Aprepitant's roles in abating seizures, behavioral, and cognitive deficits in mice model of epilepsy.

BACKGROUND: Aprepitant (APR), a neurokinin 1 receptor antagonist, is an approved drug for treating chemotherapy-induced nausea and vomiting. OBJECTIVES: Investigate the beneficial roles of APR alone or in combination with sodium valproate (VPA) against lithium pilocarpine [li-pilo]-induced seizures, behavioral changes, and cognitive deficits. METHODS: Thirty male mice were divided into five groups, each containing 6. "Vehicle Group I," "Control Group II "li-pilo, " Valproate (VPA) group III (400 mg/kg/i.p.), "APR group IV, " and "Combination Group V." Videos of mice were recorded, and they were watched for episodes of spontaneous recurring seizures (SRS). Behavioral Tests were performed. At the end of the study, animal brains were taken for biochemical assays and gene expression studies. RESULTS: APR partially protected against SRS with partial restoration of average behavioral and standard cognitive skills associated with a significant increase in brain SOD activity and a significant decrease in MDA, IL-1ß, NF-КB, and SP-3 levels in relation to the control group. Interestingly, a combination of APR with VPA in epileptic mice showed complete protection against li-pilo-induced behavioral changes and cognitive deficits, a significant increase in brain SOD activity, and a considerable decrease in MDA, IL-1ß, NF-ΚB, and SP levels to normal. CONCLUSION: Using APR as an adjuvant to VPA is more effective in protecting against li-pilo-induced seizures, behavioral changes, and cognitive deficits due to its antioxidant, anti-inflammatory, and NK1 antagonist effects than using APR alone as drug therapy.

Assessing the impact of aprepitant on response to dose-intensive cyclophosphamide, etoposide, and cisplatin (DICEP).

BACKGROUND: Despite evidence demonstrating the effectiveness of aprepitant for chemotherapy-induced nausea and vomiting (CINV), its use in stem cell transplant settings across Canada is not standard. While pharmacokinetic data exists, the clinical significance of cytochrome P450 3A4 (CYP 3A4) inhibition of cyclophosphamide by aprepitant is unclear. Reduced activation of cyclophosphamide may reduce the effectiveness of dose-intensive cyclophosphamide, etoposide, and cisplatin (DICEP). OBJECTIVES: To compare response rates to DICEP in patients with Hodgkin lymphoma (HL) and diffuse large B-cell lymphoma (DLBCL) in the presence and absence of aprepitant. METHODS: A retrospective review of patients who received full-dose DICEP for relapsed/refractory HL or DLBCL between June 1995 and September 2018 at the Foothills Medical Centre (FMC) in Calgary, Alberta, Canada was conducted. Descriptive statistics were used to assess response rate, as defined by the 2007 International Working Group response criteria. RESULTS: Of the 218 patients included in this study, 87.6% of patients in the control group and 88.5% of patients in the aprepitant group responded to DICEP (difference 0.025 [95% CI, -0.066 to 0.114], p = 0.827). Univariate analyses for age, sex, type of cancer, stage of cancer, number of prior relapses, and relapse status were not significant. No significant differences were observed for secondary outcomes. CONCLUSION: Response rates to DICEP in relapsed/refractory HL and DLBCL patients were similar regardless of aprepitant use. Considering these results and the effectiveness of aprepitant in CINV, its addition to standard antiemetic therapy in patients receiving DICEP should be given strong consideration in the transplant setting.

Enhanced anti-angiogenic effects of aprepitant-loaded nanoparticles in human umbilical vein endothelial cells.

Recent advancements in cancer therapy have led to the development of novel nanoparticle-based drug delivery systems aimed at enhancing the efficacy of chemotherapeutic agents. This study focuses on evaluating aprepitant-loaded PLGA and Eudragit RS 100 nanoparticles for their potential antiangiogenic effects. Characterization studies revealed that aprepitant-loaded nanoparticles exhibited particle sizes ranging from 208.50 to 238.67 nm, with monodisperse distributions (PDI < 0.7) and stable zeta potentials (between - 5.0 and - 15.0 mV). Encapsulation efficiencies exceeding 99% were achieved, highlighting the efficacy of PLGA and Eudragit RS 100 as carriers for aprepitant. Cellular uptake studies demonstrated enhanced internalization of aprepitant-loaded nanoparticles by HUVEC cells compared to free aprepitant, as confirmed by fluorescence microscopy. Furthermore, cytotoxicity assays revealed significant dose-dependent effects of aprepitant-loaded nanoparticles on HUVEC cell viability, with IC50 values at 24 h of 11.9 µg/mL for Eudragit RS 100 and 94.3 µg/mL for PLGA formulations. Importantly, these nanoparticles effectively inhibited HUVEC cell migration and invasion induced by M2c supernatant, as evidenced by real-time cell analysis and gene expression studies. Moreover, aprepitant-loaded nanoparticles downregulated VEGFA and VEGFB gene expressions and reduced VEGFR-2 protein levels in HUVEC cells, highlighting their potential as antiangiogenic agents. Overall, this research underscores the promise of nanoparticle-based aprepitant formulations in targeted cancer therapy, offering enhanced therapeutic outcomes through improved drug delivery and efficacy against angiogenesis.

Effects of Selective and Mixed-Action Kappa and Delta Opioid Receptor Agonists on Pain-Related Behavioral Depression in Mice.

We recently developed a series of nalfurafine analogs (TK10, TK33, and TK35) that may serve as non-addictive candidate analgesics. These compounds are mixed-action agonists at the kappa and delta opioid receptors (KOR and DOR, respectively) and produce antinociception in a mouse warm-water tail-immersion test while failing to produce typical mu opioid receptor (MOR)-mediated side effects. The warm-water tail-immersion test is an assay of pain-stimulated behavior vulnerable to false-positive analgesic-like effects by drugs that produce motor impairment. Accordingly, this study evaluated TK10, TK33, and TK35 in a recently validated assay of pain-related behavioral depression in mice that are less vulnerable to false-positive effects. For comparison, we also evaluated the effects of the MOR agonist/analgesic hydrocodone (positive control), the neurokinin 1 receptor (NK1R) antagonist aprepitant (negative control), nalfurafine as a selective KOR agonist, SNC80 as a selective DOR agonist, and a nalfurafine/SNC80 mixture. Intraperitoneal injection of dilute lactic acid (IP lactic acid) served as a noxious stimulus to depress vertical and horizontal locomotor activity in male and female ICR mice. IP lactic acid-induced locomotor depression was alleviated by hydrocodone but not by aprepitant, nalfurafine, SNC80, the nalfurafine/SNC80 mixture, or the KOR/DOR agonists. These results suggest that caution is warranted in advancing mixed-action KOR/DOR agonists as candidate analgesics.

Efficacy of aprepitant for refractory pruritus in patients with epidermolysis bullosa and atopic dermatitis: A retrospective study.

INTRODUCTION: At a single-center pediatric hospital, the neurokinin-1 receptor antagonist aprepitant was used to treat refractory pruritus in epidermolysis bullosa (EB) and atopic dermatitis (AD). METHODS: Thirty-seven patients were included (24 EB patients, 13 AD patients), ages 10 months to 37 years. RESULTS: 58% (14/24) of patients with EB and 85% (11/13) of patients with AD reported aprepitant was effective in decreasing their pruritus, with age-related differences in efficacy observed in EB patients, and access to the medication by insurance denial or availability of the drug as a barrier to use. CONCLUSIONS: Aprepitant shows promise in controlling refractory pruritus in pediatric EB and AD patients and deserves further study.

The Efficacy of Aprepitant in Preventing Post-bariatric Surgery Nausea and Vomiting: Evidence from Clinical Trials.

INTRODUCTION: This study aims to evaluate the effectiveness of aprepitant in preventing postoperative nausea and vomiting (PONV) following metabolic bariatric surgery (MBS). METHODS: Clinical trials meeting the inclusion criteria were identified through searches of PubMed, Embase, and the Cochrane Library databases, as well as clinical trials registered at clinicaltrials. gov. These trials compared aprepitant with the control or placebo groups among patients who underwent MBS. Meta-analysis was performed using StataSE 17.0 software to calculate the pooled risk ratio (RR) and its 95% confidence interval (CI) to assess the effectiveness of aprepitant in preventing PONV following MBS. RESULTS: A total of five articles comprising six studies including 929 patients undergoing MBS were included. Meta-analysis revealed a significant reduction in the incidence of PONV among patients receiving aprepitant (pooled RR = 0.51, 95% CI: 0.38-0.68, P < 0.05). Subgroup analysis indicated that aprepitant effectively reduced PONV incidence at 0, 6, and 12 h postoperatively in patients with MBS, but did not decrease PONV occurrence at 24 and 48 h postoperatively. CONCLUSION: Aprepitant demonstrated significant clinical efficacy in preventing PONV following MBS, effectively reducing patient discomfort, and improving postoperative recovery. Therefore, aprepitant should be considered a preventive measure in patients undergoing MBS to enhance patient satisfaction and recovery rates. Additionally, to maintain an effective drug concentration, aprepitant should be administered within the first 24 h postoperatively. PROSPERO REGISTRATION: CRD 42024528154.

Evaluation of Efficacy of Adding Aprepitant to Palonosetron and Dexamethasone in Carboplatin and Etoposide Therapy.

Although carboplatin (CBDCA) is classified as a moderately emetogenic agent, the majority of guidelines recommend the use of a neurokinin-1 receptor antagonist in addition to a 5-hydroxytryptamine type 3 receptor antagonist with dexamethasone (DEX) for CBDCA-containing chemotherapy because of its higher emetogenic risk. However, the additional efficacy of aprepitant (APR) in CBDCA-containing treatment remains controversial, and data on multiple-day treatments are limited. Etoposide (ETP) was administered on days 1-3 in the CBDCA + ETP regimen, and it is important to evaluate suitable antiemetic therapy for the regimen. Therefore, we evaluated the efficacy of additional APR in CBDCA + ETP. Patients were divided into two groups and retrospectively evaluated. One was the control group, which was prophylactically administered palonosetron (PALO) and DEX, and the other was the APR group, which received APR orally with PALO and DEX. The primary endpoint was complete response (CR) between the groups. The overall CR rates were 75.0 and 76.4% in the control and APR groups, respectively, with no significant difference (p = 1.00). In the acute phase, it was 88.9 and 97.2%, respectively, and 86.1 and 79.2% in the delayed phase, respectively, without significant differences (p = 0.10 and 0.38, respectively). The incidence and severity of nausea, vomiting, and anorexia were not significantly different between the two groups in the acute and delayed phases. Our findings suggest that combining APR with PALO and DEX does not improve the CR rate in CBDCA + ETP therapy.

Anti-Emetics in Children Receiving Chemotherapy for Solid Tumors and Leukemia: Pharmacology and Optimization of Therapy for Nausea and Vomiting.

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/m2/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.

PVP/aprepitant microcapsules produced by supercritical antisolvent process.

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.

Opioid-induced respiratory depression suspected of drug interaction in a prostate cancer patient: a case report.

BACKGROUND: Many of the drugs used for the treatment and alleviation of symptoms in cancer patients are known to inhibit or induce cytochrome P450 (CYP). Therefore, it is important to pay attention to the drug interactions of opioid analgesics that are metabolized by CYPs, because for example when using oxycodone metabolized by CYP3A4, it is possible that the effect will be attenuated or enhanced by the concomitant use of drugs that induce or inhibit CYP3A4. Aprepitant, an antiemetic drug used in many patients receiving anticancer drugs, is known as a moderate competitive inhibitor of CYP3A4. We experienced a case of respiratory depression caused by opioids, which was suspected to be caused by a drug interaction with antiemetics especially aprepitant. CASE DESCRIPTION: The patient was a 72-year-old man. He had been treated with continuous oxycodone infusion for perianal pain associated with the rectal invasion of prostate cancer. No comorbidities other than renal dysfunction were observed. Oxycodone treatment was started at 48 mg/day, and was increased to 108 mg/day, and then the pain decreased. Once the pain was controlled, chemotherapy was planned. Antiemetics (dexamethasone, palonosetron, and aprepitant) were administered before anticancer drug administration. Approximately 3 hours after antiemetics administration and before the administration of the anticancer drugs, a ward nurse noticed that oversedation and respiratory depression had occurred. When the patient was called, he immediately woke up and was able to talk normally, so the anticancer drugs were administered as scheduled. About 2 hours after the nurse noticed oversedation, the attending physician reduced the dose of oxycodone infusion to 48 mg/day. After that, his drowsiness persisted, but his respiratory condition improved. Despite reducing the dose of oxycodone to less than half, the pain remained stable at numeric rating scale (NRS) 0-1, without the use of a rescue dose. The patient was discharged from the hospital 36 days after the administration of anticancer drugs, without any problems. CONCLUSIONS: The cause of respiratory depression in this case was thought to be a combination of factors, including drug interactions between oxycodone and antiemetics, and oxycodone accumulation due to renal dysfunction.

Risk Factors Associated with Chemotherapy-Induced Nausea and Vomiting Among Women with Breast Cancer Receiving Highly Emetogenic Chemotherapy: Individual Patient-Based Analysis of Three Prospective Antiemetic Trials.

Purpose: Although risk factors related to chemotherapy-induced nausea and vomiting (CINV) have been identified in previous studies, only a few studies have evaluated the risk factors associated with contemporary antiemetic prophylaxis, including olanzapine/aprepitant- or NEPA-containing regimens. This study aimed to identify the risk factors associated with CINV development in Chinese breast cancer patients receiving doxorubicin and cyclophosphamide chemotherapy. Methods: Data from 304 patients enrolled in 3 previously reported prospective antiemetic studies were included. Multivariate logistic regression models were used to predict risk factors associated with CINV occurrence. Additionally, the likelihood of treatment failure in relation to the number of risk factors in individual patients was evaluated. Results: Multivariate analysis of the entire study group revealed that obesity status (defined as body mass index/= 25.0 kg/m2) and the use of olanzapine/aprepitant- or NEPA-containing anti-emetic regimens were associated with a high likelihood, while a history of motion sickness was associated with a lower likelihood, complete response (CR), and "no nausea" in the overall phase. A history of vomiting during pregnancy was also associated with a lower likelihood of an overall CR. Patients with an increasing number of risk factors had a higher likelihood of treatment failure and shorter time to first vomiting. Those who did not achieve CR and "no nausea" in the first cycle were less likely to achieve these parameters in the subsequent cycle of chemotherapy. Conclusion: The present study confirmed previously reported risk factors for CINV in Chinese breast cancer patients receiving doxorubicin and cyclophosphamide. Further optimization of CINV control is required for patients with identifiable risk factors; olanzapine/aprepitant- or NEPA- containing prophylaxis are the preferred contemporary anti-emetics regimens for Chinese breast cancer patients undergoing doxorubicin and cyclophosphamide chemotherapy.

Aprepitant Alleviates Poststroke Pneumonia in a Mouse Model of Middle Cerebral Artery Occlusion.

Elevated substance P can be utilized to predict early mortality during the first week of cerebral infarction. Whether aprepitant, a substance P receptor blocker could be utilized to alleviate poststroke pneumonia which is investigated in this study. Intraluminal monofilament model of middle cerebral artery occlusion (MCAO) was constructed in C57BL/6J male mice, and the relative expression of substance P was detected in collected bronchoalveolar lavage fluid (BALF) and lung tissue homogenate at 24 hours, 48 hours, and 72 hours poststroke. On the other hand, different concentrations of aprepitant (0.5, 1, and 2 mg/kg) were atomized and inhaled into MCAO mice. Inflammation cytokines and bacterial load were detected in collected BALF and lung tissue homogenate at 72-hour poststroke, and lung injury was revealed by histological examination. Aprepitant administration decreased total proteins, total cells, neutrophils, and macrophages in BALF. The concentrations of interleukin (IL)-6, IL-1ß, tumor necrosis factor-α, interferon γ, monocyte chemoattractant protein-1, and IL-10 in lung tissue homogenates were also diminished by the administration of aprepitant. In conclusion, aprepitant could attenuate poststroke pneumonia in mice suggesting its potential therapeutic use in the clinic.

Impact of grinding balls on the size reduction of Aprepitant in wet ball milling procedure.

One of the widely used approaches for improving the dissolution of poorly water-soluble drugs is particle size reduction. Ball milling is a mechanical, top-down technique used to reduce particle size. The effect of ball number, ball size, and milling speed on the properties of milled Aprepitant is evaluated. A full factorial design was employed to investigate the influence of affecting factors on particle size reduction. The initial suspension was made by suspending the drug in distilled water using excipients followed by milling in a planetary ball mill. Ball size, ball number, and milling speed modulated particle size distribution of Aprepitant. Increasing the number of balls from minimum to maximum for each ball size led to approximately a 28% reduction in mean particle size, a 37% decrease in D90%, and a 25% decrease in the ratio of volume mean particle diameter to numeric mean particle diameter. On average, using 10 mm balls instead of 30 mm balls reduced mean particle size by 1.689 µm. As a result, ball size, ball number, and milling speed are three effective factors in the process of ball milling. By increasing the ball number and decreasing the ball size, efficient micronization of drug particles takes place and the particle size is more uniform.

Neurokinin-1 receptor antagonist aprepitant regulates autophagy and apoptosis via ROS/JNK in intrahepatic cholangiocarcinoma.

BACKGROUND: Intrahepatic cholangiocarcinoma (iCCA) has a poor prognosis and limited treatment options. Aprepitant, a selective NK-1R antagonist, can inhibit the growth of various tumours in vitro and in vivo. However, it remains unclear whether aprepitant has cytotoxic effects on iCCA. METHODS: We measured the expression of SP/NK-1R in clinical samples of iCCA by immunohistochemistry. Then, we detected the cytotoxic effects of aprepitant on iCCA cells via MTT, EdU and colony formation assay. We constructed a subcutaneous xenograft model of BALB/c nude mice by using HCCC-9810 and RBE cell lines to explore the effects of aprepitant in vivo. To elucidate the potential mechanisms, we explored the pro-apoptotic effect of aprepitant by flow cytometric, western blotting, ROS detection and JC-1 staining. Furthermore, we detected the autophagic level of HCCC-9810 and RBE by western blotting, mRFP-eGFP-LC3 adenovirus transfection and electron microscope. RESULTS: SP/NK-1R is significantly expressed in iCCA. Aprepitant inhibited human iCCA xenograft growth and dose-dependently decreased the viability of RBE and HCCC-9810 cells. Aprepitant-induced mitochondria-dependent apoptosis through ROS/JNK pathway. Additionally, pretreatment with z-VAD-fmk partly reversed the effect of aprepitant on cell viability, while NAC completely attenuated the cytotoxic effects of aprepitant in vitro. Furthermore, we observed the dynamic changes of autophagosome in RBE and HCCC-9810 cells treated with aprepitant. CONCLUSION: SP/NK-1R signalling is significantly activated in iCCA and promotes the proliferation of iCCA cells. By contrast, aprepitant can induce autophagy and apoptosis in iCCA cells via ROS accumulation and subsequent activation of JNK.

The impact of Aprepitant on Nausea and Vomiting following Laparoscopic Sleeve Gastrectomy: A Blinded 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.

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% vs. 79%, P=0.018<0.05). Modest differences were seen in CR rates during the delayed phase (71% vs. 66%, P=0.586), and overall response rate (69% vs. 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.

The effect of SP/NK1R on expression and activity of glutaredoxin and thioredoxin proteins in prostate cancer cells.

Substance P (SP), an important neuropeptide, has a crucial role in the progression of several cancers, including prostate cancer, through interacting with the neurokinin-1 receptor (NK1R). Oxidative stress is also involved in the onset and progression of prostate cancer. However, no studies have been performed on the cross-talk between the SP/NK1R system and cellular redox balance in prostate cancer, and how it is involved in tumorogenesis. We aimed to investigate the effect of the SP/NK1R system and the blockage of NK1R with its specific antagonist (aprepitant) on the cellular redox status of the prostate cancer cell line (PC3 and LNCaP). We performed the resazurin assay to evaluate the toxicity of the aprepitant on the PC3 and LNCaP cell lines. The intracellular reactive oxygen species (ROS) level was measured after SP and aprepitant treatment. The alterations of expression and activity of two crucial cellular oxidoreductases, glutaredoxin, and thioredoxin were evaluated by qRT-PCR and commercial kits (ZellBio GmbH), respectively. Our results revealed that SP increased ROS production and decreased the expression and activity of glutaredoxin and thioredoxin. On the other hand, treatment of cells with aprepitant showed reverse results. In conclusion, we found that the SP/NK1R system could promote prostate cancer progression by inducing oxidative stress. In addition, the inhibition of NK1R by aprepitant modulated the effect of the SP/NK1R system on the cellular redox system. Aprepitant might therefore be introduced as a candidate for the treatment of prostate cancer; however, more studies are required to confirm the validation of this hypothesis.

Mechanism Underlying Conflicting Drug-Drug Interaction Between Aprepitant and Voriconazole via Cytochrome P450 3A4-Mediated Metabolism.

Background: Voriconazole is an antifungal drug for which therapeutic monitoring is recommended to prevent side effects. Temporary administration of the antiemetic drug fosaprepitant remarkably decreases the plasma concentration of voriconazole from the therapeutic range. The ratio of the major metabolite voriconazole N-oxide to voriconazole exceeded that at any other time for a patient who started chemotherapy during voriconazole therapy. We attributed this unpredictable result to cytochrome P450 3A4 induced by aprepitant that was converted from fosaprepitant in vivo. Methods: Concentrations of voriconazole and voriconazole N-oxide were measured using liquid chromatography-mass spectrometry/mass spectrometry in primary human hepatocytes after incubation with aprepitant. Aprepitant suppressed voriconazole N-oxide formation within 24 h, followed by a continuous increase. Levels of drug-metabolizing cytochrome P450 mRNA were measured using real-time PCR in primary human hepatocytes incubated with aprepitant. Results: Cytochrome P450 3A4 and 2C9 mRNA levels increased ~4- and 2-fold, respectively, over time. Cytochrome P450 3A4 induction was confirmed using reporter assays. We also assessed L-755446, a major metabolite of aprepitant that lacks a triazole ring. Both compounds dose-dependently increased reporter activity; however, induction by L-755446 was stronger than that by aprepitant. Conclusion: These results indicate that aprepitant initially inhibited voriconazole metabolism via its triazole ring and increased cytochrome P450 3A4 induction following L-755446 formation. The decrease in plasma voriconazole concentration 7 days after fosaprepitant administration was mainly attributed to cytochrome P450 3A4 induction by L-755446.

Comparing the Efficacy of Fosnetupitant, an NK1 Receptor Antagonist in CDDP-Based Regimens, with That of Fosaprepitant and Aprepitant: A Retrospective Observational Study.

Existing antiemetic therapy against emetic-risk agents across malignancies 24 h post-dose in the acute period in cisplatin (CDDP)-based regimens yields a satisfactory complete response (CR) rate of ≥90%. However, the control rate after 24 h in the delayed period is unsatisfactory. This study compared the efficacy of fosnetupitant (F-NTP), a neurokinin 1 receptor antagonist, with that of fosaprepitant (F-APR) and aprepitant (APR) in the treatment of patients with cancer at high emetic risk due to chemotherapy. In this retrospective case-control study involving patients receiving cisplatin-containing regimens and neurokinin 1 receptor antagonists, patients were divided into three groups based on prophylactic antiemetic therapy: F-NTP, F-APR, and APR. The CR rate was evaluated for each period up to 168 h and further subdivided into acute (0-24 h), delayed (24-120 h), overall (0-120 h), and beyond-delayed (120-168 h) periods. Eighty-eight patients were included in the F-NTP group, 66 in the F-APR group, and 268 in the APR group. The CR rates at 0-168 and 120-168 h after cisplatin administration were significantly higher in the F-NTP group than in the F-APR and APR groups. After adjusting for confounding factors, F-NTP use was an independent factor in the multivariate analysis. Prophylactic antiemetic therapy, including F-NTP, was effective and well-tolerated during the delayed period. The efficacy of F-NTP in managing chemotherapy-induced nausea and vomiting was superior to those of F-APR and APR during the study period.

The combined anti-tumor effects of 5-fluorouracil and neurokinin receptor inhibitor, aprepitant, against colorectal cancer: In vitro and in vivo study.

BACKGROUND: Colorectal cancer (CRC) is one of the world's largest health concerns with growing global incidence and mortality. The potential value of the neurokinin-1 receptor as a therapeutic target has been reported in several tumor types, including CRC. Here we examined the potential anti-tumor effects of a clinically approved neurokinin-1 receptor antagonist, aprepitant, alone and its combination with 5-Fluorouracil (5-FU) as a first choice CRC chemotherapeutic drug, in both in vitro and in vivo models of CRC. METHODS: MTT assay was employed for assessing cell proliferation. mRNA expression levels were determined by quantitative real-time PCR (qRT-PCR). Flow cytometric analysis of apoptosis was performed using an Annexin-V/propidium iodide assay kit. We finally conducted an in vivo experiment in a mouse model of CRC to confirm the in vitro antiproliferative activity of aprepitant and 5-FU. RESULTS: We found that aprepitant and 5-FU significantly reduced CRC cell viability. The combination of drugs exhibited potent synergistic growth inhibitory effects on CRC cells. Moreover, aprepitant and 5-FU induced apoptosis and altered the levels of apoptotic genes (up-regulation of Bax, and p53 along with downregulation of Bcl-2). Importantly, the aprepitant and 5-FU combination showed a more pronounced impact on apoptosis and associated genes than either of the agents alone. Furthermore, aprepitant reduced tumor growth in vivo and led to significantly longer survival time, and this effect was more prominent when using the aprepitant and 5-FU combination. CONCLUSIONS: Collectively, combinatory treatment with aprepitant and 5-FU potentially exerts synergistic growth inhibition and apoptosis induction in CRC, deserving further consideration as a novel strategy for CRC patients.