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1.
M. S. Beer J. A. Stanton Y. Bevan A. Heald A. J. Reeve L. J. Street V. G. Matassa R. J. Hargreaves D. N. Middlemiss 《British journal of pharmacology》1993,110(3):1196-1200
1. The 5-hydroxytryptamine (5-HT) receptor binding selectivity profile of a novel, potent 5-HT1D receptor agonist, L-694,247 (2-[5-[3-(4-methylsulphonylamino)benzyl-1,2,4-oxadiazol-5-yl ]- 1H-indole-3-yl]ethylamine) was assessed and compared with that of the 5-HT1-like receptor agonist, sumatriptan. 2. L-694,247 had an affinity (pIC50) of 10.03 at the 5-HT1D binding site and 9.08 at the 5-HT1B binding site (sumatriptan: pIC50 values 8.22 and 5.94 respectively). L-694,247 retained good selectivity with respect to the 5-HT1A binding site (pIC50 = 8.64), the 5-HT1C binding site (6.42), the 5-HT2 binding site (6.50) and the 5-HT1E binding site (5.66). The pIC50 values for sumatriptan at these radioligand binding sites were 6.14, 5.0, < 5.0 and 5.64 respectively. Both L-694,247 and sumatriptan were essentially inactive at the 5-HT3 recognition site. 3. L-694,247, like sumatriptan, displayed a similar efficacy to 5-HT in inhibiting forskolin-stimulated adenylyl cyclase in guinea-pig substantia nigra although L-694,247 (pEC50 = 9.1) was more potent than sumatriptan (6.2) in this 5-HT1D receptor mediated functional response. L-694,247 (pEC50 = 9.4) was also more potent than sumatriptan (6.5) in a second 5-HT1D receptor mediated functional response, the inhibition of K(+)-evoked [3H]-5-HT release from guinea-pig frontal cortex slices.(ABSTRACT TRUNCATED AT 250 WORDS) 相似文献
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Trophic effects of unsulfated cholecystokinin on mouse pancreas and human pancreatic cancer. 总被引:2,自引:0,他引:2
The effect of unsulfated cholecystokinin on pancreatic growth was evaluated in two experimental models in vivo and in vitro. Mice were injected with sulfated cholecystokinin (CCKs) or unsulfated cholecystokinin (CCKu) (10 or 20 micrograms/kg) or vehicle twice daily for 15 days. Animals were then killed and pancreatic weights, protein, amylase, and DNA content were evaluated. In vitro, growth was evaluated by DNA synthesis and viable cell counts. MIA PaCa-2 and BxPC-3 human pancreatic cancer cells were treated with CCKs or CCKu (10(-12) to 10(-9) M) for 48 or 72 h in the presence of [3H]thymidine to evaluate DNA synthesis. Viable cell counts were performed on both cell lines grown in the presence or absence of unsulfated CCK (10(-12) to 10(-9) M) for 96 h. Pancreatic weight, protein, amylase, and DNA were significantly increased in animals treated with either CCKs or CCKu. However, pancreatic weight, protein, and amylase were significantly higher in mice treated with CCKs compared to CCKu (p less than 0.005). DNA content and index of hyperplasia were the same whether mice were treated with CCKs or CCKu. CCKu was as potent a stimulus for DNA synthesis as CCKs in MIA PaCa-2 and BxPC-3 cells. Finally, CCKu increased cell counts in both pancreatic cancer cell lines. These data suggest that the mechanisms responsible for CCK-induced growth of normal pancreas and pancreatic cancer may differ from those that regulate secretion. 相似文献
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In this open-label, randomized, cross-over study, 12 healthy subjects received four doses of a new sustained-release formulation of diltiazem hydrochloride for six consecutive days. Blood samples were drawn on days 5 and 6 for determination of plasma diltiazem and desacetyldiltiazem levels. The peak concentrations after 120, 240, 360, and 480 mg of diltiazem were 48.1, 112.6, 180.9, and 276.8 ng/ml, respectively, while the mean minimum concentrations were 6.3, 14.6, 24.9, and 44.6 ng/ml. The areas under the concentration-time curves were 702, 1,642, 2,622, and 4,004 ng.hr/ml. Prolonged, continuous absorption of diltiazem was noted over the 24-hour dosing period. The dose-adjusted mean steady-state plasma diltiazem levels after the four doses were significantly different, consistent with diltiazem's nonlinear absorption, but the plasma profiles were similar, indicating that the diltiazem release rate was not dose-dependent. Therapeutic plasma diltiazem levels (greater than or equal to 40 ng/ml) were maintained for 24 hours after the three larger doses. The changes in the pharmacokinetics of desacetyldiltiazem over the four diltiazem doses were similar to those of diltiazem. The number of adverse treatment experiences tended to increase with the higher doses, but none were severe. The results indicate that, according to their pharmacokinetic profiles, doses of 240 mg to 480 mg of diltiazem are suitable for once-daily administration. 相似文献
5.
R G Morris J J Downes B J Sahakian J L Evenden A Heald T W Robbins 《Journal of neurology, neurosurgery, and psychiatry》1988,51(6):757-766
The higher level cognitive function of planning was studied in a group of medicated Parkinson's disease patients and a group of matched control subjects, using a computerised version of Shallice's Tower of London task. Baseline measurement of the ability to execute a given plan of action, to generate low level strategies required for efficient searching, and spatial working memory capacity, all of which contribute to performance on the planning task, established that the Parkinson's disease group was unimpaired on any of these measures. On the Tower of London task, the Parkinson's disease group was also unimpaired in terms of the average number of moves required to solve a problem. However, a specific planning deficit was evident when "thinking" times were analysed, and this was after the confounding influence of motor initiation and execution times had been carefully extracted from total performance times. This finding is discussed in relation to putative functions of the frontal lobes and basal ganglia, and an attention-switching hypothesis is developed to account for it. 相似文献
6.
Comparative evaluation of the API 20S system and the automicrobic system gram-positive identification card for species identification of streptococci. 总被引:3,自引:9,他引:3
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P C Appelbaum M R Jacobs J I Heald W M Palko A Duffett R Crist P A Naugle 《Journal of clinical microbiology》1984,19(2):164-168
Two commercial methods, the API 20S system (API; Analytab Products, Inc., Plainview, N.Y.) and the Gram-Positive Identification Card (GPI; Vitek Systems, Inc., Hazelwood, Mo.), were evaluated without additional tests for the identification of 241 streptococcus strains. Organisms included 60 beta-hemolytic strains, 36 group D strains, 26 Streptococcus pneumoniae strains, and 119 viridans streptococcus strains. API correctly identified to species 68.3% of beta-hemolytic strains, 86.1% of group D strains, 53.9% of S. pneumoniae strains, and 12.6% of viridans streptococci. This method provided excellent identification of group A and B and S. faecalis strains. Overall, API correctly identified 41.9% of strains to species, with 41.1% good likelihood but low selectivity, 15.8% incorrect, and 1.2% not identified. GPI correctly identified to species 58.3% of beta-hemolytic strains, 97.2% of group D strains, 80.8% of S. pneumoniae strains, and 57.2% of viridans streptococci. Group A, B, and D strains were all accurately identified by this system. Overall, GPI correctly identified to species 66.0% of strains, with 8.7% correct preliminary identification, 20.8% incorrect, and 4.6% not identified. Both methods represent a worthwhile advance in streptococcal identification. Neither system, however, can be recommended for species identification of the viridans group at this time. 相似文献
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Alison E. Heald Patrick L. Iversen Jay B. Saoud Peter Sazani Jay S. Charleston Tim Axtelle Michael Wong William B. Smith Apinya Vutikullird Edward Kaye 《Antimicrobial agents and chemotherapy》2014,58(11):6639-6647
Two identical single-ascending-dose studies evaluated the safety and pharmacokinetics (PK) of AVI-6002 and AVI-6003, two experimental combinations of phosphorodiamidate morpholino oligomers with positive charges (PMOplus) that target viral mRNA encoding Ebola virus and Marburg virus proteins, respectively. Both AVI-6002 and AVI-6003 were found to suppress disease in virus-infected nonhuman primates in previous studies. AVI-6002 (a combination of AVI-7537 and AVI-7539) or AVI-6003 (a combination of AVI-7287 and AVI-7288) were administered as sequential intravenous (i.v.) infusions of a 1:1 fixed dose ratio of the two subcomponents. In each study, 30 healthy male and female subjects between 18 and 50 years of age were enrolled in six-dose escalation cohorts of five subjects each and received a single i.v. infusion of active study drug (0.005, 0.05, 0.5, 1.5, 3, and 4.5 mg/kg per component) or placebo in a 4:1 ratio. Both AVI-6002 and AVI-6003 were safe and well tolerated at the doses studied. A maximum tolerated dose was not observed in either study. The four chemically similar PMOplus components exhibited generally similar PK profiles. The mean peak plasma concentration and area under the concentration-time curve values of the four components exhibited dose-proportional PK. The estimated plasma half-life of all four components was 2 to 5 h. The safety of the two combinations and the PK of the four components were similar, regardless of the target RNA sequence. 相似文献