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Constipation is a disorder of the gastrointestinal (GI) and some of the main etiological mechanisms are directly related to changes in GI physiology. The capacity to carry out paired assessments and measure GI parameters under the influence of constipation is a relevant point in selecting a suitable methodology. We aimed to perform a non-invasive investigation of gastrointestinal motility in constipated rats using the alternating current biosusceptometry system (ACB). The animals were split into two groups: the pre-induction stage (CONTROL) and post-induction loperamide stage (LOP). We assessed GI motility parameters using the ACB system. Colon morphometric and immunohistochemical analyses were performed for biomarkers (C-kit) for interstitial cells of Cajal (ICC). Our results showed a significant increase in gastrointestinal transit in the LOP group in addition to a reduction in the dominant frequency of gastric contraction and an arrhythmic profile. A change in colonic contractility profiles was observed, indicating colonic dysmotility in the LOP group. We found a reduction in the number of biomarkers for intestinal cells of Cajal (ICC) in the LOP group. The ACB system can evaluate transit irregularities and their degrees of severity, while also supporting research into novel, safer, and more efficient treatments for constipation.

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Loperamide is a synthetic opioid commonly used as an antidiarrheal due to its activation of u-opioid receptors in the myenteric plexus. In therapeutic doses, it inhibits peristalsis and has anti-secretory and anti-motility effects, until metabolized by intestinal and hepatic CYP3A4 and CYP2C8 into inactive metabolites. Furthermore, loperamide also inhibits L-type voltage-gated calcium (Ca2+) channels, increases action potential duration, and can induce arrhythmias and even cardiotoxicity, particularly when taken in extremely high doses. Thus, the aim of this study was to perform an integrative review of the available evidence in the recent literature on the cardiac risks of acute and chronic use of loperamide. In electrocardiogram (ECG) analysis, the most common finding was QTc prolongation in 27 cases, followed by QRS prolongation, first-degree atrioventricular (AV) block, torsades de pointes, ventricular tachycardia, and right bundle branch block. As for the symptoms encountered, syncope, weakness, palpitations, lightheadedness, shortness of breath, nausea, vomiting, bradycardia, and cardiac arrest were the most common. Loperamide can inhibit hERG voltage-gated potassium (K+) channels (Kv11.1), leading to the prolongation of repolarization, QTc interval prolongation, and increased risk of torsades de pointes. In addition, loperamide can inhibit voltage-gated sodium (Na+) channels (Nav1.5), impairing electrical cardiac conduction and potentiating QRS interval widening. Therefore, QTc prolongation, torsades de pointes, and other ECG alterations are of particular concern regarding loperamide toxicity, particularly when overdosed.

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ETHNOPHARMACOLOGICAL RELEVANCE: Anacardium occidentale L. (Anacardiaceae) is commonly known as the cashew tree. It is native to tropical America and extracts of the leaves, bark, roots, chestnut net and exudate have been traditionally used in northeast Brazil for the treatment of various diseases. The exudate of the cashew tree (cashew gum) has been exploited by locals since ancient times for multiple applications, including the treatment of diarrheal diseases. AIM OF THE STUDY: The primary aim of the present study is to evaluate the antidiarrheal activity of cashew gum (CG), a complex heteropolysaccharide from the exudate of the cashew tree, using various models. MATERIALS AND METHODS: The antidiarrheal activity of cashew gum (CG) against acute diarrhea was investigated using the castor oil-induced diarrhea model. The effects of CG on gastrointestinal transit and castor oil- and PGE2- induced enteropooling were also examined in rodents. In addition, the effect of CG against secretory diarrhea was investigated using a model of fluid secretion in cholera toxin-treated intestinal closed loops in live mice. RESULTS: Cashew gum (30, 60, and 90 mg/kg, p.o.) showed a significant (P<0.05-0.01) antidiarrheal effect in rats with castor oil-induced diarrhea, inhibiting the total amount of stool and diarrheal stools. The 60 mg/kg dose of CG exhibited excellent antidiarrheal activity and significantly reduced the severity of diarrhea (diarrhea scores) in rats. CG (60 mg/kg) significantly (P<0.05) decreased the volume of castor oil- and PGE2-induced intestinal fluid secretion (enteropooling). In addition, similar to loperamide (standard drug, 5 mg/kg, p.o.), CG treatment reduced the distance traveled by a charcoal meal in the 30-min gastrointestinal transit model by interacting with opioid receptors. In cholera toxin-induced secretory diarrhea, CG (60 mg/kg) significantly inhibited the intestinal fluid secretion and decreased Cl(-) ion loss in the cholera toxin(-)treated isolated loops model of live mice by competitively binding to cholera toxin-GM1 receptors. CONCLUSIONS: In conclusion, our results indicate that a complex heteropolysaccharide extracted from the exudate of A. occidentale L. has antidiarrheal activity in acute, inflammatory, and secretory diarrhea models, which could justify its traditional use in the treatment of diarrhea in northeast Brazil. The antidiarrheal activity might be explained by the capacity of CG to inhibit gastrointestinal motility and thereby reduce the accumulation of intestinal fluid and the secretion of water and chloride ions in the lumen of the intestine.

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Objetivo: Determinar las posibles interacciones farmacológicas de las hojas de Maytenus macrocarpa, con fármacos estimulantes e inhibitorios de la motilidad intestinal. Métodos: Se utilizaron 110 ratones albinos machos, con pesos medios de 25 g, se empleó el método de Arbos y col, se administró carbón activado al 5

vía oral, dosis de 0.1ml/10g, como marcador intestinal. Los grupos experimentales fueron: control (agua destilada 0,3ml), hojas de chuchuhuasi 1 (500mg/kg), hojas de chuchuhuasi 2 (3000mg/kg), atropina (1,5mg/kg), loperamida (5mg/kg), neostigmina (0,4mg/kg), metoclopramida (10mg/kg), hojas de chuchuhuasi 1 con metoclopramida, hojas de chuchuhuasi 1 con loperamida, hojas de chuchuhuasi 2 con metoclopramida y hojas de chuchuhuasi 2 con loperamida. Para la validación estadística se usó la prueba de Wilconxon, ANOVA y Tukey. Resultados: El porcentaje de recorrido intestinal de carbón activado fue de 27,04, 34,15, 31,66, 25,57, 15,89, 43,30, 33,99, 32,40, 27,90, 49,34 y 25,36 respectivamente, el test de ANOVA de dos colas revelo una p=0,0007. El test de Tukey indico p<0.05 versus el control para neostigmina, loperamida y la interacción chuchuhuasi 3000 mg/kg con metoclopramida, en este último, el test de Wilconxon presento un valor p<0,05. Conclusiones: Se observó interacciones farmacológicas de antagonismo sobre la motilidad intestinal, entre chuchuhuasi y Loperamida y sinergismo entre chuchuhuasi y metoclopramida.

Objectives: To determine the possible pharmacological interactions from the leaves of Maytenus macrocarpa with inhibitory and stimulating bowel motility drugs. Methods: We used 110 male albino mice with average weight of 25g, Arbos and others method was applied. Activated charcoal was administered at 5

at dose of 0.1ml/10g, as an intestinal marker. The experimental groups included 0.1 ml/10 g of distilled water, leave extract of M. macrocarpa 1 (500mg/kg), leave extract of M. macrocarpa 2 (3000 mg/kg), 1,5mg/kg of atropine, 5mg/kg of loperamide, 0.4mg/kg of neostigmine, 10mg/kg of metoclopramide, leave extract of M. macrocarpa 1 with metoclopramide, leave extract of M. macrocarpa 1 with loperamide, leave extract of M. macrocarpa 2 with metoclopramide and leave extract of M. macrocarpa 2 with loperamide. The statistical validation was based on Wilconxon, ANOVA and Tukey test. Results: The intestinal charcoal run percentage was 27.04, 34.15, 31.66, 25.57, 15.89, 43.30, 33.99, 32.40, 27.9, 49.34 and 25.36 respectively. The ANOVA test result in p= 0.0007. The Tukey test indicated p <0.05 versus the control group for neostigmine, loperamide, and the interaction between leave extract of M. macrocarpa 2 with metoclopramide, for the last the Wilcoxon test result in p <0.05. Conclusions: It was observed antagonism drug interactions on gastrointestinal motility between leaves extract of M. macrocarpa with loperamide and synergism interactions with metoclopramide.

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