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Scientific Reports May 2024The supercritical antisolvent (SAS) process was a green alternative to improve the low bioavailability of insoluble drugs. However, it is difficult for SAS process to...
The supercritical antisolvent (SAS) process was a green alternative to improve the low bioavailability of insoluble drugs. However, it is difficult for SAS process to industrialize with limited production capacity. A coaxial annular nozzle was used to prepare the microcapsules of aprepitant (APR) and polyvinylpyrrolidone (PVP) by SAS with N, N-Dimethylformamide (DMF) as solvent. Meanwhile, the effects of polymer/drug ratio, operating pressure, operating temperature and overall concentration on particles morphology, mean particle diameter and size distribution were analyzed. Microcapsules with mean diameters ranging from 2.04 μm and 9.84 μm were successfully produced. The morphology, particle size, thermal behavior, crystallinity, drug content, drug dissolution and residual amount of DMF of samples were analyzed. The results revealed that the APR drug dissolution of the microcapsules by SAS process was faster than the unprocessed APR. Furthermore, the drug powder collected every hour is in the kilogram level, verifying the possibility to scale up the production of pharmaceuticals employing the SAS process from an industrial point of view.
Topics: Capsules; Povidone; Solvents; Aprepitant; Particle Size; Solubility; Dimethylformamide; Drug Liberation; Drug Compounding; Temperature
PubMed: 38724534
DOI: 10.1038/s41598-024-60323-z -
Pharmaceuticals (Basel, Switzerland) May 2024The management of chemotherapy-induced nausea and vomiting (CINV) in children remains challenging due to differences in the chemotherapy regimens, their relative... (Review)
Review
The management of chemotherapy-induced nausea and vomiting (CINV) in children remains challenging due to differences in the chemotherapy regimens, their relative emetogenicity compared to that in adults and differences in drug metabolism and the available formulations. The common four classes of anti-emetics used for the treatment and prophylaxis of CINV in children include dexamethasone, neurokinin-1 receptor antagonists, 5-hydroxytryptamine-3 receptor antagonists (5HT3RAs), and olanzapine. The appropriate dose of dexamethasone for CINV prophylaxis in children is unknown, with a significant variability in dosage ranging between 6 and 32 mg/m/day. The dose of dexamethasone is decreased by 30% when this drug is combined with (fos)aprepitant in children, in contrast to a decrease of 50% required in adults. The use of aprepitant in younger children (<12 years) is often hampered by the non-availability of oral suspension formulations in many countries; alternatively, 80 mg capsules are administered for 1-3 days in certain institutes to children weighing between 15 and 40 kg. Among the different 5HT3RAs, palonosetron is comparatively metabolized faster in children than in adults, requiring a higher dosage for similar efficacy to that achieved in adults. Olanzapine is a newer agent, used in doses between 0.1 and 0.14 mg/kg/day in children, with good anti-emetic efficacy, but has sedation and hyperglycemia as concerning adverse effects. Drug interactions between anti-emetics and between anti-emetics and chemotherapy/supportive agents (azole antifungals, cyclosporine, arsenic trioxide), especially QTc prolongation, should be considered during prescription.
PubMed: 38794186
DOI: 10.3390/ph17050616 -
Advances in Anesthesia Dec 2023This article's objective is to present the latest evidence and information on the management of postoperative nausea and vomiting (PONV). PONV continues to affect 30% of... (Review)
Review
This article's objective is to present the latest evidence and information on the management of postoperative nausea and vomiting (PONV). PONV continues to affect 30% of the surgical population causing patient dissatisfaction, extending length of stay, and increasing overall costs. This review includes the introduction of 2 new intravenous formulations of antiemetics (amisulpride, aprepitant), updates on nontraditional therapies, suggestions for combination prophylaxis, emerging data on rescue treatment, and considerations for special populations and settings. Both of the new antiemetics provide promising options for pharmacologic interventions for PONV with favorable safety profiles.
Topics: Humans; Postoperative Nausea and Vomiting; Antiemetics; Combined Modality Therapy; Aprepitant; Administration, Intravenous
PubMed: 38251617
DOI: 10.1016/j.aan.2023.05.002 -
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 -
Journal of Cancer Research and Clinical... Aug 2023Exosomes are membrane-derived nano-vesicles upregulated in pathological conditions like cancer. Therefore, inhibiting their release is a potential strategy for the...
PURPOSE
Exosomes are membrane-derived nano-vesicles upregulated in pathological conditions like cancer. Therefore, inhibiting their release is a potential strategy for the development of more efficient combination therapies. Neutral sphingomyelinase 2 (nSMase2) is a key component in exosome release; however, a clinically safe yet efficient nSMase2 inhibitor remains to be used discovered. Accordingly, we made an effort to identify potential nSMase2 inhibitor(s) among the approved drugs.
METHODS
Virtual screening was performed and aprepitant was selected for further investigation. To evaluate the reliability of the complex, molecular dynamics were performed. Finally, using the CCK-8 assay in HCT116 cells, the highest non-toxic concentrations of aprepitant were identified and the nSMase2 activity assay was performed to measure the inhibitory activity of aprepitant, in vitro.
RESULTS
To validate the screening results, molecular docking was performed, and the retrieved scores were in line with the screening results. The root-mean-square deviation (RMSD) plot of aprepitant-nSMase2 showed proper convergence. Following treatment with different concentrations of aprepitant in both cell-free and cell-dependent assays, nSMase2 activity was remarkably decreased.
CONCLUSION
Aprepitant, at a concentration as low as 15 µM, was able to inhibit nSmase2 activity in HCT116 cells without any significant effects on their viability. Aprepitant is therefore suggested to be a potentially safe exosome release inhibitor.
Topics: Humans; Exosomes; Sphingomyelin Phosphodiesterase; Aprepitant; Molecular Docking Simulation; Reproducibility of Results; Early Detection of Cancer; Neoplasms
PubMed: 36884117
DOI: 10.1007/s00432-023-04674-6 -
Translational Pediatrics Jan 2024Neurokinin-1 receptor antagonists have improved the management of chemotherapy-induced nausea and vomiting (CINV), but to date there has been no prospective comparison...
Comparison of oral aprepitant and intravenous fosaprepitant for prevention of chemotherapy-induced nausea and vomiting in pediatric oncology patients: a randomized phase III trial.
BACKGROUND
Neurokinin-1 receptor antagonists have improved the management of chemotherapy-induced nausea and vomiting (CINV), but to date there has been no prospective comparison between oral aprepitant and intravenous fosaprepitant in pediatric oncology patients.
METHODS
Our study was a double-parallel study, and the distribution ratio was 1:1. Children aged 2-12 years who were undergoing moderate or highly emetogenic chemotherapy (MEC or HEC) were randomly assigned to receive ondansetron and dexamethasone combined with either a single dose of intravenous fosaprepitant (arm A), or 3 days of oral aprepitant (arm B). The primary outcome measure was the rate of complete response (CR) of CINV within the acute phase, defined as from the start through 24 hours after the last chemotherapy dose. Response during the delayed phase, overall response, and use of rescue antiemetics were also assessed.
RESULTS
We prospectively evaluated 108 eligible patients, including 55 receiving fosaprepitant. Study observations were made during a single cycle for each patient. The occurrence of CR in the acute phase was statistically higher for patients receiving fosaprepitant (95% 79%, P=0.018<0.05). Modest differences were seen in CR rates during the delayed phase (71% 66%, P=0.586), and overall response rate (69% 57%, P=0.179). The use of antiemetic rescue medicines was similar between arms A (11%) and B (7%).
CONCLUSIONS
Fosaprepitant produced more CRs of CINV in the acute phase than did aprepitant, although there were no statistical differences in delayed phase response, overall response, or use of rescue antiemetics. This study confirms the safety, efficacy, and potential advantages of fosaprepitant in reducing CINV in pediatric oncology patients.
TRIAL REGISTRATION
ClinicalTrials.gov identifier: NCT04873284.
PubMed: 38323173
DOI: 10.21037/tp-23-598 -
Obesity Surgery Apr 2024Laparoscopic sleeve gastrectomy (LSG) is associated with postoperative nausea and vomiting (PONV). We aimed to compare the effects of aprepitant on the incidence of PONV... (Randomized Controlled Trial)
Randomized Controlled Trial
INTRODUCTION
Laparoscopic sleeve gastrectomy (LSG) is associated with postoperative nausea and vomiting (PONV). We aimed to compare the effects of aprepitant on the incidence of PONV after LSG.
METHODS
In this double-blind, randomized controlled trial, the case group received the standard care regimen for PONV (dexamethasone 10 mg, ondansetron 4 mg, and metoclopramide 10 mg) plus prophylactic oral aprepitant 80 mg 1 h preoperatively. The control group received standard care plus a placebo. Comparative analyses using the Rhodes index were performed at 0, 6, 12, and 24 h postoperatively.
RESULTS
A total of 400 patients (201 in the aprepitant group and 199 in the placebo group) underwent LSG. The groups were homogeneous. The aprepitant group experienced less PONV: early, 69 (34.3%) vs. 103 (51.7%), p ≤ 0.001; 6 h, 67 (33.3%) vs. 131 (65.8%), p ≤ 0.001; 12 h, 41 (20.4%) vs. 115 (57.8%), p ≤ 0.001; and 24 h, 22 (10.9%) vs. 67 (33.7%), p ≤ 0.001. Fewer patients in the aprepitant group vomited: early, 3 (1.5%) vs. 5 (2.5%), p = 0.020; 6 h, 6 (3%) vs. 18 (9%), p = 0.020; 12 h, 2 (1%) vs. 17 (8.5%), p = 0.006; and 24 h, 1 (0.5%) vs. 6 (3%), p = 0.040. Patients in the aprepitant group required less additional PONV medication: early, 61 (30.3%) vs. 86 (43.2), p = 0.008; 6 h, 7 (3.5%) vs. 34 (17%), p = 0.001; 12 h, 6 (3%) vs. 31 (15.6%), p ≤ 0.001; and 24 h, 5 (2.5%) vs. 11 (5.5%), p ≤ 0.001.
CONCLUSIONS
Prophylactic aprepitant improved PONV between 0 h (early) and 24 h postoperatively in patients undergoing LSG.
Topics: Humans; Aprepitant; Antiemetics; Postoperative Nausea and Vomiting; Obesity, Morbid; Gastrectomy; Double-Blind Method; Laparoscopy
PubMed: 38429485
DOI: 10.1007/s11695-024-07129-0 -
Investigational New Drugs Feb 2024Dexamethasone is one of the key antiemetic agents and is widely used even now. However, dexamethasone has been associated with several adverse reactions even after...
Dexamethasone is one of the key antiemetic agents and is widely used even now. However, dexamethasone has been associated with several adverse reactions even after short-term administration. Therefore, developing a steroid-free antiemetic regimen is an important issue to consider. Thus, the purpose of this study was to investigate the efficacy and safety of palonosetron, aprepitant, and olanzapine in a multi-institutional phase II study. Chemotherapy-naive patients scheduled to receive cisplatin were enrolled and evaluated for the occurrence of chemotherapy-induced nausea and vomiting during 120 h after chemotherapy. The primary endpoint of the study was total control (TC) in the overall phase. The key secondary endpoint was complete response (CR), which was assessed in the acute, delayed, and overall phase, respectively. Adverse events were evaluated according to the Common Terminology Criteria for Adverse Events. Eighty-five patients were enrolled from 8 centers in Japan, of which 83 were evaluable for analyses. The percentage of patients who achieved TC during the overall phase was 31.3%. CR was achieved in 61.4%, 84.3%, and 65.1% of patients during the overall, acute, and delayed phases, respectively. The most frequently reported adverse event was anorexia. The primary endpoint was below the threshold and we could not find benefit in the dexamethasone-free regimen, but CR during the overall phase was similar to that of the conventional three-drug regimen. This antiemetic regimen without dexamethasone might be an option for patients for whom corticosteroids should not be an active application.
Topics: Humans; Antiemetics; Aprepitant; Cisplatin; Dexamethasone; Olanzapine; Palonosetron; Pathologic Complete Response
PubMed: 38055127
DOI: 10.1007/s10637-023-01414-y -
European Journal of Medicinal Chemistry Jan 2024Different studies using Aprepitant, a NK1R antagonist currently used as a clinical drug for treating chemotherapy-related nausea and vomiting, have demonstrated that...
Different studies using Aprepitant, a NK1R antagonist currently used as a clinical drug for treating chemotherapy-related nausea and vomiting, have demonstrated that pharmacological inhibition of NK1R effectively reduces the growth of several tumor types such as neuroblastoma (NB). In a previous work, we demonstrated that a series of carbohydrate-based Aprepitant analogs, derived from either d-galactose or l-arabinose, have shown high affinity and NK1R antagonistic activity with a broad-spectrum anticancer activity and an important selectivity. In this new study, we explore the selective cytotoxic effects of these derivatives for the treatment of NB. Furthermore, we describe the design and stereoselective synthesis of a new generation of d-glucose derivatives as Aprepitant analogs, supported by docking studies. This approach showed that most of our carbohydrate-based analogs are significantly more selective than Aprepitant. The galactosyl derivative 2α, has demonstrated a marked in vitro selective cytotoxic activity against NB, with IC values in the same range as those of Aprepitant and its prodrug Fosaprepitant. Interestingly, the derivative 2α has shown similar apoptotic effect to that of Aprepitant. Moreover, we can select the glucosyl amino derivative 10α as an interesting hit exhibiting higher in vitro cytotoxic activity against NB than Aprepitant, being 1.2 times more selective.
Topics: Humans; Aprepitant; Neurokinin-1 Receptor Antagonists; Vomiting; Antineoplastic Agents; Neuroblastoma; Carbohydrates; Antiemetics
PubMed: 38086194
DOI: 10.1016/j.ejmech.2023.116021 -
Current Medicinal Chemistry Oct 2023Different studies have highlighted the role of Substance P / Neurokinin 1 Receptor (SP/NK-1R) axis in multiple hallmarks of cancer including cell transformation,...
Different studies have highlighted the role of Substance P / Neurokinin 1 Receptor (SP/NK-1R) axis in multiple hallmarks of cancer including cell transformation, proliferation, and migration as well as angiogenesis and metastasis of a wide range of solid tumors including colorectal cancer. Until now, the selective high-affinity antagonist of human SP/NK1-R aprepitant (Emend) has been authorized by the Food and Drug Administration as a low dosage medication to manage and treat chemotherapy-induced nausea. However, increasing evidence in recent years support the potential utility of high doses of aprepitant as an antitumor agent and thus, opening the possibility to the pharmacological repositioning of SP/NK1-R antagonists as an adjuvant therapy to conventional cancer treatments. In this review, we summarize current knowledge on the molecular basis of colorectal cancer as well as the pathophysiological importance of SP/NK1-R and the potential utility of SP/NK-1R axis as a therapeutic target in this malignancy.
PubMed: 37861026
DOI: 10.2174/0109298673261625230924114406