Nocturnal Acid Breakthrough Research Articles

Effect on Intragastric pH of a PPI with a Prolonged Plasma Half-Life: Comparison between Tenatoprazole and Esomeprazole on the Duration of Acid Suppression in Healthy Male Volunteers

To compare the inhibitory effect of a novel proton pump inhibitor (PPI), tenatoprazole 40 mg once daily, with esomeprazole 40 mg once daily on intragastric acidity. A randomized, investigator-blind, two-way, crossover study was conducted in 30 healthy Helicobacter pylori negative male volunteers. Tenatoprazole 40 mg or esomeprazole 40 mg was administered once daily for 7 consecutive days with a 4-wk washout period between treatments. Ambulatory 24-h intragastric pH was recorded at baseline, after 7 days' treatment, and 3 and 5 days after treatment was stopped. At presumed steady-state (day 7), median 24-h pH values were 5.02 and 4.79 for tenatoprazole and esomeprazole, respectively. There was a significant difference between tenatoprazole and esomeprazole during the nocturnal period when mean pH was 4.64 +/- 0.67 versus 3.61 +/- 0.90, respectively (p < 0.0001), as well as a significantly higher mean percentage of time with pH >4 on tenatoprazole (72.5 +/- 14.9 vs 62.2 +/- 13.6, p < 0.0001). The effect of tenatoprazole was still present 5 days after treatment withdrawal especially during the night-time. The mean area under the plasma concentration-time curve and elimination half-time was significantly higher in the tenatoprazole group as compared with the esomeprazole group. Tenatoprazole 40 mg daily provides a prolonged duration of acid suppression and a shorter nocturnal acid breakthrough in healthy volunteers, even after stopping the drug. Thus, tenatoprazole may provide greater clinical efficacy for patients in whom a once daily PPI is ineffective. Further studies are indicated.

Unlike delayed-release pantoprazole, immediate-release omeprazole reduces nocturnal acid breakthrough

Unlike delayed-release pantoprazole, immediate-release omeprazole reduces nocturnal acid breakthrough

Comparison of the effects of immediate‐release omeprazole powder for oral suspension and pantoprazole delayed‐release tablets on nocturnal acid breakthrough in patients with symptomatic gastro‐oesophageal reflux disease

Many patients treated with a proton-pump inhibitor for gastro-oesophageal reflux disease or erosive oesophagitis still have substantial night-time gastric acidity. A previous trial of a new immediate-release omeprazole oral suspension suggested that nocturnal gastric acidity could be more effectively controlled with a bedtime dose of immediate-release omeprazole than with a delayed-release proton-pump inhibitor administered before dinner or at bedtime. To compare the ability of immediate-release omeprazole with pantoprazole to control nocturnal gastric acidity, when they were dosed once daily and twice daily. Thirty-six patients with nocturnal gastro-oesophageal reflux disease symptoms received immediate-release omeprazole and pantoprazole in this open-label, randomized-crossover trial. Median gastric pH, the percentage of time with gastric pH > 4 and the percentage of patients with nocturnal acid breakthrough, were evaluated with 24-h pH monitoring. Repeated once daily (bedtime) dosing with immediate-release omeprazole suspension produced significantly better nocturnal gastric acid control than repeated once daily (predinner) or twice daily (prebreakfast and bedtime) dosing with pantoprazole delayed-release tablets (median pH: 4.7 vs. 2.0 and 1.7; percentage of time pH > 4: 55 vs. 27 and 34; nocturnal acid breakthrough: 53 vs. 78 and 75). Twice daily dosing (prebreakfast and bedtime) with immediate-release omeprazole 20 and 40 mg achieved the best night-time control of gastric acidity. Repeated once daily bedtime dosing with immediate-release omeprazole 40 mg and twice daily dosing with pantoprazole 40 mg gave similar 24-h pH control. No safety issues were associated with either drug in this trial. Dosed once daily at bedtime, immediate-release omeprazole reduced nocturnal gastric acidity to a degree not observed with once daily dosing of delayed-release proton-pump inhibitors.

Control of intra-oesophageal and intra-gastric pH with proton pump inhibitors in patients with Barrett's oesophagus

Background. A significant percentage of patients with Barrett's oesophagus (BE) will continue to manifest abnormal intra-oesophageal pH profiles regardless of proton pump inhibitor (PPI) therapy. Aims. We conducted a prospective study in order to determine whether a change in PPI therapy would alter intra-oesophageal and intra-gastric acid suppression in BE patients. Patients. Seventeen Helicobacter pylori-negative BE patients (16 males, 1 female; mean ± S.D. age, 63.5 ± 13.2). Methods. Twenty-four-hour pH monitoring was performed on omeprazole or lansoprazole, followed by repeat pH monitoring on rabeprazole at a dose titrated for symptom relief. Patients completed validated symptom and health-related quality-of-life (HRQL) surveys while on and off therapy. Results. Ten (59%) of the 17 patients had abnormal baseline intra-oesophageal pH profiles. Oesophageal pH monitoring values on rabeprazole were abnormal in five out of five (100%) of the omeprazole cohort and three out of five (60%) of the lansoprazole cohort that had abnormal pH profiles on initial testing. Intra-gastric pH control was inadequate in BE patients on all PPIs; the mean percentage time with intra-gastric pH below 4.0 was 46% on omeprazole, 71% on lansoprazole and 51% on rabeprazole ( p = 0.25). All of the patients demonstrated the phenomenon of nocturnal acid breakthrough while undergoing PPI therapy. Conclusions. Change in PPI therapy did not alter intra-oesophageal or intra-gastric control in patients with BE.

Comparison of an increased dosage regimen of rabeprazole versus a concomitant dosage regimen of famotidine with rabeprazole for nocturnal gastric acid inhibition in relation to cytochrome P450 2C19 genotypes

A concomitant dosage regimen of a histamine 2 receptor antagonist with a proton pump inhibitor (PPI) effectively decreases the incidence of nocturnal acid breakthrough, which is one of the problems encountered when acid-related diseases are treated with a PPI alone. We compared the effectiveness of an increased dosage regimen of rabeprazole with that of a concomitant dosage regimen of rabeprazole with famotidine, relative to cytochrome P450 (CYP) 2C19 genotype status, on nocturnal acid inhibition. Fifteen Helicobacter pylori-negative volunteers, consisting of 5 homozygous extensive metabolizers (EMs), 6 heterozygous EMs, and 4 poor metabolizers (PMs) of CYP2C19, took 20 mg rabeprazole, 40 mg rabeprazole, and 20 mg rabeprazole plus 20 mg famotidine at bedtime (at 10 PM) for 8 days. The subjects then underwent 24-hour intragastric pH monitoring on day 8. For the 20-mg rabeprazole, 40-mg rabeprazole, and concomitant dosage regimens, the median percent times and ranges when nocturnal intragastric pH values were lower than 4.0 were 78.8% (47.5%-98.0%), 45.3% (29.0%-52.2%), and 15.5% (0.0%-40.8%), respectively, for homozygous EMs; 51.0% (7.0%-91.6%), 41.3% (33.0%-59.0%), and 18.5% (8.4%-31.9%), respectively, for heterozygous EMs; and 4.5% (2.0%-31.2%), 9.5% (0.0%-31.1%), and 9.3% (0.0%-14.7%), respectively, for PMs. Although significant differences in acid inhibition between the different CYP2C19 genotypes were observed when rabeprazole alone was given (P = .016 for 20 mg rabeprazole and P = .023 for 40 mg rabeprazole), such differences were not observed when famotidine was concomitantly given (P = .206). The combination regimen of famotidine plus rabeprazole is more effective for nocturnal acid inhibition in homozygous and heterozygous EMs than the increased dosage regimen of rabeprazole. This concomitant therapy could be a rescue regimen for patients with nocturnal acid breakthrough refractory to a standard PPI therapy who are likely to be CYP2C19 EMs.

Barrett′s oesophagus: Is there a need for laparoscopic anti-reflux surgery?

Barrett′s oesophagus: Is there a need for laparoscopic anti-reflux surgery?

Contemporary diagnostic and management techniques for extraesophageal reflux disease

To review recent advances in the diagnosis and treatment of extraesophageal reflux. For most patients, the diagnosis of extraesophageal reflux relies on history and laryngoscopic exam. The reliability and reproducibility of reporting these measures may be improved with validated symptom questionnaires and standardized scoring of physical exam findings. Though dual probe pH monitoring has been the gold standard for diagnosis, it does not measure non-acid reflux events. Intraluminal impedance monitoring has the capability of measuring all esophageal reflux events (liquid, solid, gas) and may be useful in the diagnosis of non-acid reflux. Proton pump inhibitors have replaced histamine receptor antagonists as the mainstay of treatment for extraesophageal reflux. Histamine receptor antagonists are used predominantly for nocturnal acid breakthrough, or step-down therapy. Promotility and cytoprotective agents are used less commonly. Baclofen is currently being evaluated for its ability to decrease the incidence of transient lower esophageal sphincter relaxations and reduce post-prandial acid and non-acid reflux events. For individuals refractory to medical therapy, laparoscopic fundoplication techniques have proven efficacy in relieving some symptoms; the long-term benefit is not yet known. There is yet no established data on the effects of endoluminal therapies on extraesophageal reflux symptoms. The diagnosis of extraesophageal reflux for most patients relies on history and laryngoscopic exam. The diagnosis can be further verified by dual probe pH and impedance monitoring. Proton pump inhibitors are the mainstay of treatment. Laparoscopic fundoplication is proven to relieve symptoms, but there is yet no data on the effects of endoluminal therapies on extraesophageal reflux symptoms.

PROTON PUMP INHIBITORS HAVE A MORE PROFOUND EFFECT ON GASTRIC ACID SECRETION IN FEMALE AND OLDER GERD PATIENTS

Purpose: Proton pump inhibitor (PPI) therapy is believed to be equally effective in all patients with upper GI symptoms. However, data is lacking on the degree of PPI efficacy in various subgroups including males, females, the young and old where acid secretion rates may differ (Gas-troenterology 1991; 101: 977-990). Therefore, our aim was to assess the influence of gender and age in PPI inhibition of basal and pentagas-trin (Pg)-stimulated gastric acid secretion (GAS) in symptomatic GERD patients. Methods: A total of 36 GAS studies were conducted in 15 male (22–69 y) and 10 female (35–67 y) HP-negative GERD patients on a daily AM dose of PPI therapy for 8–10 days. Basal and Pg (6 mcg/kg, s.c.)-stimulated GAS was measured during the trough period (22–24 h post-dose). Gastric acid was continuously aspirated via a nasogastric tube, aspirate volume recorded, [H+] measured by titration to pH 7.0, pH determined and GAS calculated. Results: In females, PPIs had a more significant effect on both basal and Pg-stimulated GAS compared to males (Table; median data; *+P <0.03). The same was true for inhibition of Pg-stimulated GAS in older (age >44 y) compared to younger (age <44 y) patients (Table). Differences in GAS were due to significant decreases in gastric [H] and volume secretion in female and older patients (Table). Interestingly, median intragastric pH under basal conditions was pH 2.0 or less during steady state conditions. Furthermore, median Pg-stimulated gastric volumes were over 100 ml/h in males and younger patients.Table: PPI-inhibition of GAS in GERD PatientsConclusions: In GERD patients on daily PPI therapy: 1. PPIs have a more profound effect on GAS in female and older subjects; and 2. Despite steady-state conditions, significant gastric acid secretion was noted. We speculate that these findings may explain the variability in PPI efficacy in GERD as is seen in clinical practice, and may have implications in nocturnal acid breakthrough.

OMEPRAZOLE IMMEDIATE-RELEASE ORAL SUSPENSION IS MORE EFFECTIVE THAN PANTOPRAZOLE DELAYED-RELEASE CAPSULES IN REDUCING NIGHTTIME GASTRIC ACIDITY IN GERD PATIENTS

Purpose: The present trial was conducted to evaluate nighttime dosing of omeprazole imediate-release oral suspension (OME-IR[SUSP]) in once- and twice-daily regimens, comparing the effect of OME-IR on nocturnal gastric acidity to that of pantoprazole (P), the only PPI with FDA-approved labeling for reduction in rate of nighttime heartburn symptoms. Methods: Thirty-two patients with nocturnal GERD symptoms were enrolled in a crossover trial with 40-mg doses of P (Protonix®, Wyeth-Ayerst, Philadelphia) given at 2200 hrs (bedtime) on Day 1 and prior to dinner on Days 2–6 and 40-mg OME-IR(SUSP) (Santarus, San Diego) given at 2200 hrs on Days 1-6. On Day 7, both PPIs were given 1 hr prior to breakfast and at 2200 hrs: P 40 mg (n = 32); OME-IR 40 mg (n = 17) and 20 mg (n = 15). Continuous 24-hr gastric pH monitoring (Medtronic) was performed on Days 1, 6, and 7. Median gastric pH,% time pH was >4, and the proportion of patients with “nocturnal acid breakthrough” (NAB) (> 1 hr of continuous pH <4) were determined for the nighttime period (2200-0600 hrs). Results: Nighttime median gastric pH on Day 6 is shown below. For this 8-hr period, median % time pH was >4 was greater for OME-IR (5 5%) than for P (27%) (p <0.001); median pH was 4.7 for OME-IR and 2.0 for P (p <0.001); and NAB occurred in fewer OME-IR-treated patients (17/32) than P-treated patients. (25/32) (p = 0.005). For the 8-hr nighttime period after twice-daily dosing, median % time pH was >4 was greater for OME-IR (40 mg and 20 mg) than for P (92% vs. 37% and 79% vs. 31%, p <0.001 each); median pH was also higher (6.5 vs. 1.5 and 5.8 vs. 1.9, p <0.001 each). NAB occurred in fewer OME-IR-treated patients than P-treated patients (2/17 vs. 12/17 and 7/15 vs. 12/15, p<0.025 each). Conclusions: OME-IR(SUSP) is more effective in reducing nighttime gastric acidity than P. These results suggest that OME-IR may also be more effective than delayed-release PPIs in controlling nighttime symptoms of GERD when dosed at bedtime.[figure 1]Figure

NIGHTTIME DOSING OF OMEPRAZOLE IMMEDIATE-RELEASE ORAL SUSPENSION RAPIDLY DECREASES NOCTURNAL GASTRIC ACIDITY

Purpose: Proton pump inhibitors (PPIs) suppress gastric acid secretion sufficiently to treat most symptoms of GERD. However, in some patients, PPIs fail to control nighttime gastric acid secretion and also fail to control nighttime GERD symptoms. The PPIs used to treat these symptoms have all been delayed-release formulations with enteric coatings. A new omeprazole immediate-release suspension (OME-IR[SUSP]) has been developed, using sodium bicarbonate to protect the acid-labile PPI, rather than the traditional delayed-release enteric coating. The present trial was conducted to evaluate the effectiveness of OME-IR(SUSP) in controlling nighttime gastric acidity after twice-daily (b.i.d.) dosing. Methods: Seventeen healthy subjects were enrolled in this open-label trial. Single 20-mg doses of OME-IR(SUSP) (Santarus, San Diego) were given 1 hr prior to breakfast (qAM) for 7 days. On Day 8, the 20-mg suspension was given b.i.d.: at 0830 hrs (1 hr prior to a standardized high-fat breakfast) and at 2200 hrs (bedtime). On Days 7 and 8, standardized lunch and dinner were given at 1300 and 1800 hrs. Gastric pH was continuously monitored (Medtronic) for 24 hrs following the morning doses on Days 7 and 8. The percent time pH was >4 was assessed for the 8-hr nighttime period (2200-0600 hrs) and for the 24-hr period following the morning dose. The proportion of subjects with “nocturnal acid breakthrough” (NAB) (> 1 hr of continuous pH <4) was assessed for the 8-hr nighttime period. Results: The figure below displays the 24-hr median gastric pH profile at steady state for b.i.d. dosing of OME-IR 20 mg. After the bedtime dose, OME-IR 20 mg abruptly raised the gastric pH and sustained this effect for approximately 8 hrs. The median % time pH was >4 was greater for b.i.d dosing (87%) than for qAM dosing (39%) (p <0.001). NAB occurred in fewer subjects dosed b.i.d. (5/17 [29%]) than dosed qAM (13/17 [76%]) (p = 0.005).[figure 1]FigureConclusions: Twice-daily dosing (before breakfast and at bedtime) with OME-IR(SUSP) is effective in controlling nighttime acidity. Nighttime administration of OME-IR(SUSP) may be more effective in controlling nighttime GERD symptoms than delayed-release PPIs.

Nocturnal acid breakthrough: pH, drugs and bugs.

Nocturnal acid breakthrough (NAB) was defined by Peghini et al. in 1998 as the presence of at least 60 continuous minutes of intragastric pH < 4 during the overnight period (22:00-06:00 h) in patients taking a proton pump inhibitor (PPI) twice-daily before meals. NAB was shown to occur in more than 70% of patients on PPI therapy but can be decreased or eliminated by adding a histamine-2 receptor antagonist (H2RA) at bedtime. Helicobacter pylori status influences intragastric acid control on PPI therapy: H. pylori-positive patients having better gastric acid control compared with their H. pylori-negative counterparts. Recent data indicate that NAB might not occur in H. pylori-positive subjects on twice-daily PPI, suggesting there is no need for combined PPI twice-daily and H2RA therapy to control night-time gastric acid secretion in these individuals. The clinical importance of NAB has been debated ever since this concept was introduced. The importance of NAB in healthy subjects and asymptomatic, uncomplicated gastro-oesophageal reflux disease patients on PPI therapy may be low, but ignoring it in patients with poor oesophageal motility and Barrett's oesophagus may result in suboptimal treatment. Further studies are warranted to investigate whether leaving H. pylori to 'assist'acid suppression obtained by PPI twice-daily, adding bedtime H2RAs after successful H. pylori eradication or other approaches to eliminate NAB results in better clinical outcomes.

Are there unmet needs in acid suppression?

The development of proton-pump inhibitors (PPIs) caused impressive improvements in the control of gastric acid secretion. The clinically related consequences are most clearly expressed in the therapy of gastroesophageal reflux disease (GERD). Despite these glamorous outcomes, there still are unmet clinical needs. Ideally, full 24-h control of gastric acid secretion should be available to fine tune acid suppressant therapy to the individual clinical needs. Full control of acid secretion with oral PPI therapy in the presence of a healthy non-Helicobacter pylori-infected gastric mucosa is difficult, if not impossible, at present. However, there are circumstances in which full control is desirable if not essential (intensive care, esophageal columnar metaplasia, etc.). In particular, the so-called nocturnal acid breakthrough is difficult to control, particularly in patients with esophageal columnar metaplasia. But even for ordinary GERD, full symptom control and patient satisfaction is often lacking, necessating additional over-the-counter medication for control of remaining symptoms. A recent Gallup interview of 1000 symptomatic GERD patients stressed the frequency of nocturnal symptoms, insufficiently controlled with standard PPI therapy. Current PPIs are also suboptimal for 'on-demand' therapy in Non-Erosive Reflux Disease (NERD)/GERD. Moreover, rebound acid secretion after abrupt stopping of PPI therapy may favour early symptomatic relapse, necessating step-down therapy to prevent prolongation of the need of acid suppression.

Rabeprazole 10 mg twice daily is superior to 20 mg once daily for night-time gastric acid suppression.

Insufficient acid suppression is one of the main causes of proton pump inhibitor-refractory gastro-oesophageal reflux disease. To achieve more potent and long-lasting acid suppression, different dosage regimens of rabeprazole were compared in relation to the CYP2C19 genotype status. In a cross-over study, 18 healthy Helicobacter pylori-negative males (six homozygous extensive metabolizers, six heterozygous extensive metabolizers and six poor metabolizers) were given rabeprazole 10 mg once daily, 20 mg once daily or 10 mg twice daily, or water only (baseline data), for 7 days each. On day 7 of each regimen, 24-h intragastric pH-metry was performed. No significant differences were observed in median pH values and pH>4 holding time ratios between rabeprazole 10 mg once daily and 20 mg once daily. However, with rabeprazole 10 mg twice daily, these parameters were significantly higher than those with 20 mg once daily. The potency of acid suppression by rabeprazole was influenced by the CYP2C19 genotype status. The differences were somewhat significant but not large. The incidence of nocturnal acid breakthrough was lowest with rabeprazole 10 mg twice daily. Rabeprazole 10 mg twice daily, not 20 mg once daily, should be administered to achieve more potent and long-lasting acid suppression.

Nocturnal gastric acid breakthrough may not be a problem of acid secretion only

Nocturnal gastric acid breakthrough may not be a problem of acid secretion only

New developments in the pathophysiology of gastro-oesophageal reflux disease (GERD): implications for patient management.

The spectrum of gastro-oesophageal reflux disease (GERD) has expanded; indeed the majority of individuals with symptomatic GERD do not have erosive reflux disease (ERD); this group has been referred to as nonerosive or negative-endoscopy reflux disease (NERD). There may be important differences between NERD and ERD in terms of pathophysiology and management. Thus, NERD patients appear relatively resistant to proton pump inhibitors and may not be good surgical candidates. The clinician caring for patients with GERD must therefore be aware of the full spectrum of GERD and of the pathophysiological and therapeutic implications of NERD. Recent twin studies have revealed that genetic factors play a role in GERD and form the basis for future studies on the role of inheritance in the various manifestations of GERD. Several recent investigations have reaffirmed the primacy of acid reflux in the pathogenesis of GERD and have also provided insights into the pathophysiology of postprandial heartburn. Transient lower oesophageal sphincter relaxations and hiatal hernias have emerged as major and interacting factors in the genesis of reflux events and in the potentiation of acid exposure; the former are attracting considerable attention as a potential therapeutic target. Nocturnal acid breakthrough, which has been implicated in the failure of some patients to respond to high doses of proton pump inhibitors, appears, on further examination, to be a gastric rather than an oesophageal phenomenon, and may not be of clinical or therapeutic importance.

Nocturnal acid breakthrough: clinical significance and correlation with esophageal acid exposure

Objectives Previous studies suggest that the addition of H2 receptor antagonist (H2RA) therapy is more effective than proton pump inhibitor (PPI) therapy alone in reducing nocturnal acid breakthrough (NAB). However, the clinical significance of NAB with respect to esophageal acid control has not been investigated. The aim of this study was to evaluate prospectively the degree of upright and supine esophageal and gastric acid suppression using various PPI regimens in comparison to the addition of an H2RA at bedtime. Methods A total of 22 subjects (13 with gastroesophageal reflux disease and nine who served as control subjects) were prospectively evaluated by serial combined esophageal and gastric 24-h pH monitoring. Studies were performed at baseline off antireflux medical therapy and subsequent to completion of the following four drug regimens: 1) omeprazole 20 mg b.i.d. for 2 wk; 2) omeprazole 20 mg b.i.d. plus ranitidine 300 mg HS for 4 wk; 3) omeprazole 20 mg QAM and QHS for 2 wk; and 4) omeprazole 20 mg every 8 h for 2 wk. A dual pH probe was placed 5 cm above and 10 cm below the manometrically defined LES for a minimum of 18 h. Median total, upright, and supine pH values were compared among treatment regimens. All subjects underwent Helicobacter pylori serology testing. Results A total of 17 men and eight women (mean age 37 yr ± 2.4 yr, range 22–71 yr) were enrolled in the study. Total, upright, and supine median percentage of the time that gastric pH was <4 were significantly less than baseline values in all treatment regimens. Although patients treated with Q8 h omeprazole had significantly ( p < 0.01) more gastric acid suppression, there was a high degree of overlap among regimens. Treatment regimens resulted in NAB elimination of 9–41%. However, no single treatment regimen resulted in more significant NAB suppression than the others. Despite continued NAB with all treatment regimens, esophageal acid reflux (90%) and patient symptoms (100%) were well controlled. In addition, there were no differences in the esophageal median percentage of time that pH was <4 for any treatment regimen. Conclusions NAB is an isolated gastric phenomenon that is poorly controlled even with most aggressive acid suppressive therapy. Esophageal acid suppression and symptom control are not dependent on the degree of NAB elimination.

Nocturnal Acid Breakthrough in Perspective: Let's Not Throw Out the Baby With the Bath Water

Nocturnal Acid Breakthrough in Perspective: Let's Not Throw Out the Baby With the Bath Water

Novel therapeutic strategies in acid-related disorders

Acid-related disorders of the upper gut encompass diseases of the oesophagus, stomach and duodenum, such as gastro-oesophageal reflux disease (GORD), gastric and duodenal (peptic) ulcers, Zollinger–Ellison syndrome and iatrogenic ulcers and gastrointestinal bleeding mostly induced by non-steroidal anti-inflammatory drugs (NSAIDs). Gastric acid and pepsin are largely involved in their pathophysiology, both factors acting with Helicobacter pylori (especially in peptic ulcers) or with either NSAIDs, stress or smoking. All these diseases can benefit from agents that neutralise gastric acid or inhibit its secretion. Neutralising acid with antacids or decreasing acid secretion with histamine H2-receptor antagonists (H2-RAs) was the standard of care before the introduction of proton pump inhibitors (PPIs), which have been one of the major advances in the field of gastrointestinal pharmacology. Their superior efficacy in acid-related disorders with respect to other acid reducing drugs is now widely recognised. PPIs are also used to control atypical GORD symptoms, such as laryngitis, asthma and cough associated with reflux. In spite of their clinical efficacy in a number of conditions, the emerging need for new therapeutic approaches, such as ‘on-demand’ treatment for GORD symptoms, requires some features (e.g., fast onset of action at day 1 with an acid suppressant effect throughout the day and night, to avoid the nocturnal acid breakthrough) that currently available PPIs only partially achieve. Moreover, a subset of patients with GORD still do not respond to the available therapeutic regimens. Novel agents (or novel formulations of available PPIs) have recently been patented to try to overcome these problems.

The pharmacology and clinical relevance of proton pump inhibitors.

Gastroesophageal reflux disease is a complex, multifaceted disorder affecting a large proportion of the US population. Its management is based on the principle of optimal antisecretory therapy, mainly with proton pump inhibitors (PPIs). The optimal treatment outcome is complete symptom relief, which can be achieved with optimal use of PPIs. PPI treatment requires an understanding of the pharmacology of these agents as well as their clinical efficacy, strengths, and weaknesses. This paper reviews the pharmacology of PPIs, the principles of optimal dosing, nocturnal gastric acid breakthrough and its clinical importance, and a treatment approach to gastroesophageal reflux disease using these agents.

An evaluation of the clinical implications of acid breakthrough in patients on proton pump inhibitor therapy.

Some patients with gastro-oesophageal reflux disease continue to experience symptoms despite therapy with proton pump inhibitors. One recently proposed cause is the occurrence of nocturnal acid breakthrough. : To investigate the relationship between acid breakthrough occurrence (nocturnal and daytime) and refractory symptoms among patients with gastro-oesophageal reflux disease on proton pump inhibitors. Fifty-two consecutive patients with persistent symptoms of gastro-oesophageal reflux disease despite proton pump inhibitor therapy underwent 24-h pH study at the Mayo Clinic between January 1 and November 10, 1999. Relevant data were extracted and analysed. Fifty-two patients, 18 males and 34 females, were eligible for the study. The mean age was 53 +/- 2.2 years. Thirty-seven patients (71%) had nocturnal acid breakthrough, and 36 (69%) had daytime acid breakthrough. Sixty per cent of patients experienced both nocturnal and daytime acid breakthrough, whereas 19% had neither. Among those with nocturnal and daytime acid breakthrough, only 36% and 33% of symptoms, respectively, were associated with gastro-oesophageal reflux episodes. The proportion of patients with symptoms and the mean symptom scores were not significantly different between those with and without acid breakthrough. Gastric acid breakthrough occurs nocturnally and during the daytime in patients on proton pump inhibitor therapy. With less than 36% of refractory symptoms associated with gastro-oesophageal reflux, gastric acid breakthrough cannot explain symptom refractoriness to proton pump inhibitor therapy in a significant majority of patients evaluated by 24-h pH study.