Tranexamic acid through intravenous,intramuscular and oral routes: an individual participant data meta‐analysis of pharmacokinetic studies in healthy volunteers

Tranexamic acid (TXA) is an antifibrinolytic drug that reduces surgical blood loss and death due to bleeding after trauma and post‐partum haemorrhage. One key issue for treatment success is early administration. While usually given intravenously, oral and intramuscular use would be useful in specific circumstances. Therefore, an understanding of TXA pharmacokinetics when given via different routes is valuable. The aim of this study was to perform an individual participant data meta‐analysis of pharmacokinetic studies with TXA given to healthy volunteers via different routes. We searched the following databases: PubMed, Web of Science, Wiley Online Library, Elsevier Science Direct and J‐STAGE. Individual subject data were extracted when available, otherwise arithmetic means were used. A population pharmacokinetic model was developed using nonlinear mixed effect modelling. Seven studies were included in the analysis with data from 10 patients for the IV route, six patients for the IM route and 114 patients for the oral route. The pharmacokinetics was ascribed to a two‐compartment model, and the main covariate was allometrically scaled bodyweight. Oral and IM bioavailabilities were 46 and 105%, respectively. For a 70 kg bodyweight, the population estimates were 7.6 L/h for clearance, 17.9 L for the volume of the central compartment, 2.5 L/h for the diffusional clearance and 16.6 L for the peripheral volume of distribution. Larger well‐designed studies are needed to describe the pharmacokinetics of TXA when given IM or as an oral solution before these can be recommended as alternatives to IV.     

Laparoscopy in transplantation.

BACKGROUND: Solid-organ transplantation has become the treatment of choice for patients with end-stage renal disease, end-stage liver failure, and some patients with type 1 diabetes mellitus. Similarly, surgical expertise and mechanical improvements have led to significant advances in laparoscopic surgery. Laparoscopic interventions are sometimes not pursued in transplant recipients due to the lack of strong supporting evidence for the use of laparoscopic techniques in these patients. METHODS: Using an extensive literature search, we review herein the available data on the utility of laparoscopic interventions in transplant recipients, with particular attention to the risks and benefits, indications, and contraindications for this complex patient population. RESULTS: Although randomized trials are few, multiple case reports indicate that many transplant recipients have benefited from laparoscopic interventions. CONCLUSION: The well-known benefits of laparoscopy could be extended to transplant recipients.     

Design of noninflammatory synthetic siRNA mediating potent gene silencing in vivo.

Targeted silencing of disease-associated genes by synthetic short interfering RNA (siRNA) holds considerable promise as a novel therapeutic strategy. However, unmodified siRNA can be potent triggers of the innate immune response, particularly when associated with delivery vehicles that facilitate intracellular uptake. This represents a significant barrier to the therapeutic development of siRNA due to toxicity and off-target gene effects associated with this inflammatory response. Here we show that immune stimulation by synthetic siRNA can be completely abrogated by selective incorporation of 2'-O-methyl (2'OMe) uridine or guanosine nucleosides into one strand of the siRNA duplex. These noninflammatory siRNA, containing less than 20% modified nucleotides, can be readily generated without disrupting their gene-silencing activity. We show that, coupled with an effective systemic delivery vehicle, 2'OMe-modified siRNA targeting apolipoprotein B (apoB) can mediate potent silencing of its target mRNA, causing significant decreases in serum apoB and cholesterol. This is achieved at therapeutically viable siRNA doses without cytokine induction, toxicity, or off-target effects associated with the use of unmodified siRNA. This approach to siRNA design and delivery should prove widely applicable and represents an important step in advancing synthetic siRNA into a broad range of therapeutic areas.     

SPARC, an extracellular matrix glycoprotein containing the follistatin module, is expressed by astrocytes in synaptic enriched regions of the adult brain

Although extracellular matrix (ECM) glycoproteins play important roles in neural development, their levels are generally believed to decrease in the adult brain. Immunohistochemical analysis indicates that the anti-adhesive ECM glycoprotein SPARC/osteonectin, which contains a follistatin ‘module’, is expressed in the adult rabbit nervous system. In the cerebellum, SPARC is present in Bergmann glia, with a strong signal along their radial fibres. SPARC, while enriched in membrane fractions, is not a transmembrane protein. In the hippocampus, colocalization of SPARC is observed in cells which express the astrocytic marker GFAP. The expression of SPARC by a subset of astrocytes, particularly in synaptic enriched areas, suggests a continuing role for the ECM in the adult brain.     

Human balancing of an inverted pendulum: position control by small, ballistic-like, throw and catch movements

In standing, there are small sways of the body. Our interest is to use an artificial task to illuminate the mechanisms underlying the sways and to account for changes in their size. Using the ankle musculature, subjects balanced a large inverted pendulum. The equilibrium of the pendulum is unstable and quasi-regular sway was observed like that in quiet standing. By giving full attention to minimising sway subjects could systematically reduce pendulum movement. The pendulum position, the torque generated at each ankle and the soleus and tibialis anterior EMGs were recorded. Explanations about how the human inverted pendulum is balanced usually ignore the fact that balance is maintained over a range of angles and not just at one angle. Any resting equilibrium position of the pendulum is unstable and in practice temporary; movement to a different resting equilibrium position can only be accomplished by a biphasic 'throw and catch' pattern of torque and not by an elastic mechanism. Results showed that balance was achieved by the constant repetition of a neurally generated ballistic-like biphasic pattern of torque which can control both position and sway size. A decomposition technique revealed that there was a substantial contribution to changes in torque from intrinsic mechanical ankle stiffness; however, by itself this was insufficient to maintain balance or to control position. Minimisation of sway size was caused by improvement in the accuracy of the anticipatory torque impulses. We hypothesise that examination of centre of mass and centre of pressure data for quiet standing will duplicate these results.     

Risk factors for rhabdomyolysis with simvastatin and atorvastatin.

OBJECTIVE: To assess the frequency of risk factors for rhabdomyolysis with simvastatin and atorvastatin in cases reported to the Australian Adverse Drug Reactions Advisory Committee (ADRAC). DESIGN: Reports meeting the definition of rhabdomyolysis were reviewed for risk factors including age > or = 70 years, dose > or = 40 mg, hepatic dysfunction, diabetes mellitus, hyperkalaemia, hypothyroidism and the use of concomitant interacting medications. RESULTS: Only one report associated with simvastatin and five reports associated with atorvastatin did not list any risk factors for rhabdomyolysis. Interacting medicines featured in 77% of reports of rhabdomyolysis associated with simvastatin and 44% of reports associated with atorvastatin. A comparison of the age profile for reports of atorvastatin- and simvastatin-associated rhabdomyolysis with that for all adverse drug reaction reports received, and for all reports of muscle disorders, suggested a trend towards an increasing risk of rhabdomyolysis with increasing age with simvastatin but not with atorvastatin. Similarly, comparing prescribed tablet strengths from Pharmaceutical Benefits Scheme data with the HMG-CoA reductase inhibitor ('statin') doses in reports of rhabdomyolysis suggested a dose-related risk with simvastatin, but a less increased risk with high-dose atorvastatin. CONCLUSION: Risk factors for rhabdomyolysis featured in nearly all of the reports of statin-associated rhabdomyolysis and the majority of reports listed multiple risk factors, although dependence on risk factors appeared to be stronger with simvastatin than atorvastatin. The multiplication of risk factors in patients taking simvastatin and atorvastatin should be minimised.