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141.
D Nagarathnam JM Wetzel SW Miao MR Marzabadi G Chiu WC Wong X Hong J Fang C Forray TA Branchek WE Heydorn RS Chang T Broten TW Schorn C Gluchowski 《Canadian Metallurgical Quarterly》1998,41(26):5320-5333
We report the synthesis and evaluation of novel alpha1a adrenoceptor subtype-selective antagonists. Systematic modification of the lipophilic 4,4-diphenylpiperidinyl moiety of the dihydropyridine derivatives 1 and 2 provided several highly selective and potent alpha1a antagonists. From this series, we identified the 4-(methoxycarbonyl)-4-phenylpiperidine analogue SNAP 5540 (-) [(-)-63] for further characterization. When examined in an isolated human prostate tissue assay, this compound was found to have a Ki of 2.8 nM, in agreement with the cloned human receptor binding data (Ki = 2.42 nM). Further evaluation of the compound in isolated dog prostate tissue showed a Ki of 3.6 nM and confirmed it to be a potent antagonist (Kb = 1.6 nM). In vivo, this compound effectively blocked the phenylephrine-stimulated increase in intraurethral pressure (IUP) in mongrel dogs, at doses which did not significantly affect the arterial pressure (diastolic blood pressure, DBP), with a DBP Kb/IUP Kb ratio of 16. In addition, (-)-63 also showed greater than 40 000-fold selectivity over the rat L-type calcium channel and 200-fold selectivity over several G protein-coupled receptors, including histamine and serotonin subtypes. These findings prove that alpha1a adrenoceptor-subtype selective antagonists such as (-)-63 may be developed as uroselective agents for an improved treatment of BPH over nonselective alpha1 antagonists such as prazosin and terazosin, with fewer side effects. 相似文献
142.
TW Woo MS Chang YK Chung KB Kim SK Sohn SG Kim WS Choi 《Canadian Metallurgical Quarterly》1998,21(1):6-11
The use of an episiotomy for vaginal delivery is a controversial topic in modern obstetrics. If one is done, however, correct technique of perineal trauma repair is important. The usual episiotomy has traditionally been closed with interrupted suture. The use of a less reactive material, e.g. polyglycolic acid (Dexon), seem to be suitable for subcutaneous skin closure and beneficial in terms of acute postpartum discomfort and healing. The comparison of healing and patient comfort parameters between interrupted and subcutis polyglycolic acid suture used for episiotomy repair after delivery was done. Patients had follow-up during hospital stay, and two months after delivery a self administered questionnaire was sent to all women who participated, enquiring about perineal pain, resumption of sexual intercourse and cosmetics of suture line. Of 52 patients who had repair with interrupted suture, 21 were lost to follow-up. Of 65 gravidas who had repair with subcutis suture, 23 were lost to follow-up. At the 3rd day postpartum examination, patients with subcutis sutures had significantly better healing. An inflammatory process was present in 2 of 52 patients with interrupted sutures comparable with 1 of 65 in the subcutis group, and a gaping wound in 0 of 52 and 1 of 65, respectively. Recovery of function, measured by resumption of sexual activity by 8 weeks, was demonstrated in 5 of 31 patients with interrupted sutures versus 24 of 42 patients who had subcutis sutures. Episiotomy repair with subcutis polyglycolic acid (Dexon) offers significant advantages over traditional interrupted suture, both in terms of wound healing and resumption of sexual activity. 相似文献
143.
A large body of data suggest that brain cholecystokinin (CCK) systems are involved in the regulation of anxiety, and numerous studies have demonstrated that CCK-4, a CCKB agonist, reliably induces panic attacks in patients with panic disorder. Recently, pentagastrin, a commercially available CCKB agonist, has been reported to have similar anxiogenic properties. To further explore the utility of pentagastrin as a challenge agent and to determine whether its effects are dose-related, a dose-response study was conducted in ten healthy volunteers. Pentagastrin (0.2 microgram/kg, 0.6 microgram/kg and 1.0 microgram/kg) and inactive placebo were infused over one minute on four separate challenge days in a double-blind fashion. Subjects received pentagastrin while participating in a structured social interaction task. Repeated measures of anxiety, blood pressure, pulse, ACTH, and cortisol were taken at baseline and postinfusion. Pentagastrin administration led to increases in anxiety, pulse, ACTH, cortisol and physical symptoms of panic, in a dose-related manner. Participation in the social interaction task led to increases in measures of anxiety as well as increases in pulse and blood pressure. Few differences were found between the 0.2 microgram/kg dose of pentagastrin and placebo, or between the 0.6 microgram/kg and the 1.0 microgram/kg doses of pentagastrin. These findings support the notion that CCK systems are involved in the regulation of anxiety, and suggest that the 0.6 microgram/kg dose may be optimal for increasing symptoms of anxiety while minimizing unpleasant side effects. The powerful anxiogenic effects of the social interaction task underscore the importance of contextual variables in challenge studies. 相似文献
144.
D Schrenk A Michalke TW Gant PC Brown JA Silverman SS Thorgeirsson 《Canadian Metallurgical Quarterly》1996,52(9):1453-1460
Overexpression of P-glycoprotein in tumor cells can represent a severe drawback for cancer chemotherapy. P-glycoprotein acts as an efflux transporter for a variety of chemotherapeutic agents. It is encoded by multidrug resistance (mdr) genes of the subfamily 1 in humans (MDR1) and rodents (mdr1a and 1b). Because mdr1 gene expression is inducible in cultured rat hepatocytes and in rat liver with chemical carcinogens such as 2-acetylaminofluorene or aflatoxin B1, which form DNA-binding electrophiles during their metabolism, we investigated whether the DNA-damaging chemotherapeutic drug mitoxantrone may induce multidrug resistance in rodents and in hepatocytes in primary culture. In H4IIE rat hepatoma cells stably transfected with a luciferase construct containing the rat mdr1b promoter, mitoxantrone caused a concentration-dependent increase in promoter activity. Mdr1 gene expression in cultured rat hepatocytes was enhanced at mitoxantrone concentrations greater than or equal to 0.1 microM and in mouse hepatocytes at 5 microM. In hepatocytes from both species, a correlation was found between mdr1 induction and the inhibition of protein synthesis. In vivo, mitoxantrone was a very powerful inducer of mdr1 gene expression in rat liver and small intestine. In rat kidney, induction of mRNA was lower, and a marginal effect was seen in lung. In contrast with rats, no significant induction of mdr1 gene expression was obtained in mouse liver. Probably as a consequence of inhibition of protein synthesis, mitoxantrone did not lead to a pronounced elevation of P-glycoprotein levels in rat liver and kidney. 相似文献
145.
We studied the effect of gravity on cerebral cortical blood flow (CBF), mean arterial blood pressure (BPa) and heart rate in six rabbits exposed to parabolic flights. The CBF was obtained using a laser-Doppler probe fixed on to a cranial window. Before weightlessness, the animals were exposed to chest-to-back directed acceleration (1.8-2.0 g). The CBF values were expressed as a percentage of CBFo (mean CBF during 60 s before the 1st parabola). Propranolol (1 mg x kg[-1] i.v.) was given after the 11th parabola and pentobarbital (12-15 mg x kg[-1] i.v.) after the 16th parabola. Before the administration of the drugs, CBF increased (P < 0.01) during hypergravity [i.e. maximal CBF 151 (SD 64)% CBFo. Simultaneously BPa increased [maximal BPa, 119 (SD 11) mmHg (P < 0.01)]. At the onset of weightlessness, CBF and BPa reached maximal values [194 (SD 96)% CBFo (P < 0.01) and 127 (SD 19) mmHg, (P < 0.01) respectively]. The microgravity-induced increase in CBF was transient since CBF returned to its baseline value after 8 (SD 2) s of microgravity. After propranolol administration, CBF was not statistically different during hypergravity but an elevation of CBF was still observed in weightlessness. The increases in CBF and BPa also persisted during weightlessness after pentobarbital administration. These data would indicate that CBF of nonanesthetized rabbits increases during the first seconds of weightlessness and demonstrate the involvement of rapid active regulatory mechanisms since CBF returned to control values within 8 (SD 2) s. We concluded that this elevation in blood flow was not related to stress because it persisted after the administration of propranolol and pentobarbital. 相似文献
146.
The amygdala has long been thought to be involved in emotional behaviour, and its role in anxiety and conditioned fear has been highlighted. Individual amygdaloid nuclei have been shown to project to various cortical and subcortical regions implicated in affective processing. Here we show that some of these nuclei have separate roles in distinct mechanisms underlying conditioned fear responses. Rats with lesions of the central nucleus exhibited reduction in the suppression of behaviour elicited by a conditioned fear stimulus, but were simultaneously able to direct their actions to avoid further presentations of this aversive stimulus. In contrast, animals with lesions of the basolateral amygdala were unable to avoid the conditioned aversive stimulus by their choice behaviour, but exhibited normal conditioned suppression to this stimulus. This double dissociation demonstrates that distinct neural systems involving separate amygdaloid nuclei mediate different types of conditioned fear behaviour. We suggest that theories of amygdala function should take into account the roles of discrete amygdala subsystems in controlling different components of integrated emotional responses. 相似文献
147.
JA Yaccino YS Chang TM Hollis TW Gardner JM Tarbell 《Canadian Metallurgical Quarterly》1997,16(8):761-768
PURPOSE: To characterize baseline transport properties: hydraulic conductivity (Lp), albumin permeability (Pe), and transendothelial electrical resistance (TER) of bovine retinal microvascular endothelial cells (RMEC) in the development of an in vitro model of the blood-retinal barrier (BRB). METHODS: RMEC were grown on porous, polycarbonate filters for determination of the number of days required to achieve minimal transport rates. Lp, Pe, and TER were measured by utilizing a bubble tracking spectrophotometer, by quantifying the diffusional movement of fluorescein isothiocyanate-labeled albumin, and by utilizing a Millipore electrical resistance meter, respectively. RESULTS: Lp decreased significantly from 7.82 +/- 0.85 x 10(-7) (mean +/- SEM) cm/sec/cm H2O at post-plating Day 5 to 1.44 +/- 0.26 x 10(-7) cm/sec/cm H2O at Day 9. Pe of the monolayer also decreased progressively with days post-plating from 3.44 +/- 0.53 x 10(-6) cm/sec at Day 7 to a minimum of 1.95 +/- 0.29 x 10(-6) cm/sec at Day II. Peak TER fluctuated until Day 7, when it began to steadily increase from 17.14 ohm-cm2 to a peak value of 25.42 ohm-cm2 at Day 10, decreasing from then on to 22.24 ohm.cm2 on Day 12. Known disrupters of the BRB, NECA and VEGF, elicited significant increase in RMEC Lp showing the sensitivity of this model to pharmacological alterations. CONCLUSIONS: Our data indicate that RMEC grown on polycarbonate filters form a restrictive monolayer of cells, which exhibit dynamic alterations in response to pharmacological agents, thus demonstrating an in vitro model of the BRB. Future studies with the model may offer insights into the pathogenesis of retinal vascular diseases and allow convenient testing of pharmacological interventions. 相似文献
148.
In 95 women taking reduced-level-oral contraceptives and in 24 same-aged women controls, the measure of erythrocyte and serum folate led to the following conclusions: 1) Folate levels in women consuming the pill were generally found to be of the same range as those of controls. 2) No significant difference could be shown between results for different kinds of contraceptives. 相似文献
149.
CB Bratton D Casper A Ciocio R Claus M Crouch ST Dye S Errede W Gajewski M Goldhaber TJ Haines TW Jones D Kielczewska WR Kropp JG Learned JM LoSecco J Matthews R Miller M Mudan LR Price F Reines J Schultz S Seidel D Sinclair HW Sobel JL Stone L Sulak R Svoboda G Thornton van der Velde JC 《Canadian Metallurgical Quarterly》1988,37(12):3361-3363
150.
TW Smith S Nikulasson U De Girolami LJ De Gennaro 《Canadian Metallurgical Quarterly》1993,12(6):335-342
Synapsin I is a phosphoprotein localized to the cytoplasmic surface of synaptic vesicles and is one of the best characterized neuron-specific proteins. Synaptophysin is an integral membrane glycoprotein, also located on presynaptic vesicles, which has been shown to be a useful immunohistochemical marker for neuroendocrine/neuronal differentiation in tumor diagnosis. The sensitivity and specificity of immunohistochemical staining for these two proteins in formalin-fixed, paraffin-embedded tissues was studied in a series of 67 neuroectodermal, neuroendocrine, and non-neural tumors. Intense immunoreactivity for both synapsin I and synaptophysin was observed in tumors containing well-differentiated neurons (gangliocytoma, ganglioglioma, neurocytoma). In these tumors, immunostaining was primarily concentrated along the outer surface of the cell membrane of the neuronal cells. Primitive neuroectodermal tumors (PNETs) (cerebral PNET, medulloblastoma, neuroblastoma) and most neuroendocrine tumors generally showed less intense and more variable immunoreactivity for these proteins. In most cases, immunostaining for synapsin I was sharper and often more intense than for synaptophysin. Some PNETs and neuroendocrine tumors that were immunoreactive for synapsin I did not stain for synaptophysin. We conclude that synapsin I is a reliable, sensitive immunohistochemical marker for neuronal/neuroendocrine differentiation in human neoplasms and may offer some advantages over synaptophysin when applied to formalin-fixed, paraffin-embedded tissues, particularly in the evaluation of primitive neuroectodermal tumors and neuroendocrine tumors. 相似文献