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121.
P N Palma M J Bonifácio A I Loureiro L C Wright D A Learmonth P Soares-da-Silva 《Drug metabolism and disposition》2003,31(3):250-258
Catechol-O-methyltransferase (COMT, EC 2.1.1.6) plays a central role in the metabolic inactivation of neurotransmitters and neuroactive xenobiotics possessing a catechol motif. 1-(3,4-Dihydroxy-5-nitrophenyl)-2-phenyl-ethanone (BIA 3-202) is a novel nitrocatechol-type inhibitor of COMT, the potential clinical benefit of which is currently being evaluated in the treatment of Parkinson's disease. In the present work we characterize the molecular interactions of BIA 3-202 within the active site of COMT and discuss their implication on the regioselectivity of metabolic O-methylation. Unrestrained flexible-docking simulations suggest that the solution structure of this complex is better described as an ensemble of alternative binding modes, in contrast to the well defined bound configuration revealed by the X-ray structures of related nitrocatechol inhibitors, co-crystallized with COMT. The docking results wherein presented are well supported by experimental evidence, where the pattern of in vitro enzymatic O-methylation and O-demethylation reactions are analyzed. We propose a plausible explanation for the paradoxical in vivo regioselectivity of O-methylation of BIA 3-202, as well as of its related COMT inhibitor tolcapone. Both compounds undergo in vivo O-methylation by COMT at either meta or para catechol hydroxyl groups. However, results herein presented suggest that, in a subsequent step, the p-O-methyl derivatives are selectively demethylated by a microsomal enzyme system. The overall balance is the accumulation of the m-O-methylated metabolites over the para-regioisomers. The implications for the general recognition of nitrocatechol-type inhibitors by COMT and the regioselectivity of their metabolic O-methylation are discussed. 相似文献
122.
123.
The epidemiology of deaths from volatile substance abuse (VSA) in those under 18 years that occurred in the UK from 1981-90 is described. The analysis of deaths is based on a national register, which has information obtained from a regular survey of coroners, the Office of Population Censuses and Surveys, and a press clippings agency. Altogether 605 people under 18 died from VSA during this period. Seventy per cent of deaths occurred between the ages of 14 and 16. The largest number of deaths were attributed to butane gas lighter refills. There was a large north-south gradient in age specific mortality ratios (Scotland 180, south east England 87) and nearly four times as many deaths occurred in social class V compared with social class I. Deaths from VSA are an important and preventable cause of deaths in those under 18. Strategies aimed at prevention should include measures to reduce experimentation, intervention to reduce socioeconomic deprivation, and health education campaigns aimed at schools and parents. 相似文献
124.
Nefazodone: preclinical pharmacology of a new antidepressant 总被引:3,自引:0,他引:3
A S Eison M S Eison J R Torrente R N Wright F D Yocca 《Psychopharmacology bulletin》1990,26(3):311-315
Recent pharmacologic studies suggest that nefazodone may possess antidepressant activity. Nefazodone is active in behavioral models predictive of antidepressant potential. It is active in reversing learned helplessness, prevents reserpine-induced ptosis, and enhances response efficiency in the differential reinforcement for low rates of response paradigm. In in vitro studies, nefazodone inhibits the binding of [3H]ketanserin to cortical serotonin2 (5-HT2) binding sites, whereas in vivo, it antagonizes the 5-HT2-mediated quipazine-induced head shake in rats. In ex vivo studies, acute oral administration of nefazodone inhibits cortical serotonin uptake and occupies frontal cortical 5-HT2 receptor binding sites. Chronic administration of nefazodone produces a reduction in 5-HT2-mediated behavior and decreases cortical 5-HT2 receptor binding site density. Further, a chronic high-dose nefazodone regimen significantly potentiates 5-HT1A-mediated behavioral responses in rats. Nefazodone exhibits decreased anticholinergic, alpha-adrenolytic, and sedative activity relative to other antidepressants. 相似文献
125.
J T Wright 《Geriatrics》1988,43(8):55-62
The traditional, stepped-care approach to the treatment of hypertension has been challenged by the introduction of new and more expensive medications. Because hypertensive patients include those who can least afford high-priced medication, such prescribing patterns may result in noncompliance and, further, may cause patients to switch to physicians or managed-care systems more considerate of their economic needs. Physicians should therefore consider cost-effectiveness in treatment of hypertensive patients. 相似文献
126.
The trend towards community living for people with learning disabilities puts pressure on traditional hierarchical lines of resource management. A sample of 150 community residential facilities is surveyed in order to describe the systems used to manage resources in the community and to assess the impact they have on the quality of service provided. There are marked differences amongst provider agencies in the degree to which responsibility for resource management is devolved to facility managers and this has a direct effect on the quality of care. Residential homes which operate under centralised management systems are more institutional in their care practices and less responsive to individual clients' needs. In contrast, homes in which responsibility is delegated to the facility manager provide a service more in keeping with current philosophies of care. The results of this survey suggest that more responsibility for resource management can be delegated to facility managers without losing control of expenditure and with improvements in the efficiency and effectiveness of care. 相似文献
127.
S. G. George J. Wright J. Conroy 《Archives of environmental contamination and toxicology》1995,29(4):530-534
Activities of the petroleum-inducible mixed function oxygenase CYP1A (EROD) were measured in livers of inshore demersal fish species at various sites around the coast of Shetland to determine the sub-lethal impact of oil spilled after the wreck of the tanker M.V. Braer in January 1993. Visible coastal pollution by the oil was only apparent for some two weeks after the incident and tissue PAH levels in muscle of gadoid fish such as rockling from these areas were not elevated 3 months afterwards, while hepatic EROD activities were elevated some 7-to 9-fold. A 6.5-fold elevation was still observed 5 months afterwards; however, the levels had returned to those of fish from non-polluted environments 7 months after the incident and remained at baseline levels after the following winter's storm action. These data demonstrate the usefulness of enzymatic analysis as a sensitive method for assessing the temporal and spatial impact of an oil spill. 相似文献
128.
Marilyn Ross Kelly Brewer F Virginia Wright Anne Agur 《Pediatric physical therapy》2007,19(4):288-295
PURPOSE: The purpose of our study was to obtain a clear understanding of the various diagnoses within the closed neural tube defect (NTD) groups included in the large database of clients in our Spina Bifida Clinic and a clear picture of the outcomes for the various NTD groups. METHODS: One hundred and four clients with closed NTD were categorized using a classification system devised by Tortori-Donati et al. Various clinical markers were investigated, including ambulation and the need for orthoses and wheelchairs. RESULTS: Most clients are ambulatory, requiring an orthoses, but not a wheelchair, despite the high incidence of ankle/foot abnormalities. CONCLUSIONS: This classification system has enhanced our knowledge of this group of clients, provided a greater understanding of the varied outcomes of these children and clinical management required. 相似文献
129.
Psychophysical measures of hue (wavelength) discrimination and spectral sensitivity were collected over a 3-year-period on a rhesus monkey whose right eye had been exposed to intense blue light 10 years prior and had shown a pronounced loss of blue sensitivity in an increment-threshold, spectral-sensitivity task. Hue discrimination, to a somewhat greater degree than spectral sensitivity, revealed large differences between the normal and blue-exposed eye. The difference limens were in some cases 100 nm for the blue-exposed eye compared to 10-15 nm for the normal eye. The hue-discrimination functions from the blue-exposed eye were similar in form to those from human tritanopes (blue-blind humans), and those from the monkey's normal eye were similar to those from normal humans. Detailed functions, where the variable wavelength was shorter as opposed to longer than the reference wavelength, were shown separately for each of the monkey's eyes; those from the blue-exposed eye were very similar to analogous functions from the one case where they have been shown separately for a human tritanope. 相似文献
130.
Use of the Splenic and Hepatic Artery for Renal Revascularization in Patients with Atherosclerotic Renal Artery Disease 总被引:1,自引:0,他引:1
George Geroulakos J. Gordon Wright J. Chadwick Tober Louise Anderson William L. Smead 《Annals of vascular surgery》1997,11(1):85-89
p = 0.17) and the average number of antihypertensive medications decreased to 1.9 (p= 0.001). During the median follow-up of 33 months, 10 patients died, mainly from cardiac causes. Our experience indicates
that the splenic and hepatic arteries provide useful alternatives to renal revascularization in selected circumstances with
an acceptable rate of perioperative mortality and morbidity. The expected long-term survival in this group of patients is
low. 相似文献