Salvage radical prostatectomy for recurrent prostate cancer after radiation therapy

Salvage radical prostatectomy is considered for patients with locally recurrent prostate cancer after external beam radiotherapy. Between 2001 and 2004, 32 men treated with curative intent with radiotherapy for prostate cancer were subsequently treated with salvage surgery for clinically localized prostate cancer. We assessed the morbidity associated with this procedure and the outcome of the patients. Thirty-two patients underwent salvage radical prostatectomy. Initial pre-radiation median prostate-specific antigen was 13 ng/ml. Pre-radiation disease was clinical stage T1b in five cases, T2a in 10, T2b in 10 and T3a in seven. Mean operative time was 122 minutes, intraoperative blood loss was 550 ml and hospital stay and catheterization time were 5 and 12 days, respectively. There was biochemical failure in eight patients after salvage radical prostatectomy and 24 patients are biochemical non evidence of disease (bNED). In recurrent prostate local disease with prostate-specific antigen <10 ng/ml and life expectancy greater than 10 years, salvage radical prostatectomy is a reasonable treatment option.     

Application of the phosphoramidate ProTide approach to 4'-azidouridine confers sub-micromolar potency versus hepatitis C virus on an inactive nucleoside

We report the application of our phosphoramidate ProTide technology to the ribonucleoside analogue 4'-azidouridine to generate novel antiviral agents for the inhibition of hepatitis C virus (HCV). 4'-Azidouridine did not inhibit HCV, although 4'-azidocytidine was a potent inhibitor of HCV replication under similar assay conditions. However 4'-azidouridine triphosphate was a potent inhibitor of RNA synthesis by HCV polymerase, raising the question as to whether our phosphoramidate ProTide approach could effectively deliver 4'-azidouridine monophosphate to HCV replicon cells and unleash the antiviral potential of the triphosphate. Twenty-two phosphoramidates were prepared, including variations in the aryl, ester, and amino acid regions. A number of compounds showed sub-micromolar inhibition of HCV in cell culture without detectable cytotoxicity. These results confirm that phosphoramidate ProTides can deliver monophosphates of ribonucleoside analogues and suggest a potential path to the generation of novel antiviral agents against HCV infection. The generic message is that ProTide synthesis from inactive parent nucleosides may be a warranted drug discovery strategy.     

Nongenomic actions of bile acids. Synthesis and preliminary characterization of 23- and 6,23-alkyl-substituted bile acid derivatives as selective modulators for the G-protein coupled receptor TGR5

23-Alkyl-substituted and 6,23-alkyl-disubstituted derivatives of chenodeoxycholic acid are identified as potent and selective agonists of TGR5, a G-protein coupled receptor for bile acids (BAs). In particular, we show that methylation at the C-23(S) position of natural BAs confers a marked selectivity for TGR5 over FXR, while the 6alpha-alkyl substitution increases the potency at both receptors. The present results allow for the first time a pharmacological differentiation of genomic versus nongenomic effects mediated by BA derivatives.     

Nanohybrids for controlled antibiotic release in topical applications

New polymeric composite materials containing a nanohybrid to be used for the controlled release of an antibiotic molecule, chloramphenicol succinate, have been formulated, prepared and characterised. The nanohybrid consists of a layered double hydroxide of Mg-Al hydrotalcite-type, in which the nitrate anions present in the host galleries were replaced with chloramphenicol succinate anions (CFS(-)) by a simple ion-exchange reaction. Different amounts of the hybrid material were incorporated in polycaprolactone and processed as films of 0.15mm thickness. The composite materials were analysed by X-ray diffractometry and thermogravimetry and their mechanical properties were determined. They showed properties even better than those of the pristine polymer. The release process of the antibiotic molecules was found to be very interesting and promising for tuneable drug delivery. It consists of two stages: an initial stage of a very rapid burst, in which a small fraction of drug is released; and a second stage that is much slower, extending for a longer and longer time. This behaviour is profoundly different and much slower than that of a sample in which the antibiotic molecule is directly incorporated into the polymeric matrix. The parameters influencing drug release have been individuated and discussed.     

From ubiquitous antigens to joint-specific inflammation: could local vascular permeability be the missing link?

The mechanisms underlying organ-specific autoimmune diseases are incompletely understood. In particular, it is still unclear how autoantibodies, often against ubiquitous antigens, can cause pathology preferentially in certain tissues. Recently, Binstadt and colleagues, using observations in the K/BxN murine arthritis model, suggested novel pathways underlying the site-specific localization of inflammation driven by immune complexes. In this commentary, we discuss these findings, the problems related to their general applicability and the implications for future research.     

Occlusion of cortical ascending venules causes blood flow decreases, reversals in flow direction, and vessel dilation in upstream capillaries

The accumulation of small strokes has been linked to cognitive dysfunction. Although most animal models have focused on the impact of arteriole occlusions, clinical evidence indicates that venule occlusions may also be important. We used two-photon excited fluorescence microscopy to quantify changes in blood flow and vessel diameter in capillaries after occlusion of single ascending or surface cortical venules as a function of the connectivity between the measured capillary and the occluded venule. Clotting was induced by injuring the target vessel wall with femtosecond laser pulses. After an ascending venule (AV) occlusion, upstream capillaries showed decreases in blood flow speed, high rates of reversal in flow direction, and increases in vessel diameter. Surface venule occlusions produced similar effects, unless a collateral venule provided a new drain. Finally, we showed that AVs and penetrating arterioles have different nearest-neighbor spacing but capillaries branching from them have similar topology, which together predicted the severity and spatial extent of blood flow reduction after occlusion of either one. These results provide detailed insights into the widespread hemodynamic changes produced by cortical venule occlusions and may help elucidate the role of venule occlusions in the development of cognitive disorders and other brain diseases.