effects a antiarrhythmic agent- qx-5721-ontherapy · ofthese drugs, lignocaine, fails, however, in...

British Heart Journal, I974, 36, 8iI-82I.

Effects of a long-acting antiarrhythmic agent-QX-5721-on therapy resistant ventriculartachyarrhythmias

Lars Ryden, Ake Hjalmarson, Harbans Wasir,2 and Lars WerkoFrom Department of Medicine I, Sahlgrenska Hospital, S-4I3 45 Gdteborg, Sweden

N,N-bis (phenylcarbamoylmethyl) dimethylammonium chloride (QX-572) was given to I2 patients withventricular tachyarrhythmias resistant to other antiarrhythmic drugs, especially lignocaine. Most patientshad acute myocardial infarction. The drug was slowly infused intravenously (8 mg/kg during 30 minutes)and wasfound very potent with afully developed effect after about 20 munutes. In 9 of the patients the antiar-rhythmic effect of a single infusion of QX-572 lasted more than i5 hours. A mild degree of tachycardiaoccurred in all patients during the infusion period. Blood pressure response was more unpredictable. In one

patient there was a substantial increase in blood pressure after completion of the QX-572 infusion. A slightblood pressure increase after completed QX-572 infusion was observed also in some of the other patients. Slightcircumoral paraesthesia was felt by all patients. Only minor side effects were found and they were consideredof little clinical importance. There was no clear correlation between tachycardia and blood pressure changesand the antiarrhythmic effect of the drug. Its effectiveness in therapy-resistant ventricular arrhythmias and itslong duration of action with no important side effects at therapeutically effective dosage might make QX-572a valuable antiarrhythmic drug.

The most commonly used drugs for the treatmentof ventricular tachyarrhythmias are quinidine,procainamide, and lignocaine. The most effectiveof these drugs, lignocaine, fails, however, in term-inating ventricular arrhythmias in up to 20 per centof the affected patients (Bigger and Heissenbuttel,I969; Harrison and Alderman, I972). There arealso other drawbacks with these antiarrhythmicdrugs. Side effects such as depression of myocardialcontractility, hypotension, and conduction abnor-malities have especially been described with the useof quinidine and procainamide but can be seen withother drugs (Mason et al., I973). Lignocaine isshort acting and repeated injections or continuousintravenous infusion are required (Harrison andAlderman, I972).

N,N-bis (phenylcarbamoylmethyl) dimethyl-ammonium chloride (QX-572) is a quaternaryammonium compound and a lignocaine derivative(Fig. i). In previous studies this new antiarrhythmicReceived I5 January, I974.3 QX-572 manufactured and supplied by Astra (Sodertlije,Sweden).2 Present address: Department of Cardiology, All IndiaInstitute of Medical Sciences, New Delhi i6, India.

drug was found to be effective against ventriculararrhythmias in animals (Covino and Rachwall,I964; Katz, I964; Madan, Khanna, and Madan,I967) as well as in man (Katz, I965; Schwartz,Stapleton, and Covino, I967). Interest in the drugfaded at that time probably because it has to be ad-ministered intravenously. This is because of itsnature as a quaternary ammonium compound(Goodman and Gilman, I970). Despite this limi-tation, such an antiarrhythmic agent might still beof value within a coronary care unit. The presentinvestigation was undertaken to study the effect ofQX-572 in patients with ventricular tachyar-rhythmia, caused mainly by acute myocardial infarc-tion, and resistant to common antiarrhythmic drugs,especially lignocaine. It was felt that QX-572 couldhave specific advantages by being very potent andlong acting. Another advantage might be that thedrug as a quaternary ammonium compound doesnot penetrate the blood brain barrier (Goodman andGilman, I970).

Subjects and methodsThe drug was studied in I2 patients treated in a coronary

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8I2 Ryddn, Hjalmarson, Wasir, and Werko

CH3IZ N ~~~~~~~~~~~~~~~~~~~~~~I

NHCOCH2 -N-CH2CONHICH3

QX-572N,N -bis (phenylcarbamoylmethyt) dimethylammoniumchloride

FIG. I Structuralformula of QX-572.

care unit. All patients had ventricular tachyarrhythmiaswhich were considered resistant to other antiarrhythmicdrugs. A brief case report of each patient is givenbelow. A continuous electrocardiogram was recorded ata paper speed of IO mm/sec on a Mingograf 34 (Elema-Schonander, Sweden), from 30 minutes before until 6ominutes after the start of the infusion of QX-572. Sub-sequently a one-minute long electrocardiograph strip(paper speed 25 to 50 mm/sec) was taken every fullhour after the start of QX-572. Besides this all patientswere under continuous oscilloscopic electrocardiographicmonitoring according to the routine of the ward (Hen-ning and Holmberg, I97i). Electrocardiograms werealso recorded when ventricular arrhythmias wereobserved from the routine monitors by the nurses. Heartrate and brachial artery pressure using a cuff were meas-ured every 5 to IO minutes during 30 minutes before and6o minutes after the start of QX-572 infusion and thenat least once every hour. On admittance to the coronarycare unit all patients had a short polyethylene catheterintroduced into an arm vein. QX-572 was infused intra-venously at a dose 8 mg/kg body weight over a period of

60

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Results

The results are given as individual case reports and inFig. 2 to IO.

Case i

A 69-year-old man, with coronary heart disease and oneearlier myocardial infarction, was admitted with an

acute myocardial infarction complicated by left heartfailure and persistent therapy-resistant ventriculararrhythmia often in bigeminy. Lignocaine (2 mg/minsupplemented with bolus injections of ioo mg), quini-dine (i-6 g daily; serum level 3-5-4-8 mg/I.), diphenylhy-dantoin (oral dose 03 g daily and ioo mg intramuscular),procainamide (oral dose 2.0 g daily) as well as practolol(30 mg intravenously) did not suppress the arrhythmia.Treatment with these drugs, including simultaneousadministration of lignocaine and quinidine, was con-tinued for several days. QX-572 was tried after the drugshad been stopped for at least 24 hours. The ventricular

-30 0 30 60 2 4 8 12 16 20 24min hours

FIG. 2 Antiarrhythmic effect and response of heart rate and blood pressure to QX-572 inCase I. Abbreviations used in this and the following figures: VPC= ventricular prematurecontractions; HR = heart rate; BP= blood pressure.

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Effects of a long-acting antiarrhythmic agent-QX-572 813

8 12 16 20 24hours

FIG. 3 Antiarrhythmic effect and response of heart rate and blood pressure to QX-572 inCase 2.

arrhythmia vanished rapidly, and the effect persistedfor about i6 hours as can be seen from Fig. 2. At the endof the QX-572 infusion the patient experienced mod-erately severe short lasting central chest pain similar toearlier angina pectoris. This was most likely caused bytachycardia (97 beats/min) and disappeared within afew minutes after completing the infusion.

Case 2A 68-year-old man with moderate hypertension, cor-onary heart disease, and a myocardial infarction twomonths before admission to hospital had a new myo-cardial infarction which was complicated by repetitivemultifocal ventricular ectopic beats often in bigeminy.The ectopic beats persisted also during lignocaine infu-sion (2-3 mg/min) as well as when diphenylhydantoinwas given (oral dose 0o3 g daily). The patient did nottolerate procainamide (rash) or quinidine (diarrhoea).QX-572 8 mg/kg body weight was planned to be infusedduring 30 minutes, but the infusion was stopped after25 minutes (=6'7 mg/kg) as right bundle-branch blockappeared. This persisted for 6 hours. The patient hadshown intermittent bundle-branch block on severalearlier occasions. The effect of QX-572 on the ectopicbeats is shown in Fig. 3. The ventricular arrhythmiareappeared 34 hours after the QX-572 administration.

Case 3A so-year-old woman, with obscure cardiomyopathypossibly caused by myocarditis, was brought to the cor-onary care unit because of moderate left ventricularfailure and frequent multifocal ventricular prematurebeats. Lignocaine (2 mg/min) decreased the number ofpremature beats but did not stop the arrhythmia com-

pletely. Quinidine (i2. g daily), procainamide (oral dose2@o g daily), and diphenylhydantoin (oral dose o 6 gdaily) did not affect the arrhythmia. After withdrawal ofother drugs QX-572 was infused. The ventricularectopics were abolished for 8 hours (Fig. 4) and returnedthereafter with similar frequency.

Case 4A 34-year-old man with subvalvar aortic stenosiscaused by obstructive cardiomyopathy, had postextra-systolic pressure gradient across the aortic valve ofgo mmHg. He showed numerous multifocal ventricularpremature beats mostly as bigeminy and had short burstsof ventricular tachycardia. Alprenolol (oral dose o04 gdaily) and practolol (30 mg intravenously) did not in-fluence the arrhythmias. Procainamide produced dizzi-ness and paraesthesia, and quinidine could not be givenbecause of diarrhoea. QX-572 was infused with goodresponse (Fig. 5) lasting for i6 hours. Later the patientwas given ajmaline with satisfactory reduction in fre-quency of the ventricular premature beats.

Case 5A 66-year-old man was admitted with acute myocardialinfarction and frequent ventricular premature beats.Lignocaine (300 mg intramuscular) had a short-lastingeffect (20 minutes). The arrhythmia reappeared and ashort run of ventricular tachycardia was also noted.Intravenous lignocaine (ioo mg bolus followed by2 mg/min) gave rise to cerebral confusion and aggressive-ness though some effect on the arrhythmia was recorded.After QX-572 the ectopic beats were completely abol-ished. The antiarrhythmic effect persisted for about i6hours (Fig. 6).

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Case 6A 59-year-old man developed ventricular tachycardia I2days after an acute myocardial infarction. The onset waspreceded by multiple ventricular premature beats whichcould not be suppressed with lignocaine (4 mg/minsupplemented with bolus injections) though the patienthad convulsions. Procainamide (o 5 g intravenously) pro-duced hypotension but the ventricular tachycardia per-sisted. Twenty minutes after the start of an infusion ofQX-572 the ventricular tachycardia was abolished.Sinus rhythm was maintained for about 4 hours whenventricular bigeminy appeared. However, further QX-572 (4 mg/kg) restored sinus rhythm for another 3 hours.When ventricular ectopic beats again reappeared,QX-572 (2 mg/kg) was effective for only one hour(Fig. 7). Ventricular tachycardia reappeared later.Different ways were subsequently tried to stop the tachy-cardia. Practolol (30 mg intravenously) did not affect therhythm nor did ajmaline (50 mg intravenously), ligno-caine (4 mg/min supplemented with bolus injections ofIOO mg), or quinidine (I-2 g daily) which producedanorexia when used for two days. With DC cardio-version the patient responded only to 400 joules, andstable sinus rhythm was obtained for just a few minutes.Since other antiarrhythmic agents were ineffective,further injections of QX-572 were administered. Eachtime the antiarrhythmic effect was almost predictable asdescribed above, with an initial response to 8 mg/kg. Anadditional dose ofQX-572 was needed after 4 hours. Theventricular tachycardia subsided after 6 days. Duringthat time the patient had received totally 2-962 g ofQX-572 (three times 8 mg/kg, three times 4 mg/kg, and

once 2 mg/kg). The patient received digoxin (0-25 mgdaily, serum level 2@3 ng/ml with the red cell 86Rb tech-nique) when developing the ventricular tachycardia. Thearrhythmia was finally interpreted as induced by digi-talis.

Case 7A 52-year-old man with left ventricular aneurysm afteran acute myocardial infarction was admitted to hospitalbecause of left ventricular failure and ventricular fibrilla-tion. After DC conversion there were frequent ven-tricular premature beats not responding to lignocaine(4 mg/min supplemented by several bolus injections).QX-572 was administered initially without effect. Atthat time serum potassium was found to be low (2-7mEq/l.). Infusion of potassium was started and theectopic beats disappeared. The patient was on digitalistherapy and the arrhythmia was thought to depend onincreased digitalis sensitivity caused by low serumpotassium. However, quite frequent ventricular ectopicbeats remained during the following days despite normalserum potassium and withdrawal of digitalis. Thisarrhythmia was resistant to lignocaine (4 mg/min whichgave a serum level of 7-2 jig/ml). Lignocaine was with-drawn and a new trial with QX-572 was performed. Theresponse was favourable for five hours. At that time theectopic beats reappeared. Lignocaine was now effectiveup to i8 hours after the start of QX-572 infusion (Fig. 8).No side effects from QX-572 were observed, except asubstantial increase in blood pressure and heart rateafter the second QX-572 injection. After the first injec-

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tion blood pressure increased from I5o/8o to 180/95mmHg and heart rate from 88 to I02.

Case 8A 54-year-old woman was resuscitated from ventricularfibrillation IO days after an acute myocardial infarction.Despite lignocaine (4 mg/min supplemented with bolus

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injections), which was stopped after cerebral sideeffects developed, and procainamide (i i g intravenous),ventricular fibrillation occurred 14 times during thenext I5 hours. Between the attacks of ventricular fibrilla-tion there were numerous ventricular ectopic beats andruns of ventricular tachycardia. QX-572 was admin-istered and at the same time lignocaine was stopped.

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8 12 16 20 24hours

Antiarrhythmic effect and response of heart rate and blood pressure to QX-572 inFIG. 8Case 7.

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After QX-572 the ventricular ectopic beats disappearedalmost completely. No further attacks of ventriculartachycardia or fibrillation occurred. The patient im-proved and was dismissed from hospital.About three weeks later she was readmitted because

of syncope. The electrocardiogram showed ventricularectopic beats and short bursts of ventricular tachycardia.Lignocaine (4 mg/min supplemented with bolus injec-tions) and procainamide (oral dose i-o g) did not affectthe arrhythmia. QX-572 was infused (planned dose8 mg/kg=6oo mg) and lignocaine withdrawn. After270 mg QX-572, the patient had nausea and vomited.Immediately afterwards the blood pressure fell to asystolic pressure of 65 mmHg and the heart rate wasreduced from 87 to 70 beats/min. The injection of QX-572 was stopped and the legs were raised. Five minuteslater the blood pressure returned to normal. No ectopicbeats were seen during three and a half hours. At thattime ventricular ectopic beats and tachycardia re-appeared. A second injection of 330 mg QX-572 wasgiven to complete the planned total dose. This time therewas only a slight fall in blood pressure and the heart rateincreased somewhat. After the second QX-572 infusionthe arrhythmia totally disappeared for another 2 hours.Thereafter ventricular ectopic beats reappeared and onerun of ventricular tachycardia was recorded. Lignocaine(2 to 4 mg/min), which had previously been ineffective,now abolished the arrhythmia during the remaining partof the observation period of 24 hours. A left ventricularaneurysm complicating the first myocardial infarctionwas suspected.

Case 9A 69-year-old man with previous hypertension developedacute myocardial infarction. The first day ventriculararrhythmia appeared and responded to lignocaine. Whenthe infusion rate exceeded 2 mg/min the patient showedcerebral side effects in the form of confusion, agitation,drowsiness, and seizures. On the twelfth day the patient

had attacks of ventricular tachycardia without frequentpreceding ventricular ectopic beats. Lignocaine provedeffective only in a dosage of 3 to 4 mg/min but was againfollowed by cerebral side effects. When infusion was re-duced ventricular tachycardia reappeared. During thenext 4 days lignocaine induced cerebral side effects whenan amount sufficient to suppress the arrhythmia wasused. Finally QX-572 was infused and lignocaine waswithdrawn. No further ventricular arrhythmias werenoted. Quinidine (I2 g daily) was started 12 hours afterQX-572 and proved effective.

Case IO

A 54-year-old man with one earlier myocardial infarctionwas admitted with an acute anterior infarction compli-cated by left ventricular failure. Digitalis and diureticswere administered. The patient improved, but on thefifth day after infarction he developed ventriculartachycardia. The only effect of various antiarrhythmicagents administered intravenously was a reduction ofventricular rate after ajmaline (Fig. 9). DC conversion wasnot used as digitalis was suspected to be the cause of thearrhythmia. Twenty minutes after the start of QX-572infusion sinus rhythm was restored. The arrhythmiasdid not return.

Case iiA 67-year-old man, without earlier signs of cardiacdisease, developedventricular ectopic beats which initiallyresponded to quinidine (I2 g daily). Five months laterthe patient deteriorated. At this time there were numer-ous multifocal ventricular ectopic beats and runs ofventricular tachycardia. Diphenylhydantoin (oral doseo-6 g daily) was added with effect only for a few days.These drugs were then withdrawn and intravenousantiarrhythmic treatment was started. Lignocaine (4 mg/min supplemented with bolus injections) did not preventthe arrhythmias. Single injections of procainamide

160BP *

a 120

HR. 80

40OX-572AjmaLinc SOmg 4 65mg4DPH 250 mg 1PractoLoL 20 mg ILignoc. bolus 75 mg ?j 25mg

Lignocaine 4 rmg /min 21VT _#

560mg #35mg4

12 2422/12 -1L

24 12.1 24/12

FIG. 9 Antiarrhythmic effect and response of heart rate and blood pressure to QX-572 inCase io. DPH= diphenylhydantoin; VT= ventricular tachycardia.

TimeDay

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160BP o

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QX-572 590 mg #AjmalineDPH 100 mg ILignoc. bolus 50mg 4

Lignocaine .4mg /min 2 [4

VPCTmin 1- -

VTIE 2l

590 rng#50mg 4

75mg 4

Time 18 06 18" 18 06 18Day 28/9 - 29/9 30/9 - 1/10

FIG. io Antiarrhythmic effect and response of heart rate and blood pressure to QX-572 inCase I i.

TABLE Data in I2 patients treated with QX-572

Case Age Diagnosis Ventricular Previous therapy QX-572No. (yr) arrhythmia Effect

sex

I 69 M Acute myocardial Ventricular premature Lig; quin; DPH; Excellentinfarction beats; bigeminy proc; pract

2 68 M Acute myocardial Ventricular premature Lig; DPH; proc; Excellentinfarction beats; bigeminy quin

3 5o F Cardiomyopathy Ventricular premature Lig; quin; proc; DPH Excellentbeats

4 34 M Obstructive cardio- Ventricular premature Alp; pract; proc; quin Excellentmyopathy beats; bigeminy;

ventricular tachycardia5 66 M Acute myocardial Ventricular premature Lig Excellent

infarction beats; ventriculartachycardia

6 a 59 M Acute myocardial Ventricular tachycardia Lig; proc; ajm; quin; Excellentb infarction; digitalis practc toxicity

7 a 52 M Coronary heart disease; Ventricular premature Lig Noneleft ventricular beats

b aneurysm Ventricular premature Lig Goodbeats

8 a 54 F Acute myocardial Ventricular fibrillation Lig; proc Excellentinfarction

b Coronary heart disease; Ventricular premature Lig; proc Goodleft ventricular beats; ventricularaneurysm tachycardia

9 69 M Acute myocardial Ventricular premature Lig Excellentinfarction beats; ventricular

tachycardiaIO 54 M Acute myocardial Ventricular tachycardia Lig; aim; DPH; pract Excellent

infarction; digitalistoxicity

iI a 67 M Cardiomyopathy? Ventricular tachycardia Lig; proc; pract; aim; Excellentb DPH

I2 a 63 M Acute myocardial Ventricular tachycardia; Lig; proc; DPH Excellentb infarction ventricular fibrillation

pract = practolol, ajm= ajmaline, alp =Lig = lignocaine, Quin = quinidine, DPH = diphenylhydantoin, proc = procainamide,alprenolol, RBBB= right bundle-branch block. * = QX-572 effective with lignocaine.

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(0-2 g), practolol (I5 mg), ajmaline (50 mg), diphenylhyd-antoin (0.25 g), were added successively to the lignocaineinfusion but had no effect. Finally the patient developedpersistent ventricular tachycardia. QX-572 was then in-fused. Sinus rhythm was restored 20 minutes after thestart of the infusion and remained for more than 20hours though some ventricular ectopic beats occurredafter I3 hours. When the patient again developed per-sistent ventricular tachycardia 48 hours after the firstQX-572 infusion (Fig. io), another infusion was givenwith similar good result.

Case I2A 63-year-old man with hypertension had an acutemyocardial infarction with ventricular tachyarrhythmia.Despite lignocaine (4 mg/min supplemented by bolusinjections) and procainamide (o 5 g intravenously andinfusion of go mg/hour) rapid ventricular tachycardiaand ventricular fibrillation occurred ii times during 8hours. QX-572 was infused. No further attacks of ven-tricular tachycardia, fibrillation, or any ventricular

Duration of Side effects Remarkseffect (hours)

i6 Chest pain

> 20 RBBB ?

8

i6

i6

4 (a) Response to QX-5723 (b) similar every timeI (c)o (a) BP increase Digitalis toxicity+ hypo-5 (+ I2*) (b) kalaemia (a)

> 20 (a) BP drop3-5+2(+I2*) (b)

> 15

>20

20 (a) Response to QX-572i8 (b) similar both times28 (a)6 (b)

ectopic beats were seen during the following 28 hours.The ectopic beats and runs of ventricular tachycardiathen reappeared. Lignocaine was reinstituted and com-bined with diphenylhydantoin (o025 g intravenously).This did not prevent some further attacks of ventricularfibrillation. QX-572 was then once more administered.During the next 6 hours short runs of ventricular tachy-cardia occurred twice. There were also some ventricularpremature beats. Ventricular fibrillation, however, didnot recur. Later quinidine and diphenylhydantoin wasadministered orally in combination. This regimen keptthe ventricular arrhythmia under control.

To summarize the results (Table), QX-572 was in-jected 22 times in I2 patients with ventriculararrhythmias resistant to conventional treatment. In7 patients (Cases I, 2, 5, 6, 9, I0, I2) the arrhyth-mias were caused by coronary heart disease com-plicated by acute myocardial infarction. In 2 ofthese cases (Cases 6 and io) digitalis toxicity and inone (Case 7) 'digitalis toxicity due to hypokalae-mia were considered the important arrhythmia-provoking factors. Two patients (Cases 7 and 8)had coronary heart disease and previous myocardialinfarction complicated by left ventricular aneurysm.Three patients (Cases 3, 4 and II) suffered fromcardiomyopathy. The amount of QX-572 was, oni8 occasions, 8 mg/kg body weight infused over aperiod of 30 minutes. In one of the patients (Case 6)this was supplemented with infusion of4 mg/kg threetimes and 2 mg/kg once. QX-572 effectively abol-ished the arrhythmia in almost every case. The fullantiarrhythmic effect was usually seen about 20minutes after the start of QX-572 infusion. Theantiarrhythmic effect was noted for more than IShours in 9 of the patients. In 2 cases (Cases 7 and 8)it seemed that ventricular arrhythmias resistant tolignocaine and QX-572 alone were abolished by thecombination of these drugs.

Side effectsCircumoral paraesthesia and numbness were re-ported by all patients from about I5 to 20 minutesafter the start of QX-572 infusion and lasting until5 to I0 minutes after the completion of the drugadministration. Heart rate increased in all patientsexcept those with ventricular tachycardia. Themaximal increase of about 20 beats/minute wasreached at the end of the QX-572 infusion. Usuallyheart rate returned to control levels within 30 min-utes. The blood pressure reaction was more un-predictable. Clinically important changes were notobserved except in two patients. In one (Case 8) theblood pressure dropped to a systolic level of 65mmHg in conjunction with nausea and vomiting.



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On other occasions this patient received QX-572without important blood pressure changes and sinceheart rate decreased at the time of blood pressuredrop it was felt that vagal mechanisms could be ofimportance. The second patient (Case 7) exper-ienced a substantial increase in blood pressure afterthe QX-572 infusion had been completed. Theblood pressure spontaneously fell to ordinarylevels during the next hour. This patient had alsoreceived QX-572 on an earlier occasion and at thattime no untoward blood pressure change was

observed. One patient (Case i) experienced chestpain interpreted as angina pectoris at the end ofQX-572 infusion. A combination of a slight in-crease of blood pressure and heart rate was prob-ably responsible. The chest pain disappeared withina few minutes after completing the infusion. Onepatient (Case 2) who had shown intermittent rightbundle-branch block on several occasions de-veloped such a block 20 minutes after the start ofQX-572. Consequently the drug was stopped but theexact correlation with QX-572 was uncertain. Thehighest total amount of QX-572 given to a singlepatient was 2.962 g (Case 6). This was given over

a period of 5 days. Neither in this case nor any of theother patients were there any changes in laboratoryfindings conceming blood and liver or renal func-tion which could be related to QX-572.

DiscussionIn earlier studies QX-572 was found to abolishacetylcholine-induced atrial fibrillation in dogs(D'Amato and Truant, I962). The drug has alsoproved effective in the treatment of ventriculartachyarrhythmias in animals induced by variousmeans (Covino, I962; D'Amato and Truant, I962;Katz, i963, i964; Madan et al., i967). It was alsoshown that intracoronary infusion of QX-572 indogs produced a positive inotropic effect and in-creased cardiac output and coronary blood flow(Katz, i963). Covino and Rachwall (i964) studiedthe influence of the drug on isolated papillarymuscles as well as in intact animals. They statedthat QX-572 increased the diastolic threshold poten-tial and prolonged the refractory period. They alsonoted a decrease in myocardial conduction velocity.QX-572 prolonged the refractory period more thanquinidine while the increase in diastolic thresholdpotential was more pronounced after quinidine.Conduction velocity was lower after quinidine thanQX-572 but decreased after both drugs.

Earlier clinical studies in man demonstrated thatQX-572 was ineffective in the termination of chronicatrial fibrillation (Schwartz et al., I967). In patientswho developed ventricular tachyarrhythmias duringgeneral anaesthesia with various drugs, QX-572 in

dosages of 2 to 8 mg/kg effectively abolished thearrhythmias in all cases (Katz, I965). When QX-572 was given to patients with ventricular tachy-arrhythmia complicating varying cardiac diseases,successful results were obtained in I7 out of 20cases (Schwartz et al., I967). The most common sideeffect noted in these studies referred to was cir-cumoral paraesthesia. Tachycardia was noted insome patients as well as moderate hypotension. Thedevelopment of hypotension was thought to berelated to the vasodilating action of QX-572 dem-onstrated earlier in animal studies (Schwartz et al.,i967).The present study confirms earlier reports of

QX-572 as a potent agent against ventriculartachyarrhythmias. The antiarrhythmic effect ofQX-572 in these rather malignant arrhythmias wasobvious. In cases where repeated infusions weregiven reproducible response was obtained. All thepatients in this study were treated with otherantiarrhythmic agents before QX-572 was tried. Inthis study QX-572 was often given against life-threatening ventricular tachyarrhythmias. It was,therefore, not possible to require that earlier drugsshould be totally excreted before QX-572 was given.Actually QX-572 was considered life saving in someof the present cases. Furthermore, the antiarrhyth-mic effect of QX-572 was found to be of long dura-tion. This makes it reasonable to believe that possibleeffects of previously given antiarrhythmic drugscould be excluded. The long duration of action ofQX-572 has been noted earlier (Schwartz et al.,i967). This has also been found for other quater-nary ammonium compounds (D'Amato and Truant,I962).The side effects of QX-572 noted here are in

accordance with earlier findings. In the presentstudy it should be noticed that many patients werein a poor clinical condition when receiving QX-572.This makes it difficult to evaluate the backgroundfor and importance ofthe observed reactions in bloodpressure and heart rate. In some patients the cor-relation between these haemodynamic side effectsand QX-572 was uncertain. The observed sideeffects were furthermore not considered of greatclinical importance. A more pronounced fall inblood pressure has been described earlier in somepatients (Katz, I965; Schwartz et al., I967). It was,therefore, considered important to inject the drugvery slowly when the present study was planned.The slow rate of QX-572 infusion obviously re-duced the risk of blood pressure drop. The mech-anism behind the substantial increase in bloodpressure observed once in one patient after comple-tion of QX-572 infusion is unknown. A slight ten-dency to a blood pressure increase after a completed



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Effects of a long-acting antiarrhythmic agent-QX-572 82I

QX-572 infusion has been observed also in some ofthe other patients, which might indicate a correla-tion between QX-572 and this blood pressurereaction.

Overdrive is a well-known technique in thetreatment of ventricular tachyarrhythmia. Usuallythe heart rate increased when the drug was given.However, there does not seem to be any correlationbetween the tachycardia, blood pressure changes,and the antiarrhythmic effect of QX-572. That theantiarrhythmic effect remains after the heart ratereturns to normal also indicates that the heart rateeffect per se does not contribute to the antiarrhyth-mic effect of the drug.

Since QX-572 as a quaternary ammonium com-pound is not absorbed orally, the use of the sub-stance has earlier been considered to be of limitedvalue (Schwartz et al., I967). However, the potencyof QX-572 in therapy resistant ventricular tachy-arrhythmias, its long duration of action, andapparent lack of dangerous side effects at thera-peutically effective dosage, even in patients with aseverely damaged myocardium, may make this druga useful addition in the treatment of ventriculararrhythmias especially in coronary care units orduring cardiovascular surgery.A final judgment of QX-572 should, however, not

be based only upon studies such as the present.For more valid conclusions concerning its anti-arrhythmic activity and possible drawbacks con-trolled studies have to be performed. Such studiesare in progress as well as studies on the electro-physiological and haemodynamic properties of thedrug. The metabolism of the compound and thepharmacokinetics of its action are also under in-vestigation.

This study was supported by Swedish Medical ResearchCouncil and Swedish National Association against Heartand Chest Diseases.We wish to thank Dr. T. B. Conradson, Dr. B. Olsson,

and Dr. A. Waldenstr6m for helpful assistance andvaluable criticism of the manuscript.

ReferencesBigger, J. T., and Heissenbuttel, R. H. (I969). The use of

procainamide and lidocaine in the treatment of cardiacarrhythmias. Progress in Cardiovascular Diseases, II, 515.

Covino, B. G. (I962). Antiarrhythmic effects of Astra Com-pound QX-572 in hypothermia. Federation Proceedings,2I, 124.

Covino, B. G., and Rachwall, P. (I964). Comparative cardiaceffects of quinidine and N,N-bis (phenylcarbamoyl-methyl)-dimethylammonium chloride (QX-572), a newantiarrhythmic agent. JIournal of New Drugs, 4, 30.

D'Amato, H. E., and Truant, A. P. (1962). Antiarrhythmicactivity of a series of quarternary ammonium derivatives ofLidocaine. Federation Proceedings, 21, I27.

Goodman, L. S., and Gilman, A. (I970). The Pharmaco-logical Basis of Therapeutics, p. 536. Macmillan, NewYork.

Harrison, D. C., and Alderman, E. L. (1972). The pharma-cology and clinical use of lidocaine as an antiarrhythmicdrug-I972. Modern Treatment, 9, 139.

Henning, R., and Holmberg, S. (I97i). Erfarenheter franSahlgrenska sjukhusets hjirtinfarktavdelning. Ldkartid-ningen, 68, 3603.

Katz, R. L. (I963). Cardiovascular action of N,N-bis (phenyl-carbamoylmethyl) dimethyl ammonium chloride (QX-572). Pharmacologist, 5, 260.

Katz, R. L. (I964). Antiarrhythmic action of N,N-bis(phenylcarbamoylmethyl) dimethylammonium chloride(QX-572) in cat and dog. Anesthesiology, 25, 29I.

Katz, R. L. (1965). Antiarrhythmic and neuromusculareffects of QX-572 in man. Acta Anaesthesiologica Scandi-navica, 9, 73.

Madan, B. R., Khanna, V. K., and Madan V. (I967). Somelocal anesthetics in experimental cardiac arrhythmias.Indian3Journal of Physiology and Pharmacology, II, 45.

Mason, D. T., De Maria, A. N., Amsterdam, E. A., Zelias, R.,and Massumi, R. A. (I973). Antiarrhythmic agents. I:Mechanisms of action and clinical pharmacology. Drugs, 5,26I.

Schwartz, M. L., Stapleton, J., and Covino, B. G. (I967).Clinical pharmacology of N,N-bis (phenylcarbamoyl-methyl) dimethylammonium chloride (QX-572). A newantiarrhythmic agent. Journal of Clinical Pharmacology, 7,278.

Requests for reprints to Dr. Lars Ryden, DepartmentofMedicine I, Sahlgrenska Hospital, S-4I3 45 Goteborg,Sweden.



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