional motility disorders. Promotility drugs accelerate gastric emptying or colonic transit and these properties may contribute to their efficacy in treating symptoms associated with gastroparesis, functional dyspepsia or constipation. 5-Hydroxytryptamine4 receptors are targets for drugs (tegaserod, renzapride) that treat symptoms in constipated irritable bowel syndrome patients and in gastroparesis. Drugs acting at motilin (erythromycin) and cholecystokinin-1 (dexloxiglumide) receptors accelerate gastric emptying. Dexloxiglumide might be useful in the treatment of functional dyspepsia particularly that associated with lipid intake. Alvimopan is a mu-opioid receptor antagonist that does not cross the blood brain barrier. Alvimopan is effective in treating postsurgical ileus and perhaps opiate-induced bowel dysfunction. Successes and failures of recent efforts to develop promotility agents revealed opportunities and challenges for developing new promotility drugs. The pharmacological properties of partial agonists might be exploited to develop effective promotility drugs. However, opposing actions of promotility agents on motility (increased contraction vs decreased accommodation) limit the clinical efficacy of drugs with these opposing actions. Selection of appropriate patient populations for evaluation of new drugs is also critical.
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PMID:Basic and clinical pharmacology of new motility promoting agents. 1618 2

Cholecystokinin is the main hormonal regulator of gallbladder motility. Dexloxiglumide, the active enantiomer of loxiglumide, interacts competitively with CCK1 receptors as determined in preclinical studies, such as specific radioligand binding assays or functional studies on isolated guinea pig gallbladder, where it inhibited smooth muscle cell contractions induced by cholecystokinin-octapeptide (CCK-8), the most prominent active forms of cholecystokinin. Dexloxiglumide has a potent antagonistic effect, of a competitive nature, on human gallbladder cholecystokinin type 1 receptors. In isolated human gallbladder, dexloxiglumide produced a concentration-dependent rightward shift of the cholecystokinin-octapeptide curve, without affecting its maximal response. Gallbladder motility was evaluated in clinical studies. Dexloxiglumide, orally administered to healthy volunteers at putative therapeutic doses, did not interfere with post-prandial gallbladder kinetics, despite an increase of fasting gallbladder volume. At present, dexloxiglumide is in an advanced stage of clinical research in gastroenterology. Overall, clinical observations suggest that dexloxiglumide may become an effective treatment in several gastrointestinal disorders. Moreover, the beneficial effects can be obtained without increasing the risk of gallstones formation, a potential hazard subsequent to the inhibition of gallbladder contractions and the resulting bile stasis. The potent and selective antagonist dexloxiglumide may offer a possible therapeutic tool for use not only in functional gastrointestinal disorders, such as irritable bowel syndrome, constipation, gastroesophageal reflux disease and functional dyspepsia, but also in other pathologies, such as biliary colics, pancreatic diseases and gastrointestinal tumors.
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PMID:CCK1 receptor antagonist, dexloxiglumide: effects on human isolated gallbladder. Potential clinical applications. 1648 60

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

A population of rat lumbar laminae VII and X putative spinothalamic (STT) neurons that co-contain cholecystokinin-8 (CCK) and galanin (GAL) are sexually dimorphic. Males have a significantly greater number of these neurons, as well as having greater optical densities for both neuropeptides than females. Optical densities for GAL and CCK immunoreactivities in these lumbar neurons in rats that have the testicular feminization mutation (Tfm) are not significantly different from females; however, the number of these lumbar neurons in Tfm rats is significantly smaller than in females. These data suggest that androgens, as well as functional androgen receptors (that Tfm rats lack), are necessary for the establishment of these sexual dimorphisms. Functionally, these CCK- and GAL-containing neurons in the deep lumbar laminae may contribute to the establishment of known sex differences in the affective component of somatic and visceral nociception, as well as the sexually dimorphic nature of some pelvic diseases, e.g., irritable bowel syndrome or cystitis.
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PMID:Androgens regulate the sexually dimorphic production of co-contained galanin and cholecystokinin in lumbar laminae VII and X neurons. 1676 34


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