Antiemetic Research Articles

Bendamustine-bortezomib-dexamethasone in relapsed/refractory multiple myeloma.

e20051 Background: Bendamustine is an old bi-functional alkylating agent which has proved to be effective in relapsed, refractory and in new diagnosed Multiple Myeloma (MM). Thus, aiming to provide further insights in this field, also in novel agents’era, we present here a retrospective, real-life analysis of patients with relapsed/refractory MM (rrMM), who had received salvage therapy with bendamustine in combination with bortezomib and dexamethasone (BVD). Methods: 81 patients (44 M/37 F), with rrMM, median age at diagnosis 59.4 years (r. 36-82), median age at start of treatment 63.6 years (r.37-86) treated with several lines of treatments (median 6, r. 2-11), every refractory to all the drugs previously received (also Bortezomib), received BVD (B 90 mg/sqm days 1,2; V 1.3 mg/sqm days 1,4,8,11, D 20 mg days 1,2,4,5,8,9,11,12, Pegfilgrastim day +4) every 28 days, until progression. Setting and Patients: All patients had previously received bortezomib-based and IMIDs-based treatments, and 32% (26/81) had also received radiotherapy. 69% (56/81) had undergone single or double autologous and three (2%) allogeneic stem cell transplant. Results: Bendamustine was well tolerated, with grade 3-4 transfusion-dependent anemia in 56% (46/81) of patients, and 43% (35/81) grade 3-4 neutropenia (no ospedalization was required, no septic shocks were observed). No severe extrahematologic toxicity was observed, only grade 1 gastrointestinal side effect (nausea), treated by common antiemetic drugs. ORR was 63% (51/81: 7 CR, 18 VGPR, 15 PR, 11 MR) with 11 PD and 19 patients in SD, impressive result in this subset of rrMM patients. In particular, for 11 patients, BVD was, after having achieved at least a PR, a bridge to second auSCT, and for two patients a bridge to alloSCT. Eight patients have surprisingly achieved a notable PR after failure of novel agents (i.e. Carfilzomib, Daratumumab and Pomalidomide). Median time to response was 1.3 months (r.1-3), median OS from diagnosis was 67.3 months (r.6-151), median OS from start of Bendamustine was 9.6 months (r.2-36). Conclusions: BVD has shown significant efficacy in a particularly severe setting of patients, relapsed and refractory to all available therapeutic resources, and, in particular cases, it could be considered as a bridge to SCT, also after failure of novel agents. Clinical trial information: FEDII 2022000378 .

Formulation and Characterization of Oral Dispersible Tablet of Aprepitant

The oral route of drug administration is more common and convenient where tablets and capsules emerged as popular dosage form but many patients have dysphasia or difficulty in swallowing which is currently affecting 35% general population. Aprepitant is anti-emetic drug and used in the treatment of chemotherapy in cancer. Fast onset of action is required in this indication there for it was thought to prepare Oral Dispersible Tablet of Aprepitant which would help to avoid first pass metabolism and improve bioavailability also Aprepitant is insoluble in water so, to increase the solubility solid dispersion method (kneading method) was used. Here, Aprepitant ODT is prepared by direct compression method using Polyplasdone XL10 as superdisitegrant and optimized by 32 Full factorial design. Here, Polyplasdone XL10 (x1) and Mannitol(x2) is use as independent variable. while dependent variable are disintegration time and wetting time. Optimized formulation F8 batch showed drug content (98.41±0.91); disintegration time is (18.02±1.20) Wetting time (22.53±0.43). The formulation is stable at 40ºc/75% RH for 30days.

Simulation of drug-drug interactions between breast cancer chemotherapeutic agents and antiemetic drugs.

Chemotherapy-induced nausea and vomiting are commonly experienced side effects in breast cancer (BCa) patients. Antiemetic drugs used in BCa treatment are either inhibitors or inducers of cytochrome P450 (CYP) enzymes, while anticancer drugs are metabolized by CYPs. The purpose of the present work was to evaluate in silico drug-drug interaction (DDI) potential between BCa chemotherapeutic drugs and antiemetic agents. The Drug-Drug Interaction™ module of GastroPlus™ was employed to assess CYP-related interactions between antiemetic and anticancer therapy combinations. The CYP inhibitory or inducing parameters (IC50, Ki, EC50) used in simulations were obtained fromthe literature. Analyses of twenty-three BCa drugs indicated that 22% of the chemotherapeutic drugs do not need an antiemetic agent due to their low emetogenicity, whereas 30% of the anticancer drugs are not metabolized by CYPs. The remaining eleven anticancer drugs metabolized by CYPs generated ninety-nine combinations with nine antiemetics. Simulation of DDIs suggest that about half of the pairs did not demonstrate any potential for DDI, whereas 30%, 10%, and 9%of the pairs showed weak, moderate, and strong interaction potential, respectively. In the present study, netupitant was the only antiemetic that showed strong inhibitory interactions (predicted AUC ratio > 5) with CYP3A4-metabolzied anticancer therapies (e.g., docetaxel, ribociclib, olaparib). Moderate to no interactions were observed with ondansetron, aprepitant, rolapitant, and dexamethasone in combination with anticancer agents. It is critical to recognize that these interactions can get amplified in cancer patients because of the severity of the disease and chemotherapy toxicities. Clinicians need to be aware of the DDI likelihood of the drug combinations used in BCa treatment.

Therapeutic study of the nausea and vomiting caused by chemotherapy medications by olanzapine to triple antiemetic therapy in Iraqi cancer patients

Background:Chemotherapy-caused nausea and vomiting is a health problem in cancer patients. Olanzapine is used with serotonin receptor antagonists plus dexamethasone post Neurokinin 1 receptor antagonists as the antiemetic.
 Objective: The study aimed to determine the efficacy of (5 and 10) mg of olanzapine with antiemetic drugs against chemotherapy-induced nausea and vomiting.
 Methods: The study groups are Group S: received triple antiemetic therapy aprepitant at (1-3) day, dexamethasone at (1-4) day, and ondansetron only on the first day. Group O5: received olanzapine 5 mg with triple antiemetic therapy aprepitant (1-3) days, dexamethasone (1-4) day, ondansetron the first day, and olanzapine 5 mg (1-4) days. Group O10: received (olanzapine 10 mg with triple antiemetic therapy) aprepitant (1-3) days, dexamethasone (1-4) days, ondansetron day 1, and olanzapine 10 mg (1-4) days. The cancer was diagnosed by mamograph; the MAT score was used to control chemotherapy-caused nausea and vomiting.
 Results: Higher acute and delayed nausea was observed in group S than in groups O5 and O10. Overall, nausea control was increased in group S than in groups O5 and O10. There was no significant difference between the different study groups.
 Conclusion: Olanzapine 5 mg and 10 mg could treat nausea more than triple antiemetic in patients with nausea.

Exploration of new solid forms of anti-emetic drug domperidone: Novel salts with enhanced solubility and dissolution

Domperidone (DMP) is an anti-emetic agent used for treatments like dyspepsia, indigestion, epigastric pain, nausea, and vomiting. DMP belongs to BCS class II having poor aqueous solubility and high permeability. In the current work, nine novel salts of DMP with coformers namely acetic acid (ACA), oxalic acid (OXC), Fumaric acid (FMA), Glutaric acid (GLA), Adipic acid (ADA), Saccharin (SAH), Salicylic acid (SAL), 4-Hydroxybenzoic acid (4HBA), and Theophylline-7-acetic acid (THA) have been reported. The crystal structures have been determined by Single-Crystal X-ray Diffraction (SC-XRD). In the SC-XRD study, proton transfer from coformer to piperidine ‘N’ of DMP was observed in all the salts. The prepared salts were further characterized by spectroscopic (FT-IR), thermal (DSC and TGA), and Powder X-ray Diffraction (PXRD) techniques. The solubility study in purified water (pH=6.5) showed 127 and 51-fold enhancement in DMP-GLA and DMP-ACA salts. The salts namely, DMP-ACA, DMP-GLA, and DMP-SAL disintegrate to parent DMP after attaining equilibrium in water medium. In 0.1 N HCl medium, DMP-ACA, DMP-GLA, DMP-ADA, and DMP-4HBA exhibited a two-fold increment in solubility compared to DMP. The in-vitro dissolution study in purified water showed faster drug release in DMP-ACA, DMP-GLA, and DMP-ADA salts.

A Novel Semi-Solid Self-Emulsifying Formulation of Aprepitant for Oral Delivery: An In Vitro Evaluation.

Aprepitant is the first member of a relatively new antiemetic drug class called NK1 receptor antagonists. It is commonly prescribed to prevent chemotherapy-induced nausea and vomiting. Although it is included in many treatment guidelines, its poor solubility causes bioavailability issues. A particle size reduction technique was used in the commercial formulation to overcome low bioavailability. Production with this method consists of many successive steps that cause the cost of the drug to increase. This study aims to develop an alternative, cost-effective formulation to the existing nanocrystal form. We designed a self-emulsifying formulation that can be filled into capsules in a melted state and then solidified at room temperature. Solidification was achieved by using surfactants with a melting temperature above room temperature. Various polymers have also been tested to maintain the supersaturated state of the drug. The optimized formulation consists of CapryolTM 90, Kolliphor® CS20, Transcutol® P, and Soluplus®; it was characterized by DLS, FTIR, DSC, and XRPD techniques. A lipolysis test was conducted to predict the digestion performance of formulations in the gastrointestinal system. Dissolution studies showed an increased dissolution rate of the drug. Finally, the cytotoxicity of the formulation was tested in the Caco-2 cell line. According to the results, a formulation with improved solubility and low toxicity was obtained.

COMPARISON OF ONDANSETRON AND ONDANSETRON PLUS DEXAMETHASONE FOR PREVENTING POSTOPERATIVE NAUSEAAND VOMITING IN PATIENTS UNDERGOING LAPAROSCOPIC CHOLECYSTECTOMY

Background and Aims: Postoperative nausea and vomiting (PONV), the most common and distressing symptoms experienced by patients after laparoscopic cholecystectomy often need prophylactic antiemetic therapy. Multimodal prophylactic antiemetic therapy is found to be more effective than any single antiemetic drug. The primary objective of the study was to compare efcacy of ondansetron and ondansetron plus dexamethasone for preventing PONV in patients undergoing laparoscopic cholecystectomy. Material and Methods:Aprospective, randomized, comparative, double blinded study was carried out on 60 ASA Grade I and II patients of either sex aging 26-60 years undergoing laparoscopic cholecystectomy under general anaesthesia. Patients were divided into 2 groups of 30 each by systemic randomization method. Group O: received Ondansetron 4 mg IV, and Group OD: received Ondansetron 4 mg plus Dexamethasone 8mg IV, 10 min before induction of anaesthesia. PONV was assessed immediately after surgery and at 30-min intervals for 2 hours in the recovery room and then in the ward at 6, 12 and 24 hours postsurgery. The occurrence of nausea and vomiting was evaluated on a 3-point ordinal scale. 0 = no nausea or vomiting, 1 = nausea only, 2 = retching and / or vomiting. The primary end point was a “complete response”, dened as no episode of PONV during the rst 24 hrs after recovery from anaesthesia. Failure of prophylaxis was considered as a need for rescue antiemetic. Results: 13 (43.33%) and 22 (73.33%) patients from Group O and Group OD respectively had complete response (p=0.018). 17 (56.66%) patients in Group O and 8 (26.66%) patients in Group OD, who had episode of PONV, 12 and 5 patients respectively needed rescue antiemetic (p>0.05). The duration of hospital stay was longer in Group O than Group OD (p<0.05). Conclusion: In patients undergoing laparoscopic cholecystectomy, prevention of postoperative nausea and vomiting is better with combination of ondansetron plus dexamethasone than ondansetron alone.

Predictive ability of physicochemical properties of antiemetic drugs using degree‐based entropies

AbstractAntiemetic drugs are prescribed to help with nausea and vomiting, which are side effects of other drugs. Topological indices/Entropies are used in QSPR research to predict the bioactivity of chemical substances. This paper proposes predicting physical properties using degree‐based entropies. A Maple‐based program is being developed to make the computation of degree‐based entropy easier. A QSPR analysis is an effective statistical tool for determining pharmacological activity or binding mode for various receptors. Using a linear regression model, we found that the Augmented Zagreb entropy helps predict Complexity and the first Zagreb entropy and Balaban entropy help predict Heavy Atom Count, Topological Polar Surface Area, Monoisotopic Mass and Molecular Weight. In multiple linear regression, the results exhibit that the , , , , and entropies statistically significantly predict the Heavy Atom Count, Topological Polar Surface Area, Complexity, Monoisotopic Mass & Molecular Weight. This analysis may help chemists and other working in the pharmaceutical industry predict the properties of antiemetic drugs without experimenting.

The clinical research study for fosaprepitant to prevent chemotherapy-induced nausea and vomiting: A review.

In recent years, chemotherapy-induced nausea and vomiting (CINV) has become the most common adverse effect of chemotherapy in oncology patients. The CINV may reduce the quality of life in mild cases, or even make the patients resist or delay further treatment. Fosaprepitant is a newly marketed neurokinin-1 receptor antagonist (NK-1RA), which can be combined with 5-hydroxytryptamine 3 receptor antagonists (5-HT3RAs) and dexamethasone to prevent chemotherapy-induced vomiting. The dimeglumine salt form of fosaprepitant can be utilized as an intravenous injectable drug, which surpasses aprepitant's oral admistration limits. Fosaprepitant is effective and safe in the control of CINV in cancer patients receiving highly emetogenic chemotherapy (HEC), and may be an alternative option for antiemetic therapy. In general, fosaprepitant is worthy of clinical promotion and has a large market potential. This article reviews the clinical studies on fosaprepitant conducted in recent years, with the aim of providing a basis for the rational clinical selection of antiemetic drugs.

Evaluation of the effectiveness of an aromatherapy treatment with lavender essential oil to reduce post-operative nausea and vomiting: study protocol of a randomised controlled trial

Background: The most common post-operative symptoms are nausea and vomiting. Aromatherapy has been shown to reduce post-operative nausea and vomiting and thus could be used as a complementary therapy to antiemetic drugs; however, no studies have considered the exclusive use of Lavender in these patients. The study’s aim is to assess aromatherapy in reducing nausea and vomiting in post-operative patients. Materials and Methods: A 2-arm randomised controlled interventional study was carried out in the Neurosurgery, General Surgery, Vascular Surgery, and Gynaecology facilities of the SS Antonio e Biagio e Cesare Arrigo Hospital of Alessandria. Study inclusion criteria: patients over the age of 18, who sign an informed consent form, have had an anaesthesiologic examination, have had general anaesthesia, and are clinically stable with a nausea score of NRS>0. Multiple instruments will be used, including a numerical rating scale, a Likert rating scale, and a Likert rating scale to assess Vomiting and the degree of satisfaction. Conclusions: The use of complementary non-pharmacological methods such as aromatherapy may help patients feel more comfortable in the post-operative period.

Ondansetron Use During Pregnancy: Birth Defects and Obstetric Outcomes

Ondansetron is a widely administered medication for nausea and vomiting of pregnancy. Further examination of its teratogenic capacity is necessary. This study examines the association between ondansetron treatment during pregnancy and birth defects and adverse obstetric outcomes. Patient data were extracted from Clalit Health Services, Israel. A propensity-score analysis was performed matching those exposed to ondansetron with those who were not. Findings identified 774 women exposed to ondansetron, matched 1:1 with unexposed control patients. No significant differences were found between the groups for: cleft palate, cardiovascular congenital abnormalities, spina bifida occulta, preterm delivery, or small for gestational age. Ondansetron may be a useful and safe alternative as treatment for women who suffer from hyperemesis gravidarum and do not respond to other antiemetic drugs. Notwithstanding, additional prospectively designed research is needed to establish the safety of ondansetron treatment during pregnancy.

The efficacy and safety of complementary and alternative medicine in the treatment of nausea and vomiting during pregnancy: A systematic review and meta-analysis.

Complementary and alternative medicine (CAM) therapies are widely used for nausea and vomiting during pregnancy (NVP) due to the limitations of conventional medicine. However, their efficacy and safety remain controversial. Therefore, this meta-analysis was performed to assess the improvement of CAM therapy on NVP. Randomized controlled trials (RCTs) were searched for where the trial group was CAM and the control group was a conventional medicine or a placebo for NVP. This was done via 8 databases, including PubMed, EMBASE, the Cochrane Library, Web of Science, China National Knowledge Infrastructure, Wanfang, SinoMed, and VIP, from inception to October 25, 2022. The Grades of Recommendation, Assessment, Development and Evaluation (GRADE) was used to assess the quality of evidence. The Stata 15.0 software was used to perform the meta-analysis. Thirty-three RCTs were included in this study. The acupuncture treatment was superior to conventional medicine at the effective rate [RR = 1.71, 95% CI (1.02, 2.86), P = 0.042; Low-quality evidence]. Ginger had more significant effects than conventional medicine at the Rhodes index [WMD = -0.52, 95% CI (-0.79, -0.24), P ≤ 0.001; Moderate-quality evidence] and it had the same effect as drugs to relieve vomiting [SMD = 0.30, 95% CI (-0.12, 0.73), P = 0.160; Low-quality evidence]. Compared with placebo, ginger had a higher effective rate [RR = 1.68, 95% CI (1.09, 2.57), P = 0.018; Low-quality evidence], and lower Visual analog scale (VAS) of Nausea [WMD = -1.21, 95% CI (-2.34, -0.08), P = 0.036; Low-quality evidence]. Ginger had the same antiemetic effect as placebo [WMD = 0.05, 95% CI (-0.23, 0.32), P = 0.743; Low-quality evidence]. Acupressure was superior to conventional medicine at the reduction of antiemetic drugs [SMD = -0.44, 95% CI (-0.77, -0.11), P = 0.008; Low-quality evidence], and at the effective rate [RR = 1.55, 95% CI (1.30, 1.86), P ≤ 0.001; Low-quality evidence]. Acupressure had the same effect as placebo at the effective rate [RR = 1.25, 95% CI (0.94, 1.65), P = 0.124; Low-quality evidence]. Overall, CAM therapy was safer than conventional medicine or a placebo. The results showed that CAM therapies were able to alleviate NVP. However, due to the low quality of existing RCTs, more RCTs with large sample sizes are needed to validate this conclusion in the future.

Population pharmacokinetic analysis reveals no impact of aprepitant on the pharmacokinetics of ifosfamide, 2-dechloroifosfamide, and 3-dechloroifosfamide

PurposeSeveral case reports and retrospective series have clearly pointed to the role of aprepitant, an antiemetic drug, in the development of encephalopathy when used with ifosfamide. Described as an inhibitor of several CYP metabolic pathways, aprepitant is suspected of drug-drug-interaction on ifosfamide pharmacokinetics. The pharmacokinetics of ifosfamide and two of its metabolites (2-dechloroifosfamide and 3-dechloroifosfamide) was studied in patients with soft tissue sarcomas to evaluate the impact of aprepitant administration. MethodsA population pharmacokinetic approach was applied to analyze data obtained in 42 patients at cycle 1 (without aprepitant) and cycle 2 (with aprepitant for 34 of them). ResultsA previously published pharmacokinetic model including a time-dependency process well fit the data. Aprepitant had no impact on ifosfamide or its two metabolite pharmacokinetic parameters. ConclusionThis study suggests that aprepitant does not lead to a significant modification of ifosfamide metabolization, even though other metabolites such as 4 hydroxyifosfamide and chloroacetaldehyde were not monitored in this study.

A Comparative Study of Propofol Vs Midazolam for Sedation and Anti Emetic Effect in Spinal Anesthesia

A Comparative Study of Propofol Vs Midazolam for Sedation and Anti Emetic Effect in Spinal Anesthesia

Estimating the physicochemical properties of antiemetics using degree-based topological descriptors

Antiemetics are medications that are used to treat or prevent vomiting or nausea. These two common symptoms are the results of different conditions that include procedures, therapies, and medications. In most cases, antiemetics are required to control vomiting, especially in cases of severe dehydration. Topological descriptors are numerical numbers associated with the chemical substances and used in Quantitative Structure-Property Relationship (QSPR) research to predict their physical and chemical properties. In this work, we used linear and multiple regression models to estimate the physical and chemical properties of antiemetic drugs by using topological descriptors as independent variables. Moreover, a Maple-based algorithm is developed to compute the degree-based topological descriptors.

Preparation and characterization of fast-release oral film formulation containing ondansetron hydrochloride solid dispersion

Ondansetron has been widely applied as an antiemetic drug in the treatment or prevention of nausea and vomiting caused by emetic cancer chemotherapy . Fast-release films have the advantages of rapid drug release and improved patients’compliance, especially for the disabled bedridden, the elderly or pediatric patients.The basic film-forming materials were studied through single factor tests and the crystal inhibitors were optimized using solid dispersion technique. The ratio of drug and polymers were optimized by X-ray diffraction (XRD) and Differential Scanning Calorimetry (DSC) which revealed there was no presence of crystal in the optimized solid dispersion. The final film was white thin films and was smooth in surface without obvious bubbles or cracks. Mean weight of each film was 40~50mg. Mean thichness was 60~70μm. Surface pH was 6.4~6.6. The films could release 85% of drug with 1.5min in 0.1mol/L HCl and within 30min in pH6.8PBS. Pharmacolinetic experiment of Ondansetron Hydrochloric solution, marketed films Zuplenz® and the preparation were carried out in rats. As a result, the films of Ondansetron Hydrochloric containing ondansetron solid dispersion had the advantages of fast drug release, improved patient compliance, higher bioavalibility compared to oral solution and the marketed films.

Effect of Mirtazapine for the Prevention of Nausea and Vomiting in Patients With Thoracic Cancer Receiving Platinum-based Chemotherapy.

Mirtazapine, which exerts an antagonistic effect on 5-hydroxytryptamine type 5-HT2A, 5-HT2C, 5-HT3 and H1 receptors, is considered useful for the prophylaxis of chemotherapy-induced nausea and vomiting (CINV). This study investigated the efficacy and safety of mirtazapine for the prevention of CINV in patients with thoracic cancer receiving platinum-based chemotherapy. A retrospective cohort study was conducted in patients with thoracic cancer receiving platinum-based chemotherapy with 15 mg mirtazapine once daily as a prophylactic antiemetic drug between January 2014 and December 2021. The effects of mirtazapine added to the standard antiemetic regimen for the prevention of CINV were evaluated in patients who had poor control of CINV in a preceding cycle and in patients who received the standard antiemetic therapy plus mirtazapine from their first cycle. A total of 35 patients were evaluated. Of these, 14 had poor control of CINV in a preceding cycle and received the standard antiemetic therapy plus mirtazapine in the next cycle. The rate of complete response in the delayed period in these patients was significantly improved from the preceding cycle to the next cycle (35.7% vs. 85.7%, p=0.018). In contrast, the other 21 patients had received the standard antiemetic regimen plus mirtazapine from the first cycle. The rate of complete response in the delayed period in these patients receiving the triplet antiemetic regimen plus mirtazapine as part of a cisplatin-based or carboplatin-based regimen and in patients receiving a doublet antiemetic regimen plus mirtazapine in a carboplatin-based regimen was 100%, 85.7% and 100%, respectively. No severe adverse events, including somnolence, were observed with the addition of mirtazapine. The addition of mirtazapine to the standard antiemetic regimen for CINV may be beneficial with acceptable safety when administered in association with platinum-based regimens to patients with thoracic cancer.

Use of AgNOR staining to determine the effect of metoclopramide on neural tube development in early chick embryos

ABSTRACT Nausea and vomiting during pregnancy are common problems and prolonged pharmacological treatment often is needed; however, the teratogenic effects of anti-emetic drugs on neural tube (NT) development are not clear. We investigated the effects of different doses of metoclopramide on NT development in 48 and 72 h chick embryos using an argyrophilic nucleolar organizing region (AgNOR) staining method. We used 150 fertile, specific pathogen-free eggs incubated for 28 h, then randomly divided into five equal groups: group A, sham control was administered 0.9% saline; groups B – E were administered 0.15 mg/egg, 0.3 mg/egg, 0.6 mg/egg and 1.2 mg/egg, respectively. Half of the eggs in each group were taken from the incubator at 48 h incubation and the other half at 72 h incubation. After incubation, eggs were opened, embryos were dissected from their membranes, fixed with 10% formalin and examined by light microscopy. The NT status, i.e., open or closed, and somite number, crown-rump length, morphological features and gross developmental abnormalities were recorded. Excised embryos were sectioned and stained using hematoxylin and eosin or the AgNOR procedure and examined for morphology and histopathology. Delayed NT closure was observed in all 48 h drug exposed embryos, but in the 72 h groups, this occurred only in high-dose groups. Somite number was reduced significantly in groups C – E compared to the control group. Crown-rump length was decreased in both 48 and 72 h embryos. We found a decreased total AgNOR area:nuclear area ratio in 48 and 72 h embryos of all experimental groups. We found that metoclopramide delayed NT closure in chick embryos in a dose-dependent manner.

Sodium nitrite poisoning: A series of 20 fatalities in which post-mortem blood nitrite and nitrate concentrations are reported

Sodium nitrite has several industrial applications however its accidental or intentional ingestion has been associated with severe toxicity and death. We present a series of 20 cases over 2 years in which evidence of sodium nitrite ingestion was found at the scene and supported by biochemical analysis of post-mortem blood nitrite and nitrate levels. Routine toxicological screening was performed on post-mortem blood samples received at University Hospitals of Leicester (UHL) NHS Trust, including ethanol analysis by headspace gas chromatography–flame ionisation detection (HS GC-FID), drug screening by high resolution accurate mass–mass spectrometry (HRAM-MS) and confirmatory drug quantitation by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Cases in which the history indicated the possibility of nitrite salts present at the scene, purchase of a suicide kit or a dusky-ash appearance of skin on post-mortem were referred to a specialist laboratory for nitrite and nitrate analysis. Analysis was based upon the gas-phase chemiluminescent reaction between nitric oxide (NO) and ozone; NO levels were determined using an NOA 280A, Sievers NO analyser. Twenty post-mortem cases in which sodium nitrite ingestion was the most probable cause of death were reported between January 2020 and February 2022; mean age was 31 years (range 14–49) with 9/20 (45%) female. 16/20 (80%) of cases had a history of depression and / or mental health issues. In half of the cases, anti-depressant / anti-psychotic drugs were prescribed; these drugs were detected in 8/20 (40%) cases. Ethanol was detected in 4/20 (20%) cases and anti-emetic drugs in 7/20 (35%) cases; anti-emetic drugs may be used to aid retention of sodium nitrite. Illicit drugs (amphetamine, cannabis and cocaine) were present in 3/20 cases (15%). Nitrite was found to be elevated in all but one case (95%), and nitrate was elevated in 17/20 (85%) cases. This paper highlights a surge in numbers of deaths across England and Wales due to sodium nitrite toxicity. Although, nitrite poisoning remains a rare cause of death, it is worthwhile considering its use in individuals with suicidal ideation given its unregulated availability online. The detection and quantitation of nitrite and nitrate requires specialised, highly reliable methodology currently only available in research laboratories. Implication of sodium nitrite ingestion also relies heavily upon circumstantial evidence combined with quantification. The provision of a quantitative nitrite / nitrate analytical service greatly assists in determining the cause of death in these cases.

Asymmetric Catalytic Access to Piperazin-2-ones and Morpholin-2-ones in a One-Pot Approach: Rapid Synthesis of an Intermediate to Aprepitant.

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.