Population pharmacokinetics of perhexiline from very sparse, routine monitoring data

Using NONMEM, the population pharmacokinetics of perhexiline were studied in 88 patients (34 F, 54 M) who were being treated for refractory angina. Their mean +/- SD (range) age was 75 +/- 9.9 years (46-92), and the length of perhexiline treatment was 56 +/- 77 weeks (0.3-416). The sampling time after a dose was 14.1 +/- 21.4 hours (0.5-200), and the perhexiline plasma concentrations were 0.39 +/- 0.32 mg/L (0.03-1.56). A one-compartment model with first-order absorption was fitted to the data using the first-order (FO) approximation. The best model contained 2 subpopulations (obtained via the $MIXTURE subroutine) of 77 subjects (subgroup A) and 11 subjects (subgroup B) that had typical values for clearance (CL/F) of 21.8 L/h and 2.06 L/h, respectively. The volumes of distribution (V/F) were 1470 L and 260 L, respectively, which suggested a reduction in presystemic metabolism in subgroup B. The interindividual variability (CV%) was modeled logarithmically and for CL/F ranged from 69.1% (subgroup A) to 86.3% (subgroup B). The interindividual variability in V/F was 111%. The residual variability unexplained by the population model was 28.2%. These results confirm and extend the existing pharmacokinetic data on perhexiline, especially the bimodal distribution of CL/F manifested via an inherited deficiency in hepatic and extrahepatic CYP2D6 activity.

Population pharmacokinetics of magnesium in preeclampsia

OBJECTIVE: The purpose of this study was to determine the population pharmacokinetics of magnesium from sparse observational data in patients with preeclampsia. STUDY DESIGN: Serum magnesium concentrations (1-11 per patient) were obtained retrospectively from the records of 116 patients with preeclampsia who had a loading dose of magnesium sulfate (16 or 20 mmol), followed by a maintenance dose (1 mmol/h) over an average of 28 hours. Population clearance, volume of distribution, and the baseline magnesium concentration were estimated using the NONMEM program. RESULTS: The following population typical values, together with the interpatient variability (expressed as coefficient of variation) were obtained with the use of a 1-compartment model: systemic clearance, 4.28 L/h (37.3%); volume of distribution, 32.3 L (32.1%); baseline concentration, 0.811 mmol/L (18.5%). The average half-life was 5.2 hours. Clonus was not obtunded in 4 patients whose serum magnesium concentrations were similar to the average concentration of 1.7 mmol/L. The variability remaining unexplained after the population model was fitted to the data was 6.5% to 10.8%. CONCLUSION: This study extended knowledge of the pharmacokinetic disposition of magnesium in preeclampsia. The results are potentially useful for the calculation of loading and maintenance doses, particularly when the relationship between serum concentration and effect in preeclampsia is clarified.

Synthesis and stereochemistry of some bicyclic gamma-lactones from parasitic wasps (Hymenoptera : Braconidae). Utility of hydrolytic kinetic resolution of epoxides and palladium(II)-catalyzed hydroxycyclization-carbonylation-lactonization of ene-diols

A palladium(II)-catalyzed hydroxycyclization-carbonylation-lactonization sequence with appropriate pent-4-ene-1,3-diols provides efficient access to the bicyclic gamma -lactones, 5-n-butyl- and 5-n-hexyltetrahydrofuro-[3,2-b]furan-2(3H)-ones (3) and (4), respectively, in both racemic and enantiomeric forms. Some of the substrate pent-4-ene-1,3-diols of high enantiomeric excess (ee) have been derived from racemic terminal epoxides by hydrolytic kinetic resolution (HKR) using cobalt (III)-salen complexes. (9Z,12R)-(+)-Ricinoleic acid also serves as a chiral pool source of other pent-4-ene-1,3-diols. These syntheses and enantioselective gas chromatography confirm the structures and absolute stereochemistry of the lactones in some species of parasitic wasps (Hymenoptera: Braconidae). The highly abundant 5-n-hexyltetrahydrofuro-[3,2-b]furan-2(3H)-one (4) in Diachasmimorpha kraussii and D. longicaudata is of high ee (> 99%) with (3aR,5R,6aR) stereochemistry.

A proposal for developing a large patient population cohort for longterm safety monitoring in rheumatoid arthritis

This paper proposes the creation of an objectively acquired reference database to more accurately characterize the incidence and longterm risk of relatively infrequent, but serious, adverse events. Such a database would be maintained longitudinally to provide for ongoing comparison with new rheumatologic drug safety databases collecting the occurrences and treatments of rare events, We propose the establishment of product-specific registries to prospectively follow a cohort of patients with rheumatoid arthritis (RA) who receive newly approved therapies. In addition, a database is required of a much larger cohort of RA patients treated with multiple second line agents of sufficient size to enable case-controlled determinations of the relative incidence of rare but serious events in the treated (registry) versus the larger disease population, The number of patients necessary for agent-specific registries and a larger patient population adequate to supply a matched case-control cohort will depend upon estimates of the detectability of an increased incidence over background. We suggest a system to carry out this proposal that will involve an umbrella organization. responsible for establishment of this large patient cohort, envisioned to be drawn from around the world.

Generalized quasi mode theory of macroscopic canonical quantization in cavity quantum electrodynamics and quantum optics II. Application to reflection and refraction at a dielectric interface

The generalization of the quasi mode theory of macroscopic quantization in quantum optics and cavity QED presented in the previous paper, is applied to provide a fully quantum theoretic derivation of the laws of reflection and refraction at a boundary. The quasi mode picture of this process involves the annihilation of a photon travelling in the incident region quasi mode, and the subsequent creation of a photon in either the incident region or transmitted region quasi modes. The derivation of the laws of reflection and refraction is achieved through the dual application of the quasi mode theory and a quantum scattering theory based on the Heisenberg picture. Formal expressions from scattering theory are given for the reflection and transmission coefficients. The behaviour of the intensity for a localized one photon wave packet coming in at time minus infinity from the incident direction is examined and it is shown that at time plus infinity, the light intensity is only significant where the classical laws of reflection and refraction predict. The occurrence of both refraction and reflection is dependent upon the quasi mode theory coupling constants between incident and transmitted region quasi modes being nonzero, and it is seen that the contributions to such coupling constants come from the overlap of the mode functions in the boundary layer region, as might be expected from a microscopic theory.

Cardiostimulant effects of urotensin-II in human heart in vitro

The effects of the recently identified human peptide urotensin-II (hU-II) were investigated on human cardiac muscle contractility and coronary artery tone. In right atrial trabeculae from non-failing hearts, hU-II caused a concentration-dependent increase in contractile force (pEC(50)=9.5+/-0.1; E-max= 31.3+/-4.8% compared to 9.25 mM Ca2+; n = 9) with no change in contraction duration. In right ventricular trabeculae from explanted hearts, 20 nM hU-II caused a small increase in contractile force (7.8+/-1.4% compared to 9.25 mM Ca2+; n= 3/6 tissues from 2 out of 4 patients). The peptide caused arrhythmic contractions in 3/26 right atrial trabeculae from 3/9 patients in an experimental model of arrhythmia and therefore has less potential to cause arrhythmias than ET-1. hU-II (20 nM) increased tone (17.9% of the response to 90 mM KCI) in 7/7 tissues from 1 patient, with no response detected in 8/8 tissues from 2 patients. hU-II is a potent cardiac stimulant with low efficacy.

Development and implementation of the population Fisher information matrix for the evaluation of population pharmacokinetic designs.

In population pharmacokinetic studies, the precision of parameter estimates is dependent on the population design. Methods based on the Fisher information matrix have been developed and extended to population studies to evaluate and optimize designs. In this paper we propose simple programming tools to evaluate population pharmacokinetic designs. This involved the development of an expression for the Fisher information matrix for nonlinear mixed-effects models, including estimation of the variance of the residual error. We implemented this expression as a generic function for two software applications: S-PLUS and MATLAB. The evaluation of population designs based on two pharmacokinetic examples from the literature is shown to illustrate the efficiency and the simplicity of this theoretic approach. Although no optimization method of the design is provided, these functions can be used to select and compare population designs among a large set of possible designs, avoiding a lot of simulations.

Population pharmacokinetics of lamotrigine

The present study estimated the population pharmacokinetics of lamotrigine in patients receiving oral lamotrigine therapy with drug concentration monitoring, and determined intersubject and intrasubject variability. A total of 129 patients were analyzed from two clinical sites. Of these, 124 patients provided spare data (198 concentration-time points); nine patients (four from a previous group plus five from the current group) provided rich data (431 points). The population analysis was conducted using P-PHARM (TM) (SIMED Scientific Software, Cedex, France), a nonlinear mixed-effect modeling program. A single exponential elimination model (first-order absorption) with heteroscedastic weighting was used. Apparent clearance (CL/F) and volume of distribution (V/F) were the pharmacokinetic parameters estimated. Covariate analysis was performed to determine which factors explained any of the variability associated with lamotrigine clearance. Population estimates of CL/F and V/F for lamotrigine generated in the final model were 2.14 +/- 0.81 L/h and 78.1 +/- 5.1 L/kg. Intersubject and intrasubject variability for clearance was 38% and 38%, respectively. The covariates of concomitant valproate and phenytoin therapy accounted for 42% of the intersubject variability of clearance. Age, gender, clinic site, and other concomitant antiepileptic drugs did not influence clearance. This study of the population pharmacokinetics of lamotrigine in patients using the drug clinically provides useful data and should lead to better dosage individualization for lamotrigine.

Population pharmacokinetics of tacrolimus in children who receive cut-down or full liver transplants

Background. The aim of this study was to investigate the population pharmacokinetics of tacrolimus in pediatric liver transplant recipients and to identify factors that may explain pharmacokinetic variability. Methods. Data were collected retrospectively from 35 children who received oral immunosuppressant therapy with tacrolimus. Maximum likelihood estimates were sought for the typical values of apparent clearance (CL/F) and apparent volume of distribution (V/F) with the program NONMEM. Factors screened for influence on the pharmacokinetic parameters were weight, age, gender, postoperative day, days since commencing tacrolimus therapy, transplant type (whole child liver or cut-down adult liver), liver function tests (bilirubin, alkaline phosphatase [ALP], aspartate aminotransferase [AST], gamma -glutamyl transferase [GGT], alanine aminotransferase [ALT]), creatinine clearance, hematocrit, corticosteroid dose, and concurrent therapy with metabolic inducers and inhibitors of tacrolimus. Results. No clear correlation existed between tacrolimus dosage and blood concentrations (r(2) =0.003). Transplant type, age, and liver function test values were the most important factors (P

Population screening for HFE-associated haemochromatosis: should we have to pay for our genes?

Haemochromatosis associated with mutations in the HFE gene is the most common inherited disorder in Caucasian populations. Early diagnosis and treatment allows for normal life expectancy whereas there is considerable morbidity and early mortality in those patients diagnosed late or untreated. Unfortunately, the development of symptoms and signs in haemochromatosis is usually associated with significant iron overload. For this reason, many clinicians and geneticists have advocated population screening. The recent identification of the HFE gene and the availability of a simple DNA-based diagnostic test have led to international debate as to the most cost-effective means of population screening for HFE-associated haemochromatosis. The present paper summarizes the evidence in favour of population screening and analyses the relative advantages of genotypic (DNA test) versus phenotypic (transferrin saturation) testing.

Effect of hemochromatosis genotype and lifestyle factors on iron and red cell indices in a community population

Background: Heterozygotes for the C282Y mutation of the HFE gene may have altered hematology indices and higher iron stores than wild-type subjects. Methods: We performed a cross-sectional analysis of 1488 females and 1522 males 20-79 years of age drawn from the Busselton (Australia) population study to assess the effects of HFE genotype, age, gender, and lifestyle on serum iron and hematology indices. Results: Male C282Y heterozygotes had increased transferrin saturation compared with the wild-type genotype. Neither male nor female heterozygotes had significantly increased ferritin values compared with the wild-type genotype. Younger (20-29 years) wild-type males, but not heterozygous males, had significantly lower ferritin values than wild-type males in the older age groups. Compound heterozygous subjects had increased means for serum iron, transferrin saturation, corpuscular volume, and corpuscular hemoglobin compared with the wild-type genotype, and the males also had increased ferritin values (medians 323 vs 177 mug/L; P = 0.003). In both male and female wild-type subjects, an increased body mass index was associated with decreased serum iron and transferrin saturation and increased ferritin values. There was a significant increase in ferritin concentrations in both genders with increasing frequency of red meat consumption above a baseline of 1-2 times per week and alcohol intakes >10 g/day. Conclusions: Male C282Y heterozygotes had significantly increased transferrin saturation values. Compound heterozygous (C282Y/H63D) subjects formed a separate category of C282Y heterozygotes in whom both iron and red cell indices were significantly increased compared with the wild-type genotype. (C) 2001 American Association for Clinical Chemistry.