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1.
Am J Surg ; 234: 162-171, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-38724293

RESUMEN

BACKGROUND: Felcisetrag (5-hydroxytryptamine-4 receptor [5-HT4] agonist) is under investigation as prophylaxis or active treatment for accelerating resolution of gastrointestinal function post-surgery. METHODS: Phase 2, randomized, placebo-controlled, parallel five-arm, double-blind, multicenter study (NCT03827655) in 209 adults undergoing open or laparoscopic-assisted bowel surgery. Patients received intravenous placebo, felcisetrag 0.1 mg/100 â€‹mL or 0.5 mg/100 â€‹mL pre-surgery only, or pre-surgery and daily post-surgery until return of gastrointestinal function or for up to 10 days. PRIMARY ENDPOINT: time to recovery of gastrointestinal function. RESULTS: Median time to recovery of gastrointestinal function was 2.6 days for both felcisetrag 0.5 â€‹mg daily and 0.5 â€‹mg pre-surgery versus 1.9 days for placebo (p â€‹> â€‹0.05). There were no notable differences in adverse events between treatment arms. CONCLUSIONS: Felcisetrag was well tolerated with no new safety concerns. However, no clinically meaningful difference in time to recovery of gastrointestinal function versus placebo was observed. Further investigation of the utility of 5-HT4 agonists in complicated, open abdominal surgeries may be warranted.


Asunto(s)
Complicaciones Posoperatorias , Agonistas del Receptor de Serotonina 5-HT4 , Humanos , Método Doble Ciego , Masculino , Persona de Mediana Edad , Agonistas del Receptor de Serotonina 5-HT4/uso terapéutico , Femenino , Complicaciones Posoperatorias/prevención & control , Adulto , Anciano , Enfermedades Gastrointestinales/cirugía , Procedimientos Quirúrgicos del Sistema Digestivo/efectos adversos , Laparoscopía/efectos adversos , Recuperación de la Función/efectos de los fármacos , Resultado del Tratamiento
2.
Am Surg ; 90(6): 1682-1701, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38530772

RESUMEN

BACKGROUND: Prolonged postoperative ileus (PPOI) contributes to morbidity and prolonged hospitalization. Prucalopride, a selective 5-hydroxytryptamine receptor agonist, may enhance bowel motility. This review assesses whether the perioperative use of prucalopride compared to placebo is associated with accelerated return of bowel function post gastrointestinal (GI) surgery. METHODS: OVID, CENTRAL, and EMBASE were searched as of January 2024 to identify randomized controlled trials (RCTs) comparing prucalopride and placebo for prevention of PPOI in adult patients undergoing GI surgery. The primary outcomes were time to stool, time to flatus, and time to oral tolerance. The secondary outcomes were incidence of PPOI, length of stay (LOS), postoperative complications, adverse events, and overall costs. The Cochrane risk of bias tool for randomized trials and the Grading of Recommendations, Assessment, Development, and Evaluations framework were used. An inverse variance random effects model was used. RESULTS: From 174 citations, 3 RCTs with 139 patients in each treatment group were included. Patients underwent a variety of GI surgeries. Patients treated with prucalopride had a decreased time to stool (mean difference 36.82 hours, 95% CI 59.4 to 14.24 hours lower, I2 = 62%, low certainty evidence). Other outcomes were not statistically significantly different (very low certainty evidence). Postoperative complications and adverse events could not be meta-analyzed due to heterogeneity; yet individual studies suggested no significant differences (very low certainty evidence). DISCUSSION: Current RCT evidence suggests that prucalopride may enhance postoperative return of bowel function. Larger RCTs assessing patient important outcomes and associated costs are needed before routine use of this agent.


Asunto(s)
Benzofuranos , Procedimientos Quirúrgicos del Sistema Digestivo , Ileus , Complicaciones Posoperatorias , Ensayos Clínicos Controlados Aleatorios como Asunto , Humanos , Benzofuranos/uso terapéutico , Procedimientos Quirúrgicos del Sistema Digestivo/efectos adversos , Motilidad Gastrointestinal/efectos de los fármacos , Ileus/prevención & control , Ileus/etiología , Tiempo de Internación/estadística & datos numéricos , Complicaciones Posoperatorias/prevención & control , Agonistas del Receptor de Serotonina 5-HT4/uso terapéutico
3.
Clin Transl Gastroenterol ; 15(5): e00687, 2024 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-38357940

RESUMEN

INTRODUCTION: This real-world US-based claims study compared constipation-related symptoms and complications 6 months before and after prucalopride initiation in adults with chronic idiopathic constipation (CIC). METHODS: This observational, retrospective cohort analysis used the IBM MarketScan Commercial Claims and Encounters Database and the Medicare Supplemental Database (January 2015-June 2020). Prucalopride-treated patients (≥18 years old) who had ≥1 constipation-related International Classification of Diseases, Tenth Revision, Clinical Modification ( ICD-10-CM ) diagnosis code during the baseline or study period were included. The proportions of patients with constipation-related symptoms (abdominal pain, abdominal distension [gaseous], incomplete defecation, and nausea) and constipation-related complications (anal fissure and fistula, intestinal obstruction, rectal prolapse, hemorrhoids, perianal venous thrombosis, perianal/perirectal abscess, and rectal bleeding) were examined. Constipation-related symptoms and complications were identified using ICD-10-CM , ICD-10 - Procedure Coding System , or Current Procedural Terminology codes. Data were stratified by age (overall, 18-64 years, and ≥65 years). RESULTS: This study included 690 patients: The mean (SD) patient age was 48.0 (14.7) years, and 87.5% were women. The proportions of patients overall with constipation-related symptoms decreased 6 months after prucalopride initiation (abdominal pain [50.4% vs 33.3%, P < 0.001]; abdominal distension [gaseous] [23.9% vs 13.3%, P < 0.001]; and nausea [22.6% vs 17.7%, P < 0.01]; no improvements observed for incomplete defecation). Similarly, the proportions of patients overall with constipation-related complications decreased 6 months after prucalopride initiation (intestinal obstruction [4.9% vs 2.0%, P < 0.001]; hemorrhoids [10.7% vs 7.0%, P < 0.05]; and rectal bleeding [4.1% vs 1.7%, P < 0.05]). DISCUSSION: This study suggests that prucalopride may be associated with improved constipation-related symptoms and complications 6 months after treatment initiation.


Asunto(s)
Benzofuranos , Estreñimiento , Humanos , Estreñimiento/tratamiento farmacológico , Benzofuranos/uso terapéutico , Benzofuranos/efectos adversos , Femenino , Masculino , Persona de Mediana Edad , Adulto , Estados Unidos/epidemiología , Estudios Retrospectivos , Enfermedad Crónica , Anciano , Adulto Joven , Resultado del Tratamiento , Adolescente , Dolor Abdominal/tratamiento farmacológico , Dolor Abdominal/etiología , Agonistas del Receptor de Serotonina 5-HT4/uso terapéutico , Agonistas del Receptor de Serotonina 5-HT4/efectos adversos , Agonistas del Receptor de Serotonina 5-HT4/administración & dosificación
4.
Am J Gastroenterol ; 118(6): 955-960, 2023 06 01.
Artículo en Inglés | MEDLINE | ID: mdl-36927957

RESUMEN

Prokinetic agents, specifically 5-hydroxytryptamine type 4 (5-HT 4 ) receptor agonists, have been shown to provide relief in chronic idiopathic constipation (CIC). The first-generation 5-HT 4 agonists were initially withdrawn from use owing to associations with serious cardiovascular (CV) events. This review summarizes CV safety data for prucalopride, a high-affinity 5-HT 4 agonist approved in the United States in 2018 for adults with CIC. No significant effects of prucalopride on CV safety were observed in animal models or early-phase clinical studies, including a thorough QT study at therapeutic (2 mg) or supratherapeutic (10 mg) doses. Among 1,750 patients with CIC who received prucalopride (2-4 mg) in 5 phase 3 studies, no trends in CV adverse events, electrocardiogram parameters, or blood pressure were documented; ≤1.0%-2.0% of patients had prolonged QT interval corrected for heart rate (HR) using Fridericia formula after placebo or prucalopride treatment, and low HR occurred in ≤6.1% and ≤3.3% of these patients, respectively. In two 24-month observational studies among 2,468 patients, changes in electrocardiogram parameters over time were minor, except at occasional time points when significant changes from baseline were reported for HR or QT interval. In a real-world European CV safety study among 35,087 patients (prucalopride, 5,715; polyethylene glycol 3350 [PEG3350], 29,372), results were consistent for no evidence of increased risk of major adverse CV events among patients treated with prucalopride vs PEG3350 (incidence rate ratio = 0.64; 95% confidence interval 0.36-1.14). Studies to date have not raised concerns regarding the impact of prucalopride treatment on CV parameters.


Asunto(s)
Laxativos , Serotonina , Humanos , Laxativos/efectos adversos , Serotonina/uso terapéutico , Estreñimiento/inducido químicamente , Estreñimiento/tratamiento farmacológico , Agonistas del Receptor de Serotonina 5-HT4/uso terapéutico , Enfermedad Crónica , Resultado del Tratamiento
5.
Adv Exp Med Biol ; 1383: 329-334, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36587170

RESUMEN

Because of their importance in the regulation of gut functions, several therapeutic targets involving serotonin-related proteins have been developed or repurposed to treat motility disorders, including serotonin transporter inhibitors, tryptophan hydroxylase blockers, 5-HT3 antagonists, and 5-HT4 agonists. This chapter focuses on our discovery of 5-HT4 receptors in the epithelial cells of the colon and our efforts to evaluate the effects of stimulating these receptors. 5-HT4 receptors appear to be expressed by all epithelial cells in the mouse colon, based on expression of a reporter gene driven by the 5-HT4 receptor promoter. Application of 5-HT4 agonists to the mucosal surface causes serotonin release from enterochromaffin cells, mucus secretion from goblet cells, and chloride secretion from enterocytes. Luminal administration of 5-HT4 agonists speeds up colonic motility and suppresses distention-induced nociceptive responses. Luminal administration of 5-HT4 agonists also decreases the development of, and improves recovery from, experimental colitis. Recent studies determined that the prokinetic actions of minimally absorbable 5-HT4 agonists are just as effective as absorbable compounds. Collectively, these findings indicate that targeting epithelial receptors with non-absorbable 5-HT4 agonists could offer a safe and effective strategy for treating constipation and colitis.


Asunto(s)
Colitis , Serotonina , Ratones , Animales , Serotonina/metabolismo , Agonistas del Receptor de Serotonina 5-HT4/farmacología , Agonistas del Receptor de Serotonina 5-HT4/uso terapéutico , Agonistas del Receptor de Serotonina 5-HT4/metabolismo , Estreñimiento/tratamiento farmacológico , Receptores de Serotonina 5-HT4/metabolismo , Colon/metabolismo , Colitis/inducido químicamente , Colitis/tratamiento farmacológico , Inflamación/metabolismo , Motilidad Gastrointestinal/fisiología
7.
J Gastroenterol Hepatol ; 36(2): 362-366, 2021 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-32483847

RESUMEN

BACKGROUND AND AIM: Paralytic ileus is a common intestinal dysfunction in critically ill patients, which results in complications and poor hospital outcomes. There are still no established effective medications, except correcting the primary causes and prokinetics trial, which have limited efficacy and potential adverse events. This study aims to evaluate the efficacy of prucalopride on paralytic ileus in critically ill patients. METHODS: A randomized, double-blind, placebo-controlled trial of five consecutive days treatment periods was conducted. Critically ill patients with paralytic ileus were included. The primary endpoint was the improvement of bowel dilatation on plain abdominal radiography. The secondary endpoint was the change of abdominal circumference. RESULTS: Twenty patients were consecutively enrolled in the study. There was no significant difference in baseline characteristics of patients. The common causes of hospitalization were infection and respiratory problems. The maximum large bowel diameters dramatically decreased in prucalopride group and reached maximum point on the third day after intervention when compared with placebo (-2.1 [± 1.8] vs 0.3 [± 1.5] cm, P = 0.01). The maximum small bowel diameters were noticeably less decreased and were not significantly different when compared with placebo. The abdominal circumferences notably decreased and significantly diverged from placebo on the third day. CONCLUSIONS: Prucalopride was an effective enterokinetic agent to improve non-severe inflammatory/ischemic bowel conditions related paralytic ileus in critically ill patients. Its effect was predominant on large intestine but could not be well demonstrated on small bowel in this study. Future study or concomitant other prokinetics for upper gut motility should be further evaluated.


Asunto(s)
Benzofuranos/uso terapéutico , Enfermedad Crítica , Seudoobstrucción Intestinal/tratamiento farmacológico , Método Doble Ciego , Femenino , Humanos , Seudoobstrucción Intestinal/patología , Intestino Grueso/patología , Intestino Delgado/patología , Masculino , Persona de Mediana Edad , Proyectos Piloto , Agonistas del Receptor de Serotonina 5-HT4/uso terapéutico , Resultado del Tratamiento
8.
Neurogastroenterol Motil ; 33(4): e14026, 2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-33185015

RESUMEN

BACKGROUND: 5-HT4 receptor (5-HT4 R) agonists exert prokinetic actions in the GI tract, but non-selective actions and potential for stimulation of non-target 5-HT4 Rs have limited their use. Since 5-HT4 Rs are expressed in the colonic epithelium and their stimulation accelerates colonic propulsion in vitro, we tested whether luminally acting 5-HT4 R agonists promote intestinal motility. METHODS: Non-absorbed 5-HT4 R agonists, based on prucalopride and naronapride, were assessed for potency at the 5-HT4 R in vitro, and for tissue and serum distribution in vivo in mice. In vivo assessment of prokinetic potential included whole gut transit, colonic motility, fecal output, and fecal water content. Colonic motility was also studied ex vivo in mice treated in vivo. Immunofluorescence was used to evaluate receptor distribution in human intestinal mucosa. KEY RESULTS: Pharmacological screening demonstrated selectivity and potency of test agonists for 5-HT4 R. Bioavailability studies showed negligible serum detection. Gavage of agonists caused faster whole gut transit and colonic motility, increased fecal output, and elevated fecal water content. Prokinetic actions were blocked by a 5-HT4 R antagonist and were not detected in 5-HT4 R knockout mice. Agonist administration promoted motility in models of constipation. Evaluation of motility patterns ex vivo revealed enhanced contractility in the middle and distal colon. Immunoreactivity for 5-HT4 R is present in the epithelial layer of the human small and large intestines. CONCLUSIONS AND INFERENCES: These findings demonstrated that stimulation of epithelial 5-HT4 Rs can potentiate propulsive motility and support the concept that mucosal 5-HT4 Rs could represent a safe and effective therapeutic target for the treatment of constipation.


Asunto(s)
Colon/fisiología , Motilidad Gastrointestinal/fisiología , Mucosa Intestinal/fisiología , Receptores de Serotonina 5-HT4/fisiología , Agonistas del Receptor de Serotonina 5-HT4/farmacología , Animales , Células CHO , Colon/efectos de los fármacos , Estreñimiento/tratamiento farmacológico , Estreñimiento/fisiopatología , Cricetinae , Cricetulus , Motilidad Gastrointestinal/efectos de los fármacos , Humanos , Mucosa Intestinal/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Agonistas del Receptor de Serotonina 5-HT4/uso terapéutico
9.
Psychol Med ; 51(7): 1111-1120, 2021 05.
Artículo en Inglés | MEDLINE | ID: mdl-32241310

RESUMEN

Animal experimental studies suggest that 5-HT4 receptor activation holds promise as a novel target for the treatment of depression and cognitive impairment. 5-HT4 receptors are post-synaptic receptors that are located in striatal and limbic areas known to be involved in cognition and mood. Consistent with this, 5-HT4 receptor agonists produce rapid antidepressant effects in a number of animal models of depression, and pro-cognitive effects in tasks of learning and memory. These effects are accompanied by molecular changes, such as the increased expression of neuroplasticity-related proteins that are typical of clinically useful antidepressant drugs. Intriguingly, these antidepressant-like effects have a fast onset of their action, raising the possibility that 5-HT4 receptor agonists may be a particularly useful augmentation strategy in the early stages of SSRI treatment. Until recently, the translation of these effects to humans has been challenging. Here, we review the evidence from animal studies that the 5-HT4 receptor is a promising target for the treatment of depression and cognitive disorders, and outline a potential pathway for the efficient and cost-effective translation of these effects into humans and, ultimately, to the clinic.


Asunto(s)
Antidepresivos/uso terapéutico , Depresión/tratamiento farmacológico , Receptores de Serotonina 5-HT4/metabolismo , Agonistas del Receptor de Serotonina 5-HT4/uso terapéutico , Animales , Ratones , Inhibidores Selectivos de la Recaptación de Serotonina/uso terapéutico
10.
Neurogastroenterol Motil ; 33(5): e14046, 2021 05.
Artículo en Inglés | MEDLINE | ID: mdl-33252179

RESUMEN

BACKGROUND: Postoperative ileus is common and is a major clinical problem. It has been widely studied in patients and in experimental models in laboratory animals. A wide variety of treatments have been tested to prevent or modify the course of this disorder. PURPOSE: This review draws together information on animal studies of ileus with studies on human patients. It summarizes some of the conceptual advances made in understanding the mechanisms that underlie paralytic ileus. The treatments that have been tested in human subjects (both pharmacological and non-pharmacological) and their efficacy are summarized and graded consistent with current clinical guidelines. The review is not intended to provide a comprehensive overview of ileus, but rather a general understanding of the major clinical problems associated with it, how animal models have been useful to elucidate key mechanisms and, finally, some perspectives from both scientists and clinicians as to how we may move forward with this debilitating yet common condition.


Asunto(s)
Sistema Nervioso Entérico/fisiopatología , Motilidad Gastrointestinal/fisiología , Ileus/fisiopatología , Complicaciones Posoperatorias/fisiopatología , Sistema Nervioso Simpático/fisiopatología , Anestesia Epidural , Animales , Benzofuranos/uso terapéutico , Goma de Mascar , Colinérgicos/uso terapéutico , Medios de Contraste/uso terapéutico , Inhibidores de la Ciclooxigenasa/uso terapéutico , Diatrizoato de Meglumina/uso terapéutico , Procedimientos Quirúrgicos del Sistema Digestivo/métodos , Recuperación Mejorada Después de la Cirugía , Nutrición Enteral , Fluidoterapia , Fármacos Gastrointestinales/uso terapéutico , Ghrelina/uso terapéutico , Humanos , Ileus/inmunología , Ileus/prevención & control , Ileus/terapia , Inflamación/inmunología , Seudoobstrucción Intestinal/inmunología , Seudoobstrucción Intestinal/fisiopatología , Seudoobstrucción Intestinal/prevención & control , Seudoobstrucción Intestinal/terapia , Intubación Gastrointestinal , Laparoscopía , Mastocitos/inmunología , Piperidinas/uso terapéutico , Complicaciones Posoperatorias/inmunología , Complicaciones Posoperatorias/prevención & control , Complicaciones Posoperatorias/terapia , Agonistas del Receptor de Serotonina 5-HT4/uso terapéutico , Simpaticolíticos/uso terapéutico
11.
Neurogastroenterol Motil ; 33(1): e13958, 2021 01.
Artículo en Inglés | MEDLINE | ID: mdl-32743954

RESUMEN

BACKGROUND: Gastroparesis, defined by delayed gastric emptying in the absence of mechanical outlet obstruction, is a frequent neuropathic complication of diabetes mellitus, and effective treatments are lacking. Prucalopride is a pan-gut prokinetic with selective agonist effects on serotonin 5-HT4 receptors in the gut. This study aimed to assess the effect of prucalopride 4 mg daily on Gastroparesis Cardinal Symptom Index (GCSI), meal-related symptom score (MRSS), and gastric emptying rate in diabetic or connective tissue disease (CTD)-related gastroparesis patients. METHODS: This was a double-blind crossover trial of four-week treatment periods with prucalopride or placebo divided by two weeks of washout. GSCI, MRSS, gastric emptying scintigraphy, PAGI-SYM, and PAGI-QoL were assessed at baseline and the end of each treatment period. Daily bowel movement (BM) frequency and gastrointestinal symptoms were recorded in each period. KEY RESULTS: Fifteen gastroparesis patients (13 diabetic, 2 CTD) were enrolled. GCSI scores were lower than baseline but not different between treatment arms. MRSS scores over time or cumulative score were not significantly different between groups. Gastric emptying was more rapid in the prucalopride treatment period, with mean four-hour meal retention of 22 ± 6% in PRU period vs 40 ± 9% in the placebo period (P = 0.05). Weekly BM frequency was significantly higher in prucalopride than placebo periods (10.5 ± 1.8 vs 7.5 ± 0.8, P < 0.0001). Perception of weight loss was higher in patients on prucalopride. Analysis of diabetic gastroparesis (n = 13) population did not change the conclusions. CONCLUSION AND INFERENCE: Prucalopride at 4 mg accelerates gastric emptying and bowel movement frequency but does not appear to ameliorate gastroparesis or meal-related symptoms in this study.


Asunto(s)
Benzofuranos/uso terapéutico , Gastroparesia/tratamiento farmacológico , Agonistas del Receptor de Serotonina 5-HT4/uso terapéutico , Adulto , Estudios Cruzados , Complicaciones de la Diabetes/diagnóstico por imagen , Complicaciones de la Diabetes/tratamiento farmacológico , Complicaciones de la Diabetes/etiología , Complicaciones de la Diabetes/fisiopatología , Diabetes Mellitus Tipo 1/complicaciones , Diabetes Mellitus Tipo 2/complicaciones , Femenino , Vaciamiento Gástrico , Gastroparesia/diagnóstico por imagen , Gastroparesia/etiología , Gastroparesia/fisiopatología , Humanos , Masculino , Persona de Mediana Edad , Prolapso de la Válvula Mitral/complicaciones , Miopía/complicaciones , Proyectos Piloto , Calidad de Vida , Cintigrafía , Esclerodermia Sistémica/complicaciones , Enfermedades de la Piel/complicaciones , Resultado del Tratamiento
12.
Am J Emerg Med ; 38(12): 2625-2628, 2020 12.
Artículo en Inglés | MEDLINE | ID: mdl-33041133

RESUMEN

OBJECTIVE: Post dural puncture headache (PDPH) is a common complication in patients following diagnostic or therapeutic lumbar puncture, procedures requiring epidural access, and spinal surgery. Epidural blood patch (EBP), the gold standard for the treatment of this pathology requires training not provided to emergency physicians. In addition, the presence of concomitant pathology and abnormal laboratory values are contraindications to perform EBP. In presence of these limitations, we sought for a non-interventional management of PDPH utilizing high-flow oxygen and pro-serotonin agents. We reviewed the mechanism of action of this therapy METHODS: To illustrate our proposal, we report a series of twelve consecutive patients with PDPH treated with high-flow oxygen therapy at 12 L/min via a non-rebreathing mask and intravenous metoclopramide. RESULTS: All patients were treated with this conservative therapy, no adverse reactions were observed. After the intervention, the headache resolved without further indications for PDPH. CONCLUSION: Our series suggests that combining high-flow oxygen and pro-serotonin agents such metoclopramide in the ED might be a feasible option as effective as the invasive methods used in treating PDPH. This therapy appears to be efficient and to minimize risk, cost and side effects. It presents an easily accessible alternative that should be considered when PDPH is not a viable option.


Asunto(s)
Metoclopramida/uso terapéutico , Terapia por Inhalación de Oxígeno/métodos , Cefalea Pospunción de la Duramadre/terapia , Antagonistas del Receptor de Serotonina 5-HT3/uso terapéutico , Agonistas del Receptor de Serotonina 5-HT4/uso terapéutico , Adulto , Anciano , Tratamiento Conservador , Femenino , Humanos , Masculino , Persona de Mediana Edad , Resultado del Tratamiento
13.
Aliment Pharmacol Ther ; 52(3): 430-441, 2020 08.
Artículo en Inglés | MEDLINE | ID: mdl-32583907

RESUMEN

BACKGROUND: Agonists of 5-hydroxytryptamine 4 receptor are potential agents for irritable bowel syndrome with predominant constipation (IBS-C). However, only tegaserod has been approved for a very limited population in the US. AIM: To evaluate the efficacy and safety of minesapride in patients with Rome IV defined IBS-C. METHODS: A double-blind, placebo-controlled, dose-finding study was performed. Overall, 411 patients were randomised to receive minesapride at 10, 20 or 40 mg/d, or placebo for 12 weeks. The primary endpoint was Food and Drug Administration (FDA) composite endpoint (responder: a patient who reported an increase in one or more complete spontaneous bowel movements from baseline and improvement of ≥30% from baseline in weekly average of worst abdominal pain score, both in the same week for ≥6/12 weeks). RESULTS: The FDA composite responder rate was 13.6% (14/103) in the placebo group, 13.6% (14/103) in the 10 mg group, 19.2% (20/104) in the 20 mg group and 14.9% (15/101) in the 40 mg group, and no dose-response relationship was found. A greater percentage of minesapride 40 mg-treated patients than placebo-treated patients met both responder requirements for ≥9/12 weeks as the stricter composite evaluation (P < 0.05). Furthermore, minesapride 40 mg significantly increased SBM frequency compared with placebo (adjusted P < 0.001 at Week 12). The most common adverse event was mild diarrhoea. CONCLUSIONS: Minesapride was safe and well-tolerated. Although the primary endpoint was negative, minesapride 40 mg is likely to improve the stricter composite endpoint and SBM frequency. Japan Pharmaceutical Information Center Number: Japic CTI-163459.


Asunto(s)
Dolor Abdominal/tratamiento farmacológico , Estreñimiento/tratamiento farmacológico , Fármacos Gastrointestinales/uso terapéutico , Síndrome del Colon Irritable/tratamiento farmacológico , Morfolinas/uso terapéutico , Piperidinas/uso terapéutico , Agonistas del Receptor de Serotonina 5-HT4/uso terapéutico , Adulto , Diarrea/inducido químicamente , Método Doble Ciego , Femenino , Fármacos Gastrointestinales/efectos adversos , Humanos , Masculino , Persona de Mediana Edad , Morfolinas/efectos adversos , Piperidinas/efectos adversos , Agonistas del Receptor de Serotonina 5-HT4/efectos adversos , Resultado del Tratamiento , Adulto Joven
14.
Expert Opin Pharmacother ; 21(6): 701-707, 2020 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-32037901

RESUMEN

INTRODUCTION: Constipation is common in patients with Parkinson's disease (PD). Due to the considerable negative outcomes of constipation, significant efforts have been made to prevent and manage chronic constipation in these patients. AREAS COVERED: Herein, the authors review some of the known pathophysiological causes for slow gastrointestinal (GI) transit in PD patients and the different pharmacological options. All relevant clinical and experimental data found through online databases were included. Bulking agents, osmotic and stimulant laxatives, chloride channel activators, ghrelin agonists, 5-HT4 receptor agonists, and probiotics are some of the proposed medicinal agents. of the authors further review the evidence on alpha-synuclein and botulinum neurotoxin in these patients. It should be noted, however, that some of these interventions are required to be further validated. EXPERT OPINION: Reduction of GI transit and dysfunction of the anorectum is obvious in PD, affecting the incidence of constipation and thus, quality of life (QOL). Furthermore, due to an inadequate and delayed absorption of oral anti PD medications, dose adjustments and changes in the route of administration are recommended.


Asunto(s)
Estreñimiento/tratamiento farmacológico , Tránsito Gastrointestinal/efectos de los fármacos , Laxativos/uso terapéutico , Enfermedad de Parkinson/tratamiento farmacológico , Probióticos/uso terapéutico , Agonistas del Receptor de Serotonina 5-HT4/uso terapéutico , Enfermedad Crónica , Estreñimiento/complicaciones , Relación Dosis-Respuesta a Droga , Humanos , Enfermedad de Parkinson/complicaciones , Calidad de Vida
15.
Neuropharmacology ; 166: 107969, 2020 04.
Artículo en Inglés | MEDLINE | ID: mdl-31982703

RESUMEN

The latest estimates from world health organization suggest that more than 450 million people are suffering from depression and other psychiatric conditions. Of these, 50-60% have been reported to have progression of gut diseases. In the last two decades, researchers introduced incipient physiological roles for serotonin (5-HT) receptors (5-HTRs), suggesting their importance as a potential pharmacological target in various psychiatric and gut diseases. A growing body of evidence suggests that 5-HT systems affect the brain-gut axis in depressive patients, which leads to gut comorbidity. Recently, preclinical trials of 5-HT4R agonists and antagonists were promising as antipsychotic and prokinetic agents. In the current review, we address the possible pharmacological role and contribution of 5-HT4R in the pathophysiology of chronic depression and associated gut abnormalities. Physiologically, during depression episodes, centers of the sympathetic and parasympathetic nervous system couple together with neuroendocrine systems to alter the function of hypothalamic-pituitary-adrenal (HPA) axis and enteric nervous system (ENS), which in turn leads to onset of gastrointestinal tract (GIT) disorders. Consecutively, the ENS governs a broad spectrum of physiological activities of gut, such as visceral pain and motility. During the stages of emotional stress, hyperactivity of the HPA axis alters the ENS response to physiological and noxious stimuli. Consecutively, stress-induced flare, swelling, hyperalgesia and altered reflexes in gut eventually lead to GIT disorders. In summary, the current review provides prospective information about the role and mechanism of 5-HT4R-based therapeutics for the treatment of depressive disorder and possible consequences for the gut via brain-gut axis interactions. This article is part of the special issue entitled 'Serotonin Research: Crossing Scales and Boundaries'.


Asunto(s)
Depresión/epidemiología , Depresión/metabolismo , Enfermedades Gastrointestinales/epidemiología , Enfermedades Gastrointestinales/metabolismo , Microbioma Gastrointestinal/fisiología , Receptores de Serotonina 5-HT4/metabolismo , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Comorbilidad , Depresión/tratamiento farmacológico , Enfermedades Gastrointestinales/tratamiento farmacológico , Microbioma Gastrointestinal/efectos de los fármacos , Humanos , Agonistas del Receptor de Serotonina 5-HT4/farmacología , Agonistas del Receptor de Serotonina 5-HT4/uso terapéutico , Antagonistas del Receptor de Serotonina 5-HT4/farmacología , Antagonistas del Receptor de Serotonina 5-HT4/uso terapéutico
16.
Invest New Drugs ; 38(2): 311-320, 2020 04.
Artículo en Inglés | MEDLINE | ID: mdl-31087223

RESUMEN

The Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) signaling pathway plays central roles in cancer cell growth and survival. Drug repurposing strategies have provided a valuable approach for developing antitumor drugs. Zelnorm (tegaserod maleate) was originally designed as an agonist of 5-hydroxytryptamine 4 receptor (5-HT4R) and approved by the FDA for treating irritable bowel syndrome with constipation (IBS-C). Through the use of a high-throughput drug screening system, Zelnorm was identified as a JAK/STAT3 signaling inhibitor. Moreover, the inhibition of STAT3 phosphorylation by Zelnorm was independent of its original target 5-HT4R. Zelnorm could cause G1 cell cycle arrest, induce cell apoptosis and inhibit the growth of a variety of cancer cells. The present study identifies Zelnorm as a novel JAK/STAT3 signaling inhibitor and reveals a new clinical application of Zelnorm upon market reintroduction.


Asunto(s)
Antineoplásicos/uso terapéutico , Indoles/uso terapéutico , Quinasas Janus/antagonistas & inhibidores , Neoplasias/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Factor de Transcripción STAT3/antagonistas & inhibidores , Agonistas del Receptor de Serotonina 5-HT4/uso terapéutico , Animales , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Puntos de Control de la Fase G1 del Ciclo Celular/efectos de los fármacos , Humanos , Indoles/farmacología , Quinasas Janus/metabolismo , Ratones Desnudos , Neoplasias/genética , Neoplasias/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Receptores de Serotonina 5-HT4/genética , Factor de Transcripción STAT3/metabolismo , Agonistas del Receptor de Serotonina 5-HT4/farmacología , Transducción de Señal/efectos de los fármacos
17.
Nat Rev Gastroenterol Hepatol ; 17(1): 21-39, 2020 01.
Artículo en Inglés | MEDLINE | ID: mdl-31690829

RESUMEN

Functional constipation is common in children and adults worldwide. Functional constipation shows similarities in children and adults, but important differences also exist regarding epidemiology, symptomatology, pathophysiology, diagnostic workup and therapeutic management. In children, the approach focuses on the behavioural nature of the disorder and the initial therapeutic steps involve toilet training and laxatives. In adults, management focuses on excluding an underlying cause and differentiating between different subtypes of functional constipation - normal transit, slow transit or an evacuation disorder - which has important therapeutic consequences. Treatment of adult functional constipation involves lifestyle interventions, pelvic floor interventions (in the presence of a rectal evacuation disorder) and pharmacological therapy. When conventional treatments fail, children and adults are considered to have intractable functional constipation, a troublesome and distressing condition. Intractable constipation is managed with a stepwise approach and in rare cases requires surgical interventions such as antegrade continence enemas in children or colectomy procedures for adults. New drugs, including prokinetic and prosecretory agents, and surgical strategies, such as sacral nerve stimulation, have the potential to improve the management of children and adults with intractable functional constipation.


Asunto(s)
Estreñimiento/terapia , Fármacos Gastrointestinales/uso terapéutico , Laxativos/uso terapéutico , Agonistas del Receptor de Serotonina 5-HT4/uso terapéutico , Adulto , Ácidos y Sales Biliares/uso terapéutico , Biorretroalimentación Psicológica , Niño , Agonistas de los Canales de Cloruro/uso terapéutico , Inhibidores de la Colinesterasa/uso terapéutico , Estreñimiento/diagnóstico , Estreñimiento/fisiopatología , Dietoterapia , Fibras de la Dieta , Manejo de la Enfermedad , Terapia por Estimulación Eléctrica , Enema , Microbioma Gastrointestinal , Tránsito Gastrointestinal , Agonistas de la Guanilato Ciclasa C/uso terapéutico , Humanos , Manometría , Educación del Paciente como Asunto , Prebióticos , Probióticos , Control de Esfínteres
18.
Int J Mol Sci ; 20(21)2019 Oct 26.
Artículo en Inglés | MEDLINE | ID: mdl-31717815

RESUMEN

Previously, we found that 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson's disease (PD) model mice (PD mice) showed facilitation of hippocampal memory extinction via reduced cyclic adenosine monophosphate (cAMP)/cAMP-dependent response element-binding protein (CREB) signaling, which may cause cognitive impairment in PD. Serotonergic neurons in the median raphe nucleus (MnRN) project to the hippocampus, and functional abnormalities have been reported. In the present study, we investigated the effects of the serotonin 5-HT4 receptor (5-HT4R) agonists prucalopride and velusetrag on the facilitation of memory extinction observed in PD mice. Both 5-HT4R agonists restored facilitation of contextual fear extinction in PD mice by stimulating the cAMP/CREB pathway in the dentate gyrus of the hippocampus. A retrograde fluorogold-tracer study showed that γ-aminobutyric acid-ergic (GABAergic) neurons in the reticular part of the substantia nigra (SNr), but not dopaminergic (DAergic) neurons in the substantia nigra pars compacta (SNpc), projected to serotonergic neurons in the MnRN, which are known to project their nerve terminals to the hippocampus. It is possible that the degeneration of the SNpc DAergic neurons in PD mice affects the SNr GABAergic neurons, and thereafter, the serotonergic neurons in the MnRN, resulting in hippocampal dysfunction. These findings suggest that 5HT4R agonists could be potentially useful as therapeutic drugs for treating cognitive deficits in PD.


Asunto(s)
Hipocampo/metabolismo , Enfermedad de Parkinson/metabolismo , Neuronas Serotoninérgicas/efectos de los fármacos , Agonistas del Receptor de Serotonina 5-HT4/uso terapéutico , Animales , Proteína de Unión a CREB/genética , Proteína de Unión a CREB/metabolismo , AMP Cíclico/metabolismo , Modelos Animales de Enfermedad , Dopamina/metabolismo , Neuronas Dopaminérgicas/metabolismo , Miedo/efectos de los fármacos , Hipocampo/citología , Hipocampo/efectos de los fármacos , Masculino , Memoria/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/psicología , Núcleos del Rafe/efectos de los fármacos , Receptores de Serotonina 5-HT4/metabolismo , Neuronas Serotoninérgicas/citología , Neuronas Serotoninérgicas/metabolismo , Sustancia Negra/metabolismo
19.
Neurogastroenterol Motil ; 31(10): e13708, 2019 10.
Artículo en Inglés | MEDLINE | ID: mdl-31524331

RESUMEN

The prokinetic effects of 5-HT4 receptor (5-HT4 R) agonists have been utilized clinically for almost three decades to relieve symptoms of constipation. Surprisingly, the mechanism(s) of action of these compounds is still being debated. Recent studies highlight luminal 5-HT4 Rs as an alternative and effective target for these prokinetic agents. These include the study by Shokrollahi et al (2019, Neurogastroenterol Motil, e13598) published in the current issue of Neurogastroenterology and Motility, who found that activation of mucosal 5-HT4 Rs by intraluminal prucalopride, significantly enhanced propulsive motor patterns in rabbit colon. The authors highlight the idea that development of agonists targeting luminal 5-HT4 Rs in the colonic mucosa might be more effective and safer in achieving prokinetic effects on intestinal motility. The purpose of this mini-review is to discuss the evidence for luminal 5-HT4 Rs as an emerging target for prokinetic agents in facilitating propulsive motor patterns in the colon.


Asunto(s)
Colon/metabolismo , Estreñimiento/tratamiento farmacológico , Motilidad Gastrointestinal/fisiología , Mucosa Intestinal/metabolismo , Receptores de Serotonina 5-HT4/metabolismo , Agonistas del Receptor de Serotonina 5-HT4/uso terapéutico , Compuestos de Azabiciclo/farmacología , Compuestos de Azabiciclo/uso terapéutico , Benzamidas/farmacología , Benzamidas/uso terapéutico , Benzofuranos/farmacología , Benzofuranos/uso terapéutico , Colon/efectos de los fármacos , Motilidad Gastrointestinal/efectos de los fármacos , Humanos , Laxativos/farmacología , Laxativos/uso terapéutico , Terapia Molecular Dirigida , Pirimidinas/farmacología , Pirimidinas/uso terapéutico , Quinuclidinas/farmacología , Quinuclidinas/uso terapéutico , Agonistas del Receptor de Serotonina 5-HT4/farmacología
20.
Am J Gastroenterol ; 114(8): 1265-1274, 2019 08.
Artículo en Inglés | MEDLINE | ID: mdl-31295161

RESUMEN

OBJECTIVES: Prokinetics are considered the preferred treatment option for gastroparesis, but evidence of their efficacy is scarce. Prucalopride, a selective 5-hydroxytryptamine 4 receptor agonist used in the treatment of constipation, is able to enhance the gastric emptying rate. In a double-blind, randomized, placebo-controlled crossover study, we evaluated the efficacy of prucalopride to improve the gastric emptying rate and symptoms in patients with gastroparesis. METHODS: Thirty-four patients with gastroparesis (28 idiopathic, 7 men, mean age 42 ± 13 years) were evaluated in a double-blind crossover trial of 4-week treatment periods with placebo or prucalopride 2 mg q.d., separated by 2 weeks of washout. The primary end point was the change in symptom severity, assessed by the Gastroparesis Cardinal Symptom Index; secondary end points comprised the Patient Assessment of Upper Gastrointestinal Disorders-Symptom Severity Index, the Patient Assessment of Upper Gastrointestinal Disorders-Quality of Life, and daily diaries, and the gastric emptying rate was assessed by the C-octanoic acid breath test. RESULTS: Three patients were lost to follow-up. One serious adverse event occurred (small bowel volvulus in the prucalopride group), and 3 patients dropped out because of adverse events of nausea and headache (all prucalopride). For the entire patient group, compared with placebo, prucalopride significantly improved the total Gastroparesis Cardinal Symptom Index (1.65 ± 0.19 vs 2.28 ± 0.20, P < 0.0001) and the subscales of fullness/satiety, nausea/vomiting, and bloating/distention. Prucalopride significantly improved the overall Patient Assessment of Upper Gastrointestinal Disorders-Quality of Life score (1.15 ± 0.16 vs 1.44 ± 0.16, P < 0.05) and the domains of clothing and diet. The gastric half emptying time was significantly enhanced by prucalopride compared with placebo and baseline (98 ± 10 vs 143 ± 11 and 126 ± 13 minutes, P = 0.005 and <0.001, respectively). These significant improvements were also found when considering only the idiopathic gastroparesis subgroup. DISCUSSION: In a cohort of patients with predominantly idiopathic gastroparesis, 4 weeks of prucalopride treatment significantly improved symptoms and quality of life and enhanced gastric emptying compared with placebo.


Asunto(s)
Benzofuranos/uso terapéutico , Gastroparesia/tratamiento farmacológico , Agonistas del Receptor de Serotonina 5-HT4/uso terapéutico , Adulto , Pruebas Respiratorias , Estudios Cruzados , Método Doble Ciego , Femenino , Vaciamiento Gástrico/efectos de los fármacos , Humanos , Masculino , Calidad de Vida , Índice de Severidad de la Enfermedad
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