小剂量普萘洛尔口服治疗婴儿血管瘤的近期疗效与安全性评价

目的 评价小剂量普萘洛尔口服治疗婴儿血管瘤的近期疗效与安全性.方法 2008年10月至2009年5月,共58例血管瘤患儿在山东省临沂市肿瘤医院和上海交通大学医学院附属第九人民医院接受并完成普萘洛尔治疗.男19例,女39例;年龄1～12个月,平均4个月;血管瘤大小为1.5 cm×1.0 cm～18.0 cm×5.0 cm,浅表血管瘤27例,深部血管瘤9例,混合型血管瘤22例;病变位于头颈部41例,四肢和躯干12例,阴唇2例,肛周、会阴、阴囊各1例.普萘洛尔1.0～1.5 mg/kg,每天1次顿服,连续服用.住院治疗7～10 d后,出院连续服药,每2周复诊,动态观察和记录血管瘤大小、质地、颜色变化,观察并随时处理治疗过程中出现的不良反应.按4级评分法对近期疗效进行评价.结果 服药后24 h,所有患儿瘤体张力均有不同程度减小,颜色开始变淡,体积开始缩小,5～7 d内变化最显著.服药2个月者7例,3个月者22例,4个月者21例,5个月者8例.随访5～9个月,疗效评定为Ⅳ级(优)者10例(17.2%),Ⅲ级(好)35例(60.4%),Ⅱ级(中)12例(20.7%),Ⅰ级(差)1例(1.7%).深部血管瘤的疗效显著优于浅表型血管瘤(P<0.05),但不同部位血管瘤之间疗效差异无统计学意义(P>0.05).主要不良反应为心率减慢(100%),腹泻(37例,63.8%)和睡眠改变(21例,30.2%),均未造成严重影响,经对症处理,全部恢复正常.结论 普萘洛尔小剂量口服治疗婴儿血管瘤近期疗效良好,不良反应轻微,可作为婴儿血管瘤的一线治疗药物.     

Propranolol blocks chronic risperidone treatment-induced enhancement of spatial working memory performance of rats in a delayed matching-to-place water maze task

Rationale Atypical antipsychotics improve cognitive function, including working memory, in schizophrenia. Some atypical antipsychotics have been reported to activate the locus coeruleus and induce beta-adrenoceptor antagonist sensitive c-Fos-like immunoreactivity in the prefrontal cortex. Materials and methods The present study investigated the effects of chronic treatment of rats with risperidone (1 mg kg⁻¹ day⁻¹ s.c.), clozapine (10 mg kg⁻¹ day⁻¹ s.c.), or acidified saline vehicle control for 2, 4, or 8 weeks on spatial working memory performance in a delayed matching-to-place water maze task with a 60-s inter-trial retention interval with and without acute challenge with propranolol (10 mg/kg i.p.). Results Treatment with risperidone for 8 weeks, but not 2 or 4 weeks, significantly improved working memory performance. In contrast, treatment with clozapine for up to 8 weeks did not improve working memory. Acute challenge with propranolol blocked the improvement in working memory produced by chronic treatment with risperidone, but had no significant effect on performance in saline- or clozapine-treated animals. Conclusions The delayed matching-to-place water maze task may prove valuable in the investigation of the behavioural pharmacology of the cognitive effects of antipsychotic drugs. These data suggest that beta adrenoceptors may contribute to the cognitive effects of chronic treatment with atypical antipsychotics.     

Influence of beta-blocker coadministration on the kinetics of isosorbide mononitrate and dinitrate

Summary The influence of beta-blocker coadministration on the kinetics of oral isosorbide-5-mononitrate (ISMN) and isosorbide dinitrate (ISDN) was studied in healthy volunteers. In the first study, 12 subjects ingested 20 mg ISMN on three occasions in the control state, during coadministration of metipranolol (20 mg 3 times daily), or during metoprolol (100 mg twice daily). There were no significant differences among the three phases in peak serum ISMN concentration (470 ng/ml), the time of peak (0.6 h after dose), elimination half-life (4.5 h), or oral clearance (142 ml/min). In the second study, 10 subjects received 20 mg ISDN in the control state and again during coadministration of propranolol (80 mg 3 times daily). There were no differences between the two phases in peak serum ISDN concentration (20 ng/ml) or the time of peak (0.6 h). Propranolol increased, although not significantly, ISDN clearance (16.5 vs 12.3 L/min,P<0.1), and had no effect on total area under the curve for ISMN, the major metabolite of ISDN. Thus, therapeutic doses of these beta-blockers have a minimal influence on the kinetics of single doses of ISMN or ISDN in healthy individuals.Abbreviations AUC Area under curve - ISDN Isosorbide dinitrate - ISMN Isosorbide-5-mononitrate Supported in part by grant OC 10/6-4 from the Deutsche Forschungsgemeinschaft, and a grant from Boehringer Mannheim, Federal Republic of Germany     

氰联吡啶酮的正性肌力作用及其机制的初步探讨

利用心得安制备豚鼠和家兔心衰模型,静注氰联吡啶酮10～15μg/kg,继之以0.5～0.75μg/kg/min恒速静注,可使衰竭心脏Lvdp/dt mex升高约40%,但心率影响不明显。离体豚鼠心室乳头肌和心房实验表明,氰联吡啶酮(0.1～6.4μg/ml)可剂量依赖性地加强心肌收缩力,小剂量(0.1～1.6μg/ml)对心率影响不明显,大剂量时显著加快心率。较高浓度钙离子拮抗剂戊脉安(2×10~(-6)M)可显著减小氰联吡啶酮的正性肌力作用,而β受体阻断剂心得安(5×10~(-7)M)和H_2受体阻断剂西米替丁(5×10~(-3)M)则无此对抗作用。上述结果提示,氰联吡啶酮的正性肌力作用可能也与钙离子经钙通道内流的增加有关,而与β受体、H_2受体无关。     

Effects of serotonergic agonists on firing rates of photically responsive cells in the hamster suprachiasmatic nucleus

Serotonergic neurons from the midbrain raphe nuclei innervate the suprachiasmatic nucleus (SCN) of the hypothalamus, which functions as the dominant pacemaker for mammalian circadian rhythms. We investigated the effects of serotonin (5-HT) on firing rates of light-activated SCN cells in urethane-anesthetized hamsters. Micro-iontophoretic application of 5-HT or 5-HT_1A agonists (8-OH-DPAT and 5-CT) causeda dose-dependent inhibition of spontaneous activity and photic responses in the majority of SCN cells tested. Application of metergoline alone, a non-selective 5-HT antagonist, slightly increased firing rates during darkness and light exposure, suggesting a tonic serotonergic suppression of SCN activity. Metergoline also effectively attenuated suppression induced by the three 5-HT agonists. In addition, the effects of 8-OH-DPAT were blocked by a 5-HT_1A antagonist, SDZ 216-525. However, other putative 5-HT antagonists were weak (propranolol and NAN-190) or ineffective (ketanserin) in blocking the action of 8-OH-DPAT. These results indicate that serotonin has a potent role in reducing photic effects on retinally activated SCN cells in hamsters, and that these effects are mediated by a receptor with properties similar to those of the 5-HT_1A subtype.     

Ouabain-induced tachyarrhythmias and cell damage in isolated perfused guinea-pig hearts: I. Protection by propranolol

An arrhythmogenic concentration of ouabain (1.37 × 10^?6 m) was added to the media perfusing guinea-pig Langendorff hearts after a 60 min period for establishment of a steady-state. Within 15 min following the addition of ouabain, a significant though transient increase in ventricular cyclic-AMP occurred. The first appearance of electrocardiographic abnormalities occurred at a mean time of +22.6 (±5.1) min following ouabain, a fall in ATP, coronary flow and myocardial oxygen consumption (MVO₂) at +28 min, tachycardia at +33.9 (±6.7) min, and asystole (due to fibrillation) at 42.2 (±2.6) min. When ATP levels, coronary flow and MVO₂ declined, they remained depressed for the duration of the experiments. While these changes were occurring following ouabain, creatine kinase (CK) activity in the coronary effluent began a progressive increase at +45 min, as did lactate dehydrogenase (LDH) at +60 min, indicative of cellular damage. Electron microscopic analysis of tissues exposed to ouabain for 1 h revealed changes in the mitochondria (e.g. swelling, fragmentation or loss of cristae and loss of calcium granules) similar to those seen in anoxia and ischemia. The prior administration of propranolol (3.38 × 10^?6 m) attenuated the rise in creatine kinase activity, and abolished all other effects elicited by ouabain. Neither increasing coronary flow, alpha-adrenergic blockade with phentolamine (1 × 10^?6 m) nor “washing” preparations with drug-free media for 1 h affected the results observed with ouabain.On the basis of these results, we conclude that arrhythmogenic doses of ouabain activate the formation of cyclic-AMP, lending support to the hypothesis that increased levels of the nucleotide may act as a triggering event for the subsequent development of arrhythmias. The sequence of events obtained suggests that arrhythmogenic doses of ouabain produce an oxygen deficit similar to that observed in ischemia, as evidenced by the fall in coronary flow, MVO₂ and ATP, the rise in released LDH and CK, and changes in mitochondrial ultrastructure. This deficit, at least in part, appears to be responsible for the development and maintenance of arrhythmias induced by the concentration of ouabain used in this model.     

Prereactivation propranolol fails to reduce skin conductance reactivity to prepared fear‐conditioned stimuli

Pharmacologic blockade of memory reconsolidation has been demonstrated in fear‐conditioned rodents and humans and may provide a means to reduce fearfulness in anxiety disorders and posttraumatic stress disorder. Studying the efficacy of potential interventions in clinical populations is challenging, creating a need for paradigms within which candidate reconsolidation‐blocking interventions can be readily tested. We used videos of biologically prepared conditioned stimuli (tarantulas) to test the efficacy of propranolol in blocking reconsolidation of conditioned fear in healthy young adults. Strong differential conditioning, measured by skin conductance, was observed among a screened subset of participants during acquisition. However, subsequent propranolol failed to reduce reactivity to the reactivated conditioned stimulus. These results are consistent with other recent findings and point to a need for testing other candidate drugs.     

β肾上腺素受体在舌癌CAL-27细胞系的表达及β受体阻滞剂对其增殖、迁移、侵袭的影响

目的: 研究舌癌CAL-27细胞系中β-AR的表达及β受体阻滞剂对其增殖、迁移、侵袭的影响。方法: 采用Pan CK抗体对培养的正常口腔上皮细胞进行鉴定;免疫组织化学法及qRT-PCR法检测β-AR在舌癌CAL-27细胞的表达;CCK-8法、细胞划痕实验、Transwell法分别检测普萘洛尔及美托洛尔对CAL-27细胞增殖、迁移、侵袭的影响。采用SPSS16.0软件包对数据进行统计学分析。结果: β1-AR、β2-AR在CAL-27细胞的表达均显著高于正常口腔上皮细胞（P<0.05）;β2-AR在CAL-27细胞的mRNA水平表达低于正常口腔上皮细胞而β1-AR表达高于正常口腔上皮细胞;两种药物对CAL-27细胞增殖均有抑制作用,药物浓度>50 μmol/L时,普萘洛尔抑制增殖的作用更强（P<0.05）;2种药物浓度>2.5 μmol/L,对CAL-27细胞迁移均有抑制作用,普萘洛尔的抑制作用更强;药物浓度>1.0 μmol/L,2种药物对CAL-27细胞侵袭均有抑制作用（P<0.05）,普萘洛尔对CAL-27细胞迁移抑制作用更强。结论: 在舌癌CAL-27细胞中, β1-AR在mRNA水平的表达高于正常口腔上皮细胞而β2-AR的表达低于正常口腔上皮细胞;低浓度普萘洛尔及美托洛尔对CAL-27细胞的增殖无明显抑制作用,但能抑制CAL-27的迁移和侵袭。