Vofopitant

Abstract: Nausea and vomiting are both components of the body’s defensive system to protect against the effects of accidentally ingested toxins. Whilst these responses have survival value in the wild, they can also be induced by diseases and disease treatments with one of the most unpleasant examples being the treatment of cancer using cytotoxic drugs and radiation. Understanding the mechanisms by which this occurs has been a major impetus to the identification of novel anti-emetic agents. The recent licensing of an NK1 receptor antagonist for the treatment of chemotherapy-induced emesis provides the first example of a drug acting to block the effects of substance P. Whilst the blockade of emesis by selective NK1 receptor antagonists provides the most powerful evidence implicating substance P in emesis there is a considerable body of supporting evidence including: presence of substance P (usually by immunohistochemistry) in relevant sites (e.g. vagal afferents, nucleus tractus solitarius, gastrointestinal mucosa); presence of NK1, receptors in relevant sites (e.g. nucleus tractus solitarius); induction of emesis by administration of NK1 receptor agonists. Pre-clinical studies in a variety of species revealed the broad-spectrum anti-emetic effects of NK1 receptor antagonists against stimuli including the anti-cancer agent cisplatin (acute and delayed phases), radiation, opioids, copper sulphate, apomorphine, motion and electrical stimulation of abdominal vagal afferents. Species differences in response to NK1 receptor antagonists and species-specific iso-forms of the receptor are discussed and the potential implications for transfer of data from these animal models to humans reviewed. The spectrum of antiemetic effects against stimuli acting via both peripheral and centrally acting emetic stimuli, a requirement for brain penetration and blockade of emesis by microinjection of antagonists into the brain stem all support a central site of action with the nucleus tractus solitarius and the vicinity of the Botzinger complex being the favoured locations although definitive studies are awaited. Evidence for a contribution from a peripheral site in the delayed phase of cytotoxic druginduced emesis is reviewed. The unique pre-clinical profile and especially the observation that NK1, receptor antagonists could block both the acute and delayed phase of cisplatin-induced emesis prompted clinical trials of a number of agents [CJ11974 (ezlopitant), GR205171 (vofopitant), MK869/L754030 (aprepi-tant)] in patients undergoing chemotherapy. These studies and others in motion and post-operative nausea and vomiting are reviewed in detail. In general the trials in chemotherapy show NK1 receptor antagonists have demonstrable efficacy against acute (first 24 h after therapy) emesis when given alone and enhance the efficacy of 5-hydroxytryptamine3 receptor antagonists and dexamethasone when given in combination. Of particular clinical significance is the efficacy of NK1 receptor antagonists given in combination with dexamethasone to reduce emesis in the delayed phase (days 2–5) as this phase of emesis is poorly con trolled using current treatments. Efficacy against nausea has been reported but to date the effects appear less clear than against emesis and further studies are required. The availability of NK1 receptor antagonists in the clinic will provide a useful tool to further investigate the involvement of NK1 receptors in emesis and to explore the roles of central and peripheral substance P in health and disease.

Abstract: Introduction: The substance P (SP)/neurokinin (NK)-1 receptor system is involved in many pathological processes. NK-1 receptor antagonists have many promising therapeutic indications. However, the ...

Abstract: Summary Purpose: Many patients with epilepsy are refractory to anticonvulsant drugs or do not tolerate side effects associated with the high doses required to fully prevent seizures. Antagonists of neurokinin-1 (NK1) receptors have the potential to reduce seizure severity, although this potential has not been fully explored in animals or humans. The present study was designed to evaluate the efficacy of the NK1-receptor antagonist, vofopitant, alone and in combination with different anticonvulsant drugs. Methods: Studies were conducted in rats using a model of generalized seizure induced by electroshock. Drug concentrations in blood and brain were determined in parallel to distinguish pharmacodynamic from pharmacokinetic interactions. Results: The NK1-receptor antagonist, GR205171 (vofopitant) had no anticonvulsant efficacy by itself, but could potentiate the anticonvulsant efficacy of lamotrigine and other sodium channel blockers. However, GR205171 had no effect on the anticonvulsant potency of either valproate or gabapentin. GR205171 did not produce central nervous system (CNS) side effects at the doses tested, and it did not potentiate side effects induced by high doses of lamotrigine. The NK1-receptor inactive enantiomer of GR205171, GR226206 did not potentiate the efficacy of lamotrigine, suggesting that effects observed with GR205171 were mediated by NK1 receptors. Analysis of the dose–effect relationship for GR205171 indicated that a high (>99%) occupancy of NK1 receptors is required for effect, consistent with previous behavioral and human clinical studies with this pharmacologic class. Discussion: These results suggest that there may be benefit in adding treatment with a suitable NK1-receptor antagonist to treatment with a sodium channel blocker in patients with refractory epilepsy.