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1.
Einstein (Sao Paulo) ; 18: eAO4876, 2020.
Artigo em Inglês, Português | MEDLINE | ID: mdl-31576909

RESUMO

OBJECTIVE: To investigate the effects of sericin extracted from silkworm Bombyx mori cocoon on morphophysiological parameters in mice with obesity induced by high-fat diet. METHODS: Male C57Bl6 mice aged 9 weeks were allocated to one of two groups - Control and Obese, and fed a standard or high-fat diet for 10 weeks, respectively. Mice were then further subdivided into four groups with seven mice each, as follows: Control, Control-Sericin, Obese, and Obese-Sericin. The standard or high fat diet was given for 4 more weeks; sericin (1,000mg/kg body weight) was given orally to mice in the Control-Sericin and Obese-Sericin Groups during this period. Weight gain, food intake, fecal weight, fecal lipid content, gut motility and glucose tolerance were monitored. At the end of experimental period, plasma was collected for biochemical analysis. Samples of white adipose tissue, liver and jejunum were collected and processed for light microscopy analysis; liver fragments were used for lipid content determination. RESULTS: Obese mice experienced significantly greater weight gain and fat accumulation and had higher total cholesterol and glucose levels compared to controls. Retroperitoneal and periepididymal adipocyte hypertrophy, development of hepatic steatosis, increased cholesterol and triglyceride levels and morphometric changes in the jejunal wall were observed. CONCLUSION: Physiological changes induced by obesity were not fully reverted by sericin; however, sericin treatment restored jejunal morphometry and increased lipid excretion in feces in obese mice, suggesting potential anti-obesity effects.


Assuntos
Fármacos Antiobesidade/uso terapêutico , Dieta Hiperlipídica , Obesidade/tratamento farmacológico , Sericinas/uso terapêutico , Tecido Adiposo/patologia , Animais , Fármacos Antiobesidade/farmacologia , Peso Corporal/efeitos dos fármacos , Colesterol/análise , Dieta Hiperlipídica/efeitos adversos , Ingestão de Alimentos/efeitos dos fármacos , Fígado Gorduroso/patologia , Trânsito Gastrointestinal/efeitos dos fármacos , Teste de Tolerância a Glucose , Fígado/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Obesos , Obesidade/etiologia , Obesidade/fisiopatologia , Reprodutibilidade dos Testes , Sericinas/farmacologia , Fatores de Tempo , Resultado do Tratamento , Triglicerídeos/análise , Ganho de Peso/efeitos dos fármacos
2.
Acta Cir Bras ; 34(10): e201901004, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31851212

RESUMO

PURPOSE: To evaluate the effects of infliximab on the inflammation of the colonic mucosa devoid from fecal stream. METHODS: Twenty-four rats were submitted to a Hartmann's procedure. They remained for 12 weeks with the fecal derivation to development of diversion colitis on excluded colorectal stump. After this period, they were divided into 3 groups: one group received intervention with saline (2.0 mL / week), other group infliximab at doses of 5 mg/kg/week and the other 10 mg/kg/week for five consecutively weeks. Concluded the intervention period, the animals were euthanized to remove colon segments with and without fecal stream. Colitis was diagnosed by histological analysis and the degree of inflammation by validated score. The neutrophilic infiltrate was evaluated by tissue expression of myeloperoxidase identified by immunohistochemical. The tissue content of myeloperoxidase was measured by computer-assisted image analysis. RESULTS: The inflammatory score was high in colonic segments without fecal stream. The intervention with infliximab reduced the inflammatory score in excluded colonic segments. The content of myeloperoxidase was reduced in colonic segments of animals treated with infliximab mainly in high concentrations. CONCLUSION: Intervention with infliximab reduced the inflammation and the neutrophil infiltrate in colonic segments devoid of the fecal stream.


Assuntos
Colite/tratamento farmacológico , Fármacos Gastrointestinais/farmacologia , Infliximab/farmacologia , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Animais , Colite/patologia , Colo/efeitos dos fármacos , Colo/patologia , Fezes , Trânsito Gastrointestinal/efeitos dos fármacos , Processamento de Imagem Assistida por Computador , Imuno-Histoquímica , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/patologia , Masculino , Infiltração de Neutrófilos/efeitos dos fármacos , Peroxidase/análise , Ratos Wistar , Reprodutibilidade dos Testes , Fatores de Tempo , Resultado do Tratamento
3.
J Med Food ; 22(10): 1009-1021, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31536448

RESUMO

Constipation is a common gastrointestinal disorder characterized by changes in intestinal habits. Increasing evidence indicates that long-term use of irritant laxatives causes serious side effects. Meanwhile, more than 50% of patients are dissatisfied with sense of use of non-prescriptional laxatives. ß-glucans are natural polysaccharides widely found in yeast, fungus, and plants, which have been reported to exhibit various pharmacological effects. The aim of this study was to characterize the effect of ß-glucans extracted from the bread yeast cell wall on loperamide-induced constipation mice. Forty mice were fed with loperamide (10 mg/kg) to make the constipation model and a diet supplemented with 2.5, 5, and 10 mg/kg ß-glucan. We assessed the defecation frequency, intestinal transit function of mice, as well as used high-throughput sequencing to analyze the intestinal microbiota composition and functional biological profiles data. Meanwhile, we detected expression of neurotransmitters including acetylcholinesterase, substance P, and serotonin (5-HT) and expression of tight junction protein (TJP) including zonula occludens-1 and mucin-2 in distal colon to characterize the possible molecular mechanisms. ß-glucans significantly enhanced intestinal motility and provided a possibility to regulate the expression of neurotransmitters and TJP in mice. The intestinal microecological portion of the treatment group partially recovered and was closer to the normal group. This study showed that ß-glucans can influence the intestinal microbiota and restore microecological balance to regulate the express of neurotransmitters and TJP to recover intestinal epithelial mechanical barrier. We suggested that ß-glucans could be used as an active nutritional supplement to protect the damaged intestinal barrier and help patients who have constipation complications and dysbiosis.


Assuntos
Constipação Intestinal/tratamento farmacológico , Microbioma Gastrointestinal , Loperamida/efeitos adversos , Saccharomyces cerevisiae/química , beta-Glucanas/farmacologia , Acetilcolinesterase/metabolismo , Animais , Constipação Intestinal/induzido quimicamente , Defecação/efeitos dos fármacos , Trânsito Gastrointestinal/efeitos dos fármacos , Masculino , Metagenoma , Camundongos , Camundongos Endogâmicos BALB C , Mucina-2/metabolismo , Serotonina/metabolismo , Substância P/metabolismo , Proteína da Zônula de Oclusão-1/metabolismo
4.
Med Sci Monit ; 25: 5028-5035, 2019 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-31280283

RESUMO

BACKGROUND The aim of this study was to evaluate the effects of a new type of dietary fiber - high specific volume polysaccharide (HSVP) - on fecal properties, serum vasoactive intestinal peptide (VIP) concentration, intestinal flora count, and expression of the VIP-cAMP-PKA-AQP3 signaling pathway. MATERIAL AND METHODS Compound diphenoxylate was used in 48 healthy Wistar rats to establish a constipation model. Rats were divided into a normal control group, a constipation model group, an HSVP low-dose group, an HSVP medium-dose group, an HSVP high-dose group, and a fructose control group. We used colony count method, ELISA, WB, and RT-PCR to determine fecal moisture content, fecal hardness, fecal passage time, serum VIP concentration, number of intestinal bacteria, and VIP-cAMP-PKA-AQP3 signal pathway protein expression. RESULTS The constipation model was established successfully. HSVP (the medium dose was 10% and the high dose was 15%) improved fecal moisture content, reduced hardness, shortened fecal emptying time, increased intestinal bacteria, reduced serum VIP concentration, downregulated cAMP and PKAm RNA transcription, reduced protein expression, and reduced intestinal AQP3 expression. CONCLUSIONS HSVP improved constipation, increased the number of intestinal bacteria, and elevated expression of the VIP-cAMP-PKA-AQP3 signaling pathway. The mechanism of HSVP in regulating intestinal water metabolism in constipated rats may occur through the VIP-cAMP-PKA-AQP3 signaling pathway, and be closely related to changes in intestinal bacteria. The important role of the brain-gut-microbiome axis in the pathogenesis of constipation has been confirmed in this study.


Assuntos
Constipação Intestinal/tratamento farmacológico , Fibras na Dieta/uso terapêutico , Intestinos/efeitos dos fármacos , Polissacarídeos/uso terapêutico , Água/metabolismo , Animais , Aquaporina 3/genética , Aquaporina 3/metabolismo , Constipação Intestinal/sangue , Constipação Intestinal/genética , Constipação Intestinal/fisiopatologia , AMP Cíclico/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Fibras na Dieta/farmacologia , Fezes , Microbioma Gastrointestinal/efeitos dos fármacos , Trânsito Gastrointestinal/efeitos dos fármacos , Dureza , Umidade , Polissacarídeos/química , Polissacarídeos/farmacologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos Wistar , Transcrição Genética/efeitos dos fármacos , Resultado do Tratamento , Peptídeo Intestinal Vasoativo/sangue , Peptídeo Intestinal Vasoativo/genética
5.
Biomed Pharmacother ; 116: 109002, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31154270

RESUMO

Berberine (BBR) is a non-prescription drug to treat various bacteria-associated diarrheas. However, BBR has also been reported to cause diarrhea in clinic, with underlying mechanisms poorly understood. Because altered gut microbial ecology is a potential basis for diarrhea, this study was conducted to investigate the impact of BBR on gut microbiota of treatment-emergent diarrhea. BBR treatment (200 mg/kg, i.g.) in normal rats exhibited no significant changes in serum biochemical parameters but mild diarrhea occurred, accompanied with the decreased gastrointestinal transit time and increased fecal moisture, suggestive of the local effects of BBR in the intestine. Colon histology revealed the decreased abundance of mucus-filled goblet cells in BBR group. Although BBR-treated rats had the enlarged cecum with watery caecal digesta, short-chain fatty acids concentration was significantly lower than control group. Additionally, BBR caused gut microbiota dysbiosis by evaluating the decreased observed species number and Shannon index. BBR increased the relative abundances of families Porphyromonadaceae and Prevotellaceae as well as genera Parabacteroides, Prevotellaceae_UCG-001 and Prevotellaceae_NK3B31_group. Spearman's correlation analysis revealed family Prevotellaceae and genus Prevotellaceae_UCG-001 as the most prominent drivers of the BBR treatment-emergent diarrhea, correlating positively with fecal moisture but negatively with gastrointestinal transit time. This study therefore demonstrated that the treatment-emergent mild diarrhea of BBR was most likely due to the dysbiosis of the gut microbiota.


Assuntos
Berberina/efeitos adversos , Diarreia/induzido quimicamente , Diarreia/microbiologia , Disbiose/complicações , Disbiose/microbiologia , Microbioma Gastrointestinal , Animais , Biodiversidade , Ceco/patologia , Colo/efeitos dos fármacos , Colo/patologia , Colo/fisiopatologia , Diarreia/fisiopatologia , Disbiose/fisiopatologia , Ácidos Graxos/metabolismo , Fezes/química , Microbioma Gastrointestinal/efeitos dos fármacos , Trânsito Gastrointestinal/efeitos dos fármacos , Masculino , Tamanho do Órgão , Ratos Wistar , Estatísticas não Paramétricas
6.
J Nutr Sci ; 8: e18, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31080591

RESUMO

Functional gastrointestinal disorders including constipation affect up to 14 % of the world's population. Treatment is difficult and challenging resulting in a need for alternative safe and effective therapies. The present study investigated whether daily consumption of three gold-fleshed kiwifruit could alleviate constipation and improve gastrointestinal discomfort in mildly constipated individuals with and without pain. A total of thirty-two participants were enrolled in a 16-week randomised, single-blind, crossover study. Participants received either three 'Zesy002' kiwifruit or 14·75 g Metamucil® (5 g dietary fibre/d (a positive control)) for 4 weeks each with a 4-week washout between treatments. A 2-week washout period was included at the beginning and end of the study. Daily bowel habit diaries were kept throughout the study. The primary outcome measure was differences in the number of complete spontaneous bowel movements (CSBM). Secondary outcome measures were bowel movement frequency and stool form as well as digestive symptoms and comfort. The number of CSBM per week was significantly greater during daily consumption of three kiwifruit compared with the baseline (6·3 v. 3·3; P < 0·05) and the Metamucil® treatment (6·3 v. 4·5; P < 0·05). Stool consistency was also improved, with kiwifruit producing softer stools and less straining (P < 0·05). Gastrointestinal discomfort was also improved compared with baseline for abdominal pain, constipation and indigestion (P < 0·05) during the kiwifruit intervention and constipation during the Metamucil® intervention (P < 0·05). This randomised controlled trial demonstrates that daily consumption of three gold-fleshed kiwifruit is associated with a significant increase of two CSBM per week and reduction in gastrointestinal discomfort in mildly constipated adults.


Assuntos
Actinidia/química , Constipação Intestinal/tratamento farmacológico , Frutas/química , Trato Gastrointestinal/efeitos dos fármacos , Extratos Vegetais/uso terapêutico , Psyllium/uso terapêutico , Dor Abdominal/complicações , Adolescente , Adulto , Idoso , Estudos Cross-Over , Defecação , Método Duplo-Cego , Fezes , Feminino , Trânsito Gastrointestinal/efeitos dos fármacos , Humanos , Intestinos/efeitos dos fármacos , Síndrome do Intestino Irritável/complicações , Síndrome do Intestino Irritável/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Nova Zelândia , Método Simples-Cego , Resultado do Tratamento , Adulto Jovem
7.
Int J Colorectal Dis ; 34(6): 1013-1019, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30937526

RESUMO

PURPOSE: Colectomy with ileorectal anastomosis (IRA) is the most common surgical procedure for slow transit constipation (STC). A hemicolectomy has been suggested as an alternative to IRA with good short-term results. However, long-term results are unknown. The aim of this study was to evaluate the long-term results after hemicolectomy as a treatment for STC. METHODS: Fifty patients with STC were selected for right- or left-sided hemicolectomy after evaluation with colonic scintigraphy from 1993 to 2008. Living patients (n = 43) received a bowel function questionnaire and a questionnaire about patient-reported outcome. RESULTS: After a median follow-up of 19.8 years, 13 patients had undergone rescue surgery (n = 12) or used irrigation (n = 1) and were classified as failures. In all, 30 were evaluable for functional outcome and questionnaire data for 19 patients (due to 11 non-responding) could be analysed. Two reported deterioration after several years and were also classified as failures. Median stool frequency remained increased from 1 per week at baseline to 5 per week at long-term follow-up (p = 0.001). Preoperatively, all patients used laxatives, whereas 12 managed without laxatives at long-term follow-up (p = 0.002). There was some reduction in other constipation symptoms but not statically significant. In the patients' global assessment, 10 stated a very good result, seven a good result and two a poor result. CONCLUSIONS: Hemicolectomy for STC increases stool frequency and reduces laxative use. Long-term success rate could range between 17/50 (34%) and 35/50 (70%) depending on outcome among non-responders.


Assuntos
Colo/fisiopatologia , Colo/cirurgia , Constipação Intestinal/fisiopatologia , Constipação Intestinal/cirurgia , Trânsito Gastrointestinal/fisiologia , Adulto , Idoso , Colo/diagnóstico por imagem , Colo/efeitos dos fármacos , Constipação Intestinal/diagnóstico por imagem , Feminino , Seguimentos , Trânsito Gastrointestinal/efeitos dos fármacos , Humanos , Laxantes/farmacologia , Masculino , Pessoa de Meia-Idade , Cuidados Pré-Operatórios , Inquéritos e Questionários , Fatores de Tempo , Resultado do Tratamento
8.
Gastroenterology ; 157(1): 179-192.e2, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30930024

RESUMO

BACKGROUND & AIMS: Reduced gastrointestinal (GI) motility is a feature of disorders associated with intestinal dysbiosis and loss of beneficial microbes. It is not clear how consumption of beneficial commensal microbes, marketed as probiotics, affects the enteric nervous system (ENS). We studied the effects of the widely used probiotic and the commensal Lactobacillus rhamnosus GG (LGG) on ENS and GI motility in mice. METHODS: Conventional and germ free C57B6 mice were gavaged with LGG and intestinal tissues were collected; changes in the enteric neuronal subtypes were assessed by real-time polymerase chain reaction, immunoblots, and immunostaining. Production of reactive oxygen species (ROS) in the jejunal myenteric plexi and phosphorylation (p) of mitogen-activated protein kinase 1 (MAPK1) in the enteric ganglia were assessed by immunoblots and immunostaining. Fluorescence in situ hybridization was performed on jejunal cryosections with probes to detect formyl peptide receptor 1 (FPR1). GI motility in conventional mice was assessed after daily gavage of LGG for 1 week. RESULTS: Feeding of LGG to mice stimulated myenteric production of ROS, increased levels of phosphorylated MAPK1, and increased expression of choline acetyl transferase by neurons (P < .001). These effects were not observed in mice given N-acetyl cysteine (a ROS inhibitor) or LGGΩSpaC (an adhesion-mutant strain of LGG) or FPR1-knockout mice. Gavage of mice with LGG for 1 week significantly increased stool frequency, reduced total GI transit time, and increased contractions of ileal circular muscle strips in ex vivo experiments (P < .05). CONCLUSIONS: Using mouse models, we found that LGG-mediated signaling in the ENS requires bacterial adhesion, redox mechanisms, and FPR1. This pathway might be activated to increase GI motility in patients.


Assuntos
Motilidade Gastrointestinal/fisiologia , Trânsito Gastrointestinal/fisiologia , Íleo/metabolismo , Jejuno/metabolismo , Lactobacillus rhamnosus , Plexo Mientérico/metabolismo , Neurônios/metabolismo , Probióticos , Espécies Reativas de Oxigênio/metabolismo , Acetilcisteína/farmacologia , Animais , Antioxidantes/farmacologia , Colina O-Acetiltransferase/metabolismo , Sistema Nervoso Entérico/citologia , Sistema Nervoso Entérico/metabolismo , Motilidade Gastrointestinal/efeitos dos fármacos , Trânsito Gastrointestinal/efeitos dos fármacos , Vida Livre de Germes , Íleo/efeitos dos fármacos , Íleo/inervação , Hibridização in Situ Fluorescente , Jejuno/efeitos dos fármacos , Jejuno/inervação , Camundongos , Camundongos Knockout , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Contração Muscular/efeitos dos fármacos , Plexo Mientérico/citologia , Neurônios/efeitos dos fármacos , Fosforilação , Reação em Cadeia da Polimerase em Tempo Real , Receptores de Formil Peptídeo/genética
9.
J Chin Med Assoc ; 82(2): 87-91, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30839496

RESUMO

This review evaluates published studies regarding alpha-melanocyte stimulating hormone (α-MSH) in ghrelin-elicited feeding and gut motility. We have sought to integrate all available evidences to provide a complete review on the properties of melanocortin receptors (MCR) and the potential clinical treatment of α-MSH after ghrelin-elicited feeding and gut motility. The available studies were grouped into four categories: food intake, gastric emptying, small intestinal transit, and colonic transit. As we describe, the literature provides evidence of the ability of ghrelin to increase food intake, gastric emptying, small intestinal transit, and colonic transit. α-MSH, which displays high affinity for the MC3 and MC4 receptors, can competitively activate MCRs with agouti-related protein stimulated by ghrelin, and partly attenuates the effect of acyl ghrelin on food intake. Central ghrelin-induced acceleration of gastric emptying is not mediated by MCRs, but the acceleration of the small intestinal transit is at least partly mediated via MCRs in the brain. Similar to fecal pellets and total fecal weight, distal colonic motility and secretion are partly mediated by MCRs in the brain. The interplay between acyl ghrelin and MCRs may provide a new therapeutic avenue to ameliorate anorexia and constipation.


Assuntos
Ingestão de Alimentos/efeitos dos fármacos , Motilidade Gastrointestinal/efeitos dos fármacos , Grelina/farmacologia , alfa-MSH/farmacologia , Animais , Esvaziamento Gástrico/efeitos dos fármacos , Trânsito Gastrointestinal/efeitos dos fármacos , Humanos , Receptores de Melanocortina/fisiologia
10.
Eur J Pharm Biopharm ; 136: 221-230, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30703546

RESUMO

In preclinical research, Beagle dogs are an important model for formulation development and for evaluation of food effects on drug absorption. In this study, the gastrointestinal transit conditions in Beagle dogs were studied with a telemetric motility capsule at different intake conditions. In a cross-over study design, the SmartPill® was given to six Beagle dogs to measure transit times, pH values, pressures and temperatures in the different parts of the canine GI tract. Moreover, the effects of commonly applied pre-treatments as with pentagastrin and famotidine on GI transit conditions were investigated. The gastric transit time in fasted state was short (0.57 ±â€¯0.37 h) and only slightly affected by the pre-treatments. In fed state, gastric transit was clearly prolonged (2.94 ±â€¯0.91 h). The mean intestinal transit time was in the range of 1-2 h and not affected by the intake conditions. The gastric pH values in fasted and fed Beagle dogs were highly variable, but pre-treatment with pentagastrin and famotidine clearly decreased variability. Pre-treatment with pentagastrin resulted in minimum pH values around 0.5 pH units lower than without pre-treatment. Oral administration of famotidine led to constantly elevated pH values of pH 7-8. The maximum pressures in the canine GI tract did not vary significantly between the study arms and typically, maximum pressures of up to 800 mbar were observed in the stomach. The comparison of the data from this study with recent SmartPill® data from humans revealed that major differences could be observed with respect to gastric transit times in fed state, small intestinal transit times as well as maximum pressures arising during GI transit. These differences should be kept in mind if the dog model is used to assess the in vivo performance of solid oral dosage forms intended for use in humans.


Assuntos
Absorção Gastrointestinal/fisiologia , Trânsito Gastrointestinal/fisiologia , Pentagastrina/administração & dosagem , Telemetria/métodos , Administração Oral , Animais , Cápsulas , Estudos Cross-Over , Cães , Feminino , Absorção Gastrointestinal/efeitos dos fármacos , Trânsito Gastrointestinal/efeitos dos fármacos , Humanos , Masculino , Pentagastrina/farmacocinética , Telemetria/instrumentação
11.
Drug Res (Stuttg) ; 69(8): 439-444, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30665254

RESUMO

Milicia excelsa (Moraceae) plant is used as an antidiarrheal agent in ethnomedicine but there is no scientific rationale for its claim. Hence, this study examined the acute toxicity (LD50) and anti-diarrheal effect of methanol root bark extract of Milicia excelsa per oral in rats as well as the probable phytoconstituents responsible for this effect. The LD50 was>5000 mg/kg, suggesting its safety. The extract significantly (p<0.05) reduced the total number of feces and wet feces in castor oil-induced diarrhea with percentage inhibitions of 41.36 and 50.88% at 200 and 400 mg/kg respectively; it also significantly (p<0.05) reduced the distance travelled by charcoal in a dose dependent manner with percentage inhibitions of 33.85, 43.07 and 50.76% at 100, 200 and 400 mg/kg respectively in gastrointestinal motility test indicating anti-diarrheal potentials. The extract significantly (p<0.05) reduced the intestinal fluid accumulation with percentage inhibitions of 33.28 and 45.61% at 200 and 400 mg/kg respectively, suggesting antisecretory effect. Furthermore, the extract significantly (p<0.05) inhibited the intestinal propulsion of the charcoal meal through the gastrointestinal tract in castor oil-induced gastrointestinal transit suggesting antimotility effect. Total flavonoids and tannins are the most abundant phytoconstituents therein. This study therefore concluded that the anti-diarrhea action of the extract may at least in part be mediated via antisecretory and antimotility mechanisms, which could be due to the additive, synergy or counter interaction of the phytoconstituents therein, thus supporting its ethnomedicinal claim.


Assuntos
Diarreia/tratamento farmacológico , Moraceae/química , Extratos Vegetais/uso terapêutico , Alcaloides/análise , Animais , Óleo de Rícino/toxicidade , Catárticos/toxicidade , Diarreia/induzido quimicamente , Feminino , Flavonoides/análise , Motilidade Gastrointestinal/efeitos dos fármacos , Trânsito Gastrointestinal/efeitos dos fármacos , Dose Letal Mediana , Masculino , Fenóis/análise , Casca de Planta/química , Extratos Vegetais/química , Extratos Vegetais/toxicidade , Raízes de Plantas/química , Ratos , Ratos Wistar , Espectrofotometria , Taninos/análise
12.
Bioorg Med Chem ; 27(4): 630-643, 2019 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-30626554

RESUMO

It is well known that opioid analgesics produce side effects including tolerance and constipation. Since neuropeptide FF (NPFF) receptor antagonists reversed opioid-induced hyperalgesia and analgesic tolerance, the present work was performed to synthetize two branched peptidomimetics, EKR and RKE, containing the opioid peptide endomorphin-2 (EM-2) and the NPFF receptor antagonist RF9. Our data obtained from the in vitro cyclic adenosine monophosphate experiment demonstrated that EKR functioned as a mixed mu-, delta-opioid receptors agonist and NPFF1 receptor antagonist/NPFF2 receptor partial agonist, whereas RKE acted as a multi-functional peptidomimetic with the mu-opioid agonism and the NPFF1 antagonism/NPFF2 partial agonism. Furthermore, EKR and RKE completely blocked the NPFF2 receptor-mediated neurite outgrowth of Neuro 2A cells. In vivo antinociception studies found that supraspinal administration of EKR and RKE dose-dependently produced potent antinociception via the mu-opioid receptor in the tail-flick test. In carrageenan inflammatory pain model, spinal administration of EKR and RKE induced dose-related analgesia, which was significantly reduced by the opioid antagonist naloxone and the NPFF antagonist RF9. Notably, compared with morphine, intracerebroventricular repeated administration of EKR and RKE maintained prolonged antinociceptive effectiveness. In addition, at the antinociceptive doses, these two branched peptidomimetics did not significantly inhibit gastrointestinal transit. Taken together, the present work suggest that EKR and RKE behave as multi-functional ligands with the opioid agonism and the NPFF1 antagonism/NPFF2 partial agonism, and produce prolonged antinociception with limited side effects. Moreover, our results imply that EKR and RKE might be interesting pharmacological tools for further investigating the biological function of the NPFF and opioid systems.


Assuntos
Analgésicos Opioides/farmacologia , Descoberta de Drogas , Peptidomiméticos/farmacologia , Analgésicos Opioides/síntese química , Analgésicos Opioides/uso terapêutico , Animais , Linhagem Celular Tumoral , Agonismo Parcial de Drogas , Trânsito Gastrointestinal/efeitos dos fármacos , Células HEK293 , Humanos , Hiperalgesia/tratamento farmacológico , Masculino , Camundongos , Morfina/farmacologia , Naloxona/farmacologia , Naltrexona/análogos & derivados , Naltrexona/farmacologia , Crescimento Neuronal/efeitos dos fármacos , Peptidomiméticos/síntese química , Peptidomiméticos/uso terapêutico , Receptores de Neuropeptídeos/agonistas , Receptores de Neuropeptídeos/antagonistas & inibidores , Receptores Opioides delta/metabolismo , Receptores Opioides mu/metabolismo
13.
Neurogastroenterol Motil ; 31(2): e13492, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30353623

RESUMO

BACKGROUND: Linaclotide is efficacious in the management of irritable bowel syndrome with constipation (IBS-C), yet relatively little is known regarding its effect on human gastrointestinal physiology. The primary aim of the study was to examine the effect of linaclotide on change in pH across the ileocecal junction (ICJ), a proposed measure of cecal fermentation, and its relationship to symptoms and quality of life (QoL) in IBS-C. METHODS: A total of 13 participants with Rome III IBS-C underwent a standardized wireless motility capsule (WMC). Stool consistency was measured using the Bristol stool form scale (BSFS) and frequency with spontaneous bowel movements (SBM). Gastrointestinal symptoms and QoL were assessed using validated questionnaires. The WMC and questionnaires were repeated after 28 days of linaclotide 290 g po od. KEY RESULTS: Linaclotide reduced the change in pH across the ICJ (-2.4 ± 0.2 vs -2.1 ± 0.4, P = 0.01) as a function of a relative alkalinization of the cecum (5.2 ± 0.2 vs 5.5 ± 0.3, P = 0.02). Linaclotide accelerated colonic transit time (2650 minutes (2171-4038) vs. 1757 (112-3011), P = 0.02), increased colonic log motility index (15 ± 1.8 vs. 16.5 ± 1.8, P = 0.004) but had no effect of gastric emptying or small bowel transit. Change in pH across the ICJ correlated with improvement in symptom intensity, unpleasantness, and visceral sensitivity index (r = 0.62, P = 0.03, r = 0.63, P = 0.02, r = 0.62, P = 0.02) and with increases in BSFS type and SBM (r = 0.9, P < 0.0001, r = 0.6, P = 0.02). CONCLUSIONS & INFERENCES: Linaclotide's effects are confined to the colon where it increases cecal pH, potentially representing a reduction in cecal fermentation and accelerates colonic motility.


Assuntos
Ceco/efeitos dos fármacos , Agonistas da Guanilil Ciclase C/uso terapêutico , Concentração de Íons de Hidrogênio/efeitos dos fármacos , Síndrome do Intestino Irritável/tratamento farmacológico , Peptídeos/uso terapêutico , Adulto , Ceco/química , Ceco/fisiopatologia , Colo/efeitos dos fármacos , Constipação Intestinal/tratamento farmacológico , Feminino , Motilidade Gastrointestinal/efeitos dos fármacos , Trânsito Gastrointestinal/efeitos dos fármacos , Humanos , Valva Ileocecal/química , Valva Ileocecal/efeitos dos fármacos , Valva Ileocecal/fisiopatologia , Síndrome do Intestino Irritável/fisiopatologia , Masculino , Pessoa de Meia-Idade
14.
J Pharmacol Exp Ther ; 368(1): 116-124, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30377215

RESUMO

The gastrointestinal (GI) prokinetic effects of ghrelin occur through direct peripheral effects on ghrelin receptors within the enteric nervous system and via the ghrelin receptor on the vagus nerve, which activate a centrally mediated mechanism. However, the relative contribution of peripheral versus central effects to the overall prokinetic effect of ghrelin agonists requires further investigation. Here, we investigated the central versus peripheral prokinetic effect of ghrelin by using two novel ghrelin agonists: HM01 (N'-[(1S)-1-(2,3-dichloro-4-methoxyphenyl)ethyl]-N-methyl-N-[1,3,3-trimethyl-(4R)-piperidyl]-urea HCL) with high brain penetration compared with HM02 (N'-[(1S)-1-(2,3-dichloro-4-methoxyphenyl)ethyl]-N-hydroxy-N-(1-methyl-4-piperidinyl)-urea), a more peripherally acting ghrelin agonist. The pharmacokinetic profiles of both ghrelin agonists were evaluated after intravenous and oral administration in rats. The efficacy of HM01 and HM02 was assessed in a rat model of postoperative ileus (POI) induced by abdominal surgery and in a rodent defecation assay. Pharmacokinetic results in our models confirmed that HM01, but not HM02, was a brain-penetrant ghrelin agonist. Administration of either HM01 or HM02 reversed the delayed upper and lower gastrointestinal transit induced by abdominal surgery to levels resembling the non-POI controls. In the defecation test, HM01, but not HM02, significantly increased the weight of fecal pellets. Our findings suggest that, in a rodent model of POI, synthetic ghrelin agonists stimulate GI transit through a peripheral site of action. However, in the defecation assay, our data suggest that a ghrelin-mediated mechanism is located at a central site. Taken together, a ghrelin agonist with both central and peripheral prokinetic activity may show therapeutic potential to treat delayed GI transit disorders.


Assuntos
Materiais Biomiméticos/administração & dosagem , Trânsito Gastrointestinal/fisiologia , Grelina/administração & dosagem , Grelina/agonistas , Piperidinas/administração & dosagem , Administração Intravenosa , Administração Oral , Animais , Relação Dose-Resposta a Droga , Motilidade Gastrointestinal/efeitos dos fármacos , Motilidade Gastrointestinal/fisiologia , Trânsito Gastrointestinal/efeitos dos fármacos , Masculino , Ratos , Ratos Sprague-Dawley
15.
Am J Physiol Gastrointest Liver Physiol ; 316(3): G332-G337, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30520691

RESUMO

Dietary fat, and particularly fatty acids (FAs) from hydrolyzed triglycerides (TGs), reduces appetite, whereas paradoxically, a high-fat diet leads to excess calorie intake. We therefore hypothesized that the appetite-regulating effects of FAs are perturbed in obesity. Ten men with severe obesity [median body mass index (BMI) of 51.0 kg/m2 (range of 47.9-69.0)] and 10 men without obesity [BMI of 24.6 kg/m2 (range of 21.7-26.8)] were recruited for a double-blind randomized crossover study. On two occasions, participants were given isocaloric (2,660 kJ) and isovolemic (80 ml) loads of either oleic acid (long-chain FA) or olive oil (TG) containing radiolabeled lipid and water markers. Postload scintigraphy, blood sampling, and assessment of appetite were performed for 10 h, after which an ad libitum meal was served. Compared with olive oil, oleic acid slowed gastric mean emptying time (GMET) for lipids ( P < 0.001), accelerated orocoecal transit time (OCTT; P = 0.005), increased postload cholecystokinin section ( P < 0.001), and suppressed ad libitum energy intake ( P = 0.028) in men with severe obesity, and similar effects were seen in the nonobese group (no group × lipid interactions). However, independent of lipid loads, GMET and OCTT were slower (GMETlipid P = 0.046; GMETwater P = 0.003; OCTT P = 0.001), and basal and postload secretion of glucagon-like peptide-1 (GLP-1) was attenuated ( P = 0.045 and P = 0.048, respectively) in men with severe obesity compared with men without obesity. We conclude that the more potent appetite-regulating effects of oleic acid versus olive oil are unimpaired in men with severe obesity. However, regardless of lipid formulations, severe obesity is associated with slowed gastrointestinal transit and attenuated GLP-1 secretion. NEW & NOTEWORTHY Orally ingested fatty acids more efficiently reduce appetite and energy intake than triglycerides also in men with severe obesity. Men with severe obesity have delayed gastrointestinal transit and attenuated early gut hormone responses after an oral lipid load compared with men without obesity.


Assuntos
Ingestão de Energia/efeitos dos fármacos , Ácidos Graxos/sangue , Hormônios Gastrointestinais/sangue , Obesidade/complicações , Triglicerídeos/farmacologia , Adulto , Gorduras na Dieta , Ingestão de Energia/fisiologia , Esvaziamento Gástrico/efeitos dos fármacos , Trânsito Gastrointestinal/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Triglicerídeos/sangue
16.
An Acad Bras Cienc ; 91(1): e20170932, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30569966

RESUMO

This study investigated the effects of the ethanolic extract from the bark of Combretum leprosum (ECL) on intestinal transit and castor-oil induced diarrhea in mice. The oral administration of ECL (750 and 1000 mg/kg) slowed intestinal transit (ID50 of 455 mg/kg). The ECL (250-1000 mg/kg) reduced castor-oil induced diarrhea, in a time- and dose-dependent manner (p < 0.05). To determine if antidiarrheal effect of ECL involves α2-adrenergic or opioid receptor activation, the mice were pretreated with antagonists of these receptors, yohimbine or naloxone respectively. None of these drugs inhibited the antidiarrheal effect of ECL. To test if antidiarrheal effect of ECL is due to an antisecretory action, we realized the enteropooling assay on rats. The ECL increased bowel content and did not inhibit intestinal fluid secretion increase induced by misoprostol (100 µg/kg, s.c.). To determine if antimotility effect of ECL is due to a reduction on gastric motility, we realized the organ bath assay in the rat fundus stomach. Isotonic recordings show that the carbachol /KCl - induced contraction was not reversed by the addition of ECL. In conclusion, our results suggest that ECL contains antidiarrheal compounds and these compounds could induce a reduction of intestinal tract motility.


Assuntos
Antidiarreicos/uso terapêutico , Combretum/química , Diarreia/tratamento farmacológico , Extratos Vegetais/uso terapêutico , Animais , Antidiarreicos/farmacologia , Óleo de Rícino , Diarreia/etiologia , Feminino , Trânsito Gastrointestinal/efeitos dos fármacos , Secreções Intestinais/efeitos dos fármacos , Camundongos , Extratos Vegetais/farmacologia , Distribuição Aleatória , Ratos Wistar , Receptores Adrenérgicos alfa/efeitos dos fármacos , Receptores Opioides/efeitos dos fármacos , Reprodutibilidade dos Testes , Fatores de Tempo , Resultado do Tratamento
17.
Indian J Gastroenterol ; 37(5): 416-423, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30406392

RESUMO

OBJECTIVE: Gut microbe-derived methane may slow colon transit causing chronic constipation (CC). Effect of rifaximin on breath methane and slow-transit CC was evaluated. METHOD: Bristol stool form, frequency, colon transit time (CTT), and breath methane were evaluated in 23 patients with CC (10 patients with constipation-predominant irritable bowel syndrome [IBS-C], 13 functional constipation, Rome III) and m-ethane production compared with 68 non-constipating IBS. Methane-producing CC (basal ≥ 10 PPM and/or post-lactulose rise by > 10 PPM) was randomized (double-blind) to rifaximin (400-mg thrice/day, 2-weeks) or placebo. Stool forms, frequency, breath methane, and CTT were recorded afterward. RESULTS: CC patients tended to be methane producer more often (13/23 [56.5%] vs. 25/68 [36.5%], p = 0.07) and had greater area under curve (AUC) for methane (2415 [435-23,580] vs. 1335 [0-6562.5], p = 0.02) than non-constipating IBS. Methane producers (8/13 [61.5%]) and 5/10 (50%) non-producers had abnormal CTT (marker retention: 36-h, 53 [0-60] vs. 19 [8-56], p = 0.06; 60-h, 16 [0-57] vs. 13 [3-56], p = 0.877). Six and 7/13 methane producers were randomized to rifaximin and placebo, respectively. Rifaximin reduced AUC for methane more (6697.5 [1777.5-23,580] vs. 2617.5 [562.5-19,867.5], p = 0.005) than placebo (3945 [2415-12,952.5] vs. 3720 [502.5-9210], p = 0.118) at 1 month. CTT normalized in 4/6 (66.7%) on rifaximin (36-h retention, 54 [44-57] vs. 36 [23-60], p = 0.05; 60-h, 45 [3-57] vs. 14 [11-51], p = 0.09) but none on placebo (p = 0.02) (36-h, 31 [0-60] vs. 25 [0-45], p = 0.078; 60-h, 6 [0-54] vs. 12 [0-28], p = 0.2). Weekly stool frequency (3 [1-9] and 7 [1-14], p = 0.05) and forms improved with rifaximin than placebo. CONCLUSION: Rifaximin improves CC by altering methane production and colon transit. TRIAL REGISTRATION: Clinical Trial Registry, India: REF/2012/01/003216 ᅟ ᅟ.


Assuntos
Constipação Intestinal/tratamento farmacológico , Fármacos Gastrointestinais/farmacologia , Trânsito Gastrointestinal/efeitos dos fármacos , Metano/metabolismo , Rifaximina/farmacologia , Adolescente , Adulto , Idoso , Testes Respiratórios , Colo/fisiopatologia , Constipação Intestinal/fisiopatologia , Método Duplo-Cego , Fezes/química , Feminino , Humanos , Lactulose/metabolismo , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Resultado do Tratamento , Adulto Jovem
18.
J Nutr Sci Vitaminol (Tokyo) ; 64(5): 357-366, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30381626

RESUMO

The effects of fructo-oligosaccharides (FOS) on gut-barrier function are still controversial in human and animal studies. Diet conditions would be a major factor for the controversy in animal studies. We fed rats a semi-purified (SP) or a non-purified diet (NP) with or without FOS (60 g/kg diet) for 9 (experiment 1) or 10 d (experiment 2). We assessed microbial fermentation, gut permeability, and inflammatory responses in the cecum (experiment 1), and mucus layer in the cecum, intestinal transit time and microbiota composition (experiment 2). FOS supplementation induced a very acidic fermentation due to the accumulation of lactate and succinate in SP, while short-chain fatty acids were major products in NP. Gut permeability estimated by urinary chromium-EDTA excretion, bacterial translocation into mesenteric lymph nodes, myeloperoxidase activity, and expressions of the inflammatory cytokine genes in the cecal mucosa were greater in SP+FOS than in SP, but these alterations were not observed between NP and NP+FOS (experiment 1). FOS supplementation destroyed the mucus layer on the epithelial surface in SP, but not in NP. Intestinal transit time was 3-fold longer in SP+FOS than in SP, but this was not the case between NP and NP+FOS. Lower species richness of cecal microbiota was manifest solely in SP+FOS (experiment 2). These factors suggest that impact of FOS on gut permeability and inflammatory responses in the cecal mucosa quite differs between SP and NP. Increased gut permeability in SP+FOS could be evoked by the disruption of the mucus layer due to stasis of the very acidic luminal contents.


Assuntos
Ração Animal , Ceco/efeitos dos fármacos , Dieta , Microbioma Gastrointestinal/efeitos dos fármacos , Inflamação , Mucosa Intestinal/efeitos dos fármacos , Oligossacarídeos/farmacologia , Animais , Translocação Bacteriana/efeitos dos fármacos , Ceco/metabolismo , Ceco/microbiologia , Ceco/patologia , Cromo/urina , Citocinas/metabolismo , Digestão , Ácido Edético/urina , Ácidos Graxos Voláteis/metabolismo , Fermentação , Frutose/farmacologia , Trânsito Gastrointestinal/efeitos dos fármacos , Inflamação/etiologia , Inflamação/metabolismo , Inflamação/prevenção & controle , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiologia , Mucosa Intestinal/patologia , Ácido Láctico/metabolismo , Masculino , Permeabilidade , Peroxidase/metabolismo , Prebióticos , Ratos Wistar , Ácido Succínico/metabolismo
19.
Nutrients ; 10(10)2018 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-30322081

RESUMO

Fortified milk drinks are predominantly manufactured from bovine (cow) sources. Alternative formulations include those prepared with hydrolysed bovine milk proteins or from alternate bovidae species, such as caprine (goat) milk. Currently, there is little data on protein digestive and metabolic responses following ingestion of fortified milk drinks. To examine the digestive and metabolic responses to commercially-available fortified milks, young adults (n = 15 males: 15 females), in a randomised sequence, ingested isonitrogenous quantities of whole cow-protein (WC), whole goat-protein (WG), or partially-hydrolysed whey cow-protein (HC), commercial fortified milks. Plasma amino acid (AA) and hormonal responses were measured at baseline and again at 5 h after ingestion. Paracetamol recovery, breath hydrogen, and subjective digestive responses were also measured. Postprandial plasma AA was similar between WC and WG, while AA appearance was suppressed with HC. Following HC, there was a negative incremental AUC in plasma branched-chain AAs. Further, HC had delayed gastric emptying, increased transit time, and led to exaggerated insulin and GLP-1 responses, in comparison to whole protein formulas. Overall, WC and WG had similar protein and digestive responses with no differences in digestive comfort. Contrastingly, HC led to delayed gastric emptying, attenuated AA appearance, and a heightened circulating insulin response.


Assuntos
Proteínas na Dieta/metabolismo , Digestão , Alimentos Fortificados , Leite/química , Período Pós-Prandial , Hidrolisados de Proteína/metabolismo , Proteínas do Soro do Leite/metabolismo , Adolescente , Adulto , Aminoácidos/sangue , Animais , Bebidas , Glicemia/metabolismo , Bovinos , Feminino , Esvaziamento Gástrico/efeitos dos fármacos , Trânsito Gastrointestinal/efeitos dos fármacos , Peptídeo 1 Semelhante ao Glucagon/sangue , Cabras , Humanos , Insulina/sangue , Masculino , Proteínas do Leite/metabolismo , Adulto Jovem
20.
J Pharmacol Exp Ther ; 367(3): 551-563, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30275151

RESUMO

Opioid-based therapies remain a mainstay for chronic pain management, but unwanted side effects limit therapeutic use. We compared efficacies of brain-permeant and -impermeant inhibitors of fatty acid amide hydrolase (FAAH) in suppressing neuropathic pain induced by the chemotherapeutic agent paclitaxel. Paclitaxel produced mechanical and cold allodynia without altering nestlet shredding or marble burying behaviors. We compared FAAH inhibitors that differ in their ability to penetrate the central nervous system for antiallodynic efficacy, pharmacological specificity, and synergism with the opioid analgesic morphine. (3'-(aminocarbonyl)[1,1'-biphenyl]- 3-yl)-cyclohexylcarbamate (URB597), a brain-permeant FAAH inhibitor, attenuated paclitaxel-induced allodynia via cannabinoid receptor 1 (CB1) and cannabinoid receptor 2 (CB2) mechanisms. URB937, a brain-impermeant FAAH inhibitor, suppressed paclitaxel-induced allodynia through a CB1 mechanism only. 5-[4-(4-cyano-1-butyn-1-yl)phenyl]-1-(2,4-dichlorophenyl)-N-(1,1-dioxido-4-thiomorpholinyl)-4-methyl-1H-pyrazole-3-carboxamide (AM6545), a peripherally restricted CB1 antagonist, fully reversed the antiallodynic efficacy of N-cyclohexyl-carbamic acid, 3'-(aminocarbonyl)-6-hydroxy[1,1'- biphenyl]-3-yl ester (URB937) but only partially reversed that of URB597. Thus, URB937 suppressed paclitaxel-induced allodynia through a mechanism that was dependent upon peripheral CB1 receptor activation only. Antiallodynic effects of both FAAH inhibitors were reversed by N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (AM251). Antiallodynic effects of URB597, but not URB937, were reversed by 6-iodo-2-methyl-1-[2-(4-morpholinyl)ethyl]-1H-indol-3-yl](4-methoxyphenyl)methanone (AM630). Isobolographic analysis revealed synergistic interactions between morphine and either URB597 or URB937 in reducing paclitaxel-induced allodynia. A leftward shift in the dose-response curve of morphine antinociception was observed when morphine was coadministered with either URB597 or URB937, consistent with morphine sparing. However, neither URB937 nor URB597 enhanced morphine-induced deficits in colonic transit. Thus, our findings suggest that FAAH inhibition may represent a therapeutic avenue to reduce the overall amount of opioid needed for treating neuropathic pain with potential to reduce unwanted side effects that accompany opioid administration.


Assuntos
Amidoidrolases/metabolismo , Analgésicos Opioides/farmacologia , Antineoplásicos/efeitos adversos , Encéfalo/efeitos dos fármacos , Trânsito Gastrointestinal/efeitos dos fármacos , Morfina/farmacologia , Nociceptividade/efeitos dos fármacos , Animais , Ácidos Araquidônicos/farmacologia , Benzamidas/farmacologia , Encéfalo/metabolismo , Canabinoides/farmacologia , Carbamatos/farmacologia , Hiperalgesia/tratamento farmacológico , Hiperalgesia/metabolismo , Indóis/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Morfolinas/farmacologia , Neuralgia/tratamento farmacológico , Neuralgia/metabolismo , Piperidinas/farmacologia , Pirazóis/farmacologia , Receptor CB1 de Canabinoide/metabolismo , Receptor CB2 de Canabinoide/metabolismo
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