Malcolm Robinson

Mesalamine capsules for the treatment of active Crohn's disease: Results of a 16-week trial

BACKGROUNDnMesalamine is released from sulfasalazine in the colon and benefits colonic Crohns disease. The mesalamine used in this study releases the drug throughout the small bowel and colon. Therefore, this study was designed to detect benefit for Crohns disease involving the small bowel alone or both the colon and small bowel.nnnMETHODSnThis double-blind, randomized, multicenter prospective controlled trial compared placebo and three daily doses of mesalamine in 310 patients. The primary outcome criterion was change in the Crohns Disease Activity Index (CDAI) from baseline to final study visit.nnnRESULTSnPatients taking 4 g/day mesalamine experienced a decrease of 72 CDAI points compared with 21 points in the placebo group (P < 0.01). Remission occurred in 43% of the 4-g group and 18% of the placebo group. Patients with ileum-only disease showed a 93-point improvement on 4 g mesalamine, compared with a 2-point improvement in similar patients on placebo. Mesalamine in this trial was not associated with clinically significant toxicity.nnnCONCLUSIONSnThis controlled-release mesalamine preparation is safe and effective at 4 g/day as a single agent in treatment of active Crohns disease of the ileum and colon.

Effect of ranitidine gastroduodenal mucosal damage induced by nonsteroidal antiinflammatory drugs

The effect of ranitidine in preventing mucosal damage caused by nonsteroidal antiinflammatory drugs (NSAIDs) was evaluated for eight weeks in a prospective study of 144 patients requiring NSAIDs. Patients with normal endoscopic findings were randomly assigned to receive either ranitidine 150 mg twice daily or placebo for eight weeks, along with either ibuprofen, indomethacin, naproxen, sulindac, or piroxicam. Duodenal damage was significantly less in the ranitidine group compared with the placebo group by weeks 4 and 8 (P≤0.01). Duodenal ulcers did not develop in any patients on ranitidine (0/57) compared with 4/49 patients (8%) on placebo (P=0.02). No significant difference was found between treatment groups with respect to gastric damage; 6/60 (10%) in the ranitidine group compared with 6/50 (12%) in the placebo group developed gastric ulcers. These findings suggest that acid suppression is of greater importance for mucosal protection in the duodenum than in the stomach, where other defense mechanisms may be operative. While ranitidine is an effective prophylaxis for NSAID-induced damage in the duodenum, further studies are needed to define specific risk groups and to assess the potential usefulness of more complete acid suppression in preventing gastric mucosal damage.

Clinical pharmacology of proton pump inhibitors: what the practising physician needs to know.

Proton pump inhibitors (PPIs) [omeprazole, lansoprazole, pantoprazole, rabeprazole and esomeprazole] are widely utilised for the treatment of gastro-oesophageal reflux disease, as well as other acid-related disorders. All PPIs suppress gastric acid secretion by blocking the gastric acid pump, H+/K+-adenosine triphosphatase (ATPase), but the physicochemical properties of these drugs result in variations in the degree of acid suppression, as well as the speed of onset of acid inhibition. Such differences may impact on the clinical performance of PPIs, and this manuscript discusses data that may help clinicians choose between the available PPIs for specific clinical situations and indications. The characteristics of PPIs that have been developed subsequent to omeprazole offer several advantages over this prototype PPI, particularly with respect to the onset of acid suppression and reduced potential for inter-individual pharmacokinetic variation and drug interactions. Newer agents inhibit H+/K+-ATPase more rapidly than omeprazole and emerging clinical data support potential clinical benefits resulting from this pharmacological property.Although key pharmacokinetic parameters (time to maximum plasma concentration and elimination half-life) do not differ significantly among PPIs, differences in the hepatic metabolism of these drugs can produce inter-patient variability in acid suppression, in the potential for pharmacokinetic drug interactions and, quite possibly, in clinical efficacy. All PPIs undergo significant hepatic metabolism. Because there is no direct toxicity from PPIs, there is minimal risk from the administration of any of them — even to patients with significant renal or hepatic impairment. However, there are significant genetic polymorphisms for one of the cytochrome P450 (CYP) isoenzymes involved in PPI metabolism (CYP2C19), and this polymorphism has been shown to substantially increase plasma levels of omeprazole, lansoprazole and pantoprazole, but not those of rabeprazole. Hepatic metabolism is also a key determinant of the potential for a given drug to be involved in clinically significant pharmacokinetic drug interactions. Omeprazole has the highest risk for such interactions among PPIs, and rabeprazole and pantoprazole appear to have the lowest risk.Thus, whereas all PPIs have been shown to be generally effective and safely used for the treatment of acid-mediated disorders, there are chemical, pharmacodynamic and pharmacokinetic differences among these drugs that may make certain ones more, or less, suitable for treating different patient subgroups. Of course, the absolute magnitude of risk from any PPI in terms of drug-drug interactions is probably low — excepting interactions occurring as class effects related to acid suppression (e.g. increased digoxin absorption or inability to absorb ketoconazole).

Two doses of omeprazole versus placebo in symptomatic erosive esophagitis: The U.S. multicenter study

Two hundred thirty patients with reflux symptoms and endoscopically proven erosive esophagitis were enrolled from 15 U.S. centers into a randomized, double-blind, dose-ranging study comparing placebo with omeprazole, 20 or 40 mg given once daily in the morning. Esophagitis grade 2 was present in 44% of patients, grade 3 in 37% of patients, and grade 4 in 19% of patients. Endpoints, defined as complete relief of heartburn and complete esophageal mucosal healing, were assessed after 4 and 8 weeks of treatment. Both omeprazole doses were significantly superior to placebo in complete endoscopic healing. After 8 weeks of treatment, 73.5% of patients in the 20-mg omeprazole group and 74.7% in the 40-mg omeprazole group, compared with 14.0% in the placebo group, had complete healing of the esophageal mucosa. At the end of the study, complete relief of daytime heartburn was obtained in 79.5% of patients in the 20-mg omeprazole group, 81.6% in the 40-mg omeprazole group, and 37.2% in the placebo group (P less than or equal to 0.05). Complete relief of nighttime heartburn was noted by 79.5% of patients in the 20-mg omeprazole group, 85.1% in the 40-mg omeprazole group, and 34.9% in the placebo group (P less than or equal to 0.05). The median time to complete relief of daytime and nighttime heartburn occurred earlier in the 40-mg group than in the 20-mg group (9 vs. 17 days and 9 vs. 20 days, respectively); however, these differences were not statistically significant. Relief of acid regurgitation and dysphagia also occurred earlier in the 40-mg group. Omeprazole was well tolerated in this group of patients. No unexpected adverse experiences occurred. The results of this study confirm those of six multicenter, international trials in which omeprazole in doses of 20-60 mg provided a degree of esophageal mucosal healing and complete relief of reflux symptoms superior to any other medical treatment.

Acid clearance during sleep in the pathogenesis of reflux esophagitis

Impaired esophageal clearing of refluxed gastric contents during sleep has been implicated in the pathogenesis of reflux esophagitis. To more directly evaluate this hypothesis, 13 symptomatic patients with esophagitis and 13 normal controls had 15 ml of 0.1 N HCl instilled into the esophagus in the recumbent position while awake and during polygraphically monitored sleep. When sleep was maintained for the majority of the acid-clearing duration, the clearance times for both patients and controls were significantly prolonged when compared to those while awake (P<0.01). However, when sleep was maintained for less than 50% of the acid-clearing interval, the patients showed significantly longer acid clearance times. The swallowing rate did not differentiate the two groups under any condition. These data show that sleep impairs esophageal acid clearance. Acid clearance occurred predominantly in association with arousals from sleep. The defective acid clearance found in patients with esophagitis probably plays a major role in the pathogenesis of this disorder.

Budesonide enema for the treatment of active, distal ulcerative colitis and proctitis: A dose-ranging study

BACKGROUND & AIMSnBudesonide is a highly potent topical glucocorticosteroid that is characterized by low systemic availability as a result of high first-pass hepatic metabolism. The aim of this study was to evaluate the efficacy and safety of three doses of an enema preparation of budesonide in patients with active distal ulcerative colitis/proctitis.nnnMETHODSnIn a double-blind multicenter trial, 233 patients were randomized to receive either a placebo enema or budesonide enema at a dose of 0.5 mg/100 mL, 2.0 mg/100 mL, or 8.0 mg/100 mL. The primary efficacy variables were an improvement of sigmoidoscopic inflammation grade, total histopathology score, and remission rates. Effects on cortisol concentrations were also assessed.nnnRESULTSnAfter 6 weeks of treatment, there was significant improvement in sigmoidoscopy and histopathology scores in the budesonide 2.0-mg and 8.0-mg dose groups compared with placebo. Remission was achieved in 19% of patients in the 2.0-mg budesonide group (P </= 0.050) and 27% of patients in the 8.0-mg budesonide group (P </= 0.001) compared with 4% in the placebo group. More than 90% of all budesonide patients had a normal adrenocorticotropin (ACTH)-stimulated cortisol response at the last visit. The budesonide enemas were well tolerated.nnnCONCLUSIONSnBudesonide enema is both effective and safe for the treatment of active distal ulcerative colitis/proctitis. A dose of 2. 0 mg/100 mL budesonide is the lowest effective dose.

Effective maintenance treatment of reflux esophagitis with low-dose lansoprazole. A randomized, double-blind, placebo-controlled trial.

In most patients, erosive reflux esophagitis can be temporarily healed by using short-term therapy with acid-suppressing agents [1, 2]. A recent review [1], which combined healing rate results from published reports of randomized studies by drug class, found that histamine-2-receptor antagonists resulted in endoscopically documented healing in 48% of patients and that omeprazole produced healing in 78% of patients. After esophagitis has healed, however, a maintenance regimen must be considered. Erosive esophagitis is a chronic disorder, and 28% to 80% of patients, depending on disease severity [3-7], have relapse within the first 6 months after short-term treatment. For long-term therapy for esophagitis, a physician can choose to follow patients and treat relapses over the short-term with acid-suppressing agents in full healing doses. Another strategy is to prescribe daily maintenance treatment. However, lower doses of currently available therapies, including omeprazole, ranitidine, famotidine, and cimetidine, have not been found to be as effective as full healing doses in maintaining healing [8-11]. Lansoprazole, a new proton pump inhibitor, effectively suppresses production of gastric acid over 24 hours when consumed once every morning [12]. Lansoprazole has been shown to be highly effective for treating erosive esophagitis, with healing rates similar to those of omeprazole [13]. In the belief that lansoprazole would provide effective maintenance treatment and to determine the lowest effective maintenance dose, we compared two doses of lansoprazolethe effective healing dose of 30 mg and a lower dose of 15 mgwith placebo in a yearlong study. The first portion of the study design followed the standard approach to measuring the effectiveness of maintenance treatment in erosive esophagitis. Patients with healed esophagitis were treated until relapse or, if they remained healed, for as long 1 year. In the primary efficacy analysis, we compared the effect of lansoprazole with that of placebo on the time until endoscopically documented recurrence of erosion. However, the study differed from usual maintenance studies at the point at which patients had a documented relapse. After the first recurrence, patients were not immediately withdrawn from the study. Instead, patients who had relapse entered the second portion of the study and were treated with open-label lansoprazole, 30 mg/d for 8 weeks. If erosion rehealed with this treatment, the patient continued in the study and received double-blind therapy in a manner that matched the original randomization code. Patients could thus remain in the study after one or more recurrences, but they could remain no longer than 12 months. This portion of the study design was used to meet a secondary objective: to compare the number of times erosion recurred while patients received daily maintenance treatment (lansoprazole treatment groups) with the number of recurrences that developed while patients received active treatment only at the time of a diagnosed recurrence (placebo group). Methods Study Design This multicenter study was conducted at 25 centers ( 20 patients/center) and enrolled 186 patients who had a recent history of erosive reflux esophagitis. Investigators enrolled patients who showed healing of erosive esophagitis at the end of an 8-week short-term study [14]. In addition, new patients (recruited primarily from the investigators existing patient sample) who met entrance criteria similar to those in the short-term study and patients who were not healed at the end of short-term study received open-label lansoprazole, 30 mg/d for 8 weeks. At the end of this open-label lead-in phase, patients with endoscopically proven healing of erosive esophagitis entered the double-blind maintenance phase of the study. Healing was documented within 7 days before patients entered the maintenance study. At entry into the 12-month maintenance study, patients were randomly assigned in such a way that the treatment groups at each site had similar numbers of patients. We used double-blind procedures and separate randomization schedules with consecutive numbering for each site to assign patients to receive placebo, 15 mg of lansoprazole, or 30 mg of lansoprazole in a single daily dose before breakfast. All medications were similar in appearance, taste, and directions for use. All study personnel (including participants, investigators, endoscopists, study monitors, pharmacists, statisticians, and pathologists) were blinded to treatment during the study. Endoscopy was done after 1, 2, 3, 6, 9, and 12 months. In addition, at any time during the maintenance period, a patient who reported symptoms suggesting recurrence of esophagitis was examined by endoscopy. If an erosive recurrence, symptomatic or asymptomatic, was documented on endoscopy, the patient received open-label lansoprazole, 30 mg/d for 8 weeks. If repeated endoscopy showed healing after 8 weeks of open-label treatment, the patient returned to the originally assigned treatment. Patients could be treated in this manner as many times as necessary during the 12-month period. If erosions did not heal, the patient was dropped from the study. Patients who completed the 12-month maintenance phase entered a 3-month post-treatment phase in which no acid-suppressive medication was administered. Patients had endoscopy after 1 month and at the end of this period. Patients were given Gelusil tablets [Parke-Davis, Morris Plains, New Jersey] for relief of discomfort as needed. Patients were not allowed to take other acid-suppressive or ulcerogenic medications during any phase of the study except for 1) 325 mg or less of aspirin per day for cardiovascular indications or two doses of a nonsteroidal anti-inflammatory drug per week for any indication and 2) systemic or topical corticosteroids not exceeding 10 mg of prednisone (or equivalent) per day. Evaluations were scheduled before randomization and took place monthly for the first 3 months and then at 6, 9, and 12 months. Each regular study visit included endoscopic assessment; evaluation of symptoms, Gelusil use, and adverse events; physical examination and recording of vital signs data; and clinical laboratory evaluations, including measurement of the fasting serum gastrin level. Gastric biopsies were done at each scheduled endoscopy. To standardize the grading scale and biopsy procedures, endoscopists were trained at an investigator meeting. At each site, efforts were made to ensure that the same endoscopist would do all endoscopies for a particular patient. All biopsy specimens were evaluated at a central location under the direction of Drs. Walter Rubin, Barbara Atkinson, and Marian Haber at the Medical College of Pennsylvania in consultation with Dr. Juan Lechago from Baylor College of Medicine. Patients Patients enrolled in the study had completed an earlier study of short-term lansoprazole treatment for erosive esophagitis [14] or had received a diagnosis of erosive esophagitis and had never received lansoprazole therapy. Patients showed endoscopic evidence of grade 2 or higher esophagitis on the modified Savary-Miller scale (that is, at least one or more erosions proximal to the squamocolumnar junction) before receiving short-term healing treatment. Patients were required to have endoscopic evidence of healing within 7 days of entering the double-blind maintenance phase. Healing was defined as a return of the esophageal mucosa to grade 0 or grade 1 (that is, no evidence of erosion). The investigational review board at each site approved the protocol and patient consent form for study participation. Patients were excluded from the trial if they were younger than 18 years of age or had not given informed consent. Study End Points The primary efficacy variable was the time to the first recurrence of erosive esophagitis, symptomatic or asymptomatic, as determined by endoscopy. Erosive recurrence was defined as grade 2 or higher. Other measures of efficacy during this period included maintenance of symptom relief, severity of daytime and nighttime heartburn, and frequency of Gelusil use. Throughout the 12-month maintenance period, we also analyzed the number of erosive relapses and the frequency of Gelusil use; at the final treatment visit, we analyzed the severity of symptoms. We did not measure baseline Gelusil use. Safety variables included assessments of adverse events, measurement of clinical laboratory variables (including gastrin levels), physical examination, electrocardiogram, and vital signs data. Full-mucosal thickness biopsy specimens from the greater curvature were obtained in a subset of patients in the clinical trial. Slides were evaluated qualitatively for patterns of enterochromaffin-like cell hyperplasia according to the Solcia classification of gastric endocrine cell growth [15]. Statistical Analysis We used the SAS software program (SAS Institute, Cary, North Carolina) to do all statistical analyses. Analyses were based on two-tailed tests, and significance was defined as a P value 0.05 or less. We compared the percentage of patients whose erosive esophagitis remained healed among treatment groups. Because this analysis used data obtained until the first erosive recurrence only, it did not differ from what would have occurred had patients been dropped after the first recurrence. Probabilities of remaining healed after months 1, 2, 3, 6, 9, or 12 of maintenance therapy were estimated using a life-table method [16], in which it is assumed that patients who withdrew from the study would have the same rate of recurrence as those who did not withdraw. The P values in pairwise comparisons of maintenance rates among treatment groups were based on Cochran-Mantel-Haenszel tests, with time as the stratification factor [16]. Endoscopies done more than 5 days after the last day of dosing in any treatment period were not used in the analysis. At each visit, the investigators classifi

Esophageal hypersensitivity may be a major cause of heartburn

OBJECTIVE:Little is known about esophageal nociceptive thresholds in chronic heartburn sufferers with normal clinical findings. The aim of this study was to evaluate and to characterize the pathogenesis of heartburn in subjects who chronically use antacids and had not sought medical attention.METHODS:Subjects (N = 152) with chronic heartburn of ≥3 months duration underwent endoscopic grading of the esophagus, esophageal manometry, Bernstein testing, intraesophageal balloon distention (IEBD), and 24-h esophageal pH monitoring.RESULTS:Normal acid contact time (ACT ≤6%) was observed in 43% of these subjects with recurrent heartburn. Of subjects with normal ACT, 64% had normal LES pressure (≥10 mm Hg), 79% had normal esophageal endoscopy, 89% developed heartburn during Bernstein acid infusion, and 52% perceived IEBD as painful.CONCLUSIONS:Approximately 30% of individuals chronically using antacids for heartburn had esophageal sensitivity to mechanical or chemical stimuli despite negative endoscopy and pH monitoring. Our findings suggest that a significant subset of typical heartburn sufferers have a lower threshold for esophageal sensation and pain, which may influence options for pharmacological intervention in such subjects.

Onset of symptom relief with rabeprazole: a community-based, open-label assessment of patients with erosive oesophagitis.

In numerous clinical trials, proton pump inhibitors have demonstrated potent acid suppression and healing of erosive oesophagitis, as well as successful symptom relief for the entire spectrum of gastro‐oesophageal reflux disease.

Review article: the pharmacodynamics and pharmacokinetics of proton pump inhibitors: overview and clinical implications

During the past two decades, enormous changes occurred in the management of gastric acid‐related diseases. First, the histamine2‐receptor antagonists were introduced, offering patients the first single‐agent therapy that effectively reduced gastric acid secretion. Proton pump inhibitors became widely available in the early 1990s, and they generally appeared to be superior to the histamine2‐receptor antagonists in acid‐suppressing activity, symptom control and healing. Most physicians now use proton pump inhibitors as first‐line treatment for many patients with acid‐peptic disorders, including erosive gastro‐oesophageal reflux disease (GERD), nonerosive reflux disease (NERD) and duodenal and gastric ulcers. Although proton pump inhibitors are often thought to be interchangeable, some differences have emerged in their pharmacological properties, which may be reflected in some aspects of clinical efficacy. Such differences include potency, speed of onset and duration of pH ‘holding times’. Helicobacter pylori has now been recognized as an important factor in the pathogenesis of acid‐peptic disorders. It is clear that H. pylori eradication can dramatically reduce the chronicity of gastric and duodenal ulcers, and accepted therapeutic regimens for H. pylori eradication now include proton pump inhibitors and two or more antibiotics. Although all accepted proton pump inhibitor‐based ‘triple therapies’ are roughly equivalent in efficacy, there is now a shortened regimen available that will potentially enhance compliance and decrease cost. This review examines the relative advantages of proton pump inhibitors vs. histamine2‐receptor antagonists in the context of acid suppression and in various gastric acid‐related diseases. A brief overview presents the pharmacodynamics and pharmacokinetics of the proton pump inhibitors with particular attention paid to rabeprazole, one of the newer drugs in its class.