Influence of dosing time on the efficacy and safety of finasteride in rats

Finasteride (FIN), a widely used medication for the treatment of androgen-dependent diseases, blocks the conversion of testosterone to a more potent androgen, dihydrotestosterone (DHT). In this study, we investigated a dosing time-dependent effect and safety of FIN in rats. Androgen receptor (AR) mRNA and nuclear protein levels exhibited clear daily rhythms with the peak during the dark period in the prostate and during the light period in the liver. Repeated oral administration of FIN (5 or 100 mg/kg) at 3 h after lights on (HALO) for 2 weeks decreased serum DHT concentration throughout a 24-h period, whereas the dosing of the agent at 15 HALO decreased its level only transiently even in the higher dose group. FIN caused laboratory abnormalities in the 3 HALO group but not in the 15 HALO group. However, the effect of FIN on the prostate weight was not influenced by the dosing time. These results suggest that the safety, but not effect, of FIN depends on its dosing time in rats. The dosing of FIN in the active period might be a rational dosage regimen, which is needed to be confirmed in human subjects.     

Oncology IVR--application to palliative medicine

Oncology IVR is a minimum invasive and locoregional treatment by newly developed interventional techniques consisting of transarterial chemoembolization (TACE), radiofrequency ablation, cryoablation and percutaneous bone plasty (PBP), etc. These treatment methods are considered to be effective to rapid tumor reduction and palliation. The redistributed subclavian arterial infusion chemotherapy via an implanted catheter-port system which was newly developed by authors would be effective for local recurrence of breast cancer. The combination therapy of these interventional techniques can offer new treatment strategies for an improvement of patient's quality of life and more effective palliative medicine.     

New internalized distraction device for craniofacial plastic surgery using Ni-free, Ti-based shape memory alloy

This study was undertaken to examine effects and biocompatibility of a new internalized distraction device made from newly developed Ti-Nb-Al shape memory alloy (SMA). Crania of Wistar rats were expanded using a U-shaped wire of this SMA set on each cranium in an experimental group. At 2 or 4 weeks after operation, the rats were killed; width measurements and three-dimensional observations of crania were conducted using soft x-ray and microfocus x-ray computed tomography photography. After photography, histologic sections were made and stained with hematoxylin and eosin. No pathologic change in the experimental duration was observed macroscopically or histologically. Significantly increased size was found for the rat crania in the experimental group compared with the control group. Results demonstrated the feasibility and biocompatibility of internalized distraction osteogenesis using Ni-free, Ti-based SMA in craniofacial plastic surgery for craniofacial deformities.     

Hypertension as a predictive factor of effect of bevacizumab in treatment of colorectal cancer

Bevacizumab is a monoclonal antibody that targets vascular endothelial growth factor (VEGF) for treatment of metastatic colorectal cancer. Recently, much evidence has suggested that bevacizumab-induced hypertension might be predictive of the effect of bevacizumab. The aim of our study is to retrospectively assess the relationship between the onset of hypertension and the activity of bevacizumab in Japanese metastatic colorectal cancer patients. Between July 2007 and December 2010, 36 patients (median age 66 years; 36-81 years) with metastatic colorectal cancer were assigned to receive bevacizumab in combination with either mFOLFOX6 (5-FU, levofolinate and oxaliplatin) or FOLFIRI (5-FU, levofolinate and irinotecan) at the Tokushima University Hospital. A patient who had increase by >20 mmHg in diastolic blood pressure or had increase to >150/100 mmHg or received antihypertensive treatment was defined as hypertensive. The objective response rate (ORR), disease control rate (DCR) and progression-free survival (PFS) were compared between the hypertensive group (n=10) and non-hypertensive group (n=26). ORR and DCR were 60.0% and 100%, respectively, in the hypertensive group and ORR and DCR were 23.1% and 80.8%, respectively, in the non-hypertensive group. These differences were statistically significant (p<0.05). The median PFS tended to be longer in the hypertensive group (65.0 weeks) than in the non-hypertensive group (40.0 weeks). Our data suggested that bevacizumab-induced hypertension may be predictive of the effect of bevacizumab in Japanese metastatic colorectal cancer patients.     

Association of IL28B genotype and viral response of hepatitis C virus genotype 2 to interferon plus ribavirin combination therapy

The impacts of IL28B genotype to treatment response of hepatitis C virus (HCV) genotype 2 are still not clear. A total of 381 consecutive Japanese patients infected with HCV genotype 2, who could complete combination therapy with interferon (IFN) plus ribavirin for 24 weeks, were evaluated to investigate pretreatment predictors. Patients, who could not achieve sustained virological response at the first course of 24‐week IFN plus ribavirin, were recruited into the study protocol of total 48‐week IFN plus ribavirin. In 24‐week regimen, rates of sustained virological response and rapid virological response were 82% and 50%, respectively. There were no significant differences in rates of sustained virological response and rapid virological response, according to IL28B genotype. Multivariate analysis identified younger age, higher level of albumin, absence of past history of IFN, and lower level of viremia as significant determinants of sustained virological response. As significant or marginal significant determinants of non‐sustained virological response regardless of rapid virological response, multivariate analysis identified IL28B rs8099917 genotype TG + GG and lower level of albumin. In 48‐week regimen to 10 patients of non‐sustained virological response at the first course of 24‐week regimen, sustained virological response rates were 70%. All of six patients, with IL28B TT and relapse at the first course of 24‐week regimen, could achieve sustained virological response, but two patients with IL28B TG could not achieve sustained virological response. In conclusion, the present results suggest that IL28B genotype might partly affect viral response of HCV genotype 2 to combination therapy. J. Med. Virol. 84:1593–1599, 2012. © 2012 Wiley Periodicals, Inc.     

Prevalence of anemia and chronic kidney disease in cancer patients: clinical significance for 1-year mortality

Prevalence of anemia, stratified by severity grades, and chronic kidney disease (CKD) was studied in cancer patients receiving chemotherapy. In addition, their relevance to 1-year survival was estimated. We investigated the demographics and clinical findings of 231 cancer patients (male : 142, female : 89) who were admitted to the Division of Chemotherapy at the Cancer and Infectious Disease Center, Tokyo Metropolitan Komagome Hospital between April and September, 2008. Mean age was 63.6 +/- 12.7 years. Anemia was defined as a hemoglobin (Hb)level less than 12 g/dL and the anemia severity grades were classified according to the Anemia Toxicity Scales. Estimated glomerular filtration rate was calculated based on the formula of the Modification of Diet in Renal Disease modified for the Japanese. CKD was defined as stage 3 or more according to the K/DOQI criteria. To assess the clinical relevance of anemia and CKD to 1-year survival, we drew Kaplan-Meier curves, stratifying patients according to the anemia severity grades and the presence or absence of CKD. The joint impact of anemia grades and presence of CKD on 1-year mortality was assessed using the Cox proportional hazard analysis, adjusted for age and gender. Prevalence of anemia was 81% : 6.9% for grade 4 (Hb < 6.5 g/dL); 13.9% for grade 3(6.5 = Hb < 8.0 g/dL); 29.0% for grade 2 (8.0 = Hb < 10.0 g/dL); 31.2% for grade I (10.0 = Hb < 12.0 g/dL) and 19.0% for non-anemia cases. Prevalence of CKD was 25%. Survival probability of the overall or non-CKD cancer patients with anemia severity > or = grade 2 significantly decreased, as compared to that with no anemia. Survival probability of patients with CKD significantly decreased, as compared to that with no CKD. Statistically, the hazard ratio of mortality for patients with both grade 4-anemia and CKD was 14-fold higher than that for patients with neither anemia nor CKD. In conclusion, the prevalence of anemia and CKD were unexpectedly high in cancer patients. The combination of high-grade anemia and CKD is likely to be a significant risk factor for 1-year mortality of these patients.     

Evaluating Anisotropic Properties in the Porcine Temporomandibular Joint Disc Using Nanoindentation

The objective of this study was to determine the viscoelastic properties present within the intermediate zone of the porcine temporomandibular joint (TMJ) disc using nanoindentation. A 50-μm conospherical indenter tip using a displacement-controlled ramp function with a 600 nm/s loading and unloading rate, a 3000-nm peak displacement with a holding period of 30 s was used to indent the samples. Experimental load-relaxation tests were performed on the TMJ disc to determine the response in three different directions; the mediolateral, anteroposterior, and articular surface directions. The experimental data were analyzed using a generalized Maxwell model to obtain values for short- and long-time relaxation modulus and of material time constants. The short time relaxation modulus E _I values were 180.92, 64.99, and 487.77 kPa for testing done on the articular surface, mediolateral, and anteroposterior directions, respectively. Corresponding values for the long-time relaxation modulus E _∞ were 45.9, 14.97, and 133.5 kPa. The method confirmed anisotropy present within the central intermediate zone of the porcine TMJ disc due to the directional orientation of the collagen fibers.     

Electroencephalographic background activity and blood biochemistry data in patients with chronic renal failure during chronic hemodialysis

There is no particular electroencephalographic activity known to be associated with consciousness disturbance in uremic patients; however, a slow wave activity is generally observed during consciousness disturbance. Abnormal electroencephalographic activity was observed in 30 (67%) of 45 chronic renal failure patients during chronic hemodialysis without consciousness disturbance, and slow wave activity was observed in 58%. The frequency of the electroencephalographic background activity correlated with blood urea nitrogen (BUN) and serum Ca levels, but not with K, IP, and creatinine levels. Electroencephalographic activity can be estimated with reference to BUN or serum Ca levels in the blood of uremic patients.