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Biomedical subjects

W D Wosilait

Publications and source records attributed to W D Wosilait.

At least 19 recordsLinked to original sources
PubMed1995

Mathematical representation of organ growth in the human embryo/fetus.

During human pregnancy, there is a huge increase in the total weight of the embryo/fetus from conception to term. The total growth, which is the summation of growth of the various organs and tissues that make up the organism, was analyzed in a previous paper and fitted to the Gompertz equation for growth. In the present study, allometry, the quantitative representation of the consequence of size, was utilized to describe the correlation of individual fetal organ/tissue weights with the total fetal weight. The organ/tissue weight and the total fetal weight data used in the analyses were pooled from various sources that provided data ranging from 25 days to 300 days post-conception. Allometric equations are presented for 16 embryo/fetal organs and tissues. The standard allometric equation gave adequate fits for embryo/fetal adrenal, bone, bone marrow, brain, heart, liver, pancreas, plasma, skeletal muscle, extracellular water, thymus and thyroid; but it was necessary to use a quadratic form of the allometric equation for embryo/fetal fat, kidney, lung and spleen. Parameters were also calculated for crown-to-rump and crown-to-heels for fetal lengths that occur during pregnancy.

Adipose Tissue↗
PubMed1994

A physiologically based pharmacokinetic computer model for human pregnancy.

A physiologically based pharmacokinetic (PBPK) model for human pregnancy must incorporate many factors that are not usually encountered in PBPK models of mature animals. Models for pregnancy must include the large changes that take place in the mother, the placenta and the embryo/fetus over the period of pregnancy. The embryo/fetal weight change was modeled using the Gompertz equation for growth which gave a good fit to extensive pooled weight data of the human embryo/fetus from 25 to 300 days of gestation. This equation is based on a growth rate that is proportional to the total weight of the organism with the proportionality factor decreasing exponentially with time. Allometric equations, which are widely used to relate organ weights, blood flow rates and other attributes of mature animals to total weight, were adapted to correlate fetal organ weights with total fetal weight. Allometric relationships were also developed for plasma flow rates and other organ-related parameters. The computer model, written in FORTRAN 77, included 27 compartments for the mother and 16 for the fetus; it also accommodates two substances allowing representation of a parent compound and a metabolite (or a second drug or environmental substance). Although this model is large, the inherent sparsity in the equations allow it to be solved numerically in a reasonable time on currently available, reasonably priced desktop computers. A nonlinear regression routine is included to fit key model parameters to experimental data. Concentrations of chemicals administered and measured in the mother may be simulated in both maternal and fetal organs at any day(s) between 25 days and 300 days of gestation. Allometric relationships are also utilized to adopt this human model for use with data obtained from animal experiments.

Abnormalities, Drug-Induced↗
PubMed1992

A mathematical analysis of human embryonic and fetal growth data.

There is no set of growth data from a single source for the human embryo/fetus which spans the full range of pregnancy. For mathematical and statistical analysis of the full gestational period, it was necessary to pool data from several sources. Three growth equations, which have been reported in the literature for various purposes, were tested and compared for possible use as a tool to describe the growth of the human embryo/fetus. Parameters were estimated using statistical procedures on the pooled data for the Verhulst logistic equation, a polynomial equation, and the Gompertz equation. The polynomial and Gompertz equations provided the best fit for the growth of the normal human embryo/fetus over the broadest range of 25 to 300 days, and especially in the critical period of development (gestational days 40 to 70). The relative rate of growth of the embryo/fetus was about 15% per day on the 25th day and declined progressively thereafter; the absolute rate of growth was the greatest at about the 240th day.

Embryonic and Fetal Development↗
PubMed1988

Multifactorial modeling, drug interactions, liver damage and aging.

A well designed physiological flow model can be used not only to describe and analyze the basic elimination of a drug but also it can form the basis for multifactorial analysis in situations of multiple organ dysfunction and drug therapy. Physiological flow models use existent knowledge of anatomical structure and physiological processes along with the biochemical basis of drug elimination to calculate concentration-vs-time profiles of drugs in various organs and tissue regions. A tissue region or organ must be included in the model if it is an important site of storage, toxicity, elimination, or other significant pharmacological action. Such models can be a powerful tool in medicine providing a rational basis for multiple drug therapy in high risk patients with altered organ function--especially for drugs with a narrow margin of safety. For some specific types of drug systems, physiological flow model models exist which can accurately describe drug concentration profiles in tissues for a variety of situations. A definitive general model is theoretically possible; but, in practice, has not yet been developed. Future research could provide the necessary information to make multifactorial analysis a clinically useful tool in rational drug therapy.

Aging↗
PubMed1987

Drug interactions affecting the elimination of doxorubicin in the rat.

Radioactive 14C-doxorubicin (10 mg/kg iv; 2 microCi/kg) disappeared rapidly from the plasma of anaesthetized male Sprague-Dawley rats. Radioactivity appeared in the bile within 5 to 7 min, reached a peak concentration in 10 to 15 min and declined rapidly thereafter for 150 min during which about 22% of the injected dose appeared in the bile. Tissue concentrations measured 10 min after injection were compared with tissue samples obtained at 150 min. Polyexponential analysis of the amount of doxorubicin remaining in the body (based upon the amount injected minus the cumulative amount excreted) suggested a two-compartment model. In acute studies, the injection of bromosulphophthalein (50 mg/kg) or rifampicin (53 mg/kg) 60 min after the injection of doxorubicin reduced the excretion of doxorubicin. The daily administration of phenobarbital (75 mg/kg X 3) increased the cumulative excretion of doxorubicin; the administration of CCl4 (1 ml/kg, ip) 24 hrs before the experiment reduced the cumulative excretion of doxorubicin.

Animals↗
PubMed1986

Estimation of drug binding parameters.

Many methods have been suggested and tested to estimate the association constants and binding capabilities of ligand-macromolecule interactions from experimental data. This problem is a subset of the general problem of parameter estimation for nonlinear algebraic models where both the independent and dependent variables are subject to measurement error. It is often difficult to anticipate the effect on the parameter estimates that is caused by error in the primary measurements. In this work, a computer algorithm is described which finds the maximum likelihood estimate for the true values of the parameters and also estimates for the values of the measurements. It is applied to experimental binding data in two examples for fitting the association constants and binding capacities.

Dicumarol↗
PubMed1985

A mathematical model and computer program for adriamycin distribution and elimination.

A mathematical physiological flow model is described for the distribution and elimination of adriamycin in the rat. The model includes the volume or mass of, and blood flow to the following tissues: heart, plasma, muscle, skin, kidney, bone marrow, gut, liver and bile. A compartment is also included for tight or almost irreversible binding which occurs with this drug. The program was written in FORTRAN to compute the concentration of drug in each tissue as a function of time after bolus injection or short term infusion. The computed data is printed on a line printer and recorded on disk for use in a SAS program GPLOT to obtain precision plots.

Animals↗
PubMed1981

Competition between serum albumin and soluble fraction of liver for binding of warfarin and other drugs.

The binding of Warfarin by human serum albumin (HSA) and subcellular fractions from rat liver was investigated to evaluate the roles of such interactions in the pharmacokinetic properties of the anticoagulant. In vitro intracellular distribution studies showed that Warfarin was bound primarily by the soluble fraction of rat liver. Equilibrium dialysis studies were carried out to test the hypothesis that the hepatic extraction of Warfarin and drug interactions between Warfarin and other drugs involved competition between albumin and the soluble fraction of liver. A three compartment dialysis cell was designed and constructed for such studies. Three types of competitive binding interactions were identified. Iopanoic acid displaced Warfarin from HSA resulting in increased Warfarin in the protein-free compartment and in the compartment containing the soluble fraction. On the other hand, tolbutamide displaced Warfarin from HSA to the liver soluble fraction with relatively little effect on unbound anticoagulant. Sulfinpyrazone produced a third type of interaction characterized by displacement of Warfarin from HSA with an increase in the concentration of unbound drug. It was concluded that competitive binding between albumin and soluble liver proteins, is important in the hepatic uptake of Warfarin. The three compartment dialysis cells may be useful to simulate the distribution of drugs and drug combinations between non-dialyzable macromolecules.

Animals↗
PubMed1980

Physiological flow model for drug elimination interactions in the rat.

Drug elimination interactions in the rat are modelled based on physiological blood flow rates and organ weights. A previous model has been substantially improved by the addition of a compartment representing the skin and the interactions are computed using Michaelis-Menten kinetics for competitive inhibition in the shared pathways. Furthermore, the results of repetitive dosing may also be simulated. The programs, which are extensively annotated and user oriented, are illustrated on the results of an acute warfarin--BSP interaction experiment in rats.

Animals↗
PubMed1979

Drug elimination interactions: analysis using a mathematical model.

A mathematical model was developed to analyze the elimination kinetics of drug interactions in the rat. The model is based on physiological blood flow rates and organ weights and includes Michaelis-Menten equations for enzymatic processes which are involved in the elimination of the drug; competitive inhibition interactions are computed for shared pathways. Using data from the single drugs, the model can simulate the results of experiments of the acute warfarin-BSP interactions in rats.

Animals↗
PubMed1979

The effects of oleic acid, tolbutamide, and oxyphenbutazone on the binding of warfarin by human serum albumin.

Equilibrium dialysis studies showed that, at low levels, stearate, palmitate and oleate enhanced the binding of warfarin by human serum albumin, but at high levels of FFA, warfarin was displaced. Tolbutamide and oxyphenbutazone separately desplaced warfarin, and this dispplacement was reduced by the presence of low concentrations of oleate while at higher concentrations of oleate displacement occurred. Thus, the binding of warfarin was affected in a complex fashion depending upon the drugs present and the concentration of the FFA.

Binding, Competitive↗
PubMed1978

A program to simulate drug elimination interactions: warfarin and BSP - an illustrative example.

The kinetics of drug elimination of interactive drug systems is stimulated by a set of differential equations based on mass balances, the mass of organs and blood flow rates. Experimentally determined concentration profiles of the drugs in the plasma and bile are used to evaluate clearance rate parameters. An example is shown in which the clearance of the anticoagulant warfarin is reduced to less than 50% of its normal rate due to the interference by BSP.

Computers↗
PubMed1977

A theoretical analysis of the distribution of thyroxine among sites on thyroid binding globulin, thyroid binding prealbumin, and serum albumin.

A mathematical analysis was made of the distribution of free and bound thyroxine among the following: one site on thyroid binding globulin, and two sets of sites on thyroid binding prealbumin and human serum albumin. Computations were carried out using reported association constants and binding capacities as input values for a recently developed computer program. Most of the thyroxine was bound by thyroid binding globulin and the high affinity sites on thyroid binding prealbumin and human serum albumin. Computations were carried out for normal and abnormal levels of thyroxine and the binding proteins.

Binding Sites↗