A comparison of budesonide/formoterol maintenance and reliever therapy vs. conventional best practice in asthma management.

OBJECTIVE: To study the effectiveness and safety of budesonide/formoterol (Symbicort) Maintenance And Reliever Therapy (Symbicort SMART, AstraZeneca, Södertalje, Sweden), a simplified management approach with one inhaler compared with conventional best practice (CBP) with multiple inhalers in patients with persistent asthma. DESIGN: Open-label randomised controlled parallel group trial, 6-month treatment. PARTICIPANTS: A total of 908 patients > or = 12 years of age, with persistent asthma receiving treatment with inhaled corticosteroids (ICS), either alone or in conjunction with long-acting beta(2)-agonist. MAIN OUTCOME MEASURES: Time to first severe asthma exacerbation and number of severe asthma exacerbations. RESULTS: No difference between groups was seen in time to first severe exacerbation (p = 0.75). Exacerbation rates were low in both groups. A total of 12 patients in the Symbicort SMART group experienced a total of 14 severe asthma exacerbations, and 19 patients in the CBP group experienced a total of 25 severe asthma exacerbations (annual rate 0.07 vs. 0.13 p = 0.09). The mean daily dose of ICS expressed in BDP equivalent was significantly lower in the Symbicort SMART group (including as-needed use) vs. in the CBP group (749 microg vs. 1059 microg; p < 0.0001). Mean scores in Asthma Control Questionnaire, 5 question version improved significantly in the SMART group compared with the CBP group (p = 0.0026). Symbicort SMART and CBP were equally well tolerated. The mean drug cost/patient/month was significantly lower for the patients in the Symbicort SMART group compared with patients receiving CBP (51.3 euros vs. 66.5 euros; p < 0.0001). CONCLUSIONS: In Belgian patients, a simplified regimen using budesonide/formoterol maintenance and reliever therapy was at least as effective at improving clinical control compared with CBP with a significantly lower ICS dose and significantly lower drug costs.

Evaluation of the GERD Impact Scale, an international, validated patient questionnaire, in daily practice. Results of the ALEGRIA study.

BACKGROUND AND STUDY AIMS: Gastroesophageal reflux disease (GERD) is a common chronic disease that is primarily diagnosed based on symptom severity and frequency. This study gathered epidemiological data in a population of GERD patients and evaluated the added-value of the GERD Impact Scale (GIS), a novel, validated patient questionnaire, as a tool for initial and long-term patient management. PATIENTS AND METHODS: This observational study recruited patients (296 study centers) with symptomatic GERD and a history of erosive, or reflux, esophagitis. Symptoms were assessed by GIS and physician-subject interview and recorded at baseline (visit 1), at 4-6 weeks (visit 2) and 8-14 weeks (visit 3); also recorded at each visit was the physician's assessment of GERD severity and treatment changes. Analyses were performed on an intent-to-treat basis. RESULTS: Subjects (n = 1919; mean age, 55 years) were 54% female. Lifestyle characteristics included stress (approximately 70% of subjects), mean daily consumption of five cups of caffeine-containing beverages (approximately 70%), alcohol consumption of approximately nine units per week (approximately 50%) and smoking/ex-smoker (41%). Proton pump inhibitors were prescribed in 99% of cases: mainly esomeprazole (82%), with a median dose of 40 mg. Prescribed therapy was changed (mainly dosage levels) between visits in approximately 60% of subjects. The severity of GERD symptoms and GIS scores decreased substantially throughout the study. Mean GIS scores correlated positively with increasing GERD severity and clinical judgment at all visits. Physicians reported that the GIS helped them define the appropriate treatment for the patient and to evaluate the patient's response to treatment in 81% of cases. CONCLUSIONS: This study demonstrates the added-value and usefulness of the patient self-assessment GIS as a management tool for GERD.

An open multicentre pilot study examining the safety, efficacy and tolerability of fast titrated (800 mg/day by day 4) quetiapine in the treatment of schizophrenia/schizoaffective disorder.

Objective. Rapid dose escalation of quetiapine could offer prompt and effective therapy to patients requiring hospitalization for schizophrenia or schizoaffective disorder. This study evaluated the safety, tolerability, and efficacy of a rapid dose escalation of quetiapine to 800 mg/day over 4 days in patients with severe psychotic symptoms diagnosed as schizophrenia or schizoaffective disorder. Methods. In this open-label, multicenter, pilot study, 14 patients aged 18 years or older, requiring hospitalization for schizophrenia or schizoaffective disorder, received quetiapine orally twice daily for 14 days. Quetiapine was administered according to the schedule: 200, 400, 600, and 800 mg/day on the first four treatment days, followed by flexible dosing within the range 400-800 mg/day during the next 10 days. The primary endpoint was to evaluate the safety and tolerability of a fast titration of quetiapine (200, 400, 600, 800 mg/day on the first four treatment days). Effectiveness of a fast titration of quetiapine was the secondary objective of this investigation. Efficacy assessments in the intent-to-treat (ITT) population included changes in the Positive and Negative Syndrome Scale (PANSS) and the Clinical Global Impression Severity of Illness (CGI-S) scores from Day 1 (baseline) to Day 14. Results. In 4 days 14 patients were titrated up to a dose of 800 mg/day. Ten patients were diagnosed with schizophrenia, one subject was suffering from schizoaffective disorder of the depressive type and three patients were diagnosed with schizoaffective disorder of the bipolar type. Eleven patients (79%) completed the study. Two patients discontinued the trial because of non-compliance and one patient because of a prolonged QTcB interval. Overall, 29 AEs were reported during this trial, all were considered mild or moderate in severity. During the first 7 days of the trial, 25 AEs were reported in 11 patients. The majority of AEs were considered as possibly related to the study medication. No deaths or serious adverse events were reported. Physical examination at the last trial visit revealed no clinically relevant changes versus baseline and there were no consistent changes over time in vital signs. The BARS and SAS scores indicated an improvement of EPS during the study. After 4 days of fast titration, the mean total PANSS score decreased from 92.8 at baseline to a value of 87.4, there was a further decrease to 78.2 at endpoint. This corresponds to a statistically significant decrease by 14.6 versus baseline (P<0.01). After 4 days of fast titration, the mean CGI-S score was improved from 4.7 at baseline to a value of 4.3 and improved further to 3.8 at endpoint, corresponding to a statistically significant decrease of 0.9 points versus baseline (P<0.01). Conclusion. In this study, fast titration of quetiapine to 800 mg/day over 4 days was generally well tolerated and effective in reducing psychotic symptoms in patients requiring hospitalization for schizophrenia/schizoaffective disorder.

Gefitinib monotherapy in advanced nonsmall cell lung cancer: a large Western community implementation study.

Epidermal growth factor receptor tyrosine kinase inhibitors represent a new treatment option for patients with advanced nonsmall cell lung cancer (NSCLC). This retrospective study examined to what extent previous clinical trial experience matches large-scale Western community implementation of this treatment. In the Belgian expanded access programme, the data from 513 patients with advanced or metastatic NSCLC, not suitable for further chemotherapy and receiving oral gefitinib 250 mg.day(-1) until disease progression, death or unacceptable toxicity, were analysed. The median (range) duration of gefitinib treatment was 2.3 months (0.0-32.7). Its use was predominantly in second- or third-line treatment. The overall response and disease control rates were 8.9 and 41.2%, respectively. In univariate analysis, response was more common in females and never-smokers. In multivariate analysis, female sex was the only significant predictive factor (odds ratio (OR) (95% confidence interval (CI)) 0.329 (0.129-0.839)). Symptom improvement was reported in 108 patients of whom 32 (29.6%) had an objective response, 66 (61.1%) experienced disease stabilisation and 10 (9.3%) progressed. Gefitinib was well tolerated; only 7.8% of the patients reported grade 3 or 4 toxicity. The overall median survival was 4.7 months, with a 1-yr survival rate of 21%. Survival was strongly influenced by a better performance status (PS) (good PS: hazard ratio (HR) (95%CI) 0.110 (0.077-0.157)) and adenocarcinoma with bronchioloalveolar carcinoma features histology (HR (95%CI) 0.483 (0.279-0.834)). In conclusion, the activity of gefitinib was confirmed in the present large Western community implementation study. Response, present in a small subgroup, led to a rewarding survival and could be predicted by sex only. Baseline performance status and adenocarcinoma with bronchioloalveolar carcinoma features histology were significant factors for survival.

Improvement of the eradication rate of Helicobacter pylori gastritis in children is by adjunction of omeprazole to a dual antibiotherapy.

AIM: The possible improvement of efficacy and tolerability of a 7-day dual antibiotherapy amoxicillin-clarithromycin (AC) on the eradication of Helicobacter pylori (H. pylori) gastritis in children by the adjunction of omeprazole (OAC) was studied. METHODS: Forty-six children presenting with H. pylori gastritis, assessed at inclusion by endoscopy, H. pylori urease test, histology and/or culture were randomised to a twice-daily regimen of AC or OAC. A (13)C-urease breath test was performed 4-6 weeks after the end of the treatment period to evaluate H. pylori eradication. RESULTS: A larger proportion of patients was H. pylori negative (69%) in the OAC regimen treatment 4-6 weeks after eradication treatment compared with those who received dual AC therapy (15%). A total of seven patients (three in the OAC and four in the AC group) reported adverse events (AEs). Only vomiting was reported in more than one patient (one in each treatment regimen) and only one AE was severe (urticaria: in the OAC group, but considered not related to treatment). CONCLUSION: A larger eradication rate of H. pylori was obtained in the triple OAC group than in the dual AC group. Both therapy regimens can be safely administered to children for 7 days.

Regulation of expression of galectin-7 in human nasal polyps by budesonide.

BACKGROUND: Nasal polyposis is a model for the study of inflammatory processes. We analyzed the expression of galectin-7, a growth regulator, in surface epithelium, glandular epithelium, and connective tissue in human nasal polyps, and examined the effect of the glucocorticoid budesonide on its expression in human nasal polyps ex vivo. METHODS: Using quantitative, computer-assisted microscopy and immunohistochemistry, we measured galectin-7 expression in nine nasal polyps obtained by surgical resection. Five polyps came from allergic patients and four came from non-allergic patients. RESULTS: Galectin-7 was expressed in all three polyp tissues analyzed. Treatment of polyps from allergic and non-allergic patients with 50 ng/ml budesonide increased the extent of galectin-7 expression in the connective tissue (p = 0.01). Conversely, budesonide at this concentration did not apparently affect galectin-7 expression in glandular epithelium; only a slight decrease in the percentage of the galectin-7-immunopositive cells was observed. In the surface epithelium of nasal polyps from non-allergic patients, the percentage of galectin-7-immunopositive cells was decreased (p = 0.03) by treatment with 250 ng/ml budesonide. In nasal polyps from allergic patients, this percentage was increased by treatment with 50 ng/ml budesonide (p = 0.0001). CONCLUSIONS: These data are consistent with a role for galectin-7 in the regulation of cell growth through a pro-apoptotic effect. Galectin-7 expression coincides with the degree of epithelial stratification, and is subject to upregulation in the connective tissue in response to treatment with 50 ng/ml budesonide. Budesonide modulates galectin-7 expression differently in the surface epithelia of polyps from allergic and non-allergic patients.

A 15-month evaluation of the effects of repeated subgingival minocycline in chronic adult periodontitis.

BACKGROUND: A double-blind, randomized, parallel, comparative study was designed to evaluate the long-term safety and efficacy of subgingivally administered minocycline ointment versus a vehicle control. METHODS: One hundred four patients (104) with moderate to severe adult periodontitis (34 to 64 years of age; mean 46 years) were enrolled in the study. Following scaling and root planing, patients were randomized to receive either 2% minocycline ointment or a matched vehicle control. Study medication was administered directly into the periodontal pocket with a specially designed, graduated, disposable applicator at baseline; week 2; and at months 1, 3, 6, 9, and 12. Scaling and root planing was repeated at months 6 and 12. Standard clinical variables (including probing depth and attachment level) were evaluated at baseline and at months 1, 3, 6, 9, 12, and 15. Microbiological sampling using DNA probes was done at baseline; at week 2; and at months 1, 3, 6, 9, 12, and 15. RESULTS: Both treatment groups showed significant and clinically relevant reductions in the numbers of each of the 7 microorganisms measured during the entire 15-month study period. When differences were detected, sites treated with minocycline ointment always produced statistically significantly greater reductions than sites which received the vehicle control. For initial pockets > or =5 mm, a mean reduction in probing depth of 1.9 mm was seen in the test sites, versus 1.2 mm in the control sites. Sites with a baseline probing depth > or =7 mm and bleeding index >2 showed an average of 2.5 mm reduction with minocycline versus 1.5 mm with the vehicle. Gains in attachment (0.9 mm and 1.1 mm) were observed in minocycline-treated sites, with baseline probing depth > or =5 mm and > or =7 mm, respectively, compared with 0.5 mm and 0.7 mm gain at control sites. Subgingival administration of minocycline ointment was well tolerated. CONCLUSIONS: Overall, the results demonstrate that repeated subgingival administration of minocycline ointment in the treatment of adult periodontitis is safe and leads to significant adjunctive improvement after subgingival instrumentation in both clinical and microbiologic variables over a 15-month period.

Comparative activity of piperacillin/tazobactam against 5625 isolates from hospitalised patients. Multicentre Study Group.

The comparative activities of piperacillin/tazobactam and other antibiotics against 5625 Gram-negative and Gram-positive bacteria freshly isolated from hospitalized patients was examined. The percentage of Enterobacteriaceae susceptible to piperacillin/tazobactam, ceftazidime, imipenem and ciprofloxacin was very similar and varied from 81% to 84% in the Enterobacteriaceae with inducible type 1 beta-lactamases and from 93 to 97% in the non-inducible organisms. Piperacillin/tazobactam was similar in activity to ceftazidime against Pseudomonas aeruginosa and more active than imipenem or ciprofloxacin. Piperacillin/tazobactam is more active than ceftazidime against Gram-positive bacteria (staphylococci, enterococci) and seems to be a promising antibiotic for nosocomial infections.

Bisoprolol and atenolol in essential hypertension: effects on systemic and renal hemodynamics and on ambulatory blood pressure.

The acute and short-term responses to bisoprolol and to atenolol on systemic and renal hemodynamics and on ambulatory blood pressure (BP) were compared in a randomized double-blind cross-over study including 14 patients with mild to moderate essential hypertension. After a 4-week placebo period, the patients received either bisoprolol (10 mg once daily, o.d.) or atenolol (100 mg o.d.) for 4 weeks and were switched to the other drug after a new 4-week placebo period. Cardiac output (CO) was measured by Doppler echography, and renal blood flow (RBF) and glomerular filtration rate (GFR) were measured by constant infusion techniques using [123I]iodohippurate and [51Cr]EDTA, respectively. Bisoprolol and atenolol decreased diurnal and nocturnal blood pressure (BP). Both drugs decreased heart rate (HR) and BP both acutely and after 4 weeks. During short-term treatment, CO was maintained with bisoprolol but reduced by atenolol (by 17%). RBF decreased after the first drug intake (by 9 and 12%, respectively) but returned to its baseline value after 4 weeks, so that calculated renal vascular resistance (RVR) was reduced (by 12 and 15%, respectively). Overall, GFR was not affected by treatment. Bisoprolol and atenolol are effective antihypertensive agents that preserve renal hemodynamics during short-term treatment.

Determination of leucovorin and 5-fluorouracil in plasma by high-performance liquid chromatography.

A method was developed for the determination of (6R)- and (6S)-leucovorin and 5-fluorouracil in plasma. As leucovorin diastereoisomers cannot be separated on a classical reversed-phase column, it was necessary to use a chiral stationary phase. The method presented is based on the same principle as the method described by Wainer and Stiffin [J. Chromatogr., 424 (1988) 158], i.e., coupling of a bovine serum albumin phase to an achiral stationary phase. Before the chromatography, the drug was isolated from the plasma matrix by solid-phase extraction. For 5-fluorouracil, chromatography was performed on a classical RP-18 column after extraction from the plasma by liquid-liquid extraction. Both methods were validated and applied to the analysis of patients' samples.