FYI
CRH Antagonist Reduces IBS Responses to Stress
Yael Waknine
June 30, 2004 ¾ Peripheral administration of the nonselective corticotropin-releasing hormone (CRH) antagonist α-helical CRH9-41 (αhCRH) improves gastrointestinal motility, visceral perception, and negative mood in response to gut stimulation without affecting the hypothalamo-pituitary-adrenal axis in patients with irritable bowel syndrome (IBS), according to the results of a preliminary study published in the July issue of Gut.
"IBS is presumed to be a disorder of the brain-gut link associated with an exaggerated response to stress," write Y. Sagami, MD, and colleagues of the Department of Psychosomatic Medicine at the Tohoku University School of Medicine in Sendai, Japan. "CRH is considered to be a major mediator of stress responses in the brain-gut axis."
The investigators enrolled 10 healthy subjects and 10 subjects diagnosed with diarrhea-predominant IBS according to the Rome II criteria. IBS medication was discontinued one week prior to the study.
A barostat bag and three transducers were inserted into the proximal portion of the descending colon of each subject and connected to an analog-digital converter and a visceral stimulator. An electrode catheter was set in the rectum for electrical stimulation of the mucosa.
The study was conducted in two segments, one using a 20-mL saline bolus followed by continuous infusion, and the other using a 2 µg/kg αhCRH bolus followed by 8 µg/kg continuous infusion. Both segments included baseline, rectal electrical stimulation, recovery, and tracking phases. Colonic tone was evaluated by noting the lowest volume in the barostat bag at which the subject felt pressure. Subjective symptoms were self-assessed by subjects on an ordinate scale.
Basal bag volume tended to be lower in IBS subjects than controls, indicating higher colonic tone. Administration of αhCRH resulted in significantly increased baseline barostat bag volume in control subjects (from a mean [standard error of the mean (SEM)] of 105.8 [30.5] mL to 148.3 [37.4]; P = .004) but not IBS subjects. IBS subjects responded to electrical stimulation with significantly decreased bag volume both in the first segment (P = .01) and after the αhCRH infusion (P = .004). Electrical stimulation did not reduce bag volume in the control subjects.
"Colonic tone in IBS patients increased throughout our experiment and was even exaggerated by electrical stimulation of the rectum," the authors note. "[T]he increased sensitivity of the gut to CRH in IBS patients may account for [this] phenomenon."
Motility indices of the colon induced by electrical stimulation were significantly higher in IBS patients compared with control subjects (mean [SEM], 421.5 [171.6] vs. 124.5 [46.5]; P = .04). This exaggerated motility response in IBS subjects was significantly attenuated by αhCRH (P < .05).
In IBS subjects, αhCRH significantly decreased evaluations of abdominal pain (P = .02) and anxiety (P < .0001) resulting from electrical stimulation.
Administration of αhCRH had no inhibitory effects on the hypothalamo-pituitary-adrenal axis; levels of plasma adrenocorticotropic hormone and serum cortisol were not reduced.
"Because of the small number of subjects included in the study, this initial clinical investigation warrants replication in a larger group of IBS patients and further assessment using a placebo control group," comments Y. Taché, MD, from the Digestive Diseases Research Center in Los Angeles, California, in an accompanying editorial, adding that the findings also support the testing of more potent CRH antagonists.
The authors report no pertinent financial disclosures.
Gut. 2004;53:919-921, 958-964
Reviewed by Gary D. Vogin, MD
http://www.medscape.com/viewarticle/482218
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