Current Trends and Future Directions in the Management of Delayed Nausea and Vomiting

The prophylaxis of chemotherapy-induced nausea and vomiting benefited greatly from the introduction of neurokinin-1 (NK1) receptor antagonists (RAs). Current emesis guidelines recommend that NK1 receptor antagonists be combined with 5-HT3 receptor antagonists and dexamethasone for highly emetic chemotherapy and moderately emetic chemotherapy. The first such medication, aprepitant, was approved in the US in 2003. Fosaprepitant, an intravenous prodrug of aprepitant, is also available as a single dose on day 1 in combination with other antiemetics. Fosaprepitant is rapidly converted to the active aprepitant and exhibits a similar half-life to orally administered aprepitant. In addition, receptor-binding studies have shown aprepitant striatal NK1 receptor occupancy of 90 % for over 48 hours after exposure. These characteristics may allow aprepitant, fosaprepitant and the newer NK1 RAs to be administered in a single dose on day 1. Olanzapine may prove to be a novel approach in the treatment of CINV, particularly in the management of nausea.

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Investigating racial disparities in use of NK1 receptor antagonists to prevent chemotherapy-induced nausea and vomiting among women with breast cancer

Breast Cancer Research and Treatment ◽

10.1007/s10549-016-3747-6 ◽

2016 ◽

Vol 156 (2) ◽

pp. 351-359 ◽

Cited By ~ 6

Author(s):

Devon K. Check ◽

Katherine E. Reeder-Hayes ◽

Ethan M. Basch ◽

Leah L. Zullig ◽

Morris Weinberger ◽

...

Keyword(s):

Breast Cancer ◽

Racial Disparities ◽

Nausea And Vomiting ◽

Nk1 Receptor ◽

Receptor Antagonists ◽

Nk1 Receptor Antagonists

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NK1 receptor antagonists for the prevention of chemotherapy-induced nausea and vomiting: An updated meta-analysis.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.e20506 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. e20506-e20506

Author(s):

Lucas Vieira dos Santos ◽

Andre Tesainer Brunetto ◽

Andre Deeke Sasse ◽

Fabiano Hahn Souza ◽

Joao Paulo Lima

Keyword(s):

Infection Rate ◽

Safety Issue ◽

Rescue Therapy ◽

Meta Analysis ◽

Severe Infection ◽

Complete Response ◽

Nausea And Vomiting ◽

Nk1 Receptor ◽

Receptor Antagonists ◽

Nk1 Receptor Antagonists

e20506 Background: We have previously shown (dos Santos JNCI 2012) that NK1 receptor antagonists (NK1RA), such as aprepitant and casopitant, improve chemotherapy-induced nausea and vomiting (CINV) at the cost of increasing severe infection risk. Herein, we update our results. Methods: We searched MEDLINE, EMBASE, CENTRAL and meeting proceedings to identify randomized controlled trials (RCTs) comparing standard antiemetic therapy (dexamethasone + 5-HT3R inhibitors) versus NK1RA plus standard therapy for CINV prevention. Complete response (CR) was defined as absence of emesis and rescue therapy. The endpoints were CR post-chemotherapy in the overall phase (first 120 hours), CR in the acute phase (first 24 hours), and the delayed phase (24–120 hours), nausea, and toxicity. Subgroup analyses evaluated the type of NK1RA, the emetogenic potential of the chemotherapy, and prolonged use of 5-HT3R inhibitor. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using a random-effects model. Results: A total of 20 trials (9,935 patients) were included. NK1RA increased CR rate and nausea in all phases and subgroups. The CR in overall phase improved from 56% to 72% (OR = 0.52, 95% CI = 0.46 to 0.59, P < .00001, NNT=6). The side effects of NK1RA followed our previous report: the severe infection rate increased from 2.4% to 5.6% in the NK1RA group (four trials, 1656 patients; OR = 2.87; 95% CI = 1.58 to 5.19, P = .0005, NNH=31). Conclusions: NK1RA consistently improve CINV control in the acute, delayed, and overall phases, either for moderately or highly emetogenic chemotherapy regimens. Their use might be associated with increased infection rate, and a patient-level meta-analysis is warranted to clarify this safety issue.

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Lack of efficacy of L-759274, a novel neurokinin 1 (substance P) receptor antagonist, for the treatment of generalized anxiety disorder

The International Journal of Neuropsychopharmacology ◽

10.1017/s1461145712000065 ◽

2013 ◽

Vol 16 (1) ◽

pp. 1-11 ◽

Cited By ~ 22

Author(s):

David Michelson ◽

Richard Hargreaves ◽

Robert Alexander ◽

Paulette Ceesay ◽

Jarmo Hietala ◽

...

Keyword(s):

Clinical Trial ◽

Anxiety Disorder ◽

Substance P ◽

Generalized Anxiety Disorder ◽

Receptor Occupancy ◽

Generalized Anxiety ◽

Proof Of Concept ◽

Nk1 Receptor ◽

Neurokinin 1 ◽

Nk1 Receptor Antagonists

Abstract Preclinical studies suggest that substance P acting at neurokinin 1 (NK1) receptors may be involved in stress responses and NK1 receptor antagonists show activity in tests of anxiety. These data raise the possibility that NK1 receptor antagonists could be potential anxiolytic treatments in humans. We evaluated this hypothesis clinically using the NK1 antagonist L-759274. This is a randomized, double-blind, placebo- and active-controlled, multicentre, proof-of-concept trial. Patients with generalized anxiety disorder were randomized 1:1:1 to 6 wk of treatment with 40 mg L-759274 (n = 73), 1–6 mg lorazepam (n = 69) or placebo (n = 71). Efficacy was assessed using the Hamilton Anxiety Scale (HAMA). A positron emission tomography (PET) study was also performed in 16 healthy subjects to determine the relationship between NK1 receptor occupancy and plasma levels of L-759274 to verify adequate target engagement by the doses tested during the clinical trial. No statistically significant difference in mean change from baseline HAMA score at 6 wk was seen for L-759274 vs. placebo [difference = 1.0 (95% confidence intervals (CI) −1.2 to 3.2), p = 0.359] whereas the lorazepam group did show a significant improvement vs. placebo (difference = −2.7, 95% CI −5.0 to −0.4, p = 0.020) and L-759274 (difference = 3.7, 95% CI 1.5–6.0, p = 0.001]. Results from the PET study indicated that the L-759274 dosing regimen used in the clinical trial likely provided high levels of NK1 receptor occupancy (>90%), supporting the view that it was an adequate proof-of-concept trial. The NK1 receptor antagonist L-759274 does not appear to be efficacious for the treatment of generalized anxiety disorder.

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Chemotherapy-Induced Delayed Emesis: What is the Role of 5-HT3Antagonists?

Journal of Pharmacy Technology ◽

10.1177/875512250301900506 ◽

2003 ◽

Vol 19 (5) ◽

pp. 287-297

Author(s):

Kwong H Ng

Keyword(s):

English Language ◽

Current Data ◽

Cytotoxic Agents ◽

Delayed Emesis ◽

Nk1 Receptor ◽

Receptor Antagonists ◽

Medline Search ◽

Neurokinin 1 ◽

Nk1 Receptor Antagonists

Objective: To review the current literature assessing the efficacy of different antiemetics, with a focus on comparison between serotonin (5-HT3) antagonists and other antiemetics, in the treatment of delayed emesis induced by either cisplatin or non-cisplatin cytotoxic agents. Data Sources: A MEDLINE search (1966–July 2002) was performed using delayed emesis, vomiting, nausea, chemotherapy, cisplatin, moderately emetogenic, selective serotonin subtype-3 (5-HT3) receptor antagonists, metoclopramide, domperidone, corticosteroids, dexamethasone, prognostic factors, risk factors, and neurokinin-1 (NK1) receptor antagonists as key words or subject headings. Only English-language articles were identified and included. Additional references were retrieved from selected articles. Data Synthesis: Various antiemetic consensus guidelines have recommended the use of different pharmacologic treatment, including the use of 5-HT3 antagonists, for the prevention of chemotherapy-induced delayed emesis. In some instances, it has been suggested that combinations containing a 5-HT3 antagonist may be superior to others. Current data have been synthesized in an attempt to demonstrate the efficacy of 5-HT3 antagonists in the treatment of chemotherapy-induced delayed emesis. Conclusions: Dexamethasone has consistently shown its antiemetic efficacy for delayed emesis induced by cisplatin and non-cisplatin agents, whereas the role of 5-HT3 antagonists alone remains controversial. Metoclopramide has been shown to be as efficacious as 5-HT3 antagonists when combined with dexamethasone for the prevention of delayed emesis. As a result, 5-HT3 antagonists should be reserved as second-line agents to metoclopramide in addition to dexamethasone. NK1 receptor antagonists have shown some early promising results. However, many questions need to be addressed before their extensive use in clinical practice.

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Prevention of chemotherapy-induced nausea: the role of neurokinin-1 (NK1) receptor antagonists

Supportive Care in Cancer ◽

10.1007/s00520-017-3585-z ◽

2017 ◽

Vol 25 (5) ◽

pp. 1661-1671 ◽

Cited By ~ 17

Author(s):

Snežana M. Bošnjak ◽

Richard J. Gralla ◽

Lee Schwartzberg

Keyword(s):

Nk1 Receptor ◽

Receptor Antagonists ◽

Neurokinin 1 ◽

Nk1 Receptor Antagonists

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Mechanisms and latest clinical studies of new NK1 receptor antagonists for chemotherapy-induced nausea and vomiting: Rolapitant and NEPA (netupitant/palonosetron)

Cancer Treatment Reviews ◽

10.1016/j.ctrv.2015.09.005 ◽

2015 ◽

Vol 41 (10) ◽

pp. 904-913 ◽

Cited By ~ 16

Author(s):

Camilo Rojas ◽

Barbara S. Slusher

Keyword(s):

Clinical Studies ◽

Nausea And Vomiting ◽

Nk1 Receptor ◽

Receptor Antagonists ◽

Nk1 Receptor Antagonists

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Neurokinin-1 Receptor Antagonists Inhibit the Recruitment of Opioid-containing Leukocytes and Impair Peripheral Antinociception

Anesthesiology ◽

10.1097/01.anes.0000291454.90754.de ◽

2007 ◽

Vol 107 (6) ◽

pp. 1009-1017 ◽

Cited By ~ 26

Author(s):

Heike L. Rittner ◽

Christian Lux ◽

Dominika Labuz ◽

Shaaban A. Mousa ◽

Michael Schäfer ◽

...

Keyword(s):

Endothelial Cells ◽

Adhesion Molecule ◽

T Test ◽

Leukocyte Recruitment ◽

Receptor Blockade ◽

Nk1 Receptor ◽

Receptor Antagonists ◽

Nk1 Receptors ◽

Neurokinin 1 ◽

Nk1 Receptor Antagonists

Background Neurokinins (e.g., substance P) contribute to pain transmission in the central nervous system, peripheral neurogenic inflammation, and leukocyte recruitment in inflammation. Leukocyte recruitment involves (1) up-regulation of adhesion molecule expression through neurokinin-1 (NK1) receptors on endothelial cells, (2) augmented chemokine production, or (3) chemotaxis through NK1 receptors on leukocytes. In inflammation, leukocytes can trigger endogenous antinociception through release of opioid peptides and activation of opioid receptors on peripheral sensory neurons. The authors hypothesized that NK1 receptor antagonists impair recruitment of opioid-containing leukocytes and stress-induced antinociception. Methods Rats were treated intraperitoneally and intrathecally with peripherally restricted (SR140333) or blood-brain barrier-penetrating (L-733,060) NK1 receptor antagonists and were evaluated for paw pressure thresholds, numbers of infiltrating opioid-containing leukocytes and leukocyte subpopulations, expression of adhesion molecules, NK1 receptors, and chemokines 24-48 h after complete Freund adjuvant-induced hind paw inflammation. Results Systemic and peripherally selective, but not intrathecal, NK1 receptor blockade reduced stress-induced antinociception (control: 177 +/- 9 g, L-733,060: 117 +/- 8 g, and control: 166 +/- 30 g, SR140333: 89 +/- 3 g; both P < 0.05, t test) without affecting baseline hyperalgesia. In parallel, local recruitment of opioid-containing leukocytes was decreased (L-733,060 and SR140333: 56.0 +/- 4.3 and 59.1 +/- 7.9% of control; both P < 0.05, t test). NK1 receptors were expressed on peripheral neurons, infiltrating leukocytes and endothelial cells. Peripheral NK1 receptor blockade did not alter endothelial expression of intercellular adhesion molecule-1 or local chemokine and cytokine production, but decreased polymorphonuclear cell and macrophage recruitment. Conclusions Endogenous inhibition of inflammatory pain is dependent on NK1 receptor-mediated recruitment of opioid-containing leukocytes.

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