TREATMENT OF VENTRICULAR ARRHYTHMIAS WITH MEXILETINE (KÖ1173)

399

The blood-transfusion resulted in an increase in cell mass and was reflected by corresponding changes in both nitrogen and potassium. The relation between total-body potassium and nitrogen has been explored in our entire series of patients by simultaneous studies (163) (fig. 6). The relation on the whole is satisfactory (r= )0’88, P>0.0005), although three apparently anomalous points exist well outside the 95% confidence limits on the regression lines. These three patients were anthropomorphically very unusual: two had gross obesity and the third was an advanced acromcgalic weighing 135 lb.; all appeared to have low body nitrogen relative to body potassium. It is likely that the nitrogen measurements on these patients were underestimated because of increased fat thickness producing changes in both neutron moderation and y-ray absorption. Such an effect can be simulatcd on phantoms and it should be possible to apply a correction factor for the very obese in future work. We have not seen any patients with low body potassium relative to body nitrogen. This is of great interest because many of our patients have potassium values which would be regarded as very low when expressed as criteria relating potassium Our data suggest that the low to body dimensions. values found in these patients may simply potassium reflect reduced protein/muscle mass consequent on the underlying disease. This may be the explanation for the low body potassium levels recorded by ourselves and others in hepatic cirrhosis," rheumatoid arthritis, and muscular dystrophy.12 Such patients are probably cell-dcpletcd rather than potassium depleted per se. This would accord with the finding that experimental potassium depletion is invariably associated with a negative nitrogen balance."," At present the method expresses body nitrogen in relative rather than absolute units. We believe this to be of no great disadvantage, since clinical studies are primarily concerned with changes rather than absolute quantities. Indeed, measurement in absolute terms would introduce the problem of defining normal values, ranges, and limits for age and sex and of assessing methods of expression relative to body dimensions. The current knowledge of body nitrogen is largely derived from inferences of laborious balance studies supplemented by a very few cadaver analyses; we believe our technique offers a valuable new research tool. We thank Prof. M. J. Chamberlain, Dr H. C. Biggin, W. D. Morgan, and R. Nowotny for help with the development of this subject over the past three years; F. R. Stewart, E. E. Cartwright, D. Bush, Dr C. W. Crane, and staff, Mrs B. Fairclough, Dr Clifford Hawkins, Dr Margaret Farr and the physicians and surgeons of the Birmingham hospitals for assistance; and Prof. John Hardwicke for advice and interest. Cadaver studies were carried out with the permission of the Home Office (Dr D. Dooley) and the assistance of Prof. J. T. Eayrs’ staff in the Department of Anatomy. The work was financed by the Medical Research Council, and S. J. was in receipt of a Sheldon Fellowship.

Requests for reprints should be addressed to T. C. H., Department of Experimental Pathology, University of Birmingham, Birmingham B15 2TJ.

TREATMENT OF VENTRICULAR ARRHYTHMIAS WITH MEXILETINE

(KÖ 1173) R. A. CLARK M. NEILSON L. F. PRESCOTT

R. G. TALBOT J. NIMMO D. G. JULIAN

J. M.

Departments of Cardiology, Therapeutics, and Medical Physics, Royal Infirmary, Edinburgh EH3 9YW Summary

Mexiletine

was

given

to

59

patients

chronic ventricular arrhythmias. Efficacy was assessed by long-term taperecording of electrocardiograms with computer analysis. mexiletine Intravenous successfully suppressed acute ventricular arrhythmias in 31 of 43 patients, with partial control in a further 9. After intravenous bolus injections initial high rates of infusion were required to maintain therapeutic plasma concentrations. Cardiovascular toxicity occurred in 6, and severe non-cardiac toxicity in 9. Oral mexiletine was well absorbed and suppressed non-acute ventricular arrhythmias in 12 of 16 patients, with partial control in 3. Therapeutic plasma concentrations were in the range 0·5-2·0 µg. per ml., while toxicity was usually associated with levels above 3·0 µg. per ml. The mean plasma half-life was 18·7 hours in patients and 10·2 hours in healthy volunteers. Although intravenous mexiletine was effective in the treatment of acute ventricular arrhythmias, its main potential appears to be as a long-term oral antiarrhythmic agent. with

acute

or

Introduction VENTRICULAR arrhythmias often difficult to control.

are

be dangerous and None of the available

can

antiarrhythmic drugs has proved consistently successful, and in particular there is no drug that can be administered orally over several months which is safe, effective, and has an acceptable dose regimen. Such a therapeutic agent is potentially of great DR HARVEY AND OTHERS: REFERENCES 1.

2.

3. 4. 5. 6.

7.

8. 9. 10. 11. 12.

13. 14.

Anderson, J., Osborn, S. B., Tomlinson, R. W. S., Newton, D., Rundo, J., Salmon, L., Smith, J. W. Lancet, 1964, ii, 1201. Chamberlain, M. J., Fremlin, J. H., Holloway, I., Peters, D. K. Int. J. appl. Radiat. Isotopes, 1970, 21, 725. Palmer, H. E., Nelp, W. B., Murano, R., Rich, C. Physics Med. Biol. 1968, 13, 269. Cohn, S. H., Dombrowski, C. S. J. nucl. Med. 1971, 12, 499. Cohn, S. H., Cinque, T. J., Dombrowski, C. S., Letteri, J. M. J. Lab. clin. Med. 1972, 79, 978. Biggin, H. C., Chen, N. S., Ettinger, K. V., Fremlin, J. H., Morgan, W. D., Nowotny, R., Chamberlain, M. J. Nature New Biol. 1972, 236, 187. Biggin, H. C., Chen, N. S., Ettinger, K. V., Fremlin, J. H., Morgan, W. D., Nowotny, R., Chamberlain, M. J. Nuclear Activation Techniques in the Life Sciences; p. 639. International Atomic Energy Agency, Vienna, 1972. Chen, N. S., Ettinger, K. V., Filkin, J., Thomas, B. J. J. Phys. Instr. (in the press). Isaksson, B., Sjogrcn, B. Proc Nutr. Soc. 1967, 26, 106. Querido, A. in Protein Metabolism (edited by F. Gross); p. 2. Berlin, 1962. Tyson, I., Genna, S., Jones, R. L., Bikerman, V. Burrows, B. A. J. nucl. Med. 1970, 11, 426. Nagai, T., Sugita, H., Iinuma, H., Furukawa, T., Yashiro, S. ibid. 1969, 10, 1. Fourman, P. Clin. Sci. 1954, 13, 93. Sagild, U., Anderson, V., Andreasen, P. B. Acta med. scand. 1961, 169, 243.

400

Fig. 1-Structural formulae of mexiletine (a)

and

lignocaine (b).

in prevention of sudden death in ischaemic heart-disease. In this paper we describe preliminary work with mexiletine (KO 1173), a new antiarrhythmic

importance

ventricular induced arrhythmias, particularly by digitalis.1.2 Like lignocaine, it depresses the maximal rate of ventricular depolarisation without altering the resting potential or duration of the action Mexiletine has no significant betapotential. adrenergic blocking activity.2 Mexiletine (1-[2,6dimethylphenoxy] 2-aminopropane), is a primary amine which has certain structural similarities to lignocaine (fig. 1) although its pharmacokinetic properties differ.

drug

which

suppresses

Fig. 2-Computer write-out of distribution of ventricular extrasystole coupling intervals. Upper pretreatment trace shows a discrete group of R-on-T extrasystoles with coupling intervals of about 250 msec., preceding the majority of extrasystoles. After mexiletine, the middle and lower traces show progressive merging of the previous R-on-T extrasystoles with the main group. H.R. =heart rate.

experimental those

Patients and Methods Patients 59 patients,

aged from 32 to 83 years, with ventricular arrhythmias were treated with mexiletine. The drug was given intravenously to 43 patients-32 with ventricular arrhythmias after myocardial infarction or

cardiac surgery, 7 with digitalis toxicity, and 4 with chronic ischaemic heart-disease. 16 patients received the drug orally for up to 14 months after acute myocardial infarction or for long-term treatment of other recurrent ventricular arrhythmias. The indications for treatment with mexiletine were: 1. Ventricular extrasystoles:

(a) " R on T " phenomenon. (b) Coupled beats with an R-R

interval of less than

0-40 seconds.

2. Ventricular tachycardia-runs of three or more ventricular extrasystoles at a rate greater than 100 per minute. 3. Following successful direct-current cardioversion for ventricular fibrillation. 4. Ventricular arrhythmias thought to be due to

digitalis toxicity.

Fig. 3-Correlation between antiarrhythmic effect of oral mexiletine and plasma concentrations in a 33-year-old man with chronic symptomatic ventricular tachycardia. Time-scales of the computer write-out of ventricular extrasystoles (VEs per min.) and plasma levels are identical. Pretreatment extrasystole count was typical of continuous recordings during the preceding 72 hours.

401 E.C.G. Monitoring Where possible, electrocardiograms (E.C.G.) were continuously recorded on 24-hour tapes. Ventricular arrhythmias were observed on a screen during playback at 60 times real speed, and appropriate sequences written The out on paper at normal speed for detailed analysis. also fed into a was hybrid analogue-digital tape output computer programmed to identify ventricular extrasystoles and ventricular tachycardia.3 The number of ventricular extrasystoles per minute was presented graphically by the computer (fig. 3). In some patients, only short periods of the pretreatment E.C.G. could be recorded on tape because of the urgency of the situation, but 24-hour baseline E.C.G. tapes were obtained in most cases before oral therapy was started.

Monitoring

and continuous E.c.G. tape-recordings were usually continued for 2-3 days. In outpatients, progress was followed by frequent checking of 5-minute E.c.G. rhythm strips or readmission for further long-term E.c.G. monitoring. More recently, portable tape-recorders have been used to check 24-hour E.C.G.s during long-term

oral

Results

Antiarrhythmic Activity The results of treatment with mexiletine are summarised in table I. Therapy was regarded as successful when the arrhythmia was abolished or when the frequency of extrasystoles was reduced by more than 95% with abolition of ventricular tachycardia. Partial success was defined as reduction of the extrasystole-count by more than 75% with abolition of ventricular tachycardia, or prolongation of the coupling interval so that ventricular extrasystoles no longer fell on the preceding T wave (fig. 2). Treatment with mexiletine was successful in 43 (72%) and partly successful in 12 (20%) of the 59 patients. In only 4 patients (7%) was there no TABLE I-RESULTS OF MEXILETINE THHRAPY IN

59

PATIENTS WITH

VENTRICULAR ARRHYTHMIAS

therapy.

AdmiJlistration and Patient Management Initially, mexiletine was given intravenously under E.C.G. control to patients with digitalis-induced ventricular arrhythmias in doses of 30-250 mg. over 10-30 minutes. The patients with acute ventricular arrhythmias received 75-300 mg. intravenously over 5-15 minutes, followed by infusions of 1’5-3’0 g. over 36-48 hours. Oral therapy was initiated with a loading dose of 400600 mg. in capsules followed by maintenance doses of 150--300 mg. 6-8-hourly. The 30 patients with arrhythmias after acute myocardial infarction were managed according to the standard coronary-care-unit regimen.4 Intravenous lignocaine was usually given first, and if this failed practolol and then procainamide were tried. Mexiletine was given first in Unless anticoagulation was some of the later cases. contraindicated, patients were given warfarin. Morphine with cyclizine (’ Cyclimorph’) was given for analgesia. Other drug therapy included diazepam, digoxin, and

Dn<

frusemide.

Biochemical and Haematological Investigations Full blood-counts, antinuclear factor, serum urea, electrolytes, uric acid, and folate, and liver-function tests (bilirubin, alanine aminotransferase, and alkaline phosphatase) were checked every 2-6 weeks in patients receiving long-term oral therapy. Plasnia Gonce1ltrations of Mexiletine Serial plasma concentrations of mexiletine were measured at intervals to establish antiarrhythmic and toxic concentrations and to determine the optimum dosage schedules. The first blood-samples were usually drawn at least 15 minutes after bolus injections of mexiletine. The plasma drug half-life was measured in 15 patients after the drug was discontinued. Mexiletine was estimated by gas/liquid chromatography with a nitrogen-sensitive flame ionisation detector using the 4-methyl analogue as internal standard.5 The drug was extracted from alkaline plasma into ether, acylated, and chromatographed at 220°C as the acetyl or butyryl derivative on a 6-foot glass column using 1 ° cyclohexanedimethanol succinate as the liquid phase.

Investigations in Healthy Volunteers Plasma and urinary concentrations of mexiletine were determined in 6 fasting healthy volunteers aged 30-39 years after ingestion of 3 mg. per kg. mexiletine in solution. Similar measurements were made after 100 mg. of the drug given intravenously over 4 minutes with monitoring of the pulse-rate, blood-pressure, and E.C.G.

to the drug. 26 of the 32 patients with ventricular arrhythmias had previously not responded to standard doses of intravenous lignocaine, and in 13 of these procainamide, practolol, or Plasmaphenytoin had also been ineffective. lignocaine concentrations at the time of starting mexiletine therapy were above 1.4 p.g. per ml. in 14 of 17 patients in whom this was measured. (The reported therapeutic range of plasma-lignocaine is 1.4-4 g per m1.6) Mexiletine successfully suppressed ventricular arrhythmias in 5 of the 6 patients (83%) to whom it was given intravenously as initial therapy. In at least 2 of the patients where treatment was classified as partly successful, inadequate doses of mexiletine had been given. 3 patients who showed no response had left-ventricular aneurysms with

response acute

refractory ventricular

supraventricular tachycardia, frequent extrasystoles, and runs of ventricular

tachycardia. Ventricular arrhythmias were adequately controlled in all 6 patients treated with oral mexiletine for 6 Another 10 weeks after myocardial infarction. patients with recurrent and potentially dangerous ventricular arrhythmias received oral mexiletine for Treatment was successful in 6, up to 14 months. a minor increase in dosage was sometimes but to maintain control. An example of the necessary efficacy of oral mexiletine is shown in fig. 3. In 2

402 TABLE II-TOXICITY OF MEXILETINE

Biochemical and Haematological Investigations No biochemical or hxmatological abnormalities were observed in any of the patients on long-term oral

therapy.

Plasma Concentrations of Mexiletine After initial intravenous injection, the drug disappeared rapidly from the circulation and a total of 500-750 mg. was required during the first 3 hours to maintain effective antiarrhythmic plasma concentrations. However, after the initial distribution phase, the drug was eliminated very slowly and plasma concentrations oftencontinued to rise during intravenous infusions of 500-1000 mg. of mexiletine of the 3 patients with partial suppression, adequate control was obtained with mexiletine in combination with quinidine or practolol. The individual drugs alone had failed in maximum tolerated doses.

Toxicity Adverse reactions to mexiletine are summarised in table n. Severe, non-cardiac toxicity consisting of nausea, vomiting, dizziness, dysarthria, diplopia, drowsiness, confusion, tremor, and paraesthesiae occurred in 9 patients given the drug intravenously for acute ventricular arrhythmias. Mild ataxia, tremor, and parxsthesiae were noted in 4 other patients treated intravenously and in 4 patients on long-term oral therapy. These symptoms were readily abolished by reduction in dose. Cardiovascular toxicity was observed after intravenous mexiletine in 6 patients with acute ventricular arrhythmias. 1 had a conduction defect after cardiac surgery, in a second patient there was previous bifascicular block and impaired renal function, and a third received very large intravenous doses because of resistant ventricular tachycardia. In the last 2 patients plasma concentrations of mexiletine were very high. The other 3 patients were extremely ill, and administration of mexiletine was followed by hypotension accompanied by sinus bradycardia, atrial fibrillation with slow ventricular response, and rapid atrial fibrillation, respectively. Otherwise, no effects on heart-rate, blood-pressure, or cardiac rhythm were observed. TABLE III-PLASMA CONCENTRATIONS OF MEXILETINE IN RELATION TO THERAPEUTIC AND TOXIC EFFECTS

per 24 hours.

and toxic plasma concentrations of shown in table ill. The minimum therapeutic plasma concentration-i.e., the lowest concentration at which ventricular arrhythmias were suppressed-was determined in 37 patients by correlation of serial plasma concentrations with the continuously recorded E.C.G. data. In 9 cases it was possible to obtain several estimates of the minimum effective concentration, when arrhythmias recurred as the plasma concentration of mexiletine declined after dose reduction. Arrhythmias were usually controlled with plasma concentrations in the range 0.52.0 µg. per ml. The effective concentrations in the patients with digitalis intoxication and non-acute ventricular arrhythmias tended to be lower than those required to control acute arrhythmias. Mild toxicity was associated with plasma concentrations of 0-8-3-0 jug. per ml., while severe toxicity occurred within the range 1-0-4-4 µg. per ml. Although there was a relatively small margin between therapeutic and toxic plasma concentrations

Therapeutic

mexiletine

some

are

patients tolerated " steady-state

"

plasma

con-

centrations of more than 5 ;ng. per ml. without incident. Oral loading-doses of 400-600 mg. produced peak plasma concentrations of 1.0-2.5 µg. per ml., and therapeutic concentrations of 1-0-2-0 µg. per ml. were easily maintained with doses of 150-300 mg. every 6-8 hours. No cardiovascular toxicity was observed in patients receiving mexiletine orally, and other adverse reactions (nausea, dizziness, tremor) were relatively rare, mild, and easily abolished by reducing the dose.

ofAction Arrhythmias responding

Onset

to mexiletine were usually controlled within 1-2 minutes of a single intravenous injection, but in some patients arrhythmias recurred 20-40 minutes later when plasma concentrations fell below the therapeutic range as a result of tissue uptake. In patients receiving oral mexiletine, control was usually achieved within 2 hours of the loading dose.

Plasma Half-lifee When therapy was stopped, plasma concentration of mexiletine declined exponentially. The plasma half-life in 15 patients ranged from 11 hours to 26 hours, with a mean of 187 ± 18 (S.D.) hours. in Healthy Volunteers oral dose of 3 mg. per kg. of

Investigations .

No toxicity encountered.

After

an

mexiletine

403 in 6 healthy, fasting volunteers, peak plasma concentrations of 03--04 µg. per ml. were observed within 2-3 hours. In 5 volunteers intravenous doses of 1.5 mg. per kg. produced no significant change in blood-pressure, cardiac rhythm, or E.c.G., but 1 sub-

ject reported transient light-headedness. The mean plasma half-life during the elimination phase was Mexiletine is apparently largely 10-2 ± 08 hours. metabolised, since only 5-10% of the dose was excreted unchanged in the urine in 5 days. The apparent volume of distribution is about 5 1. per kg. and preliminary work using an ultrafiltration technique indicates plasma-protein binding to the extent of about 70 ’" (2.5 µg. per ml.). Discussion It is difficult

evaluate the efficacy of antiarrhythmic drugs because arrhythmias are apt to resolve or recur suddenly and unpredictably.7 Furthermore, there may be poor correlation between the dose of drug and its effects because of individual variation in absorption, distribution, and elimination. These problems have, to some extent, been overcome in our investigation by combining computer analysis of the E.C.G. tape-recordingswith frequent estimations of the plasma concentration of the drug. The computer also provided a frequency distribution of potentially dangerous ventricular extrasystoles falling on the preceding T wave. The criteria for efficacy were strict, particularly in patients with acute arrhythmias, yet complete suppression was seen in 22 of 32 such patients. Treatment in a further 7 patients in this group was classified as partly Even though ventricular extrasystoles successful. persisted, termination of ventricular tachycardia or prolongation of the coupling interval with abolition of the R-on-T phenomenon is undoubtedly of great importance.8-10 4 patients (7%) failed to respond to mexiletine and in 2 the dose was inadequate. to

Our observations suggest that mexiletine is at as effective as the other drugs now available for suppression of ventricular arrhythmias: in a substantial number of cases it corrected acute arrhythmias which were resistant to lignocaine and other agents. Furthermore, oral therapy was effective, simple, and relatively free from adverse effects. The incidence of toxicity was high after intravenous administration, particularly in patients who could not be controlled by large doses of other drugs. The cardiotoxic effects of mexiletine were usually seen in patients who were in extremis and who had received large amounts of other antiarrhythmic drugs. However, hypotension, asystole, ventricular arrhythmias, and central-nervous-system toxicity have all been observed during routine therapy with other antiarrhythmic drugs.11-13 Patients sometimes had nausea and vomiting immediately after intravenous doses of as little as 100 mg. of mexiletine. These effects may have been potentiated by other drugs such as narcotic analgesics, since toxicity was not observed in healthy volunteers given 1-5 mg. per kg. intravenously. The margin between therapeutic and toxic plasma concentrations of mexiletine is rather small-particularly in patients with acute

least

arrhythmias, in whom higher concentrations may be required for control. On the other hand, toxic effects were mild and infrequent when the drug was given orally and were readily reversed by reduction in dosage. Although there was a good correlation between the antiarrhythmic effects of mexiletine and plasma concentrations, the relationship with toxic effects was less clear. For example, nausea and vomiting were observed at concentrations as low as 0.8 µg. per ml., while some patients tolerated levels of 5 µg. per ml. Mexiletine hasa large apparent volume of distribution, and rapid rates of infusion are necessary initially to maintain therapeutic plasma concentrations of 075-20 µg. per ml. However, once distribution equilibrium has been reached the infusion-rate must be reduced, since the drug is eliminated slowly, with a half-life of 11-26 hours. As with lignocaine,14,15 mexiletine is metabolised more slowly in patients with myocardial infarction than in healthy volunteers. Mexiletine is well absorbed from the gastrointestinal tract, and effective plasma concentrations can be maintained with a dosage interval of 8 hours. In this respect it has an advantage over procainamide, which must be given every 3 hours to maintain acceptable stability of plasma levels.’ The following dose regimen was the most satisfactory: an initial intravenous bolus of 150-200 mg. given over 10 minutes followed by infusion of 250 mg. in 30 minutes, a further 250 mg. over the next 2thours, and then 500 mg. over 8 hours. Plasma concentrations of 1-2 µg. per ml. are usually maintained by infusion of 250-500 mg. every 12 hours. Oral therapy is started with a loading dose of 400-600 mg., followed by doses of 200-300 mg. 8-hourly. Mexiletine is effective treatment for ventricular arrhythmias, though the incidence of side-effects, and perhaps the complexity of the intravenous dose regimen, may limit its use in the acute situation. In our experience, it is useful additional or alternative therapy in acute cases uncontrolled by other drugs. Its main potential appears to be as a long-term oral antiarrhythmic agent, particularly in patients with ischæmic heart-disease who are at risk of sudden death from recurrent ventricular arrhythmias. We thank Dr P. A. Knowlson and Boehringer Ingelheim Ltd. for supplies of mexiletine and financial assistance; and we also acknowledge support from the Scottish Hospital Endowments Research Trust.

Requests for reprints should be addressed to R. G. T., Department of Cardiology, Royal Infirmary, Edinburgh EH3 9YW. REFERENCES 1. 2. 3.

4. 5. 6. 7.

8.

Allen, J. D., Kofi Ekue, J. M., Shanks, R. G., Zaidi, S. A. Br. J. Pharmac. 1970, 39, 183. Singh, B. N., Vaughan-Williams, E. M. ibid. 1972, 44, 1. Neilson, J. M. M., Vellani, C. W. in Quantitation in Cardiology (edited by H. A. Snellen and H. C. Hemker). Leiden, 1972. Oliver, M. F., Julian, D. G. W.H.O. Manual on Intensive Coronary Care 1970, Euro. 5020(2). Kelly, J. G., Nimmo, J., Rae, R., Shanks, R. G., Prescott, L. F. J. Pharm. Pharmac. 1973, 25, 550. Harrison, D. C., Alderman, E. L. Modern Treatment, 1972, 9, 139. Julian, D. G., Valentine, P. A., Miller, G. G. Am. J. Med. 1964, 37, 915. Mogensen, L. Acta med. scand. 1970, suppl. 513.

404

MEXILETINE (KÖ 1173) IN THE MANAGEMENT OF VENTRICULAR DYSRHYTHMIAS N. P. S. CAMPBELL J. G. KELLY R. G. SHANKS

TABLE I—ÆTIOLOGY OF THE ARRHYTHMIAS

N. C. CHATURVEDI J. E. STRONG J. F. PANTRIDGE

Departments of Cardiology, Royal Victoria Hospital, Belfast, and Ulster Hospital, Dundonald, and Department of Therapeutics and Pharmacology, Queen’s University, Belfast

Preliminary studies on the effects of (KÖ 1173) on ventricular are dysrhythmias presented. A good response to the was obtained in 68% of patients in whom its drug effects could be assessed. It was frequently effective where lignocaine had failed. Side-effects were common. Bradycardia associated with hypotension occurred in 14% of all patients treated. Sum ary

mexiletine

*

Myocardial infarction within previous

3 months.

t Acute coronary insufficiency.

I Chronic ischaemic heart-disease without

recent

chest

pain.

were excluded from the investigaThe arrhythmias treated included ventricular extrasystoles, ventricular tachycardia, and ventricular fibrillation. Response to the drug was assessed by comparing the number of ectopics after administration of the drug with that during control periods at least 5 minutes before intravenous therapy and one hour before oral therapy. Greater than 75% reduction in ectopics was graded as a good response; between 50% and 75% reduction as fair, and less than 50% as none. In addition, decrease in the number of consecutive ectopics or prolongation of the coupling interval was classed as fair. Where spontaneous disappearance of the dysrhythmia could not be excluded, the response was regarded as unassessable. The response was estimated in the intravenous study from a continuously recorded cardiogram, and in the oral study from 5-minute or 10-minute recording of the cardiogram every 30 minutes; alternatively, the ectopics were counted by a skilled nurse or technician. During the first twenty-four hours of therapy the electrocardiogram was under continuous surveillance. Thereafter, while maintenance treatment continued, patients remaining in hospital were examined daily, and the cardiogram was recorded at least twice weekly. After discharge from hospital the patients were seen initially every two weeks, when they were examined clinically and had a cardiogram. All patients on maintenance therapy had periodic estimation of serum glutamicpyruvic and glutamic-oxaloacetic transaminases, lactic dehydrogenase, bilirubin, calcium, phosphorus, uric acid, B12, and folate, hæmatological investigation, and search for antinuclear factor. Patients were always monitored electrocardiographically during drug withdrawal. In many patients, plasma-mexiletine was estimated9 to assess the effective therapeutic plasma-level and the plasma-level associated with side-effects.

atrioventricular block,

Introduction ALL agents now available for the control of ventricular dysrhythmias have disadvantages. Lignocaine is the most frequently used intravenous antiarrhythmic agent, but clinicallyand experimentallyit is comparatively ineffective in the acute stage of myocardial infarction. The drugs given orally for longterm control of ventricular dysrhythmias have sideeffects. Procainamide may cause lupus erythematosus and quinidine may produce gastrointestinal upset and cardiac arrest.’ Beta-blocking agents may cause bradycardia and cardiac failure.5,6 There is thus a place for an antiarrhythmic agent which can be given orally and intravenously. Mexiletine (Ko 1173), which is structurally related to lignocaine, has been shown to control three varieties of experimental ventricular dysrhythmias-those induced by ouabain, those by halothane and adrenaline, and those after coronary-artery ligation.’ We present here our initial clinical experience with

mexiletine. Patients and Methods The effects of mexiletine on ventricular dysrhythmias have been studied in 86 patients (table 1). 30 of the patients with acute myocardial infarction (as previously defined 8) received mexiletine within forty-eight hours of the onset of symptoms. Patients with severe leftventricular

failure, cardiogenic shock, or supraventricular tachyarrhythmia, and those with untreated bradyarrhythmia, whether sinus bradycardia or second or third degree

tion.

Results DR TALBOT AND OTHERS :

REFERENCES—continued

Lown, B., Fakhor, A. M., Hood, W. B., Jr., Thorn, G. W. J. Am. med. Ass. 1967, 199, 188. 10. Lown, B., Vassaux, C., Hood, W. B., Jr., Fakhor, A. M., Kaplinsy, E., Roberge, G. Am. J. Cardiol. 1967, 20, 494. 11. Rosen, M. R., Gelband, H. Am. Heart J. 1971, 81, 428. 12. Wood, R. A. Br. med. J. 1971, i, 645. 13. Lippestad, C. Th., Forfang, K. ibid. p. 537. 14. Prescott, L. F., Nimmo, J. in Lidocaine in the Treatment of Ventricular Arrhythmias (edited by D. B. Scott and D. G. Julian). Edinburgh, 1971. 15. Thomson, P. D., Rowland, M., Melmon, K. L. Am. Heart J. 1971, 82, 417. 16. Koch Weser, J. Ann. N.Y. Acad. Sci. 1971, 179, 370. 9.

The investigation was in 2 stages. Stage I comprised the preliminary work done to determine whether the drug was of clinical value. Details of the 19 patients are given in table i. 13 patients received single intravenous doses of the drug; and, in 6, single doses were followed by constant intravenous infusion. The results are shown in table 11. Doses greater than 100 mg. were required to reduce consistently the number of ectopic beats. After a total dose of 350 mg., 2 patients developed bradycardia and hypotension and 3 had