The Pharmacology of TD-8954, a Potent and Selective 5-HT4 Receptor Agonist with Gastrointestinal Prokinetic Properties

Beattie, David T.; Armstrong, Scott R.; Vickery, Ross G.; Tsuruda, Pamela R.; Campbell, Christina; Richardson, Carrie; McCullough, Julia L.; Daniëls, O.; Kersey, Kathryn; Li, Yu Ping; Kim, Karl H.S.

doi:10.3389/fphar.2011.00025

Cited by 38 publications

(32 citation statements)

References 56 publications

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“…The increased cecum to colon transit found for prucalopride is consistent with its localized effect in the human large intestine where 0.5–4 mg/kg/day over 7 days accelerated colonic transit . It is also consistent with acute prucalopride treatment in guinea pigs that show increased colonic transit in vivo and increased motility in the proximal colon in vitro . The effect of prucalopride on gastric emptying in humans, however, is less clear, it accelerated gastric emptying in one study but not in another …”

Section: Discussionsupporting

confidence: 67%

Tracking gastrointestinal transit of solids in aged rats as pharmacological models of chronic dysmotility

Dalziel

Young

Bercík

et al. 2016

Neurogastroenterology Motil

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Key Points• Understanding conditions of gastrointestinal dysmotility and impaired GI-transit requires accurate noninvasive techniques to monitor the precise location of ingested content.• We demonstrate a non-invasive high resolution X-ray imaging technique to track transit of solid material in vivo, under two specific pharmacological treatment conditions.• Our data indicate GI tract region-specific effects of the modulatory drugs on transit of contents.• We provide evidence that loperamide slows stomach emptying and GI transit, and that prucalopride increases stomach emptying and accelerates colonic transit in aged rats. AbstractBackground Dysmotility in the gastrointestinal (GI) tract often leads to impaired transit of luminal contents leading to symptoms of diarrhea or constipation. The aim of this research was to develop a technique using high resolution X-ray imaging to study pharmacologically induced aged rat models of chronic GI dysmotility that mimic accelerated transit (diarrhea) or constipation. The 5-hydroxytryptamine type 4 (5-HT 4 ) receptor agonist prucalopride was used to accelerate transit, and the opioid agonist loperamide was used to delay transit. Methods Male rats (18 months) were given 0, 1, 2, or 4 mg/kg/day prucalopride or loperamide (in dimethyl sulfoxide, DMSO) for 7 days by continuous 7-day dosing. To determine the GI region-specific effect, transit of six metallic beads was tracked over 12 h using high resolution X-ray imaging. An established rating scale was used to classify GI bead location in vivo and the distance beads had propagated from the caecum was confirmed postmortem. Key Results Loperamide (1 mg/kg) slowed stomach emptying and GI transit at 9 and 12 h. Prucalopride (4 mg/kg) did not significantly alter GI transit scores, but at a dose of 4 mg/kg beads had moved significantly more distal than the caecum in 12 h compared to controls. Conclusions & Inferences We report a novel high-resolution, non-invasive, X-ray imaging technique that provides new insights into GI transit rates in live rats. The results demonstrate that loperamide slowed overall transit in aged rats, while prucalopride increased stomach emptying and accelerates colonic transit.

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Section: Discussionsupporting

confidence: 67%

Tracking gastrointestinal transit of solids in aged rats as pharmacological models of chronic dysmotility

Dalziel

Young

Bercík

et al. 2016

Neurogastroenterology Motil

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“…Subcutaneous administration of TD-8954 (0.03–3mg/kg) increased colonic transit of carmine red dye in guinea pigs, and it evoked a dose dependent (10 and 30μg/kg) relaxation of the esophagus in rats. Oral administration of a single dose of TD-8954 (0.1–20mg) on conscious dogs increased contractility of the proximal small intestine, and in human subjects it increased bowel movement frequency and reduced time to first stool for all doses compared to placebo [44]. …”

Section: Early Investigational Therapeuticsmentioning

confidence: 99%

Early investigational therapeutics for gastrointestinal motility disorders: from animal studies to Phase II trials

Valentin

Acosta

Camilleri

2015

Expert Opinion on Investigational Drugs

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Introduction The most common gastrointestinal disorders which include evidence of dysmotility include: gastroparesis, the lower functional gastrointestinal disorders associated with altered bowel function [such as chronic (functional) diarrhea, chronic idiopathic constipation (CIC)], and opioid induced constipation (OIC). These conditions, which are grouped as gastrointestinal motility and functional disorders, are characterized by abnormal motor, sensory, or secretory functions that alter bowel function and result in a significant disease burden, since currently available treatments do not completely alleviate symptoms. New drugs are being developed for these disorders, targeting mechanisms involved in the pathophysiology of these diseases, specifically, motor function, intestinal secretion and bile acid modulation. Areas Covered The article provides a brief overview of motility disorders and the drugs approved and currently available for these indications. It also provides an evaluation of the efficacy, safety and possible mechanisms of the drugs currently under investigation for the treatment of gastroparesis, chronic diarrhea, CIC and OIC, based on animal to phase II studies. Medications with complete phase III trials are excluded from this discussion. Expert opinion Treatment of gastrointestinal motility disorders requires the understanding of the pathophysiological mechanisms, biomarkers to identify subgroups of these disorders, and robust pharmacological studies from animal to phase II studies. These are prerequisites for the development of efficacious medications and individualizing therapy in order to enhance the treatment of these patients.

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“…5-HT 4 receptor agonists , after withdrawal of tegaserod, now include prucalopride, naronapride, velusetrag (Camilleri, 2010b), and TD-8954 (Beattie et al, 2011). These agents are thought to act on intrinsic neurons to stimulate gastric, small bowel, and colonic transit in health, in constipation and in IBS with constipation (Bouras et al, 1999; Poen et al, 1999; Degen et al, 2001).…”

Section: Classes Of Drugs Used or Under Development In Ibsmentioning

confidence: 99%

Drug Development for the Irritable Bowel Syndrome: Current Challenges and Future Perspectives

Ponti¹

2013

Front. Pharmacol.

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Medications are frequently used for the treatment of patients with the irritable bowel syndrome (IBS), although their actual benefit is often debated. In fact, the recent progress in our understanding of the pathophysiology of IBS, accompanied by a large number of preclinical and clinical studies of new drugs, has not been matched by a significant improvement of the armamentarium of medications available to treat IBS. The aim of this review is to outline the current challenges in drug development for IBS, taking advantage of what we have learnt through the Rome process (Rome I, Rome II, and Rome III). The key questions that will be addressed are: (a) do we still believe in the “magic bullet,” i.e., a very selective drug displaying a single receptor mechanism capable of controlling IBS symptoms? (b) IBS is a “functional disorder” where complex neuroimmune and brain-gut interactions occur and minimal inflammation is often documented: do we need to target gut motility, visceral sensitivity, or minimal inflammation? (c) are there validated biomarkers (accepted by regulatory agencies) for studies of sensation and motility with experimental medications in humans? (d) do animal models have predictive and translational value? (e) in the era of personalized medicine, does pharmacogenomics applied to these medications already play a role? Finally, this review will briefly outline medications currently used or in development for IBS. It is anticipated that a more focused interaction between basic science investigators, pharmacologists, and clinicians will lead to better treatment of IBS.

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The Pharmacology of TD-8954, a Potent and Selective 5-HT4 Receptor Agonist with Gastrointestinal Prokinetic Properties

Cited by 38 publications

References 56 publications

Tracking gastrointestinal transit of solids in aged rats as pharmacological models of chronic dysmotility

Tracking gastrointestinal transit of solids in aged rats as pharmacological models of chronic dysmotility

Early investigational therapeutics for gastrointestinal motility disorders: from animal studies to Phase II trials

Drug Development for the Irritable Bowel Syndrome: Current Challenges and Future Perspectives

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