Chengde Fan

Effects of Amiodarone and Its Active Metabolite Desethylamiodarone on the Ventricular Defibrillation Threshold

OBJECTIVES We evaluated whether the reported difference in the ventricular defibrillation threshold (DFT) between short-term intravenous and oral amiodarone is due to the effect of amiodarones active metabolite desethylamiodarone (DEA). BACKGROUND Amiodarone is frequently used in patients with implantable cardioverter-defibrillator devices (ICD). Long-term oral amiodarone raises the DFT, but intravenous amiodarone has not been shown to have this effect. DEA, an active metabolite of amiodarone, has different electrophysiologic properties than its parent compound and may be responsible for the observed different effects of intravenous and oral amiodarone on DFT. METHODS We ascertained the DFT in 24 pigs randomized to receive intravenous amiodarone, DEA or vehicle. Defibrillation was delivered through a transvenous lead system using a biphasic waveform. The DFT was determined using an up-down DFT algorithm and defined as the average minimal energies resulting in successful defibrillation delivered from ascending and descending serial shocks. RESULTS Amiodarone caused a dose-response increase in DFT (mean +/- SD) from 22.7 +/- 4.1 (baseline) to 26.1 +/- 2.9 (10 mg/kg body weight), p = 0.11, to 34.9 +/- 8.2 J (after an additional 15 mg/kg), p = 0.035. DEA (10 mg/kg) caused an increase in DFT from 20.5 +/- 6.3 to 33.9 +/- 13.6 J, p < 0.01. Addition of 15 mg/kg of DEA resulted in hemodynamic instability and thus DFT was not obtained. In the control group, DFT decreased from 26.8 +/- 7.7 at baseline to 23.1 +/- 7.4 (dose 1), p = 0.19, to 22.8 +/- 6.2 J (dose 2), p = 0.18. CONCLUSIONS DEA increases DFT by a greater amount than its parent drug amiodarone. There is an effect of intravenous amiodarone on DFT that is dose dependent.

An Evaluation of the Hemostatic Effects of Hydrophilic, Alcohol, and Lipophilic Extracts of Notoginseng

Study Objective. To compare the hemostatic effects of hydrophilic, alcohol, or lipophilic extract of notoginseng with those of the control and placebo.

An Evaluation of the Hemostatic Effect of Externally Applied Notoginseng and Notoginseng Total Saponins

No effective hemostatic agents are available for external use. This project was conducted to evaluate the hemostatic effects of notoginseng using a hemorrhagic rat model. Rats (n = 40) were divided into four groups, and their tails were transected 5 mm from the tip. Group 1 received no treatment (control), while the other groups received external powder applied to the wound. Group 2 received placebo (flour), group 3 received ground notoginseng, and group 4 received a saponin extract of notoginseng. The total bleeding time was determined and compared between groups. The notoginseng group had lower bleeding times (9.60 ± 1.50 min) than the control group (19.23 ± 4.09 min, p < 0.001) or the placebo group (15.18 ± 2.24 min, p < 0.001). Likewise, the saponin extract group had significantly lower bleeding times (11.70 ± 2.53 min) than the control and placebo groups (p < 0.001 for both comparisons). No differences were found between the notoginseng and the saponin extract groups (p = 0.35). Notoginseng and a saponin extract from notoginseng provide hemostatic effects when applied externally.

Efficacy of Intravenous Granisetron in Suppressing the Bradycardia and Hypotension Associated with a Rabbit Model of the Bezold-Jarisch Reflex

This study investigated whether granisetron, a 5‐HT3 receptor antagonist, can alter the Bezold‐Jarisch reflex (i.e., hypotension and inappropriate heart rate slowing). A hemorrhagic rabbit model that has been shown to induce the Bezold‐Jarisch reflex was used. In 11 rabbits (3.8 kg), catheters were placed in the carotid arteries one day before experimental hemorrhage. On the day of the study, the rabbits were given intravenous granisetron (50 μg/kg) or an equal volume of saline. Five minutes after administration of granisetron or saline, hemorrhage was induced by continuous blood withdrawal at 5 mL/min and blood pressure (BP) and heart rates were obtained at frequent intervals until systolic BP declined to 80 mmHg. Six rabbits received saline and five granisetron. An average of 77.6 mL ± 16.4 mL of blood was removed in the group receiving granisetron (compared with 56.5 mL ± 13.1 mL for the saline group) before achieving the target systolic BP of 80 mmHg. The group receiving granisetron demonstrated the same ability to increase their heart rate from baseline as the saline group. However, the granisetron group had a final heart rate that was closer to their maximal heart rate than the saline group. In this animal model, granisetron was significantly more effective at preventing inappropriate heart rate slowing and allowed significantly more blood to be removed before reaching the target blood pressure. This implies that granisetron may be effective in preventing vasovagal syncope, although further study should be carried out to verify these potentially interesting findings.

Evaluation of CYP2D6 Oxidation of Dextromethorphan and Propafenone in a Chinese Population with Atrial Fibrillation

The objective of this study was to determine the percentage of patients with paroxysmal atrial fibrillation who were poor metabolizers of CYP2D6 in a Chinese population from Hong Kong and to assess the relationship between the dextromethorphan/dextrorphan ratio and the propafenone/5‐hydroxypropafenone ratio or the steady‐state propafenone concentration. Patients (n = 60) were recruited from the Arrhythmia Clinic at the University of Hong Kong and given dextromethorphan 30 mg. The dextromethorphan and dextrorphan concentrations in urine over the next 8 hours were used to determine metabolizer status. If the metabolic ratio was greater than 0.3, the patient was determined to be a poor metabolizer. In phase 2, patients (n = 38) were given propafenone 150 mg twice daily, and at steady state, the propafenone and 5‐OH propafenone plasma concentrations were determined. It was found that 15% of the patients were poor metabolizers of dextromethorphan. There was a significant correlation between the metabolic ratios of dextromethorphan/dextrorphan and propafenone/5‐OH propafenone (r = 0.49, p = 0.0019) and between the dextromethorphan/dextrorphan ratio and the concentration of propafenone (r = 0.32, p = 0.05). No correlations were found in the extensive or poor metabolizer subgroups. It was concluded that the percentage of poor metabolizers in atrial fibrillation patients from Hong Kong was much larger than in previous studies of Chinese patients who were not from Hong Kong. The ability to metabolize dextromethorphan to dextrorphan is related to the ability to metabolize propafenone to 5‐hydroxypropafenone.

The Effect of Amiodarone on the Ventricular Fibrillation Threshold

We evaluated the antifibrillatory effect of two different doses of amiodarone after cardiac arrest with a cardiopulmonary resuscitation (CPR) model in 19 pigs. Ventricular fibrillation was induced by pacing the right ventricle using a primary drive train at a cycle length of 270 msec for 8 beats. The minimum current strength necessary to induce sustained ventricular fibrillation was defined as the ventricular fibrillation threshold (VFT) measured in mA. Three VFT determinations were made at baseline, followed by 9 minutes of continuous CPR with two determinations of VFT, and three after stabilization. The pigs were placed into one of three groups: amiodarone 2 or 5 mg/kg, or placebo. The average poststabilization VFT in each group was compared with the average baseline VFT. Pigs receiving amiodarone 2 mg/kg had significantly higher VFT after stabilization than at baseline (22.88 ± 12.76 to 27.10 ± 10.18 mA, p=0.048), as did those receiving 5 mg/kg (17.03 ± 7.01 to 28.08 ± 11.58 mA, p=0.002). The ΔVFT was significantly greater with amiodarone 5 mg/kg than with vehicle (placebo), but not with 2 mg/kg. There were no changes in VFT in any group during CPR versus baseline. When active treatments were combined, the trend was toward better survival in the amiodarone groups (13/13) compared with the placebo group (4/6, p=0.076).

Antifibrillatory effect of esmolol alone and in combination with lidocaine.

The primary objective of this study was to determine the effect of esmolol, administered alone and in combination with lidocaine, on ventricular fibrillation threshold (VFT) in pigs. A secondary objective was to determine the relationship between blood esmolol concentrations and VFT. We determined VFT using a train of electrical stimuli delivered to the right ventricle after eight paced beats at a basic cycle length of 285 ms. Current was increased in 2-mA increments until VF occurred. VFT determinations were performed during administration of esmolol 1,000 mu g/kg/min, during a continuous infusion of lidocaine, and during infusion of esmolol and lidocaine in combination. Mean increases in VFT from baseline during infusion of esmolol and lidocaine alone were 32.3 +/- 12.9 and 8.5 +/- 7.2 mA, respectively (p < 0.05, each drug compared with baseline; p < 0.05, esmolol vs. lidocaine). Mean increase in VFT from baseline during infusion of the combination was 52.0 +/- 22.0 mA (p < 0.05 as compared with baseline and with esmolol or lidocaine alone). The relationship between blood esmolol concentrations and VFT was described by a counterclockwise hysteresis curve, suggesting delay in equilibration of esmolol between blood and site of effect. The antifibrillatory efficacy of esmolol is significantly greater than that of lidocaine in this model. Administration of the two agents in combination resulted in significantly greater antifibrillatory efficacy than that associated with either drug administered alone.

Simple and rapid high-performance liquid chromatographic assay for esmolol

A procedure for determining esmolol concentrations in blood is described. Dichloromethane was used to extract esmolol from the blood and to inhibit the activity of blood esterases. Blood esmolol concentrations were determined by high-performance liquid chromatography using 3-methoxy-O-demethylencainide as the internal standard. The limit of detection of this assay was 5 ng/ml. The relationship between the peak-height ratio of esmolol and the internal standard was linear in the concentration ranges 10-30,000 ng/ml. The mean absolute and relative recoveries of esmolol from blood were 84 and 89%, with coefficients of variation less than 3%. This method has been used in our laboratory for pharmacokinetic and pharmacodynamic studies.

Assessment of the drug interaction between alteplase and nitroglycerin: an in vitro study.

Alteplase is the most commonly administered thrombolytic agent in the United States. However, concurrent therapy with nitroglycerin reduces plasma alteplase concentrations and its clinical efficacy. We sought to determine if this interaction is concentration and pH dependent. Seventy plasma samples were prepared and divided into three groups: alteplase 500 IU/ml alone (group 1), alteplase 500 IU/ml plus nitroglycerin 5 ng/ml (group 2), and alteplase 500 IU/ml plus nitroglycerin 200 ng/ml (group 3). The samples were analyzed at time zero and 3 hours (incubated at 37°C). Group 1 had significantly higher plasma alteplase concentrations than group 3 (p<0.001). When alteplase and nitroglycerin are combined, the degradation of alteplase in plasma is enhanced.