Investigating the efficacy and safety of olanzapine prophylaxis for opioid-induced nausea and vomiting (JORTC-PAL20): a study protocol for an open-label, single-arm exploratory study.

INTRODUCTION: In opioid therapy for cancer pain, opioid-induced nausea and vomiting (OINV) occur in 20%-40% of patients during initial opioid treatment or increasing opioid doses. OINV result in failure to achieve pain relief due to poor opioid adherence. Therefore, antiemetics are used to prevent OINV, but their efficacy and safety in this context have not yet been fully elucidated. Olanzapine is a promising antiemetic for the prophylaxis of chemotherapy-induced nausea and vomiting. METHODS AND ANALYSIS: This single-arm, single-centre exploratory study will evaluate the prophylactic antiemetic efficacy and safety of 5 mg olanzapine in patients with cancer pain who are withholding initial regular opioid therapy. Thirty-five patients will be enrolled. The primary endpoint is the proportion of patients achieving complete control (CC) of OINV during 5 days of opioid treatment. CC was defined as the absence of emetic episodes, no need for rescue medication to treat nausea, and minimal or no nausea (3 or less on an 11-point categorical scale). Secondary endpoints include the complete response, defined as no emetic episodes and no use of rescue medication during the overall assessment period, the time from opioid initiation to first emetic episode, the time from opioid initiation to first rescue antiemetic administration, and adverse events graded by Patient-Reported Outcome (PRO) Common Terminology Criteria for Adverse Events (CTCAE) version 1.0 and CTCAE version 5.0. ETHICS AND DISSEMINATION: This study protocol was approved by National Cancer Center Hospital Certified Review Board. The results will be used as preliminary data to conduct a validation study. TRIAL REGISTRATION NUMBER: Japan Registry of Clinical Trials (jRCT) jRCTs031220008.

Comparing the Efficacy of Fosnetupitant, an NK1 Receptor Antagonist in CDDP-Based Regimens, with That of Fosaprepitant and Aprepitant: A Retrospective Observational Study.

Existing antiemetic therapy against emetic-risk agents across malignancies 24 h post-dose in the acute period in cisplatin (CDDP)-based regimens yields a satisfactory complete response (CR) rate of ≥90%. However, the control rate after 24 h in the delayed period is unsatisfactory. This study compared the efficacy of fosnetupitant (F-NTP), a neurokinin 1 receptor antagonist, with that of fosaprepitant (F-APR) and aprepitant (APR) in the treatment of patients with cancer at high emetic risk due to chemotherapy. In this retrospective case-control study involving patients receiving cisplatin-containing regimens and neurokinin 1 receptor antagonists, patients were divided into three groups based on prophylactic antiemetic therapy: F-NTP, F-APR, and APR. The CR rate was evaluated for each period up to 168 h and further subdivided into acute (0-24 h), delayed (24-120 h), overall (0-120 h), and beyond-delayed (120-168 h) periods. Eighty-eight patients were included in the F-NTP group, 66 in the F-APR group, and 268 in the APR group. The CR rates at 0-168 and 120-168 h after cisplatin administration were significantly higher in the F-NTP group than in the F-APR and APR groups. After adjusting for confounding factors, F-NTP use was an independent factor in the multivariate analysis. Prophylactic antiemetic therapy, including F-NTP, was effective and well-tolerated during the delayed period. The efficacy of F-NTP in managing chemotherapy-induced nausea and vomiting was superior to those of F-APR and APR during the study period.

Impact of enhanced recovery after surgery (ERAS) guidelines implementation in cesarean delivery: A systematic review and meta-analysis.

BACKGROUND: Cesarean delivery rate is increasing, with no prediction of this rate to drop. Implementation of Early Recovery After Surgery (ERAS) program adapted to this high prevalent obstetrical surgical procedure proposes better peri-operative care achievement with improved maternal medical care, namely reduced morbidity, faster return to normal daily activities and improved impact on quality of life. Our aim was to analyze the outcomes of ERAS guidelines implementation in cesarean sections (CS). MATERIAL AND METHODS: A systematic review was performed across 3 databases (MEDLINE (Pubmed), Scopus and Web of Science), with no time or language filters, for articles comparing outcomes on pregnant women who delivered via CS with ERAS guidelines implementation versus the traditional approach without ERAS implementation. Outcomes established: primary - hospital length of stay; secondary - opioid consumption, readmission rates and maternal complications (overall, surgical site infection and emetic morbidity). Statistical analyses were conducted using Review Manager 5.4 and its results were expressed as mean difference, standardized mean difference and odds ratio, with 95% of confidence intervals. This systematic review was reported according to the PRISMA statement. RESULTS: This systematic review included 16 studies (3 randomized controlled trials (RCT), 4 prospective cohorts and 9 retrospective cohorts), with a pool analysis of 19,001 women (9752 with the traditional approach and 9249 following ERAS guidelines). Our results showed a significative decrease in length of hospital stay (MD: -13.78 h; CI 95 % -19.28 to -8.28; p < 0.00001) and opioid consumption (SMD: -0.91; CI 95 % -1.51 to -0.32; p = 0.003), with similar readmission rates (OR: 0.85; CI 95 % 0.50 to 1.44; p = 0.53) and maternal complications, namely: overall (OR: 0.87; CI 95 % 0.56 to 1.35; p = 0.53); surgical site infection (OR: 1.13; CI 95 % 0.72 to 1.77; p = 0.60) and emetic morbidity (OR: 0.78; CI 95 % 0.31 to 1.96; p = 0.60). CONCLUSIONS: ERAS guidelines applied at CS management are associated with decreased length of stay and opioid consumption, without negatively impact on readmission rates and overall maternal complications, including surgical site infection and emetic morbidity. The reduced number of RCT studies and the heterogeneity of the studies (heterogeneous inter-study protocols) constitutes the major limitation of the evidence found. Still, these findings may be a foremost help to confirm the beneficial impact of an ERAS approach during peri-cesarean management.

Torsade de pointes secondary to long QT syndrome after intragastric balloon placement. A rare but severe complication.

The obesity pandemic is becoming one of the most prevalent diseases nowadays. There is a wide spectrum of treatment, ranging from hygienic-dietary measures to bariatric surgery. Endoscopic intragastric balloon placement is becoming increasingly more frequent, due to its technical simplicity, safety and short-term success(1). Although complications are rare some can be severe, so pre-endoscopic evaluation must be carried out carefully. A 43-year-old woman with a history of grade I obesity (BMI 32.7) had an Orbera® intragastric balloon implanted successfully. After the procedure she presented frequent nausea and vomiting, partially controlled with antiemetics. She attended the Emergency Department(ED) with a persistent emetic syndrome - oral intolerance and short-term loss of consciousness(syncope), for which she was admitted. Lab tests showed metabolic alkalosis with severe hypokalemia(K+ 1.8mmol/L), so fluid therapy was initiated for hydroelectrolytic replacement. During the patient's stay in the ED, two episodes of polymorphic ventricular tachychardia "Torsades de Pointes" (PVT-TDP) occurred, leading to cardiac arrest and requiring electrical cardioversion to restore sinus rhythm, in addition to a temporary pacemaker placement. Telemetry showed a corrected QT interval of >500ms, compatible with Long QT Syndrome(LQTS). Once the patient was hemodynamically stabilized a gastroscopy was performed. The intragastric balloon located in the fundus was removed using an extraction kit, puncturing and aspirating 500ml of saline solution, and extracting the collapsed balloon without any complications. The patient achieved an adequate oral intake afterwards, and no recurrence of emetic episodes were noticed. Previous ECGs revealed a prolonged QT interval and a genetic study confirmed a congenital type 1 LQTS. Treatment was initiated with beta-blockers and a bicameral automatic defibrillator was implanted in order to prevent recurrences. Intragastric balloon placement is generally a safe procedure, serious complications present in 0.70% of cases(2). It is essential to have a proper pre-endoscopic evaluation, including patient's medical history and comorbidities. Episodes of PVT-TDP may present precipitated by certain medications (eg. metoclopramide) or hydroelectrolytic imbalances (eg, hypokalemia)(3). A standardized evaluation of ECG before intragastric balloon placement may be useful to prevent these rare but serious complications.

Allosteric inhibition of phosphodiesterase 4D induces biphasic memory-enhancing effects associated with learning-activated signaling pathways.

RATIONALE: Phosphodiesterase 4D negative allosteric modulators (PDE4D NAMs) enhance memory and cognitive function in animal models without emetic-like side effects. However, the relationship between increased cyclic adenosine monophosphate (cAMP) signaling and the effects of PDE4D NAM remains elusive. OBJECTIVE: To investigate the roles of hippocampal cAMP metabolism and synaptic activation in the effects of D159687, a PDE4D NAM, under baseline and learning-stimulated conditions. RESULTS: At 3 mg/kg, D159687 enhanced memory formation and consolidation in contextual fear conditioning; however, neither lower (0.3 mg/kg) nor higher (30 mg/kg) doses induced memory-enhancing effects. A biphasic (bell-shaped) dose-response effect was also observed in a scopolamine-induced model of amnesia in the Y-maze, whereas D159687 dose-dependently caused an emetic-like effect in the xylazine/ketamine anesthesia test. At 3 mg/kg, D159687 increased cAMP levels in the hippocampal CA1 region after conditioning in the fear conditioning test, but not in the home-cage or conditioning cage (i.e., context only). By contrast, 30 mg/kg of D159687 increased hippocampal cAMP levels under all conditions. Although both 3 and 30 mg/kg of D159687 upregulated learning-induced Fos expression in the hippocampal CA1 30 min after conditioning, 3 mg/kg, but not 30 mg/kg, of D159687 induced phosphorylation of synaptic plasticity-related proteins such as cAMP-responsive element-binding protein, synaptosomal-associated protein 25 kDa, and the N-methyl-D-aspartate receptor subunit NR2A. CONCLUSIONS: Our findings suggest that learning-stimulated conditions can alter the effects of a PDE4D NAM on hippocampal cAMP levels and imply that a PDE4D NAM exerts biphasic memory-enhancing effects associated with synaptic plasticity-related signaling activation.

2023 updated MASCC/ESMO consensus recommendations: controlling nausea and vomiting with chemotherapy of low or minimal emetic potential.

PURPOSE: Review the literature to update the MASCC guidelines from 2016 for controlling nausea and vomiting with systemic cancer treatment of low and minimal emetic potential. METHODS: A working group performed a systematic literature review using Medline, Embase, and Scopus databases between June 2015 and January 2023 of the management of antiemetic prophylaxis for anticancer therapy of low or minimal emetic potential. A consensus committee reviewed recommendations and required a consensus of 67% or greater and a change in outcome of at least 10%. RESULTS: Of 293 papers identified, 15 had information about managing systemic cancer treatment regimens of low or minimal emetic potential and/or compliance with previous management recommendations. No new evidence was reported that would change the current MASCC recommendations. No antiemetic prophylaxis is recommended for minimal emetic potential therapy, and single agents recommended for low emetic potential chemotherapy for acute emesis, but no prophylaxis is recommended for delayed emesis. Commonly, rescue medication includes antiemetics prescribed for the next higher level of emesis. CONCLUSION: There is insufficient data to change the current guidelines. Future studies should seek to more accurately determine the risk of emesis with LEC beyond the emetogenicity of the chemotherapy to include patient-related risk assessment.

2023 Updated MASCC/ESMO Consensus Recommendations: prevention of radiotherapy- and chemoradiotherapy-induced nausea and vomiting.

PURPOSE: Radiotherapy and chemoradiotherapy-induced nausea and vomiting (RINV and C-RINV) are common and distressing, and there is a need for guidance for clinicians to provide up to date optimal antiemetic prophylaxis and treatment. Through a comprehensive review of the literature concerning RINV and C-RINV, this manuscript aims to update the evidence for antiemetic prophylaxis and rescue therapy and provide a new edition of recommendations for the MASCC/ESMO antiemetic guidelines for RINV and C-RINV. METHODS: A systematic review of the literature including data published from May 1, 2015, to January 31, 2023, was performed. All authors assessed the literature. RESULTS: The searches yielded 343 references; 37 met criteria for full article review, and 20 were ultimately retained. Only one randomized study in chemoradiation had the impact to provide new recommendations for the antiemetic guideline. Based on expert consensus, it was decided to change the recommendation for the "low emetic risk" category from "prophylaxis or rescue" to "rescue" only, while the drugs of choice remain unchanged. CONCLUSION: As for the previous guideline, the serotonin receptor antagonists are still the cornerstone in antiemetic prophylaxis of nausea and vomiting induced by high and moderate emetic risk radiotherapy. The guideline update provides new recommendation for the management of C-RINV for radiotherapy and concomitant weekly cisplatin. To avoid overtreatment, antiemetic prophylaxis is no longer recommended for the "low emetic risk" category.

2023 updated MASCC/ESMO consensus recommendations: prevention of nausea and vomiting following high-emetic-risk antineoplastic agents.

PURPOSE: This systematic review updates the MASCC/ESMO recommendations for high-emetic-risk chemotherapy (HEC) published in 2016-2017. HEC still includes cisplatin, carmustine, dacarbazine, mechlorethamine, streptozocin, and cyclophosphamide in doses of > 1500 mg/m2 and the combination of cyclophosphamide and an anthracycline (AC) in women with breast cancer. METHODS: A systematic review report following the PRISMA guidelines of the literature from January 1, 2015, until February 1, 2023, was performed. PubMed (Ovid), Scopus (Google), and the Cochrane Database of Systematic Reviews were searched. The literature search was limited to randomized controlled trials, systematic reviews, and meta-analyses. RESULTS: Forty-six new references were determined to be relevant. The main topics identified were (1) steroid-sparing regimens, (2) olanzapine-containing regimens, and (3) other issues such as comparisons of antiemetics of the same drug class, intravenous NK1 receptor antagonists, and potentially new antiemetics. Five updated recommendations are presented. CONCLUSION: There is no need to prescribe steroids (dexamethasone) beyond day 1 after AC HEC, whereas a 4-day regimen is recommended in non-AC HEC. Olanzapine is now recommended as a fixed part of a four-drug prophylactic antiemetic regimen in both non-AC and AC HEC. No major differences between 5-HT3 receptor antagonists or between NK1 receptor antagonists were identified. No new antiemetic agents qualified for inclusion in the updated recommendations.

Emetic risk classification and evaluation of the emetogenicity of antineoplastic agents-updated MASCC/ESMO consensus recommendation.

PURPOSE: Our goal was to identify new anticancer agents approved by the US Food and Drug Administration (FDA) and the European Medical Agency (EMA) since the 2016 MASCC/ESMO antiemetic update and classify their emetic potential. METHODS: The MASCC/ESMO Expert Panel classified the emetogenicity of the identified new antineoplastic agents based on nonsystematic reviews of randomized controlled trials, analysis of product labeling, and evaluation of emetic classification in other international guidelines and informal consensus. The emetogenic classification system for oral anticancer agents was revised into two emetic risk categories (minimal-low; moderate-high) to be consistent with the system reported by ASCO (American Society of Clinical Oncology) in their 2017 guideline update. The previously employed four emetic risk classification categories for intravenously administered antineoplastic agents were retained for this update. RESULTS: From June 2015 to January 2023, 107 new antineoplastic agents (44 intravenously administered and 63 orally administered agents) were identified. The reported incidence of vomiting varied significantly across studies for many agents, especially for oral anticancer agents. CONCLUSION: The MASCC/ESMO Expert Panel acknowledges the limitations of our efforts to classify the emetic potential of anticancer agents, especially the imprecision associated with oral agents. However, we have attempted to provide a reasonable approximation of the emetic risk associated with new antineoplastic agents by searching the available literature and reviewing other available international antiemetic guidelines.

2023 updated MASCC/ESMO Consensus recommendations: Prevention of nausea and vomiting following moderately emetic risk antineoplastic agents.

PURPOSE: Review the literature to update the MASCC guidelines from 2015 for controlling nausea and vomiting with systemic cancer treatment of moderate emetic potential. METHODS: A systematic literature review was completed using Medline, Embase, and Scopus databases. The literature search was done from June 2015 to January 2023 of the management of antiemetic prophylaxis for anticancer therapy of moderate emetic potential. RESULTS: Of 342 papers identified, 19 were relevant to update recommendations about managing antiemetic prophylaxis for systemic cancer treatment regimens of moderate emetic potential. Important practice changing updates include the use of emetic prophylaxis based on a triple combination of neurokinin (NK)1 receptor antagonist, 5-HT3 receptor antagonist, and steroids for patients undergoing carboplatin (AUC ≥ 5) and women < 50 years of age receiving oxaliplatin-based treatment. A double combination of 5-HT3 receptor antagonist and steroids remains the recommended prophylaxis for other MEC. Based on the data in the literature, it is recommended that the administration of steroids should be limited to day 1 in moderately emetogenic chemotherapy regimens, due to the demonstration of non-inferiority between the different regimens. More data is needed on the emetogenicity of new agents at moderate emetogenic risk. Of particular interest would be antiemetic studies with the agents sacituzumab-govitecan and trastuzumab-deruxtecan. Experience to date with these agents indicate an emetogenic potential comparable to carboplatin > AUC 5. Future studies should systematically include patient-related risk assessment in order to define the risk of emesis with MEC beyond the emetogenicity of the chemotherapy and improve the guidelines for new drugs. CONCLUSION: This antiemetic MASCC-ESMO guideline update includes new recommendations considering individual risk factors and the optimization of supportive anti-emetic treatments.

A re-consideration of neural/receptor mechanisms in chemotherapy-induced nausea and vomiting: current scenario and future perspective.

The neural mechanisms and the receptors behind the course of chemotherapy-induced nausea and vomiting (CINV) are well described and considered mechanistically multifactorial, whereas the neurobiology of nausea is not completely understood yet. Some of the anti-neoplastic medications like cisplatin result in biphasic vomiting response. The acute phase of vomiting is triggered mainly via the release of serotonin from the enterochromaffin (EC) cells in the gastrointestinal tract (GIT) and results in stimulation of dorsal vagal complex (DVC) of the vomiting center and the vomiting is initiated by downward communication to the gut via vagal efferents. Agonism of 5HT3 receptors is majorly involved in the mediation of the acute phase. Therefore, antagonists at 5HT3 receptors are effective in the management of acute-phase vomiting episodes. Likewise, Dopamine type 2 (D2) receptors, dopamine neurotransmitter, Muscarinic receptors (M3), GLP1 receptors, and histaminergic receptors (H1) are also implicated in the vomiting act as well. In continuation, Cannabinoid type 1 (CB1) receptors are also recommended and included in the guidelines as agonism of presynaptically located CB1 receptors inhibits the release of excitatory neurotransmitters responsible for vomiting initiation. The delayed phase involves the release of "Substance P" in the gut and results in the stimulation of neurokinin-1 (NK1) receptors centrally in the area postrema (AP) and nucleus tractus solitarius (NTS), subsequently the vomiting response. The current understanding is the existence of overlapping mechanisms of neurotransmitters, serotonin, dopamine, and substance P throughout the time course of CINV. Furthermore, the emetic neurotransmitters are released via calcium ion (Ca++)-dependent mechanisms, implicating the molecular targets of intracellular Ca++ signaling in emetic circuitry. The current review entails the neurobiology of nausea and vomiting induced by cancer chemotherapeutic agents and the recent approaches in the management.

Intraspecific Diversity and Pathogenicity of Bacillus thuringiensis Isolates from an Emetic Illness.

This study describes an emetic food-borne intoxication associated with a Bacillus cereus group species and the characterization of the bacterial isolates from the incident in aspects of molecular tying, genetic factors, cytotoxicity, and pathogenic mechanisms relating to emetic illness. Through the polyphasic identification approach, all seven isolates obtained from food and clinical samples were identified as Bacillus thuringiensis. According to multilocus sequence typing (MLST) analysis, intraspecific diversity was found within the B. thuringiensis isolates. Four allelic profiles were found, including two previously known STs (ST8 and ST15) and two new STs (ST2804 and ST2805). All isolates harbored gene fragments located in the cereulide synthetase (ces) gene cluster. The heat-treated culture supernatants of three emetic B. thuringiensis isolates, FC2, FC7, and FC8, caused vacuolation and exhibited toxicity to Caco-2 cells, with CC50 values of 56.57, 72.17, and 79.94 µg/mL, respectively. The flow cytometry with the Annexin V/PI assay revealed both apoptosis and necrosis mechanisms, but necrosis was the prominent mechanism that caused Caco-2 cell destruction by FC2, the most toxic isolate.

Pica caused by emetic drugs in laboratory rats with kaolin, gypsum, and lime as test substances.

Pica refers to eating nonfood substances. The pica behavior has been the focus of attention in physiological and pharmacological studies, because its consumption is a good marker of nausea in laboratory rats, which cannot vomit due to neuroanatomical reasons. Almost all pica studies with rats have used kaolin clay pellets as nonfood substances. The present study primarily aimed to explore an alternative (or more suitable) substance to kaolin for detection of nausea induced by emetic drugs. Two calcium compounds, gypsum and lime, were evaluated in this study. An injection of lithium chloride (LiCl) increased pica behavior not only in the rats given kaolin but also in the rats given gypsum, suggesting that gypsum consumption could be used as an indicator of nausea. However, its sensitivity was no greater than that of kaolin consumption. In addition, lime is not a useful marker for nausea because the size of pica was small in the LiCl-injected rats, and did not differ from the control in the cisplatin-injected rats. In short, the superiority of kaolin as a test substance for nausea could not be overturned. However, the fact that nauseous rats displayed pica behavior with gypsum and lime refutes the claim that aluminosilicate, the main component of kaolin, is the critical determinant of emetic-caused pica in laboratory rats.

From cis-Lobeline to trans-Lobeline: Study on the Pharmacodynamics and Isomerization Factors.

Lobeline is an alkaloid derived from the leaves of an Indian tobacco plant (Lobelia inflata), which has been prepared by chemical synthesis. It is classified as a partial nicotinic agonist and has a long history of therapeutic usage ranging from emetic and respiratory stimulant to tobacco smoking cessation agent. The presence of both cis and trans isomers in lobeline is well known, and many studies on the relationship between the structure and pharmacological activity of lobeline and its analogs have been reported. However, it is a remarkable fact that no studies have reported the differences in pharmacological activities between the two isomers. In this article, we found that different degrees of isomerization of lobeline injection have significant differences in respiratory excitatory effects in pentobarbital sodium anesthetized rats. Compared with cis-lobeline injections, the respiratory excitatory effect was significantly reduced by 50.2% after administration of injections which contained 36.9% trans-lobeline. The study on the influencing factors of isomerization between two isomers shown that this isomerization was a one-way isomerism and only converted from cis to trans, where temperature was the catalytic factor and pH was the key factor. This study reports a new discovery. Despite the widespread use of ventilators, first-aid medicines such as nikethamide and lobeline has retired to second line, but as a nonselective antagonist with high affinity for a4b2 and a3b2 nicotinic acetylcholine receptors (nAChRs). In recent years, lobeline has shown great promise as a therapeutic drug for mental addiction and nervous system disorders, such as depression, Alzheimer disease and Parkinson disease. Therefore, we suggest that the differences between two isomers should be concerned in subsequent research papers and applications.

Cost-effectiveness analysis of NEPA, a fixed-dose combination of netupitant and palonosetron, for the prevention of highly emetogenic chemotherapy-induced nausea and vomiting: an international perspective.

PURPOSE: The aim of this study was to assess the cost-effectiveness of NEPA, a fixed-dose combination of oral netupitant (300 mg) and palonosetron (0.5 mg), compared to available treatments in Spain after aprepitant generic introduction in the market, and to discuss results in previously performed analyses in different wordwide settings. METHODS: A Markov model including three health states, complete protection, complete response at best and incomplete response, was used to evaluate the cost-effectiveness of NEPA versus common treatment options in Spain during 5 days after chemotherapy. Incremental costs including treatment costs and treatment failure management cost as well as incremental effects including quality adjusted life days (QALDs) and emesis-free days were compared between NEPA and the comparator arms. The primary outcomes were cost per avoided emetic event and cost per QALDs gained. RESULTS: NEPA was dominant (more effective and less costly) against aprepitant combined with palonosetron, and fosaprepitant combined with granisetron, while, compared to generic aprepitant plus ondansetron, NEPA showed an incremental cost per avoided emetic event of €33 and cost per QALD gained of €125. CONCLUSION: By most evaluations, NEPA is a dominant or cost-effective treatment alternative to current antiemetic standards of care in Spain during the first 5 days of chemotherapy treatment in cancer patients, despite the introduction of generics. These results are in line with previously reported analyses throughout different international settings.

[Prophylaxis of nausea and vomiting after medical cancer treatment : Guidelines on supportive treatment-Part II]. / Prophylaxe von Übelkeit und Erbrechen nach medikamentöser Tumortherapie : Leitlinien zur Supportivtherapie ­ Teil II.

The frequency and severity of nausea and/or vomiting in patients receiving anticancer drugs are influenced by numerous factors, e.g., by the specific therapeutic agent, the dosage, the schedule and the form of administration. They are also influenced by individual factors of the patients, e.g., young age, female gender, previous cancer treatment, low or no alcohol consumption, morning sickness, travel sickness and states of anxiety. The emetogenicity of parenteral and oral medications is classified into high, moderate and minimal. For prophylaxis of highly emetogenic chemotherapy (HEC), neurokinin­1 receptor antagonists (NK1-RA), 5­hydroxytryptamine­3 receptor antagonists (5-HT3-RA), dexamethasone (DEX) and olanzapine (OLANZ) are used in combination. For moderate emetogenicity DEX and 5­HT3-RA are used together for prophylaxis of acute emesis and for low emetogenicity a monotherapy with 5­HT3-RA, DEX or metoclopramide is used. For minimal emetogenicity routine prophylaxis is not necessary. Standards are also prescribed for delayed emesis and oral anticancer medications. Guideline-conform prophylaxis is an indispensable component of medical oncological treatment.

Glucose-Dependent Insulinotropic Polypeptide and Substance P Mediate Emetic Response Induction by Masked Trichothecene Deoxynivalenol-3-Glucoside through Ca2+ Signaling.

Deoxynivalenol (DON), the most naturally-occurring trichothecenes, may affect animal and human health by causing vomiting as a hallmark of food poisoning. Deoxynivalenol-3-glucoside (D3G) usually co-occurs with DON as its glucosylated form and is another emerging food safety issue in recent years. However, the toxicity of D3G is not fully understood compared to DON, especially in emetic potency. The goals of this research were to (1) compare emetic effects to D3G by oral and intraperitoneal (IP) routes and relate emetic effects to brain-gut peptides glucose-dependent insulinotropic polypeptide (GIP) and substance P (SP) in mink; (2) determine the roles of calcium-sensing receptor (CaSR) and transient receptor potential (TRP) channel in D3G's emetic effect. Both oral and IP exposure to D3G elicited marked emetic events. This emetic response corresponded to an elevation of GIP and SP. Blocking the GIP receptor (GIPR) diminished emetic response induction by GIP and D3G. The neurokinin 1 receptor (NK-1R) inhibitor Emend® restrained the induction of emesis by SP and D3G. Importantly, CaSR antagonist NPS-2143 or TRP channel antagonist ruthenium red dose-dependently inhibited both D3G-induced emesis and brain-gut peptides GIP and SP release; cotreatment with both antagonists additively suppressed both emetic and brain-gut peptide responses to D3G. To summarize, our findings demonstrate that activation of CaSR and TRP channels contributes to D3G-induced emesis by mediating brain-gut peptide exocytosis in mink.

Emetic Response to T-2 Toxin Correspond to Secretion of Glucagon-like Peptide-17-36 Amide and Glucose-Dependent Insulinotropic Polypeptide.

The T-2 toxin, a major secondary metabolite of Fusarium Gramineae, is considered a great risk to humans and animals due to its toxicity, such as inducing emesis. The mechanism of emesis is a complex signal involving an imbalance of hormones and neurotransmitters, as well as activity of visceral afferent neurons. The T-2 toxin has been proven to induce emesis and possess the capacity to elevate expressions of intestinal hormones glucagon-like peptide-17-36 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), both of which are important emetic factors. In addition, the activation of calcium-sensitive receptor (CaSR) and transient receptor potential (TRP) channels are engaged in intestinal hormone release. However, it is unknown whether hormones GLP-1 and GIP mediate T-2 toxin-induced emetic response through activating CaSR and TRP channels. To further assess the mechanism of T-2 toxin-induced emesis, we studied the hypothesis that T-2 toxin-caused emetic response and intestinal hormones GLP-1 and GIP released in mink are associated with activating calcium transduction. Following oral gavage and intraperitoneal injection T-2 toxin, emetic responses were observed in a dose-dependent manner, which notably corresponded to the secretion of GLP-1 and GIP, and were suppressed by pretreatment with respective antagonist Exending9-39 and Pro3GIP. Additional research found that NPS-2143 (NPS) and ruthenium red (RR), respective antagonists of CaSR and TRP channels, dramatically inhibited both T-2 toxin-induced emesis response and the expression of plasma GLP-1 and GIP. According to these data, we observed that T-2 toxin-induced emetic response corresponds to secretion of GLP-1 and GIP via calcium transduction.

Efficacy of Olanzapine 5 mg versus 10 mg for the Prophylaxis of Chemotherapy-Induced Nausea and Vomiting in Patients Receiving High Emetic Risk Chemotherapy without Neurokinin-1 Receptor Antagonist.

OBJECTIVE: To compare the efficacy and safety of two different dosage levels of olanzapine for the prevention of chemotherapy-induced nausea and vomiting (CINV) in patients receiving high emetic risk chemotherapy. METHODS: This study was a randomized, double-blind, controlled trial designed to show non-inferiority in the efficacy of olanzapine 5 mg compared to 10 mg in patients treated with high dose cisplatin or doxorubicin/cyclophosphamide. Non-inferiority was defined as a lower margin of the 95% confidence interval (95% CI) that not lower than the margin set at -25%. RESULT: A total of 140 patients were randomized to 5 mg group (n=70) or 10 mg group (n=70) of olanzapine. The complete response (CR) rate in the overall phase of olanzapine 5 and 10 mg was 58.6% v 62.9% (95%CI: -20.4, 11.8). The CR rate comparison between olanzapine 5 and 10 mg was 81.4% v 74.3% (95%CI: -6-6, 20.8) and 66.7% v 76.1% (95%CI: -23.5, 6.3) for the acute and delayed phase, respectively. No nausea rates in acute, delayed and overall phase were 70.0% v 68.6% (95%CI: -13.8, 16.6), 45.7% v 48.6% (95%CI: -19.4, 13.6) and 43.5% v 47.9% (95%CI: -19.2, 13.6). The rate of adverse events (AE) including somnolence were not different between the 5 and 10 mg groups. CONCLUSION: The two dosage levels of olanzapine were not different in terms of the efficacy and AE in the prophylaxis of CINV.

GC-MS analysis of organic fractions of Chrozophora tinctoria (L.) A.Juss. and their prokinetic propensity in animal models.

Chrozophora tinctoria (L.) A.Juss. is herbaceous, monecious annual plant used traditionally to cure gastrointestinal disorders. The present study was carried out to find the bioactive compounds by Gas Chromatography-Mass Spectrometry, the acetylcholinesterase inhibitory potential acute toxicity, and emetic activity present in the ethyl acetate fraction of Chrozophora tinctoria (EAFCT) and dichloromethane fraction of Chrozophora tinctoria (DCMFCT). The compounds detected in both fractions were mostly fatty acids, with about seven compounds in EAFCT and 10 in DCMFCT. These included pharmacologically active compounds such as imipramine, used to treat depression, or hexadecanoic acid methyl ester, an antioxidant, nematicide, pesticide, hypocholesterolemic, 9,12,15-Octadecatrienoic acid, ethyl ester, (Z,Z,Z)- is used as a cancer preventive, antiarthritic, antihistaminic, hepatoprotective, insectifuge, nematicide, Pentadecanoic acid, 14-methyl-, methyl ester have antifungal, antimicrobial and antioxidant activities, 10-Octadecanoic acid, methyl ester have the property to decrease blood cholesterol, Antioxidant and antimicrobial, 1-Eicosanol is used as an antibacterial, 1-Hexadecene has antibacterial, antioxidant, and antifungal activities. Both DCMFCT and EAFCT fractions inhibited acetylcholinesterase (AChE) activity with IC50 values of 10 µg and 130 µg, respectively. Both the fractions were found to be toxic in a dose-dependent manner, inducing emesis at 0.5g onward and lethargy and mortality from 3-5 g upwards. Both the fractions combined with distilled water showed highly emetic activity. The significant increase in the number of vomits was shown by EAFCT plus distilled water which are 7.50±1.29, 7.25±3.10, and 11.75±2.22 number of vomits at 1g, 2g, and 3g/kg concentration respectively, while DCMFCT plus distilled water showed 5.25±2.22, 7.50±2.52 and 10.25±2.22 number of vomits at 1g, 2, and 3g/kg correspondingly. The antiemetic standard drug metoclopramide has a higher impact against the emesis induced by both the fractions than dimenhydrinate. Metoclopramide decreases the number of vomits caused by EAFCT to 1.00±0.00, 2.00±0.00, 4.00±1.00 at 1g, 2, and 3g/kg sequentially, while dimenhydrinate decreases the number of vomits to 1.33±0.58, 2.33±1.15, 4.33±0.58 at 1g, 2, and 3g respectively. In the same way, Metochloprimide decreases the number of emesis caused by DcmCt from 5.25±2.22, 7.50±2.52, 10.25±2.22 to 1.33±0.58, 2.33±1.1, 4.33±0.58 at 1g, 2, and 3g/kg concentrations. The present study is the first documented report that scientifically validates the folkloric use of Chrozophora tinctoria as an emetic agent.