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Drugs Jul 2021Netupitant/palonosetron (NEPA; Akynzeo), available in oral and intravenous (IV) formulations, is a fixed-dose combination of the neurokinin 1 (NK1) receptor antagonist... (Review)
Review
Netupitant/palonosetron (NEPA; Akynzeo), available in oral and intravenous (IV) formulations, is a fixed-dose combination of the neurokinin 1 (NK1) receptor antagonist netupitant (or the prodrug, fosnetupitant, in the IV formulation) and the second-generation serotonin 3 (5-HT) receptor antagonist palonosetron. Administered as a single dose, (fos)netupitant/palonosetron (in combination with dexamethasone) is indicated for the prevention of acute and delayed chemotherapy-induced nausea and vomiting (CINV) in adults. In clinical trials, (fos)netupitant/palonosetron plus dexamethasone was associated with high complete response rates (no emesis and no rescue medication) in the acute, delayed and overall phases in patients receiving highly or moderately emetogenic chemotherapy, with efficacy maintained over multiple cycles. Further, oral netupitant/palonosetron was found to be superior to palonosetron and non-inferior to aprepitant plus granisetron in preventing CINV in individual trials. Both the oral and IV formulations of the drug combination are well tolerated. The fixed-dose combination is concordant with guideline recommendations and provides a simple and convenient option for prophylaxis against acute and delayed CINV in patients receiving highly or moderately emetogenic chemotherapy.
Topics: Administration, Intravenous; Administration, Oral; Antiemetics; Antineoplastic Agents; Clinical Trials as Topic; Dexamethasone; Drug Combinations; Drug Interactions; Humans; Isoquinolines; Nausea; Pyridines; Quinuclidines; Vomiting
PubMed: 34292534
DOI: 10.1007/s40265-021-01558-2 -
Journal of Clinical Medicine Jun 2020Acute myeloid leukemia (AML) is a heterogeneous hematological malignancy. To treat the disease successfully, new therapeutic strategies are urgently needed. One of these... (Review)
Review
Acute myeloid leukemia (AML) is a heterogeneous hematological malignancy. To treat the disease successfully, new therapeutic strategies are urgently needed. One of these strategies can be the use of neurokinin-1 receptor (NK-1R) antagonists (e.g., aprepitant), because the substance P (SP)/NK-1R system is involved in cancer progression, including AML. AML patients show an up-regulation of the NK-1R mRNA expression; human AML cell lines show immunoreactivity for both SP and the NK-1R (it is overexpressed: the truncated isoform is more expressed than the full-length form) and, via this receptor, SP and NK-1R antagonists (aprepitant, in a concentration-dependent manner) respectively exert a proliferative action or an antileukemic effect (apoptotic mechanisms are triggered by promoting oxidative stress via mitochondrial Ca overload). Aprepitant inhibits the formation of AML cell colonies and, in combination with chemotherapeutic drugs, is more effective in inducing cytotoxic effects and AML cell growth blockade. NK-1R antagonists also exert an antinociceptive effect in myeloid leukemia-induced bone pain. The antitumor effect of aprepitant is diminished when the NF-κB pathway is overactivated and the damage induced by aprepitant in cancer cells is higher than that exerted in non-cancer cells. Thus, the SP/NK-1R system is involved in AML, and aprepitant is a promising antitumor strategy against this hematological malignancy. In this review, the involvement of this system in solid and non-solid tumors (in particular in AML) is updated and the use of aprepitant as an anti-leukemic strategy for the treatment of AML is also mentioned (a dose of aprepitant (>20 mg/kg/day) for a period of time according to the response to treatment is suggested). Aprepitant is currently used in clinical practice as an anti-nausea medication.
PubMed: 32492831
DOI: 10.3390/jcm9061659 -
Cancer Chemotherapy and Pharmacology Jun 2023Oral aprepitant has a large interindividual variation in clinical responses in advanced cancer. This study aimed to characterize plasma aprepitant and its N-dealkylated...
PURPOSE
Oral aprepitant has a large interindividual variation in clinical responses in advanced cancer. This study aimed to characterize plasma aprepitant and its N-dealkylated metabolite (ND-AP) based on the cachexia status and clinical responses in head and neck cancer patients.
METHODS
Fifty-three head and neck cancer patients receiving cisplatin-based chemotherapy with oral aprepitant were enrolled. Plasma concentrations of total and free aprepitant and ND-AP were determined at 24 h after a 3-day aprepitant treatment. The clinical responses to aprepitant and degrees of cachexia status were assessed using a questionnaire and Glasgow Prognostic Score (GPS).
RESULTS
Serum albumin level was negatively correlated with the plasma concentrations of total and free aprepitant but not ND-AP. The serum albumin level had a negative correlation with the metabolic ratio of aprepitant. The patients with GPS 1 or 2 had higher plasma concentrations of total and free aprepitant than those with GPS 0. No difference was observed in the plasma concentration of ND-AP between the GPS classifications. The plasma interleukin-6 level was higher in patients with GPS 1 or 2 than 0. The absolute plasma concentration of free ND-AP was higher in patients without the delayed nausea, and its concentration to determine the occurrence was 18.9 ng/mL. The occurrence of delayed nausea had no relation with absolute plasma aprepitant.
CONCLUSION
Cancer patients with a lower serum albumin and progressive cachectic condition had a higher plasma aprepitant level. In contrast, plasma free ND-AP but not aprepitant was related to the antiemetic efficacy of oral aprepitant.
Topics: Humans; Aprepitant; Vomiting; Cachexia; Morpholines; Antiemetics; Nausea; Cisplatin; Head and Neck Neoplasms; Dexamethasone; Antineoplastic Agents
PubMed: 37140601
DOI: 10.1007/s00280-023-04537-4 -
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 -
Alimentary Pharmacology & Therapeutics May 2023Drugs which can inhibit nausea/vomiting and/or increase gastric emptying are used to treat gastroparesis, mostly 'off-label'. Within each category, they act at different... (Review)
Review
BACKGROUND
Drugs which can inhibit nausea/vomiting and/or increase gastric emptying are used to treat gastroparesis, mostly 'off-label'. Within each category, they act at different targets and modulate different physiological mechanisms.
AIMS
Address the questions: In gastroparesis, why should blocking one pathway causing vomiting, be more appropriate than another? Why might increasing gastric emptying via one mechanism be more appropriate than another?
METHODS
Drugs used clinically were identified via consensus opinions and reviews, excluding the poorly characterised. Their pharmacology was defined, mapped to mechanisms influencing vomiting and gastric emptying, and rationale developed for therapeutic use.
RESULTS
Vomiting: Rationale for 5-HT , D , H or muscarinic antagonists, and mirtazapine, amitriptyline, nortriptyline, are poor. Arguments for inhibiting central consequences of vagal afferent transmission by NK antagonism are complicated by doubts over effects on nausea. Gastric emptying: Confusion emerges because of side-effects of drugs increasing gastric emptying: Metoclopramide (5-HT agonist, D and 5-HT antagonist; also blocks some emetic stimuli and causes tardive dyskinesia) and Erythromycin (high-efficacy motilin agonist, requiring low doses to minimise side-effects). Limited trials with selective 5-HT agonists indicate variable efficacy.
CONCLUSIONS
Several drug classes inhibiting vomiting have no scientific rationale. NK antagonism has rationale but complicated by limited efficacy against nausea. Studies must resolve variable efficacy of selective 5-HT agonists and apparent superiority over motilin agonists. Overall, lack of robust activity indicates a need for novel approaches targeting nausea (e.g., modulating gastric pacemaker or vagal activity, use of receptor agonists or new targets such as GDF15) and objective assessments of nausea.
Topics: Humans; Gastroparesis; Gastric Emptying; Motilin; Serotonin; Vomiting; Nausea
PubMed: 36919196
DOI: 10.1111/apt.17466 -
Polymers Jun 2022There has been very limited work on the control loading and release of the drugs aprepitant and sofosbuvir. These drugs need a significant material for the control of...
There has been very limited work on the control loading and release of the drugs aprepitant and sofosbuvir. These drugs need a significant material for the control of their loading and release phenomenon that can supply the drug at its target site. Magnetic nanoparticles have characteristics that enable them to be applied in biomedical fields and, more specifically, as a drug delivery system when they are incorporated with a biocompatible polymer. The coating with magnetic nanoparticles is performed to increase efficiency and reduce side effects. In this regard, attempts are made to search for suitable materials retaining biocompatibility and magnetic behavior. In the present study, silica-coated iron oxide nanoparticles were incorporated with core-shell particles made of poly(2-acrylamido-2-methylpropane sulfonic acid)@butyl methacrylate to produce a magnetic composite material (MCM-PA@B) through the free radical polymerization method. The as-prepared composite materials were characterized through Fourier-transform infrared (FTIR)spectroscopy, scanning electron microscopy (SEM), X-ray diffraction analysis (XRD), energy-dispersive X-Ray Analysis (EDX), and thermogravimetric analysis (TGA), and were further investigated for the loading and release of the drugs aprepitant and sofosbuvir. The maximum loading capacity of 305.76 mg/g for aprepitant and 307 mg/g for sofosbuvir was obtained at pH 4. Various adsorption kinetic models and isotherms were applied on the loading of both drugs. From all of the results obtained, it was found that MCM-PA@B can retain the drug for more than 24 h and release it slowly, due to which it can be applied for the controlled loading and targeted release of the drugs.
PubMed: 35808726
DOI: 10.3390/polym14132681 -
Bioanalysis Mar 2021The assessment of efficacy should be paralleled with extensive pharmacokinetic parameters, and a valid bioanalytical method is a pre-condition for accurate plasma...
The assessment of efficacy should be paralleled with extensive pharmacokinetic parameters, and a valid bioanalytical method is a pre-condition for accurate plasma concentration. A simple, specific, rapid and sensitive LC-MS/MS method has been developed for quantitative analysis of aprepitant in rat plasma. A C18 column was used as stationary phase and the mobile phase consisted of a mixture of formic acid in water and formic acid in acetonitrile. Quantification was performed using multiple reaction monitoring mode. The selectivity, linearity, accuracy, precision, robustness and ruggedness of the method were evaluated in accordance with bioanalytical method validation guideline of ICH and all results were within the acceptable range. The validated LC-MS/MS method was found to be useful for the quantitative analysis of aprepitant in rat plasma samples.
Topics: Animals; Aprepitant; Chromatography, Liquid; Male; Rats; Rats, Sprague-Dawley; Tandem Mass Spectrometry
PubMed: 33682445
DOI: 10.4155/bio-2020-0293 -
International Urology and Nephrology May 2023Acute kidney injury (AKI) is a growing global health problem with increased mortality and morbidity. Cisplatin is achemotherapy drug first introduced in 1978, and since... (Review)
Review
Acute kidney injury (AKI) is a growing global health problem with increased mortality and morbidity. Cisplatin is achemotherapy drug first introduced in 1978, and since then, it became one of the most widely used and successful anti-cancer medication. However, there are risks associated with cisplatin administration, such as nephrotoxicity. Mechanisms of nephrotoxicity include proximal tubular injury, DNA damage, apoptosis, inflammation, oxidative stress, and vascular injury. Although various protocols are being used in clinical practice in nephrotoxicity prevention due to cisplatin, there are no clear guidelines regarding this approach. Most recommendations include hydration and avoiding additional nephrotoxic drugs. To prevent nephrotoxicity, future perspectives could rely on natural products, such as flavonoids or saponins or pharmacological products, such as aprepitant, but data are scarce in this direction. Repetitive administration of cisplatin could cause subclinical kidney injury, which over time, leads to chronic kidney disease (CKD). Therefore, more studies are needed to determine possible ways to prevent nephrotoxicity and avoid the burden of CKD worldwide.
Topics: Humans; Cisplatin; Acute Kidney Injury; Kidney; Renal Insufficiency, Chronic; Neoplasms; Apoptosis
PubMed: 36508071
DOI: 10.1007/s11255-022-03418-8 -
International Journal of Clinical... 2022The significance of this article is to talk about aprepitant and olanzapine 5 mg, compare them, and deeply explore the safety or effectiveness during the whole process... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
The significance of this article is to talk about aprepitant and olanzapine 5 mg, compare them, and deeply explore the safety or effectiveness during the whole process of multiple-day cisplatin chemotherapy-induced vomiting and nausea.
METHODS
This trial was randomized and prospective. It is needed to receive cisplatin chemotherapy (25 mg/m2/d) for three days. Its patients would need to choose to use 5 mg olanzapine or aprepitant for this treatment, combined with 5-HT3 receptor antagonist plus dexamethasone. The primary endpoints were the total protection (TP) during the acute phase (AP) (0-24 hours), delayed phase (DP) (25-120 hours), and overall phase (OP) (0-120 h) between the two groups. The secondary endpoints were the complete response (CR) and total control (TC) during the three phases. The first time of the whole process is particularly important and needs to be observed vigorously. However, the time of the patient's first vomiting symptom is also compared accurately by using the Kaplan-Meier curve. The functional life index vomiting (FLIE) was used to calculate and carefully evaluate the serious impact of nausea and vomiting (CINV) induced by the whole chemotherapy process on the quality of life. About olanzapine, its related symptoms and other side effects and aprepitant were also recorded.
RESULTS
(1) The primary endpoint TP rates of the olanzapine and aprepitant groups were similar; for the AP, they were 94.23% (98/104) vs. 95.45% (98/106) =0.61(=0.61); for the DP, they were 54.81% (57/104) vs. 54.72% (58/106) (=0.99), and for the OP, the values were 53.79% (58/105) and 55.31% (56/104), respectively (=0.99). The secondary endpoints, the TC rates, and CR rates were also comparable in the three phases ( > 0.05). (2) After research and display, the results showed that there was no significant difference between the two groups when they were used for the first time of vomiting and the FLIE index ( > 0.05). (3) The main olanzapine-related adverse event was drowsiness, while that of aprepitant was constipation.
CONCLUSION
The efficacy of 5 mg olanzapine was similar to that of aprepitant, and it also showed an advantageous economic potency ratio in preventing CINV induced by multiple-day cisplatin chemotherapy with increased sedation side effects.
Topics: Antiemetics; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Aprepitant; Cisplatin; Dexamethasone; Humans; Nausea; Olanzapine; Prospective Studies; Quality of Life; Receptors, Serotonin, 5-HT3; Vomiting
PubMed: 36128262
DOI: 10.1155/2022/5954379 -
Best Practice & Research. Clinical... Dec 2020Postoperative nausea and vomiting (PONV) afflict approximately 30% of patients overall and up to 80% of high-risk patients after surgery. Optimal pharmacological... (Review)
Review
Postoperative nausea and vomiting (PONV) afflict approximately 30% of patients overall and up to 80% of high-risk patients after surgery. Optimal pharmacological prophylaxis of PONV is challenging as it necessitates the consideration of PONV risk, drug efficacy, and potential adverse effects. Despite significant advances in our understanding of the pathophysiology and risk factors of PONV, its incidence has remained largely unchanged. Newer antiemetics have been introduced that may have improved safety profiles, longer duration of action, and better efficacy. This review aims to summarize the recent developments pertaining to these new agents and their potential application toward the management of PONV.
Topics: Antiemetics; Aprepitant; Disease Management; Dopamine Antagonists; Drug Therapy, Combination; Humans; Neurokinin-1 Receptor Antagonists; Palonosetron; Postoperative Nausea and Vomiting; Randomized Controlled Trials as Topic; Serotonin 5-HT3 Receptor Antagonists
PubMed: 33288125
DOI: 10.1016/j.bpa.2020.11.004