Activity

In this study, we have investigated the enzyme shikimate 5-dehydrogenase from the causative agent of tuberculosis, Mycobacterium tuberculosis. We have employed a mixture of computational techniques, including molecular dynamics, hybrid quantum chemical/molecular mechanical potentials, relaxed surface scans, quantum chemical descriptors and free-energy simulations, to elucidate the enzyme’s reaction pathway. Overall, we find a two-step mechanism, with a single transition state, that proceeds by an energetically uphill hydride transfer, followed by an energetically downhill proton transfer. Our mechanism and calculated free energy barrier for the reaction, 64.9 kJ mol- 1, are in good agreement with those predicted from experiment. An analysis of quantum chemical descriptors along the reaction pathway indicated a possibly important, yet currently unreported, role of the active site threonine residue, Thr65.

Teicoplanin is a highly protein-bound antibiotic, increasingly used to treat serious Gram-positive infections in critically ill children. Maturational and pathophysiological intensive care unit-related changes often lead to altered pharmacokinetics. In this study, the objectives were to develop a pediatric population-pharmacokinetic model of unbound and total teicoplanin concentrations, to investigate the impact of plasma albumin levels and renal function on teicoplanin pharmacokinetics, and to evaluate the efficacy of the current weight-based dosing regimen.

An observational pharmacokinetic study was performed and blood samples were collected for quantification of unbound and total concentrations of teicoplanin after the first dose and in assumed steady-state conditions. A population-pharmacokinetic analysis was conducted using a standard sequential approach and Monte Carlo simulations were performed for a probability of target attainment analysis using previously published pharmacokinetic-pharmacodynamiatric patients. The highly variable unbound fraction of teicoplanin could not be predicted using albumin levels, which may support the use of therapeutic drug monitoring of unbound concentrations. Poor target attainment was shown for the most commonly used dosing regimen, regardless of the pharmacokinetic-pharmacodynamic target evaluated.

Vericiguat, a direct stimulator of soluble guanylate cyclase, has been developed as a first-in-class therapy for symptomatic chronic heart failure (HF) and ejection fraction < 45%.

Safety, pharmacodynamic (PD), and pharmacokinetic (PK) interactions between vericiguat and drugs used in HF (sacubitril/valsartan [SV] and aspirin [acetylsalicylic acid]) or with a narrow therapeutic index (warfarin) were evaluated in three phase I studies.

Vericiguat 15mg (single dose [SD]) had no effect on bleeding time or platelet aggregation when coadministered with aspirin 1000mg versus aspirin alone estimated differences in least squares means 2.7% (95% confidence interval [CI] - 90.4 to 95.8) and 2.4% (95% CI - 7.0 to 11.8) turbidimetry, respectively. Navarixin Vericiguat 10mg (once daily) had no effect on coagulation inhibition elicited by warfarin 25mg (SD; mean ratios of area under the concentration-time curve from time zero to 96h for clotting parameter treatment comparisons approximated 100.0%). There were no clinically relevant PD changes whether SV 97/103mg was administered with single or multiple doses of vericiguat 2.5mg or placebo (differences in systolic blood pressure [BP] - 1.66mmHg [90% CI - 4.22 to 0.90]; diastolic BP - 1.80mmHg [90% CI - 3.24 to - 0.36]; heart rate - 0.33 beats/min [90% CI - 2.25 to 1.60]). Vericiguat demonstrated no PK interactions when coadministered with aspirin, warfarin, or SV at steady state. Treatments were well tolerated.

Coadministration of vericiguat with SV, aspirin, or warfarin was well tolerated. No clinically relevant PD or PK interactions were observed, supporting concomitant use of these drugs, commonly used by patients with HF, with vericiguat and no dose adjustment.

2014-000765-52; 2014-004880-19; 2015-004809-16.

2014-000765-52; 2014-004880-19; 2015-004809-16.

Differentiated thyroid cancer has been treated with radioiodine for almost 80 years, although controversial questions regarding radiation-related risks and the optimisation of treatment regimens remain unresolved. Multi-centre clinical studies are required to ensure recruitment of sufficient patients to achieve the statistical significance required to address these issues. Optimisation and standardisation of data acquisition and processing are necessary to ensure quantitative imaging and patient-specific dosimetry.

A European network of centres able to perform standardised quantitative imaging of radioiodine therapy of thyroid cancer patients was set-up within the EU consortium MEDIRAD. This network will support a concurrent series of clinical studies to determine accurately absorbed doses for thyroid cancer patients treated with radioiodine. Five SPECT(/CT) systems at four European centres were characterised with respect to their system volume sensitivity, recovery coefficients and dead time.

System voer dosimetry-based studies.

This study aimed to evaluate the diagnostic aptitude of a modified Adams forward bending test (MAFBT), which addresses the coupling phenomenon of axial rotation with reference to the side-bending movement. Also, this evaluation was facilitated by the introduction of our rotational flexibility index (RFI).

Thirty-two female and eight male AIS patients were included in this study from a single institution. In the MAFBT, subjects were asked to bend to the convex side of the curve in the forward bending position. Scoliometric measurements were done during the AFBT and MAFBT. Utilizing anteroposterior standing plain radiographs curve flexibility indices were calculated. The diagnostic aptitude of the MAFBT was evaluated based on the receiver operating characteristic (ROC) curves and area under the curve (AUC). The RFI was also assessed, which considered AFBT and MAFBT parameters as a specified function.

Significant correlations were noted between the Cobb angle and AFBT (p = 0.005), fulcrum bending and the MAFBT (p = 0.