-
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 -
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 -
Translational Vision Science &... Feb 2024This study aims to assess the efficacy of two aprepitant formulations (X1 and X2), in a preclinical model of dry eye disease (DED) induced by benzalkonium chloride (BAK).
PURPOSE
This study aims to assess the efficacy of two aprepitant formulations (X1 and X2), in a preclinical model of dry eye disease (DED) induced by benzalkonium chloride (BAK).
METHODS
Two aprepitant formulations were tested on 7 to 8-week-old male mice for their efficacy. In vivo corneal fluorescein staining assessed epithelial damage as the primary end point on days 0, 3, 5, 7, 9, 12, and 14 using slit-lamp microscopy. The DED model was induced with 0.2% BAK twice daily for the first week and once daily for the next week. Mice were randomly assigned to 5 treatment groups: Aprepitant X1 (n = 10) and X2 (n = 10) formulation, 2 mg/mL dexamethasone (n = 10), control vehicle X (n = 10), 0.2% hyaluronic acid (n = 10), or no treatment (n = 10). Eye wiping, phenol red, and Cochet Bonnet tests assessed ocular pain, tear fluid secretion, and nerve function. After 7 days, the mice were euthanized to quantify leukocyte infiltration and corneal nerve density.
RESULTS
Topical aprepitant X1 reduced BAK-induced corneal damage and pain compared to gel vehicle X (P = 0.007) and dexamethasone (P = 0.021). Aprepitant X1 and X2 improved corneal sensitivity versus gel vehicle X and dexamethasone (P < 0.001). Aprepitant X1 reduced leukocyte infiltration (P < 0.05) and enhanced corneal nerve density (P < 0.001). Tear fluid secretion remained statistically unchanged in both the X1 and X2 groups.
CONCLUSIONS
Aprepitant formulation X1 reduced pain, improved corneal sensitivity and nerve density, ameliorated epitheliopathy, and reduced leukocyte infiltration in male mouse corneas.
TRANSLATIONAL RELEVANCE
Aprepitant emerges as a safe, promising therapeutic prospect for the amelioration of DED's associated symptoms.
Topics: Male; Mice; Animals; Aprepitant; Cornea; Fluorescein; Pain; Dexamethasone
PubMed: 38345550
DOI: 10.1167/tvst.13.2.9 -
Pharmaceutics Mar 2022Currently, the search for promising NK1R-positive tumor-targeting radiopharmaceuticals based on the structure of small molecular antagonists of neurokinin-1 receptor can...
Currently, the search for promising NK1R-positive tumor-targeting radiopharmaceuticals based on the structure of small molecular antagonists of neurokinin-1 receptor can be observed. Following this trend, we continued our evaluation of aprepitant-based Lu-radioconjugates in terms of future oncological applications. For this purpose, three novel aprepitant homologues were synthesized to broaden the previously obtained derivative portfolio, functionalized with the DOTA chelator and labeled with Ga and Lu. The newly evaluated radioconjugates showed the intended significant increase in lipophilicity compared to the previous ones, while maintaining stability in the human serum. Then, in a receptor binding study to the human NK1 receptor, we compared the two series of Lu-radioconjugates of aprepitant with each other and with the reference Substance P derivative currently used in glioblastoma therapy, clearly indicating the high affinity and better binding capacity of the novel radioconjugates. The in vitro experimental results included in the presented study, supported by labeling optimization, radioconjugate characterization and docking modeling of new aprepitant-derived radioagents, confirm our assumptions about the usefulness of aprepitant as a NK1R targeting vector and point out the perspectives for the forthcoming first in vivo trials.
PubMed: 35335981
DOI: 10.3390/pharmaceutics14030607 -
Biomedical Papers of the Medical... Jun 2023Postdischarge nausea and vomiting (PDNV) cause substantial pediatric morbidity with potentially serious postoperative complications. However, few studies have addressed... (Review)
Review
Postdischarge nausea and vomiting (PDNV) cause substantial pediatric morbidity with potentially serious postoperative complications. However, few studies have addressed PDNV prevention and treatment in pediatric patients. Here we searched the literature and processed it in a narrative review describing PDNV incidence, risk factors, and management in pediatric patients.. A successful strategy for reducing PDNV considers both the pharmacokinetics of the antiemetic agents and the principle of multimodal prophylaxis, utilizing agents of different pharmacologic classes. Since many highly effective antiemetic agents have relatively short half-lives, a different approach must be used to prevent PDNV. A combination of oral and intravenous medications with longer half-lives, such as palonosetron or aprepitant, can be used. In addition, we designed a prospective observational study with the primary objective of determining PDNV incidence. In our study group of 205 children, the overall PDNV incidence was 14.6% (30 of 205), including 21 children suffering from nausea and 9 suffering from vomiting.
Topics: Humans; Child; Antiemetics; Postoperative Nausea and Vomiting; Aftercare; Patient Discharge; Prospective Studies; Observational Studies as Topic
PubMed: 37222143
DOI: 10.5507/bp.2023.020 -
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 -
PeerJ 2018Concomitant drug administration is a general phenomenon in patients with chronic diseases such as diabetes mellitus. Among the currently available oral antidiabetic...
BACKGROUND
Concomitant drug administration is a general phenomenon in patients with chronic diseases such as diabetes mellitus. Among the currently available oral antidiabetic drugs, gliclazide is a commonly prescribed drug considering its multiple benefits in diabetic patients. Aprepitant is a commonly prescribed antiemetic drug which is mainly metabolized by CYP3A4, reported to have modest inductive and inhibitory effects on CYP2C9 and CYP3A4, respectively. Since gliclazide is metabolized by CYP2C9 (major) and CYP3A4 (minor), it is very difficult to predict the influence of aprepitant and its metabolic interaction with gliclazide. Considering the complexity associated with the combination of aprepitant and gliclazide, this study was designed to evaluate the influence of aprepitant on the pharmacodynamics (PD) and pharmacokinetics (PK) of gliclazide in animal models.
METHODS
The PD interaction studies were conducted in both rodent (normal and alloxan-induced diabetic rats) and non-rodent (rabbits) animal models ( = 6) while the PK interaction study was conducted in normal rabbits ( = 6). An extrapolated human therapeutic oral dose of gliclazide, aprepitant and their combination were administered to rats and rabbits with 7 days washout between each treatment. For the multiple-dose interaction study, the same groups were administered with an interacting drug (aprepitant) for 7 days and then the combination of aprepitant and gliclazide on the 8th day. From the collected animal blood samples, blood glucose (by Glucose-Oxidase/Peroxidase method), insulin (by ELISA method) and gliclazide concentration levels (by HPLC method) were determined. Non-compartmental PK analysis was conducted by Phoenix WinNonlin software to determine the PK parameters of gliclazide. Statistical analysis was performed by student's paired -test.
RESULTS
The pharmacodynamic activity (blood glucose reduction and insulin levels) of gliclazide was significantly ( < 0.05) influenced by aprepitant in normal and diabetic condition without any convulsions in animals. There was a significant ( < 0.05) increase in concentration levels and Area Under the Curve of gliclazide while significant ( < 0.05) decrease in clearance levels of gliclazide in rabbits. The PK interaction with gliclazide is relatively more with the multiple dose treatment of aprepitant over single dose treatment.
CONCLUSION
In combination, aprepitant significantly influenced the pharmacodynamic activity of gliclazide in animal models. Considering this, care should be taken when this combination is prescribed for the clinical benefit in diabetic patients.
PubMed: 29844963
DOI: 10.7717/peerj.4798 -
Future Virology Jun 2021The newly emerged human coronavirus, SARS-CoV-2, had begun to spread last year and sparked worldwide. In this study, molecular docking is utilized to test some...
The newly emerged human coronavirus, SARS-CoV-2, had begun to spread last year and sparked worldwide. In this study, molecular docking is utilized to test some previously approved drugs against the SARS-CoV-2 nonstructural protein 15 (Nsp15). We screened 23 drugs, from which three (saquinavir, valrubicin and aprepitant) show a paramount predicted binding affinity (-9.1, -9.6 and -9.2 kcal/mol, respectively) against SARS-CoV-2 Nsp15. Moreover, saquinavir and aprepitant make nonbonded interactions with Leu201 in the active site cavity of Nsp15, while the drug valrubicin interacts with Arg199 and Leu201. This binding pattern may be effective against the targeted protein, leading to Nsp15 blockage and virus abolition. Additionally, the pharmacological properties of the screened drugs are known since they have been approved against different viruses.
PubMed: 34290822
DOI: 10.2217/fvl-2020-0233 -
Yakugaku Zasshi : Journal of the... 2019Cancer chemotherapy has progressed remarkably with conventional and molecular-targeted anticancer drugs as well as immune checkpoint inhibitors. However, adverse drug... (Review)
Review
Cancer chemotherapy has progressed remarkably with conventional and molecular-targeted anticancer drugs as well as immune checkpoint inhibitors. However, adverse drug reaction (ADR) management remains a challenge in cancer chemotherapy. Therefore, improving the quality of medical care through clinical pharmacology research is warranted. Intravenous injection of bendamustine in patients with follicular or mantle cell lymphoma frequently causes venous irritation. Because the underlying mechanisms are not clear, we investigated the factors responsible for bendamustine-induced venous irritation. Based on the results of our analysis, we altered the administration regimen and observed that the incidence of venous irritation, which manifested in a concentration-dependent manner following conventional approaches, significantly decreased when following the modified regimen. Guidelines on the management of chemotherapy-induced nausea and vomiting recommend aprepitant, a selective neurokinin-1 (NK-1) receptor antagonist, 5-hydroxytryptamine 3 (5-HT) receptor antagonists, and dexamethasone as prophylactic antiemetics. Pretreatment with high-dose chemotherapy before hematopoietic stem cell transplantation has extremely high emetogenic potential. This can be countered by using aprepitant in combination with conventional antiemetics. However, the safety and efficacy of such combinations are unexplored. Upon evaluation, we observed improved antiemetic effects without an increase in ADRs. At this symposium, I highlight the significance of clinical pharmacology research for promoting individualized cancer chemotherapy.
Topics: Antiemetics; Antineoplastic Agents; Aprepitant; Bendamustine Hydrochloride; Dose-Response Relationship, Drug; Humans; Injections, Intravenous; Nausea; Neoplasms; Pharmacology, Clinical; Precision Medicine; Quality of Health Care; Research
PubMed: 31155534
DOI: 10.1248/yakushi.18-00213-1 -
European Journal of Pharmaceutics and... Jul 2022Drug solubility in intestinal fluid is a key parameter controlling absorption after the administration of a solid oral dosage form. To measure solubility in vitro...
Drug solubility in intestinal fluid is a key parameter controlling absorption after the administration of a solid oral dosage form. To measure solubility in vitro simulated intestinal fluids have been developed, but there are multiple recipes and the optimum is unknown. This situation creates difficulties during drug discovery and development research. A recent study characterised sampled fasted intestinal fluids using a multidimensional approach to derive nine bioequivalent fasted intestinal media that covered over 90% of the compositional variability. These media have been applied in this study to examine the equilibrium solubility of twenty one exemplar drugs (naproxen, indomethacin, phenytoin, zafirlukast, piroxicam, ibuprofen, mefenamic acid, furosemide, aprepitant, carvedilol, tadalafil, dipyridamole, posaconazole, atazanavir, fenofibrate, felodipine, griseofulvin, probucol, paracetamol, acyclovir and carbamazepine) to determine if consistent solubility behaviour was present. The bioequivalent media provide in the majority of cases structured solubility behaviour that is consistent with physicochemical properties and previous solubility studies. For the acidic drugs (pKa < 6.3) solubility is controlled by media pH, the profile is identical and consistent and the lowest and highest pH media identify the lowest and highest solubility in over 70% of cases. For weakly acidic (pKa > 8), basic and neutral drugs solubility is controlled by a combination of media pH and total amphiphile concentration (TAC), a consistent solubility behaviour is evident but with variation related to individual drug interactions within the media. The lowest and highest pH × TAC media identify the lowest and highest solubility in over 78% of cases. A subset of the latter category consisting of neutral and drugs non-ionised in the media pH range have been identified with a very narrow solubility range, indicating that the impact of the simulated intestinal media on their solubility is minimal. Two drugs probucol and atazanavir exhibit unusual behaviour. The study indicates that the use of two appropriate bioequivalent fasted intestinal media from the nine will identify in vitro the maximum and minimum solubility boundaries for drugs and due to the media derivation this is probably applicable in vivo. These media could be applied during discovery and development activities to provide a solubility range, which would assist placement of the drug within the BCS/DCS and rationalise drug and formulation decisions.
Topics: Administration, Oral; Atazanavir Sulfate; Hydrogen-Ion Concentration; Intestinal Absorption; Pharmaceutical Preparations; Probucol; Solubility
PubMed: 35605926
DOI: 10.1016/j.ejpb.2022.05.010