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SummaryWe conducted a study to assess pharmacokinetics of high-dose tranexamic acid for 24 h after administration of the drug in patients undergoing cardiac surgery with cardiopulmonary bypass. High-dose tranexamic acid involved a bolus of 30 mg.kg )1 infused over 15 min followed by a 16 mg.kg.h )1 infusion until chest closure with a 2 mg.kg )1 load within the pump prime. Tranexamic acid followed first-order kinetics best described using a two-compartment model, with a total body clearance that approximated the glomerular filtration rate. Mean plasma tranexamic acid concentrations during the intra-operative period and in the first 6 postoperative hours were consistently higher than the suggested threshold to achieve 100% inhibition and 80% inhibition of tissue plasminogen activator. With recent studies implicating high-dose tranexamic acid as a possible aetiology of postoperative seizures following cardiac surgery, the minimum effective yet safe dose of tranexamic acid in high-risk cardiac surgery needs to be refined. Tranexamic acid, a synthetic antifibrinolytic, is a lysine derivative that competitively inhibits the activation of plasminogen, thereby reducing the conversion of plasminogen to plasmin, an enzyme that degrades fibrin clots, fibrinogen, and other plasma proteins, including the procoagulant factors V and VIII [1]. At higher doses, tranexamic acid directly inhibits plasmin activity [2][3][4][5]. Tranexamic acid thus inhibits fibrinolysis, a putative mechanism of bleeding after cardiopulmonary bypass (CPB) [6]. Hence, this compound is routinely used during cardiac surgery procedures involving CPB, to reduce blood loss [1][2][3][4][5]. Tranexamic acid is considered to have a good safety profile. However, this has been challenged recently as several studies have found an association between high-dose tranexamic acid administration and an increased incidence in postoperative

Background Our understanding of the natural history of idiopathic Parkinson's disease (PD) remains limited. In the era of potential disease modifying therapies, there is an urgent need for studies assessing the natural evolution of treated PD from onset so that relevant outcome measures can be identified for clinical trials. No previous studies have charted progression in unselected patients followed from the point of diagnosis. Methods A representative cohort of 132 PD patients was followed from diagnosis for up to 7.9 years (mean 5.2 years). Comprehensive clinical and neuropsychological evaluations were performed every 18 months. Disease progression was evaluated using well validated clinical measures (motor progression and development of dyskinesia on the Unified PD Rating Scale and HoehneYahr scale, dementia onset according to DSM-IV criteria). Multi-level linear modelling was used to chart the nature and rate of progression in parkinsonian symptoms and signs over time. The prognostic importance of baseline demogr'aphic, clinical and genetic variables was evaluated using survival analysis.Results Axial (gait and postural) symptoms evolve more rapidly than other motor features of PD and appear to be the best index of disease progression. Conversely, conventional outcome measures are relatively insensitive to change over time. Earlier onset of postural instability (HoehneYahr stage 3) is strongly associated with increased age at disease onset and has a significant impact on quality of life. Conclusions Dementia risk is associated with increased age, impaired baseline semantic fluency and the MAPT H1/H1 genotype. The efficacy of disease modifying therapies may be more meaningfully assessed in terms of their effects in delaying the major milestones of PD, such as postural instability and dementia, since it is these that have the greatest impact on patients.

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