Pharmacokinetic Disposition of Multiple-Dose Transdermal Nicotine in Healthy Adult Smokers

The pharmacokinetics and cardiovascular effects of nicotine and its major metabolite, cotinine, were characterized during repeated once-daily application for 5 days of a 30-cm² nicotine transdermal system, Nicotine TTS (Habitrol), to nine healthy, black, adult, male smokers. Subjects abstained from smoking throughout the study. Pharmacokinetic analysis indicated that nicotine was delivered from Nicotine TTS for the 24-hr application period averaging 0.76 mg/ cm²/24 hr, and at a relatively constant rate compared to other modes of drug administration. The transdermal clearance of nicotine, 1351 ml/min, coincided with reported values following intravenous nicotine administration; however, the terminal-phase half-life, 5.0 hr, did not. An analysis of the components of variance contributing to the variability in nicotine delivery from repetitive application of Nicotine TTS indicated that the in vivo transdermal permeation of nicotine is rate limited by both the device and the intrinsic skin conductivity. Clinical cardiovascular side effects were negligible as an apparent result of subclinical vasopressive nicotine concentrations, although drug activity with regard to other effects was manifested.     

A comparative study of alternative estimators for the unbalanced two‐way error component regression model

This paper considers the unbalanced two‐way error component model studied by 15 . Alternative analysis of variance (ANOVA), minimum norm quadratic unbiased and restricted maximum likelihood (REML) estimation procedures are proposed. The mean squared error performance of these estimators are compared using Monte Carlo experiments. Results show that for the estimates of the variance components, the computationally more demanding maximum likelihood (ML) and minimum variance quadratic unbiased (MIVQUE) estimators are recommended, especially if the unbalanced pattern is severe. However, focusing on the regression coefficient estimates, the simple ANOVA methods perform just as well as the computationally demanding ML and MIVQUE methods and are recommended.     

Weighted serum pools in comparison to the trapezoidal rule for estimating AUCs for ethinyl estradiol

The concept of a weighted pool for estimating the area under the curve (AUC) is presented and set in relationship to the trapezoidal rule. An example from a pharmacokinetic study on ethinyl estradiol is used to demonstrate the use of variance component analysis for relating the intraindividual variance of the AUC, trapezoidal rule and weighted pool to the variance of the determination process. Depending on the sampling times, the theoretical variance of the weighted pool is greater than the theoretical variance of the trapezoidal rule. In the example presented, it was shown that this difference is of no importance in relation to the interindividual variance of the AUC, which dominates the total variance. In the example study, routine quality control samples were also determined in each assay, which allowed independent confirmation of the discussed results on the intraindividual variance of the AUCs.     

Measurement processes and spatial principal components analysis

Summary Spatial principal components analysis (SPCA) applied to the ongoing EEG yields factor loadings which, when mapped, consistently reveal symmetrical patterns resembling the spherical harmonics. In this paper, we consider the mechanisms responsible for these characteristic patterns. In doing so, we demonstrate that volume conduction is one of a family of processes capable of generating such patterns with SPCA. It is shown that any series of measurements on a sphere in which the covariance is only a function of measurement site angular separation (shift invariant processes) will yield the spherical harmonics as the eigenvectors or factor loadings of the covariance matrix. Simulations further indicate that this effect is robust and not determined by the geometry of the measurement sites. In situations where shift invariant signals coexist with those generated at specific sites (anatomically specific processes), such as evoked potentials and some artifacts, it is shown that the anatomically specific signals do not influence the eigenvectors of the covariance matrix in a uniform or random fashion. The factors most influenced are those whose symmetry is similar to that of the site specific signal.Acknowledgements: The authors are happy to acknowledge the technical assistance of Andrew Pipingas, Geoff Nield, Guy Burkitt and Glen Thomas. The authors also acknowledge the suggestions made by Joseph Ciorciari and Mark Schier on an earlier draft of this paper.     

The design and performance of an experimental external fixator with variable axial stiffness and a compressive force transducer

A unilateral external fixator has been designed for controlled experiments into the effects of micromovement on fracture healing. The experimental model used is based on a diaphyseal osteotomy of the right tibia of the sheep. The main bar has linear bearings, which allows free axial movement. This is then controlled by a spring whose stiffness can be varied. The resulting axial micromovement can be calculated from the measured compressive force and the known axial stiffness of the fixator. The transducer has limits of error of + 13.3 N and − 44.5 N. Preliminary measurements showed maximum micromovement at the fracture site of 0.48 mm during slow walking.     

Comparison of Three Methods for Obtaining Principal Components from Family Data in Genetic Analysis of Complex Disease

Three multivariate techniques used to derive principal components (PCs) from family data were compared for their ability to model family data and power to detect linkage. Using the simulated data from Genetic Analysis Workshop 12, the five quantitative traits were first adjusted for age, sex, and environmental factors 1 and 2. Then, standard PCs, PCs obtained from between‐family covariance, and PCs obtained from within‐family genetic covariance were derived and subjected to multivariate sib pair linkage analysis. The standard PCs obtained from the overall correlation matrix allowed identification of key features of the true genetic model more readily than did the other methods. For detection of linkage, standard PCs and PCs obtained from the between‐family genetic covariance performed similarly in terms of both power and type 1 error, and both methods performed better than the PCs obtained from within‐family genetic covariance. © 2001 Wiley‐Liss, Inc.     

The Effect of Pedigree Complexity on Quantitative Trait Linkage Analysis

Due to the computational difficulties of performing linkage analysis on large complex pedigrees, most investigators resort to simplifying such pedigrees by some ad hoc strategy. In this paper, we suggest an analytical method to compare the power of various pedigree simplification schemes by using the asymptotic distribution of the likelihood‐ratio statistic. We applied the method to the large Hutterite pedigree. Our results indicate that the breaking and reduction of inbreeding loops can greatly diminish the power to localize quantitative trait loci. We also present an efficient Monte Carlo method for estimating identity‐by‐descent allele sharing in large complex pedigrees. This method is used to facilitate a linkage analysis of serum IgE levels in the Hutterites without simplifying the pedigree. © 2001 Wiley‐Liss, Inc.     

A simple method for elution of IgA deposits from the skin of patients with dermatitis herpetiformis

Summary To better understand the role of autoimmunity in the pathogenesis of dermatitis herpetiformis, linear IgA bullous dermatosis or other skin disorders, the antigenic specificity of the immune reactants bound in vivo in the skin must be identified. In order to do so, one must first be able to elute these immune reactants from the skin. We describe here a simple method of eluting not only specifically bound IgG, but also IgA and other immunoglobulins and complement components from skin biopsy material. The method involves cutaneous washing of the entrapped serum proteins in PBS pH 7 and pH 5 buffers followed by specific immunoglobulin elutions at pH 3 and 2. The IgA deposits which could not be removed by this treatment were eluted by a combination of low pH (0.5 M citrate pH 2) and a chaotropic agent (2 M NaCl). The relative concentration of IgA in eluates when quantitated by fluoroimmunoassay were three-to five-fold higher in dermatitis herpetiformis skin biopsy specimens, than in eluates of bullous pemphigoid or normal skin biopsy specimens.     

Quantification of loss of haemoglobin components from the circulating red blood cell in vivo

Abstract: Previous studies have shown that a considerable amount of haemoglobin is lost from the intact red cell during its lifespan. The aim of this study was to determine the relative contribution of all the haemoglobin components to this process. Therefore, the relative amount of haemoglobins A0, A2, F and the glycated haemoglobins were determined in 24 fractions of different cell age. These fractions were obtained by the combination of counterflow and density centrifugation. When the absolute amount of all haemoglobin components were calculated using the MCH-values of each fraction, it appeared that the mean red cell loss of haemoglobins A0, A2, F, an unknown X and “rest” comprised, respectively, 440, 23, 1, 4 and 1 amol per cell, while the mean gain of the glycated haemoglobins was 84 amol per cell. This resulted in a net loss of 385 amol of haemoglobin per cell. One of the glycated haemoglobins (HbA1e2) turned out to be the product of further carbamylation. It was concluded that in the first half of the red cell lifespan HbA0 and HbA2 decreased by glycation and carbamylation and that in the second half some of the HbA0 and HbA2 but also some of the glycated and carbamylated haemoglobin components leave the red cell. The total loss amounted to about 20%.     

The concentration pattern of laminin, hyaluronan, and aminoterminal propeptide of type III procollagen in seminal fluid

The extracellular matrix components laminin, N-terminal propeptide of type III procollagen (PIIINP) and hyaluronan (HA) were determined in seminal fluids of 119 patients submitted for diagnosis of infertility. The concentrations of laminin and HA, but not those of PIIINP, were elevated in seminal fluid in comparison to their ranges of concentration in normal sera. Only weak correlations were observed between the concentrations of the three matrix components. The concentration of HA was negatively correlated with sperm count and ejaculate volume. Laminin was positively correlated with sperm count, the age of patients, and highly significantly with the concentrations of acrosin. A highly significant positive correlation was also found between PIIINP and fructose. By analysis of variance it could be shown that patients with azoospermia and oligozoospermia have significantly higher levels of HA than those with normospermia. Patients with terato- and asthenozoospermia showed no characteristic pattern of the matrix components.