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SPECIFIC THERAPY FOR VAGINAL MYCOSIS

AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY 1955年第2期70卷 403-408页

作者： HESSELTINE, HC From the Department of Obstetrics and Gynecology the University of Chicago and the Chicago Lying-in Hospital Chicago Ill.

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Prognostic importance of the oxidized product of catecholamines, adrenolutin, in patients with severe heart failure

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AMERICAN HEART JOURNAL 2003年第5期145卷 926-932页

作者： Rouleau, JL Pitt, B Dhalla, NS Dhalla, KS Swedberg, K Hansen, MS Stanton, E Lapointe, N Packer, M Univ Hlth Network Div Cardiol Toronto ON Canada Mt Sinai Hosp Toronto ON M5G 1X5 Canada Univ Michigan Dept Med Ann Arbor MI 48109 USA St Boniface Gen Hosp Inst Cardiovasc Sci Winnipeg MB R2H 2A6 Canada Gothenburg Univ Dept Med Gothenburg Sweden Columbia Univ Ctr Heart Failure New York NY USA

Objectives The purpose of this study was to assess whether adrenolutin, the inert product of the highly reactive molecules aminochromes, is increased in severe chronic heart failure and whether it is associated with a poor prognosis. Background Experimental evidence suggests that oxidative products of catecholamines, aminochromes, are more cardiotoxic than unoxidized catecholamines and may be increased in heart failure. Methods Adrenolutin was measured at baseline and at 1 and 3 months in 263 patients with chronic New York Heart Association class III or IV heart failure and a left ventricular ejection fraction of 22% +/- 7%. Adrenolutin levels were compared with normal levels, and their relation to prognosis was evaluated. Results Baseline adrenolutin was increased (55 +/- 911 pg/mL vs 8.4 +/- 9.1 pg/mL for control, P < .02) and remained increased at 1 month (49 +/- 65 pg/mL). During a mean follow-up of 309 +/- 148 days (22-609 days), 57 patients died. Baseline adrenolutin levels correlated with mortality rates by univariate and multivariate analyses (relative risk 1.06, 95% CI 1.01-1.10 for each 17.9-pg/mL rise, P = .032). Left ventricular ejection fraction (P = .1313) and New York Heart Association class (P = .009) were the only other variables associated with survival. Age, sex, plasma creatinine, plasma N-terminal atrial natriuretic peptide, and plasma norepinephrine levels were not retained in our model. Adrenolutiin levels 1 month after random assignment were not significantly correlated with total mortality rate (P = .061) but were correlated with mortality rate from low output (relative risk 1.14, 95% CI 1.06-1.22, P = .002). Conclusions Plasma adrenolutin is increased in patients with heart failure and correlates with a poor prognosis independent of other important predictors of survival. This finding has potentially important pathophsiologic, prognostic, and therapeutic implications.

关键词：方差分析生物学标记/血液加拿大儿茶酚胺类/血液慢性病吲哚类/血液预后喹啉类/治疗应用参考值每搏输出量血管舒张药/治疗应用老年人女(雌)性人类男(雄)性中年人

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Opioid-induced cardioprotection against myocardial infarction and arrhythmias: Mitochondrial versus sarcolemmal ATP-sensitive potassium channels

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JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 2000年第2期294卷 451-457页

作者： Fryer, RM Hsu, AK Nagase, H Gross, GJ Med Coll Wisconsin Dept Pharmacol & Toxicol Milwaukee WI 53226 USA Toray Ind Kanagawa Japan

We examined the role of the sarcolemmal and mitochondrial ATP-sensitive potassium (K-ATP) channel in a rat model of myocardial infarction after stimulation with the selective delta(1)-opioid receptor agonist TAN-67. Hearts were subjected to 30 min of regional ischemia and 2 h of reperfusion. Infarct size was expressed as a percentage of the area at risk. TAN-67 significantly reduced infarct size/area at risk (29.6 +/- 3.3) versus control (63.1 +/- 2.3). The sarcolemmal-selective K-ATP channel antagonist HMR 1098, administered 10 min before TAN-67, did not significantly attenuate cardioprotection (26.0 +/- 7.3) at a dose (3 mg/kg) that had no effect in the absence of TAN-67 (56.3 +/- 4.3). Pretreatment with the mitochondrial selective antagonist 5-hydroxydecanoic acid (5-HD) 5 min before the 30-min occlusion completely abolished TAN- 67-induced cardioprotection (54.3 +/- 2.7), but had no effect in the absence of TAN-67 (62.6 +/- 4.1), suggesting the involvement of the mitochondrial K-ATP channel. Additionally, we examined the antiarrhythmic effects of TAN-67 in the presence or absence of 5-HD and HMR 1098 during 30 min of ischemia. Control animals had an average arrhythmia score of 10.40 +/- 2.41. TAN-67 significantly reduced the arrhythmia score during 30 min of ischemia (2.38 +/- 0.85). 5-HD and HMR 1098 in the absence of TAN-67 produced an insignificant decrease in the arrhythmia score (8.80 +/- 2.56 and 4.20 +/- 1.07, respectively). 5-HD administration before TAN-67 treatment abolished its antiarrhythmic effect (4.71 +/- 1.11). However, HMR 1098 did not abolish TAN-67-induced protection against arrhythmias (1.67 +/- 0.80). These data suggest that delta(1)-opioid receptor stimulation is cardioprotective against myocardial ischemia and sublethal arrhythmias and suggest a role for the mitochondrial K-ATP channel in mediating these cardioprotective effects.

关键词：腺苷三磷酸/生理学镇痛药阿片类/拮抗剂和抑制剂镇痛药阿片类/治疗应用抗心律失常药/拮抗剂和抑制剂抗心律失常药/药理学心律失常心性/预防和控制苯甲酰胺类/药理学血压/药物作用癸酸类/药理学药物相互作用心率/药物作用羟酸类/药理学线粒体心脏/药物作用线粒体心脏/生理学心肌梗死/预防和控制心肌缺血/并发症心肌再灌注损伤/预防和控制钾通道阻滞剂钾通道/药物作用钾通道/生理学喹啉类/拮抗剂和抑制剂喹啉类/治疗应用大鼠 Wistar 受体阿片样 δ/激动剂肌膜/药物作用肌膜/生理学心室颤动/预防和控制动物男(雄)性大鼠

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TRANSFERRED DRUG-RESISTANCE IN EIMERIA-MAXIMA

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PARASITOLOGY 1975年第DEC期71卷 385-392页

作者： JOYNER, LP NORTON, CC MINIST AGR FISHERIES & FOOD CENT VET LABWEYBRIDGESURREYENGLAND

A series of experiments is described in which two drug-resistant strains of Eimeria maxima were passaged together in untreated chicks. The resultant oocysts were then inoculated into chicks treated with both drugs. When strains resistant to methyl benzoquate and sulphaquinoxaline or clopidol and sulphaquinoxaline were used the resultant infections were not controlled by the double treatment, indicating the acquisition of resistance factors by one strain from the other. When strains resistant to clopidol and methyl benzoquate were used the phenomenon was not observed.

关键词：鸡氯吡多/药理学氯吡多/治疗应用球虫病/药物疗法球虫病/兽医学抗药性艾美球虫属/药物作用家禽疾病/药物疗法喹啉类/药理学喹啉类/治疗应用磺胺喹恶啉/药理学磺胺喹恶啉/治疗应用动物男(雄)性

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ANTIMALARIALS .7. 2,8-BIS(TRIFLUOROMETHYL)-4-QUINOLINEMETHANOLS

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JOURNAL OF MEDICINAL CHEMISTRY 1975年第11期18卷 1122-1126页

作者： BLUMBERGS, P AO, MS LAMONTAGNE, MP MARKOVAC, A NOVOTNY, J COLLINS, CH STARKS, FW ASH STEVENS INC DETROITMI 48202 STARKS ASSOC INC BUFFALONY 14213

Based on the high antilalarial activity of alpha-(2-piperidyl)-2,8-bis(trifluoromethyl)-4-quinolinemethanol, ten additional 2,8-bis(trifluoromethyl)-4-quinolinemethanols were prepared in which the amino alcohol side chain was structurally varied. Synthesis of the compounds is described and antimalarial activity data against Plasmodium berghei are presented and discussed in terms of the structure variations.

关键词：抗疟药/化学合成抗疟药/治疗应用疟疾/药物疗法甲醇/化学合成伯氏疟原虫喹啉类/化学合成喹啉类/治疗应用构效关系动物小鼠

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Estrogen is associated with improved survival in aging women with congestive heart failure: Analysis of the vesnarinone studies

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JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY 2000年第2期36卷 529-+页

作者： Reis, SE Holubkov, R Young, JB White, BG Cohn, JN Feldman, AM Univ Pittsburgh Med Ctr Cardiovasc Inst Pittsburgh PA 15213 USA Cleveland Clin Fdn Cleveland OH 44195 USA Clin Cardiovasc Res Gaithersburg MD USA Univ Minnesota Minneapolis MN USA

OBJECTIVES This study sought to evaluate the effects of postmenopausal estrogen use on mortality in aging women with congestive heart failure (CHF). BACKGROUND The age-related increase in CHF mortality in women may be related to a menopause-associated increased incidence of coronary artery disease. In addition to inhibiting coronary atherosclerosis, estrogen may also have protective effects on cardiac myocytes independent of the coronary vasculature. We hypothesized that estrogen use is associated with improved survival in elderly women with CHF. METHODS Associations between survival, estrogen use and patient characteristics were assessed in 1,134 women who were at least 50 years of age, had CHF and left ventricular ejection fraction (EF) less than or equal to 30% and were enrolled in one of three clinical trials of vesnarinone. RESULTS All-cause 12-month mortality was 15.0% among the 237 estrogen users versus 27.1% among the 897 estrogen nonusers (p = 0.004 for unadjusted comparison of survival). Similar results were observed for cardiac mortality. Regression analysis demonstrated that estrogen use was independently associated with improved survival (relative risk of mortality = 0.68, 95% confidence interval 0.48 to 0.96, p = 0.03). Advanced age, low EF, New York Heart Association class IV CHF, Caucasian race and abnormal serum creatinine, sodium, potassium and transaminase were independently associated with increased mortality. CONCLUSIONS Estrogen use among older women with CHF is associated with decreased overall and cardiac mortality. (C) 2000 by the American College of Cardiology.

关键词：强心药/治疗应用雌二醇同源物/治疗应用雌激素替代疗法心力衰竭/药物疗法心力衰竭/死亡率多中心研究(主题) 喹啉类/治疗应用随机对照试验(主题) 存活率分析老年人女(雌)性人类中年人

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THE CURATIVE EFFECT OF ETHIDIUM BROMIDE AGAINST TRYPANOSOMA-VIVAX INFECTIONS OF ZEBU CATTLE IN WEST AFRICA, WITH OBSERVATIONS ON THE TOXICITY OF THE DRUG

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ANNALS OF TROPICAL MEDICINE AND PARASITOLOGY 1954年第3期48卷 229-236页

作者： UNSWORTH, K Veterinary Section West African Institute for Trypanosomiasis Research Vom Nigeria

Zebu bulls infected with T. vivax by blood inoculation were given single injections with ethidium bromide, in aqueous solution, subcutaneously at the side of the neck 14 days after infection. Cures were obtained with doses of 1 mg per kg and in a few cases even smaller doses were effective. Blood hemoglobin values quickly returned to normal after treatment. Doses of 2.5 mg per kg and over caused severe local reaction. Doses of 4 mg per kg and over resulted in the appearance of abnormal amounts of fat in the liver, and a dose of 30 mg per kg caused death within 24 hours. No delayed toxic reactions were observed which were attributable to the drug.

关键词：非洲西部牛疾病胡米胺喹啉类/治疗应用活跃锥虫锥虫病/治疗动物牛

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D₁ dopamine receptor agonists are more effective in alleviating advanced than mild parkinsonism in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated monkeys

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JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 2000年第2期292卷 714-724页

作者： Goulet, M Madras, BK Harvard Univ New England Reg Primate Res Ctr Sch Med Dept PsychiatDiv Neurochem Southborough MA 01772 USA

Selective D-1 dopamine receptor agonists exert antiparkinsonian effects in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) monkey model of Parkinson's disease and in human Parkinson's disease. Motor impairment in idiopathic Parkinson's disease progresses from mild to severe, but the therapeutic potential of D1 dopamine receptor agonists in early and advanced stages of parkinsonism is not known. To compare the effectiveness of D-1 agonists at different levels of impairment, we developed a model of mild and advanced parkinsonism in nonhuman primates and a rating scale that differentiated the two models. D-1 dopamine receptor agonists (SKF 81297, dihydrexidine) and D-2 dopamine receptor agonists [quinelorane, (+)-PHNO were administered to monkeys (Macaca fascicularis) displaying either mild parkinsonism (two doses of 0.6 mg/kg i.v. MPTP 1 month apart) or advanced parkinsonism (three doses of 0.6 mg/kg i.v. MPTP within 10 days). In normal monkeys (n = 3), SKF 81297 and dihydrexidine did not promote increased motor activity. In advanced parkinsonism (n = 4), D-1 and D-2 dopamine agonists effectively reversed the motor deficits. In contrast, the therapeutic benefits of D-1 agonists SKF 81297 and dihydrexidine were relatively limited in mild parkinsonism (n = 4). The D-2 agonists quinelorane and (+)-PHNO alleviated some symptoms in mild parkinsonism but also reduced balance and induced more dyskinesias than did D-1 agonists. Mild and advanced parkinsonism in nonhuman primates can be produced with fixed dosing regimens of MPTP. Based on the therapeutic efficacy and side effect profiles derived from these models, D-1 agonists are more promising for the treatment of advanced than of mild Parkinson's disease.

关键词： 1-甲基-4-苯基-1 2 3 6-四氢吡啶/治疗应用行为动物/药物作用苯丙氮|艹卓|类/治疗应用多巴胺药/治疗应用多巴胺激动剂/治疗应用运动障碍药物性成束猴运动活动/药物作用运动技能/药物作用恶嗪类/治疗应用帕金森障碍/药物疗法菲啶类/治疗应用喹啉类/治疗应用受体多巴胺D1/药物作用动物女(雌)性男(雄)性

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Neurohormonal activation in severe heart failure: Relations to patient death and the effect of treatment with flosequinan

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AMERICAN HEART JOURNAL 2000年第4期139卷 587-595页

作者： Moe, GW Rouleau, JL Charbonneau, L Proulx, G Arnold, JMO Hall, C de Champlain, J Barr, A Sirois, P Packer, M St Michaels Hosp Terrence Donnelly Heart Ctr Toronto ON M5B 1W8 Canada

Background Flosequinan is a direct-acting vasodilator that exerts beneficial hemodynamic effects and improves the exercise tolerance of patients with heart failure. However, a multicenter trial has demonstrated that long-term administration of flosequinan is associated with increased mortality rate. To explore a possible role of neurohormonal activation on this adverse outcome, we conducted a substudy to examine the plasma levels of 3 neurohormonal systems known to have prognostic implications in heart failure. Methods At 20 participating Canadian centers, paired plasma samples at baseline and 1 month after randomization for the measurement of N-terminal atrial natriuretic peptide (N-ANP), angiotensin Ii, and norepinephrine were obtained in 234 patients (114 receiving flosequinan and 120 receiving placebo). Results Treatment with flosequinan was associated with a decline in median plasma N-ANP levels (2139 pmol/L at base line to 1625 pmol/L at 1 month [P = .0001]), unchanged plasma angiotensin II levels (40 to 50 pmol/L [P = .2700]), and a modest increase in plasma norepinephrine levels (391 to 439 pg/mL [P = .002]). These changes were riot observed in the placebo group. Multivariate analysis of baseline variables revealed that plasma norepinephrine level predicted patients' death whereas analysis incorporating both baseline and 1-month variables indicated that plasma N-ANP level predicted patients' death. Furthermore, in the flosequinan group, a significant decline in plasma N-ANP level was observed in the survivors only. On multivariate analysis of baseline and 1-month data, the increase in plasma norepinephrine level did not predict the increase in heart rate associated with the use of flosequinan, suggesting that the 2 effects might be mediated by separate mechanisms. Conclusions Results of our study demonstrate that in patients with severe heart failure, baseline norepinephrine level pre diets death. Flosequinan increases plasma norepinephrine level and heart r

关键词：血管紧张素Ⅱ/生理学心钠素/生理学死亡原因队列研究去甲肾上腺素/生理学预后蛋白质前体/生理学喹啉类/治疗应用存活率血管舒张药/治疗应用老年人女(雌)性人类男(雄)性中年人

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Substituted indoles as potent and orally active 5-lipoxygenase activating protein (FLAP) inhibitors

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BIOORGANIC & MEDICINAL CHEMISTRY LETTERS 1999年第16期9卷 2391-2396页

作者： Frenette, R Hutchinson, JH Léger, S Thérien, M Brideau, C Chan, CC Charleson, S Ethier, D Guay, J Jones, TR McAuliffe, M Piechuta, H Riendeau, D Tagari, P Girard, Y Merck Frosst Ctr Therapeut Res Pointe Claire PQ H9R 4P8 Canada Merck & Co Inc W Point PA 19486 USA

This paper reports on the SAR investigation of inhibitors of 5-lipoxygenase activating protein (FLAP) based on MK-0591. Emphasis was made on modifications to the nature of the link between the indole and the quinoline moieties, to the substitution pattern around the two heterocycles and to possible replacements of the quinoline moiety. Lead optimization culminated in (3-[1-(4-chlorobenzyl)-3-(t-butylthio)-5-(pyridin-2-ylmethoxy)-indol-2-yl]-2,2-dimethylpropanoic acid (18k), as a potent inhibitor of leukotriene biosynthesis that is well absorbed and active in functional models. (C) 1999 Elsevier Science Ltd. All rights reserved.

关键词： 5-脂氧合酶活化蛋白类载体蛋白质类/拮抗剂和抑制剂吲哚类/化学吲哚类/药理学吲哚类/治疗应用脂氧合酶抑制剂/化学脂氧合酶抑制剂/药理学脂氧合酶抑制剂/治疗应用膜蛋白质类/拮抗剂和抑制剂喹啉类/化学喹啉类/药理学喹啉类/治疗应用构效关系动物狗人类大鼠

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