Evidence that drug flux across synthetic membranes is described by normally distributed permeability coefficients.

Over recent decades, the use of in vitro diffusion cell studies to assess skin permeability has evolved into a major research tool, providing key insights into the relationships between skin, drug and formulation. Sometimes, such studies involve synthetic membranes as this approach can yield useful inferences with respect to drug-skin partitioning and diffusion phenomena. Yet despite the popularity of such studies, it is still not at all known whether typical solute transport across synthetic barriers results in a normal distribution of permeability coefficients or alternatively some type of skewed distribution. The present study aims to shed light on this issue. To this end, five compounds (testosterone, oestradiol, corticosterone, aldosterone and adenosine) exhibiting a broad range of octanol-water partition coefficient values were selected as test penetrants. The protocol involved taking multiple replicate measurements of each drug's passive steady state flux through poly(dimethylsiloxane) membrane. Each penetrant's resultant permeability coefficient database was subjected to a Kolmogorov-Smirnov (KS) test for normality. It was found that the permeability coefficients of all five drugs were distributed in a Gaussian-normal fashion. The theoretical significance and practical impact of these findings are discussed.     

Histamine and tryptase modulate asthmatic airway smooth muscle GM-CSF and RANTES release.

Degranulating mast cells are increased in the airway smooth muscle (ASM) of asthmatics, where they may influence ASM function. The aim of the present study was to determine whether histamine and tryptase modulate ASM cell granulocyte-macrophage colony-stimulating factor (GM-CSF) and RANTES (regulated on activation, normal T-cell expressed and secreted) release and also to examine which receptors are involved in this release. Confluent, quiescent ASM cells from asthmatic and nonasthmatic donors were treated with histamine (1 microM-100 microM) with and without histamine receptor antagonist pre-treatment, or the protease-activated receptor (PAR)-2 agonists tryptase (0.5-5 nM) and SLIGKV (100 and 400 microM). The cells were then stimulated with interleukin (IL)-1beta and/or tumour necrosis factor (TNF)-alpha (10 ng.mL(-1)) or left unstimulated for 24 h. Release of GM-CSF and RANTES was determined by ELISA and prostaglandin (PG)E(2) measured by enzyme immunoassay. Neither histamine nor tryptase induced ASM GM-CSF or RANTES secretion. However, histamine increased IL-1beta-induced GM-CSF release and markedly reduced TNF-alpha-induced RANTES release by both asthmatic and nonasthmatic cells to a similar extent, but did not modulate PGE(2) release. All changes involved activation of the histamine H1 receptor as they were partially or fully blocked by chlorpheniramine, but not ranitidine. Tryptase, via its proteolytic activity, also potentiated GM-CSF, but not RANTES, release from asthmatic and nonasthmatic ASM cells induced by both cytokines. PAR-2 involvement in the tryptase potentiation was unlikely because SLIGKV had no effect. In conclusion, mast cells, through histamine and tryptase, may locally modulate airway smooth muscle-induced inflammation in asthma.     

Executive functions and adaptive functioning in young adult attention-deficit/hyperactivity disorder.

Attention-deficit/hyperactivity disorder (ADHD) is associated with impairments in occupational, social, and educational functioning in adults. This study examined relations of adaptive impairment to ADHD symptom domains (inattentive-disorganized and hyperactive-impulsive) and to deficits in executive functioning (EF) in 195 well-characterized adults (105 ADHD, 90 non-ADHD, between ages 18 and 37). Participants completed a battery of EF measures as well as assessments of adaptive functioning. Confirmatory factor analyses were used to validate latent factors for adaptive functioning and EF. In a measurement model, weaker EF was associated with poorer adaptive functioning (r = -.30). When multi-informant composite variables for current inattentive-disorganized and hyperactive-impulsive ADHD symptoms were included in the structural model, EF no longer predicted adaptive functioning. While both symptom composites were similarly related to EF (inattentive-disorganized r = .36; hyperactive-impulsive r = .29), inattentive-disorganized symptoms accounted for more variance in adaptive functioning (67.2% vs. 3.6%). Furthermore, for retrospectively reported childhood symptoms of ADHD, only the inattentive-disorganized symptom domain was related to EF or adaptive impairment. These results suggest that, in adults with ADHD, inattentive-disorganized symptoms may be the primary contributor to key aspects of poorer adaptive function and may be the behavioral path through which EF deficits lead to adaptive impairment.     

Calcium intake in the elderly: validation of a dietary questionnaire

Epidemiological studies of calcium and osteoporosis have been hampered by the lack of a suitable tool for assessing calcium intake. This report describes a new frequency and amount questionnaire for measuring present and past calcium intake in the elderly. The validity of the questionnaire was tested against two commonly used standards of dietary assessment, five-day duplicate diets and seven-day weighed dietary inventories. The resulting correlation coefficients were, respectively, r = 0.76 and r = 0.69, while that for repeatability was r = 0.84. Furthermore, the questionnaire categorized subjects into thirds of the distribution of intake with almost no gross misclassification. It is suggested that the present findings may be extended to the majority of normal, healthy elderly subjects, implying wide application for the questionnaire in the assessment of calcium intake in the elderly.     

Epicardial distribution of ST segment and T wave changes produced by stimulation of intrathoracic ganglia or cardiopulmonary nerves in dogs

Sixty-three ventricular epicardial electrograms were recorded simultaneously in 8 atropinized dogs during stimulation of acutely decentralized intrathoracic autonomic ganglia or cardiopulmonary nerves. Three variables were measured: (1) isochronal maps representing the epicardial activation sequence, (2) maps depicting changes in areas under the QRS complex and T wave (regional inhomogeneity of repolarization), and (3) local and total QT intervals. Neural stimulations did not alter the activation sequence but induced changes in the magnitude and polarity of the ST segments and T waves as well as in QRST areas. Stimulation of the same neural structure in different dogs induced electrical changes with different amplitudes and in different regions of the ventricles, except for the ventral lateral cardiopulmonary nerve which usually affected the dorsal wall of the left ventricle. Greatest changes occurred when the right recurrent, left intermediate medial, left caudal pole, left ventral lateral cardiopulmonary nerves and stellate ganglia were stimulated. Local QT durations either decreased or did not change, whereas total QT duration as measured using a root-mean-square signal did not change, indicating the regional nature of repolarization changes. Taken together, these data indicate that intrathoracic efferent sympathetic neurons can induce regional inhomogeneity of repolarization without prolonging the total QT interval.