Pharmacokinetics of ethambutol under fasting conditions, with food, and with antacids.
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Ethambutol (EMB) is the most frequent "fourth drug" used for the empiric treatment of Mycobacterium tuberculosis and a frequently used drug for infections caused by Mycobacterium avium complex. The pharmacokinetics of EMB in serum were studied with 14 healthy males and females in a randomized, four-period crossover study. Subjects ingested single doses of EMB of 25 mg/kg of body weight under fasting conditions twice, with a high-fat meal, and with aluminum-magnesium antacid. Serum was collected for 48 h and assayed by gas chromatography-mass spectrometry. Data were analyzed by noncompartmental methods and by a two-compartment pharmacokinetic model with zero-order absorption and first-order elimination. Both fasting conditions produced similar results: a mean (+/- standard deviation) EMB maximum concentration of drug in serum (Cmax) of 4.5 +/- 1.0 micrograms/ml, time to maximum concentration of drug in serum (Tmax) of 2.5 +/- 0.9 h, and area under the concentration-time curve from 0 h to infinity (AUC0-infinity) of 28.9 +/- 4.7 micrograms.h/ml. In the presence of antacids, subjects had a mean Cmax of 3.3 +/- 0.5 micrograms/ml, Tmax of 2.9 +/- 1.2 h, and AUC0-infinity of 27.5 +/- 5.9 micrograms.h/ml. In the presence of the Food and Drug Administration high-fat meal, subjects had a mean Cmax of 3.8 +/- 0.8 micrograms/ml, Tmax of 3.2 +/- 1.3 h, and AUC0-infinity of 29.6 +/- 4.7 micrograms.h/ml. These reductions in Cmax, delays in Tmax, and modest reductions in AUC0-infinity can be avoided by giving EMB on an empty stomach whenever possible. (+info)
Prescription of acid-suppressing drugs in relation to endoscopic diagnosis: a record-linkage study.
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BACKGROUND: Although widely used, few data are available on the appropriateness of prescribing of acid-suppressing drugs (ASDs), despite guidelines on the investigation and treatment of dyspeptic patients. METHODS: We created a database of 62 000 endoscopy examinations and record-linked these to a prescribing database. Endoscopic diagnoses were classified into peptic, nonpeptic and others. The H2-antagonists, omeprazole and misoprostol, were studied. RESULTS: 35 000 patients had one or more endoscopies during 1978-93; two-thirds were over 45 years of age at first endoscopy. A quarter of all patients who had been endoscoped had consistently normal examinations. Peptic oesophageal pathology was the commonest positive finding. A quarter of those prescribed ASDs between 1989 and 1993 had been endoscoped between 1978 and 1993. In those with a peptic diagnosis prescribed any ASD, the pathologies found were: oesophageal (42.9%), duodenal (36.3%) and gastro-pyloric (21.3%). Patients prescribed omeprazole were more likely to have undergone endoscopy than those prescribed other ASDs, and they were also more likely to have peptic oesophageal pathology. Long-term prescribing (>56 days per year) occurred in two-thirds of patients prescribed ASDs and 40% had at least one endoscopy. In those prescribed short-term ASDs, 20% had undergone at least one endoscopy. Peptic and nonpeptic endoscopic pathology was associated with increased ASD prescribing, but a normal endoscopy did not reduce prescribing. CONCLUSION: ASD prescribing appeared to be mainly symptom-driven. Positive endoscopic findings increased the prescribing of ASDs, but normal findings did not reduce it. (+info)
Pharmacokinetics of gatifloxacin and interaction with an antacid containing aluminum and magnesium.
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The pharmacokinetics of gatifloxacin (400 mg orally) and the influence of the antacid aluminum magnesium hydroxide (20 ml of Maalox 70) on the bioavailability of gatifloxacin in 24 healthy volunteers were assessed. In an open, randomized, six-period crossover study, the volunteers received either gatifloxacin alone (treatments A and D); aluminum magnesium hydroxide concomitant with gatifloxacin (treatment C); or aluminum magnesium hydroxide 2 h before (treatment B), 2 h after (treatment E), or 4 h after gatifloxacin administration (treatment F). Gatifloxacin concentrations were measured by a validated bioassay and high-performance liquid chromatography. Pharmacokinetics of a single 400-mg dose of gatifloxacin alone were characterized as follows (mean +/- standard deviation): peak concentration (Cmax), 3.8 +/- 0. 5 (treatment A) and 3.4 +/- 0.9 (treatment D) microgram/ml; time to Cmax, 1.4 +/- 0.8 (treatment A) and 1.7 +/- 0.7 (treatment D) h; area under the curve from time zero to infinity (AUC0-infinity), 33. 5 +/- 5.9 (treatment A) and 31.4 +/- 3.4 (treatment D) microgram. h/ml; urine recovery, (83 +/- 6)% (treatment A) and (84 +/- 8)% (treatment D). Comparison of the results obtained by bioassay showed a good correlation. Aluminum magnesium hydroxide administration 2 h before (treatment B) or concomitant with (treatment C) gatifloxacin decreased the Cmax by 45% (2.1 +/- 1.2 microgram/ml) or even 68% (1.2 +/- 0.4 microgram/ml) highly significantly (P < 0.01). AUC0-infinity was significantly reduced from 33.5 +/- 5.9 to 19.4 +/- 6.9 microgram. h/ml (by 42%) or even to 11.9 +/- 3.3 microgram. h/ml (by 64%) (P < 0. 01). If aluminum magnesium hydroxide was given 2 h after gatifloxacin (treatment E), there was no significant reduction of concentration in serum but AUC0-infinity was significantly reduced from 31.4 +/- 3.4 to 25.9 +/- 5.3 microgram. h/ml (18%) (P < 0.01). Aluminum magnesium hydroxide given 4 h after gatifloxacin (treatment F) showed no influence on the gatifloxacin pharmacokinetics. Therefore, the optimal time between gatifloxacin application and the intake of an aluminum-containing antacid should be 4 h. (+info)
Salmonellosis in North Thames (East), UK: associated risk factors.
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We assessed the rate of salmonella infections and risk factors associated with infection in North East Thames in 1993. Cases of culture confirmed infection were identified through microbiology laboratories and environmental health officers in the North East Thames. A total of 1730 cases were reported and 209 of these individuals (those who could be contacted within a 3-week interval after onset of symptoms) and matched controls were interviewed by telephone. In addition randomly selected controls were interviewed over a 4-month period about recent gastric acid lowering medication and antimicrobial ingestion. Sixty-six serotypes were identified: S. enteritidis was isolated from 1179 (69%) cases, S. typhimurium from 221 (13%), S. virchow from 77 (4%) and S. newport 25 (1%). Infections were more frequent in summer months. Highest rates were documented in children under 2 years of age for S. enteritidis (108/100,000) and under 1 year for S. typhimurium (36/100,000). Using the Townsend score, highest isolation rates of S. enteritidis were in more prosperous areas (36/100,000 vs. 27/100,000; odds ratio (OR) 1.3, 95% confidence intervals (CIs) 1.2-1.6, P < 0.0001), while for S. typhimurium, there was no relation between deprivation index and isolation rates areas (6.4/100,000 vs. 6.1/100,000; OR 1.1, 95% CIs 0.8-1.5, P = 0.77). The case control study showed a significant association between ingestion of products containing raw eggs and S. enteritidis infection (8/111 cases vs. 0/110 controls; OR undefined, lower 95% CIs 3.4). Individuals with salmonella infection were significantly more likely to have travelled abroad in the week before the onset of illness [42/186 (23%) vs. 1/182 (0.5%); OR 40, 95% CIs = 5.5-291, P < 0.001] and to report gastroduodenal disease [11/143 (7%) vs. 3/143 (2%); OR 5.0, 95% CIs = 1.1-23, P = 0.04]. There was an association between illness and gastric acid-lowering medications [unmatched controls OR 22.3 (95% CIs 1.5-3.7, P = 0.0002), matched controls OR 3.7 (95% CIs 1.0-3.8, P = 0.07)], but no association with antimicrobial ingestion. (+info)
Evaluation of treatment regimens to cure Helicobacter pylori infection--a meta-analysis.
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OBJECTIVE: To assess effectiveness of treatment to cure Helicobacter pylori infection. DATA SYNTHESIS: Meta-analysis of 666 manuscripts (full papers, abstracts, letters to the editor) identified through Medline and a manual search (1986 to January 1998). Data were overviewed by regression analysis with weighted random effects models. SUBJECTS: 53 228 patients with H. pylori infection. INTERVENTIONS: Patients were treated with 132 different medication combinations. MAIN OUTCOME MEASURE: Cure of H. pylori infection per protocol and intention-to-treat basis at least 28 days after treatment. RESULTS: The nationality of the patients and therapeutic regimen have a significant impact on the results, after correction for the heterogeneity in the precision of the cure rate caused by different study sizes and random effect for study. On the basis of the original sample size, cure rates of 80-85% were achieved using combinations of a proton-pump inhibitor or ranitidine bismuth citrate with two antibiotics including clarithromycin, amoxycillin and metronidazole or tinidazole. Comparable cure rates were also achieved using a combination of a proton-pump inhibitor or H2-receptor antagonist with bismuth subcitrate or tripotassium dicitrato bismuthate, metronidazole and tetracycline. The dose of clarithromycin influenced cure rates. Treatment duration did not influence the outcome. CONCLUSION: Several therapeutic regimens are eligible to cure H. pylori infection. However, none of the medication combinations were able to cure H. pylori infection in more than 85% of the patients assessed by intention-to-treat. The countries in which the studies were performed also had a significant impact on eradication rates. (+info)
The effect of Helicobacter pylori eradication on gastro-oesophageal reflux.
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BACKGROUND: Increased prevalence of oesophagitis has been reported following eradication of Helicobacter pylori. We hypothesized that H. pylori eradication might increase gastro-oesophageal acid reflux in patients with reflux oesophagitis. METHODS: Twenty-five consecutive patients (13 male, 12 female) with H. pylori infection and reflux oesophagitis grade I (22 patients) or II (three patients) were enrolled; mean age 49.9 (range 33-75) years. Twenty-four hour intra-oesophageal pH recording was performed before and 12 weeks after eradication of H. pylori, which was achieved using bismuth subnitrate suspension 150 mg q.d.s., oxytetracycline 500 mg q.d.s. and metronidazole 400 mg t.d.s. for 10 days. Eradication was confirmed by 14C-urea breath test 12 weeks after completion of treatment. The patients did not receive acid-suppressive medication. RESULTS: All patients had abnormal gastro-oesophageal reflux before anti-H. pylori treatment. After treatment, there was no significant change in the percentage of total time oesophageal pH < 4 (P=0.46) in the 23 patients in whom the infection had been cured. Nine of the cured patients had increased acid exposure, whereas 14 had decreased acid exposure. No significant change in reflux symptom scores was found. There was no relationship between change in acid exposure and symptom improvement. CONCLUSIONS: Twelve weeks after H. pylori eradication there was no consistent change in gastro-oesophageal acid reflux in patients with mild or moderate reflux oesophagitis. (+info)
Outcome of oesophagogastric carcinoma in young patients.
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The survival of young patients (< or = 50 years of age) with carcinoma of the oesophagus or stomach has been reported to be poorer than that of their older counterparts. The aim of the current study was to review the outcome of such young patients with oesophagogastric cancer and to compare the outcome in patients with carcinoma of the oesophagus/cardia with patients with carcinoma of the more distal stomach. The study population was 50 patients. Tumour location was oesophagus/cardia (n = 33) and gastric body/antrum (n = 17). The most common presenting symptoms were weight loss (66%), epigastric pain (54%), dysphagia (50%), and heartburn (40%). Seventeen patients had experienced foregut symptoms for a period of > or = 6 months. These patients were more likely to have symptoms of gastro-oesophageal reflux disease and to have received acid suppression therapy than patients with shorter symptom durations. Only 20 patients underwent a potentially curative resection, while 10 underwent open and close laparotomy. The overall median survival was 7 months and the 5-year survival was 8%. Multivariate analysis revealed that surgical resection and UICC stage were the only factors that significantly influenced survival. There was no difference in the survival of patients with proximally situated tumours compared to those with distally located tumours. Wide variations in clinical practice were seen between different surgeons. Consequently, a multidisciplinary team designed to manage all patients with oesophagogastric cancer according to nationally agreed protocols has been established in our hospital. Earlier diagnosis of these tumours is to be encouraged, even if this necessitates the more liberal use of endoscopy in the evaluation of young patients with persistent foregut symptoms. (+info)
Review article: drug interactions with agents used to treat acid-related diseases.
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Patients with acid-related diseases often need to take multiple medications. Treatment of Helicobacter pylori infection often includes either a histamine type 2 (H2)-receptor antagonist or a proton pump (H+,K(+)-ATPase) inhibitor (proton pump inhibitor), administered in conjunction with one or more antimicrobials. Also, treatment for acid-related diseases often requires extended therapy during which many concomitant medications may be administered for concurrent disease states. Polypharmacy may be the result, particularly in elderly patients, who are at increased risk for both acid-related and many other diseases. Thus, it is important to understand the potential for clinically significant drug-drug interactions in this setting. H2-receptor antagonists and proton pump inhibitors can influence the pharmacokinetic profiles of other commonly administered medications by elevating intragastric pH, which can alter drug absorption, and by interacting with the cytochrome P (CYP) 450 enzyme system, which can affect drug metabolism and clearance. Such interactions are particularly important when they affect the pharmacokinetics of drugs with narrow therapeutic ranges (e.g. warfarin, digoxin). In these cases, drug-drug interactions can result in significant toxicity and even death. There are marked differences among H2-receptor antagonists and proton pump inhibitors in their potential for such interactions. The oldest drugs in each class, cimetidine and omeprazole, respectively, have the greatest potential to alter CYP activity and change the pharmacokinetics of other drugs. The most recently developed H2-receptor antagonist, famotidine, and the newer proton pump inhibitors, rabeprazole and pantoprazole, are much less likely to induce or inhibit CYP and thereby change the metabolism of other medications. These differences are important when choosing medications for the safe treatment of patients with acid-related diseases. (+info)