Optimization of buprenorphine dosing in pregnant women

The primary objective of this work was to optimize buprenorphine (BUP) dosing based on exposure in treating opioid addiction in pregnant women. A combination of clinical pharmacokinetic study and modeling and simulation was used to accomplish this. The clinical study evaluated BUP pharmacokinetics (PK) during pregnancy and postpartum. Up to 3 studies were performed in each participant during 1st-, 2nd -half of pregnancy, and postpartum. At each study visit, multiple blood samples and specific pharmacodynamics measurements were collected. Plasma concentrations of BUP were quantified using UPLC-MS/MS. In this study BUP exposure was lower during pregnancy compared to postpartum. A physiologically-based pharmacokinetic (PBPK) model of intravenous and sublingual BUP was developed and verified using 14 independent BUP PK studies. This PBPK model predicted decreased BUP exposure during pregnancy compared to postpartum, consistent with the observations from the clinical study. Non-linear mixed effects modeling using a first-order conditional estimation with interaction to analyze changes in BUP PK in pregnant women was conducted. Buprenorphine PK data were well-characterized by a two-compartment model with first-order absorption with enterohepatic recirculation and first-order elimination. The model estimated population apparent clearance (CL/F) of BUP in a typical pregnant woman was 469 L/h. Pregnancy was associated with a 1.64 folds increase in CL/F of BUP compared to postpartum period. A pharmacodynamic (PD) analysis showed that the average area under curves of COWS scores during pregnancy were significantly greater than postpartum period following administration of BUP, which is consistent with the v observed lower buprenorphine exposure during pregnancy. The relationship between pupillary diameters and BUP concentration was described by a sigmoidal Emax model with a hypothetical effect compartment. The calculated IC50 of BUP concentration for pupillary diameter changes was not significantly different during pregnant and postpartum, suggesting that there may not be any significant change in the sensitivity and /or number of µ-opioid receptors in the brain in pregnant women compared to non-pregnant women. Overall, the clinical observations and the two different modeling approaches demonstrated that BUP exposure is decreased during pregnancy and this alteration in BUP exposure is associated a decreased response to BUP in pregnancy

Spontaneous fission half-lives of heavy and superheavy nuclei within a generalized liquid drop model

We systematically calculate the spontaneous fission half-lives for heavy and superheavy nuclei between U and Fl isotopes. The spontaneous fission process is studied within the semi-empirical WKB approximation. The potential barrier is obtained using a generalized liquid drop model, taking into account the nuclear proximity, the mass asymmetry, the phenomenological pairing correction, and the microscopic shell correction. Macroscopic inertial-mass function has been employed for the calculation of the fission half-life. The results reproduce rather well the experimental data. Relatively long half-lives are predicted for many unknown nuclei, sufficient to detect them if synthesized in a laboratory.Comment: 20 pages, 5 figures, 2 tables, accepted version by Nucl. Phys.

Limiting Behavior of Constraint Minimizers for Inhomogeneous Fractional Schr\"{o}dinger Equations

This paper is devoted to the $L^2$-constraint variational problem \begin{equation*} We study $L^2$-normalized solutions of the following inhomogeneous fractional Schr\"{o}dinger equation \begin{equation*} (-\Delta)^{s} u(x)+V(x)u(x)-a|x|^{-b}|u|^{2\beta^2}u(x)=\mu u(x)\ \ \mbox{in}\ \ \R^{N}. \end{equation*} Here $s\in(\frac{1}{2},1)$, $N>2s$, $a>0$, $0<b<\min\{\frac{N}{2},1\}$, $\beta=\sqrt{\frac{2s-b}{N}}$ and $V(x)\geq 0$ is an external potential. We get $L^2$-normalized solutions of the above equation by solving the associated constrained minimization problem. We prove that there exists a critical value $a^*>0$ such that minimizers exist for $0<a<a^*$, and minimizers do not exist for any $a>a^*$. In the case of $a=a^*$, one can obtain the classification results of the existence and non-existence for constraint minimizers, which are depended strongly on the value of $V(0)$. For $V(0)=0$, the limiting behavior of nonnegative minimizers is also analyzed when $a$ tend to $a^*$ from below