Functional GI disorders: From animal models to drug development

Emeran A Mayer ^1*, Sylvie Bradesi ¹, Lin Chang ¹, Brennan M.R. Spiegel ¹, Joshua A. Bueller ¹ and Bruce D. Naliboff ¹

¹ UCLA, United States

^* To whom correspondence should be addressed. E-mail: emayer{at}ucla.edu.

Accepted 8 September 2007

Abstract

Despite considerable efforts by academic researchers and by the pharmaceutical industry, the development of novel pharmacological treatments for irritable bowel syndrome (IBS) and other functional gastrointestinal (GI) disorders has been slow and disappointing. The traditional approach to identifying and evaluating novel drugs for these symptom-based syndromes has relied on a fairly standard algorithm using animal models, experimental medicine models and clinical trials. In the current article, we review the empirical basis for this process, focusing on the utility of the assessment of visceral hypersensitivity and GI transit, both in animals and humans as well as the predictive validity of preclinical and clinical models of IBS for identifying successful treatments for IBS symptoms and IBS-related quality of life impairment. A review of published evidence suggests that abdominal pain, defecation-related symptoms (urgency, straining) and psychological factors all contribute to overall symptom severity and to health-related quality of life. Correlations between readouts obtained in preclinical and clinical models and respective symptoms are small, and the ability to predict drug effectiveness for specific as well as for global IBS symptoms is limited. One possible drug development algorithm is proposed which focuses on pharmacological imaging approaches in both preclinical and clinical models, with decreased emphasis on evaluating compounds in symptom-related animal models, and more rapid screening of promising candidate compounds in man.

Keywords: gastrointestinal disorders, irritable bowel syndrome, symptom-based syndromes, visceral hypersensitivity

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?