Scott R. Horton

Maximum Recommended Dosage of Lithium for Pregnant Women Based on a PBPK Model for Lithium Absorption

Treatment of bipolar disorder with lithium therapy during pregnancy is a medical challenge. Bipolar disorder is more prevalent in women and its onset is often concurrent with peak reproductive age. Treatment typically involves administration of the element lithium, which has been classified as a class D drug (legal to use during pregnancy, but may cause birth defects) and is one of only thirty known teratogenic drugs. There is no clear recommendation in the literature on the maximum acceptable dosage regimen for pregnant, bipolar women. We recommend a maximum dosage regimen based on a physiologically based pharmacokinetic (PBPK) model. The model simulates the concentration of lithium in the organs and tissues of a pregnant woman and her fetus. First, we modeled time-dependent lithium concentration profiles resulting from lithium therapy known to have caused birth defects. Next, we identified maximum and average fetal lithium concentrations during treatment. Then, we developed a lithium therapy regimen to maximize the concentration of lithium in the mothers brain, while maintaining the fetal concentration low enough to reduce the risk of birth defects. This maximum dosage regimen suggested by the model was 400 mg lithium three times per day.

Signatures of the Rayleigh‐Plateau Instability Revealed by Imposing Synthetic Perturbations on Nanometer‐Sized Liquid Metals on Substrates

Fluid jets destabilize into droplets according to the well known Rayleigh Plateau (RP) instability. The applicability of the RP model to a nanoscale liquid metal supported on a substrate (a so called rivulet) was investigated using molecular dynamics (MD) simulations as it has important implications for nanoscale materials assembly. Stochastic fluctuations were found to affect rivulet stability and dynamics when compared with microscopic predictions of rivulet break up; here a broad and delayed distribution of break up times was observed. Yet, hallmark characteristics of the RP theory were observed; (1) a critical wavelength demarcating stability, (2) stable and unstable growth modes and (3) neck formation induced by axial pressure gradients. Notably, MD simulations implementing synthetic perturbations, yielded significantly reduced dispersion in the final nanodroplet spacing and clearly revealed the underlying physics driving rivulet break up.

Molecule-based modeling of heavy oil

A molecular-level kinetics model has been developed for the pyrolysis of heavy residual oil. Resid structure was modeled in terms of three attribute groups: cores, inter-core linkages, and side chains. The concentrations of attributes were constrained by probability density functions (PDFs) that were optimized by minimizing the difference between the properties of the computational representation—which were obtained by juxtaposing the attributes—to measured properties, which were obtained by analytical chemistry measurements. Computational tools were used to build a reaction network that was constructed based upon model compounds and their associated kinetics. For cases with an intractable number of species, equations were written in terms of the three attribute groups and the molecular composition was retained implicitly through the juxtaposition. These modeling methods were applied to the Shengli and Daqing resids. The composition of the simulated molecular feedstock fit well with analytical chemistry measurements. After simulated pyrolysis, both resids showed representative increases in the weight fractions of lighter hydrocarbons. Relevant end-use properties were predicted for the product mixtures.

Enhancing the value of detailed kinetic models through the development of interrogative software applications

Abstract A suite of user-friendly software tools was developed to help increase the accessibility of detailed kinetic models to a wide range of users from modelers to research collaborators to process engineers. The aims of these users were the basis for the software development. The tools are illustrated for development, analysis and usage of a detailed catalytic naphtha reforming model. After initial model construction, the Reaction Network Visualizer and KME (Kinetic Model Editor) Results Analyzer helped in understanding the characteristics of the reaction pathways, molecular profile and also assisted in tuning the kinetic parameters. The I/O (Input/Output) Converter permits execution of a molecular-level model in a manner which focuses on only measurable inputs and outputs. The KME Reactor Flowsheet tool increased the core kinetics model capabilities by allowing the model building to be based on data from a pilot or commercial reactor, including schemes with split feed streams and reactor bypasses.

Molecular-Level Composition and Reaction Modeling for Heavy Petroleum Complex System

A new methodology for the molecule-based modeling of heavy petroleum mixtures has been developed. Molecules in the heavy feedstock have been described in terms of three essential structural attributes (cores, side chains, and inter-core linkages) and then statistically juxtaposed into a set of representative molecular compositions that can be constrained by a set of probability density functions (pdfs). In order to obtain the optimal molecular composition, an optimization loop was employed to minimize an objective function in terms of available measurements via adjusting the limited parameters of the pdfs. An example of resid feedstock containing 400,000 components was created using only O(30) parameters. To limit the kinetic model to a practical size, the reaction model was described in terms the reactions of the three constituent types and a set of irreducible molecules. Subsequent product property estimation was a straightforward juxtaposition of attributes. For example, a model for resid coking was built in terms of 2,839 attributes and equations but kept the full compositional details of the 400,000-molecule mixture.