Three-dimensional bladder ultrasonography with the BladderScan® overestimates post void residual one week after delivery.

OBJECTIVE: Postpartum urinary retention is a frequent complication after childbirth. It is usually a temporary condition. However, unrecognised urinary retention can lead to considerable morbidity due to bladder over distention, detrusor atony and long term voiding dysfunction. In our clinic we noticed an overestimation of post void residual measured with the BladderScan® in comparison with catheterization in women one week after delivery. STUDY DESIGN: We included 25 women in this prospective pilot study. These women had a urinary retention over 1000 ml within 4-5 h postpartum. Conform our local protocol, an indwelling catheter was inserted for one week. After removal of the indwelling catheter, a micturition trial was conducted. The post void residual was first measured with BladderScan® (BVI 3000), directly followed by clean intermittent catheterization which is the golden standard at this moment. RESULTS: There was a significant mean difference in post void residual measurements with the BladderScan® and catheterization of 312 ml (95% CI 220-404 ml) (p < 0.001). According to our post void residual definition of 200 ml, the sensitivity and specificity of the BladderScan® was respectively 100% and 17.6%. The positive predictive value was 36%. CONCLUSION: The BladderScan® (BVI 3000) is a non-reliable instrument to measure post void residual one week postpartum. For now clean intermittent catherization remains the golden standard.

Synthesis, biological properties, and molecular modeling investigations of novel 3,4-diarylpyrazolines as potent and selective CB(1) cannabinoid receptor antagonists.

A series of novel 3,4-diarylpyrazolines was synthesized and evaluated in cannabinoid (hCB(1) and hCB(2)) receptor assays. The 3,4-diarylpyrazolines elicited potent in vitro CB(1) antagonistic activities and in general exhibited high CB(1) vs CB(2) receptor subtype selectivities. Some key representatives showed potent pharmacological in vivo activities after oral dosing in both a CB agonist-induced blood pressure model and a CB agonist-induced hypothermia model. Chiral separation of racemic 67, followed by crystallization and an X-ray diffraction study, elucidated the absolute configuration of the eutomer 80 (SLV319) at its C(4) position as 4S. Bioanalytical studies revealed a high CNS-plasma ratio for the development candidate 80. Molecular modeling studies showed a relatively close three-dimensional structural overlap between 80 and the known CB(1) receptor antagonist rimonabant (SR141716A). Further analysis of the X-ray diffraction data of 80 revealed the presence of an intramolecular hydrogen bond that was confirmed by computational methods. Computational models and X-ray diffraction data indicated a different intramolecular hydrogen bonding pattern in the in vivo inactive compound 6. In addition, X-ray diffraction studies of 6 revealed a tighter intermolecular packing than 80, which also may contribute to its poorer absorption in vivo. Replacement of the amidine -NH(2) moiety with a -NHCH(3) group proved to be the key change for gaining oral biovailability in this series of compounds leading to the identification of 80.

Antisense oligonucleotides reach mRNA targets via the RNA matrix: downregulation of the 5-HT1A receptor.

Successful application of antisense oligonucleotides (ODNs) in cell biology and therapy will depend on the ease of design, efficiency of (intra)cellular delivery, ODN stability, and target specificity. Equally essential is a detailed understanding of the mechanism of antisense action. To address these issues, we employed phosphorothioate ODNs directed against specific regions of the mRNA of the serotonin 5HT1A receptor, governed by sequence and structure. We demonstrate that rather than various intracellular factors, the gene sequence per se primarily determines the antisense effect, since 5HT1a autoreceptors expressed in RN46A cells, postsynaptic receptors expressed in SN48 cells, and receptors overexpressed in LLP-K1 cells are all efficiently downregulated following ODN delivery via a cationic lipid delivery system. The data also reveal that the delivery system as such is a relevant parameter in ODN delivery. Antisense ODNs bound extensively to the RNA matrix in the cell nuclei, thereby interacting with target mRNA and causing its subsequent degradation. Antisense delivery effectively diminished the mRNA pool, thus resulting in downregulation of newly synthesized 5HT1A proteins, without the appearance of truncated protein fragments. In conjunction with the selected mRNA target sequences of the ODNs, the latter data indicated that effective degradation rather than a steric blockage of the mRNA impedes protein expression. The specificity of the antisense approach, as described in this study, is reflected by the effective functional downregulation of the 5-HT1A receptor.