-
The Journal of Organic Chemistry Jun 2023A one-pot Knoevenagel reaction/asymmetric epoxidation/domino ring-opening cyclization (DROC) has been developed from commercial aldehydes, (phenylsulfonyl)acetonitrile,...
A one-pot Knoevenagel reaction/asymmetric epoxidation/domino ring-opening cyclization (DROC) has been developed from commercial aldehydes, (phenylsulfonyl)acetonitrile, cumyl hydroperoxide, 1,2-ethylendiamines, and 1,2-ethanol amines to provide 3-aryl/alkyl piperazin-2-ones and morpholin-2-ones in yields of 38 to 90% and up to 99% ee. Two out of the three steps are stereoselectively catalyzed by a quinine derived urea. The sequence has been applied for a short enantioselective entry to a key intermediate, in both absolute configurations, involved in the synthesis of the potent antiemetic drug Aprepitant.
Topics: Aprepitant; Aldehydes; Amines; Cyclization; Catalysis
PubMed: 36808952
DOI: 10.1021/acs.joc.2c02491 -
British Journal of Anaesthesia Jul 2023
Topics: Humans; Postoperative Nausea and Vomiting; Vomiting; Antiemetics; Dexamethasone; Quinuclidines
PubMed: 36737386
DOI: 10.1016/j.bja.2023.01.005 -
PloS One 2023Chemotherapy-induced hiccups are understudied but can cause sleep deprivation, fatigue, pain in the chest and abdomen, poor oral intake, aspiration, and even death. As a...
BACKGROUND
Chemotherapy-induced hiccups are understudied but can cause sleep deprivation, fatigue, pain in the chest and abdomen, poor oral intake, aspiration, and even death. As a critical next step toward investigating better palliative methods, this study reported patient-reported incidence of hiccups after oxaliplatin- or cisplatin-based chemotherapy.
METHODS
The current study relied on 2 previous studies that sought to acquire consecutive direct patient report of hiccups among patients who had recently received chemotherapy with cisplatin or oxaliplatin. These patient-reported data in conjunction with information from the medical record are the focus of this report.
RESULTS
Of 541 patients, 337 were successful contacted by phone; and 95 (28%; 95% CI: 23%, 33%) of these contacted patients reported hiccups. In univariable analyses, male gender (odds ratio (OR): 2.17 (95% confidence ratio (95% CI): 1.30, 3.62); p = 0.002), increased height (OR: 1.03 (95% CI: 1.00, 1.06); p = 0.02), and concomitant aprepitant/fosaprepitant (OR: 2.23 (95% CI: 1.31, 3.78); p = 0.002) were associated with hiccups. In multivariable analyses, these statistically significant associations persisted except for height.
CONCLUSIONS
These patient-reported data demonstrate that oxaliplatin- or cisplatin-induced hiccups occur in a notable proportion of patients with cancer. Male gender and concomitant aprepitant/fosaprepitant appear to increase risk.
Topics: Humans; Male; Cisplatin; Oxaliplatin; Aprepitant; Antiemetics; Hiccup; Neoplasms; Patient Reported Outcome Measures
PubMed: 36706101
DOI: 10.1371/journal.pone.0280947 -
Frontiers in Endocrinology 2022Diabetes is a global disease with huge impacts on patients due to its complications, among which non-healing wounds and depression are common and challenging. The...
Diabetes is a global disease with huge impacts on patients due to its complications, among which non-healing wounds and depression are common and challenging. The neurokinin 1 receptor (NK1R) inhibitor, aprepitant has been broadly applied for an antidepressant effect in depressive patients. Recent literature has indicated a therapeutic effect of downregulation in NK1R to diabetes-related fracture, cardiomyopathy, gastroparesis, and ocular surface disorders. In this study, differential expression genes in diabetes and depression were analyzed based on several RNA sequencing datasets from the GEO database to confirm NK1R in the overlapping set. Interaction network and gene set enrichment analysis were subsequently conducted. As a result, NK1R-related genes took part in angiogenesis, epithelial-mesenchymal transition (EMT), collagen deposition, and inflammation in diabetes and depression. , the downregulation of NK1R was proved to promote vascular proliferation and enhance diabetic wound healing, which provides a potential therapeutic target for the management of diabetic non-healing wounds and depression.
Topics: Humans; Neurokinin-1 Receptor Antagonists; Depression; Aprepitant; Antidepressive Agents; Receptors, Neurokinin-1; Diabetes Mellitus
PubMed: 36686487
DOI: 10.3389/fendo.2022.1077514 -
Cancer Communications (London, England) Feb 2023Highly emetogenic chemotherapy induces emesis in cancer patients without prophylaxis. The purpose of this study was to evaluate the efficacy and safety of a... (Randomized Controlled Trial)
Randomized Controlled Trial
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 models were used to assess the risk factors of CR and 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/m ), 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.
Topics: Humans; Female; Cisplatin; Antiemetics; Aprepitant; Antineoplastic Agents; Nausea; Vomiting; Neoplasms
PubMed: 36545810
DOI: 10.1002/cac2.12397 -
Acta Cirurgica Brasileira 2022The present study explored the role and mechanism involved in aprepitant-induced cardioprotective effects in rat model of ischemia-reperfusion injury.
PURPOSE
The present study explored the role and mechanism involved in aprepitant-induced cardioprotective effects in rat model of ischemia-reperfusion injury.
METHODS
The isolated hearts of Wistar male albino rats were subjected to ischemia-reperfusion injury on Langendorff apparatus. The extent of myocardial injury was assessed by measuring lactate dehydrogenase 1 and CK-MB release in the coronary effluent. The rats were treated with aprepitant (5, 10 and 20 mg/kg) before isolating hearts. After injury, the levels of HIF-1α, p-AkT, p-GSK-3β/GSK-3β were measured in heart homogenates. LY294002 was employed as PI3K inhibitor.
RESULTS
Ischemia-reperfusion led to significant myocardial injury and decreased the levels of HIF-1α, p-AkT and ratio of p-GSK-3β/GSK-3β. Aprepitant attenuated myocardial injury and restored the biochemical changes in a dose-dependent manner. Pre-treatment with LY294002 (10 and 20 mg/kg) abolished aprepitant-mediated cardioprotective effects and restored the biochemical parameters in the heart homogenate.
CONCLUSIONS
Aprepitant may be effective in preventing ischemia-reperfusion-induced myocardial injury, which may be due to activation of PI3K-AkT-GSK-3β and HIF-1α signaling pathway.
Topics: Animals; Rats; Male; Proto-Oncogene Proteins c-akt; Glycogen Synthase Kinase 3 beta; Phosphatidylinositol 3-Kinases; Aprepitant; Myocardial Reperfusion Injury; Rats, Wistar; Signal Transduction; Ischemia
PubMed: 36542041
DOI: 10.1590/acb371004 -
European Journal of Pharmaceutical... Feb 2023Drug-drug interactions (DDIs) are a major concern for the safe use of medications. Breast cancer resistance protein (BCRP) is a clinically relevant ATP-binding cassette...
Drug-drug interactions (DDIs) are a major concern for the safe use of medications. Breast cancer resistance protein (BCRP) is a clinically relevant ATP-binding cassette (ABC) transporter for drug disposition. Inhibition of BCRP increases the plasma concentrations of BCRP substrate drugs, which potentially could lead to adverse drug reactions. The aim of the present study was to identify BCRP inhibitors amongst a library of 232 commonly used drugs and anticancer drugs approved by the United States Food and Drug Administration (FDA). BCRP inhibition studies were carried out using the vesicular transport assay. We found 75 drugs that reduced the relative transport activity of BCRP to less than 25% of the vehicle control and were categorized as strong inhibitors. The concentration required for 50% inhibition (IC) was determined for 13 strong inhibitors that were previously poorly characterized for BCRP inhibition. The IC ranged from 1.1 to 11 µM, with vemurafenib, dabigatran etexilate and everolimus being the strongest inhibitors. According to the drug interaction guidance documents from the FDA and the European Medicines Agency (EMA), in vivo DDI studies are warranted if the theoretical intestinal luminal concentration of a drug exceeds its IC by tenfold. Here, the IC values for eight of the drugs were 100-fold lower than their theoretical intestinal luminal concentration. Moreover, a mechanistic static model suggested that vemurafenib, bexarotene, dabigatran etexilate, rifapentine, aprepitant, and ivacaftor could almost fully inhibit intestinal BCRP, increasing the exposure of concomitantly administered rosuvastatin over 90%. Therefore, clinical studies are warranted to investigate whether these drugs cause BCRP-mediated DDIs in humans.
Topics: Humans; Female; Pharmaceutical Preparations; ATP Binding Cassette Transporter, Subfamily G, Member 2; Dabigatran; Vemurafenib; Neoplasm Proteins; ATP-Binding Cassette Transporters; Drug Interactions; Biological Transport; Breast Neoplasms
PubMed: 36529162
DOI: 10.1016/j.ejps.2022.106362 -
Plants (Basel, Switzerland) Dec 2022Cisplatin is a chemotherapeutic agent that is widely used to treat various types of cancers. However, its side effects, most commonly nausea and vomiting, limit its... (Review)
Review
Cisplatin is a chemotherapeutic agent that is widely used to treat various types of cancers. However, its side effects, most commonly nausea and vomiting, limit its widespread use. Although various drugs, such as ondansetron and aprepitant, are used to alleviate these side effects, their efficacy is still debated. This review aims to summarize the results of 14 studies on the effects of seven single herbal extracts, one multiple herbal extract, and one ginger sub-component (i.e., [6]-gingerol) on cisplatin-induced nausea and vomiting. The results of the included studies were subdivided into four categories: kaolin consumption, retching and vomiting, food intake, and weight loss. Most studies used rodents, whereas four studies used minks or pigeons. The doses of cisplatin used in the studies varied from 3 mg/kg to 7.5 mg/kg, and only a single injection was used. Nine studies analyzed the mechanisms of action of herbal medicines and assessed the involvement of neurotransmitters, cytokines, enzymes, and various hematological parameters. Although further research is needed, this review suggests herbal medicine as a viable treatment option for cisplatin-induced neuropathic pain.
PubMed: 36501434
DOI: 10.3390/plants11233395 -
ACS Omega Nov 2022This study focused on improving the physicochemical characteristics of aprepitant with poor water solubility by preparing solid dispersion (SD). To prepare the SD with...
This study focused on improving the physicochemical characteristics of aprepitant with poor water solubility by preparing solid dispersion (SD). To prepare the SD with HPMCAS-LF, the solvent evaporation method was applied. Based on dissolution analysis, the dissolution rate of SD increased by five times compared with aprepitant. In addition, scanning electron microscopy (SEM), X-ray powder diffraction (XRPD), and differential scanning calorimetry (DSC) results suggested the presence of amorphous-form aprepitant inside SD. According to Fourier transform infrared (FTIR) spectroscopy, intermolecular hydrogen bonds were detected between polymer and aprepitant. The Caco-2 cell experiment proved that SD did not lower the transepithelial electrical resistance (TEER) values but improved the permeation amount of aprepitant. Additionally, the SD of aprepitant displayed excellent stability.
PubMed: 36385804
DOI: 10.1021/acsomega.2c04021 -
Viruses Oct 2022The repurposing of licenced drugs for use against COVID-19 is one of the most rapid ways to develop new and alternative therapeutic options to manage the ongoing...
The repurposing of licenced drugs for use against COVID-19 is one of the most rapid ways to develop new and alternative therapeutic options to manage the ongoing pandemic. Given circa 7817 licenced compounds available from Compounds Australia that can be screened, this paper demonstrates the utility of commercially available ex vivo/3D airway and alveolar tissue models. These models are a closer representation of in vivo studies than in vitro models, but retain the benefits of rapid in vitro screening for drug efficacy. We demonstrate that several existing drugs appear to show anti-SARS-CoV-2 activity against both SARS-CoV-2 Delta and Omicron Variants of Concern in the airway model. In particular, fluvoxamine, as well as aprepitant, everolimus, and sirolimus, has virus reduction efficacy comparable to the current standard of care (remdesivir, molnupiravir, nirmatrelvir). Whilst these results are encouraging, further testing and efficacy studies are required before clinical use can be considered.
Topics: Humans; SARS-CoV-2; Pandemics; Lung; Antiviral Agents; COVID-19 Drug Treatment
PubMed: 36366514
DOI: 10.3390/v14112417