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Comparison of safety and efficacy of carvedilol and metoprolol in stable angina pectoris

AMERICAN JOURNAL OF CARDIOLOGY 1999年第5期83卷 643-649页

作者： van der Does, R Hauf-Zachariou, U Pfarr, E Holtbrügge, W Konig, S Griffiths, M Lahiri, A Boehringer Mannheim GmbH Dept Clin Res D-68305 Mannheim Germany Northwick Pk Hosp & Clin Res Ctr Harrow HA1 3UJ Middx England

In a double-blind, randomized, 3-month multicenter study, the safety and tolerability and the antianginal and anti-ischemic efficacy of carvedilol 25 to 50 mg twice daily were assessed in comparison with metoprolol 50 ta 100 mg twice daily in younger and elderly patients with stable angina. After a 7-day placebo run-in at the end of which a symptom-limited bicycle ergometric exercise was performed, 368 patients were randomly allocated to the parallel treatment groups. After 4 weeks of therapy with a low dose, a further exercise test was performed and patients were titrated in single-blind fashion to the higher dose if the increase in total exercise time was <1 minute, and there was no safety concern. After a further 8 weeks of treatment a third exercise test was performed. Carvedilol low dose/high dose was shown to be at least as safe and well tolerated as metoprolol low dose/high dose both in younger and elderly patients. There were no thitherto unknown adverse events and no marked change in the types of events after increase of the doses. Early adverse events after treatment initiation or uptitration were equal with both medications, indicating no particular risk associated with carvedilol's vasodilatory action. No rebound phenomena were observed. Both drugs showed good antianginal and anti-ischemic efficacy, with marked increases on uptitration including patients greater than or equal to 65 years of age. However, in the doses selected, which appeared equipment with respect to beta blockade, carvedilol's improvement of time to 1-mm ST-segment depression was statistically significantly greater than that of metoprolol. This could be due to its additional vasodilatory or antioxidative actions. Based on the safety and efficacy data of the present study, use of the higher of the 2 recommended doses of carvedilol and metoprolol appears justified in younger and elderly patients without adequate therapeutic control at lower doses. (C)1999 by Excerpta Medico, Inc.

关键词：肾上腺素能α拮抗剂/投药和剂量肾上腺素能α拮抗剂/治疗应用肾上腺素能β受体拮抗剂/投药和剂量肾上腺素能β受体拮抗剂/治疗应用年龄因素心绞痛/药物疗法抗氧化剂/投药和剂量抗氧化剂/治疗应用卡唑类/投药和剂量卡唑类/治疗应用双盲法心电描记术/药物作用运动试验随访研究美托洛尔/投药和剂量美托洛尔/治疗应用心肌缺血/预防和控制安慰剂丙醇胺类/投药和剂量丙醇胺类/治疗应用危险因素安全单盲法时间因素血管舒张药/投药和剂量血管舒张药/治疗应用老年人女(雌)性人类男(雄)性中年人

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Intravenous nicorandil can preserve microvascular integrity and myocardial viability in patients with reperfused anterior wall myocardial infarction

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JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY 1999年第3期33卷 654-660页

作者： Ito, H Taniyama, Y Iwakura, K Nishikawa, N Masuyama, T Kuzuya, T Hori, M Higashino, Y Fujii, K Minamino, T Sakurabashi Watanabe Hosp Div Cardiol Kita Ku Osaka 5300001 Japan Osaka Univ Sch Med Dept Med 1 Osaka 553 Japan

OBJECTIVES We assessed whether the intravenous administration of nicorandil, an adenosine triphosphate (ATP)-sensitive K+ channel opener, exerts beneficial effect-on microvascular function and functional and clinical outcomes in patients with acute myocardial infarction (AMI). BACKGROUND Experimental studies documented that ATP-sensitive K+ channel opener exerts cardioprotection after prolonged ischemia. METHODS We randomly divided 81 patients with a first anterior AMI into two groups, nicorandil (n = 40) and control groups (n = 41). All patients received successful coronary angioplasty within 12 h after the symptom onset and underwent myocardial contrast echcardiography (MCE) with the intracoronary injection of sonicated microbubbles. In the nicorandil group, we injected 4 mg of nicorandil followed by the infusion at 6 mg/h for 24 h and by oral nicorandil (15 mg/day). RESULTS The improvement in regional left ventricular function, nail motion score and regional wall motion was significantly better in the nicorandil group then in the control group. Intractable congestive heart failure, malignant ventricular arrhythmia and pericardial effusion were more frequently found in the control group than in the nicorandil group (15% vs. 37%, 5% vs. 20% and 8% vs. 37%, p < 0.05, respectively). The frequency of sizable MCE no reflow phenomenon was significantly lower in the nicorandil group than in the control group (15% vs. 33%, p < 0.05). CONCLUSIONS Intravenous nicorandil in conjunction with coronary angioplasty is associated with better functional and clinical outcomes compared to angioplasty alone in patients with an anterior AMI. Myocardial contrast echocardiography findings imply that an improvement in microvascular function with nicorandil may be attributable to this better outcome. CT Am (C) 1999 by the American College of Cardiology.

关键词：血管成形术气囊冠状动脉冠状血管造影术冠状血管/药物作用冠状血管/病理生理学超声心动描记术随访研究心室/药物作用心室/代谢注射静脉内心肌收缩/药物作用心肌梗死/病因学心肌梗死/病理生理学心肌梗死/外科学心肌再灌注损伤/并发症心肌再灌注损伤/病理生理学尼可地尔/投药和剂量尼可地尔/治疗应用钾通道/药物作用钾通道/代谢预后放射性核素心室显像术回顾性研究钠钾交换ATP酶/药物作用钠钾交换ATP酶/代谢血管舒张药/投药和剂量血管舒张药/治疗应用女(雌)性人类男(雄)性中年人

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Assessment of left internal mammary artery graft patency and flow reserve alter minimally invasive direct coronary artery bypass

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AMERICAN JOURNAL OF CARDIOLOGY 1999年第7期84卷 795-801页

作者： Katz, WE Zenati, M Mandarino, WA Cohen, HA Gorcsan, J Univ Pittsburgh Med Ctr Div Cardiol Pittsburgh PA 15213 USA Univ Pittsburgh Med Ctr Div Cardiothorac Surg Pittsburgh PA 15213 USA

Despite its merits, minimally invasive direct coronary artery bypass surgery (MIDCAB) has been criticized for variable left internal mammary artery (LIMA) graft patency rates, prompting the frequent use of postoperative LIMA angiography. Noninvasive transthoracic Doppler interrogation of LIMA grafts has recently been shown to have utility for assessing potency and flow: reserve after conventional bypass surgery, but data after MIDCAB has been limited. The objective of this study was to assess LIMA graft anatomy and physiology in 54 patients after MIDCAB using angiography and noninvasive LIMA Doppler imaging. The right internal mammary artery (RIMA) was studied as a control. LIMA flow reserve in response to adenosine was evaluated in a subgroup of 18 randomly chosen patients with parent grafts, LIMA angiographic patency was 93%. Forty-four patients (81%) had obtainable LIMA:Doppler data. Patent grafts had a diastolic dominant flow pattern with a peak diastolic/systolic velocity ratio of 1.3 +/- 0.6 and a percent diastolic time-velocity integral (TVI) of 70 +/- 11%. These data were significantly different than the RIMA control valves of 0.2 +/- 0.1 and 30 +/- 10%, respectively (p < 0.05). Occluded grafts had absent flow or a systolic dominant pattern. Adenosine-induced increases in LIMB peak:diastolic velocity from 48 +/- 20 to 105 +/- 28 cm/s (p < 0.05 vs baseline) and diastolic TVI from 21 +/- 10 to: 37 +/- 19 cm (p < 0.05 vs baseline), yielding adenosine/baseline ratios of 2.4 +/- 0.9 and 2.0 +/- 0.7, respectively, which was consistent with normal flow reserve. The diastolic flow velocity reserve response was inversely related to baseline diastolic flow (r = -0.69). In conclusion, MIDCAB can be associated with a high rate of LIMA potency and favorable physiologic Doppler flow patterns. Correlation of these findings to long-term patient outcome offer MIDCAB is warranted. (C) 1999 by Excerpta Medica, Inc.

关键词：腺苷/投药和剂量方差分析血流速度冠状血管造影术冠状动脉分流术/方法冠心病/外科学冠心病/超声检查冠状血管/超声检查超声心动描记术多普勒胸廓内动脉-冠状动脉吻合术线性模型乳房动脉/超声检查局部血流外科手术微创性胸廓切开术/方法血管未闭血管舒张药/投药和剂量老年人女(雌)性人类男(雄)性中年人

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Effect of omeprazole on the metabolism of cilostazol

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CLINICAL PHARMACOKINETICS 1999年第2-Sup期37卷 53-59页

作者： Suri, A Bramer, SL Otsuka Amer Pharmaceut Inc Dept Clin Pharmacokinet Pharmacodynam & Metab Rockville MD 20850 USA

Objective: In vitro results suggest that cilostazol is metabolised by cytochrome P450 (CYP) isoforms 1A2, 2D6, 3A4 and 2C19. This study was designed to evaluate the effect of concomitant administration of omeprazole (a CYP2C19 inhibitor) on the pharmacokinetics of a single 100mg oral dose of cilostazol. Design: This study was conducted as a single-centre, open-label, nonrandomised, 2-period, crossover pharmacokinetic trial. A single 100mg dose of cilostazol was administered orally on days 0 and 14. Oral omeprazole (40mg every day) was administered on days 7 to 18. Study Participants: 20 healthy nonsmoking male and female volunteers. Main Outcome Measures: Serial blood samples were collected before and after cilostazol administration to characterise the pharmacokinetics of cilostazol and its metabolites. Results: Following omeprazole coadministration, the increases in cilostazol maximum plasma concentration (C-max) and area under the plasma concentration-time curve at time t (AUC(t)) were 18% (p = 0.062) and 26% (p < 0.001), respectively. For the 2 major circulating metabolites, OPC-13015 and OPC-13213, the OPC-13015 C-max and AUC(t) increased by 29 and 69%, respectively (p < 0.001). However, for OPC-13213, the Cmax and AUC(t) decreased by 22 and 31%, respectively (p < 0.001). The plasma protein binding of cilostazol was unaffected by coadministration of omeprazole. Conclusions: Coadministration of cilostazol with omeprazole resulted in an increase in the systemic exposure of cilostazol and its active metabolite, OPC-13015, by 26 and 69%, respectively. For the other active metabolite, OPC-13213, systemic exposure decreased by 31% because of inhibition of cilostazol metabolism to this metabolite. These changes in systemic exposure were well tolerated. A dose of 50mg cilostazol twice a day should be considered during coadministration of inhibitors of CYP2C19, such as omeprazole.

关键词：投药口服曲线下面积血蛋白质类/代谢色谱法高压液相交叉研究药物相互作用酶抑制剂/药理学半衰期奥美拉唑/药理学四唑类/投药和剂量四唑类/血液四唑类/代谢四唑类/药代动力学血管舒张药/投药和剂量血管舒张药/血液血管舒张药/代谢血管舒张药/药代动力学成年人女(雌)性人类男(雄)性中年人

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Integrated evaluation of relation between coronary lesion features and stress echocardiography results: The importance of coronary lesion morphology

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JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY 1999年第3期33卷 717-726页

作者： Beleslin, BD Ostojic, M Djordjevic-Dikic, A Babic, R Nedeljkovic, M Stankovic, G Stojkovic, S Marinkovic, J Nedeljkovic, I Stepanovic, J Saponjski, J Petrasinovic, Z Nedeljkovic, S Kanjuh, V Univ Belgrade Ctr Clin Serbia Dept Diagnost & Catheterizat Labs Inst Cardiovasc Dis YU-11000 Belgrade Yugoslavia

OBJECTIVES The aim of this study was to analyze, in the same group of patients, the relationship between multiple variables of coronary lesion and results of exercise, dobutamine and dipyridamole stress echocardiography tests. BACKGROUND Integrated evaluation of the relation between stress echocardiography results and angiographic variables should include not only the assessment of stenosis severity but also evaluation of other quantitative and qualitative features of coronary stenosis. METHODS Study population consisted of 168 (138 male, 30 female, mean age 51 +/- 9 years) patients, on whom exercise (Bruce treadmill protocol), dobutamine (up to 40 mcg/kg/min) and dipyridamole (0.84 mg/kg over 10 min) stress echocardiography tests were performed. Stress echocardiography test was considered positive for myocardial ischemia when a new wall motion abnormality was observed. One-vessel coronary stenosis ranging from mild stenosis to complete obstruction of the vessel was present in 153 patients, and 15 patients had normal coronary arteries. The observed angiographic variables included particular coronary vessel, stenosis location, the presence of collaterals, plaque morphology according to Ambrose classification, percent diameter stenosis and obstruction diameter as assessed by quantitative coronary arteriography. RESULTS Covariates significantly associated with the results of physical and pharmacological stress tests included for all three stress modalities presence of collateral circulation, percent diameter stenosis and obstruction diameter, as well as lesion morphology (p < 0.05 for all, except collaterals for dobutamine stress test, p = 0.06). By stepwise multiple logistic regression analysis, the strongest predictor of the outcome of exercise echocardiography test was only percent diameter stenosis (p = 0.0002). However, both dobutamine and particularly dipyridamole stress echocardiography results were associated not only with stenosis severity-percent diameter ste

关键词：强心药/投药和剂量冠状血管造影术冠心病/诊断显像冠心病/病理生理学双嘧达莫/投药和剂量多巴酚丁胺/投药和剂量超声心动描记术/方法运动试验可行性研究随访研究心率输注静脉内心肌收缩敏感性与特异性疾病严重程度指数血管舒张药/投药和剂量成年人老年人女(雌)性人类男(雄)性中年人

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Titration of vasodilator therapy in chronic heart failure according to plasma brain natriuretic peptide concentration: Randomized comparison of the hemodynamic and neuroendocrine effects of tailored versus empirical therapy

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AMERICAN HEART JOURNAL 1999年第6期138卷 1126-1132页

作者： Murdoch, DR McDonagh, TA Byrne, J Blue, L Farmer, R Morton, JJ Dargie, HJ Univ Glasgow Clin Res Initiat Heart Failure Glasgow G12 8QQ Lanark Scotland Univ Glasgow Western Infirm Dept Cardiol Glasgow G11 6NT Lanark Scotland

Background Most patients with chronic heart failure (CHF) receive the same dose of angiotensin-converting enzyme (ACE) inhibitors because there is currently no measure of treatment efficacy. We sought to determine whether titration of vasodilator therapy according to plasma brain natriuretic peptide (BNP) concentration may be of value in the individual optimization of vasodilator therapy in CHF. Methods and Results Twenty patients with mild to moderate CHF receiving stable conventional therapy including an ACE inhibitor were randomly assigned to titration of ACE inhibitor dosage according to serial measurement of plasma BNP concentration (BNP group) or optimal empirical ACE inhibitor therapy (clinical group) for 8 weeks. Only the BNP-driven approach was associated with significant reductions in plasma BNP concentration throughout the duration of the study and a significantly greater suppression when compared with empiric therapy after 4 weeks [-42.1% (-58.2, -19.7) vs -12.0% (-31.8, 13.8), P = .03]. Both treatment strategies were well tolerated and associated with favorable neurohormonal and hemodynamic effects;however, in comparison between groups, mean heart rate fell (P = .02) and plasma renin activity rose (P = .03) in the BNP group when compared with the clinical group. Conclusions Plasma BNP concentration may be chronically reduced by tailored vasodilator therapy in CHF. Furthermore, titration of vasodilator therapy according to plasma BNP was associated with more profound inhibition of the renin-angiotensin-aldosterone system and significant fall in heart rate when compared with empiric therapy.

关键词：血管紧张素转换酶抑制药/投药和剂量慢性病利钠肽脑/血液肾素-血管紧张素系统/药物作用单盲法滴定分析法血管舒张药/投药和剂量老年人老年人 80以上女(雌)性人类男(雄)性中年人

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Photoplethysmographic assessment of pulse wave reflection -: Blunted response to endothelium-dependent beta₂-adrenergic vasodilation in type II diabetes mellitus

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JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY 1999年第7期34卷 2007-2014页

作者： Chowienczyk, PJ Kelly, RP MacCallum, H Millasseau, SC Andersson, TLG Gosling, RG Ritter, JM Änggård, EE Univ Lund Hosp Dept Clin Pharmacol Inst Lab Med S-22185 Lund Sweden Univ London St Bartholomews Hosp Med Coll William Harvey Res Inst London EC1M 6BQ England Univ London Kings Coll Dept Clin Pharmacol Ctr Cardiovasc Biol & Med London WC2R 2LS England

OBJECTIVES We sought to determine whether a simple index of pressure wave reflection may be derived from the digital volume pulse (DVP) and used to examine endothelium-dependent vasodilation in patients with type II diabetes mellitus. BACKGROUND The DVP exhibits a characteristic notch or inflection point that can be expressed as percent maximal DVP amplitude (IPDVP). Nitrates lower IPDVP, possibly by reducing pressure wave reflection. Response of IPDVP to endothelium-dependent vasodilators may provide a measure of endothelial function. METHODS The DVP was recorded by photoplethysmography. Albuterol (salbutamol) and glyceryl trinitrate (GTN) were administered locally by brachial artery infusion or systemically. Aortic pulse wave transit time from the root of the subclavian artery to aortic bifurcation (T-Ao) was measured by simultaneous Doppler velocimetry. RESULTS Brachial artery infusion of drugs producing a greater than threefold increase in forearm blood flow within the infused limb was without effect on IPDVP whereas systemic administration of albuterol and GTN produced dose-dependent reductions in IPDVP. The time between the first and second peak of the DVP correlated with T-Ao (r = 0.75, n = 20, p < 0.0001). The effects of albuterol but not GTN on IPDVP were attenuated by N-G-monomethyl-L-arginine. The IPDVP response to albuterol (400 mu g by inhalation) was blunted in patients with type II diabetes mellitus as compared with control subjects (fall 5.9 +/- 1.8% vs. 11.8 +/- 1.8%, n = 20, p < 0.02), but that to GTN (500 mu g sublingually) was preserved (fall 18.3 +/- 1.2% vs. 18.6 +/- 1.9%, p = 0.88). CONCLUSIONS The IPDVP is influenced by pressure wave reflection. The effects of albuterol on IPDVP are mediated in part through the nitric oxide pathway and are impaired in patients with type II diabetes. (C) 1999 by the American College of Cardiology.

关键词：肾上腺素能β-2受体激动剂肾上腺素能β激动剂/投药和剂量血流速度/药物作用血压/药物作用血压/生理学肱动脉/诊断显像肱动脉/药物作用肱动脉/病理生理学糖尿病 2型/病理生理学剂量效应关系药物投药途径内皮血管/病理生理学酶抑制剂/投药和剂量心率/药物作用输注动脉内光体积描记术脉搏锁骨下动脉/诊断显像锁骨下动脉/药物作用锁骨下动脉/病理生理学超声检查多普勒血管舒张/药物作用血管舒张/生理学血管舒张药/投药和剂量成年人女(雌)性人类男(雄)性中年人

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Effect of multiple cilostazol doses on single dose lovastatin pharmacokinetics in healthy volunteers

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CLINICAL PHARMACOKINETICS 1999年第2-Sup期37卷 69-77页

作者： Bramer, SL Brisson, J Corey, AE Mallikaarjun, S Otsuka Amer Pharmaceut Inc Dept Clin Pharmacokinet Pharmacodynam & Metab Rockville MD 20850 USA

Objective: To assess the effects of cilostazol on lovastatin pharmacokinetics. Design: This was a single-centre, open-label, multiple dose, sequential treatment study. Participants received single oral doses of lovastatin 80mg on days 1, 7 and 9, as well as oral cilostazol 100mg twice daily on days 2 to 8, followed by a single oral 150mg cilostazol dose on day 9. Study Participants: 15 healthy, nonsmoking male or female volunteers (aged 18 to 60 years) were enrolled, and 12 completed the study. Main Outcome Measures: Pharmacokinetic parameters were calculated using plasma concentrations of lovastatin and its beta-hydroxy metabolite and of cilostazol and its metabolites. Differences in the pharmacokinetics of each drug when given alone or in combination were assessed by analysis of variance. Results: The maximum observed plasma concentration (C-max) of lovastatin or its metabolite did not differ significantly when lovastatin was given alone and when it was given with 100mg of cilostazol. The mean ratios of the area under the plasma concentration-time curve from zero to the time of the last measurable concentration (AUC(t)) for lovastatin coadministered with 100mg of cilostazol to that with lovastatin given alone were 1.6 for lovastatin and 1.7 for its metabolite. With 150mg of cilostazol, lovastatin Cmax did not change, whereas Cmax of the metabolite increased 2.2-fold. The mean AUC(t) ratios for lovastatin given with 150mg cilostazol/lovastatin given alone were 1.6 and 2.0 for lovastatin and its metabolite, respectively. All increases in lovastatin and metabolite AUC were statistically significant, except for the 1.6-fold increase in lovastatin AUC with 150mg of cilostazol. Maximum steady-state plasma drug concentration (C(ss)max) and AUC during a dosage interval (AUC(tau)) for cilostazol 100mg twice daily decreased 14 and 15%, respectively, upon lovastatin coadministration. Conclusions: Lovastatin and metabolite exposure is increased only by up to 2-fold when cilos

关键词：方差分析抗胆固醇血症药/血液抗胆固醇血症药/代谢抗胆固醇血症药/药代动力学曲线下面积色谱法高压液相剂量效应关系药物用药计划表药物相互作用半衰期肠吸收/药物作用洛伐他汀/血液洛伐他汀/代谢洛伐他汀/药代动力学参考值四唑类/投药和剂量四唑类/血液四唑类/药代动力学四唑类/药理学血管舒张药/投药和剂量血管舒张药/血液血管舒张药/药代动力学血管舒张药/药理学成年人女(雌)性人类男(雄)性中年人

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Usefulness of the response of flow velocity in the left anterior descending coronary artery to the cold pressor test for evaluating endothelium-dependent vascular relaxation in the coronary microvasculature by transesophageal echocardiography in subjects with angiographically normal coronary arteries

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AMERICAN JOURNAL OF CARDIOLOGY 1999年第11期84卷 1362-+页

作者： Chandraratna, PAN Nimalasuriya, AR Vlachonassios, KD Mathews, SJ Kedes, W Marwah, OS Saad, M Univ So Calif Sch Med Div Cardiol Med Ctr Los Angeles CA 90033 USA

Measurement of flow velocity in the left anterior descending coronary artery by transesophageal echocardiography in subjects without risk factors for coronary artery disease (group 1) and in subjects with normal coronary arteries but conditions associated with endothelial dysfunction (group 2) revealed that there was a significantly impaired coronary flow velocity response to the cold presser test in group 2 subjects. Thus, transesophageal echocardiography provides a minimally invasive tool for the functional assessment of endothelium and can be valuable in evaluating endothelial dysfunction and recovery in a variety of disease states.

关键词：腺苷/投药和剂量腺苷/诊断应用血流速度/药物作用冷冠状血管造影术冠状动脉循环/药物作用冠心病/诊断冠状血管/药物作用冠状血管/生理学冠状血管/超声检查超声心动描记术多普勒彩色超声心动描记术经食管内皮血管/药物作用内皮血管/生理学运动试验输注静脉内危险因素血管舒张/药物作用血管舒张/生理学血管舒张药/投药和剂量血管舒张药/诊断应用成年人老年人女(雌)性人类男(雄)性中年人

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Inhibition of CYP2D6 by quinidine and its effects on the metabolism of cilostazol

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CLINICAL PHARMACOKINETICS 1999年第2-Sup期37卷 41-51页

作者： Bramer, SL Suri, A Otsuka Amer Pharmaceut Inc Dept Clin Pharmacokinet Pharmacodynam & Metab Rockville MD 20850 USA

Objective: In vitro results are inconclusive as to whether cilostazol is metabolised by cytochrome P450 isoenzyme 2D6 (CYP2D6). The goals of this study were (1) to assure the dose of quinidine and timing relative to cilostazol used in this study were adequate to cause inhibition of CYP2D6, (2) to evaluate carryover effects of quinidine administration, and (3) to evaluate the effect of CYP2D6 deficiency and administration of quinidine (a CYP2D6 inhibitor) on the pharmacokinetics of a single 100mg oral dose of cilostazol. Design: This study was conducted as a single-centre, open-label, randomised sequence, 2-period, crossover pharmacokinetic trial. Water alone (treatment without quinidine) or two 200mg oral doses of quinidine sulfate with water were administered 25 hours and 1 hour prior to a single 100mg dose of cilostazol in period 1. Study participants were crossed over to opposite treatment in period 2. Metoprolol 25mg, used as a positive control, was administered 1 hour after quinidine sulfate with water or using water alone to assess the magnitude of CYP2D6 inhibition by quinidine. Study Participants: 22 healthy nonsmoking Caucasian (14 male and 8 female) volunteers participated in the study. Main Outcome Measures: Serial blood and urine samples were collected at predose and after cilostazol administration to characterise cilostazol and its metabolite pharmacokinetics. Additional plasma samples were taken to assess the pharmacokinetics of quinidine. Urine samples were collected to measure metoprolol and hydroxymetoprolol. Results: Administration of metoprolol with quinidine caused a significant (p < 0.001) decrease in the urinary 4-hydroxymetoprolol/metoprolol ratio compared with administration of metoprolol alone (42-fold decrease, 0.065 vs 2.707). Hence, quinidine effectively converted extensive metabolisers of CYP2D6 to poor metabolisers of CYP2D6. The 21-day washout period was adequate to have complete recovery from quinidine inhibition of CYP2D6. The analys

关键词：投药口服肾上腺素能β受体拮抗剂/代谢肾上腺素能β受体拮抗剂/尿方差分析曲线下面积交叉研究细胞色素P450CYP2D6/拮抗剂和抑制剂药物相互作用酶抑制剂/药代动力学酶抑制剂/药理学半衰期代谢清除率美托洛尔/代谢美托洛尔/尿奎尼丁/药代动力学奎尼丁/药理学四唑类/投药和剂量四唑类/代谢四唑类/药代动力学血管舒张药/投药和剂量血管舒张药/代谢血管舒张药/药代动力学成年人女(雌)性人类男(雄)性中年人

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