Review article: safety of infliximab in clinical trials.
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Infliximab, a chimeric monoclonal antibody to tumour necrosis factor-alpha, contains murine protein elements and targets the immune system, raising concerns about the potential for immune sensitization and immunosuppressive sequelae. However, long-standing inflammatory disease with high activity and chronic immunosuppressant therapy can also predispose patients to immunosuppressive sequelae. Patients with Crohn's disease, rheumatoid arthritis and other indications received single or multiple doses of infliximab and their condition was followed for up to 3 years. Adverse events, most frequently headache, nausea, and upper respiratory tract infection, were generally mild and occurred in 76% of infliximab-treated patients vs. 57% of placebo-treated recipients. Human antichimeric antibodies developed in 13% of patients, increasing the potential for subsequent infusion reactions. Antibodies to double-stranded DNA developed in a small percentage of patients. Other antinuclear antibodies characteristic of serum lupus erythematosus were not found; no patient developed a true lupus syndrome and no other autoimmune disorders were reported. Infliximab is not associated with typical immunosuppressive sequelae, such as infections and malignancy, or with autoimmune disorders. Infliximab therapy was well tolerated, serious adverse events were infrequent, successfully managed with medication and without sequelae, and overall mortality was within the expected incidence for this patient population. (+info)
Review article: the efficacy of infliximab in Crohn's disease--healing of fistulae.
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In the management of fistulae, the current therapeutic approach is the use of a combination of antibiotics and/or a combination of immunomodulatory agents. However, clinicians treating patients with fistulae, particularly those with fistulizing Crohn's disease, have little data from controlled clinical trials of these pharmacologic agents or regimens to substantiate their use in treating this complication. Therapy with the anti-tumour necrosis factor-alpha antibody, infliximab, has shown promise in treating patients with Crohn's disease and those with the disease complicated by fistulae. A recent clinical trial was designed specifically to evaluate infliximab in the treatment of fistulizing Crohn's disease. Study results demonstrated infliximab to be the first therapeutic agent to show statistical efficacy in fistulae closure in a placebo-controlled trial. Therapy with the chimeric monoclonal antibody was characterized by a rapid onset of closure and a lasting benefit of action. Two patient cases from the clinical trial are presented to exemplify the dramatic effectiveness of this novel therapeutic approach in modulating the immune response of patients with this debilitating complication of Crohn's disease. (+info)
Review article: economic issues in Crohn's disease--assessing the effects of new treatments on health-related quality of life.
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The advent of highly effective yet costly new treatments for Crohn's disease will force clinicians, patients, and society to make important choices regarding the allocation of resources. Pharmacoeconomic analyses can be useful in deciding whether new technologies are of good value in comparison to established treatment regimens. In Crohn's disease conventional cost-effectiveness analyses are of limited use because surgery, death, and disease-related complications occur relatively infrequently. Alternatively, cost-utility models relate the incremental cost of new treatments to improvements in health-related quality of life. These analyses require the collection of valid cost and utility inputs that have only recently become available. Ultimately, cost-utility models should allow decision makers to make sensible choices for patients and society. This article describes the techniques of pharmacoeconomic analysis and reviews existing data on the measurement of costs and quality-of-life outcomes in Crohn's disease. (+info)
Role of HERG-like K(+) currents in opossum esophageal circular smooth muscle.
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An inwardly rectifying K(+) conductance closely resembling the human ether-a-go-go-related gene (HERG) current was identified in single smooth muscle cells of opossum esophageal circular muscle. When cells were voltage clamped at 0 mV, in isotonic K(+) solution (140 mM), step hyperpolarizations to -120 mV in 10-mV increments resulted in large inward currents that activated rapidly and then declined slowly (inactivated) during the test pulse in a time- and voltage- dependent fashion. The HERG K(+) channel blockers E-4031 (1 microM), cisapride (1 microM), and La(3+) (100 microM) strongly inhibited these currents as did millimolar concentrations of Ba(2+). Immunoflourescence staining with anti-HERG antibody in single cells resulted in punctate staining at the sarcolemma. At membrane potentials near the resting membrane potential (-50 to -70 mV), this K(+) conductance did not inactivate completely. In conventional microelectrode recordings, both E-4031 and cisapride depolarized tissue strips by 10 mV and also induced phasic contractions. In combination, these results provide direct experimental evidence for expression of HERG-like K(+) currents in gastrointestinal smooth muscle cells and suggest that HERG plays an important role in modulating the resting membrane potential. (+info)
Effects of SK-951, a benzofuran derivative, as a prokinetic agent in rats and dogs.
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The gastrokinetic activity of SK-951 ((-)4-amino-N-[2-(1-azabicyclo[3.3.0]octan-5-yl)ethyl]-5-chloro-2,3-dihy dro-2-methylbenzo[b]furan-7-carboxamide hemifumarate), a benzofuran derivative with 5-hydroxytryptamine (5-HT)4-receptor agonist activity, was studied in rats and dogs. The effects of SK-951 were also investigated in a model of vagotomy-induced gastroparesis in comparison with cisapride. In rats, both SK-951 and cisapride enhanced gastric emptying of liquids (phenol red) at a dose of 1-100 mg/kg, p.o. Gastric emptying of liquid (acetaminophen) in fasted beagle dogs was enhanced significantly by SK-951 (1.0 mg/kg, i.v.), whereas the effect of cisapride (0.2-1.0 mg/kg, i.v.) was not statically significant. Similar results were found when radiopaque markers were given with standard meal to dogs with vagotomy-induced gastroparesis. The delayed gastric emptying of radiopaque markers by vagotomy was reversed by SK-951 (1.0 mg/kg, i.v.), whereas cisapride showed no effect at doses from 0.1 to 1.0 mg/kg, i.v. These results indicated that oral and intravenous administration of SK-951 accelerates gastric emptying of both liquids and solids in animal models. Thus, SK-951 may be a highly potent and useful prokinetic agent in comparison to cisapride. (+info)
The efficacy of a 40-mg extended-release formulation of cisapride in the treatment of patients with gastro-oesophageal reflux.
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BACKGROUND: This study was conducted to assess the efficacy of a novel 40-mg extended-release formulation of cisapride in reducing gastro-oesophageal reflux. METHODS: According to a double-blind, randomized, placebo-controlled design, 19 patients with pathological gastro-oesophageal reflux were treated with extended (40 mg o.d.) or immediate (10 mg q.d.s.) release formulations for two periods of 4 days each (pH-monitoring on day four). Patients received identical treatments in both periods to allow limits of agreement defining equivalent potency of both formulations to be derived from intra-individual variability of treatment effects. RESULTS: The extended-release formulation decreased total and upright reflux times by 5.5 +/- 1.3% and 8.1 +/- 2.1% (P < 0.001), respectively. It did not change the percentage supine reflux time but diminished the mean duration of reflux episodes by 1.0 +/- 0.4 min (P=0.005). The total number of reflux episodes remained unaltered with both formulations. Immediately-released cisapride decreased total, upright, and supine acid exposures by 5.8 +/- 1.3%, 6.8 +/- 1.6% (P < 0.002) and 3.6 +/- 1.8%, respectively, and mean duration of episodes by 0.9 +/- 0.2 min (P +info)
The effect of orally administered cisapride on intestinal motility in conscious horses.
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Seven Thoroughbred horses were laparotomized and Force Transducers were fixed on the proximal jejunal and cecal serosa. After observation of the digestive tract motility in consciousness, cisapride (0, 0.5, 0.75 or 1 mg/kg) was orally administered. In horses treated with 0.75 mg/kg or 1.0 mg/kg cisapride, the migrating contraction (MC) of the jejunum was significantly increased in frequency. (+info)
Gastric acid suppression does not promote clostridial diarrhoea in the elderly.
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Gastric acid prevents bacterial colonization of the stomach and suppression of its secretion might predispose to Clostridium difficile (CD) diarrhoea. We retrospectively studied elderly patients admitted to medical wards of an acute hospital to determine whether the incidence of CD diarrhoea was greater among those previously treated with gastric acid suppressants. From records of stool CD toxin tests undertaken in 1995 and 1996, we found 126 cases with positive results, and selected 126 controls with negative results. Information about pre-morbid illness, predisposing factors for CD and medication received in the preceding 16 weeks was obtained from case-notes. A greater number of CD positive cases had received antibiotics such as Cefuroxime, ciprofloxacin or macrolides with or without metronidazole, were more severely disabled, required assistance for feeding, or had hypoalbuminaemia before the onset of diarrhoea. A greater number of controls had received lactulose, suggesting either that its laxative effect resembled CD infection prompting frequent stool tests, or that it offered protection against CD in this group. Both groups were similar for the use of proton-pump inhibitors or H2-receptor antagonists, suggesting that susceptible elderly patients are not more likely to develop CD diarrhoea after receiving gastric acid suppression therapy. (+info)