[Novel trends in pharmacotherapy of chronic obstructive pulmonary disease--prevention of exacerbations (focus on roflumilast)].

This report summarizes results of controlled clinical studies designed to evaluate the effectiveness and safety of roflumilast, a phosphodiesterase-4 (PDE-4) inhibitor in patients with COPD and to identify the main groups of patients to whom prescription of this medication is indicated and results in reduction of repeated exacerbations. Generally speaking, roflumilast therapy appears justified for patients with symptoms of chronic bronchitis, severe or very severe bronchial obstruction (forced expiratory volume below 50%) and/or frequent exacerbations of the disease (= > 2/12 mo). Manifestations of symptomatic COPD (dyspnea, cough, expectoration, tolerance of physical exercises, etc.) are immaterial for taking decision to introduce roflumilast in combined therapy of COPD.

Declining efficacy in controlled trials of antidepressants: effects of placebo dropout.

Drug-placebo differences (effect-sizes) in controlled trials of antidepressants for major depressive episodes have declined for several decades, in association with selectively increasing clinical improvement associated with placebo-treatment. As these trends require adequate explanation, we tested the hypothesis that decreasing trial-dropout rates may be an important contributor. We gathered reports of peer-reviewed, placebo-controlled trials of antidepressants (1980-2011) by computerized literature searching, and applied meta-analysis, meta-regression and multiple linear regression methods to evaluate associations of dropout rates and other factors of interest, to reporting year and reported efficacy [standardized mean drug-placebo difference (SMD) as Hedges' g-statistic]. In 56 trials meeting inclusion and exclusion criteria, we confirmed significant overall efficacy of antidepressants but declining drug-placebo contrasts over the past three decades. Among other changes, there was a corresponding increase in placebo-associated improvement with a decline in placebo-dropout rate, mainly for lack of efficacy. These effects were found only when last-observation-carried-forward (LOCF) analyses were used. Other trial-design and subject factors, including drug-responses and drug-dropout rates, were much less associated with efficacy. We propose that declining placebo-dropout rates ascribed to inefficacy combined with use of LOCF analyses led to increasing improvement in placebo-arms that contributed to declining antidepressant-placebo contrasts in controlled treatment trials since the 1980s.

Comparison of global versus Asian clinical trial strategies supportive of registration of drugs in Japan.

The number of worldwide and Asian multiregional clinical trials (MRCTs) submitted for Japanese New Drug Applications increased markedly between 2009 and 2013, with an increasing number performed for simultaneously submission in the USA, EU, and Japan. Asian studies accounted for 32% of MRCTs (14/44 studies) and had comparatively small sample sizes (<500 subjects). Moreover, the number of Japanese subjects in Asian studies was 2.1- to 13.4-fold larger than the sample size estimated using the method described in Japanese MRCT guidelines, whereas the ratio for worldwide studies was 0.05- to 4.9-fold. Before the introduction of this guidelines, bridging or domestic clinical development strategies were used as the regional development strategy in accordance with ICH E5 guidelines. The results presented herein suggest that Asian studies were conducted when the drug had already been approved in the US/EU, when phase 3 clinical trials were not be planned in the USA/EU, when there was insufficient knowledge of ethnic differences in drug efficacy and safety, or when Caucasian data could not be extrapolated to the Japanese population. New strategies with Asian studies including the Japanese population could be conducted instead of Japanese domestic development strategy.

Placebo group improvement in trials of pharmacotherapies for alcohol use disorders: a multivariate meta-analysis examining change over time.

OBJECTIVE: Placebo group improvement in pharmacotherapy trials has been increasing over time across several pharmacological treatment areas. However, it is unknown to what degree increasing improvement has occurred in pharmacotherapy trials for alcohol use disorders or what factors may account for placebo group improvement. This meta-analysis of 47 alcohol pharmacotherapy trials evaluated (1) the magnitude of placebo group improvement, (2) the extent to which placebo group improvement has been increasing over time, and (3) several potential moderators that might account for variation in placebo group improvement. METHOD: Random-effects univariate and multivariate analyses were conducted that examined the magnitude of placebo group improvement in the 47 studies and several potential moderators of improvement: (a) publication year, (b) country in which the study was conducted, (c) outcome data source/type, (d) number of placebo administrations, (e) overall severity of study participants, and (f) additional psychosocial treatment. RESULTS: Substantial placebo group improvement was found overall and improvement was larger in more recent studies. Greater improvement was found on moderately subjective outcomes, with more frequent administrations of the placebo, and in studies with greater participant severity of illness. However, even after controlling for these moderators, placebo group improvement remained significant, as did placebo group improvement over time. CONCLUSIONS: Similar to previous pharmacotherapy placebo research, substantial pretest to posttest placebo group improvement has occurred in alcohol pharmacotherapy trials, an effect that has been increasing over time. However, several plausible moderator variables were not able to explain why placebo group improvement has been increasing over time.

Decline in placebo-controlled trial results suggests new directions for comparative effectiveness research.

The Affordable Care Act offers strong support for comparative effectiveness research, which entails comparisons among active treatments, to provide the foundation for evidence-based practice. Traditionally, a key form of research into the effectiveness of therapeutic treatments has been placebo-controlled trials, in which a specified treatment is compared to placebo. These trials feature high-contrast comparisons between treatments. Historical trends in placebo-controlled trials have been evaluated to help guide the comparative effectiveness research agenda. We investigated placebo-controlled trials reported in four leading medical journals between 1966 and 2010. We found that there was a significant decline in average effect size or average difference in efficacy (the ability to produce a desired effect) between the active treatment and placebo. On average, recently studied treatments offered only small benefits in efficacy over placebo. A decline in effect sizes in conventional placebo-controlled trials supports an increased emphasis on other avenues of research, including comparative studies on the safety, tolerability, and cost of treatments with established efficacy.

Content and quality of 10,000 controlled trials in schizophrenia over 60 years.

OBJECTIVE: To carry out an up-to-date comprehensive survey of the content and quality of intervention trials relevant to the treatment of people with schizophrenia. DESIGN: Data were extracted and analyzed from 10,000 trials on the Cochrane Schizophrenia Group's Register. MAIN OUTCOME MEASURES: Source, type and date of publication, country of origin, language, size of trial, interventions, and outcome measures. RESULTS: In the last decade, there has been a great increase in the number of trials relevant to schizophrenia and an improvement in the accessibility to reports. The number of trials per year is rising (currently ∼600/year) with China now producing 25% of the annual total. The number of reports of trials is increasing at an even greater rate due to multiple publications. Drug trials still dominate (83%) although an increasing proportion of studies are now evaluating psychological therapies (21%). Trials remain small (median 60 people) and often employ new nonvalidated outcomes scales (2194 different scales were employed with every fifth trial introducing a new rating instrument). CONCLUSIONS: A more collaborative, pragmatic, and patient-centered approach is necessary to produce larger schizophrenia trials. Wider consultation and careful consideration of all relevant perspectives would result in trials with greater clinical utility and direct value to people with the illness and their families or carers.

The evidence-based pharmacotherapy of social anxiety disorder.

Social anxiety disorder (SAD) is a highly prevalent and often disabling disorder. This paper reviews the pharmacological treatment of SAD based on published placebo-controlled studies and published meta-analyses. It addresses three specific questions: What is the first-line pharmacological treatment of SAD? How long should treatment last? What should be the management of treatment-resistant cases? Based on their efficacy for SAD and common co-morbid disorders, tolerability and safety, selective serotonin reuptake inhibitors (SSRIs) and venlafaxine should be considered the first-line treatment for most patients. Less information is available regarding the optimal length of treatment, although individuals who discontinue treatment after 12-20 wk appear more likely to relapse than those who continue on medication. Even less empirical evidence is available to support strategies for treatment-resistant cases. Clinical experience suggests that SSRI non-responders may benefit from augmentation with benzodiazepines or gabapentin or from switching to monoamine oxidase inhibitors, reversible inhibitors of monoamine oxidase A, benzodiazepines or gabapentin. Cognitive-behavioural is a well-established alternative first line therapy that may also be a helpful adjunct in non-responders to pharmacological treatment of SAD.

Clinically significant drug interactions with newer antidepressants.

After the introduction of selective serotonin reuptake inhibitors (SSRIs), other newer antidepressants with different mechanisms of action have been introduced in clinical practice. Because antidepressants are commonly prescribed in combination with other medications used to treat co-morbid psychiatric or somatic disorders, they are likely to be involved in clinically significant drug interactions. This review examines the drug interaction profiles of the following newer antidepressants: escitalopram, venlafaxine, desvenlafaxine, duloxetine, milnacipran, mirtazapine, reboxetine, bupropion, agomelatine and vilazodone. In general, by virtue of a more selective mechanism of action and receptor profile, newer antidepressants carry a relatively low risk for pharmacodynamic drug interactions, at least as compared with first-generation antidepressants, i.e. monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants (TCAs). On the other hand, they are susceptible to pharmacokinetic drug interactions. All new antidepressants are extensively metabolized in the liver by cytochrome P450 (CYP) isoenzymes, and therefore may be the target of metabolically based drug interactions. Concomitant administration of inhibitors or inducers of the CYP isoenzymes involved in the biotransformation of specific antidepressants may cause changes in their plasma concentrations. However, due to their relatively wide margin of safety, the consequences of such kinetic modifications are usually not clinically relevant. Conversely, some newer antidepressants may cause pharmacokinetic interactions through their ability to inhibit specific CYPs. With regard to this, duloxetine and bupropion are moderate inhibitors of CYP2D6. Therefore, potentially harmful drug interactions may occur when they are coadministered with substrates of these isoforms, especially compounds with a narrow therapeutic index. The other new antidepressants are only weak inhibitors or are not inhibitors of CYP isoforms at usual therapeutic concentrations and are not expected to affect the disposition of concomitantly administered medications. Although drug interactions with newer antidepressants are potentially, but rarely, clinically significant, the use of antidepressants with a more favourable drug interaction profile is advisable. Knowledge of the interaction potential of individual antidepressants is essential for safe prescribing and may help clinicians to predict and eventually avoid certain drug combinations.

Updates on the antinociceptive mechanism hypothesis of botulinum toxin A.

Botulinum toxin A has been traditionally viewed as a motor nerve specific treatment. However, clinical uses for botulinum toxin A have continued to expand, with increased use in conditions implicating sensory pain nerve dysfunction. Chronic pain is associated with excess pain fiber activity. When the site of this excess activity resides in the peripheral portion of the pain pathway, a condition of peripheral sensitization can establish. During this state, excess pain signaling reaches the central nervous system, which can then lead to a condition of central sensitization, manifesting as the symptoms associated with chronic pain (i.e. burning, electric pain, lowered pain threshold to normal stimuli, etc). Experimentally, botulinum toxin type A has been shown to reduce neuropeptides and neurotransmitter release from treated cells or nerve endings and to attenuate nociception in both neuropathic and non-neuropathic pain models. This review summarizes the literature to update the hypothesis for the mechanism by which botulinum toxin type A can modulate chronic pain.

Vascular risk factors and dementia: how to move forward?

In recent years, accumulating evidence has suggested that vascular risk factors contribute to Alzheimer disease (AD). Vascular dementia had been traditionally considered secondary to stroke and vascular disease. It has been traditionally distinguished from AD, considered to be a purely neurodegenerative form of dementia. However, in light of this more recent literature, it appears that there is a spectrum: ranging from patients with pure vascular dementia to patients with pure AD and including a large majority of patients with contributions from both Alzheimer and vascular pathologies. In this article, we discuss the impact of vascular risk factors on AD and its consequences at the individual level and at the population level by highlighting the concept of attributable risk. We then discuss the key questions and next steps involved in designing a therapeutic trial to control vascular risk factors for the prevention of dementia.

Disciplined analyses in clinical trials: the dark heart of the matter.

Clinical research analyses must balance the desire to ;learn all that is learnable' from the database with the observation that sample-based data commonly lead to conclusions that are perfectly correct for the sample, but wholly incorrect for the population from which the data were based. Investigators who defend exploratory analyses as reliable, misuse important tools that have taken over three hundred years to develop. Statistical estimators in clinical trials function appropriately when they incorporate random data that is gathered in response to a fixed research question. Their prediction ability degrades rapidly when the selection of the research question is itself random, that is, left to the data. Operating like blind guides, these estimators mislead the medical community about what it would see in the population, based on sample observations. The result is a wavering research focus, leaping from one provocative but misleading finding to the next on the powerful waves of sampling error. Therefore, a primary purpose of the prospective design is to fix the research questions prospectively, thereby anchoring the analysis plan. Prospective statements of the research questions and rejection of tempting databased changes to the protocol preserve the best estimates of effect sizes, standard errors, confidence intervals and p-values. Embracing these principles promotes the prosecution of a successful research program, that is, the construction and protection of a research environment that permits an objective assessment of the therapy or exposure being studied. If there is any fixed star in the research constellation, it is that sample-based research must be hypothesis-driven and concordantly executed to have real meaning for both the scientific community and the patient populations that we serve.

Identifying barriers to the rapid administration of appropriate antibiotics in community-acquired pneumonia.

BACKGROUND: Despite multiple guidelines for management of community-acquired pneumonia (CAP), barriers to guideline use are rarely evaluated. METHODS: We performed quantitative and qualitative surveys of junior doctors before implementation of a CAP management pathway. After implementation, we identified patient-related determinants of pathway adherence by multivariate analysis. RESULTS: We surveyed 83 (77%) of the 108 junior doctors working in acute medicine between August 2001 and July 2002 and selected 8 for in-depth interview. We identified five main themes that influence pathway adherence. First, education (recognized to be insufficient on antimicrobial therapy) and experience: increasing clinical experience was associated with greater knowledge of pathway content, but decreasing likelihood of consulting the pathway. Second, attitudes to CAP: doctors recognized that they had not treated CAP with respect early on. Third, work intensity and lack of senior support were barriers to good practice. Fourth, guideline factors: they need to be simple enough to be easy to use while containing enough information to be useful. Fifth, CAP is sometimes difficult to diagnose on admission. Notably, when given three clinical scenarios only six (7%) of respondents assessed CAP severity correctly. In the intervention study, early administration of antibiotics was associated (P < 0.05) with indicators of increased severity of illness (pulse, respiratory rate, oxygenation and temperature) in addition to being admitted to the intervention hospital (P < 0.001). CONCLUSIONS: Some of the identified barriers could be overcome by undergraduate and postgraduate education. However, equally important are organizational barriers that can only be overcome by systems redesign.