RESUMEN
BACKGROUND: We aimed to examine the common adverse drug reactions (ADRs) of metoclopramide, FDA-approved for treating many gastrointestinal conditions including gastroparesis, and prucalopride, FDA-approved for treating chronic idiopathic constipation but used off-label for other gastrointestinal conditions including gastroparesis. RESEARCH DESIGN AND METHODS: The FDA Adverse Event Reporting System (FAERS) was analyzed from January 2013 to December 2023. ADR reports regarding use of only metoclopramide or prucalopride were analyzed following exclusion of reports indicating use for treatment of non-gastrointestinal conditions. RESULTS: Analysis of 1,085 reports on metoclopramide revealed tardive dyskinesia (n = 393, 36.2%) and dystonia (n = 170, 15.7%) among the most reported ADRs in addition to QTc prolongation (n = 16, 1.5%) with progression to Torsade de pointes (n = 5, 0.5%) and triggering of pheochromocytoma crisis (n = 24, 2.2%). Analysis of 865 reports on prucalopride revealed headache (n = 120, 13.9%), diarrhea (n = 116, 13.4%), and abdominal pain (n = 100, 11.6%) as the most common ADRs with 22 reports (2.5%) of dystonia with the use of prucalopride. CONCLUSIONS: This FAERS database analysis shows post-marketing reports of ADRs from metoclopramide most frequently include tardive dyskinesia, dystonia, and tremor in addition to potentially fatal arrhythmias such as Torsade de pointes. Consumers of prucalopride may also be at risk of dystonia and other ADRs.
Asunto(s)
Sistemas de Registro de Reacción Adversa a Medicamentos , Benzofuranos , Gastroparesia , Metoclopramida , United States Food and Drug Administration , Humanos , Metoclopramida/efectos adversos , Metoclopramida/uso terapéutico , Gastroparesia/tratamiento farmacológico , Gastroparesia/inducido químicamente , Estados Unidos , Benzofuranos/efectos adversos , Benzofuranos/uso terapéutico , Masculino , Femenino , Persona de Mediana Edad , Adulto , Anciano , Adulto Joven , Bases de Datos Factuales , Adolescente , Antagonistas de los Receptores de Dopamina D2/efectos adversos , Discinesia Tardía/inducido químicamente , Discinesia Tardía/tratamiento farmacológicoRESUMEN
Initially developed as medications for diabetes mellitus, GLP-1 agonists have gained much popularity in the treatment of obesity and weight loss. The present case describes a 69-year-old woman with a history of peptic ulcer and use of NSAIDs, who presented with abdominal pain and oral intolerance refractory to conventional management, for which an upper digestive endoscopy was performed, diagnosing severe gastroparesis. Asking more about the story, revealed surreptitious use of semaglutide. She continued with supportive therapy and the symptoms resolved spontaneously. The present case report aims to warn of the potential risks of the use of GLP-1 analogues in the context of endoscopy with sedation.
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Gastroparesia , Agonistas Receptor de Péptidos Similares al Glucagón , Pérdida de Peso , Anciano , Femenino , Humanos , Gastroparesia/inducido químicamente , Agonistas Receptor de Péptidos Similares al Glucagón/administración & dosificación , Agonistas Receptor de Péptidos Similares al Glucagón/uso terapéutico , Péptidos Similares al Glucagón/uso terapéutico , Péptidos Similares al Glucagón/análogos & derivados , Péptidos Similares al Glucagón/efectos adversos , Índice de Severidad de la Enfermedad , Pérdida de Peso/efectos de los fármacosRESUMEN
Prescriptions and use of glucagon-like peptide-1 (GLP-1) receptor agonists are increasing dramatically, as indications are expanding from the treatment of diabetes mellitus to weight loss for people with obesity. As GLP-1 receptor agonists delay gastric emptying, perioperative healthcare practitioners could be concerned about an increased risk for pulmonary aspiration during general anaesthesia. We summarise relevant medical literature and provide evidence-based recommendations for perioperative care for people taking GLP-1 receptor agonists. GLP-1 receptor agonists delay gastric emptying; however, ongoing treatment attenuates this effect. The risk of aspiration during general anaesthesia is unknown. However, we advise caution in patients who recently commenced on GLP-1 receptor agonists. After over 12 weeks of treatment, standard fasting times likely suffice to manage the risk of pulmonary aspiration for most otherwise low-risk patients.
Asunto(s)
Diabetes Mellitus Tipo 2 , Gastroparesia , Humanos , Hipoglucemiantes/efectos adversos , Gastroparesia/inducido químicamente , Péptido 1 Similar al Glucagón/uso terapéutico , Péptido 1 Similar al Glucagón/agonistas , Vaciamiento GástricoRESUMEN
This systematic review investigates the effect of botulinum neurotoxin (BoNT) therapy on cancer-related disorders. A major bulk of the literature is focused on BoNT's effect on pain at the site of surgery or radiation. All 13 published studies on this issue indicated reduction or cessation of pain at these sites after local injection of BoNTs. Twelve studies addressed the effect of BoNT injection into the pylorus (sphincter between the stomach and the first part of the gut) for the prevention of gastroparesis after local resection of esophageal cancer. In eight studies, BoNT injection was superior to no intervention; three studies found no difference between the two approaches. One study compared the result of intra-pyloric BoNT injection with preventive pyloromyotomy (resection of pyloric muscle fibers). Both approaches reduced gastroparesis, but the surgical approach had more serious side effects. BoNT injection was superior to saline injection in the prevention of esophageal stricture after surgery (34% versus 6%, respectively, p = 0.02) and produced better results (30% versus 40% stricture) compared to steroid (triamcinolone) injection close to the surgical region. All 12 reported studies on the effect of BoNT injection into the parotid region for the reduction in facial sweating during eating (gustatory hyperhidrosis) found that BoNT injections stopped or significantly reduced facial sweating that developed after parotid gland surgery. Six studies showed that BoNT injection into the parotid region prevented the development of or healed the fistulas that developed after parotid gland resection-parotidectomy gustatory hyperhidrosis (Frey syndrome), post-surgical parotid fistula, and sialocele. Eight studies suggested that BoNT injection into masseter muscle reduced or stopped severe jaw pain after the first bite (first bite syndrome) that may develop as a complication of parotidectomy.
Asunto(s)
Toxinas Botulínicas Tipo A , Gastroparesia , Neoplasias , Sudoración Gustativa , Humanos , Toxinas Botulínicas Tipo A/uso terapéutico , Sudoración Gustativa/inducido químicamente , Sudoración Gustativa/tratamiento farmacológico , Gastroparesia/inducido químicamente , Gastroparesia/tratamiento farmacológico , Dolor/tratamiento farmacológico , Neoplasias/tratamiento farmacológicoRESUMEN
BACKGROUND/AIMS: We examined the contributions of gastric emptying and duodenogastric bile reflux in the formation of gastric antral ulcers induced by NSAIDs in mice. METHODS: We used the murine re-fed indomethacin (IND) experimental ulcer model. Outcome measures included the appearance of gastric lesions 24 h after IND treatment and the assessment of gastric contents and the concentration of bile acids 1.5 h after re-feeding. The effects of atropine, dopamine, SR57227 (5-HT3 receptor agonist), apomorphine, ondansetron, haloperidol, and dietary taurocholate and cholestyramine were also examined. RESULTS: IND (10 mg/kg, s.c.) induced severe lesions only in the gastric antrum in the re-fed model. The antral lesion index and the amount of food intake during the 2-h refeeding period were positively correlated. Atropine and dopamine delayed gastric emptying, increased bile reflux, and worsened IND-induced antral lesions. SR57227 and apomorphine worsened antral lesions with increased bile reflux. These effects were prevented by the anti-emetic drugs ondansetron and haloperidol, respectively. The anti-emetic drugs markedly decreased the severity of antral lesions and the increase of bile reflux induced by atropine or dopamine without affecting delayed gastric emptying. Antral lesions induced by IND were increased by dietary taurocholate but decreased by the addition of the bile acid sequestrant cholestyramine. CONCLUSIONS: These results suggest that gastroparesis induced by atropine or dopamine worsens NSAID-induced gastric antral ulcers by increasing duodenogastric bile reflux via activation of 5-HT3 and dopamine D2 receptors.
Asunto(s)
Antieméticos , Reflujo Biliar , Reflujo Duodenogástrico , Gastroparesia , Úlcera Gástrica , Ratones , Animales , Indometacina , Dopamina , Úlcera , Gastroparesia/inducido químicamente , Serotonina , Apomorfina/efectos adversos , Antieméticos/efectos adversos , Ondansetrón/farmacología , Resina de Colestiramina/efectos adversos , Haloperidol/efectos adversos , Úlcera Gástrica/inducido químicamente , Antiinflamatorios no Esteroideos/efectos adversos , Atropina/efectos adversosRESUMEN
BACKGROUND: Dopamine antagonists are the main pharmacological options to treat gastroparesis. The aim of this study was to conduct a systematic literature review (SLR) to evaluate the profile of adverse events (AEs) of dopamine antagonists used in the treatment of children and adults with gastroparesis. METHODS: We searched EMBASE and MEDLINE up to March 25, 2021, for relevant clinical trials and observational studies. We conducted a proportional meta-analysis to estimate the pooled occurrence of AEs (%), with 95% confidence interval (CI), from arm-level data across studies and the comparative occurrence of AEs from placebo-controlled clinical trials (odds ratio [OR] with 95% CI). RESULTS: We identified 28 studies assessing AEs experienced by patients treated for gastroparesis with domperidone and metoclopramide; 22 studies contributed data to the meta-analyses. Cardiovascular, neurological, and endocrine AEs were commonly observed, with point incidences varying from 1 to > 50%. Clinically important AEs, such as QTc prolongation, occurred in 5% of patients treated with domperidone (95% CI: 3.32-8.62). Restlessness, an extrapyramidal AE, occurred in 15% of patients (95% CI: 7.48-26.61) treated with metoclopramide, with a 7-fold increase compared with patients receiving placebo (OR: 7.72; 95% CI: 1.27-47.05). Variation in terminology to describe extrapyramidal events precluded further pooled analyses. Additional meta-analyses were not feasible due to discrepancies in the assessment and reporting of the AEs. CONCLUSIONS: The evidence confirms concerns of cardiovascular, extrapyramidal, and endocrine AEs in patients with gastroparesis treated with domperidone and metoclopramide. Imprecise AE reporting limits firm interpretation and conclusions. REGISTRATION: PROSPERO international prospective register of systematic reviews (registration number: CRD42021248888).
Asunto(s)
Domperidona , Gastroparesia , Adulto , Niño , Humanos , Domperidona/efectos adversos , Metoclopramida/efectos adversos , Gastroparesia/inducido químicamente , Gastroparesia/tratamiento farmacológico , Antagonistas de Dopamina/efectos adversosRESUMEN
BACKGROUND: Methods to study gastric emptying in rodents are time consuming or terminal, preventing repetitive assessment in the same animal. Magnetic resonance imaging (MRI) is a non-invasive technique increasingly used to investigate gastrointestinal function devoid of these shortcomings. Here, we evaluated MRI to measure gastric emptying in control animals and in two different models of gastroparesis. METHODS: Mice were scanned using a 9.4 Tesla MR scanner. Gastric volume was measured by delineating the stomach lumen area. Control mice were scanned every 30 min after ingestion of a 0.2 g meal and stomach volume was quantified. The ability of MRI to detect delayed gastric emptying was evaluated in models of morphine-induced gastroparesis and streptozotocin-induced diabetes. KEY RESULTS: Magnetic resonance imaging reproducibly detected increased gastric volume following ingestion of a standard meal and progressively decreased with a half emptying time of 59 ± 5 min. Morphine significantly increased gastric volume measured at t = 120 min (saline: 20 ± 2 vs morphine: 34 ± 5 mm3 ; n = 8-10; p < 0.001) and increased half emptying time using the breath test (saline: 85 ± 22 vs morphine: 161 ± 46 min; n = 10; p < 0.001). In diabetic mice, gastric volume assessed by MRI at t = 60 min (control: 23 ± 2 mm3 ; n = 14 vs diabetic: 26 ± 5 mm3 ; n = 18; p = 0.014) but not at t = 120 min (control: 21 ± 3 mm3 ; n = 13 vs diabetic: 18 ± 5 mm3 ; n = 18; p = 0.115) was significantly increased compared to nondiabetic mice. CONCLUSIONS AND INFERENCES: Our data indicate that MRI is a reliable and reproducible tool to assess gastric emptying in mice and represents a useful technique to study gastroparesis in disease models or for evaluation of pharmacological compounds.
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Diabetes Mellitus Experimental , Gastroparesia , Ratones , Animales , Gastroparesia/inducido químicamente , Gastroparesia/diagnóstico por imagen , Diabetes Mellitus Experimental/inducido químicamente , Diabetes Mellitus Experimental/diagnóstico por imagen , Vaciamiento Gástrico , Imagen por Resonancia Magnética/métodos , Derivados de la MorfinaRESUMEN
Food ingestion is a major symptom trigger in functional esophageal and gastroduodenal disorders and gastroparesis. This review summarizes current knowledge and identifies areas of research on the role of food factors and the opportunities for dietary intervention in these disorders. While many patients experiencing functional esophageal and gastroduodenal disorders identify specific food items as symptom triggers, available data do not allow the identification of specific nutrient groups that are more likely to induce symptoms. In functional dyspepsia (FD), recent studies have shown the potential efficacy of a diet low in fermentable oligosaccharides, disaccharides, monosaccharides, and polyols, although the underlying mechanism of action is unclear. Reports of favorable responses to gluten elimination in patients with FD are confounded by the concomitant benefit of reduced intake of fructans, fermentable oligosaccharides, disaccharides, monosaccharides, and polyols present in wheat. Emerging data based on a 6-food elimination diet and confocal laser endomicroscopic evaluation of mucosal responses to food proteins suggest a role for duodenal allergic reactions in FD symptom generation. In patients with gastroparesis, a low-residue diet has been shown to improve symptoms. Novel dietary approaches under evaluation are the Mediterranean diet and the heating/cooling diet approach.
Asunto(s)
Dispepsia , Gastroparesia , Síndrome del Colon Irritable , Encéfalo , Dieta , Disacáridos/efectos adversos , Fermentación , Gastroparesia/inducido químicamente , Humanos , Monosacáridos/efectos adversos , Oligosacáridos/efectos adversosRESUMEN
Domperidone is an effective antiemetic used worldwide, but there have been reports of possible cardiotoxicity. Our goal was to explore the cardiac safety and clinical efficacy of long-term domperidone, titrated as high as 120 mg/day, in patients not responding or unable to tolerate other therapies for gastroparesis (GP).This retrospective cohort study was conducted at a single tertiary care academic center. We objectively assessed the safety and efficacy of domperidone through questionnaires, clinical follow-up and frequent ECGs as mandated by the Food and Drug Administration. We excluded patients with a history of dangerous arrhythmias, prolonged QTc, clinically significant electrolyte disturbances, gastrointestinal hemorrhage or obstruction, presence of a prolactinoma, pregnant or breastfeeding females, or allergy to domperidone. A total of 21 patients met the inclusion criteria for eligibility in this study (52.4% white, 42.9% Hispanic; mean age 50.1 years; 90.5% female). The mean duration of domperidone therapy was 52.3 (range 16-97) months with a mean highest dose of 80 mg/day (range 40-120 mg). Two patients (9.5%) taking 120 mg/day experienced asymptomatic meaningful QTc prolongation (>450 ms in males, >470 ms in females). One-third of patients had asymptomatic non-meaningful QTc prolongation. Palpitations or chest pain was reported in 19% of patients without ECG abnormalities or adverse cardiac events. The mean severity of vomiting and nausea was improved by 82% and 55%, respectively.Long-term treatment with high doses of domperidone (40-120 mg/day) improved GP symptoms in patients previously refractory to other medical therapies and with a satisfactory cardiovascular risk profile.
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Gastroparesia , Síndrome de QT Prolongado , Domperidona/efectos adversos , Femenino , Gastroparesia/inducido químicamente , Gastroparesia/tratamiento farmacológico , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
Gastroparesis is a commonly diagnosed gastrointestinal disorder with a high prevalence globally and high disease burden to those afflicted with it. Etiologies are variable with idiopathic and diabetes being the most common causes of gastroparesis. Management of gastroparesis depends on the etiology, and accurate diagnosis is required for better targeted therapy. Medication-induced gastroparesis is reversible, and discontinuing the medication is generally curative. This case report discusses 2 cases of medication-induced gastroparesis which were initially diagnosed as diabetic gastroparesis, and thorough history taking revealed the cause to be medication induced. Repeat studies following medication discontinuation revealed improvement in symptoms and resolution of gastroparesis. Further research needs to be done to assess the frequency of misdiagnosing diabetic patients with gastroparesis due to medications, specifically glucagon-like peptide-1 receptor agonists which are increasingly being used in diabetics.
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Diabetes Mellitus , Gastroparesia , Gastroparesia/inducido químicamente , Gastroparesia/tratamiento farmacológico , HumanosRESUMEN
Despite advances in medical and interventional management of acute myocardial infarction, treatment of the associated chest pain has remained relatively unchanged since opioids were first utilized in the 1930's. This dominance can be partially attributed to initial studies suggesting hemodynamic benefits with opioid treatment. However, delayed gastrointestinal absorption of P2Y12 inhibitors due to opioids and the consequent impairment in antiplatelet activity of this established therapy is cause for concern. Coupled with the lack of randomized clinical trial evidence to support widespread opioid use, there is now an opportunity to re-evaluate our approach to analgesia in myocardial infarction. This review characterizes the mechanism of the opioid-P2Y12 inhibitor interaction, strategies aimed at mitigating the interaction and appraises promising alternative agents to opioid therapy in patients with myocardial infarction.
Asunto(s)
Analgésicos Opioides/uso terapéutico , Dolor en el Pecho/tratamiento farmacológico , Dolor en el Pecho/etiología , Infarto del Miocardio/complicaciones , Antagonistas del Receptor Purinérgico P2Y/farmacología , Analgésicos Opioides/administración & dosificación , Analgésicos Opioides/efectos adversos , Analgésicos Opioides/farmacología , Ensayos Clínicos como Asunto , Interacciones Farmacológicas , Gastroparesia/inducido químicamente , Humanos , Activación Plaquetaria/efectos de los fármacos , Inhibidores de Agregación Plaquetaria/uso terapéutico , Antagonistas del Receptor Purinérgico P2Y/farmacocinética , Receptores Opioides mu/metabolismoRESUMEN
BACKGROUND: Immune checkpoint inhibitors (ICI) have improved outcomes in patients with various malignancies; however, they can cause immune-related hepatitis and enterocolitis. Patients on ICI may also develop upper gastrointestinal symptoms and undergo measurement of gastric emptying. AIMS: Our aim was to review records of patients with gastroparesis following ICI therapy at two medical centers. METHODS: We performed a retrospective review of all patients at Mayo Clinic and Brigham and Women's/Dana-Farber Cancer Center (BWH/DFCC) who underwent gastric scintigraphy for the assessment of symptoms of gastroparesis following ICI treatment up to January 2020. Clinical presentation, medical history, laboratory evaluation, imaging, treatment, and outcomes were retrieved from the records. Gastroparesis was diagnosed as delayed gastric emptying (GE) measured by gastric scintigraphy. RESULTS: At Mayo Clinic, 2 patients (median age 59 years, 1 male [M], 1 female [F]) had delayed GE, while 4 patients (median age 53 years, 3M, 1F) had normal GE following ICI use. Of those with delayed GE (diagnosed after 38 and 2 months of ICI initiation), 1 patient was treated for non-Hodgkin's lymphoma and melanoma with ipilimumab; a second patient with breast cancer was treated with pembrolizumab. At BWH/DFCC, 2 patients (median age 56 years, 1M, 1F) had normal GE after ICI treatment, while a 62-year-old female with non-small cell lung cancer developed gastroparesis 3 months following initiation of nivolumab. CONCLUSION: This report documents gastroparesis as a potential adverse effect of ICI. Further studies should explore the potential for ICI therapy to damage anti-inflammatory macrophages that preserve the enteric neurons.
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Gastroparesia/inducido químicamente , Gastroparesia/diagnóstico , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Adulto , Anciano , Femenino , Vaciamiento Gástrico/efectos de los fármacos , Vaciamiento Gástrico/fisiología , Gastroparesia/inmunología , Humanos , Masculino , Persona de Mediana Edad , Cintigrafía/métodos , Estudios RetrospectivosRESUMEN
Inhibitors of cAMP-phosphodiesterase 4 (PDE4) exert a number of promising therapeutic benefits, but adverse effects, in particular emesis and nausea, have curbed their clinical utility. Here, we show that PAN-selective inhibition of PDE4, but not inhibition of PDE3, causes a time- and dose-dependent accumulation of chow in the stomachs of mice fed ad libitum without changing the animals' food intake or the weight of their intestines, suggesting that PDE4 inhibition impairs gastric emptying. Indeed, PDE4 inhibition induced gastric retention in an acute model of gastric motility that traces the passage of a food bolus through the stomach over a 30 minutes time period. In humans, abnormal gastric retention of food is known as gastroparesis, a syndrome predominated by nausea (>90% of cases) and vomiting (>80% of cases). We thus explored the abnormal gastric retention induced by PDE4 inhibition in mice under the premise that it may represent a useful correlate of emesis and nausea. Delayed gastric emptying was produced by structurally distinct PAN-PDE4 inhibitors including Rolipram, Piclamilast, Roflumilast, and RS25344, suggesting that it is a class effect. PDE4 inhibitors induced gastric retention at similar or below doses commonly used to induce therapeutic benefits (e.g., 0.04 mg/kg Rolipram), thus mirroring the narrow therapeutic window of PDE4 inhibitors in humans. YM976, a PAN-PDE4 inhibitor that does not efficiently cross the blood-brain barrier, induced gastroparesis only at significantly higher doses (≥1 mg/kg). This suggests that PDE4 inhibition may act in part through effects on the autonomic nervous system regulation of gastric emptying and that PDE4 inhibitors that are not brain-penetrant may have an improved safety profile. The PDE4 family comprises four subtypes, PDE4A, B, C, and D. Selective ablation of any of these subtypes in mice did not induce gastroparesis per se, nor did it protect from PAN-PDE4 inhibitor-induced gastroparesis, indicating that gastric retention may result from the concurrent inhibition of multiple PDE4s. Thus, potentially, any of the four PDE4 subtypes may be targeted individually for therapeutic benefits without inducing nausea or emesis. Acute gastric retention induced by PDE4 inhibition is alleviated by treatment with the widely used prokinetic Metoclopramide, suggesting a potential of this drug to alleviate the side effects of PDE4 inhibitors. Finally, given that the cause of gastroparesis remains largely idiopathic, our findings open the possibility that a physiologic or pathophysiologic downregulation of PDE4 activity/expression may be causative in a subset of patients.
Asunto(s)
Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4/metabolismo , Gastroparesia/inducido químicamente , Inhibidores de Fosfodiesterasa 4/efectos adversos , Aminopiridinas/efectos adversos , Animales , Benzamidas/efectos adversos , Ciclopropanos/efectos adversos , Modelos Animales de Enfermedad , Femenino , Ratones , Ratones Desnudos , Piridinas/efectos adversos , Pirimidinonas/efectos adversos , Rolipram/efectos adversosRESUMEN
We previously found that equol, a metabolite of intestinal bacterial conversion from soy isoflavone daidzein, has female-specific anorectic effects. In the present study, we used seven-week-old female ovariectomized (OVX) Sprague Dawley rats to test the hypothesis that the anorectic effect of dietary daidzein may be attributed to delayed gastric emptying. Results suggest that dietary daidzein delays gastric emptying and that it has an anorectic effect with residual gastric contents, but not without gastric contents. Dietary equol significantly decreased daily food intake in the OVX rats without sleeve gastrectomy, but not in those with sleeve gastrectomy, suggesting that the accumulation of food in the stomach is required for the anorectic effect of equol to occur. These results support the hypothesis that the anorectic effect of dietary daidzein is attributed to delayed gastric emptying.
Asunto(s)
Depresores del Apetito/farmacología , Suplementos Dietéticos , Ingestión de Alimentos/efectos de los fármacos , Vaciamiento Gástrico/efectos de los fármacos , Isoflavonas/farmacología , Ovariectomía , Animales , Equol/farmacología , Femenino , Gastrectomía , Gastroparesia/inducido químicamente , Ratas , Ratas Sprague-DawleyRESUMEN
Gastrointestinal motility is regulated by neural factors and humoral factors. Both motilin and ghrelin improve gastrointestinal motility, but many issues remain unclear. We prepared human motilin receptor transgenic (Tg) mice and performed experiments evaluating the effects of motilin, erythromycin (EM), and ghrelin. EM and ghrelin promoted gastric emptying (GE) when administered either peripherally or centrally to Tg mice. Atropine (a muscarinic receptor antagonist) counteracted GE induced by centrally administered EM, but not that induced by peripherally administered EM. The administration of EM in this model promoted the effect of mosapride (a selective serotonin 5-hydroxytryptamine 4 (5-HT4) receptor agonist), and improved loperamide (a µ-opioid receptor agonist)-induced gastroparesis. The level of acyl-ghrelin was significantly attenuated by EM administration. Thus, we have established an animal model appropriate for the evaluation of motilin receptor agonists. These data and the model are expected to facilitate the identification of novel compounds with clinical potential for relieving symptoms of dyspepsia and gastroparesis.
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Ghrelina/farmacología , Receptores de la Hormona Gastrointestinal/agonistas , Receptores de Neuropéptido/agonistas , Animales , Benzamidas/farmacología , Eritromicina/administración & dosificación , Eritromicina/farmacología , Vaciamiento Gástrico/efectos de los fármacos , Gastroparesia/sangre , Gastroparesia/inducido químicamente , Gastroparesia/tratamiento farmacológico , Gastroparesia/fisiopatología , Ghrelina/sangre , Humanos , Loperamida/efectos adversos , Masculino , Ratones Endogámicos C57BL , Ratones Transgénicos , Morfolinas/farmacología , Periodo Posprandial , ARN Mensajero/genética , ARN Mensajero/metabolismo , Receptores de la Hormona Gastrointestinal/genética , Receptores de la Hormona Gastrointestinal/metabolismo , Receptores de Ghrelina/genética , Receptores de Ghrelina/metabolismo , Receptores de Neuropéptido/genética , Receptores de Neuropéptido/metabolismo , Estómago/efectos de los fármacos , Estómago/patología , Estómago/fisiopatología , Nervio Vago/efectos de los fármacos , Nervio Vago/fisiologíaRESUMEN
Recent years, widespread long non-coding RNAs (lncRNAs) were identified and known as regulator of gene expression. Diabetic gastroparesis (DGP) is one of the most common chronic complications of diabetes mellitus. There was no research reported the role of lncRNAs in DGP. In this study, we firstly established a rat model of DGP by STZ injection. Then, we detected the expression of MALAT1 and found that expression of MALAT1 was up-regulated in rat model of DGP, comparing to the control group (Pâ¯<â¯.01). Furthermore, we revealed that MALAT1 expression was increased in the samples from diabetic patients with DGP symptoms, in comparison with the control. In addition, we demonstrated that the inhibition of MALAT1 increased the expression of α-SMA and SM myosin heavy chains, reduced the cell viability, inhibited the potential of cell migration and induced cell apoptosis in human gastric smooth muscle cells (SMCs). Ultimately, we found that the regulation of MALAT1 expression modulated the function of high-glucose stimulation in human gastric SMCs. Therefore, our study firstly indicated that MALAT1 was up-regulated in DGP and played an important role in the pathogenesis of DGP.
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Diabetes Mellitus Experimental/genética , Neuropatías Diabéticas/genética , Mucosa Gástrica/metabolismo , Gastroparesia/genética , Miocitos del Músculo Liso/metabolismo , ARN Largo no Codificante/genética , Actinas/genética , Actinas/metabolismo , Animales , Apoptosis/efectos de los fármacos , Apoptosis/genética , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Diabetes Mellitus Experimental/inducido químicamente , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Experimental/metabolismo , Neuropatías Diabéticas/inducido químicamente , Neuropatías Diabéticas/complicaciones , Neuropatías Diabéticas/metabolismo , Vaciamiento Gástrico , Gastroparesia/inducido químicamente , Gastroparesia/complicaciones , Gastroparesia/metabolismo , Regulación de la Expresión Génica , Glucosa/farmacología , Humanos , Masculino , Miocitos del Músculo Liso/efectos de los fármacos , Miocitos del Músculo Liso/patología , Cadenas Pesadas de Miosina/genética , Cadenas Pesadas de Miosina/metabolismo , Cultivo Primario de Células , ARN Largo no Codificante/metabolismo , Ratas , Ratas Sprague-Dawley , Transducción de Señal , Estómago/efectos de los fármacos , Estómago/patología , EstreptozocinaRESUMEN
Despite the availability of effective antiemetics, control of acute and delayed chemotherapy-induced nausea and vomiting (CINV) is often suboptimal and there is need of an inexpensive and safer alternative. Thus, this study was designed to evaluate the effect of Emblica officinalis Gaertn (Euphorbiaceae) fruit extract (EEEO) on cisplatin-induced delayed gastric emptying in Sprague-Dawley rats so that Emblica officinalis can be clarified for its application in CINV as a potential candidate. Groups I, II, III, IV, and V rats were pretreated orally with 1% carboxymethyl cellulose (CMC, 1 mL/kg), 1% CMC (1 mL/kg), EEEO (250 mg/kg), EEEO (500 mg/kg), and ondansetron (3 mg/kg), respectively, for 5 consecutive days. Then, Group I rats received 0.1 mL of normal saline and Groups II-V rats received 10 mg/kg body weight of cisplatin intraperitoneally. Immediately after that, a test meal (1.5 mL/rat) was administered to each group, and after 30 minutes, rats were euthanized to evaluate the percentage of gastric emptying. EEEO at the specified doses reversed the cisplatin-induced delayed gastric emptying. EEEO (500 mg/kg body weight) pretreatment for 5 days before cisplatin challenge in Group IV rats significantly (p < .05) increased gastric emptying to 74.25% ± 7.19%. Reversal of cisplatin-induced delay in gastric emptying by EEEO (500 mg/kg body weight) in Group IV was significantly (p < .05) comparable to that of the ondansetron treated Group V. EEEO possesses the property to reverse the cisplatin-induced delayed gastric emptying and can be used as an antiemetic for the prevention of CINV.
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Cisplatino/efectos adversos , Frutas/química , Gastroparesia/inducido químicamente , Gastroparesia/tratamiento farmacológico , Phyllanthus emblica , Extractos Vegetales/uso terapéutico , Animales , Antineoplásicos/efectos adversos , Femenino , Vaciamiento Gástrico/efectos de los fármacos , Masculino , Fitoterapia , Extractos Vegetales/administración & dosificación , Ratas , Ratas Sprague-DawleyRESUMEN
BACKGROUND: Clopidogrel is an irreversible antagonist of P2Y12 receptors (P2Y12Rs) used as an antiplatelet drug to reduce risk of thrombosis. P2Y12Rs are expressed in gastrointestinal (GI) tract where they might regulate GI function. AIM: To evaluate if blockade of P2Y12Rs by clopidogrel is associated with higher incidence of GI symptoms in patients with irritable bowel syndrome (IBS). METHODS: A retrospective analysis of our institutional database was conducted for a 13-year period. IBS patients were identified, and their demographics, GI symptoms and clopidogrel therapy were collected. Logistic regression models were used to characterize symptoms in clopidogrel versus no-clopidogrel IBS-groups, adjusting for Age and Sex differences. An additional study characterized the P2Y12R distribution in human gut. RESULTS: The search identified 7217 IBS patients (6761 no-clopidogrel/456 clopidogrel). There were a higher proportion of patients with GI symptoms on clopidogrel (68%) compared to controls (60%, p = 0.0011) that were Females (70 vs. 60%, p = 0.0003) not Males (61 vs. 60%; p = 0.8312). In Females, clopidogrel was associated with higher incidence of GI symptoms (Age adjusted; p < 0.0001) for pain, constipation, gastroparesis (p ≤ 0.0001) and psychogenic pain (p = 0.0006). Age or Sex (adjusted models) influenced one or more GI symptoms (i.e., pain, p < 0.0001; constipation, p < 0.0001/p = 0.008; diarrhea, flatulence, p = 0.01). P2Y12R immunoreactivity was abundant in human ENS; glial-to-neuron ratio of P2Y12Rs expressed in Females â« Males. CONCLUSIONS: Irreversible blockade of P2Y12R by clopidogrel is associated with higher incidence of GI symptoms in Female IBS patients, although Age or Sex alone contributes to symptomatology. Prospective studies can determine clinical implications of P2Y12Rs in IBS.
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Sistema Nervioso Entérico/efectos de los fármacos , Intestinos/inervación , Síndrome del Colon Irritable/epidemiología , Inhibidores de Agregación Plaquetaria/efectos adversos , Antagonistas del Receptor Purinérgico P2Y/efectos adversos , Ticlopidina/análogos & derivados , Dolor Abdominal/inducido químicamente , Dolor Abdominal/epidemiología , Adolescente , Adulto , Factores de Edad , Anciano , Clopidogrel , Estreñimiento/inducido químicamente , Estreñimiento/epidemiología , Bases de Datos Factuales , Diarrea/inducido químicamente , Diarrea/epidemiología , Registros Electrónicos de Salud , Sistema Nervioso Entérico/química , Sistema Nervioso Entérico/fisiopatología , Femenino , Flatulencia/inducido químicamente , Flatulencia/epidemiología , Gastroparesia/inducido químicamente , Gastroparesia/epidemiología , Humanos , Incidencia , Síndrome del Colon Irritable/diagnóstico , Síndrome del Colon Irritable/fisiopatología , Modelos Logísticos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Oportunidad Relativa , Receptores Purinérgicos P2Y12/análisis , Estudios Retrospectivos , Factores de Riesgo , Factores Sexuales , Ticlopidina/efectos adversos , Factores de Tiempo , Adulto JovenRESUMEN
INTRODUCTION: Lead toxicosis occurs in veterinary patients, with few reports involving rabbits, and no previous reports using oral calcium disodium EDTA. CASE REPORT: A 7-year-old male castrated Lionhead rabbit presented to the Cornell University Hospital for Animals (CUHA) for evaluation after a 2-day history of lethargy and a 2-week history of hyporexia. The patient had been observed pulling paint from the walls of the home, a house built circa 1900, in the months prior to presentation. The patient was moderately anemic with a hematocrit of 21% with red blood cell morphological changes consistent with lead toxicosis, including basophilic stippling, nucleated red blood cells, and polychromasia. Radiographic images of the abdomen revealed excessive accumulation of gas in the gastrointestinal tract in a pattern consistent with gastric stasis and numerous small mineral to metallic opacities in the cecum. The blood lead concentration was 792 µg/dL, confirming the diagnosis of lead toxicosis with secondary gastrointestinal stasis. The rabbit was hospitalized for treatment with oral and subcutaneous calcium disodium EDTA for 4 days and then discharged home to the care of the owners. DISCUSSION: Severe lead toxicosis in a rabbit can be treated successfully with oral and subcutaneous calcium disodium EDTA and aggressive supportive treatment.