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Anesthetic profile of dexmedetomidine identified by stimulus-response and continuous measurements in rats

JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 1999年第1期291卷 153-160页

作者： Bol, CJJG Vogelaar, JPW Mandema, JW Stanford Univ Sch Med Dept Anesthesia Stanford CA 94305 USA Stanford Univ Sch Med Dept Pharmacol Stanford CA 94305 USA Leiden Univ Leiden Amsterdam Ctr Drug Res Leiden Netherlands

This study characterizes the anesthetic profile of dexmedetomidine on the basis of steady-state plasma concentrations using defined stimulus-response, ventilatory, and continuous electroencephalographic (EEG) and cardiovascular effect measures in rats. At constant plasma concentrations of dexmedetomidine (range, 0.5-19 ng/ml), targeted and maintained by target-controlled infusion, the whisker reflex, righting reflex, startle reflex (to noise), tail clamp response, hot water tail-flick latency, and attenuation of heart rate (HR) increase associated with tail-flick (sympathoadrenal block) and corneal reflex, were assessed in 22 rats. EEG (power in 0.5- to 3.5-Hz frequency band), mean arterial pressure, and HR were recorded continuously. Blood gas values and arterial drug concentrations were determined regularly. The following steady-state plasma EC50 values of dexmedetomidine (mean +/- S.E. nanograms per milliter) were estimated: HR decrease (0.51 +/- 0.04), EEG (1.02 +/- 0.08), whisker reflex (1.09 +/- 0.10), sympathoadrenal block (1.85 +/- 0.80), mean arterial blood pressure increase (1.99 +/- 0.44), righting reflex (2.13 +/- 0.15), tail-flick latency (3.65 +/- 0.87), startle reflex (3.75 +/- 0.64), tail clamp (5.49 +/- 1.34), and corneal reflex (24.5 +/- 12.3). At the EC50 value of tail clamp, ventilatory depression was minor. In rats, dexmedetomidine creates bradycardia, sedation/hypnosis, sympathoadrenal blocking effects, and blood pressure-increasing effects at plasma concentrations below 2.5 ng/ml. Higher plasma concentrations are needed to loose the startle reflex, tail-flick, tail clamp, and corneal reflex responses. Ventilatory depressant effects are minor. The applied EEG measure seems to reflect sedation/hypnosis but seems to have limited value to predict the deeper levels of analgesia and anesthesia of dexmedetomidine.

关键词：镇痛药非麻醉/药代动力学镇痛药非麻醉/药理学心血管系统/药物作用脑电描记术/药物作用心率/药物作用咪唑类/药代动力学咪唑类/药理学美托咪啶疼痛测定大鼠 Wistar 动物男(雄)性大鼠

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Pharmacokinetics of medetomidine in ponies and elaboration of a medetomidine infusion regime which provides a constant level of sedation

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RESEARCH IN VETERINARY SCIENCE 1999年第1期67卷 41-46页

作者： Bettschart-Wolfensberger, R Clarke, KW Vainio, O Aliabadi, FS Demuth, D Univ Zurich Vet Surg Clin Zurich Switzerland Royal Vet Coll Hatfield Herts England Univ Turku Turku Finland

The pharmacokinetics of intravenous (i.v.) medetomidine (7 meg kg(-1)) were best described by a two-compartment model in five ponies. Total body clearance was 4 (SD 0.60) 1 kg h,(-1) t(1/2 alpha) 7.6 (0.91) minutes and t(1/2 alpha) 51.3 (13.09) minutes. In one pony the one-compartmental model was best fit, and total body clearance was 4.2 1 kg h(-1) and t(1/2) was 11 minutes. Medetomidine plasma levels had fallen below the limits of quantification (0.05 ng ml(-1)) within 4 hours. Medetomidine 5 meg kg(-1) i.v. followed by an infusion of 3.5 meg kg h(-1) for two hours provided a constant level of sedation reaching steady state plasma medetomidine levels of 1-1.5 ng ml(-1) within 30 minutes. Sedation was reversed effectively by atipamezole (60 meg kg(-1)) i.v. The pharmacokinetics of medetomidine make it suitable for prolonged use by infusion, such as is required as part of a total intravenous anaesthetic technique in horses.

关键词：马/血液马/代谢催眠药和镇静药/血液催眠药和镇静药/药代动力学咪唑类/血液咪唑类/药代动力学美托咪啶时间因素意识丧失/化学诱导动物

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Synthesis, structure, and neuroprotective properties of novel imidazolyl nitrones

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JOURNAL OF MEDICINAL CHEMISTRY 2000年第11期43卷 2165-2175页

作者： Dhainaut, A Tizot, A Raimbaud, E Lockhart, B Lestage, P Goldstein, S Inst Rech Servier Chem Res Div A F-92150 Suresnes France Inst Rech Servier Mol Modeling Dept F-92150 Suresnes France Inst Rech Servier Cerebral Pathol Div F-78290 Croissy Sur Seine France

A new series of imidazolyl nitrones spin traps has been synthesized and evaluated pharmacologically. The salient structural feature of these molecules is the presence of an imidazole moiety substituted by aromatic or heteroaromatic cycles. This connectivity imparts to the nitrone superior neuroprotective properties in vivo and in parallel reduced side effects and toxicity. Thus compound 6a (a 2-phenylimidazolyl nitrone) administered intraperitoneally protects (80%) mice from lethality induced by an intracerebroventricular administration of tert-butyl hydroperoxide (t-BHP) an oxidant capable of inducing neurodegenerative processes. Administration of the archetypal nitrone phenyl-tert-butyl nitrone (PBN) at an equimolar dose also affords some protection (60%) in this test. However, this activity is accompanied by hypothermia, whereas no such effect is apparent for 6a. Moreover, previously prepared nonsubstituted or alkyl-substituted imidazolyl nitrones were shown to be extremely toxic to rats in contrast to the compounds prepared in this study. The observed activities in vivo correlate well with the calculated partition coefficients (ClogP) and HOMO energy level.

关键词：血脑屏障/生理学体温/药物作用咪唑类/化学合成咪唑类/化学咪唑类/药代动力学咪唑类/药理学神经保护药/化学合成神经保护药/化学神经保护药/药代动力学神经保护药/药理学氧化氮类/化学合成氧化氮类/化学氧化氮类/药代动力学氧化氮类/药理学构效关系动物男(雄)性小鼠大鼠

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Metabolic activation of carcinogens and expression of various cytochromes P450 in human prostate tissue

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CARCINOGENESIS 2000年第9期21卷 1683-1689页

作者： Williams, JA Martin, FL Muir, GH Hewer, A Grover, PL Phillips, DH Inst Canc Res Haddow Labs Sutton SM2 5NG Surrey England Kings Coll Hosp London Dept Urol London SE5 9RS England

Epidemiological evidence suggests a link between meat consumption and prostate cancer. In this study, benign prostatic hyperplasia tissues, obtained by transurethral resection or radical retropubic prostatectomy from UK-resident individuals (n = 18), were examined for CYP1 expression and for their ability, in short-term organ culture, to metabolically activate carcinogens found in cooked meat. Semi-quantitative RT-PCR analysis of CYP1 expression detected CYP1A2 mRNA transcripts in the prostates of four individuals, as well as mRNA transcripts from CYP1A1 and CYP1B1, The compounds tested for metabolic activation were 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP;500 mu M, n = 9) and its metabolite N-hydroxy PhIP (20 mu M, n = 8), 2-amino-3-methylimidazo[4,5-f]quinoline (IQ;500 mu M, n = 6) and benzo[a]pyrene (B[a]P;50 mu M, n = 5), After incubation (PFMR medium, 22 h, 37 degrees C), DNA was isolated from tissue fragments and DNA adducts were detected and quantified by P-32-postlabelling analysis. DNA adduct formation was detected in all samples incubated with PhIP (mean, adducts per 10(8) nucleotides), N-hydroxy-PhIP (2736/10(8)) or B[a]P (1/10(8)), IQ-DNA adducts were detected in 5/6 tissues (mean, 1/10(8)). The CYP1 inhibitor alpha-naphthoflavone (10 mu M) reduced B[a]P-DNA adduct formation in tissues from two individuals by 96 and 64%, respectively. This pilot study shows that human prostate tissue can metabolically activate 'cooked meat' carcinogens, a process that could contribute to prostate cancer development.

关键词：芳基烃羟化酶类苯并芘/药代动力学生物转化致癌物/药代动力学细胞色素P450CYP1A1/生物合成细胞色素P450CYP1A1/遗传学细胞色素P450CYP1A1/代谢细胞色素P450CYP1A2/生物合成细胞色素P450CYP1A2/遗传学细胞色素P450CYP1A2/代谢细胞色素P450酶系统/生物合成细胞色素P450酶系统/遗传学细胞色素P450酶系统/代谢 DNA/遗传学 DNA/代谢基因表达咪唑类/药代动力学器官培养技术前列腺切除术前列腺增生/酶学前列腺增生/遗传学前列腺增生/外科学吡啶类/药代动力学喹啉类/药代动力学 RNA 信使/遗传学 RNA 信使/代谢成年人人类男(雄)性

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Design and synthesis of potent, selective, and orally bioavailable tetrasubstituted imidazole inhibitors of p38 mitogen-activated protein kinase

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JOURNAL OF MEDICINAL CHEMISTRY 1999年第12期42卷 2180-2190页

作者： Liverton, NJ Butcher, JW Claiborne, CF Claremon, DA Libby, BE Nguyen, KT Pitzenberger, SM Selnick, HG Smith, GR Tebben, A Vacca, JP Varga, SL Agarwal, L Dancheck, K Forsyth, AJ Fletcher, DS Frantz, B Hanlon, WA Harper, CF Hofsess, SJ Kostura, M Lin, J Luell, S O'Neill, EA Orevillo, CJ Pang, M Parsons, J Rolando, A Sahly, Y Visco, DM O'Keefe, SJ Merck Res Labs Dept Med Chem W Point PA 19486 USA Merck Res Labs Dept Drug Metab W Point PA 19486 USA Merck Res Labs Dept Inflammat Res Rahway NJ 07065 USA Merck Res Labs Dept Pharmacol Rahway NJ 07065 USA

Novel potent and selective diarylimidazole inhibitors of p38 MAP (mitogen-activated protein) kinase are described which have activity in both cell-based assays of tumor necrosis factor-alpha (TNF-alpha) release and an animal model of rheumatoid arthritis;The SAR leading to the development of selectivity against c-Raf and JNK2 alpha 1 kinases is presented, with key features being substitution of the 4-aryl ring with m-trifluoromethyl and substitution of the 5-heteroaryl ring with a a-amino substituent. Cell-based activity was significantly enhanced by incorporation of a 4-piperidinyl moiety at the 2-position of the imidazole which also enhanced aqueous solubility. In general, oral bioavailability of this class of compounds was found to be poor unless the imidazole was methylated on nitrogen. This work led to identification of 48, a potent (p38 MAP kinase inhibition IC50 0.24 nM) and selective p38 MAP kinase inhibitor which inhibits lipopolysaccharide-stimulated release of TNF-alpha from human blood with an IC50 2.2 nM, shows good oral bioavailability in rat and rhesus monkey, and demonstrates significant improvement in measures of disease progression in a rat adjuvant-induced arthritis model.

关键词：咪唑类/化学合成咪唑类/化学咪唑类/药代动力学咪唑类/药理学恒河猴丝裂原激活蛋白激酶类刺激化学性构效关系肿瘤坏死因子α/生物合成 p38丝裂原活化蛋白激酶类女(雌)性人类小鼠大鼠

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Comparison of manual versus ambulatory blood pressure measurements with pharmacokinetic-pharmacodynamic modeling of antihypertensive compounds:: Application to moxonidine

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CLINICAL PHARMACOLOGY & THERAPEUTICS 2000年第1期68卷 18-27页

作者： Trocóniz, IF de Alwis, DP Tillmann, C Callies, S Mitchell, M Schaefer, HG Eli Lilly & Co Ltd Dept Clin Pharmacol Windlesham GU20 6PH Surrey England Univ Navarra Fac Pharm Dept Pharm & Pharmaceut Technol E-31080 Pamplona Spain

Objectives: To compare the results of the pharmacokinetic-pharmacodynamic analyses of 24-hour ambulatory blood pressure measurements and manual blood pressure data in patients receiving moxonidine, Methods: 32 patients with borderline to mild-to-moderate hypertension were enrolled in a double-blind, placebo-controlled phase II study. After receiving placebo for 1 week (run-in phase), the patients were randomly allocated to the placebo or the 0,6-, 0,9-, or 1,2-mg dose groups. Placebo and moxonidine were administered once daily for 1 week (drug-treatment phase). Pour 24-hour ambulatory blood pressure measurement profiles were obtained for each individual. Plasma samples (n = 9) and four measurements of manual blood pressure were taken at the start and end of the drug-treatment phase. Two additional manual blood pressure measurements were taken during the run-in and drug-treatment phases. Results: Pharmacokinetics was described by a one-compartment model. For the 24-hour ambulatory blood pressure measurements, baseline circadian patterns were described with a two-cosine function model that included interindividual and interoccasion variability, Pharmacodynamics was described with use of an effect-compartment model [k(e)0 = 0.37 (1/h)] and an E-max model. For diastolic blood pressure the maximum drug-induced decrease (E-max) was 30.9 mm Hg and the steady-state plasma drug concentration eliciting half of maximum effect (C-50) was 1.33 mu g/L. Interindividual variability was estimated for k(e0) (24.8%) and E-max (33.3%). For the manual blood pressure measurements, data was described by a time-invariant baseline model combined with an effect-compartment model and an E-max,, model. Mean population estimates were in agreement with those obtained during the analysis of 24-hour ambulatory blood pressure measurements. However, interindividual variability could be estimated for the baseline parameter only. Conclusions: Although similar typical population estimates for the drug

关键词：抗高血压药/药理学血压/药物作用血压测定/仪器和设备血压测定/方法血压监测便携式双盲法用药计划表高血压/药物疗法咪唑类/投药和剂量咪唑类/药代动力学咪唑类/药理学模型统计学疾病严重程度指数时间因素成年人老年人女(雌)性人类男(雄)性中年人

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Modeling of sertindole pharmacokinetic disposition in healthy volunteers in short term dose-escalation studies

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JOURNAL OF PHARMACEUTICAL SCIENCES 1998年第12期87卷 1629-1631页

作者： Wong, SL Granneman, GR Abbott Labs Dept Pharmacokinet & Biopharmaceut Abbott Pk IL 60064 USA

The pharmacokinetics of sertindole were studied in young, healthy volunteers after single and multiple oral dose administered under an escalating manner. In a low-dose study (study 1), subjects received 4-8 mg with a maintenance dose period of 7 days. Ina high-dose study (study 2), subjects received 4 mg daily for 2 days, and the dose was increased by 4 mg increments every third day until reaching 20 mg daily. The mean terminal t(1/2) was 73 h after the final 8 mg dose in study 1 and 60 h after the 20 mg dose in study 2. The terminal elimination phase appeared to be monophasic in all the study subjects, suggesting that Michaelis-Menten saturable metabolism was not involved in the elimination of sertindole. Compartmental analyses suggested that the disproportional increase of the C(max) and AUC values from 4 mg to 20 mg during multiple dosing may be explained by saturable presystemic elimination of sertindole, leading to a higher fraction of sertindole available for-absorption at higher doses.

关键词：投药口服抗精神病药/投药和剂量抗精神病药/药代动力学用药计划表半衰期咪唑类/投药和剂量咪唑类/药代动力学吲哚类/投药和剂量吲哚类/药代动力学青少年成年人人类男(雄)性

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Development of trans-2-[lH-imidazol-4-yl] cyclopropane derivatives as new high-affinity histamine H₃ receptor ligands

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JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 1999年第2期289卷 1160-1168页

作者： Tedford, CE Phillips, JG Gregory, R Panlowski, GP Fadnis, L Khan, MA Ali, SM Handley, MK Yates, SL Gliatech Inc Cleveland OH 44122 USA

Previously, a novel series of 1H-4-substituted imidazole compounds were described as potent and selective histamine (HA) H-3 receptor ligands (Yates et al., 1999). The present studies extend the structure-activity relationships for optimal HA H-3 receptor affinity and central nervous system penetration by incorporation of a conformationally restricted cyclopropane nucleus. Moreover, the current studies extend our understanding of ligand-receptor interactions at the HA H-3 receptor with the development of high affinity HA H-3 receptor antagonists containing a stereochemical presentation. Structure-activity relationships were established from in vitro HA H-3 receptor-binding affinities using [H-3]N-alpha-methylhistamine and rat cortical tissue homogenates. Systematic optimization of multiple structural features critical for HA H-3 receptor affinity provided some of the most potent HA H-3 receptor agents described. For example, GT-2331 was determined to bind to a single population of HA H-3 receptors with a K-i of 0.125 nM. In vivo, GT-2331 has a favorable central nervous system penetration profile with an ED50 of 0.08 mg/kg (i.p.) in rats and a long duration of action (T-1/2 > 4 h). In addition, GT-2331 was extremely selective for the HA H-3 receptor versus other HA receptors and a battery of neurotransmitter, neuropeptide, hormone, or enzyme systems. Several compounds were tested in vitro which suggested HA H-3 receptor heterogeneity and are discussed in terms of structure-activity relationships for the HA H-3 receptor.

关键词：结合竞争性缓冲剂大脑皮质/药物作用大脑皮质/代谢组胺拮抗药/化学合成组胺拮抗药/药代动力学组胺拮抗药/药理学咪唑类/化学合成咪唑类/药代动力学咪唑类/药理学配体放射配体测定大鼠 Sprague-Dawley 受体组胺H3/药物作用受体组胺H3/代谢构效关系动物人类男(雄)性大鼠

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N-acetyltransferase-dependent activation of 2-hydroxyamino-1-methyl-6-phenylimidazo[4,5-b]pyridine:: formation of 2-amino-1-methyl-6-(5-hydroxy)phenylimidazo [4,5-b]pyridine, a possible biomarker for the reactive dose of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine

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CARCINOGENESIS 2000年第6期21卷 1197-1203页

作者： Frandsen, H Alexander, J Inst Food Safety & Toxicol DK-2860 Soborg Denmark Natl Inst Publ Hlth Dept Environm Med N-0403 Oslo Norway

2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is a mutagenic and carcinogenic heterocyclic amine formed during ordinary cooking. PhIP is metabolically activated to the ultimate mutagenic metabolite by CYP P450-mediated N-hydroxylation followed by phase II esterification, Incubation of N-hydroxy-PhIP (N-OH-PhIP) with cytosol, acetyl coenzyme A (AcCoA) and 2'-deoxyguanosine for 24 h resulted in the formation of three different adducts: N-2-(deoxyguanosin-8-yl)-PhIP, N-2-(guanosin-8-yl) -PhIP and PhIP-xanthine. One additional product, 5-hydroxy-PhIP (5-OH-PhIP), was also identified in the incubation mixtures. 5-hydroxy-PhIP is formed as a degradation product of conjugates formed from N-acetoxy-PhIP and protein, glutathione or buffer constituents, A similar spectrum of products was obtained using 3'-phosphoadenosine-5'-phosphosulfate (PAPS) instead of acetyl CoA, Addition of glutathione (3 mM) to the incubation mixture resulted in a 50% reduction in both adducts and 5-hydroxy-PhIP formation in liver cytosol, The main product detected was PhIP, suggesting glutathione-dependent reduction of the N-acetoxy-PhIP, Addition of glutathione to incubation mixtures from the other cytosolic preparations had less dramatic effects, In addition, increasing the amount of N-OH-PhIP in the incubation mixture resulted in proportional increased amounts of total adducts and 5-OH-PhIP, Incubation of rat and human S9 with PhIP resulted in the formation of only traces of 5-OH-PhIP, Fortification with AcCoA clearly increased the formation of 5-OH-PhIP, Addition of the CYP 450 1A2 inhibitor, furafylline, completely inhibited the formation of 5-OH-PhIP in incubations with human S9, These results indicate that both PhIP adducts and 5-OH-PhIP are formed by similar routes of activation of N-OH-PhIP. 5-OH-PhIP may therefore serve as a biomarker for the formation of the ultimate mutagenic metabolite of PhIP, A rat dosed orally with PhIP excreted 1% of the dose as 5-OH-PhIP in the urine at 24

关键词：芳基胺N-乙酰转移酶/代谢生物学标记/分析生物转化色谱法高压液相谷胱甘肽/代谢咪唑类/代谢咪唑类/药代动力学咪唑类/药理学吡啶类/代谢吡啶类/药代动力学大鼠 Wistar 动物人类男(雄)性大鼠

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