Logical approach to lignocaine therapy.

Plasma lignocaine concentrations were measured during and after lignocaine infusions administered for suppressing ventricular dysrhythmias. Twenty-four patients with a primary diagnosis of acute myocardial infarction without gross circulatory disturbance received, after a bolus of lignocaine, either 4 mg/min for 30 minutes, 2 mg/min for two hours, then 1 mg/min thereafter or 1 mg/min throughout. The higher dose regimen produced continous therapeutic levels of lignocaine, which were achieved only after four hours by the lower dose. On the other hand, in patients who had undergone cardiac surgery and who had circulatory and heptic dysfunction the lower dose regimen achieved therapeutic levels early. The plasma half life was longer in the surgical group (P less than 0.02). The higher initial infusion rate is recommended for patients with acute myocardial infarction without gross circulatory impairment.     

胺碘酮与艾司洛尔治疗老年患者急性心肌梗死合并室性心律失常的短期疗效与安全性比较

目的 比较老年急性心肌梗死（AMI）合并严重室性心律失常患者静脉应用胺碘酮或艾司洛尔48 h内疗效及不良反应,为临床安全用药提供依据. 方法 2009年1月至2013年6月在中国医科大学附属盛京医院心脏内科连续住院治疗的老年AMI合并严重室性心律失常患者纳入研究,分为胺碘酮组与艾司洛尔组.胺碘酮组患者在10 min内静脉注射胺碘酮150 mg＋ 5％葡萄糖注射液20 ml后经微量注射泵静脉输注胺碘酮1 mg/min共6h,减量至0.5 mg/min静脉输注24～48 h,之后口服胺碘酮0.2g,3次/d,共7d.艾司洛尔组患者在1 min内静脉注射艾司洛尔注射液0.5 mg/kg后经微量注射泵静脉输注艾司洛尔0.1 mg/（kg·min）共6h,减量至0.05 mg/（kg·min）静脉输注24 ～ 48 h,之后口服美托洛尔25 mg,2次/d,共7d.胺碘酮组和艾司洛尔组静脉应用胺碘酮或艾司洛尔6h后仍有室速发作者,分别加用上述艾司洛尔或胺碘酮治疗方案.比较2组患者治疗48 h内有效率和不良反应发生率. 结果 胺碘酮组和艾司洛尔组48 h内有效率分别为92.1％（35/38）和75.0％（27/36）,组间差异有统计学意义（P=0.046）;不良反应发生率分别为39.5％（15/38）和19.4％（7/36）,组间差异无统计学意义（P =0.060）.胺碘酮组2例伴有心力衰竭患者静脉用药24 h后出现急性肝损伤,停药并对症治疗2周后肝功能恢复正常. 结论 静脉应用胺碘酮治疗老年患者AMI合并严重室性心律失常有效率优于艾司洛尔.胺碘酮与艾司洛尔均较安全.高龄AMI且伴心力衰竭者静脉应用胺碘酮时需密切监测肝功能,出现肝损伤需立即停药并给予对症治疗.     

BB-882 is a Potent Antagonist of the Haemodynamic Changes Induced by Platelet-Activating Factor in Pigs

Abstract: The effects of bolus doses (0.2-2 μg) of platelet-activating factor (PAF) on systemic and pulmonary arterial pressures were tested in five juvenile pigs, and were demonstrated to have a biphasic effect. There was an initial drop in the mean systemic arterial pressure within seconds, followed by an increase within 1-2 min., whereas mean pulmonary arterial pressure only rose. The response was dose-related and did not include tachyphylaxis. The pressures returned to baseline within 10 min. After confirming these results a novel specific PAF receptor antagonist (BB-882) was given as a 1 mg/kg bolus followed by a continous infusion of 2 mg/kg/hr, and a third dose response curve was repeated with ten-fold higher PAF doses (2-20 μg). BB-882 effectively counteracted these effects. Six pigs were given a continous infusion of BB-882 33 mg/kg/hr for 5 hr and were compared with another group of five pigs given vehicle only. In this high dose BB-882 did not affect the intravascular pressures. These results indicate that BB-882 is a potent PAF receptor antagonist in juvenile pigs.     

The pharmacokinetics and pharmacodynamics of lignocaine and MEGX in healthy subjects

Lignocaine clearance declines during continuous intravenous infusion in man and in vitro studies suggest that this may partly be due to inhibition by MEGX, a metabolite of lignocaine. MEGX is pharmacologically active in animals, but this is not yet proven in man. This study examined the pharmacokinetics and pharmacodynamics of lignocaine and MEGX in eight healthy male volunteers given lignocaine HCl 120 mg, MEGX HCl 120 mg, lignocaine HCl 120 mg + MEGX HCl 120 mg, and placebo, administered according to a randomized double-blind protocol. One-, two-, or three-compartment models were fitted to drug and metabolite blood concentration-time profiles and clearance, volume (Vss), and half-life values were calculated and compared by paired t-test. Systolic time intervals and QT interval were recorded and compared by repeated measures ANOVA. When administered in combination with MEGX, lignocaine clearance was significantly reduced from 58 +/- 18 to 48 +/- 13 L hr-1 (p less than 0.02). The Vss was unchanged and there was a trend toward an increase in terminal half-life. Lignocaine, MEGX, and the combination significantly reduced QT interval up to 30 min after injection and this was maintained to 2 hr with the lignocaine and the combination. Transient side effects were experienced with all active treatments, but were most pronounced with the combination. Thus, lignocaine clearance was inhibited by MEGX, which was pharmacologically active in man.     

静脉注射胺碘酮治疗老年充血性心力衰竭伴房颤

目的观察静脉注射胺碘酮治疗老年充血性心力衰竭并发心房颤动的有效性及安全性。方法对56例充血性心力衰竭伴房颤患者,给予胺碘酮150mg,15～20min后无效再给予75mg,之后以0．5～1．0mg/min静脉滴注24h(24h总量＜1200mg)。结果平均负荷量为150～300(170±38)mg,38例转为窦性心律,转复率67．9%,18例仍为房颤,但心室率下降为100次/min以下,不良反应发生率10．7%,无1例心功能恶化。结论静脉注射胺碘酮治疗老年充血性心力衰竭并心房颤动是有效和安全的。     

胺碘酮不同给药途径治疗非瓣膜病快心室率房颤的疗效

目的本研究主要观察胺碘酮静脉(急性)和口服(慢性)两种不同给药途径治疗非瓣膜病快心室率房颤的临床效果及安全性。方法 156例非瓣膜病快心室率房颤患者随机分为两组,A组82例,先用胺碘酮5μg/kg静脉注射15min(负荷量),接着以1～1.5mg/min的速度静脉滴注,维持24～48h,同时口服胺碘酮200mg/d;B组74例,口服胺碘酮600mg/d。给药后持续心电及血压监测,每日记录心电图变化,观察2组间转复时间及24h、48h、1周、1月的转复率。结果两组的房颤转复率没有差别(P>0.05),但A组的房颤转复时间明显缩短(P<0.05)。给药后1周、1月两组均未转律仍保持房颤的患者心室率明显降低(P<0.05)。A组有2例浅静脉炎。两组患者在用药后血压一直保持稳定。结论胺碘酮可有效地治疗非瓣膜病快心室率房颤,静脉用药可显著缩短房颤的转复时间,有效降低心室率,安全可靠。     

Effects of lignocaine and propranolol on experimental cardiac arrhythmias

1. The effects of intravenous injection of lignocaine and propranolol were studied in dogs.2. Ventricular ectopic beats produced by intravenous injection of adrenaline in anaesthetized dogs respired with halothane were abolished in four out of six dogs by lignocaine. Propranolol was effective in all three dogs tested.3. Intravenous infusion of lignocaine at (0.2 and 1.0 mg/kg)/min to total doses of 3.0 +/- 1.0 and 2.2 +/- 0.5 mg/kg, respectively, abolished the ventricular tachycardia produced in anaesthetized dogs by ouabain. A similar effect was produced by infusion of propranolol at (0.2 mg/kg)/min to a total dose of 1.9 +/- 0.4 mg/kg. Intravenous injection of single doses of lignocaine (4.0-8.0 mg/kg) also abolished the arrhythmia.4. The frequency of the ventricular ectopic beats occurring in conscious dogs 20-44 h after ligation of the anterior descending branch of the left coronary artery was reduced, with an increase in the number of sinus beats, after intravenous injection of lignocaine (8.0 mg/kg). Larger doses produced excitement. Propranolol (4.0 mg/kg) had a greater effect than the same dose of lignocaine but after 8.0 mg/kg, three of the four dogs died.5. Propranolol was more effective than lignocaine in abolishing the three different types of arrhythmia.6. Dose-response curves showed that lignocaine was more active in abolishing the ouabain induced arrhythmia than the halothane-adrenaline arrhythmia and was least active on the arrhythmia caused by ligation of the coronary artery.     

Effect of glucagon on amitriptyline-induced cardiovascular toxicity in rats

The aim of this study was to investigate the effect of glucagon on cardiovascular parameters in anesthetized rat model of tricyclic antidepressant overdose. Toxicity was induced by infusion of amitriptyline 0.94 mg/kg/min until a 40-45% of reduction in mean arterial pressure was observed. Amitriptyline infusion rats were then randomized into three groups. Control group of rats (group 1) received a bolus of 5% dextrose followed by the continuous infusion of dextrose, whereas treatment groups received 1 mg/kg (group 2) or 2 mg/kg (group 3) bolus doses of glucagon followed by continuous infusion (0.1 mg/kg/min) of glucagons for 60 min. Mean arterial pressure, heart rate, and electrocardiogram were recorded. Amitriptyline caused a significant decrease in mean arterial pressure and a prolongation in QRS, yet it did not change the heart rate. High-bolus dose of glucagon (2 mg/kg) followed by glucagon infusion significantly increased mean arterial pressure at 40, 50, and 60 min (P < 0.05) and shortened the prolonged QRS at 50 and 60 min (P < 0.05) when compared with control group. There was also a significant increase in heart rate. In conclusion, bolus doses followed by a continuous infusion of glucagon were found to be effective in reversing the hypotension and QRS prolongation in the rat model of amitriptyline toxicity. Further studies are needed to reveal the exact mechanism of the proposed effect.     

Minimal toxicity to myeloid progenitor cells of weekly 24-hr infusion of high-dose 5-fluorouracil: direct evidence from colony forming unit-granulocyte and monocyte (CFU-GM) clonogenic assay

Although very high doses of 5-fluorouracil was used in the weekly 24-h infusion, high-dose 5-fluorouracil (2600 mg/m2/week) and leucovorin (500 mg/m2/week) protocol, myelosuppression was surprisingly low. The current study was conducted to investigate the possible mechanism underlying the low myelosuppression. To mimic the clinical situation, peripheral blood progenitor cells collected from 12 patients were used for colony forming unit-granulocyte and monocyte clonogenic assay; and 2 representative modes of 5-fluorouracil exposure (30 min. versus 24 hr) were examined for cytotoxic effects on human myeloid progenitor cells. Previous pharmacokinetic studies have estimated the concentrations of 5-fluorouracil in the bone marrow to be 200-400 microM and 1-2 microM for the 30 min. infusion (600-900 mg/m2) and the 24 hr-infusion (1000-2000 mg/m2) regimens, respectively. The results of our colony-forming unit-granulocyte and monocyte clonogenic assay showed that 24-hr exposure to 5-fluorouracil (2 microM) and 30 min. exposure to 5-fluorouracil (100 microM) resulted in 27.2% and 78.2% inhibition of the colony formation, respectively. Our data provided direct evidence which may explain why myelotoxicity is significantly less in weekly 24 hr infusion of fluorouracil than in the conventional bolus regimens.     

Minimal Toxicity to Myeloid Progenitor Cells of Weekly24‐Hr Infusion of High‐Dose 5‐Fluorouracil: Direct Evidence from Colony Forming Unit‐Granulocyte andMonocyte (CFU‐GM) Clonogenic Assay

Although very high doses of 5‐fluorouracil was used in the weekly 24‐h infusion, high‐dose 5‐fluorouracil (2600 mg/m²/week) and leucovorin (500 mg/m²/week) protocol, myelosuppression was surprisingly low. The current study was conducted to investigate the possible mechanism underlying the low myelosuppression. To mimic the clinical situation, peripheral blood progenitor cells collected from 12 patients were used for colony forming unit‐granulocyte and monocyte clonogenic assay; and 2 representative modes of 5‐fluorouracil exposure (30 min. versus 24 hr) were examined for cytotoxic effects on human myeloid progenitor cells. Previous pharmacokinetic studies have estimated the concentrations of 5‐fluorouracil in the bone marrow to be 200–400 μM and 1–2 μM for the 30 min. infusion (600–900 mg/m²) and the 24 hr‐infusion (1000–2000 mg/m²) regimens, respectively. The results of our colony‐forming unit‐granulocyte and monocyte clonogenic assay showed that 24‐hr exposure to 5‐fluorouracil (2 μM) and 30 min. exposure to 5‐fluorouracil (100 μM) resulted in 27.2% and 78.2% inhibition of the colony formation, respectively. Our data provided direct evidence which may explain why myelotoxicity is significantly less in weekly 24 hr infusion of fluorouracil than in the conventional bolus regimens.     

Pharmacokinetics of mexiletine in the elderly

The effect of advancing age on the kinetics of the antiarrhythmic agent mexiletine was studied by comparing various kinetic parameters calculated after administration of a single oral dose of mexiletine hydrochloride to seven elderly and eight young healthy volunteers. The rate of absorption of the drug from the gastrointestinal tract was significantly slower in the elderly (1.37 +/- 0.51 hr-1) than in the young group (2.25 +/- 0.79 hr-1). The mean values for elimination half-life and oral clearance were 12.3 +/- 3.7 hr and 10.3 +/- 5.4 mL/min/kg respectively in the young group and 14.4 +/- 4.5 hr and 8.5 +/- 2.9 mL/min/kg respectively in the elderly group. Neither of these parameters was significantly different between the two groups. The amount of mexiletine eliminated in urine up to 48 hours postdose was identical in both groups and represented less than 5% of the administered dose. It is concluded that the age-related modifications in the kinetics of mexiletine are not clinically important during chronic administration of the drug.     

Effect of growth hormone on caffeine metabolism in hypophysectomized rats

Two groups of six male Sprague-Dawley hypophysectomized rats (operated on day 0), 8 weeks old, treated by sc tetracosactid (ACTH, 10 micrograms every 24 hr), thyroxine (5 micrograms/100 g every 24 hr) and desmopressin (240 ng/kg/24 hr continuous infusion) received SC either saline (group I) or human growth hormone (hGH, 120 micrograms/24 hr) (group II) continuous infusion. ACTH and thyroxine were administered on days 7-19 and desmopressin and hGH on days 8-19, after surgery. They received po caffeine 4 mg/kg as citrate salt on day 15. The 0-12, 12-24 and 24-48 hr urine samples were collected after caffeine administration. Caffeine and metabolites concentrations in urines were determined using HPLC. Effect on hGH on caffeine metabolism was assessed comparing group I and group II. In 0-48-hr urine, 1-methylxanthine (154 +/- 169 pmol/g) and 3-7-dimethyluric acid (5.57 +/- 19.3 pmol/g) in group II were significantly lower than in group I (391 +/- 340 pmol/g and 262 +/- 338 nmol/g, respectively) (p less than 0.05). Other metabolites (6-amino-5-(N-methyl formylamino)-1,3-dimethyluracil included) excretion was not altered. Total, N3-, N7- and N1-demethylation ratios on 0-48 hr urine were not modified by hGH treatment. However, demethylation ratios on 12-24 and 24-48 hr (N3 + N7 + N1) and on 24-48 hr urine samples (N3 and N7) were significantly reduced in group II (p less than 0.05) suggesting an increase in the rate of appearance of demethylated metabolites during hGH treatment.(ABSTRACT TRUNCATED AT 250 WORDS)     

Tocainide. A review of its pharmacological properties and therapeutic efficacy

Tocainide is an antiarrhythmic drug structurally related to lignocaine with similar electrophysiological, haemodynamic and antiarrhythmic effects. In contrast to lignocaine (lidocaine) it is well absorbed after oral administration and has a plasma half-life of about 15 hours. In several open and controlled therapeutic trials in patients with ventricular arrhythmias, often following a myocardial infarction, tocainide has been relatively effective and usually well tolerated. In treating ventricular ectopic beats and/or ventricular tachycardia tocainide has demonstrated effective suppression in 60 to 70% of patients in both open and controlled studies. It has an acute effect when infused in patients with ventricular arrhythmias complicating myocardial infarction, as well as a prophylactic effect when given orally. The majority of these studies have demonstrated tocainide to be more effective than placebo, but trials against other antiarrhythmic agents are few in number and vary in design. One study combining an infusion of tocainide with oral therapy compared to a bolus injection of lignocaine followed by a constant infusion in patients after myocardial infarction, found the two agents to be of similar efficacy. The most common adverse effects are neurological and gastrointestinal in nature, nausea and dizziness occurring most frequently. Adverse effects resulting in termination of therapy have been reported in about 16% of patients. Aggravation of pre-existing heart failure, increased ventricular arrhythmia, deterioration of conduction disturbances, convulsions, and cases of lupus erythematosus syndrome have occasionally been reported. Thus, tocainide appears to offer a worthwhile addition to the other antiarrhythmic agents available for ventricular arrhythmias. However, its relative place in therapy compared with other antiarrhythmic drugs is not yet clearly established.     

Mexiletine protects myocardium during acute ischemia by opening sarcolemmal K-ATP channel: studies in closed-chest acute ischemia model in rabbits

OBJECTIVES: Although we have previously shown that mexiletine might protect myocardium during acute ischemia, the precise mechanism was unclear. In the present study, the mechanism of this effect was examined by using selective K-ATP channel blockers in closed-chest acute ischemia model in rabbits. METHODS: In 40 rabbits, the large left ventricular branch (LLVB) of the left coronary artery was occluded for 30 minutes by inserting a catheter bead (varphi0.5-0.7 x 1.5 mm) through the left carotid artery and was then reperfused. The rabbits were divided into the following 5 groups: (1) control group (n = 8); (2) mexiletine (Mex) group (n = 8, continuous infusion of Mex 24 mg/kg/h); (3) Mex + 5-hydroxydecanoate (5HD) group (n = 8, preadministration of 5HD, 5 mg/kg, followed by Mex infusion); (4) Mex + HMR1098 (selective sarcolemmal K-ATP channel blocker) group (n = 8, preadministration of HMR1098, 3 mg/kg, followed by Mex infusion); and (5) pilsicainide (Pil) group (n = 8, continuous infusion of Pil 18 mg/kg/h). The incidence of ventricular arrhythmia, hemodynamics, left ventricular ejection fraction (LVEF), and infarction size were evaluated and compared among the 5 groups. RESULTS: The incidence of ventricular arrhythmia was lower in groups treated with Mex than the control. The hemodynamics did not show significant differences among the 5 groups. Although the LVEF at 30 minutes after reperfusion was lower in the Mex group (41 +/- 3%, P < 0.001) than the control group (48 +/- 3%), the LVEF at 360 minutes after reperfusion had recovered and became higher in the Mex group (62 +/- 3%, P < 0.001) than the control group (55 +/- 3%). The infarction size was smaller in the Mex group (30 +/- 5%, P = 0.028) than the control group (51 +/- 8%). These effects of Mex were negated by HMR1098 but not by 5HD and were larger than the effects of Pil. CONCLUSIONS: Mex showed improvement in the LVEF in the later phase after reperfusion as well as a reduction in ventricular arrhythmia. The cardioprotective effect of Mex was considered to appear through its action on the sarcolemmal K-ATP channel.     

The pharmacokinetics and pharmacodynamics of lignocaine and MEGX in healthy subjects

Lignocaine clearance declines during continuous intravenous infustion in man and in vitrostudies suggest that this may partly be due to inhibition by MEGX, a metabolite of lignocaine, MEGX is pharmacologically active in animals, but this is not yet proven in man. This study examined the pharmacokinetics and pharmacodynamics of lignocaine and MEGX in eight healthy male volunteers given lignocaine HCl 120mg, MEGX HCl 120 mg, lignocaine HCl 120 mg+MEGX HCl 120 mg, and placebo, administered according to a randomized double-blind protocol. One-, two-, or three-compartment models were fitted to drug and metabolite blood concentration-time profiles and clearance, volume (V _ss ), andhalf-life values were calculated and compared by paired t-test. Systolic time intervals and QTinterval were recorded and compared by repeated measures ANOVA. When administered in combination with MEGX, lignocaine clearance was significantly reduced from 58±18 to 48±13 L hr(su–1) (p <0.02). The V(inss) was unchanged and there was a trend toward an increase in terminal half-life. Lignocaine, MEGX, and the combination significantly reduced QTinterval up to 30 min after injection and this was maintained to 2 hr with the lignocaine and the combination. Transient side effects were experienced with all active treatments, but were most pronounced with the combination. Thus, lignocaine clearance was inhibited by MEGX, which was pharmacologically active in man.     

Continuous i.v. infusion versus multiple bolus doses of metoclopramide for prevention of cisplatin-induced emesis

Continuous infusion of metoclopramide was compared with bolus dosing in a randomized, double-blind study in 27 patients receiving cisplatin therapy. Hospitalized patients receiving their first course of cisplatin (120 mg/sq m administered i.v. over four hours) were randomized to receive either bolus doses or a continuous infusion of metoclopramide. In the infusion group (14 patients), a loading dose of metoclopramide 3 mg/kg (total body weight) as the hydrochloride salt was infused over one hour immediately before the administration of cisplatin, followed by a continuous infusion of metoclopramide 0.5 mg/kg/hr (as the hydrochloride salt) for 12 hours. Each patient received a total metoclopramide dose of 9 mg/kg over 13 hours. These patients also received five bolus doses of 5% dextrose injection (as placebo) over 15 minutes, with the first dose given one hour before the cisplatin and four more doses at two-hour intervals. In the bolus-dose group (13 patients), metoclopramide 2 mg/kg as the hydrochloride salt was added to each of the bolus doses, while the continuous infusion was a placebo of 5% dextrose injection. All patients also received dexamethasone 10 mg i.v. and diphenhydramine hydrochloride 50 mg i.v. Patients were monitored for 24 hours after initiation of metoclopramide administration for number of emesis episodes and for adverse effects. In the infusion group, 11 of 14 (79%) patients had two or fewer episodes of emesis. In the bolus group, 10 of 13 (77%) had two or fewer vomiting episodes. Mild sedation occurred in both the infusion (79%) and bolus-dose (77%) groups. Despite the use of diphenhydramine, extrapyramidal reactions were seen in one bolus-dose patient and two infusion patients.(ABSTRACT TRUNCATED AT 250 WORDS)     

Impaired Lignocaine metabolism in patients with myocardial infarction and cardiac failure.

Plasma concentrations of lignocaine were measured during and after infusion of lignocaine at 1.4 mg/min for 36-46 hours in 12 patients with myocardial infarction and one patient with cardiac failure due to uncontrolled ventricular tachycardia. In six patients without cardiac failure the plasma concentrations of lignocaine rose progressively during the infusion and the mean lignocaine half life was 4.3 hours compared with 1.4 hours in healthy subjects. Mean plasma lignocaine concentrations were significantly higher in seven patients with cardiac failure, and concentrations also rose during the infusion and the half life was considerably prolonged to 10.2 hours. Lignocaine concentrations rose rapidly to toxic levels when cardiogenic shock developed in one patient and did not fall when the infusion was stopped. The mean plasma antipyrine half life was moderately prolonged (19.4 hours) in a larger group of patients with myocardial infarction and cardiac failure but returned to normal during convalescence (13.2 hours). The metabolism of lignocaine is grossly abnormal in patients with cardiac failure and cardiogenic shock after myocardial infarction.     

The Effectiveness and Safety of Landiolol Hydrochloride, an Ultra-Short-Acting β1-Blocker, in Postoperative Patients with Supraventricular Tachyarrhythmias: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study

Background

Persistent postoperative supraventricular tachyarrhythmias (SVTs) increase cardiac burden and aggravate cardiac hemodynamics. Therefore, for patients in unstable conditions after surgery, prompt and sustained control of heart rate is essential. The importance of β-adrenoceptor antagonists (β-blockers) in controlling such postoperative atrial fibrillation or atrial flutter has been established, and the usefulness of ultra-short-acting β₁-blockers with high β₁ selectivity has been suggested based on their safety and efficacy under such circumstances.

Objectives

Our objectives were to evaluate the effectiveness and safety of landiolol hydrochloride, an ultra-short-acting β₁-selective blocker, in the treatment of postoperative SVT in patients with a high risk of myocardial ischemia, or in patients after highly invasive surgery, in a multicenter, randomized, double-blind, placebo-controlled, group-comparative study.

Methods

A total of 165 patients were randomly allocated to three groups and received LM or MH doses of landiolol hydrochloride or placebo. LM group: dose L (1-min loading dose at a rate of 0.03 mg/kg/min, followed by a 10-min infusion at 0.01 mg/kg/min) followed by dose M (1-min loading at a rate of 0.06 mg/kg/min, followed by a 10-min infusion at 0.02 mg/kg/min); MH group: dose M followed by dose H (1-min loading dose at a rate of 0.125 mg/kg/min, followed by a 10-min infusion at 0.04 mg/kg/min); placebo (PP) group: dose P (1-min loading dose at a rate of 0 mg/kg/min, followed by a 10-min infusion at 0 mg/kg/min) followed by another round of dose P. If the targeted heart-rate reduction was not obtained at the end of the first 10-min infusion, the higher dose was started. The primary endpoint was the percentage of patients who met the heart-rate reduction criteria (≥20 % reduction and <100 beats/min). The safety endpoint was the incidence of adverse events in each of the three groups.

Results

The percentages of patients who met the heart-rate reduction criteria (≥20 % reduction and <100 beats/min) were 0.0, 60.4, and 42.0 % in the PP, LM, and MH groups, respectively. There were significant differences in the LM and MH groups relative to the PP group, but there was no significant difference between the LM and MH groups. No significant difference was observed in the incidence of adverse events among the three groups: 29.6 % in the PP group, 45.5 % in the LM group, and 43.1 % in the MH group.

Conclusion

Landiolol hydrochloride is effective and safe for patients with postoperative SVT.     

Pharmacokinetics of eltanolone following bolus injection and constant rate infusion

Disposition of intravenous anaesthetic eltanolone was studied when administered as a bolus injection (B) of 0.75 mg/kg and constant rate intravenous infusion at 2 mg/kg/hr (I2) and 3.5 mg/kg/hr (I3.5) for 2 hr in healthy male volunteers. Venous blood samples were collected for 12 hr and 20 hr following bolus injection and intravenous infusion, respectively. Serum eltanolone concentrations were determined by a specific gas chromatographic mass spectrometric assay. Using a nonlinear regression analysis, the individual data sets were best fitted by a three-compartment mamillary model with central elimination. Derived pharmacokinetic parameters expressed as median and 95% confidence intervals indicated an initial fast distribution with a half-life of 1.80 (0.23–5.47) min (B), 1.44 (0.97–2.06) min (I2) and 1.44 (0.95–2.39) min (I3.5), an intermediate phase with a half-life of 35.4 (28.7–45.2) min (B), 39.6 (31.0–47.9) min (I2) and 35.4 (33.3–44.9) min (I3.5) and a moderately short terminal phase with a half-life of 3.8 (2.7–5.9) hr (B), 5.0 (4.2–6.1) hr (I2) and 4.6 (4.0–4.8) hr (I3.5). The serum clearance after bolus injection was 1.37 (1.23–1.67) L/hr/kg and after infusion was 1.36 (1.25–1.52) L/hr/kg (I2) and 1.17 (1.11–1.31) L/hr/kg (I3.5). The pharmacokinetics of eltanolone appear to be linear over the dosage range studied. Pharmacokinetic parameters obtained after bolus injection were very much similar to the parameters obtained after infusion with the exception of t_1/2β which was longer after the infusion (significant) and the volume of central compartment which was lower after infusion (not significant). Context sensitive times were estimated for a 30%, 50% and 80% drop in the concentration of eltanolone after different infusion times. A 30% drop in concentration is estimated to take about 2 to 3 min. A 50% drop in concentration, is estimated to take about 8 min when duration of infusion is 3 hr and reaches a value of about 10 min by a duration of infusion of 10 hr. A 80% drop in concentration is estimated to take about 55 min following an infusion of 1 hr and it reaches a value of 70–80 min following an infusion of 10 hr.     

Pharmacokinetics, pharmacodynamics, tolerability and safety of single doses of bivalirudin in healthy chinese subjects

The objectives of the present study were to assess pharmacokinetics, pharmacodynamics, tolerability and safety of intravenous administration of bivalirudin, a direct thrombin inhibitor, in healthy Chinese subjects. 48 subjects were equally divided into 4 groups (0.5 mg/kg, 0.75 mg/kg, 1.05 mg/kg intravenous bolus, and 0.75 mg/kg intravenous bolus followed by an infusion of 1.75 mg/kg per hour for 4 h) by a randomized, single-blind and placebo-controlled (bivalirudin groups: n=9/group; placebo groups: n=3/group) design. The safety observations showed that bivalirudin was well tolerated in the studied dose range, all adverse events were mild in severity. The half-life of bivalirudin was approximately 0.57 h (34 min), exposure increased in a dose-dependent manner. In group receiving a 0.75 mg/kg intravenous bolus followed by 1.75 mg/kg per hour infusion for 4 h, bivalirudin concentrations remained at 5000-5500 μg/l within the 4 h infusion period, which was similar to the reported data of Caucasian patients and can provide the desired anticoagulant effects. There was a strong correlation between bivalirudin concentration and anticoagulant effect. A Sigmoid model was used to fit the pharmacodynamic parameters activated clotting time (ACT), activated partial thromboplastin time (APTT) and prothrombin time (PT) and bivalirudin concentrations. The findings of this study suggest that the same dosing regimens of bivalirudin may be administered to Chinese and Caucasian patients. Ongoing and future studies in large populations may add further information.