Pharmacological agents currently in clinical trials for disorders in neurogastroenterology

Abstract

Esophageal, gastrointestinal, and colonic diseases resulting from disorders of the motor and sensory functions represent almost half the patients presenting to gastroenterologists. There have been significant advances in understanding the mechanisms of these disorders, through basic and translational research, and in targeting the receptors or mediators involved, through clinical trials involving biomarkers and patient responses. These advances have led to relief of patients' symptoms and improved quality of life, although there are still significant unmet needs. This article reviews the pipeline of medications in development for esophageal sensorimotor disorders, gastroparesis, chronic diarrhea, chronic constipation (including opioid-induced constipation), and visceral pain. IntroductionGastrointestinal motility and functional disorders result in either abnormal propulsion of content or excessive sensation of normal or abnormal functions in different regions of the gut. These conditions constitute about 40% of referrals to gastroenterologists, and they result in significant disease burden. Advances in clinical management of these disorders are based on understanding the basic mechanisms involved in sensorimotor and secretory functions, coupled with clinical investigation and trial methodology.The most frequent gastrointestinal motility and functional disorders are esophagitis, gastroparesis, chronic diarrhea, chronic idiopathic constipation (CIC), opioid-induced constipation (OIC), and visceral pain. This review summarizes the pathophysiology, lists commonly used current medications, and focuses on pharmacological agents in development for each disorder. At present, several approved medications relieve constipation and diarrhea; the major unmet needs are in gastroparesis, OIC, and visceral pain.

Intestinal Secretory Mechanisms in Irritable Bowel Syndrome–Diarrhea

“…These agents are effective in the overall relief of IBS-D and, particularly, in the normalization of bowel function and reduction of urgency in these patients. 28,29 …”

Prokinetics in the Management of Functional Gastrointestinal Disorders

“…Also, with the emergence of new ideas relating to the pathophysiology of such common disorders as irritable bowel syndrome (IBS), a whole new set of therapeutic targets came in to range; from the central nervous system to the enteric immune system and the gut microbiota. To cover all agents that have been developed, or are in development, to address any one or a combination of these factors is beyond the scope of this review and the reader is referred to an elegant and recent review by Camilleri 1 for a more comprehensive overview of this area.…”

Opioid-induced constipation in chronic noncancer pain

“…OIC occurs because opiate-based pain treatment targets primarily one of three selective G protein-coupled opioid receptors (m, k, and d), namely the m-opioid receptor, expressed in the enteric nervous system of the digestive tract [12,17,[22][23][24][25][26][27][28]. Initial management and prevention of OIC, include the use of stool softeners, osmotic agents, and stimulant laxatives, however, their efficacy in advanced illness and chronic noncancer pain patients is limited and targeted pharmacological therapy is often needed, [14,20,[29][30][31][32] including prokinetic agents and peripheral m-opioid receptor antagonists [12,17,22,24,25,[32][33][34]35 && ].…”

“…Initial management and prevention of OIC, include the use of stool softeners, osmotic agents, and stimulant laxatives, however, their efficacy in advanced illness and chronic noncancer pain patients is limited and targeted pharmacological therapy is often needed, [14,20,[29][30][31][32] including prokinetic agents and peripheral m-opioid receptor antagonists [12,17,22,24,25,[32][33][34]35 && ]. Methylnaltrexone (MNTX) became the first FDAapproved peripheral m-opioid receptor antagonist (PAMORA) for OIC in patients with advanced illness in 2008 [32,36] (www.accessdata.fda.gov/ drugsatfda_docs/nda/2008/021964s000TOC.cfm).…”