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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The haemodynamic changes caused by intravenous mexiletine were studied in 12 patients. Initially the drug was given rapidly at the rate of 3 mg/kg/min for 10 minutes and then slowly at a rate of 0,06 mg/kg/min for 30 minutes. The plasma Mexiletine level measured after 20 minutes was used to divide the series of patients into two groups: in Group A the level was over 0,7 g/ml (0,961 +/- 0,109 microgram/ml) whilst in Group B the level was only 0,547 +/- 0,101 microgram/ml. The mean aortic pressure, heart rate and left ventricular end diastolic volume did not vary significantly in the two groups. The left ventricular end diastolic pressure rose, and the cardiac index and the ejection fraction fell in Group A. The indices of left ventricular contractility fell in all patients of the start of the injection. This depression only persisted to the end of the injection in Group A. Mexiteline did not cause significant changes in post extrasystolic potentialisation in the 5 cases in which this phenomenon was studied.
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PMID:[Hemodynamic effects of mexiletine]. 12 Jan 53

Time-dependent inhibition of sodium channels by class I antiarrhythmic drugs has been observed in isolated cardiac muscles or cells. We examined coupling interval-related effects of class I antiarrhythmic drugs, mexiletine, cibenzoline and disopyramide, on ventricular activation in canine infarcted myocardium. A ventricular stimulation with various coupling intervals was applied to the right ventricle, and activation delays (time intervals between the initiation of a deflection and the final rapid deflection of a bipolar electrocardiogram) of infarcted and normal zones were measured. The premature stimulation produced a delayed activation and in some animals, caused reentrant beats. Mexiletine (3 and 10 mg/kg), cibenzoline (1 and 4 mg/kg) and disopyramide (1 and 4 mg/kg) further enhanced or blocked the delayed activation. The effects of these drugs were more marked at shorter coupling intervals, although cibenzoline and disopyramide showed significant effects also at long coupling intervals. The effect of these drugs on the activation in the normal zone was less than that in the infarcted zone. In conclusion, mexiletine, cibenzoline and disopyramide showed a coupling interval-related depression of delayed activation in infarcted myocardium, which may be a reflection of their time-dependent inhibition of sodium channels.
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PMID:Coupling interval-related effects of class I antiarrhythmic drugs, mexiletine, cibenzoline and disopyramide, on ventricular activation in canine myocardial infarction. 180 64

Using standard microelectrode techniques, the authors compared the effects of 15 to 125 microM concentrations of mexiletine, 31 to 500 microM concentrations of sotalol and 15 to 125 microM of mexiletine combined with 125 microM sotalol, on the beat-to-beat maximum rate of depolarization of phase 0 of the action potential (Vmax) of porcine papillary muscles and Purkinje fibres stimulated by 30 beat trains at a frequency of 1 Hz. Sotalol alone had no effect on Vmax. Mexiletine caused both tonic and use-dependent depression of Vmax in papillary muscle. In the presence of sotalol, tonic Vmax depression was exaggerated, while use-dependent depression was attenuated. In Purkinje fibres, mexiletine exposure resulted in tonic Vmax depression, but no use-dependence could be demonstrated at this frequency. These results are best explained in the context of the modulated receptor hypothesis with the added consideration of two receptors--one within and one external to the sodium channel.
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PMID:The cellular electropharmacology of mexiletine combined with sotalol in porcine papillary muscle and Purkinje fibre. I. Alteration of mexiletine-induced Vmax depression. 217 59

The blocking effects of local anesthetics, mexiletine and disopyramide on the sodium currents (INa) of enzymatically isolated, single cells from rat ventricle were studied under voltage clamp conditions. A suction pipette technique was used for voltage clamp and internal perfusion. Potassium currents were blocked by replacing K+ with Cs+ in the internal and external solutions; calcium currents were blocked by replacing Ca2+ with Co2+ in the external solution to isolate INa. When the cells were stimulated infrequently (less than 1 Hz), both drugs produced dose-dependent depression of INa, which was correlated with one-to-one binding to sodium channel. A half-blocking concentration (KD) of 2.8 X 10(-5) M was observed for both agents. The shape of the current-voltage curve along the voltage axis remained unchanged in the presence of either drug. Both drugs shifted the inactivation curve of INa to more negative potentials. Mexiletine produced a marked use-dependent blockage of INa, whereas disopyramide did not produce significant use-dependent block under similar experimental conditions. Both drugs prolonged the recovery of INa from inactivation. The results suggested that both drugs interact with the inactivation mechanism of the sodium channels of rat myocardial cells.
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PMID:Blockage of the sodium current in isolated single cells from rat ventricle with mexiletine and disopyramide. 241 42

Effects of SUN 1165, disopyramide, lorcainide, and mexiletine were studied either on the kinetics of onset of and recovery from rate-dependent depression of maximum rate of rise of phase 0 action potential (Vmax) in isolated guinea pig papillary muscles using standard microelectrode techniques or on intraventricular conduction time of extrasystoles evoked at varied coupling intervals in anesthetized dogs. SUN 1165 and lorcainide produced a slow-developing rate-dependent block of Vmax with the rate constant of 0.12 AP-1 and 0.09 AP-1, respectively. Mexiletine also produced a rate-dependent block of Vmax, but with very rapid onset so as not to be fitted by a single exponential curve. Disopyramide produced an intermediate rate-dependent block of Vmax with the rate constant of 0.46 AP-1. The time constants for recovery from the rate-dependent block for SUN 1165, lorcainide and disopyramide were 27.3-28.2, 23.2, and 17.0 s, respectively, while that for mexiletine was 0.118 s. SUN 1165, lorcainide, and disopyramide slowed ventricular conduction time of extrasystoles at all coupling intervals of 800-250 ms. On the other hand, mexiletine slowed conduction time at short coupling intervals of 500-250 ms. These findings suggest that, like lorcainide, SUN 1165 belongs to class Ic antiarrhythmic agents, and that SUN 1165 and lorcainide as well as disopyramide with slow and intermediate kinetics and mexiletine with fast kinetics may inhibit ventricular extrasystoles conducted at long and short range of coupling intervals, respectively.
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PMID:Effect of SUN 1165, a new potent antiarrhythmic agent, on the kinetics of rate-dependent block of Na channels and ventricular conduction of extrasystoles. 245 43

To determine if combinations of mexiletine and sotalol retain Class I and III electrophysiologic actions, using standard microelectrode techniques, we examined the electrophysiologic effects on canine Purkinje fibers of solutions of mexiletine (3.1-100 microM), sotalol (3.1-400 microM), and combinations of the two drugs, at stimulation frequencies of 1.5 and 2.0 Hz. The combinations consisted of 12.5 microM of one drug combined with 3.1, 12.5, and 50 microM of the other. Mexiletine caused a concentration dependent depression of Vmax, the degree of depression always being greater at the more rapid frequency. At concentrations above 50 microM, sotalol depressed Vmax slightly. Increasing the stimulation frequency did not result in further Vmax depression. The addition of sotalol did not alter the Vmax depression produced by mexiletine but prior exposure to sotalol attenuated the effect of subsequent mexiletine. Both drugs reduced action potential amplitude and in combination their effects on this parameter were additive. Sotalol prolonged and mexiletine shortened action potential duration. Low concentrations of mexiletine reversed the prolongation caused by sotalol, whereas the addition of sotalol did not alter the effect of mexiletine. Mexiletine shortened the effective refractory period at low concentrations and prolonged it at high concentrations. Sotalol prolonged the effective refractory period at all concentrations. Exposure to a low concentration of sotalol did not alter the effects on the effective refractory period of subsequent exposure to mexiletine but a low concentration of mexiletine reduced the prolongation from subsequent sotalol. Thus, the combination of mexiletine and sotalol may add a Class II action to the Class I effects of mexiletine but the mexiletine prevents the Class III effects of sotalol.
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PMID:A comparison of the cellular electrophysiology of mexiletine and sotalol, singly and combined, in canine Purkinje fibers. 246

The effects of antiarrhythmic drugs, aprindine, mexiletine and lidocaine, on rat erythrocytes, isolated rat hepatocytes and DPPC-liposomes were studied at various concentrations. Maximal inhibition of aprindine on the hypotonic hemolysis was observed at a concentration of 2 X 10(-4) M. In isolated rat hepatocytes, aprindine caused an increase in GOT leakage above 4 X 10(-4) M. Mexiletine and lidocaine caused a slight decrease in GOT. Only aprindine caused an increase in LDH leakage above 2 X 10(-4) M. In the relationship between the surface tension and pH conditions (pH 5.7, 7.4 and 8.0), aprindine and mexiletine indicated a depression of surface tension at a dose of 10(-4) M to 10(-3) M under all pH conditions. Lidocaine indicated a depression of surface tension at a dose of 10(-4) M at pH 8.0 only. Aprindine and mexiletine depressed the phase transition temperature (Tc) of DPPC-liposomes. The depression of Tc by aprindine was greater than that by mexiletine. The rank by order of surface activity was the same as that of enzyme leakage from hepatocytes, hemolysis of erythrocytes and depression of Tc in DPPC-liposomes in vitro. These results suggest that differences in membrane damage produced by antiarrhythmic drugs may by related to surface activity, which in turn may determine the extent of adsorption onto cell membranes.
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PMID:[Effects of antiarrhythmic drugs on rat erythrocytes, isolated hepatocytes and dipalmitoyl phosphatidyl choline (DPPC)-liposomes]. 384 Jan 13

We studied the effect of the antiarrhythmic compound mexiletine on the maximal rate of rise (V max) on the action potential and on conduction velocity in isolated papillary muscles of guinea pigs. Action potentials and V max were measured by means of conventional microelectrodes. The conduction velocity was determined from extracellular recordings Mexiletine (concentrations, 4.6 x 10(-5) and 1.15 x 10(-4) mol/L) caused a depression of V max that depended on the condition examined. The h infinity curve relating V max of the action potential to the resting membrane potential was shifted along the voltage axis to more negative membrane potentials. Qualitatively equal effects were observed on the curve of membrane responsiveness relating V max to the membrane potential during the phase of repolarization of the preceding action potential. Eventually, marked prolongation of the recovery kinetics of V max by mexiletine, as well as frequency-dependent reduction of V max, could be demonstrated. The action of mexiletine on conduction velocity was very similar to its influence on V max. Thus, prolongation of the recovery kinetics was found of about the same magnitude as that measured in V max. Similarly, in experiments with K + -induced depolarizations, a dependence on the membrane potential of the action of mexiletine on the conduction velocity could be demonstrated. The results suggest that mexiletine may exert antiarrhythmic effects mainly in damaged cardiac cells exhibiting a moderately reduced resting potential.
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PMID:Effects of mexiletine on steady-state characteristics and recovery kinetics of V max and conduction velocity in guinea pig myocardium. 617 6

The influence of stimulation rate on the ability of mexiletine, disopyramide, and encainide to depress the maximum rate of depolarisation (Vmax) of intracellular action potentials has been studied in guinea pig ventricular myocardium, using standard microelectrode techniques. Mexiletine and disopyramide produced modest depression of Vmax even in the absence of stimulation (resting block), while encainide did not. All three drugs produced progressive depression of Vmax as stimulation rate was increased over a wide range of interstimulus intervals (rate-dependent block). This relationship between interstimulus interval (ISI) and depression of Vmax was steepest for mexiletine, least marked for disopyramide, and intermediate for encainide. Mexiletine also exhibited the fastest response to a sudden change of frequency. During a train of stimuli at ISI of 300 ms after a rest period, Vmax fell rapidly, reaching 61% of its final value by the second beat. In response to a similar train of stimuli, disopyramide and encainide produced exponential falls of Vmax with rate constants of -0.113 AP (AP = action potential) and -0.025 AP, respectively. Similar trends were seen in the recovery of cells from this rate-dependent block at the end of a train of stimuli. Time constants for this process for mexiletine, disopyramide, and encainide were 471.2 ms, 12.2 s, and 20.3 s, respectively. It is concluded that the rapid onset of and recovery from rate-dependent block seen with mexiletine may explain its lack of effect on conduction of sinus beats at concentrations that suppress extrasystoles and tachycardias.
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PMID:Resting and rate-dependent depression of maximum rate of depolarisation (Vmax) in guinea pig ventricular action potentials by mexiletine, disopyramide, and encainide. 618 5

Mexiletine is a class I antiarrhythmic agent that is active after both oral and intravenous administration and similar in structure and activity to lidocaine. It decreases phase O maximal rate of depolarization (Vmax) by fast sodium channel blockade. The marked rate dependence of Vmax depression may explain mexiletine's lack of effect on normal conduction and its efficacy against ventricular tachyarrhythmias. Mexiletine significantly decreases the relative refractory period in His-Purkinje fibers without changing the sinus rate or atrioventricular and His-Purkinje conduction times. Action potential duration is usually shortened. Mexiletine may aggravate preexisting impairment of impulse generation and conduction. Uptake and distribution of mexiletine are rapid, systemic bioavailability is about 90%, and tissue distribution is extensive. Mexiletine is primarily metabolized in the liver; 10% to 15% is excreted unchanged in the urine. Elimination half-life is 9 to 11 hours after intravenous or oral administration. Microsomal enzyme induction shortens mexiletine's elimination half-life, whereas hepatic disease and acute myocardial infarction prolong it. Renal disease has little effect, although hemodialysis increases mexiletine clearance. Plasma concentrations from 0.75 to 2.0 mg/L are usually associated with a desirable therapeutic response.
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PMID:Pharmacology, electrophysiology, and pharmacokinetics of mexiletine. 632 58


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