Elinzanetant, a new combined neurokinin-1/-3 receptor antagonist for the treatment of postmenopausal vasomotor symptoms.

INTRODUCTION: In many postmenopausal women, quality of life is decreased due to vasomotor symptoms. Efficient and well-tolerated non-hormonal treatment options are needed. AREAS COVERED: The present review summarizes what is known about the etiology of postmenopausal vasomotor symptoms as a rationale for the mechanism of action of Elinzanetant, a new neurokinin (NK)-1/-3 receptor antagonist, as well as its efficacy and side effect profile. EXPERT OPINION: Elinzanetant likely exerts an antagonistic effect on the NK-3 receptor in the preoptic thermoregulatory zone, but also an additional antagonistic effect on the NK-1 receptor possibly leading to a reduction in vasodilatation and heat-sensing neuro-activity. Elinzanetant's reported peak drug concentrations are reached within one hour and the terminal elimination half-life is approximately 15 hours. Two phase IIb clinical trials evaluated the safety profile and efficacy of several doses. There were no serious adverse events, which also included a lack of evidence of drug-related hepatotoxicity. Overall, Elinzanetant seems to be well-tolerated. In the SWITCH-1 study, the 120 mg/day and 160 mg/day regimen showed good efficacy for the treatment of vasomotor symptoms and led to significant improvements in quality of life. Thus, 120 mg oral Elinzanetant/day was used in phase III trials, whose results have not yet been published.

Identification of an Intravenous Injectable NK1 Receptor Antagonist for Use in Traumatic Brain Injury.

Traumatic brain injuries represent a leading cause of death and disability in the paediatric and adult populations. Moderate-to-severe injuries are associated with blood-brain barrier dysfunction, the development of cerebral oedema, and neuroinflammation. Antagonists of the tachykinin NK1 receptor have been proposed as potential agents for the post-injury treatment of TBI. We report on the identification of EUC-001 as a potential clinical candidate for development as a novel TBI therapy. EUC-001 is a selective NK1 antagonist with a high affinity for the human NK1 receptor (Ki 5.75 × 10-10 M). It has sufficient aqueous solubility to enable intravenous administration, whilst still retaining good CNS penetration as evidenced by its ability to inhibit the gerbil foot-tapping response. Using an animal model of TBI, the post-injury administration of EUC-001 was shown to restore BBB function in a dose-dependent manner. EUC-001 was also able to ameliorate cerebral oedema. These effects were associated with a significant reduction in post-TBI mortality. In addition, EUC-001 was able to significantly reduce functional deficits, both motor and cognitive, that normally follow a severe injury. EUC-001 is proposed as an ideal candidate for clinical development for TBI.

Advances in the research and application of neurokinin-1 receptor antagonists. / 神经激肽1å—ä½“æ‹®æŠ—å‰‚çš„ç ”ç©¶ä¸Žåº”ç”¨è¿›å±•.

Recently, the substance P (SP)/neurokinin-1 receptor (NK-1R) system has been found to be involved in various human pathophysiological disorders including the symptoms of coronavirus disease 2019 (COVID-19). Besides, studies in the oncological field have demonstrated an intricate correlation between the upregulation of NK-1R and the activation of SP/NK-1R system with the progression of multiple carcinoma types and poor clinical prognosis. These findings indicate that the modulation of SP/NK-1R system with NK-1R antagonists can be a potential broad-spectrum antitumor strategy. This review updates the latest potential and applications of NK-1R antagonists in the treatment of human diseases and cancers, as well as the underlying mechanisms. Furthermore, the strategies to improve the bioavailability and efficacy of NK-1R antagonist drugs are summarized, such as solid dispersion systems, nanonization, and nanoencapsulation. As a radiopharmaceutical therapeutic, the NK-1R antagonist aprepitant was originally developed as radioligand receptor to target NK-1R-overexpressing tumors. However, combining NK-1R antagonists with other drugs can produce a synergistic effect, thereby enhancing the therapeutic effect, alleviating the symptoms, and improving patients quality of life in several diseases and cancers.

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.

Dexamethasone-sparing on days 2-4 with combined palonosetron, neurokinin-1 receptor antagonist, and olanzapine in cisplatin: a randomized phase III trial (SPARED Trial).

BACKGROUND: This study evaluated the non-inferiority of dexamethasone (DEX) on day 1, with sparing on days 2-4 in cisplatin-based chemotherapy. METHODS: Patients with malignant solid tumors who were treated with cisplatin (≥50 mg/m²) were randomly assigned (1:1) to receive either DEX on days 1-4 (Arm D4) or DEX on day 1 (Arm D1) plus palonosetron, NK-1 RA, and olanzapine (5 mg). The primary endpoint was complete response (CR) during the delayed (24-120 h) phase. The non-inferiority margin was set at -15%. RESULTS: A total of 281 patients were enrolled, 278 of whom were randomly assigned to Arm D4 (n = 139) or Arm D1 (n = 139). In 274 patients were included in the efficacy analysis, the rates of delayed CR in Arms D4 and D1 were 79.7% and 75.0%, respectively (risk difference -4.1%; 95% CI -14.1%-6.0%, P = 0.023). However, patients in Arm D1 had significantly lower total control rates during the delayed and overall phases, and more frequent nausea and appetite loss. There were no significant between-arm differences in the quality of life. CONCLUSION: DEX-sparing is an alternative option for patients receiving cisplatin; however, this revised administration schedule should be applied on an individual basis after a comprehensive evaluation. CLINICAL TRIALS REGISTRY NUMBER: UMIN000032269.

2023 updated MASCC/ESMO Consensus recommendations: Prevention of nausea and vomiting following moderately emetic risk antineoplastic agents.

PURPOSE: Review the literature to update the MASCC guidelines from 2015 for controlling nausea and vomiting with systemic cancer treatment of moderate emetic potential. METHODS: A systematic literature review was completed using Medline, Embase, and Scopus databases. The literature search was done from June 2015 to January 2023 of the management of antiemetic prophylaxis for anticancer therapy of moderate emetic potential. RESULTS: Of 342 papers identified, 19 were relevant to update recommendations about managing antiemetic prophylaxis for systemic cancer treatment regimens of moderate emetic potential. Important practice changing updates include the use of emetic prophylaxis based on a triple combination of neurokinin (NK)1 receptor antagonist, 5-HT3 receptor antagonist, and steroids for patients undergoing carboplatin (AUC ≥ 5) and women < 50 years of age receiving oxaliplatin-based treatment. A double combination of 5-HT3 receptor antagonist and steroids remains the recommended prophylaxis for other MEC. Based on the data in the literature, it is recommended that the administration of steroids should be limited to day 1 in moderately emetogenic chemotherapy regimens, due to the demonstration of non-inferiority between the different regimens. More data is needed on the emetogenicity of new agents at moderate emetogenic risk. Of particular interest would be antiemetic studies with the agents sacituzumab-govitecan and trastuzumab-deruxtecan. Experience to date with these agents indicate an emetogenic potential comparable to carboplatin > AUC 5. Future studies should systematically include patient-related risk assessment in order to define the risk of emesis with MEC beyond the emetogenicity of the chemotherapy and improve the guidelines for new drugs. CONCLUSION: This antiemetic MASCC-ESMO guideline update includes new recommendations considering individual risk factors and the optimization of supportive anti-emetic treatments.

The Repurposing of Non-Peptide Neurokinin-1 Receptor Antagonists as Antitumor Drugs: An Urgent Challenge for Aprepitant.

The substance P (SP)/neurokinin-1 receptor (NK-1R) system is involved in cancer progression. NK-1R, activated by SP, promotes tumor cell proliferation and migration, angiogenesis, the Warburg effect, and the prevention of apoptosis. Tumor cells overexpress NK-1R, which influences their viability. A typical specific anticancer strategy using NK-1R antagonists, irrespective of the tumor type, is possible because these antagonists block all the effects mentioned above mediated by SP on cancer cells. This review will update the information regarding using NK-1R antagonists, particularly Aprepitant, as an anticancer drug. Aprepitant shows a broad-spectrum anticancer effect against many tumor types. Aprepitant alone or in combination therapy with radiotherapy or chemotherapy could reduce the sequelae and increase the cure rate and quality of life of patients with cancer. Current data open the door to new cancer research aimed at antitumor therapeutic strategies using Aprepitant. To achieve this goal, reprofiling the antiemetic Aprepitant as an anticancer drug is urgently needed.

Efficacy and safety of 5HT3RA, DEX, and NK1RA for the prevention of FOLFIRINOX-induced nausea and vomiting in patients with pancreatic cancer: a retrospective cohort study.

PURPOSE: Modified FOLFIRINOX (mFFX), a standard chemotherapy regimen for advanced pancreatic cancer (APC), is expected to be associated with a higher risk of chemotherapy-induced nausea and vomiting (CINV). Herein, we conducted a retrospective cohort study to evaluate the efficacy and safety of a three-drug combination of 5-hydroxytryptamine-3 receptor antagonists (5HT3RA), dexamethasone (DEX), and neurokinin 1 receptor antagonists (NK1RA) for the prevention of CINV during mFFX therapy. METHODS: This study enrolled patients with APC who received mFFX as initial therapy with a combination of 5HT3RA, DEX, and NK1RA as antiemetic prophylaxis. The primary endpoint was the complete response (CR) rate during cycle 1, which was defined as no emetic episodes and no rescue medication use during the overall period (0-120 h). Safety was also evaluated with a focus on hyperglycemia, which is a concern in patients with APC. RESULTS: Seventy patients were eligible for this retrospective analysis. The CR rate during the overall period was 51.4%. Significant nausea, defined as grade 2 or higher, peaked to 77.1% on days 4-5, but remained above 65% until day 7. Hyperglycemia occurred in 37.1% of patients, and 34.3% were grade 3 hyperglycemia. CONCLUSIONS: CINV induced by mFFX was poorly controlled even with prophylactic antiemetic therapy using 5HT3RA, DEX, and NK1RA, and was found to persist beyond 5 days. Enhanced antiemetic measures for mFFX are desirable. However, in patients with diabetes mellitus complications, sparing of steroids and glycemic control should be considered.

An assessment of the effects of neurokinin1 receptor antagonism against nausea and vomiting: Relative efficacy, sites of action and lessons for future drug development.

A broad-spectrum anti-vomiting effect of neurokinin1 receptor antagonists (NK1 RA), shown in pre-clinical animal studies, has been supported by a more limited range of clinical studies in different indications. However, this review suggests that compared with vomiting, the self-reported sensation of nausea is less affected or possibly unaffected (depending on the stimulus) by NK1 receptor antagonism, a common finding for anti-emetics. The stimulus-independent effects of NK1 RAs against vomiting are explicable by actions within the central pattern generator (ventral brainstem) and the nucleus tractus solitarius (NTS; dorsal brainstem), with additional effects on vagal afferent activity for certain stimuli (e.g., highly emetogenic chemotherapy). The central pattern generator and NTS neurones are multifunctional so the notable lack of obvious effects of NK1 RAs on other reflexes mediated by the same neurones suggests that their anti-vomiting action is dependent on the activation state of the pathway leading to vomiting. Nausea requires activation of cerebral pathways by projection of information from the NTS. Although NK1 receptors are present in cerebral nuclei implicated in nausea, and imaging studies show very high receptor occupancy at clinically used doses, the variable or limited ability of NK1 RAs to inhibit nausea emphasizes: (i) our inadequate understanding of the mechanisms of nausea; and (ii) that classification of a drug as an anti-emetic may give a false impression of efficacy against nausea vs. vomiting. We discuss the potential mechanisms for the differential efficacy of NK1 RA and the implications for future development of drugs that can effectively treat nausea, an area of unmet clinical need.

Neurokinin-1 receptor antagonists for the prevention of postoperative nausea and vomiting.

Despite the availability of several classes of antiemetics, postoperative nausea and vomiting (PONV) remains a substantial burden for patients following surgery, resulting in patient dissatisfaction and prolonged stays in post-anesthesia care units and ultimately increasing the cost of care. Enhanced recovery protocols and PONV management guidelines are now centered on the assessment of the individual patient's risk for developing PONV, as well as multimodal prophylaxis using antiemetics targeting different mechanisms of action. Over the last two decades, the neurokinin-1 receptor (NK1R) has emerged as a therapeutic target for the management of PONV. This review of the literature explains the role of the NK1R and its ligand-substance P-in vomiting, describes the pharmacologic and pharmacokinetic properties of NK1R antagonists (NK1RAs) and summarizes the clinical evidence supporting NK1RAs for PONV prophylaxis in patients undergoing surgery. In particular, we discuss the therapeutic application of NK1RA in PONV prophylaxis protocols owing to their advantages over other antiemetic classes in efficacy, duration of efficacy, safety, pharmacology, and ease of administration. Future studies will be aimed at further investigating the efficacy and safety of NK1RA-based multimodal combinations, particularly among vulnerable populations (e.g., children and elderly).

The in vitro anti-cancer synergy of neurokinin-1 receptor antagonist, aprepitant, and 5-aminolevulinic acid in glioblastoma.

Glioblastoma multiforme (GBM) is the most malignant type of cerebral neoplasm in adults with a poor prognosis. Currently, combination therapy with different anti-cancer agents is at the forefront of GBM research. Hence, this study aims to evaluate the potential anti-cancer synergy of a clinically approved neurokinin-1 receptor antagonist, aprepitant, and 5-aminolevulinic acid (5-ALA), a prodrug that elicits fluorescent porphyrins in gliomas on U-87 human GBM cells. We found that aprepitant and 5-ALA effectively inhibited GBM cell viability. The combinatorial treatment of these drugs exerted potent synergistic growth inhibitory effects on GBM cells. Moreover, aprepitant and 5-ALA induced apoptosis and altered the levels of apoptotic genes (up-regulation of Bax and P53 along with downregulation of Bcl-2). Furthermore, aprepitant and 5-ALA increased the accumulation of protoporphyrin IX, a highly pro-apoptotic and fluorescent photosensitizer. Aprepitant and 5-ALA significantly inhibited GBM cell migration and reduced matrix metalloproteinases (MMP-2 and MMP-9) activities. Importantly, all these effects were more prominent following aprepitant-5-ALA combination treatment than either drug alone. Collectively, the combination of aprepitant and 5-ALA leads to considerable synergistic anti-proliferative, pro-apoptotic, and anti-migratory effects on GBM cells and provides a firm basis for further evaluation of this combination as a novel therapeutic approach for GBM.

The Role of Substance P Receptor Antagonists in Allergic Rhinitis: Ovalbumin-Induced Rat Model.

OBJECTIVE: Substance P is a peptide from the tachykinin family, which is found in peripheral and central nervous systems, causing vasodilation and increased secretion in the nasal mucosa. In this study, we aimed to investigate whether the experimental model of allergic rhinitis will cause allergic changes in the larynx and to compare the effects of aprepitant, a substance P antagonist, on nasal symptoms in allergic rhinitis, and histopathological changes in the nasal and laryngeal mucosa with antihistamine and leukotriene receptor antagonists (LTRA). STUDY DESIGN: An experimental animal study. METHOD: The study was carried out on 34 healthy 8-12 weeks old female Sprague Dawley rats in 5 groups. The rats in which an experimental allergic rhinitis model was created with ovalbumin were scored by observing their nasal symptoms, and nasal and laryngeal mucous membranes included in the study were evaluated histopathologically after medications. RESULTS: As a result of the analysis of the data obtained from the study, antihistamine and LTRA significantly reduced the symptoms of nose scratching and sneezing, while aprepitant did not affect nasal symptoms. In the histopathological examination of the larynx, effects that would make a significant difference were found in the allergy group when compared to the control group. On the larynx, aprepitant reduced pseudostratification significantly compared to the allergy group. CONCLUSION: Aprepitant provides histopathological changes in the treatment of allergic rhinitis, but does not have sufficient effect on nasal symptoms. The effect of aprepitant on the larynx has not been clearly demonstrated. LEVEL OF EVIDENCE: NA Laryngoscope, 133:2891-2897, 2023.

Combination Therapy of Chemotherapy or Radiotherapy and the Neurokinin-1 Receptor Antagonist Aprepitant: A New Antitumor Strategy?

BACKGROUND: Although chemotherapy is predominantly used for cancer treatment, it can be ineffective and can induce serious side effects and lead to chemoresistance. It is essential to discover novel drugs that can enhance the antitumor activity and at the same time, counteract the severe side effects, of chemotherapy. The substance P (SP)/neurokinin-1 receptor (NK-1R) interaction system is known to play a key role in the pathogenesis of cancer. Studies with NK-1R antagonists (such as aprepitant) denote that the NK-1R is a potential target for the treatment of cancer. Aprepitant combined with major chemotherapeutic drugs has shown the potential to increase antitumor activity and decrease side effects. OBJECTIVE: Since malignant tumor cancer cells overexpress the NK-1R, this combination therapy is a promising approach for the treatment of all kinds of cancer. Since aprepitant shows potential of being a broad-antitumor drug, the repurposing of this NK-1R antagonist as an antitumor agent is warranted. Studies pertaining to combination therapy of aprepitant/radiotherapy will also be outlined in this review. The aim of this review is to provide an update on combinational studies pertaining to chemotherapy/radiotherapy and NK-1R antagonist in cancer. CONCLUSION: This combination strategy once confirmed, might open the door to a new era in chemotherapy and radiotherapy with greater antitumor activity and fewer side effects. This treatment strategy could possibly translate into higher cure rates, better quality of life and fewer sequelae in cancer patients.

The current and emerging treatment landscape for chronic cough.

Cough serves a protective physiologic function as a vital defensive reflex preventing aspiration. However, exposure to viral infections or other triggers induces, in some individuals, a chronic cough (CC) that causes a significant symptomatic burden. Most cases of CC are due to conditions that respond to appropriate therapeutic trials (upper airway cough syndrome; asthma; reflux). Unfortunately, a significant subgroup of patients will have refractory CC, which does not respond to treatment of known underlying causes of CC. Currently, available therapeutic options for refractory CC are inadequate due to limited efficacy and frequently intolerable adverse effects. Current professional society guideline recommendations are discussed, and a promising pipeline of antitussive drugs in development is introduced, including purinergic 2X3 receptor antagonists, neurokinin-1 receptor antagonists, oral mixed ĸ-opioid receptor agonists/µ-opioid receptor antagonists, and voltage-gated sodium channel blockers.

Managed care considerations for the treatment of chronic cough.

Chronic cough (CC), defined as a daily cough lasting longer than 8 weeks in adults, is a common condition in the United States. CC is a diagnosis of exclusion associated with a substantial economic burden related to increased healthcare and medication utilization, decreased work productivity, a greater incidence of cough-related comorbidities, and reduced quality of life. CC treatment guidelines recommend stepwise treatment with specific nonpharmacologic therapies and pharmacologic agents. However, many patients may still have incomplete or no symptom relief, encounter response attenuation over time, or experience intolerable adverse effects. New targeted therapies for refractory CC are currently under development, including the purinergic 2X3 receptor antagonists gefapixant, BLU-5937, and sivopixant (S-600918) and the neurokinin-1 receptor antagonist orvepitant. These targeted agents may have improved efficacy and safety profiles, helping fill unmet treatment needs. If approved, managed care organizations must develop formulary placement and utilization management criteria based on clinical guideline recommendations, expert opinion, and cost-effectiveness analyses to support the clinically appropriate use of these targeted therapies for best patient outcomes.

The Potential In Vitro Inhibitory Effects of Neurokinin-1 Receptor (NK-1R) Antagonist, Aprepitant, in Osteosarcoma Cell Migration and Metastasis.

Background: Osteosarcoma, the most frequent osteogenic malignancy, has become a serious public health challenge due to its high morbidity rates and metastatic potential. Recently, the neurokinin-1 receptor (NK-1R) is proved to be a promising target in cancer therapy. This study is aimed at determining the effect of aprepitant, a safe and Food and Drug Administration (FDA) approved NK-1R antagonist, on osteosarcoma cell migration and metastasis, and to explore its underlying mechanism of action. Methods: Colorimetric MTT assay was employed to assess cell viability and cytotoxicity. A wound-healing assay was used to examine migration ability. The desired genes' protein and mRNA expression levels were measured by western blot assay and quantitative real-time PCR (qRT-PCR), respectively. Gelatinase activity was also measured by zymography. Results: We found that aprepitant inhibited MG-63 osteosarcoma cell viability in a dose-dependent manner. We also observed that aprepitant inhibited the migrative phenotype of osteosarcoma cells and reduced the expression levels and activities of matrix metalloproteinases (MMP-2 and MMP-9). Aprepitant also reduced the expression of an angiogenic factor, VEGF protein, and NF-κB as an important transcriptional regulator of metastasis-related genes. Conclusion: Collectively, our observations indicate that aprepitant modulates the metastatic behavior of human osteosarcoma cells, which may be applied to an effective therapeutic approach for patients with metastatic osteosarcoma.

[Prophylaxis of nausea and vomiting after medical cancer treatment : Guidelines on supportive treatment-Part II]. / Prophylaxe von Übelkeit und Erbrechen nach medikamentöser Tumortherapie : Leitlinien zur Supportivtherapie ­ Teil II.

The frequency and severity of nausea and/or vomiting in patients receiving anticancer drugs are influenced by numerous factors, e.g., by the specific therapeutic agent, the dosage, the schedule and the form of administration. They are also influenced by individual factors of the patients, e.g., young age, female gender, previous cancer treatment, low or no alcohol consumption, morning sickness, travel sickness and states of anxiety. The emetogenicity of parenteral and oral medications is classified into high, moderate and minimal. For prophylaxis of highly emetogenic chemotherapy (HEC), neurokinin­1 receptor antagonists (NK1-RA), 5­hydroxytryptamine­3 receptor antagonists (5-HT3-RA), dexamethasone (DEX) and olanzapine (OLANZ) are used in combination. For moderate emetogenicity DEX and 5­HT3-RA are used together for prophylaxis of acute emesis and for low emetogenicity a monotherapy with 5­HT3-RA, DEX or metoclopramide is used. For minimal emetogenicity routine prophylaxis is not necessary. Standards are also prescribed for delayed emesis and oral anticancer medications. Guideline-conform prophylaxis is an indispensable component of medical oncological treatment.

Efficacy of Olanzapine 5 mg versus 10 mg for the Prophylaxis of Chemotherapy-Induced Nausea and Vomiting in Patients Receiving High Emetic Risk Chemotherapy without Neurokinin-1 Receptor Antagonist.

OBJECTIVE: To compare the efficacy and safety of two different dosage levels of olanzapine for the prevention of chemotherapy-induced nausea and vomiting (CINV) in patients receiving high emetic risk chemotherapy. METHODS: This study was a randomized, double-blind, controlled trial designed to show non-inferiority in the efficacy of olanzapine 5 mg compared to 10 mg in patients treated with high dose cisplatin or doxorubicin/cyclophosphamide. Non-inferiority was defined as a lower margin of the 95% confidence interval (95% CI) that not lower than the margin set at -25%. RESULT: A total of 140 patients were randomized to 5 mg group (n=70) or 10 mg group (n=70) of olanzapine. The complete response (CR) rate in the overall phase of olanzapine 5 and 10 mg was 58.6% v 62.9% (95%CI: -20.4, 11.8). The CR rate comparison between olanzapine 5 and 10 mg was 81.4% v 74.3% (95%CI: -6-6, 20.8) and 66.7% v 76.1% (95%CI: -23.5, 6.3) for the acute and delayed phase, respectively. No nausea rates in acute, delayed and overall phase were 70.0% v 68.6% (95%CI: -13.8, 16.6), 45.7% v 48.6% (95%CI: -19.4, 13.6) and 43.5% v 47.9% (95%CI: -19.2, 13.6). The rate of adverse events (AE) including somnolence were not different between the 5 and 10 mg groups. CONCLUSION: The two dosage levels of olanzapine were not different in terms of the efficacy and AE in the prophylaxis of CINV.

Sustained endosomal release of a neurokinin-1 receptor antagonist from nanostars provides long-lasting relief of chronic pain.

Soft polymer nanoparticles designed to disassemble and release an antagonist of the neurokinin 1 receptor (NK1R) in endosomes provide efficacious yet transient relief from chronic pain. These micellar nanoparticles are unstable and rapidly release cargo, which may limit the duration of analgesia. We examined the efficacy of stable star polymer nanostars containing the NK1R antagonist aprepitant-amine for the treatment of chronic pain in mice. Nanostars continually released cargo for 24 h, trafficked through the endosomal system, and disrupted NK1R endosomal signaling. After intrathecal injection, nanostars accumulated in endosomes of spinal neurons. Nanostar-aprepitant reversed mechanical, thermal and cold allodynia and normalized nociceptive behavior more efficaciously than free aprepitant in preclinical models of neuropathic and inflammatory pain. Analgesia was maintained for >10 h. The sustained endosomal delivery of antagonists from slow-release nanostars provides effective and long-lasting reversal of chronic pain.