缓释剂长效盐酸二氢奎尼丁药物动力学和药效学的…

对服用缓释剂长效盐酸二氢奎尼丁的８例健康者及３１例心律失常患者。采用反相高效液相色谱法检测血药浓度，用Ｈｏｌｔｅｒ评判疗效，以研究口服Ｓｅｒｅｃｏｒ后的药物动力学和药效学。研究表明：１．健康者单剂量口服和心律失常患者多剂量口服达稳态时药－时曲线均符合一室开放模型。２．口服Ｓｅｒｅｃｏｒ后，抗室性和房性心律失常的总有效率分别为８８．９％和７５．０％。慢性心房颤动的复律成功率为５０．０％。最后平均有效     

缓释丙吡胺（异脉停）治疗心律失常疗效及安全性观察

目的：丙吡胺为Ｉａ类抗心律失常药，缓释丙吡胺为其长效剂型。本文旨在探讨该药的疗效和安全性。方法：采用随机分组自身单盲对照法对５８例室性和房性心律失常病人进行口服缓释丙吡胺（Ａ组３９例，０．５ｇ／日；Ｂ组１９例，０．２５ｇ／日）的临床研究。全部受试者在眼药前和眼药２周后行Ｈｏｌｔｅｒ、心电图等检查。结果：缓释丙吡胺治疗Ａ、Ｂ两组室性心律失常的有效率分别为８３％、７３％，治疗房性心律失常分别为８３％、７３％。服药后Ａ组病人的ＱＴｃ和ＪＴｃ间期分别延长９．３％和１０．９％（与治疗前比，Ｐ均＜０．００１），Ｂ组中ＱＴｃ和ＪＴｃ间期眼药前后无明显差异。该药非心脏方面的副作用主要有视觉障碍和排尿困难。结论：口服缓释丙吡胺对室性和房性心律失常均有效，并有长效、眼药方便、副作用较少等特点，可供临床进一步使用。     

心律平药动学和药效学观察

应用高效液相色谱法测定１１例阵发性室上性心动过速静脉注射心律平和１５例室性心律失常口服心律平的药浓度时间曲线。静脉注射者药动学符合二室开放模型，主要药动学参数：分布相半衰期（Ｔ（１／２）α）０．０５５±０．０１ｈ，清除半衰期（Ｔ（１／２）β）２．９９±０．５３ｈ，中央分布容积（Ｖｃ）０．０４８±０．０１１Ｌ／ｋｇ，终止室上性心动过速有效血浓度１０３２．６±６２４．１μｇ／ｍｌ。口服者药动学参数Ｔ（１／２）α０．３３±０．２ｈ，Ｔ（１／２）β６．８９±２．７ｈ，ＴＰＫ１．９５±０．４ｈ，ＣＳＴ２４３±１６１μｇ／ｍｌ。１３例口服４５０ｍｇ／ｄ控制室性早搏有效率６９．２％，有效血浓度２９７．７±２６４．６ｎｇ／ｍｌ。提示心律平代谢９３％为强代谢型，应用同等剂量，血浓度差别甚大，有效血浓度个体间差异也不小，因此不能根据剂量估测血浓度高低，也不能根据血浓度预测疗效和促心律失常反应，其治疗应根据临床观察、个体化剂量予以调整。     

索他洛尔对致命性心律失常的作用

本文通过非盲试验评价索他洛尔治疗持续性快速室性心律失常的作用、剂量和副作用。当每日剂量３２０－６４０ｍｇ，血浆浓度２－３μｇ／ｍｌ时，多数可抑制ＰＥＳ诱发ＶＴ。各电生理参数９ＥＲＰ、ＱＴ）新时期、ＴＱｃ及ＳｃＬ等）不能预测其疗效。少数病例因素出现第Ⅱ、Ⅲ类抗心律失常药的副作用而停药。经双盲研究比较药效略优于普卡因胺。     

用体外培养模型研究硒氟对VYS结构及功能的影响

用体外全胚胎培养模型系统探讨了硒、氟对大鼠脏层卵黄囊（ＶＹＳ）功能和结构的影响。结果表明：随着硒、氟浓度的增加，对ＶＹＳ的损害亦逐渐增强．高浓度响（≥２．０μｇ／ｍｌ）和氟（≥１０．０μｇ／ｍｌ）可导致ＶＹＳ直径和血管形成得分值降低，ＶＹＳ三层结构变薄，微绒毛数量减少、结构不规，溶酶体数量减少，线粒体、内质网数量减少和肿胀，畸胎率增高等后果．但在一定浓度范围内（Ｓｅ０．５μｇ／ｍｌ～２．０μｇ／ｍｌ，Ｆ２．５μｇ／ｍｌ～１０．０μｇ／ｍｌ），二者呈相互桔抗作用．ＶＹＳ结构基本恢复正常，畸胎率也明显降低。结果揭示硒、氟对ＶＹＳ营养功能的损害可能是其致畸机制之一。     

心内直视手术中大剂量芬太尼的药代动力学研究

目的：研究心内直视手术中大剂量芬太尼的药代动力学。方法：随机选择１１例心内直视手术患者，芬太尼６０μｇ／ｋｇ静脉注射后，采集２４小时桡动脉血标本，应用气相色谱—质谱法检测血浆芬太尼浓度，ＮＯＮＬＩＮ软件计算药代动力学参数。结果：芬太尼药代动力学符合开放性三室模型。静脉注射芬太尼后血药浓度立刻达１２６．９～２５９．０ｎｇ／ｍｌ，在静脉注射后６０分钟血药浓度下降为１２．９ｎｇ／ｍｌ，有９３．１％的芬太尼从血浆中被清除。有７例患者在不同时间血药浓度出现第２次和第３次高峰。手术后８小时血药浓度仍可再次增高达３．９８±１．７６ｎｇ／ｍｌ。结论：在大剂量芬太尼麻醉时，手术后呼吸支持应超过８小时，尤其在患者清醒、体温恢复及有随意活动时，血浆芬太尼浓度增高，可引起再发性呼吸抑制     

硒和碘对新生大鼠大脑皮层神经细胞生长及原癌基因产物c—fos？…

目的 研究硒，碘及两者联用对新生鼠大脑皮层神经细胞培养的影响，方法 应用新生大鼠大脑皮层神经网络体外培养技术，培养基中加入不同剂量碘（４０μｇ／ｍｌ，８０μｇ／ｍｌ，１２０μｇ／ｍｌ），硒（０．２５μｇ／ｍｌ，０．５０μｇ／ｍｌ，０．７５μｇ／ｍｌ）及硒＋硒，３７℃ＣＯ２培养后，观察细胞生长，突起长度。以免疫组化法测原癌基因ｃ－ｆｏｓ蛋白产物表达。结果 各加药组细胞大小，突起长度和原癌基因ｃ－ｆｐ     

氧氟沙星和环丙沙星对快速生长分支杆菌最低抑菌浓度测定

以Ｂａｃｔｅｃ４６０ＴＢ检测议测定了氧氟沙星（ＯＦＬＸ）和环丙沙星（ＣＰＦＸ）对１１株快速生长（速生）分支杆菌、３株标准菌株的最低抑菌浓度（ＭＩＣ＿９９），结果两药对龟型分支杆菌龟亚种ＭＩＣ＿９９最高，分别为１．０和１．０～２．０μｇ／ｍｌ，对龟型分支杆菌脓肿亚种及偶发分支杆菌ＭＩＣ＿９９相近，分别为０．２５和０．５～１．０μｇ／ｍｌ，对１株转黄和１株待定型速生分支杆菌ＭＩＣ＿９９分别为≤０．１２５，０．５和≤０．１２５，１．０μｇ／ｍｌ。结果表明，体外两药对速生分支杆菌有强抑菌作用，值得进行临床验证。     

加减薯蓣丸对D－半乳糖致大鼠衰老作用的影响

５０日龄Ｗｉｓｔａｒ大鼠每日皮下注射Ｄ－半乳糖４８ｍｇ／ｋｇ，连续４０日，造成亚急性衰老模型，在注射Ｄ－半乳糖的同时，给予加减薯蓣丸口服。结果：与对照组比较，给药组能显著恢复衰老模型大鼠红细胞超氧化物歧化酶（ＳＯＤ，分别为１３６０±３２６μｇ／ｇ·Ｈｂ及８２３±１６６μｇ／ｇ·Ｈｂ）的酶活性（Ｐ＜０．０１），降低血清过氧化脂质（ＬＰＯ，分别为４．８４±０．２０ｎｍｏｌ／ｍｌ及５．０９±０．１７ｎｍｏｌ／ｍｌ）的含量（Ｐ＜Ｏ．０１），减少脑组织脂褐素（ＬＰＦ，分别为１２．１５±４．２８μｇ／ｇ及１６．６６±２．６５μｇ／ｇ）的形成（Ｐ＜０．０５），抑制脑Ｂ型单胺氧化酶（ＭＡＯ－Ｂ，分别为３６．６５±２８．７５ｎｍｏ１／ｍｇ蛋白及８２．６１＋５１．４４ｎｍｏｌ／ｍｇ蛋白）的活性（Ｐ＜０．０５）。还观察到给药组各指标均接近于空白组（Ｐ＞０．０５）。     

硒和碘对新生大鼠大脑皮层神经细胞生长及原癌基因产物c-fos表达的影响

目的研究硒、碘及两者联用对新生鼠大脑皮层神经细胞培养的影响。方法应用新生大鼠大脑皮层神经细胞体外培养技术，培养基中加入不同剂量碘（４０μｇ／ｍｌ、８０μｇ／ｍｌ、１２０μｇ／ｍｌ）、硒（０．２５μｇ／ｍｌ、０．５０μｇ／ｍｌ、０．７５μｇ／ｍｌ）及碘＋硒，３７℃ＣＯ２培养后，观察细胞生长、突起长度。以免疫组化法测原癌基因ｃ－ｆｏｓ蛋白产物表达。结果各加药组细胞大小、突起长度和原癌基因ｃ－ｆｏｓ蛋白产物表达皆较对照组增大，但在体外培养未看到硒碘协同作用。结论碘、硒和两者联用对大脑皮层神经细胞生长和原癌基因ｃ－ｆｏｓ蛋白产物表达有重要作用     

Plasma propafenone concentration in the evaluation of anti-arrhythmic efficacy

The anti-arrhythmic drug efficacy of oral propafenone therapy (300 mg to 900 mg per day) was studied in relation to propafenone and hydroxy-propafenone plasma concentrations in 70 outpatients (46 males, 24 females, mean age 57 +/- 12 years) followed up for 24 +/- 32 months. On average 1.7 plasma concentration measurements were performed per patient. The arrhythmias were effectively controlled in 32 patients, but in another 32 patients propafenone therapy was ineffective; in six patients the evaluation was unclear. The therapy was effective in 66% of patients with ventricular premature beats, in 50% with complex ventricular arrhythmias, in 40% with ventricular tachycardia and in 20% with supraventricular tachycardia. Fifty per cent of patients with coronary heart disease and electrical disease, but only 20% with dilated cardiomyopathy and Wolff-Parkinson-White syndrome were effectively treated. Measurement of peak plasma propafenone levels performed 4.5 +/- 2 h after oral drug administration revealed no statistically significant dose-plasma concentration relation. Optimal propafenone drug efficacy was documented at propafenone plasma concentrations ranging from 0.20 to 0.60 micrograms/ml (63% of patients considered as effectively treated). There was a trend to decrease propafenone efficacy at plasma concentrations below 0.20 micrograms/ml and above 0.60 micrograms/ml. Analysis of hydroxypropafenone identified four patients as poor metabolizers with unusually high propafenone and low hydroxypropafenone plasma concentrations; only one of these four patients showed drug efficacy. Monitoring of propafenone and hydroxypropafenone plasma concentrations was a practical procedure to assess patient's compliance, to identify poor metabolizers and to guide anti-arrhythmic drug therapy.     

Control of late postoperative ventricular arrhythmias with phenytoin in young patients

Ventricular arrhythmias probably initiate the events leading to sudden death in patients who have recovered uneventfully from surgery for congenital heart disease. It is therefore recommended that antiarrhythmic therapy be given to all patients who have had surgery for congenital heart defects and who have ventricular arrhythmias found in a routine electrocardiogram taken after the immediate postoperative period. The response of ventricular arrhythmias to treatment was studied in six ambulatory patients aged 7 to 27 years (mean 16.5) who had had surgery a mean of 10.7 years before the arrhythmia was recognized. Four patients had unsatisfactory repair of the congenital defect; the two other patients had only a palliative operation. Each patient's electrocardiogram was monitored continually by tape recording. Each received phenytoin, 3.75 mg/kg body weight, every 6 hours for four doses, then 1.9 mg/kg every 6 hours until the serum concentration of phenytoin was 15 to 20 μg/ml. This serum concentration was maintained with the daily administration of 2.5 to 3 mg/kg every 12 hours. In the 24 hours before treatment, two patients had ventricular tachycardia, two had paired premature ventricular complexes and two had 10 or more single premature ventricular complexes/hour. After treatment, all patients had “effective control” (one or less premature ventricular complex/hour for 12 consecutive hours). This control was achieved with phenytoin in five patients, but one patient required the addition of disopyramide (2 mg/kg every 6 hours). All five patients undergoing a treadmill test before treatment had premature ventricular complexes during or after exercise; after treatment, only one had premature ventricular complexes after exercise. The patient who required two drugs was unable to perform a treadmill test. The mean effective serum phenytoin concentration, 15.7 μg/ml (range 8.5 to 20.0), was reached at a mean time of 61.2 hours (range 42 to 80) after the start of phenytoin therapy. Ataxia occurred in two patients with serum phenytoin concentrations of 16 and 20 μg, but not in the other four, three of whom had serum concentrations greater than 20 μg/ml. Echocardiographic, hematopoletic, hepatic and renal function indexes remained constant with treatment.It is concluded that (1) phenytoin suppressed ventricular arrhythmias in six children and young adults after surgery for congenital heart disease; (2) the effective serum concentration of phenytoin was approximately 15 μg/ml, but varied widely; and (3) this concentration was achieved within 48 to 72 hours when an oral loading dose was administered.     

Antiarrhythmic action of disopyramide: a study of plasma levels]

The action of dysopyramide was studied in 13 patients, 11 with ventricular and 2 with supraventricular arrhythmias. The drug was given parenterally at first and then by mouth. The patients were monitored with an arrhythmia counter and the plasma levels of disopyramide measured throughout the treatment period. The plasma level was stable at about 4 micrograms/ml during the different phases. Toxic levels of 10 microgram/ml were observed in 1 patient in renal failure. The antiarrhythmic action was very effective (70% success), especially on the ventricular arrhythmias. Two of the four patients who failed to respond to treatment had low, non-therapeutic plasma levels. The dosage should be adapted with respect to the patient's weight and renal function.     

Suppression of arrhythmias within hours after a single oral dose of amiodarone and relation to plasma and myocardial concentrations

In 65 patients a single oral dose of amiodarone (30 mg/kg) produced an antiarrhythmic effect on supraventricular or ventricular arrhythmias within 3 to 8 hours and lasted for 17 to 19 hours. On the second day a 15-mg/kg dose reproduced this effect within 3 to 9 hours. Plasma concentration of amiodarone increased to a maximum (2.2 +/- 1.7 mg/liter) mean +/- standard deviation) at 6 +/- 3.5 hours and plasma levels of N-desethylamiodarone (NDA) rose to 0.2 +/- 0.08 mg/liter at 12 +/- 6.4 hours. Sixty-one other patients were given a single 30-mg/kg dose 7 hours to 4 days before open heart surgery. Biopsies of the right atrial and left ventricular walls were taken during surgery. Myocardial concentration of amiodarone was maximal in the atrium after 7 hours (13 +/- 8 mg/kg) and in the ventricle after 24 hours (17 +/- 11 mg/kg). NDA myocardial concentration increased progressively until 24 hours and then remained stable over 4 days (1.5 mg/kg). The amiodarone myocardial to plasma concentration ratio was similar in the atrium and in the ventricle and averaged 22 and 10 for amiodarone and NDA, respectively. A significant relation existed between amiodarone concentration and the effect on ventricular premature complexes (r = 0.74, p less than 0.001) and between amiodarone plasma concentration and the effect on the atrioventricular conduction (r = 0.58, p less than 0.001). The plasma concentration of amiodarone corresponding to a 60% decrease in arrhythmias averaged 1.5 to 2 mg/liter.(ABSTRACT TRUNCATED AT 250 WORDS)     

Anti-arrhythmic effect of amiodarone in the 24 hours following a single oral loading dose. Clinical and pharmacological study

This study demonstrated the rapid antiarrhythmic effects of oral amiodarone (Am). A single 30 mg/kg dose was given to 67 patients, 18 with supraventricular arrhythmias (atrial extrasystoles: 11 cases, reciprocating tachycardia: 4 cases, intraatrial reentrant tachycardia: 2 cases, paroxysmal atrial fibrillation, AF: 1 case). Eighteen patients had permanent AF. Thirty-one patients had ventricular arrhythmias (ventricular extrasystoles, VES, isolated or in salvos: 22 cases, and ventricular tachycardia, VT: 19 cases). The effect on atrial extrasystoles was significant 4 to 13 hours after AM and maximal (-98% +/- 3.6%) at 7.7 +/- 1 hours. They recurred in 3 cases at the 18th hour. No significant effects were observed on the other supraventricular tachycardias. The effect on the atrioventricular node (AVN) assessed by the ventricular response to permanent AF, was significant after the 3rd hour and maximal ( = 38 +/- 6 bpm) at the 7th hour. The reduction in the frequency of VES was significant from the 5th to the 19th hour of treatment. Control of VT was obtained in 5 cases between the 3rd and 8th hours. The treatment was well tolerated as no side effects were reported. The plasma concentration (PC) of amiodarone (54 patients) and of N-desethylamiodarone (NDA) (36 patients) were measured; the maximal values were 2.53 +/- 1.5 mg/l for Am and 0.22 +/- 0.1 mg/l for NDA. A 60% decrease in the number of VES was observed with PC of Am of 1.90 +/- 0.3 mg/l and a 20% reduction in the ventricular response to AF at PC of Am of 1.50 +/- 0.33 mg/l.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of L-carnitine on arrhythmias during hemodialysis

The therapeutic effect of L-carnitine on arrhythmias during hemodialysis was evaluated in 17 patients with chronic renal disease undergoing intermittent hemodialysis. In 11 of 17 patients (65%), ventricular or supraventricular premature beats appeared at 20 to 30 min after the start of hemodialysis and continued throughout the dialysis. Plasma carnitine was at a lower level in the predialysis period (24.8 +/- 7.9 n mole/ml) as compared with the normal human levels (46.1 +/- 8.6 n mole/ml), and decreased markedly by the end of dialysis (8.2 +/- 5.9 n mole/ml). Plasma free fatty acids rapidly increased immediately after the start of dialysis, reached the maximum levels after 20 min (from 0.23 +/- 0.09 to 1.31 +/- 0.64 mEq/L) and maintained higher levels even at the end of dialysis (0.76 +/- 0.29 mEq/L). Administration of L-carnitine (2 Gm orally), 2 hours before the start of dialysis maintained plasma carnitine within normal levels throughout the dialysis and suppressed the increase in plasma free fatty acids. Both the incidence and the severity of premature beats during hemodialysis were significantly reduced by oral administration of L-carnitine (2 Gm daily) for 4 to 8 weeks. These results suggest that L-carnitine is useful for the treatment of hemodialysis arrhythmias, presumably by restoring impaired oxidation of free fatty acids.     

The Clinical Pharmacology of Propafenone

Propafenone is a potent type Ic antiarrhythmic agent that has activity against a wide variety of supraventricular and ventricular arrhythmias. Clinical administration must be individualized, based on an appreciation of propafenone pharmacokinctics and dose-response relationships, which are quite complex. Although a "therapeutic" plasma concentration is achieved in most patients with 300 mg orally every eight hours and plasma concentrations reach steady state after three days, marked interpatient differences in plasma concentrations occur. In addition, the effective plasma concentration required for arrhythmia suppression varies markedly in individual patients. Oral propafenone is subjected to a marked "first-pass" hepatic elimination via a saturable oxidative pathway. This can result in a tenfold increase in plasma concentrations as the dose is increased from 150 to 450 mg. Accumulation of metabolites, notably 5-OH propafenone, probably contributes to the net antiarrhythmic effect of oral propafenone during chronic oral administration. Propafenone may exacerbate ventricular arrhythmias in 20–15% of patients. This does not appear to be dose-dependent, nor is it associated with a definite prolongation in QT interval.     

Paired comparisons of efficacy of intravenous and oral procainamide in patients with inducible sustained ventricular tachyarrhythmias

Thirty-eight patients who had inducible sustained ventricular tachycardia during baseline programmed electrical stimulation underwent electrophysiologic testing after both intravenous and oral administration of procainamide. Each had presented clinically with documented sustained ventricular tachycardia or out of hospital cardiac arrest not associated with acute myocardial infarction. In 23 patients (61%) (Group I) the arrhythmia became noninducible during an intravenous infusion of procainamide. Oral procainamide was subsequently administered and retesting was carried out after dose titration to match plasma concentration at the end of the intravenous study. Among the 23 patients in Group I the mean (+/- SD) plasma procainamide level was 7.2 +/- 2.8 micrograms/ml after intravenous dosing and 7.9 +/- 2.5 micrograms/ml after oral dosing (p = 0.09). In 15 (65%) of the 23 patients, sustained ventricular arrhythmia was inducible on oral therapy with comparable plasma procainamide levels (intravenous = 6.3 +/- 2.1 micrograms/ml, oral = 7.5 +/- 2.1 micrograms/ml). The other eight patients (35%) had concordant responses to repeat testing with comparable intravenous (mean 9.0 +/- 3.3 micrograms/ml) and oral (8.8 +/- 3.1 micrograms/ml) plasma procainamide levels. In the additional 15 patients (Group II) sustained ventricular tachyarrhythmia remained inducible on intravenous procainamide therapy and the patients were retested on oral therapy with similar plasma concentration (p = 0.05). In seven patients (47%) sustained ventricular tachyarrhythmia was noninducible on treatment with oral procainamide (mean plasma level 7.6 +/- 2.7 micrograms/ml) after failure of intravenous procainamide (mean plasma level 10.3 +/- 2.3 micrograms/ml).(ABSTRACT TRUNCATED AT 250 WORDS)     

Plasma levels of lidocaine after intramuscular administration

Lidocaine has proved to be an effective ventricular antiarrhythmic agent at plasma levels of 1 to 1.5 μg/ml. Since serious ventricular arrhythmias are most likely to occur within the first hour after myocardial infarction, lidocaine administered before the patient reaches the hospital may be of prophylactic value.     

Tocainide for drug-resistant ventricular arrhythmias: Efficacy,side effects,and lidocaine responsiveness for predicting tocainide success

Tocainide therapy has been evaluated in 38 patients with ventricular arrhythmias. Thirty-one had recurrent sustained ventricular tachycardia and/or fibrillation and 29 required prior cardioversions. These arrhythmias could not be managed with quinidine, procainamide, disopyramide, or propranolol. Tocainide doses averaged 1,500 mg/day (range 600 to 2,400) and the majority of patients had plasma concentrations from 6 to 12 μg/ml. Twenty-two patients (61%) had their arrhythmias controlled with tocainide and 16 (39%) did not. Tocainide dose and plasma concentrations were similar for responders and nonresponders. Lidocaine was effective in 26 patients and 16 (63%) of these had their arrhythmias controlled with tocainide. Of 12 patients in whom lidocaine was known to be ineffective or who had not been previously treated, only two (17%) had arrhythmias controlled with tocainide (P < 0.02). Side effects occurred in approximately two thirds of patients but required discontinuation of long-term tocainide in only three patients.