24-hour bronchodilation following a single dose of the novel ß(2)-agonist olodaterol in COPD.

BACKGROUND: Current guidelines recommend long-acting bronchodilators as maintenance therapy in COPD when symptoms are not adequately controlled with short-acting agents. Olodaterol is a novel long-acting ß(2)-adrenoceptor agonist with a pre-clinical profile that suggests 24-h bronchodilation may be achieved with once-daily administration. OBJECTIVE: To assess dose- and time-response in terms of bronchodilator efficacy, and to evaluate pharmacokinetics, safety and tolerability of single doses of olodaterol administered via Respimat(®) Soft Mist™ Inhaler in COPD patients. METHODS: A single-center, double-blind, placebo-controlled, 5-way crossover study including 24-h spirometry (FEV(1), FVC), safety, tolerability and pharmacokinetics (in a subset of patients) following dosing of olodaterol 2 µg, 5 µg, 10 µg and 20 µg; the washout period between test-days was at least 14 days. Primary endpoint of the study was the 24-h post-dosing FEV(1). Patients participating in the pharmacokinetic assessments continued in an open-label extension phase to establish pharmacokinetics of olodaterol 40 µg. RESULTS: 36 patients were assigned to treatment; mean baseline prebronchodilator FEV(1) was 1.01 L (37% predicted normal). All doses of olodaterol provided significantly greater bronchodilation compared to placebo in 24-h FEV(1) post-dose (p < 0.001); a clear dose-response relationship was observed, with values ranging from 0.070 L for olodaterol 2 µg to 0.119 L for olodaterol 20 µg. Similarly, olodaterol was superior to placebo (p < 0.001) in peak FEV(1) (0.121 L to 0.213 L) and average FEV(1) both during the daytime (0-12 h; ranging from 0.099 L to 0.184 L) and night-time (12-24 h; ranging from 0.074 L to 0.141 L). FVC results were consistent with those observed for FEV(1). Pharmacokinetic evaluation of the peak plasma concentrations and renal excretion suggested no obvious deviation from dose-proportionality over the investigated dose range of 2 µg-40 µg; in most patients, no plasma levels could be detected following the 2 µg dose. All treatments were well tolerated with no apparent dose relation in terms of adverse events. CONCLUSIONS: Olodaterol appears to be a promising long-acting ß(2)-adrenoceptor agonist,with bronchodilation maintained over 24 h that offers an opportunity for once-daily dosing in patients who require maintenance bronchodilator therapy for the management of COPD symptoms.

Effects of medroxyprogesterone acetate on appetite, weight, and quality of life in advanced-stage non-hormone-sensitive cancer: a placebo-controlled multicenter study.

PURPOSE: To investigate the effects of medroxyprogesterone acetate (MPA) on appetite, weight, and quality of life (QL) in patients with advanced-stage, incurable, non-hormone-sensitive cancer. PATIENTS AND METHODS: Two hundred six eligible patients were randomized between double-blind MPA 500 mg twice daily or placebo. Appetite (0 to 10 numerical rating scale), weight, and QL (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire [EORTC-QLQ-C30]) were assessed before the start of treatment (t = 0), and 6 weeks (t = 6) and 12 weeks (t = 12) thereafter. RESULTS: One hundred thirty-four patients (68 MPA and 66 placebo) were assessable at t = 6 and 99 patients (53 MPA and 46 placebo) at t = 12. A beneficial effect of MPA on appetite was observed after both 6 weeks (P = .008) and 12 weeks (P = .01) of treatment. After 12 weeks, a mean weight gain of 0.6 +/- 4.4 kg was seen in the MPA, versus an ongoing mean weight loss of 1.4 +/- 4.6 kg in the placebo group. This difference of 2.0 kg was statistically significant (P = .04). During the study, several areas of QL deteriorated in the total group of patients. With the exception of an improvement in appetite and possible also a reduction in nausea and vomiting, no measurable beneficial effects of MPA on QL could be demonstrated. The side effects profile of MPA was favorable: only a trend toward an increase in (usually mild) peripheral edema was observed. CONCLUSION: In weight-losing, advanced-stage non-hormone-sensitive cancer patients, MPA exhibits a mild side effects profile, has a beneficial effect on appetite, and may prevent further weight loss. However, general QL in the present study was not measurably influenced by MPA treatment.

Clinical significance of intranodal and extranodal growth in lymph node metastases of non-small cell lung cancer.

In non-small cell lung cancer with mediastinal lymph node metastasis, intranodal growth is regarded as prognostically more favourable than extranodal growth. We evaluated the clinical implications. Mediastinal lymph node metastases removed at mediastinoscopy and/or surgery were classified as intranodal, extranodal or indefinite. "Minimal N2 disease" denoted a solitary, intranodal metastasis, "extranodal" at least one extranodal lymph node metastasis, and "indefinite" more than one intranodal or at least one indefinite metastasis. Although in patients with resected N2 disease, c. 21% of the nodal metastases were "indefinite", survival was significantly better in minimal N2 disease than in the combined groups with extranodal and indefinite lymph node metastases. Of the metastatic nodes removed at mediastinoscopy, 75% were unsuitable for definite classification as only intranodal or extranodal. Only 1 of 49 patients had purely intranodal N2 disease. Thus, it was seldom feasible to classify mediastinoscopic lymph node involvement as intranodal or extranodal, and this classification is unhelpful as regards decisions on thoracotomy. However, when nodal involvement in resected N2 disease was limited to a single node with intranodal growth, the prognosis was better than in patients with extranodal disease or more than one intranodal metastasis or indefinite nodes.