Non-inferiority trial between two dry-powder inhalers containing fluticasone/salmeterol in asthmatic patients.

Asthma is an increasing pathology with poor compliance. Achievement of control is possible but under intensive treatment. In this setting, fluticasone/salmeterol association delivered by dry powder inhalers is a valuable and proved option. A prospective, parallel, open-label, phase IV, multicentre non-inferiority study was conducted to determine therapeutic similarity between 2 different inhalers: Generic DPI and Diskus®, which both deliver a fluticasone/salmeterol association (CAS 80474-14-2/CAS 89365-50-4). A 103 uncontrolled asthmatic patients were randomly assigned in 2 groups, Generic (G) and Diskus® (D), and received the association for 18 weeks through the appropriate device. They were evaluated according to Asthma Quality of Life Questionnaire and GINA/NIH guidelines. To demonstrate non-inferiority, the estimation of the Relative Risk between the Global Score Rate per group with its 95% confidence interval was calculated and compared against a non-inferiority margin obtained from a previous study. The Global Score Rate was 82% for G Group and 83% for D Group. The RR was 1.0124 (95% CI: 0.847-1.210). The margin set at 0.832 was not reached by the lower 95% CI (z=-2.097; p=0.018) pointing out non-inferiority. The results have demonstrated non-inferiority between groups. Thus, the 2 products are therapeutically similar.

Efficacy and safety of ipratropium bromide/albuterol delivered via Respimat inhaler versus MDI.

We compared the efficacy and safety of ipratropium bromide/albuterol delivered via Respimat inhaler, a novel propellant-free inhaler, versus chlorofluorocarbon (CFC)-metered dose inhaler (MDI) and ipratropium Respimat inhaler in patients with COPD. This was a multinational, randomized, double-blind, double-dummy, 12-week, parallel-group, active-controlled study. Patients with moderate to severe COPD were randomized to ipratropium bromide/albuterol (20/100mcg) Respimat inhaler, ipratropium bromide/albuterol MDI [36mcg/206mcg (Combivent Inhalation Aerosol MDI)], or ipratropium bromide (20mcg) Respimat inhaler. Each medication was administered four times daily. Serial spirometry was performed over 6h (0.15min, then hourly) on 4 test days. The primary efficacy variable was forced expiratory volume in 1s (FEV(1)) change from test day baseline at 12 weeks. A total of 1209 of 1480 randomized, treated patients completed the study; the majority were male (65%) with a mean age of 64 yrs and a mean screening pre-bronchodilator FEV(1) (percent predicted) of 41%. Ipratropium bromide/albuterol Respimat inhaler had comparable efficacy to ipratropium bromide/albuterol MDI for FEV(1) area under the curve at 0-6h (AUC(0-6)), superior efficacy to ipratropium Respimat inhaler for FEV(1) AUC(0-4) and comparable efficacy to ipratropium Respimat inhaler for FEV(1) AUC(4-6). All active treatments were well tolerated. This study demonstrates that ipratropium bromide/albuterol 20/100mcg inhaler administered four times daily for 12 weeks had equivalent bronchodilator efficacy and comparable safety to ipratropium bromide/albuterol 36mcg/206mcg MDI, and significantly improved lung function compared with the mono-component ipratropium bromide 20 mcg Respimat inhaler. [Clinical Trial Identifier Number: NCT00400153].

[Physiopathology, diagnosis and treatment of severe chronic hypoxemia. Role of residential chronic oxygen therapy]. / Fisiopatología, diagnostico y tratamiento de la hipoxemia crónica grave. Rol de la oxigenoterapia crónica domiciliaria.

The purpose of this article is to review the etiological and pathophysiological aspects of chronic severe hypoxemia (CSH) and to determine the indications of long-term oxygen therapy (LTOT). Three hypothesis are presented and analyzed: 1) CSH is harmful to the economy; 2) LTOT is therefore useful; 3) LTOT is not toxic and does not imply major risks than the benefits that it offers. Changes are produced by prolonged exposure to low levels of O2 leading to a sustained increase in pulmonary artery pressure. Secondary pulmonary hypertension (SPH) due to chronic hypoxemia is much more subtle and less symptomatic than that produced by other pathologies. Chronic obstructive pulmonary disease is the most common cause of CSH; these patients have a poor prognosis associated to the hypoxemia and its effects, being a PaO2 below 60 mmHg one of the most precise factors of mortality. Patients selection criteria for LTOT different sources for home oxygen therapy, methods of administration and finally an update of LTOT situation in our country and abroad are discussed.

In patients with COPD, treatment with a combination of formoterol and ipratropium is more effective than a combination of salbutamol and ipratropium : a 3-week, randomized, double-blind, within-patient, multicenter study.

STUDY OBJECTIVES: To compare the efficacy of adding formoterol or salbutamol to regular ipratropium bromide treatment in COPD patients whose conditions were suboptimally controlled with ipratropium bromide alone. DESIGN: A randomized, double-blind, double-dummy, two-period, crossover clinical trial. SETTING: Twenty-four clinics and university medical centers in nine countries. PATIENTS: One hundred seventy-two patients with baseline FEV(1) < or = 65% predicted, with FEV(1) reversibility to salbutamol not exceeding the normal variability of the measurement, and symptomatic despite regular treatment with ipratropium bromide. INTERVENTIONS: Each patient received two treatments in random order: either inhaled formoterol dry powder, 12 microg bid, in addition to ipratropium bromide, 40 microg qid for 3 weeks, followed by salbutamol, 200 microg qid, in addition to ipratropium, 40 microg qid for 3 weeks, or vice versa. MEASUREMENTS AND RESULTS: Efficacy end points included morning premedication peak expiratory flow (PEF) during the last week of treatment (primary end point), the area under the curve (AUC) for FEV(1) measured for 6 h after morning dose on the last day of treatment, and symptom scores (from daily diary recordings). Morning PEF and the AUC for FEV(1) were significantly better for formoterol/ipratropium than for salbutamol/ipratropium (p = 0.0003 and p < 0.0001, respectively). The formoterol/ipratropium combination also induced a greater improvement in mean total symptom scores (p = 0.0042). The safety profile of the two treatments was comparable. CONCLUSIONS: In COPD patients requiring combination bronchodilator treatment, the addition of formoterol to regular ipratropium treatment is more effective than the addition of salbutamol.

Fisiopatología, diagnostico y tratamiento de la hipoxemia crónica grave. Rol de la oxigenoterapia crónica domiciliaria. / [Physiopathology, diagnosis and treatment of severe chronic hypoxemia. Role of residential chronic oxygen therapy]

The purpose of this article is to review the etiological and pathophysiological aspects of chronic severe hypoxemia (CSH) and to determine the indications of long-term oxygen therapy (LTOT). Three hypothesis are presented and analyzed: 1) CSH is harmful to the economy; 2) LTOT is therefore useful; 3) LTOT is not toxic and does not imply major risks than the benefits that it offers. Changes are produced by prolonged exposure to low levels of O2 leading to a sustained increase in pulmonary artery pressure. Secondary pulmonary hypertension (SPH) due to chronic hypoxemia is much more subtle and less symptomatic than that produced by other pathologies. Chronic obstructive pulmonary disease is the most common cause of CSH; these patients have a poor prognosis associated to the hypoxemia and its effects, being a PaO2 below 60 mmHg one of the most precise factors of mortality. Patients selection criteria for LTOT different sources for home oxygen therapy, methods of administration and finally an update of LTOT situation in our country and abroad are discussed.

CD4+ T-lymphocytopenia in severe pulmonary tuberculosis without evidence of human immunodeficiency virus infection.

SETTING: A large public hospital in Buenos Aires, Argentina. OBJECTIVE: To determine the number of blood CD4 and CD8 T-lymphocytes in male human immunodeficiency virus (HIV) negative patients with severe pulmonary tuberculosis. DESIGN: Seventeen patients with severe pulmonary tuberculosis (SPT), with a mean age of 44.1 years, all HIV negative, had on admission lost 20% or more of their normal weight. Ten male HIV negative pulmonary tuberculosis patients (PT), with a mean age of 25.2 years, in good general condition, acted as a control group. Patients from both groups had a blood CD4/CD8 count before treatment. RESULTS: In the SPT patients, the CD4/CD8 count before treatment yielded a mean of 341.25 +/- 142.73/ mm3 for CD4 and 259.33 +/- 100.89/mm3 for CD8. Three patients died a few weeks after starting treatment; on admission they had 180,220 and 280 CD4/ mm3, respectively. Patients in good general condition yielded 721.40 +/- 272.20 for CD4 (P < 0.01, t = 4.216) and 416.67 for CD8. At the same time, five normal volunteers, with a mean age of 35.60 +/- 10.45 years, had mean CD4 and CD8 counts of 906 +/- 75.37 and 360 +/- 190.79, respectively. CONCLUSION: Based on the findings of this study, we feel that it is of value to measure the CD4 and CD8 T-lymphocyte counts in STP patients with a compromised general condition and with significant weight loss at the beginning of treatment. Those patients with a CD4 count of < 300/mm3 have a very poor prognosis and, in addition to the regular antituberculosis drugs, will require intensive care during the first weeks of treatment.

[Pharmacokinetic interaction of ketoconazole, isoniazid and rifampicin]. / Interacción farmacocinética entre ketoconazol, isoniacida y rifampicina.

Eight male tuberculous patients, between 20 and 60 years of age, were given Isoniazid 5 mg/kg and Ketoconazole 200 mg, first one at a time and then associated. Plasma concentrations were measured 0, 2 and 5 hs after taking the drugs. Isoniazid was measured by spectrophotometry and Ketoconazole by the microbiologic method with Candida albicans as test microorganism. When both drugs were given simultaneously Ketoconazole plasma concentration decreased 75% at 2 hs (p less than 0.025) and 85% at 5 hs (p less than 0.05), whereas that of Isoniazid remained unchanged (Table 1). Mean half-life of Isoniazid was 3.9 +/- 1.4 hs in 7 slow acetylators and 1.1 hs in one fast acetylator when given one at a time and 4.4 +/- 1.5 hs when given simultaneously. A similar study was conducted on 11 tuberculous patients who were given Rifampicin 10 mg/kg and Ketoconazole 200 mg, one at a time and concurrently. Rifampicin was measured by high pressure liquid chromatography. When Rifampicin and Ketoconazole were given concurrently plasma concentration of both drugs was reduced: Ketoconazole decreased 85% at 2 hs (p less than 0.025) and 98% at 5 hs (p less than 0.025) whereas Rifampicin decreased 45% at 2 hs (p less than 0.005) and 40% at 5 hs (p less than 0.005) (Table 2). Mean half-life of Rifampicin was 3.5 +/- 0.8 and 4.2 +/- 1.1 hs, respectively, when it was given alone and concurrently. Studies on chemical interactions between Isoniazid and Ketoconazole and between Rifampicin and Ketoconazole yielded negative results.(ABSTRACT TRUNCATED AT 250 WORDS)

Interacción farmacocinética entre ketoconazol, isoniacida y rifampicina. / [Pharmacokinetic interaction of ketoconazole, isoniazid and rifampicin]

Eight male tuberculous patients, between 20 and 60 years of age, were given Isoniazid 5 mg/kg and Ketoconazole 200 mg, first one at a time and then associated. Plasma concentrations were measured 0, 2 and 5 hs after taking the drugs. Isoniazid was measured by spectrophotometry and Ketoconazole by the microbiologic method with Candida albicans as test microorganism. When both drugs were given simultaneously Ketoconazole plasma concentration decreased 75

at 2 hs (p less than 0.025) and 85

at 5 hs (p less than 0.05), whereas that of Isoniazid remained unchanged (Table 1). Mean half-life of Isoniazid was 3.9 +/- 1.4 hs in 7 slow acetylators and 1.1 hs in one fast acetylator when given one at a time and 4.4 +/- 1.5 hs when given simultaneously. A similar study was conducted on 11 tuberculous patients who were given Rifampicin 10 mg/kg and Ketoconazole 200 mg, one at a time and concurrently. Rifampicin was measured by high pressure liquid chromatography. When Rifampicin and Ketoconazole were given concurrently plasma concentration of both drugs was reduced: Ketoconazole decreased 85

at 2 hs (p less than 0.025) and 98

at 5 hs (p less than 0.025) whereas Rifampicin decreased 45

at 2 hs (p less than 0.005) and 40

at 5 hs (p less than 0.005) (Table 2). Mean half-life of Rifampicin was 3.5 +/- 0.8 and 4.2 +/- 1.1 hs, respectively, when it was given alone and concurrently. Studies on chemical interactions between Isoniazid and Ketoconazole and between Rifampicin and Ketoconazole yielded negative results.(ABSTRACT TRUNCATED AT 250 WORDS)

Liver alterations in antituberculosis regimens containing pyrazinamide.

A group of alcoholic tuberculous patients was given a pyrazinamide-containing regimen, and the liver was studied on admission and after two months of intensive treatment with IRSZ. Alterations in liver histology and in liver function tests found on admission improved or disappeared after two months' chemotherapy. A control group, give IRSE, showed similar results. A third group of nonalcoholic patients was given Z alone for 15 days, and liver tolerance was also excellent. These data support the conclusion that tuberculous alcoholic patients, in the absence of significant and persistent hepatic dysfunction, can be given Z-containing regimens. In all cases, a careful monitoring of hepatic function, with monthly SGPT and bilirubin determinations, is recommended.