Antiarrhythmic and circulatory effects of astra W36095

EXPERIMENTAL STUDIES

Antiarrhythmic

and Circulatory Effects of Astra W36095

A New Lidocaine-Like

D. JOHN

COLTART,

THEODORE

MD,

B. BERNDT,

ROBERT

KERNOFF

DONALD

C.

HARRISON,

Agent

MRCP’ MD MD,

FACC

Stanford, California

Although lidocaine ts an effective antiarrhythmic agent, it must be administered parenterally and tts duration of activity Is short. Astra W36095 has a basic chemical structure similar to that of lidocaine but has a plasma half-life of 6 to 12 hours after administration to conscious dogs. Ventricular arrhythmias were produced in unanesthetized dogs, using ameroid constrictors on the proxlmal left anterior descending and circumflex coronary arteries. Stable ectopic beats were completely suppressed with plasma levels of 15 to 30 pg/ml of W36095. The duration of effect was 0.25 to 5 hours. In anesthetized dogs, an effective antiarrhythmic concentration of W36095 produced some depression of cardiac function. Thus, W36095 appears to be a long-acting, orally absorbed antiarrhythmic agent requiring clinical trials and metabolic studies. In addition, the arrhythmia model provides a sensitive method for studying new antiarrhythmic drugs. Early detection and treatment of cardiac arrhythmias in the immediate period after myocardial infarction have been the most important reasons for the decrease in mortality of patients. More than half of the 600,000 patients who die of coronary artery disease in the United. States each year do not reach the hospital alive,’ the terminal event resulting from ventricular fibrillation2 There is thus a major need for a drug that can be administered safely to patients judged to be at high risk of such sudden death. Although lidocaine has been the drug most widely used in the coronary care unit for abolishing ventricular arrhythmias, it cannot be used in the prophylaxis of the sudden death syndrome, since it can produce therapeutic blood concentrations only after parenteral administration. Recently it has been shown that depot injections of lidocaine intramuscularly can effect therapeutic blood levels for several hours,3,4 but this technique is obviously unacceptable for long-term prophylaxis. We therefore studied a new antiarrhythmic drug, W36095, with a structure similar to that of lidocaine (Fig. 1). In this paper we describe our early hemodynamic and antiarrhythmia studies with this agent in a canine model.

From the Cardiology Division, Stanford University School of Medicine, Stanford, Calif. This work was supported in part by Grants HL-5709 and HL-5966 from the National lnstiiutes of Health, Bethesda, Md. Manuscript accepted December 5, 1973. Supported by the Peel Medical Research Trust of Great Britain and the Lilly International Fellowship Program. Present address: Cardiovascular Research Unit, Royal Postgraduate Medical School, Hammersmith Hospital, London W 12, England. Address for reprints: Donald C. Harrison, MD. Cardiology Division, Stanford University School of Medicine, Stanford, Calii. 94305. l

Methods Absorption Studies In nine conscious, fasting dogs W36095 (100 or 50 mg/kg body weight) was administered orally in gelatin capsules. Blood samples were taken for estimation of plasma drug levels at hourly intervals for 6 hours, and then at 24 hours after administration of the drug in three dogs receiving 100 mg/kg and in six dogs receiving 50 mg/kg. The plasma concentration was determined by a gas chromatographic technique developed by Astra Laboratories. Two milliliters of plasma was alkalinized with sodium hydroxide and extracted with methylene chloride. The organic solvent was evaporated, and heptafluorobutyryl imidazole (HFBI) used as a carrier for gas chromatography. Appropriate internal standards and calibration curves were utilized to determine drug concentration.

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/Am3

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After instrumentation, the animals were allowed 30 minutes to reach a stabilized condition before each study, and a tube was passed orally and positioned in the stomach during this period. The animals were separated into two groups of four dogs each, and a solution of either 120 mglkg or 60 mg/kg of W36095 was given through the stomach tube; the hemodynamic effects were measured at hourly intervals for 6 hours, and plasma samples were taken for assessment by gas chromatography. An additional group of four control dogs received an isovolumic amount of saline solution. Antiarrhythmia

Arrhythmias were produced in five adult mongrel dogs in a model of long-term ischemia. These dogs were anesthetized with phenobarbital, 30 mg/kg intravenously, intubated and ventilated with room air by means of a Harvard respirator. With aseptic precautions, the chest was opened through the fifth intercostal space; the pericardium was incised along a line anterior and parallel to the left phrenic nerve and retracted. With careful dissection, the origin of the left coronary artery from the aorta and its bifurcation into the left anterior descending and left circumflex arteries was isolated. Care was taken to mobilize the coronary vein away from the coronary artery. Ameroid constrictors were placed around the left circumflex and left anterior descending arteries immediately adjacent to their bifurcation. The lungs were expanded and the chest was closed in layers. After an interval of 6 or more hours, the dogs were gently restrained on the floor and their electrocardiograms monitored. They were subsequently monitored every day to determine when they were suitable for inclusion in the antiarrhythmia study.

W36095

FIGURE 1. Chemical structure of lidocaine and Astra W36095.

Hemodynamic

Studies

Twelve mongrel dogs weighing 11 to 23 kg were premedicated with morphine sulfate, 2 mg/kg intramuscularly, then anesthetized with chloralose, 85 mglkg, and urethane, 625 mg/kg, given intravenously. The animals were intubated with a cuffed endotracheal tube and ventilated with room air, using a Harvard respirator. Arterial blood samples were analyzed frequently with a model AMEAstrup micromanometer, and tidal volume and respiratory rate adjusted to maintain the level of arterial PO2 above 80 mm Hg and pH between 7.30 and 7.50. Catheters were placed in the ascending aorta by way of the carotid artery and in the jugular vein for sampling of blood, and the chest was opened by a midline sternotomy. A BT-250 Bio-Tee solid state pressure transducer (Bio-Tee Instruments, Pasadena, Calif.) was then placed through a stab wound into the apex of the left ventricle. Mean aortic blood flow was measured with a gated sine wave electromagnetic flowmeter (Biotronex Laboratory, Silver Spring, Md.) calibrated as previously described.5 The aortic flow probe was placed around the ascending aorta immediately distal to the coronary arteries. Recordings were made on a multichannel photographic recorder (Honeywell Electronics Medical Systems, Denver, Colo.). The zero level for all pressure measurements was taken at mid-chest level. Aortic pressure was recorded using a Statham P23Db transducer. Left ventricular pressure was recorded with the Bio-Tee 250 solid-state transducer. The first derivative of the left ventricular pressure curve (dP/dt) was measured with a resistance-capacitance differentiating circuit, which had a frequency response to a calibrated triangular wave that was linear to signals of more than 100 Hz. Aortic mean pressure was derived electronically.

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Criteria for Inclusion in the Study Animals were included in the study if the following criteria were met: 1. The number of abnormal beats was 30 percent or more of the total number of beats per minute. 2. This frequency of abnormal beats remained constant after a 3 hour monitoring period. If so, W36095 was administered orally, and hourly monitoring of the electrocardiogram was performed with hourly blood sampling for estimation of plasma levels of the drug. 3. Surgery had been performed not less than 6 hours before drug administration. 4. After drug administration, when there was no longer a plasma therapeutic concentration of the drug, the number of abnormal beats was the same or greater than the control number of abnormal beats per total beats per minute.

Results Absorption Studies In Figure 2 the blood levels of W36095 plotted on a logarithmic scale in grams per milliliter are shown after the oral absorption of the gelatin capsules by conscious dogs. After administration of 100 mg/kg, a half-life of 12 hours for the drug was observed; after administration of 50 mg/kg, the half-life was 8.5 hours. No animal had any obvious adverse reaction or change in hematologic variables or liver function indexes for 3 days after administration of the drug, as determined by routine blood and liver function studies.

NEW LIDDCAINE-LIKE AGENT-COLTART

N=3 N=6

a lOOmg/kg. . 50

ET AL.

mg/kg.

10. 9 6 7 6 5 4

FIGURE 2. The logarithmic plasma concentration of Astra W36095 after oral administration (gelatin capsules of 50 and 100 mg/kg body weight) to fasting conscious dogs.

I

tlh==8.5 HRS

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TIME (HOURS) I

+

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6 DOGS GIVEN f20mgIkg w36095

ORALLY

.I.

HEART RATE

x..==x

LV df+d+

a=‘o8’a AORTfC FLOW * P(O.05

FIGURE 3. The hemodynamic effects of 120 n-@/kg of W36095 on heart rate, left ventricular dP/dt (LV dp/dt) and aortic flow in anesthetized dogs. Results are expressed as mean percent change from values in control animals.

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AGENT-COLTART

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cantly depressed for 1 to 3 hours (15 to 29 percent of control values) after administration of the drug. Aortic flow was moderately decreased (15 to 12 percent from control values) 3 and 4 hours after administration of the drug, but this reduction was not statistically significant, since only four animals were studied. Figure 4 shows the effect of W36095, 120 mglkg, on mean aortic and left ventricular end-diastolic pressures. There was no significant change in mean aortic pressure, but left ventricular end-diastolic pressure was increased 1 l/2 and 6 hours after administration of the drug. Figure 5 illustrates the logarithmic plasma level of drug observed during the hemo-

Studies

The mean percent effect of 120 mg/kg of W36095 on the heart rate, left ventricular dP/dt and aortic flow in four animals when compared with values in four control animals is shown in Figure 3. There was a statistically significant decrease in heart rate from 24 to 32 percent of control values 1 hour after administration of the drug. The decrease in heart rate was not attributable to beta adrenergic receptor blockade since a bolus injection of isoproterenol produced the same dose-response curve before and after administration of W36095. Left ventricular dP/dt was signifi-

DOGS GIVEN 120 mg/ kg W 36093 ORALLY

‘-.

MEAN AORTIC PRESSURE

, . . . . . r, L ED l

TIME

120mglkg.

0

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W 36095

2

P

P( 0.05

FIGURE 4. The hemodynamic effect of 120 mgfkg of W36095 on mean aortic and left ventricular end-diastolic pressure (LVEDP) in anesthetized dogs. Results are mean percent expressed as change from values in control animals.

MS.)

ordly

3 Time

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6

(Hrs. 1

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FIGURE 5. The logarithmic plasma concentration of W36095 (mean f standard deviatbn) correlating with hemodynamic studies.

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dynamic observations. There was no significant on the circulatory system after administration mg/kg of W36095.

effect of 60

Antiarrhythmia Studies Of seven dogs successfully operated on, five met the full criteria for inclusion in the study. Figure 6 illustrates the typical result in one of these animals (Dog 12). At time zero, 100 mg/kg of W36095 pro-

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duced an immediate suppression of abnormal beats. Figure 7 presents a representative strip from an electrocardiogram taken throughout this study in the same dog. Five hours after administration of W36095 some abnormal beats reappeared; 22.5 hours after drug administration, the abnormal beats had returned to a greater frequency (32 percent of the total beats) in relation to the control frequency. The plasma W36095 levels obtained throughout the study are

100mg W 36095 (g&fin capsules)

FIGURE 6. Dog 12. Histogram of percent abnormal beats before and after oral administration of 100 mg/kg of W36095. The plasma concentration of W36095 is shown by the contlnuow heavy line and relates to the scale on the right vertical axis.

TIME

(hws)

CHf?oNlC lscHAEMlc MOOEL (GIVEN ORALLY) 100mg KgW36G95

Jo l4INS.

22.5

FIGURE 7. Dog 12. Representative graphic rhythm strips.

HRS

electrocardio-

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CHRONIC

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ISCHAEMIC

ET AL.

MODEL

POST-OPERATIVE

OAY

DAY

Antiarrhythmia and chronic ischemia model in dogs: The antiarrhythmia model that we developed

4

7

DAYS

DAY 9

DAY IO

FIGURE 8. Serial electrocardiograms of a dog in which the model of chronic ischemia does not produce arrhythmias. Sudden death occurred on day 12.

also shown in Figure 6. A quantitatively and qualitatively similar response was seen in the four other dogs meeting the full criteria for inclusion in the study. Plasma levels were again determined by a gas chromatographic technique.

Discussion Oral administration of lidocaine has produced very low blood levels of the drug.6 Lidocaine toxicity occurs much more frequently after oral dosage and at much lower blood levels than after intravenous administration.” Lidocaine absorbed from the intestinal tract must pass through the liver by the portal vein and obviously undergoes considerable metabolism during a single circulation through the liver.7 It appears that the toxicity that occurs almost uniformly after oral administration of lidocaine can be explained by the resulting high level of metabolites. By small alterations in the basic chemical structure of lidocaine (Fig. 11, W36095 can be produced. Thus, this agent has a long half-life of plasma concentration with a reasonable spectrum of antiarrhythmic actions at concentrations that produce only minimal myocardial depression. Whether the degree of such depression found in our study in dogs will be clinically acceptable in man must await the result of initial clinical trials. Extrapolation of data from animals to man is notoriously misleading, and at best must be used as a guide to predicting possible effects. Clearly, depressed ventricular function may occur at higher plasma concentrations of W36095. The metabolic pathway of W36095 has not yet

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been elucidated but probably, like lidocaine, this agent may be metabolized by the microsomal fraction of the liver. Thus, with little change in basic chemical structure, a totally different pharmacokinetic compound is produced. The effect of alteration in hepatic blood flow on the pharmacokinetic pathway of W36095 is unknown.

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and used in this study provides a sensitive method for estimating antiarrhythmic effects when the strict criteria for inclusion in the study are met. Care must be taken during the operation to ensure that the constrictors are placed close to the bifurcation of the left coronary artery and that no branches, either septal or marginal, arising proximal to the constrictors are missed. If it is not technically feasible to include these branches distal to the constrictors, they must be ligated separately, since preservation of a single branch results in a substantial collateral circulation and, thus, in failure to produce a long-term model of ischemia. Care must also be taken to avoid ligation or compromise of the branch of the left circumflex artery that supplies the left atrium. In our early experience with this model, ligation or constriction of this branch tended to produce a high rate of supraventricular arrhythmias in dogs. Our long-term model of ischemia (Fig. 8) produces progressive ischemic changes in the repolarization phase of the electrocardiogram over a period of 2 to 3 weeks. All dogs that satisfactorily met the criteria for inclusion in the antiarrhythmia study experienced sudden death between the second and third weeks after operation. This model would appear to be a sensitive, reproducible method of evaluating antiarrhythmic drugs. Antiarrhythmic property of W36095: In doses of 100 mg/kg, W36095 has a potent antiarrhythmic effect on arrhythmias induced by gradual constriction of the coronary arteries. This dose was chosen for study because pharmacokinetic observations suggested that long plasma half-life concentrations of this agent were possible. It is unfortunate that different doses of the drug were administered in the hemodynamic studies performed before blood level and antiarrhythmic data were available. Nevertheless, our findings suggest that in doses of 100 mg/kg, W36095 can be expected to produce moderate reduction in ventricular function, but to have potent antiarrhythmic effects. We conclude that W36095 may have an important role in preventing and treating arrhythmias produced by coronary arterial obstruction. However, it may produce depression of ventricular function, and further studies are necessary to determine its role in patients with myocardial infarction and cardiac arrhythmias. The long duration of plasma levels and effects on arrhythmias found in our study are promising. Further documentation of other dose levels for antiarrhythmic action is necessary. Studies in both animal models and in man are now in progress to define these variables.

NEW LIDOCAINE-LIKE AGENT-COLTART

Acknowledgment We are grateful to Astra Pharmaceuticals, Worcester, Mass., and to Dr. M. Meyer, for the generous supply of W36095, to Mr. Duce for analysis of plasma W36095 and to

ET AL.

Mr. J. B. Keenaghan for the measurements of blood concentration. We also thank Mr. George Snidow for his expert technical assistance and Louise Carlstrand, Dorothy McCain and Linda Mokrejs for their secretarial aid.

References Kuller L, Cooper M, Perper J: Epidemiology of sudden death. Arch intern Med 129:714-719. 1972 Lown B, Woff M: Approaches to sudden death from coronary heart disease. Circulation 44: 130-142, 197 1 Cohen L, Rosenthal J, Horner D, et al: Plasma levels of lidocaine after intramuscular administration. Am J Cardiol 29:520-523, 1972 Zener JZ, Kerber RE, Splvack AP, et al: Blood lidocaine levels and kinetics following high dose intramuscular administration. Circulation 46:984-988, 1973

5. Marlon AM, Adams MH. Bates BL, et al: A simplified method for the in vitro calibration of electromagnetic flowmeters. Cardiovasc Res 7:290-296, 1973 6. Scott DE: Blood levels of lidocaine following various routes of administration. In. Lidocaine in the Treatment of Ventricular Arrhythmias (Scott DB, Julian DG, ed). E & S Livingstone, Edinburgh, 1971, p 153-158 7. Stenson RE, Constantlno RT, Harrison DC: Interrelationships of hepatic blood flow, cardiac output and blood levels in man. Circulation 43:205-211, 1971

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