Guidelines on uncomplicated urinary tract infections are difficult to follow: perceived barriers and suggested interventions

Contains fulltext : 88451.pdf (publisher's version ) (Open Access)BACKGROUND: Urinary tract infections (UTI) are among the most common health problems seen in general practice. Evidence-based guidelines on UTI are available, but adherence to these guidelines varies widely among practitioners for reasons not well understood. The aim of this study was to identify the barriers to the implementation of a guideline on UTI perceived by Dutch general practitioners (GPs) and to explore interventions to overcome these barriers. METHODS: A focus group study, including 13 GPs working in general practices in the Netherlands, was conducted. Key recommendations on diagnosis and treatment of uncomplicated UTI were selected from the guideline. Barriers to guideline adherence and possible interventions to address these barriers were discussed. The focus group session was audio-taped and transcribed verbatim. Barriers were classified according to an existing framework. RESULTS: Lack of agreement with the recommendations, unavailable and inconvenient materials (i.e. dipslides), and organisational constraints were perceived as barriers for the diagnostic recommendations. Barriers to implementing the treatment recommendations were lack of applicability and organisational constraints related to the availability of drugs in pharmacies. Suggested interventions were to provide small group education to GPs and practice staff members, to improve organisation and coordination of care in out of hour services, to improve the availability of preferred dosages of drugs, and to pilot-test guidelines regionally. CONCLUSIONS: Despite sufficient knowledge of the recommendations on UTI, attitudinal and external barriers made it difficult to follow them in practice. The care concerning UTI could be optimized if these barriers are adequately addressed in implementation strategies. The feasibility and success of these strategies could be improved by involving the target group of the guideline in selecting useful interventions to address the barriers to implementation

Functional selectivity of adenosine receptor ligands

Adenosine receptors are plasma membrane proteins that transduce an extracellular signal into the interior of the cell. Basically every mammalian cell expresses at least one of the four adenosine receptor subtypes. Recent insight in signal transduction cascades teaches us that the current classification of receptor ligands into agonists, antagonists, and inverse agonists relies very much on the experimental setup that was used. Upon activation of the receptors by the ubiquitous endogenous ligand adenosine they engage classical G protein-mediated pathways, resulting in production of second messengers and activation of kinases. Besides this well-described G protein-mediated signaling pathway, adenosine receptors activate scaffold proteins such as β-arrestins. Using innovative and sensitive experimental tools, it has been possible to detect ligands that preferentially stimulate the β-arrestin pathway over the G protein-mediated signal transduction route, or vice versa. This phenomenon is referred to as functional selectivity or biased signaling and implies that an antagonist for one pathway may be a full agonist for the other signaling route. Functional selectivity makes it necessary to redefine the functional properties of currently used adenosine receptor ligands and opens possibilities for new and more selective ligands. This review focuses on the current knowledge of functionally selective adenosine receptor ligands and on G protein-independent signaling of adenosine receptors through scaffold proteins

Time course of action of three adenosine A1 receptor agonists with differing lipophilicity in rats: comparison of pharmacokinetic, haemodynamic and EEG effects

In this study we investigated the relationship between the pharmacokinetics and the cardiovascular and electroencephalogram (EEG) effects of three adenosine agonists with differing lipophilicity. Conscious normotensive rats received either 600 microg/kg N6-(p-sulphophenyl) adenosine (SPA), 200 microg/kg N6-cyclopentyladenosine (CPA) or 600 microg/kg 1-deaza-2-chloro-N6-cyclopentyladenosine (DCCA) in a 5-min intravenous infusion. Changes in haemodynamics and EEG were monitored in conjunction with arterial blood sampling to determine blood concentrations of the compounds. The three adenosine agonists showed large differences in pharmacokinetic properties, resulting in terminal half-lives of 66 +/- 10, 8.2 +/- 0.4 and 24 +/- 1 min (mean +/- SEM) for SPA, CPA, and DCCA respectively. SPA had a significantly lower blood clearance relative to CPA and DCCA, whereas DCCA had the largest volume of distribution and degree of plasma protein binding. The relationship between concentration and heart rate could be described adequately by the sigmoidal Emax model. For SPA, CPA, and DCCA the EC50 values based on free drug concentrations were 423 +/- 92, 1.8 +/- 0.4 and 9.5 +/- 1.1 nM respectively. These in vivo values correlated closely with the affinity of the compounds for the adenosine A1 receptor as determined in radioligand binding studies, with corresponding Ki values of 1410 +/- 220, 4.7 +/- 0.6 and 102 +/- 74 nM (mean +/- SEM) respectively. In the EEG, only CPA produced a small decrease in the amplitude of beta waves. This study demonstrates that the three adenosine analogues have large differences in pharmacokinetics, which complicates comparison of their cardiovascular and central responses simply on the basis of dose. The application of an integrated PK/PD approach permits estimates of potency and activity which are independent of underlying dose and pharmacokinetic

Depression and anxiety related subtypes in Parkinson's disease

Background: Depression and anxiety are common in Parkinson's disease (PD) and although clinically important remain poorly understood and managed. To date, research has tended to treat depression and anxiety as distinct phenomena. There is growing evidence for heterogeneity in PD in the motor and cognitive domains, with implications for pathophysiology and outcome. Similar heterogeneity may exist in the domain of depression and anxiety. Objective: To identify the main anxiety and depression related subtype(s) in PD and their associated demographic and clinical features. Methods: A sample of 513 patients with PD received a detailed assessment of depression and anxiety related symptomatology. Latent Class Analysis (LCA) was used to identify putative depression and anxiety related subtypes. Results: LCA identified four classes, two interpretable as 'anxiety related': one anxiety alone (22.0%) and the other anxiety coexisting with prominent depressive symptoms (8.6%). A third subtype (9%) showed a prominent depressive profile only without significant anxiety. The final class (60.4%) showed a low probability of prominent affective symptoms. The validity of the four classes was supported by distinct patterns of association with important demographic and clinical variables. Conclusion: Depression in PD may manifest in two clinical phenotypes, one 'anxious - depressed' and the other 'depressed'. However, a further large proportion of patients can have relatively isolated anxiety. Further study of these putative phenotypes may identify important differences in pathophysiology and other aetiologically important factors and focus research on developing more targeted and effective treatment