Synergistic Effect of Dofetilide and Mexiletine on Prevention of Atrial Fibrillation.

BACKGROUND: Although atrial fibrillation (AF) is the most common abnormal heart rhythm and its prevalence continues to rise, there is a marked paucity of effective and safe antiarrhythmic drugs for AF. This study was done to test whether combined use of dofetilide and mexiletine exhibits not only a synergistic effect on AF suppression but also a safer profile in drug-induced ventricular proarrhythmias. METHODS AND RESULTS: The effects of dofetilide plus mexiletine on atrial effective refractory period (ERP), AF inducibility, QT, and QT-related ventricular arrhythmias were studied using the isolated arterially perfused rabbit atrial and ventricular wedge preparations. Dofetilide or mexiletine alone mildly to moderately prolonged atrial ERP, but their combined use produced a markedly rate-dependent increase in atrial ERP. Dofetilide (3 nmol/L) plus mexiletine (10 µmol/L) increased the ERP by 28.2% from 72.2±5.7 to 92.8±5.9 ms (n=9, P<0.01) at a pacing rate of 0.5 Hz and by 94.5% from 91.7±5.2 to 178.3±12.0 ms (n=9, P<0.01) at 3.3 Hz. Dofetilide plus mexiletine strongly suppressed AF inducibility. On the other hand, dofetilide at 10 nmol/L produced marked QT and Tp-e prolongation, steeper QT-BCL and Tp-e-BCL slopes, and induced early afterdepolarizations and torsade de pointes in the ventricular wedges. Mexiletine at 10 µmol/L reduced dofetilide-induced QT and Tp-e prolongation, QT-BCL and Tp-e-BCL slopes, and abolished early afterdepolarizations and torsade de pointes. CONCLUSIONS: In rabbits, combined use of dofetilide and mexiletine not only synergistically increases atrial ERP and effectively suppresses AF inducibility, but also markedly reduces QT liability and torsade de pointes risk posed by dofetilide alone.

Synthesis, antiarrhythmic activity, and toxicological evaluation of mexiletine analogues.

Four mexiletine analogues have been tested for their antiarrhythmic, inotropic, and chronotropic effects on isolated guinea pig heart tissues and to assess calcium antagonist activity, in comparison with the parent compound mexiletine. All analogues showed from moderate to high antiarrhythmic activity. In particular, three of them (1b,c,e) were more active and potent than the reference drug, while exhibiting only modest or no negative inotropic and chronotropic effects and vasorelaxant activity, thus showing high selectivity of action. All compounds showed no cytotoxicity and 1b,c,d did not impair motor coordination. All in, these new analogues exhibit an interesting cardiovascular profile and deserve further investigation.

Detecting drug-induced prolongation of the QRS complex: new insights for cardiac safety assessment.

BACKGROUND: Drugs slowing the conduction of the cardiac action potential and prolonging QRS complex duration by blocking the sodium current (I(Na)) may carry pro-arrhythmic risks. Due to the frequency-dependent block of I(Na), this study assesses whether activity-related spontaneous increases in heart rate (HR) occurring during standard dog telemetry studies can be used to optimise the detection of class I antiarrhythmic-induced QRS prolongation. METHODS: Telemetered dogs were orally dosed with quinidine (class Ia), mexiletine (class Ib) or flecainide (class Ic). QRS duration was determined standardly (5 beats averaged at rest) but also prior to and at the plateau of each acute increase in HR (3 beats averaged at steady state), and averaged over 1h period from 1h pre-dose to 5h post-dose. RESULTS: Compared to time-matched vehicle, at rest, only quinidine and flecainide induced increases in QRS duration (E(max) 13% and 20% respectively, P<0.01-0.001) whereas mexiletine had no effect. Importantly, the increase in QRS duration was enhanced at peak HR with an additional effect of +0.7 ± 0.5 ms (quinidine, NS), +1.8 ± 0.8 ms (mexiletine, P<0.05) and +2.8 ± 0.8 ms (flecainide, P<0.01) (calculated as QRS at basal HR-QRS at high HR). CONCLUSION: Electrocardiogram recordings during elevated HR, not considered during routine analysis optimised for detecting QT prolongation, can be used to sensitise the detection of QRS prolongation. This could prove useful when borderline QRS effects are detected. Analysing during acute increases in HR could also be useful for detecting drug-induced effects on other aspects of cardiac function.

Synthesis and toxicopharmacological evaluation of m-hydroxymexiletine, the first metabolite of mexiletine more potent than the parent compound on voltage-gated sodium channels.

The first synthesis of m-hydroxymexiletine (MHM) has been accomplished. MHM displayed hNav1.5 sodium channel blocking activity, and tests indicate it to be ∼2-fold more potent than the parent mexiletine and to have more favorable toxicological properties than mexiletine. Thus, MHM and possible related prodrugs might be studied as agents for the treatment of arrhythmias, neuropathic pain, and myotonias in substitution of mexiletine (metabolite switch), which has turned out to be tainted with common toxicity.

Relative potency of mexiletine, lidocaine, and tocainide as inhibitors of rat liver CYP1A1 activity.

Mexiletine and tocainide are lidocaine congeners that share similar chemical structures. Clinical studies suggest that the in vivo inhibitory effect of mexiletine on the CYP1A family of isoforms is substantially greater than that of tocainide. We investigated the inhibitory property of mexiletine, lidocaine, and tocainide on the in vitro activity of the cytochrome P4501A1 (CYP1A1) isozyme in the rat. Hepatic microsomes were prepared from rat livers induced with 3-methylcholanthrene. The rate of ethoxyresorufin-O-dealkylation (EROD) was used as an index of CYP1A1 activity. Vmax and KM of the reactions were determined from Lineweaver-Burk plots. The Ki values for the inhibitors were derived from Dixon plots. Results showed that mexiletine is a competitive inhibitor, lidocaine is a mixed inhibitor, and tocainide is a noncompetitive inhibitor of EROD. The Ki values for mexiletine and tocainide were 0.30 +/- 0.02 mM and 12.4 +/- 0.7 mM, respectively. Two Ki values for lidocaine were determined. They were 0.65 +/- 0.07 mM and 4.1 +/- 1.3 mM, respectively. The relative inhibitory potency of these agents on rat CYP1A1 activity is mexiletine > lidocaine > tocainide. This difference in potency, which is most likely attributable to the change in the chemical composition in the aliphatic chain among the compounds, suggests that these compounds may be useful probes for studying the mechanism of the interaction with the active site of CYP1A1.

Prolongation of intraventricular conduction time associated with fatal [correction of fetal] impairment of defibrillation efficiency during treatment with class I antiarrhythmic agents.

To test whether fatal deterioration of defibrillation efficiency during antiarrhythmic therapy can be prevented by avoiding extreme decrease in ventricular prevented by avoiding extreme decrease in ventricular conduction or toxic plasma drug levels, we determined the defibrillation threshold (DFT) before and during infusion of incremental doses of disopyramide (n = 8), mexiletine (n = 9), or flecainide (n = 9) in anesthetized dogs. Disopyramide did not alter DFT [from 4.4 +/- 1.5 to 4.4 +/- 1.6 J (3.1 +/- 1.2 micrograms/ml)]. Mexiletine tended to increase DFT [from 4.6 +/- 1.2 to 6.1 +/- 2.0 J (1.8 +/- 0.6 micrograms/ml); p < 0.05], and defibrillation eventually was unsuccessful in 3 of the 9 dogs. Although the plasma mexiletine level before refractory fibrillation was far beyond the human therapeutic range, prolongation of intraventricular conduction time (CT) was moderate (16 +/- 3%). Flecainide increased DFT from 4.2 +/- 1.3 to 6.1 +/- 1.5 J at a plasma level of 1.04 +/- 0.37 micrograms/ml (p < 0.0005). In 3 of 5 dogs that developed refractory fibrillation, plasma flecainide level before terminal ventricular fibrillation (VF) was not toxic, but prolongation of CT in the 5 dogs was remarkable (30 +/- 9%). Thus, VF resistant to defibrillation is not necessarily associated with both toxic plasma drug level and remarkably decreased conduction. Reliability of these valuables as indicators of fatally deteriorated defibrillation efficiency may vary among antiarrhythmic agents.

Mexiletine's antifibrillatory actions are limited by the occurrence of convulsions in conscious animals.

The antiarrhythmic actions of the racemate and enantiomers of mexiletine were studied in conscious and anaesthetised rats. Racemate or enantiomers, at 20 mg/kg i.v., had little effect on ischaemia-induced ventricular fibrillation in conscious or anaesthetised rats. In conscious rats 20 mg/kg caused convulsions in 78-89% of rats when the plasma concentration of racemate was 20 +/- 2 microM. In anaesthetized animals a higher dose (40 mg/kg) of racemate could be given; this completely prevented ischaemia-induced fibrillation when the plasma concentration was 26 +/- 2 microM. Racemate and enantiomers accumulated in the heart and brain of conscious animals to give tissue: plasma ratios of 7.5 and 23, respectively. With electrical stimulation, both racemate and enantiomers dose dependently (4-32 mg/kg) increased threshold currents for induction of ventricular fibrillation, increased refractory period and minimally changed the ECG; findings expected with a Class Ib antiarrhythmic. The above studies failed to show major differences between racemate or enantiomers except for consistently lower (20-30%) plasma concentrations of R(-) at all dose levels. In conclusion, mexiletine prevented ischaemia-induced ventricular fibrillation in anaesthetised animals but only when given at doses producing convulsions in conscious animals.

Changes in cardiac output determined by continuous-wave Doppler echocardiography during propafenone or mexiletine drug testing.

Antiarrhythmic drugs may induce congestive heart failure in patients with malignant ventricular arrhythmias and depressed left ventricular (LV) function. Whether Doppler echocardiography can detect drug-induced depression in LV function was assessed. Continuous-wave Doppler measurements of ascending aortic blood flow velocity were obtained in 16 patients while not receiving antiarrhythmic drugs on 2 consecutive days to assess day-to-day variability, as well as while receiving maximally tolerated oral doses of mexiletine (11 patients) and propafenone (9 patients). While receiving propafenone, a drug with moderate negative inotropic activity, peak flow velocity declined by 9 +/- 8% (p less than 0.05), the flow velocity integral (termed stroke distance, representing stroke volume) declined by 8 +/- 11% (p less than 0.10), the rate-corrected stroke distance declined by 9 +/- 8% (p less than 0.02) and the minute distance, representing cardiac output, declined by 10 +/- 12% (p less than 0.05). In contrast, while receiving mexiletine, a drug with minimal negative inotropic activity, none of these parameters changed significantly. Five of 9 patients (56%) treated with propafenone showed a decline in rate-corrected stroke distance exceeding the 95% confidence limit of day-to-day variability, which was +/- 13 percent. Two of these 5 patients developed clinical signs of congestive heart failure. Continuous-wave Doppler echocardiography can detect antiarrhythmic drug-induced LV dysfunction and may be used to anticipate the development of significant clinically overt congestive heart failure.

General pharmacological studies on N-(2,6-dimethylphenyl)-8-pyrrolizidineacetamide hydrochloride hemihydrate. 1st communication: effect on the central nervous system.

The pharmacological actions of N-(2,6-dimethylphenyl)-8-pyrrolizidineacetamide hydrochloride hemihydrate (SUN 1165), a new antiarrhythmic agent, on the central nervous system were studied in various experimental animals as compared with those of disopyramide, mexiletine and lidocaine, and the following results were obtained. 1. Acute toxicity of SUN 1165 in mice was similar to that of mexiletine, and twice as potent as compared with that of disopyramide and lidocaine. Main acute toxic symptoms of SUN 1165 were muscle relaxation, ataxia, clonic convulsions, tremor and a decrease in spontaneous activity in mice, rats and rabbits. In addition to these symptoms, vomiting in dogs was observed. These toxic symptoms were similar to those of lidocaine. In the case of disopyramide, ataxia, tremor and a decrease in spontaneous activity were observed in mice and rats. On the other hand, mexiletine caused central nervous excitatory symptoms, that is, tremor, Straub tail, clonic convulsions, jumping, running and opisthotonus in mice and rats, and vomiting in dogs. 2. SUN 1165 even at large doses (50-100 mg/kg p.o.) exerted no significant effects on the following changes: hexobarbital-induced induced hypnosis, oxotremorine-induced tremor, apomorphine-induced hypothermia, reserpine-induced ptosis and hypothermia, 5-hydroxytryptophan syndrome and fighting behavior in mice, and conditioned avoidance response in rats. 3. An ineffective dose of SUN 1165 (12.5 mg/kg p.o.) on spontaneous locomotor activity was lower than of disopyramide and lidocaine, however, higher than that of mexiletine. 4. SUN 1165 at large doses showed antagonistic action on toxic extensor seizures induced by maximal electroshock, picrotoxin, or strychnine in mice, but anticonvulsive effects of SUN 1165 were less potent than those of mexiletine and lidocaine. SUN 1165 had no effect on clonic convulsions induced by pentetrazol and pictrotoxin in mice, while both mexiletine and lidocaine prolonged the duration of clonic convulsions. 5. The muscle relaxant effect of SUN 1165 (50%-toxic dose, TD50 = 30 mg/kg p.o.) was more marked than that of lidocaine (TD50 = 92 mg/kg p.o.) on traction test in mice. However, effect of SUN 1165 (TD50 = 62 mg/kg p.o.) on motor incoordination was similar to that of disopyramide, mexiletine and lidocaine on the rotarod test in mice. 6. The analgesic effect of SUN 1165 was as weak as that of disopyramide, mexiletine and lidocaine on chemically and mechanically-induced pain response in mice.(ABSTRACT TRUNCATED AT 250 WORDS)

Antiarrhythmic efficacy of combined intravenous and oral mexiletine in acute myocardial infarction. A double blind placebo-controlled study.

The antiarrhythmic efficacy of mexiletine in acute myocardial infarction (AMI) was studied in 99 patients randomized to mexiletine or placebo treatment. The loading dose was 250 mg i.v. and 400 mg orally followed by 200 mg orally 2 h later, and thereafter 200 mg t.i.d. up to 42 h. Arrhythmias occurring during 48 h were analysed from continuous electrocardiographic recordings. AMI was verified in 35 of 50 mexiletine patients and in 38 of 49 placebo patients. No deaths or instances of ventricular fibrillation occurred in the AMI patients. The number of patients who had any event of accelerated idioventricular rhythm (AIVR; P less than 0.05) runs of ventricular premature beats (VPBs; P less than 0.01), ventricular tachycardia (P less than 0.01) and Ron T beats (P less than 0.05) was smaller in the mexiletine group than in the placebo group. The number of all VPBs (P less than 0.05), hours with occurrence of AIVR (P less than 0.05), runs (P less than 0.01) and Ron T beats (P less than 0.05) was smaller in the mexiletine than in the placebo group. Serum levels of mexiletine tended to be low throughout the study. The half-life of the elimination was 13.7 +/- 7.2 h (means +/- S.D.). Adverse effects were infrequent, and the treatment was well-tolerated. Combined iv. and oral mexiletine prophylaxis significantly suppressed repetitive ventricular tachyarrhythmias and Ron T beats. However, no clinical benefit from mexiletine treatment could be shown in a coronary care unit with a low frequency of primary ventricular fibrillation.

The amino acid cerebral pool after toxic doses of lidocaine and mexiletine. An experimental study on guinea pigs.

Lidocaine and Mexiletine are two anti-arrhythmic drugs which when administered in toxic doses cause alterations in the central nervous system (convulsions, tremors, coma). An experimental study was carried out to clarify some neurological side-effects caused by these two drugs, by studying the variations of the brain amino acid pool. With Lidocaine one can observe an increase of phenyl-alanine and tyrosine, a decrease of glycine, GABA, alanine, aspartate and glutamate, while taurine and ammonia showed no significant changes. After Mexiletine one can observe an increase of ammonia, a decrease of GABA, glutamine, glycine and alanine, while glutamate, taurine, phenyl-alanine and tyrosine remain within normal values. In conclusion, on the basis of the data obtained by comparing the two drugs, one could say that Lidocaine has a greater interference on the catecholaminic precursors which are little influenced by Mexiletine. For the rest, the data obtained are practically super- imposable .

Possible adverse effects on the cardiovascular system of an antiarrhythmic drug mexiletine.

Mexiletine (MXT) is a drug endowed with a marked antiarrhythmic activity which may be included in 1B class of drugs employed in the therapy of arrhythmias. In experimental cardiovascular research, MXT at very high doses induces a decrease in the arterial blood pressure and cardiac performance of dogs. MXT reduces the carotid baroreceptor responses, the fall in blood pressure following pharadic stimulation of the peripheral trunk of the vagus nerve and it also inhibits catecholamine uptake. All these effects may be related to the local anaesthetic activity which MXT possesses and which need careful consideration in the clinical use of the drug.

Hemodynamic, electrocardiographic and toxic effects of the intravenous administration of increasing doses of mexiletine in the dog. Comparison with similar effects produced by other antiarrhythmics.

The hemodynamic and electrocardiographic effects of intravenous injections of mexiletine in progressively increased doses, starting from 1.5 and 3 mg, have been studied in two series of 8 and 6 dogs anaesthetized with pentobarbital. The analysis of the results showed that absence of change in aortic pressure, heart rate and output when the minimal doses are injected, is due to the interaction of opposite effects: a direct depressing effect on the myocardial contractility, and a sympathic reflex stimulation secondary to a peripheral vasodilation. The comparison of hemodynamic, electrocardiographic and toxic effects of mexiletine with those produced by other antiarrhythmics showed that mexiletine placed itself among the better tolerated antiarrhythmics during the administration of progressively increasing doses.