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Annals of Palliative Medicine Apr 2021Researchers have not clearly determined whether adding aprepitant (ADH) to dexamethasone and one 5-HT3 receptor antagonist (DH) is clinically effective at preventing... (Meta-Analysis)
Meta-Analysis
Use of dexamethasone and a 5-HT3 receptor antagonist with or without aprepitant to prevent chemotherapy-induced nausea and vomiting among patients with lung cancer who are treated with platinum-based chemotherapy: a systematic review and meta-analysis of randomized controlled trials.
BACKGROUND
Researchers have not clearly determined whether adding aprepitant (ADH) to dexamethasone and one 5-HT3 receptor antagonist (DH) is clinically effective at preventing chemotherapy-induced nausea and vomiting (CINV) among patients with lung cancer (LC) treated with platinum-based chemotherapy (PBC). Therefore, we conducted a meta-analysis to examine the efficacy and safety of ADH and DH.
METHODS
We searched the PubMed, ScienceDirect, Cochrane Library, and Scopus databases, among others, for relevant studies. The primary outcomes were the complete response (CR) and the no nausea rate (NNR). The secondary endpoints were the number of patients who needed rescue antiemetic treatment (RAT), adverse events (AEs), and the Functional Living Index Emesis (FLIE) score.
RESULTS
We initially screened 2,118 articles; ultimately, four randomized controlled trials (RCTs) with 518 patients were included. The ADH group had a superior overall CR [risk ratio (RR): 1.16 (1.06, 1.27), P=0.002] and a lower number of patients who needed RAT [RR: 0.44 (0.29, 0.65), P<0.0001]. The ADH group also had a better overall NNR [RR: 1.11 (0.97, 1.26), P=0.12] and delayed CR [RR: 1.12 (0.97, 1.31), P=0.13]. No significant differences were observed in acute CR, acute NNR, or delayed NNR. In the subgroup analysis of the overall CR and NNR, ADH was superior in certain clinical characteristics (China, cisplatin-based chemotherapy, 2nd-generation 5-HT3 receptor antagonist, ADC <50%, and Eastern Cooperative Oncology Group (ECOG) score of 0-2). No significant differences in the AEs characterized as hematological or nonhematological toxicity were observed between the groups.
CONCLUSIONS
Compared with DH, ADH appears to be superior at preventing CINV and achieving a better CR among patients with LC treated with PBC.
Topics: Antiemetics; Antineoplastic Agents; Aprepitant; China; Dexamethasone; Humans; Lung Neoplasms; Morpholines; Nausea; Platinum; Randomized Controlled Trials as Topic; Receptors, Serotonin, 5-HT3; Vomiting
PubMed: 33894731
DOI: 10.21037/apm-20-2290 -
JAMA Network Open Apr 2021The prevention of chemotherapy-induced nausea and vomiting has an important role in the overall management of cancer treatment. (Randomized Controlled Trial)
Randomized Controlled Trial
IMPORTANCE
The prevention of chemotherapy-induced nausea and vomiting has an important role in the overall management of cancer treatment.
OBJECTIVE
To evaluate whether adding aprepitant to palonosetron and dexamethasone can further prevent the incidence and severity of nausea and vomiting caused by FOLFIRI (fluorouracil, leucovorin, and irinotecan) or FOLFOX (fluorouracil, leucovorin, and oxaliplatin) chemotherapy regimens among women with gastrointestinal cancer at higher risk.
DESIGN, SETTING, AND PARTICIPANTS
This phase 3, double-blind, placebo-controlled randomized clinical trial recruited young women (age ≤50 years) who drank little or no alcohol and had gastrointestinal cancer for which they received FOLFOX or FOLFIRI chemotherapy. A total of 248 women were enrolled and assigned in the ratio 1:1 to intervention and control groups from August 4, 2015, to March 31, 2020. Intention-to-treat analysis was used to evaluate patient baseline characteristics and efficacy. The analysis was conducted on October 30, 2020.
INTERVENTIONS
Patients were randomly assigned to the aprepitant group (aprepitant, 125 mg, orally 60 minutes before initiation of chemotherapy on day 1 and 80 mg orally each morning of days 2 and 3; palonosetron, 0.25 mg, intravenously; and dexamethasone, 6 mg, orally 30 minutes before chemotherapy initiation on day 1) or the placebo group (placebo, 125 mg, orally 60 minutes before initiation of chemotherapy on day 1 and 80 mg orally on each morning of days 2 and 3; palonosetron, 0.25 mg, intravenously; and dexamethasone, 12 mg, orally 30 minutes before chemotherapy initiation on day 1).
MAIN OUTCOMES AND MEASURES
The primary end point was the complete response (CR) rate, defined as the proportion of patients without emesis episodes or rescue medication use during the overall phase of the first cycle. Other efficacy indicators, such as no vomiting and no nausea, were measured as the secondary and exploratory end points.
RESULTS
A total of 248 women from 4 clinical centers in China entered this study, and 243 patients (aprepitant regimen, 125 patients [51.4%]; placebo regimen, 118 patients [48.5%]) were evaluable for efficacy and safety; mean (SD) age of the total population was 40.1 (7.3) years. The CR rate was significantly higher in the aprepitant group vs the control group overall (107 [87.0%] vs 80 [66.7%]; P < .001) and in the acute (114 [92.7%] vs 91 [75.8%]; P = .001) and delayed (109 [88.6%] vs 84 [70.0%]; P = .001) phases of the trial. The incidence of adverse events was similar between the 2 groups (100 [80.0%] vs 96 [81.3%]; P = .79), and no grade 3 or 4 aprepitant treatment-related adverse events were observed. Multivariable analysis revealed that aprepitant use was the only independent factor associated with CR during the overall phase.
CONCLUSIONS AND RELEVANCE
The combination of aprepitant with palonosetron and dexamethasone provided increased antiemetic efficacy in the FOLFOX or FOLFIRI chemotherapy regimen and was well tolerated by younger women with gastrointestinal cancer who have a history of little or no alcohol consumption.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT03674294.
Topics: Adult; Antiemetics; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Aprepitant; Camptothecin; China; Double-Blind Method; Female; Fluorouracil; Humans; Leucovorin; Middle Aged; Nausea; Organoplatinum Compounds; Stomach Neoplasms; Vomiting
PubMed: 33835174
DOI: 10.1001/jamanetworkopen.2021.5250 -
Cancers Mar 2022Glioblastoma stem-like cells (GSCs) drive tumor initiation, cancer invasion, immune evasion, and therapeutic resistance and are thus a key therapeutic target for...
Glioblastoma stem-like cells (GSCs) drive tumor initiation, cancer invasion, immune evasion, and therapeutic resistance and are thus a key therapeutic target for improving treatment for glioblastoma multiforme (GBM). We previously identified calcium/calmodulin-dependent protein kinase II (CaMKII) as an emerging molecular target for eliminating GSCs. In this study, we aim to explore a new CaMKII-targeted synthetic lethal therapy for GSCs. Through high-throughput drug combination screening using CaMKII inhibitors and a bioactive compound library in GSCs, neurokinin 1 receptor (NK1R) inhibitors such as SR 140333 and aprepitant are found to be potential anticancer agents that exhibit chemical synthetic lethal interactions with CaMKII inhibitors, including hydrazinobenzoylcurcumin (HBC), berbamine, and KN93. Combined treatment with NK1R and CaMKII inhibitors markedly suppresses the viability and neurosphere formation of U87MG- and U373MG-derived GSCs. In addition, the combination of HBC and NK1R inhibitors significantly inhibits U87MG GSC tumor growth in a chick embryo chorioallantoic membrane (CAM) model. Furthermore, the synthetic lethal interaction is validated using RNA interference of CaMKIIγ and NK1R. Notably, the synthetic lethal effects in GSCs are associated with the activation of caspase-mediated apoptosis by inducing p53 expression and reactive oxygen species generation, as well as the suppression of stemness marker expression by reducing nuclear factor-kappa B (NF-κB) activity. This follows the downregulation of phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling and a decrease in intracellular calcium concentration. Moreover, NK1R affects CaMKIIγ activation. These findings demonstrate that NK1R is a potential synthetic lethal partner of CaMKII that is involved in eradicating GSCs, and they suggest a new CaMKII-targeted combination therapy for treating GBM.
PubMed: 35267623
DOI: 10.3390/cancers14051315 -
Hematology, Transfusion and Cell Therapy 2023This study was performed to evaluate the degree of 3-day chemotherapy-induced nausea and vomiting (CINV) in children with cancer who received highly emetogenic...
Evaluating Aprepitant single-dose plus granisetron and dexamethasone in children receiving highly emetogenic chemotherapy for the prevention of chemotherapy-induced nausea and vomiting: A triple-blinded randomized clinical trial.
INTRODUCTION
This study was performed to evaluate the degree of 3-day chemotherapy-induced nausea and vomiting (CINV) in children with cancer who received highly emetogenic chemotherapy (HEC) to ascertain the efficacy of aprepitant single-dose on dayL 1 plus granisetron and dexamethasone (DEX).
METHODS
This clinical trial study was conducted on 120 patients in the age range of 5 to 18 years old who received chemotherapy. Patients were divided into two groups; Group A received aprepitant at 125 mg/kg on day 1 orally, followed by 80 mg/kg daily on days 2 and 3 and Group B received a single dose of aprepitant 125 mg/kg on day 1 orally and placebo on days 2 and 3. All groups received granisetron 3 mg/m on day 1 and DEX on days 1 to 3. The primary and secondary endpoints were to evaluate the proportion of patients with acute, delayed and overall CINV within each group.
RESULTS
There were no significant differences between the two groups for vomiting, nausea or the use of rescue therapy. The number of patients without vomiting on day 1 was similar in both groups (96.5% vs. 98.3%, respectively; p = 0.848).
CONCLUSION
According to the results of this study, a single dose of aprepitant 125 mg/kg was as effective as administering three doses of aprepitant on 3 days. Therefore, the use of a single dose of aprepitant in combination with other standard treatment regimens to prevent CINV in children who received HEC was safe and efficacious and can be beneficial.
PubMed: 35428609
DOI: 10.1016/j.htct.2022.02.004 -
Journal of Zhejiang University.... Feb 2024Recently, the substance P (SP)/neurokinin-1 receptor (NK-1R) system has been found to be involved in various human pathophysiological disorders including the symptoms of... (Review)
Review
Recently, the substance P (SP)/neurokinin-1 receptor (NK-1R) system has been found to be involved in various human pathophysiological disorders including the symptoms of coronavirus disease 2019 (COVID-19). Besides, studies in the oncological field have demonstrated an intricate correlation between the upregulation of NK-1R and the activation of SP/NK-1R system with the progression of multiple carcinoma types and poor clinical prognosis. These findings indicate that the modulation of SP/NK-1R system with NK-1R antagonists can be a potential broad-spectrum antitumor strategy. This review updates the latest potential and applications of NK-1R antagonists in the treatment of human diseases and cancers, as well as the underlying mechanisms. Furthermore, the strategies to improve the bioavailability and efficacy of NK-1R antagonist drugs are summarized, such as solid dispersion systems, nanonization, and nanoencapsulation. As a radiopharmaceutical therapeutic, the NK-1R antagonist aprepitant was originally developed as radioligand receptor to target NK-1R-overexpressing tumors. However, combining NK-1R antagonists with other drugs can produce a synergistic effect, thereby enhancing the therapeutic effect, alleviating the symptoms, and improving patients quality of life in several diseases and cancers.
Topics: Humans; Neurokinin-1 Receptor Antagonists; Quality of Life; Substance P; Receptors, Neurokinin-1; Neoplasms
PubMed: 38303494
DOI: 10.1631/jzus.B2300455 -
Journal of Research in Medical Sciences... Apr 2015Depending on the site of irradiation, about 40-80% of patients undergoing radiotherapy (RT) will experience nausea and/or vomiting. The current study aimed to...
BACKGROUND
Depending on the site of irradiation, about 40-80% of patients undergoing radiotherapy (RT) will experience nausea and/or vomiting. The current study aimed to investigate the efficacy of ondansetronas as a single agent and with a combination to aprepitant on preventing RT-induced nausea and vomiting (RINV).
MATERIALS AND METHODS
In a clinical randomized controlled trial (from September 2010 to September 2011), conducted in Radiation Oncology Department of Seyed-al-Shohada Hospital, Isfahan University of Medical Sciences, 40 abdominopelvic malignancies cancer patients were allocated into two aliquots using block randomization of size. Patients in the first group (group I) received ondansetron alone while those patients in the remaining group (group II) received ondansetron and aprepitant. Then, developing of RINV and its severity and benefit of adding aprepitant to ondansetron, in comparison with ondansetron as a single drug therapy were evaluated.
RESULTS
The average age of the patients in group I was 61.15 ± 12.27 years while in group II it was 50.1 ± 13.27 years. No statistically significant gender differences were found between the two groups. In patients treated with ondansetron single drug therapy (group I), frequency and grade of RINV were significantly more than the group treated simultaneously by aprepitant and ondansetron (group II) (odds ratio [OR] = 21.2; P < 0.01). Compared with RT alone, the patients whom underwent RT along with chemotherapy showed lower probability of experiencing RINV (OR = 0.13; P < 0.05).
CONCLUSION
The present study indicated a significant superiority of combination of ondansetron and aprepitant in management of RINV, in patients undergoing RT, compared to ondansetron as a single agent therapy. More accurate follow-up studies are needed for the evaluation of the efficacy of ondansetron with combination to aprepitant on preventing the RINV.
PubMed: 26109986
DOI: No ID Found -
ACS Chemical Neuroscience Sep 2022Recent high-resolution structures of alpha-synuclein (aSyn) fibrils offer promise for rational approaches to drug discovery for Parkinson's disease and Lewy body...
Recent high-resolution structures of alpha-synuclein (aSyn) fibrils offer promise for rational approaches to drug discovery for Parkinson's disease and Lewy body dementia. Harnessing the first such structures, we previously used molecular dynamics and free energy calculations to suggest that threonines 72 and 75─which line water-filled cavities within the fibril stacks─may be of central importance in stabilizing fibrils. Here, we used experimental mutagenesis of both wild-type and A53T aSyn to show that both threonine residues play important but surprisingly disparate roles in fibril nucleation and elongation. The T72A mutant, but not T75A, resulted in a large increase in the extent of fibrillization during primary nucleation, leading us to posit that T72 acts as a "brake" on run-away aggregation. An expanded set of simulations of five recent high-resolution fibril structures suggests that confinement of cavity waters around T72 correlates with this finding. In contrast, the T75A mutation led to a modest decrease in the extent of fibrillization. Furthermore, both T72A and T75A completely blocked the initial fibril elongation in seeded fibrillization. To test whether these threonine-lined cavities are druggable targets, we used computational docking to identify potential small-molecule binders. We show that the top-scoring hit, aprepitant, strongly promotes fibril growth while specifically interacting with aSyn fibrils and not monomer, and we offer speculation as to how such compounds could be used therapeutically.
Topics: Humans; Lewy Body Disease; Mutation; Parkinson Disease; Threonine; alpha-Synuclein
PubMed: 36001084
DOI: 10.1021/acschemneuro.2c00327 -
Gastroenterology Jan 2018There are few effective treatments for nausea and other symptoms in patients with gastroparesis and related syndromes. We performed a randomized trial of the ability of... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND & AIMS
There are few effective treatments for nausea and other symptoms in patients with gastroparesis and related syndromes. We performed a randomized trial of the ability of the neurokinin-1 receptor antagonist aprepitant to reduce symptoms in patients with chronic nausea and vomiting caused by gastroparesis or gastroparesis-like syndrome.
METHODS
We conducted a 4-week multicenter, double-masked trial of 126 patients with at least moderate symptoms of chronic nausea and vomiting of presumed gastric origin for a minimum of 6 months. Patients were randomly assigned to groups given oral aprepitant (125 mg/day, n = 63) or placebo (n = 63). The primary outcome from the intention-to-treat analysis was reduction in nausea, defined as a decrease of 25 mm or more, or absolute level below 25 mm, on a daily patient-reported 0-to-100 visual analog scale (VAS) of nausea severity. We calculated relative risks of nausea improvement using stratified Cochran-Mental-Haenszel analysis.
RESULTS
Aprepitant did not reduce symptoms of nausea, based on the primary outcome measure (46% reduction in the VAS score in the aprepitant group vs 40% reduction in the placebo group; relative risk, 1.2; 95% CI, 0.8-1.7) (P = .43). However, patients in the aprepitant group had significant changes in secondary outcomes such as reduction in symptom severity (measured by the 0-5 Gastroparesis Clinical Symptom Index) for nausea (1.8 vs 1.0; P = .005), vomiting (1.6 vs 0.5; P = .001), and overall symptoms (1.3 vs 0.7; P = .001). Adverse events, predominantly mild or moderate in severity grade, were more common in aprepitant (22 of 63 patients, 35% vs 11 of 63, 17% in the placebo group) (P = .04).
CONCLUSIONS
In a randomized trial of patients with chronic nausea and vomiting caused by gastroparesis or gastroparesis-like syndrome, aprepitant did not reduce the severity of nausea when reduction in VAS score was used as the primary outcome. However, aprepitant had varying effects on secondary outcomes of symptom improvement. These findings support the need to identify appropriate patient outcomes for trials of therapies for gastroparesis, including potential additional trials for aprepitant. ClinicalTrials.gov no: NCT01149369.
Topics: Adult; Antiemetics; Aprepitant; Chronic Disease; Double-Blind Method; Female; Gastroparesis; Humans; Male; Middle Aged; Morpholines; Nausea; Treatment Outcome; Vomiting
PubMed: 29111115
DOI: 10.1053/j.gastro.2017.08.033 -
OncoTargets and Therapy 2018To examine pharmacologic and clinical characteristics of neurokinin 1 (NK)-receptor antagonists (RAs) for preventing chemotherapy-induced nausea and vomiting (CINV)... (Review)
Review
To examine pharmacologic and clinical characteristics of neurokinin 1 (NK)-receptor antagonists (RAs) for preventing chemotherapy-induced nausea and vomiting (CINV) following highly or moderately emetogenic chemotherapy, a literature search was performed for clinical studies in patients at risk of CINV with any approved NK RAs in the title or abstract: aprepitant (capsules or oral suspension), HTX019 (intravenous [IV] aprepitant), fosaprepitant (IV aprepitant prodrug), rolapitant (tablets or IV), and fixed-dose tablets combining netupitant or fosnetupi-tant (IV netupitant prodrug) with the 5-hydroxytryptamine type 3 (5HT) RA palonosetron (oral or IV). All NK RAs are effective, but exhibit important differences in efficacy against acute and delayed CINV. The magnitude of benefit of NK-RA-containing three-drug vs two-drug regimens is greater for delayed vs acute CINV. Oral rolapitant has the longest half-life of available NK RAs, but as a consequence should not be administered more frequently than every 2 weeks. In general, NK RAs are well tolerated; however, IV rolapitant was recently removed from US distribution, due to hypersensitivity and anaphylaxis, and IV fosaprepitant is associated with infusion-site reactions and hypersensitivity presumed related to its polysorbate 80 excipient. Also, available NK RAs have potential drug-drug interactions. Adding an NK RA to 5HT RA and dexamethasone significantly improves CINV control vs the two-drug regimen. Newer NK RAs offer more formulation options, higher acute-phase plasma levels, or improved tolerability, and increase clinicians' opportunities to maximize benefits of this important class of antiemetics.
PubMed: 30323622
DOI: 10.2147/OTT.S158570