Article

Effect of hyoscine N-butylbromide on gastroesophageal reflux in normal subjects and patients with gastroesophageal reflux disease

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Objectives: Recent studies have shown that atropine reduces gastroesophageal reflux in normal subjects and patients with gastroesophageal reflux. The aim of the study has been to assess the effects of an atropine derivative, hyoscine N-butylbromide in normal subjects and patients with gastroesophageal reflux disease by recording esophageal and gastric pH-metry for a 24-h period. Methods: Ten normal subjects and 10 patients with gastroesophageal reflux disease were evaluated. PH-metry was performed using two glass pH flexible probes with distal incorporated electrodes. The two catheters were introduced nasally under fluoroscopy. One probe was positioned in the gastric body; the other was placed 5 cm above the lower esophageal sphincter which had been evaluated manometrically before the study. Recording lasted without interruption for 48 h. Patients and normal subjects were assigned to receive hyoscine N-butylbromide (10 mg p.o. t.i.d.) for 24 h followed by a placebo for another 24 h or vice versa in a random manner. The pH was analyzed for a total number of acid refluxes and percentage of the period with pH <4 in the esophagus and the mean gastric pH in 24 h, before and after treatment with hyoscine N-butylbromide. Results: The number of reflux episodes was significantly greater with hyoscine N-butylbromide in comparison with a placebo in patients with gastroesophageal reflux disease and normal subjects (p < 0.02). The percentage of time with pH <4, was also significantly greater in patients with gastroesophageal reflux disease and in controls (p < 0.05). The mean 24-h gastric pH after hyoscine N-butylbromide was not different from placebo in gastroesophageal reflux disease and controls. Conclusions: Hyoscine N-butylbromide, an anticholinergic agent, increases the total number of esophageal acid refluxes in patients with gastroesophageal reflux disease and in controls, therefore it is not recommended in the treatment of gastroesophageal reflux disease.

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... Frontiers in Pharmacology frontiersin.org anticholinergics (Koerselman et al., 1999;Ciccaglione et al., 2001) and benzodiazepines (e.g., diazepam) (Rushnak and Leevy, 1980), as well as aminophylline (theophylline) (Mungan and Pınarbaşı Şimşek, 2017); substances that exert a direct corrosive effect on the oesophageal mucosa and diminish its protective properties, including bisphosphonates (Grima et al., 2010;Ang et al., 2016) and a range of antibiotics (e.g., tetracycline, doxycycline, clindamycin, ciprofloxacin, ornidazole, rifampicin.) (Harirforoosh et al., 2013); and medications that delay gastric emptying, exemplified by calcium channel blockers (Findling et al., 1996). ...
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Background This study analyzed the FDA’s Adverse Event Reporting System (FAERS) data to investigate the correlation between oral bisphosphonates (BPs) and oesophageal adverse events (AEs). Methods We systematically extracted data on adverse reactions to oral alendronate, risedronate, and ibandronate from the FAERS database, covering the period from the 2004 Q1 to the 2023 Q4. The role_code of AEs mainly includes primary suspect (PS), secondary suspect (SS), concomitant (C), and interaction (I). This study targeted reports with a role_code of “PS.” According to the FDA deduplication rule, the latest FDA_DT is selected when the CASEID is the same, and the higher PRIMARYID is selected when the CASEID and FDA_DT are the same. Our analysis leveraged four statistical methods, including the reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian confidence propagation neural network (BCPNN), and the multi-item gamma Poisson shrinker (MGPS), to assess the relationship between oral bisphosphonates and oesophageal AEs. The Kaplan-Meier method was utilized to evaluate the cumulative incidence of oesophageal toxicity, while the log-rank test examined the temporal onset profiles of these toxicities. Additionally, the Pearson chi-squared test was employed to identify any significant differences in mortality and hospitalization rates associated with the oesophageal AEs caused by these medications. Results The FAERS database had 41,590 AE reports for oral BPs, with 3,497 (8.41%) related to oesophageal AEs. Our findings indicate that oral BPs are disproportionately associated with an increased incidence of gastrointestinal system AEs at the system organ class (SOC) level. The adverse events identified at the preferred terms (PTs) level encompassed conditions such as gastroesophageal reflux disease, oesophagitis, and oesophageal pain. A significant divergence in the cumulative incidence of oesophageal AEs was observed among patients treated with the three different oral bisphosphonates, as confirmed by the log-rank test (p < 0.0001). Hospitalization rates varied significantly among patients receiving different BPs (p < 0.05), but no significant difference in mortality rates was found. Conclusion The study establishes a significant link between oral BPs and oesophageal toxicity, highlighting the need for further research into the mechanisms of BP-induced oesophageal toxicity and potential preventive measures.
... 51 By comparison, in studies of esophageal acid exposure following oral hyoscyamine, the observed increase in acid exposure still remained within the normal range in subjects without underlying GERD. 52,53 We recognize that these study findings are limited by the retrospective analysis of the data and the relatively small sample size. We Long-term oral anticholinergic therapy may be associated with side effects such as blurred vision, dry mouth, reduced sweating, dizziness, urinary retention, and constipation. ...
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Background Esophageal hypercontractility (EHC) is considered a major esophageal motor disorder of unclear etiology. Different mechanisms have been proposed, including an imbalance in inhibitory and excitatory esophageal innervation. We hypothesized that patients with EHC suffer from cholinergic hyperactivity. Aim To interrogate the excitatory and inhibitory neurotransmission in EHC by assessing the esophageal motor response to atropine (ATR) and cholecystokinin (CCK), respectively, in EHC patients. Method We retrospectively reviewed patients who underwent high‐resolution manometry (HRM) with pharmacologic challenge in a tertiary referral center between 2007 and 2017. We identified 49 EHC patients who were categorized based on frequency of hypercontractile peristaltic sequence into “frequent” and “infrequent” and motility diagnosis groups. Deglutitive pressure metrics and esophageal motor responses to ATR (12 mcg/kg iv) and CCK (40 ng/kg iv) were analyzed across groups. Results Atropine abolished hypercontractility across all groups studied, converting nearly half of patients to a motor pattern of ineffective esophageal motility. Abnormal CCK responses primarily occurred in the patient groups with concomitant outflow obstruction. Conclusions Hypercontractility is cholinergically mediated in all esophageal motor disorders. Most patients with isolated EHC appear to have excessive cholinergic drive, rather than loss of inhibitory innervation, and might be candidates for treatment with anticholinergic agents.
... It has been reported that disturbances in the ANS can increase the frequency of lower esophageal sphincter relaxation by reducing the muscular control at the lower esophageal sphincter (25). Several previous studies have found a reduced sympathetic activity in GERD (26,27). ...
Article
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... Антихолинергические препараты, препараты теофиллинового ряда и β2-агонисты. В двух РКИ продемонстрировано, что антихолинергические средства увеличивают время кислотного рефлюкса с рН <4 в 3-5 раз как у здоровых людей, так и у пациентов с ГЭРБ (p<0,05) [35,36], что связано со значительным уменьшением клиренса пищевода и снижением среднего базального уровня давления в НПС. В недавно проведенном перекрестном исследовании применение антихолинергических средств (ипратропия бромид) сопровождалось значительным риском манифестации симптомов ГЭРБ (ОР 13,12; 95% ДИ 0,16-26,09) [37]. ...
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From the standpoint of evidence - based medicine, the ability of various drugs to induce the development of gastroesophageal reflux disease and esophagitis is considered. Thus, all known drugs can be divided into 3 groups: drugs that have the ability to reduce pressure in the lower esophageal sphincter, for example, β-adrenoreceptor agonists, α-adrenoreceptor antagonists, anticholinergics, calcium channel blockers, nitrates, benzodiazepines (diazepam), estrogen, progesterone, aminophylline (theophylline), tricyclic antidepressants, selective serotonin reuptake inhibitors, glucocorticosteroids; means providing a direct damaging effect on the esophageal mucosa, as well as lowering its resistance reflyuktatu, e.g., bisphosphonates, acetylsalicylic acid / non - steroidal anti - inflammatory agents, anticoagulants, antiplatelet drugs, iron preparations, ascorbic acid, potassium chloride, quinidine, phenytoin, calcium dobesilate, 131I sodium iodide, antibiotics (tetracycline, doxycycline, clindamycin, ciprofloxacin, ornidazole, clindamycin, rifampicin), antitumor agents; drugs that impede gastric emptying: calcium channel blockers, anticholinergics. These data can be used in practice in the choice of treatment tactics, especially in individuals with a diagnosis of gastroesophageal reflux disease or heartburn.
... In the literature, three randomized controlled studies investigating this issue have been conducted. Ciccaglione et al. (33) compared hyoscine N-butyl bromide (HNB) (3×10 mg/day orally), an anticholinergic agent, with a placebo in 10 healthy adults and in 10 GERD patients by 48-h pH monitoring analysis. It was shown that HNB increased the occurrence of acidic esophageal reflux both in healthy people and in GERD patients (increase in the number of reflux episodes and increase in the percentage of time for which pH remained <4). ...
Article
Gastroesophageal reflux disease (GERD), which is common in many communities, is associated with structural factors, eating habits, and the use of certain drugs. The use of such drugs can lead to the emergence of GERD and can also exacerbate existing reflux symptoms. These drugs can contribute to GERD by directly causing mucosal damage, by reducing lower esophageal sphincter pressure (LESP), or by affecting esophagogastric motility. In this article, we report our investigation of the relationships between GERD and medications within the scope of the "Turkish GERD Consensus Group." For the medication groups for which sufficient data were obtained (Figure 1), a systematic literature review in English was conducted using the keywords "gastroesophageal reflux" [MeSH Terms] and "anti-inflammatory agents, non-steroidal" [MeSH Terms], "gastroesophageal reflux" [MeSH Terms] and "acetylsalicylic acid" [MeSH Terms], "gastroesophageal reflux" [All Fields] and "estrogenic agents" [All Fields], "gastroesophageal reflux" [All Fields] and "progesterones" [All Fields], "gastroesophageal reflux" [All Fields] and "hormone replacement therapy" [All Fields], "gastroesophageal reflux" [MeSH Terms] and "diphosphonates" [MeSH Terms] OR "diphosphonates" [All Fields], "calcium channel blockers" [MeSH Terms] and "gastroesophageal reflux" [MeSH Terms], "gastroesophageal reflux" [MeSH Terms] and "nitrates" [MeSH Terms], "gastroesophageal reflux" [MeSH Terms] and "antidepressive agents" [MeSH Terms], "gastroesophageal reflux" [MeSH Terms] and "benzodiazepines" [MeSH Terms] and "hypnotic drugs" [MeSH Terms], "gastroesophageal reflux" [MeSH Terms] and "cholinergic antagonists" [MeSH Terms], "gastroesophageal reflux" [MeSH Terms] and "theophylline" [MeSH Terms], and "gastroesophageal reflux [MeSH Terms] AND "anti-asthmatic agents" [MeSH Terms]. The studies were analyzed and the results are presented here.
... The observed autonomic dysfunction is supposed to cause intrinsic inhibitory reflex disturbances, abnormal fundal accommodation and gastric emptying, and consequently, an increased number of transient lower esophageal sphincter relaxations [13] . Some reports also found a decreased sympathetic function or a generalized autonomic decline in patients with GERD [13,14] . Campo et al [13] outlined that there is some evidence for a slightly decreased sympathetic function in patients with GERD that is inversely correlated with total time reflux. ...
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To investigate autonomic nervous function in patients with a diagnosis of gastroesophageal reflux disease (GERD). The investigation was performed on 29 patients (14 men), aged 18-80 years (51.14 ± 18.34), who were referred to our Neurocardiology Laboratory at the Clinical and Hospital Center "Bezanijska Kosa" with a diagnosis of GERD. One hundred sixteen healthy volunteers matched in age and sex with the examinees served as the control group. The study protocol included the evaluation of autonomic function and hemodynamic status, short-term heart rate variability (HRV) analysis, 24 h ambulatory ECG monitoring with long-term HRV analysis and 24 h ambulatory blood pressure monitoring. Pathologic results of cardiovascular reflex test were more common among patients with reflux compared to the control group. Severe autonomic dysfunction was detected in 44.4% of patients and in 7.9% of controls (P < 0.001). Parameters of short-term analysis of RR variability, which are the indicators of vagal activity, had lower values in patients with GERD than in the control group. Long-term HRV analysis of time-domain parameters indicated lower values in patients with reflux disease when compared to the control group. Power spectral analysis of long-term HRV revealed lower low- and high-frequency values. Detailed 24 h ambulatory blood pressure analysis showed significantly higher values of systolic blood pressure and pulse pressure in the reflux group than in the control group. Patients with GERD have distortion of sympathetic and parasympathetic components of the autonomic nervous system, but impaired parasympathetic function appears more congruent to GERD.
... HBB is known to have inhibitory effect on the motor activity of the stomach and intestine and thus decreases the gastric emptying [21] without the change of gastric pH [28]. In this study, with HBB the occurrence of breath UBT peak have been slightly delayed as compared to fasting protocol. ...
... Prokinetic agents such as cisapride have been shown to reduce meal induced reflux symptoms 14 but use has been limited due to serious side effects. 15 Dicyclomine, a peripheral anticholinergic agent, induces a decrease in the number of reflux episodes only in the first postprandial hour, 16 hyoscine Nbutylbromide, a peripheral anticholinergic agent, in contrast increases the number of reflux episodes, 17 while pirenzepine, a muscarinic subtype 1 receptor antagonist, appears to be no better than placebo. 18 Atropine seems to produce a favourable effect on reflux when administered before a meal, with a significant reduction in the postprandial number of refluxes. ...
Article
The gamma-aminobutyric acid (GABA(B)) agonist baclofen has been shown to reduce reflux episodes during the first three postprandial hours in patients with gastro-oesophageal reflux disease (GORD) and in normal controls. The aim of the study was to assess the effect of acute (one day) and chronic (four weeks) administration of baclofen on 24 hour pH metry and symptoms in GORD patients and normal controls. Acute study: 28 patients with GORD with none or mild oesophagitis at endoscopy and 15 controls underwent oesophageal and gastric 48 hour pH metry in which baclofen or placebo was given for 24 hours in a double blinded manner. Chronic study: 16 GORD patients received baclofen (10 mg four times daily) or placebo for four weeks. Twenty four hour oesophageal pH metry and reflux symptom scores were evaluated before and at the end of treatment. Acute study: the number of reflux episodes and per cent time with pH <4 was significantly lower after baclofen in GORD patients and controls (p<0.003; p<0.0007). Gastric pH increased significantly in GORD patients and controls (p<0.001; p<0.05). Chronic study: four weeks after initial administration of baclofen, the number of reflux episodes and percentage of time with pH <4 significantly decreased in all GORD patients (p<0.003; p<0.02). Symptom scores significantly improved after treatment with baclofen (p<0.0007). The GABA(B) agonist baclofen reduces 24 hour gastro-oesophageal reflux and increases gastric pH in GORD patients and controls. When given for one month to GORD patients, baclofen reduces oesophageal acid refluxes and significantly improves symptoms. Baclofen may be useful in the therapy of GORD.
... In contrast to the effects on reflux in postprandial upright position, the study showed a significant increase in the acid exposure time with dicyclomine during the first 2 h supine after a bedtime snack. Another study was initiated to measure the effect of anticholinergics on oesophageal pH with a 24-h pH measurement period [39] . As the administration of atropine for a 24-h period is not feasible in humans, the investigators used hyoscine N -butylbromide (HNB), which is an anticholinergic agent that does not cross the blood-brain barrier. ...
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The most important risk factor of oesophageal adenocarcinoma is gastro-oesophageal reflux disease. Gastro-oesophageal reflux disease is in itself a common disorder, giving bothersome symptoms. In daily clinical practice, anticholinergic drugs are believed to increase the risk of gastro-oesophageal reflux through effects on the lower oesophageal sphincter. In this review we discuss the available literature on the potential association between the use of drugs with anticholinergic properties and the risk of gastro-oesophageal reflux-related disorders.
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Background: Little is known about the direction of causality among asthma, posttraumatic stress disorder (PTSD), and onset of gastroesophageal reflux symptoms (GERS) after exposure to the 9/11/2001 World Trade Center (WTC) disaster. Methods: Using data from the WTC Health Registry, we investigated the effects of early diagnosed post-9/11 asthma and PTSD on the late onset and persistence of GERS using log-binomial regression, and examined whether PTSD mediated the asthma-GERS association using structural equation modeling. Results: Of 29,406 enrollees, 23% reported GERS at follow-up in 2011-2012. Early post-9/11 asthma and PTSD were each independently associated with both the persistence of GERS that was present at baseline and the development of GERS in persons without a prior history. PTSD mediated the association between early post-9/11 asthma and late-onset GERS. Conclusions: Clinicians should assess patients with post-9/11 GERS for comorbid asthma and PTSD, and plan medical care for these conditions in an integrated fashion. Am. J. Ind. Med. 59:805-814, 2016. © 2016 Wiley Periodicals, Inc.
Article
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The study evaluates the triggering and characteristics of secondary oesophageal peristalsis in 25 healthy volunteers. Secondary peristalsis was stimulated by rapid intraoesophageal injection of boluses of air and water, and by a five second oesophageal distension with a balloon. Air and water boluses triggered secondary peristalsis that started in the proximal oesophagus regardless of injection site. Response rates were volume dependent with 83% of the 20 ml air boluses triggering secondary peristalsis compared with 2% for the 2 ml water bolus (p < 0.0001). Response rates for air and water were similar for equal bolus volumes and were not influenced by the site of injection. In contrast, balloon distension usually induced a synchronous contraction above the balloon, with secondary peristalsis starting below the balloon after deflation. The peristaltic response rate to balloon distension was also volume dependent and the middle balloon was more effective in triggering secondary peristalsis than either the upper or lower balloons (p < 0.001). Secondary peristaltic amplitude was less than that of primary peristalsis (p < 0.001). Secondary peristaltic velocity with a water bolus was slower (p = 0.001) than that of primary peristalsis. Intravenous atropine significantly reduced secondary peristaltic responses to all stimuli. There was also a significant reduction in pressure wave amplitude for air stimulated secondary peristalsis while those for the water responses were similar. Secondary peristaltic velocity with air and water boluses was not changed by atropine. The reproducibility of testing secondary peristalsis was examined six volunteers and did not show any significant differences on separate test days in response rate and peristaltic amplitude or velocity. It is concluded that in normal subjects, secondary peristalsis can be more reliably triggered by intraoesophageal air or water infusion than balloon distension. Secondary peristaltic amplitude and velocity are stimulus but not site or volume dependent and propagation is partially mediated by cholinergic nerves.
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Atropine reduces the rate of reflux episodes in normal subjects by inhibition of transient lower oesophageal sphincter (LOS) relaxations. The aim of this study was to investigate the effect of atropine on the rate and mechanisms of reflux in patients with reflux disease. Oesophageal motility and pH were recorded for one hour after a meal in 15 patients with reflux disease. On separate days, atropine (15 micrograms/kg bolus intravenously, 4 micrograms/kg/h infusion) or saline were given and maintained for the recording period. Atropine significantly reduced basal LOS pressure from 7.1 (2.2) to 2.9 (1.3) mm Hg (mean (SEM)). Atropine also reduced the rate of reflux episodes from 5.0 (2.0-8.75) to 1.0 (0-6.25) per hour (median (interquartile range)) largely because of a decrease in the rate of transient LOS relaxations from 2.0 (0-4.75) to 0 (0-0) per hour and abolition of reflux during swallow induced LOS relaxation. There was no change in the rate of reflux episodes because of absent basal LOS pressure. Atropine inhibits reflux in patients with reflux disease largely by inhibition of transient LOS relaxations and swallow induced LOS relaxation. These findings suggest that pharmacological control of reflux through control of transient LOS relaxations is possible in patients with reflux disease.
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OBJECTIVE:There is controversy in the literature on the effects of anticholinergic drugs on gastroesophageal reflux. Our aim was to study more extensively the effects of an oral anticholinergic drug on esophageal motility and gastroesophageal reflux in normal ambulant subjects under different circumstances: upright, supine, fed, and fasted state.METHODS:Fifteen healthy subjects (seven men, eight women), mean age 34 yr (range, 22–61 yr) underwent randomized placebo-controlled 16-h evening and overnight ambulatory esophageal motility/pH study. After a 3-day loading dose of either oral dicyclomine (Dic) 20 mg four times daily or placebo (Pla), an ambulatory esophageal motility/pH study was performed while taking medication or placebo. Each study was analyzed for meal, first and second h postprandial, upright and supine periods, and first 2 h supine after bedtime snack.RESULTS:The mean number of reflux episodes decreased with dicyclomine during the first h postprandial (Dic, 1.9 vs Pla, 2.5; p < 0.05). During the first 2 h supine, mean number of reflux episodes increased with dicyclomine (Dic, 1.4 vs Pla, 0.8; p < 0.09), as did mean percent time pH < 4 (Dic, 2.6 vs Pla, 0.5; p < 0.04), with an increase in clearance time (Dic, 0.9 vs Pla, 0.3; p < 0.05; in min). Mean peristaltic amplitude decreased with dicyclomine during the 2nd h postprandial (Dic, 48.8 vs Pla, 56.3; p < 0.04).CONCLUSIONS:Oral dicyclomine caused a decrease in early postprandial upright reflux episodes, but also significantly increased the percent time pH
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Unlabelled: To correlate lower esophageal (LES) pressure and gastroesophageal (GE) reflux, esophageal manometry and GE scintiscanning have been used to study 40 consecutive patients. Serial scintiscanning was performed as the GE pressure gradient was increased in increments. Reflux was calculated from the ratio of esophageal to gastric radioactivity. The relationship between GE reflux and LES pressure was inverse (r = 0.60, P less than 0.005). Two subgroups of 10 patients were studied further. After atropine, LES pressure decreased from 11.2 +/- 1.1 to 5.3 +/- 0.9 mm Hg (P less than 0.01) at 20 min. The GE reflux index increased from 8.3 +/- 2.1 to 13.4 +/- 2.2% (P less than .05). After bethanechol, LES pressure increased from 8.9 +/- 0.8 to 18.5 +/- 1.0 mm Hg (P less than 0.001) at 30 min. GE reflux decreased from 11.9 +/- 2.4 to 5.8 +/- 1.7% (P less than 0.01). Conclusions: first, GE reflux correlated with basal LES pressure by an inverse relationship; second, atropine decreased LES pressure and increased reflux; third, bethanechol increased LES pressure and decreased reflux. These data suggest that LES pressure is an important determinant of GE competence.
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A muscarinic receptor subtype 1 (M1) antagonist, pirenzepine, recently has been shown to be relatively free of the usual anticholinergic side effects on esophageal smooth muscle and thus has been implicated for the treatment of gastroesophageal reflux disease (GERD). However, the effect of pirenzepine on GERD remains to be defined. Thirteen patients who demonstrated GERD in a baseline 24-hr ambulatory intraesophageal pH monitoring study were randomized in a double-blind crossover fashion to receive pirenzepine and placebo. An ambulatory 24-hr intraesophageal pH monitor was used to assess reduction in reflux (esophageal pH less than 4.0) with respect to position (upright vs supine), to total number of reflux episodes, and to episodes greater than 5 min. A significant effect for pirenzepine was seen for episodes greater than 5 min (t = 2.61, P = 0.023) and a trend towards significance was seen for total (upright and supine positions combined) percent time of reflux (t = 2.13, P = 0.055). Although not statistically significant, pirenzepine consistently showed greater reduction in all parameters of reflux tested. A greater reduction in percent time of reflux in supine vs upright positions (pirenzepine: 58.9% vs 21.4%; placebo: 43.6% vs 7.3%) may be clinically important in prevention of esophageal injury due to reflux in the recumbent position. Pirenzepine may provide a unique alternative for some GERD patients who may be refractory to other therapies of GERD.
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Esophageal acid clearance normally occurs as a two-step process. The initial step of emptying most of the fluid volume contained within the esophagus occurs quickly by gravity or by one or two peristaltic sequences. However, volume clearance is distinct from acid clearance, and esophageal pH is restored to normal after volume clearance as the 1 mL or so of residual acid is neutralized by swallowed saliva in a stepwise fashion. A considerable body of evidence has accumulated suggesting that about half of patients with reflux disease have markedly prolonged acid clearance times. Within this group abnormalities or both volume clearance and salivation have been demonstrated. Volume clearance may be impaired as a result of a breakdown of the peristaltic mechanism commonly seen with severe esophagitis or by "re-reflux" of cleared fluid from within a hiatal hernia. Either way, the result is increased residual acidic fluid within the esophagus. The increased residual acid must be titrated with saliva that has so slight a neutralizing capacity that it takes about 7 minutes for the average person to secrete enough saliva to titrate 1 mL of 0.1 N HCl. Salivation itself is reduced in cigarette smokers and in patients using anticholinergic medications, thereby prolonging the process of mucosal neutralization in such persons. Whatever the mechanism of prolonged acid clearance for a particular individual, the overall result is of prolonged esophageal mucosal acid exposure, which makes the development of peptic esophagitis more likely.
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1. The effects of atropine on gastric emptying, paracetamol absorption, salivary flow and heart rate were examined in young and elderly subjects. 2. Seven healthy young male subjects of age 23 +/- 1.3 years (mean +/- s.e. mean) and seven fit elderly subjects of age 70 +/- 1.6 years received placebo (P), 300 micrograms atropine (A300) or 600 micrograms atropine (A600) in randomized order at weekly intervals. After 10 min they ingested a 500 ml orange drink containing 1 g paracetamol. Gastric emptying was measured by ultrasound, blood samples were taken to measure plasma paracetamol concentration by h.p.l.c., salivary flow was measured by dental cotton wool cylinder technique and pulse rate was recorded. 3. In young subjects, the gastric 5 min volumes were 260.1 +/- 17.9 ml (s.e. mean) with P, 310.6 +/- 10.5 ml with A300 and 317.9 +/- 8.9 ml with A600. In elderly subjects, the gastric 5 min volumes were 166.7 +/- 10.1 ml with P, 252.6 +/- 13.7 ml with A300 and 266.0 +/- 14.8 ml with A600. Thus the early adaptive phase of gastric emptying was more rapid in the elderly than the young with all treatments (P less than 0.05). The gastric emptying half-lives were 18.8 +/- 2.5 min with P, 30.0 +/- 2.7 min with A300 and 34.5 +/- 3.3 min with A600 in young subjects (P less than 0.01). In elderly subjects, the gastric emptying half-lives were 16.1 +/- 2.5 min with P, 23.7 +/- 2.4 min with A300 and 30.0 +/- 2.9 min with A600 (P less than 0.01). Thus atropine intravenously in therapeutic dose (300 and 600 micrograms) delayed gastric emptying in both young and elderly subjects. The inhibitory effect of atropine on the early adaptive phase of gastric emptying appeared to be greater in the elderly. The maximum plasma concentration (Cmax) of paracetamol was greater in the elderly than young with all treatments (P less than 0.05). There was a close relationship between the early adaptive phase of gastric emptying and paracetamol absorption (P less than 0.05). Atropine reduced salivary flow and increased resting heart rate in both young and old subjects. The effect of atropine on salivary flow was greater in the elderly. 4. The dose-response relationship varied in the three systems (stomach, salivary glands and heart rate) studied. Age had an effect on the magnitude of the response, but not on the slope of the dose-response curve for the two doses of atropine studied.(ABSTRACT TRUNCATED AT 400 WORDS)
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The effects of five anticholinergic drugs were compared on gastric secretion, gastric emptying, and pupil diameter in the rat. Gastric secretion was obtained from the acute gastric fistula rat preparation while gastric emptying was measured by the passage of amberlite resin pellets out of the stomach. On oral administration, atropine sulfate and dicyclomine affected pupil size before the other parameters. Atropine depressed acid output and gastric emptying at the same dose, while dicyclomine depressed gastric emptying before gastric acid output. Atropine methyl bromide, scopolamine methyl iodide, and propantheline bromide first inhibited acid output, next changed pupil size, and then depressed gastric emptying. Propantheline, although not the most potent drug, had the highest ratios of acid output inhibition to pupil diameter and gastric emptying. Comparison of the drugs after subcutaneous administration showed that all drugs studied increased pupil diameter before affecting acid output or gastric emptying. Atropine sulfate and scopolamine methyl iodide depressed acid output before gastric emptying while the reverse was true with atropine methyl bromide and propantheline. Gastric acid output and gastric emptying were depressed at essentially equal doses by dicyclomine. The study suggested that relationship of secondary drug actions (pupil size and gastric emptying) to the desired action of gastric acid inhibition is more important than the absolute potency of the drugs.
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To establish whether radially determined lower esophageal sphincter pressure responds symmetrically or asymmetrically to anticholinergic medication, we compared the rightward and leftward pressure responses to intravenous atropine injection. In 12 normal adult volunteers, the decrease in highest leftward lower esophageal sphincter pressure with atropine was more marked (40% decrease) than rightward (20% decrease). The result of this differential response to atropine was to reduce right-left pressure asymmetry. Mean highest leftward pressure fell 15-30 min postinjection from 35 to 21 mmHg and mean highest rightward pressure fell from 22 to 18 mmHg. Studies of the pharmacologic effect of drugs on the human lower esophageal sphincter may give variable results depending on sampling orientation within the sphincter. These radial differences should be considered in interpreting the effect of drugs on the human lower esophageal sphincter.
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Modern manometric and scintigraphic techniques were employed in an effort to determine the relationships between esophageal contractions and esophageal transit and clearance. The effects of direct cholinergic stimulation with bethanechol and blockade with atropine were evaluated in a total of 20 normal subjects and 13 patients with symptomatic gastroesophageal reflux. Bethanechol increased the amplitudes of deglutition-induced and distention-induced esophageal contractions, but diminished their propagation velocities. Both esophageal transit and clearance were decreased in patients with reflux, but both were improved after bethanechol. Atropine sulfate decreased the amplitudes of contractions, accelerated their propagation velocities, and delayed esophageal transit and clearance. Both transit and clearance were diminished significantly when reflux patients were compared with normal subjects. The amplitudes of esophageal contraction were significantly lower in patients with reflux than in normal subjects. Neither bethanechol nor atropine affected the incidence of deglutition-induced esophageal contractions. These studies suggest that the efficiency of esophageal emptying may be determined by the amplitudes of esophageal contractions.
Article
Low basal lower esophageal sphincter (LES) pressure is believed to be an important mechanism of reflux. The effects of atropine on the frequency and mechanisms of gastroesophageal reflux under the experimental conditions of a low basal LES pressure in 13 normal subjects were studied. LES pressure, esophageal pressures, esophageal pH, and crural diaphragm electromyogram were recorded simultaneously in the postprandial period for 30 minutes before and two 30-minute periods after the injection of atropine. Atropine reduced the basal LES pressure from 16.4 +/- 3 to 8.7 +/- 2 mm Hg. The frequencies of reflux in the control and two postatropine periods were 3.5 +/- 0.5, 0.4 +/- 0.2, and 0.8 +/- 0.3, respectively (P < 0.05). The frequencies of transient LES relaxations decreased from 3.5 +/- 0.5 in the control to 0.4 +/- 0.2 and 1.5 +/- 0.4 in the two postatropine periods (P < 0.05). Transient LES relaxation and associated inhibition of the crural diaphragm was the major mechanism of reflux under conditions of low LES pressure induced by atropine. Atropine-induced low LES pressure does not predispose to reflux in normal healthy subjects. Atropine reduces the frequency of reflux by its inhibitory effect on the frequency of transient LES relaxation.
Article
Traditionally, gastro-oesophageal reflux is deemed to have occurred when oesophageal pH falls below 4. Other 'non-traditional' pH changes that do not fall below pH 4, that fall below 4 for only brief intervals, or that occur when basal pH is less than 4 are usually disregarded. The aim of this study was to determine whether these non-traditional pH changes represent gastro-oesophageal reflux or are artefactual. The 3-h postprandial combined oesophageal pH and manometric records of 22 patients referred for investigation of suspected gastro-oesophageal reflux were reviewed. All pH falls of > or = 0.5 pH units were analysed for manometric evidence of reflux that was classified as definite, probable, or possible. In total, 196 traditional and 223 non-traditional pH events were scored and analysed. The majority of traditional (80%) and non-traditional (60%) events were associated with definite manometric evidence of reflux, although a greater proportion of non-traditional events were associated with only probable evidence of reflux (33%) compared with traditional events (18%). The proportions of possible reflux were similar in the two groups. Limiting pH events to only those satisfying traditional criteria excluded an additional 32% with definite manometric evidence of reflux and 49% with definite or probable evidence of reflux. Most pH falls that remained above 4 or fell across 4 for < 15 sec occurred in the 1st h postprandially, compared with traditional pH events, which occurred equally throughout the 3-h period. We conclude that traditional criteria for scoring pH episodes substantially underestimate the number of reflux episodes.
Article
Atropine decreases the frequency of transient lower oesophageal sphincter relaxation (TLOSR) through an unknown mechanism. Gastric distension and pharyngeal receptor excitation are two possible sources for the afferent stimulus responsible for TLOSR. To determine whether atropine affects gastric distension induced TLOSR and pharyngeal receptor mediated lower oesophageal sphincter (LOS) relaxation. Oesophageal manometry and pH recordings were performed in 10 healthy volunteers on two separate days in the postprandial setting, following either atropine (15 micrograms/kg intravenous bolus and 4 micrograms/kg/h as a maintenance dose) or placebo. Pharyngeal receptor mediated LOS relaxation was studied in nine subjects by rapid injection of minute amounts of water (0.05, 0.1, 0.2, 0.3, and 0.4 ml) in the pharynx before and after atropine. Gastric distension mediated TLOSR was studied in eight subjects by insufflating the stomach with 300, 600 and 900 ml of CO2 before and after atropine. Atropine reduced the frequency of spontaneous gastro-oesophageal reflux and TLOSR compared with placebo (p < 0.05). Pharyngeal stimulation resulted in bolus volume dependent LOS relaxation. Atropine decreased the frequency and amplitude of pharyngeal receptor mediated LOS relaxation at bolus volumes of 0.05, 0.1, and 0.2 ml. Gastric distension resulted in intermittent episodes of TLOSR. The frequency of gastric distension induced TLOSR was significantly decreased by atropine. (1) Atropine reduces the frequency of spontaneous reflux and TLOSR in normal subjects; and (2) gastric distension induced TLOSR and pharyngeal receptor mediated LOS relaxation is inhibited by atropine.
Article
There is controversy in the literature on the effects of anticholinergic drugs on gastroesophageal reflux. Our aim was to study more extensively the effects of an oral anticholinergic drug on esophageal motility and gastroesophageal reflux in normal ambulant subjects under different circumstances: upright, supine, fed, and fasted state. Fifteen healthy subjects (seven men, eight women), mean age 34 yr (range, 22-61 yr) underwent randomized placebo-controlled 16-h evening and overnight ambulatory esophageal motility/pH study. After a 3-day loading dose of either oral dicyclomine (Dic) 20 mg four times daily or placebo (Pla), an ambulatory esophageal motility/pH study was performed while taking medication or placebo. Each study was analyzed for meal, first and second h postprandial, upright and supine periods, and first 2 h supine after bedtime snack. The mean number of reflux episodes decreased with dicyclomine during the first h postprandial (Dic, 1.9 vs Pla, 2.5; p < 0.05). During the first 2 h supine, mean number of reflux episodes increased with dicyclomine (Dic, 1.4 vs Pla, 0.8; p < 0.09), as did mean percent time pH < 4 (Dic, 2.6 vs Pla, 0.5; p < 0.04), with an increase in clearance time (Dic, 0.9 vs Pla, 0.3; p < 0.05; in min). Mean peristaltic amplitude decreased with dicyclomine during the 2nd h postprandial (Dic, 48.8 vs Pla, 56.3; p < 0.04). Oral dicyclomine caused a decrease in early postprandial upright reflux episodes, but also significantly increased the percent time pH < 4 during the first two h supine. Therefore, its effects are dependent on body position and fasted or fed state. Our results justify additional studies with oral anticholinergic agents in patients with gastroesophageal reflux disease.
Article
Atropine, an anticholinergic agent with central and peripheral actions, reduces gastro-oesophageal reflux (GOR) in normal subjects and patients with gastro-oesophageal reflux disease (GORD) by inhibiting the frequency of transient lower oesophageal sphincter relaxation (TLOSR). To compare the effect of methscopolamine bromide (MSB), a peripherally acting anticholinergic agent, with atropine on the rate and mechanism of GOR in patients with GORD. Oesophageal motility and pH were recorded for 120 minutes in 10 patients with GORD who were studied on three separate occasions. For the first two recording periods, either atropine (15 microg/kg bolus, 4 microg/kg/h infusion) or saline were infused intravenously. MSB (5 mg orally, four times daily) was given for three days prior to the third recording period. Atropine significantly reduced basal LOS pressure (12.6 (0.17) mm Hg to 7.9 (0.17) mm Hg), and the number of TLOSR (8.1 (0.56) to 2.8 (0. 55)) and reflux episodes (7.0 (0.63) to 2.0 (0.43)) (p<0.005 for all comparisons). MSB reduced basal LOS pressure (12.6 (0.17) to 8.7 (0. 15) mm Hg, p<0.005), but had no effect on the frequency of TLOSR (8. 1 (0.56) to 7.5 (0.59)) and reflux episodes (7.0 (0.63) to 4.9 (0. 60)) (p>0.05). In contrast to atropine, MSB has no effect on the rate of TLOSR or GOR in patients with GORD. Atropine induced inhibition of TLOSR and GOR is most likely mediated through a central cholinergic blockade.
Article
Ambulatory 24-hr esophageal pH monitoring is considered the gold standard for diagnosing gastroesophageal reflux disease (GERD). The current approach is to encourage patients to pursue their everyday activity in order to obtain near-physiological recordings. However, the effect of the test itself on reflux-provoking activities has never been evaluated. Thus, the aim of our study was to assess daily food consumption, habits, symptoms, sleep, and perceived experience of patients undergoing pH testing as compared to an off test (normal) day. Patients reported type and time spent in each activity pursued, food ingested and length of each meal, habits, frequency and severity of GERD and other related symptoms, sleep disturbances, side effects, and overall perceived experience during pH testing and four weeks later, during a normal day. Fifty-four patients enrolled. pH testing significantly reduced time spent being active, number of meals and cups of coffee consumed, and frequency of GERD symptoms. Almost half of the patients reported having dysphagia during the test. Most patients experienced side effects and stated that the test bothered them most of the time. In conclusion, pH testing has a significant effect on decreasing reflux-provoking activities-patients tend to assume a more sedentary lifestyle. This may influence the reliability of the test as a physiologic measure of acid reflux.
Article
Esophageal acid exposure is higher in gastroesophageal reflux disease (GERD) patients with hiatus hernia than in those without. We investigated the effect of a sliding hiatus hernia on the mechanisms underlying spontaneous gastroesophageal reflux over 24 hours. Twelve GERD patients with and 10 GERD patients without hiatus hernia were studied for 24 hours. Combined esophageal pH and manometric recordings of the pharynx, lower esophageal sphincter (LES), and stomach were performed using a multiple-lumen assembly incorporating a Dent sleeve connected to a portable water-perfused manometric system and a pH glass electrode. Patients with hiatus hernia had greater esophageal acid exposure (7.6% vs. 3.3%; P < 0.01) and more reflux episodes (3.1 vs. 1.8/h; P < 0.001) than those without. LES pressure, the incidence of transient LES relaxations (TLESRs), and the proportion of TLESRs associated with acid reflux were comparable in both groups. Both groups had equal numbers of reflux episodes associated with TLESRs and swallow-associated prolonged LES relaxations. Patients with hiatus hernia had more reflux associated with low LES pressure, swallow-associated normal LES relaxations, and straining during periods with low LES pressure. The excess reflux in GERD patients with hiatus hernia compared with those without is caused by malfunction of the gastroesophageal barrier during low LES pressure, swallow-associated normal LES relaxations, deep inspiration, and straining.
Inhibition of TLESR by atropine reexamined. Primary or secondary effect? Gastroen-terology
  • Joseph S G Shi
  • Brasseur
  • Jg
Joseph S, Shi G, Brasseur JG, et al. Inhibition of TLESR by atropine reexamined. Primary or secondary effect? Gastroen-terology 2000;118:A861. 2311 AJG – August, 2001