British journal of clinical pharmacology
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Br J Clin Pharmacol · Aug 2013
ReviewA next step in adeno-associated virus-mediated gene therapy for neurological diseases: regulation and targeting.
Recombinant adeno-associated virus (rAAV) vectors mediating long term transgene expression are excellent gene therapy tools for chronic neurological diseases. While rAAV2 was the first serotype tested in the clinics, more efficient vectors derived from the rh10 serotype are currently being evaluated and other serotypes are likely to be tested in the near future. In addition, aside from the currently used stereotaxy-guided intraparenchymal delivery, new techniques for global brain transduction (by intravenous or intra-cerebrospinal injections) are very promising. ⋯ Therapeutic effects however, were modest, emphasizing the need for higher doses of the therapeutic transgene product which could be achieved using more efficient vectors or expression cassettes. This will require re-addressing pharmacological aspects, with attention to which cases require either localized and cell-type specific expression or efficient brain-wide transgene expression, and when it is necessary to modulate or terminate the administration of transgene product. The ongoing development of targeted and regulated rAAV vectors is described.
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Br J Clin Pharmacol · Jul 2013
ReviewDrug induced QT prolongation: the measurement and assessment of the QT interval in clinical practice.
There has been an increasing focus on drug induced QT prolongation including research on drug development and QT prolongation, following the removal of drugs due to torsades de pointes (TdP). Although this has improved our understanding of drug-induced QT prolongation there has been much less research aimed at helping clinicians assess risk in individual patients with drug induced QT prolongation. This review will focus on assessment of drug-induced QT prolongation in clinical practice using a simple risk assessment approach. ⋯ The nomogram has an 'at risk' line and QT-HR pairs above this line have been shown in a systematic study to be associated with TdP and the line is more sensitive and specific than Bazett's QTc of 440 ms or 500 ms. Plotting the QT-HR pair for patients on drugs suspected or known to cause QT prolongation allows assessment of the QT interval based on normal population QT variability. This risk assessment then allows the safer commencement of drugs therapeutically or management of drug induced effects in overdose.
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Br J Clin Pharmacol · Mar 2013
ReviewNutrition and neurodegeneration: epidemiological evidence and challenges for future research.
The prevention of dementias, such as Alzheimer's disease (AD), is a growing public health concern, due to a lack of effective curative treatment options and a rising global prevalence. Various potential risk or preventive factors have been suggested by epidemiological research, including modifiable lifestyle factors such as diet. Current epidemiological data are in favour of a protective role of certain micronutrients (B vitamins related to homocysteine metabolism, the anti-oxidant vitamins C and E, flavonoids, polyunsatured omega-3 fatty acids, vitamin D) and macronutrients (fish) in the prevention of cognitive decline and dementia/AD. ⋯ Designing such trials remains very challenging for researchers. The main objective of this paper is to review the epidemiologic data linking potential protective factors to cognitive decline or dementia/AD, focusing particularly on the roles of adiposity, caloric restriction, micro (group B vitamins related to homocysteine metabolism, the anti-oxidant vitamins C and E, flavonoids, polyunsatured omega-3 fatty acids, vitamin D) and macronutrients (fish). Limitations of the current data, divergence with results of interventional prevention studies and challenges for future research are discussed.
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Br J Clin Pharmacol · Nov 2012
Review Meta AnalysisThe role of statin therapy in the prevention of atrial fibrillation: a meta-analysis of randomized controlled trials.
Atrial fibrillation (AF) is the most common clinically significant cardiac arrhythmia, and AF is associated with relatively higher all-cause mortality in both men and women. However, there are limited treatment options for AF. Statins are hypothesized to have a benefit against arrhythmias in addition to well-established secondary prevention benefit for atherosclerotic coronary artery disease, yet the data are inconsistent ⋯ Statin therapy was significantly associated with a decreased risk of incidence or recurrence of AF. Heterogeneity was explained by differences in statin types, patient populations and surgery types. The benefit of statin therapy seemed more pronounced in secondary than in primary prevention.
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There is much variation in the implementation of the best available evidence into clinical practice. These gaps between evidence and practice are often a result of multiple individual decisions. When making a decision, there is so much potentially relevant information available, it is impossible to know or process it all (so called 'bounded rationality'). ⋯ The processing of information and decision making may be influenced by a number of cognitive biases, of which the decision maker may be unaware. Interventions to encourage appropriate use of System 1 and System 2 processing have been shown to improve clinical decision making. Increased understanding of decision making processes and common sources of error should help clinical decision makers to minimize avoidable mistakes and increase the proportion of decisions that are better.