2020 ASCO, 2023 NCCN, 2023 MASCC/ESMO, and 2019 CCO: a comparison of antiemetic guidelines for the treatment of chemotherapy-induced nausea and vomiting in cancer patients.

Chemotherapy-induced nausea and vomiting (CINV) is a common toxicity that may impair the quality of life of patients with various malignancies ranging from early to end stages. In light of frequent changes to the guidelines for optimal management of CINV, we undertook this narrative review to compare the most recent guidelines published by ASCO (2020), NCCN (2023), MASCC/ESMO (2023), and CCO (2019). The processes undertaken by each organization to evaluate existing literature were also described. Although ASCO, NCCN, MASCC/ESMO, and CCO guidelines for the treatment and prevention of CINV share many fundamental similarities, the literature surrounding low and minimal emetic risk regimens is lacking. Current data regarding adherence to these guidelines is poor and warrants further investigation to improve care.

Exploring the role of ghrelin and des-acyl ghrelin in chemotherapy-induced nausea and vomiting.

Ghrelin and its mimetics have been shown to reduce cisplatin-induced emesis in preclinical studies using ferrets and shrews. This study investigated the effectiveness of ghrelin and des-acyl ghrelin (DAG) in antagonizing cisplatin-induced emesis and physiological changes indicative of nausea in Suncus murinus. Animals implanted with radiotelemetry devices were administered ghrelin (0.2, 1.0, and 5.0 µg/day), DAG (0.2, 1.0, and 5.0 µg/day), or saline (14 µL/day) intracerebroventricularly 4 days before and 3 days after treatment with cisplatin (30 mg/kg). At the end, the anti-apoptotic potentials of ghrelin and DAG were assessed by measuring Bax expression and cytochrome C activity. Neurotransmitter changes in the brain were evaluated using liquid chromatography-mass spectrometry analysis. Ghrelin and DAG reduced cisplatin-induced emesis in the delayed (24-72 h) but not the acute phase (0-24 h) of emesis. Ghrelin also partially reversed the inhibitory effects of cisplatin on food intake without affecting gastrointestinal myoelectrical activity or causing hypothermia; however, ghrelin or DAG did not prevent these effects. Ghrelin and DAG could attenuate the cisplatin-induced upregulation of Bax and cytochrome C in the ileum. Cisplatin dysregulated neurotransmitter levels in the frontal cortex, amygdala, thalamus, hypothalamus, and brainstem, and this was partially restored by low doses of ghrelin and DAG. Our findings suggest that ghrelin and DAG exhibit protective effects against cisplatin-induced delayed emesis. The underlying antiemetic mechanism may involve GHSR and/or unspecified pathways that modulate the neurotransmitters involved in emesis control in the brain and an action to attenuate apoptosis in the gastrointestinal tract.

Nausea and Vomiting as Initial Manifestations of Pediatric NMOSD.

Intractable nausea and vomiting are commonly attributed to gastrointestinal (GI) conditions but can sometimes be a symptom of an underlying central nervous system disease. One potentially overlooked neurologic cause of intractable nausea and vomiting that is refractory to antiemetics is area postrema syndrome (APS). APS is a condition characterized by lesions of the dorsal caudal medulla and is considered a core clinical feature of neuromyelitis optica spectrum disorder (NMOSD). APS is present in up to 30% of patients ultimately diagnosed with NMOSD and can be the first presenting symptom of NMOSD in 12% of patients, as our case illustrates. Importantly, APS is highly responsive to immunotherapy. We present the case of a 14-year-old female with a history of migraines who presented to the emergency department multiple times for persistent nausea, vomiting, and hiccups. Multiple GI diagnoses were considered until she developed additional neurologic symptoms that prompted further workup and revealed the final diagnosis of NMOSD-APS. We posit that NMOSD-APS should be considered in the differential diagnosis for patients with intractable nausea and vomiting, especially in patients with a negative GI workup result and poor response to antiemetics.

Clinical Study of Flumazenil Antagonizing Remimazolam on Nausea and Vomiting After Gynecologic Day Surgery.

Purpose: To evaluate the effect of flumazenil antagonizing remimazolam on postoperative nausea and vomiting (PONV) after gynecologic day surgery. Patients and Methods: 141 cases of gynaecological daycase surgery patients in Weifang People's Hospital were selected, randomized into group F (flumazenil group, 71 cases) and group C (control group, 70 cases). Dexamethasone 5 mg, flurbiprofen axetil 50 mg, and droperidol 1 mg were given intravenously before induction of anesthesia in both groups. Anesthesia induction: Remimazolam 0.25mg / kg was injected within 1 minute. After the patient fell asleep, mivacurium chloride 0.2mg / kg was injected for 30 seconds and alfentanil 20ug / kg was injected for 30 seconds. Anesthesia maintenance: Remimazolam 1mg/kg/h and alfentanil 40ug/kg/h were continuously pumped by micro pump. Stopping the injection of remimazolam and alfentanil at the end of the operation. Flumazenil 0.2 mg was given to antagonize remimazolam in group F after 1 minute. Group C was given an equal volume of saline. The incidence of PONV in the postoperative PACU and over a 24-hour period, patient awakening time, and general patient information were recorded. Results: The incidence of PONV in both groups within 24 hours was 50.70% in group F was significantly higher than 32.86% in group C. The difference was statistically significant (P < 0.05). The incidence of PONV in the PACU was 5.6% in group F and 8.6% in group C. The difference was not statistically significant (p > 0.05). Conclusion: Flumazenil antagonism of remimazolam increases the incidence of PONV within 24 hours in gynecologic day surgery patients and has no significant effect on the incidence of PONV in the PACU.

Effect of dexamethasone and ramosetron on the prevention of postoperative nausea and vomiting in low-risk patients: a randomized, double-blind, placebo-controlled, multicenter trial.

BACKGROUND: Several studies have investigated the effect of antiemetics on postoperative nausea and vomiting (PONV) in high-risk groups. However, few studies have investigated the effect of antiemetics in patients at low risk of developing PONV. METHODS: In this prospective, randomized, double-blinded trial, 177 patients undergoing surgery under general anesthesia were randomly allocated to three groups. Patients allocated to group C (control group) received 2 mL of intravenous 0.9% saline, those allocated to group R (ramosetron group) received 0.3 mg of intravenous ramosetron, and those allocated to group DR (ramosetron plus dexamethasone group) received 5 mg of intravenous dexamethasone and 0.3 mg of intravenous ramosetron. RESULTS: Finally, 174 patients completed the study, and the types of surgeries were orthopedic (n = 80), rhinologic (n = 47), urologic (n = 29), and others (n = 18). The incidence of PONV up to 48 h postoperatively was significantly lower in group DR than in group C. The incidence of PONV up to 0-1 h postoperatively was significantly lower in groups R and DR than in group C. The usage pattern of rescue antiemetics was consistent with the incidence of PONV. The percentage of patients requiring rescue analgesics 0-1 h postoperatively was significantly lower in groups R and DR than in group C. CONCLUSIONS: The combination of dexamethasone and ramosetron demonstrated a superior effect in preventing PONV for 48 h after surgery under general anesthesia than saline in patients at low risk of developing PONV. Compared with saline injections, ramosetron injections yielded better outcomes for the incidence of PONV and the use of rescue antiemetics and rescue analgesics 0-1 h postoperatively. TRIAL REGISTRATION: Clinical trial registration number: criskorea@korea.kr, KCT0006749.

Antiemetic effects of sclareol, possibly through 5-HT3 and D2 receptor interaction pathways: In-vivo and in-silico studies.

BACKGROUND: Emesis is a complex physiological phenomenon that serves as a defense against numerous toxins, stressful situations, adverse medication responses, chemotherapy, and movement. Nevertheless, preventing emesis during chemotherapy or other situations is a significant issue for researchers. Hence, the majority view contends that successfully combining therapy is the best course of action. In-vivo analysis offers a more comprehensive grasp of how compounds behave within a complex biological environment, whereas in-silico evaluation refers to the use of computational models to forecast biological interactions. OBJECTIVES: The objectives of the present study were to evaluate the effects of Sclareol (SCL) on copper sulphate-induced emetic chicks and to investigate the combined effects of these compounds using a conventional co-treatment approach and in-silico study. METHODS: SCL (5, 10, and 15 mg/kg) administered orally with or without pre-treatment with anti-emetic drugs (Ondansetron (ODN): 24 mg/kg, Domperidone (DOM): 80 mg/kg, Hyoscine butylbromide (HYS): 100 mg/kg, and Promethazine hydrochloride (PRO): 100 mg/kg) to illustrate the effects and the potential involvement with 5HT3, D2, M3/AChM, H1, or NK1 receptors by SCL. Furthermore, an in-silico analysis was conducted to forecast the role of these receptors in the emetic process. RESULTS: The results suggest that SCL exerted a dose-dependent anti-emetic effect on the chicks. Pretreatment with SCL-10 significantly minimized the number of retches and lengthened the emesis tendency of the experimental animals. SCL-10 significantly increased the anti-emetic effects of ODN and DOM. However, compared to the ODN-treated group, (SCL-10 + ODN) group considerably (p < 0.0001) extended the latency duration (109.40 ± 1.03 s) and significantly (p < 0.01) decreased the number of retches (20.00 ± 0.70), indicating an anti-emetic effect on the test animals. In in-silico analysis, SCL exhibited promising binding affinities with suggesting receptors. CONCLUSION: SCL-10 exerted an inhibitory-like effect on emetic chicks, probably through the interaction of the 5HT3 and D2 receptors. Further studies are highly appreciated to validate this study and determine the precise mechanism(s) behind the anti-emetic effects of SCL. We expect that SCL-10 may be utilized as an antiemetic treatment in a single dosage form or that it may function as a synergist with other traditional medicines.

Guías antieméticas: ¿hemos incorporado los cambios referentes a carboplatino y antraciclinas? / Antiemetic guidelines: Have we incorporated the changes concerning carboplatin and anthracyclines?

Objetivo: en 2016 se publicaron las guías de la MASCC/ESMO que incorporaron los esquemas de antraciclinas como quimioterapia altamente emetógena (QAE) proponiendo la triple terapia antiemética, así como para los esquemas de carboplatino. Los objetivos fueron analizar el nivel de concordancia entre las guías y la profilaxis antiemética utilizada en el hospital de día de hematooncología, evaluar su efectividad y determinar el ahorro de la inclusión de netupitant/palonosetrón (NEPA) oral con dexametasona intravenosa (NEPAd) respecto a fosaprepitant con ondansetrón y dexametasona (FOD intravenosa). Método estudio observacional prospectivo registrando variables demográficas, esquema de quimioterapia recibido, localización tumoral, riesgo emetógeno del paciente, pauta antiemética prescrita, concordancia con guía MASCC/ESMO y su efectividad, utilización de medicación de rescate y registro de visitas a urgencias o ingresos por emesis.Se llevó a cabo un estudio farmacoeconómico de minimización de costes. Resultados se incluyeron 61 pacientes, 70% mujeres, mediana edad 60,5.Los esquemas de platino fueron más frecuentes en el periodo 1, siendo el 87,5% respecto al 67,6% en el periodo 2. Los esquemas con antraciclinas fueron del 21,6 y 10% respectivamente en cada periodo. Un 21,1% de las pautas antieméticas no coincidían con las recomendaciones MASCC/ESMO, siendo en su totalidad en el periodo 1. La puntuación de los cuestionarios de efectividad fue de protección total en el 90,9% en las náuseas agudas, del 100% en los vómitos agudos y en las náuseas retardadas, y del 72,7% en los vómitos retardados. La frecuencia de uso de medicación de rescate fue del 18,7% en el periodo 1 y no fue necesaria en el periodo 2.No se detectaron visitas a urgencias ni ingresos en ninguno de los periodos. El uso de NEPAd comportó una reducción del 28% de los costes con respecto al empleo de FOD. Conclusiones: ... (AU)

Objective: Latest MASCC/ESMO guidelines of the recommendations for the prophylaxis of acute and delayed emesis induced by moderately emetogenic chemotherapy was published in 2016 incorporating anthracycline schemes as highly emetogenic chemotherapy (HEC), proposing triple antiemetic therapy to control nausea and vomiting. Likewise, they recommend triple therapy for carboplatin. The objectives of this study were to analyze the degree of concordance between guidelines and antiemetic prophylaxis used in the Chemotherapy Outpatient Unit in patients undergoing treatment with HEC and carboplatin, to evaluate its effectiveness and to determine the savings due to the use of netupitant/palonosetron (NEPA) oral (or) with intravenous (iv) dexamethasone (NEPAd) compared to iv Fosaprepitant with ondansetron and dexamethasone (FOD iv).MethodsProspective observational study recording demographic variables, chemotherapy protocol, tumor location, patient emetogenic risk, antiemetic regimen prescribed, concordance with the MASCC/ESMO guideline, and effectiveness, evaluated by MASCC survey, use of rescue medication and visits to the Emergency Department or hospitalization due to emesis.A cost minimization pharmacoeconomic study was carried out. Results 61 patients were included; 70% women; median age 60.5. Platinum schemes were more frequent in period 1, being 87.5% compared to 67.6% in period 2. Anthracycline schemes were 21.6% and 10% respectively in each period.A 21.1% of the antiemetic regimens did not coincide with the MASCC/ESMO recommendations, being entirely in period 1. The score of the effectiveness questionnaires was total protection in 90.9% in acute nausea, from 100% in acute vomiting and delayed nausea, and 72.7% in delayed vomiting.The frequency of use of rescue medication was 18.7% in period 1 and was not necessary in period 2.No visits to the emergency room or admissions were detected in any of the periods. Conclusions: ...(AU)

An assessment of the effects of neurokinin1 receptor antagonism against nausea and vomiting: Relative efficacy, sites of action and lessons for future drug development.

A broad-spectrum anti-vomiting effect of neurokinin1 receptor antagonists (NK1 RA), shown in pre-clinical animal studies, has been supported by a more limited range of clinical studies in different indications. However, this review suggests that compared with vomiting, the self-reported sensation of nausea is less affected or possibly unaffected (depending on the stimulus) by NK1 receptor antagonism, a common finding for anti-emetics. The stimulus-independent effects of NK1 RAs against vomiting are explicable by actions within the central pattern generator (ventral brainstem) and the nucleus tractus solitarius (NTS; dorsal brainstem), with additional effects on vagal afferent activity for certain stimuli (e.g., highly emetogenic chemotherapy). The central pattern generator and NTS neurones are multifunctional so the notable lack of obvious effects of NK1 RAs on other reflexes mediated by the same neurones suggests that their anti-vomiting action is dependent on the activation state of the pathway leading to vomiting. Nausea requires activation of cerebral pathways by projection of information from the NTS. Although NK1 receptors are present in cerebral nuclei implicated in nausea, and imaging studies show very high receptor occupancy at clinically used doses, the variable or limited ability of NK1 RAs to inhibit nausea emphasizes: (i) our inadequate understanding of the mechanisms of nausea; and (ii) that classification of a drug as an anti-emetic may give a false impression of efficacy against nausea vs. vomiting. We discuss the potential mechanisms for the differential efficacy of NK1 RA and the implications for future development of drugs that can effectively treat nausea, an area of unmet clinical need.

Olanzapine With or Without Fosaprepitant for Preventing Chemotherapy Induced Nausea and Vomiting in Patients Receiving Highly Emetogenic Chemotherapy: A Phase III Randomized, Double-Blind, Placebo-Controlled Trial (ALLIANCE A221602).

PURPOSE: A protocol was developed to evaluate the value of an NK-1 receptor antagonist for preventing nausea and vomiting resulting from highly emetogenic chemotherapy when an olanzapine-based antiemetogenic regimen was used. MATERIALS AND METHODS: A221602, a prospective double-blind, placebo-controlled clinical trial, was developed to compare 2 -olanzapine-containing antiemetic regimens, one with an NK-1 receptor antagonist (aprepitant or fosaprepitant) and one without. Trial patients had a malignant disease for which they received intravenous highly emetogenic chemotherapy (single day cisplatin ≥ 70 mg/m2 or doxorubicin plus cyclophosphamide on 1 day). Patients on both arms received commonly administered doses of a 5-HT3 receptor antagonist, dexamethasone, and olanzapine. Additionally, patients were randomized to receive an NK-1 receptor antagonist (fosaprepitant 150 mg IV or aprepitant 130 mg IV) or a corresponding placebo. The primary objective was to compare the proportion of patients with no nausea for 5 days following chemotherapy between the 2 study arms. This trial was designed to test for the noninferiority of deleting the NK-1 receptor antagonist, with noninferiority defined as a decrease in freedom from nausea by less than 10%. RESULTS: A total of 690 patients were entered on this trial, 50% on each arm. The proportion of patients without nausea for the complete 5-day study period was 7.4% lower (upper limit of the one-sided 95% confidence interval was 13.5%) in the arm without an NK-1 receptor antagonist compared with the arm with an NK-1 receptor antagonist. CONCLUSION: This trial did not provide sufficient evidence to support that deletion of the NK-1 receptor antagonist was as good as keeping it, as a part of a 4-drug antiemetic regimen for highly emetogenic chemotherapy (ClinicalTrials.gov Identifier: NCT03578081).

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

BACKGROUND: 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. OBJECTIVES: The purpose of the present work was to evaluate in silico drug-drug interaction (DDI) potential between BCa chemotherapeutic drugs and antiemetic agents. METHODS: 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 from the literature. RESULTS: 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. CONCLUSION: 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.

Gastroparesis syndromes: emerging drug targets and potential therapeutic opportunities.

INTRODUCTION: Gastroparesis (Gp) and related disorders such as chronic unexplained nausea and vomiting and functional dyspepsia, known as gastropareis syndromes (GpS), have large unmet needs. Mainstays of GpS treatments are diet and drugs. AREAS COVERED: The purpose of this review is to explore potential new medications and other therapies for gastroparesis. Before discussing possible new drugs, the currently used drugs are discussed. These include dopamine receptor antagonists, 5-hydroxytryptamine receptor agonists and antagonists, neurokinin-1 receptor antagonists and other anti-emetics. The article also considers future drugs that may be used for Gp, based on currently known pathophysiology. EXPERT OPINION: Gaps in knowledge about the pathophysiology of gastroparesis and related syndromes are critical to developing therapeutic agents that will be successful. Recent major developments in the gastroparesis arena are related to microscopic anatomy, cellular function, and pathophysiology. The major challenges moving forward will be to develop the genetic and biochemical correlates of these major developments in gastroparesis research.

The efficacy of 5HT3-receptor antagonists in postoperative nausea and vomiting: the role of pharmacogenetics.

INTRODUCTION: Genetic variants may affect drug efficacy on postoperative nausea and vomiting (PONV). The understanding of these mechanisms will help to identify the surgical patients who might benefit from specific prophylactic and therapeutic antiemetic treatment. The aim of the present review was to investigate gene polymorphisms that influence 5-hydroxytryptamine (serotonin) type 3 receptor antagonists (5HT3RA) efficacy in PONV. EVIDENCE AQUISITION: We included articles published from 2005 to 2022, utilizing the electronic databases PUBMED, EMBASE, COHRANE Library and ScienceDirect. To explore the relationship between genetic variations and 5HT3 receptor antagonist efficacy in PONV we focused on three different gene polymorphisms: the cytochrome P450 mono-oxygenase system gene (CYP2D6), the adenosine triphosphate (ATP)-binding cassette subfamily B gene (ABCB1) as well as the 5HT3 receptor gene (5HT3R). We also explored the relationship between the above genetic variations and their impact on 5HT3RA efficacy in the context of chemotherapy induced nausea and vomiting. EVIDENCE SYNTHESIS: Our search retrieved a total of 70 articles; 29 of them were included in the present review. Regarding polymorphisms of the CYP2D6 gene and the efficacy of serotonin antagonists in PONV, the ultra-rapid metabolizer genotype was associated with reduced efficacy of ondansetron, dolasetron and tropisetron, with the latter presenting more pronounced failure in these patients, while granisetron's efficacy remained unaffected. Regarding variations in the ABCB1 gene, three polymorphisms ("2677G>T/A" in exon 21; "3435C>T" in exon 27; "C1236T" in exon 12) were associated with a better response to ondansetron and ramosetron, while they did not affect palonosetron's efficacy. Additionally, polymporphisms of the 5-HT3B receptor gene were associated with ondancetron's postoperative efficacy; the "100_-102AAG" deletion variant was associated with reduced efficacy, while the Y129S variant did not show any effect on the drug's antiemetic effect. CONCLUSIONS: This review highlights that inefficacy of a specific drug in managing PONV could be attributed to specific genetic profiles and patients would possibly benefit from a drug switch.

Evaluation of Sex Differences in the Potential of Δ9-Tetrahydrocannabinol, Cannabidiol, Cannabidiolic Acid, and Oleoyl Alanine to Reduce Nausea-Induced Conditioned Gaping Reactions in Sprague-Dawley Rats.

Introduction: Cancer patients report nausea as a side effect of their chemotherapy treatment. Using the pre-clinical rodent model of acute nausea-lithium chloride (LiCl)-induced conditioned gaping-our group has demonstrated that exogenous cannabinoids may have antinausea potential. Materials and Methods: With the goal of evaluating the role of sex as a factor in pre-clinical research, we first compared the conditioned gaping reactions produced by varying doses of LiCl in male and female rats using the taste reactivity test (Experiment 1). Results: LiCl produced dose-dependent conditioned gaping similarly in male and female rats with the highest dose (127.2 mg/kg) producing robust conditioned gaping, with this dose used in subsequent experiments. Next, we examined the antinausea potential of THC (Experiment 2), CBD (Experiment 3), cannabidiolic acid (CBDA; Experiment 4) and oleoyl alanine (OlAla; Experiment 5) in both male and female rats. THC, CBD, CBDA, and OlAla dose dependently reduced conditioned gaping in both male and female rats in a similar manner. Conclusions: These results suggest that cannabinoids may be equally effective in treating nausea in both males and females.

Intranasal ondansetron microemulsion counteracting the adverse effects of cisplatin: animal study.

BACKGROUND: Cisplatin is considered one of the most effective and commonly used chemotherapeutic drugs, but despite its high therapeutic effectiveness, most patients treated with cisplatin suffer from nausea and vomiting, neurotoxic side effects, and cerebral psychiatric disorders such as depression. Therefore, the aim of the current work was to explore whether a selective 5-HT3 receptor antagonist (Ondansetron) administered via the oral route or intranasally in microemulsion form would alleviate cisplatin's adverse effects. METHODS: The selected ondansetron microemulsion was characterized in vitro for particle size, polydispersity, zeta potential, morphology, and nasal permeation, and in vivo in terms of anti-emetic and antidepressant activity, with the assessment of biochemical markers in brain homogenates. RESULTS: Results revealed that both orally administered ondansetron and intranasally administered microemulsion were able to counteract the pica effect by increasing food consumption, water intake, and decreasing kaolin intake. They were also able to increase BDNF, normalize IL-6, increase serotonin, and normalize NOx, MDA, GSSH/GSH as well as 8OHdG levels in rats' brain homogenates. The intranasal ondansetron microemulsion displayed superiority compared to oral conventional ondansetron in terms of increasing food intake, reduction of stomach content, and normalization of serotonin turnover. CONCLUSION: Ondansetron microemulsion can be administered by an alternative route of administration (intranasal) rather than oral, for patients on cisplatin chemotherapy.

Gastrointestinal inflammation plays a critical role in chemotherapy-induced nausea and vomiting.

Chemotherapy-induced nausea and vomiting (CINV) is a common side effect of patients with cancer receiving chemotherapeutic drugs. However, the pathological mechanism of CINV is biologically multifaceted and has not yet been fully elucidated. Despite this, increasing evidence indicates that gastrointestinal (GI) inflammation dramatically contributes to the incidence of CINV. It is well established that 5-hydroxytryptamine and substance P are critical meditators in both of CINV and GI inflammation by binding to their corresponding receptors. Meanwhile, antiemetic drugs used for the prophylaxis of CINV have demonstrated surprising effects on relieving GI inflammation, and anti-inflammatory drugs are also effective in preventing CINV. The commonalities between the pathogenesis and clinical treatment of GI inflammation and CINV indicate that GI inflammation is an essential mechanism in CINV. In this review, we provide novel insights into the crucial role of GI inflammation in CINV, with the aim to discover the novel antiemetic drugs against CINV from the perspective of alleviating GI inflammation.

Olanzapine for the Prevention and Treatment of Chemotherapy-Induced Nausea and Vomiting: A Review to Identify the Best Way to Administer the Drug.

Common treatment methods for malignant tumors include surgery, chemotherapy, radiotherapy, immunotherapy, targeted therapy, etc., among which chemotherapy plays an important role. However, chemotherapy brings corresponding side effects while killing tumor cells, and nausea and vomiting are the most common adverse reactions induced by chemotherapy. It not only affects the patient's appetite, resulting in malnutrition and electrolyte disturbances, but also reduces the patient's compliance with treatment, which further aggravates the disease. Thus, it is important to quickly prevent and cure nausea and vomiting induced by chemotherapy (CINV). In addition, with the continuous development of medicine, more and more antiemetic drugs have been developed. At present, the most common antiemetic agents for chemotherapy-induced nausea and vomiting are NK-1R antagonists, 5-HT3R antagonists, and dexamethasone. Surprisingly, olanzapine, often used as a psychotropic drug, has been found to be an effective antiemetic and is similar to other regimens on the safety of medicine. However, although there are numerous studies on the antiemetic effects of olanzapine, its comprehensive application remains unclear. Therefore, this review will elaborate the antiemetic effect of olanzapine in terms of the antiemetic mechanism and the safety, economic cost, dose, administration time, and drug delivery aspects.

Study of the Mechanism of Antiemetic Effect of Lavandula angustifolia Mill. Essential Oil Based on Ca2+/CaMKII/ERK1/2 Pathway.

Purpose: To investigate the effective components and possible mechanism of action of Lavandula angustifolia Mill. essential oil (LEO) in preventing vomiting through the olfactory pathway. Materials and Methods: A new network pharmacology-based method was established to analyze main components and pathways of LEO involved in antiemetic effects by introducing component content; biological activities of key proteins of the olfactory pathway and their corresponding compounds were verified by molecular docking technique; and finally pica in a rat model was established to verify the molecular mechanism of antiemetic effects of LEO by enzyme-linked immunosorbent assay (ELISA) to determine the serum 5-HT, substance P, and DA levels in each group and by immunohistochemistry to determine the contents of 5-HT3R, CaMKII and ERK1/2 proteins in the medulla oblongata tissue. Results: Network pharmacology combined with molecular docking analysis showed that the mechanism of the antiemetic effect of LEO may be related to (2Z)-3,7-dimethyl-2,6-octadienyl acetate, linalyl acetate, butanoic acid, hexyl ester, 4-hexen-1-ol, 5-methyl-2-(1-methylethenyl)-, acetate, .tau.-cadinol and other active ingredients, which regulate the cyclic adenosine monophosphate (cAMP) signaling pathway and the expression of BRAF, PDE and other targets on the pathway. An ELISA revealed that LEO reduced the levels of 5-hydroxytryptamine (5-HT), substance P, and dopamine in serum compared with the model group (P <0.05). Immunohistochemical analysis showed that LEO decreased the expression of 5-HT3R, CaMKII, and ERK1/2 proteins in the medulla oblongata of rats compared with the model group (P <0.01). Conclusion: LEO may achieve the antiemetic effect by reducing the content of 5-HT and inhibiting its related receptors, thereby regulating downstream Ca2+/CaMKII/ERK1/2 pathway of the cAMP signaling pathway.

Inhibition of dengue virus infection by trifluoperazine.

Dengue virus (DENV), a member of the genus Flavivirus, family Flaviviridae, is the most widespread viral pathogen transmitted to humans by mosquitoes. Despite the increased incidence of DENV infection, there are no antiviral drugs available for treatment or prevention. Phenothiazines are heterocyclic compounds with various pharmacological properties that are very adaptable for drug repurposing. In the present report, we analyzed the antiviral activity against DENV and the related Zika virus (ZIKV) of trifluoperazine (TFP), a phenothiazine derivative in clinical use as an antipsychotic and antiemetic agent. TFP exhibited dose-dependent inhibitory activity against the four DENV serotypes and ZIKV in monkey Vero cells at non-cytotoxic concentrations with 50% effective concentration values in the range 1.6-6.4 µM. A similar level of antiviral efficacy was exhibited by TFP against flavivirus infection in the human cell lines A549 and HepG2. Mechanistic studies, performed using time-dependent infectivity assays, real-time RT-PCR, Western blot, and immunofluorescence techniques, indicated that uncoating of the virus during penetration into the cell was the main target for TFP in infected cells, but the compound also exerted a minor effect on a late stage of the virus multiplication cycle. This study demonstrates that TFP, a pharmacologically active phenothiazine, is a selective inhibitor of DENV multiplication in cell culture. Our findings open perspectives for the repositioning of phenothiazines like TFP with a wide spectrum of antiviral efficacy as potential agents for the control of pathogenic flaviviruses.

Potential biomedical applications of Araucaria araucana as an antispasmodic, bronchodilator, vasodilator, and antiemetic: Involvement of calcium channels.

ETHNOPHARMACOLOGICAL RELEVANCE: Since pre-Columbian era, the resin of Araucaria araucana tree has been used traditionally for the treatment of ulcers and wounds. Araucaria species have also been used to treat inflammation, respiratory problems, viral infections, ulcers, and rheumatoid, cardiovascular, and neurological disorders. AIMS AND OBJECTIVE: Due to its popular use, the authors aimed to scrutinize the potential of this plant as an antispasmodic and an antiemetic agent. Furthermore broncho- and vasodilatory effects of this plant was explored to rationalize its folkloric uses. MATERIALS AND METHODS: Araucaria araucana crude extract (Aa.Cr) was evaluated in isolated preparations of rabbit jejunum, trachea, aorta, and atria to investigate the antispasmodic, bronchodilator, and vasodilator effects. The potential mechanistic approaches were compared with the standard drug 'verapamil'. The antiemetic activity was determined and compared with the standard drug 'domperidone' via chick emesis model. RESULTS: Aa.Cr dose-dependently relaxed both spontaneous and K+-induced contractions in the isolated jejunum preparations of rabbits. In concentration-response curves of calcium (Ca++), Aa.Cr also triggered the rightward shift like verapamil. Applying carbachol and phenylephrine (1 µM) and K+ (80 mM) to the isolated tracheal and aortic tissue preparation, respectively, resulted in broncho- and vasodilatory activities, respectively which may be due to the inhibition of Ca++ channels. Aa.Cr inhibited atrial force and spontaneous contractions in the rabbit's right atria. Aa.Cr exhibited significant antiemetic activity (P < 0.001 vs. saline) in dose-dependent (50-150 mg/kg) manner like domperidone. In silico molecular docking was performed to investigate the biological targets of purified components of Aa.Cr which revealed that cadinol dominantly targets ß2 receptors to cause bronchodilation, however, eudesmin binds non-specifically to all the selected targets, while secoisolariciresinol mediated high hydrogen bonding with muscarinic receptors (M1 and M3) and Ca++ channels, thus shows the suggested mechanistic pathways of targeted activities. CONCLUSIONS: The results of this study indicates that Aa.Cr may exhibit antispasmodic activity, bronchodilation, and vasodilation by inhibiting voltage-dependent Ca++ channels and release of subcellular calcium. This explains its folkloric use in hypertension, bronchospasms, gastrointestinal spasms, and emesis.