Synthesis and Development of Indole Based 5-HT3 Receptor Antagonists as Anti-Emetic Drugs in Oncology: An Update.

An important group of antiemetic drugs used in the treatment of nausea and vomiting after chemotherapy containing an indole moiety in their structures, working as 5- hydroxytryptamine type 3 serotonin receptor antagonist (5-HT3). This study focuses on compounds bearing an indole core that present a 5-HT3 receptor antagonist activity, which have been successfully used as antiemetic drugs for reducing chemotherapy adverse secondary effects during cancer treatment. Their synthesis, biological activities, and some outstanding characteristics are discussed, providing a general outlook towards the development of more efficient antiemetic drugs.

Terapia combinada en la profilaxis de las náuseas y vómitos postoperatorios en cirugía laparoscópica / Combined therapy and prophylaxis in postoperative nausea and vomiting in laparoscopic surgery

Introducción: Las náuseas y vómitos postoperatorios representan un problema frecuente tanto para el paciente como para el médico anestesiólogo. Se estima que la incidencia está en un 25 a 30 por ciento de los pacientes postoperados. Objetivo: Profundizar en los conocimientos relacionados con la terapia combinada en la profilaxis de las náuseas y vómitos postoperatorios. Métodos: Se realizó una revisión de los artículos publicados en las bases de datos Pubmed, Scielo, Medline y Cochrane, relacionados con el tema. Desarrollo: La naturaleza multifactorial de las náuseas y vómitos postoperatorios requiere de un enfoque multimodal para su tratamiento, el cual debe ser profiláctico más que terapéutico, con el objetivo de minimizar el riesgo. No es factible modificar sustancialmente las variables dependientes del paciente y de la intervención quirúrgica, pero se puede influir directamente sobre las anestésicas. En varios estudios se han identificado los diferentes factores de riesgo para náuseas y vómitos postoperatorios y a partir de estos se han desarrollado modelos predictivos que permiten evaluar la probabilidad del evento. Conclusiones: Las náuseas y vómitos postoperatorios constituyen un fenómeno frecuente en el postoperatorio. Para su profilaxis es recomendable el uso de terapias combinadas (antidopaminérgicos, antihistamínicos, anticolinérgicos, antagonistas de la serotonina, esteroides y antagonistas de la neurokinina-1) dado su componente multifactorial. Esta forma de afrontar dicho problema permite disminuir la frecuencia de estos síntomas, las complicaciones postoperatorias y facilitar la recuperación más inmediata del paciente(AU)

ABSTRACT Introduction: Postoperative nausea and vomiting represent a frequent problem for both the patient and the anesthesiologist. It is estimated that the incidence of these are present in 25-30 percent of postoperative patients. Objective: To go deepen in the knowledge related to physiopathology and combination therapy in the prophylaxis of postoperative nausea and vomiting. Method: A bibliographic review was made of the articles published in the Pubmed, Scielo, Medline and Cochrane data bases, related to the topic, belonging to authors dedicated to the study of this problem. Development: The multifactorial nature of postoperative nausea and vomiting requires a multimodal approach to its treatment, which should be prophylactic rather than therapeutic, with the objective of minimizing risk. It is not reasonable to modify the dependent variables of the patient and of the surgical intervention, but it is possible to directly influence the anesthetics. In several studies, the different risk factors for PONV have been identified and, from these, predictive models have been developed to evaluate the probability of the event. Conclusions: postoperative nausea and vomiting are a frequent phenomenon in the postoperative period. For its prophylaxis the use of combination therapies (antidopaminergic, antihistaminic, anticholinergic, serotoninantagonists, steroids and neurokinin-1 antagonists) is recommended, givenits multifactorial component. This way of dealing with this problema allows us to reduce the frequency of these symptoms, postoperative complications and facilitate the patient's most immediate recovery(AU)

SEOM Clinical Guideline update for the prevention of chemotherapy-induced nausea and vomiting (2016).

Chemotherapy-induced nausea and vomiting is one of the most worrisome adverse effects of chemotherapy for cancer patients. It can cause severe discomfort and affect the quality of life. In recent years, the incorporation of new drugs has increased the efficacy of antiemetic treatments in the control of emesis associated with chemotherapy. This guideline, in which we give some treatment recommendations with level of evidence and grade of recommendation, provides an update of the previously published guideline of the Spanish Society of Medical Oncology and represents our continued commitment to improving supportive care in cancer patients.

Ondansetron and promethazine have differential effects on hypothermic responses to lithium chloride administration and to provocative motion in rats.

We recently reported that provocative motion (rotation in a home cage) causes hypothermic responses in rats, similar to the hypothermic responses associated with motion sickness in humans. Many stimuli inducing emesis in species with an emetic reflex also provoke hypothermia in the rat, therefore we hypothesized that a fall in body temperature may reflect a "nausea-like" state in these animals. As rats do not possess an emetic reflex, we employed a pharmacological approach to test this hypothesis. In humans, motion- and chemically-induced nausea have differential sensitivity to anti-emetics. We thus tested whether the hypothermia induced in rats by provocative motion (rotation at 0.7 Hz) and by the emetic LiCl (63 mg/kg i.p.) have a similar differential pharmacological sensitivity. Both provocations caused a comparable robust fall in core body temperature (-1.9 ± 0.3°C and -2.0 ± 0.2°C for chemical and motion provocations, respectively). LiCl(-)induced hypothermia was completely prevented by ondansetron (2mg/kg, i.p., a 5-HT3 receptor antagonist that reduces cancer chemotherapy-induced nausea and vomiting), but was insensitive to promethazine (10 mg/kg, i.p., a predominantly histamine-H1 and muscarinic receptor antagonist that is commonly used to treat motion sickness). Conversely, motion-induced hypothermia was unaffected by ondansetron but promethazine reduced the rate of temperature decline from 0.20 ± 0.02 to 0.11 ± 0.03°C/min (P < 0.05) with a trend to decrease the magnitude. We conclude that this differential pharmacological sensitivity of the hypothermic responses of vestibular vs. chemical etiology in rats mirrors the observations in other pre-clinical models and humans, and thus supports the idea that a "nausea-like" state in rodents is associated with disturbances in thermoregulation.

In vivo antipyretic, antiemetic, in vitro membrane stabilization, antimicrobial, and cytotoxic activities of different extracts from Spilanthes paniculata leaves

BACKGROUND: The study was conducted to evaluate the in vitro antimicrobial activity, cytotoxic, and membrane stabilization activities, and in vivo antiemetic and antipyretic potentials of ethanolic extract, n-hexane and ethyl acetate soluble fractions of Spilanthes paniculata leaves for the first time widely used in the traditional treatments in Bangladesh. RESULTS: In antipyretic activity assay, a significant reduction (P < 0.05) was observed in the temperature in the mice tested. At dose 400 mg/kg-body weight, the n-hexane soluble fraction showed the effect (36.7 ± 0.63°C ) as like as the standard (dose 150 mg/kg-body weight) after 5 h of administration. Extracts showed significant (P < 0.001) potential when tested for the antiemetic activity compared to the standard, metoclopramide. At dose 50 mg/kg-body weight, the standard showed 67.23% inhibition, whereas n-hexane and ethyl acetate soluble fractions showed 37.53% and 24.93% inhibition of emesis respectively at dose 400 mg/kg-body weight. In antimicrobial activity assay, the n-hexane soluble fraction (400 µg/disc) showed salient activity against the tested organisms. It exerts highest activity against Salmonella typhi (16.9 mm zone of inhibition); besides, crude, and ethyl acetate extracts showed resistance to Bacillus cereus and Bacillus subtilis, and Vibrio cholera respectively. All the extracts were tested for lysis of the erythrocytes. At the concentration of 1mg/ml, ethanol extract, and n-hexane and ethyl acetate soluble fractions significantly inhibited hypotonic solution induced lysis of the human red blood cell (HRBC) (27.406 ± 3.57, 46.034 ± 3.251, and 30.72 ± 5.679% respectively); where standard drug acetylsalicylic acid (concentration 0.1 mg/ml) showed 77.276 ± 0.321% inhibition. In case of heat induced HRBC hemolysis, the plant extracts also showed significant activity (34.21 ± 4.72, 21.81 ± 3.08, and 27.62 ± 8.79% inhibition respectively). In the brine shrimp lethality bioassay, the n-hexane fraction showed potent (LC50 value 48.978 µg/ml) activity, whereas ethyl acetate fraction showed mild (LC50 value 216.77 µg/ml) cytotoxic activity. CONCLUSIONS: Our results showed that the n-hexane extract has better effects than the other in all trials. In the context, it can be said that the leaves of S. paniculata possess remarkable pharmacological effects, and justify its folkloric use as antimicrobial, antipyretic, anti-inflammatory, and antiemetic agent. Therefore, further research may be suggested to find possible mode of action of the plant part.

Estudio farmacoeconómico de esquemas de tratamiento antiemético en quimioterapia moderada y altamente emetógena / Pharmacoeconomic study of antiemetic treatment in moderate and highly emethogenic chemotherapy

INTRODUCCIËN: Las náuseas y vómitos por quimioterapia (NVIQ) constituyen una complicación importante. La introducción de los antiserotoninérgicos 5HT3 (AR 5HT3 ) unida a los esteroides, ha posibilitado un mayor control de estos síntomas. OBJETIVO: evaluar económicamente dos alternativas para el tratamiento antiemético en cáncer. MÉTODOS: se utilizaron varias técnicas de evaluación económica para dos alternativas de tratamiento antiemético. Para la primera línea, la técnica de minimización de costos (MC), que incluyó los esquemas de granisetron más dexametasona y ondansetron más dexametasona. El análisis de costoefectividad (ACE) evaluó el tratamiento alternativo después del fallo del esquema que contiene ondansetron, se realizaron los análisis de relación costo-efectividad medio (ACEM) y costo-efectividad incremental (ACEI). También análisis de sensibilidad. RESULTADOS: para los esquemas de tratamientos utilizados en la primera línea por cada paciente tratado, se logró un ahorro de $0,76 en la quimioterapia moderadamente emetógena (QME) y la quimioterapia altamente emetógena (QAE). En el ACEM, la opción que utilizó ondansetron como tratamiento de segunda línea para la QME es de $22,77 y de $4,034 para el esquema que utilizó el granisetron, para cada caso controlado. La terapia para QAE que utilizó ondansetron necesita $ 65,41 y la opción que utilizó granisetron $ 13,45, para cada paciente controlado respectivamente. En el ACEI se obtuvo un resultado no satisfactorio para el esquema que contiene ondansetron de $1,490/ caso adicional controlado en la QME y de $3,140/ caso adicional controlado para la QAE. CONCLUSIONES: el tratamiento antiemético que produjo mayor ahorro económico como terapia antiemética de primera línea es el que utilizó ondansetron, y en segunda línea el esquema que utilizó granisetron(AU)

INTRODUCTION: the occurrence of nauseas and vomiting from chemotherapy are a significant complication. With appearance of antiserotoninergics 5HT3 (AR 5HT3) combined with steroids, have allowed a great control of these symptoms. OBJECTIVE: The aim of present paper is to asses in a economic way two alternatives for antiemetic tratment in cancer. METHODS: Some techniques of economical assessment to two alternatives of antiemetic treatment were used. For the first line, the cost minimization (CM) technique including the Granisetron hydrochloride schemes plus Dexamethasone and Ondansetron hydrochloride plus Dexamethasone. The cost-effectiveness analysis (CEA) assessed the alternative treatment after the scheme failure containing Ondansetron; we performed mean cost-effectiveness (MCE) and incremental cost-effectiveness (ICE) analyses, as well as the sensitivity analysis. RESULTS: For the treatment schemes used in the first line by patient with treatment, it is possible to achieve a saving of $0.76 in the moderately emethogenic chemotherapy (MECM) and the highly emethogenic chemotherapy (HECT). In MCE, the option using Ondansetron as a second line treatment for MECM is of $22.77 and of $4.034 for scheme uses Granisetron for each controlled case. Therapy for HECT using Ondansetron needs percent65,41 and option using Granisetron needs $13.45 for each controlled patient, respectively. In the case of ICE a non-satisfactory result of $1.490 for scheme containing Ondansetron/controlled additional case in MECM, and of $3.140/controlled additional case for HECT. CONCLUSIONS: Antiemetic treatments with a higher economical save as first-line antiemetic therapy is that using Ondansetron, and in second line the scheme using Granisetron(AU)

Estudio farmacoeconómico de esquemas de tratamiento antiemético en quimioterapia moderada y altamente emetógena / Pharmacoeconomic study of antiemetic treatment in moderate and highly emethogenic chemotherapy

INTRODUCCIËN: Las náuseas y vómitos por quimioterapia (NVIQ) constituyen una complicación importante. La introducción de los antiserotoninérgicos 5HT3 (AR 5HT3 ) unida a los esteroides, ha posibilitado un mayor control de estos síntomas. OBJETIVO: evaluar económicamente dos alternativas para el tratamiento antiemético en cáncer. MÉTODOS: se utilizaron varias técnicas de evaluación económica para dos alternativas de tratamiento antiemético. Para la primera línea, la técnica de minimización de costos (MC), que incluyó los esquemas de granisetron más dexametasona y ondansetron más dexametasona. El análisis de costoefectividad (ACE) evaluó el tratamiento alternativo después del fallo del esquema que contiene ondansetron, se realizaron los análisis de relación costo-efectividad medio (ACEM) y costo-efectividad incremental (ACEI). También análisis de sensibilidad. RESULTADOS: para los esquemas de tratamientos utilizados en la primera línea por cada paciente tratado, se logró un ahorro de $0,76 en la quimioterapia moderadamente emetógena (QME) y la quimioterapia altamente emetógena (QAE). En el ACEM, la opción que utilizó ondansetron como tratamiento de segunda línea para la QME es de $22,77 y de $4,034 para el esquema que utilizó el granisetron, para cada caso controlado. La terapia para QAE que utilizó ondansetron necesita $ 65,41 y la opción que utilizó granisetron $ 13,45, para cada paciente controlado respectivamente. En el ACEI se obtuvo un resultado no satisfactorio para el esquema que contiene ondansetron de $1,490/ caso adicional controlado en la QME y de $3,140/ caso adicional controlado para la QAE. CONCLUSIONES: el tratamiento antiemético que produjo mayor ahorro económico como terapia antiemética de primera línea es el que utilizó ondansetron, y en segunda línea el esquema que utilizó granisetron

INTRODUCTION: the occurrence of nauseas and vomiting from chemotherapy are a significant complication. With appearance of antiserotoninergics 5HT3 (AR 5HT3) combined with steroids, have allowed a great control of these symptoms. OBJECTIVE: The aim of present paper is to asses in a economic way two alternatives for antiemetic tratment in cancer. METHODS: Some techniques of economical assessment to two alternatives of antiemetic treatment were used. For the first line, the cost minimization (CM) technique including the Granisetron hydrochloride schemes plus Dexamethasone and Ondansetron hydrochloride plus Dexamethasone. The cost-effectiveness analysis (CEA) assessed the alternative treatment after the scheme failure containing Ondansetron; we performed mean cost-effectiveness (MCE) and incremental cost-effectiveness (ICE) analyses, as well as the sensitivity analysis. RESULTS: For the treatment schemes used in the first line by patient with treatment, it is possible to achieve a saving of $0.76 in the moderately emethogenic chemotherapy (MECM) and the highly emethogenic chemotherapy (HECT). In MCE, the option using Ondansetron as a second line treatment for MECM is of $22.77 and of $4.034 for scheme uses Granisetron for each controlled case. Therapy for HECT using Ondansetron needs percent65,41 and option using Granisetron needs $13.45 for each controlled patient, respectively. In the case of ICE a non-satisfactory result of $1.490 for scheme containing Ondansetron/controlled additional case in MECM, and of $3.140/controlled additional case for HECT. CONCLUSIONS: Antiemetic treatments with a higher economical save as first-line antiemetic therapy is that using Ondansetron, and in second line the scheme using Granisetron