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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 -
Medical Oncology (Northwood, London,... Feb 2024Colorectal cancer (CRC) is one of the world's largest health concerns with growing global incidence and mortality. The potential value of the neurokinin-1 receptor as a...
BACKGROUND
Colorectal cancer (CRC) is one of the world's largest health concerns with growing global incidence and mortality. The potential value of the neurokinin-1 receptor as a therapeutic target has been reported in several tumor types, including CRC. Here we examined the potential anti-tumor effects of a clinically approved neurokinin-1 receptor antagonist, aprepitant, alone and its combination with 5-Fluorouracil (5-FU) as a first choice CRC chemotherapeutic drug, in both in vitro and in vivo models of CRC.
METHODS
MTT assay was employed for assessing cell proliferation. mRNA expression levels were determined by quantitative real-time PCR (qRT-PCR). Flow cytometric analysis of apoptosis was performed using an Annexin-V/propidium iodide assay kit. We finally conducted an in vivo experiment in a mouse model of CRC to confirm the in vitro antiproliferative activity of aprepitant and 5-FU.
RESULTS
We found that aprepitant and 5-FU significantly reduced CRC cell viability. The combination of drugs exhibited potent synergistic growth inhibitory effects on CRC cells. Moreover, aprepitant and 5-FU induced apoptosis and altered the levels of apoptotic genes (up-regulation of Bax, and p53 along with downregulation of Bcl-2). Importantly, the aprepitant and 5-FU combination showed a more pronounced impact on apoptosis and associated genes than either of the agents alone. Furthermore, aprepitant reduced tumor growth in vivo and led to significantly longer survival time, and this effect was more prominent when using the aprepitant and 5-FU combination.
CONCLUSIONS
Collectively, combinatory treatment with aprepitant and 5-FU potentially exerts synergistic growth inhibition and apoptosis induction in CRC, deserving further consideration as a novel strategy for CRC patients.
Topics: Animals; Mice; Humans; Fluorouracil; Aprepitant; Colorectal Neoplasms; Xenograft Model Antitumor Assays; Drug Synergism; Apoptosis; Cell Proliferation; Cell Line, Tumor
PubMed: 38340190
DOI: 10.1007/s12032-024-02312-w -
Journal of Clinical Medicine Feb 2024Prior speculation suggests that selective 5-hydroxytryptamine-3 receptors and neurokinin-1 receptor antagonists may increase arrhythmia risk and induce...
Effect of Selective 5-Hydroxytryptamine-3 Receptor and Neurokinin-1 Receptor Antagonists on Hemodynamic Changes and Arrhythmogenic Potential in Patients Receiving Chemotherapy: A Retrospective, Observational Study.
Prior speculation suggests that selective 5-hydroxytryptamine-3 receptors and neurokinin-1 receptor antagonists may increase arrhythmia risk and induce electrocardiographic changes. This study examined the effect of anti-emetic medications on arrhythmogenic potential and hemodynamic alterations. We considered patients aged 18 or above receiving chemotherapy between June 2013 and December 2013. Patients were grouped by anti-emetic medication: intravenous granisetron (Group G), oral aprepitant plus IV granisetron (Group AG), IV palonosetron (Group P), and oral aprepitant plus IV palonosetron (Group AP). We recorded blood pressure and electrocardiography initially and at the thirtieth minute post-medication, focusing on P dispersion, QTc dispersion, and systolic/diastolic blood pressure alterations. The study included 80 patients (20 per group). Baseline systolic/diastolic blood pressure and P dispersion showed no significant variance. However, the baseline QTc dispersion was significantly lower in Groups P and AP than G and AG. The thirtieth-minute systolic/diastolic blood pressures were significantly lower than the baseline for Groups AG and AP, and the heart rates decreased in all groups. Group P showed significantly fewer blood pressure changes. We found no arrhythmogenic potential linked to granisetron, palonosetron, and aprepitant. Hypotension was more frequent at 30 min post-medication in granisetron or aprepitant recipients. Considering no hypotension occurred when using palonosetron alone, this treatment was deemed safer.
PubMed: 38337537
DOI: 10.3390/jcm13030843 -
Naunyn-Schmiedeberg's Archives of... Feb 2024Substance P (SP), an important neuropeptide, has a crucial role in the progression of several cancers, including prostate cancer, through interacting with the...
Substance P (SP), an important neuropeptide, has a crucial role in the progression of several cancers, including prostate cancer, through interacting with the neurokinin-1 receptor (NK1R). Oxidative stress is also involved in the onset and progression of prostate cancer. However, no studies have been performed on the cross-talk between the SP/NK1R system and cellular redox balance in prostate cancer, and how it is involved in tumorogenesis. We aimed to investigate the effect of the SP/NK1R system and the blockage of NK1R with its specific antagonist (aprepitant) on the cellular redox status of the prostate cancer cell line (PC3 and LNCaP). We performed the resazurin assay to evaluate the toxicity of the aprepitant on the PC3 and LNCaP cell lines. The intracellular reactive oxygen species (ROS) level was measured after SP and aprepitant treatment. The alterations of expression and activity of two crucial cellular oxidoreductases, glutaredoxin, and thioredoxin were evaluated by qRT-PCR and commercial kits (ZellBio GmbH), respectively. Our results revealed that SP increased ROS production and decreased the expression and activity of glutaredoxin and thioredoxin. On the other hand, treatment of cells with aprepitant showed reverse results. In conclusion, we found that the SP/NK1R system could promote prostate cancer progression by inducing oxidative stress. In addition, the inhibition of NK1R by aprepitant modulated the effect of the SP/NK1R system on the cellular redox system. Aprepitant might therefore be introduced as a candidate for the treatment of prostate cancer; however, more studies are required to confirm the validation of this hypothesis.
PubMed: 38334824
DOI: 10.1007/s00210-024-02996-x -
Translational Pediatrics Jan 2024Neurokinin-1 receptor antagonists have improved the management of chemotherapy-induced nausea and vomiting (CINV), but to date there has been no prospective comparison...
Comparison of oral aprepitant and intravenous fosaprepitant for prevention of chemotherapy-induced nausea and vomiting in pediatric oncology patients: a randomized phase III trial.
BACKGROUND
Neurokinin-1 receptor antagonists have improved the management of chemotherapy-induced nausea and vomiting (CINV), but to date there has been no prospective comparison between oral aprepitant and intravenous fosaprepitant in pediatric oncology patients.
METHODS
Our study was a double-parallel study, and the distribution ratio was 1:1. Children aged 2-12 years who were undergoing moderate or highly emetogenic chemotherapy (MEC or HEC) were randomly assigned to receive ondansetron and dexamethasone combined with either a single dose of intravenous fosaprepitant (arm A), or 3 days of oral aprepitant (arm B). The primary outcome measure was the rate of complete response (CR) of CINV within the acute phase, defined as from the start through 24 hours after the last chemotherapy dose. Response during the delayed phase, overall response, and use of rescue antiemetics were also assessed.
RESULTS
We prospectively evaluated 108 eligible patients, including 55 receiving fosaprepitant. Study observations were made during a single cycle for each patient. The occurrence of CR in the acute phase was statistically higher for patients receiving fosaprepitant (95% 79%, P=0.018<0.05). Modest differences were seen in CR rates during the delayed phase (71% 66%, P=0.586), and overall response rate (69% 57%, P=0.179). The use of antiemetic rescue medicines was similar between arms A (11%) and B (7%).
CONCLUSIONS
Fosaprepitant produced more CRs of CINV in the acute phase than did aprepitant, although there were no statistical differences in delayed phase response, overall response, or use of rescue antiemetics. This study confirms the safety, efficacy, and potential advantages of fosaprepitant in reducing CINV in pediatric oncology patients.
TRIAL REGISTRATION
ClinicalTrials.gov identifier: NCT04873284.
PubMed: 38323173
DOI: 10.21037/tp-23-598 -
Journal of Zhejiang University.... Feb 2024Recently, 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... (Review)
Review
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.
Topics: Humans; Neurokinin-1 Receptor Antagonists; Quality of Life; Substance P; Receptors, Neurokinin-1; Neoplasms
PubMed: 38303494
DOI: 10.1631/jzus.B2300455 -
The Ocular Surface Apr 2024
PubMed: 38286217
DOI: 10.1016/j.jtos.2024.01.011 -
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 -
Pediatric Blood & Cancer Apr 2024NK-1 receptor antagonists (NK1-RA) are key agents for chemotherapy-induced nausea and vomiting (CINV) prevention in patients receiving highly emetogenic chemotherapy....
NK-1 receptor antagonists (NK1-RA) are key agents for chemotherapy-induced nausea and vomiting (CINV) prevention in patients receiving highly emetogenic chemotherapy. Current pediatric practice guidelines recommend the use of intravenous fosaprepitant or oral aprepitant. However, there are reports of hypersensitivity reactions with fosaprepitant due to polysorbate 80. Intravenous aprepitant does not contain polysorbate 80, but its use in pediatric patients has not been described. In this retrospective, single-center study, 106 pediatric patients received either fosaprepitant or intravenous aprepitant as part of their antiemetic regimen. Intravenous aprepitant was well tolerated and did not lead to any instances of hypersensitivity reactions requiring discontinuation.
Topics: Humans; Child; Aprepitant; Retrospective Studies; Polysorbates; Antineoplastic Agents; Antiemetics; Vomiting; Neoplasms; Hypersensitivity; Morpholines
PubMed: 38267822
DOI: 10.1002/pbc.30882 -
Advances in Anesthesia Dec 2023This article's objective is to present the latest evidence and information on the management of postoperative nausea and vomiting (PONV). PONV continues to affect 30% of... (Review)
Review
This article's objective is to present the latest evidence and information on the management of postoperative nausea and vomiting (PONV). PONV continues to affect 30% of the surgical population causing patient dissatisfaction, extending length of stay, and increasing overall costs. This review includes the introduction of 2 new intravenous formulations of antiemetics (amisulpride, aprepitant), updates on nontraditional therapies, suggestions for combination prophylaxis, emerging data on rescue treatment, and considerations for special populations and settings. Both of the new antiemetics provide promising options for pharmacologic interventions for PONV with favorable safety profiles.
Topics: Humans; Postoperative Nausea and Vomiting; Antiemetics; Combined Modality Therapy; Aprepitant; Administration, Intravenous
PubMed: 38251617
DOI: 10.1016/j.aan.2023.05.002