Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P20366 (substance P)
 21,176 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Aprepitant, a selective high-affinity antagonist of human substance P/neurokinin 1 (NK1) receptors, is the active ingredient of EMEND which has recently been approved by the FDA for the prevention of chemotherapy-induced nausea and vomiting (CINV). Aprepitant undergoes extensive metabolism, primarily via CYP3A4 mediated oxidation. It is eliminated primarily by metabolism and is not renally excreted. The apparent terminal half-life in humans ranged from 9 to 13 hours. Early development studies led to the development of a nanoparticle formulation to enhance exposure and minimize food effects. Two large randomized trials accruing 1099 patients studied the effect in patients receiving cisplatin of adding aprepitant to ondansetron and dexamethasone on day 1 then to dexamethasone on days 2 and 3 to control delayed emesis. The complete response of no vomiting and no rescue medication overall from days 1 to 5 improved from 48% to 68% (p<0.001), a 13% improvement in acute emesis but a 21% improvement in delayed emesis with the improvement from 51% to 72% (p<0.001). Similarly, 866 patients treated with cyclophosphamide plus either doxorubicin or epirubicin, received either ondansetron, dexamethasone, and aprepitant on day 1 followed by aprepitant on days 2 and 3 or ondansetron and dexamethasone on day 1 and dexamethasone on days 2 and 3. The overall complete response rate over 5 days was better for the aprepitant group 50.8% vs 42.5% (p=0.015). Complete responses were reported in more patients taking aprepitant in both the acute (76% vs 69%, p=0.034) and delayed (55% vs 49%, p=0.064) phases of vomiting. There were no clinically relevant differences in toxicity by adding aprepitant and improvements in the quality of life of patients on chemotherapy were recorded.
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PMID:Nanomedicines in the treatment of emesis during chemotherapy: focus on aprepitant. 1772 7

The pharmacology of tachykinin NK receptors varies greatly among species. The aim of the present study was to assess the role of NK(1) and NK(2) receptors in mediating colorectal distension-evoked nociception and psychological stress-induced defecation in gerbils, a species with human-like NK receptor pharmacology. The effects of the selective NK(1) and NK(2) receptor antagonists, aprepitant and saredutant, on acute (1 h) restraint stress-evoked defecation and plasma adenocorticotropin (ACTH) levels in gerbils were assessed. The effects of antagonists alone or in combination on colorectal distension-evoked visceral pain in conscious gerbils were evaluated using the visceromotor response as a surrogate marker of pain. Restraint stress increased fecal pellet output 2-3-fold and plasma ACTH levels 9-fold. Aprepitant inhibited the defecatory and endocrine responses to stress by 50%, while saredutant completely normalized the same parameters. Visceral pain responses during colorectal distension were attenuated by both compounds, but aprepitant (19+/-6% inhibition, P<0.01) was slightly more effective than saredutant (10+/-9% inhibition, P<0.05). A combination of both compounds resulted in an additive effect (30+/-10% inhibition, P<0.01). The results demonstrate that NK(1) and NK(2) receptors are involved in stress-related colonic motor alterations and visceral pain responses in gerbils and that combined antagonism provides enhanced inhibition of visceral pain responses. This suggests that for therapeutic use in for instance functional gastrointestinal disorders, dual NK(1)/NK(2) receptor antagonists may provide better clinical outcome than selective compounds.
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PMID:Role of tachykinin NK(1) and NK(2) receptors in colonic sensitivity and stress-induced defecation in gerbils. 1823 89

Despite progress in the area of supportive care in oncology in the last two decades, nausea and vomiting continue to be significant side effects of cancer therapy. These symptoms can escalate over time and can result in patients' refusal to continue with chemotherapy. Introduction of serotonin (5-HT3) receptor antagonists was a major therapeutic advance in the treatment of chemotherapy-induced nausea and vomiting with enhanced efficacy when corticosteroids were added. However, these agents have limited protection in the acute phase of chemotherapy-induced nausea and vomiting with little or no effect over the delayed phase. The aim of this review was to introduce a new class of antiemetics, a selective high-affinity antagonist at human substance P neurokinin 1 (NK(1)) receptors-aprepitant. Its pharmacological characteristics as well as its efficacy are reviewed. Aprepitant appears to be well tolerated but, due to its inhibitory effect on cytochrome P450 isoenzyme 3A4, it can lead to significant drug interactions, resulting in need for dose modification of concomitant therapy. The addition of aprepitant to 5-HT(3) receptor antagonists and corticosteroids was found to be superior to the combination of 5-HT(3) receptor antagonists and corticosteroids alone in patients treated with highly and moderately emetogenic chemotherapy. Clinical trials with aprepitant and other antiemetic agents are warranted to determine a regimen that will ensure complete protection from both acute and delayed chemotherapy-induced nausea and vomiting, thus contributing to improved supportive care and patients' quality of life (QoL).
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PMID:Aprepitant--where do we stand in the control of chemotherapy-induced nausea and vomiting? 1897 46

Aprepitant is a selective high-affinity antagonist of human substance P (SP)/Neurokinin-1 (NK-1) receptors. Until now this drug has been used as anxiolytic, antidepressant and antiemetic. It has been demonstrated that SP induces cell proliferation and NK-1 receptor antagonists different to aprepitant inhibit growth in several human cancer cell lines, where NK-1 receptors are overexpressed. The purpose of this study is to demonstrate the antitumor action of aprepitant. We performed an in vitro study of the growth inhibition capacity of the NK-1 receptor antagonist aprepitant against glioma, neuroblastoma, retinoblastoma and pancreas, larynx, gastric and colon carcinomas cell lines. Coulter counter was used to determine viable cell numbers followed by application of the MTS colorimetric method. Furthermore, a DAPI method was applied to demonstrate apoptosis. We have demonstrated: aprepitant at (5-70 microM) concentration elicits growth cell inhibition in a concentration dependent manner in all tumor cell line studied. Maximum inhibition (100%) was observed when the aprepitant was administered at a concentration of > or = 70 microM in all tumor cell lines studied. The specific antitumor action of aprepitant occurs through the NK-1 receptor and tumor cells death was by apoptosis pathway. These findings reported here for the first time indicate that aprepitant is a new and promising broad spectrum antitumor drug in the treatment of cancer.
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PMID:The NK-1 receptor antagonist aprepitant as a broad spectrum antitumor drug. 1914 78

Despite major advances, emesis remains a major problem in the context of cancer chemotherapy and in the postoperative period. A better understanding of the relevant neurocircuitry, especially the central pattern generator responsible for emesis and the central role of substance P, led to the development of a new class of antiemetics: the neurokinin-1 (NK1) receptor antagonists. Aprepitant is the first NK1 receptor antagonist approved for use in postoperative nausea and vomiting, but several other compounds are currently being investigated for their potential as antiemetics in the postoperative and cancer chemotherapy settings.
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PMID:Neurokinin-1 receptor antagonists in the prevention of postoperative nausea and vomiting. 1954 1

Aprepitant (Emend) is a neurokinin-1 (NK(1)) receptor antagonist that is able to alleviate the emetic effects of substance P. When combined with a standard regimen of a corticosteroid (dexamethasone) and a serotonin 5-HT(3) receptor antagonist (ondansetron), oral aprepitant (125 mg on day 1 then 80 mg once daily on days 2 and 3) was effective in the prevention of acute and delayed chemotherapy-induced nausea and vomiting (CINV) associated with single or multiple cycles of highly emetogenic chemotherapy (HEC). This aprepitant regimen was also effective in the prevention of CINV in patients treated with single or multiple cycles of moderately emetogenic chemotherapy (MEC). A single oral dose of aprepitant 40 mg administered prior to patients undergoing abdominal surgery was also effective in the prevention of postoperative nausea and vomiting (PONV). Aprepitant was generally well tolerated. Aprepitant is a recommended option for the treatment of PONV, and when combined with a corticosteroid and 5-HT(3) receptor antagonist is a recommended regimen for the treatment of CINV.
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PMID:Aprepitant: a review of its use in the prevention of nausea and vomiting. 1971 36

Aprepitant (Emend, Merck Inc., Whitehouse Station, NJ), a neurokin-1 (NK1) receptor antagonist, is a first-in-class agent approved for the prevention of acute and delayed chemotherapy-induced nausea and vomiting (CINV). It competitively binds to NK1 receptors, blocks the binding of substance P, the natural ligand, and prevents signal transduction. Early clinical trials showed that aprepitant combined with standard therapy (corticosteroids and serotonin receptor antagonists) provided improved antiemetic protection in patients receiving highly emetogenic chemotherapy. The results of three randomized, double blind, placebo-controlled trialsthat compared aprepitant plus standard therapy with standard therapy plus placebo showed significant improvements in complete response rates (defined as no emesis and no use of rescue medication) with the addition of aprepitant (58.8% to 71% vs. 43.3% to 52.3%; P < .05 for all). Benefits were found in the acute phases, delayed phases, and in the overall study periods. Multiple secondary endpoints also favored the addition of aprepitant, particularly in the delayed phases and overall study periods. In extended trials in which treatment was continued for up to 6 cycles of highly emetogenic chemotherapy, the antiemetic effect was maintained and remained statistically greater for the aprepitant plus standard therapy group compared with standard therapy and placebo. The addition of aprepitant was well tolerated, and common adverse events were similar to those seen with standard therapy plus placebo. A clinically significant drug interaction with CYP3A4-metabolized cytotoxic agents was reported in one trial, but not confirmed in the others. The additional protection confirmed by aprepitant translated into a decreased impact of CINV on patients' daily lives as measured by the Functional Living Index-Emesis questionnaire. Aprepitant adds additional antiemetic protection to standard therapy and should be considered in all patients receiving highly emetogenic chemotherapy.
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PMID:Antiemetic studies on the NK1 receptor antagonist aprepitant. 1978 Feb 56

Melanoma, the most deadly form of skin cancer, is aggressive and resistant to current therapies. It has been previously reported that the substance P and neurokinin-1 (NK-1) receptor antagonists induce cell proliferation and cell inhibition, respectively, in human melanoma cell lines. Aprepitant is a selective high-affinity antagonist of the human NK-1 receptor. Until now, this drug has been used as an anxiolytic, antidepressant and antiemetic. Moreover, the antitumor action of aprepitant has been previously reported. However, the presence of NK-1 receptors in human melanomas and whether the antitumor action of the NK-1 receptor antagonist aprepitant is exerted on human malignant melanomas have not been previously described. The aims of this study are to show the presence of NK-1 receptors in human malignant melanomas and the antitumoral action of aprepitant against several human melanoma cell lines. Immunoblot analysis was used to determine the presence of NK-1 receptors in human melanoma cell lines, and immunohistochemistry was used to demonstrate NK-1 receptors in human melanoma samples. We performed an in vitro study of the cytotoxicity of the NK-1 receptor antagonist aprepitant on human melanoma cell lines. A coulter counter was used to determine viable cell numbers, followed by application of the tetrazolium compound MTS. The DAPI method was applied to demonstrate apoptosis. We observed that NK-1 receptors were present in all the melanoma samples studied as well as in human melanoma cell lines. We also showed that melanoma cell lines expressed mRNA for the NK-1 receptor. Moreover, after using a knockdown method, we showed that NK-1 receptors are involved in the viability of tumor cells. In this study, we also report that aprepitant, at 10-60 microM concentrations, elicits cell growth inhibition in a concentration-dependent manner in all melanoma cell lines studied, that the specific antitumor action of aprepitant occurs through the NK-1 receptor and that melanoma cell death is due to apoptosis. These findings show for the first time that the NK-1 receptor may be a promising new target and that the NK-1 receptor antagonist aprepitant could be a candidate as a new antitumor drug in the treatment of human melanoma.
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PMID:The NK-1 receptor is expressed in human melanoma and is involved in the antitumor action of the NK-1 receptor antagonist aprepitant on melanoma cell lines. 2045 80

A 50-year-old-woman underwent high anterior resection for sigmoid colon adenocarcinoma. Modified oxaliplatin/l / -LV/ 5-FU(mFOLFOX6)was started as adjuvant treatment due to final-stage III b. Granisetron 3 mg and dexamethasone 8 mg for prophylaxis chemotherapy-induced nausea and vomiting (CINV) were administered intravenously 30 min before oxaliplatin administration. Grade 3 delayed CINV was observed at course 4. CINV could not be controlled by any rescue medications. We adopted a neurokinin-1 receptor antagonist (aprepitant) that alleviated the emetic effects of substance P. The oral aprepitant dose was 125 mg on day 1 and 80 mg on days 2 and 3. Afterward, delayed vomiting was completely controlled and chemotherapy could be continued to course 12. Aprepitant is a very active antiemetic drug for the prevention of delayed nausea and vomiting induced by mFOLFOX6 regimen.
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PMID:[Clinical usefulness of oral aprepitant for alleviation of delayed nausea and vomiting induced by mFOLFOX6--report of a case]. 2116 Feb 74

Chemotherapy can be a life-prolonging treatment for many cancer patients, but it is often associated with profound nausea and vomiting that is so distressing that patients may delay or decline treatment to avoid these side effects. EMEND (aprepitant) is the first and only neurokinin-1 (NK-1) receptor antagonist available on the market for the prevention of acute and delayed chemotherapy-induced nausea and vomiting (CINV). Aprepitant acts centrally at NK-1 receptors in vomiting centers within the central nervous system to block their activation by substance P released as an unwanted consequence of chemotherapy. By controlling nausea and vomiting, EMEND helps improve patients' daily living and their ability to complete multiple cycles of chemotherapy. The development of aprepitant included a novel nanoparticle formulation to optimize oral absorption and innovative chemistry to discover a prodrug form suitable for intravenous administration to improve compliance and convenience for healthcare professionals and cancer patients.
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PMID:Development of aprepitant, the first neurokinin-1 receptor antagonist for the prevention of chemotherapy-induced nausea and vomiting. 2143 41


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