Evaluation of the mechanism of action of paracetamol, drotaverine, and peppermint oil and their effects in combination with hyoscine butylbromide on colonic motility: human ex-vivo study.

Introduction: Drotaverine, paracetamol, and peppermint oil are often prescribed for the treatment of gastrointestinal spasm and pain. This study aimed to evaluate the effect of these drugs alone and combined with the well-known antispasmodic hyoscine butylbromide on the human colon. Methods: Colon samples were obtained from macroscopically normal regions of 68 patients undergoing surgery and studied in muscle bath. Drotaverine, paracetamol, and peppermint oil were tested alone and in combination with hyoscine butylbromide on (1) spontaneous contractility induced by isometric stretch (in the presence of 1 µM tetrodotoxin) and (2) contractility induced by 10-5 M carbachol and after (3) electrical field stimulation-induced selective stimulation of excitatory (in the presence of 1 mM Nω-nitro-L-arginine and 10 µM MRS2179) and (4) inhibitory (under non-adrenergic, non-cholinergic conditions) pathways. (5) Drotaverine alone was also tested on cAMP-dependent pathway activated by forskolin. Results: Compared with the vehicle, drotaverine and paracetamol (10-9-10-5 M) did not modify spontaneous contractions, carbachol-induced contractions, and responses attributed to selective activation of excitatory pathways. The addition of hyoscine butylbromide (10-7-10-5 M), concentration-dependently reduced myogenic contractions and carbachol- and electrical field stimulation-induced contractile responses. The association of paracetamol (10-4 M) and hyoscine butylbromide (10-7-10-5 M) was not different from hyoscine butylbromide alone (10-7-10-5 M). At higher concentrations (10-3M-3*10-3 M), paracetamol decreased myogenic and carbachol-induced contractions. The adenylate cyclase activator, forskolin, concentration-dependently reduced contractility, leading to smooth muscle relaxation. The effect of forskolin 10-7 M was concentration-dependently enhanced by drotaverine (10-6M-10-5M). Discussion: Peppermint oil reduced myogenic activity and carbachol- and electrical field stimulation-induced contractions. The association of hyoscine butylbromide and peppermint oil was synergistic since the interaction index measured with the isobologram was lower than 1. No effect was seen on the neural-mediated inhibitory responses with any of the drugs studied although peppermint oil reduced the subsequent off-contraction. Drotaverine and hyoscine butylbromide have a complementary effect on human colon motility as one stimulates the cAMP inhibitory pathway and the other inhibits the excitatory pathway. Peppermint oil is synergic with hyoscine butylbromide suggesting that a combination therapy may be more effective in treating patients. In contrast, at therapeutic concentrations, paracetamol does not modify colonic contractility, suggesting that the association of paracetamol and hyoscine butylbromide has independent analgesic and antispasmodic properties.

New insights into the characterization of the mechanism of action of hyoscine butylbromide in the human colon ex vivo.

INTRODUCTION: Hyoscine butylbromide (HBB) is one of the most used antispasmodics in clinical practice. Recent translational consensus has demonstrated a similarity between human colonic motor patterns studied ex vivo and in vivo, suggesting ex vivo can predict in vivo results. It is unclear whether the mechanism of action of antispasmodics can predict different use in clinical practice. The aim of the present study is to bridge this gap dissecting HBB's role in excitatory and inhibitory neural pathways. METHODS: 309 colon samples from 48 patients were studied in muscle bath experiments. HBB was tested on: 1-spontaneous phasic contractions (SPCs); 2-carbachol-induced contractility; electrical field stimulation (EFS)-induced selective stimulation of 3-excitatory and 4-inhibitory pathways and 5- SPCs and EFS-induced contractions enhanced by neostigmine. Atropine, AF-DX116 (M2 blocker) and DAU-5884 (M3 blocker) were used as comparators. RESULTS: In the presence of tetrodotoxin (TTX), HBB and atropine 1 µM reduced SPCs. HBB and atropine concentration-dependently reduced carbachol- and EFS-induced contractions. Inhibitory effects of DAU-5884 on EFS-induced contractions were more potent than of AF-DX116. HBB did not affect the off-response associated to neural inhibitory responses. Neostigmine enhanced both SPCs and EFS-induced contractions. In the presence of TTX and ω-conotoxin (GVIA), neostigmine still enhanced SPCs. Addition of HBB and atropine reduced these responses. CONCLUSIONS: This study demonstrates that HBB inhibits neural cholinergic contractions associated to muscarinic (mainly M3) receptors. HBB has a potential role in reducing colonic spasm induced by the release of acetylcholine from enteric motor neurons and from an atypical source including a potential non-neuronal origin.

Current insights on chronic intestinal dysmotility: pseudo-obstruction and enteric dysmotility.

Chronic intestinal dysmotility is a rare and debilitating digestive disorder characterized by symptoms of mechanical obstruction without an organic lesion. It has diverse causes and involves various pathological mechanisms. Small bowel manometry is the preferred diagnostic method, particularly for patients with severe and progressive symptoms. The condition can be categorized as intestinal pseudo-obstruction and enteric dysmotility, both entities share abnormal small bowel motility, but with important differences in prognosis and management.

Underlying etiology associated with the diagnosis of absent contractility on high resolution esophageal manometry.

BACKGROUND/AIMS: Absent contractility is considered a disorder of peristalsis. The literature about the etiology and clinical characteristics is scarce and the evidence on systemic diseases associated with this esophageal disorder is limited. Therefore, we aimed to determine the etiology of absent contractility in our population using the clinical algorithm recently described in the literature. METHODS: We conducted a retrospective, descriptive study at a single tertiary hospital of all patients diagnosed of absent contractility between May 2018 and February 2020. Data on demographic characteristics, medication, comorbidities, and laboratory and paraclinical tests were recorded from clinical records. RESULTS: A total of 72 patients with absent contractility were included for analysis. There was a predominance of female sex (n=43, 59.7%), with a mean age of 55.4 (±15.0) years. We identified a systemic disorder associated with absent contractility in 64 (88.9%) patients. From these, 31 (43.1%) patients were diagnosed with a systemic autoimmune disease, 26 (36.1%) patients were considered to have absent contractility secondary to pathological exposure to acid-reflux and 15 (20.8%) patients were diagnosed with other non-autoimmune systemic disorders. In the remaining eight (11.1%) patients, there were no underlying systemic disorders that could justify the diagnosis of absent contractility. CONCLUSIONS: A systematic approach to search for an underlying cause in patients diagnosed with absent contractility is warranted. Up to 90% of patients with absent contractility have a systemic disorder associated with this condition.

Síndrome de rumiación, revisión crítica / Rumination syndrome: Critical review

El síndrome de rumiación es un trastorno funcional caracterizado por la regurgitación involuntaria de los alimentos recientemente ingeridos desde el estómago hacia la boca, donde puede ser remasticados o expulsados. Desde el punto de vista clínico, se caracteriza por episodios repetidos de regurgitación de alimentos sin esfuerzo, con vómitos frecuentes como queja habitual. El mecanismo físico que genera los eventos de regurgitación depende de un proceso involuntario que altera las presiones abdominal y torácica, acompañado de una unión esofagogástrica permisiva. El diagnóstico del síndrome de rumiación es clínico: destaca la importancia de realizar una anamnesis exhaustiva sobre las características de los síntomas. Las pruebas complementarias se utilizan para corroborar el diagnóstico o descartar otra enfermedad orgánica. El tratamiento está enfocado a terapias conductuales como primera línea, reservando las terapias farmacológicas y quirúrgicas para casos refractarios.

Rumination syndrome is a functional disorder characterized by the involuntary regurgitation of recently swallowed food from the stomach into the mouth, from where it can be re-chewed or expelled. Clinically, it is characterized by repeated episodes of effortless food regurgitation. The most usual complaint is frequent vomiting. The physical mechanism that generates regurgitation events is dependent on an involuntary process that alters abdominal and thoracic pressures accompanied by a permissive oesophageal-gastric junction. The diagnosis of rumination syndrome is clinical, highlighting the importance of performing an exhaustive anamnesis on the characteristics of the symptoms. Complementary tests are used to corroborate the diagnosis or rule out organic pathology. Treatment is focused on behavioural therapies as the first line, reserving pharmacological and surgical therapies for refractory cases.

Opioid-induced esophageal dysfunctio — Prevalence and manometric findings

Background: prescription opioid use is on the rise. There has been an increasing recognition that chronic opioid consumption can result in esophageal motility disorders, and this association has been named opioid-induced esophageal dysfunction (OIED).Aims: to analyze the prevalence of chronic opioid consumption in patients referred for esophageal motility testing in a European center; to describe the clinical characteristics and the association of opioid consumption with esophageal motility disorders.Methods: a retrospective, descriptive study in patients who had undergone an HRM in a single center. The clinical history in the electronic medical records was reviewed. Results: the prevalence of opioid prescription in patients referred to our institution was 10.1 %, and 4.8 % of themwere chronic active opioid users. There was a 32 % prevalence of OIED. Comparing chronic active opioid users(CAOU) with OIED and CAOU patients without OIED, there was a higher prevalence of males (43.8 % vs 8.8 %; p-value = 0.007). Converting the different opioid medications to morphine milligram equivalent daily dose (MMED), CAOU patients with OIED had a higher MMED than CAOU patients without OIED (125.2 ± 31.3 vs 33.4 ± 5.7 MME; p = 0.041). Dysphagia was the most common indication for performing an HRM in 60.0 % of CAOU patients. Furthermore, dysphagia was more frequent in CAOU patients with OIED (87.5 % vs 47.0 %; p = 0.019).Conclusions: chronic opioid users with OIED complained mostly of dysphagia. There was an association of male sex and a higher dose of opioids in CAOU patients with esophageal motility disorders. (AU)

Opioid-induced esophageal dysfunction - Prevalence and manometric findings.

BACKGROUND: prescription opioid use is on the rise. There has been an increasing recognition that chronic opioid consumption can result in esophageal motility disorders, and this association has been named opioid-induced esophageal dysfunction (OIED). AIMS: to analyze the prevalence of chronic opioid consumption in patients referred for esophageal motility testing in a European center; to describe the clinical characteristics and the association of opioid consumption with esophageal motility disorders. METHODS: a retrospective, descriptive study in patients who had undergone an HRM in a single center. The clinical history in the electronic medical records was reviewed. RESULTS: the prevalence of opioid prescription in patients referred to our institution was 10.1 %, and 4.8 % of them were chronic active opioid users. There was a 32 % prevalence of OIED. Comparing chronic active opioid users (CAOU) with OIED and CAOU patients without OIED, there was a higher prevalence of males (43.8 % vs 8.8 %; p-value = 0.007). Converting the different opioid medications to morphine milligram equivalent daily dose (MMED), CAOU patients with OIED had a higher MMED than CAOU patients without OIED (125.2 ± 31.3 vs 33.4 ± 5.7 MME; p = 0.041). Dysphagia was the most common indication for performing an HRM in 60.0 % of CAOU patients. Furthermore, dysphagia was more frequent in CAOU patients with OIED (87.5 % vs 47.0 %; p = 0.019). CONCLUSIONS: chronic opioid users with OIED complained mostly of dysphagia. There was an association of male sex and a higher dose of opioids in CAOU patients with esophageal motility disorders.

Rumination syndrome: Critical review. / Síndrome de rumiación, revisión crítica.

Rumination syndrome is a functional disorder characterized by the involuntary regurgitation of recently swallowed food from the stomach into the mouth, from where it can be re-chewed or expelled. Clinically, it is characterized by repeated episodes of effortless food regurgitation. The most usual complaint is frequent vomiting. The physical mechanism that generates regurgitation events is dependent on an involuntary process that alters abdominal and thoracic pressures accompanied by a permissive oesophageal-gastric junction. The diagnosis of rumination syndrome is clinical, highlighting the importance of performing an exhaustive anamnesis on the characteristics of the symptoms. Complementary tests are used to corroborate the diagnosis or rule out organic pathology. Treatment is focused on behavioural therapies as the first line, reserving pharmacological and surgical therapies for refractory cases.

Propagation patterns of jejunal motor activity measured by high-resolution water-perfused manometry.

BACKGROUND: The manometric diagnosis of severe intestinal dysmotility is performed at most institutions using catheters with 2-8 sensors 5-10 cm apart. The recent application of high-resolution manometry catheters with closely spaced sensors to other gut segments has been highly successful. The objective of the present study was to determine the feasibility of a jejunal high-resolution manometry method and to carry out a descriptive analysis of normal jejunal motor function. METHODS: A 36-channel high-resolution water-perfused manometry catheter (MMS-Laborie, Enschede, The Netherlands) was orally placed in the jejunum of 18 healthy subjects (10 men, eight women; 21-38 age range). Intestinal motility was recorded during 5 h, 3 during fasting, and 2 after a 450 kcal solid-liquid meal. Analysis of motility patterns was supported by computerized tools. KEY RESULTS: All healthy subjects except one showed at least one complete migrating motor complex during the 3 h fasting period. Phase III activity lasted 5 ± 1 min and migrated aborally at a velocity of 7 ± 3 cm/min. High-resolution spatial analysis showed that during phase III each individual contraction propagated rapidly (75 ± 37 cm/min) over a 32 ± 10 cm segment of the jejunum. During phase II, most contractile activity corresponded to propagated contractile events which increased in frequency from early to late phase II (0.5 ± 0.9 vs 2.5 ± 1.3 events/10 min, respectively; p < 0.001). After meal ingestion, non-propagated activity increased, whereas propagated events were less frequent than during late phase II. CONCLUSIONS & INFERENCES: Jejunal motility analysis with high-resolution manometry identifies propagated contractile patterns which are not apparent with conventional manometric catheters.