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Cancer Medicine Aug 2023Non-inferiority of NEPA (fixed combination of NK receptor antagonist (RA), netupitant, and 5-HT RA, palonosetron) versus an aprepitant regimen was previously shown in a... (Randomized Controlled Trial)
Randomized Controlled Trial
INTRODUCTION
Non-inferiority of NEPA (fixed combination of NK receptor antagonist (RA), netupitant, and 5-HT RA, palonosetron) versus an aprepitant regimen was previously shown in a pragmatic study in patients receiving anthracycline cyclophosphamide (AC) and non-AC moderately emetogenic chemotherapy (MEC). In the MEC group a numerically higher complete response (CR: no emesis, no rescue) rate was seen for NEPA during the overall 0-120 h phase (NEPA 76.1% vs. 63.1% aprepitant). As NEPA exhibits long-lasting efficacy, this study evaluated a prolonged period up to 144 h, beyond the traditional 120 h post-chemotherapy. In this post-hoc analysis we explore the comparative efficacy of NEPA versus the aprepitant regimen in the MEC group up to 144 h, while also assessing the impact of risk factors on CINV prevention.
METHODS
This was a pragmatic, multicenter, randomized, prospective study. Oral NEPA was administered as a single dose on day 1, while aprepitant was given on days 1-3 + ondansetron on day 1; all patients were to receive dexamethasone on days 1-4. Patients were chemotherapy-naïve and receiving MEC, with a subset evaluation of those with a risk factor for developing CINV (i.e., female, male <60 years, male ≥60 years who received carboplatin, or male ≥60 years with anxiety). CR rates were compared during the extended overall (0-144 h) phase.
RESULTS
The MEC group included 211 patients; of these 181 were in the risk factor subset. Significantly higher CR rates were seen for NEPA than aprepitant during the extended overall phase for the total MEC group (NEPA 77.1%, aprepitant 57.8%, p = 0.003) and also in the subset of patients with CINV risk factors (NEPA 73.9%, aprepitant 56.2%, p = 0.012).
CONCLUSION
A single dose of NEPA, administered on day 1 only, was more effective than a 3-day aprepitant regimen in preventing CINV for an extended duration in patients receiving MEC and in those with emetic risk factors.
Topics: Humans; Male; Female; Aprepitant; Antiemetics; Vomiting; Prospective Studies; Isoquinolines; Quinuclidines; Drug Combinations; Nausea; Cyclophosphamide; Anthracyclines; Antineoplastic Agents; Dexamethasone
PubMed: 37537943
DOI: 10.1002/cam4.6121 -
The efficacy of aprepitant for the prevention of postoperative nausea and vomiting: A meta-analysis.Medicine Jul 2023Postoperative nausea and vomiting (PONV) is one of the common adverse reactions after surgery. Recent randomized controlled trials (RCTs) investigating antiemetic drugs... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Postoperative nausea and vomiting (PONV) is one of the common adverse reactions after surgery. Recent randomized controlled trials (RCTs) investigating antiemetic drugs suggest that aprepitant has the strongest antiemetic effect of any single drug. This meta-analysis aimed to explore the efficacy of aprepitant for preventing PONV based on the existing literature.
METHODS
To identify RCTs investigating the use of aprepitant for PONV prevention, we searched PubMed, Embase, and Cochrane Library databases for articles published prior to March 20, 2022. Seventeen RCTs were identified, with 3299 patients, meeting the inclusion criteria. PONV incidence, complete response, 80 mg aprepitant combined with dexamethasone and ondansetron, vomiting, nausea, and analgesic dose-response were the main outcomes measured.
RESULTS
Compared with the control group, PONV incidence was significantly reduced among those receiving aprepitant (odds ratio [OR]: 0.34; 95% confidence interval [CI]: 0.26, 0.44; P < .0001), with a more complete response (OR: 1.35; 95% CI: 1.14, 1.59; P = .0004). Supplementation of 80 mg aprepitant in combination with dexamethasone and ondansetron substantially improved the effects of PONV (OR: 0.36; 95% CI: 0.16, 0.82; P = .01). Further, administration of 80 mg aprepitant was better at preventing vomiting than nausea (OR: 8.6; 95% CI: 3.84, 19. 29; P < .00001). No statistically significant difference between the dose-response of analgesics was identified (mean difference: -1.09; 95% CI: -6.48, 4.30; P = .69). The risk of bias was assessed independently by paired evaluators.
CONCLUSION
Aprepitant effectively reduces the incidence of PONV; however, the effects of postoperative analgesia require further exploration.
Topics: Humans; Aprepitant; Postoperative Nausea and Vomiting; Ondansetron; Morpholines; Antiemetics; Vomiting; Dexamethasone
PubMed: 37478247
DOI: 10.1097/MD.0000000000034385 -
Frontiers in Genetics 2023Almost all patients treated with androgen deprivation therapy (ADT) eventually develop castration-resistant prostate cancer (CRPC). Our research aims to elucidate the...
Almost all patients treated with androgen deprivation therapy (ADT) eventually develop castration-resistant prostate cancer (CRPC). Our research aims to elucidate the potential biomarkers and molecular mechanisms that underlie the transformation of primary prostate cancer into CRPC. We collected three microarray datasets (GSE32269, GSE74367, and GSE66187) from the Gene Expression Omnibus (GEO) database for CRPC. Differentially expressed genes (DEGs) in CRPC were identified for further analyses, including Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and gene set enrichment analysis (GSEA). Weighted gene coexpression network analysis (WGCNA) and two machine learning algorithms were employed to identify potential biomarkers for CRPC. The diagnostic efficiency of the selected biomarkers was evaluated based on gene expression level and receiver operating characteristic (ROC) curve analyses. We conducted virtual screening of drugs using AutoDock Vina. experiments were performed using the Cell Counting Kit-8 (CCK-8) assay to evaluate the inhibitory effects of the drugs on CRPC cell viability. Scratch and transwell invasion assays were employed to assess the effects of the drugs on the migration and invasion abilities of prostate cancer cells. Overall, a total of 719 DEGs, consisting of 513 upregulated and 206 downregulated genes, were identified. The biological functional enrichment analysis indicated that DEGs were mainly enriched in pathways related to the cell cycle and metabolism. CCNA2 and CKS2 were identified as promising biomarkers using a combination of WGCNA, LASSO logistic regression, SVM-RFE, and Venn diagram analyses. These potential biomarkers were further validated and exhibited a strong predictive ability. The results of the virtual screening revealed Aprepitant and Dolutegravir as the optimal targeted drugs for CCNA2 and CKS2, respectively. experiments demonstrated that both Aprepitant and Dolutegravir exerted significant inhibitory effects on CRPC cells ( < 0.05), with Aprepitant displaying a superior inhibitory effect compared to Dolutegravir. The expression of CCNA2 and CKS2 increases with the progression of prostate cancer, which may be one of the driving factors for the progression of prostate cancer and can serve as diagnostic biomarkers and therapeutic targets for CRPC. Additionally, Aprepitant and Dolutegravir show potential as anti-tumor drugs for CRPC.
PubMed: 37476415
DOI: 10.3389/fgene.2023.1184704 -
European Journal of Pharmacology Sep 2023Capsaicin and allyl isothiocyanate (AITC) activate transient receptor potential (TRP) vanilloid-1 (TRPV1) and TRP ankyrin-1 (TRPA1), respectively. TRPV1 and TRPA1...
Capsaicin and allyl isothiocyanate (AITC) activate transient receptor potential (TRP) vanilloid-1 (TRPV1) and TRP ankyrin-1 (TRPA1), respectively. TRPV1 and TRPA1 expression have been identified in the gastrointestinal (GI) tract. GI mucosal functions remain largely undefined for TRPV1 and TRPA1 with side-dependence and regional differences in signalling unclear. Here we investigated TRPV1- and TRPA1-induced vectorial ion transport as changes in short-circuit current (ΔI), in defined segments of mouse colon mucosa (ascending, transverse and descending) under voltage-clamp conditions in Ussing chambers. Drugs were applied basolaterally (bl) or apically (ap). Capsaicin responses were biphasic, with primary secretory and secondary anti-secretory phases, observed with bl application only, which predominated in descending colon. AITC responses were monophasic and secretory, with ΔI dependent on colonic region (ascending vs. descending) and sidedness (bl vs. ap). Aprepitant (neurokinin-1 (NK1) antagonist, bl) and tetrodotoxin (Na channel blocker, bl) significantly inhibited capsaicin primary responses in descending colon, while GW627368 (EP4 receptor antagonist, bl) and piroxicam (cyclooxygenase inhibitor, bl) inhibited AITC responses in ascending and descending colonic mucosae. Antagonism of the calcitonin gene-related peptide (CGRP) receptor had no effect on mucosal TRPV1 signalling, while tetrodotoxin and antagonists of the 5-hydroxytryptamine-3 and 4 receptors, CGRP receptor, and EP1/2/3 receptors had no effect on mucosal TRPA1 signalling. Our data demonstrates the regional-specificity and side-dependence of colonic TRPV1 and TRPA1 signalling, with involvement of submucosal neurons and mediation by epithelial NK1 receptor activation for TRPV1, and endogenous prostaglandins and EP4 receptor activation for TRPA1 mucosal responses.
Topics: Mice; Animals; Transient Receptor Potential Channels; TRPA1 Cation Channel; Capsaicin; Tetrodotoxin; Colon; Mucous Membrane; TRPV Cation Channels
PubMed: 37394028
DOI: 10.1016/j.ejphar.2023.175897 -
The Oncologist Aug 2023A protocol was developed to evaluate the value of an NK-1 receptor antagonist for preventing nausea and vomiting resulting from highly emetogenic chemotherapy when an... (Randomized Controlled Trial)
Randomized Controlled Trial
Olanzapine With or Without Fosaprepitant for Preventing Chemotherapy Induced Nausea and Vomiting in Patients Receiving Highly Emetogenic Chemotherapy: A Phase III Randomized, Double-Blind, Placebo-Controlled Trial (ALLIANCE A221602).
PURPOSE
A protocol was developed to evaluate the value of an NK-1 receptor antagonist for preventing nausea and vomiting resulting from highly emetogenic chemotherapy when an olanzapine-based antiemetogenic regimen was used.
MATERIALS AND METHODS
A221602, a prospective double-blind, placebo-controlled clinical trial, was developed to compare 2 -olanzapine-containing antiemetic regimens, one with an NK-1 receptor antagonist (aprepitant or fosaprepitant) and one without. Trial patients had a malignant disease for which they received intravenous highly emetogenic chemotherapy (single day cisplatin ≥ 70 mg/m2 or doxorubicin plus cyclophosphamide on 1 day). Patients on both arms received commonly administered doses of a 5-HT3 receptor antagonist, dexamethasone, and olanzapine. Additionally, patients were randomized to receive an NK-1 receptor antagonist (fosaprepitant 150 mg IV or aprepitant 130 mg IV) or a corresponding placebo. The primary objective was to compare the proportion of patients with no nausea for 5 days following chemotherapy between the 2 study arms. This trial was designed to test for the noninferiority of deleting the NK-1 receptor antagonist, with noninferiority defined as a decrease in freedom from nausea by less than 10%.
RESULTS
A total of 690 patients were entered on this trial, 50% on each arm. The proportion of patients without nausea for the complete 5-day study period was 7.4% lower (upper limit of the one-sided 95% confidence interval was 13.5%) in the arm without an NK-1 receptor antagonist compared with the arm with an NK-1 receptor antagonist.
CONCLUSION
This trial did not provide sufficient evidence to support that deletion of the NK-1 receptor antagonist was as good as keeping it, as a part of a 4-drug antiemetic regimen for highly emetogenic chemotherapy (ClinicalTrials.gov Identifier: NCT03578081).
Topics: Humans; Antiemetics; Olanzapine; Aprepitant; Prospective Studies; Receptors, Neurokinin-1; Vomiting; Nausea; Antineoplastic Agents; Double-Blind Method; Dexamethasone
PubMed: 37284847
DOI: 10.1093/oncolo/oyad140 -
Daru : Journal of Faculty of Pharmacy,... Dec 2023Chemotherapy-induced nausea and vomiting are commonly experienced side effects in breast cancer (BCa) patients. Antiemetic drugs used in BCa treatment are either...
BACKGROUND
Chemotherapy-induced nausea and vomiting are commonly experienced side effects in breast cancer (BCa) patients. Antiemetic drugs used in BCa treatment are either inhibitors or inducers of cytochrome P450 (CYP) enzymes, while anticancer drugs are metabolized by CYPs.
OBJECTIVES
The purpose of the present work was to evaluate in silico drug-drug interaction (DDI) potential between BCa chemotherapeutic drugs and antiemetic agents.
METHODS
The Drug-Drug Interaction™ module of GastroPlus™ was employed to assess CYP-related interactions between antiemetic and anticancer therapy combinations. The CYP inhibitory or inducing parameters (IC, K, EC) used in simulations were obtained from the literature.
RESULTS
Analyses of twenty-three BCa drugs indicated that 22% of the chemotherapeutic drugs do not need an antiemetic agent due to their low emetogenicity, whereas 30% of the anticancer drugs are not metabolized by CYPs. The remaining eleven anticancer drugs metabolized by CYPs generated ninety-nine combinations with nine antiemetics. Simulation of DDIs suggest that about half of the pairs did not demonstrate any potential for DDI, whereas 30%, 10%, and 9% of the pairs showed weak, moderate, and strong interaction potential, respectively. In the present study, netupitant was the only antiemetic that showed strong inhibitory interactions (predicted AUC ratio > 5) with CYP3A4-metabolzied anticancer therapies (e.g., docetaxel, ribociclib, olaparib). Moderate to no interactions were observed with ondansetron, aprepitant, rolapitant, and dexamethasone in combination with anticancer agents.
CONCLUSION
It is critical to recognize that these interactions can get amplified in cancer patients because of the severity of the disease and chemotherapy toxicities. Clinicians need to be aware of the DDI likelihood of the drug combinations used in BCa treatment.
Topics: Humans; Female; Antiemetics; Breast Neoplasms; Antineoplastic Agents; Aprepitant; Drug Interactions
PubMed: 37223851
DOI: 10.1007/s40199-023-00463-1 -
Drug Delivery Dec 2023In present, there was no detailed report on the formulation optimization and quality evaluation of aprepitant (APT) injectable lipid emulsion (APT-IE). The aim of the...
In present, there was no detailed report on the formulation optimization and quality evaluation of aprepitant (APT) injectable lipid emulsion (APT-IE). The aim of the present investigation was to prepare and evaluate its properties of APT-IE loaded with an APT phospholipid complex (APT-PC) and . APT-PC was obtained by solvent evaporation with APT and phospholipids, then analyzed by -ray diffraction, Fourier transform infrared spectroscopy and differential scanning calorimetry. Lipid emulsions are a new formulation that can reduce side effects and improve drug loading.APT-IE prepared by High-pressure homogenization and optimized by response surface methodology (RSM). The proportion of sodium oleate, poloxamer 188 and soybean oil were selected as variables for the optimization. The optimal formulation of ATP-IE had the following characteristics: particle size, 82.83 ± 1.89 nm; polydispersity index, 0.243 ± 0.008; zeta potential, -59.0 ± 2.54 mV; encapsulation efficiency, 98.84%±1.43%; drug loading, 7.08 ± 0.16 mg/mL; and osmotic pressure, 301 ± 2.15 mOsmol/kg. Transmission electron microscopy images indicated that the particle diameter of APT-IE was approximately 100 nm, with a morphology of spheroidal or spherical. APT-IE exhibited sufficient stability after storage at 4 ± 2 °C for more than 6 months. The results of the pharmacokinetic study demonstrated that APT-IE had the advantages of better safety, higher bioavailability, and obvious liver targeting than APT solution (APT-SL). The area under the curve (AUC) of APT-IE was 3-fold enhanced compared with APT-SL. The targeted enhancement multiple of APT-IE to liver tissue was greater than that of APT-SL. These results suggested that APT-IE has broad clinical application and industrial production potential.
Topics: Aprepitant; Phospholipids; Emulsions; Biological Availability; Administration, Intravenous; Particle Size
PubMed: 36843571
DOI: 10.1080/10717544.2023.2183834