Pharmacokinetics and pharmacodynamics of tenecteplase in fibrinolytic therapy of acute myocardial infarction

Tenecteplase is a novel fibrinolytic protein bioengineered from human tissue plasminogen activator (alteplase) for the therapy of acute ST-segment elevation myocardial infarction. Specific mutations at three sites in the alteplase molecule result in 15-fold higher fibrin specificity, 80-fold reduced binding affinity to the physiological plasminogen activator inhibitor PAI-1 and 6-fold prolonged plasma half-life (22 vs 3.5 minutes). Consequently, tenecteplase can be administered as a single intravenous bolus of 30-50mg (0.53 mg/kg bodyweight) over 5-10 seconds, in contrast to the 90-minute accelerated infusion regimen of alteplase. Tenecteplase plasma concentration-time profiles have been obtained from a total of 179 patients with acute myocardial infarction. Tenecteplase exhibited biphasic disposition; the initial disposition phase was predominant with a mean half-life of 17-24 minutes, and the mean terminal half-life was 65-132 min. Over the clinically relevant dose range of 30-50mg, mean clearance (CL) was 105 ml/min. The mean initial volume of distribution V(1) was 4.2-6.3L, approximating plasma volume, and volume of distribution at steady state was 6.1-9.9L, suggesting limited extravascular distribution or binding. Bodyweight and age were found to influence significantly both CL and V(1). Total bodyweight explained 19% of the variability in CL and 11% of the variability in V(1), and a 10kg increase in total bodyweight resulted in a 9.6 ml/min increase in CL. This relationship aided the development of a rationale for the weight-adjusted dose regimen for tenecteplase. Age explained only a further 11% of the variability in CL. The percentage of patients who achieved normal coronary blood flow was clearly related to AUC. More than 75% of patients achieved normal flow at 90 minutes after administration when their partial AUC(2-90) exceeded 320 microg.min/ml, corresponding to an average plasma concentration of 3.6 microg/ml. Systemic exposure to tenecteplase at all times after bolus administration of 30-50mg was higher than for alteplase 100mg. Tenecteplase has demonstrated equivalent efficacy and improved safety compared with the current gold standard alteplase in a large mortality trial (ASSENT-2). This suggests that the reduced clearance, greater fibrin specificity and higher PAI-1 resistance of tenecteplase allow higher plasma concentrations and thus a more rapid restoration of coronary patency to be attained, while providing a reduction in major non-cerebral bleeding events.     

Safety and efficacy of tenecteplase in acute myocardial infarction

The use of intravenous thrombolytic agents has revolutionised the treatment of acute myocardial infarction. However, the improved mortality achieved with these drugs is tempered by the risk of serious bleeding complications, especially intracranial haemorrhage (ICH). Tenecteplase (TNKase, Genetech Inc.) is an engineered variant of alteplase (Activase, Genentech Inc.) designed to have increased fibrin specificity, greater efficacy and a longer half-life. The longer half-life of tenecteplase compared to alteplase allows for convenient single bolus administration of the drug. In addition, tenecteplase dosing is based on actual or estimated patient weight, which enhances both the safety and efficacy outcomes. Large clinical trials have demonstrated equivalence in mortality and ICH between tenecteplase and alteplase. Compared to alteplase, tenecteplase use leads to lower rates of bleeding complications and a decreased risk of ICH among low weight, elderly women.     

Safety and efficacy of tenecteplase in acute myocardial infarction

The use of intravenous thrombolytic agents has revolutionised the treatment of acute myocardial infarction. However, the improved mortality achieved with these drugs is tempered by the risk of serious bleeding complications, especially intracranial haemorrhage (ICH). Tenecteplase (TNKase?, Genetech Inc.) is an engineered variant of alteplase (Activase^®, Genentech Inc.) designed to have increased fibrin specificity, greater efficacy and a longer half-life. The longer half-life of tenecteplase compared to alteplase allows for convenient single bolus administration of the drug. In addition, tenecteplase dosing is based on actual or estimated patient weight, which enhances both the safety and efficacy outcomes. Large clinical trials have demonstrated equivalence in mortality and ICH between tenecteplase and alteplase. Compared to alteplase, tenecteplase use leads to lower rates of bleeding complications and a decreased risk of ICH among low weight, elderly women.     

Pharmacokinetics of intravenous mexiletine in patients with acute myocardial infarction

Acute myocardial infarction (AMI) is known to alter the pharmacokinetics of several antiarrhythmic agents. To study the effects of AMI on the kinetics of mexiletine (MEX), a single intravenous dose of 200 mg MEX HCl was infused over 30 min in 11 patients with AMI. The study was performed within 24 h of the onset of pain (study I) and repeated about 2 weeks later in seven patients at discharge (study II). MEX was quantitated in plasma and urine samples by a gas-liquid chromatographic method. The decline of MEX in plasma was three-exponential, with a terminal half-life of 14.7 +/- 3.4 (mean +/- SE) h in study I and 11.3 +/- 2.4 h (p less than 0.05) in study II, in the seven patients studied in both phases. The steady-state volume of distribution averaged 578 +/- 97 L in study I and 415 +/- 33 L in study II (p less than 0.05). The total plasma clearance, renal clearance, and recovery of MEX in urine were similar in the two studies, as was the plasma protein binding of MEX (64 +/- 2 vs. 57 +/- 3%, NS). Thus, an increase in the volume of distribution with consequent prolongation of the elimination half-life of MEX occurs in the acute phase of AMI, whereas the rate of elimination remains unchanged.     

Pharmacokinetics of intravenous timolol in patients with acute myocardial infarction and in healthy volunteers

Summary Disappearance pharmacokinetics, pharmacodynamics and general tolerance of i.v. timolol were compared in 12 healthy volunteers and 10 patients with a definite or proven acute myocardial infarction. The drug was administered to the patients immediately on arrival at the hospital after a median delay time of 4 h. Tolerance to the injections was good in both volunteers and patients. The study revealed disappearance pharmacokinetics that were similar in volunteers and patients.     

急性心肌梗死患者血浆NT-ProBNP预后相关性研究

目的：探讨血浆NT-ProBNP水平在急性心肌梗死患者预后中的价值。方法：选取本院2010年1月～2011年1月收治的36例急性心肌梗死患者,并抽取同期48例非心肌梗死心衰者（对照组）,比较两组入选者NT-ProBNP水平,同时在患病组中分析重构与非重构、不同心功能分级NT-ProBNP水平的差异。结果：患病组NT-ProBNP水平明显高于对照组（P〈0.05）;重构组NT-ProBNP水平高于非重构组（P〈0.05）;心功能级别越高,NT-ProBNP水平越高（P〈0.05）。结论：血浆、NT-ProBNP水平能够作为急性心肌梗死患者早期诊断和预后的指标之一。     

急性心肌梗塞早期血钾含量的临床研究

目的：探讨急性心肌梗塞（AMI）患者早期血钾含量与室性心律失常和梗塞部位的关系。方法：测定60例AMI发病6h内的血钾含量,室性心律失常发生率及梗塞部位,并分析其相关性,结果：不同梗塞部位组间血钾含量,经统计学处理有显著差异（P＜0．05）,血钾低于3．5mmol/L的以右室,前壁梗塞为主,低血钾组室性心律失常的发生率为92．11％,结论：右室,前壁易发生低钾血症,低血钾症易发生心律失常,故AMI早期应及时补钾,提高AMI抢救成功率。     

Mortality of patients with acute myocardial infarction

Summary

Pentazocine does not cause the hypotension associated with the use of opiates in patients with myocardial infarction but some haemodynamic studies have suggested that the drug could be hazardous. An analysis is described of 457 consecutive patients admitted to a Coronary Care Unit, of whom 250 (55%) received pentazocine for relief of chest pain, while the remainder did not require analgesics and, therefore, acted as a control.

Utilising a coronary prognostic index no significant difference in the mortality rate between the two groups was demonstrated, nor was the mortality dependent on the total dosage. Furthermore, no clinical disadvantage arose from the administration of pentazocine to patients with elevated systolic blood pressure on admission.     

舒适护理在急性心肌梗死患者康复中的应用

目的探讨使急性心肌梗死患者早日康复、减少并发症、提高治疗满意度的方法。方法通过舒适护理,提供优质护理服务,使患者达到心理、生理、精神、社会等方面的愉悦,减少并发症,和谐医患关系,减少纠纷,提高治疗满意度。结果本组128例患者通过舒适护理无并发症及医患纠纷发生,对治疗护理满意度达100%。结论舒适护理在急性心肌梗死患者中的应用,不但及时解除患者生理上的疾苦,而且使患者心理、精神、社会等方面处于愉快状态,对患者的康复具有巨大的促进作用。     

Disopyramide pharmacokinetics in patients with acute myocardial infarction

To study the effects of acute myocardial infarction on the pharmacokinetics of disopyramide a single oral dose of disopyramide base (200 mg) was administered to 6 patients with myocardial infarction both in the acute (Study I) and recovery (Study II) phases. An intravenous tracer dose of 14C-disopyramide (2.5 micrograms/0.3 mg) was given simultaneously with the oral dose. On the basis of the intravenous tracer data, the volume of distribution, binding to plasma proteins, total plasma clearance, renal clearance and elimination half-life of disopyramide and mono-N-dealkyl disopyramide were the same in Studies I and II. The peak serum concentrations of disopyramide after oral dosing in Studies I and II were 2.6 +/- 1.2 (SEM) and 6.4 +/- 1.9 microgram/ml, respectively (p less than 0.05), the peak times 3.29 +/- 1.22 and 1.21 +/- 0.39 h (N.S.) and the AUCINF 38.0 +/- 7.7 and 60.7 +/- 9.9 micrograms . h . ml-1 (p less than 0.05). The recovery of disopyramide in urine over 3 days averaged 46% and 47% of dose, and that of mono-N-dealkyl disopyramide 22% and 16% of the dose, respectively. Thus, the gastrointestinal absorption of disopyramide was disturbed, resulting in low plasma concentrations after oral dosing, whereas the elimination of disopyramide was unaltered in the acute phase of myocardial infarction.     

瑞舒伐他汀与阿托伐他汀对急性心肌梗死患者心肌纤维化干预的对照研究

目的 探讨不同类型、不同剂量的他汀类药物对急性心肌梗死（AMI）患者心肌纤维化干预的效果,找到更为安全可靠的AMI治疗药物。方法 选取中国中医科学院望京医院2016年2月-2018年1月收治的AMI患者160例,根据随机数字表法分为4组,各40例。A组采用常规剂量阿托伐他汀（20 mg/次,1次/d）,B组采用负荷剂量阿托伐他汀（40 mg/次,1次/d）,C组采用常规剂量瑞舒伐他汀（10 mg/次,1次/d）,D组采用负荷剂量瑞舒伐他汀（20 mg/次,1次/d）。治疗前、治疗1周、治疗4周,分别检测并比较4组患者血脂指标、炎性指标[超敏C反应蛋白（hs-CRP）、白细胞介素-6（IL-6）]、心肌纤维化指标[转化生长因子β1（TGF-β1）、Ⅰ型前胶原羟基末端肽（PICP）、半乳凝素-3（Gal-3）、结缔组织生长因子（CTGF）、Ⅲ型前胶原氨基端肽（PⅢNP）及Ⅰ型胶原羟基末端肽（ⅠCTP）],同时观察安全性。结果 治疗前,4组患者血脂指标、炎性指标、心肌纤维化指标水平比较,差异均无统计学意义;治疗1、4周后,4组患者血脂指标、炎性指标均改善,且D组改善最为显著,与其他3组比较,差异有统计学意义（P<0.05）;治疗1周,4组患者心肌纤维化指标水平均升高,且A组升高最为显著（P<0.05）;治疗4周后,4组患者各心肌纤维化指标水平均较治疗1周有降低,但D组降低幅度最为显著,后依次为C组、B组、A组,组间比较差异有统计学意义（P<0.05）。全部患者在治疗期间均未发生明显不良反应。结论 瑞舒伐他汀对AMI患者血脂、炎性反应、心肌纤维化的影响较阿托伐他汀更佳,在为患者加大负荷剂量后,心肌纤维化改善效果提升,药物毒副反应未增加,故在AMI耐受的条件下可为其使用大剂量瑞舒伐他汀治疗。     

Pharmacokinetics and haemodynamic effects of tocainide in patients with acute myocardial infarction complicated by left ventricular failure.

The pharmacokinetics and haemodynamic effects of tocainide, an orally active structural analogue of lignocaine, were studied in patients with acute myocardial infarction complicated by left ventricular failure. Fourteen patients (mean age 65 years) with acute myocardial infarction complicated by mild left ventricular failure were studied, following a single dose of tocainide (250 mg) by intravenous infusion, over 30 min. Heart rate, systemic arterial pressure, pulmonary artery pressure and cardiac output were monitored. Plasma tocainide levels were estimated by gas chromatography. The mean plasma level of tocainide achieved was 2.95 micrograms/ml (15.37 mmol/l). The mean plasma half-life was 15.6 h. The mean cardiac index was reduced 5 min after completion of the infusion, from 2.24 1 min-1 m-2 (+/- 0.40) to 2.07 1 min-1 m-2 (+/- 0.29) (P less than 0.01). At 90 min the cardiac index had returned to pre-treatment levels. Small changes were seen in the heart rate, arterial blood pressure and the pulmonary artery pressure but these changes were not statistically significant. The pharmacokinetics of tocainide were not significantly altered in patients with acute myocardial infarction complicated by mild left ventricular failure.     

心脏电机械标测系统对急性心肌梗死患者存活心肌的标测

目的探讨研究心脏电机械标测系统(NOGA)对急性心肌梗死(AMI)患者存活心肌的标测。方法11例AMI患者持续性胸痛发作12 h内急诊入院,急诊行经皮冠状动脉介入治疗(PCI)后第7天分别进行NOGA标测、心脏超声及核素心肌显像测定。结果NOGA系统测定出梗死区域的单极电压(UVP)显著低于非梗死区域[(6.8±3.1)与(10.9±3.1)mV,P<0.01],同时梗死区域内膜下心肌短缩率(LLS)明显小于非梗死区域心肌[(4.3±3.5)与(10.4±5.5)%,P<0.01]。特征性曲线分析NOGA判断心肌存活状态的UVP界定值为8.0 mV(敏感性及特异性均为73%)。结论LLS与心肌核素扫描及心脏超声相关性良好,当UVP≥8.0 mV时提示心肌处于存活状态。     

瑞替普酶和尿激酶治疗急性心肌梗死的临床研究

目的对比观察瑞替普酶（r-PA）与尿激酶用于急性心肌梗死（AMI）静脉溶栓治疗的效果及安全性。方法将98例发病12h内的AMI患者随机分为2组：瑞替普酶组48例,瑞替普酶10MU间隔30min分2次静脉推注;尿激酶组50例,150万U30min内静脉滴注。观察两组溶栓再通率、急性期病死率、心肌梗死并发症和不良事件发生率。结果溶栓后120min瑞替普酶组临床判断再通率高于尿激酶组,两组差异有显著性意义（P〈0．05）。瑞替普酶组48例,41例显示梗死相关血管再通为85．42％;尿激酶组50例,36例相关血管再通为72％。35d瑞替普酶组死亡2例（4．16％）,尿激酶组死亡5例（10％）。结论瑞替普酶静脉溶栓治疗AMI比较安全,尿激酶能更早地使梗死相关血管开通,并有较高的血管开通率及较低的急性期病死率。     

Use of nitrates in patients with acute myocardial infarction

The use of nitrates in treating acute myocardial infarction is reviewed; proposed mechanisms of action and pertinent pathophysiology are discussed. Oral and sublingual nitrates were first tested in acute myocardial infarction patients with mixed results. Later studies with sublingual nitroglycerin followed by phenylephrine infusion indicated that nitrates were effective in limiting myocardial ischemia and necrosis. I.V. nitroglycerin was then studied; beneficial results were documented by quantifying ECG changes and visualizing the areas of myocardial necrosis with radioisotopes. Mortality was also reduced in nitrate-treated patients. Patients who developed left ventricular failure after acute myocardial infarction benefitted the most from nitrate therapy. The preferred route of nitroglycerin administration is intravenous infusion. The dose is initially 5 micrograms/min and is increased by 5-10 micrograms/min every 5-10 minutes until mean arterial pressure is reduced 10-20% or pulmonary capillary wedge pressure is reduced to 15 mm Hg. Final infusion rates average 40-60 micrograms/min. Nitrates appear to have a role in reducing morbidity and mortality from acute myocardial infarction.