化疗止吐药aprepitant

1商品名 Emend 2开发与上市厂商 由美国默克公司研制,2003年3月首次在美国上市.

Prevention of Postoperative Nausea and Vomiting in Elective Hysterectomy: A Prospective, Randomized, Placebo Controlled Outcomes Trial of Aprepitant NK-1-Receptor Antagonist

Objectives: Current prophylactic interventions fail to completely eliminate postoperative nausea and vomiting (PONV) for a substantial number of patients. A new antiemetic (aprepitant) has been effective in preventing chemotherapy induced nausea and vomiting (CINV). We hypothesized that adding aprepitant to our current prophylactic regimen of dexamethasone and ondansetron would reduce the incidence of PONV in our elective hysterectomy population. Methods: 256 patients undergoing elective hysterectomy were enrolled in this prospective, randomized, double blinded, placebo controlled trial. Subjects received either oral aprepitant 40 mg or oral placebo 30 minutes prior to induction of standardized anesthesia. The primary outcome was vomiting within the first 24 hours after surgery. Postoperative nausea, vomiting, and use of rescue antiemetics were documented over a 24 h period. Additionally, adverse events, hospitalization days, and readmissions for PONV were compared. Results: There was a trend towards reduction of postoperative nausea and vomiting in the aprepitant group. Nausea and vomiting were noted for 24% and 17% of women in the aprepitant group versus 38% and 29% of women in the Placebo group, respectively. Supplemental antiemetic medication was used by 42% of women in the aprepitant group versus 60% of women in the Placebo group. No adverse events were substantially more common in the aprepitant group than the Placebo group. Conclusions: Preemptive use of aprepitant prior to elective hysterectomy may reduce the incidence of PONV and diminish the need for rescue antiemetics postoperatively. Further studies with larger power are needed to confirm the trends observed in this study.

The use of aprepitant and palonosetron in preventing chemotherapy-related nausea and vomiting inlung cancer patients

Objective The aim of this study was to explore the clinical efficacy and toxicity of a combination aprepitant and palonosetron hydrochloride therapy in preventing chemotherapy-induced nausea and vomiting associated with a cisplatinum-based regimen in patients with lung cancer. Methods Sixty-eight patients with lung cancer were randomly assigned to receive either aprepitant plus palonosetron hydrochloride(group A, n = 38) or tropisetron(group B, n = 30). Acute(0–24 h) and delayed(2–5 d) emetic episodes, nausea, vomiting, constipation, and dizziness were compared between the two groups in the five days following cisplatinum-based chemotherapy.Results Group A had a higher complete control rate for both acute and delayed emetic episodes than Group B(36.8% vs. 13.3% and 31.6% vs. 13.3%, respectively; P < 0.05 for both). There was no significant difference in the constipation rate between the two groups. Conclusion Aprepitant combined with palonosetron hydrochloride is active and well tolerated in both acute and delayed emetic episodes in patients with lung cancer treated by a cisplatinum-based regimen.

Validation of different personalized risk models of chemotherapy-induced nausea and vomiting:results of a randomized,double-blind,phase III trial of fosaprepitant for cancer patients treated with high-dose cisplatin

Background:Highly emetogenic chemotherapy induces emesis in cancer patients without prophylaxis.The purpose of this study was to evaluate the efficacy and safety of a fosaprepitant-based triple antiemetic regimen for the prevention of chemotherapy-induced nausea and vomiting(CINV)in patients with solid malignant tumors,determine risk factors and externally validate different personalized risk models for CINV.Methods:This phase III trial was designed to test the non-inferiority of fosaprepitant toward aprepitant in cancer patients who were to receive the first cycle of single-day cisplatin chemotherapy.The primary endpoint was complete response(CR)during the overall phase(OP)with a non-inferiority margin of 10.0%.Logistic regression modelswere used to assess the risk factors ofCRand no nausea.To validate the personalized risk models,the accuracy of the risk scoring systems was determined by measuring the specificity,sensitivity and area under the receiver operating characteristic(ROC)curve(AUC),while the predictive accuracy of the nomogram was measured using concordance index(C-index).Results:A total of 720 patients were randomly assigned.CR during the OP in the fosaprepitant group was not inferior to that in the aprepitant group(78.1%vs.77.7%,P=0.765)with a between-group difference of 0.4%(95%CI,-5.7%to 6.6%).Female sex,higher cisplatin dose(≥70 mg/m2),no history of drinking and larger body surface area(BSA)were significantly associated with nausea.The AUC for the acute and delayed CINV risk indexes was 0.68(95%CI:0.66-0.71)and 0.66(95%CI:0.61-0.70),respectively,and the C-index for nomogram CINV prediction was 0.59(95%CI,0.54-0.64).Using appropriate cutoff points,the three models could stratify patients with high-or low-risk CINV.No nausea and CR rate were significantly higher in the low-risk group than in the high-risk group(P<0.001).Conclusions:Fosaprepitant-based triple prophylaxis demonstrated non-inferior control for preventing CINV in patients treated with cisplatin-base chemotherapy.Female cancer patients without a history of alcohol consumption,with larger BSA and received high-dose cisplatin might be more vulnerable to CINV.Three personalized prediction models were well-validated and could be used to optimize antiemetic therapy for individual patients.

Synthesis of the major isomers of Aprepitant and Fosaprepitant

The synthesis of two isomers of Aprepitant （APT） and three isomers of Fosaprepitant （FPT）, crucial components for quality control in manufacturing, is described. Herein, three chiral centers in the isomers of Aprepitant are established in high yield by induced crystallization and chiral reduction. Additionally, the isomers of Aprepitant are utilized to synthesize the isomers of Fosaprepitant with the same stereochemistry. All the target compounds were confirmed by elemental analyses, 1R, NMR and MS data analysis.

Identification of optimal contemporary antiemetic prophylaxis for doxorubicin-cyclophosphamide chemotherapy in Chinese cancer patients: post-hoc analysis of 3 prospective studies

Objective:Chemotherapy-induced nausea and vomiting(CINV)are common with doxorubicin-cyclophosphamide(AC)chemotherapy.Recommended antiemetic regimens incorporate neurokinin-1 receptor antagonist(NK1 RA),5-hydroxytryptamine type-3 receptor antagonist(5 HT3 RA),corticosteroid,and dopamine antagonists.This post-hoc analysis compared results of 3 prospective antiemetic studies conducted among Chinese breast cancer patients who received(neo)adjuvant AC,in order to identify optimal antiemetic prophylaxis.Methods:A total of 304 patients were included:Group 1,ondansetron/dexamethasone(D1);Group 2,aprepitant/ondansetron/dexamethasone(D1);Group 3,aprepitant/ondansetron/dexamethasone(D1–3);Group 4,aprepitant/ondansetron/dexamethasone(D1–3)/olanzapine;and Group 5,netupitant/palonosetron/dexamethasone(D1–3).Antiemetic efficacies of Groups 3,4,and 5 during cycle 1 of AC were individually compared with Group 1.In addition,emesis outcomes of patients in Groups 3 and 5,and those of Groups 2 and 3,were compared.Results:When comparing efficacies of a historical doublet(5 HT3 RA/dexamethasone)with triplet antiemetic regimens(NK1 RA/5 HT3 RA/dexamethasone)with/without olanzapine,complete response(CR)percentages and quality of life(QOL)in overall phase of cycle 1 AC were compared between Group 1 and the other groups:Group 1 vs.3,41.9%vs.38.3%(P=0.6849);Group 1 vs.4,41.9%vs.65.0%(P=0.0107);and Group 1 vs.5,41.9%vs.60.0%(P=0.0460).Groups 4 and 5 achieved a better QOL.When comparing netupitant-based(Group 3)with aprepitant-based(Group 5)triplet antiemetics,CR percentages were 38.3%vs.60.0%,respectively(P=0.0176);Group 5 achieved a better QOL.When comparing 1 day(Group 2)vs.3 day(Group 3)dexamethasone,CR percentages were 46.8%and 38.3%,respectively(P=0.3459);Group 3 had a worse QOL.Conclusions:Aprepitant-containing triplets were non-superior to doublet antiemetics.Netupitant-containing triplets and adding olanzapine to aprepitant-containing triplets were superior to doublets.Netupitant/palonosetron/dexamethasone was superior to aprepitant/ondansetron/dexamethasone.Protracted administration of dexamethasone provided limited additional benefit.

Controlling Chemotherapy-Induced Nausea and Vomiting with Neurokinin-1 Receptor Antagonists in Patients on AC-Based Chemotherapy—Are We There Yet?

Chemotherapy-induced nausea and vomiting (CINV) are distressing side effects of chemotherapy. Neurokinin-1 receptor antagonists (NK1-RAs) have been incorporated in the contemporary management of CINV. However, clinical studies on NK1-RAs have shown mixed results in reducing CINV risk. Most studies focused on the use of aprepitant (APR) and casopitant (CAS) in breast cancer patients receiving AC-type (doxorubicin and cyclophosphamide) chemotherapy. In this study, we compared the study design and clinical efficacies of these NK1-RAs in reducing CINV risk. Among the selected eight studies, 4 APR Randomized Controlled Trials (RCTs), 2 APR Observational Studies (OSs) and 2 CAS RCTs were identified. Patient-related characteristics such as the proportion of females (60.0% - 100.0%), age (46.5 - 59.5 years), histories of motion (5.6% - 47.0% in NK1-RA arms) and morning sicknesses (14.2% - 45.0% in NK1-RA arms) and types of antiemetic regimens;as well as chemotherapy-related characteristics such as the proportion of patients on AC chemotherapy (15.0% - 100.0%) varied greatly. In terms of efficacies, both APR and CAS improved overall CR and vomiting in majority of the studies. None of the studies, however, demonstrated that NK1-RA could provide adequate nausea control. To conclude, NK1-RAs are effective in improving vomiting and overall CR, but not useful in controlling nausea or attaining CC, the ideal CINV endpoint. A shift in paradigm is needed for future CINV research. As healthcare providers continue to strive for optimum CINV control in their patients, we hope this review can help them make better informed clinical decisions.

Possible Mechanism of Action of Neurokinin-1 Receptors （NK1R） Antagonists

Recently, NK1R （Neurokinin-1 receptors） take attention as new and promising target in anticancer drug development area. It has been proved that non-peptide NK1R antagonists L-733,060, aprepitant and L-732,138 inhibited tumor growth in several cancer cell lines. For the development of novel NK1R antagonists as antitumor agents, heterocyclic compounds which were previously synthesized by our team, tested for their cytotoxic activities in several cancer cell lines in this study. Among the tested compounds, a benzothiazole derivative BSN-009 inhibited colon cancer cell lines growth by 57.53% by comparing the activity to the control drug aprepitant. Molecular modeling studies such as molecular docking and pharmacophore generation were performed with known NK1R antagonists and BSN-009 by using Discovery Studio 3.5 in order to explain their binding modes to NK1R. BSN-009 may be a good anticancer drug candidate as a possible NK1R antagonist and is worthy to carry on the anticancer studies.

Computational study of some potential inhibitors of COVID-19:A DFT analysis

Background:There is an urgent demand of drug or therapy to control the COVID-19.Until July 22,2021 the worldwide total number of cases reported is more than 192 million and the total number of deaths reported is more than 4.12 million.Several countries have given emergency permission for use of repurposed drugs for the treatment of COVID-19 patients.This report presents a computational analysis on repurposing drugs—tenofovir,bepotastine,epirubicin,epoprostenol,tirazavirin,aprepitant and valrubicin,which can be potential inhibitors of the COVID-19.Method:Density functional theory(DFT)technique is applied for computation of these repurposed drug.For geometry optimization,functional B3LYP/6-311G(d,p)is selected within DFT framework.Results:DFT based descriptors—highest occupied molecular orbital(HOMO)-lowest unoccupied molecular orbital(LUMO)gap,molecular hardness,softness,electronegativity,electrophilicity index,nucleophilicity index and dipole moment of these species are computed.IR and Raman activities are also analysed and studied.The result shows that the HOMO-LUMO gap of these species varies from 1.061 eV to 5.327 eV.Compound aprepitant with a HOMOLUMO gap of 1.419 eV shows the maximum intensity of IR(786.176 km mol‒1)and Raman spectra(15036.702 a.u.).Conclusion:Some potential inhibitors of COVID-19 are studied by using DFT technique.This study shows that epirubicin is the most reactive compound whereas tenofovir is found to be the most stable.Further analysis and clinical trials of these compounds will provide more insight.