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Medicine Nov 2023Most cancer patients suffer from the pain of chemotherapy-induced nausea and vomiting (CINV). This meta-analysis was performed to evaluate the efficacy and safety of a... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Most cancer patients suffer from the pain of chemotherapy-induced nausea and vomiting (CINV). This meta-analysis was performed to evaluate the efficacy and safety of a regimen consisting of aprepitant, dexamethasone, and 5-HT3 receptor antagonists in the prevention and treatment of CINV.
METHODS
A systematic literature search was conducted across multiple databases, including PubMed, EMbase, Cochrane Library, MEDLINE, CENTRAL, HEED, CNKI, Wanfang, and VIP, to identify randomized controlled trials (RCTs) investigating the use of triple therapy (aprepitant, 5-HT3 receptor antagonist, and dexamethasone) to prevent and treat CINV. Meta-analysis was performed using RevMan 5.4 and Stata17 software, employing either a fixed-effect or random-effect model based on statistical heterogeneity.
RESULTS
A meta-analysis of 23 randomized controlled trials (RCTs) involving 7956 patients was conducted. Efficacy: Results showed significantly improved complete responses (CRs) for CINV in the test group versus the control group in the overall, acute, and delayed phases. Furthermore, in the test group, substantial alleviation of nausea symptoms was observed in the delayed and overall phases but not in the acute phase. Safety: There was no statistically significant difference in the incidence of febrile neutropenia, diarrhea, anorexia, and headache between the 2 groups. The incidence of fatigue and hiccups in the test group was higher than that in the control group; however, the incidence of constipation was significantly lower.
CONCLUSIONS
Aprepitant-containing triple therapy is highly effective in the prevention and treatment of CINV, with reliable medication safety.
Topics: Humans; Aprepitant; Antiemetics; Receptors, Serotonin, 5-HT3; Morpholines; Antineoplastic Agents; Vomiting; Nausea; Dexamethasone
PubMed: 38013306
DOI: 10.1097/MD.0000000000035952 -
Frontiers in Genetics 2023Almost all patients treated with androgen deprivation therapy (ADT) eventually develop castration-resistant prostate cancer (CRPC). Our research aims to elucidate the...
Almost all patients treated with androgen deprivation therapy (ADT) eventually develop castration-resistant prostate cancer (CRPC). Our research aims to elucidate the potential biomarkers and molecular mechanisms that underlie the transformation of primary prostate cancer into CRPC. We collected three microarray datasets (GSE32269, GSE74367, and GSE66187) from the Gene Expression Omnibus (GEO) database for CRPC. Differentially expressed genes (DEGs) in CRPC were identified for further analyses, including Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and gene set enrichment analysis (GSEA). Weighted gene coexpression network analysis (WGCNA) and two machine learning algorithms were employed to identify potential biomarkers for CRPC. The diagnostic efficiency of the selected biomarkers was evaluated based on gene expression level and receiver operating characteristic (ROC) curve analyses. We conducted virtual screening of drugs using AutoDock Vina. experiments were performed using the Cell Counting Kit-8 (CCK-8) assay to evaluate the inhibitory effects of the drugs on CRPC cell viability. Scratch and transwell invasion assays were employed to assess the effects of the drugs on the migration and invasion abilities of prostate cancer cells. Overall, a total of 719 DEGs, consisting of 513 upregulated and 206 downregulated genes, were identified. The biological functional enrichment analysis indicated that DEGs were mainly enriched in pathways related to the cell cycle and metabolism. CCNA2 and CKS2 were identified as promising biomarkers using a combination of WGCNA, LASSO logistic regression, SVM-RFE, and Venn diagram analyses. These potential biomarkers were further validated and exhibited a strong predictive ability. The results of the virtual screening revealed Aprepitant and Dolutegravir as the optimal targeted drugs for CCNA2 and CKS2, respectively. experiments demonstrated that both Aprepitant and Dolutegravir exerted significant inhibitory effects on CRPC cells ( < 0.05), with Aprepitant displaying a superior inhibitory effect compared to Dolutegravir. The expression of CCNA2 and CKS2 increases with the progression of prostate cancer, which may be one of the driving factors for the progression of prostate cancer and can serve as diagnostic biomarkers and therapeutic targets for CRPC. Additionally, Aprepitant and Dolutegravir show potential as anti-tumor drugs for CRPC.
PubMed: 37476415
DOI: 10.3389/fgene.2023.1184704 -
Translational Vision Science &... Feb 2024This study aims to assess the efficacy of two aprepitant formulations (X1 and X2), in a preclinical model of dry eye disease (DED) induced by benzalkonium chloride (BAK).
PURPOSE
This study aims to assess the efficacy of two aprepitant formulations (X1 and X2), in a preclinical model of dry eye disease (DED) induced by benzalkonium chloride (BAK).
METHODS
Two aprepitant formulations were tested on 7 to 8-week-old male mice for their efficacy. In vivo corneal fluorescein staining assessed epithelial damage as the primary end point on days 0, 3, 5, 7, 9, 12, and 14 using slit-lamp microscopy. The DED model was induced with 0.2% BAK twice daily for the first week and once daily for the next week. Mice were randomly assigned to 5 treatment groups: Aprepitant X1 (n = 10) and X2 (n = 10) formulation, 2 mg/mL dexamethasone (n = 10), control vehicle X (n = 10), 0.2% hyaluronic acid (n = 10), or no treatment (n = 10). Eye wiping, phenol red, and Cochet Bonnet tests assessed ocular pain, tear fluid secretion, and nerve function. After 7 days, the mice were euthanized to quantify leukocyte infiltration and corneal nerve density.
RESULTS
Topical aprepitant X1 reduced BAK-induced corneal damage and pain compared to gel vehicle X (P = 0.007) and dexamethasone (P = 0.021). Aprepitant X1 and X2 improved corneal sensitivity versus gel vehicle X and dexamethasone (P < 0.001). Aprepitant X1 reduced leukocyte infiltration (P < 0.05) and enhanced corneal nerve density (P < 0.001). Tear fluid secretion remained statistically unchanged in both the X1 and X2 groups.
CONCLUSIONS
Aprepitant formulation X1 reduced pain, improved corneal sensitivity and nerve density, ameliorated epitheliopathy, and reduced leukocyte infiltration in male mouse corneas.
TRANSLATIONAL RELEVANCE
Aprepitant emerges as a safe, promising therapeutic prospect for the amelioration of DED's associated symptoms.
Topics: Male; Mice; Animals; Aprepitant; Cornea; Fluorescein; Pain; Dexamethasone
PubMed: 38345550
DOI: 10.1167/tvst.13.2.9 -
Cell Biochemistry and Biophysics Dec 2023Numerous molecules have been introduced to participate in the formation of breast cancer, the most common malignancy in women. Among them, neuropeptide substance P (SP)...
BACKGROUND
Numerous molecules have been introduced to participate in the formation of breast cancer, the most common malignancy in women. Among them, neuropeptide substance P (SP) and its related receptor neurokinin-1 receptor (NK1R) have attracted unprecedented attention in tumorigenesis processes. In this study, we investigated the effect of the SP/NK1R pathway on the induction of oxidative stress in breast cancer and examine the therapeutic potential of NK1R inhibition in this malignancy.
METHODS
MCF-7 cells were treated with varying concentrations of SP and aprepitant, an FDA-approved NK1R antagonist, either as a single drug or in a combined modality. Resazurin assay was used to evaluate the anti-cancer ability of aprepitant. The alteration in the intracellular levels of reactive oxygen species (ROS) and gene expression were determined using ROS assay and the qRT-PCR analysis, respectively.
RESULTS
The stimulation of the SP/NK1R axis in the MCF-7 cells was coupled with the accumulation of ROS as well as upregulation of NF-κB and its related pro-inflammatory cytokines, including tumor necrosis factor (TNF)-α and IL-6. In contrast, the suppression of NK1R by aprepitant halted the viability of MCF-7 cells, at least partly due to p53-mediated upregulation of p21. Moreover, aprepitant attenuated the oncogenic properties of SP by preventing the oxidative property of this neuropeptide.
CONCLUSION
Overall, our results suggest that the SP/NK1R pathway might play a critical role in breast cancer pathogenesis, probably through inducing ROS/NF-κB-mediated inflammatory responses. Moreover, it seems that blockage of the axis has promising therapeutic value against breast cancer cells. Schematic representation proposed for the plausible mechanism by which the stimulation of the SP/NK1R might induce oxidative stress in breast cancer-derived MCF-7 cells. Once SP interacts with NK1R, this signaling axis could disturb the balance between the expression of p53 and NF-κB, an event that leads to the accumulation of ROS within MCF-7 cells. The produced ROS, in turn, elevates the expression of pro-inflammatory cytokines (TNF-α and IL-6) and downregulates the expression of p21. On the other hand, aprepitant, an antagonist of NK1R, could reduce the survival of proliferative capacity of MCF-7 cells by decreasing the intracellular levels of ROS and p53-mediated up-regulation of p21. Along with the effect on p53, aprepitant could also reduce the expression of NF-κB and its related pro-inflammatory cytokines.
Topics: Female; Humans; Receptors, Neurokinin-1; Substance P; NF-kappa B; Aprepitant; Breast Neoplasms; Interleukin-6; Reactive Oxygen Species; Tumor Suppressor Protein p53; Cytokines; Cell Proliferation
PubMed: 37740877
DOI: 10.1007/s12013-023-01171-y -
Cell & Bioscience Nov 2023Tachykinins and their cognate receptors, neurokinin receptors (NKs) including NK1, NK2, and NK3 play vital roles in regulating various physiological processes including...
BACKGROUND
Tachykinins and their cognate receptors, neurokinin receptors (NKs) including NK1, NK2, and NK3 play vital roles in regulating various physiological processes including neurotransmission, nociception, inflammation, smooth muscle contractility, and stimulation of endocrine and exocrine gland secretion. Their abnormal expression has been reported to be associated with neurological disorders, inflammation, and cancer. Even though NKs are expressed in the same cells with their expression being inversely correlated in some conditions, there is no direct evidence to prove their interaction. Understanding the functional crosstalk between NKs in mediated downstream signaling and cellular responses may elucidate the roles of each receptor in pathophysiology.
RESULTS
In this study, we showed that NKs were co-expressed in some cells. However, different from NK3, which only forms homodimerization, we demonstrated a direct interaction between NK1 and NK2 at the protein level using co-immunoprecipitation and NanoBiT-based protein interaction analysis. Through heterodimerization, NK2 downregulated substance P-stimulated NK1 signals, such as intracellular Ca mobilization and ERK phosphorylation, by enhancing β-arrestin recruitment, even at the ligand concentration that could not activate NK2 itself or in the presence of NK1 specific antagonist, aprepitant. In A549 cells with receptors deleted and reconstituted, NK2 exerted a negative effect on substance P/NK1-mediated cell migration.
CONCLUSION
Our study has provided the first direct evidence of an interaction between NK1 and NK2, which highlights the functional relevance of their heterodimerization in cellular responses. Our findings demonstrated that through dimerization, NK2 exerts negative effects on downstream signaling and cellular response mediated by NK1. Moreover, this study has significant implications for understanding the complexity of GPCR dimerization and its effect on downstream signaling and cellular responses. Given the important roles of tachykinins and NKs in pathophysiology, these insights may provide clues for developing NKs-targeting drugs.
PubMed: 37968728
DOI: 10.1186/s13578-023-01165-6 -
Journal of Perianesthesia Nursing :... Aug 2023The purpose of this project was to improve the consistency of verbal and written discharge instructions for women of childbearing age (13-55 years) taking hormonal...
PURPOSE
The purpose of this project was to improve the consistency of verbal and written discharge instructions for women of childbearing age (13-55 years) taking hormonal contraceptives who receive aprepitant perioperatively, to address the need to use a secondary form of birth control for 28 days, as well as to increase the knowledge and confidence of Registered Nurses when providing discharge instructions.
DESIGN
This quality improvement project used a pre-/postdesign to evaluate two separate groups of patients and registered nurses.
METHODS
The patient sample consisted of 30 total women of childbearing age who received aprepitant during the perioperative period (15 pre and 15 post). The PACU nurse sample included 15 ambulatory surgery center nurses and 58 main hospital nurses for a combined sample of 73 PACU nurses. The PACU nurses were provided with educational in-service regarding information about aprepitant and its drug interactions. PACU nurses were additionally instructed to provide patient discharge instructions using both a written and verbal format. Patients were called postoperatively before and after both the written after visit summary (AVS) changes and the PACU nurse in-services, PACU nurses were evaluated on their knowledge, confidence, and frequency of discharge teaching before and after their educational in-service. The PACU nurses were surveyed 90 days after the intervention to assess their long-term knowledge retention.
FINDINGS
There was a significant increase in nurse knowledge about aprepitant from preimplementation to postimplementation (61.39% vs 81.95%, P < .001). Nursing knowledge showed a nonsignificant decline at 90-days postimplementation (81.95% vs 73.68%, P = .096) although remained significantly higher than preimplementation scores (73.68% vs 61.39%, P = .003). There was an overall 33.3% increase in the percentage of patients who were able to recall receiving aprepitant and the need to use a secondary form of birth control when comparing the preintervention group to the postintervention group (26.7% vs 60%, P = .123).
CONCLUSIONS
The findings suggest that providing a standardized presentation about aprepitant may improve the PACU nurses' ability to verbalize key information about aprepitant, including the need for patients to use a secondary form of birth control. This increase in nursing knowledge and confidence, along with improved written discharge instructions, may have led to improved patient comprehension of aprepitant discharge education. Additionally, there was an increase in the percentage of patients who were able to recall the need to use a secondary form birth control for 28 days, to reduce the likelihood of an unintentional pregnancy.
Topics: Humans; Female; Adolescent; Young Adult; Adult; Middle Aged; Aprepitant; Hormonal Contraception; Clinical Competence; Nurses; Patient Education as Topic
PubMed: 36599790
DOI: 10.1016/j.jopan.2022.09.008 -
The Oncologist Aug 2023A protocol was developed to evaluate the value of an NK-1 receptor antagonist for preventing nausea and vomiting resulting from highly emetogenic chemotherapy when an... (Randomized Controlled Trial)
Randomized Controlled Trial
Olanzapine With or Without Fosaprepitant for Preventing Chemotherapy Induced Nausea and Vomiting in Patients Receiving Highly Emetogenic Chemotherapy: A Phase III Randomized, Double-Blind, Placebo-Controlled Trial (ALLIANCE A221602).
PURPOSE
A protocol was developed to evaluate the value of an NK-1 receptor antagonist for preventing nausea and vomiting resulting from highly emetogenic chemotherapy when an olanzapine-based antiemetogenic regimen was used.
MATERIALS AND METHODS
A221602, a prospective double-blind, placebo-controlled clinical trial, was developed to compare 2 -olanzapine-containing antiemetic regimens, one with an NK-1 receptor antagonist (aprepitant or fosaprepitant) and one without. Trial patients had a malignant disease for which they received intravenous highly emetogenic chemotherapy (single day cisplatin ≥ 70 mg/m2 or doxorubicin plus cyclophosphamide on 1 day). Patients on both arms received commonly administered doses of a 5-HT3 receptor antagonist, dexamethasone, and olanzapine. Additionally, patients were randomized to receive an NK-1 receptor antagonist (fosaprepitant 150 mg IV or aprepitant 130 mg IV) or a corresponding placebo. The primary objective was to compare the proportion of patients with no nausea for 5 days following chemotherapy between the 2 study arms. This trial was designed to test for the noninferiority of deleting the NK-1 receptor antagonist, with noninferiority defined as a decrease in freedom from nausea by less than 10%.
RESULTS
A total of 690 patients were entered on this trial, 50% on each arm. The proportion of patients without nausea for the complete 5-day study period was 7.4% lower (upper limit of the one-sided 95% confidence interval was 13.5%) in the arm without an NK-1 receptor antagonist compared with the arm with an NK-1 receptor antagonist.
CONCLUSION
This trial did not provide sufficient evidence to support that deletion of the NK-1 receptor antagonist was as good as keeping it, as a part of a 4-drug antiemetic regimen for highly emetogenic chemotherapy (ClinicalTrials.gov Identifier: NCT03578081).
Topics: Humans; Antiemetics; Olanzapine; Aprepitant; Prospective Studies; Receptors, Neurokinin-1; Vomiting; Nausea; Antineoplastic Agents; Double-Blind Method; Dexamethasone
PubMed: 37284847
DOI: 10.1093/oncolo/oyad140 -
Journal of Cancer 2023Trastuzumab deruxtecan is classified as an anticancer agent that poses a moderate emetic risk in the international guidelines for antiemetic therapy. The guidelines...
Trastuzumab deruxtecan is classified as an anticancer agent that poses a moderate emetic risk in the international guidelines for antiemetic therapy. The guidelines recommend emesis prophylaxis using a two-drug combination therapy comprising a 5-hydroxytryptamine-3 receptor antagonist (5-HT3RA) and dexamethasone (DEX). However, the high incidence of nausea and vomiting associated with trastuzumab deruxtecan is problematic. The National Comprehensive Cancer Network guideline version 1.2023 classified trastuzumab deruxtecan as having a high risk of emesis and changed its recommendation to a triplet regimen including a neurokinin-1 receptor antagonist (NK1RA). However, the emetogenic potential of trastuzumab-deruxtecan and the optimal antiemetic prophylaxis are controversial. Hence, this exploratory phase 2 study aimed to assess the efficacy and safety of treatment comprising 5-HT3RA and DEX with or without a NK1RA in preventing trastuzumab deruxtecan-induced nausea and vomiting. We conducted an open-label and randomized exploratory phase 2 study at 14 centers in Japan. Patients with breast cancer who were scheduled to receive trastuzumab deruxtecan were enrolled in this study. The patients were randomly assigned to receive granisetron and DEX (arm GD) or granisetron, DEX, and aprepitant (fosaprepitant; arm GDA). The primary endpoint was complete response (CR; no emesis or no rescue therapy) during the overall phase (120 h after the start of trastuzumab deruxtecan). Between September 2020 and March 2023, 40 patients were randomly assigned to the GD (n = 19) or GDA (n = 21) arm. In the GDA arm, one patient who did not complete the use of the rescue medication listed in the diary was excluded from the efficacy analysis, which included the use of rescue medication. The CR rates during the overall phase were 36.8% and 70.0% in the GD and GDA arms, respectively (odds ratio 0.1334; 95% confidence interval [CI]: 0.0232-0.7672; P = 0.0190), with a difference of 33.2%. No grade 3 or 4 toxicity related to antiemetic therapy was observed. Patients receiving trastuzumab deruxtecan require triple therapy, including mandatory NK1RA administration.
PubMed: 37779870
DOI: 10.7150/jca.87169 -
The Laryngoscope Nov 2023Substance 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...
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.
Topics: Rats; Female; Animals; Ovalbumin; Neurokinin-1 Receptor Antagonists; Rats, Sprague-Dawley; Aprepitant; Substance P; Rhinitis, Allergic; Nasal Mucosa; Histamine Antagonists; Disease Models, Animal
PubMed: 36856158
DOI: 10.1002/lary.30628 -
Cell Death & Disease Jan 2024Transient receptor potential melastatin 8 (TRPM8) is a cold sensory receptor in primary sensory neurons that regulates various neuronal functions. Substance P (SP) is a...
Transient receptor potential melastatin 8 (TRPM8) is a cold sensory receptor in primary sensory neurons that regulates various neuronal functions. Substance P (SP) is a pro-inflammatory neuropeptide secreted by the neurons, and it aggravates colitis. However, the regulatory role of TRPM8 in SP release is still unclear. Our study aimed to investigate TRPM8's role in SP release from primary sensory neurons during colitis and clarify the effect of SP on colonic epithelium. We analyzed inflammatory bowel disease patients' data from the Gene Expression Omnibus dataset. Dextran sulfate sodium (DSS, 2.5%)-induced colitis in mice, mouse dorsal root ganglion (DRG) neurons, ND7/23 cell line, and mouse or human colonic organoids were used for this experiment. Our study found that TRPM8, TAC1 and WNT3A expression were significantly correlated with the severity of ulcerative colitis in patients and DSS-induced colitis in mice. The TRPM8 agonist (menthol) and the SP receptor antagonist (Aprepitant) can attenuate colitis in mice, but the effects were not additive. Menthol promoted calcium ion influx in mouse DRG neurons and inhibited the combination and phosphorylation of PKAca from the cAMP signaling pathway and GSK-3β from the Wnt/β-catenin signaling pathway, thereby inhibiting the effect of Wnt3a-driven β-catenin on promoting SP release in ND7/23 cells. Long-term stimulation with SP inhibited proliferation and enhanced apoptosis in both mouse and human colonic organoids. Conclusively, TRPM8 inhibits SP release from primary sensory neurons by inhibiting the interaction between PKAca and GSK-3β, thereby inhibiting the role of SP in promoting colonic epithelial apoptosis and relieving colitis.
Topics: Humans; Mice; Animals; Substance P; Glycogen Synthase Kinase 3 beta; Menthol; Colitis; Sensory Receptor Cells; Epithelium; TRPM Cation Channels; Dextran Sulfate; Mice, Inbred C57BL; Ganglia, Spinal; Membrane Proteins
PubMed: 38280896
DOI: 10.1038/s41419-024-06480-5