Pharmacokinetics of chlordesmethyldiazepam after single-dose oral administration in humans

The pharmacokinetics of chlordemethyldiazepam--a pharmacologically very active new 1,4-benzodiazepine derivative--in healthy subjects after administration of a single oral dose of 2 mg, was studied. Peak concentrations were reached in 1.2 +/- 0.2 hours. Plasma levels declined with a biphasic pattern, and the elimination phase had a half-life of 82.9 +/- 14.1 hours. The concentrations of the main metabolite of chlordemethyldiazepam, lorazepam, were about 7% of those of the parent compound. In urine only conjugated lorazepam could be found its 96 hour excretion reaching about 15% of the administered dose of parent drug.     

Subclavian cannulation. Valuable dialysis access alternative

The subclavian vein was used for temporary dialysis access in 67 patients. There were 733 dialysis treatments performed using a total of 87 catheters during the study period. The catheters were left in place for an average of 24.5 days per patient and 18.9 days per catheter. A mean of 10.9 dialysis treatments per patient, and 8.4 dialysis treatments per catheter were performed. Seven patients expired with their catheters indwelling. None of these deaths were related to the catheter. There were 21 associated catheter complications. Twelve of these catheter complications were corrected by changing the catheter over a guide wire. The technique for catheter insertion, proper catheter care including home care, and complications due to the catheters are discussed. Subclavian catheter dialysis access appears to be a valuable adjunct for dialysis and has replaced the use of Scribner shunts and repeated femoral catheterizations for temporary access in our institution.     

Lymphoid organ development in rabbits: major lymphocyte subsets

Although rabbits represent an important animal model, little is known about the lymphoid organ development in this species. In the present study, lymphocyte subsets in peripheral blood, spleen, mesenteric and popliteal lymph nodes in newborn and 2-, 4-, 6- and 8-week old and adult were characterized. Lymphocyte subsets were detected using flow cytometry and monoclonal antibodies against rabbit CD4, CD8, T-cell-specific antigen and cross-reactive antibody against B-cell antigen CD79alpha. In neonates, lower numbers of T cells were detected in both peripheral blood and spleen than in mesenteric lymph nodes. In comparison with other compartments, CD79alpha(+) cells prevailed in the spleen. Post-natal development was characterized by a decreased CD4(+)/CD8(+) ratio due to increasing frequency of CD8(+) lymphocytes in all organs but mesenteric lymph nodes, where it was due to decreased numbers of CD4(+) lymphocytes. Another significant feature was the increase of B cells in peripheral blood and mesenteric lymph nodes.     

Matched comparison of outcomes following open and minimally invasive radical prostatectomy for high-risk patients

Purpose

Comparative data related to the use of open and minimally invasive surgical approaches for the treatment of high-risk prostate cancer (PCa) remain limited. We determined outcomes of open radical prostatectomy (RRP), laparoscopic RP (LRP), and robot-assisted RP (RARP) in matched cohorts of patients with high-risk prostate cancer.

Materials and methods

A total of 805 patients with high-risk PCa [prostate-specific antigen (PSA) >20 ng/mL, Gleason score ≥8, or clinical stage ≥cT2c] were identified. A total of 407 RRP cases were propensity score (PS) matched 1:1 to 398 LRP or RARP cases to yield 3 cohorts (RARP, LRP, and RRP) of 110 patients each for analysis. PS matching variables included the following: age, clinical stage, preoperative PSA, biopsy Gleason score, surgeon experience, and nerve-sparing technique. Overall survival (OS) and recurrence-free survival (RFS) were compared with log-rank test. RFS predictor analysis was calculated within Cox regression models.

Results

Pathological Gleason scores <7, =7, and >7 were found in 3.3, 50.9, and 45.8 % of patients. There were no statistically significant differences for pathological stage and positive surgical margins between surgical techniques. Mean 3-year RFS was 41.4, 77.9, and 54.1 %, for RARP, LRP, and RRP, respectively (p < 0.0001 for RARP vs. LRP). There were no significant differences for mean estimated 3-year OS for patients treated with RARP, LRP, or RRP (95.4, 98.1, and 100 %).

Conclusions

RARP demonstrated similar oncologic outcomes compared to RRP and LRP in a PS-matched cohort of patients with high-risk prostate cancer.     

Diagnostic accuracy and agreement between whole-body diffusion MRI and bone scintigraphy in detecting bone metastases

Purpose

This study was done to determine the diagnostic value of whole-body magnetic resonance using diffusion-weighted imaging with background suppression (WB-DWIBS) for detecting bone metastases compared with whole-body bone scintigraphy (WB-BS).

Materials and methods

Twenty-three patients with solid tumours underwent both WB-DWIBS imaging and WBBS. A nuclear medicine specialist interpreted WB-BS images and two blinded radiologists, first independently and then jointly, interpreted the WB-DWIBS images by completing a reading grid categorising the skeletal segments. Cohen’s k statistic was used to determine interobserver agreement in reading the WB-DWIBS images and the agreement between WB-BS and WB-DWIBS. Sensitivity and specificity were calculated per patient and per lesion.

Results

Interobserver agreement in reading the WBDWIBS images was substantial or good, with κ=0.68. Analysis of agreement between the nuclear physician’s and the radiologists’ readings provided κ=0.87 [95% confidence interval (CI)=0.76–0.98)] Per-lesion analysis gave a sensitivity of 80% (95% CI=75–85) and a specificity of 98.2% (95% CI=96.5–99.8).

Conclusions

We found a good level of interobserver agreement for the WB-DWIBS images and an excellent level of agreement in the subjective judgement of presence or absence of disease between WB-BS and WB-DWIBS after consensual double reading. WB-DWIBS has the same specificity as WB-BS in detecting bone metastases. The anatomical sites exhibiting the highest level of disagreement between WB-DWIBS and WB-BS are the pelvis, the coccyx, and the sternum, all sites at which detection with WB-BS has the greatest limitations.     

Antiplatelet Versus Anticoagulation Therapy After Extracardiac Conduit Fontan: A Systematic Review and Meta-Analysis

The benefits of prophylactic anticoagulation or antiplatelet therapy for patients undergoing extracardiac conduit (ECC) Fontan procedure still are a matter of debate. Through a systematic review and meta-analysis, this study aimed to determine the incidence of thromboembolism among patients undergoing ECC Fontan who received anticoagulation or antiplatelet therapy. Until February 2010, MEDLINE studies describing the incidence of thromboembolic events after ECC Fontan were reviewed. Information on type of drugs and clinical outcome was extracted. The 20 studies analyzed involved 1,075 patients: 220 (20.4%) in the antiplatelet group and 855 (79.5%) in the anticoagulation group. The mean follow-up period ranged from 2 to 144 months. The overall thromboembolism rate was 5.2% (95% confidence interval [CI], 3.8–7%; I² = 0%; p_het = 0.32). The effect of different therapeutic strategies on the occurrence of thromboembolic and bleeding events was analyzed. Interestingly, the anticoagulation therapy compared with the antiplatelet therapy was not associated with a significant reduction in the incidence of overall thromboembolic complications (5% vs 4.5%, respectively; I² = 0%; p_het = 0.80). Only two cases of bleeding were observed among patients receiving anticoagulant therapy at the time of the event. For patients undergoing ECC Fontan, the rate of thromboembolic and bleeding events associated with antiplatelet therapy is similar to that associated with anticoagulation therapy.     

Hamartomatous polyps: Diagnosis,surveillance, and management

Hereditary polyposis syndrome can be divided into three categories: Adenomatous, serrated, and hamartomatous polyps. Hamartomatous polyps, malformations of normal tissue presenting in a disorganized manner, are characterized by an autosomal dominant inheritance pattern. These syndromes exhibit hamartomatous gastrointestinal polyps in conjunction to extra-intestinal manifestations, which require conscientious and diligent monitoring. Peutz-Jeghers syndrome, Cowden syndrome, and juvenile polyposis...     

Identification of novel molecular scaffolds for the design of MMP-13 inhibitors: a first round of lead optimization

Osteoarthritis (OA) is the leading cause of joint pain and disability in middle-aged and elderly patients, and is characterized by progressive loss of articular cartilage. Among the various matrix metalloproteinases (MMPs), MMP-13 is specifically expressed in the cartilage of human OA patients and is not present in normal adult cartilage. Thus, MMP-13-selective inhibitors are promising candidates in osteoarthritis therapy. Recently, we designed an N-isopropoxy-arylsulfonamide-based hydroxamate inhibitor, which showed low nanomolar activity and high selectivity for MMP-13. In parallel to further studies aiming to assess the in?vivo activity of our compound, we screened the Life Chemicals database through computational docking to seek for novel scaffolds as zinc-chelating non-hydroxamate inhibitors. Experimental evaluation of 20 selected candidate compounds verified five novel leads with IC(50) in the low μM range. These newly discovered inhibitors are structurally unrelated to the ones known so far and provide useful scaffolds to develop compounds with more desirable properties. Finally, a first round of structure-based optimization on lead 1 was accomplished and led to an increase in potency of more than 5 fold.     

Involvement of the spinal cord in Parkinson's disease

Parkinson's disease (PD) has traditionally ascribed to alpha-synucleinopathy of the substantia nigra; however, several studies have showed widespread alpha-synucleinopathy inside and outside the brain. The potential role of the spinal cord in the genesis of some symptoms has been quite neglected despite the frequent and precocious presence of alpha-synucleinopathy in the spinal cord of PD patients. We examined the literature about the pathology of the spinal cord in PD and the possible relevance of this pathology in the genesis of some nonmotor symptoms including urinary, sexual, and gastrointestinal, as well as of some motor symptoms.