Pharmacoeconomic comparison of treatments for the eradication of Helicobacter pylori.

BACKGROUND: Patients with Helicobacter pylori-induced duodenal ulcer should have their infection eradicated. The optimal choice of antibiotic therapy, however, is less clear. OBJECTIVE: To evaluate costs and outcomes of treatment with 8 antibiotic regimens with documented activity against H pylori vs maintenance therapy with histamine2-receptor antagonists (H2RA). METHODS: A meta-analysis for 119 studies enrolling 6416 patients to determine aggregate eradication rates. The complexity of each regimen was used to determine the anticipated compliance rate and actual effectiveness. A decision analytic model with Monte Carlo simulation determined annual costs and health outcomes. RESULTS: Average annual total costs of testing for H pylori infection and antibiotic treatment ranged from $223 to $410 and prevented ulcer recurrence in 70% to 86% of patients. The H2RA maintenance therapy cost $425 and prevented recurrence in 72% of patients. The lowest costs and recurrence rates were achieved by 3 regimens: standard triple therapy (a combination of bismuth subsalicylate, metronidazole, and tetracycline hydrochloride) for 14 days ($223, with 18% recurrence); a combination of clarithromycin, metronidazole, and a proton pump inhibitor for 7 days ($235, with 15% recurrence); and standard triple therapy with a proton pump inhibitor for 7 days ($236, with 14% recurrence). CONCLUSION: Treatment with any regimen resulted in lower costs compared with H2RA maintenance therapy. Three antibiotic regimens had consistently lower costs and better outcomes: standard triple therapy for 14 days, metronidazole, clarithromycin, and a proton pump inhibitor for 7 days, and standard triple therapy plus a proton pump inhibitor for 7 days.

The rationale for continuous maintenance treatment of reflux esophagitis.

Reflux esophagitis is a chronic process associated with frequent episodes of relapse in many patients. In addition, the disease may be progressive in at least some patients. Erosion of the esophageal mucosa precedes the development of some of the complications of the condition. There is accumulating evidence that continuous treatment of patients with erosive esophagitis effectively maintains symptomatic remission and absence of esophageal erosions. Whether such treatment will prevent the development of complications has not yet been demonstrated. We investigated a number of questions concerning the natural history and complications of erosive esophagitis and the need for maintenance treatment for patients with severe manifestations of disease as well as the impact of continuous maintenance treatment on the natural history of reflux esophagitis and its complications.

Rationalizing cyclooxygenase (COX) inhibition for maximal efficacy and minimal adverse events.

New information indicates that cyclooxygenase-2 (COX-2) is constitutively expressed in several tissues, including brain, lung, pancreas, kidney, and ovary, and plays an important role in renal and gastrointestinal function. Selective COX-2 inhibition has been associated in animal studies with impairment of ulcer healing and renal function and inhibition of prostacyclin, an effect that inhibits vasodilation without inhibiting platelet aggregation. The clinical consequences, if any, of these effects remain to be determined in long-term studies in humans. The premise that selective COX-2 inhibitors will cause less gastrointestinal toxicity than nonsteroidal antiinflammatory drugs that inhibit both COX isoforms needs to take into account the low toxicity of nabumetone. The gastrointestinal safety profile of this nonacidic, dual COX inhibitor that does not undergo enterohepatic circulation has been evaluated in extensive clinical trials. The data submitted to the US Food and Drug Administration in the New Drug Application for nabumetone (Relafen), the comparative trials subsequently completed, the published databases of the comparative gastrointestinal toxicity of various nonsteroidal anti-inflammatory drugs (NSAIDs), and the meta-analysis published in this issue of The American Journal of Medicine (Schoenfeld, page 48S) indicate that nabumetone has the lowest incidence of gastrointestinal toxicity among the extensively studied NSAIDs. Overall, the incidence is approximately 10-fold less than with comparator drugs. This rate is an appropriate current reference against which the gastrointestinal toxicity of COX-2 inhibitors can be compared.

Safety perspectives on parenteral H2-receptor antagonists.

Much controversy has been associated with the similarities and differences among the histamine (H2)-receptor antagonists with respect to safety. The safety issues, including those recently identified with the use of parenteral H2-receptor antagonists, are analyzed here with the intent of placing these data into proper perspective. The focus of the analysis is on a few of the more important issues: central nervous system effects and clinically significant drug interactions. A review of the voluminous safety literature on these agents indicates that, as a class, they have enviable safety records. When individual agents are compared, some small differences in safety profiles emerge, but, on the whole, similarities are more striking.

Osteomalacia associated with anticonvulsant drug therapy in mentally retarded children.

A survey of 289 severely retarded inpatients at a school for retarded children in American Fork; Utah revealed 67 patients with osteomalacia as defined by hypocalcemia, hypophosphatemia, elevated serum alkaline phosphatase levels, and appropriate bone changes. Investigation of the variables which might influence bone mineralization revealed no differences in age, sex, physical activity, sunshine exposure, or dietary intake of vitamin D between the osteomalacia and nonosteomalacia groups. However, all of the patients with osteomalacia were receiving anticonvulsant medications, either phenobarbital, diphenylhydantoin, or both. Duration of anticonvulsant therapy was the most important contributing factor to the development of osteomalacia. Seventy-five percent of patients who had received anticonvulsants for more than ten years had osteomalacia. The single most costly medical problem at the school is the treatment of pathologic bone fractures due to demineralized bone.

Future prospects for proton pump inhibitors.

Future prospects for proton pump inhibitors depend on their efficacy and safety relative to H2-receptor antagonists, the therapeutic standard for acid peptic disorders. As safety concerns diminish, efficacy considerations become more important as these may pertain to cost effectiveness. Comparative, controlled trials show that omeprazole and lansoprazole are somewhat more effective than H2-blockers in healing duodenal and gastric ulcers, providing faster relief of symptoms. Relapse after cessation of therapy is similar between the two classes. The proton pump inhibitors are substantially more effective in healing lesions and relieving symptoms in patients with reflux oesophagitis, and are particularly effective in cases that have failed to heal after 12 weeks of treatment with H2-blockers. Relapse rates of oesophagitis are significantly less with prolonged treatment with omeprazole than ranitidine. A proton pump inhibitor combined with amoxicillin is less effective than triple therapy with antibiotics and bismuth in eradicating Helicobacter pylori infections, but is more convenient and associated with fewer side-effects. Efficacy might be improved by more optimal dosing regimens. Prospects for reversible proton pump inhibitors depend on the balance between their theoretical advantages and their acid inhibition profile which, at present, closely resembles that of H2-blockers.

Review article: role of proton pump inhibitors in non-H. pylori-related ulcers.

The proportion of ulcers that are not associated with Helicobacter pylori infection is increasing, especially in the United States and Australia. The alarming increase in this type of ulcer warrants an analysis of the diagnostic and treatment approaches to H. pylori-negative ulcers, which was the aim of this study. The medical literature was reviewed to gather information about the prevalence, aetiology, and treatment of H. pylori-negative ulcers. The reports indicated that up to 52% of duodenal ulcers and 47% of gastric ulcers are not caused by H. pylori infection. The cause of H. pylori-negative ulceration appears to be multifactorial. Contributing factors include covert non-steroidal anti-inflammatory drug use, false-negative H. pylori tests, genetic predisposition, and in rare cases, Crohn's disease or Zollinger-Ellison syndrome. H. pylori-negative ulcers tend to be associated with hypersecretion and can have serious clinical sequelae. H. pylori-negative ulcers are often refractory to treatment, possibly because they lack the beneficial effect of H. pylori infection on antisecretory therapy. Proton pump inhibitors (PPIs) appear to effectively treat both H. pylori-positive and H. pylori-negative ulcers. We conclude that H. pylori-negative ulcers are becoming more prevalent in the United States and Australia. These ulcers may have an aggressive clinical course and can be refractory to treatment. PPI therapy is indicated for treating and preventing H. pylori-negative peptic ulcers.

Review article: approaches to the long-term management of adults with GERD-proton pump inhibitor therapy, laparoscopic fundoplication or endoscopic therapy?

The goals of gastro-oesophageal reflux disease (GERD) treatment are to control symptoms, heal the injured oesophageal mucosa, and prevent complications. Pharmacological therapy is effective in producing acute symptom relief and mucosal healing, as well as the long-term maintenance of remission. Proton pump inhibitors are the mainstay of GERD therapy. However, the need for daily administration, failure to provide complete symptom relief and costs of these agents may limit their use in some patients, prompting a consideration of alternative treatment strategies. Laparoscopic fundoplication may achieve symptom relief and healing of the oesophagitis in these individuals, but its invasiveness, cost and inherent surgical risks have created an interest in endoscopic therapies for GERD, with several emerging during the past few years. These interventions may either be viewed as an alternative therapy or as 'bridge' therapy, with patients still choosing to be treated with acid anti-secretory drugs or fundoplication if the endoscopic procedure fails to provide adequate symptom relief or if symptoms recur. Patient selection is critical for the success of fundoplication as well as endoscopic procedures, with ideal candidates being those with well-established endoscopically documented GERD, abnormal pH monitoring, normal oesophageal motility studies, and who have experienced at least partial symptom relief with proton pump inhibitor therapy. Hiatal hernia is not a contra-indication to fundoplication, while endoscopic intervention is best suited for those with a hiatal hernia of less than 3 cm in length. The long-term efficacy, cost-effectiveness, and impact of endoscopic procedures on extra-oesophageal manifestations of GERD and risk for GERD-related complications has not been determined.

A novel option in proton pump inhibitor dosing: lansoprazole orally disintegrating tablet dispersed in water and administered via nasogastric tube.

BACKGROUND: Lansoprazole orally disintegrating tablet, which rapidly disintegrates on the tongue or in water, provides a dosing alternative for patients with difficulty in swallowing. Gastric and nasogastric tubes are increasingly placed in patients with more severe swallowing disorders. AIM: This study assessed the pharmacokinetic profile of lansoprazole orally disintegrating tablet dispersed in a small volume of water and administered through a small-bore nasogastric tube. METHODS: Forty healthy adult men and women (18-43 years) received two single 30 mg lansoprazole orally disintegrating tablet doses (one administered directly onto the tongue without water, and one dispersed in water and administered via nasogastric tube) in a randomized, crossover fashion. RESULTS: The total plasma exposure to lansoprazole was comparable following both dosing regimens; mean AUC values for the lansoprazole orally disintegrating tablet nasogastric dispersion were < or =8.6% greater than those for the intact lansoprazole orally disintegrating tablet. Lansoprazole Cmax for the lansoprazole orally disintegrating tablet nasogastric dispersion was 20.9% greater than that for the intact lansoprazole orally disintegrating tablet, a difference of no clinical significance. CONCLUSIONS: Dispersion of the lansoprazole orally disintegrating tablet in a small volume of water and administering via nasogastric tube does not reduce the pharmacokinetic profile of the intact lansoprazole orally disintegrating tablet. This alternative dosing method may be useful in patients with nasogastric or gastric tubes.

Comparative pharmacokinetics and safety of lansoprazole oral capsules and orally disintegrating tablets in healthy subjects.

BACKGROUND: Many individuals with acid-related gastrointestinal disorders have difficulty in swallowing oral agents. AIM: To compare the bio-availability of a single dose of lansoprazole orally disintegrating tablet with that of an intact capsule. METHODS: One hundred and twenty healthy subjects participated in two prospective, Phase I, open-label, two-period cross-over studies to receive lansoprazole, 15 mg or 30 mg. Within each study, subjects were randomized into two parallel cohorts consisting of 30 subjects per regimen, dispensed in opposing sequence over two periods separated by a 7-day washout period. Blood samples were collected on day 1 of both periods to determine the pharmacokinetic parameters. RESULTS: Tmax occurred at 1.8 and 2.0 h with the 15-mg and 30-mg tablets, respectively. Dose proportional increases in Cmax, AUCt and AUC infinity were observed in the 15-mg and 30-mg groups. The terminal elimination half-lives (t1/2) were identical in both dose groups (1.18 h). Lansoprazole administered as the orally disintegrating tablet was bio-equivalent to the intact capsule formulation with respect to Cmax, AUCt and AUC infinity. CONCLUSIONS: Lansoprazole orally disintegrating tablets, 15 mg and 30 mg, are bio-equivalent to the respective dose administered as the intact capsule. This novel dosage formulation represents an option for patients who have difficulty in swallowing oral agents.

Evaluation of the pharmacokinetics and pharmacodynamics of intravenous lansoprazole.

AIM: To compare the pharmacokinetics and pharmacodynamics of lansoprazole 30 mg administered intravenously in 0.9% NaCl or in polyethylene glycol, or orally. METHODS: Twenty-nine subjects received lansoprazole orally on days 1-7 and intravenous lansoprazole in NaCl on days 8-14. Blood samples were collected on days 1, 7, 8 and 14. Fasting basal acid output and pentagastrin-stimulated maximal acid output were determined on days -1, 8, 9 and 15. Thirty-six different subjects received one of four regimen sequences: intravenous lansoprazole in NaCl, intravenous in polyethylene glycol, per orally, or intravenous placebo, each for 5 days. Twenty-four hour intragastric pH was recorded on days 1 and 5. RESULTS: Intravenous and per oral lansoprazole for 7 days produced equivalent basal acid output and maximal acid output suppression. Pharmacokinetics and mean pH values with intravenous lansoprazole in NaCl or polyethylene glycol were equivalent. Both produced mean pH and percentages of time pH above 3, 4, 5 and 6 that were significantly greater than did per orally. CONCLUSIONS: Intravenous lansoprazole inhibits acid secretion as effectively in NaCl as in polyethylene glycol, and its onset of action is faster than per oral lansoprazole.

A double-blind evaluation of the nocturnal antisecretory effects of anisotropine methylbromide in man. Dose response and duration of action studies.

The effects of graded doses of anisotropine methylbromide on nocturanl gastric secretion were investigated in a double-blind crossover study in man. Single doses considerably higher than those usually employed for daytime use in adjunctive therapy of peptic ulcer disease significantly reduced acid secretion without significantly influencing heart rate, blood pressure, visual acuity, or visual accommodation. The duration of action of large doses was then evaluated in fasted and nonfasted subjects. A single dose reduced acid secretion for up to 8 hours, eliminating the nocturnal elevation of acid secretion characteristic of the normal circadian pattern. Near visual acuity and accommodation decreased, an effect more pronounced in fasted subjects, but the magnitude of visual impairment was small. These findings provide the basis for a controlled trial of high-dose nighttime therapy in peptic ulcer disease.

The influence of phenobarbital on biotransformation of 25-hydroxycholecalciferol.

Altered vitamin D metabolism has been implicated as a cause of anticonvulsant-induced osteomalacia. Previous studies have demonstrated accelerated biotransformation of vitamin D3 to 25-hydroxycholecalciferol (25-OHD3). However, it is not known whether the 25-OHD3 is metabolized to 1,25-dihydroxycholecalciferol (1,25-(OH)2D3), the tissue-active metabolite of vitamin D3. This study using rats was undertaken to study the influence of phenobarbital on the biotransformation of 25-OHD3 to 1,25-(OH)2D3. The disappearance rate of 25-OHD3 was virtually the same in the pheno-barbital-treated group (re = 0.0615 pmole/min) and the control group (re - 0.0549 pmole/min). Similarly, the appearance rate of 1,25-(OH)2D3 was virtually the same in the treated group (ra = 0.0133 pmole/min) and the control group (ra = 0.0134 pmole/min). These data suggest that phenobarbital does not affect the biotransformation of 25-OHD3 to 1,25-(OH)2D3. The implication of this observation is that altered vitamin D metabolism does not account for phenobarbital-induced osteomalacia.

Effect of nighttime anisotropine methyl bromide of duodenal ulcer healing and pain: a double-blind controlled trial.

Anisotropine methyl bromide, an anticholinergic, 80 mg given orally at 8 P.M., suppresses gastric acid secretion through the night without significant side effects. Thirty patients with endoscopy-proved symptomatic duodenal ulcer disease completed a randomized, double-blind, placebo-controlled trial of nighttime anisotropine methyl bromide therapy. Eleven (69 per cent) of 16 anisotropine methyl bromide-treated and six (43 per cent) of 14 placebo-treated subjects healed their ulcers within two weeks of starting treatment. The anisotropine methyl bromide-treated subjects averaged 0.63 +/- 0.27 (mean +/- S.E.) episodes of nocturnal pain during the treatment period versus 2.71 +/- 1.08 episodes in the placebo group (P = 0.06). This is the first reported study of this type designed to evaluate the efficacy of an anticholinergic agent in the healing of duodenal ulcers. Although not conclusive, the results suggest nighttime anisotropine methyl bromide therapy may be useful in the treatment of duodenal ulcer disease. Further studies seem warranted.

Absorption and biotransfomation of cholecalciferol in drug-induced osteomalacia.

The gastrointestinal absorption of vitamin D3 and its biotransformation to 25-hydroxycholecalciferol was studied in patients with drug-induced osteomalacia. The mean coefficient of absorption was virtually identical in the drug-treated group (82.8%) and the control (83.8%). The biotransformation of vitamin D3 to 25-hydroxycholecalciferol was significantly accelerated (P less than 0.03) in the drug-treated group compared to the control group. These data suggest that vitamin D absorption is not significantly altered but that biotransformation of vitamin D3 to 25-hydroxycholecalciferol is accelerated in drug-induced osteomalacia.

Safety profile of Lansoprazole: the US clinical trial experience.

OBJECTIVE: Lansoprazole has undergone extensive clinical evaluation for the treatment of acid-peptic diseases. The aim of this study was to define the safety profile of lansoprazole and compare it to that of other therapeutic agents evaluated in the same controlled trials. METHODS: The clinical safety profile of lansoprazole and comparative agents (placebo, ranitidine and omeprazole) was reviewed for 3281 patients who participated in short term (up to 8 weeks) and long term (up to 56 months) clinical trials conducted in the US. Adverse events, laboratory value changes and gastric biopsy changes that occurred during treatment were compared statistically for differences between treatments. RESULTS: The incidence of adverse events and number of patients discontinuing treatment because of adverse events was similar for lansoprazole and comparative agents. Other than elevated serum gastrin levels, a known effect of proton pump inhibitors, no trends in laboratory changes were observed. Median values for gastrin levels remained within the normal range; about 2% of patients had gastrin levels >400 pg/ml at any time, while <1% had 2 or more gastrin values >500 pg/ml. Values returned to baseline levels after therapy was discontinued. No significant changes in gastric endocrine cell growth from baseline to final visit were observed, nor was there evidence of dysplasia or neoplasia. CONCLUSION: Lansoprazole is well tolerated for both short and long term treatment of acid-related disease. The tolerability of lansoprazole is comparable to that of ranitidine, omeprazole and placebo in the treatment of these diseases.

Helicobacter pylori-negative peptic ulcers: frequency and implications for management.

Most patients with peptic ulcers are infected with Helicobacter pylori, but the infection may not be responsible for the ulcer. It is increasingly recognized that different causes of ulcers coexist in a given patient, confounding determination of the exact cause of the ulcer. For example, in infected patients with ulcers who also are using nonsteroidal anti-inflammatory drugs (NSAIDs), it is not possible to establish the ulcer's cause. Moreover, recent studies in the United States in infected patients with duodenal ulcers who were treated with various regimens to prove their efficacy in eradicating H. pylori and preventing ulcer recurrence found that approximately 20% of patients suffered an ulcer recurrence despite successful H. pylori eradication. The infection clearly did not cause their ulcers but was originally thought to have done so. Thus, as many as one-fifth of patients with ulcers may have the cause falsely attributed to H. pylori infection. When this number is added to that of ulcer patients who are H. pylori-negative upon original presentation--at least 20% in other recent U.S. studies--it is evident that the proportion of non-H. pylori ulcer patients is larger than originally believed. This proportion is likely to increase with the declining incidence of H. pylori infection. Other causes of ulcers include the use of aspirin and NSAIDs (which may be surreptitious), hypersecretory states, Crohn's disease, and patients with "idiopathic" ulcers. Patients with "idiopathic" ulcers are characterized by postprandial hypersecretion of acid and hypergastrinemia with accelerated gastric emptying. H. pylori ulcers may be difficult to manage because antisecretory drugs are less effective in inhibiting gastric acidity in the absence of H. pylori infection.

Critical issues in the management of gastroesophageal reflux disease.

AIM: To discuss some of the critical issues in the management of gastroesophageal reflux disease (GERD). OPINION: GERD is a chronic relapsing disease characterized by pathological exposure of the distal esophagus to gastric acid. Diagnosis of the condition can often be made on the basis of symptomatology alone. Endoscopy can help in assessing the degree of esophageal damage, influencing the choice of therapy, and should be performed at least once during a symptomatic patient's lifetime to exclude a diagnosis of Barrett's esophagus. However, endoscopy is mandatory at diagnosis if alarm symptoms are present. Treatment should aim to provide the lowest degree of acid suppression needed for the control of symptoms. Proton pump inhibitors (PPIs) represent the most cost-effective treatment option for the short- and long-term management of GERD. Compared with standard- and high-dose H2-receptor antagonists, PPIs result in superior and faster healing and symptom relief across all grades of esophagitis and are more effective at maintaining patients in symptomatic and endoscopic remission. Treatment with PPIs has also been shown to reduce the rate of recurrent stricture after initial dilatation. PPIs are generally well tolerated, and to date there have been no reports of gastric dysplasia resulting from their long-term use. Anti-reflux surgery should be reserved for patients who are unresponsive to continuous PPI therapy or perhaps for young patients. It will be several years before the impact of laparoscopic fundoplication as a cost-beneficial therapy for GERD can be assessed. CONCLUSION: The superior clinical efficacy of PPIs when compared with any other drug regimen for GERD make them the treatment of choice for the short- and long-term management of this troublesome condition.

Peptic ulcers in the elderly: unique features and management.

Contrary to the general trend, peptic ulcers are on the rise in the elderly in terms of frequency, complications, and mortality, possibly due to the use of and complications from nonsteroidal anti-inflammatory drugs (NSAIDs). Unfortunately, the infrequency of abdominal pain and the frequent presence of serious concomitant diseases complicate both the diagnosis and management of peptic ulcers in the elderly. Ulcers heal equally when treated with H2-receptor antagonists, antacids, or sucralfate. Patients with a history of silent, complicated ulcers and patients with serious concomitant diseases require low-dose maintenance H2-blockers to prevent ulcer recurrence. The frequency of NSAID-related ulcers may be reduced in selected patients with misoprostol in the case of gastric ulcers, or misoprostol or H2-blockers in the case of duodenal ulcers. NSAID-related ulcers heal when treated with H2-blockers.

Emerging strategies for managing peptic ulcer disease.

The relationship between the inhibition of intragastric acidity and healing has been determined for both duodenal and gastric ulcers, with a stronger correlation being evident in duodenal ulcer. Omeprazole is clearly more effective than H2-receptor antagonists in healing duodenal ulcers and in the resolution of attendant symptoms. As the recommended treatment periods are shorter with omeprazole (e.g. 2-4 weeks) than with H2-receptor antagonists (4-8 weeks), omeprazole has also been shown to be more cost-effective. Long-term management strategies for peptic ulcer are evolving rapidly in the light of evidence that Helicobacter pylori eradication reduces or eliminates ulcer relapse. Regimens, such as omeprazole in combination with amoxycillin or clarithromycin, that both eradicate H. pylori and heal ulcers rapidly are appealing because they are simple, well tolerated, convenient and efficient in both healing ulcers and preventing relapse. This comprehensive approach appears to be evolving as the dominant strategy for the future treatment of peptic ulcer diseases. Gastric ulcer disease is also treated more effectively with omeprazole than with H2-receptor antagonists, both in terms of speed and reliability of healing, and in terms of symptom resolution. At 4 weeks, symptom resolution has been specifically examined in six comparative trials; in three of these, omeprazole was superior to the H2-receptor antagonist, and in the other three was at least as good as the H2-receptor antagonist. Omeprazole, 40 mg once daily, effectively heals non-steroidal anti-inflammatory drug (NSAID)-induced ulcers in about 90% of cases, even if NSAID therapy is continued, and is probably the treatment of choice for patients with ulcers requiring continued NSAID therapy.(ABSTRACT TRUNCATED AT 250 WORDS)