Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0042963 (vomiting)
 31,883 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In this study, we report the use of attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FT-IR) for the identification and quantitation of two polymorphs of Aprepitant, a substance P antagonist for chemotherapy-induced emesis. Mixtures of the polymorph pair were prepared by weight and ATR-FT-IR spectra of the powdered samples were obtained over the wavelength range of 700-1500 cm(-1). Significant spectral differences between the two polymorphs at 1140 cm(-1) show that ATR-FT-IR can provide definitive identification of the polymorphs. To investigate the feasibility of ATR-FT-IR for quantitation of polymorphic forms of Aprepitant, a calibration plot was constructed with known mixtures of the two polymorphs by plotting the peak ratio of the second derivative of absorbance spectra against the weight percent of form II in the polymorphic mixture. Using this novel approach, 3 wt % of one crystal form could be detected in mixtures of the two polymorphs. The accuracy of ATR-FT-IR in determining polymorph purity of the drug substance was tested by comparing the results with those obtained by X-ray powder diffractometry (XRPD). Indeed, polymorphic purity results obtained by ATR-FT-IR were found to be in good agreement with the predictions made by XRPD and compared favorably with actual values in the known mixtures. The present study clearly demonstrates the potential of ATR-FT-IR as a quick, easy, and inexpensive alternative to XRPD for the determination of polymorphic identity and purity of solid drug substances. The technique is ideally suited for polymorph analysis, because it is precise, accurate, and requires minimal sample preparation.
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PMID:Characterization and quantitation of aprepitant drug substance polymorphs by attenuated total reflectance fourier transform infrared spectroscopy. 1258 91

Recently, a new class of agents, the substance P antagonists, has heralded a novel approach for the control of emesis. Aprepitant (Emend, Merck & Co., Inc.), the first of this class, was recently approved by the FDA for the prevention of both acute and delayed chemotherapy-induced nausea and vomiting (CINV). Of interest is the vast array of processes in which substance P is involved such as pain, anxiety, depression and inflammation and the potential wide applicability of substance P antagonists to a number of medical conditions outside of the nausea and vomiting realm. The following review provides an overview of aprepitant including pharmacokinetics, pharmacology and clinical evidence for its use in CINV. A brief discussion of other possible indications for aprepitant will also be presented.
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PMID:Aprepitant--a novel NK1-receptor antagonist. 1464 Sep 27

Aprepitant (Emend) is the first commercially available drug from a new class of agents, the neurokinin NK(1) receptor antagonists. Oral aprepitant, in combination with other agents, is indicated for the prevention of acute and delayed chemotherapy-induced nausea and vomiting (CINV) associated with highly emetogenic chemotherapy in adults. In three randomised, double-blind, placebo-controlled trials comparing aprepitant (125 mg day 1, 80mg once daily on days 2 and 3 or 2-5) plus standard therapy (intravenous ondansetron and oral dexamethasone) with standard therapy plus placebo, overall complete responses (primary endpoint, defined as no emesis and no rescue therapy) were seen in significantly more patients in the aprepitant arms (63-73% versus 43-52%, p < 0.01 for all comparisons). Complete responses and complete protection during the acute and delayed phase, and overall complete protection were also observed in significantly more patients in the aprepitant arms. The difference between treatment groups was more marked in the overall and delayed phases than in the acute phase. The antiemetic efficacy of aprepitant plus standard therapy in the prevention of CINV was maintained for up to six cycles of chemotherapy. Where assessed, more patients in the aprepitant plus standard therapy arms than the standard therapy plus placebo arms reported no impact of CINV on daily life, as assessed by the Functional Living Index-Emesis. Aprepitant is generally well tolerated. The most common adverse events in randomised trials were asthenia or fatigue. Other adverse events experienced by aprepitant recipients include anorexia, constipation, diarrhoea, nausea (after day 5 of the study) and hiccups. In addition to being a substrate for cytochrome P450 (CYP) 3A4, aprepitant is also a moderate inhibitor and inducer of this isoenzyme as well as an inducer of CYP2C9. Thus, aprepitant has the potential to interact with other agents metabolised by hepatic CYP isoenzymes. In one trial, there was a higher incidence of serious infection or febrile neutropenia in the aprepitant plus standard therapy arm than the standard therapy plus placebo arm; this was attributed to a pharmacokinetic interaction between aprepitant and dexamethasone. In subsequent trials, a modified dexamethasone regimen was used. In conclusion, when added to standard therapy (a serotonin 5-HT(3) receptor antagonist and a corticosteroid), aprepitant is effective and generally well tolerated in the prevention of CINV associated with highly emetogenic chemotherapy in adults. Despite marked advances in the prevention of CINV, standard therapy does not protect all patients. The addition of aprepitant to standard therapy provides an advance in the prevention of both acute and delayed CINV in adults with cancer.
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PMID:Aprepitant: a review of its use in the prevention of chemotherapy-induced nausea and vomiting. 1502 55

Aprepitant is an oral neurokinin-1 receptor antagonist which acts centrally to block chemotherapy-induced emesis. Its main pathway of elimination is by the cytochrome p450 isozyme CYP3A4, which is the basis for drug interactions with dexamethasone and oral contraceptives. Aprepitant is well tolerated, and phase II trials in high-dose cisplatin-induced emesis showed that it is most effective when 125 mg orally is added to a 5-hydroxytryptamine-3 receptor antagonist and dexamethasone for acute emesis and then an 80 mg oral dose continued with dexamethasone on days 2 and 3 to prevent delayed emesis. Two pivotal phase III trials enrolling a total of 1099 patients showed that the complete control of emesis improved by 20% in patients receiving aprepitant as compared with standard therapy, with the most impressive differences being in delayed emesis. Control was maintained over multiple cycles and occurred in both males and females and young and old adults.
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PMID:Aprepitant in antiemetic combinations to prevent chemotherapy-induced nausea and vomiting. 1505 69

Although the development of serotonin receptor antagonists has greatly improved treatment for chemotherapy-induced nausea and vomiting, patients receiving chemotherapy continue to experience this troublesome side effect. On March 26, 2003, the U.S. Food and Drug Administration approved aprepitant (Emend, Merck & Co., Inc., Whitehouse Station, NJ) for use in combination with standard antiemetic agents for acute and delayed nausea and vomiting with initial and repeat courses of highly emetogenic therapy. Aprepitant appears to provide superior control of acute and delayed emesis compared to standard antiemetic therapy. Aprepitant was well tolerated in phase III studies, with side effects similar to standard therapy. Healthcare providers need to be aware of potential drug interactions with aprepitant. Oncology nurses continue to play a key role in helping patients adhere to their antiemetic schedules, stressing the importance of prevention of nausea and vomiting.
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PMID:Aprepitant for chemotherapy-induced nausea and vomiting. 1520 24

Chemotherapy-induced nausea and vomiting (CINV) is associated with a significant deterioration in quality of life. The emetogenicity of the chemotherapeutic agents, repeated chemotherapy cycles, and patient risk factors (female gender, younger age, alcohol consumption, history of motion sickness) are the major risk factors for CINV. The use of 5-hydroxytryptamine3 (5-HT3) receptor antagonists plus dexamethasone has significantly improved the control of acute CINV, but delayed nausea and vomiting remains a significant clinical problem. Although the 5-HT3 receptor antagonists, dexamethasone, and metoclopramide have been used to prevent delayed CINV, only dexamethasone appears to have much efficacy with acceptable toxicity. Recent studies have introduced two new agents, palonosetron and aprepitant, for the prevention of both acute and delayed CINV. Palonosetron is a new 5-HT3 receptor antagonist with a longer half life and a higher binding affinity than older 5-HT3 receptor antagonists. It improves the complete response rate (no emesis, no need for rescue) of acute and delayed CINV in patients receiving moderately emetogenic chemotherapy compared to the older 5-HT3 receptor antagonists. The other agent, aprepitant, is the first agent available in the new drug class of neurokinin-1 receptor antagonists. When added to a standard regimen of a 5-HT3 receptor antagonist and dexamethasone in patients receiving highly emetogenic chemotherapy, it improves the complete response rate of acute CINV. Aprepitant also improves the complete response of delayed CINV when compared to placebo and when used in combination with dexamethasone compared to dexamethasone alone. Acute and delayed nausea may also be improved by aprepitant when used in combination with a 5-HT3 and dexamethasone prechemotherapy or with daily dosing for 3-5 days following chemotherapy. Based on these studies, new guidelines for the prevention of CINV are proposed. Future studies may consider the use of palonosetron and aprepitant with current and other new agents (olanzapine, gabapentin) in moderately and highly emetogenic chemotherapy, as well in the clinical settings of multiple-day chemotherapy and bone marrow transplantation.
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PMID:Pathogenesis-based treatment of chemotherapy-induced nausea and vomiting--two new agents. 1535 52

Aprepitant (Emend), the first neurokinin-1-receptor antagonist (NK-1-RA), represents a new class of antiemetics. Aprepitant has been approved for the prevention and treatment of acute (0-24 h after chemotherapy) and delayed (1-5 days after chemotherapy) emesis resulting from cisplatin-based chemotherapy and moderately emetogenic chemotherapy. The addition of aprepitant to standard antiemetic therapy in cisplatin-based chemotherapy significantly improves emesis protection in general and, in particular, in the delayed phase by approximately 20%. Results from a recently published study in patients receiving moderately emetogenic chemotherapy suggest a benefit of aprepitant when combined with dexamethasone and a 5-HT(3) receptor antagonist for the prevention of acute emesis, followed by aprepitant as a single agent in the prevention of delayed emesis. Altogether, the addition of aprepitant to the standard antiemetic regimen (5-HT(3) receptor antagonist and dexamethasone) significantly improves the protection against vomiting in the acute as well as in the delayed phase in highly and moderately emetogenic chemotherapies. Therefore, the combination of a 5-HT(3) receptor antagonist, dexamethasone and aprepitant should be considered as a new standard antiemetic therapy.
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PMID:Neurokinin-1-receptor antagonists: a new approach in antiemetic therapy. 1651 55

Substance P (SP)/Neurokinin 1 (NK1) receptor pathways have been repeatedly implicated in the pathophysiology of central, pulmonary, and gastric disorders. A large body of evidence that has been generated from animal experiments indicates that treatment with selective NK1 receptor antagonists might be effective in the treatment of certain forms of disorders, analgesia, depression, migraine, asthma, or gastrointestinal disorders. Accordingly, numerous NK1 receptor antagonists have either been synthesized and are under clinical development, or have already been tested in clinical trials. However, the initial encouraging clinical results were followed by repeated demonstration of a lack of effectiveness. Up to now, only one NK1 receptor antagonist, aprepitant, is available for therapeutical use. Aprepitant is a selective high-affinity human SP/NK1 receptor antagonist approved by the FDA in 2003. Aprepitant is indicated for prophylaxis of acute- and delayed-phase nausea and emesis caused by chemotherapy regimens. It is used in combination with a 5-hydroxytryptamine (5-HT3) antagonist and a corticosteroid. It is the first antiemetic agent that acts by binding the NK1 receptor. Research continues and novel molecules may show better pharmacokinetic and pharmacodynamic properties and, therefore, may achieve therapeutic success.
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PMID:[Neurokinin 1 receptor antagonists--between hope and disappointment]. 1679 96

The neurokinin-1 (NK1) receptor antagonist aprepitant has become part of standard antiemetic therapy for high-dose cisplatin. Recent results indicate that chemotherapy for breast cancer that contains an anthracycline plus cyclophosphamide is more emetogenic than has been previously realised. One large randomised trial demonstrated that aprepitant substantially reduces the risk of vomiting or retching when added to a corticosteroid and a 5-hydroxytryptamine 3 (HT3) receptor antagonist. The adverse effects of standard antiemetics and chemotherapy do not appear to be increased by the addition of this novel antiemetic agent. Aprepitant should now also be considered to be part of prophylactic antiemetic therapy for women who receive chemotherapy that contains an anthracycline and cyclophosphamide. The role of NK1 receptor antagonists in preventing emesis due to other cytotoxic agents that are deemed to be moderately emetogenic is still unclear.
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PMID:The neurokinin1 receptor antagonist aprepitant as an antiemetic for moderately emetogenic chemotherapy. 1687 68

Nausea and vomiting are considered to be among the most distressing consequences of cytotoxic chemotherapies. Currently, there are several novel 5-HT(3) receptor antagonists for the treatment of chemotherapy-induced nausea and vomiting (CINV), including ondansetron, granisetron, and dolasetron. These agents provide significant improvement in the management of acute emesis but are ineffective at preventing delayed emesis. In 2003, a new 5-HT(3) receptor antagonist, palonosetron HCL (Aloxi), was introduced to the U.S. market. Palonosetron was found to be effective in preventing delayed CINV. Indeed, palonosetron was the first and only 5-HT(3) receptor antagonist approved by the FDA for the prevention of both acute and delayed CINV. More recently, studies on the role of substance P in the emetic process led to the development of aprepitant (Emend) for the prevention of delayed emesis in combination with 5-HT(3) receptor antagonists. Despite these major advances, CINV remains uncontrolled in some patients. Current efforts are focused on treating refractory emesis and include both the clinical evaluation of compounds marketed for other indications and the preclinical evaluation of novel molecules targeting other transmitters in the emetic pathway. Ongoing work in pharmacogenomics has postulated several candidate genes that could be involved in emetic sensitivity and responsiveness to antiemetic therapy. Investigations into the pharmacogenomics of CINV may someday be able to aid in the identification of high risk patients and patients unlikely to respond to conventional therapies.
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PMID:New approaches to chemotherapy-induced nausea and vomiting: from neuropharmacology to clinical investigations. 1703 70


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