Chronic obstructive pulmonary disease (COPD) remains a leading cause of death worldwide, yet only one new drug class has been approved in the last decade. However, resurgence in COPD treatment has been recently fueled by a greater understanding of the pathophysiology and natural history of the disease, as well as a growing prevalence and an aging population. Currently, there are nearly 25 novel drug targets in development. Furthermore, the indication has undergone some fundamental changes over the last couple of years, including an updated diagnosis paradigm, validation, and approval of patient-reported outcome questionnaires for clinical trials, and drug development tools, such as a prognostic biomarker for patient selection. In the context of clinical trials, this review aims to summarize recent changes to the diagnosis and evaluation of COPD and to provide an overview of US and European regulatory guidance. CHRONIC OBSTRUCTIVE PULMONARY DISEASE LANDSCAPE

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S inhibitory effect were not significantly different between hetEMs and homEMs, although there was a trend towards an increased AUC and acid-inhibitory effect in hetEMs. Therefore we compared the acid-inhibitory effect of LPZ and OPZ to baseline.Compared with baseline median 24 h pH and % of time pH > 4 at day 1 were significantly increased in hetEMs, but not in homEMs for both LPZ and OPZ. At day 6 the differences in acid-inhibitory effect between hetEMs and homEMs were not significant.At day 1 of administration acid inhibitory effect of LPZ 15 mg and OPZ 10 mg is affected by CYP2C19 polymorphism. Compared with baseline, there was at day 1 a significant acid-inhibitory effect in hetEMs, but not in homEMs.

Mental stress tests are frequently used in drug research. However, the reproducibility of the test is largely unknown particularly after repeated performance. Eight healthy volunteers performed mental arithmetic for 6 min (mental stress test) on 2 occasions separated by 14 days (during morning and afternoon session). During the tests, heart rate (HR) and systolic (SBP) and diastolic blood pressure (DBP) were determined on a beat‐to‐beat basis. Before testing baselines of BP and HR were assessed over one minute intervals. Data are shown as means ± SD and comparisons were made using paired Student's t‐tests. Baseline values and responses to mental stress are summarised in the table. Baseline HR was lower in the morning than in the afternoon on both occasions, but was not different between occasions. Baseline DBP values were lower during the second occasion, but no circadian variation was noted. No differences in SBP were observed. Except for a slightly higher HR response at the first test performance, no differences were found for the reponses to mental stress. (See Table) Although baseline values for HR were different in the morning and afternoon, responses to mental stress were similar, except for a slightly higher response at the first test, which may reflect some habituation to the test with regard to HR. Thus, the response to mental stress appeared reproducible over multiple test sessions and may be a suitable tool to be used in drug research. Clinical Pharmacology & Therapeutics (2004) 75, P54–P54; doi: Occasion 1 Occasion 2 a.m. p.m. a.m. p.m. baseline HR66 ± 673 ± 6#65 ± 572 ± 7#HR response21 ± 617 ± 615 ± 4*16 ± 6baseline SBP128 ± 20121 ± 14114 ± 14115 ± 13SBP response12 ± 914 ± 1118 ± 1211 ± 8baseline DBP76 ± 1368 ± 764 ± 7*62 ± 6*DBP response11 ± 611 ± 714 ± 810 ± 5 * p<0.05 between occasion 1 and 2.# p<0.05 between a.m. and p.m.

Decreases in gallbladder volume have been suggested as a biomarker for motilin activity in man. Yet, this could not be confirmed in 4 placebo‐controlled cross‐over studies with 10–12 subjects each. Therefore a meta‐analysis was done on the data from these studies to investigate a motilin effect on gallbladder volume in healthy volunteers and patients with functional dyspepsia (FD). Forty‐three healthy volunteers and 10 patients with FD received motilin (4 pmol/kg/min) or placebo in four separate double‐blind, randomised, placebo‐controlled, cross‐over studies. Gallbladder volume was measured by ultrasonography. Analysis of variance of the combined data of these studies was performed to allow differentiation between patients and healthy volunteers. Baseline gallbladder volume was similar for placebo and motilin treatment, and between patients and healthy volunteers. Motilin significantly decreased gallbladder volume in healthy volunteers (p=0.003) and patients (p<0.0001) with the decrease being greater in patients (p=0.03). A linear concentration‐response relationship was observed. The motilin effect was consistent across the 4 studies. Interdigestive gallbladder volume is a non‐invasive endpoint for motilin activity, displaying a consistent response to motilin and a clear concentration‐response relationship. However, it is less suitable as biomarker for future pharmacological studies on motilin agonist or antagonists as the effect is probably indirect and as a large study population is required. Clinical Pharmacology & Therapeutics (2004) 75, P57–P57; doi: