RESUMO
AIM: The nocebo effect, such as nausea and vomiting, is one of the major reasons patients discontinue therapy. The underlying mechanisms remain unknown due to a lack of reliable experimental models. The goal of this study was to develop a new animal model of nocebo-related nausea by combining observational learning and Pavlovian conditioning paradigms. METHODS: Male Sprague-Dawley rats with nitroglycerin-induced migraine were given 0.9% saline (a placebo) or LiCl (a nausea inducer) following headache relief, according to different paradigms. RESULTS: Both strategies provoked nocebo nausea responses, with the conditioning paradigm having a greater induction impact. The superposition of two mechanisms led to a further increase in nausea responses. A preliminary investigation of the underlying mechanism revealed clearly raised peripheral and central cholecystokinin (CCK) levels, as well as specific changes in the 5-hydroxytryptamine and cannabinoid systems. Brain networks related to emotion, cognition, and visceral sense expressed higher c-Fos-positive neurons, including the anterior cingulate cortex (ACC), insula, basolateral amygdala (BLA), thalamic paraventricular nucleus (PVT), hypothalamic paraventricular nucleus (PVN), nucleus tractus solitarius (NTS), periaqueductal gray (PAG), and dorsal raphe nucleus-dorsal part (DRD). We also found that nausea expectances in the model could last for at least 12 days. CONCLUSION: The present study provides a useful experimental model of nocebo nausea that might be used to develop potential molecular pathways and therapeutic strategies for nocebo.
Assuntos
Efeito Nocebo , Núcleo Solitário , Humanos , Ratos , Masculino , Animais , Ratos Sprague-Dawley , Núcleo Solitário/metabolismo , Colecistocinina/metabolismo , Colecistocinina/farmacologia , Náusea/induzido quimicamente , Náusea/metabolismo , Proteínas Proto-Oncogênicas c-fos/metabolismoRESUMO
OBJECTIVE: The behavioral mechanisms and the neuronal pathways mediated by amylin and its long-acting analog sCT (salmon calcitonin) are not fully understood and it is unclear to what extent sCT and amylin engage overlapping or distinct neuronal subpopulations to reduce food intake. We here hypothesize that amylin and sCT recruit different neuronal population to mediate their anorectic effects. METHODS: Viral approaches were used to inhibit calcitonin gene-related peptide (CGRP) lateral parabrachial nucleus (LPBN) neurons and assess their role in amylin's and sCT's ability to decrease food intake in mice. In addition, to test the involvement of LPBN CGRP neuropeptidergic signaling in the mediation of amylin and sCT's effects, a LPBN site-specific knockdown was performed in rats. To deeper investigate whether the greater anorectic effect of sCT compared to amylin is due do the recruitment of additional neuronal pathways related to malaise multiple and distinct animal models tested whether amylin and sCT induce conditioned avoidance, nausea, emesis, and conditioned affective taste aversion. RESULTS: Our results indicate that permanent or transient inhibition of CGRP neurons in LPBN blunts sCT-, but not amylin-induced anorexia and neuronal activation. Importantly, sCT but not amylin induces behaviors indicative of malaise including conditioned affective aversion, nausea, emesis, and conditioned avoidance; the latter mediated by CGRPLPBN neurons. CONCLUSIONS: Together, the present study highlights that although amylin and sCT comparably decrease food intake, sCT is distinctive from amylin in the activation of anorectic neuronal pathways associated with malaise.
Assuntos
Depressores do Apetite , Polipeptídeo Amiloide das Ilhotas Pancreáticas , Animais , Anorexia/induzido quimicamente , Depressores do Apetite/efeitos adversos , Depressores do Apetite/metabolismo , Calcitonina , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Polipeptídeo Amiloide das Ilhotas Pancreáticas/metabolismo , Camundongos , Náusea/metabolismo , Neurônios/metabolismo , Ratos , VômitoRESUMO
Gastric inhibitory peptide (GIP) is best known for its role as an incretin hormone in control of blood glucose concentrations. As a classic satiation signal, however, the literature illustrates a mixed picture of GIP involvement with an at best weak anorectic response profile being reported for GIP receptor (GIPR) signaling. Not surprisingly, the pursuit of exploiting the GIP system as a therapeutic target for diabetes and obesity has fallen behind that of the other gastrointestinal-derived incretin, glucagon-like peptide 1 (GLP-1). However, recent discoveries highlighted here support potential therapeutic advantages of combinatorial therapies targeting GIP and GLP-1 systems together, with perhaps the most surprising finding that GIPR agonism may have antiemetic properties. As nausea and vomiting are the most common side effects of all existing GLP-1 pharmacotherapies, the ability for GIP agonism to reduce GLP-1-induced illness behaviors but retain (if not enhance) weight loss and glycemic control may offer a new era in the treatment of obesity and diabetes.
Assuntos
Polipeptídeo Inibidor Gástrico/metabolismo , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Náusea/metabolismo , Saciação/fisiologia , Animais , Diabetes Mellitus Tipo 2/metabolismo , Humanos , Obesidade/metabolismoRESUMO
Cannabis was extensively utilized for its medicinal properties till the 19th century. A steep decline in its medicinal usage was observed later due to its emergence as an illegal recreational drug. Advances in technology and scientific findings led to the discovery of delta-9-tetrahydrocannabinol (THC), the primary psychoactive compound of cannabis, that further led to the discovery of endogenous cannabinoids system consisting of G-protein-coupled receptors - cannabinoid receptor 1 and cannabinoid receptor 2 along with their ligands, mainly anandamide and 2-arachidonoylglycerol. Endocannabinoid (EC) is shown to be a modulator not only for physiological functions but also for the immune system, endocrine network, and central nervous system. Medicinal research and meta-data analysis over the last few decades have shown a significant potential for both THC and cannabidiol (CBD) to exert palliative effects. People suffering from many forms of advanced stages of cancers undergo chemotherapy-induced nausea and vomiting followed by severe and chronic neuropathic pain and weight loss. THC and CBD exhibit effective analgesic, anxiolytic, and appetite-stimulating effect on patients suffering from cancer. Drugs currently available in the market to treat such chemotherapy-induced cancer-related ailments are Sativex (GW Pharmaceutical), Dronabinol (Unimed Pharmaceuticals), and Nabilone (Valeant Pharmaceuticals). Apart from exerting palliative effects, THC also shows promising role in the treatment of cancer growth, neurodegenerative diseases (multiple sclerosis and Alzheimer's disease), and alcohol addiction and hence should be exploited for potential benefits. The current review discusses the nature and role of CB receptors, specific applications of cannabinoids, and major studies that have assessed the role of cannabinoids in cancer management.
Assuntos
Antineoplásicos/efeitos adversos , Agonistas de Receptores de Canabinoides/uso terapêutico , Canabinoides/uso terapêutico , Náusea/tratamento farmacológico , Neoplasias/tratamento farmacológico , Neuralgia/tratamento farmacológico , Antineoplásicos/administração & dosagem , Humanos , Náusea/induzido quimicamente , Náusea/metabolismo , Neuralgia/induzido quimicamente , Neuralgia/metabolismo , Receptores de Canabinoides/metabolismoRESUMO
OPINION STATEMENT: In cancer patients, the management of nausea and vomiting that is not directly related to treatment is challenging. Much current practice is based on expert opinion and anecdote. Fortunately, over recent years, a number of quality trials have been undertaken to strengthen the evidence base that guides the care of our patients with these distressing symptoms. Much is still unknown however. In this article, we present the latest literature that addresses some of the outstanding issues.
Assuntos
Suscetibilidade a Doenças , Náusea/etiologia , Náusea/terapia , Neoplasias/complicações , Vômito/etiologia , Vômito/terapia , Analgésicos Opioides/farmacologia , Analgésicos Opioides/uso terapêutico , Antieméticos/farmacologia , Antieméticos/uso terapêutico , Biomarcadores , Gerenciamento Clínico , Quimioterapia Combinada , Humanos , Obstrução Intestinal/etiologia , Maconha Medicinal/farmacologia , Maconha Medicinal/uso terapêutico , Terapia de Alvo Molecular , Náusea/diagnóstico , Náusea/metabolismo , Prognóstico , Antagonistas da Serotonina/farmacologia , Antagonistas da Serotonina/uso terapêutico , Resultado do Tratamento , Vômito/diagnóstico , Vômito/metabolismoRESUMO
BACKGROUND: While vomiting is well controlled with current antiemetic regimens, unrelieved chemotherapy-induced nausea (CIN) is a significant clinical problem. Perturbations in endocytotic and apoptotic pathways in the gut can influence the functioning of the microbiome-gut-brain-axis and the occurrence of gastrointestinal (GI) symptoms. However, limited information is available on the mechanisms that underlie unrelieved CIN. OBJECTIVES: The purpose of this study was to evaluate for perturbed biological pathways associated with endocytosis and apoptosis in oncology patients who did (n = 353) and did not (n = 275) report CIN prior to their second or third cycle of chemotherapy (CTX). METHODS: Oncology patients (n = 735) completed study questionnaires in the week prior to their second or third cycle of CTX. CIN occurrence was evaluated using the Memorial Symptom Assessment Scale. Pathway impact analyses (PIA) were performed in 2 independent samples using RNA-sequencing (sample 1, n = 334) and microarray (sample 2, n = 294) methodologies. Fisher's combined probability method was used to identify signaling pathways related to endocytotic and apoptotic mechanisms that were significantly perturbed between the 2 nausea groups across both samples. RESULTS: CIN was reported by 63.6% of the patients in sample 1 and 48.9% of the patients in sample 2. Across the 2 samples, PIA identified 4 perturbed pathways that are involved in endocytosis (i.e., endocytosis, regulation of actin cytoskeleton) and apoptosis (i.e., apoptosis, PI3K/Akt signaling). CONCLUSIONS: Our findings suggest that CTX-induced inflammation of the GI mucosa, that results in the initiation of endocytotic and apoptotic processes in the gut, is associated with the occurrence of CIN.
Assuntos
Apoptose/efeitos dos fármacos , Endocitose/efeitos dos fármacos , Náusea/induzido quimicamente , Actinas/metabolismo , Antineoplásicos/efeitos adversos , Humanos , Náusea/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/epidemiologia , Fosfatidilinositol 3-Quinases/metabolismo , Transdução de Sinais/efeitos dos fármacos , Inquéritos e QuestionáriosRESUMO
Chemotherapy, radiotherapy, surgery and depression are the conditions that run in parallel fashions. All these conditions cause the release of an increased amount of serotonin in the body. Serotonin acts on these 5HT3 receptors and causes nausea and vomiting. Ondansetron acts by blocking serotonin from acting on the receptors and thus is useful in decreasing episodes of nausea and vomiting but when used concomitantly with SSRIs (selective serotonin reuptake inhibitors) as cancer patient also suffered from depression. This combination tends to decrease the efficacy of ondansetron. The present study was carried out to observe the modulatory role of ondansetron on ileal smooth muscle motility in vitro. Experiments were performed in four groups (n=6) and ileal smooth muscle activity was recorded on the power lab (USA). The effects of increasing concentrations of serotonin, ondansetron and paroxetine alone were observed. In the fourth group effects of paroxetine in the presence of fixed concentration (1ml) of ondansetron (10-6M) was observed. The maximum response obtained by serotonin served as a control for our study (100%). Paroxetine response on intestinal motility was completely blocked in the presence of ondansetron. Our findings hence, reinforce the hypothesis that paroxetine decreases the antiemetic activity of serotonin antagonist ondansetron, by super sensitization of serotonergic receptors resulting in an increased incidence of nausea and vomiting in cancer patient despite adequate antiemetic prophylaxis.
Assuntos
Antieméticos/farmacologia , Motilidade Gastrointestinal/efeitos dos fármacos , Íleo/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Ondansetron/farmacologia , Paroxetina/farmacologia , Receptores de Serotonina/efeitos dos fármacos , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Antagonistas da Serotonina/farmacologia , Animais , Interações Medicamentosas , Feminino , Íleo/metabolismo , Masculino , Músculo Liso/metabolismo , Náusea/induzido quimicamente , Náusea/metabolismo , Náusea/fisiopatologia , Paroxetina/toxicidade , Coelhos , Receptores de Serotonina/metabolismo , Inibidores Seletivos de Recaptação de Serotonina/toxicidade , Vômito/induzido quimicamente , Vômito/metabolismo , Vômito/fisiopatologiaAssuntos
Infecções por Coronavirus/fisiopatologia , Doenças do Sistema Digestório/fisiopatologia , Pneumonia Viral/fisiopatologia , Dor Abdominal/etiologia , Dor Abdominal/metabolismo , Dor Abdominal/fisiopatologia , Dor Abdominal/terapia , Assistência Ambulatorial , Anorexia/etiologia , Anorexia/metabolismo , Anorexia/fisiopatologia , Anorexia/terapia , Antibacterianos/efeitos adversos , Antipiréticos/efeitos adversos , Antivirais/efeitos adversos , Betacoronavirus , COVID-19 , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/fisiopatologia , Doença Hepática Induzida por Substâncias e Drogas/terapia , China , Infecções por Clostridium/diagnóstico , Infecções por Clostridium/tratamento farmacológico , Infecções por Coronavirus/complicações , Infecções por Coronavirus/metabolismo , Infecções por Coronavirus/terapia , Diarreia/etiologia , Diarreia/metabolismo , Diarreia/fisiopatologia , Diarreia/terapia , Doenças do Sistema Digestório/etiologia , Doenças do Sistema Digestório/metabolismo , Doenças do Sistema Digestório/terapia , Endoscopia do Sistema Digestório , Gastroenterologia , Humanos , Hepatopatias/etiologia , Hepatopatias/metabolismo , Hepatopatias/fisiopatologia , Hepatopatias/terapia , Náusea/etiologia , Náusea/metabolismo , Náusea/fisiopatologia , Náusea/terapia , Pandemias , Pneumonia Viral/complicações , Pneumonia Viral/metabolismo , Pneumonia Viral/terapia , Probióticos/uso terapêutico , SARS-CoV-2 , Sociedades Médicas , Vômito/etiologiaRESUMO
BACKGROUND: Anorexia-cachexia syndrome (ACS) is a complex condition in advanced cancer patients, defined by disproportionate loss of skeletal muscle mass, and a lack or loss of appetite. This condition greatly lowers the quality of life and limits the treatment options. ACS is commonly associated with gastrointestinal symptoms such as nausea and vomiting. Ginger has been successful in treating these symptoms but has not yet been tested on patients with advanced cancer. Electrogastrography is a technology that allows the direct recording of the gastric myoelectrical activity (GMA). PURPOSE: The aim of this study is to (1) determine the effects of ginger on the GMA in these patients, (2) evaluate the subjective symptoms using 3 validated scales, and (3) correlate the level of inflammatory factors and ghrelin in this patient population. METHODS: Patients with ACS and advanced cancer were recruited from the Palliative Rehabilitation outpatient program at Elisabeth Bruyère Hospital. Patients were instructed to take a daily capsule of 1650 mg of ginger for 14 days and outcome measures were recorded at pre- and post-intervention, which included a blood test for analysis of CRP, albumin and ghrelin levels, 3 self-administered surveys (DSSI, PG-SGA, ESAS), patient-reported symptoms, and an EGG diagnosis. RESULTS: Fifteen patients with a median age of 58 and varying cancer diagnoses were enrolled. EGG diagnosis showed that 9 of the 15 patients had a direct improvement in their GMA, and all patients showed improvement in reported symptoms, most notably nausea, dysmotility- and reflux-like symptoms. There was no correlation found for ginger administration and inflammatory factors. CONCLUSION: These findings suggest that ginger may improve GMA as measured by EGG and may have a notable effect on symptom improvement.
Assuntos
Anorexia/tratamento farmacológico , Caquexia/tratamento farmacológico , Neoplasias/metabolismo , Zingiber officinale , Adulto , Anorexia/metabolismo , Caquexia/metabolismo , Feminino , Grelina/metabolismo , Humanos , Masculino , Náusea/tratamento farmacológico , Náusea/metabolismo , Fitoterapia/métodos , Qualidade de Vida , Vômito/tratamento farmacológico , Vômito/metabolismoRESUMO
Rolapitant is a neurokinin-1 receptor antagonist that is approved in combination with other antiemetic agents in adults for the prevention of delayed nausea and vomiting (CINV) associated with initial and repeat courses of emetogenic cancer chemotherapy, including but not limited to highly emetogenic chemotherapy. Here, we assessed the absorption, metabolism, and excretion of 14C-labeled rolapitant in healthy male subjects. Rolapitant was administered as a single 180-mg oral dose containing approximately 100 µCi of total radioactivity, with plasma, urine, and fecal samples collected at defined intervals after dosing. Rolapitant had a large apparent volume of distribution, indicating that it is widely distributed into body tissues. Rolapitant was slowly metabolized and eliminated with a mean half-life of 186 h. Exposure to the major metabolite of rolapitant, C4-pyrrolidinyl hydroxylated rolapitant or M19, was approximately 50% of rolapitant exposure in plasma. Renal clearance was not a significant elimination route for rolapitant-related entities. Total radioactivity recovered in urine accounted for 14.2% of the dose, compared to 72.7% recovery in feces. Adverse events (AEs) were generally mild; there were no serious AEs, and no clinically significant changes in laboratory or electrocardiogram parameters were observed. The combination of rolapitant safety, its long half-life, extensive tissue distribution, and slow elimination via the hepatobiliary route (rather than renal excretion) suggest suitability that a single dose of rolapitant may provide protection against CINV beyond the first 24 h after chemotherapy administration.
Assuntos
Antieméticos/administração & dosagem , Náusea/metabolismo , Antagonistas dos Receptores de Neurocinina-1/administração & dosagem , Compostos de Espiro/administração & dosagem , Vômito/metabolismo , Adulto , Antieméticos/farmacocinética , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Náusea/tratamento farmacológico , Antagonistas dos Receptores de Neurocinina-1/farmacocinética , Compostos de Espiro/farmacocinética , Distribuição Tecidual , Vômito/tratamento farmacológicoRESUMO
Chemotherapy-induced nausea and vomiting (CINV) remain the most common and devastating side-effects associated with cancer chemotherapy. In recent decades, several lines of research emphasize the importance of 5-hydroxytryptamine3 (5-HT3; serotonin) receptors in the pathogenesis and treatment of CINV. 5-HT3 receptors are members of ligand-gated ion channels that mediate the rapid and transient membrane-depolarizing effect of 5-HT in the central and peripheral nervous system. These receptors play important roles in nausea and vomiting, as well as regulation of peristalsis and pain transmission. The development of antagonists for 5-HT3 receptor dramatically improved the treatment of CINV in cancer patients. In fact, the most common use of 5-HT3 receptor antagonists to date is the treatment of nausea and vomiting. In recent years, there has been an increasing tendency to use natural plant products as important therapeutic entities in the treatment of various diseases. In this article, we examined the results of earlier studies on the actions of natural compounds on the functional properties of 5-HT3 receptors. It is likely that these natural modulators of 5-HT3 receptors can be employed as lead structures for the synthesis of therapeutic agents for treating CINV in future clinical studies.
Assuntos
Náusea/metabolismo , Receptores 5-HT3 de Serotonina/metabolismo , Antagonistas do Receptor 5-HT3 de Serotonina/farmacologia , Vômito/metabolismo , Regulação Alostérica , Antineoplásicos/efeitos adversos , Sítios de Ligação , Canabidiol/farmacologia , Zingiber officinale/química , Humanos , Náusea/induzido quimicamente , Antagonistas do Receptor 5-HT3 de Serotonina/química , Terpenos/farmacologia , Vômito/induzido quimicamenteRESUMO
Background The MET tyrosine kinase and its ligand, hepatocyte growth factor (HGF) also known as scatter factor, are associated with tumourigenesis and metastasis by promotion of scattering, proliferation, angiogenesis, motility and invasion. ASLAN-002 is a potent inhibitor of MET as well as related kinases. A phase I dose escalation study was conducted to determine the safety and pharmacokinetics of ASLAN-002 in patients with advanced cancer. Methods Patients with advanced or metastatic solid tumours, who had progressed on standard therapy or for whom standard therapy was not known, were administered ASLAN-002 orally. The starting dose was 100 mg once daily (QD) with subsequent cohorts to receive doses of 200 mg QD, 300 mg QD, 450 mg QD, 600 mg QD, 300 mg twice daily (BID), 450 mg BID, and 600 mg BID. Results Forty patients were included across 7 dose cohorts. Cohort 8 (600 mg BID) was not opened due to the lack of appreciable pharmacokinetic (PK) differences between 300 mg BID and 450 mg BID and higher incidences of grade 3 or 4 adverse events (AE) in Cohort 7 (450 mg BID). Fifteen patients (37.5%) experienced a grade 3 or 4 AE. The most commonly reported AEs were nausea (55%), fatigue (47.5%) and constipation (30%). One dose limiting toxicity (DLT) of atrial fibrillation was observed with 450 mg BID. Conclusions ASLAN-002 is well tolerated at 300 mg BID and is the recommended dose for future phase II studies (RP2D). Clinical Trials Registry Number: NCT01721148 .
Assuntos
Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Fibrilação Atrial/tratamento farmacológico , Fibrilação Atrial/metabolismo , Relação Dose-Resposta a Droga , Esquema de Medicação , Fadiga/induzido quimicamente , Fadiga/metabolismo , Feminino , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Náusea/induzido quimicamente , Náusea/metabolismo , Neoplasias/metabolismoRESUMO
Hyperemesis gravidarum (HG), severe nausea and vomiting of pregnancy, occurs in 0.3-2% of pregnancies and is associated with maternal and fetal morbidity. The cause of HG remains unknown, but familial aggregation and results of twin studies suggest that understanding the genetic contribution is essential for comprehending the disease etiology. Here, we conduct a genome-wide association study (GWAS) for binary (HG) and ordinal (severity of nausea and vomiting) phenotypes of pregnancy complications. Two loci, chr19p13.11 and chr4q12, are genome-wide significant (p < 5 × 10-8) in both association scans and are replicated in an independent cohort. The genes implicated at these two loci are GDF15 and IGFBP7 respectively, both known to be involved in placentation, appetite, and cachexia. While proving the casual roles of GDF15 and IGFBP7 in nausea and vomiting of pregnancy requires further study, this GWAS provides insights into the genetic risk factors contributing to the disease.
Assuntos
Fator 15 de Diferenciação de Crescimento/genética , Hiperêmese Gravídica/genética , Proteínas de Ligação a Fator de Crescimento Semelhante a Insulina/genética , Náusea/genética , Placenta/metabolismo , Complicações na Gravidez/genética , Vômito/genética , Adulto , Apetite/genética , Cromossomos Humanos Par 19 , Cromossomos Humanos Par 4 , Estudos de Coortes , Feminino , Expressão Gênica , Genoma Humano , Estudo de Associação Genômica Ampla , Fator 15 de Diferenciação de Crescimento/metabolismo , Humanos , Hiperêmese Gravídica/metabolismo , Hiperêmese Gravídica/fisiopatologia , Proteínas de Ligação a Fator de Crescimento Semelhante a Insulina/metabolismo , Náusea/etiologia , Náusea/metabolismo , Náusea/fisiopatologia , Fenótipo , Placenta/patologia , Gravidez , Complicações na Gravidez/metabolismo , Complicações na Gravidez/fisiopatologia , Locos de Características Quantitativas , Fatores de Risco , Índice de Gravidade de Doença , Vômito/metabolismo , Vômito/fisiopatologiaRESUMO
BACKGROUND: Cannabinoid hyperemesis syndrome (CHS) is characterized by symptoms of cyclic abdominal pain, nausea, and vomiting in the setting of prolonged cannabis use. The transient receptor potential vanilloid 1 (TRPV1) receptor may be involved in this syndrome. Topical capsaicin is a proposed treatment for CHS; it binds TRPV1 with high specificity, impairing substance P signaling in the area postrema and nucleus tractus solitarius via overstimulation of TRPV1. This may explain its apparent antiemetic effect in this syndrome. PURPOSE: We describe a series of thirteen cases of suspected cannabis hyperemesis syndrome treated with capsaicin in the emergency departments of two academic medical centers. METHODS: A query of the electronic health record at both centers identified thirteen patients with documented daily cannabis use and symptoms consistent with CHS who were administered topical capsaicin cream for symptom management. RESULTS: All 13 patients experienced symptom relief after administration of capsaicin cream. CONCLUSION: Topical capsaicin was associated with improvement in symptoms of CHS after other treatments failed.
Assuntos
Dor Abdominal/tratamento farmacológico , Antieméticos/administração & dosagem , Capsaicina/administração & dosagem , Serviço Hospitalar de Emergência , Abuso de Maconha/complicações , Fumar Maconha/efeitos adversos , Náusea/tratamento farmacológico , Fármacos do Sistema Sensorial/administração & dosagem , Vômito/tratamento farmacológico , Dor Abdominal/diagnóstico , Dor Abdominal/etiologia , Dor Abdominal/metabolismo , Adulto , Antieméticos/efeitos adversos , Área Postrema/efeitos dos fármacos , Área Postrema/metabolismo , Capsaicina/efeitos adversos , Registros Eletrônicos de Saúde , Feminino , Humanos , Masculino , Massachusetts , Pessoa de Meia-Idade , Missouri , Náusea/diagnóstico , Náusea/etiologia , Náusea/metabolismo , Estudos Retrospectivos , Fármacos do Sistema Sensorial/efeitos adversos , Núcleo Solitário/efeitos dos fármacos , Núcleo Solitário/metabolismo , Síndrome , Canais de Cátion TRPV/antagonistas & inibidores , Canais de Cátion TRPV/metabolismo , Resultado do Tratamento , Vômito/diagnóstico , Vômito/etiologia , Vômito/metabolismo , Adulto JovemRESUMO
BACKGROUND: Chemotherapy-induced nausea and vomiting (CINV) can negatively affect quality of life and treatment compliance in breast cancer patients. Habitual alcohol consumption reportedly shows an inverse correlation with CINV, though the underlying mechanism is unknown. Acetaldehyde dehydrogenase 2 (ALDH2), one of the two ALDH isozymes, is reportedly the major factor among several genetic polymorphisms possibly affecting alcohol metabolism. More than 40% of Japanese have ALDH2 mutations, while almost all Westerners have the wild type. We hypothesized that ALDH2 polymorphism status might relate to the metabolism of emetic chemotherapeutic drugs. Relationships among habitual alcohol consumption, ALDH2 polymorphisms, and CINV in Japanese breast cancer patients given adjuvant chemotherapy containing high-emetic drugs were, thus, investigated. METHODS: We enrolled 81 women, between 20 and 55 years of age, who had been diagnosed with primary breast cancer and received (neo-) adjuvant chemotherapy at our institution. ALDH2 genotypes were analyzed employing the smart amplification process in peripheral blood samples. RESULTS: The wild type (ALDH2*1/*1), heterozygote (ALDH2*1/*2), and mutant homozygote (ALDH2*2/*2) genotypes were found in 53, 44, and 3% of patients, respectively. Complete response, i.e., no vomiting without rescue anti-emetics, was more frequent in patients who habitually consumed alcohol than in those who did not (p = 0.036). This trend remained only in ALDH2 heterozygotes when patients were categorized according to ALDH2 genotype. Logistic regression analysis revealed alcohol intake to be an independent predictive factor for complete response (p = 0.013). CONCLUSIONS: Our results revealed habitual alcohol intake to be related to a lower CINV incidence. The impact of alcohol intake on CINV in patients with ALDH2 polymorphisms merits further investigation.
Assuntos
Consumo de Bebidas Alcoólicas/epidemiologia , Antineoplásicos/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Etanol/metabolismo , Náusea/epidemiologia , Vômito/epidemiologia , Adulto , Consumo de Bebidas Alcoólicas/genética , Consumo de Bebidas Alcoólicas/metabolismo , Aldeído-Desidrogenase Mitocondrial/genética , Aldeído-Desidrogenase Mitocondrial/metabolismo , Neoplasias da Mama/genética , Quimioterapia Adjuvante/efeitos adversos , Quimioterapia Adjuvante/métodos , Feminino , Genótipo , Heterozigoto , Homozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Náusea/induzido quimicamente , Náusea/genética , Náusea/metabolismo , Polimorfismo Genético , Qualidade de Vida , Vômito/induzido quimicamente , Vômito/genética , Vômito/metabolismo , Adulto JovemRESUMO
Despite advances in antiemetic therapy, chemotherapy-induced nausea and vomiting (CINV) still poses a significant burden to patients undergoing chemotherapy. Nausea, in particular, is still highly prevalent in this population. Ginger has been traditionally used as a folk remedy for gastrointestinal complaints and has been suggested as a viable adjuvant treatment for nausea and vomiting in the cancer context. Substantial research has revealed ginger to possess properties that could exert multiple beneficial effects on chemotherapy patients who experience nausea and vomiting. Bioactive compounds within the rhizome of ginger, particularly the gingerol and shogaol class of compounds, interact with several pathways that are directly implicated in CINV in addition to pathways that could play secondary roles by exacerbating symptoms. These properties include 5-HT3, substance P, and acetylcholine receptor antagonism; antiinflammatory properties; and modulation of cellular redox signaling, vasopressin release, gastrointestinal motility, and gastric emptying rate. This review outlines these proposed mechanisms by discussing the results of clinical, in vitro, and animal studies both within the chemotherapy context and in other relevant fields. The evidence presented in this review indicates that ginger possesses multiple properties that could be beneficial in reducing CINV.
Assuntos
Antieméticos/uso terapêutico , Antineoplásicos/efeitos adversos , Modelos Biológicos , Náusea/prevenção & controle , Rizoma/química , Vômito/prevenção & controle , Zingiber officinale/química , Animais , Anti-Inflamatórios não Esteroides/análise , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/uso terapêutico , Antieméticos/análise , Antieméticos/química , Antioxidantes/análise , Antioxidantes/química , Antioxidantes/uso terapêutico , Catecóis/análise , Catecóis/metabolismo , Catecóis/uso terapêutico , Etnofarmacologia , Álcoois Graxos/análise , Álcoois Graxos/metabolismo , Álcoois Graxos/uso terapêutico , Humanos , Náusea/induzido quimicamente , Náusea/metabolismo , Náusea/fisiopatologia , Vômito/induzido quimicamente , Vômito/metabolismo , Vômito/fisiopatologiaRESUMO
BACKGROUND: GLP-1 receptor agonists are utilised for the treatment of Type-2 diabetes but can be associated with undesirable effects of nausea and vomiting. OBJECTIVES: To investigate the role of GLP-1 receptors in mechanisms of emesis, behaviours indicative of nausea (BIN) and food intake in the ferret. RESULTS: Exendin-4 (10 and 30nmol, i.c.v.) induced emesis, inhibited food intake, and increased the frequency of BIN. Increases in c-Fos in the brainstem, midbrain and forebrain occurred in animals exhibiting emesis; no activation of the brainstem occurred in animals not vomiting. Exendin-4 (10nmol, i.c.v.) when preceded by i.c.v. saline (15µl), was not emetic but induced BIN and inhibited food intake; exendin (9-39) (100nmol) reduced BIN only. c-Fos showed that consistent with the absence of emesis in saline/exendin-4 treated animals there was no increase in c-Fos in the brainstem, but it increased in midbrain and forebrain nuclei. Excepting the amygdala, exendin (9-39) was without efffect on the increases in c-Fos. Analysis of c-Fos data showed a positive linear relationship between midbrain and forebrain areas irrespective of the occurrence of emesis induced by exendin-4. In contrast, brainstem and midbrain c-Fos levels were positively correlated, but only in animals with emesis. CONCLUSIONS: The brainstem is critical for exendin-4-induced emesis but suppression of food intake and BIN involves more rostral brain sites. Exendin-4-induced BIN and c-Fos activation of the amygdala are sensitive to exendin (9-39), whereas the suppression of food intake is not implicating separate control mechanisms for emesis and BIN.
Assuntos
Encéfalo/efeitos dos fármacos , Eméticos/farmacologia , Náusea/induzido quimicamente , Peptídeos/farmacologia , Peçonhas/farmacologia , Vômito/induzido quimicamente , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Cateteres de Demora , Relação Dose-Resposta a Droga , Ingestão de Alimentos/efeitos dos fármacos , Ingestão de Alimentos/fisiologia , Exenatida , Furões , Peptídeo 1 Semelhante ao Glucagon/agonistas , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Imuno-Histoquímica , Injeções Intraventriculares , Masculino , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Náusea/metabolismo , Náusea/patologia , Vias Neurais/efeitos dos fármacos , Vias Neurais/metabolismo , Vias Neurais/patologia , Proteínas Proto-Oncogênicas c-fos/metabolismo , Vômito/metabolismo , Vômito/patologiaRESUMO
Neurokinin-1 (NK1) receptor antagonists (RAs) are commonly coadministered with serotonin (5-HT3) RAs (e.g. palonosetron (PALO)) to prevent chemotherapy-induced nausea/vomiting. Netupitant/palonosetron (NEPA), an oral fixed combination of netupitant (NETU)-a new NK1 RA-and PALO, is currently under development. In vitro data suggest that NETU inhibits CYP3A4 and is a substrate for and weak inhibitor of P-glycoprotein (P-gp). This review evaluates potential drug-drug interactions between NETU or NEPA and CYP3A4 substrates/inducers/inhibitors or P-gp substrates in healthy subjects. Pharmacokinetic (PK) parameters were evaluated for each drug when NETU was coadministered with PALO (single doses) and when single doses of NETU or NEPA were coadministered with CYP3A4 substrates (erythromycin (ERY), midazolam (MID), dexamethasone (DEX), or oral contraceptives), inhibitors (ketoconazole (KETO)), or inducers (rifampicin (RIF)), or a P-gp substrate (digoxin (DIG)). Results showed no relevant PK interactions between NETU and PALO. Coadministration of NETU increased MID and ERY exposure and significantly increased DEX exposure in a dose-dependent manner; NETU exposure was unaffected. NEPA coadministration had no clinically significant effect on oral contraception, although levonorgestrel exposure increased. NETU exposure increased after coadministration of NEPA with KETO and decreased after coadministration with RIF; PALO exposure was unaffected. NETU coadministration did not influence DIG exposure. In conclusion, there were no clinically relevant interactions between NETU and PALO, or NEPA and oral contraceptives (based on levonorgestrel and ethinylestradiol exposure). Coadministration of NETU or NEPA with CYP3A4 inducers/inhibitors/substrates should be done with caution. Dose reduction is recommended for DEX. Dose adjustments are not needed for NETU coadministration with P-gp substrates.
Assuntos
Isoquinolinas/administração & dosagem , Isoquinolinas/farmacocinética , Piridinas/administração & dosagem , Piridinas/farmacocinética , Quinuclidinas/administração & dosagem , Quinuclidinas/farmacocinética , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Animais , Dexametasona/efeitos adversos , Combinação de Medicamentos , Interações Medicamentosas/fisiologia , Humanos , Náusea/induzido quimicamente , Náusea/tratamento farmacológico , Náusea/metabolismo , Palonossetrom , Antagonistas da Serotonina/administração & dosagem , Antagonistas da Serotonina/farmacocinética , Vômito/induzido quimicamente , Vômito/tratamento farmacológico , Vômito/metabolismoRESUMO
OBJECTIVE: Acupuncture has been shown to be effective for the treatment of chemotherapy-related nausea and vomiting. The aim of this study was to explore the mechanisms of action underlying the anti-emetic effect of electroacupuncture (EA). DESIGN: Forty-eight rats received saline (n=12) or 6â mg/kg cisplatin (n=36) to establish a chemotherapy-induced nausea and vomiting model. EA was performed at CV12 (n=12), bilateral PC6 (n=12), or sham points (n=12) 3â days before and 1-2â days after cisplatin administration (4-5 times in total), at 0.5-1â mA intensity and 2/15â Hz frequency for 10â min. Kaolin intake, food intake and bodyweight change were evaluated as markers of nausea and vomiting severity. Concentrations of serotonin (5-hydroxytryptamine, 5-HT) in the duodenum and c-Fos expression in the nucleus of the solitary tract (NTS) were measured using high performance liquid chromatography and immunohistochemistry, respectively. RESULTS: Cisplatin administration led to increased kaolin intake and reduced food intake and bodyweight over the following 2â days. EA at CV12 significantly reversed the cisplatin-induced change in kaolin intake (on days 1 and 2) and food intake and bodyweight (on day 1). EA at CV12 also attenuated the cisplatin-induced increase in 5-HT in the duodenum and suppressed c-Fos expression in the NTS. EA at PC6 influenced kaolin intake (on day 1 only) and c-Fos expression, but had no statistically significant effect on food intake, bodyweight or 5-HT expression. CONCLUSIONS: This study demonstrated beneficial effects of EA on chemotherapy-induced nausea and vomiting in a rat model. The anti-emetic effect of EA may be mediated through inhibition of 5-HT secretion in the duodenum and activity of the NTS.
Assuntos
Antineoplásicos/efeitos adversos , Cisplatino/efeitos adversos , Eletroacupuntura , Náusea/terapia , Animais , Antineoplásicos/administração & dosagem , Cisplatino/administração & dosagem , Ingestão de Alimentos , Humanos , Caulim/metabolismo , Masculino , Náusea/etiologia , Náusea/metabolismo , Náusea/fisiopatologia , Ratos , Ratos Wistar , Vômito/etiologia , Vômito/metabolismo , Vômito/fisiopatologia , Vômito/terapiaRESUMO
Cannabinoid (CB) agonists suppress nausea in humans and animal models; yet, their underlying neural substrates remain largely unknown. Evidence suggests that the visceral insular cortex (VIC) plays a critical role in nausea. Given the expression of CB1 receptors and the presence of endocannabinoids in this brain region, we hypothesized that the VIC endocannabinoid system regulates nausea. In the present study, we assessed whether inhibiting the primary endocannabinoid hydrolytic enzymes in the VIC reduces acute lithium chloride (LiCl)-induced conditioned gaping, a rat model of nausea. We also quantified endocannabinoid levels during an episode of nausea, and assessed VIC neuronal activation using the marker, c-Fos. Local inhibition of monoacylglycerol lipase (MAGL), the main hydrolytic enzyme of 2-arachidonylglycerol (2-AG), reduced acute nausea through a CB1 receptor mechanism, whereas inhibition of fatty acid amide hydrolase (FAAH), the primary catabolic enzyme of anandamide (AEA), was without effect. Levels of 2-AG were also selectively elevated in the VIC during an episode of nausea. Inhibition of MAGL robustly increased 2-AG in the VIC, while FAAH inhibition had no effect on AEA. Finally, we demonstrated that inhibition of MAGL reduced VIC Fos immunoreactivity in response to LiCl treatment. Taken together, these findings provide compelling evidence that acute nausea selectively increases 2-AG in the VIC, and suggests that 2-AG signaling within the VIC regulates nausea by reducing neuronal activity in this forebrain region.