A Novel Partial 5HT3 Agonist DDP733 after a Standard Refluxogenic Meal Reduces Reflux Events: A Randomized, Double-Blind, Placebo-Controlled Pharmacodynamic Study

Choung, Rok Seon; Ferguson, Dawn D.; Murray, Joseph A.; Kammerer, Patricia P.; Dierkhising, Ross A.; Zinsmeister, Alan R.; Nurbhai, Suhail; Landau, Steven B.; Talley, Nicholas J.

doi:10.14309/00000434-200709002-00086

Cited by 3 publications

(7 citation statements)

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“…17 The observed baseline data for the primary endpoints were similar to that observed for the corresponding variation observed post-treatment (pooled over treatment groups). The ANCOVA models would have provided similar power to detect somewhat smaller differences by incorporating the baseline values as covariates and making the specified transformations (to stabilize variances across treatment groups).…”

Section: Sample Size Assessmentsupporting

confidence: 68%

“…Patients with at least a 3-month history of symptoms of GERD (heartburn, regurgitation) who developed at least moderate heartburn and/or regurgitation (at least a 4 on a 0-10 categorical scale) within 2 h following ingestion of the refluxogenic meal while in the supine position 17 were enrolled. Only subjects on PPI were enrolled if they took a stable PPI regimen for the duration of the study; subjects did not undergo a baseline endoscopy.…”

Section: Study Subjectsmentioning

confidence: 99%

“…17 Briefly, study participants underwent the multichannel intraluminal impedance and pH (MII-pH) assessment (Sandhill Scientific) after eating a standard refluxogenic meal. 17,20 Subjects were placed in the right lateral decubitus position and esophageal intraluminal impedance, and pH was recorded for 2 h to identify the total number of reflux episodes, including acid and weakly acidic reflux events.…”

Section: Multichannel Intraluminal Impedance and Phmentioning

confidence: 99%

“…Moreover, in a recent human study, this 5HT3 partial agonist was shown to reduce the rate of reflux episodes after a refluxogenic meal in healthy subjects. 17 However, there is no study of the effects of pumosetrag on esophageal parameters in GERD subjects, including subjects with PPI refractory GERD.…”

Section: Introductionmentioning

confidence: 99%

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Novel partial 5HT3 agonist pumosetrag reduces acid reflux events in uninvestigated GERD patients after a standard refluxogenic meal: a randomized, double‐blind, placebo‐controlled pharmacodynamic study

Choung

Locke

Francis

et al. 2013

Neurogastroenterology Motil

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Section: Sample Size Assessmentsupporting

confidence: 68%

Section: Study Subjectsmentioning

confidence: 99%

Section: Multichannel Intraluminal Impedance and Phmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Novel partial 5HT3 agonist pumosetrag reduces acid reflux events in uninvestigated GERD patients after a standard refluxogenic meal: a randomized, double‐blind, placebo‐controlled pharmacodynamic study

Choung

Locke

Francis

et al. 2013

Neurogastroenterology Motil

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“…DDP733 increased LES basal pressure in experimental animal models. In addition, DDP733 significantly reduced the rate of reflux events and increased the mean amplitude of the distal esophageal contractions without changing the LES basal pressure in healthy human subjects 63 …”

Section: Drugs In the Pipelinementioning

confidence: 88%

The lower esophageal sphincter

Hershcovici

Mashimo

Fass

2011

Neurogastroenterology Motil

101

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Correspondence 823 Pethidine, metoclopramide and the gnstro-oesophageal sphincter Gastro-oesophageal reflux after pethidine? We were interested to read the paper by Hey ef al. (Anaesthesia 1981; 3 6. 173-6) but feel that they have failed to provide direct support for their suggestion that pethidine increases the possibility of gastro-oesopha-geal reflux, and that metoclopramide is a useful adjunct in the prevention of reflux in patients receiving pethi-dine. Their study would have been much more valuable if they had actually demonstrated acid reflux which can be easily done with an intra-oesophageal pH probe at the same time as manometric measurements. They have demonstrated lowering of lower oesophageal sphincter (LOS) pressure with pethidine and conclude that this must lead to the increased possibility of reflux because a study of Hall et a1.l quoted by them suggested that this was so. However, in contrast, atropine is also known to lower LOS pressure in man2 but it does not increase epidsodes of acid reflux.) It is true that Hall et aZ.I did find some correlation between gastro-oesophageal re-flux and lowering of the LOS pressure, this has not been the finding of other workers and there is a considerable overlap between the LOS pressure in those who reflux and the pressure in those who do not."7 Indeed Bennett6 showed that individuals with a LOS pressure as low as 8 cmH2O may not reflux whereas those with a LOS pressure as high as 32 cmHzO do. There is, therefore, a lack of precise correlation between LOS pressure and the presence or absence of reflux. This is probably related, in part, to the problem of determining a pressure reading from what is not a single pressure but a group of varying pressures which depend on the position of the manometric probe in the moreover the LOS does not have a static of fixed pressure, and it varies considerably with mechanical stress, hormonal factors, and even emotional fac-It is unwise to imply that lowering the LOS pressure with pethidine is likely to lead to reflux without demonstrating acid reflux into the oesophagus, and it is even more unwise to assume that, because metoclopra-mide appears to oppose the effect of pethidine on LOS pressure, it actually would prevent any gastro-oesopha-geal reflux that might occur. DB. The effects of premedication drugs on the lower oesophageal high pressure zone acid and reflux status of Rhesus monkeys and man. Gut 1975; 1 6 347-52. 2. LIND JS, CRISPIN JS, MCIWR DK. The effect ofatropine on the gastroesophageal sphincter. Canadian Journal of Physiology and Pharmacology 1968; 46.233-8. 3. SKINNER DB, CAMP TF. Relation of esophageal reflux to lower esophageal sphincter pressures decreased by atro-pine. Gastroenterology 1968; 54: 543-51. 4. POPE CE. A dynamic test of sphincter strength: its application to the lower esophageal sphincter. Gastroenterology 1967; 5 2 779-86. 5. HADDAD JK. Relation of gastroesophageal reflux to yield sphincter pressures. Gastroenterology 1970; 58: 175-84. 6. BENNETT JR. The physician's problem. Gut 1973; 14: 24...

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Partial Agonism of 5-HT₃ Receptors: A Novel Approach to the Symptomatic Treatment of IBS-D

Moore

Sargent

Manning

et al. 2012

ACS Chem. Neurosci.

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Irritable bowel syndrome (IBS) is a functional bowel disorder characterized by abdominal pain, discomfort, and altered bowel habits, which have a significant impact on quality of life for approximately 10−20% of the population. IBS can be divided into three main types IBS-D (diarrhea predominant), IBS-C (constipation predominant), and mixed or alternating IBS. 5-HT 3 receptor antagonism has proved to be an efficacious treatment option for IBS-D. For example, alosetron displays efficacy in the treatment of multiple symptoms, including abdominal pain, discomfort, urgency, stool frequency and consistency. However, significant constipation occurred in approximately 25% of patients, leading to withdrawal of up to 10% of patients in clinical trials. Targeting compounds with partial agonist activity at the 5-HT 3 receptor represents a mechanistic departure from the classic 5-HT 3 receptor antagonist approach and should result in agents that are applicable to a broader array of IBS patient populations. Attenuation of the activity of the ion channel without completely abolishing its function may control or normalize bowel function without leading to a total block associated with severe constipation. We have identified a new class of selective, orally active 5-HT 3 receptor ligands with high 5-HT 3 receptor affinity and low partial agonist activity currently in preclinical development that should offer a significant advantage over existing therapies. KEYWORDS: 5-HT 3 receptor, partial agonist, irritable bowel syndrome, IBS W ith the special edition ACS Chemical Neuroscience to mark the 25th anniversary of the Serotonin club, this is a good opportunity to revisit the role of 5-HT within the gastrointestinal tract, particularly with respect to the function of 5-HT 3 receptors. Many may think of the 5-HT 3 receptor as an "old" target that does not have the "sexy" appeal of a "novel" target, but there is still a lot to learn about 5-HT 3 receptors and many opportunities for it to be a valuable target for drug discovery. Although there is a lot of comment about the lack of innovation in the pharmaceutical industry, we would like to suggest that despite the claims that the "low hanging fruit" has been picked that there are still many opportunities to explore these "older/established" targets. We will discuss how using a partial agonist approach to this "established" target may lead to significant therapeutic advantages in the treatment of irritable bowel syndrome (IBS). Partial agonism as an approach is well established in other therapeutic areas; for example, aripiprazole is a dopamine receptor partial agonist for the treatment of schizophrenia, 1 and varenicline is a nicotinic partial agonist used for smoking cessation.2 In this brief review we will discuss the background to the concept and some key data; this is not intended to be a definitive review of IBS and 5-HT 3 , and there are numerous detailed reviews.3−5 The concept of partial agonism as an approach will be expanded on later, but the key aim of this approa...

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A Novel Partial 5HT3 Agonist DDP733 after a Standard Refluxogenic Meal Reduces Reflux Events: A Randomized, Double-Blind, Placebo-Controlled Pharmacodynamic Study

Cited by 3 publications

References 0 publications

Novel partial 5HT3 agonist pumosetrag reduces acid reflux events in uninvestigated GERD patients after a standard refluxogenic meal: a randomized, double‐blind, placebo‐controlled pharmacodynamic study

Novel partial 5HT3 agonist pumosetrag reduces acid reflux events in uninvestigated GERD patients after a standard refluxogenic meal: a randomized, double‐blind, placebo‐controlled pharmacodynamic study

The lower esophageal sphincter

Partial Agonism of 5-HT₃ Receptors: A Novel Approach to the Symptomatic Treatment of IBS-D

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A Novel Partial 5HT3 Agonist DDP733 after a Standard Refluxogenic Meal Reduces Reflux Events: A Randomized, Double-Blind, Placebo-Controlled Pharmacodynamic Study

Cited by 3 publications

References 0 publications

Novel partial 5HT3 agonist pumosetrag reduces acid reflux events in uninvestigated GERD patients after a standard refluxogenic meal: a randomized, double‐blind, placebo‐controlled pharmacodynamic study

Novel partial 5HT3 agonist pumosetrag reduces acid reflux events in uninvestigated GERD patients after a standard refluxogenic meal: a randomized, double‐blind, placebo‐controlled pharmacodynamic study

The lower esophageal sphincter

Partial Agonism of 5-HT3 Receptors: A Novel Approach to the Symptomatic Treatment of IBS-D

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Partial Agonism of 5-HT₃ Receptors: A Novel Approach to the Symptomatic Treatment of IBS-D