Structure-hepatic disposition relationships for cationic drugs in isolated perfused rat livers: Transmembrane exchange and cytoplasmic binding process

This work studied the structure-hepatic disposition relationships for cationic drugs of varying lipophilicity using a single-pass, in situ rat liver preparation. The lipophilicity among the cationic drugs studied in this work is in the following order: diltiazem. propranolol. labetalol. prazosin. antipyrine. atenolol. Parameters characterizing the hepatic distribution and elimination kinetics of the drugs were estimated using the multiple indicator dilution method. The kinetic model used to describe drug transport (the two-phase stochastic model) integrated cytoplasmic binding kinetics and belongs to the class of barrier-limited and space-distributed liver models. Hepatic extraction ratio (E) (0.30-0.92) increased with lipophilicity. The intracellular binding rate constant (k(on)) and the equilibrium amount ratios characterizing the slowly and rapidly equilibrating binding sites (K-S and K-R) increase with the lipophilicity of drug (k(on) : 0.05-0.35 s(-1); K-S : 0.61-16.67; K-R : 0.36-0.95), whereas the intracellular unbinding rate constant (k(off)) decreases with the lipophilicity of drug (0.081-0.021 s(-1)). The partition ratio of influx (k(in)) and efflux rate constant (k(out)), k(in)/k(out), increases with increasing pK(a) value of the drug [from 1.72 for antipyrine (pK(a) = 1.45) to 9.76 for propranolol (pK(a) = 9.45)], the differences in k(in/kout) for the different drugs mainly arising from ion trapping in the mitochondria and lysosomes. The value of intrinsic elimination clearance (CLint), permeation clearance (CLpT), and permeability-surface area product (PS) all increase with the lipophilicity of drug [CLint (ml . min(-1) . g(-1) of liver): 10.08-67.41; CLpT (ml . min(-1) . g(-1) of liver): 10.80-5.35; PS (ml . min(-1) . g(-1) of liver): 14.59-90.54]. It is concluded that cationic drug kinetics in the liver can be modeled using models that integrate the presence of cytoplasmic binding, a hepatocyte barrier, and a vascular transit density function.

Epstein-Barr virus encephalitis in a renal allograft recipient diagnosed by polymerase chain reaction on cerebrospinal fluid and successfully treated with ganciclovir

Epstein–Barr virus (EBV) encephalitis has been reported rarely in the context of solid-organ and bone-marrow transplantation [1]. We report a case of a renal transplant recipient who developed EBV encephalitis following OKT3 therapy for acute allograft rejection. The diagnosis was expedited by the detection of EBV DNA in the cerebrospinal fluid (CSF) by nested polymerase chain reaction (PCR). Moreover, clinical recovery and clearance of CSF EBV DNA appeared to follow the institution of parenteral ganciclovir treatment.

Solid-state NMR structure determination of melittin in a lipid environment

Solid-state C-13 NMR spectroscopy was used to investigate the three-dimensional structure of melittin as lyophilized powder and in ditetradecylphosphatidylcholine (DTPC) membranes. The distance between specifically labeled carbons in analogs [1-C-13]Gly3-[2-C-13]Ala4, [1-C-13]Gly3-[2-C-13]Leu6, [1-C-13]Leu13-[2-C-13]Ala15, [2-C-13]Leu13-[1-C-13]Ala15, and [1-C-13]Leu13-[2-C-13]Leu16 was measured by rotational resonance. As expected, the internuclear distances measured in [1-C-13]Gly3-[2-C-13]Ala4 and [1-C-13]Gly3-[2-C-13]Leu6 were consistent with alpha -helical structure in the N-terminus irrespective of environment. The Internuclear distances measured in [1-C-13]Leu13-[2-C-13]Ala15, [2-C-13]Leu13-[1-C-13]Ala15, and [1-C-13]Leu13-[2-C-13]Leu16 revealed, via molecular modeling, some dependence upon environment for conformation in the region of the bend in helical structure induced by Pro14. A slightly larger interhelical angle between the N- and C-terminal helices was indicated for peptide in dry or hydrated gel state DTPC (139 degrees -145 degrees) than in lyophilized powder (121 degrees -139 degrees) or crystals (129 degrees). The angle, however, is not as great as deduced for melittin in aligned bilayers of DTPC in the liquid-crystalline state (similar to 160 degrees) (R. Smith, F. Separovic, T. J. Milne, A. Whittaker, F. M. Bennett, B. A. Cornell, and A. Makriyannis, 1994, J. Mol, Biol 241:456-466). The study illustrates the utility of rotational resonance in determining local structure within peptide-lipid complexes.

Increasing relevance of pharmacogenetics of drug metabolism in clinical practice

Much of the individual variation in drug response is due to genetic drug metabolic polymorphisms. Clinically relevant examples include acetylator status; cytochrome P450 2D6, 2C9 and 2C19 polymorphisms; and thiopurine methyltransferase deficiency. It is important to be aware of which drugs are subject to pharmacogenetic variability. In the future, population-based pharmacogenetic testing will allow more individualized drug treatment and will avoid the current empiricism.

James Parkinson (1755-1824): A pioneer of child care

James Parkinson (1755-1824) of Parkinson's disease, is well recognized as a pioneer of clinical neurology; and is even more famous as a founder of modem palaeontology. We have reviewed from primary sources his extensive contributions to clinical child care and his pioneering advocacy for child welfare, protection and safety. His writings, outreach and advocacy for children's health characterizes him as one whose influence was an important springboard from which evolved the modern specialty of paediatrics. Parkinson was one of the first to write on child-rearing practices and in this context antedated Benjamin Spock by 150 years. Parkinson was a pioneer of child safety and the prevention of childhood trauma. He wrote of the resuscitation of near-drowned children and of first aid for injured children. This critical analysis reviews his pioneering description of child abuse and the development of post-abuse hydrocephalus. He wrote the datum description (in English) of the pathophysiology and pathology of appendicitis in children, of fatal rabies in children and highlighted the risk of death even when the biting dog was not clinically rabid. His advocacy for social reform for children's welfare was courageous and pioneering. James Parkinson, hitherto unacknowledged, was a significant founder of the evolving discipline of paediatrics and child health.

Step size control for efficient discrete element simulation

The step size determines the accuracy of a discrete element simulation. The position and velocity updating calculation uses a pre-calculated table and hence the control of step size can not use the integration formulas for step size control. A step size control scheme for use with the table driven velocity and position calculation uses the difference between the calculation result from one big step and that from two small steps. This variable time step size method chooses the suitable time step size for each particle at each step automatically according to the conditions. Simulation using fixed time step method is compared with that of using variable time step method. The difference in computation time for the same accuracy using a variable step size (compared to the fixed step) depends on the particular problem. For a simple test case the times are roughly similar. However, the variable step size gives the required accuracy on the first run. A fixed step size may require several runs to check the simulation accuracy or a conservative step size that results in longer run times. (C) 2001 Elsevier Science Ltd. All rights reserved.

The chemistry and biological effects of malondialdehyde-acetaldehyde adducts

This article represents the proceedings of a workshop at the 2000 ISBRA Meeting in Yokohama, Japan. The chairs were Geoffrey M. Thiele and Simon Worrall. The presentations were (1) The chemistry of malondialdehyde-acetaldehyde (MAA) adducts, by Dean J. Tuma; (2) The formation and clearance of MAA adducts in ethanol-fed rats, by Simon Worrall; (3) Immune responses to MAA adducts may play a role in the development of alcoholic liver disease, by Lynell W. Klassen; (4) Unique biological responses to MAA-modifled proteins that may play a role in the development and/or progression of alcoholic liver disease, by Geoffrey M. Thiele; (5) MAA-adducted bovine serum albumin activates protein kinase C and stimulates interleukin-8 release in bovine bronchial epithelial cells, by Todd A. Wyatt; and (6) An enzyme immune assay for serum antiacetaldehyde adduct antibody using low-density lipoprotein-adduct and its significance in alcoholic liver injury and ALDH2 heterozygotes, by Naruhiko Nagata.

Elucidation of reaction scheme describing malondialdehyde-acetaldehyde-protein adduct formation

Malondialdehyde and acetaldehyde react together with proteins and form hybrid protein conjugates designated as MAA adducts, which have been detected in livers of ethanol-fed animals. Our previous studies have shown that MAA adducts are comprised of two distinct products. One adduct is composed of two molecules of malondialdehyde and one molecule of acetaldehyde and was identified as the 4-methpl-1,4-dihydropyridine-3,5-dicarbaldehyde derivative of an amino group (MHHDC adduct). The other adduct is a 1:1 adduct of malondialdehyde and acetaldehyde and was identified as the 2-formyl-3-(alkylamino)butanal derivative of an amino group (FAAB adduct). In this study, information on the mechanism of MAA adduct formation was obtained, focusing on whether the FAAB adduct serves as a precursor for the MDHDC adduct. Upon the basis of chemical analysis and NMR spectroscopy, two initial reaction steps appear to be a prerequisite for MDHDC formation. One step involves the reaction of one molecule of malondialdehyde and one of acetaldehyde with an amino group of a protein to form the FAAB product, while the other step involves the generation of a malondialdehyde-enamine. It appears that generation of the MDHDC adduct requires the FAAB moiety to be transferred to the nitrogen of the MDA-enamine. For efficient reaction of FAAB with the enamine to take place, additional experiments indicated that these two intermediates likely must be in positions on the protein of close proximity to each other. Further studies showed that the incubation of liver proteins from ethanol-fed rats with MDA resulted in a marked generation of MDHDC adducts, indicating the presence of a pool of FAAB adducts in the liver of ethanol-fed animals. Overall, these findings show that MDHDC-protein adduct formation occurs via the reaction of the FAAB moiety with a malondialdehyde-enamine, and further suggest that a similar mechanism may be operative in vivo in the liver during prolonged ethanol consumption.

Adolescents' perceptions of social status: Development and evaluation of a new indicator

Objective. Eliminating health disparities, including those that are a result of socioeconomic status (SES), is one of the overarching goals of Healthy People 2010. This article reports on the development of a new, adolescent-specific measure of subjective social status (SSS) and on initial exploratory analyses of the relationship of SSS to adolescents' physical and psychological health. Methods. A cross-sectional study of 10 843 adolescents and a subsample of 166 paired adolescent/mother dyads who participated in the Growing Up Today Study was conducted. The newly developed MacArthur Scale of Subjective Social Status (10-point scale) was used to measure SSS. Paternal education was the measure of SES. Indicators of psychological and physical health included depressive symptoms and obesity, respectively. Linear regression analyses determined the association of SSS to depressive symptoms, and logistic regression determined the association of SSS to overweight and obesity, controlling for sociodemographic factors and SES. Results. Mean society ladder ranking, a subjective measure of SES, was 7.2 ± 1.3. Mean community ladder ranking, a measure of perceived placement in the school community, was 7.6 ± 1.7. Reliability of the instrument was excellent: the intraclass correlation coefficient was 0.73 for the society ladder and 0.79 for the community ladder. Adolescents had higher society ladder rankings than their mothers (µteen = 7.2 ± 1.3 vs µmom = 6.8 ± 1.2; P = .002). Older adolescents' perceptions of familial placement in society were more closely correlated with maternal subjective perceptions of placement than those of younger adolescents (Spearman's rhoteens