Insomnia medication: Do published studies reflect the complete picture of efficacy and safety?

Selective publication can have a deleterious effect on evidence based medicine, health policy decision making and treatment guidelines. Using the European Public Assessment Reports (EPARs) as reference, this study examined selective publication and selective reporting of efficacy and safety of insomnia medication.EPARs of with three insomnia medications were used to identify all clinical trials that were performed between 1998 and 2007 for the purpose of registration in the EU. The matching publication for each trial was searched through a systematic literature search. Accuracy of information in the publications was examined by comparison to the information in the EPARs.Only 55% of the trials with insomnia medications identified in EPARs were published. Positive trials were approximately two times more likely to be published. The lag time from study completion to publication was shorter for the positive compared to the negative trials. Sample size did not correlate with publication of negative trials. The meta-analysis of the effect size of insomnia medication was 1.6 times larger in the published data compared to the complete data. While the primary end points of the trials were reported reliably in the publications, remarkable inconsistencies were detected in the reporting of the secondary end points, methods, results and, especially safety. In conclusion, selective publication and reporting lead to an overestimation of efficacy and underestimation of safety of insomnia products. Authors of treatment guidelines should be aware of this bias. EPARs/FDA reviews provide a more unbiased view of the benefit-risk balance of insomnia and other medications and hence these documents should be consulted by e.g. authors of meta-analyses and of treatment guidelines.     

The EU paediatric regulation:: Effects on paediatric psychopharmacology in Europe

Child and adolescent psychiatry is a relatively young field and the recognition, classification, and treatment of disorders in children and adolescents lag behind those in adults. In recent years there is an increasing awareness of the differences between children and adults in psychopathology and pharmacology. Related to this new paediatric regulations have been introduced. This article reviews the regulatory and legislative measures that were adopted in the EU in 2007 and the subsequent impact of these measures on the field of paediatric psychopharmacology.The consequences of the paediatric regulation in the EU are reflected in several domains: regulatory, research aimed at drug development and clinical practices. In the regulatory domain, the consequences include: new paediatric indications, inclusion of special (class) warnings, specification of dose regimens, and information on safety specific to children and adolescents, and development of new medicinal formulations.The paediatric regulation leads to timely development of paediatric friendly formulations and better quality of the clinical evidence. In clinical practices, an increased awareness of the uniqueness of paediatric pharmacology is emerging among medical professionals, and subsequent improvement of medical care (i.e. correct doses, appropriate formulation, monitoring for expected adverse events). In addition, clinical guidelines will have to be revised more frequently in order to integrate the recently acquired knowledge.The new regulations stimulate transparency and discussions between academia, pharmaceutical industry, and regulators. The purpose is to optimize clinical research and obtain evidence for paediatric psychopharmacology, thereby providing adequate support for treatment.     

Dopaminergic-induced changes in Mauthner cell excitability disrupt prepulse inhibition in the startle circuit of goldfish

Prepulse inhibition (PPI) is a widespread sensorimotor gating phenomenon characterized by a decrease in startle magnitude if a nonstartling stimulus is presented 20-1,000 ms before a startling stimulus. Dopaminergic agonists disrupt behavioral PPI in various animal models. This provides an important neuropharmacological link to schizophrenia patients that typically show PPI deficits at distinct (60 ms) prepulse-pulse intervals. Here, we study time-dependent effects of dopaminergic modulation in the goldfish Mauthner cell (M-cell) startle network, which shows PPI-like behavioral and physiological startle attenuations. The unique experimental accessibility of the M-cell system allows investigating the underlying cellular mechanism with physiological stimuli in vivo. Our results show that the dopaminergic agonist apomorphine (2 mg/kg body wt) reduced synaptic M-cell PPI by 23.6% (n = 18; P = 0.009) for prepulse-pulse intervals of 50 ms, whereas other intervals showed no reduction. Consistently, application of the dopamine antagonist haloperidol (0.4 mg/kg body wt) restored PPI to control level. Current ramp injections while recording M-cell membrane potential revealed that apomorphine acts through a postsynaptic, time-dependent mechanism by deinactivating a M-cell membrane nonlinearity, effectively increasing input resistance close to threshold. This increase is most pronounced for prepulse-pulse intervals of 50 ms (47.9%, n = 8; P < 0.05) providing a time-dependent, cellular mechanism for dopaminergic disruption of PPI. These results provide, for the first time, direct evidence of dopaminergic modulation of PPI in the elementary startle circuit of vertebrates and reemphasize the potential of characterizing temporal aspects of PPI at the physiological level to understand its underlying mechanisms.     

Eosinophil cell: pray tell us what you do!

PURPOSE OF REVIEW: We will review the role of the eosinophil as an innate immune cell. There have been recent advances in the regulatory mechanisms of the eosinophil, in terms of priming and migration. Additionally, we will discuss certain pulmonary diseases that are associated with eosinophilia. RECENT FINDINGS: Rapid binding of immunoglobulin A-coated beads can prime the eosinophil cell in the trafficking process. Tissue factor has been shown to be expressed within eosinophil granules. It is believed to serve as a critical eosinophil mediator within the peripheral bloodstream. Interleukin-8 serves as a chemoattractant through IL8RA and IL8RB receptors, but patients with an IL8RA-B ht2 have peripheral eosinophilia. Interleukin-10 and eotaxin correlate with eosinophilia and an active infection prior to therapy. After therapy, interleukin-5 and 6 correlated appropriately with eosinophilia. A wide differential diagnosis exists for peripheral eosinophilia. One study has shown that 86 out of 103 patients with unknown causes for peripheral eosinophilia had positive toxocara enzyme-linked immunosorbent assay results. SUMMARY: The effect of the cytotoxic eosinophil cell is not only harmful to foreign invaders within the body, but through an intricate immunological pathway, eosinophils can become detrimental to the host organs.     

Prevalence of coeliac disease in the adult population of central Greece

OBJECTIVES: Recent studies from several countries have shown that coeliac disease (CD) is increasingly being diagnosed in adults, as the availability of new, accurate serologic tests has made screening in the general population possible. No data exist regarding the prevalence of CD in Greece. The aim of this study was the implementation of a serologic screening procedure for CD in the adult general population of Thessaly, an area of central Greece, using a novel diagnostic algorithm. METHODS: The study included 2230 participants (1226 women, 1004 men, median age 46 years, range 18-80 years), selected by systematic random sampling, from the adult general population of Thessaly. All the serum samples were tested for total immunoglobulin A (IgA)-serum levels, to exclude IgA deficiency. Samples with total IgA within the normal range were tested for IgA antibodies against native human-tissue transglutaminase (anti-tTG); samples that were anti-tTG positive were tested for IgA antiendomysial antibodies (EmA). Samples from participants with selective IgA deficiency were examined for IgG antigliadin antibodies. Participants who were EmA-positive or antigliadin antibody-positive were referred for intestinal biopsy and human leucocyte antigen (HLA) typing. RESULTS: No participant with selective IgA deficiency was detected. Four individuals tested positive for EmA, all of whom were biopsy-proven coeliacs. Therefore, the CD prevalence in this general population sample is 1 : 558 or 1.8 per 1000 (SE 0.13). The four new patients with abnormal histology (two men, two women) were aged between 18 and 35 years. Two of them were considered to be asymptomatic and two presented with a subclinical course. All four had the heterodimer HLA-DQ2. CONCLUSIONS: This first serological screening study for CD in Greece has demonstrated that CD prevalence in Thessaly is among the lowest reported in Europe.     

Association between the plasminogen activator inhibitor-1 4G/5G polymorphism and venous thrombosis. A meta-analysis

The effect of the 675 insertion/deletion (4G/5G) polymorphism of plasminogen activator inhibitor-1 (PAI-1) gene on the risk of venous thromboembolism (VTE) remains controversial. In this study, we performed a meta-analysis of published data regarding this issue. A comprehensive electronic search was carried out up until September 2006. A total of 22 articles were included in the analysis that was performed using random effects models. Eighteen papers, concerning patients without another known risk factor, comprised 2,644 cases and 3,739 controls. The alleles contrast (4G vs. 5G allele) yielded a statistically significant odds ratio (OR) of 1.153 (95% confidence interval [CI]: 1.068-1.246). In a sub-analysis of five studies that included 256 cases with another genetic risk factor and 147 controls, the combined per-allele OR was still significant (OR: 1.833,95% CI: 1.325-2.536). On the contrary, the analysis of five studies regarding cases with a non-genetic risk factor for VTE (antiphospholipid antibody syndrome, Behcet disease) provided insignificant results in all aspects. There was no evidence for heterogeneity and publication bias in all analyses. Based on our findings, the 4G allele appears to increase the risk of venous thrombosis, particularly in subjects with other genetic thrombophilic defects. Recommendation for detection of this polymorphism in evaluating thrombophilia in such patients might be considered.     

A psychometric evaluation of the Chinese version of the Cardiovascular Limitations and Symptoms Profile in patients with coronary heart disease

Aims and objectives. The aim of this study was to translate from English and evaluate the validity, reliability and cultural relevance of the Cardiovascular Limitations and Symptoms Profile (CLASP) as a health‐related quality‐of‐life (HRQL) measure in Chinese patients with coronary heart disease. Background. Improvement in HRQL is increasingly used as a primary outcome in determining the treatment benefit using a generic instrument. However, disease‐specific instruments are being cited as more responsive and sensitive in detecting even the smallest changes in health status. Therefore, valid and reliable disease‐specific measures for patients with coronary heart disease are now being developed and evaluated. Design. Questionnaire design. Methods. The translation equivalence and content validity of the Chinese version of CLASP were evaluated by an expert panel. Measurement performance was tested on a convenience sample of 369 Chinese coronary heart disease patients. Results. The instrument demonstrated good content validity (content validity index 0·94), acceptable internal consistency (>0·70), except for two subscales of angina and tiredness and significant positive correlations among the subscales of CLASP, Hospital Anxiety Depression Scale and the Short Form 36 Health Survey. Principal components analysis revealed nine factors that together explained 69% of the variance. Conclusions. The results of this study support that CLASP is a valid and reliable disease‐specific health status measure for Chinese patients with coronary heart disease. However, further item modifications and testings are needed when considering the cross‐cultural context. Relevance to clinical practice. The use of disease‐specific HRQL measures could effectively evaluate nursing interventions in clinical practice. Further validations of CLASP among different diagnostic groups, such as patients with heart failure and those who have survived an acute myocardial infarction, would provide further empirical support for its use with all patients with heart disorders.