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Intestinal permeability as a clinical surrogate endpoint in the development of future Crohn's disease therapies
1Division of Gastroenterology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA. xiaonan.han@cchmc.org
Insights
Intestinal hyper-permeability is crucial in pediatric Crohn
Area of Science:
- Gastroenterology
- Pediatric Pathology
- Pharmacology
Background:
- Inflammatory bowel disease (IBD), encompassing Ulcerative Colitis (UC) and Crohn's disease (CD), significantly impacts pediatric gastrointestinal health.
- Intestinal hyper-permeability is a key factor in pediatric CD etiology, influencing pathogen entry and macromolecule penetration, and is vital in drug development.
Purpose of the Study:
- To explore the potential of intestinal permeability as a clinical endpoint for pediatric Crohn's disease trials.
- To review current investigations and patents related to intestinal permeability measurements and therapeutic interventions in pediatric CD.
Main Methods:
- Intestinal permeability is assessed in vivo using mannitol and lactulose tests, yielding a permeability index.
- These tests demonstrate superior sensitivity and specificity compared to other surrogate markers used in CD clinical trials.
Main Results:
- Treatments like Somatropin (Growth Hormone) and Infliximab (anti-TNFalpha) reduce intestinal hyper-permeability.
- These therapeutic agents improve gastrointestinal inflammation and electrolyte balance in pediatric CD patients and animal models.
Conclusions:
- Intestinal permeability measurement holds promise as a viable clinical endpoint for evaluating treatments in pediatric CD.
- Further validation and integration into clinical trial protocols are recommended for this sensitive biomarker.
Abstract:
Inflammatory bowel disease (IBD) including Ulcerative colitis (UC) and Crohn's disease (CD) is a major cause of gastrointestinal pathology in children and adolescents. Intestinal hyper-permeability plays a critical role in the etiology of pediatric CD by affecting the penetration of pathogens, toxic compounds and macromolecules; it also plays a central role in pharmaceutical product development. The mechanisms of barrier function and defects in permeability have great potential for guiding the development of novel drugs for treatment of IBD. Intestinal permeability is typically measured with the mannitol and lactulose tests in vivo; the results are expressed as the permeability index. The sensitivity and specificity of these tests are superior to other currently used surrogate markers in current CD clinical trials. However, the measurement of intestinal permeability has not been listed as a clinical endpoint. Somatropin (Growth Hormone) and Infliximab (anti-TNFalpha) have been used to treat pediatric CD. These agents significantly improve the inflammation in the GI tract and the imbalance of electrolytes in animals with colitis and CD patients by decreasing intestinal hyperpermeability. Herein, we discuss the feasibility of using intestinal permeability as an endpoint in the clinical trials of CD by current investigations and relevant patents.
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