Dexmedetomidine pharmacokinetics in pediatric intensive care – a pooled analysis

Background: Published dexmedetomidine pharmacokinetic studies in children are limited by participant numbers and restricted pathology. Pooling the available studies allows investigation of covariate effects. Methods: Data from four studies investigating dexmedetomidine pharmacokinetics after i.v. administration (n = 95) were combined to undertake a population pharmacokinetic analysis of dexmedetomidine time–concentration profiles (730 observations) using nonlinear mixed effects modeling (NONMEM). Estimates were standardized to a 70‐kg adult using allometric size models. Results: Children had a mean age of 3.8 (median 3 years, range 1 week–14 years) and weight of 16.0 kg (median 13.3 kg, range 3.1–58.9 kg). Population parameter estimates (between subject variability) for a two‐compartment model were clearance (CL) 42.1 (CV 30.9%) l·h^?1·70 kg^?1, central volume of distribution (V1) 56.3 (61.3%) l·70 kg^?1, inter‐compartment clearance (Q) 78.3 (37.0%) l·h^?1·70 kg^?1 and peripheral volume of distribution (V2) 69.0 (47.0%) l·70 kg^?1. Clearance maturation with age was described using the Hill equation. Clearance increases from 18.2 l·h^?1·70 kg^?1 at birth in a term neonate to reach 84.5% of the mature value by 1 year of age. Children given infusion after cardiac surgery had 27% reduced clearance compared to a population given bolus dose. Simulation of published infusion rates that provide adequate sedation for intensive care patients found a target therapeutic concentration of between 0.4 and 0.8 μg·l^?1. Conclusions: The sedation target concentration is similar to that described for adults. Immature clearance in the first year of life and a higher clearance (when expressed as l·h^?1·kg^?1) in small children dictate infusion rates that change with age. Extrapolation of dose from children given infusion in intensive care after cardiac surgery may not be applicable to those sedated for noninvasive procedures out of intensive care.     

Tobacco‐Control Policies in Tobacco‐Growing States: Where Tobacco Was King

Context

The 5 major tobacco-growing states (Kentucky, North Carolina, South Carolina, Tennessee, and Virginia) are disproportionately affected by the tobacco epidemic, with higher rates of smoking and smoking-induced disease. These states also have fewer smoke-free laws and lower tobacco taxes, 2 evidence-based policies that reduce tobacco use. Historically, the tobacco farmers and hospitality associations allied with the tobacco companies to oppose these policies.

Methods

This research is based on 5 detailed case studies of these states, which included key informant interviews, previously secret tobacco industry documents (available at http://legacy.library.ucsf.edu), and media articles. This was supplemented with additional tobacco document and media searches specifically for this article.

Findings

The tobacco companies were particularly concerned about blocking tobacco-control policies in the tobacco-growing states by promoting a pro-tobacco culture, beginning in the late 1960s. Nevertheless, since 2003, there has been rapid progress in the tobacco-growing states’ passage of smoke-free laws. This progress came after the alliance between the tobacco companies and the tobacco farmers fractured and hospitality organizations stopped opposing smoke-free laws. In addition, infrastructure built by National Cancer Institute research projects (COMMIT and ASSIST) led to long-standing tobacco-control coalitions that capitalized on these changes. Although tobacco production has dramatically fallen in these states, pro-tobacco sentiment still hinders tobacco-control policies in the major tobacco-growing states.

Conclusions

The environment has changed in the tobacco-growing states, following a fracture of the alliance between the tobacco companies and their former allies (tobacco growers and hospitality organizations). To continue this progress, health advocates should educate the public and policymakers on the changing reality in the tobacco-growing states, notably the great reduction in the number of tobacco farmers as well as in the volume of tobacco produced.     

Development of early postnatal peripheral nerve abnormalities in Trembler-J and PMP22 transgenic mice

Mutations in the gene for peripheral myelin protein 22 ( PMP22 ) are associated with peripheral neuropathy in mice and humans. Although PMP22 is strongly expressed in peripheral nerves and is localised largely to the myelin sheath, a dual role has been suggested as 2 differentially expressed promoters have been found. In this study we compared the initial stages of postnatal development in transgenic mouse models which have, in addition to the murine pmp22 gene, 7 (C22) and 4 (C61) copies of the human PMP22 gene and in homozygous and heterozygous Trembler-J ( Tr ^J ) mice, which have a point mutation in the pmp22 gene. The number of axons that were singly ensheathed by Schwann cells was the same in all groups indicating that PMP22 does not function in the initial ensheathment and separation of axons. At both P4 and P12 all mutants had an increased proportion of fibres that were incompletely surrounded by Schwann cell cytoplasm indicating that this step is disrupted in PMP22 mutants. C22 and homozygous Tr ^J animals could be distinguished by differences in the Schwann cell morphology at the initiation of myelination. In homozygous Tr ^J animals the Schwann cell cytoplasm had failed to make a full turn around the axon whereas in the C22 strain most fibres had formed a mesaxon. It is concluded that PMP22 functions in the initiation of myelination and probably involves the ensheathment of the axon by the Schwann cell, and the extension of this cell along the axon. Abnormalities may result from a failure of differentiation but more probably from defective interactions between the axon and the Schwann cell.     

Hematin and Bilirubin Binding to Human Serum Albumin and Newborn Serum

ABSTRACT. In jaundiced newborn infants, hemolytic disease is considered a risk factor for kernicterus due to the suspected competition between bilirubin and other hemoglobin breakdown products for albumin binding. We have studied the effect of hematin on bilirubin-albumin binding using the peroxidase assay and a light-scattering technique for measuring unbound bilirubin. Our results show that hematin does not affect bilirubin-albumin binding. To determine if other albumin binding functions are affected by hematin, we used a microdialysis rate technique employing two ligands, diazepam and monoacetyldiaminodiphenyl sulfone (MADDS). Hematin does not utilize the diazepam binding function of albumin, but does decrease the albumin binding of MADDS. The results of this study indicate that the MADDS and bilirubin binding functions are not identical. The clinical usefulness of reserve albumin equivalent determination using MADDS is discussed.     

THE GRANULOMATOUS REACTION IN HERPETIC STROMAL KERATITIS: IMMUNOHISTOLOGICAL AND ULTRASTRUCTURAL FINDINGS

A granulomatous reaction was identified in six corneal buttons obtained from patients with herpetic stromal keratitis. The inflammation, characterized by lymphocytes, plasma cells, macrophages and multinucleate giant cells, was associated with Descemet's membrane in five cases and with a break in Bowman's membrane in one case. The ultrastructural changes were documented by scanning electron microscopy in all cases. Transmission electron microscopy, performed in four cases, failed to disclose the presence of viral inclusions. Immunoperoxidase stains utilizing antibodies to the herpes simplex virus were done on all cases. Positivity (the presence of herpes simplex virus antigen or herpes simplex-like antigen) was detected within epithelium (three cases), within stroma (three cases), and within some inflammatory cells of the granulomatous reaction at Bowman's membrane. Positive staining was not detected in cells of the granulomatous reaction at Descemet's membrane. These results suggest that the reaction at Descemet's membrane, which has been found in a variety of corneal conditions, may be due to a poorly understood alteration in the antigenicity of Descemet's membrane.