Dual site ambulatory pH monitoring: a probe across the lower esophageal sphincter does not induce gastroesophageal reflux.

BACKGROUND: Twenty-four-hour ambulatory pH studies have traditionally been performed with placement of the pH electrodes proximal to the lower esophageal sphincter (LES). More recently, simultaneous gastric and esophageal pH monitoring studies have been performed to allow the simultaneous assessment and correlation of esophageal and gastric pH. OBJECTIVES: The purpose of this study was to determine if pH probe placement across the LES increases esophageal acid exposure either in asymptomatic, healthy volunteers or in symptomatic patients with a documented history of erosive esophagitis. METHODS: Ten healthy volunteers (five female, five male; mean age 27 yr) and 13 patients with endoscopically confirmed erosive esophagitis (seven female, six male; mean age 35 yr) were randomly assigned, in cross-over fashion, into two protocols. The first protocol required placement of a dual antimony pH electrode catheter (2.1-mm outside diameter) across the LES with pH electrodes positioned 5 cm above and 10 cm below the manometrically identified LES. The second protocol required catheter placement 5 cm and 20 cm above the LES. Twenty-four-hour pH monitoring was performed on all subjects. Healthy volunteers were permitted an unrestricted diet and were studied in an out-patient setting. Symptomatic patients were assessed in an inpatient setting on a standardized diet with a refluxogenic dinner meal. RESULTS: The total number of reflux episodes, number of reflux episodes greater than 5 min, and the fraction of time that pH was less than 4 were evaluated over the total 24-h time period in the upright and supine positions. Nonparametric paired tests including a Wilcoxon signed rank test and a Robust analysis were used for statistical assessment. There was no significant increase in gastroesophageal reflux observed with placement of the pH probe across the LES either in the asymptomatic healthy volunteers or in patients with documented erosive esophagitis. Neither upright nor supine esophageal acid exposures were modified by catheter placement. CONCLUSIONS: Our study results indicate that placement of a 2.1-mm diameter pH probe across the LES does not induce reflux in asymptomatic healthy volunteers or in patients with GERD. Dual site ambulatory pH monitoring with trans-sphincteric pH catheter placement is a valid diagnostic technique that can be applied clinically when required.

Omeprazole is superior to ranitidine plus metoclopramide in the short-term treatment of erosive oesophagitis.

Histamine H2-receptor antagonists are moderately effective in symptomatic treatment and healing of erosive oesophagitis, but they are not as effective as the proton pump inhibitor omeprazole. In some studies prokinetic agents seem to increase the effectiveness of H2-antagonists, but no study comparing the efficacy of omeprazole to H2-antagonists plus prokinetic agents has been performed. The purpose of this study was to compare the efficacy and tolerability of 20 mg omeprazole daily with 150 mg ranitidine b.d.s. plus the prokinetic agent 10 mg metoclopramide q.d.s. in patients with erosive oesophagitis. After both 4 and 8 weeks of treatment, omeprazole healed the mucosa in significantly more patients than did ranitidine plus metoclopramide. Omeprazole also provided significantly greater relief from daytime heartburn, nighttime heartburn, and acid regurgitation, and was associated with decreased concomitant antacid use. Although the overall incidence of adverse events was similar in the two treatment groups, a significantly higher number of treatment-related adverse events and more treatment-related withdrawals from the study occurred in the ranitidine plus metoclopramide treatment group. Omeprazole is more effective and better tolerated than the combination of standard dose ranitidine plus metoclopramide for patients with erosive oesophagitis.

Famotidine (20 mg) b.d. relieves gastrooesophageal reflux symptoms in patients without erosive oesophagitis. Famotidine/GERD Investigation Group.

Previous clinical trials have evaluated a large number of symptomatic individuals with heartburn. Most studies have documented the need for multiple daily dosing with H2-antagonists to achieve clinical and statistical efficacy for symptom relief. The purpose of this study was to compare the safety profile and efficacy of famotidine oral dosing regimens, 40 mg nocte and 20 mg b.d. with placebo in the relief of symptoms in patients suffering from frequent heartburn found to have endoscopically normal oesophageal mucosa or mild non-erosive oesophagitis. Famotidine (20 mg) b.d. reduced and eventually completely relieved gastro-oesophageal reflux disease symptoms in most patients during the 6-week trial. Global assessment of improvement at 2 and 6 weeks indicated significantly greater improvement with a b.d. treatment regimen than with either a 40 mg nocte or placebo treatment. No statistically significant differences between famotidine and placebo in the number of patients who experienced clinical adverse experiences were noted and no serious adverse events attributable to famotidine occurred. Based upon these findings, patients with gastro-oesophageal reflux symptoms experience good relief of their complaints with twice daily famotidine in standard doses.

Prevalence of gastroesophageal reflux in elderly patients in a primary care setting.

Despite the aging of our population, there remains a paucity of information about gastroesophageal reflux (GER) in the elderly. To assess the prevalence and characteristics of GER within this patient population, questionnaires evaluating symptoms associated with GER were administered to 313 consecutive patients 62 yr old or older from a primary care setting. Fourteen percent of these patients reported having at least weekly heartburn. Ambulatory 24-h esophageal pH monitoring was accomplished in 54 of the 313 patients surveyed. Twenty percent (11/54) of this subgroup exhibited increased acid contact time (pH less than 4 for more than 6% of the monitoring period). Twenty-two percent (12/54) complained of heartburn, yet only six individuals (11%) exhibited both symptomatic and objective indications of acid reflux. Surprisingly, 31% (17/54) of the patients studied exhibited significant alkalinity within the distal esophagus (pH greater than 8 for greater than 1.5% of the monitoring period). Whereas 29% of these patients (5/17) reported heartburn, 40% of those reporting heartburn (2/5) had acid GER as well as excessive alkalinity. In contrast to patients with acid GER--none of whom reported pulmonary symptoms--24% (4/17) of these patients with esophageal alkalinity reported wheezing, nocturnal cough, or paroxysmal nocturnal dyspnea. Of the four patients with significant distal esophageal exposure to both acid and alkali, two reported heartburn and a third reported dysphagia. In addition to the somewhat higher prevalence of acid reflux than anticipated, a surprisingly high prevalence of esophageal alkalinity was observed.

Gastroprotective and ulcer healing profile of the mast cell stabilizer quazolast in rats.

Quazolast, a mast cell stabilizer, was evaluated for efficacy against acid independent (alcohol, HCl), or dependent (aspirin, indomethacin) gastric damage in rats. Its gastroprotective profile was compared to that of ranitidine. In addition, the antisecretory and gastric ulcer (acetic acid induced) healing capabilities of these agents were examined. Quazolast, in direct contrast to ranitidine, protected the rat gastric mucosa from acid-independent, but not acid-dependent gastric damage. Quazolast lacked antisecretory activity in rats; however, it did heal acetic acid induced gastric ulcers in this species. On day 15 after acetic acid injection, quazolast significantly healed such ulcers, while ranitidine did not. Although the exact mechanisms of gastroprotection and ulcer healing action for quazolast remain to be determined, it may be an effective agent for the treatment of gastric ulcers.

Experience with omeprazole in erosive oesophagitis.

Omeprazole is a potent, highly specific, and clinically efficacious anti-secretory agent. Current clinical data suggest that omeprazole could be a useful drug in the short-term treatment of patients with severe erosive oesophagitis resistant to standard H2-receptor antagonist therapy. The magnitude of omeprazole's eventual role in the treatment of acid secretory-related disorders will depend on the results of its expanded postmarketing clinical experience and upon resolution of concerns regarding potential adverse effects associated with long-term administration.

RG 12915: a potent 5-hydroxytryptamine-3 antagonist that is an orally effective inhibitor of cytotoxic drug-induced emesis in the ferret and dog.

RG 12915 [4-[N-(1-azabicyclo[2.2.2.]octan-3-(S)-yl)]2-chloro-cis 5a-(S)-9a-(S)-5a,6,7,8,9,9a-hexahydrobenzofurancarboxamide hydrochloride] is a potent and effective agent against cisplatin-induced emesis in the ferret after i.v. or p.o. administration. This agent (p.o.) is also highly protective against cisplatin-induced emesis in the dog, as well as cyclophosphamide/doxorubicin-induced emesis in the ferret. When administered either p.o. or i.v., RG 12915 has a lower ED50 value (0.004 mg/kg) than GR 38032F, BRL 43694 and metoclopramide for attenuating cisplatin-induced emetic episodes in the ferret. It also has a long duration of action against cisplatin-induced emesis in the ferret. In contrast to metoclopramide, RG 12915 lacks significant antidopaminergic activity both in vitro [( 3H]spiroperidol displacement), as well as in vivo (apomorphine-induced emesis). In radioligand binding assays, RG 12915 is a potent and selective displacer of binding of 5-hydroxytryptamine (5-HT)3 binding sites (IC50 value = 0.16 nM), whereas failing to displace binding of ligands for the alpha-1, alpha-2 and beta adrenergic, 5-HT1 or 5-HT2 or cholinergic-muscarinic sites with IC50 values less than 1 microM. At a p.o. dose (1 mg/kg) in which RG 12915 is highly protective against cisplatin-induced emesis in the dog, RG 12915 has no significant gastroprokinetic activity in the same species. In summary, RG 12915 is a potent and p.o. effective agent against cytotoxic drug-induced emesis in animal models. The antiemetic potency of RG 12915 against cisplatin is unrelated to antidopaminergic or gastroprokinetic activity, but may be related to its affinity for 5-HT3 binding sites.

Gastroesophageal reflux: clinical diagnosis, current therapy, future trends.

In the usual clinical setting, symptomatic gastroesophageal reflux can be equated with heartburn; however, the diagnosis of gastroesophageal reflux disease (GERD) can be obscure. Recent improvements in the quality of fiberoptic endoscopy along with other imaging and diagnostic techniques have permitted a more complete understanding of the pathophysiology of gastroesophageal reflux. The continued development of antisecretory, prokinetic, and mucosal protective agents allows the gastroenterologist a choice of effective therapeutic approaches to deal with contributing factors such as gastric acid secretion, lower esophageal sphincter pressure, or gastric motility. Although standard doses of potent H2-receptor antagonists are the focus of current reflux disease therapy, increasingly aggressive regimens will probably become available for refractory patients.

Antiinflammatory effects of various drugs on acetic acid induced colitis in the rat.

The efficacy of various drugs used to treat ulcerative colitis, (sulfasalazine, 5-aminosalicylate, hydrocortisone) was investigated in a model of acetic acid-induced colitis in the rat. Subsequently, we tested the ability of antioxidant/5-lipoxygenase inhibitors (gossypol and nordihydroguiaretic acid [NDGA]) and a cyclooxygenase inhibitor (indomethacin) to attenuate the macroscopic colonic damage and/or neutrophil influx (myeloperoxidase activity [MPO]) associated with this model of colitis. Oral pretreatment with either sulfasalazine, gossypol, or NDGA significantly decreased colonic MPO activity induced by acetic acid. Intrarectal administration of such drugs resulted in an even larger reduction of the colonic inflammation, with gossypol being the most potent compound. Oral or intrarectal administration of corticosteroids (dexamethasone, hydrocortisone) also attenuated the parameters of acetic acid induced colitis. In contrast, pretreatment with indomethacin was ineffective, or when administered daily after colitis induction, indomethacin actually increased colonic neutrophil influx significantly. Our data suggest that both the route of drug administration and dosing regimen employed affect the antiinflammatory potency and/or efficacy of compounds on colitis induced by acetic acid in the rat. Drugs which were effective against this colitis may act by scavenging of oxygen derived free radicals.

Esophageal motility, heartburn, and gastroesophageal reflux: variations in clinical presentation of esophageal dysphagia.

Dysphagia is a potentially important symptom, often leading to the finding of an anatomical or motility disorder of the esophagus. Dysphagia and heartburn represent two of the most common symptoms associated with esophageal motility disorders. To explore the relationship of symptomatic esophageal dysphagia and heartburn and their association with primary esophageal motor disorders, we have performed a retrospective assessment of 1035 patient evaluations performed at our gastrointestinal laboratory. A clear statistical association of symptomatic dysphagia and heartburn was established; however, no pattern diagnostic of a specific motility disorder was discernible. A sizable fraction of our patient population with dysphagia demonstrated normal esophageal motility. A significant portion of dyspeptic patients exhibited both normal motility and acid exposure. The differences observed between the incidence of subjective symptoms and objective dysfunction may be explained in part by an altered or increased esophageal sensitivity of these patients.

Acute effects of ranitidine, famotidine and omeprazole on plasma gastrin in the rat.

In the rat, treatment with gastric inhibitory drugs may result in hypergastrinemia, an effect thought to be in response to increased gastric pH caused by inhibition of acid secretion. This study compared 24-hr profiles of plasma gastrin levels associated with three different compounds at equivalent, highly effective antisecretory doses. Ranitidine, famotidine and omeprazole at 60, 20 and 40 mg/kg p.o., respectively, inhibited basal acid secretion of chronic gastric fistula rats by greater than 95% and raised intraluminal pH to above 7.0 for 5 hr. The peak plasma gastrin levels associated with each agent were observed 5 hr after dosing. Ranitidine, famotidine and omeprazole induced statistically significant and distinct peak hypergastrinemic responses of 312 +/- 20, 483 +/- 28 and 616 +/- 27 pg/ml, respectively. After 8 hr ranitidine and famotidine associated gastrin values returned to control levels, whereas those of omeprazole remained substantially above control values until the 12th hr. Differences in peak gastrin levels between compounds disappeared at increased dose levels of 500 mg/kg for ranitidine, 200 or 2000 mg/kg for famotidine and 140 mg/kg for omeprazole. Unlike high dose famotidine, omeprazole (140 mg/kg) maintained peak plasma gastrin levels at 8, 12, and 16 hr after dosing. These studies demonstrate clearly hypergastrinemic responses to single dose administration of ranitidine, famotidine and omeprazole. The differences observed in peak plasma gastrin levels at equivalent antisecretory doses of these agents suggests the presence of luminal acid independent components that effect gastrin release. Moreover, these studies indicate that, in the rat, the most unique aspect of omeprazole-associated hypergastrinemia is the magnitude of its prolonged response.

Substituted 2-[(2-benzimidazolylsulfinyl)methyl]anilines as potential inhibitors of H+/K+ ATPase.

A series of substituted 2-[(2-benzimidazolylsulfinyl)methyl]anilines were synthesized as potential inhibitors of the acid secretory enzyme H+/K+ ATPase. Substitutions on the aniline nitrogen atom resulted in potent enzyme inhibition in vitro but weak activity in gastric fistula dogs. Electron-donating substituents on the aniline ring enhanced in vitro and in vivo potency relative to the unsubstituted analogue. The potency showed a correlation to the calculated pKa of the aniline nitrogen atom. Substitutions on the aniline and benzimidazole rings did not further enhance potency. Di- and trisubstituted aniline derivatives were potent inhibitors of the enzyme system. The preferred combination of substituents were a methoxy group on the benzimidazole ring and a single alkyl group on the aniline ring. One such compound, 76, was an effective inhibitor of acid secretion in the dog and was selected for further pharmacological study.

Effect of metoclopramide, bethanechol and the cholecystokinin receptor antagonist, L-364,718, on gastric emptying in the rat.

The prokinetic effects of metoclopramide, bethanechol and L-364,718 on a semisolid meal and solid pellet gastric emptying were evaluated and compared. Each compound increased the rate of meal emptying as measured 90 min post-dose. L-364,718, a non-peptide CCK antagonist, was the most potent of these three agents with statistically significant activity observed at 0.03, 0.1 and 0.3 mg/kg p.o. Only metoclopramide significantly enhanced pellet emptying in a dose-dependent manner (3-30 mg/kg p.o.). The effects of each test agent and the potential physiologic role of cholecystokinin in regulating gastric emptying are discussed.

Lidamidine inhibits intrinsic contractile patterns of the rat proximal colon.

Lidamidine is a clinically effective antidiarrheal agent that inhibits intestinal secretion, reduces intestinal transit, and inhibits smooth muscle contraction. Yet, its specific effects upon colonic motility have not been thoroughly examined. The purpose of our studies was to examine lidamidine's inhibitory effects upon colonic contractile patterns in the rat and identify the responsible receptor mechanism. Fasted male rats were anesthetised and equipped with an intraluminal cannula positioned at the proximal end of a 10 cm fluid-filled segment of the ascending colon (basal pressure, 10 cm H2O). Intraluminal pressure was monitored by a transducer attached to a closed fluid-filled system. All drugs were administered intravenously by slow infusion. A regular pattern of distinct contractile complexes was observed over a 70 min period. These contractions increased intraluminal pressure to 39 +/- 1.2 cm H2O (mean +/- S.E.), occurred at a frequency of 0.3 per min and lasted from 1 to 2.5 min. Inhibition of these contractile patterns was observed with either atropine (0.1 mg/kg) or lidamidine (3.0 mg/kg). A 20 min pretreatment with idazoxan (3.0 mg/kg) antagonized lidamidine's but not atropine's effect. Trimazosin (1 mg/kg) or propranolol (0.3 mg/kg) pretreatment did not antagonize the lidamidine-generated inhibition. These results indicate that lidamidine inhibits an intrinsically generated, cholinergically controlled pattern of colonic contractions primarily by an alpha 2-receptor-mediated mechanism.

An intracellular characterization of neurones and neural connexions within the left coeliac ganglion of cats.

Intracellular recordings were made in vitro from neurones located within the left coeliac ganglion of the cat solar plexus. Thirty percent of the neurones within left coeliac ganglia were identified as efferent neurones. Within this neuronal population, splenic-efferent and renal-efferent neurones were identified specifically. Neurones within left coeliac ganglia were characterized as either phasic (fast adapting) neurones or tonic (slowly adapting) neurones depending upon their prolonged firing behaviour. Electrophysiological properties of neurones varied considerably. The wide range of values obtained for both input resistance and input capacitance suggest that sizeable differences in either specific membrane resistance or cell geometry exist within the over-all neurone population. Frequency distributions of input resistance, time constant, input capacitance and current threshold for tonic and phasic neurones were found to be significantly different. Compound excitatory post-synaptic potentials were produced by stimulation of the ipsilateral splanchnic nerves in 69% of the neurones tested and in 3% of the neurones tested upon stimulation of the contralateral splanchnic nerves. Electrical stimulation of nerve fibres located in the coeliac plexus, the superior mesenteric plexus or the left renal nerves generated excitatory synaptic potentials in neurones located within left coeliac ganglia. It is concluded that neurones within the left coeliac ganglion are innervated by splanchnic nerve fibres primarily contained within the left splanchnic nerves, receive excitatory synaptic input from splenic, renal and other peripheral preganglionic fibres and have extremely varied electrophysiological properties.

A study of renal-efferent neurones and their neural connexions within cat renal ganglia using intracellular electrodes.

1. Intracellular recordings were made, in vitro, fron neurones located within left renal ganglia and left coeliac ganglia of cat solar plexus. 2. Forty-three percent of the neurones of the renal ganglia tested were identified by antidromic activation as renal-efferent neurones. 3. Electrical stimulation of all nerve trunks emanating from renal ganglia, other than the renal nerves, did not antidromically activate renal ganglia neurones. Neurones not antidromically activated were designated as non-efferent neurones. 4. Neurones within the renal ganglia were also characterized as phasic or tonic neurones depending on their pattern of discharge. 5. Electrical stimulation of renal nerves produced excitatory synaptic potentials (e.p.s.p.s) in 18% of the renal-efferent neurones. 6. Compounded e.p.s.p.s were produced in 50% of the renal ganglia neurones tested by stimulation of the ipsilateral splanchnic nerves and in 84% of the neurones upon stimulation of the vertebral nerve. 7. Synaptic responses demonstrating characteristics typical of those induced by activation of multisynaptic neural pathways were produced upon stimulation of renal and coeliac nerves. 8. The results of this study indicate that the electrophysiological properties of renal-efferent neurones vary considerably from neurone to neurone and that these neurones receive synaptic inputs from a variety of preganglionic fibres and possibly from other neurones having their soma located within the solar plexus.