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Purpose To assess, from a United States (US) perspective, the cost-effectiveness of chemotherapy-induced nausea and vomiting (CINV) prophylaxis using a single dose of netupitant and palonosetron in a fixed combination (NEPA) versus aprepitant plus granisetron (APR + GRAN), each in combination with dexamethasone, in chemotherapy-naïve patients receiving highly emetogenic chemotherapy (HEC). Methods We analyzed patient-level outcomes over a 5-day post-HEC period from a randomized, double-blind, phase 3 clinical trial of NEPA ( n  = 412) versus APR + GRAN ( n  = 416). Costs and CINV-related utilities were assigned to each subject using published sources. Parameter uncertainty was addressed via multivariate probabilistic sensitivity analyses (PSA). Results Compared to APR + GRAN, NEPA resulted in a gain of 0.09 quality-adjusted life-days (QALDs) (4.04 vs 3.95; 95% CI −0.06 to 0.25) and a significant total per-patient cost reduction of $309 ($943 vs $1252; 95% CI $4–$626), due principally to $258 in lower medical costs of CINV-related events ($409 vs $668; 95% CI −$46 to $572) and $45 in lower study drug costs ($531 vs $577). In the PSA, NEPA resulted in lower costs and higher QALD in 86.5% of cases and cost ≤ $25,000 per quality-adjusted life-year gained in 97.8% of cases. Conclusions This first-ever economic analysis using patient-level data from a phase 3 trial comparing neurokinin-1 receptor antagonist (NK1 RA) antiemetic regimens suggests that NEPA is highly cost-effective (and in fact cost-saving) versus an aprepitant-based regimen in post-HEC CINV prevention. Actual savings may be higher, as we focused only on the first chemotherapy cycle and omitted the impact of CINV-related chemotherapy discontinuation.

Aldosterone, produced by the adrenals and under the control of plasma angiotensin and potassium levels, regulates hydromineral homeostasis and blood pressure. Here we report that the neuropeptide substance P (SP) released by intraadrenal nerve fibres, stimulates aldosterone secretion via binding to neurokinin type 1 receptors (NK1R) expressed by aldosterone-producing adrenocortical cells. The action of SP is mediated by the extracellular signal-regulated kinase pathway and involves upregulation of steroidogenic enzymes. We also conducted a prospective proof-of-concept, double blind, placebo-controlled clinical trial aimed to investigate the impact of the NK1R antagonist aprepitant on aldosterone secretion in healthy male volunteers (EudraCT: 2008-003367-40, ClinicalTrial.gov: NCT00977223). Participants received during two 7-day treatment periods aprepitant (125 mg on the 1 st day and 80 mg during the following days) or placebo in a random order at a 2-week interval. The primary endpoint was plasma aldosterone levels during posture test. Secondary endpoints included basal aldosterone alterations, plasma aldosterone variation during metoclopramide and hypoglycaemia tests, and basal and stimulated alterations of renin, cortisol and ACTH during the three different stimulatory tests. The safety of the treatment was assessed on the basis of serum transaminase measurements on days 4 and 7. All pre-specified endpoints were achieved. Aprepitant decreases aldosterone production by around 30% but does not influence the aldosterone response to upright posture. These results indicate that the autonomic nervous system exerts a direct stimulatory tone on mineralocorticoid synthesis through SP, and thus plays a role in the maintenance of hydromineral homeostasis. This regulatory mechanism may be involved in aldosterone excess syndromes. Adrenal aldosterone production is regulated by plasma angiotensin and potassium levels. Here the authors report that the neuropeptide substance P stimulates aldosterone production via neurokinin type 1 receptors (NK1R), and report a proof-of-concept placebo controlled clinical trial showing that a NK1R antagonist decreases aldosterone levels.

NEPA is the only fixed combination antiemetic, comprised of an NK1RA (netupitant) and a 5‐HT3RA (palonosetron). In the first head‐to‐head trial to compare NK1RA‐containing regimens, a single oral dose of NEPA was non‐inferior to a 3‐day aprepitant/granisetron (APR/GRAN) regimen for the primary endpoint of overall (0‐120 hours) complete response (no emesis/no rescue). This pre‐specified analysis evaluates the efficacy of NEPA versus APR/GRAN in the subset of Chinese patients in the study. In addition, efficacy in patients at greatest emetic risk receiving high‐dose cisplatin (≥70 mg/m2) was explored. Chemotherapy‐naïve patients with solid tumors in this randomized, double‐blind study received either a single dose of NEPA prior to cisplatin‐based chemotherapy or a 3‐day regimen of APR/GRAN, both with dexamethasone on Days 1‐4. Efficacy was evaluated through complete response, no emesis, and no significant nausea rates during the acute (0‐24 hours), delayed (25‐120 hours) and overall phases as well as individual days post‐chemotherapy, as the daily course of CINV protection is often unstudied. The Chinese subset included 667 patients; of these, 363 (54%) received high‐dose cisplatin. Baseline characteristics were comparable. While response rates were similar for NEPA and APR/GRAN during the acute, delayed and overall phases, significantly fewer NEPA patients experienced breakthrough CINV on individual Days 3‐5 in both the Chinese patients and also in those receiving high‐dose cisplatin. As a fixed oral NK1RA/5HT3RA combination given once/cycle, NEPA is a convenient highly effective prophylactic antiemetic that may offer better protection from CINV than a 3‐day APR/GRAN regimen on Days 3‐5 following highly emetogenic chemotherapy. NEPA is a novel fixed combination antiemetic comprised of the NK1RA, netupitant, and the 5‐HT3RA, palonosetron. The simultaneous targeting of two critical antiemetic pathways, in unison with single‐dose administration, offers a simplified and convenient antiemetic with 5‐day CINV prevention. The authors report significantly better protection from CINV during Days 3‐5 post‐chemotherapy for NEPA vs a 3‐day regimen of aprepitant/granisetron in Chinese patients, and in those receiving high‐dose cisplatin, in the first head‐to‐head study comparing NK1RA‐containing regimens.

This study investigates the efficacy and toxicity profiles of pegylated liposomal doxorubicin (Doxil) compared to conventional doxorubicin. Additionally, it evaluates the potential of combination therapy involving Doxil and doxorubicin with aprepitant, an FDA-approved agent for the management of chemotherapy-induced nausea and vomiting. Using a mouse model induced with 4T1 breast cancer cells, tumor size, and weight were assessed following treatment with either single doses or combination therapies. The study also examined oxidative and antioxidant stress markers in tumor, liver, and cardiac tissues, complemented by histopathological analysis of these tissues using hematoxylin and eosin staining. Results indicated that prepared liposomal doxorubicin significantly enhanced antitumor efficacy, as evidenced by decreased tumor size and weight. Moreover, it positively influenced oxidative stress markers, promoting apoptosis in tumor tissues. Notably, Doxil also reduced adverse effects compared to standard doxorubicin, as indicated by lower oxidative stress levels and increased antioxidant activity in both cardiac and liver tissues. The combined administration of doxorubicin and aprepitant further improved therapeutic efficacy and reduced side effects. Consequently, the formulation of doxorubicin in liposomes and aprepitant-based combination therapy represents a promising strategy for enhancing treatment effectiveness while minimizing adverse effects in breast cancer management.

Abstract 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. This article compares the efficacy of NEPA- and aprepitant-based regimens in mitigating chemotherapy-induced nausea and vomiting among cancer patients, with a particular focus on evidence garnered from randomized controlled trials. Graphical Abstract Graphical Abstract

The hypothesis that sustained G protein-coupled receptor (GPCR) signaling from endosomes mediates pain is based on studies with endocytosis inhibitors and lipid-conjugated or nanoparticle-encapsulated antagonists targeted to endosomes. GPCR antagonists that reverse sustained endosomal signaling and nociception are needed. However, the criteria for rational design of such compounds are ill-defined. Moreover, the role of natural GPCR variants, which exhibit aberrant signaling and endosomal trafficking, in maintaining pain is unknown. Herein, substance P (SP) was found to evoke clathrin-mediated assembly of endosomal signaling complexes comprising neurokinin 1 receptor (NK₁R), Gαq/i, and βarrestin-2. Whereas the FDA-approved NK₁R antagonist aprepitant induced a transient disruption of endosomal signals, analogs of netupitant designed to penetrate membranes and persist in acidic endosomes through altered lipophilicity and pKa caused sustained inhibition of endosomal signals. When injected intrathecally to target spinal NK₁R+ve neurons in knockin mice expressing human NK₁R, aprepitant transiently inhibited nociceptive responses to intraplantar injection of capsaicin. Conversely, netupitant analogs had more potent, efficacious, and sustained antinociceptive effects. Mice expressing C-terminally truncated human NK₁R, corresponding to a natural variant with aberrant signaling and trafficking, displayed attenuated SP-evoked excitation of spinal neurons and blunted nociceptive responses to SP. Thus, sustained antagonism of the NK₁R in endosomes correlates with long-lasting antinociception, and domains within the C-terminus of the NK₁R are necessary for the full pronociceptive actions of SP. The results support the hypothesis that endosomal signaling of GPCRs mediates nociception and provides insight into strategies for antagonizing GPCRs in intracellular locations for the treatment of diverse diseases.

Prostate cancer is the second prevalent cancer in men. While the anti-cancer effect of Hesperidin and (Aprepitant) AP on prostate cancer cells is well documented, their combined effect and their mechanism of action are not fully investigated. Therefore, this study aimed to investigate the anti-cancer effects of Hesperidin and AP alone and in combination on prostate cancer cells. PC3 and LNCaP cell lines were treated with Hesperidin and AP alone and in combination. The Resazurin test was used for assessing cell viability. The ROS (reactive oxygen Species) level, P53, P21, Bcl-2, and Survivin gene expression were assessed. Also, a trypan blue assay was done. Hesperidin and AP reduced cell viability and increased apoptosis in PC3 and LNCaP cells. The ROS level reduced after treating the PC3 and LNCaP cells with AP with or without Hesperidin. P53 and P21 gene expression increased after treatment with Hesperidin with or without AP compared to the untreated group in the PC3 cell line. Bcl-2 and Survivin gene expression decreased with AP with or without Hesperidin in the PC3 and LNCaP cells. The current study showed the synergic anti-cancer effect of Hesperidin and AP in both PC3 and LNCaP cell lines.

G protein-coupled receptor (GPCR) structures determined by X-ray crystallography or cryo-electron microscopy include 28 receptors for which complexes with agonists and antagonists can be compared. In all these comparisons, an interatomic distance representing the size of the orthosteric ligand binding groove differs by less than 2.9 Å. In this report, 19 F-NMR observations of the NK1R-bound drug molecule aprepitant show that the orthosteric binding groove undergoes transient fluctuations with amplitudes 6 to 8 Å. We propose that this large-amplitude plasticity enables a multistep selection of functional ligands with variable efficacies. These insights into structural dynamics also provide a rationale for the observation that diffracting crystals are obtained for GPCR complexes with only few of the ligands that bind to the receptors. Comparisons of G protein-coupled receptor (GPCR) complexes with agonists and antagonists based on X-ray crystallography and cryo-electron microscopy structure determinations show differences in the width of the orthosteric ligand binding groove over the range from 0.3 to 2.9 Å. Here, we show that there are transient structure fluctuations with amplitudes up to at least 6 Å. The experiments were performed with the neurokinin 1 receptor (NK1R), a GPCR of class A that is involved in inflammation, pain, and cancer. We used 19 F-NMR observation of aprepitant, which is an approved drug that targets NK1R for the treatment of chemotherapy-induced nausea and vomiting. Aprepitant includes a bis-trifluoromethyl-phenyl ring attached with a single bond to the core of the molecule; 19 F-NMR revealed 180° flipping motions of this ring about this bond. In the picture emerging from the 19 F-NMR data, the GPCR transmembrane helices undergo large-scale floating motions in the lipid bilayer. The functional implication is of extensive promiscuity of initial ligand binding, primarily determined by size and shape of the ligand, with subsequent selection by unique interactions between atom groups of the ligand and the GPCR within the binding groove. This second step ensures the wide range of different efficacies documented for GPCR-targeting drugs. The NK1R data also provide a rationale for the observation that diffracting GPCR crystals are obtained for complexes with only very few of the ligands from libraries of approved drugs and lead compounds that bind to the receptors.

Neurokinins (or tachykinins) are peptides that modulate a wide variety of human physiology through the neurokinin G protein-coupled receptor family, implicated in a diverse array of pathological processes. Here we report high-resolution crystal structures of the human NK 1 receptor (NK 1 R) bound to two small-molecule antagonist therapeutics – aprepitant and netupitant and the progenitor antagonist CP-99,994. The structures reveal the detailed interactions between clinically approved antagonists and NK 1 R, which induce a distinct receptor conformation resulting in an interhelical hydrogen-bond network that cross-links the extracellular ends of helices V and VI. Furthermore, the high-resolution details of NK 1 R bound to netupitant establish a structural rationale for the lack of basal activity in NK 1 R. Taken together, these co-structures provide a comprehensive structural basis of NK 1 R antagonism and will facilitate the design of new therapeutics targeting the neurokinin receptor family. Neurokinin receptors are G protein-coupled receptors. Here the authors present three crystal structures of the neurokinin 1 receptor (NK 1 R) in complex with small-molecule antagonists including aprepitant and netupitant and observe that these clinically approved compounds induce a conformational change in the receptor.

δ-opioid receptor (DOR) is a promising therapeutic target for developing safer treatments for pain and neuroprotection. In this study, we applied a structure-guided drug-repurposing workflow to identify FDA-approved drugs with predicted DOR-binding and agonist-like structural features. Using a validated GNINA-based docking protocol with an active-state DOR model (PDB ID: 6PT3), we screened 2342 approved compounds and identified 39 candidates with predicted submicromolar binding affinities. These hits were further evaluated through molecular dynamics simulations, binding pocket volume analysis, and principal component analysis, which enabled the prioritization of two leading candidates, aprepitant and mavorixafor. Both compounds formed stable receptor-ligand complexes, maintained persistent interactions with Asp128, promoted contraction of the orthosteric pocket, and retained favorable redocking scores on the MD-refined receptor conformations. Overall, these results identify aprepitant and mavorixafor as promising putative DOR agonists and provide a rational foundation for their experimental validation through binding, functional, and in vivo pain studies in the future.