ABSTRACT
The bicuspid aortic valve (BAV) is a major risk factor for secondary aortopathy such as aortic dilation. The heterogeneous BAV morphotypes [left-right-coronary cusp fusion (LR), right-non-coronary cusp fusion (RN), and left-non-coronary cusp fusion (LN)] are associated with different dilation patterns, suggesting a role for hemodynamics in BAV aortopathogenesis. However, assessment of this theory is still hampered by the limited knowledge of the hemodynamic abnormalities generated by the distinct BAV morphotypes. The objective of this study was to compare experimentally the hemodynamics of a normal (i.e., non-dilated) ascending aorta (AA) subjected to tricuspid aortic valve (TAV), LR-BAV, RN-BAV, and NL-BAV flow. Tissue BAVs reconstructed from porcine TAVs were subjected to physiologic pulsatile flow conditions in a left-heart simulator featuring a realistic aortic root and compliant aorta. Phase-locked particle image velocimetry experiments were carried out to characterize the flow in the aortic root and in the tubular AA in terms of jet skewness and displacement, as well as mean velocity, viscous shear stress and Reynolds shear stress fields. While all three BAVs generated skewed and asymmetrical orifice jets (up to 1.7- and 4.0-fold increase in flow angle and displacement, respectively, relative to the TAV at the sinotubular junction), the RN-BAV jet was out of the plane of observation. The LR- and NL-BAV exhibited a 71% increase in peak-systolic orifice jet velocity relative to the TAV, suggesting an inherent degree of stenosis in BAVs. While these two BAV morphotypes subjected the convexity of the aortic wall to viscous shear stress overloads (1.7-fold increase in maximum peak-systolic viscous shear stress relative to the TAV-AA), the affected sites were morphotype-dependent (LR-BAV: proximal AA, NL-BAV: distal AA). Lastly, the LR- and NL-BAV generated high degrees of turbulence in the AA (up to 2.3-fold increase in peak-systolic Reynolds shear stress relative to the TAV) that were sustained from peak systole throughout the deceleration phase. This in vitro study reveals substantial flow abnormalities (increased jet skewness, asymmetry, jet velocity, turbulence, and shear stress overloads) in non-dilated BAV aortas, which differ from those observed in dilated aortas but still coincide with aortic wall regions prone to dilation.
ABSTRACT
The bioequivalence of tacrolimus (CAS 104987-11-3) 5 mg capsules was assessed in two single-dose, open-label, randomIzed 2-way crossover trials with a minimum washout period of 14 days; one trial was conducted under fasting condition (n = 44) and the other one under fed condition (n = 48). Blood samples were collected over a 120-h period and concentrations were assayed using a liquid chromatography tandem mass spectrometry (LCMS/MS) method. A non-compartmental method was used for calculation of pharmacokinetic parameters. Under fasting conditions, mean AUC(0-t), AUC(0-inf) and C(max) were comparable between the test (296 ng x h/mL, 318 ng x h/mL and 32 ng/ mL, respectively) and the reference formulations (289 ng x h/mL, 309 ng x h/mL and 33 ng/mL, respectively). T(max) was reached between 1.5 and 2 h post-dose. Mean AUC(0-t), AUC(0-inf) and C(max) were also comparable under fed conditions (154 ng x h/mL, 169 ng x h/mL and 7.6 ng/mL, respectively, for the test and 161 ng x h/mL, 176 ng x h/mL and 7.5 ng/mL, respectively, for the reference formulation). Under fed conditions, T(max) was reached between 5 and 6 h post-dose. 90% geometric confidence intervals were all within the acceptable 80-125% limit, suggesting bioequivalence between the generic product and the innovator product.
