Substance P Antagonists or NK1 receptor antagonists as Anti-Emetics.

Pierre Diemunsch MD, PhD* and Laurent Grélot PhD**

*Service d’Anesthésie – Réanimation Chirurgicale, Hôpitaux Universitaires de Strasbourg Hautepierre, France.

**UPRES EA 3285 – IFR Marey - Faculté des Sciences du Sport, Université de la Méditerranée, Marseille, France.

Primarily a protective reflex occurring in response to the ingestion of a hazardous compound, vomiting is also a distressing side effect associated with various medical practices[1]. Emesis remains a critical problem during recovery from surgical procedures, in anticancer cytotoxic therapy, and in circumstances involving motion and vestibular disturbances (e.g. Ménière disease). Vomiting can occur in natural circumstances where its benefits remain obscure (e.g. pregnancy sickness).

          The “vomiting centre” is thought to be located within the medulla oblongata of the brainstem ^[2]. The numerous neurochemicals involved in that circuitry are not fully identified. The introduction of selective 5-HT₃ receptor antagonists has incontestably represented a major advance in the control of acute emesis associated with cytotoxic therapy and surgery. However, further improvement would be desirable.

Tachykinins are members of a family of neuropeptides sharing the common C-terminal sequence Phe-Xaa-Gly-Leu-MetNH₂. According to the “Montreal nomenclature” ^[3], the NK₁ receptor is defined as the mediator of the biological activities encoded by the C-terminal sequence of tachykinins, for which SP is a more potent agonist than NK_A or NK_B. Since SP is believed to exert a key role within the central emetic circuitry, selective NK₁ receptor antagonists are expected to express potent anti-emetic activity.

The nucleus tractus solitarius (NTS) is a good candidate for the site of action of NK₁ receptor antagonist. Extensive SP-like immunoreactivity has been identified in this region and the tachykinins have been proposed as transmitters in vagal afferents  [4];[5],[6].

In man as well as in animals, the numerous transmitters involved in the emetic process accounts for the incomplete efficacy of single drug therapies for nausea and vomiting of various aetiologies.

Maybe due to their central role on a potential, final common pathway, NK₁ receptor antagonists have offered a broader spectrum anti-emetic activity than 5HT₃ receptor antagonists, dopamine receptor antagonists, anticholinergic agents, and corticosteroïds. It seems likely that, as was observed for pain management [7], combining medications from different classes may optimise the efficacy of NK₁ receptor antagonists for treatment of nausea and vomiting.

Data from the published clinical studies seem to confirm the usefulness of this class of drugs in man, in two types of indications: cancer-chemotherapy induced nausea and vomiting (CINV) and post operative nausea and vomiting (PONV). Conversely, the NK₁ receptor antagonists were shown to be ineffective in motion-induced nausea, either alone or in combination with a 5-HT3 receptor antagonist [8].

The five investigational drugs studied initially are: GR205171 (Glaxo Wellcome), CP-122,721 (Pfizer), CJ-11,974 (Pfizer), L-754,030 (Merck) and its prodrug L-758,298.

 

NK₁ receptor antagonists in Chemotherapy Induced Nausea and Vomiting.

The design of well conducted trials allowed comparison between arms consisting respectively of either a placebo, a NK₁ receptor antagonist, a 5-HT3 antagonist, the association of a 5-HT3 antagonist plus dexamethasone, or the association of a NK₁ receptor antagonist with either dexamethasone alone, or a 5-HT3 antagonist plus dexamethasone.

In the study arms where a NK₁ receptor antagonist was administered alone, it proved either ineffective, or not superior to ondansetron for the control of acute CINV after high doses of cisplatin. Except for this setting, the NK₁ receptor antagonists have shown dramatic antiemetic activity in cisplatin treated patients. This is true for the prevention of acute CINV in association with a 5-HT₃ receptor antagonist or with a 5-HT₃ receptor antagonist plus dexamethasone. For the prevention of delayed CINV, a single prophylactic dose of NK₁ receptor antagonist proved effective in six out of seven patients (86%) while the combination with a 5-HT₃ receptor antagonist and dexamethasone brought about this result in 8 out of 10 patients (80%). The NK₁ receptor antagonists alone proved significantly superior to ondansetron alone in the prevention of vomiting and nausea on days 2 to 7 after cisplatin administration. Compared with standard therapy (ondansetron plus dexamethasone), aprepitant (Emend*) 125 mg before cisplatin and aprepitant 80 mg on days 2 to 5 after the treatment, brings better and more sustained protection against chemotherapy-induced nausea and vomiting over multiple cycles.

 

NK₁ receptor antagonists in Post Operative Nausea and Vomiting.

Comparing CP-122,721 200 mg orally to ondansetron 4 mg i.v. and to the combination of the two agents in the prevention of PONV, Gesztesi [9] found no differences for post operative nausea scores among the three groups but a significantly lower incidence of emetic episodes when CP-122,721 was part of the prophylactic regimen. The combination of CP-122,721 and ondansetron provided no additional benefit. The same group published additional data in 2000 [10] showing in a dose ranging approach, that oral CP-122,721 200 mg was more effective than oral CP-122,721 100 mg. The combination of CP-122,721 and ondansetron significantly prolonged the time to the administration of the first rescue antiemetic drug when compared with either drug alone, and prevented the occurrence of emesis in 98% of the patients. Nevertheless, patient satisfaction was not different than after ondansetron 4 mg.

In a placebo controlled treatment, in the setting  of established PONV, Diemunsch [11] showed GR205171 25 mg i.v. as a single agent to be superior to placebo for complete control of emesis and nausea. This benefit was maintained throughout the entire 24 hour study period. The proportion of patients requiring rescue medication during the 24 hours following drug administration was also less after treatment with GR205171 (61% versus 83% after the placebo).

Aprepitan is currently tested in the PONV setting.

 

Safety.

Safety of the NK₁ receptor antagonists in man has never been a concern in the clinical studies, and all the investigational drugs were well tolerated, with no drug-related toxicity. No adverse events were reported that would preclude further studies of NK₁ receptor antagonists in man. One exception however, has been reported consisting in a serious episode of dizziness possibly related to oral L-754,030 (400 mg). Similarly an increased incidence of mild or moderate headaches was observed after oral CP-122,721 (200 mg) in the dose ranging study.

Despite the implication of substance P in pain mechanisms, no obvious effects on pain threshold or on analgesia were observed in the human PONV studies. This is in opposition with the results of one study [12] showing that the NK₁ receptor antagonist CP-99,994 was effective in pain reduction after third molar extraction.

Other potential indications of the NK₁ receptor antagonists include asthma, anxiety, arthritis, migraine, schizophrenia, glaucoma as well as ocular hypotension, neural injury and stroke. It is so far unknown, as to whether the doses required to treat CINV and PONV may provoke side effects related to this wide spectrum activity.

 

Conclusion.

The recent introduction of the NK₁ receptor antagonists seems promising firstly on a theoretical basis, since these drugs act on a final target in the emesis mechanism, secondly on a preclinical basis, since NK₁ receptor antagonists showed excellent results in various animal models of emesis, and finally if one considers the human data published so far. As in the case of the 5-HT₃ receptor antagonists, no major concern about safety has been raised after the initial human trials. Much work is needed in order to to answer questions concerning the optimal dose, the optimal schedule and duration of treatment, and the optimal antiemetic drug associations with the NK₁ receptor antagonists. Occurrence of other foreseeable effects of this class of drugs should also be controlled for, on large scale trials.

 

 

 

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