Prevention of chemotherapy-induced nausea: the role of 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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Substance P-induced inflammatory responses in guinea-pig skin: The effect of specific NK1 receptor antagonists and the role of endogenous mediators

British Journal of Pharmacology ◽

10.1111/j.1476-5381.1995.tb13354.x ◽

1995 ◽

Vol 114 (7) ◽

pp. 1343-1350 ◽

Cited By ~ 53

Author(s):

Desmond T. Walsh ◽

Vivian B. Weg ◽

Timothy J. Williams ◽

Sussan Nourshargh

Keyword(s):

Substance P ◽

Guinea Pig ◽

Inflammatory Responses ◽

Nk1 Receptor ◽

Receptor Antagonists ◽

Pig Skin ◽

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

European Oncology & Haematology ◽

10.17925/eoh.2013.09.2.84 ◽

2013 ◽

Vol 09 (02) ◽

pp. 84

Author(s):

Bernardo L Rapoport ◽

Georgia S Demetriou ◽

◽

Keyword(s):

Single Dose ◽

Receptor Occupancy ◽

Nausea And Vomiting ◽

Nk1 Receptor ◽

Binding Studies ◽

Receptor Antagonists ◽

Novel Approach ◽

Delayed Nausea ◽

Neurokinin 1 ◽

Nk1 Receptor Antagonists

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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The Role of CGRPin Nociception?

The Scientific World JOURNAL ◽

10.1100/tsw.2001.421 ◽

2001 ◽

Vol 1 ◽

pp. 19-19 ◽

Cited By ~ 3

Author(s):

R. G. Hill

Keyword(s):

Spinal Cord ◽

Pain Perception ◽

Sensory Ganglia ◽

Nk1 Receptor ◽

Receptor Antagonists ◽

Peripheral Tissues ◽

Sensory Neurones ◽

Antinociceptive Effects ◽

Nk1 Receptor Antagonists

The failure of NK1 receptor antagonists to show analgesic activity in clinical trials in spite of abundant preclinical evidence for a role of this neuropeptide in nociception, makes it somewhat dangerous to speculate on the nociceptive role of other neuropeptides, especially with respect to therapeutic utility of receptor antagonists! However, CGRP is the primary afferent peptide with the strongest evidence of a role in pain perception. It is found in a greater proportion of sensory neurones than other peptides and is a constituent of A[delta ] as well as C-fibres. Inflammation of peripheral tissues upregulates production of CGRP in sensory ganglia, coincident with the development of hyperalgesia, and CGRP knockout mice have attenuated hyperalgesic responses. CGRP is released into the dorsal horn of the spinal cord (DHSC) by noxious peripheral stimuli and excites nociceptive DHSC neurones on local application. The peptide antagonist CGRP8-37 blocks the response to exogenous CGRP and can reduce the response of DHSC neurones to noxious peripheral stimuli. CGRP8-37 has also been shown to have behavioural antinociceptive properties when given intrathecally. Conversely, injection of CGRP itself to the PAG or n. accumbens has been reported to have antinociceptive effects that are reversed by CGRP8-37. With the advent of potent non-peptide antagonists such as BIBN4096BS we should soon be able to determine whether systemic blockade of all CGRP receptors produces antinociception without limiting side effects.

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