Sensory nerves unlock the TOLL-7 gate for cancer spread.

Cancers hijack the nervous system for growth and spread. Thus, disrupting neuron-cancer crosstalk holds promise for blocking metastasis. Recently, Padmanaban et al. reported new therapeutic targets and showed that breast cancer cells activate sensory neurons to secrete the neuropeptide substance P (SP), leading to single-strand (ss)RNA release and noncanonical Toll-like receptor (TLR)7 signaling that drives metastasis.

Comparative effectiveness of netupitant-palonosetron plus dexamethasone versus aprepitant-based regimens in mitigating chemotherapy-induced nausea and vomiting: a meta-analysis of randomized controlled trials.

BACKGROUND: Despite guidelines for managing chemotherapy-induced nausea and vomiting (CINV), there remains a need to clarify the optimal use of neurokinin-1 (NK1) receptor antagonists. Comparing the effectiveness of NEPA (netupitant-palonosetron) plus dexamethasone with other NK1 antagonist-based regimens combined with a 5HT3 receptor antagonist and dexamethasone is crucial for informed decision-making and improving patient outcomes. METHODS: We conducted a systematic review of the literature to assess randomized controlled trials (RCTs) comparing the efficacy, safety, and cost-effectiveness of NEPA plus dexamethasone and other NK1 antagonist-based regimens combined with a 5HT3 receptor antagonist and dexamethasone. PubMed, Embase, and the Cochrane Library databases were systematically searched, with the latest update performed in December 2023. Data on patient demographics, chemotherapy regimen characteristics, and outcomes were extracted for meta-analysis using a random-effects model. RESULTS: Seven RCTs were analyzed. NEPA plus dexamethasone showed superior efficacy in achieving complete response in the overall (risk ratio [RR], 1.15; 95% CI, 1.02--1.30) and delayed phases (RR, 1.20; 95% CI, 1.03-1.41) of chemotherapy. It was more effective in controlling nausea (overall phase RR, 1.20; 95% CI, 1.05-1.36; delayed phase RR, 1.21; 95% CI, 1.05-1.40) and reducing rescue therapy use (overall phase RR, 1.45; 95% CI, 1.07-1.95; delayed phase RR, 1.75; 95% CI, 1.10-2.78). Adverse event rates were comparable (RR, 1.03; 95% CI, 0.96-1.10). Subgroup analysis indicated NEPA's particular efficacy in patients receiving moderately emetogenic chemotherapy (RR, 1.31; 95% CI, 1.07-1.60). CONCLUSION: NEPA plus dexamethasone regimens exhibit superior efficacy in preventing CINV, supporting their preferential inclusion in prophylactic treatment protocols. Its effective symptom control, safety profile, and cost-effectiveness endorse NEPA-based regimens as a beneficial option in CINV management.

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.

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.

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.

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.