A randomized controlled trial of tolterodine and oxybutynin on tolerability and clinical efficacy for treating Chinese women with an overactive bladder

Objective To compare the tolerability and clinical efficacy of tolterodine and oxybutynin in the treatment of Hong Kong Chinese women with an overactive bladder. Patients and methods A randomized controlled trial was conducted at two urogynaecology centres in Hong Kong. In all, 106 women with urodynamically confirmed detrusor instability were recruited. Baseline severity assessments included a visual analogue scale (VAS), urinary diary and urinary pad-test. The women were randomized to receive either oral tolterodine 2 mg or oxybutynin 5 mg twice daily for 10 weeks. Treatment responses were assessed at 4 and 10 weeks using the VAS and urinary diary. Treatment tolerability was assessed at baseline, 4 and 10 weeks using the Xerostomia Questionnaire. A urinary pad-test was repeated at 10 weeks. Results The perceived change from baseline VAS was better in the tolterodine than the oxybutynin group after 10 weeks of treatment (per-protocol analysis, P = 0.043). The two drugs were effective in reducing the symptoms of frequency (P < 0.001). Tolterodine was significantly better than oxybutynin in reducing urinary leakage (urinary pad-test; median change - 5.00 g vs 0 g, P = 0.019). Both drugs caused a significant worsening of dry mouth (overall dryness, P < 0.005; discomfort, P < 0.005; sleep, P = 0.021; speaking, P = 0.045; swallowing, P = 0.004; and liquid consumption, P = 0.017). Conclusions Both oxybutynin and tolterodine were effective in ameliorating the severity of the symptoms of detrusor instability. Tolterodine was better than oxybutynin in both subjective and objective outcome measures, but both drugs caused similar worsening of dry mouth that may limit the tolerability of these medications.     

Dosimetry of rhenium-188 diethylene triamine penta-acetic acid for endovascular intra-balloon brachytherapy after coronary angioplasty

To examine the possibility of using rhenium-188 diethylene triamine penta-acetic acid (DTPA) for endovascular intra-balloon brachytherapy after angioplasty, dose distribution around the balloon was calculated and validated by film dosimetry. Medical internal radiation dosimetry (MIRD) was calculated assuming that the balloon had ruptured and that the contents had been released into the systemic circulation. 188Re-perrhenate eluate from the 188W/188Re generator was concentrated using an ion column and used to label DTPA. The dose distribution around the angioplasty balloon (20 mm length, 3 mm diameter cylinder) was estimated by Monte Carlo simulation using the EGS4 code. The time required for 17.6 Gy to be absorbed at 1 mm from the balloon's surface following application of 3700 MBq/ml of 188Re was found to be 278 s. Fifty percent of the energy was deposited in the first millimetre of the vessel wall from the balloon's surface. The calculated radiation absorbed dose agreed with that measured by film dosimetry, which was performed using a water phantom, with errors ranging from 9.4% to 17%. Upon balloon rupture the total amount of 188Re-DTPA was presumed to enter the systemic circulation. The resulting radiation absorbed dose was calculated using the MIRDOSE3 program and residence times obtained from dogs and amounted to 0.0056 mGy/MBq to the whole body and 4.56 mGy/MBq to the urinary bladder. The absorbed dose of 188Re-DTPA to the whole body was one-tenth of that of 188Re-perrhenate. A window-based program was developed to calculate the exposure time and the radiation dose absorbed as a function of the 188Re concentration and the arbitrary distance from the balloon to the surrounding tissues. We conclude that 188Re-DTPA is easy to prepare, safe to use and suitable for intra-balloon brachytherapy after coronary angioplasty.     

Post-marketing surveillance study of the safety and efficacy of sildenafil prescribed in primary care to erectile dysfunction patients

In order to investigate the safety and efficacy of sildenafil prescribed in primary care, a post-marketing surveillance study was undertaken. A total of 651 men with erectile dysfunction (ED) were enrolled from 31 family physicians in Korea from December 1999 to July 2002. Patients were regularly followed up to ascertain the safety and efficacy of sildenafil. Of the 651 patients enrolled, 572 (87.9%) returned for safety evaluation and efficacy assessment. In all, 458 (80.1%) of 572 patients reported improved erectile function with sildenafil. Hypertension, diabetes and low-dose sildenafil were associated with poor efficacy. A total of 71 adverse events were reported among 56 patients (8.6%), with the most frequent being hot flushes (5.6%), followed by headache (2.6%), palpitation (1.0%), anxiety (0.5%) and elevated ALT (0.5%). Only six patients (1.0%) discontinued sildenafil as a direct result of adverse events. These results suggest that sildenafil prescribed by primary care physicians was well tolerated and improved erectile function in patients with ED.     

Ganglion cell densities in normal and dark-reared turtle retinas

In dark-reared, neonatal turtle retinas, ganglion cell receptive fields and dendritic trees grow faster than normal. As a result, their areas may become, on average, up to twice as large as in control retinas. This raises the question of whether the coverage factor of dark-reared ganglion cells is larger than normal. Alternatively, dark rearing may lead to smaller-than-normal cell densities by accelerating apoptosis. To test these alternatives, we investigated the effect of light deprivation on densities and soma sizes of turtle retinal ganglion cells. For this purpose, we marked these cells using retrograde labeling of fixed turtle retinas with DiI (1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate). Control turtles were maintained in a regular 12-h light/dark cycle from hatching until 4 weeks of age, whereas dark-reared turtles were maintained in total darkness for the same period. Ganglion cells in the control and dark-reared retinas were found to be similar in density and soma sizes. These results show that the mean coverage factor of turtle dark-reared ganglion cells is larger than normal.     

Small (<or= 2 cm) hepatic lesions in colorectal cancer patients: detection and characterization on mangafodipir trisodium-enhanced MRI

OBJECTIVE: The purpose of this study was to evaluate whether mangafodipir trisodium (MnDPDP)-enhanced MRI improves the detection and characterization of small ( 2.0 cm). The differences between MnDPDP-enhanced MRI and helical CT with regard to the detection rates for hepatic lesions and metastases and with regard to the false-positive rates for hepatic metastases were analyzed using the McNemar test. The performances of MnDPDP-enhanced MRI and helical CT in indicating metastases of focal liver lesions were analyzed using receiver operating characteristic curves. RESULTS: No statistically significant differences were seen between MnDPDP-enhanced MRI and helical CT in the detection of all hepatic lesions (p = 0.383) and small lesions (p = 0.210). However, concerning the differentiation between benign and metastatic lesions, MnDPDP-enhanced MRI was superior to helical CT both for all hepatic lesions (p = 0.023) and for small lesions (p = 0.015), and remained better when the analyses were restricted to patients with histopathologic confirmation (p = 0.023 for both). MnDPDP-enhanced MRI changed the diagnosis of hepatic metastasis in nine (13.0%) of 69 patients. Of 12 metastases that were found on MnDPDP-enhanced MRI and missed on helical CT, 11 lesions (91.7%) were small. MnDPDP-enhanced MRI showed a significantly greater detection rate than helical CT for small hepatic metastases (p = 0.022). MnDPDP-enhanced MRI was better when the analyses were restricted to patients with histopathologic confirmation (p = 0.043). CONCLUSION: Although MnDPDP-enhanced MRI is equal to helical CT in detection of both all hepatic lesions and small lesions in patients with colorectal carcinoma, it is superior to CT in characterization of the lesions.     

Discovery of a novel protein tyrosine phosphatase-1B inhibitor, KR61639: potential development as an antihyperglycemic agent

Protein tyrosine phosphatase-1B (PTP-1B), a negative regulator of insulin signaling, may be an attractive therapeutic target for type 2 diabetes mellitus. High throughput screening (HTS) for PTP-1B inhibitors using compounds from the Korea Chemical Bank identified several hits (active compounds). Among them, a hit with 1,2-naphthoquinone scaffold was chosen for lead development. KR61639, [4-[1-(1H-indol-3-yl)-3,4-dioxo-3,4-dihydro-naphthalen-2-ylmethyl]-phenoxy]-acetic acid tert-butyl ester, inhibited human recombinant PTP-1B with an IC(50) value of 0.65 microM in a noncompetitive manner. KR61639 showed modest selectivity over several phosphatases and increased insulin-stimulated glycogen synthesis in HepG2 cells and stimulated 2-deoxyglucose uptake in 3T3/L1 adipocytes. In addition, in vivo study using ob/ob mouse demonstrated that KR61639 exerted a hypoglycemic action when given orally. Thus, KR61639 may be a good starting point for lead optimization in developing a novel antidiabetic agent.     

Skf 525-A induces cocaine N-demethylase, ethoxyresorufin O-deethylase, and pentoxyresorufin O-dealkylase activities by induction of cytochrome p-450 2B in female B6C3F1 mice

Studies demonstrated that cocaine-induced immunosuppression is mediated by metabolites of cocaine. Although SKF 525-A inhibited cocaine N-demethylation in liver S9 fractions isolated from female B6C3F1 mice, our study showed that pretreatment of mice with SKF 525-A potentiated cocaine-induced suppression of the antibody response to sheep red blood cells. An increase in formaldehyde generation was subsequently shown following incubation of cocaine with the S9 fractions prepared from SKF 525-A-treated mice, indicating the possibility of cytochrome P-450 (CYP) induction. Therefore, the inductive effects of SKF 525-A on CYP enzyme activities and proteins were investigated in female B6C3F1 mice to elucidate the potentiation of cocaine-induced immunosuppression by SKF 525-A. When SKF 525-A was administered at 10, 20, or 40 mg/kg/d intraperitoneally for 7 consecutive days, both ethoxyresorufin O-deethylase and pentoxyresorufin O-dealkylase activities were induced dose-dependently. Furthermore, the induction of enzymatic activity was time dependent. Meanwhile, when the type of isozyme induced by SKF 525-A was analyzed by Western immunoblotting with monospecific anti-CYP 1A and anti-CYP 2B antibodies, only the CYP 2B appeared to be induced. From in vitro inhibition studies with monoclonal antibodies, it was confirmed that the induced activity of ethoxyresorufin O-deethylase by SKF 525-A was due to increased levels of CYP 2B proteins. Our present results provide an explanation for the potentiation of cocaine-induced immunosuppression by repeated exposure to SKF 525-A. Our results also indicate that ethoxyresorufin O-deethylase, a selective substrate for CYP 1A, may also be catalyzed by CYP 2B.     

Suppressive effect of inducible nitric oxide synthase (iNOS) expression by the methanol extract of Actinodaphne lancifolia

Nitric oxide (NO) produced by inducible nitric oxide synthase (iNOS) has played a crucial role in various pathophysiological processes including inflammation and carcinogenesis. Therefore, the inhibitors of NO synthesis or iNOS gene expression have been considered as potential anti-inflammatory and cancer chemopreventive agents. In our continuous search for iNOS inhibitors from natural products we have evaluated indigenous Korean plant extracts using an assay for inhibition of nitric oxide formation on lipopolysaccharide (LPS)-activated mouse macrophage RAW 264.7 cells. As a result, the methanolic stem extract of Actinodaphne lancifolia showed an inhibitory activity of NO production in a dose-dependent manner (IC50 = 2.5 microg/ml). Additional study demonstrated that the extract of Actinodaphne lancifolia significantly suppressed the iNOS protein and gene expression in a dose-dependent manner. These results suggest that Actinodaphne lancifolia could be a potential candidate for developing an iNOS inhibitor from natural products. Further elucidation of active principles for development of new cancer chemopreventive and/or anti-inflammatory agents could be warranted.     

AII amacrine cells in the mammalian retina show disabled-1 immunoreactivity

Disabled 1 (Dab1) is an adapter molecule in a signaling pathway, stimulated by Reelin, which controls cell positioning in the developing brain. It has been localized to AII amacrine cells in the mouse and guinea pig retinas. This study was conducted to identify whether Dab1 is commonly localized to AII amacrine cells in the retinas of other mammals. We investigated Dab1-labeled cells in human, rat, rabbit, and cat retinas in detail by immunocytochemistry with antisera against Dab1. Dab1 immunoreactivity was found in certain populations of amacrine cells, with lobular appendages in the outer half of the inner plexiform layer (IPL) and a bushy, smooth dendritic tree in the inner half of the IPL. Double-labeling experiments demonstrated that all Dab1-immunoreactive amacrine cells were immunoreactive to antisera against calretinin or parvalbumin (i.e., other markers for AII amacrine cells in the mammalian retina) and that they made contacts with the axon terminals of the rod bipolar cells in the IPL close to the ganglion cell layer. Furthermore, all Dab1-labeled amacrine cells showed glycine transporter-1 immunoreactivity, indicating that they are glycinergic. The peak density was relatively high in the human and rat retinas, moderate in the cat retina, and low in the rabbit retina. Together, these morphological and histochemical observations clearly indicate that Dab1 is commonly localized to AII amacrine cells and that antiserum against Dab1 is a reliable and specific marker for AII amacrine cells of diverse mammals.     

Induction of cytochrome P450s by rutaecarpine and metabolism of rutaecarpine by cytochrome P450s

Rutaecarpine is an alkaloid originally isolated from the unripe fruit of Evodia rutaecarpa. Recently, rutaecarpine has been characterized to have an anti-inflammatory activity through cyclooxygenase-2 inhibition. In the present studies, the effects of rutaecarpine on liver cytochrome P450 s (P450s) and P450 s involved in the metabolism of rutaecarpine were studied in vivo and in vitro, respectively, because the data are crucial in the early development of rutaecarpine as a new drug candidate. Oral administration to male ICR mice of rutaecarpine for 3 consecutive days induced liver P450 1A-, 2B- and 2E1-selective monooxygenase activities. The induction of P450 1A and 2B by rutaecarpine was confirmed by Western immunoblotting. When rutaecarpine was incubated with rat liver microsomes in the presence of an NADPH-generating system, five metabolites were detected by UV and mass spectral analyses. The 3-methylcholanthrene- and phenobarbital-induced microsomes greatly increased the formation of metabolites. Our present results suggest that rutaecarpine might induce P450 1A and 2B in mice, and that P450 1A and 2B might predominantly metabolize rutaecarpine in rat liver microsomes.