# New study for GSK CRF-1 antagonist



## jjohnson

This study will study cerebral blood flow after a single dose of the compound. No subtype of IBS is specified, and the study is only recruiting women.http://www.clinicaltrials.gov/ct/show/NCT00376896?order=26Hopefully GSK will start the pivotal phase II safety and efficacy study in the not too distant future as well.


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## overitnow

Brett mentioned seeing this to me. Given the amount I have gone on about the flavonoids increasing blood circulation to the brain, wouldn't it be interesting if GSK found the same cerebral impairment that was found in the Aussie study I have cited? As well, you wouldn't need to wait a number of months or years to have something that might treat it.Ha! (Maybe I'm not full of **** afterall.







)Mark


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## jjohnson

Hey Mark,I'm not sure I've seen the Australian study you mentioned. I know that one drug in development, crofelemer, is extracted from a tropical plant that is said to have a high flavonoid content. I know this compound blocks calcium and sodium channels in the gut, but I'm not sure if the flavonoids are what give it this effect or if there are even any flavonoids in the extract being studied.Personally, I did try some grape seed extract at one point but did not find it helpful. I'm really glad that the supplement you take has worked for you, and I for one never thought you were full of it at all.


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## overitnow

This is a brief newspaper report from 2002. Part of the problem is that flavonoids are not well absorbed, so you can try these things and have no real improvements. The researchers who put together Provex discoverd an answer to that problem that seems to be the key to it's effectiveness.What Glaxo is doing need have no flavonoids. They are just one way to increase that circulation. If it is a general aid to cerebral blood flow, it ought to aid fibro and cfs people as well. From what I understand, they have similar problems in other centers of the brain.Of course, if the drug proves successful, the cost will be alot more that $20 a month...Following is a newspaper account of the Australian study. It is not mentioned here, but I did confirm with Dr. Unger that all of the cosufferers (IBS and CFS) had the lowered brain circulation mentioned in the article.*****Source: Sydney Morning HeraldDate: May 4, 2002Author: Julie Robotham, Medical WriterURL: http://www.smh.com.au/articles/2002/05/03/1019441434909.html Brain link to fatigue syndrome------------------------------An area of the brain that controls the stomach receives substantially less blood in some people with chronic fatigue syndrome, a study shows. The finding adds more weight to the argument that the controversial illness is biological, not psychological.Brain scans of 40 chronic fatigue patients were carried out by Adelaide scientists and compared against the scans of healthy people. The director of nuclear medicine at Queen Elizabeth Hospital, Dr Steven Unger, who headed the study along with neurologist Dr Rey Casse, said: "There was a very strong change in cerebral blood flow in patients."The study showed a reduction in blood flow to the brain's insula cortex, which governs the smooth muscle in the gut. Unexplained stomach and bowelsymptoms are common complaints for chronic fatigue patients.The findings also showed a 20 per cent reduction in blood flow to the left lateral temporal lobe, which controls access to words, in younger chronicfatigue patients. Severe sufferers often experience difficulty expressing themselves.In separate research, endocrinologist Dr Richard Burnett, of the Royal Adelaide Hospital, has shown that chronic fatigue patients who report gastric symptoms empty fluid from their guts at less than half the speed of people who are well."Talking to patients, about half of them have some kind of [gut symptoms], such as abdominal bloating after eating a small meal," he said. "A delay in liquids means a central problem. It comes from the brain."--------© 2002 The Sydney Morning Herald


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## 23392

Wow, Mark, thanks for that article!!! Very interesting.


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## jjohnson

Thanks Mark,That was an interesting article.It would be interesting to know if this new study is taking advantage of new knowledge obtained from brain imaging in IBS patients. In any case, the principal investigator is Dr. Emeran Mayer, definitely one of the top doctors in this field of research. I also remember reading in a recent article (though I can't remember who the author was) that drugs which had only peripheral action had tended to fail in clinical studies, while there was more likely to be a benefit with substances that had both peripheral and central action.


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## jjohnson

This is a new study that was conducted in Japan that showed that injections of CRF induced rectal hypersensivity in healthy controls. So does provide a rationale for why a CRF antagonist might be effective in IBS.http://www.ncbi.nlm.nih.gov/entrez/query.f...l=pubmed_docsumThis is the first such study I have come across in humans. If anyone reading this knows of any others, please do post a link. I would also greatly appreciate it if one of our experts (like Eric, Flux, or Kathleen) could refresh my recollection on the prevalence of visceral hypersensitivity in IBS patients. All I remember is that it is not present in all patients with an IBS diagnosis. Many thanks in advance for a response.


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## eric

jjohnson Have you seen this?Evaluation of Visceral Sensation in IBS Patients Using Subliminal Stimulationhttp://ibsgroup.org/groupee/forums/a/tpc/f...261/m/988101652


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## eric

FYI"Comment from Emeran A. Mayer, M.D. -- In contrast to the common interpretation of the term "stress" as a psychological phenomenon, it should be understood as any real or perceived perturbation of an organism's homeostasis, or state of harmony or balance. For example, in this viewpoint a severe hemorrhage, starvation, extreme temperature, or worry about the unpredictable onset of abdominal pain all qualify as stressors -- some as "physical" stressors, others as "psychological" stressors. The fear to leave the house in the morning without knowing if one can make it to work without having to stop on the freeway because of an uncontrollable bowel movement, or the fear of experiencing uncontrollable abdominal discomfort during an important business meeting are sufficient stressors to activate the central stress system. *The central stress system involves the release of chemical stress mediators in the brain (such as corticotropin releasing factor), which in turn orchestrate an integrated autonomic, behavioral, neuroendocrine, and pain modulatory response. This biological response in turn will alter the way the brain and the viscera interact, and this altered brain-gut interaction can result in worsening of IBS symptoms.* Thus, pain and discomfort, fear of these symptoms, activation of the stress response, and modulation of the brain-gut interactions by stress mediators are part of a vicious cycle which need to be interrupted to produce symptom relief. The neurobiology of stress is not a theory, but a topic that can be studied in animal models, and one of the hottest topics in drug development for treatment of IBS (e.g., substance P antagonists, corticotropin releasing factor antagonists). "http://www.aboutibs.org/Publications/StressDefined.html


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## jjohnson

Thanks Eric,Your input is appreciated as always.


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## 16396

Interesting articles on crf, gut motility and mucosal function.http://www.ncbi.nlm.nih.gov/entrez/query.f...l=pubmed_DocSumhttp://www.ncbi.nlm.nih.gov/entrez/query.f...t_uids=10202204


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## jjohnson

Here is another small, new study on that Glaxo drug, this one testing the effects of this CRF-1 antagonist on hypersensitivity.http://www.clinicaltrials.gov/ct/show/NCT00385099?order=18


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## 23392

New medical study on acupuncture, btw. An MRI study, where they stimulated the right thumb [not acupuncture; just stimulation] and did an MRI--certain region of the brain lit up. Then they did ear acupuncture *for* the right thumb. Same area of the brain lit up--in the same way. This might be interesting in light of the other medical study indicating lowered blood flow to tthe brain in certain conditions such as chronic fatique syndrome, fibromyalgia, IBS and others. Now if we can just figure out which area of the brain and which acupuncture points stimulate it...  or maybe they already have, and if an MRI was done on someone with needles in the IBS points, they would find increased blood flow. Be an interesting test...


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## overitnow

It would be an interesting test; however, if the lowered blood flow is due to obstructions, then the various symptoms would probably depend upon where the obstructions occur. While this would explain why different patients have different sets of symptoms, it might require a fair amount of experimentation to find all of those accupuncture/pressure points.Out of curiosity, and because I know very little about how these therapies work, would such manipulations actually decrease the obstructive material?Mark


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## jjohnson

It looks like this drug from Neurocrine/GSK is expected to start the phase II proof-of-concept study by year's end.http://sev.prnewswire.com/health-care-hosp...02112006-1.html


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## 23392

Mark, I don't know enough about acupuncture to answer whether it could decrease an obstruction. I *suspect* that it could alter processes to alter metabolization, possibly changing the probability of future obstructions. Maybe. or maybe not.I'd have to ask about both questions--whether it could in fact remove one [which I tend to doubt; it seems to me to function like rebooting a computer--to affect neural and muscular and possibly organ function, but outright remove a plaque deposit, not so sure, since there's no muscle there to do that], and whether it could contribute to prevention.HOwever, for those who very likely have no obstruction [I have levels that make my doc ask if I'm eating *enough* fat, and zero homocysteine and c-reactive protein, as well] and still might show the decreased blood flow, especially some of my fellow young ibsers, it might be interesting.Meanwhile that was interesting about the patent on provex! Thanks for noting that.


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## 21078

This is a very confusing thread. Cpou;d someone please summarize the slaient points.Thanks


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## overitnow

The new drug being tested affects brain blood flow.My IBS-D has been long gone since 1999 with a supplement (Provex CV) that, among other things, improves vascular strength, blood flow, and is able to penetrate the blood brain barrier to work it's little miracles.A few years ago an Australian university study found a 1 to 1 relationship between Chronic Fatigue patients with IBS and lowered blood flow in the part of the brain that controls digestion. (Further inquiries on my part led to some info that similar circulatory problems in the brain stem showed up with people who had ME/CFS. This leads me to the supposition that obstructions occurring in various parts of the brain would probably cause dissimilar symptoms, depending upon what parts of the body those brain sections control.)Finally, I am convinced that increasing the vascular health, decreasing obstructions, and increasing circulation will eliminate IBS for those who share this problem. Indeed, I suspect that some percentile of those with IBS will find it a precurser of heart disease through cholesterol buildup in the brain. (And when you read of the number of people on the Board who use statins or are fighting high cholesterol readings, it seems even more possible.) Unfortunately, very few people seem to be looking at brain circulation as a cause of these seemingly mysteriously related problems. Hence, my excitement whenever I see brain circulation being looked at.Mark


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## eric

I am not sure its how much blood flow in the brain as opposed to areas of the brain that activate or dysfunction when it receive signals from the gut. There are differences in brain activation in IBS as opposed to normals.an important area of the brain and pain is the Anterior Cinculate Cortex, which is also part of the emotional areas of the brain.Physiology, pharmacology, and therapeutic relevance of urocortins in mammals: Ancient CRF paralogs.Fekete EM, Zorrilla EP. Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA; Institute of Physiology, Pecs University Medical School, 7602 Pecs, Hungary.Urocortins, three paralogs of the stress-related peptide corticotropin-releasing factor (CRF) found in bony fish, amphibians, birds, and mammals, have unique phylogenies, pharmacologies, and tissue distributions. As a result and despite a structural family resemblance, the natural functions of urocortins and CRF in mammalian homeostatic responses differ substantially. Endogenous urocortins are neither simply counterpoints nor mimics of endogenous CRF action. In their own right, urocortins may be clinically relevant molecules in the pathogenesis or management of many conditions, including congestive heart failure, hypertension, gastrointestinal and inflammatory disorders (irritable bowel syndrome, active gastritis, gastroparesis, and rheumatoid arthritis), atopic/allergic disorders (dermatitis, urticaria, and asthma), pregnancy and parturition (preeclampsia, spontaneous abortion, onset, and maintenance of effective labor), major depression and obesity. Safety trials for intravenous urocortin treatment have already begun for the treatment of congestive heart failure. Further understanding the unique functions of urocortin 1, urocortin 2, and urocortin 3 action may uncover other therapeutic opportunities.PMID: 17083971 Curr Med Chem. 2005;12(13):1503-12. Links The corticotropin-releasing factor (CRF) family of neuropeptides in inflammation: potential therapeutic applications.Gravanis A, Margioris AN. Departments of Pharmacology, School of Medicine, University of Crete, Heraklion 71110, Greece. gravanis###med.uoc.grHypothalamic CRF plays a central role in the coordination of endocrine and behavioral responses to stress and it is also involved in the pathophysiology of several neuropsychiatric diseases including depression, anxiety and addiction. In the mammals, the CRF family of peptides includes CRF, urocortin (Ucn), Ucn I, and Ucn II while was enriched with new members, the urocortins. Their biological effects are mediated by the CRF1 and CRF2 receptors, which belong to the G-protein-coupled receptor super family. Multiple research groups have demonstrated during the last decade the expression of the CRF peptides and their receptors in several components of the immune system and their participation in the ad hoc regulation of inflammatory phenomena. Non-peptide CRF1 antagonists have been recently synthesized for the treatment of CNS related diseases, such as anxiety, depression and drug abuse. In the gastrointestinal tract, these compounds open new therapeutic options in the treatment of lower-GI inflammatory diseases associated to CRF, such as the chronic inflammatory bowel syndromes, irritable bowel disease and ulcerative colitis while Ucn, Ucn I, Ucn II or synthetic non-peptide CRF2 agonists may be useful in the treatment of upper-GI inflammatory diseases. In human endometrium, CRF1 antagonists may be used as abortive agents interfering with the inflammatory phenomena taking place during the implantation of the conceptus. They thus may represent a new class of nonsteroidal inhibitors of implantation. These two examples illustrate the potential therapeutic significance of the CRH in regulating inflammatory phenomena in an ad hoc approach without affecting the rest of the immune system.PMID: 15974983 Psychoneuroendocrinology. 1995;20(8):789-819. Links Corticotropin-releasing factor receptors: physiology, pharmacology, biochemistry and role in central nervous system and immune disorders.De Souza EB.Neurocrine Biosciences Inc., San Diego, CA 92121, USA.Corticotropin-releasing factor (CRF) plays a major role in coordinating the endocrine, autonomic, behavioral and immune responses to stress through actions in the brain and the periphery. CRF receptors identified in brain, pituitary and spleen have comparable kinetic and pharmacological characteristics, guanine nucleotide sensitivity and adenylate cyclase-stimulating activity. Differences were observed in the molecular mass of the CRF receptor complex between the brain (58,000 Da) and the pituitary and spleen (75,000 Da), which appeared to be due to differential glycosylation of the receptor proteins. The recently cloned CRF receptor in the pituitary and the brain (designated as CRF1) encodes a 415 amino acid protein comprising seven putative membrane-spanning domains and is structurally related to the calcitonin/vasoactive intestinal peptide/growth hormone-releasing hormone subfamily of G-protein-coupled receptors. A second member of the CRF receptor family encoding a 411 amino acid rat brain protein with approximately 70% homology to CRF1 has recently been identified (designated as CRF2); there exists an additional splice variant of the CRF2 receptor with a different N-terminal domain encoding a protein of 431 amino acids. In autoradiographic studies, CRF receptors were localized in highest densities in the anterior and intermediate lobes of the pituitary gland, olfactory bulb, cerebral cortex, amygdala, cerebellum and the macrophage-enriched zones and red pulp regions of the spleen. CRF can modulate the number of CRF receptors in a reciprocal manner. For example, stress and adrenalectomy increase hypothalamic CRF secretion which, in turn, down-regulates CRF receptors in the anterior pituitary. CRF receptors in the brain and pituitary are also altered as a consequence of the development and aging processes. In addition to a physiological role for CRF in integrating the responses of the brain, endocrine and immune systems to physiological, psychological and immunological stimuli, recent clinical data implicate CRF in the etiology and pathophysiology of various endocrine, psychiatric, neurologic and inflammatory illnesses. Hypersecretion of CRF in the brain may contribute to the symptomatology seen in neuropsychiatric disorders, such as depression, anxiety-related disorders and anorexia nervosa. Furthermore, overproduction of CRF at peripheral inflammatory sites, such as synovial joints may contribute to autoimmune diseases such as rheumatoid arthritis. In contrast, deficits in brain CRF are apparent in neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease and Huntington's disease, as they relate to dysfunction of CRF neurons in the brain areas affected in the particular disorder. Strategies directed at developing CRF-related agents may hold promise for novel therapies for the treatment of these various disorders.PMID: 8834089


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## eric

FYI Curr Pharm Des. 2006;12(31):4071-88. Links CRF1 receptors as a therapeutic target for irritable bowel syndrome.Martinez V, Tache Y. Integrative Pharmacology--Gastrointestinal Biology, AstraZeneca R&D, Molndal, Sweden.The characterization of the corticotropin-releasing factor (CRF) family of neuroendocrine regulatory peptides, the cloning and pharmacological characterization of two CRF receptor subtypes (CRF(1) and CRF(2)), and the development of selective CRF receptor antagonists provided new insight to unravel the mechanisms of stress and the potential involvement of the CRF system in different pathophysiological conditions, including functional gastrointestinal disorders, mainly irritable bowel syndrome (IBS), and psychopathologies such as anxiety/depression. Compelling pre-clinical data showed that brain CRF administration mimics acute stress-induced colonic responses and enhances colorectal distension-induced visceral pain in rats through CRF(1) receptors. Similarly, peripheral CRF reduced the pain threshold to colonic distension and increased colonic motility in humans and rodents. These observations mimic the manifestations of IBS, characterized by abdominal bloating/discomfort and altered bowel habits. Moreover, CRF-CRF(1) pathways have been implicated in the development of anxiety/depression. These psychopathologies, together with stressful life events, have high comorbidity with IBS, and are considered significant components of the disease. From these observations, CRF(1) receptors have been suggested as a target to treat IBS. Peripherally acting CRF(1) antagonists might directly improve IBS symptoms, as related to motility, secretion and immune response. On the other hand, central actions will be beneficial as to prevent the psychopathologies that co-exist with IBS and as a way to modulate the central processing of stress- and visceral pain-related signals. Here, we review the pre-clinical and clinical data supporting these assumptions, and address the efforts done at a pharmaceutical level to develop effective therapies targeting CRF(1) receptors for functional gastrointestinal disorders.PMID: 17100612


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## jjohnson

Neurocrine and GSK announced today that they have initiated the phase II proof of concept (i.e. safety and efficacy) trial for this drug.http://www.medadnews.com/News/index.cfm?articleid=401287


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## eric

FYINeuromuscular Dysfunction and IBS: Clinical Implications"Corticotrophin-Releasing Factor AntagonistsThe hypothalamic-pituitary-adrenal axis serves as the primary endocrine stress system in humans and provides an important interface between the brain and the gut immune system. The primary hypothalamic regulatory peptide, corticotrophin-releasing factor (CRF), is recognized as an important mediator of the behavioral, endocrinologic, autonomic, and visceral responses to a variety of different types of stimuli; evidence for a potential role of CRF in GI function has emerged through the identification of CRF receptors on myenteric neurons. In humans, CRF analogue administration has been observed to accentuate colonic motility and alter visceral pain responses,[27] and blockade of CRF receptors has been shown to blunt evoked motility and abdominal pain responses in IBS patients.[28] These data are clearly preliminary, and additional large-scale trials assessing the clinical effects and safety of CRF antagonists are needed."http://www.medscape.com/viewarticle/548600_3


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## 15221

Thanks Eric, I have been checking this stuff out for a few years now but thanks to You and JJ... I have had a very renewed intrest....I thought it was going nowhere for while.....snails pace in development..... keeping my fingers crossed and praying for some good news....Have a Nice Holiday


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## eric

FYIJ Clin Invest. 2007 Jan 2;117(1):33-40.Corticotropin-releasing factor receptors and stress-related alterations of gut motor function.Tache Y, Bonaz B. CURE: Digestive Diseases Research Center, and Center for Neurovisceral Sciences & Women's Health, Department of Medicine, Division of Digestive Diseases, UCLA, and VA Greater Los Angeles Healthcare System, Los Angeles, California, USA. Groupe d'Etude du Stress et des Interactions Neuro-Digestives (EA3744), Department of Gastroenterology and Hepatology, Grenoble Faculty of Medicine and Hospital, Grenoble, France.Over the past few decades, corticotropin-releasing factor (CRF) signaling pathways have been shown to be the main coordinators of the endocrine, behavioral, and immune responses to stress. Emerging evidence also links the activation of CRF receptors type 1 and type 2 with stress-related alterations of gut motor function. Here, we review the role of CRF receptors in both the brain and the gut as part of key mechanisms through which various stressors impact propulsive activity of the gastrointestinal system. We also examine how these mechanisms translate into the development of new approaches for irritable bowel syndrome, a multifactorial disorder for which stress has been implicated in the pathophysiology.PMID: 17200704 Am J Physiol Gastrointest Liver Physiol. 2001 Feb;280(2):G173-7. Links Stress and the gastrointestinal tract III. Stress-related alterations of gut motor function: role of brain corticotropin-releasing factor receptors.Tache Y, Martinez V, Million M, Wang L. CURE: Digestive Diseases Research Center, Department of Veterans Affairs Greater Los Angeles Healthcare System, Bldg. 115, Rm. 203, 11301 Wilshire Blvd., Los Angeles, CA 90073, USA. ytache###ucla.eduAlterations of gastrointestinal (GI) motor function are part of the visceral responses to stress. Inhibition of gastric emptying and stimulation of colonic motor function are the commonly encountered patterns induced by various stressors. Activation of brain corticotropin-releasing factor (CRF) receptors mediates stress-related inhibition of upper GI and stimulation of lower GI motor function through interaction with different CRF receptor subtypes. CRF subtype 1 receptors are involved in the colonic and anxiogenic responses to stress and may have clinical relevance in the comorbidity of anxiety/depression and irritable bowel syndrome.PMID: 11208537 Gend Med. 2005 Sep;2(3):146-54. Links Role of corticotropin-releasing factor pathways in stress-related alterations of colonic motor function and viscerosensibility in female rodents.Tache Y, Million M, Nelson AG, Lamy C, Wang L. Center for Neurovisceral Sciences and Women's Health, and CURE: Digestive Diseases Research Center, David Geffen School of Medicine, University of California, Los Angeles, California, USA. ytache###mednet.ucla.eduBACKGROUND: Clinical reports have shown that irritable bowel syndrome (IBS) is comorbid with anxiety/depression and stress-related events, and that the disorder is more prevalent among women than among men. In rodents, colorectal distention (CRD) induces abdominal contractions, and this visceromotor response is used to assess visceral pain. The activation of brain corticotropin-releasing factor (CRF) pathways has a key role in the behavioral and visceral responses to stress. OBJECTIVE: In this review of experimental studies that delineate the underlying mechanisms of the stress response, we focused on CRF signaling pathways and sex hormones in modulating visceral hypersensitivity induced by CRD in rodents. METHODS: The findings of our recent research on the development of an experimental model of visceral pain in female rats and the modulation of the hyperalgesic response to CRD by CRF antagonists were integrated with those of the published literature. A MEDLINE search of the years 1981 to 2005 was conducted using the key words stress, CRF, CRH, CRF1 receptor, IBS, CRD, female rat, visceral pain, estrogen, and anxiety. RESULTS: CRF and other related mammalian peptides (urocortins) interact with the distinct CRF subtype 1 and 2 receptors. Well-documented preclinical studies have established the role of brain CRF1 receptors in mediating stress-related anxiogenic and visceral (stimulation of colonic motor function and sensitization to repeated CRD) responses in male rodents, whereas more limited studies have been performed in female rats. Our recent study indicated that the CRF1 antagonist antalarmin prevents visceral hypersensitivity induced by 2 sets of CRD in female rats. In several models of visceral pain induced by CRD, sex differences and a sensitization action of estrogen were reported. Our preliminary evidence indicated a potentiating interaction between CRF-CRF1 pathways and estrogen in the stimulation of colonic motor responses that may take place within the enteric neurons of the colon, where both CRF1 and estrogen receptors are present. CONCLUSIONS: The results of this review suggest that overactivity of CRF1 signaling in the brain and the gut may have relevance in understanding the comorbidity of anxiety/depression and IBS in diarrhea-predominant female patients. Targeting these mechanisms with CRF1 antagonists may provide a novel therapeutic strategy.PMID: 16290887Can J Gastroenterol. 1999 Mar;13 Suppl A:18A-25A. Links Corticotropin-releasing factor and the brain-gut motor response to stress.Tache Y, Martinez V, Million M, Rivier J. CURE: Digestive Diseases Research Center, West Los Angeles VA Medical Center, Los Angeles 90073, USA. ytache###ucla.eduThe characterization of corticotropin-releasing factor (CRF) and CRF receptors, and the development of specific CRF receptor antagonists selective for the receptor subtypes have paved the way to the understanding of the biochemical coding of stress-related alterations of gut motor function. Reports have consistently established that central administration of CRF acts in the brain to inhibit gastric emptying while stimulating colonic motor function through modulation of the vagal and sacral parasympathetic outflow in rodents. Endogenous CRF in the brain plays a role in mediating various forms of stressor-induced gastric stasis, including postoperative gastric ileus, and activates colonic transit and fecal excretion elicited by psychologically aversive or fearful stimuli. It is known that brain CRF is involved in the cross-talk between the immune and gastrointestinal systems because systemic or central administration of interleukin-1-beta delays gastric emptying while stimulating colonic motor activity through activation of CRF release in the brain. The paraventricular nucleus of the hypothalamus and the dorsal vagal complex are important sites of action for CRF to inhibit gastric motor function, while the paraventricular nucleus of the hypothalamus and the locus coeruleus complex are sites of action for CRF to stimulate colonic motor function. The inhibition of gastric emptying by CRF may be mediated by the interaction with the CRF2 receptors, while the anxiogenic and colonic motor responses may involve CRF1 receptors. Hypersecretion of CRF in the brain may contribute to the pathophysiology of stress-related exacerbation of irritable bowel syndrome.PMID: 10202204 Br J Pharmacol. 2004 Apr;141(8):1321-30. Links CRF1 receptor signaling pathways are involved in stress-related alterations of colonic function and viscerosensitivity: implications for irritable bowel syndrome.Tache Y, Martinez V, Wang L, Million M. CURE/Digestive Diseases Research Center, and Center for Neurovisceral Sciences and Woman's Health, West Los Angeles VA Medical Center, University of California-Los Angeles, 1130 Wilshire Boulevard, Los Angeles, CA 90073, U.S.A. ytache###ucla.edu1. The characterization of corticotropin releasing factor (CRF) and, more recently, the discovery of additional CRF-related ligands, urocortin 1, urocortin 2 and urocortin 3, the cloning of two distinct CRF receptor subtypes, 1 (CRF(1)) and 2 (CRF(2)), and the development of selective CRF receptor antagonists provided new insight to unravel the mechanisms of stress. Activation of brain CRF(1) receptor signaling pathways is implicated in stress-related endocrine response and the development of anxiety-like behaviors. 2. Compelling evidence in rodents showed also that both central and peripheral injection of CRF and urocortin 1 mimic acute stress-induced colonic response (stimulation of motility, transit, defecation, mucus and watery secretion, increased ionic permeability and occurrence of diarrhea) in rodents. Central CRF enhances colorectal distention-induced visceral pain in rats. Peripheral CRF reduced pain threshold to colonic distention and increased colonic motility in humans. 3. Nonselective CRF(1)/CRF(2) antagonists and selective CRF(1) antagonists inhibit exogenous (central or peripheral) CRF- and acute stress-induced activation of colonic myenteric neurons, stimulation of colonic motor function and visceral hyperalgesia while selective CRF(2) antagonists have no effect. None of the CRF antagonists influence basal or postprandial colonic function in nonstressed animals. 4. These findings implicate CRF(1) receptors in stress-related stimulation of colonic function and hypersensitivity to colorectal distention. Targeting CRF(1)-dependent pathways may have potential benefit against stress or anxiety-/depression-related functional bowel disorders.PMID: 15100165 New article in the IFFGD Digestive Health Matters "Stress and Irritable Bowel Syndrome: Unraveling the CodeBy: Yvette TachÃ©, Ph.D., Center for Neurovisceral Sciences and Women Health, Digestive Diseases Center, Department of Medicine, Digestive Diseases Division, University of California at Los Angeles and VA Greater Los Angeles Health Care System, CaliforniaSome common medical conditions such as irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), fibromyalgia, and migraine headaches may be stress-related. Understanding of the mind and body's responses called upon during stress may provide insight on the underlying cause of IBS and open the door to new and more effective treatment. "Stress" is a term doctors use to describe normal responses in the body that are needed for health and survival. Our bodies regularly respond to the constant flow of changes that happen around and within us. CRF is the brain's "stress hormone." When stimulated, it interacts with many systems within the body. These interactions include those between the brain and the digestive tract. They effect whether or not we feel discomfort or pain, and the way our bowels move. In some people, the stress response is overactive. When the stress response is out of balance, unwanted symptoms can result."http://www.aboutibs.org/Publications/currentParticipate.html


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## SpAsMaN*

It's getting late,are they gonna test on IBS-A?Or gas predominant?


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## eric

Excellent CRF infoStress and Irritable Bowel Syndrome: Unraveling the CodeBy: Yvette TachÃ©, Ph.D., Center for Neurovisceral Sciences and Women Health, Digestive Diseases Center, Department of Medicine, Digestive Diseases Division, University of California at Los Angeles and VA Greater Los Angeles Health Care System, CaliforniaDr. TachÃ© was the recipient of the IFFGD 2005 Research Award to Senior Investigator, Basic Science. Her early publications put the "brain-gut axis" on the map. Since then, she has been one of the pioneers in this field. In many ways, it has been her energy and enthusiasm that has ensured the continued vibrancy of the field. Her identification of the role of corticotrophin-releasing factor (CRF) signaling pathways in stress-related alterations of gut motor function and visceral pain are of major and lasting importance. "http://www.giresearch.org/Tache.htmlhttp:/....org/Tache.html


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## jjohnson

Here is the Clinicaltrials.gov listing for the phase II study.http://www.clinicaltrials.gov/ct/show/NCT00421707?order=26


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## Nanobug

> quote:Given the amount I have gone on about the flavonoids increasing blood circulation to the brain, wouldn't it be interesting if GSK found the same cerebral impairment that was found in the Aussie study I have cited?


If increases in blood flow to the brain are important in the treatment of IBS, would't stuff like vinpocetine help?


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