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141.
142.
William C Stanley Bin Li Douglas W Bonhaus Lowell G Johnson Keiho Lee Seth Porter Keith Walker Greg Martinez Richard M Eglen Roger L Whiting Sharath S Hegde 《British journal of pharmacology》1997,121(8):1803-1809
- Inhibitory modulation of sympathetic nerve function may have a favourable impact on the progression of congestive heart failure. Nepicastat is a novel inhibitor of dopamine-β-hydroxylase, the enzyme which catalyses the conversion of dopamine to noradrenaline in sympathetic nerves. The in vitro pharmacology and in vivo catecholamine modulatory effects of nepicastat were investigated in the present study.
- Nepicastat produced concentration-dependent inhibition of bovine (IC50=8.5±0.8 nM) and human (IC50=9.0±0.8 nM)dopamine-β-hydroxylase. The corresponding R-enantiomer (RS-25560-198) was approximately 2–3 fold less potent than nepicastat. Nepicastat had negligible affinity (>10 μM) for twelve other enzymes and thirteen neurotransmitter receptors.
- Administration of nepicastat to spontaneously hypertensive rats (SHRs) (three consecutive doses of either 3, 10, 30 or 100 mg kg−1, p.o.; 12 h apart) or beagle dogs (0.05, 0.5, 1.5 or 5 mg kg−1, p.o.; b.i.d., for 5 days) produced dose-dependent decreases in noradrenaline content, increases in dopamine content and increases in dopamine/noradrenaline ratio in the artery (mesenteric or renal), left ventricle and cerebral cortex. At the highest dose studied, the decreases in tissue noradrenaline were 47%, 35% and 42% (in SHRs) and 88%, 91% and 96% (in dogs) in the artery, left ventricle and cerebral cortex, respectively. When tested at 30 mg kg−1, p.o., in SHRs, nepicastat produced significantly greater changes in noradrenaline and dopamine content, as compared to the R-enantiomer (RS-25560-198), in the mesenteric artery and left ventricle.
- Administration of nepicastat (2 mg kg−1, b.i.d, p.o.) to beagle dogs for 15 days produced significant decreases in plasma concentrations of noradrenaline and increases in plasma concentrations of dopamine and dopamine/noradrenaline ratio. The peak reduction (52%) in plasma concentration of noradrenaline and the peak increase (646%) in plasma concentration of dopamine were observed on day-6 and day-7 of dosing, respectively.
- The findings of this study suggest that nepicastat is a potent, selective and orally active inhibitor of dopamine-β-hydroxylase which produces gradual modulation of the sympathetic nervous system by inhibiting the biosynthesis of noradrenaline. This drug may, therefore, be of value in the treatment of cardiovascular disorders associated with over-activation of the sympathetic nervous system, such as congestive heart failure.
143.
Increasing extraocular muscle length by regenerative growth has been proposed as a potentially useful means of treating patients with paralytic or multiple re-operation strabismus. This study evaluates the viability and pattern of regeneration of fresh, autologous extraocular muscle and temporalis muscle transplants in the canine orbit. Bilateral grafts of either inferior oblique or temporalis muscle were sewn between host lateral rectus muscles and the globe. Grafts were biopsied and examined by light and electron microscopy at survival times to 56 days. Functional responses to abducens nucleus stimulation were examined in one extraocular muscle and one temporalis muscle graft at 15 weeks post-operatively. During the first week, both graft types were characterized by loss of pre-terminal nerve from neuromuscular junctions, muscle fiber necrosis that spared the central fibers, and inflammatory cell infiltrate. Myoblasts migrated into and fused within the existing basal laminae of degenerating fibers. By 14 days, grafts were populated by immature myofibers. Neuromuscular junctions were seen by 56 days, coinciding with muscle fiber differentiation as seen by enzyme histochemistry. Only two grafts failed to show regeneration. At 15 weeks survival, both types of grafts contracted in response to abducens nucleus stimulation. Free skeletal muscle grafts to extraocular muscle survive and mature with clear evidence of contractility by 15 weeks. These data suggest that muscle graft procedures could be useful in the management of certain types of strabismus where greater muscle length is needed. 相似文献
144.
Chan SL Yew WW Porter JH McAdam KP Allen BW Dickinson JM Ellard GA Mitchison DA 《International journal of antimicrobial agents》1994,3(4):267-274
Bioavailability was measured by rifapentine (RPE) serum concentrations and by the urinary ratio between RPE and creatinine, in specimens obtained 4-50 h after 600 mg RPE preceded by food. The bioavailabilities of RPEs manufactured in China and by a Western manufacturer were similar after a standard English breakfast, and serum concentrations were also similar to those obtained in an earlier Italian study following a complex meal. Although absorption of RPE was unsatisfactory after lipid-rich biscuits or shortbread, absorption after egges and toast was excellent and was nearly as good after a fast-food sandwich. The urinary measure of bioavailability at 26 h appeared as efficient as peak serum estimations at 6, 8 and 26 h. Fast-food sandwiches are being taken before RPE in a current clinical trial of Chinese RPE in Hong Kong. 相似文献
145.
Major differences exist among states in the level of spending on mental health care, in the magnitude and direction of changes in those levels, and in the share of resources devoted to state hospital and community-based services. Using data collected by the National Association of State Mental Health Program Directors (NASMHPD) Research Institute, this article describes those differences and examines their relation to a set of state-level fiscal determinants of mental health spending. Levels of spending in 1990 and rates of change in those levels between 1985 and 1990 show virtually no correlation. Changes in spending between 1985 and 1990 are decomposed into several components. States with high growth tend to have high growth in tax capacity and high growth in mental health spending as a share of health and welfare spending. 相似文献
146.
147.
Gene targeting can be used for genetic studies of human cell lines and has significant potential for somatic cell gene therapy. These applications are however restricted by the low frequency of homologous recombination in higher eukaryotes compared to the relatively efficient nonhomologous integration of transfected DNA into the genome. As part of our attempts to overcome this problem, we compared two widely used transfection methods for their efficiency in gene targeting. To our surprise we found that, for conditions that render similar frequencies of nonhomologous integrants, lipofection is much less efficient than electroporation in generating targeted clones. This suggests that nonhomologous and homologous recombination have different requirements for DNA delivery in human cells. 相似文献
148.
Multiple gamma c-dependent cytokines regulate T-cell development 总被引:7,自引:0,他引:7
Mutations in the common gamma chain (gamma c) of cytokine receptors account for human X-linked severe combined immunodeficiency disease. gamma c contributes to ligand binding and signaling as a component of five cytokine receptors: interleukin-2-receptor (IL-2R), IL-4R, IL-7R, IL-9R and IL-15R. Here, Thomas Malek and colleagues discuss the contribution of individual gamma c-dependent cytokines in both conventional and intraepithelial T-cell development. 相似文献
149.
Certain lesions are exclusively or typically found in specific sites; these are discussed in this and the next two articles in this series. 相似文献
150.
Berman RS Yahanda AM Mansfield PF Hemmila MR Sweeney JF Porter GA Kumparatana M Leroux B Pollock RE Feig BW 《American journal of surgery》1999,178(6):530-536
BACKGROUND: Although laparoscopic splenectomy (LS) for benign hematologic disease is well accepted, its role in hematologic malignancies is not clearly defined. This study examined the efficacy and feasibility of LS for hematologic malignancies. METHODS: Records were reviewed from patients who underwent LS at two university hospitals. Charts from 77 open splenectomies for malignancy (OM) during the same period were also reviewed. RESULTS: Fifty-three patients underwent LS, 22 for hematologic malignancies (LM) and 31 for benign hematologic disorders (LB). Median splenic weight was greater in the LM group (930 g) than in the LB group (164 g, P = 0.001). LM was associated with longer operations and greater blood loss than was LB. LM had a 41% conversion rate. Morbidity, mortality, and transfusion rates were similar. Median hospital stay was shorter for LM (4 days) than for OM (6 days, P = 0.001). CONCLUSIONS: LS is feasible in hematologic malignancies but is associated with increased operative time and blood loss and a high conversion rate. Morbidity and mortality, however, was similar. Shorter hospital stays for LM compared with OM may translate into earlier recovery and initiation of antineoplastic therapy. 相似文献