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Clinical evaluation of acetyl-digitoxin
Clinical Evaluation of Acetyl-Digitoxin* JOSEPH B. VACCA, M.D., JOSEPH M. SCHUSTER,M.D.,
and WILLIAM A. KNIGHT, JR. M.D.*
St. Louis, Missouri
D
IGITALIS therapy of heart failure and the arrhythmias has been greatly extended and made more precise with the advent of the cardiac glycosides. Differences ‘exist in clinical effect from one glycoside to another and may be due to variations in degree of absorption, serum binding power, toxic cumulation and dissipation. Also, it is well-known that the individual response to digitalis is quite variable, suggesting that experimentation is highly desirable to find the right glycoside which will be most beneficial to any given patient. However, most physicians prefer to limit the number of drugs in any one category and are ever on the lookout for a single drug which will serve the greatest number of patients. In a search for a glycoside having a broad range of application, Stoll and Kreis’ isolated Acylanid@ from digitalis lanata by subjecting lanatoside A to enzyme hydrolysis. Acylanid is acetyldigitoxin, differing from digitoxin through the presence of an acetyl radical attached to the third digitoxose in the molecule. Pharmacologic study by Rothlin, Bircher, and Schalch2 has demonstrated acetyl-digitoxin to be strongly bradycardic, well-absorbed, and less toxic than digitoxin. They found acetyl-digitoxin to’ be a welldefined, pure cardiac glycoside free of biologic assay variations in contrast to digitoxin, which, though chemically well-defined, did not show uniform activity when batches from different sources were analyzed. It was found that absorption of acetyl-digitoxin from the gastrointestinal tract comes close to that of digitoxin and that its duration of action is somewhat Overdosage shorter than that of digitoxin. of acetyl-digitoxin in chronic cat experiments induced less frequent emesis, fewer irregulari* From JUNE,
1958
the Department
of Internal
Medicine,
ties, and fewer histologic changes in the heart muscle and conductive system. Better toleration, more rapid dissipation, and a lesser degree of cumulation pointed to a reduced toxicity. The clinical efficacy of acetyldigitoxin has been revealed in a number of studies which have shown it ,to be very well-tolerated and useful for both digitalization and maintenance.s-g Maher and Pullen,a Brill, Burgner, and David,4 and Crouch, Hejtmancik, and Herrmann, have noted especially and favorably that anorexia, nausea, or vomiting usually appeared as the first symptoms of overdosage, and they consider this a highly desirable warning to prevent the development of the more serious toxic arrhythmias. Also noted5 was the spread between dissipation of toxic effects within 24 to 72 hours and evidence of therapeutic effect for periods up to 17 days after discontinuation of the drug. This report details our experiences with acetyl-digitoxin in 35 patients over a period of ten months. METHODSANDMATERIALS Thirty-two patients were digitalized with acetyl-digitoxin and maintained on this glycoside for variable periods of observation. All of these patients were hospitalized, and had never been on a digitalis preparation before or had not taken any digitalis preparation for a period of at least three weeks prior to administration of acetyl-digitoxin. Administration of acetyi-digitoxin was preceded by the following determinations in each patient: venous pressure, circulation time with decholin and ether, chest roentgenogram (and fluoroscopy in some cases), vital capacity, electrocardiogram, and routine laboratory studies. All patients were placed on bed rest and
St. Louis University, School of Medicine, St. Louis, Missouri. 717
718
Clinical Evaluation of Acetyl-Digitoxin
a diet with no more than 2.0 g NaCl daily. Diuretics were withheld wherever possible during and following digitalization in order to better evaluate diuresis due to the above measures and the drug. Antihypertensive and other cardiovascular drugs were given as indicated. Acetyl-digitoxin was usually employed in doses of either 0.2 mg every four hours or 0.4 mg every six hours depending on the urgency of the need for digitalization. The ventricular rate governed this in cases of auricular fibrillation. Several patients with auricular fibrillation received single doses of 1.4 to 1.6 mg in order to determine the time of onset of effect and time of maximal effect. In most of the cases of sinus rhythm we chose to give the drugs until significant diuresis occurred or until early toxicity was noted so as to determine the nature of the toxic effects and also to be Patients assured of adequate digitaiization. with auricular fibrillation were given the drug until the ventricular rate was decreased to 60 to 75 per minute and did not increase more than 10 per cent after exercise. All patients were observed at least once daily in reference to this study and the following were recorded daily: functional class (New York Heart Association classification), body weight, blood pressure, apical and radial rates, heart rhythm, respiratory rate, heart size, edema, dyspnea, puImonary rales, liver size and tenderness, signs of toxicity, and dosage of acetyl-digitoxin. Electrocardiograms were repeated frequently. In many cases vital capacity, venous pressure, circulation times, and chest roentgenograms were repeated serially during the observation period. Tables I and II show the age ranges for the group and the type of heart disease. It can be seen that there was a rather even distribution of patients in the 5th, bth, 7th and 8th decades of life. Arteriosclerotic heart disease was the type of heart disease diagnosed in the majority of cases. There were eight male and 24 female patients in this group ; as the patients were selected for this study only on the basis of the presence of indications for digitalization, the reason for the preponderance of females is not obvious.
Nineteen of the patients had sinus mechanisms prior to digitalization: five of these had frequent supraventricular premature contractions. Seven patients had auricular fibrillation, one had paroxysmal auricular tachycardia, one had auricular tachycardia with a 2 : 1 atrioventricular block, two had sinus bradycardia, and one had a wandering pacemaker. Of the 32 patients digitalized with acetyldigitoxin, it was possible to follow 13 for periods of from several weeks to six months on maintenance doses of acetyl-digitoxin. In addition to these, there were three other patients who had been maintained previously on other cardiac glycosides who were changed to maintenance doses of acetyl-digitoxin and followed for similar periods of time. All patients were initially placed on 0.2 mg maintenance daily doses; dosage was adjusted as indicated by effect on heart rate, body weight, signs of congestion, toxic effects, etc. RESULTS
Acetyl-digitoxin
proved to be quite effective TABLE
I
Ages of Patients Digitalieed with Acetyl-digitoxin
-
Age
Number
40-50 50-60 60-70 70-80 80-90 Total
6 7 9 9 1 32
TABLE
II
Type of Heart Disease in Patients Digitaliaed with Acetyl-digitoxin Type
Number
Arteriosclerotic Cor pulmonale Hypertensive Thyrotoxic Fibrous pericarditis Rheumatic Syphilitic Tumor c?) Total
18 6 3 1 1 1 1 1 32
THE AMERICANJOURNAL OF CARDIOLOGY
Vacca, Schuster, and Knight in this group of patients. In only four patients was congestive heart failure not improved by digitalization ; two of these had previously shown no improvement when treated with digitoxin ; one of these died and was found at autopsy to have had a pulmonary embolus; the remaining two patients in whom no improvement occurred with ace+-digitoxin died during hospitalization and were discovered at autopsy to have had a fibrous pericarditis and a severe bronchopneumonia, redpectively, in addition to signs of heart failure. Two patients with auricular fibrillation converted to a sinus mechanism after receiving Paroxysmal auricular fibrilacetyldigitoxin. lation in one patient was converted to a sinus mechanism within six hours after the administration of 1.2 mg acetyl-digitoxin. A patient suspected to have metastatic carcinoma involving the heart had been having frequent episodes of paroxysmal auricular tachycardia, occurring as often as two or three times daily; after being digitalized with acetyl-digitoxin, she has not had a recurrence of the tachycardia in a two month period of observation. Auricular tachycardia with a 2 : 1 atrioventricular block changed to a sinus rhythm in another patient after acetyl-digitoxin. SPEED
OF ONSET
OF ACTION
To determine how soon cardiac effects occurred after ingestion of acetyl-digitoxin three MIN.
‘*._ . **.+ ‘. ,
170 160
u e s
NO
2 U
: : : b *...
140 130 120
E ;
llQ 106 90
(Y *
80 70 60 So
HOURS
patients with atrial fibrillation were given s’ngle oral doses of 1.4 or 1.6 mg of the drug. Apical rates were recorded at least hourly until maximal effect was attained ; the electrocardiogram was repeated at two-hour intervals in two cases. Using a 10 per cent reduction in ventricular rate as the criterion, it can be seen from Figure 1 that acetyl-digitoxin had an onset of observable cardiac effect within two to four hours after oral administration. Electrocardiographic changes (ST-T wave) attributable to digitalis were observed within four to six hours after a single oral dose in these patients (Fig. 2). Maximal effect in these cases as determined by lack of further reduction in ventricular rate occurred at 8 to 16 hours after oral administration of the drug. DIGITALIZING
DOSE
In all cases where digitalization was accomplished over a period of time longer than one day, a daily dissipation and excret:on factor of 0.2 mg of acety‘-digitoxin was subtracted from the total dosage administered during this period in computing the digitalizing dose. Also, whebever toxicity was produced during digitalization, the last dose (0.2 or 0.4 mg) was subtracted from the total. The digitalizing dose in this group ranged from 1.0 mg to 4.0 mg when calculated basis as described above. on a 24-hour (Fig. 3). It can be seen that the great majority
1.6 mg
CL
IS0
c”
719
/
*..,
k ,
w-w.
l*+
1.4 mg.
‘0
-
4
5..
.&.”
l\ ‘h._
*-.
M. 8. 44 yt. Oc, thyroioxicosh M. S. 55 yr. 0+,
ASHD.
-.-.I
E. H. 71 yr. 0+,
ASHD.
0.6 mg. ~c,
*..
0..
1.6 mg
.-..** -
..~~*~.........._*y .,.**.*
a..*
*-. . . . . . . . *.* *....** *..
‘%.-..
W.Z
ti’-‘-‘-
8
12
16
20
24
28
32
Fig. 1. Tie of ornet of action of acetyl-digitoxin given in single oral dose to three patients with auricular fibrillation. JUNE,
19%
Clinical Evaluation of Acetyl-Digitoxin required
from 1.0 to 2.0 mg for digitalization,
with well over 50 per cent of the cases falling between requiring
1.4 the
mg
and
smaller
2.0
mg.
dosages
The
group
(1 .O-1.2
mg),
71 yr. Oc; ASHD.
55 yr. Ok ASHD.
HOURS AFTER SINGLE DIGITAUZING
DOSE
and three had very severe arteriosclerotic
heart
disease. TOXIC
EFFECTS
Thirteen while
patients
being
emphasized, curred the when
however,
because
drug
There who III
effects
most
be
re-
of these
oc-
of study was to give was
produced
for digitalization were,
dosage
toxic should
toxicity in
developed
maintenance Table
that
early
the end-point
patients
It
the plan
until
clear-cut.
developed
digitalized.
toxic
while
adjusted.
the nature
TABLE
eleven
reactions
was being
summarizes
was not
addition,
of the toxic
III
Toxic Effects Observed or Induced in 24 of 35 Patients Receiving Acetyl-Digitoxin
-1
Symptoms or signs
Number
Gastrointestinal only Anorexia, nausea, and/or ing
LluI.1
I i I I I
Fig. 2. Time for electrocardiographic evidence of digitalis effect (ST-T wave) after single oral dose of acetyl-digitoxin in two patients with auricular fibrillation.
vomit-
15
Diarrhea Cardiovascular only Auricular tachycardia Auricular fibrillation Sinus bradycardia Ocular Toxic psychosis (suspected relation-
2 1 2 1 1 1
ship only) Cardiovascular and gastrointestinal Anorexia, later sinus tachycardia with varying degree A-V block Later auricular fibrillation with VPC’S. Total
MO 1.01.11.1.16I.x2.0 1.2.1.4 3.a4.0 2.62.83.0423.4.3.6 Fig. 3. Digitalking doses of acetyl-digitoxin in 32 patients, calculated on a 2Chour period of digitalixa-
1 24
effects. It can be seen that the great majority had gastrointestinal symptoms only. Cardiac abnormalities
alone
acetyl-digitoxin
ti0n.
sinus bradycardia one and auricular
pulmonary
while
several days after admis-
on the drug.
sion. Only seven other patients required more than 2.0 mg; of these, one had moderately
normalities occurred intestinal complaints.
severe
who developed
thyrotoxicosis,
two had car
pulmonale,
possibly
caused
by
in one, an epi-
sode of auricular tachycardia occurred, but was terminated without recurrence five minutes after sedation and intravenous VasoxyP; a
usually had a sinus bradycardia or a slow ventricular rate. The patient who received the largest dose, 4.0 mg, had severe car pulmonale secondary to bronchiectasis and died with a infarction
were
in four cases;
THE
(rate 40-50) occurred in fibrillation in two others In one case cardiac after
cardiac AMERICAN
ab-
the onset of gastro-
Four of the five patients abnormalities received JOURNAL
OF CARDIOLOGY
Vacca,
Schuster,
2.0 mg or more of ace+-digitoxin as the digitalizing dose. One patient developed a toxic psychosis while on acetyl-digitoxin; however, the presence of a simultaneous stormy postoperative course would not allow definite implication of this drug as the causative factor. The toxic manifestations lasted one day or less after discontinuation of the drug in over half of the cases. In only three instances did they last longer than three days; gastrointestinal complaints persisted for four days in one and five days in another of these; sinus bradycardia persisted about eight days in one case. MAINTENANCE DOSE Of the 16 patients on a maintenance regimen of acetyl-digitoxin for periods ranging from several weeks to six months, eleven were wellmaintained on 0.2 mg daily. In four patients, this dose caused toxic symptqms and was obviously too high since all were subsequently well-maintained on 0.1 mg daily. One patient was satisfactorily maintained on 0.3 mg daily. DISCUSSION This study has shown acetyl-digitoxin to be an effective and well-tolerated cardiac glycoside in the treatment of congestive heart failure and arrhythmias occurring in various types of heart disease. Diuresis, diminution of heart size, reduced venous pressure, decreased circulation time, and loss of edema fluid revealed the usefulness of acetyl-digitoxin in relieving congestive heart failure. The slowing of the ventricular rate in auricular fibrillation and the number of patients with rapid supraventricular tachycardia who reverted to sinus mechanisms after digitalization with this agent also attest to its effectiveness. In the patients we have studied, the digitalizing dose varied from 1 .O to 4.0 mg over a period of 24 hours with the majority requiring between 1.4 and 2.0 mg. This is in close agreement with the results obtained by Crouch, Hejtman&, and Herrmann, Doherty,* Brill, Burgner, and David,’ and Maher and Pullen.s Goldfarb, Thorner, and Griffith6 used somewhat larger doses as did Zilli and Luisadae who found it necessary to give 2.4 mg to 3.6 mg over a ~rmrz.,1958
and Knight
721
period of 2 to 4 days; if one allows a daily dissipation and excretion factor of 0.2 mg per day to be subtracted from these higher doses, it can be seen that the difference in digitalizing doses in their cases is not as great as it seems at first. Allowing for the above dissipation and excretion factor, most of the patients studied by Loeffler, Essellier, and Forster7 required between 2.4 mg and 5.6 mg for initial digitalization. In spite of the known individual variation in requirements and toleration to digitalis, we are unable, at the present time, to reconcile our data with those of Loeffler and his associates. Most of our patients were, well maintained on a dose of 0.1-0.2 mg of acetyl-digitox n per day. One. patient required 0.3 mg per day. These results are in agreement with those of most other investigators but lower than the 0.2 to 0.3 mg, and occasionally up to 0.6 mg maintenance dose employed by Loeffler and his associates.’ Well over one-half of our patients developed toxicity while on acetyl-digitoxin, but in most of the cases, this was deliberately produced. The fact that most experienced only gastrointestinal symptoms is of great importance. Cardiac abnormalities which might possibly be due to digitalis intoxication occurred in only four of these cases prior to the appearance of gastrointestinal symptoms. As termed by Crouch and his associates5 and noted by othersa*4 these gastrointestinal symptoms “act as a desirable safety valve measure,” a useful property resembling that obtained with digitalis leaf. In almost every case where toxicity was produced, the manifestations disappeared within 1 to 3 days, a rapid loss of toxicity which has also been noted with favor by Crouch and his associates5 and by Brill, Burgner, and David.4 SUMMARYANDCONCLUSIONS (1) Thirty-two patients were digitalized orally with acetyl-digitoxin, the digitalizing dose ranging from 1.0 mg to 4.0 mg with the majority requiring between 1.4 mg and 2.0 mg when calculated on a 24-hour period of digitalization, (2) The maintenance dose of acetyl-digitoxin ranged from 0.1 mg to 0.2 mg per day.
Clinical
722
Evaluation
(3) Acetyldigitoxin was found to be an effective, quick-acting, and well-tolerated cardiac glycoside, and a useful addition to the therapy of heart failure. (4) Toxicity was deliberately produced in most of the patients. It was observed that the initial manifestations of toxicity were usually gastrointestinal and that these subsided within three days after discontinuance of the drug in almost every case. REFERENCES 1. STOLL, A. and KREIS, W. : acetyl-digitoxin-8. 1952.
Helvet.
Acetyl-digitoxin-a und chim. acta. 35 : 1318,
2. ROTHLIN, E., BIRCHER, R., and SCHALCH, W. R.: Zur Pharmakologie des Acetyl-digitoxin-o. Schweiz. med. wchnschr. 83: 267, 1953.
of Acetyl-Digitoxin 3. MAHER, C. C. and PIJLLEN, C. W.: Acetyl-digitoxin, a new cardiac glycoside. Rocky Mountain M.J. 52: 436, 1955. 4. BRILL, I. C., BURGNER, P. R., and DAVID, N. A.: Acetyl-digitoxin (acylanid): Rapid digitalization and maintenance by oral administration. Ann. Int. Med. 44: 707, 1956. 5. CROUCH, R. B., HEJTMANCIK,M. R., and HERRMANN, G. R.: A clinical evaluation of acetyl-digitoxin. Am. Heart J. 51: 609, 1956. 6. GOLDFARB, M., THORNER, M. C., and GRIFFITH, G. C.: Clinical experience with acetyl-digitoxin: Preliminary report. Am. J. M. SC. 231: 186, 1956. 7. LOEPFLER, W., ESSELLIER, A., and FORSTER, G.: Acetyl-digitoxin. Clinical observations on the treatment of patients with advanced congestive heart failure. Am. Heart J. 47: 898, 1954. 8. DOHERTY, J.: A clinical study of acetyl-digitoxin. Am. Pratt. B Digest. Treat. 6: 1836, 1955. 9. ZILLI, A. and LIJISAOA, A.: Effects of acetyldigitoxin in ambulatory patients with congestive failure. Eqer. Med. atid Surg. 13: 118, 1955.
THE AMERICANJOURNAL OF CARDIOLOGY
and WILLIAM A. KNIGHT, JR. M.D.*
St. Louis, Missouri
D
IGITALIS therapy of heart failure and the arrhythmias has been greatly extended and made more precise with the advent of the cardiac glycosides. Differences ‘exist in clinical effect from one glycoside to another and may be due to variations in degree of absorption, serum binding power, toxic cumulation and dissipation. Also, it is well-known that the individual response to digitalis is quite variable, suggesting that experimentation is highly desirable to find the right glycoside which will be most beneficial to any given patient. However, most physicians prefer to limit the number of drugs in any one category and are ever on the lookout for a single drug which will serve the greatest number of patients. In a search for a glycoside having a broad range of application, Stoll and Kreis’ isolated Acylanid@ from digitalis lanata by subjecting lanatoside A to enzyme hydrolysis. Acylanid is acetyldigitoxin, differing from digitoxin through the presence of an acetyl radical attached to the third digitoxose in the molecule. Pharmacologic study by Rothlin, Bircher, and Schalch2 has demonstrated acetyl-digitoxin to be strongly bradycardic, well-absorbed, and less toxic than digitoxin. They found acetyl-digitoxin to’ be a welldefined, pure cardiac glycoside free of biologic assay variations in contrast to digitoxin, which, though chemically well-defined, did not show uniform activity when batches from different sources were analyzed. It was found that absorption of acetyl-digitoxin from the gastrointestinal tract comes close to that of digitoxin and that its duration of action is somewhat Overdosage shorter than that of digitoxin. of acetyl-digitoxin in chronic cat experiments induced less frequent emesis, fewer irregulari* From JUNE,
1958
the Department
of Internal
Medicine,
ties, and fewer histologic changes in the heart muscle and conductive system. Better toleration, more rapid dissipation, and a lesser degree of cumulation pointed to a reduced toxicity. The clinical efficacy of acetyldigitoxin has been revealed in a number of studies which have shown it ,to be very well-tolerated and useful for both digitalization and maintenance.s-g Maher and Pullen,a Brill, Burgner, and David,4 and Crouch, Hejtmancik, and Herrmann, have noted especially and favorably that anorexia, nausea, or vomiting usually appeared as the first symptoms of overdosage, and they consider this a highly desirable warning to prevent the development of the more serious toxic arrhythmias. Also noted5 was the spread between dissipation of toxic effects within 24 to 72 hours and evidence of therapeutic effect for periods up to 17 days after discontinuation of the drug. This report details our experiences with acetyl-digitoxin in 35 patients over a period of ten months. METHODSANDMATERIALS Thirty-two patients were digitalized with acetyl-digitoxin and maintained on this glycoside for variable periods of observation. All of these patients were hospitalized, and had never been on a digitalis preparation before or had not taken any digitalis preparation for a period of at least three weeks prior to administration of acetyl-digitoxin. Administration of acetyi-digitoxin was preceded by the following determinations in each patient: venous pressure, circulation time with decholin and ether, chest roentgenogram (and fluoroscopy in some cases), vital capacity, electrocardiogram, and routine laboratory studies. All patients were placed on bed rest and
St. Louis University, School of Medicine, St. Louis, Missouri. 717
718
Clinical Evaluation of Acetyl-Digitoxin
a diet with no more than 2.0 g NaCl daily. Diuretics were withheld wherever possible during and following digitalization in order to better evaluate diuresis due to the above measures and the drug. Antihypertensive and other cardiovascular drugs were given as indicated. Acetyl-digitoxin was usually employed in doses of either 0.2 mg every four hours or 0.4 mg every six hours depending on the urgency of the need for digitalization. The ventricular rate governed this in cases of auricular fibrillation. Several patients with auricular fibrillation received single doses of 1.4 to 1.6 mg in order to determine the time of onset of effect and time of maximal effect. In most of the cases of sinus rhythm we chose to give the drugs until significant diuresis occurred or until early toxicity was noted so as to determine the nature of the toxic effects and also to be Patients assured of adequate digitaiization. with auricular fibrillation were given the drug until the ventricular rate was decreased to 60 to 75 per minute and did not increase more than 10 per cent after exercise. All patients were observed at least once daily in reference to this study and the following were recorded daily: functional class (New York Heart Association classification), body weight, blood pressure, apical and radial rates, heart rhythm, respiratory rate, heart size, edema, dyspnea, puImonary rales, liver size and tenderness, signs of toxicity, and dosage of acetyl-digitoxin. Electrocardiograms were repeated frequently. In many cases vital capacity, venous pressure, circulation times, and chest roentgenograms were repeated serially during the observation period. Tables I and II show the age ranges for the group and the type of heart disease. It can be seen that there was a rather even distribution of patients in the 5th, bth, 7th and 8th decades of life. Arteriosclerotic heart disease was the type of heart disease diagnosed in the majority of cases. There were eight male and 24 female patients in this group ; as the patients were selected for this study only on the basis of the presence of indications for digitalization, the reason for the preponderance of females is not obvious.
Nineteen of the patients had sinus mechanisms prior to digitalization: five of these had frequent supraventricular premature contractions. Seven patients had auricular fibrillation, one had paroxysmal auricular tachycardia, one had auricular tachycardia with a 2 : 1 atrioventricular block, two had sinus bradycardia, and one had a wandering pacemaker. Of the 32 patients digitalized with acetyldigitoxin, it was possible to follow 13 for periods of from several weeks to six months on maintenance doses of acetyl-digitoxin. In addition to these, there were three other patients who had been maintained previously on other cardiac glycosides who were changed to maintenance doses of acetyl-digitoxin and followed for similar periods of time. All patients were initially placed on 0.2 mg maintenance daily doses; dosage was adjusted as indicated by effect on heart rate, body weight, signs of congestion, toxic effects, etc. RESULTS
Acetyl-digitoxin
proved to be quite effective TABLE
I
Ages of Patients Digitalieed with Acetyl-digitoxin
-
Age
Number
40-50 50-60 60-70 70-80 80-90 Total
6 7 9 9 1 32
TABLE
II
Type of Heart Disease in Patients Digitaliaed with Acetyl-digitoxin Type
Number
Arteriosclerotic Cor pulmonale Hypertensive Thyrotoxic Fibrous pericarditis Rheumatic Syphilitic Tumor c?) Total
18 6 3 1 1 1 1 1 32
THE AMERICANJOURNAL OF CARDIOLOGY
Vacca, Schuster, and Knight in this group of patients. In only four patients was congestive heart failure not improved by digitalization ; two of these had previously shown no improvement when treated with digitoxin ; one of these died and was found at autopsy to have had a pulmonary embolus; the remaining two patients in whom no improvement occurred with ace+-digitoxin died during hospitalization and were discovered at autopsy to have had a fibrous pericarditis and a severe bronchopneumonia, redpectively, in addition to signs of heart failure. Two patients with auricular fibrillation converted to a sinus mechanism after receiving Paroxysmal auricular fibrilacetyldigitoxin. lation in one patient was converted to a sinus mechanism within six hours after the administration of 1.2 mg acetyl-digitoxin. A patient suspected to have metastatic carcinoma involving the heart had been having frequent episodes of paroxysmal auricular tachycardia, occurring as often as two or three times daily; after being digitalized with acetyl-digitoxin, she has not had a recurrence of the tachycardia in a two month period of observation. Auricular tachycardia with a 2 : 1 atrioventricular block changed to a sinus rhythm in another patient after acetyl-digitoxin. SPEED
OF ONSET
OF ACTION
To determine how soon cardiac effects occurred after ingestion of acetyl-digitoxin three MIN.
‘*._ . **.+ ‘. ,
170 160
u e s
NO
2 U
: : : b *...
140 130 120
E ;
llQ 106 90
(Y *
80 70 60 So
HOURS
patients with atrial fibrillation were given s’ngle oral doses of 1.4 or 1.6 mg of the drug. Apical rates were recorded at least hourly until maximal effect was attained ; the electrocardiogram was repeated at two-hour intervals in two cases. Using a 10 per cent reduction in ventricular rate as the criterion, it can be seen from Figure 1 that acetyl-digitoxin had an onset of observable cardiac effect within two to four hours after oral administration. Electrocardiographic changes (ST-T wave) attributable to digitalis were observed within four to six hours after a single oral dose in these patients (Fig. 2). Maximal effect in these cases as determined by lack of further reduction in ventricular rate occurred at 8 to 16 hours after oral administration of the drug. DIGITALIZING
DOSE
In all cases where digitalization was accomplished over a period of time longer than one day, a daily dissipation and excret:on factor of 0.2 mg of acety‘-digitoxin was subtracted from the total dosage administered during this period in computing the digitalizing dose. Also, whebever toxicity was produced during digitalization, the last dose (0.2 or 0.4 mg) was subtracted from the total. The digitalizing dose in this group ranged from 1.0 mg to 4.0 mg when calculated basis as described above. on a 24-hour (Fig. 3). It can be seen that the great majority
1.6 mg
CL
IS0
c”
719
/
*..,
k ,
w-w.
l*+
1.4 mg.
‘0
-
4
5..
.&.”
l\ ‘h._
*-.
M. 8. 44 yt. Oc, thyroioxicosh M. S. 55 yr. 0+,
ASHD.
-.-.I
E. H. 71 yr. 0+,
ASHD.
0.6 mg. ~c,
*..
0..
1.6 mg
.-..** -
..~~*~.........._*y .,.**.*
a..*
*-. . . . . . . . *.* *....** *..
‘%.-..
W.Z
ti’-‘-‘-
8
12
16
20
24
28
32
Fig. 1. Tie of ornet of action of acetyl-digitoxin given in single oral dose to three patients with auricular fibrillation. JUNE,
19%
Clinical Evaluation of Acetyl-Digitoxin required
from 1.0 to 2.0 mg for digitalization,
with well over 50 per cent of the cases falling between requiring
1.4 the
mg
and
smaller
2.0
mg.
dosages
The
group
(1 .O-1.2
mg),
71 yr. Oc; ASHD.
55 yr. Ok ASHD.
HOURS AFTER SINGLE DIGITAUZING
DOSE
and three had very severe arteriosclerotic
heart
disease. TOXIC
EFFECTS
Thirteen while
patients
being
emphasized, curred the when
however,
because
drug
There who III
effects
most
be
re-
of these
oc-
of study was to give was
produced
for digitalization were,
dosage
toxic should
toxicity in
developed
maintenance Table
that
early
the end-point
patients
It
the plan
until
clear-cut.
developed
digitalized.
toxic
while
adjusted.
the nature
TABLE
eleven
reactions
was being
summarizes
was not
addition,
of the toxic
III
Toxic Effects Observed or Induced in 24 of 35 Patients Receiving Acetyl-Digitoxin
-1
Symptoms or signs
Number
Gastrointestinal only Anorexia, nausea, and/or ing
LluI.1
I i I I I
Fig. 2. Time for electrocardiographic evidence of digitalis effect (ST-T wave) after single oral dose of acetyl-digitoxin in two patients with auricular fibrillation.
vomit-
15
Diarrhea Cardiovascular only Auricular tachycardia Auricular fibrillation Sinus bradycardia Ocular Toxic psychosis (suspected relation-
2 1 2 1 1 1
ship only) Cardiovascular and gastrointestinal Anorexia, later sinus tachycardia with varying degree A-V block Later auricular fibrillation with VPC’S. Total
MO 1.01.11.1.16I.x2.0 1.2.1.4 3.a4.0 2.62.83.0423.4.3.6 Fig. 3. Digitalking doses of acetyl-digitoxin in 32 patients, calculated on a 2Chour period of digitalixa-
1 24
effects. It can be seen that the great majority had gastrointestinal symptoms only. Cardiac abnormalities
alone
acetyl-digitoxin
ti0n.
sinus bradycardia one and auricular
pulmonary
while
several days after admis-
on the drug.
sion. Only seven other patients required more than 2.0 mg; of these, one had moderately
normalities occurred intestinal complaints.
severe
who developed
thyrotoxicosis,
two had car
pulmonale,
possibly
caused
by
in one, an epi-
sode of auricular tachycardia occurred, but was terminated without recurrence five minutes after sedation and intravenous VasoxyP; a
usually had a sinus bradycardia or a slow ventricular rate. The patient who received the largest dose, 4.0 mg, had severe car pulmonale secondary to bronchiectasis and died with a infarction
were
in four cases;
THE
(rate 40-50) occurred in fibrillation in two others In one case cardiac after
cardiac AMERICAN
ab-
the onset of gastro-
Four of the five patients abnormalities received JOURNAL
OF CARDIOLOGY
Vacca,
Schuster,
2.0 mg or more of ace+-digitoxin as the digitalizing dose. One patient developed a toxic psychosis while on acetyl-digitoxin; however, the presence of a simultaneous stormy postoperative course would not allow definite implication of this drug as the causative factor. The toxic manifestations lasted one day or less after discontinuation of the drug in over half of the cases. In only three instances did they last longer than three days; gastrointestinal complaints persisted for four days in one and five days in another of these; sinus bradycardia persisted about eight days in one case. MAINTENANCE DOSE Of the 16 patients on a maintenance regimen of acetyl-digitoxin for periods ranging from several weeks to six months, eleven were wellmaintained on 0.2 mg daily. In four patients, this dose caused toxic symptqms and was obviously too high since all were subsequently well-maintained on 0.1 mg daily. One patient was satisfactorily maintained on 0.3 mg daily. DISCUSSION This study has shown acetyl-digitoxin to be an effective and well-tolerated cardiac glycoside in the treatment of congestive heart failure and arrhythmias occurring in various types of heart disease. Diuresis, diminution of heart size, reduced venous pressure, decreased circulation time, and loss of edema fluid revealed the usefulness of acetyl-digitoxin in relieving congestive heart failure. The slowing of the ventricular rate in auricular fibrillation and the number of patients with rapid supraventricular tachycardia who reverted to sinus mechanisms after digitalization with this agent also attest to its effectiveness. In the patients we have studied, the digitalizing dose varied from 1 .O to 4.0 mg over a period of 24 hours with the majority requiring between 1.4 and 2.0 mg. This is in close agreement with the results obtained by Crouch, Hejtman&, and Herrmann, Doherty,* Brill, Burgner, and David,’ and Maher and Pullen.s Goldfarb, Thorner, and Griffith6 used somewhat larger doses as did Zilli and Luisadae who found it necessary to give 2.4 mg to 3.6 mg over a ~rmrz.,1958
and Knight
721
period of 2 to 4 days; if one allows a daily dissipation and excretion factor of 0.2 mg per day to be subtracted from these higher doses, it can be seen that the difference in digitalizing doses in their cases is not as great as it seems at first. Allowing for the above dissipation and excretion factor, most of the patients studied by Loeffler, Essellier, and Forster7 required between 2.4 mg and 5.6 mg for initial digitalization. In spite of the known individual variation in requirements and toleration to digitalis, we are unable, at the present time, to reconcile our data with those of Loeffler and his associates. Most of our patients were, well maintained on a dose of 0.1-0.2 mg of acetyl-digitox n per day. One. patient required 0.3 mg per day. These results are in agreement with those of most other investigators but lower than the 0.2 to 0.3 mg, and occasionally up to 0.6 mg maintenance dose employed by Loeffler and his associates.’ Well over one-half of our patients developed toxicity while on acetyl-digitoxin, but in most of the cases, this was deliberately produced. The fact that most experienced only gastrointestinal symptoms is of great importance. Cardiac abnormalities which might possibly be due to digitalis intoxication occurred in only four of these cases prior to the appearance of gastrointestinal symptoms. As termed by Crouch and his associates5 and noted by othersa*4 these gastrointestinal symptoms “act as a desirable safety valve measure,” a useful property resembling that obtained with digitalis leaf. In almost every case where toxicity was produced, the manifestations disappeared within 1 to 3 days, a rapid loss of toxicity which has also been noted with favor by Crouch and his associates5 and by Brill, Burgner, and David.4 SUMMARYANDCONCLUSIONS (1) Thirty-two patients were digitalized orally with acetyl-digitoxin, the digitalizing dose ranging from 1.0 mg to 4.0 mg with the majority requiring between 1.4 mg and 2.0 mg when calculated on a 24-hour period of digitalization, (2) The maintenance dose of acetyl-digitoxin ranged from 0.1 mg to 0.2 mg per day.
Clinical
722
Evaluation
(3) Acetyldigitoxin was found to be an effective, quick-acting, and well-tolerated cardiac glycoside, and a useful addition to the therapy of heart failure. (4) Toxicity was deliberately produced in most of the patients. It was observed that the initial manifestations of toxicity were usually gastrointestinal and that these subsided within three days after discontinuance of the drug in almost every case. REFERENCES 1. STOLL, A. and KREIS, W. : acetyl-digitoxin-8. 1952.
Helvet.
Acetyl-digitoxin-a und chim. acta. 35 : 1318,
2. ROTHLIN, E., BIRCHER, R., and SCHALCH, W. R.: Zur Pharmakologie des Acetyl-digitoxin-o. Schweiz. med. wchnschr. 83: 267, 1953.
of Acetyl-Digitoxin 3. MAHER, C. C. and PIJLLEN, C. W.: Acetyl-digitoxin, a new cardiac glycoside. Rocky Mountain M.J. 52: 436, 1955. 4. BRILL, I. C., BURGNER, P. R., and DAVID, N. A.: Acetyl-digitoxin (acylanid): Rapid digitalization and maintenance by oral administration. Ann. Int. Med. 44: 707, 1956. 5. CROUCH, R. B., HEJTMANCIK,M. R., and HERRMANN, G. R.: A clinical evaluation of acetyl-digitoxin. Am. Heart J. 51: 609, 1956. 6. GOLDFARB, M., THORNER, M. C., and GRIFFITH, G. C.: Clinical experience with acetyl-digitoxin: Preliminary report. Am. J. M. SC. 231: 186, 1956. 7. LOEPFLER, W., ESSELLIER, A., and FORSTER, G.: Acetyl-digitoxin. Clinical observations on the treatment of patients with advanced congestive heart failure. Am. Heart J. 47: 898, 1954. 8. DOHERTY, J.: A clinical study of acetyl-digitoxin. Am. Pratt. B Digest. Treat. 6: 1836, 1955. 9. ZILLI, A. and LIJISAOA, A.: Effects of acetyldigitoxin in ambulatory patients with congestive failure. Eqer. Med. atid Surg. 13: 118, 1955.
THE AMERICANJOURNAL OF CARDIOLOGY