Emerging drugs for chemotherapy-induced emesis

Navari, Rudolph M.; Province, Paula S

doi:10.1517/14728214.11.1.137

Cited by 27 publications

(14 citation statements)

References 78 publications

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“…Uncontrolled emesis can adversely affect the quality of life and impair compliance with treatment in patients (1). Chemotherapeutic agents including cisplatin elicit an immediate emetic response on the day of therapy, that is, acute emesis, and also protracted nausea and vomiting lasting up to 5 days thereafter, that is, delayed emesis.…”

Section: Introductionmentioning

confidence: 99%

Long-Lasting Anti-emetic Effect of T-2328, a Novel NK1 Antagonist

Watanabe¹,

Okamoto

Ishii³

et al. 2008

J Pharmacol Sci

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Abstract. The effect of T-2328 {2-fluoro-4'-methoxy-3'-[[[(2S,3S)-2-phenyl-3-piperidinyl] amino]methyl]-[1,1'-biphenyl]-4-carbonitrile dihydrochloride}, a novel tachykinin NK 1 -receptor antagonist, was examined on cisplatin-induced emesis in ferrets. Cisplatin induced acute emesis in 24 h and delayed emesis during 24 and 72 h, respectively. Ondansetron, a 5-HT 3 antagonist, almost completely blocked the acute emesis and transiently reduced the delayed emesis. In contrast, T-2328 elicited long-lasting anti-emetic effects on both acute and delayed phases by a single intravenous administration. Suppression of delayed emesis was not due to elimination of the acute phase because the delayed emesis was also suppressed by administration after the onset of delayed emesis. Persistent blockade of NK 1 receptors in the brain was demonstrated by inhibition of the NK 1 agonist-induced foot tapping response for over 24 h. An appreciable amount of T-2328 was present in the brain 32 and 72 h after the injection. The NK 1 agonistinduced contractions of isolated ileum in guinea pigs was antagonized with IC 50 values of 1.4 nM in an insurmountable manner. It is likely that T-2328 exerts the long-lasting anti-emetic effect by not only long-term presence in the brain but also its insurmountable inhibition of NK 1 receptors.

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Section: Introductionmentioning

confidence: 99%

Long-Lasting Anti-emetic Effect of T-2328, a Novel NK1 Antagonist

Watanabe¹,

Okamoto

Ishii³

et al. 2008

J Pharmacol Sci

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“…30 The efficacy of NK-1 receptor antagonists for chemotherapy other than cisplatin was postulated based on preclinical data …”

Section: Neurokinin-1 Receptor Antagonistsmentioning

confidence: 99%

Antiemetic therapy options for chemotherapy-induced nausea and vomiting in breast cancer patients

Chan¹,

Park²

2011

BCTT

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Chemotherapy-induced nausea and vomiting (CINV) continues to be one of the most distressing side effects of chemotherapy in breast cancer patients, which can result in poor compliance to therapy that may, in turn, affect overall survival. The extent of CINV is dependent on the emetogenic potential of the individual cytotoxic agents or regimens employed as well as certain patient factors. Advances in our understanding in the pathophysiology of CINV and the identification of risk factors have enabled the utilization of appropriate antiemetic regimens to improve the control of CINV. Most of the chemotherapy regimens used in this patient population are considered to be moderately emetogenic; 60%-90% of chemotherapeutic regimens used in breast cancer patients cause nausea and vomiting, amongst which regimens doxorubicin-cyclophosphamide (AC) combination is commonly regarded as of relatively higher emetogenicity. Currently, corticosteroids, 5-hydroxytryptamine 3 (5-HT3) receptor antagonists, and neurokinin 1 (NK-1) receptor antagonists are the three classes of antiemetic agents with the highest therapeutic index, which have been supported by data from large-scale randomized clinical trials. Treatment guidelines enable physicians to integrate the latest research data into their clinical practices. This review focuses on the three classes of antiemetic therapy options for CINV in breast cancer patients, as well as their safety and tolerability profiles. Recommendations from major guidelines/consensus including from the Multinational Association for Supportive Care in Cancer/European Society of Medical Oncology (MASCC/ESMO), the American Society of Clinical Oncology (ASCO), and the US National Comprehensive Cancer Network (NCCN), are also discussed. With the correct use of antiemetic regimens, chemotherapy-induced vomiting could be prevented in the majority of patients. However, chemotherapy-induced nausea remains an important symptom and a challenge for physicians to manage.

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“…Long-lasting emesis is a major burden during chemotherapy in cancer treatment (18). Chemotherapy-induced emesis seems to consist of acute (up to 24 h) and delayed (24 h and after) phases in both humans and animals.…”

Section: Gr73632-induced Foot Tapping In Gerbilsmentioning

confidence: 99%

Pharmacological Characterization of T-2328, 2-Fluoro-4'-methoxy-3'-[[[(2S,3S)-2-phenyl-3-piperidinyl]amino]methyl]-[1,1'-biphenyl]-4-carbonitrile Dihydrochloride, as a Brain-Penetrating Antagonist of Tachykinin NK1 Receptor

Watanabe¹,

Asai²,

Ishii³

et al. 2008

J Pharmacol Sci

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Abstract. The pharmacological properties of T-2328 were evaluated as an antagonist of the tachykinin neurokinin 1 (NK 1 ) receptor. T-2328 inhibited the specific binding of [ 3 H][Sar 9 ,Met(O 2 ) 11 ]substance P to tachykinin NK 1 receptors in human lymphoblastic IM9 cells with K i of 0.08 nM. In the same assay, K i for aprepitant, a brain-penetrating NK 1 antagonist, was 1.3 nM. The antagonism of T-2328 is highly selective for the human NK 1 receptors since the affinities for human NK 2 , NK 3 receptors, and 13 other kinds of receptors and ion channels were >1000-fold lower than for NK 1 receptors. Reduction in Bmax with no change in affinity suggests the non-competitive nature of T-2328 interaction with the NK 1 receptor. T-2328 (0.03 -0.1 mg / kg, i.v.) and aprepitant (1 -3 mg / kg, i.v.) significantly prevented the GR73632 (i.c.v.)-induced foot tapping response in gerbils. The potencies of T-2328 in both in vitro and in vivo studies were more than 10 times greater than those of aprepitant. I.v. administration of T-2328 (0.1 -0.3 mg/ kg) potently blocked both acute and delayed emetic responses induced by cisplatin (5 mg / kg, i.p.) in ferrets. It is concluded that T-2328 is a potent, centrally active NK 1 antagonist. T-2328 may have potential as a novel therapeutic agent for the treatment of chemotherapyinduced emesis.

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Emerging drugs for chemotherapy-induced emesis

Cited by 27 publications

References 78 publications

Long-Lasting Anti-emetic Effect of T-2328, a Novel NK1 Antagonist

Long-Lasting Anti-emetic Effect of T-2328, a Novel NK1 Antagonist

Antiemetic therapy options for chemotherapy-induced nausea and vomiting in breast cancer patients

Pharmacological Characterization of T-2328, 2-Fluoro-4'-methoxy-3'-[[[(2S,3S)-2-phenyl-3-piperidinyl]amino]methyl]-[1,1'-biphenyl]-4-carbonitrile Dihydrochloride, as a Brain-Penetrating Antagonist of Tachykinin NK1 Receptor

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