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Effects of inhalation exposures to an M₁-receptor agonist on ventilation in rhesus monkeys

DRUG AND CHEMICAL TOXICOLOGY 1999年第4期22卷 595-611页

作者： Allen, DL Leiter, PA Tielking, RL Hoffman, WP Vidyashankar, AN van Lier, RBL Wolff, RK Eli Lilly & Co Lilly Res Labs Toxicol Res Labs Greenfield IN 46140 USA

Information was needed on effects of possible occupational inhalation exposure to an M-1-receptor agonist (xanomeline) such as might occur during the manufacturing process. Both acute and repeated inhalation exposures to xanomeline were carried out in six male rhesus monkeys using a head-dome exposure system. Exposure concentrations ranged from 0.3 to 10 mg/m(3). The exposure durations were up to 2 weeks. Decreases in tidal volume and increases in respiratory frequency were both time and concentration related during acute exposures.;These effects were blocked with ati-opine pre-treatment. Correlation with pulmonary resistance measurements in two monkeys suggested that these were bronchoconstrictive changes that increased with severity with time at a given concentration and with concentration when measured after a constant exposure time. The dose-response was relatively steep with 10 mg/m(3) becoming intolerable to the monkeys after approximately 15 minutes, but no measurable effects were observed at 0.3 mg/m(3) after up to 4 hours of exposure. To investigate the effects of repeated exposures, monkeys were exposed for 4 hr/day, 5 days/wk for 2 weeks to 0.0 (air only), 0.3 and 1.2 mg xanomeline/m(3) of air. When compared to the air-only exposure, 0.3 mg/m(3) caused no significant changes in tidal volume. In contrast, 1.2 mg/m(3) caused a rapid and significant decrease in tidal volume that was sustained throughout the 4-hr exposure. A slower rise in breathing frequency also occurred Repeated exposures did not alter the effects seen after a single exposure. It is concluded that xanomeline, a M-1-receptor agonist, can acutely alter normal ventilation in non-human primates at airborne concentrations greater than or equal to 0.6 mg/m(3) and should be carefully controlled in a manufacturing environment. The no-observed-effect concentration was 0.3 mg/m(3).

关键词：投药吸入气道阻力/药物作用大气暴露室阿托品/药理学支气管收缩剂量效应关系药物用药计划表猕猴毒蕈碱激动剂/投药和剂量毒蕈碱激动剂/毒性肺通气/药物作用肺通气/生理学吡啶类/投药和剂量吡啶类/毒性呼吸/药物作用噻二唑类/投药和剂量噻二唑类/毒性潮气量/药物作用动物男(雄)性

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Itraconazole alters the pharmacokinetics of atorvastatin to a greater extent than either cerivastatin or pravastatin

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CLINICAL PHARMACOLOGY & THERAPEUTICS 2000年第4期68卷 391-400页

作者： Mazzu, AL Lasseter, KC Shamblen, EC Agarwal, V Lettieri, J Sundaresen, P Bayer Corp Div Pharmaceut Dept Clin Pharmacol W Haven CT 06516 USA Clin Pharmacol Associoates Inc Miami FL USA

Background 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) are metabolized by distinct pathways that may alter the extent of drug-drug interactions. Cerivastatin is metabolized by cytochrome P450 (CYP)3A4 and CYP2C8. Atorvastatin is metabolized solely by CYP3A4, and pravastatin metabolism is not well defined. Coadministration of higher doses of these statins with CYP3A4 inhibitors has the potential for eliciting adverse drug-drug interactions. Objective: To determine the comparative effect of intraconazole, a potent CYP3A4 inhibitor, on the pharmacokinetics of cerivastatin, atorvastatin, and pravastatin. Methods: In this single-site, randomized, three-way crossover, open-labeled study, healthy subjects (n = 18) received single doses of cerivastatin 0.8 mg, atorvastatin 20 mg, or pravastatin 40 mg without and with itraconazole 200 mg. Pharmacokinetic parameters [AUC(0-infinity), AUC(0-tn), peak concentration (C-max), time to reach C-max (t(max)), and half-life (t(1/2))] were determined for parent statins and major metabolites. Results: Concomitant cerivastatin/itraconazole treatment produced small elevations in the cerivastatin AUC(0-infinity), C-max, and t(1/2) (27%, 25%, and 19%, respectively;P < .05 versus cerivastatin alone). Itraconazole coadministration produced similar changes in pravastatin pharmacokinetics [AUC elevated 51% (P < .05 versus pravastatin alone), 24% (C-max), and 23% (t(1/2)), respectively]. However, itraconazole dramatically increased atorvastatin AUC (150%), C-max (38%), and t(1/2) (30%) (P < .05). The elevation in atorvastatin AUC was significantly greater than that of cerivastatin (P < .005) or pravastatin (P < .005). Conclusion: Itraconazole markedly elevated atorvastatin plasma levels (2.5-fold) after 20 mg dosing, suggesting that concomitant itraconazole/atorvastatin therapy be carefully considered. Itraconazole produced modest elevations in the plasma levels of cerivastatin 0.8 mg or pravastatin 40 mg (1.3-fold and 1

关键词：伊曲康唑/投药和剂量伊曲康唑/药理学普伐他丁/投药和剂量普伐他丁/血液普伐他丁/药代动力学吡啶类/投药和剂量吡啶类/血液吡啶类/药代动力学吡咯类/投药和剂量吡咯类/血液吡咯类/药代动力学参考值时间因素男(雄)性

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Optimal end point of FR167653 administration and expression of interleukin-8 messenger RNA on extended liver resection with ischemia in dogs

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JOURNAL OF THE AMERICAN COLLEGE OF SURGEONS 2000年第3期191卷 251-258页

作者： Aiba, M Takeyoshi, I Ohwada, S Kobayashi, J Iwanami, K Sunose, Y Kawashima, Y Mastumoto, K Muramoto, M Morishita, Y Gunma Univ Sch Med Dept Surg 2 Maebashi Gumma 3718511 Japan Nippon Med Sch Dept Pathol Kawasaki Kanagawa Japan Fujisawa Pharmaceut Co Ltd Res Lab Osaka 532 Japan

Background: FR167653 is a potent suppressant of interleukin-1 and tumor necrosis factor production. We previously reported that FR167653 inhibited the expression of interleukin-l messenger RNA (mRNA) after ischemia-reperfusion and provided a protective effect against ischemia-reperfusion injury after extended liver resection. In this study we investigated the optimal end point of FR167653 administration and the inhibition of interleukin-8 (IL-8) mRNA expression caused by the administration of FR167653 during extended liver resection with ischemia in a dog model. Study Design: The right portal pedicle was clamped for 60 minutes but the left portal vein was left patent to avoid portal congestion. After reperfusion 75% of the liver was resected. Experiment I: Adult mongrel dogs were divided into three groups: the control group (n = 9);the FR-2 group (n = 6), which received FR167653 through the portal vein starting 30 minutes before the onset of ischemia until 2 hours after reperfusion;and the FR-6 group (n = 6), which received FR167653 starting 30 minutes before ischemia until 6 hours after reperfusion. Hepatic venous blood was collected to measure liver enzymes. Liver specimens were harvested for histologic study 6 hours after reperfusion and polymorphonuclear neutrophils were counted. Experiment II: The expression of IL-8 was measured by reverse-transcriptase polymerase chain reaction. Results: Aspartate aminotransferase and alanine aminotransferase levels after reperfusion and hyaluronic acid levels 6 hours after reperfusion were significantly (p < 0.05) lower in the FR-2 and FR-6 groups than in the control group. There were no significant differences between the FR-2 and FR-6 groups after reperfusion. Histologically liver tissue damage was mild in the FR-2 and FR-6 groups, and polymorphonuclear neutrophil infiltration was significantly lower in the FR-2 and FR-6 groups than in the control group. The 3-day survival rate was statistically (p < 0.05) better in the FR-

关键词：丙氨酸转氨酶/血液天冬氨酸氨基转移酶类/血液生长抑制物/投药和剂量白细胞介素8/代谢吡唑类/投药和剂量吡啶类/投药和剂量 RNA 信使/代谢再灌注损伤/代谢动物狗

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Pindolol, a putative 5-Hydroxytryptamine_1A antagonist, does not reverse the inhibition of serotonergic neuronal activity induced by fluoxetine in awake cats:: Comparison to WAY-100635

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JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 1999年第1期291卷 220-228页

作者： Fornal, CA Martin, FJ Metzler, CW Jacobs, BL Princeton Univ Dept Psychol Program Neurosci Princeton NJ 08544 USA

The ability of pindolol to enhance the clinical antidepressant response to selective serotonin reuptake inhibitors (SSRIs) is generally attributed to a blockade of the feedback inhibition of serotonergic neuronal activity mediated by somatodendritic 5-hydroxytryptamine (5-HT)(1A) autoreceptors. The current study examined the ability of pindolol to restore the single-unit activity of serotonergic dorsal raphe nucleus neurons in awake cats after acute treatment with the SSRI fluoxetine. The effects of pindolol were compared with those of N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl) cyclohexanecarboxamide (WAY-100635), a selective 5-HT1A receptor antagonist. Systemic administration of fluoxetine (0.5 and 5 mg/kg i.v.) decreased neuronal firing rates to similar to 50 and 1%, respectively, of baseline levels. The subsequent administration of cumulative doses of (+/-)-pindolol (0.1-5 mg/kg i.v.) failed to reverse the neuronal inhibition produced by either dose of fluoxetine. In addition to lacking efficacy as an antagonist in these experiments, (+/-)-pindolol produced an additional decrease in neuronal activity in animals pretreated with the low dose of fluoxetine. The active enantiomer, (-)-pindolol (1 mg/kg i.v.), also was ineffective in restoring neuronal activity after fluoxetine. In contrast, systemic administration of WAY-100635 completely reversed the effect of fluoxetine (5 mg/kg) at low doses (0.025 mg/kg i.v.), and further elevated the firing rate of these neurons above prefluoxetine baseline levels. Overall, these results indicate that pindolol, unlike WAY-100635, lacks appreciable antagonist activity at 5-HT1A autoreceptors. Thus, the clinical efficacy of pindolol in augmenting the antidepressant response to SSRIs, such as fluoxetine, may be unrelated to a restoration of serotonergic neuronal activity.

关键词：药物相互作用氟西汀/投药和剂量氟西汀/药理学神经元/药物作用神经元/代谢吲哚洛尔/投药和剂量吲哚洛尔/药理学哌嗪类/投药和剂量哌嗪类/药理学吡啶类/投药和剂量吡啶类/药理学中缝核/药物作用中缝核/代谢受体血清素/药物作用受体血清素/代谢受体血清素 5-HT1 血清素/代谢血清素拮抗药/投药和剂量血清素拮抗药/药理学血清素摄取抑制药/投药和剂量血清素摄取抑制药/药理学动物猫男(雄)性

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The dual endothelin receptor antagonist tezosentan acutely improves hemodynamic parameters in patients with advanced heart failure

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AMERICAN HEART JOURNAL 2001年第2期142卷 340-349页

作者： Schalcher, C Cotter, G Reisin, L Bertel, O Kobrin, I Guyene, TT Kiowski, W Univ Zurich Hosp Dept Med Div Cardiol CH-8091 Zurich Switzerland Stadspital Triemli Zurich Switzerland Actel Ltd Allschwil Switzerland Assaf Haroffeh Med Ctr Zriffin Israel Barzilai Govt Hosp Ashqelon Israel INSERM Paris France

Background Endothelin-1, a potent vasoconstrictor, is elevated in congestive heart failure and is postulated to play a major role in the pathogenesis of the disease. Endothelin receptor antagonism may be a specific therapeutic approach. This study was designed to determine the effective dosage range, hemodynamic effects, and tolerability of tezosentan, an intravenous dual endothelin receptor antagonist, in patients with advanced heart failure. Methods This randomized, double-blind, placebo-controlled multicenter trial enrolled 38 patients with symptomatic stable heart failure (New York Heart Association class III, left ventricular ejection fraction <35%) undergoing right heart catheterization. Patients were equally randomized to a 4-hour intravenous infusion of placebo or tezosentan in ascending doses (5, 20, 50, and 100 mg over I hour each). Angiotensin-converting enzyme inhibitors and diuretics were withheld 24-hours before the study. Hemodynamics were measured during and for 4 hours after the infusion. Results Compared with Placebo, tezosentan treatment produced a significant increase in cardiac index (treatment difference 0.59 L/min/m(2), P=.0001) and decreases in pulmonary and systemic vascular resistances (P.01) without changes in heart rate. Consistently greater decreases in pulmonary capillary wedge pressure, mean right atrial pressure, and pulmonary and arterial pressures with tezosentan did not reach statistical significance. Hemodynamic changes were dose dependent with maximal effects at 20 and 50 mg per hour. Tezosentan was well tolerated. Despite increased endothelin-1 concentrations, hemodynamic rebound was not observed. Conclusion Tezosentan rapidly and dose dependently improved hemodynamics. The favorable effects on cardiac index and pulmonary and systemic vascular resistances without changes in heart rate may be beneficial in the treatment of acute heart failure.

关键词：剂量效应关系药物双盲法内皮缩血管肽1/血液内皮缩血管肽1/药物作用肾上腺素/血液心脏功能试验/药物作用输注静脉内去甲肾上腺素/血液前瞻性研究吡啶类/投药和剂量吡啶类/血液吡啶类/药理学吡啶类/治疗应用受体内皮缩血管肽/拮抗剂和抑制剂四唑类/投药和剂量四唑类/血液四唑类/药理学四唑类/治疗应用成年人老年人女(雌)性人类男(雄)性中年人

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产妇和新生儿2倍量的nevirapine与标准抗逆转录病毒治疗对降低围产期HIV感染的随机化试验

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世界最新医学信息文摘 2002年第5期1卷 391-392页

作者：陈云茹摘译

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硝苯乙吡啶用于嗜铬细胞瘤术前准备一例报告

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中华泌尿外科杂志 1991年第4期12卷 264-264页

作者：虞湘才张绍增胡利发王惠恺史瑞萍兰州军区总医院泌尿科兰州军区总医院麻醉科

患者,男,38岁。头昏头痛,多汗,视力减退,高血压1年2个月,于1989年7月2日入院。查体、血压25.3/17.3kPa。血、尿常规及肝、肾功能化验正常。红细胞压积0.40;尿VMA49.45μmol/d(正常值:<35μmol/d);肾上腺CT扫描提示右肾上腺下方腹主... 详细信息

患者,男,38岁。头昏头痛,多汗,视力减退,高血压1年2个月,于1989年7月2日入院。查体、血压25.3/17.3kPa。血、尿常规及肝、肾功能化验正常。红细胞压积0.40;尿VMA49.45μmol/d(正常值:<35μmol/d);肾上腺CT扫描提示右肾上腺下方腹主动脉旁有3.4×4.0×4.0cm软组织包块,双肾上腺形态正常。B超示右肾上腺区有4×4cm低回声区。诊断:嗜铬细胞瘤(腹主动脉旁)。治疗经过:术前一周口服尼群地平片(硝苯乙吡啶),每次10mg,6小时1次。首次服药时血压22.6/17.3kPa,每日输液1500ml,第4日输血400ml,血压控制在15.2～20.0/10.6～13kPa。服药第7日查红细胞压积为0.30;尿VMA24.72μmol/d。1989年7月20日在全麻下行肿瘤切除术。术中见3×3×4cm肿瘤位于腔静脉与腹主动脉之间,右肾上腺下方,左肾静脉横跨于肿瘤之上。肿瘤与周围血管粘连。分离肿瘤时,血压曾一度升至29.3/20kPa,静滴异搏停5mg,血压未再上升。肿瘤切除后血压为10.6/8.0kPa,术后血压为17.3/10.6kPa。病理诊断嗜铬细胞瘤。术后恢复顺利,10天出院。

关键词：病例报告嗜铬细胞瘤/外科学手术前护理术前用药法吡啶类/投药和剂量人类

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Effects of intraseptal zolpidem and chlordiazepoxide on spatial working memory and high-affinity choline uptake in the hippocampus

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NEUROBIOLOGY OF LEARNING AND MEMORY 2000年第2期73卷 168-179页

作者： Herzog, CD Gandhi, C Bhattacharya, P Walsh, TJ Rutgers State Univ Dept Psychol New Brunswick NJ 08903 USA

Injection of GABA(A)/benzodiazepine receptor ligands into the medial septum (MS) alters the activity of cholinergic neurons that innervate the hippocampus and can produce bidirectional modulation of spatial memory. Recent evidence suggests that two subtypes of the GABAA receptor are differentially localized to either GABAergic (alpha(1)/beta(2)/gamma(2)) Or cholinergic (alpha(3)/beta(3)/gamma(2)) neurons within the MS. The present studies characterized the dose-related behavioral and neurochemical effects of intraseptal infusions of two benzodiazepine (BDZ) agonists that appear to exhibit different profiles of pharmacological specificity for these receptor subtypes. Male Sprague-Dawley rats were cannulated and then artificial CSF, chlordiazepoxide (CDP: 8 or 12 mu g), or zolpidem (4, 8, or 12 mu g) was injected into the MS. Spatial working memory was assessed in a delay radial-arm maze task and the activity of cholinergic neurons in the MS was evaluated by high-affinity choline uptake (HAChU) in the hippocampus. Intraseptal injection of either CDP or zolpidem produced dose-related impairments in spatial working memory and decreases in hippocampal HAChU. Both BDZ agonists were found to produce retrograde memory deficits and a decrease in HAChU following the highest dose tested (12 mu g). However, intraseptal injection of 8 mu g of zolpidem produced a behavioral deficit comparable to the high dose of CDP, but did not alter HAChU within the HPC. Although the cholinergic component of the septohippocampal pathway has been shown to be important in modulating hippocampal physiology and spatial memory processes, data from the present experiments suggest that the GABAergic component may also play an important role in the behavioral functions of the septohippocampal pathway. (C) 2000 Academic Press.

关键词：氯氮|艹卓|/投药和剂量氯氮|艹卓|/药理学胆碱/代谢 GABA调节剂/药理学海马/药物作用海马/代谢催眠药和镇静药/投药和剂量催眠药和镇静药/药理学注射记忆/药物作用吡啶类/投药和剂量吡啶类/药理学大鼠 Sprague-Dawley 空间知觉/药物作用动物男(雄)性大鼠

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