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1554PEfficacy of neurokinin-1 receptor antagonists in the prevention of Chemotherapy-Induced Nausea and Vomiting in patients receiving carboplatin-based chemotherapy: a systematic review and meta-analysis
... These neuropeptides have been characterized as the endogenous ligands for the neurokinin receptors NK1 (encoded by the gene tacr1), NK2 (tacr2), and NK3 (tacr3), respectively [25]. NK1 and NK2 receptors are broadly expressed across the central and peripheral nervous systems whereupon NK1 antagonists have been developed for treatment of emesis [26], and also evaluated for addiction [27], asthma, and irritable bowel [28], whereas NK2 antagonists have been evaluated principally for the treatment of gastrointestinal (GI) and inflammatory disorders [29]. ...
... KaNDy Therapeutics demonstrated that elinzanetant is effective in the treatment of VMS in a phase II trial [80]. The potent action of elinzanetant on NK1 receptors is posited to bring some benefit with regard to peripheral flushing and sleep in VMS [80], whereas the alternate effects of NK1 antagonists on centrally mediated emesis and addiction circuits [26,27], gastrointestinal pharmacology [28], and the hypothalamic-pituitary-adrenal axis [81] is of unknown consequence in menopausal women. Additional clinical testing will further characterize the NK1R/NK3R pharmacology of elinzanetant. ...
Introduction
Although international clinical practice guidelines recognize a continued role for menopausal hormone therapy (HT), particularly for symptomatic women <60 years of age or within 10 years of menopause, safety and tolerability concerns have discouraged HT use due to potential links with a perceived increased risk of hormone-dependent cancers, and an established risk of stroke and venous thromboembolism. There is therefore a need for safe, effective non-hormonal therapy for relief of vasomotor symptoms (VMS) associated with menopause.
Areas covered
This narrative review summarizes the dataset accrued for fezolinetant, a neurokinin-3 receptor (NK3R) antagonist in clinical development for menopause-associated VMS.
Expert opinion
Altered signaling in neuroendocrine circuits at menopause leads to VMS wherein NK3R activity plays a key role to modulate the thermoregulatory center in a manner conducive to triggering the ‘hot flash’ response. Thus, a new generation of NK3R antagonists has entered clinical development to specifically target the mechanistic basis of VMS. Fezolinetant is the most advanced NK3R antagonist in terms of stage of clinical development. Results to date have demonstrated rapid and substantial reduction in VMS frequency and severity and associated improvements in health-related quality of life. NK3R antagonists offer a non-hormonal alternative to HT for the treatment of menopause-related VMS.
... As the nausea and vomiting process involves various neurotransmitters and receptors (Di Maio et al., 2018), we studied the 5-HT, DA, SP, and AEA levels and 5-HT 3 R, DA 2 R, NK 1 R, and CB 1 R expressions in tissue and explored their possible change during the chronic stress process. The results suggested that 5-HT and SP elevation, as 5-HT 3 R and FIGURE 4 | Chronic stress did not alter 5-HT, DA, SP, and AEA levels, downregulated 5-HT 3 R, DA 2 R, and NK 1 R expressions, and upregulated the CB 1 R expression in the peripheral system (n = 10/group). ...
Background: Chemotherapy-induced nausea and vomiting severely impairs the treatment and prognosis of cancer patients. Depressive mood disorder might aggravate nausea and vomiting in cancer patients; however, the role of neurotransmitters and receptors involved in the mediation of emesis and nausea is still not well elaborated.
Methods: The study was carried out based on the chronic unpredictable mild stress–induced depression-like phenotype rat model and cisplatin-induced pica rat model establishment. Forty male Sprague–Dawley rats were randomized into the non-treated control group and the chronic stress group, which were exposed to 8 weeks of stress. Each group was then sub-divided into vehicle subgroups ( n = 10) and cisplatin subgroups ( n = 10) which were given cisplatin to induce pica behavior. Kaolin and food intake were recorded after administration. The medulla oblongata and ileum tissues were obtained. Neurotransmitters involved in the mediation of emesis and nausea (5-HT, DA, SP, and AEA) were detected using an ELISA kit. Vomit-related receptors (5-HT 3 R, DA 2 R, NK 1 R, and CB 1 R) in tissues were assayed for mRNA and protein expression by RT-qPCR and Western blotting.
Results: Behavioral test and sucrose preference validated that depression-like phenotype rat models were established successfully. The kaolin consumption test confirmed that chronic stress pretreatment aggravated anorexia and pica behavior. Vomiting-related molecules’ data showed that chronic stress exposure increased 5-HT and SP levels in the medulla oblongata. Vomiting-related receptor expression data showed that chronic stress pretreatment upregulated 5-HT 3 R, DA 2 R, and NK 1 R expressions and downregulated the CB 1 R expression in the medulla oblongata. However, chronic stress pretreatment downregulated 5-HT 3 R, DA 2 R, and NK 1 R expressions and upregulated the CB 1 R expression in the ileum.
Conclusion: Chronic stress pretreatment aggravates anorexia and vomiting progress, which might be via altering neurotransmitters and receptors involved in the mediation of emesis and the nausea level and expression in the central nervous system.
... The NK-1 receptor antagonists are effective agents for the prevention of CINV when added to standard antiemetic therapy, with multiple supportive studies [5]. Indeed, a recent meta-analysis of randomized trials determined that the addition of NK-1 receptor antagonists to standard therapy improved complete emesis control by approximately 5% in the acute phase (first 24 h) and by 15% in the delayed phase (days 2 to 5) of CINV [6]. Given the supportive data, the guidelines of the American Society of Clinical Oncology consider the NK-1 receptor antagonists to be a standard of care for patients receiving MEC or HEC [7]. ...
Background
Three different injectable neurokinin-1 (NK-1) receptor antagonist formulations (CINVANTI® [C] vs. intravenous Emend® [E] vs. generic formulations of fosaprepitant [GFF]) were compared with respect to nausea and vomiting control, use of rescue therapy, and the development of infusion reactions over multiple cycles of chemotherapy.
Methods
A retrospective analysis from 17 community oncology practices across the USA was conducted on patients who received moderately or highly emetogenic chemotherapy. The co-primary endpoints were the control of chemotherapy-induced nausea and vomiting (CINV) from days 1 to 5 over all cycles and the frequency of infusion-related reactions. Propensity score weighted multivariable logistic regression analysis was used to compare complete CINV control, the use of rescue therapy, and the risk of infusion reactions between groups.
Results
The study enrolled 294 patients (C = 101, E = 101, GFF = 92) who received 1432 cycles of chemotherapy. Using CINVANTI® as the reference group, comparative effectiveness was suggested in CINV control over all chemotherapy cycles (odds ratio (OR): E vs. C = 1.00 [0.54 to 1.86] and GFF vs. C = 1.12 [0.54 to 2.32]). However, use of rescue therapy was significantly higher in the EMEND® group relative to CINVANTI® (OR = 2.69; 95%CI: 1.06 to 6.84). Infusion reactions were also numerically higher in the EMEND® group, but the difference did not reach statistical significance (OR = 4.35; 95%CI: 0.83 to 22.8).
Conclusions
In this real-world analysis, patients receiving CINVANTI® had a reduced need for CINV rescue therapy and a numerically lower incidence of infusion reactions.
... 14 5-Hydroxytryptamine 3 peripheral receptors are established to be involved in pain pathways, bind to the opioid receptor, and act as their agonists. 15,16 As an α-2 adrenoceptor agonist, dexmedetomidine produced antinociceptive, sedative, and hypotensive effects 17 and, if added to regional anesthetics, can be demonstrated extremely effective in extending the duration of the peripheral nerve block. Furthermore, numerous clinical studies have documented evidence of its efficacy in prolonging the duration of sensory and motor block and on alleviating pain. ...
This trial-based paper strives to address the comparative efficacy of some ropivacaine adjuvant options, comprising dexmedetomidine, granisetron, and nitroglycerin, on pain and hemodynamic changes in intravenous anesthesia for forearm surgeries. This double-blind, placebo-controlled study enrolled four block-randomized eligible groups with patients (overall, n=128) undergoing orthopedic forearm surgeries in the dexmedetomidine, nitroglycerin, granisetron, and placebo groups. Intra- and post-operative vital signs (mean arterial pressure/heart rate/ oxygen saturation) were monitored at baseline and captured every 10 minutes until the end of the surgery, as well as the onset of sensory and motor block and length and duration of the block and mean opioid use within 24 hours. Lastly, pain was noted after tourniquet inflation (at 15, 30, and 45 minutes every 15 minutes until the end of surgery) and after deflation (every 30 minutes to 2 hours at 30, 60, 90, and 120 minutes), as well as 6, 12, and 24 hours after the tourniquet was deflated. The dexmedetomidine-sedated subjects appeared to demonstrate quicker onset and longer length and duration of sensory and motor block, plus less pain and opioid use at all scheduled times (both P = 0.0001). Dexmedetomidine is recommended as an adjuvant to regional anesthesia (Bier's block), while being coupled with the rapid onset and prolonged length and duration of sensory and motor blocks, in addition to soothed pain and diminished opioid use within postoperative 24 hours. The study was approved by Ethics Committee of Arak University of Medical Sciences (approval No. IR.ARAKMU.REC.1398.112) on July 21, 2019, and registered at Iranian Registry of Clinical Trials (registration number IRCT20141209020258N123) on November 2, 2019.
... Biochemically, the majority of these agents work as antagonists by targeting dopamine 2 (D 2 ) receptors (prochlorperazine, metoclopramide, domperidone, metopimazine), dopamine 3 (D 3 ) receptors (amisulpride), serotonin 3 (5-HT 3 ) receptors (ondansetron, granisetron, palonosetron, ramosetron), or neurokinin 1 (NK 1 ) receptors (aprepitant, netupitant, rolapitant). Cannabinoids act as agonists at cannabinoid 1 (CB 1 ) receptors, whereas the mechanism of action of corticosteroids (dexamethasone, prednisolone) is unknown [4][5][6][7][8][9]. Prior to 2017, the recommended prophylactic regimen by the American Society of Clinical Oncology (ASCO) [10] and the Multinational Association of Supportive Care in Cancer (MASCC)/European Society for Medical Oncology (ESMO) [11] was a three-drug regimen of a 5-HT 3 receptor antagonist, dexamethasone, and a NK 1 receptor antagonist for patients receiving highly emetogenic chemotherapy (HEC). ...
Purpose
Olanzapine-containing regimens have been reported to be effective in preventing CINV following highly emetogenic chemotherapy (HEC), but it is unsure whether it is cost-effective. There has been no cost-effectiveness analysis conducted for olanzapine using costs from the USA. The aim of this study is to determine whether olanzapine-containing antiemetic regimens are cost-effective in patients receiving HEC.
Methods
A decision tree model was constructed to evaluate the cost and health outcomes associated with olanzapine-containing antiemetic regimens and otherwise-identical regimens. One-way sensitivity analyses were conducted to individually investigate the effect of (i) lower complete response (CR) rates of olanzapine, closer to non-olanzapine-containing regimens; (ii) higher FLIE scores for patients who achieved no/incomplete response, closer to FLIE scores of patients achieving a complete response; (iii) differing costs of olanzapine to reflect different costs per hospitals, globally, due to different insurance systems and drug costs; and (iv) varying costs for uncontrolled CINV, to account for varying durations of chemotherapy and accompanying uncontrolled CINV.
Results
Olanzapine regimens have an expected cost of $325.24, compared with $551.23 for non-olanzapine regimens. Meanwhile, olanzapine regimens have an expected utility/index of 0.89, relative to 0.87 for non-olanzapine regimens. Olanzapine-containing regimens dominate non-olanzapine-containing regimens even if CR of olanzapine-containing regimens fall to 0.63. Only when CR is between 0.60 and 0.62 is olanzapine both more effective and more costly.
Conclusion
Olanzapine-containing regimens are both cheaper and more effective in the prophylaxis of CINV in HEC patients, compared with non-olanzapine-containing regimens. Future CINV trial resources should be allocated to understand newer antiemetics and compare them to olanzapine-containing regimens as the control arm. Further analysis should use nationally representative data to examine medication costs by payer type.
... In China, it's officially approved only for the prevention of CINV in HEC patients. There are some published systematic reviews [11][12][13] on the prevention of CINV by aprepitant plus standard regimen. However, they primarily focused on a specific chemotherapy regimen, age group, or emetogenic risk group. ...
Objective:
To systematically evaluate the efficacy and safety of antiemetic regimen with aprepitant in the prevention of chemotherapy-induced nausea and vomiting (CINV) and provide updated information for clinical practice.
Methods:
Pubmed, Embase, the Cochrane Library, and 3 Chinese literature databases were systematically searched. Randomized controlled trials comparing standard regimen (5-hydroxytryptamine-3 receptor antagonist and glucocorticoid) with aprepitant triple regimen (aprepitant plus the standard regimen) for preventing CINV were screened. Literature selection, data extraction, and quality evaluation were performed by 2 reviewers independently. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated in the meta-analysis using RevMan 5.3 software.
Results:
A total of 51 randomized controlled trials were finally included in the systematic review. Compared with the standard regimen, the aprepitant triple regimen significantly improved the complete response in the overall (OR 1.88, 95% CI 1.71-2.07), acute (OR 1.96, 95% CI 1.65-2.32) and delayed (OR 1.96, 95% CI 1.70-2.27) phases, regardless of emetogenic risk of chemotherapy. Aprepitant could also significantly enhance the proportions of patients who have no emesis, nausea, or use of rescue medication respectively in the overall, acute and/or delayed phases. Aprepitant was found to be associated with decreased risk of constipation (OR 0.85, 95% CI 0.74-0.97), but increased the incidence of hiccup (OR 1.26, 95% CI 1.05, 1.51). There were no statistically significant differences between the 2 groups on other safety outcomes.
Conclusion:
The aprepitant triple regimen is effective for the prevention of CINV in patients being treated with moderately or highly emetogenic chemotherapy, and has a significant tendency to reduce the risk of constipation and increase the incidence of hiccup.
... Multiple classes of antiemetic agents have been developed for the purpose of controlling CINV, including dopamine receptor antagonists such as prochlorperazine and metoclopramide [6], serotonin (5-HT 3 ) receptor antagonists such as ondansetron and palonosetron [7], substance P (NK-1) receptor antagonists such as aprepitant [8], and corticosteroids such as dexamethasone [9]. ...
Introduction
Chemotherapy-induced nausea and vomiting (CINV) is a burdensome adverse event frequently associated with chemotherapy treatment of cancer. Evidence suggests that cannabinoid CB2 receptors are present in brainstem neurons, and thus, there may exist a role for cannabinoids to counter CINV. The aim of this paper is to conduct a systematic review and meta-analysis of the efficacy and safety of oral cannabinoids compared with other treatments as documented in randomized controlled trials (RCTs).
Methods
A literature search was conducted using Ovid MEDLINE up until December 31, 2018; Embase Classic and Embase up until 2018 week 53; and Cochrane Central Register of Controlled Trials up until November 2018. Study data were extracted and included in this meta-analysis if they reported on at least one of the following efficacy endpoints: no nausea and no vomiting, no nausea, and no vomiting. The Mantel-Haenszel method and random effects analysis model were used, to generate odds ratio (OR) and accompanying 95% confidence intervals (CI).
Results
In the setting of prophylactic treatment against both nausea and vomiting, oral cannabinoid was more efficacious than placebo or other studied antiemetic treatments. When controlling for vomiting, oral cannabinoid was equally as efficacious as others. Against nausea, oral cannabinoid was equally as effective as other treatments. A greater percentage of patients administered oral cannabinoid for CINV experienced dysphoria, euphoria, and sedation.
Conclusion
Although there exists some evidence suggesting that oral cannabinoids may have a role in controlling for emesis from a neurophysiological perspective, these conclusions are currently not mirrored in the published RCTs to date. However, there exists only a limited number of RCTs, comparisons with older treatment regimens and a lack of standard reporting practice across published literature. Further RCTs should investigate the efficacy and safety of oral cannabinoids, to secure a better picture of the efficacy of oral cannabinoids against CINV.
... The further addition of an NK 1 RA reduced emesis in approximately 84% of patients receiving HEC [16,18]. A number of studies and recent meta-analyses have demonstrated that the triplet regimen provides superiority over 5-HT 3 RA-dexamethasone in CINV control associated with HEC, MEC, and carboplatin-based regimens [19][20][21][22][23] without added toxicities from the oral NK 1 RAs [21,22]. This review provides an overview of currently available NK 1 RAs for the prevention of CINV and discusses the similarities and differences between these agents. ...
Introduction: The addition of neurokinin-1 receptor antagonists (NK1RAs) to standard prophylaxis of 5-hydroxytryptamine-3 RA (5-HT3RA) plus dexamethasone more effectively prevents chemotherapy-induced nausea and vomiting (CINV) associated with highly and moderately emetogenic chemotherapy.
Areas covered: This review presents the evidence base for the use of oral and intravenous (IV) NK1RAs, focusing on the pharmacologic and clinical properties as a class, and highlighting differences between agents. A PubMed literature search was conducted from 2000 to 2018.
Expert opinion: Adherence to international antiemetic guidelines remains a clinical challenge. Strategies to simplify antiemetic regimens and facilitate their administration may improve compliance and treatment outcomes. The use of fixed-combination antiemetics offers clinical utility, in combining an NK1RA with a 5-HT3RA in a single oral dose. The use of long-lasting NK1RAs and administering CINV prophylaxis closer to the time of chemotherapy may also assist with guideline and treatment compliance, diminishing the need for home-based administration, and potentially reducing resource utilization. The availability of IV and oral formulations of NK1RAs and NK1RA–5-HT3RA fixed combinations offers further utility, particularly for those patients unsuited for oral administration. However, safety considerations with respect to injection site toxicity and hypersensitivity reactions of the new NK1RA IV formulations deserve close attention.
... 36,37,43,[46][47][48]51,[53][54][55] In addition, meta-analyses of randomized clinical trials have confirmed the significant and clinically relevant improvement in CR in patients receiving carboplatin-based chemotherapy when treated with the three-drug regimen containing an NK 1 RA compared with the dual-therapy combination. 57 Because female sex is a known risk factor for increased CINV, 58 some NK 1 -RA studies have analyzed CR rates in male and female participants receiving HEC. In a subgroup analysis of a trial in which patients received a 5HT 3 RA plus dexamethasone with or without oral aprepitant, CR rates in the oral aprepitant group were slightly lower in female (68.6%) than male (71.2%) participants, but still higher than with the two-drug regimen (36.8% and 55.0%, respectively). ...
To examine pharmacologic and clinical characteristics of neurokinin 1 (NK1)-receptor antagonists (RAs) for preventing chemotherapy-induced nausea and vomiting (CINV) following highly or moderately emetogenic chemotherapy, a literature search was performed for clinical studies in patients at risk of CINV with any approved NK1 RAs in the title or abstract: aprepitant (capsules or oral suspension), HTX019 (intravenous [IV] aprepitant), fosaprepitant (IV aprepitant prodrug), rolapitant (tablets or IV), and fixed-dose tablets combining netupitant or fosnetupi-tant (IV netupitant prodrug) with the 5-hydroxytryptamine type 3 (5HT3) RA palonosetron (oral or IV). All NK1 RAs are effective, but exhibit important differences in efficacy against acute and delayed CINV. The magnitude of benefit of NK1-RA-containing three-drug vs two-drug regimens is greater for delayed vs acute CINV. Oral rolapitant has the longest half-life of available NK1 RAs, but as a consequence should not be administered more frequently than every 2 weeks. In general, NK1 RAs are well tolerated; however, IV rolapitant was recently removed from US distribution, due to hypersensitivity and anaphylaxis, and IV fosaprepitant is associated with infusion-site reactions and hypersensitivity presumed related to its polysorbate 80 excipient. Also, available NK1 RAs have potential drug–drug interactions. Adding an NK1 RA to 5HT3 RA and dexamethasone significantly improves CINV control vs the two-drug regimen. Newer NK1 RAs offer more formulation options, higher acute-phase plasma levels, or improved tolerability, and increase clinicians’ opportunities to maximize benefits of this important class of antiemetics.
... The SP/NK1 system, more particularly, is associated with multiple (patho)physiological processes, including the immune system [24,31,32], hematopoiesis [33], inflammation [34], wound healing [35][36][37][38], tissue homeostasis [38], neurogenic inflammation [39,40], cell survival, and metastatic dissemination in cancer [25,[41][42][43][44][45][46][47][48][49][50]. NK1 acts as a neuromodulator contributing to brain homeostasis [51], but also to the sensory neuronal transmission associated with depression, stress [52][53][54][55], anxiety and emesis [56][57][58], and more generally, CNS disorders. The key role of NK1 was also established in the cardiovascular system as a mediator of platelet aggregation and thrombus formation [59]. ...
The neurokinins are indisputably essential neurotransmitters in numerous patho- and physiological events. Being widely distributed in the central nervous system (CNS) and peripheral tissues, their discovery rapidly promoted them to drugs targets. A necessity for molecular tools to understand the biological role of this class endogenous peptides and their receptors prompted the scientific community to design ligands displaying either agonist and antagonist activity at the three main neurokinin receptors, called NK1, NK2 and NK3. Several strategies were implemented for this purpose. With a preference for small non-peptidic ligands, many research groups invested efforts in synthesizing and evaluating a wide range of scaffolds, but only the NK1 antagonist Aprepitant (EMENDT) and its prodrug Fosaprepitant (IVEMENDT) have been approved by the Food Drug Administration (FDA) for the treatment of Chemotherapy-Induced and Post-Operative Nausea and Vomiting (CINV and PONV, respectively). While non-peptidic drugs showed limitations, especially in side effect control, peptidic and pseudopeptidic compounds progressively regained attention. Various strategies were implemented to modulate affinity, selectivity and activity of the newly designed ligands. Replacement of canonical amino acids, incorporation of conformational constraints, and fusion with non-peptidic moieties gave rise to families of ligands displaying individual or dual NK1, NK2 and NK3 antagonism, that ultimately was combined with non-neurokinin ligands (such as opioids) to target enhanced biological impact.
... plus dexamethasone.102 Another subgroup analysis reported that, compared with control, rolapitant improved quality of life in patients receiving MEC or HEC, with significant improvements in FLIE total score (114.5 versus 109.3, ...
Chemotherapy-induced nausea and vomiting (CINV) has a severe detrimental effect on the quality of life of patients with cancer receiving chemotherapy, and remains one of the most feared adverse events associated with chemotherapy. However, physicians and oncology nurses often underestimate the incidence of CINV, as well as the impact of this toxicity on patients’ daily lives. Many challenges remain in the prevention and treatment of CINV, particularly in the delayed phase. The 5-hydroxytryptamine type 3 receptor antagonists (5-HT3 RAs) have demonstrated efficacy in CINV control during the acute phase (≤24 hours) but have limited utility in the delayed phase (>24–120 hours). The more recently introduced neurokinin-1 (NK-1) RAs have represented a relevant improvement in the prevention of CINV associated with the administration of highly and moderately emetogenic chemotherapy, particularly in the delayed phase. One of these, rolapitant, when given as one dose on the first day of the chemotherapy cycle, has been shown to protect against CINV during the complete cycle of chemotherapy in randomised controlled trials, as well as being effective in multiple cycles of chemotherapy.
Considering the frequent use of netupitant in polytherapy, the elucidation of its oxidative metabolization pattern is of major importance. However, there is a lack of published research on the redox behavior of this novel neurokinin-1 receptor antagonist. Therefore, this study was performed to simulate the intensive hepatic biotransformation of netupitant using an electrochemically driven method. Most of the known enzyme-mediated reactions occurring in the liver (i.e., N-dealkylation, hydroxylation, and N-oxidation) were successfully mimicked by the electrolytic cell using a boron-doped diamond working electrode. The products were separated by reversed-phase high-performance liquid chromatography and identified by high-resolution mass spectrometry. Aside from its ability to pinpoint formerly unknown metabolites that could be responsible for the known side effects of netupitant or connected with any new perspective concerning future therapeutic indications, this electrochemical process also represents a facile alternative for the synthesis of oxidation products for further in vitro and in vivo studies.
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