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Increased autoantibodies against oxidized low-density lipoprotein in coronary circulation in patients with coronary spastic angina

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ANGIOLOGY 2001年第3期52卷 167-174页

作者： Ogawa, H Soejima, H Takazoe, K Miyamoto, S Kajiwara, I Shimomura, H Sakamoto, T Yoshimura, M Kugiyama, K Kimura, M Yasue, H Kumamoto Univ Sch Med Dept Cardiovasc Med Kumamoto 8608556 Japan TFB Inc Tokyo Japan

Oxidized low-density lipoproteins are important in the progression of atherosclerosis. Autoantibodies against malondialdehyde-modified low-density lipoproteins have been reported to be predictive of the progression of atherosclerosis. This study sought to examine whether plasma levels of autoantibodies against oxidized low-density lipoprotein increase in the coronary circulation in patients with coronary spastic angina. The authors examined plasma antioxidized low-density lipoprotein antibody levels (activity unit values (AcU)/mL) simultaneously in the coronary sinus and the aortic root in 20 patients with coronary spastic angina, 23 patients with stable exertional angina, and 15 control subjects by measuring plasma levels of immunoglobulin G (IgG) autoantibodies against malondialdehyde-modified low-density lipoproteins by enzyme-linked immunosorbent assay. The plasma antioxidized low-density lipoprotein antibody levels (AcU/mL) in the coronary sinus increased in coronary spastic angina (38 +/- 16) compared with stable exertional angina (23 +/- 7) and control subjects (20 +/- 6) (p less than or equal to 0.0001). The levels (AcU/mL) in the aortic root also increased in coronary spastic angina (33 +/- 12) compared with stable exertional angina (23 +/- 7) and control subjects (20 +/- 6) (p < 0.005). Furthermore, the coronary sinus-arterial differences of the levels (AcU/mL) were also higher in coronary spastic angina (5 9) than in stable exertional angina (0 +/- 6) and healthy subjects (-1 +/- 5) (p < 0.05). The generation of malondialdehyde-modified low-density lipoproteins is reported to be associated with atherothrombosis. These findings suggest that elevated levels of autoantibodies against malondialdehyde-modified oxidized low-density lipoproteins in coronary circulation are associated with the development of atherothrombosis from the progression of atherosclerosis rather than with the extent of coronary atherosclerosis in patients with coronary spast

关键词：乙酰胆碱/投药和剂量乙酰胆碱/诊断应用投药舌下心绞痛变异型/血液心绞痛变异型/诊断心绞痛变异型/免疫学自身抗体/免疫学生物学标记/血液冠状血管造影术冠状动脉循环/免疫学冠状血管诊断鉴别疾病恶化心电描记术酶联免疫吸附测定心脏导管插入术免疫球蛋白G/免疫学注射动脉内脂蛋白类 LDL/免疫学丙二醛/免疫学硝酸甘油/投药和剂量硝酸甘油/诊断应用氧化还原血管舒张药/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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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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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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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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Abnormal flow-mediated epicardial vasomotion in human coronary arteries is improved by angiotensin-converting enzyme inhibition - A potential role of bradykinin

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JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY 1999年第3期33卷 796-804页

作者： Prasad, A Husain, S Quyyumi, AA NHLBI Cardiol Branch NIH Bethesda MD 20892 USA

OBJECTIVES. This study nas performed to determine whether angiotensin converting enzyme (ACE) inhibition improves endothelium-dependent flow-mediated vasodilation in patients with atherosclerosis or its risk factors and whether this is mediated by enhanced bradykinin activity. BACKGROUND. Abnormal coronary vasomotion due to endothelial dysfunction contributes to myocardial ischemia in patients with atherosclerosis, and its reversal may have an antiischemic action. Previous studies have shown that ACE inhibition improves coronary endothelial responses to acetylcholine, but whether this is accompanied by improved responses to shear stress remains unknown. METHODS. In 19 patients with mild atherosclerosis, metabolic vasodilation was assessed during cardiac pacing. Pacing was repeated during separate intracoronary infusions of low-dose bradykinin (BK) and enalaprilat. Endothelium-dependent and -independent vasodilation was estimated with intracoronary BK and sodium nitroprusside respectively. RESULTS. Enalaprilat did not-alter either resting coronary vascular tone or dilation with sodium nitroprusside, but potentiated BK-mediated dilation. Epicardial segments that constricted abnormally with pacing (-5 +/- 1%) dilated (3 +/- 2%) with pacing in the presence of enalaprilat (p = 0.002). Similarly, BK at a concentration (62.5 ng/min) that did not alter resting diameter in the constricting segments also improved the abnormal response to a 6 +/- 1% dilation (p < 0.001). Cardiac pacing-induced reduction in coronary vascular resistance of 27 +/- 4% (p < 0.001) remained unchanged after enalaprilat. CONCLUSIONS. Thus ACE inhibition: A) selectively improved endothelium-dependent but not-independent dilation, and B) abolished abnormal flow-mediated epicardial vasomotion in patients with endothelial dysfunction, in part;by increasing endogenous BK activity. (C) 1999 by the American College of Cardiology.

关键词：腺苷/投药和剂量血管紧张素转换酶抑制药/药理学血流速度/药物作用缓激肽冠状动脉疾病/酶学冠状动脉疾病/病理生理学冠状血管/酶学冠状血管/病理生理学超声心动描记术多普勒依那普利拉/药理学内皮血管/药物作用内皮血管/生理学注射动脉内肌平滑血管/病理生理学硝普钠/投药和剂量肽基二肽酶A/药物作用肽基二肽酶A/代谢心包/病理生理学血管舒张/生理学血管舒张药/投药和剂量女(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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Correction of endothelial dysfunction in chronic heart failure: Additional effects of exercise training and oral L-arginine supplementation

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JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY 2000年第3期35卷 706-713页

作者： Hambrecht, R Hilbrich, L Erbs, S Gielen, S Fiehn, E Schoene, N Schuler, G Univ Leipzig Ctr Heart Div Cardiol D-04289 Leipzig Germany

OBJECTIVES The aim of this study was to analyze whether L-arginine (L-arg.) has comparable or additive effects to physical exercise regarding endothelium dependent vasodilation in patients with chronic heart failure (CHF). BACKGROUND Endothelial dysfunction in patients with CHF can be corrected by both dietary supplementation with L-arg. and regular physical exercise. METHODS Forty patients with severe CHF (left ventricular ejection fraction 19 +/- 9%) were randomized to an L-arg. group (8 g/day), a training group (T) with daily handgrip training, L-arg, and T (L-arg. + T) or an inactive control group (C). The mean internal radial artery diameter was determined at the beginning and after four weeks in response to brachial arterial administration of acetylcholine (ACh) (7.5, 15, 30 mu g/min) and nitroglycerin (0.2 mg/min) with a transcutaneous high-resolution 10 MHz A-mode echo tracking system coupled with a Doppler device. The power of the study to detect clinically significant differences in endothelium-dependent vasodilation was 96.6%. RESULTS At the beginning, the mean endothelium-dependent vasodilation in response to ACh, 30 mu g/min was 2.54 +/- 0.09% (p = NS between groups). After four weeks, internal radial artery diameter increased by 8.8 +/- 0.9% after ACh 30 mu g/min in L-arg. (p < 0.001 vs. C), by 8.6 +/- 0.9% in T (p < 0.001 vs. C) and by 12.0 +/- 0.3% in L-arg, + T (p < 0.005 vs. C, L-arg. and T). Endothelium independent vasodilation as assessed by infusion of nitroglycerin was similar in all groups at the beginning and at the end of the study. CONCLUSIONS Dietary supplementation of L-arg. as well as regular physical exercise improved agonist-mediated, endothelium-dependent vasodilation to a similar extent. Both interventions together seem to produce additive effects with respect to endothelium-dependent vasodilation. (C) 2000 by the American College of Cardiology.

关键词：乙酰胆碱/投药和剂量投药口服精氨酸/投药和剂量精氨酸/药代动力学血流速度内皮血管/药物作用内皮血管/病理生理学运动疗法心力衰竭/血液心力衰竭/病理生理学心力衰竭/康复注射动脉内硝酸甘油/投药和剂量桡动脉/诊断显像桡动脉/药物作用桡动脉/病理生理学每搏输出量治疗结果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/投药和剂量老年人人类男(雄)性中年人

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Glyceryl trinitrate for fissures: patch or paste?

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INTERNATIONAL JOURNAL OF COLORECTAL DISEASE 2000年第4期15卷 246-247页

作者： Lund, JN Derby City Hosp Dept Surg Derby DE22 3NE England

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