Pharmacokinetics and pharmacodynamics of suberoylanilide hydroxamic acid in cats.

Suberoylanilide hydroxamic acid (SAHA), or vorinostat, is a histone deacetylase inhibitor approved for use as chemotherapy for lymphoma in humans. The goal of this study was to establish pharmacological parameters of SAHA in cats. Our interest in treating cats with SAHA is twofold: as an anticancer chemotherapeutic and as antilatency therapy for feline retroviral infections. Relying solely on data from studies in other animals would be inappropriate as SAHA is partially metabolized by glucuronidation, which is absent in feline metabolism. SAHA was administered to cats intravenously (2 mg/kg) or orally (250 mg/m², ~17 mg/kg) in a cross-over study design. Clinically, SAHA was well tolerated at these dosages as no abnormalities were noted following administration. The pharmacokinetics of SAHA in cats was found to be similar to that of dogs, but the overall serum drug exposure was much less than that of humans at an equivalent dose. The pharmacodynamic effect of an increase in acetylated histone proteins in blood was detected after both routes of administration. An increased oral dose of 60 mg SAHA/kg administered to one animal resulted in a surprisingly modest increase in peak drug concentration, suggesting possible saturation of absorption kinetics. This study provides a foundation for future studies of the clinical efficacy of SAHA in treating feline disease

Peripheral and central immune cell reservoirs in tissues from asymptomatic cats chronically infected with feline immunodeficiency virus

<div><p>Feline immunodeficiency virus (FIV) infection in cats results in life-long viral persistence and progressive immunopathology. We have previously described a cohort of experimentally infected cats demonstrating a progressive decline of peripheral blood CD4+ T-cell over six years in the face of apparent peripheral viral latency. More recently we reported findings from this same cohort that revealed popliteal lymph node tissue as sites for ongoing viral replication suggesting that tissue reservoirs are important in FIV immunopathogenesis during the late asymptomatic phase of infection. Results reported herein characterize important tissue reservoirs of active viral replication during the late asymptomatic phase by examining biopsied specimens of spleen, mesenteric lymph node (MLN), and intestine from FIV-infected and uninfected control cats. Peripheral blood collected coincident with harvest of tissues demonstrated severe CD4+ T-cell depletion, undetectable plasma viral <i>gag</i> RNA and rarely detectable peripheral blood mononuclear cell (PBMC)-associated viral RNA (vRNA) by real-time PCR. However, vRNA was detectable in all three tissue sites from three of four FIV-infected cats despite the absence of detectable vRNA in plasma. A novel <i>in situ</i> hybridization assay identified B cell lymphoid follicular domains as microanatomical foci of ongoing FIV replication. Additionally, we demonstrated that CD4+ leukocyte depletion in tissues, and CD4+ and CD21+ leukocytes as important cellular reservoirs of ongoing replication. These findings revealed that tissue reservoirs support foci of ongoing viral replication, in spite of highly restricted viral replication in blood. Lentiviral eradication strategies will need address tissue viral reservoirs.</p></div

Development of a Noise Reduction Filter Algorithm for Pediatric Body Images in Multidetector CT

Recently, several types of post-processing image filter which was designed to reduce noise allowing a corresponding dose reduction in CT images have been proposed and these were reported to be useful for noise reduction of CT images of adult patients. However, these have not been reported on adaptation for pediatric patients. Because they are not very effective with small (<20 cm) display fields of view, they could not be used for pediatric (e.g., premature babies and infants) body CT images. In order to solve this restriction, we have developed a new noise reduction filter algorithm which can be applicable for pediatric body CT images. This algorithm is based on a three-dimensional post processing, in which output pixel values are calculated by multi-directional, one-dimensional median filters on original volumetric datasets. The processed directions were selected except in in-plane (axial plane) direction, and consequently the in-plane spatial resolution was not affected by the filter. Also, in other directions, the spatial resolutions including slice thickness were almost maintained due to a characteristic of non-linear filtering of the median filter. From the results of phantom studies, the proposed algorithm could reduce standard deviation values as a noise index by up to 30% without affecting the spatial resolution of all directions, and therefore, contrast-to-noise ratio was improved by up to 30%. This newly developed filter algorithm will be useful for the diagnosis and radiation dose reduction of pediatric body CT images