Newest Drugs for Chronic Unexplained Nausea and Vomiting

Hasler, William L.

doi:10.1007/s11938-016-0110-2

Cited by 12 publications

(7 citation statements)

References 97 publications

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“…Serotonin 5-HT3, muscarinic M1, histaminergic H1, and dopamine D2 receptor (D2) systems are already being studied for the treatment of gastroparesis and other indications that involve nausea. 24 NK1Rs are expressed on enteric neurons, interstitial cells of Cajal, epithelial cells, and on the lymphocytes and macrophages of the lamina propria. NK1Rs are thought to regulate neurotransmission, motility, secretion, inflammation, and pain in the gastrointestinal tract.…”

Section: Discussionmentioning

confidence: 99%

Efficacy and Safety of Tradipitant in Patients With Diabetic and Idiopathic Gastroparesis in a Randomized, Placebo-Controlled Trial

et al. 2021

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Section: Discussionmentioning

confidence: 99%

Efficacy and Safety of Tradipitant in Patients With Diabetic and Idiopathic Gastroparesis in a Randomized, Placebo-Controlled Trial

et al. 2021

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“… 1 Sneader, 2005 ; 2 Fangmann et al, 2008 ; 3 Owens et al, 1997 ; 4 Prakash et al, 1998 ; 5 Sawhney et al, 2007 ; 6 Sigwald et al, 1956 ; 7 Lal et al, 1993 ; 8 Srivastava et al, 2009 ; 9 Dietz et al, 2013 ; 10 Kennis et al, 2000 ; 11 Anttila and Leinonen, 2001 ; 12 Hasler, 2016 ; 13 Kim et al, 2006 ; 14 Kundu et al, 2014 ; 15 Coskun and Alyanak, 2011 ; 16 Chakrabarti et al, 1980 ; 17 Bymaster et al, 1996 ; 18 Navari, 2014 ; 19 Leggio et al, 2016 ; 20 Chiu et al, 2016 ; 21 Atkinson, 2014 ; 22 MacIntosh, 2016 ; 23 Hocking and Kichenadasse, 2014 ; 24 Navari, 2014 ; 25 https://www.chemistryworld.com/podcasts/gabapentin/1017577.article ; 26 Sirven, 2010 ; 27 Guttuso et al, 2003 ; 28 Guttuso, 2014 . …”

Section: Current and Future Directions In Research: Lessons From The unclassified

A History of Drug Discovery for Treatment of Nausea and Vomiting and the Implications for Future Research

Sanger

Andrews

2018

Front. Pharmacol.

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The origins of the major classes of current anti-emetics are examined. Serendipity is a recurrent theme in discovery of their anti-emetic properties and repurposing from one indication to another is a continuing trend. Notably, the discoveries have occurred against a background of company mergers and changing anti-emetic requirements. Major drug classes include: (i) Muscarinic receptor antagonists–originated from historical accounts of plant extracts containing atropine and hyoscine with development stimulated by the need to prevent sea-sickness among soldiers during beach landings; (ii) Histamine receptor antagonists–searching for replacements for the anti-malaria drug quinine, in short supply because of wartime shipping blockade, facilitated the discovery of histamine (H1) antagonists (e.g., dimenhydrinate), followed by serendipitous discovery of anti-emetic activity against motion sickness in a patient undergoing treatment for urticaria; (iii) Phenothiazines and dopamine receptor antagonists–investigations of their pharmacology as “sedatives” (e.g., chlorpromazine) implicated dopamine receptors in emesis, leading to development of selective dopamine (D2) receptor antagonists (e.g., domperidone with poor ability to penetrate the blood-brain barrier) as anti-emetics in chemotherapy and surgery; (iv) Metoclopramide and selective 5-hydroxytryptamine3 (5-HT3) receptor antagonists–metoclopramide was initially assumed to act only via D2 receptor antagonism but subsequently its gastric motility stimulant effect (proposed to contribute to the anti-emetic action) was shown to be due to 5-hydroxytryptamine4 receptor agonism. Pre-clinical studies showed that anti-emetic efficacy against the newly-introduced, highly emetic, chemotherapeutic agent cisplatin was due to antagonism at 5-HT3 receptors. The latter led to identification of selective 5-HT3 receptor antagonists (e.g., granisetron), a major breakthrough in treatment of chemotherapy-induced emesis; (v) Neurokinin1 receptor antagonists–antagonists of the actions of substance P were developed as analgesics but pre-clinical studies identified broad-spectrum anti-emetic effects; clinical studies showed particular efficacy in the delayed phase of chemotherapy-induced emesis. Finally, the repurposing of different drugs for treatment of nausea and vomiting is examined, particularly during palliative care, and also the challenges in identifying novel anti-emetic drugs, particularly for treatment of nausea as compared to vomiting. We consider the lessons from the past for the future and ask why there has not been a major breakthrough in the last 20 years.

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“…Several neurotransmitter pathways are thought to be involved in activation of nausea in gastroparesis, including serotonin 5-HT3 and NK-1 mechanisms. Serotonin 5-HT3, Muscarinic M1, Histaminergic H1, and dopamine D2 receptor (D2) systems are already being studied for treatment of gastroparesis and other indications that involve nausea 25 . NK1Rs are expressed on enteric neurons, interstitial cells of Cajal, epithelial cells, and on the lymphocytes and macrophages of the lamina propria.…”

Section: Discussionmentioning

confidence: 99%

Efficacy and Safety of Tradipitant in Diabetic and Idiopathic Gastroparesis: A Randomized, Placebo-Controlled Study

Carlin

Lieberman

Dahal

et al. 2020

Preprint

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Background and Aims: There is a high unmet need for the treatment of gastroparesis and studies of NK1-R antagonists suggest potential benefit in reducing the symptoms of nausea and vomiting. We hypothesized that tradipitant, an NK1-R antagonist, would be effective in treating patients with idiopathic or diabetic gastroparesis. Methods: In a randomized, double-blind, placebo-controlled study across 47 U.S. sites, 152 gastroparesis patients were randomized to receive oral 85mg BID tradipitant (n=77) or placebo (n=75) daily for four weeks. Symptoms were assessed using a daily symptom dairy, Gastroparesis Cardinal Symptom Index (GCSI), and other patient reported questionnaires. Results: Patients receiving tradipitant had a significant decrease in nausea score at Week 4 compared to placebo (-1.2 improvement vs -0.7, respectively, p=0.0099), and a significant increase in nausea-free days (28.8% increase on tradipitant vs 15.0% on placebo p=0.0160). Patients with both nausea and vomiting at baseline (n=101) showed an even greater decrease in nausea score (-1.4 improvement on tradipitant vs -0.4 on placebo p<0.0001) and an increase in nausea free days (32.3% improvement on tradipitant vs 7.6% on placebo p=0.0003). 32.9% of patients treated with tradipitant were nausea responders (average nausea score ≤ 1 at week 4) compared to 11.8% of patients on placebo (p=0.0013). 46.6% of patients treated with tradipitant had a greater than 1-point improvement in GCSI score compared to 23.5% of patients on placebo (p=0.0053). Conclusions: Tradipitant treatment resulted in statistically and clinically meaningful improvements in nausea and overall gastroparesis symptoms. These robust efficacy results suggest tradipitant has the potential to become a useful pharmacological treatment for gastroparesis.

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Newest Drugs for Chronic Unexplained Nausea and Vomiting

Cited by 12 publications

References 97 publications

Efficacy and Safety of Tradipitant in Patients With Diabetic and Idiopathic Gastroparesis in a Randomized, Placebo-Controlled Trial

Efficacy and Safety of Tradipitant in Patients With Diabetic and Idiopathic Gastroparesis in a Randomized, Placebo-Controlled Trial

A History of Drug Discovery for Treatment of Nausea and Vomiting and the Implications for Future Research

Efficacy and Safety of Tradipitant in Diabetic and Idiopathic Gastroparesis: A Randomized, Placebo-Controlled Study

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