Potential of Substance P Antagonists
`as Antiemetics
`Pierre Diemunsch1 and Laurent Grélot2
`1 Department of Anaesthesiology , Head of Experimental Anaesthesia Unit, IRCAD, Hôpitaux
`Universitaires de Strasbourg, Strasbourg, France
`2 UPRES – EA ‘DPAP’, Faculty of Sports Science, Université de la Méditerranée, Marseille, France
`Abstract The introduction of serotonin 5-HT3 receptor antagonists into clinical practice
`allowed for a dramatic improvement in the management of nausea and vomiting.
`Despite this, postoperative and chemotherapy-induced emesis remains a signifi-
`cant, unresolved issue in many patients even when a combination of antiemetic
`drugs is used. Numerous neurotransmitters have been implicated in triggering
`emesis; however, the tachykinin substance P, by virtue of its localisation within
`both the gastrointestinal vagal afferent nerve fibres and brainstem emetic cir-
`cuitry, and its ability to induce vomiting when administered intravenously, is
`thought to play a key role in emetic responses. Because substance P is the most
`likely endogenous ligand for the neurokinin-1 (NK
`1) receptor, the development
`of nonpeptide NK1 receptor antagonists led scientists to evaluate these com-
`pounds as antiemetics. The five NK1 receptor inhibitors that have been studied
`initially in humans are: vofopitant (GR-205171), CP-122721, ezlopitant (CJ-
`11974), MK-869 (L-754030) and its prodrug L-758298. Except for monotherapy
`in acute cisplatin-induced emesis, this new class of drugs has proven to be highly
`effective in the control of both chemotherapy-induced nausea and vomiting, and
`postoperative nausea and vomiting. No major adverse event was reported in the
`preliminary trials. Further investigation is mandatory in order to assess the opti-
`mal treatment regimen and to make sure the wide spectrum activity of the NK
`1
`receptor inhibitors does not cause significant adverse effects in the context of the
`treatment of nausea and vomiting.
`LEADING ARTICLE
`Drugs 2000 Sep; 60 (3): 533-546
`0012-6667/00/0009-0533/$25.00/0
`© Adis International Limited. All rights reserved.
`1. An Overview of the Critical Concepts
`in Antiemetic Research
`From time immemorial, vomiting (or emesis)
`has been a major concern in the practice of human
`medicine. In various ancient civilisations, the in-
`duction of vomiting with emetics was even used as
`a therapeutic tool.
`[1] At the present time, vomiting
`is viewed not as a therapy but more usually as a
`distressing adverse effect associated with various
`medical practices. V omiting, the culminating sign
`of nausea, is primarily a protective reflex occurring
`in a wide variety of vertebrates in response to the
`ingestion of a hazardous compound. However, in
`addition to this physiological response to the as-
`similation of toxins, vomiting can also occur in an
`extreme variety of circumstances which defy a sim-
`ple description. In brief, emesis remains a critical
`problem during recovery from surgical procedures
`carried out under general anaesthesia, in anticipa-
`tion of anticancer cytotoxic therapy (i.e. psycho-
`logical vomiting), and in other circumstances in-
`volving motion and vestibular disturbances (e.g.
`HELSINN EXHIBIT 2050
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`Ménière disease). Lastly, vomiting can occur in
`natural circumstances where its benefits remain ob-
`scure (e.g. pregnancy sickness).
`The essential co-ordinating circuitry for pro-
`ducing the complex act of vomiting (i.e. the ill-
`localised ‘vomiting centre’) is thought to be located
`within the medulla oblongata of the brainstem (fig.
`1).
`[2] The numerous neurochemicals involved in
`that circuitry are not fully identified. The afferent
`systems triggering emesis release various neuro-
`transmitters so that pharmacological agents exhib-
`iting an effective antiemetic profile against one
`kind of vomiting can be ineffective against emesis
`induced by other stimuli. This is obvious in animal
`models of emesis, for which compounds acting as
`serotonin 5-HT
`3 receptor antagonists exhibit potent
`antiemetic activity against acute chemotherapy-
`induced emesis but fail to block the emetic re-
`Emetic
`coordinating
`circuitry
`Medulla
`oblongata
`Area
`postrema
`Motion and space
`sickness
`Involvement of:
`acetylcholine via M1 receptor
`serotonin via 5-HT1A receptor
`histamine via H1 receptor
`Psychogenic
`vomiting
`Involvement of higher
`centres: cerebral cortex
`limbic system
`Postoperative
`vomiting
`Involvement of serotonin
`via 5-HT3 receptor
`Cancer
`chemotherapy
`Involvement of:
`serotonin
`via 5-HT3 receptor
`Radiation-
`induced emesis
`Involvement of:
`serotonin
`via 5-HT3 receptor
`Food poisoning
`Direct detection of:
`ipecac,
`copper sulfate
`bacterial enterotoxins
`Blood poisoning
`Detection of:
`apomorphine via D2 receptor
`xylazine via α2 receptor
`ipecac and LPS
`Miscellaneous
`Induction of vomiting by:
`heart afferents
`glossopharyngeal and
`trigeminal afferents
`Pregnancy sickness
`Visual afferents
`Vestibular afferents
`Digestive tract
`Fig. 1. Diagrammatic summary of different trigger inputs for vomiting. The emetic coordinating circuitry is located within the medulla
`oblongata of the brain stem. The area postrema is thought to contain a chemoreceptor trigger zone for vomiting. Neurotransmitters
`and receptor subtypes of major importance for eliciting vomiting are indicated for various inputs.D2 = dopamine type 2 receptor; H1
`= histamine type 1 receptor; LPS = lipopolysaccharide; M = muscarinic cholinergic; αα αα2 = α adrenergic type 2 receptor; 5-HT =
`5-hydroxytryptamine (serotonin). Adapted from Grélot & Miller.[2]
`534 Diemunsch & Grélot
`© Adis International Limited. All rights reserved. Drugs 2000 Sep; 60 (3)
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`sponses to other emetogens such as opioid and
`dopaminergic agonists, copper sulfate or motion.
`In humans, the introduction of selective serotonin
`5-HT
`3 receptor antagonists has incontestably rep-
`resented a major advance in the control of acute
`emesis associated with antineoplastic cytotoxic
`therapy. However, there are still areas in emesis
`control where further improvement would be de-
`sirable, e.g. motion sickness and delayed cisplatin-
`induced emesis.
`An attractive strategy to block emesis irrespec-
`tive of its eliciting stimulus would be to treat pa-
`tients (or animals) with a pharmacological agent
`able to depress the activity of neurones within the
`medullary emetic circuitry. Recently, chemicals
`acting as partial (buspirone and ipsapirone) or full
`(8-OH-DPA T and SUN-8399) agonists of the 5-HT
`1A
`receptor, have shown broad-spectrum antiemetic
`activities in several species without marked ad-
`verse effects.
`[3] Since tolerance to the antiemetic
`effects of 5-HT1A receptor agonists did not develop
`rapidly, these compounds were expected to be clin-
`ically relevant. Unfortunately, most investigations
`in various animal models have shown that 5-HT
`1A
`receptor agonists have comparatively weak anti-
`emetic properties, particularly against cisplatin-
`induced emesis, so that their clinical development
`r a p i d l ya p p e a r e dt ob ej e o p a r d i s e d .
`The pharmacological quest to develop a highly
`effective broad-spectrum antiemetic has led neuro-
`scientists to investigate the role of neurotransmit-
`ter systems other than the serotonergic one and, in
`particular, the opioid system. Indeed, the neuro-
`transmitter systems that opioid drugs modulate
`have been clearly implicated in emesis. In humans,
`morphine and related analgesic drugs, both of
`which are poorly selective opioid receptor ago-
`nists, have the potential to increase the incidence
`of postoperative nausea and vomiting. However,
`compounds such as fentanyl or sufentanil activat-
`i n gm a i n l yt h e
`μ subtype of opioid receptors have
`demonstrated a potent and broad-spectrum anti-
`emetic activity in various animal species.
`[4] Unfor-
`tunately, fentanyl enhances postoperative nausea
`and vomiting (PONV) in human patients suggest-
`ing that species-related differences exist in the way
`opioid receptors modulate the emetic reflex. Since
`it is currently still difficult to separate pharmaco-
`logically the antiemetic properties of opioid recep-
`tor agonists from other unwanted adverse effects
`(e.g. respiratory depression), clinically accessible
`opioid drugs (agonists and antagonists) cannot be
`considered as promising antiemetics.
`Recently, special attention has been focused on
`the role of neuropeptides, such as tachykinins,
`since they have been immunohistologically identi-
`fied in the dorsal vagal complex of the ferret, an
`area regarded as essential in eliciting vomiting. The
`emetic action of the tachykinin substance P (SP)
`was described by Carpenter et al.
`[5] Its putative role
`within the medullary emetic circuitry was first
`clearly pointed out by Andrews and Bhandari.
`[6]
`They demonstrated that resinferatoxin, an ultra-
`potent capsaicin analogue, exhibits antiemetic pro-
`perties in the ferret against both a centrally acting
`emetic chemical (i.e. loperamide) and 2 peripher-
`ally acting agents (i.e. radiation and copper sul-
`fate). Andrews and Bhandari
`[6] suggested that res-
`inferatoxin exerts its potent antiemetic activity by
`depleting SP at a central site in the emetic pathway.
`In this context, the development of potent and
`highly selective non-peptide neurokinin-1 (NK
`1)
`receptor antagonists, able to cross the blood-brain
`barrier to antagonise the central effects of SP , be-
`came crucial for providing powerful tools for in-
`vestigating the physiological role of SP in emesis.
`More generally, there was also strong demand for
`the development of these compounds in several
`fields other than emesis, and the main indications
`foreseen for such drugs also include pain, mi-
`graine, rheumatoid arthritis, inflammatory bowel
`disease, asthma and chronic bronchitis.
`2. The Tachykinins: Receptor Subtypes
`and Antagonists Relevant to
`Antiemetic Research
`Tachykinins are members of a family of neu-
`ropeptides sharing the common C terminal se-
`quence Phe-Xaa-Gly-Leu-MetNH
`2.I nt h ee a r l y
`1970s, the term ‘tachykinin’ was invented by
`Substance P Antagonists as Antiemetics 535
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`Ersparmer and Melchiorri,[7] to describe the rapid
`development of the contractile action produced by
`these peptides in smooth muscles. In mammals, the
`tachykinin family includes at least 6 chemicals,
`with the physiological effects of SP , neurokinin A
`(NK
`A) and neurokinin B (NKB) the most precisely
`characterised. These peptides exert a plethora of
`biological effects through 3 G-protein-coupled re-
`ceptor subtypes, identified as NK
`1,N K2 and NK3
`receptors.[7] According to the ‘Montreal nomencla-
`ture’,[8] the NK1 receptor is defined as the mediator
`of the biological activities encoded by the C termi-
`nal sequence of tachykinins, for which SP is a more
`potent agonist than NK
`A or NKB. Since SP is be-
`lieved to play a key role within the central emetic
`circuitry, selective NK1 receptor antagonists are
`expected to express potent antiemetic activity. A
`number of peptide-based NK1 receptor antagonists
`with linear or cyclic sequences have been reported
`(e.g. spantide, L-668169; GR-82334; FR-113680;
`FK-224, etc.) but their inability to gain access to
`the CNS through the blood-brain barrier was
`thought to represent a limitation to a putative clin-
`ical use for the control of emesis. In 1991, follow-
`ing a thorough screening strategy, the first non-
`peptide NK
`1 receptor antagonist was produced:
`CP-96345 ([(2S,3S)-cis-2-(diphenylmethyl)-N-
`[(2-methoxyphenyl)-methyl]-1-azabicyclo[2.2.2]-
`octan-3-amine]), and subsequently reported the
`series of piperidines exemplified by CP-99,994
`[((2S,3S)-cis-3-(2-methoxybenzylamino)-2-phenyl-
`piperidine)dihydrochloride]
`.[9] Succeeding inten-
`sive chemical and pharmacological research con-
`ducted by all the major pharmaceutical companies
`led to the disclosure of a wide variety of non-pep-
`tide NK
`1 receptor antagonists belonging to differ-
`ent chemical classes, i.e. piperidines, perhydroiso-
`indolones, quinuclidines, tryptophane derivatives
`and steroids.
`[10] The most recently synthesised com-
`pounds are highly selective, exhibiting nanomolar
`or subnanomolar affinities for human NK1 recep-
`tors expressed in various cells.
`When comparing the pharmacological effects of
`various NK1 receptor antagonists, it is essential to
`keep in mind that species-related differences exist
`in the primary sequence of the NK1 receptor pro-
`tein.[11] These variations, which do not affect the
`agonist efficacy, determine dramatic species-related
`variations in the potency of non-peptide antago-
`nists. For instance, the prototypical NK1 receptor
`antagonist CP-96345 binds with subnanomolar af-
`finity to bovine brain, but it is 35-fold less active
`in displacing [
`3H]SP binding to rat brain. There-
`fore, the antiemetic efficiency of a given com-
`pound in an animal model is not conclusively pre-
`dictive of its potential in humans.
`In addition, several factors can preclude a num-
`ber of highly selective, potent NK1 receptor antag-
`onists from being of clinical utility. More precisely,
`some of these pharmacological agents have been
`reported to bind without any enantio selectivity
`with L-type Ca
`2+ channels irrespective of the spe-
`cies. For instance, CP-96345 has an equal affinity
`for Ca
`2+ channels and NK1 receptors in the rat, so
`that many of the behavioural effects in that species
`might be due to the blockade of ion channels. Con-
`sequently, it is essential to be cautious in interpre-
`ting results with NK
`1 receptor antagonists.[12] In
`addition, this implies that NK1 compounds selected
`for clinical trials must exhibit the lowest ‘non-spe-
`cific’ binding to Ca2+ channels to avoid severe car-
`diovascular adverse effects. Obviously, this point
`has been taken into account for chemicals admin-
`istered during preliminary clinical trials, since
`CP-122721 ([(+)-(2S,3S)-3-(2-methoxy-5-trifluoro-
`methoxybenzyl)amino-2-phenylpiperidine]), a po-
`tent and noncompetitive antagonist, exhibits a high
`affinity for human NK
`1 receptors but a moderate
`one for Ca2+ channels.[13] Similarly, vofopitant [GR-
`205171] ([2-methoxy-5-(5-trifluoromethyl-tetrazol-
`1-yl)-benzyl]-(2S-phenyl-piperidin-3S-yl)amine),
`another compound tested in human patients, has a
`subnanomolar affinity to human NK
`1 receptors
`[expressed in Chinese hamster ovary (CHO) cells],
`and it is at least 1000-fold selective with respect to
`non-tachykinin receptors and ion channels.
`[14] Fi-
`nally, the affinity for the human NK1 receptor of a
`third compound tested clinically: MK-869 [L-
`754030] ([2-(R)-(1-(R)-(3,5-Bis(trifluoromethyl)-
`phenylethoxy)-3(S)-(4fluoro)phenyl-4-(3-oxo-1,2,4-
`536 Diemunsch & Grélot
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`Page 4 of 14
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`triazol-5-yl)methylmorpholine]), is similar to that
`of CP-122721 and that of vofopitant, whereas its
`affinity for the Ca
`2+ channel is negligible (i.e. IC50
`>1 μmol/L).[15]
`The final two requirements for the clinical de-
`velopment of a NK1 receptor antagonist are the
`long-lasting efficacy and the oral biodisponibility
`of the compound. Thus, the poorly orally active
`phenylpiperidine CP-99994 was further chemi-
`cally optimised but superseded in development by
`both CP-122721 and vofopitant.
`3. Antiemetic Activity of NK
`1 Receptor
`Antagonists in Animal Models
`During the last 6 years, the antiemetic profiles
`of 16 compounds have been evaluated and fully
`d e s c r i b e dt oo u rk n o w l e d g ei n2 4p u b l i c a t i o n s .T h e
`emetic challenges were conducted in the ferret, the
`house musk shrew (Suncus murinus), the cat, the
`dog, and more recently, the piglet, using 13 differ-
`ent emetogens (table I). The experimental proce-
`dures in these numerous studies presented such
`marked differences concerning the choice of the
`animal species, the way to elicit vomiting (i.e. with
`chemicals, motion, X-irradiation, electrical stimu-
`lation of afferent pathways), and the nature, the
`dose, the route and timing of administration of the
`different NK
`1 receptor antagonists, that a detailed
`description of the results would be tedious. How-
`ever, the common conclusion brought forward in
`these studies was that NK
`1 receptor antagonists
`displayed an unprecedentedly potent, and usually
`Table I. Neurokinin-1 (NK1) receptor antagonists with proved potent anti-emetic activities in animals against various emetogens
`NK1 receptor antagonists
`(route of administration)
`Animal species Emetogens Reference
`CP-99994
`(SC,IP ,IV)
`Ferret, shrewa, dog, cat a +d-CDDP , CuSO4, cyclophosphamide, ipecac,
`morphine, apomorphine, irradiation, nicotine,
`loperamide, ethanol, motion, vagal stimulation
`b
`16-25
`CP-122721 Ferret a-CDDP , CuSO4, ipecac, loperamide 26
`GR-203040 (SC,IV) Ferret, shrewa, dog a-CDDP , CuSO4, cyclophosphamide, ipecac,
`morphine, irradiation
`20,27
`Vofopitant [GR-205171] (SC,IV) Ferret, shrew a, dog, piglet a +d-CDDP , irradiation, vagal stimulationb 14, 28-31
`L-741671
`(IV,ICV)
`Ferret a-CDDP 32
`L-742694
`(IV)
`Ferret a-CDDP 20
`L-743310
`(ICV)
`Ferret a-CDDP 32
`MK-869 [L-754030]
`(IV,po)
`Ferret a-CDDP , morphine, apomorphine 15
`RP-67580
`(IP)
`Shrew Nicotine 23
`CI-1021 [PD-154075]
`(IP)
`Ferret a
`+d-CDDP 33
`Dapitant [RPR-100893]
`(IV)
`Ferret a-CDDP 20
`HSP-117
`(ICV)
`Ferret CuSO4, morphine 34
`Nolpitantium [SR-140333]
`(ICV)
`Piglet a-CDDP Grélot et al.,
`unpublished
`observations
`Sendide
`(SC)
`Ferret a-CDDP 35
`a House musk shrew ( Suncus murinus).
`b Electrical stimulation of the abdominal vagus nerves.
`a
`++ ++d-CDDP = acute and delayed cisplatin-induced vomiting;CuSO4 = copper sulfate; ICV = intracerebroventricular; IP = intraperitoneal; IV =
`intravenous; po = by mouth; SC = subcutaneous.
`Substance P Antagonists as Antiemetics 537
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`long-lasting, high antiemetic activity. This high
`level of efficacy was observed irrespective of the
`route of administration (i.e. oral, subcutaneous, in-
`traperitoneal, intravenous, intracerebroventricu-
`lar), with drugs able to penetrate the CNS.
`A concise history of the major results leading
`to the clinical development of the NK
`1 receptor
`antagonists as antiemetics is summarised in this
`section.
`The idea that these compounds could represent
`a new class of therapeutic agents for the treatment
`of emesis was first published by Bountra and co-
`workers in 1993.
`[16] In this study, CP-99994 was
`used against 5 different emetogens [cisplatin
`(CDDP), copper sulfate, cyclophosphamide, mor-
`phine and radiation] and showed exceptional anti-
`emetic properties. Using the ferret model, they
`showed that intraperitoneal administration of CP-
`99994 (racemic) 3 mg/kg reduced the total number
`of retches induced by morphine (0.5 mg/kg, subcu-
`taneously, 3-hour trial) and cyclophosphamide
`(200 mg/kg, intraperitoneally, 7-hour trial) by 84
`and 96%, respectively. The effectiveness of CP-
`99994 against the other emetogens ranged between
`these 2 observations. Tattersall et al.,
`[21] confirmed
`these results soon after, and demonstrated that the
`nearly complete control of the acute emetic re-
`sponse to cisplatin (10 mg/kg, intraperitoneally)
`achieved in the ferret with (+)CP-99994 (3 mg/kg
`intravenously) was most likely the result of a stereo-
`specific blockade of NK
`1 receptors, since CP-
`100263 (i.e. the inactive enantiomer) was totally
`ineffective at the same dose. Subsequently, the op-
`timised chemicals GR-203040,
`[27] CP-122721,[26]
`and then vofopitant,[36] have proven to have more
`potent antiemetic potential than CP-99994. In the
`ferret, CP-122721 (0.3 or 1 mg/kg, subcutaneously)
`abolished the emetic response to copper sulfate,
`loperamide, ipecac syrup and cisplatin. In fact, this
`chemical antagonised the acute emetic response to
`cisplatin during a 2-hour trial with an inhibitory
`dose (ID
`50)o f0 . 0 3m g / k g .
`The long-lasting antiemetic effects of NK1 re-
`ceptor antagonists were first reported by Gardner
`et al.[36] Indeed, vofopitant (0.3 mg/kg, subcutane-
`ously) promptly abolished cisplatin-induced eme-
`sis for a 4-hour period, and then, minimal emesis
`occurred during the subsequent 20-hour period. A
`similar observation was made in the piglet, in
`which a single administration of vofopitant (1
`mg/kg, intravenously) reduced by 91 and 86%, re-
`spectively, the number of emetic events produced
`during the acute and delayed phases of cisplatin-
`induced emesis.
`[29] Moreover, a 1 mg/kg dose ad-
`ministered at the transition between the acute and
`delayed phases abolished the delayed emetic re-
`sponse to cisplatin for at least 44 hours.
`[29] In that
`species, the long-lasting antiemetic effect of vofo-
`pitant was surprising, since a pharmacokinetic
`study revealed that vofopitant (1 mg/kg, intrave-
`nously) has a fairly short plasma half-life (3.4
`± 0.8
`hours).[29] The ability to achieve a sustained block-
`ade of central tachykinin NK1 receptors in the ab-
`sence of high plasma drug concentrationsin vivo
`was also reported in a pain model (i.e. in the for-
`malin paw test) in the gerbil with L-733060.
`[37]
`This might suggest that these two NK1 receptor
`antagonists are rapidly distributed to their sites of
`action from where there are slowly eliminated.
`This property is advantageous since it strongly lim-
`its the occurrence of unwanted nonspecific effects
`in peripheral tissues (e.g. blockade of Ca
`2+ chan-
`nels) associated with high plasma concentrations
`of the drugs.
`In animal models, several NK
`1 receptor antago-
`nists displayed a potent activity against vomiting
`elicited by some emetogens which are still difficult
`to control in human patients. Thus, CP-99994, CI-
`1021 (PD-154075) and vofopitant, provided a sat-
`isfactory control of the delayed emetic response to
`cisplatin in both the piglet and ferret.
`[19,24,25,29,33]
`The ultra-potent efficacy against both acute and de-
`layed cisplatin-induced emesis has been clearly ev-
`idenced in the laboratory of one of the authors (Dr
`Grélot). Comparison with results from our pre-
`viously published and unpublished studies per-
`formed on more than 600 piglets demonstrated that
`vofopitant has the highest ratio of antiemetic activ-
`ity/dose of any compound ever tested in our exper-
`imental model (i.e. cisplatin-induced emesis).
`[38]
`538 Diemunsch & Grélot
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`Page 6 of 14
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`This is demonstrated clearly in figure 2. The clin-
`ical potential of NK 1 receptor antagonists can
`also be extended to provocative motion (CP-
`99994),
`[18,24,25] GR-203040, [27] postanaesthesia-
`induced emesis (vofopitant),[40] and ethanol-induced
`vomiting (CP-99994).[17] Finally, in addition to the
`antiemetic effect, tachykinin NK1 receptor antago-
`nists may have potential in the treatment of drug-
`induced conditioned aversive behaviour and nau-
`sea.
`[29,41]
`4. Putative Site of Action of NK1
`Receptor Antagonists
`As mentioned in section 1, the putative involve-
`ment of SP within the central emetic circuitry was
`proposed by Andrews and Bhandari,[6] on the basis
`of the emetic action of resinferatoxin in ferrets.
`This was confirmed by Matsuki et al., [42] and
`Shiroshita et al.,[43] who demonstrated that the cap-
`saicin analogue (subcutaneous in S. murinus and
`intracerebroventricular in the dog) first induced
`transient emesis or retching, and then blocked these
`emetic responses to radiation and copper sulfate, and
`afferent vagal electrical stimulation, respectively.
`In a converging point of view, the broad-spectrum
`antiemetic profile of the NK
`1 receptor antagonists
`suggests that they might act principally at central
`sites. This assertion has been conclusively sup-
`ported by studies demonstrating that peptide-based
`potent NK1 receptor antagonists (i.e. GR-82334,
`sendide, spantide, and FK-888), unable to block
`vomiting when administered intravenously, appear
`much more effective when injected by an intra-
`cerebrovascular route.
`[20,36,44] Similarly, nolpitant-
`Number of EE / 60 hours
`15
`20
`25
`30
`0
`5
`10
`Cont Busp Nolpi Relco DexamGrani 7
`Dexam + Grani 7
`Indomet
`8-OH-DPAT
`Vagot
`Grani 7 /K78
` 1
`Vagot + Grani 9 /K78
` 1
`Vofo 1
`Vofo 10 /K78
` 1
`Acute EE
`Delayed EE
`Fig. 2. Antiemetic properties of various pharmacological treatments and surgical procedures in piglets receiving a single high dose
`of cisplatin [CDDP , intravenously (IV), 5.5 mg/kg ≈125 mg/m2], and then observed continuously for 60 hours (details in Milano et
`al.[38]). From left to right: control (Cont) animals (n = 35); buspirone (Busp), a 5-HT1A receptor agonist, 15 mg/kg 15 minutes before
`CDDP (n = 7); nolpitantium (Nolpi) [SR-140333], a selective tachykinin NK1 receptor antagonist, 3 mg/kg 15 minutes before CDDP
`(n = 8); relcovaptan (Relco) [SR-49059], a selective vasopressin V1a receptor antagonist, 3 mg/kg 15 minutes before CDDP (n = 7);
`dexamethasone (Dexam), a corticosteroid, 20mg 15 minutes before CDDP , and 10mg 12 and 36 hours after CDDP (n = 7); granisetron
`7 mg/kg (Grani 7), a selective 5-HT3 receptor antagonist, 15 minutes before CDDP (n = 7); dexamethasone 20mg 15 minutes before
`CDDP , and 10mg 12 and 36 hours after CDDP plus granisetron 7 mg/kg 15 minutes before CDDP ( Dexam + Grani 7)[ n=7 ] ;
`indomethacin (Indomet), a cyclo-oxygenase inhibitor, 10 mg/kg 1 hour before CDDP , and then 15 and 39 hours after CDDP (n = 7);
`8-OH-DPAT, a selective 5-HT 1A receptor agonist, 1 mg/kg 15 minutes before CDDP (n = 7); bilateral cervical vagotomy ( Vagot)
`performed 3 to 4 days before CDDP (n = 6); granisetron 1 mg/kg given every 5 hours during the first 30 hours post-CDDP (Grani 7
`× 1) [n = 7]; cervical bivagotomy plus granisetron 1 mg/kg given every 5 hours from the 15th to the 60th hour post-CDDP (Vagot +
`Granis 9 × 1) [n = 6]; vofopitant (Vofo 1) [GR-205171], a selective tachykinin NK1 receptor antagonist, 1 mg/kg 15 minutes before
`CDDP (n = 13); vofopitant 1 mg/kg given every 6 hours throughout the 60 hours observation period ( Vofo 10 × 1) [n = 5]. The line
`above each bar indicates the standard error of the mean (SEM) of the cumulative (acute + delayed) severity of the emetic crisis. The
`highest control of emesis was achieved by using the NK1 receptor antagonist vofopitant. Note that nolpitantium was totally ineffective,
`probably because of poor penetration in the CNS. Results from Milano et al.[38] Grélot et al.,[29,39]and personal unpublished obser-
`vations. EE = emetic events.
`Substance P Antagonists as Antiemetics 539
`© Adis International Limited. All rights reserved. Drugs 2000 Sep; 60 (3)
`Page 7 of 14
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`ium (SR-140333), a highly selective nonpeptide
`compound, inactive at the dose of 3 mg/kg (intra-
`venously) against the acute emetic response to cis-
`platin in both ferrets
`[20] and piglets, reduced this
`response by 90% in the latter species when applied
`centrally (1.5mg, intracerebrovascularly) [Grélot
`et al., unpublished observation].
`It is very strongly suspected that the nucleus
`tractus solitarius (NTS) neurons lying ventrally to
`the area postrema in the so-called subnucleus
`gelatinosus trigger the emetic act.
`[2] This medul-
`lary area is a converging site for projections arising
`from the area postrema, and the vestibular and va-
`gal afferents.
`[45] NTS is a good candidate for the
`site of action of NK1 receptor antagonists. Exten-
`sive SP-like immunoreactivity has been identified
`in this region and the tachykinins have been pro-
`posed as transmitters in vagal afferents.
`[46-48] Using
`in vitro autoradiography, Watson et al.[25] showed
`that the high density [3H]-SP binding in the NTS
`was displaced by CP-99994. Similarly, recent pos-
`itron emission tomography (PET) studies in rhesus
`monkeys have demonstrated that peripherally ad-
`ministered
`11C-labelled vofopitant has a distribu-
`tion into brain regions consistent with specific
`binding to NK 1 receptors. [49] Injection of CP-
`99994, L-741671 or MK-869 (30μg) into the vicin-
`ity of the NTS inhibited cisplatin-induced emesis
`in the ferret.[32] Moreover, the SP-induced dis-
`charge of action potentials of single NTS neurons
`recorded in slices of ferret brain stem is inhibited
`by HSP-117, an NK1 receptor antagonist with po-
`tent antiemetic activity.[34] Altogether, these results
`suggest, but do not demonstrate, that NK1 receptor
`antagonists exert their main antiemetic action by
`depressing the neural activity of NTS neurons, i.e.
`within the central emetic circuitry.
`However, a possible contribution from periph-
`eral sites to this potent antiemetic effect should not
`be ignored. Indeed, sendide (3 mg/kg, intraven-
`ously), a peptide-based drug, is active against
`cisplatin-induced emesis in the ferret probably via
`a gastrointestinal tract site of action.
`[35] The pro-
`posed mechanism underlying this effect might in-
`v o l v eab l o c k a d eo ft h eN K
`1 receptors located on
`vagal terminals in the gut. This would decrease the
`intensity of the emetic afferent message to the med-
`ullary emetic circuitry.
`[35] In that view, the periph-
`eral effect of NK 1 receptor antagonists might
`resemble that of the 5-HT3 receptor antagonists
`on the serotonergic activation of vagal terminals.
`However, this hypothesis remains to be demon-
`strated since the possibility of a nonspecific in-
`teraction of sendide on 5-HT
`3 receptors or Ca2+
`channels located on vagal terminals was not inves-
`tigated.
`5. Antiemetic Activity of NK
`1 Receptor
`Antagonists: Clinical Studies
`In humans as well as in animals, the number of
`transmitters involved in the emetic process ac-
`counts for the incomplete efficacy of single drug
`therapies for nausea and vomiting of various
`aetiologies.
`Maybe because of their central role on a poten-
`tial, final common pathway, NK
`1 receptor antago-
`nists have offered a broader spectrum antiemetic
`activity than 5-HT
`3 receptor antagonists, dopamine
`receptor antagonists, anticholinergic agents or cor-
`ticosteroids. It seems likely that, as was observed
`for pain management,
`[50] combining medications
`from different classes may optimise the efficacy of
`NK
`1 receptor antagonists for the treatment of nau-
`sea and vomiting.
`Data from the first published clinical studies
`seem to confirm the usefulness of this new class of
`drugs in humans. Investigations have been carried
`out in two types of indications: cancer chemotherapy-
`induced nausea and vomiting (CINV) and PONV .
`The 5 investigational drugs studied so far are:
`vofopitant, CP-122721, ezlopitant (CJ-11974), MK-
`869 and its prodrug L-758298.
`V ofopitant is a potent and selective NK
`1 recep-
`tor antagonist with high affinity for the human NK1
`receptor and potent antiemetic activity in various
`animal models of emesis. It is a high clearance
`compound (979 to 1821 ml
`• min–1) with a large
`volume of distribution (412 to 888L) and a moder-
`ately long elimination half-life of 5 to 8 hours in
`patients.
`[51] Ezlopitant is a selective NK1 receptor
`540 Diemunsch & Grélot
`© Adis International Limited. All rights reserved. Drugs 2000 Sep; 60 (3)
`Page 8 of 14
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`antagonist with a Ki of 0.4 nmol/L, which proved
`highly active in the ferret model of emesis. MK-
`869 a trisubstituted morpholin acetal, is a selective
`NK
`1 receptor antagonist also very active in animal
`models. MK-869, has been studied in humans
`directly and after administration of its prodrug
`L-758298.
`[52,53]
`5.1 Chemotherapy-Induced
`Nausea and Vomiting
`Five preliminary studies have dealt with the pre-
`vention of acute and/or delayed CINV after high
`dose cisplatin in patients with cancer. Four of these
`studies were double-blind, randomised studies and
`one was open labelled. Three were dose-ranging
`studies (table II).
`Despite the small numbers of patients included
`in the trials, the design allowed comparison be-
`tween arms consisting, respectively, of either a pla-
`cebo, a NK
`1 receptor antagonist, a 5-HT3 antago-
`nist, the combination of a 5-HT3 antagonist plus
`dexamethasone, or a NK1 receptor antagonist with
`a5 - H T3 antagonist plus dexamethasone.
`One study compared a NK1 receptor antagonist
`alone (L-758298) with ondansetron alone, and an-
`other compared a NK
`1 receptor antagonist alone
`(vofopitant) with its combination with ondanset-
`ron. In another report, the NK
`1 receptor antagonist
`alone (CP-122721) was compared with its combi-
`nation with ondansetron plus dexamethasone. The
`two remaining protocols were placebo-controlled
`comparisons of a usual regimen of granisetron plus
`dexamethasone with this regimen combined with
`aN K
`1 receptor antagonist (ezlopitant or MK-869)
`administered according to various regimens.
`I nt h es t u d ya r m sw h e r eaN K1 receptor antag-
`onist was administered alone, it proved either inef-
`fective or not superior to ondansetron for the con-
`trol of acute CINV after high doses of cisplatin.
`Fumoleau et al.
`[54] reported on the lack of efficacy
`of intravenous vo