Anti-emetic profile of a non-peptide neurokinin NK1 receptor antagonist, CP-99,994, in ferrets

Bountra, C; Bunce, K.T.; Dale, Timothy; Gardner, C.; Jordan, Christopher; Twissell, D.J.; Ward, P.

doi:10.1016/0014-2999(93)90673-6

Cited by 153 publications

(88 citation statements)

References 2 publications

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“…Cisplatin administration causes vomiting in ferrets, and this observation has led to the testing of antiemetics in this animal model (Bountra et al, 1993;Tattersall et al, 1994;Beattie et al, 1995;Gardner et al, 1995Gardner et al, , 1996Harrison et al, 2001). In a 4-h observation period, aprepitant (0.3, 1, or 3 mg/kg i.v.…”

Section: Discussionmentioning

confidence: 99%

“…Among the agents used to alleviate these conditions are H 1 -blockers (Bergman and Spealman, 1988;Tonato et al, 1994), D 2 -blockers (Jovanovic-Micic et al, 1995;Mystakidou et al, 1998), 5-hydroxytryptamine 3 blockers (Gregory and Ettinger, 1998;Ye et al, 2001), and cannabinoids (Abrahamov et al, 1995;Mechoulam and Hanu, 2001). More recently, efforts have been made to determine the efficacy of NK 1 receptor 1 antagonists against chemotherapy-induced nausea and vomiting (Bountra et al, 1993;Tattersall et al, 1994;Beattie et al, 1995;Gardner et al, 1995Gardner et al, , 1996Harrison et al, 2001). Using the ferret, it has been established that brain penetration of NK 1 antagonists is essential to prevent drug-induced (cisplatin) emesis, and several compounds have been shown to be efficacious in this regard (Watson et al, 1995;Gonsalves et al, 1996;Rudd et al, 1996;Tattersall et al, 1996;Rupniak et al, 1997;Singh et al, 1997;Zaman et al, 2000;Harrison et al, 2001).…”

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confidence: 99%

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Brain Penetration of Aprepitant, a Substance P Receptor Antagonist, in Ferrets

Huskey¹,

Dean²,

Bakhtiar³

et al. 2003

Drug Metab Dispos

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ABSTRACT:The pharmacokinetics, metabolism, and brain penetration of the neurokinin 1 (NK 1 ) receptor antagonist (substance P receptor antagonist), aprepitant (MK-0869), were examined in ferrets. This species exhibits human-type NK 1 receptor pharmacology and is of proven value in the identification of clinically useful drugs for the treatment of chemotherapy-induced nausea and vomiting in humans. After a single p.o. dose of aprepitant at 1 or 2 mg/kg, plasma levels of the compound were between ϳ200 and 270 ng/ml, 24 h after dosing. In the brain cortex, concentrations of aprepitant reached between ϳ80 and 150 ng/g of tissue 24 h after dosing. The predominant radioactive component present in the plasma and the brain of ferrets at 24 or 48 h after a single oral dose of [ 14 C]aprepitant at 3 mg/kg was the parent compound itself. The slow plasma clearance of aprepitant (ϳ1.5 ml/min/kg) and its abundance in ferret brain were in accord with its efficacy in blocking the retching and vomiting at 24 and 48 h postdose when ferrets were challenged with the emetic anticancer drug, cisplatin. When aprepitant and some of its metabolites were assessed for their in vitro binding affinity to the human NK 1 receptor, aprepitant demonstrated the highest affinity. Collectively, these data suggested that aprepitant, rather than its metabolites, was responsible, primarily, for the antiemetic activity of this compound in the male ferret.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Brain Penetration of Aprepitant, a Substance P Receptor Antagonist, in Ferrets

Huskey¹,

Dean²,

Bakhtiar³

et al. 2003

Drug Metab Dispos

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“…Preclinical studies have demonstrated that these agents are capable of blocking the development of emesis due to a wide spectrum of stimuli including cisplatin. [27][28][29] Early clinical trials have confirmed the activity of these agents in treating cisplatin-induced emesis. In combination with a 5-HT3 receptor antagonist and dexamethasone, they improve the control of nausea and vomiting developing in the first 24 h after chemotherapy (acute emesis) and are also active in lessening emesis during the 5 days after chemotherapy (delayed emesis).…”

Section: Discussionmentioning

confidence: 99%

Prospective evaluation of antiemetic outcome following high-dose chemotherapy with hematopoietic stem cell support

Ballen

Hesketh

Heyes

et al. 2001

Bone Marrow Transplant

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Summary:Considerable progress has been made in improving the control of chemotherapy-induced emesis. The impact of available antiemetic options for patients receiving stem cell transplants is unclear, as few prospective data have been collected. We prospectively evaluated antiemetic outcome in patients receiving stem cell transplantation over a 7-day period following the initiation of chemotherapy. The primary endpoints were the number of emetic episodes and the extent of nausea measured on a four-point scale. Eighty-two patients were evaluated. Ninety-five percent of patients had nausea during the first week of treatment; 80% had at least one emetic episode. The percentage of patients with emesis was as follows: day 1: 13%, day 2: 21%, day 3: 30%, day 4: 38%, day 5: 44%, day 6: 39%, day 7: 18%. In multivariate analysis, gender, emesis with prior chemotherapy, history of morning or motion sickness, type of transplant (auto vs allo), use of total body irradiation, or use of dexamethasone did not effect emesis control. Most patients receiving high-dose chemotherapy experience incompletely controlled emesis. Control of nausea and emesis progressively worsened with each subsequent day following initiation of chemotherapy, reaching a nadir on day 5. New treatment approaches are needed to improve emesis control in this patient population. Bone Marrow Transplantation (2001) 28, 1061-1066. Keywords: nausea; bone marrow transplantation Myeloablative chemotherapy and radiotherapy followed by autologous or allogeneic stem cell transplantation have been shown to be curative for certain hematologic malignancies, aplastic anemia, and genetic disorders. 1-3 Over the last three decades of transplantation, there have been significant advances in supportive management to lessen tox- icity and improve tolerance of autologous and allogeneic stem cell transplantation. [4][5][6][7] From the patient's standpoint, two of the most feared adverse effects of chemotherapy are treatment-induced nausea and vomiting. 8,9 Considerable progress has been made in the control of nausea and vomiting for patients receiving standard doses of chemotherapy. The use of 5-hydroxytryptamine-3 (5HT3) antagonists, such as dolasetron, granisetron and ondansetron, have contributed significantly to the control of nausea and vomiting in patients receiving moderately and highly emetogenic chemotherapy. [10][11][12][13] The great majority of patients receiving emetogenic chemotherapy at standard doses should achieve complete control of emesis at the present time.A number of patient and treatment-related factors predictive for the development of chemotherapy-induced emesis have been defined. These include age, gender, ethanol consumption history, and the intrinsic emetogenicity of the chemotherapy agents. 14 Also of importance is chemotherapy dose. The emetogenicity of a number of chemotherapy agents such as cisplatin and cyclophosphamide increases with increasing dose. 15 The outcome of antiemetic therapy has not been well studied in the setting of highdose chemo...

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“…In 1993 it was demonstrated that NK-1 receptor antagonists, blocking the release of substance P, could be candidates for a new class of antiemetic drugs. [14] The first NK-1 receptor antagonist (NK-1 RA) for human use was introduced in 1997. [15] Aprepitant, which is given orally, and its watersoluble prodrug fosaprepitant, given intravenously, are the only marketed drugs of this group at the moment, but several others will soon be registered.…”

Section: Nk-1 Receptor Antagonistsmentioning

confidence: 99%

Corticosteroids, the oldest agent in the prevention of chemotherapy-induced nausea and vomiting: What about the guidelines?

Ryckeghem

2016

Journal of Translational Internal Medicine

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Chemotherapy-induced nausea and vomiting (CINV) remains one of the most disturbing side effects of cancer treatment. Research in antiemetic therapy has progressed gradually since the early eighties, and the development of antiemetic agents continues. This review focuses on the current management of CINV based on the most recent guidelines, and adherence to the latter is examined more carefully. Setrons (5HT3 receptor antagonists), corticosteroids, and NK-1 receptor antagonists are the cornerstones of antiemetic therapy. Corticosteroids are one of the oldest agents in the prevention of CINV. They are highly effective, increase the effect of other antiemetic agents, and are cost-effective. The latest developed 5HT3 receptor antagonist palonosetron led to an update of the guidelines of CINV. Other types include benzodiazepines, cannabinoids, and olanzapine. Various factors contribute to the overall risk of developing CINV, such as patient characteristics, emetogenic potency of the chemotherapeutic agents, and correct prevention of CINV. Current guidelines determine which is the right preventive regimen for each cancer patient at risk for experiencing CINV. Adherence to these guidelines and implementation in daily practice seem to be below the optimal level. In Belgium, authorities use the guidelines as a base for reimbursement and this has increased the level of implementation.

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Anti-emetic profile of a non-peptide neurokinin NK1 receptor antagonist, CP-99,994, in ferrets

Cited by 153 publications

References 2 publications

Brain Penetration of Aprepitant, a Substance P Receptor Antagonist, in Ferrets

Brain Penetration of Aprepitant, a Substance P Receptor Antagonist, in Ferrets

Prospective evaluation of antiemetic outcome following high-dose chemotherapy with hematopoietic stem cell support

Corticosteroids, the oldest agent in the prevention of chemotherapy-induced nausea and vomiting: What about the guidelines?

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