Bioactivation of loxoprofen to a pharmacologically active metabolite and its disposition kinetics in human skin

Loxoprofen (LX) is a prodrug‐type non‐steroidal anti‐inflammatory drug which is used not only as an oral drug but also as a transdermal formulation. As a pharmacologically active metabolite, the trans‐alcohol form of LX (trans‐OH form) is generated after oral administration to humans. The objectives of this study were to evaluate the generation of the trans‐OH form in human in vitro skin and to identify the predominant enzyme for its generation. In the permeation and metabolism study using human in vitro skin, both the permeation of LX and the formation of the trans‐OH form increased in a time‐ and dose‐dependent manner after the application of LX gel to the skin. In addition, the characteristics of permeation and metabolism of both LX and the trans‐OH form were examined by a mathematical pharmacokinetic model. The K_m value was calculated to be 10.3 mm in the human in vitro skin. The predominant enzyme which generates the trans‐OH form in human whole skin was identified to be carbonyl reductase 1 (CBR1) by immunodepletion using the anti‐human CBR1 antibody. The results of the enzyme kinetic study using the recombinant human CBR1 protein demonstrated that the K_m and V_max values were 7.30 mm and 402 nmol/min/mg protein, respectively. In addition, it was found that no unknown metabolites were generated in the human in vitro skin. This is the first report in which LX is bioactivated to the trans‐OH form in human skin by CBR1. Copyright © 2015 John Wiley & Sons, Ltd.     

Acute reversible myocardial depression associated with sepsis

A 30-year-old man was admitted to our hospital for left lobar pneumonia with septic shock. Acute left-sided heart failure became evident as sepsis developed. Echocardiography revealed diffuse severe hypokinesis of the left ventricle (LV) and a pulmonary artery catheter showed Forrester subset II hemodynamics. Along with amelioration of sepsis and decrease of the serum concentrations of tumor necrosis factor-alpha and interleukin-6, LV hypokinesis improved. It is suggested that the patient's heart failure may have been due to functional depression of myocardial contractility resulting from a direct effect of the cytokines towards the cardiomyocytes, the so-called "septic myocardial depression".     

Quantitation of basal dyssynchrony and acute resynchronization from left or biventricular pacing by novel echo-contrast variability imaging

OBJECTIVES: This study sought to test a novel echocardiographic method based on contrast variability imaging (CVI), to quantify cardiac dyssynchrony and magnitude of resynchronization achieved by left ventricular (LV) and biventricular (BiV) pacing therapy. BACKGROUND: Left ventricular or BiV pacing is a promising new therapy for patients with heart failure and intraventricular conduction delay. However, precise quantitation of the extent of resynchronization achieved remains scant. METHODS: Ten patients treated with BiV or LV pacing therapy were studied. Echo-contrast was infused slowly, and gated images were acquired before and during contrast appearance. The temporally normalized variance derived from 30 to 50 sequential beats was determined at each pixel to yield the CVI image-displaying improved wall delineation. Systolic regional fractional area of radial sectors was calculated with active and temporarily suspended (AAI) pacing. All analyses were performed blinded to both patient and treatment. RESULTS: Pacing increased septal inward motion from -20.4 +/- 9.6% to -30.5 +/- 14.0%, whereas lateral wall motion occurred earlier with no net magnitude change. Both spatial and temporal dyssynchrony in the LV declined nearly 40% with LV or BiV pacing (p < or = 0.001), and this correlated with increasing ejection fraction (31% to 39%; p < 0.02; p < 0.004 for correlation with dyssynchrony). CONCLUSIONS: The new imaging and regional dyssynchrony analysis methods provide quantitative assessment of resynchronization analogous to that previously obtained only by tagged magnetic resonance imaging. This could provide a useful noninvasive method for both identifying candidates and following long-term therapy.     

Studies on murine thyroiditis: new insights from organ flow cytometry.

The pathogenesis of autoimmune diseases is frequently studied in murine models, in which disease outcome is traditionally assessed by light microscopy. To determine whether digital imaging improves reliability of the histopathologic assessment, and whether flow cytometry is applicable directly on the murine thyroid, we studied 395 CBA/J mice 3 weeks after thyroglobulin immunization, and 192 nonimmunized CBA/J mice. Digital imaging significantly improved reliability of the histopathological assessment (r = 0.988, 95% confidence interval: 0.980-0.992, p < 0.0001), and flow cytometry on the murine thyroid could be performed successfully. We also found that normal thyroids contained a higher than expected number of hematopoietic cells in the interstitium. We suggest that digital imaging offers a better means of estimating disease outcome, and that flow cytometry performed at the target organ levels reflects the autoimmune pathogenesis more closely than when performed on peripheral lymphoid organs. These methods should also be applicable to other organ systems targeted by autoimmune attack, such as heart, exocrine, and other endocrine glands.     

Evidence for Reactivation of Human Herpesvirus 6 in Generalized Lymphadenopathy in a Patient with Drug-Induced Hypersensitivity Syndrome

The present case provides direct evidence of human herpesvirus 6 reactivation in resected lymph node tissue in a patient with drug-induced hypersensitivity syndrome. This case clearly demonstrates that appropriate pathological evaluation of lymphadenopathy for drug-induced hypersensitivity syndrome, which mimics malignant lymphoma in clinical, radiological, and pathological findings, is required.