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991.
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
992.
Familial hypercholesterolaemia is a frequent, inherited, monogenic disorder, associated with accelerated development of atherosclerotic disease leading to coronary artery disease. Life expectancy of patients with familial hypercholesterolaemia is reduced by 15-30 years unless they are adequately treated with lipid-lowering therapy. Given the chronic nature of this disease, the selection of a therapeutic approach should be strongly based on its long-term safety and tolerability. The introduction of HMG-CoA reductase inhibitors has revolutionised the treatment of familial hypercholesterolaemia.Simvastatin 40-80 mg/day effectively reduces serum low density lipoprotein (LDL)-cholesterol levels. Furthermore, simvastatin reduces triglycerides and mildly raises high density lipoprotein-cholesterol levels. In addition to the hypolipidaemic effect, other potentially important effects, such as improvement of endothelial function and reduction of LDL oxidation and vascular inflammation, have been associated with HMG-CoA reductase inhibitor therapy. Simvastatin has also been shown to abolish the progression, and even facilitate the regression, of existing human atherosclerotic lesions.The good safety and tolerability profile of simvastatin is clearly highlighted by the low rate of therapy discontinuation observed in several population-based clinical trials. The most common adverse events leading to the discontinuation of therapy are gastrointestinal upset and headache. Asymptomatic elevations in liver transaminase levels and myopathy are uncommon.The overwhelming clinical evidence regarding the long-term use of HMG-CoA reductase inhibitor therapy in patients with familial hypercholesterolaemia together with the long-term safety data (particularly relating to simvastatin) provide support for the use of this drug as a first-line agent when pharmacological treatment is indicated. Early intervention with simvastatin treatment can be successfully implemented with favourable economic benefits. 相似文献
993.
M D Rodríguez R Gámez J E González H García C P Acosta E Goicochea 《Food and chemical toxicology》2003,41(1):89-93
D-003 is a mixture of long-chain fatty acids isolated and purified from sugar cane wax, the major component of which is 1-octacosanoic acid and which possesses effective antiplatelet, antithrombotic and cholesterol-lowering effects. D-003 was suspended in 1% acacia gum solution, and given daily by gavage to rats at dose levels of 5, 100 and 1000 mg/kg/day on days 6 through 15 of gestation. Cyclophosphamide, serving as a positive control, was given at the dose of 50 mg/kg/day on day 15 of gestation. Evidence of maternal or developmental toxicity was not observed in the groups treated with D-003. Maternal clinical signs of toxicity were not observed and the analysis of initial body weight and the body weight gain during the treatment period was comparable among the groups treated with D-003 and control. As expected, cyclophosphamide caused both embryotoxic and teratogenic effects in rats. Meanwhile, no adverse effects on reproductive performance, or on embryonic or fetal development, including visceral and skeletal examination, were seen in any of the groups administered D-003. It is concluded that D-003 administered up to 1000 mg/kg/day did not induce any evidence of developmental toxicity. 相似文献
994.
Van Buskirk Glenn A. González Mario A. Shah Vinod P. Barnhardt Scott Barrett Colin Berge Stephen Cleary Gary Chan Keith Flynn Gordon Foster Thomas Gale Robert Garrison Raymond Gochnour Scott Gotto Amanda Govil Sharad Gray Vivian A. Hammar James Harder Samuel Hoiberg Charles Hussain Ajaz Karp Carol Llanos Hector Mantelle Juan Noonan Patrick Swanson David Zerbe Horst 《Pharmaceutical research》1997,14(7):848-852
Pharmaceutical Research - 相似文献
995.
A rare case of primary malignant intramedullary lymphoma, localized in the cervical part of the spinal cord, is presented. The onset of clinical symptoms was associated with herpes zoster infection. Surgery led to the histological diagnosis. The clinical investigations excluded the presence of lymphoma in other sites in the central nervous system and in the extraneural organs. Postoperative irradiation and chemotherapy effected relict of neurological symptoms. 相似文献
996.
M. Radmilovich A. Fernández O. Trujillo-Cenóz 《Experimental brain research. Experimentelle Hirnforschung. Expérimentation cérébrale》1997,113(3):455-464
NADPH-diaphorase positive (NDP) neurons and nerve fibers were found in the spinal dorsal horn (DH) and sensory ganglia of
the turtle Chrysemys d’orbigny. Three well-defined types of NDP neurons were found in the DH: (a) elongated nerve cells with two radially arranged dendritic
branches, (b) neurons with rostro-caudal dendritic branches, (c) bitufted neurons with two, practically symmetric branches
that project to the ipsilateral and contralateral dorsal horns. A combination of the techniques that reveal NADPH-diaphorase
activity with the horseradish peroxidase transganglionic labeling of the dorsal root collaterals, suggested that NDP neurons
of the DH are second-order cells of the spinal sensory pathway. NDP neurons were also found in the spinal sensory ganglia
at all metameric levels. Our findings indicate that the DH of turtles, like that of mammals, contains both the enzymatic machinery
and the neural connections required to postulate the participation of nitric oxide in ”plastic phenomena” such as hyperalgesia
and central sensitization. Two other alternatives or complementary hypotheses are discussed: (a) NDP neurons in the DH and
sensory ganglia may represent specific cell populations involved in the processing of sensory visceral information; (b) NADPH-diaphorase
reactivity may indicate sustained levels of neuronal activity.
Received: 12 February 1996 / Accepted: 2 August 1996 相似文献
997.
998.
Spermatogenic function was studied in 10 patients, previously diagnosed as having primary hypothyroidism, in whom a state of hypothyroidism has been induced by discontinuation or a decrease in treatment with levothyroxine over at least one spermatogenic cycle. Most of the patients had fathered children before the study. When the results obtained in the hypothyroid state were compared with those from a group of 16 controls with proven fertility, slight anomalies were observed; these were characterized by a decrease in seminal volume (p less than 0.05), progressive forward motility (p less than 0.01), and the cumulative percentage of mobile forms (p less than 0.01). There were no anomalies in sperm density or in the percentage of spermatozoa with normal morphology. No alterations in circulating levels of testosterone and gonadotropins existed. Induction of hypothyroidism did not lead to seminal or hormonal modifications compared with the same patients in a situation of euthyroidism. Short-term postpuberal hypothyroidism did not cause seminal alterations sufficiently intense to induce male infertility. 相似文献
999.
V. Prát M. Horčičková K. Matoušovic M. Hatala 《International urology and nephrology》1990,22(3):201-207
Fifty-four patients with complicated UTI were administered ciprofloxacin in doses of 500 mg (30 subjects) and 250 mg (24 subjects)
at 12-hour intervals. While a positive effect was noted in 96–100% upon termination of therapy, the effect was still present
3 weeks later in 90% of the high-dose, but only in 71% of the low-dose group. In 23 patients with uncomplicated UTI, a positive
effect of the three-day therapy with 100 mg of ciprofloxacin at 12-hour intervals was observed in 91% of subjects.
Intolerance to the agent was found in one case only. Development of resistance to ciprofloxacin was not observed. 相似文献
1000.
A wireless device for the assessment of tardive dyskinesia by means of digital image processing is presented. Four skin-cream dots placed around the subjects' mouth are recorded by a video camera. The image is passed to a framegrabber with a signal processor, where it is converted from analogue to digital. A fast spot-detecting algorithm implemented on the signal processor tracks the dots and passes the information to a personal computer, where a Fourier transformation is performed to calculate the frequency spectrum of the movements. The device provided detailed information on the magnitude and on the frequencies of the movements. Data from a longitudinal investigation suggest a higher sensitivity and reliability than conventional rating scales to detect and evaluate abnormal perioral movements. The device might be useful for the early detection, for the longitudinal assessment (p.e. clinical trials) and in some cases for the differential diagnosis of tardive dyskinesia, thus providing a tool for both research and clinical purposes. 相似文献