A study of the antiarrhythmic action of certain beta-blocking agents

Kelliher, Gerald J.; Roberts, Jay

doi:10.1016/0002-8703(74)90171-9

Cited by 23 publications

(5 citation statements)

References 17 publications

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“…No special effort was made at this stage to optimize the absorption of EO-122, but it has been demonstrated that more than 80% of the ingested dose could be accounted for in the circulation of healthy dogs. But whereas the antiarrhythmic effect of a 100 mg/kg oral dose of tocainide was shown to last 0.25 to 5 hours when treatment was given 48 hours postligation, that of an oral dose of EO-122 in the range of [15][16][17][18][19][20] mg/kg lasted about 20 minutes when treatment was given 24 hours after ligation and 2 hours when given 48 hours postligation. Thus the relatively short t1f2 of EO-122 with respect to tocainide is not necessarily a shortcoming when oral medication is called for, since it appears to be partly compensated for by the higher potency of EO-22.…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, the latter effect seemed to be the primary cause of death. At therapeutic doses in healthy and arrhythmic dogs, no depression of cardiac function could be observed, in one case where an intravenous dose of 5 mg/kg of the drug was intentionally injected within a very short time; a transient broadening of the QRS complex followed, lasting for about 15 minutes. Remarkably, nembutal-anesthetized cats seemed to be more vulnerable to the effect of EO-122 because ECG changes already appeared after a cumulative IV dose of 3 mg/kg.…”

Section: Discussionmentioning

confidence: 99%

“…The effect of EO-122 on normal hearts was determined by administering the compound as a bolus IV injection to 5 conscious, healthy mongrel dogs of both sexes weighing [15][16][17][18][19][20] kg. In the animals lead II of the ECG was monitored for as long as 2 hours after injection.…”

Section: Methodsmentioning

confidence: 99%

“…15 Usually, ventricular tachycardia (VT) set in after administration of a total dose of 70-80 jig/kg. To demonstrate the ventricular origin of the ectopic pacemaker,14 the right vagus 16 was sectioned in two cases and the distal end was connected to a Grass stimulator model SD9; then square wave stimuli of 1.0 msec at a voltage of 1.4 V and a frequency of 20 Hz were applied for 10 seconds.…”

Section: Methodsmentioning

confidence: 99%

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A Preclinical Study ofEO-122, a New Lidocaine- Like Antiarrhythmic Drug

et al. 1980

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The 2,6-dimethylanilide of quinuclidine-3-carboxylic acid hydrochloride (EO-122), a new structural analog of lidocaine, has been shown to possess potent antiarrhythmic activity in experimentally induced arrhythmias in animals. Restoration of normal sinus rhythm and suppression of ouabain-induced arrhythmia in cats and dogs, and of coronary occlusion-induced arrhythmia in dogs, followed a single IV injection of 1--3 mg/kg, with an onset of 2 minutes and a duration of 20--240 minutes. Occlusion-induced arrhythmia was likewise suppressed after an oral dose of 10--20 mg/kg, with an onset of 11--65 minutes and a duration of 25--120 minutes. Under similar conditions, lidocaine was either totally ineffective or of ultra-short duration. The bioavailability of EO0122 by the oral route exceeded 80% of the oral dose. Therapeutic blood concentrations were in the range 0.5--7 microgram/ml. At about 5 microgram/ml there was a slight depression of cardiac function in the anesthetized cat, but not in the conscious dog. In cats, complete A-V block occurred at concentrations of 60--70 microgram/ml. The IV LD50 in mice was 22 mg/kg, and in rabbits 8.5 mg/kg. No overt signs of neurotoxicity could be observed at any dose of EO-122. The pharmacokinetic profile of the drug fits a two-compartment open model, with t1/2 congruent to 150 min and Vd (SS) congruent to 1.5 l/kg.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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A Preclinical Study ofEO-122, a New Lidocaine- Like Antiarrhythmic Drug

et al. 1980

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“…Surgical or pharmacological procedures that decrease sympathetic nerve function also decrease digitalis toxicity. Even though many groups of drugs which decrease sympathetic tone, like fl-adrenoceptor antagonists (Kelliher & Roberts, 1974;Hernandez & Serrano, 1982;, ganglion blocking agents (Gillis et al, 1975), drugs interfering with catecholamine storage and release Saito et al, 1974) were studied and found effective against cardiac arrhythmias induced by various cardiac glycosides, there has been no serious attempt to study the effect of a2-adrenoceptor agonists against digitalis-induced cardiotoxic effects. Numerous studies have proposed that clonidine reduces blood pressure by a reduction in sympathetic tone through activation of central a2-adrenoceptors (Schmitt, 1977;Isaac, 1980;Van Zwieten & Timmermans, 1983).…”

Section: Introductionmentioning

confidence: 99%

Protective action of clonidine against the arrhythmogenic and lethal effects of ouabain in guinea‐pigs

Thomas

Stephen

1991

British J Pharmacology

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1 Clonidine (1.25, 2.5 and 5.0 pugkg -) was studied for its effect on the cardiac arrhythmias and lethality induced by slow intravenous infusion of ouabain in guinea-pigs. 2 Clonidine produced significant delays in the onset of the arrhythmic stages and lethality. However, clonidine did not offer any such protection in reserpinised guinea-pigs, whereas its effects were unaltered in atropinized guinea-pigs.3 Idazoxan (l00.ugkg-1, i.v.) abolished the antiarrhythmic effect of clonidine whereas corynanthine(1 mg kg-1, i.v.) had no such effect. 4 Clonidine inhibited the rate of the ouabain-induced rise in blood pressure and the peak pressor response.5 In isolated paced left atria of the guinea-pig, clonidine (3.75 x 1O-4M) did not offer any protection against rapid and/or irregular extrasystolic contractions induced by ouabain. 6 It is concluded that the antiarrhythmic effect of clonidine is due to its effects on the indirect neural components of digitalis toxicity mediated by the stimulation of a2-adrenoceptors, without any direct antiarrhythmic effect on the myocardium.

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The Effect of C1 Spinal Cord Transection or Bilateral Adrenal Vein Ligation on Thioridazine‐Induced Arrhythmia and Death in the Cat

Lathers

Flax

Lipka

1986

The Journal of Clinical Pharma

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The phenothiazine thioridazine 1 mg/kg/min was infused intravenously into three groups of cats: (1) thioridazine alone (N = 5), (2) after bilateral adrenal ligation (N = 4), and (3) after spinal cord section at the atlanto-occipital junction (C1; N = 6). The times to arrhythmia and death with thioridazine alone were 47.8 +/- 7.8 and 72.8 +/- 5.6 minutes respectively. After bilateral adrenal ligation, arrhythmia and death occurred at 41.1 +/- 5.2 and 53.1 +/- 5.8 minutes, respectively, which showed no increase (P greater than .05) from thioridazine alone. After spinal cord section, thioridazine-induced arrhythmia and death occurred at 74.0 +/- 13.7 and 85.7 +/- 13.8 minutes, respectively, which were not increased (P greater than .05) when compared with thioridazine alone. The results of this study suggest that neither adrenomedullary catecholamines nor the central sympathetic component above C1 plays a significant role in acute thioridazine-induced arrhythmia. The action of thioridazine to induce arrhythmia in spite of transection of the spinal cord or bilateral adrenal vein ligation suggests that its cardiotoxicity is a result of a direct myocardial effect. Thioridazine depressed blood pressure without producing the sustained reflex tachycardia normally seen with hypotension. This suggests that the agent may modify the baroreceptor reflex arc.

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A study of the antiarrhythmic action of certain beta-blocking agents

Cited by 23 publications

References 17 publications

A Preclinical Study ofEO-122, a New Lidocaine- Like Antiarrhythmic Drug

A Preclinical Study ofEO-122, a New Lidocaine- Like Antiarrhythmic Drug

Protective action of clonidine against the arrhythmogenic and lethal effects of ouabain in guinea‐pigs

The Effect of C1 Spinal Cord Transection or Bilateral Adrenal Vein Ligation on Thioridazine‐Induced Arrhythmia and Death in the Cat

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