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Although clinical drug trials are indispensable in providing an appropriate background for dosage recommendations, they can provide mechanistic pharmacokinetic information only indirectly with the help of certain biomarkers for pathological, physiological and pharmacological determinants. Thus, to provide such mechanistic information of clinical value, various in vitro and in silico tests and approaches are increasingly employed in drug discovery and development. Integration of the results of these primarily preclinical studies has been made possible by various computational models, such as in vitro-in vivo extrapolation of hepatic clearance or physiologically based pharmacokinetic modelling. In this article, the current status of these modelling approaches is surveyed and some examples are given, highlighting advantages and disadvantages in applying them at various phases of drug development. A new paradigm of model-based drug development is briefly described, and the importance of the approach of integrating all of the information coming from different investigations at all levels--be it in vivo, in vitro or in silico--is emphasized. [ABSTRACT FROM AUTHOR]

Background: In early childhood, the ability to mount protective immune responses in the airways is impaired, with increased risk of allergic sensitisation to inhaled allergens. Antigen presenting cells (APC) and regulatory T cells (Treg) are important modifiers of T cell immunity but little is known about their distribution in bronchial mucosa at this age. Here the subset distribution of APC and the appearance of Foxp3+ Treg and bronchus associated lymphoid tissue (BALT) were examined immunohistochemically in children less than 2 years of age with chronic asthma-like symptoms of the lower airways. Methods: mmunophenotyping was performed in situ on bronchial biopsy specimens obtained from 45 infants, 4-23 months of age, under investigation for airway disease. Results: A well developed HLA-DR+ network of APC was present in all samples, approximately 50% of the cells being CD68+ macrophages and the remainder various subsets of dendritic cells. The density of HLA-DR+ cells increased significantly with age but was not related to atopy, clinical symptoms or lung function. Comparing the density of APC subsets and clinical parameters, only the number of intraepithelial CD1a+ dendritic cells was significantly increased in infants who had recently suffered a respiratory infection. BALT structures were identified in 22 children, with no relation to lung function, atopic status or human rhinovirus positivity. Plasmacytoid dendritic cells and Foxp3+ Treg were located primarily within these isolated lymphoid follicles. Conclusion: A bronchial network of dendritic cells and macrophages develops quite rapidly after birth, apparently independent of clinical symptoms or atopy. The high frequency of BALT structures containing putative tolerogenic dendritic cells and Treg suggests that these lymphoid follicles play an important role in bronchial immune homeostasis during infancy. [ABSTRACT FROM AUTHOR]

One major challenge in drug development is defining of the optimal animal species to serve as a model of metabolism in man. The study compared the hepatic drug metabolism characteristics of humans and six widely used experimental animal species. Classical in vitro model enzyme assays with known human cytochrome P450 (CYP) enzyme selectivity were employed and optimized to target human hepatic CYP forms. The profile of CYP activities best resembling the human was seen in mouse followed by monkey, minipig, and dog liver microsomes, with rats displaying the most divergent. The widest interindividual variability was found in CYP3A-mediated midazolam α-hydroxylase, and omeprazole sulphoxidase activities in human and monkey liver microsomes. These data demonstrate that if hepatic xenobiotic-metabolizing characteristics were to be the sole reason for the selection of animal species for toxicity studies, then the rat might not be the most appropriate model to mimic human CYP activity patterns. [ABSTRACT FROM AUTHOR]

Although the measurement of metabolite formation or substrate depletion in in vitro systems, from recombinant enzymes to tissue slices, is a relatively routine task, there are a number of more or less unresolved issues in the extrapolation of the enzymatic intrinsic clearance into hepatic metabolic clearance. Nominal concentrations of the drug added to the incubation system are not necessarily the concentration the transporter or the metabolizing enzyme sees. In addition, peculiarities of incubation set-ups should be assessed. Unbound drug fractions (concentrations) in the in vitro system itself should be measured or estimated for the appropriate assessment of enzymatic intrinsic clearance. In addition, blood and/or plasma concentrations to be encountered in the in vivo situation should be measured or estimated for the extrapolation. Extrapolation always means making a number of assumptions and the most important of these, such as scaling factors from recombinant enzymes, microsomes or hepatocytes to the mass unit of the liver, liver weight, blood flow, and distribution volume amongst others, and so on, should be explicitly stated and included in the extrapolation process. Despite all the above-mentioned reservations the in vitro-in vivo extrapolation of metabolic clearance seems to be a useful and mostly fairly precise tool for predicting the important pharmacokinetic processes of a drug. [ABSTRACT FROM AUTHOR]

Rationale: We hypothesized that the epithelial reticular basement membrane (RBM) thickening and eosinophilic inflammation characteristic of asthma would be present in symptomatic infants with reversible airflow obstruction. Methods: RBM thickness and numbers of inflammatory cells were determined in ultrathin sections of endobronchial biopsies obtained from 53 infants during clinical bronchoscopy for severe wheeze and/or cough. Group A: 16 infants with a median age of 12 months (range 3.4-26 months), with decreased specific airway conductance (sGaw) and bronchodilator reversibility; Group B: 22 infants with a median age of 12.4 months (5.1-25.9 months), with decreased sGaw but without bronchodilator reversibility; and Group C: 15 infants with a median age of 11.5 months (3.4-24.3 months) with normal sGaw. Additional comparisons were made with the following groups. Group D: 17 children, median age 10.3 years (6-16 years), with difficult asthma; Group E: 10 pediatric control subjects without asthma, median age 10 years (6-16 years); and Group F: nine adult normal, healthy control subjects, median age 27 years (21-42 years). Main Results: There were no significant differences in RBM thickness or inflammatory cell number between the infant groups. RBM thickness was similar in the infants and Groups E and F. However, the RBM in all infant groups (Group A: median 4.3 microm [range 2.8-9.2 microm]; Group B: median 4.15 microm [range 2.7-5.8 microm]; Group C: median 3.8 microm [range 2.7-5.5 microm]) was significantly less thick than that in the older children with asthma (Group D: median 8.3 microm [range 5.3-12.7 microm]; p < 0.001). Conclusion: RBM thickening and the eosinophilic inflammation characteristic of asthma in older children and adults are not present in symptomatic infants with reversible airflow obstruction, even in the presence of atopy. [ABSTRACT FROM AUTHOR]

Objectives: To compare the acceptability, reproducibility, and sensitivity of spirometric outcome measures of airway caliber during challenge testing in children.Design: FEV(1), forced expiratory volume in 0.75 s, forced expiratory volume in 0.5 s, and peak expiratory flow (PEF) were recorded during stepwise dosimetric histamine challenge tests. The responses were compared, and the reproducibility at baseline and from duplicate measurements at each challenge step was determined.Patients: One hundred five children with newly diagnosed asthma, aged 5 to 10 years.Results: Compared to PEF, FEV(1) showed better baseline reproducibility (p = 0.002) and higher sensitivity (p < 0.0001) during challenge testing, determined as the change normalized to the baseline variation, while the forced expiratory volumes were not significantly different in these respects. During challenge testing in subjects with acceptable flow-volume tracings, paired recordings of FEV(1) agreed within 0.1 L in 85% and within 0.2 L in 93% of measurements. During challenge testing, the reproducibility of FEV(1) measurements was not better than that of the other indexes. Failure to exhale long enough precluded the use of FEV(1) in 16 of the children, particularly the youngest children.Conclusions: The results demonstrated that the recently published guidelines for FEV(1) measurements during challenge tests can be applied to children. During challenge tests in asthmatic children, the advantage of the shorter fractions of forced expiratory volume was that they were more often acceptably recorded than FEV(1), while they showed as good reproducibility and were also equally sensitive in assessing changes in airway obstruction. [ABSTRACT FROM AUTHOR]

The results of 55 4-h hydrocortisone absorption tests in 38 children with atopic or seborrhoeic dermatitis were analysed to evaluate the effect of age and severity of the dermatitis on percutaneous absorption of hydrocortisone. The children were divided into three groups on the basis of the severity of the dermatitis. The absorption of hydrocortisone caused a significantly higher mean rise of serum cortisol in 20 children with severe dermatitis (Group A) than in 17 children with moderate dermatitis (Group B). The mean post-application rise of serum cortisol in 18 children with mild dermatitis (Group C) was significantly lower than in the children with moderate dermatitis. There was a significant negative linear correlation between age and the post-application rise of serum cortisol in Groups A and C. In these groups the mean post-application rise of serum cortisol was significantly higher in children aged under 18 months than in children aged 18 months or over. Severe widespread dermatitis and an age under 18 months are two relevant risk factors in the topical use of hydrocortisone. [ABSTRACT FROM AUTHOR]

Percutaneous absorption of hydrocortisone was studied in 18 children (aged from 6 weeks to 14! years) with atopic or seborrhoeic dermatitis, by measuring their serimi cortisol before and after application of 1% hydrocortisone cream. Endogenous secretion of cortisol was suppressed with dexamethasone. A 24 h absorption test was performed on nine children. In six, percutaneous absorption was detected. The highest serum cortisol level was reached within the first 6 h. A 4 h absorption test was developed on the basis of the 24 h test. This short absorption test was performed on nine children, and in eight of them absorption of hydrocortisone was detected. The rise of serum cortisol ranged from 98 to 2669 nmol/l. The 2 h ACTH test was performed to evaluate the effect of previous treatment with topical glucocorticoids. Suppressed adrenocortical function was found in five of 13 children, and was associated significantly with high post-application serum cortisol levels. This occured more often in infants with a severe skin disorder than in older children or in those with mild or moderate skin disease. [ABSTRACT FROM AUTHOR]

The effects of injected adrenaline and nebulized salbutamol on acute asthma were compared in 46 children. The results showed that salbutamol had a significantly better bronchodilatory effect than adrenaline. Nebulized salbutamol is recommended as a primary method of treatment of asthmatic attacks in childhood. [ABSTRACT FROM AUTHOR]

Purpose: Although medication-related adverse events (MRAEs) in health care are vastly studied, high heterogeneity in study results complicates the interpretations of the current situation. The main objective of this study was to form an up-to-date overview of the current knowledge of the prevalence, risk factors, and surveillance of MRAEs in health care. Methods: Electronic databases (PubMed, MEDLINE, Web of Science, and Scopus) were searched with applicable search terms to collect information on medication-related adverse events. In order to obtain an up-to-date view of MRAEs, only studies published after 2000 were accepted. Results: The prevalence rates of different MRAEs vary greatly between individual studies and meta-analyses. Study setting, patient population, and detection methods play an important role in determining detection rates, which should be regarded while interpreting the results. Medication-related adverse events are more common in elderly patients and patients with lowered liver or kidney function, polypharmacy, and a large number of additional comorbidities. However, the risk of MRAEs is also significantly increased by the use of high-risk medicines but also in certain care situations. Preventing MRAEs is important as it will decrease patient mortality and morbidity but also reduce costs and functional challenges related to them. Conclusions: Medication-related adverse events are highly common and have both immediate and long-term effects to patients and healthcare systems worldwide. Conclusive solutions for prevention of all medication-related harm are impossible to create. In the future, however, the development of efficient real-time detection methods can provide significant improvements for event prevention and forecasting. [ABSTRACT FROM AUTHOR]

The article focuses on the unaffected peak inspiratory flow (PIF) through the turbuhaler (TBH) in a histamine inhalation challenge test. It states that the multidose dry powder inhaler turbuhaler is used for the release of asthma medications. It mentions that conformity with proper use of the inhaler is significant in controlled situations that resulted in clinically relevant PIF during the use of turbuhaler. It adds that the test was suspended when the highest histamine dose has been inhaled.

An abstract of the study "True adherence with the Turbuhaler in young children with asthma," by K. Nikander et al, published in the November 19, 2010 online issue of the journal "Archives of Disease in Childhood" is presented.

Background: In a previous Swedish study it was shown that it is possible to predict which chiropractic patients with persistent LBP will not report definite improvement early in the course of treatment, namely those with LBP for altogether at least 30 days in the past year, who had leg pain, and who did not report definite general improvement by the second treatment. The objectives of this study were to investigate if the predictive value of this set of variables could be reproduced among chiropractic patients in Finland, and if the model could be improved by adding some new potential predictor variables. Methods: The study was a multi-centre prospective outcome study with internal control groups, carried out in private chiropractic practices in Finland. Chiropractors collected data at the 1st, 2nd and 4th visits using standardized questionnaires on new patients with LBP and/or radiating leg pain. Status at base-line was identified in relation to pain and disability, at the 2nd visit in relation to disability, and 'definitely better' at the 4th visit in relation to a global assessment. The Swedish questionnaire was used including three new questions on general health, pain in other parts of the spine, and body mass index. Results: The Swedish model was reproduced in this study sample. An alternative model including leg pain (yes/no), improvement at 2nd visit (yes/no) and BMI (underweight/normal/overweight or obese) was also identified with similar predictive values. Common throughout the testing of various models was that improvement at the 2nd visit had an odds ratio of approximately 5. Additional analyses revealed a dose-response in that 84% of those patients who fulfilled none of these (bad) criteria were classified as 'definitely better' at the 4th visit, vs. 75%, 60% and 34% of those who fulfilled 1, 2 or all 3 of the criteria, respectively. Conclusion: When treating patients with LBP, at the first visits, the treatment strategy should be different for overweight/obese patients with leg pain as it should be for all patients who fail to improve by the 2nd visit. The number of predictors is also important. [ABSTRACT FROM AUTHOR]

Purpose: Adverse drug events (ADEs) have been internationally recognized as a major threat to patient safety. The purpose of this study was to conduct a meta-analysis focusing on inpatient ADEs in the Western World to provide better estimate of the current state of medication safety in these countries. Methods: The studies for meta-analysis were identified through electronic search in Cochrane, Scopus, Medline, and Web of science databases. Included articles focused on adult inpatient ADEs, had commonly accepted definition for ADE, and were conducted between 2000 and 2016. Disease or ADE-specific studies were excluded. Meta-analysis was conducted on the prevalence of inpatient ADEs and fatal adverse drug reactions (FADRs). Results: The pooled estimate of the prevalence of inpatient ADEs was formed by 46,626 patient records included in 9 articles. Inpatient ADE prevalence was 19 and 32.3% of these ADEs were assessed preventable (MD 28.6%, SD 22.6%). Three articles including 3385 patients focused on inpatient FADRs, but the pooled estimate of this was disregarded due to low number and high heterogeneity of the included studies. Conclusions: ADEs are estimated to affect 19% of inpatients during hospitalization. Most of the ADEs are moderate in severity causing no permanent harm to the patient. Only a small amount of ADEs cause inpatient deaths, but in this meta-analysis, however, we were unable to give direct estimate of the prevalence. [ABSTRACT FROM AUTHOR]