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Chemotherapy-induced nausea and vomiting (CINV) is a debilitating side effect of antineoplastic agents. Several treatment regimens are used to address this problem. Fosaprepitant is a neurokinin-1 receptor blocker used in the prevention and treatment of CINV, especially for moderately and severely emetogenic chemotherapy. It is highly effective in...
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Context 1
... risk of CINV also depends on the type of chemo- therapy. The emetogenic potential is defined depending on the level of risk: minimal risk (<10%), low risk (10%-30%), moderate risk (30%-90%), and high risk (>90%) ( Table 2). CINV is classified based on the timing of occurrence: it may be acute if it occurs within initiation of chemotherapy (lasts <24 hours), delayed if it occurs after 24 hours (persist- ing for 6-7 days), or anticipatory (prior to chemotherapy administration). ...
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Purpose:
Antiemetic guidelines recommend co-administration of targeted prophylactic medications inhibiting molecular pathways involved in emesis. NEPA is a fixed oral combination of a new NK1 receptor antagonist (RA), netupitant (NETU 300 mg), and palonosetron (PALO 0.50 mg), a pharmacologically distinct 5-HT3 RA. NEPA showed superior prevention o...
Citations
... Currently, SP research has created several NK-1R/substance P antagonists. Research is underway on substance P/NK1R antagonists as antidepressants, anxiolytics, and antiinflammatory medications [160]. The first studies on NK-1R/substance P antagonists were ...
... Currently, SP research has created several NK-1R/substance P antagonists. Research is underway on substance P/NK1R antagonists as antidepressants, anxiolytics, and antiinflammatory medications [160]. The first studies on NK-1R/substance P antagonists were originally tested as antidepressants, but subsequent research revealed them to have antiemetic effects. ...
In 1931, Von Euler and Gaddum isolated substance P (SP), an undecapeptide from the tachykinin family, from equine brain and intestine tissue extracts. Numerous types of cells, including neurons, astrocytes, microglia, epithelial, and endothelial cells, as well as immune cells including T-cells, dendritic cells, and eosinophils, are responsible for its production. The corneal epithelium, immune cells, keratocytes, and neurons all express the two isoforms of NK1R, which has the highest affinity for SP. The most recent research supports SP’s contribution to corneal healing by encouraging epithelial cell migration and proliferation. Additionally, when applied to the eyes, SP has proinflammatory effects that result in miosis, intraocular inflammation, and conjunctival hyperemia. In this review article, we examine the role of substance P within the eye. We focus on the role of SP with regards to maintenance and healing of the corneal epithelium.
... Nausea and vomiting are two of the main adverse events that occur in the postoperative period and constitute a distressing experience for patients (Gan et al., 2014;Kranke et al., 2020). They cause significant increases in the length of hospital stay, in postdischarge readmissions and in costs for the health system (Candelario and Lu, 2016;Kranke et al., 2020). The management of PONV is a complex process, and several studies have been conducted focusing on this topic (Gan et al., 2014;Kono et al., 2018). ...
... The emergence of new drugs for the antiemetic management of patients undergoing cycles of highly emetogenic chemotherapy has led to their use in the anesthetic and postoperative context (Candelario and Lu, 2016;Nasir and Schwartzberg, 2016;Kono et al., 2018). To date, there are few studies available in the literature on the use of fosaprepitant in the context of PONV prophylaxis Soga et al., 2015;Atsuta et al., 2017), and we did not find a specific comparison between fosaprepitant and palonosetron in the main databases. ...
... All participants included were female. The incidence of PONV is higher in women, and these results should not be extrapolated to men (Candelario and Lu, 2016). The total time studied was limited to the first 48 h after surgery. ...
Objective: To test the hypothesis that the single use of fosaprepitant is not inferior to the use of palonosetron as antiemetic prophylaxis in the first 48 h after surgery in women undergoing laparoscopic cholecystectomy.
Method: Eighty-eight nonsmoking women (American Society of Anesthesiologists physical status I or II) aged between 18 and 60 years who underwent laparoscopic cholecystectomy received 150 mg of fosaprepitant or 75 μg of palonosetron, administered intravenously after the induction of general anesthesia.
Results: In the fosaprepitant group and in the palonosetron group, 13.6 and 18.2% of the patients, respectively, vomited in the first 48 h after surgery ( p = 0.560). There were no differences between groups in the total frequency and intensity of nausea, number of complete responders, need for rescue medication, time required for the first rescue medication dose or number of adverse events.
Conclusion: The administration of a single dose of fosaprepitant after the induction of anesthesia was as effective as the administration of a single dose of palonosetron for the prophylaxis of vomiting in the first 48 h after surgery in women undergoing laparoscopic cholecystectomy.
... It aids in prevention of both delayed and acute nausea and vomiting associated with cancer chemotherapy 24 . Fosaprepitant is a neurokinin 1 receptor (NK-1R) antagonist that binds and deactivate NK-1R leading to downstream effect such as Ca 2+ signaling through the g-protein coupled receptor (GPCR) cascade, which in turn leads to cellular sequestration resulting in vomiting [24][25][26] . Fosaprepitant exerts its effect on targeted cells by passing across the blood brain barrier (BBB) to its target destination 23 . ...
N-acetyltransferase 10 (NAT10), is an acetyltransferase that regulates RNA stability and translation processes. Association of NAT10 with several diseases including cancer, makes it a promising therapeutic target. Remodelin is the only known NAT10 inhibitor, but the structural information related to its binding with NAT10 is still obscure. Here, we predicted the human NAT10 structure using homology modeling that was not available previously and used human NAT10 to identify the novel binding site(s) of Remodelin. The alignment of the modeled human NAT10 showed 24% identity and 37% positivity with crystal structure of tRNA (Met) cytidine acetyltransferase. Molecular docking showed binding of Remodelin with NAT10 in acetyl-CoA binding pocket. Additionally, we screened a library of FDA-approved drugs for the identification of novel inhibitors of NAT10 activity. Binding score showed that four drugs namely, Fosaprepitant (− 11.709), Leucal (− 10.46), Fludarabine (− 10.347) and Dantrolene (− 9.875) bind to NAT10 and have better binding capability when compared with Acetyl-CoA (− 5.691) and Remodelin (− 5.3). Acetyl-CoA, Remodelin, and others exhibit hits for hydrophobic, hydrophilic and hydrogen interactions. Interestingly, Remodelin and others interact with the amino acid residues ILE629, GLY639, GLY641, LEU719, and PHE722 in the Acetyl-CoA binding pocket of NAT10 similar to Acetyl-CoA. Our findings revealed that Fosaprepitant, Leucal, Fludarabine, and Dantrolene are promising molecules that can be tested and developed as potential inhibitors of NAT10 acetyltransferase activity.
... 5 Chemotherapeutic agents through direct mucosal or blood born mechanism, stimulate enteroendocrine cells in gastro-intestinal cells, and peripheral mononuclear cells in blood to release mediators like 5-Hydroxytryptamine (5-HT), substance P and cholecystokinin, which then mediate the afferent impulse to central nervous system, initiating emetic response. 6,12,13 Therefore, drugs like granisetron, dexamethasone and aprepitant have definite role in management of chemotherapy induced nausea and vomiting. 7,8 Glucocorticoids inhibit the release of emetic mediators from gastrointestinal tract and peripheral blood cells, interact with serotonin receptors, inhibit nucleus tractus solitarius and they also reduce pain, thereby reducing concomitant use of opioids, which in turn reduces opioid-related nausea and vomiting. ...
... 12 To improve the compliance of anti emetic therapy, instead of aprepitant which is administered orally for 3 days ( 125 mg on Day 1, 80 mg on Day 2 and 3), intravenous prodrug of aprepitant, fosaprepitant was formulated. 13 A phase 3 trial showed that single 150 mg intravenous dose of foaprepitant could block 90% of NK-1 receptors, and was non inferior to 3 days oral aprepitant. 14 This study assessed effectiveness of NK-1 receptor antagonist, fosaprepitant in combination with 5-hydroxytryptamine-3 receptor antagonist (5-HT 3 RA) plus Dexamethasone in prevention and management of nausea and vomiting in patients receiving broad range chemotherapy regimens. ...
Introduction: Chemotherapy-induced nausea and vomiting (CINV) is one of the common side effects of cancer chemotherapy, that affects patient’s physical and psychological aspects, decreasing patients quality of life and compliance with therapy. CINV can be acute, delayed or anticipatory. This study assessed effectiveness of fosaprepitant (NK-1 receptor antagonist) in combination with 5-hydroxytryptamine-3 receptor antagonist (5-HT3 RA) plus dexamethasone in prevention and management of nausea and vomiting in patients receiving broad range of chemotherapy regimens. Materials and methods: The current study is prospective study conducted on randomly selected 72 patients during first and second cycle of standard chemotherapeutic regimens. During 144 cycles of chemotherapy patients were randomly assigned in two different anti emetic regimen; triplet regimen (aprepitant, 5-HT3 RA, dexamethasone) and duplet regimen (5-HT3 RA, dexamethasone). All the patients were interviewed using MASCC antiemesis tool (MAT) for incidence of nausea and vomiting. Nausea and vomiting was assessed for 5 days following 1st day of each chemotherapy cycle. Results: During the period of study, duplet regimen was administered in 68 cycles and triplet regimen was administered in 76 cycles of chemotherapy. Most of the chemotherapy regimen were platinum based compounds (61%). In duplet regimen 76.6 % (52/68) and 72.1% (49/68) patients had acute and delayed vomiting respectively whereas in triplet regimen 7.9% (6/76) and 5.3% (4/76) patients had acute and delayed vomiting respectively. Complete response in triplet regimen were achieved in 89 % of chemotherapy cycles which were significantly low in duplet regimen 10 % only. Conclusions: This study concludes that addition of fosaprepitant in combination with 5-HT3 RA and dexamethasone prevents CIMV in cancer patients receiving chemotherapy.
... This finding could be due to the prodrug or to differences in the formulations of these drugs. ISAEs are reported to be the major limiting adverse reaction during fosaprepitant administration [26]. ...
Aim:
Evaluate safety of HTX-019, a novel polysorbate 80- and synthetic surfactant-free intravenous formulation of neurokinin 1 receptor antagonist aprepitant for chemotherapy-induced nausea and vomiting.
Methods:
Two open-label, randomized, two-way crossover studies evaluated treatment-emergent adverse events (TEAEs) in 200 healthy subjects. Subjects received HTX-019 130 mg (30-min infusion) and fosaprepitant 150 mg (20- or 30-min infusion), with ≥7-day washout between doses.
Results:
Less than or equal to 30 min after start of infusion, TEAEs occurred in 5 (3%) HTX-019 and 30 (15%) fosaprepitant recipients. No HTX-019 recipients had infusion-site adverse events, versus 15 (8%) fosaprepitant recipients. Treatment-related dyspnea occurred in one HTX-019 and six fosaprepitant recipients. No severe/serious TEAEs occurred; all TEAEs resolved.
Conclusion:
HTX-019 may provide a safer aprepitant formulation than fosaprepitant for chemotherapy-induced nausea and vomiting prevention.
... Current cancer treatment primarily depends on surgical operations and chemotherapy to fight against cancer. Although chemotherapeutic drugs are effective at killing tumor cells, some have several drawbacks, including their nonselective distribution, drug toxicity, and unexpected side effects to normal tissues, which have limited these agents' clinical use [1][2][3]. There were few effective anticancer drugs available that would specifically kill cancer cells and not damage normal cells. ...
Background
A targeted drug nanoparticle (NP) delivery system has shown potential as a possible cancer treatment. Given its merits, such as its selective distribution at tumor sites and its controllable drug release, drug-loaded NPs can be effectively delivered to selected organs and targeted cells, thus enhancing its antitumor efficiency and reducing its toxicity.
Methods
We reported that hyaluronic acid (HA)-coated chitosan NPs promoted the drug delivery of 5-fluorouracil (5-Fu) into tumor cells that highly expressed CD44.
Results
Our new findings suggested that HA-coated chitosan NPs enhanced drug accumulation by effectively transporting NPs into CD44-overexpressed tumor cells, and they also resulted in mitochondrial damage induced by the production of reactive oxygen species (ROS). Compared to free drug and uncoated NPs, HA-coated chitosan NPs exhibited stronger inhibition rates and induced obvious apoptosis in CD44-overexpressed A549 cells.
Conclusions
Biocompatible and biodegradable HA-coated chitosan NPs were developed to encapsulate a chemotherapeutic drug (5-Fu) to enhance drug accumulation in tumor cells and to improve the agent’s antitumor efficiency by offering targeted drug delivery via CD44.
BACKGROUND
Fosnetupitant (FosNTP), an intravenous neurokinin 1 receptor antagonist, demonstrated a favorable safety profile with a potentially low risk of injection site reactions (ISRs) and promising antiemetic efficacy in patients receiving cisplatin‐based highly emetogenic chemotherapy in a previous phase 2 study. We conducted a randomized, double‐blind safety study to evaluate the safety profile of FosNTP, including ISRs, in patients receiving doxorubicin‐cyclophosphamide or epirubicin‐cyclophosphamide (AC/EC) chemotherapy.
METHODS
Patients scheduled to receive AC/EC were randomized 1:1 to receive 235 mg of FosNTP or 150 mg of fosaprepitant (FosAPR), both in combination with 0.75 mg of intravenous palonosetron and 9.9 mg of dexamethasone on day 1. The stratification factors were age category (<55 vs ≥55 years) and study site. The primary end point was the incidence of treatment‐related adverse events (TRAEs) with FosNTP.
RESULTS
Overall, 102 patients were randomized to FosNTP (n = 52) or FosAPR (n = 50), and all were treated with the study drug and evaluated for safety. The primary end point, the incidence of TRAEs, was similar with FosNTP (21.2%; 95% confidence interval [CI], 11.1%‐34.7%) and FosAPR (22.0%; 95% CI, 11.5%‐36.0%), with any‐cause ISRs observed in 5.8% and 26.0% of patients, respectively, and treatment‐related ISRs observed in 0% and 10.0%, respectively. The overall (0‐120 hour) complete response (defined as no emetic event and no rescue medication) rate, standardized by age category in the full analysis set, was 45.9% (23 of 51 patients) with FosNTP and 51.3% (25 of 49 patients) with FosAPR.
CONCLUSIONS
FosNTP demonstrated a favorable safety profile with a very low risk of ISRs in the AC/EC setting.
A proficient and distinct methodology is established for the quantification of multiple residual organic solvent impurities in fosaprepitant dimeglumine drug substance by gas chromatography with headspace sampler (HS-GC) and flame ionization detector (FID). Chromatographic separation was executed on a fused silica dimethylpolysiloxane capillary column (HP-1; USP G2 phase having dimensions, 60 m length × 0.53 mm dia & 5 μm film thickness). The validation of optimized method was carried out in accordance with relevant validation principles. The authenticated procedure was noticed to be specific, precise, linear, accurate, robust and rugged with concentration ranging from lowest quantification level (LQL) to 200% specification level for each residual organic solvent impurities (methanol, ethanol, acetone, isopropyl alcohol, dichloromethane, methyl tert-butyl ether, ethyl acetate, tetrahydrofuran, cyclohexane and toluene). The established technique was productively useful to determine the residual solvent impurities in fosaprepitant dimeglumine.
Quality by design approach has been used to develop simple, rapid, sensitive gradient RP-HPLC stability indicating method for fosaprepitant dimeglumine and its related impurities. The chromatographic method has been developed by using symmetry shield RP-18 (250 mm × 4.6 mm; 5 μm) column maintained at column temperature of 20 ºC. The mobile phase-A consisted of water and acetonitrile (800:200, v/v), added 2 mL of orthophosphoric acid and 0.17 g of tetrabutylammonium hydrogen sulphate. The mobile phase-B consisted of water and acetonitrile (200:800, v/v), added 2 mL of orthophosphoric acid and 0.17 g of tetrabutylammonium hydrogen sulphate. Gradient program was executed as time (min)/% MP-A: 0/80, 3/80, 12/40, 20/20, 24/20, 25/80, and 30/80. The UV detection was carried out at wavelength 210 nm and 20 μL of sample was injected. Sample cooler was maintained at 5 ºC. Stability of fosaprepitant dimeglumine sample was investigated in different stress condition as acid, base, oxidation, thermal, humidity and photolytic. The method was developed in two phases, screening and optimization. During the screening phase, the most suitable stationary phase, organic modifier, and solvent were identified based on the behaviour of each stationary phase with fosaprepitant dimeglumine and its impurities using each buffer and solvent. Total 18 experiments were performed to find out the best experimental condition. The optimization was done for secondary influential parameters like column temperature, gradient program, using six experiments to examine multifactorial effects of system suitability parameters and generated design space representing the robust region. A verification experiment was performed within the working design space and the model was accurate. Drug showed unstable behaviour under acid, base, oxidation, thermal, and humidity conditions. Apripetant was found as major degradation impurity. The method was validated as per ICH guideline for specificity, limit of detection (LOD), limit of quantitation (LOQ), linearity, accuracy, precision, ruggedness and robustness. Correlation coefficient is about 0.999 for all impurities, recovery is between 90% to 103% at all level. LOD value of each impurity is less than 0.01% w/w. DOE statistically based experimental designs proved to be an important approach in optimizing selectivity-controlling parameters for the organic impurities determination in FD API. The method was found to be specific, linear, accurate, precise and robust. The peak purity test results confirmed that the fosaprepitant dimeglumine peak was homogenous in all stress samples and the mass balance was found to be more than 99%, thus proving the stability indicating power of the method. Present method is found to be suitable for routine analysis in quality control laboratory.
