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71.
72.
Sterling J Herzig Y Goren T Finkelstein N Lerner D Goldenberg W Miskolczi I Molnar S Rantal F Tamas T Toth G Zagyva A Zekany A Finberg J Lavian G Gross A Friedman R Razin M Huang W Krais B Chorev M Youdim MB Weinstock M 《Journal of medicinal chemistry》2002,45(24):5260-5279
Carbamate derivatives of N-propargylaminoindans (Series I) and N-propargylphenethylamines (Series II) were synthesized via multistep procedures from the corresponding hydroxy precursors. The respective rasagiline- and selegiline-related series were designed to combine inhibitory activities of both acetylcholine esterase (AChE) and monoamine oxidase (MAO) by virtue of their carbamoyl and propargylamine pharmacophores. Each compound was tested for these activities in vitro in order to find molecules with similar potencies against each enzyme. Compounds with such dual AChE and MAO inhibitory activities are expected to have potential for the treatment of Alzheimer's disease. The observed SAR also offers insight into the requirements of the active sites on these enzymes. A carbamate moiety was found to be essential for AChE inhibition, which was absent in the corresponding hydroxy precursors. The propargyl group caused 2-70-fold decrease in AChE inhibitory activity (depending on the position of the carbamoyl group) of Series I, but had little or no effect in Series II. Thus, the 6- and 7-carbamyloxyphenyls in Series I were either equipotent to, or slightly (2- to 5-fold) less active as AChE inhibitors than, the corresponding compounds in Series II, while the 4-carbamyloxyphenyls were more potent. The presence of the carbamate moiety in 6- and 7-carbamyloxyphenyls of Series I, considerably decreased MAO-A and -B inhibitory activity, compared to that of the parent hydroxy analogues, while the opposite was true for Series II. Thus, the 6- and 7-carbamyloxyphenyls in Series I were 2-3 orders of magnitude weaker MAO inhibitors while the 4- carbamyloxyphenyls were equipotent with the corresponding compounds in Series II. In both series, N-methylation of the propargylamine enhanced the MAO (A and B equally) inhibitory activities and decreased the AChE inhibitory activity. Two candidates belonging to the indan and tetralin ring systems (24c, 27b) and one phenethylamine (53d) were identified as possible leads for further development based on the following criteria: (a) comparable AChE and MAO-B inhibitory activities, (b) good to moderate AChE inhibitory activity, and (c) lack of strong MAO-A selectivity. However, it is likely that these compounds will be metabolized to the corresponding phenols, with inhibitory activities against AChE and/or MAO-A or -B, different from those of the parent carbamates. Thus, the apparent enzyme inhibition will be a result of the combined inhibition of all of these individual metabolites. The results of our ongoing in vivo screening programs will be published elsewhere. 相似文献
73.
Efficacy and safety of transdermal oxybutynin in patients with urge and mixed urinary incontinence 总被引:3,自引:0,他引:3
Dmochowski RR Davila GW Zinner NR Gittelman MC Saltzstein DR Lyttle S Sanders SW;Transdermal Oxybutynin Study Group 《The Journal of urology》2002,168(2):580-586
PURPOSE: We evaluated the efficacy and safety of an oxybutynin transdermal delivery system (TDS) in a general population of patients with overactive bladder and urge or mixed urinary incontinence. MATERIALS AND METHODS: Following symptom stabilization or treatment withdrawal 520 adult patients were randomized to 12 weeks of double-blind daily treatment with 1.3, 2.6 or 3.9 mg. oxybutynin TDS or placebo administered twice weekly, followed by a 12-week open-label, dose titration period to assess efficacy and safety further. Evaluations included patient urinary diaries, incontinence specific quality of life and safety. RESULTS: A dose of 3.9 mg. daily oxybutynin TDS significantly reduced the number of weekly incontinence episodes (median change -19.0 versus -14.5, p = 0.0165), reduced average daily urinary frequency (mean change -2.3 versus -1.7, p = 0.0457), increased average voided volume (median change 24 versus 6 ml., p = 0.0063) and significantly improved quality of life (Incontinence Impact Questionnaire total score, p = 0.0327) compared with placebo. Average voided volume increased in the daily 2.6 mg. group (19 ml., p = 0.0157) but there were no other significant differences between 1.3 and 2.6 mg. oxybutynin TDS and placebo. The most common adverse event was application site pruritus (oxybutynin TDS 10.8% to 16.8%, placebo 6.1%). Dry mouth incidence was similar in both groups (7.0% versus 8.3%, p not significant). In the open-label period a sustained reduction of nearly 3 incontinence episodes per day was reported for all groups. CONCLUSIONS: Doses of 2.6 and 3.9 mg. oxybutynin TDS daily improve overactive bladder symptoms and quality of life, and are well tolerated. Transdermal oxybutynin is an innovative new treatment for overactive bladder. 相似文献
74.
75.
Quaresima V Ferrari M van der Sluijs MC Menssen J Colier WN 《Brain research bulletin》2002,59(3):235-243
The organisation of language in the brain of multilingual people remains controversial. Using a high temporal resolution 12-channel near-infrared continuous wave spectroscopy system, we have demonstrated that it is possible to monitor non-invasively, comfortably and, without the interferences due to intrinsic limitations of positron emission tomography (PET) and functional magnetic resonance imaging (fMRI), cortical oxygenation changes in the Broca's area in response to translation of short sentences and language switching. Eight Dutch students proficient in English translated aloud from their native language into English or vice versa or alternating (switching) short visually presented sentences. These tasks provoked, in the left inferior frontal cortex which includes the Broca's area, a consistent and incremental rise in oxyhaemoglobin accompanied by a smaller decrease in deoxyhaemoglobin. The investigated cortical areas surrounding the Broca's area showed no uniform and consistent oxygenation changes upon the three different translation tasks. These results confirm that Broca's area is involved in the translation process and its so called activation is unaffected by the direction of the translation. In addition, these results strengthen the role of near-infrared multi-point measurements as a powerful tool for investigating the spatial and temporal features of the cortical oxygenation changes during language processing. 相似文献
76.
van der Meide PH Villinger F Ansari AA Groenestein RJ de Labie MC van den Hout YJ Koornstra WH Bogers WM Heeney JL 《Vaccine》2002,20(17-18):2296-2302
The adjuvant effect of recombinant Rhesus macaque interleukin-12 (RhIL-12) on the induction of cellular and humoral immune responses elicited by the HIV-1 subunit vaccine protein gp120 in Rhesus macaques was examined. RhIL-12 in conjunction with gp120 was given at day 0, 28 and 84 intramuscularly. Coadministration resulted in an approximate 10-fold increase in plasma anti-gp120 antibody levels as compared to levels generated in control monkeys receiving gp120 alone. Potentiation of the humoral arm of the immune response was evident by both ELISA and an antiviral bioassay. In addition, RhIL-12 was found to produce a significant increase in gp120-specific proliferative responses and in the frequency of antigen-specific IFN-gamma and IL-2 producing T cells after restimulation of PBMC with gp120 in vitro indicating that RhIL-12 potentiates cell-mediated immune responses as well. A critical finding was that during the course of the study, RhIL-12 did not induce a neutralizing antibody response to the administered cytokine. The doses of RhIL-12 were well tolerated and no detectable adverse side-effects on hematopoietic and hepatic parameters were noted. The data revealed that IL-12, when coadministered intramuscularly, acts as a potent adjuvant which is able to enhance not only cellular but also humoral immune responses to gp120 in non-human primates and may have to be considered in future HIV vaccine strategies. 相似文献
77.
Landuyt W Sunaert S Farina D Meijerink M Béatse E Van Hecke P Hermans R Marchal G Lambin P Bosmans H 《Journal of magnetic resonance imaging : JMRI》2002,16(2):224-227
PURPOSE: To reduce functional magnetic resonance imaging (fMRI) susceptibility distortion at the air/tissue interphase in animal experiments. MATERIALS AND METHODS: We investigated the applicability of a body-adaptable flexible mold consisting of a fast-setting alginate. This technique was implemented for subcutaneous growing tumors in rats and for the brains of monkeys. RESULTS: The T(2)*-weighted gradient-echo, echo-planar imaging (GE-EPI) data obtained with the body-adapted mold showed a reduction of susceptibility artifacts and improved image quality. With both rat tumor and monkey brain, an optimized match with the anatomical T(1) images was possible. CONCLUSION: The present mold methodology is a rapid, easy, and inexpensive way to reduce magnetic susceptibility during animal GE-EPI. 相似文献
78.
Naoki Ishiguro Kazuya Maeda Wataru Kishimoto Asami Saito Akiko Harada Thomas Ebner Willy Roth Takashi Igarashi Yuichi Sugiyama 《Drug metabolism and disposition》2006,34(7):1109-1115
Telmisartan, a nonpeptide angiotensin II receptor antagonist, is selectively distributed to liver. In the present study, we have characterized the contribution of organic anion transporting polypeptide (OATP) isoforms to the hepatic uptake of telmisartan by isolated rat hepatocytes, human cryopreserved hepatocytes, and human transporter-expressing cells. Because it is difficult to evaluate the transport activity of telmisartan because of its extensive adsorption to cells and culture materials, we performed the uptake study in the presence of human serum albumin. The saturable uptake of telmisartan into isolated rat hepatocytes took place in a Na(+)-independent manner and was inhibited by pravastatin, taurocholate, and digoxin, which are Oatp substrates and inhibitors, but not by organic cation, tetraethylammonium, indicating the involvement of Oatp isoforms in its uptake into rat hepatocytes. To identify which human OATP transporters are important for the hepatic uptake of telmisartan, the uptake assay was carried out using OATP1B1- and OATP1B3-expressing human embryonic kidney 293 cells and cryopreserved human hepatocytes. The uptake of telmisartan by OATP1B3-expressing cells was saturable (K(m) = 0.81 microM) and significantly higher than that by vector-transfected cells. In contrast, no significant uptake was observed in OATP1B1-expressing cells. We also observed the saturable uptake of telmisartan by human hepatocytes. Thirty micromolar estrone-3-sulfate, which can selectively inhibit OATP1B1-mediated uptake compared with OATP1B3, did not inhibit the uptake of telmisartan in human hepatocytes, whereas it could inhibit the uptake of estradiol 17beta-d-glucuronide mediated by OATP1B1. These results suggest that OATP1B3 is predominantly involved in the hepatic uptake of telmisartan in humans. 相似文献
79.
Submandibular diagnostic and interventional sialendoscopy: new procedure for ductal disorders. 总被引:13,自引:0,他引:13
Francis Marchal Pavel Dulguerov Minerva Becker Gerard Barki Fran?ois Disant Willy Lehmann 《The Annals of otology, rhinology, and laryngology》2002,111(1):27-35
We present our initial experience with submandibular sialendoscopy, a new therapeutic approach for disorders of Wharton's duct. We review the sialendoscopes used and discuss their respective merits. We evaluated and treated 129 consecutive patients with suspected ductal disorders. Diagnostic sialendoscopy was used for classifying ductal lesions as sialolithiasis, stenosis, sialodochitis, or polyps. Interventional sialendoscopy was used to treat these disorders. The type of endoscope used, the type of sialolith fragmentation and/or extraction device used, the total number of procedures, the type of anesthesia, and the number and size of the sialoliths removed were the dependent variables. The outcome variable was the endoscopic clearing of the ductal tree and resolution of symptoms. Diagnostic sialendoscopy was possible in 131 of 135 glands (97%), with an average (+/-SD) duration of 28 +/- 15 minutes. Interventional sialendoscopy was attempted in 110 cases, with an average duration of 71 +/- 41 minutes, with a success rate of 82%. Multiple sialendoscopies were necessary in 25% of cases. General anesthesia was used in 12% of cases. Submandibular gland resection was performed in 4%. The average size of the stones was 4.9 +/- 2.9 mm. Multiple sialoliths were found in 31 cases (29%). Sialolith fragmentation was required in 26%. Larger and multiple stones often required longer and multiple procedures and general anesthesia, and more often resulted in failures. Semirigid endoscopes had a higher success rate (85%) than flexible sialendoscopes (54%). Complications were mostly minor, but were encountered in 10% of cases. Diagnostic sialendoscopy is a new technique for evaluating salivary duct disorders that is associated with low morbidity. Interventional sialendoscopy allows the extraction of sialoliths in most patients, thus preventing open gland excision. 相似文献
80.
BACKGROUND: Polymorphonuclear leukocytes contain a large number of enzymes and bactericidal proteins stored in granules. Neutrophil activation induces degranulation and immediate release of these bioactive substances, including human neutrophil elastase (HNE) also known as elastase-2 (ELA2), which may contaminate whole blood units and blood components. MATERIALS AND METHODS: The HNE concentration was determined in the supernatants of blood components with a commercial enzyme-linked immunosorbent assay (ELISA). The effect of leukocyte depletion and storage was evaluated by testing whole blood, buffy-coat-reduced, and leukocyte-depleted red cell units. Buffy-coat-derived platelets and plasma were also tested. RESULTS: HNE concentrations at day 1 were about 50 microg/l in all types of red cell components with the exception of leukocyte-depleted red cells (<0.26 microg/l). In leukocyte-depleted red cells, platelets and plasma, no significant increase was observed during storage. In whole-blood units and buffy-coat-reduced red cells, the HNE concentrations increased steadily and often exceeded 1,000 microg/l when the units expired. CONCLUSION: Leukocyte depletion may limit the inadvertent infusion of bioactive substances derived from polymorphonuclear leukocytes, of which HNE is but one example. The accumulation of HNE in buffy-coat-reduced red cells may be greater than that of whole blood units. HNE accumulates during storage and its quantity may have pathophysiologic significance. Platelets and plasma derived from buffy coats contain some HNE, but leukocyte-depleted red cells virtually none. However, we consider the accumulation of HNE in these components not to be clinically important. The quantities, kinetics, and occurrence in various blood components of HNE contamination differ from those observed with cytokines. 相似文献