No abstract

A flow microcalorimetric study has been carried out to investigate the interactions between phenothiazine derivatives and human plasma, human serum albumin (HSA) and alpha 1-acid glycoprotein (AGP) at pH 7.4 and 37 degrees C. The direct analyses of enthalpic titration curves allowed the determination of the binding enthalpy change (delta H), the apparent binding constant (K), and the number of the binding sites (n), as well as the evaluation of the apparent free energy (delta G), and entropy (delta S) changes. The overall binding of phenothiazines was exothermic with negative delta H, which was compensated for by changes in delta S. The values of delta G were relatively insensitive to variation in the molecular details of the binding reaction. HSA possessed two classes of binding sites for phenothiazines. The first (n1 = 1), with high affinity (K1 = 10(5)-10(6) M-1) was characterized by small negative delta H and positive delta S values due to hydrophobic interaction. The second class of sites had a low affinity (K2 = 10(3)-10(4) M-1) and high capacity (n2 = 3-8) and contributed to the negative delta H and delta S values. The binding and thermodynamic parameters were influenced by the aliphatic side chain moieties on the phenothiazine nucleus. On the other hand, the drugs were bound to AGP at a single common binding site with a binding affinity of the order of 10(4)M-1, characterized by negative delta H and delta S values, which partially reflected the effect of a van der Waals' interaction.(ABSTRACT TRUNCATED AT 250 WORDS)

We developed a new model for neonate and infant dosing of phenobarbital with good predictive performance. Clinical application of our model should permit more accurate selection of initial and maintenance doses to achieve target phenobarbital concentrations in Japanese neonates and infants, thereby enabling the clinician to achieve the desired therapeutic effect. A similar approach can be used to validate our model for use in other neonate and infant populations.

We developed a new model for elderly patient dosing of digoxin with good predictive performance. Clinical application of the findings of the present study to patient care may permit selection of an appropriate initial digoxin maintenance dose, thus enabling the clinician to achieve a desired therapeutic effect. However, the digoxin dosage regimen should be based on an appraisal of the individual patient's clinical need for the drug.

To establish the role of patient characteristics in estimating doses of digoxin for infants and young children using routine therapeutic drug monitoring data, the steady-state blood-level data (n = 245) after repetitive oral administration in 117 hospitalized infants and young children were analyzed using nonlinear mixed effects modeling (NONMEM), a computer program designed for analyzing drug pharmacokinetics in study populations through pooling of data. Analysis of the pharmacokinetics of digoxin was accomplished using a 1-compartment pharmacokinetic model. Estimates generated by NONMEM indicated that the clearance of digoxin (CL/F; L/h) was influenced by the following demographic variables: total body weight (TBW), presence of congestive heart failure (CHF), and infant-young children clearance factor (trough serum concentration of digoxin; Conc). These influences could be modeled by the equation CL/F (L/h) = 0.302 · TBW (kg)¹·¹⁷ · 0.905(CHF) · Conc (trough serum digoxin concentration >1.7 ng/mL)⁻⁰·⁵⁴⁰; F = 0.754, where CHF is 1 for presence of congestive heart failure, 0 otherwise; F is bioavailability, 1 for elixirs, 0.754 for powders; and Conc⁻⁰·⁵⁴⁰ is 1 for digoxin concentration <1.7 ng/mL. Clinical application of the model to patient care may permit selection of an appropriate initial maintenance dose, thus enabling the clinician to achieve the desired therapeutic effect. However, the digoxin dosage regimen for the individual patient should be based on a careful appraisal of his or her clinical need for the drug.