R-verapamil: pharmacokinetics and effects on PR interval, blood pressure and heart rate.

1. This study in healthy normotensive male volunteers investigated the pharmacokinetics and the effects on electrocardiographic PR interval, blood pressure and heart rate of single oral doses of the single isomer R-verapamil (250, 500 and 1000 mg) in comparison to placebo and 240 mg racemic verapamil. 2. After 500 and 1000 mg R-verapamil there were significant prolongations in PR interval, maximal at 1-2 h after dosing and coincident with peak plasma drug concentrations, but these were not significantly different from the maximum prolongation obtained with 240 mg racemic verapamil. 3. After 1000 mg R-verapamil there was a significant hypotensive effect, particularly on standing. 4. Single doses of 500 and 1000 mg R-verapamil produced peak plasma drug concentrations in the range 1000-3000 ng ml-1. If this concentration range is appropriate for adjuvant cancer chemotherapy it can be predicted that similar steady state concentrations will occur with a dosage regimen of 300 mg 3 times daily.     

Effects of 4-aminopyridine on cardiac repolarization,PR interval,and heart rate in patients with spinal cord injury

STUDY OBJECTIVE: To determine the effects of 4-aminopyridine (4-AP) on heart rate and PR, QT, and QTc intervals in patients with longstanding spinal cord injury (SCI). DESIGN: Randomized, active-treatment-controlled, dose level-blinded study, with allocation concealed. SETTING: University-affiliated, tertiary care medical center. PATIENTS: Sixty otherwise healthy male and female outpatients with traumatic SCI of more than 1 year's duration. Intervention. Oral administration and dose titration to tolerance of an immediate-release formulation of 4-AP. MEASUREMENTS AND MAIN RESULTS: The PR interval, heart rate, QT interval, and QTc interval obtained from standard 12-lead electrocardiograms (ECGs) at baseline (before administration of 4-AP) and after 1 month of treatment were compared. The QTc intervals were derived by using Bazett's formula (equation) incorporated into standard computerized analyses of 12-lead ECG printouts. The paired t test was performed to test for the significance of differences between means and variances. No statistically significant differences were noted in heart rate or between ECG time intervals measured at baseline and after 1 month of treatment with 4-AP among all patients with SCI or between subgroups stratified by injury level (tetraplegia, paraplegia) or sex. CONCLUSION: During the 1-month period that 4-AP was administered, the heart rate and PR, QT, and QTc intervals all remained unchanged and stayed well within normal range in comparison to literature-derived control values. 4-Aminopyridine does not appear to influence the length of cardiac time intervals or heart rate and, hence, is unlikely to cause potentially life-threatening ventricular dysrrhythmias when administered long-term and taken orally in dosages of up to 30 mg/day. Specifically, cardiac repolarization (QTc interval) is unaffected in patients with SCI who continuously receive 4-AP for up to 1 month.     

Ischemia reperfusion injury and histamine release in isolated and perfused guinea-pig heart: pharmacological interventions.

Experiments were carried out to provide further information on the biochemical and morphological changes occurring in the guinea-pig heart after multiple ligature and reopening of the left anterior descending (LAD) coronary artery. In isolated perfused guinea-pig heart the reopening of LAD coronary artery leads to a release of histamine related to a loss of metachromasia by cardiac mast cells. The process is associated with malonyldialdehyde (MDA) production, cellular overload of calcium and ventricular arrhythmias which can be modulated by pharmacological interventions.     

Tobacco addiction and pharmacological interventions

Even though its health consequences are well known, tobacco use continues to kill millions of smokers worldwide every year. In the US alone, tobacco use kills > 430,000 people each year. The global mortality toll is approximately 5 million annually and this is increasing. It is the powerful grip of tobacco addiction that sustains high levels of daily smoke intake and persistent smoking, with > 90% of all cigarette smokers who quit, resuming smoking within 1 year. Tobacco addiction, which places tremendous health and economic burdens on individual societies, is also becoming a global epidemic. Although tobacco addiction is a complex phenomenon, it is treatable and several effective medications are now available. In the mid-1980s, the US FDA approved nicotine gum, the first of these effective pharmacological aids. Other effective medications have subsequently become available, including nicotine transdermal patches, nasal spray, oral vapour inhaler, sublingual nicotine tablets and bupropion. These medications and the potential for development of new medications will be reviewed.     

Tobacco addiction and pharmacological interventions

Even though its health consequences are well known, tobacco use continues to kill millions of smokers worldwide every year. In the US alone, tobacco use kills > 430,000 people each year. The global mortality toll is approximately 5 million annually and this is increasing. It is the powerful grip of tobacco addiction that sustains high levels of daily smoke intake and persistent smoking, with > 90% of all cigarette smokers who quit, resuming smoking within 1 year. Tobacco addiction, which places tremendous health and economic burdens on individual societies, is also becoming a global epidemic. Although tobacco addiction is a complex phenomenon, it is treatable and several effective medications are now available. In the mid-1980s, the US FDA approved nicotine gum, the first of these effective pharmacological aids. Other effective medications have subsequently become available, including nicotine transdermal patches, nasal spray, oral vapour inhaler, sublingual nicotine tablets and bupropion. These medications and the potential for development of new medications will be reviewed.     

The prediction of individual systolic time interval v heart rate regression equations.

1. Twenty-eight sets of systolic time interval (STI) and heart rate (HR) data were available from studies in which small bolus doses of atropine had been given to alter heart rate. 2. Regression lines of the form LVET = A+B.HR and QS2 = C+D.HR were calculated. There was no significant relationship between PEP and HR. The values of the parameters A-D were normally distributed. 3. The maximum likelihood Estimation was used to obtain the most likely values of the parameters A-D for individual subjects. 4. The technique proved to be highly satisfactory and was subsequently validated with a further six sets of data.     

Lack of correlation between exercise and sibenadet-induced changes in heart rate corrected measurement of the QT interval

AIMS: We sought to investigate subject specific QT interval correction factors (SSCF) determined at rest and after exercise and to determine the validity of these factors after the administration of a probe drug known to increase heart rate without directly affecting cardiac repolarization. METHODS: Thirty-two healthy volunteers underwent graded exercise, multiple recordings of electrocardiogram during rest over a day and a treatment phase administering inhaled placebo or sibenadet (a beta(2)-adrenoceptor/dopamine D(2)-receptor agonist) at 250, 500 or one of 750 or 1000 microg. SSCF were determined from linear regression of plots of log RR interval vs. log QT after exercise (QTcX), rest (QTcR), and combined data (QTcC). The SSCFs along with Bazett & Fridericia corrections were applied to the ECGs after inhalation of sibenadet. RESULTS: SSCFs obtained from the combination of the exercise and resting day (mean QTcC = 0.41) and exercise alone (mean QTcX = 0.40) were similar with a good fit to the data (mean r(2) = 0.92 and 0.93, respectively) while data at rest resulted in a less pronounced slope (mean QTcR = 0.27) and poorer fit (mean r(2) = 0.52). After the administration of sibenadet, none of the SSCFs, Bazett or Fridericia corrections adequately corrected QT for heart rate induced changes. CONCLUSIONS: Neither a SSCF from exercise, Bazett's or Fridericia's correction factors, adequately corrected the QT interval after the administration of a sympathomimetic agonist drug to increase heart rate in healthy volunteers demonstrating the potential need for QT/RR correction factors to be tailored for each drug studied.     

Variability of heart rate correction methods for the QT interval

AIMS: To compare variability of heart rate-corrected QT intervals (QTc) using three different methods in a study of low-dose oral haloperidol. METHODS: In a randomized, double-blind, placebo-controlled, crossover trial, we studied QT interval pharmacodynamics of single doses of oral haloperidol (10 mg) in 16 healthy subjects. Heart rate correction of the QT interval was performed using Bazett's, Fridericia's and subject-specific correction methods. The subject-specific correction was performed using linear mixed modelling of placebo period QT vs RR data from each study subject. RESULTS: The subject-specific correction, in the form of QTc = QT/RRalpha, yielded a correction term alpha (slope of the log-transformed QT vs RR relationship) that ranged from 0.23 to 0.38 in individual subjects, i.e. the fixed correction term alpha = 0.5 of Bazett's correction was outside and the fixed correction term alpha = 0.33 of Fridericia's correction inside the range of individual values. The mean absolute slope of the QTcvs RR regression line using the subject-specific correction was significantly lower than the mean slopes obtained using either Bazett's or Fridericia's corrections. All three methods revealed a statistically significant greater mean QTc on haloperidol than on placebo at 10 h post-drug administration. The mean QT (95% CI) was 421.6 (410.8, 432.4), and 408.4 (398.6, 417.8) on haliperidol and placebo, respectively, using the subject-specific correction method (P = 0.0053). The mean QTc (95% CI) was 425.4 (414.3, 436.5) and 403.1 (394.3, 411.9) on haliperidol and placebo, respectively, using Bazett's correction (P = 1.7 x 10-5) and 423.1 (412.6, 433.6) and 408.2 (398.6, 417.8) on haliperidol and placebo, respectively, using Fridericia's correction (P = 7.7 x 10-4). Raw P-values were calculated using a paired t-test. Bonferroni-corrected P-values were calculated by multiplying the raw P-values by 13. CONCLUSION: Haloperidol caused a statistically significant mean QTc prolongation using the three correction methods. The QTc intervals were less dependent on RR intervals using the subject-specific method, thus decreasing the possibility of over- or under-correction. The interindividual QTc changes from baseline varied significantly depending on the method of correction used.     

Systolic time interval v heart rate regression equations using atropine: reproducibility studies.

1. Systolic time intervals (STI) were recorded in six normal male subjects over a period of 3 weeks. On one day per week, each subject received incremental doses of atropine intravenously to increase heart rate, allowing the determination of individual STI v HR regression equations. On the other days STI were recorded with the subjects resting, in the supine position. 2. There were highly significant regression relationships between heart rate and both LVET and QS2, but not between heart rate and PEP. 3. The regression relationships showed little intra-subject variability, but a large degree of inter-subject variability: they proved adequate to correct the STI for the daily fluctuations in heart rate. 4. Administration of small doses of atropine intravenously provides a satisfactory and convenient method of deriving individual STI v HR regression equations which can be applied over a period of weeks.     

Systemic availability of oral verapamil and effect on PR interval in man.

1 The plasma levels of verapamil and its major metabolite norverapamil were related to its effect as a Ca-antagonist on atrio-ventricular (AV) conduction, judged from prolongation of the PR interval in six normal volunteers. 2 Intravenous administration (0.1 mg kg-1) was compared to oral administration (120 mg) in each subject. 3 Intravenous verapamil showed a mean distribution half-life (alpha) of 8.5 min and elimination half-life (beta) of 2.0 h. The volume of distribution was about 112.1. Oral dosage gave an elimination half-life of 2.7 h, and a norverapamil half-life which averaged 4.6 h. The bioavailability of the oral dose averaged 22% (17 to 29%). 4 After the oral dose the percentage change in PR interval in the five appropriate subjects correlated significantly with the log plasma verapamil level (r = 0.732), but not with the log plasma norverapamil level (r = 0.078); norverapamil could not be detected after the intravenous dose. One subject developed Wenckebach type second degree AV block after each dose.     

兰地洛尔对Ⅱ型糖尿病患者气管插管心率变异性及QT间期的影响

目的：评价兰地洛尔在麻醉诱导气管插管时对Ⅱ型糖尿病患者心率变异性（HRV）和QT间期的影响。方法： 40例择期实施气管插管全麻手术的糖尿病患者,ASA分级Ⅱ级,随机分为兰地洛尔组（L组,n=20）和对照组（C组,n=20）,比较插管前后心率变异性和QT间期的变化。L组在插管前 2 min 静脉缓慢注射兰地洛尔 0.1 mg·kg-1·min-1 1 min,然后以 0.04 mg·kg-1·min-1 的速度持续输注至插管后 5 min;C组给予等量生理盐水。记录麻醉诱导前（T0）、插管即刻（T1）、插管后1min（T2）、插管后3min（T3）、插管后5min（T4）时HRV各参数、心率（HR）、平均动脉压（MAP）、QT间期的变化。结果：T1-4时,L组低频高频比（LF／HF）显著低于C组;C组QT1C显著长于T0时（P〈0．05）,且明显长于I。组（P〈0．05）。结论：兰地洛尔可降低LF／HF,有效抑制交感神经活性,维持交感副交感神经相对均衡,缩短与气管插管有关的QT间期的延长,可能与其抑制交感神经活性,维持交感副交感神经相对均衡有关,可降低糖尿病患者麻醉期间心脏意外的风险。     

A possible association between high normal and high dose olanzapine and prolongation of the PR interval

Two cases of light-headedness or 'fainting' in patients with schizophrenia treated with olanzapine are presented. Electrocardiogram investigation revealed first-degree heart block on high normal and high dose olanzapine, which normalized after dose reduction.     

Effects of dose and interdose interval on conditioned heart rate tolerance to smoking

The effects of an environmental cue and smoking administration on heart rate (HR) responses to smoking were investigated in 2 studies. The 1st study was performed without smoking, to rule out the possibility that the cue manipulations alone could produce HR habituation. Thirty-six male nonsmokers were exposed to 6 trials of a changing or repeating cue (segments of a story on audiotape), followed by a paced-breathing period. HR habituation was not found. In the 2nd study, 40 male smokers smoked 4 puffs every 10 min (small-dose/long-interdose interval [IDI]) or 6 puffs every 5 min (large-dose/short-IDI) in 6 trials. The same repeating or changing cue preceded smoking. Only the repeating-cue, small-dose/long-IDI group developed HR tolerance. Modifying the cue on Trial 6 did not reverse tolerance. The results indicated that (a) tolerance to smoking appears to be subject to conditioning, (b) this effect depends on the dose and IDI, and (c) the observed tolerance is not likely to be a result of the effects of the cue alone. Nonassociative tolerance to smoking a high-dose/short-IDI did not occur in this study.     

心肌梗死患者QT间期变异性和心率变异的分析

目的　探讨 QT间期变异性 (QTV)、QT间期变异系数 (QTCV )在心肌梗死患者中的意义 ,两指标与心率变异性 (HRV)是否有联系以及联系的强度。方法　对 5 4例诊断明确的心肌梗死患者和 5 0名正常人进行 2 4 h动态心电图的 QTV、QTCV、HRV的对比分析。结果　心肌梗死患者和对照组的 QTV (2 0± 6比 2 9± 9,P=0 .0 0 0 1)和 QTCV(0 .0 5 4± 0 .0 16比 0 .0 76± 0 .0 2 4 ,P=0 .0 0 0 1)差异有显著性 ;各组中 HRV和 QTV有弱相关性 (P<0 .0 5 ) ,HRV和 QTCV无相关 (P>0 .0 5 )。结论　心肌梗死患者 QTV、QTCV减低 ,HRV的变化几乎不影响两者的变化 ,QTV和 QTCV可能成为预测心律失常的新指标     

儿童血管迷走性晕厥与QT间期离散度及心率变异性分析

目的探讨儿童血管迷走性晕厥（VVS）与QT间期离散度（QTd）及心率变异性（HRV）的变化。方法采用12导联同步心电图及动态心电图对52例VVS患儿及30例健康儿童的QTd及HRV进行测量。结果VVS患儿QTd，校正QT间期离散度和最长QT间期较对照组显著增人，具有显著性差异；直立倾斜试验（HUTT）阳性组和阴性组间QTd值比较无显著差异性。SDNN、SDANN及RMDNN病例组较对照组减小，且病例组SDNN、RMDNN与对照组相比有显著差异性；HUTT阳性组和阴性组间HRV无显著差异。结论VVS的发病机制与交感神经和副交感神经调节障碍有关。HUTT作为诊断VVS的金标准，其阴性者不能除外VVS。QTd、HRV对VVS患儿发生心肌缺血、心律失常等心血管事件具有一定的预测价值。     

高血压左室肥厚QT间期离散度与室性心律失常及心率变异性之间关系的探讨

目的 探讨高血压左室肥厚（ＬＶＨ）和非左室肥大（ＮＬＶＨ）ＱＴ间期离散度（ＱＴｃｄ）与室性心律失常及心率变异性（ＨＲＶ）之间的关系。关系 对８６例高血压患者分为有或无左室肥厚两组进行ＱＴｃｄ与２４ｈ动态心电图及ＨＲＶ测定。结果 发现高血压ＬＶＨ组的ＱＴｃｄ延长和室性心律失常明显高于高血压ＮＬＶＨ组（Ｐ〈０．０１）,而高血压ＬＨＶ组的ＨＲＶ明显低于高血压ＮＬＶＨ组（Ｐ〈０．０１）。结论 高血压ＬＶＨ     

慢性心力衰竭患者心率变异性与心功能的相关性研究

目的 探讨慢性心力衰竭(CHF)患者心率变异性(heart rate variability,HRV)的特点及与心功能的相关性.方法 对59例CHF患者和65例健康对照者,行24小时动态心电图(Holter)监测,对比分析其HRV,并比较不同程度CHF患者HRV的差异.结果 HRV指标中,CHF组低频功率与高频功率比值...