- Email: [email protected]
Drug evaluation in angina pectoris: Khellin, heparin, Peritrate
DRUG
Ross C.
EVALUATION
IN ANGINA PECTORIS: HEPARIN, PERITRATE
KHELLIN,
M.D.,* ALEXANDER S. TOWNES, M.D., ROBERT EVA R. DORRIS, B.S.,* AND GEORGE R. MENEELY,
KORY,
NASHVILLE,
E. MABE, M.D.
M.D.,**
TENN.
T
HE present study is a subjective and an objective evaluation of three agents, khellin, sodium heparin, and pentaerythritol tetranitrate (Peritrate) as therapeutic agents in patients with angina pectoris. For the past several years the Levy anoxemia test has been employed in this laboratory both as a diagThe nostic aid and in connection with an investigation of the Q-T interval.‘J anoxemia test is both highly reproducible and objective. Any drug which brings about both subjective improvement and reversal of a previously positive test should be considered as an effective therapeutic agent in anginapectoris. Khellin (5, 8-dimethoxy-2-methyl-6, ‘I-furanochromone), one of the substances isolated from the plant, Ammi visnaga, has been found to be a smooth muscle relaxant3 and a coronary artery dilator.4-1” Heparin was found to affect serum lipids in early studies20-25and later was reported by Gofman and his co-workers to induce a return toward normal of abnormal serum lipoproteins?-“” and to effect clinical improvement in patients with angina pectoris.2g Several other investigators3n-35 have reassessed the clinical efficacy of sodium heparin in angina pectoris, but only one32could confirm Gofman’s results. Pentaerythritol tetranitrate (Peritrate) is a nitric acid ester of a tetrahydric alcohol, pentaerythritol, and pharmacologically is a slowly absorbed, long-acting nitrate.35-37 Clinical trial of this drug in patients with angina pectoris was reported first by French workers in 1950,3*J9 and later by Winsor and Humphreys*Q who reported ” satisfactory improvement in the precordial pain” in 78.4 per cent of 125 patients with angina pectoris. Perlman41 found Peritrate relatively nontoxic in clinical use, and only moderately effective in angina. Talley and his co-workers4? found Peritrate ineffective in fourteen patients, but Russek and associates43consider Peritrate “ . the most effective drug currently available for prolonged prophylactic therapy in angina pectoris.” From the Research Laboratory and Medical Service, Thayer Veterans and the Department of Medicine, Vanderbilt University School of Medicine, Received for publication Jan. 13. 1955. Veterans Administration Hospital, Wood, Wis *Present address: **Present address: Newell Hospital, Chattanooga. Term. 308
Administration Hospital, Nashville. Teoo.
P.M. 2 yr.
S.G. 11 yr.
coronary numerals
Key:
*All tThe index
-___T.N. 1 yr.
_--__
this
i
I-
ASHD, CS, NSR, eompensated, Class II-B
57
l-
8-25
s-1 1
7-25
---
6-21 7-8 7-18
_!I 4-30 5-18 6-1
3-8 3-24 4-7
were on limited ambulation except those “Q-T Anosemia Index” relates t.he initial correct,ed of 0.480 and above are considered abnormal. ASHD = arteriosclerotic heart disease: HCVD sclerosis; AI = aortic insufficiency: NSR = normal II and III refer to the functional capacity classification
patients
--
ASHD, CS, NSR, compensated, Class III-C; previous myocardial infarction
--
ASHD, CS, NSR, compensated, Class II-B, osteoarthritis of cervical and dorsal spine
ASHD, EH, CS, SR with PVC’S, compensated, Class II-B; previous myocardial infarction
52
52
--
l-9 l-25 2-6
HCVD, ASHD, EH, CS, NSR, compensated, Class II-B
W.T. 12 yr.
-___-G.S. 2 mo.
_-----
_~--
DATE
l-6 I-20 2-7
--
DIAGNOSIS
ASHD, CS, NSR, compensated, Class II-B; previous myocardial infarction
AGE
W.H. 5 yr.
AND DURATION OF ANGINAL SYMPTOMS
PATIENT
-
.-
= hypertensive sinus rhythm; and letters
increase
2 1
18
27 24 4
42 15 13
4 1
7
Q-T
1 1
Pos. Pos. Neg.
Neg. Neg. Neg.
Pos. Pos. Pos.
Pos. Neg. Neg.
I-
test.
Pos. Neg. Neg.
Pos. Pos. Pos.
I-
I-
I
I-
I
ANOXEMIA
anosemia
17 None
16
14
2
14
8
17
None None None
18 None None
21
11
the
---
15
11
12 13 7
28
18 16
42
i
7
during
--__
14 1 4
0 0
14
LYERAGE NO. NITRO/ GLYCERIN 1
ip
= luetic heart, disease; EH = enlarged with premature ventricular contractions. classification of the American Heart
in corrected
Moderate Moderate Moderate
Severe Moderate Very mild
Moderate Mild Moderate
Moderate Mild Very mild
Moderate Moderate Moderate
Mild Mild None
DEGREE OF SEVERITY
ATT.4CKS
I-
cardiovascular disease; LHD SR with PVC’s = Sinus rhythm I$ and (’ and D to the therapeut,ic
maximum
Initial study After 2 weeks on placebo After 2 weeks on khellin 50 mg.-t.i.d.
Initial study After 2 weeks on placebo After 2 weeks on khellii 50 mg.-t.i.d.
Initial study After 2 weeks on placebo After 2 weeks on khellin 50 mg.-t.i.d.
designated as “bedridden.” Q-T interval with the
Bedrest Bedrest Moderate
--Bedridden Bedridden Moderate
Moderate Moderate Moderate
Initial study After 2 weeks on placebo After 2 weeks on khellin 50 mg.- t.i.d.
Moderate Moderate Moderate
Initial study After 2 weeks on placebo After 2 weeks on khellin
ANGINAL
\V. NO. /WK.
OF STUDY
STATUS
RESULTS
THER.4PEUTIC
EHELLIN:
Initial study After 2 weeks on placebo After 2 weeks on khellin 50 mg.-t.i.d.
I.
Moderate Moderate Moderate
Moderate Moderate Moderate
ACTIVITY*
TAELE
Q-T
,487 ,461 ,482
,562 ,488
,499
,505 ,503 470
,526 ,481 .466
.549 492
,464
441 ,453 ,522
INDEXt
for CS = Roman Association.
Falues heart;
IA
TEST
Bedridden Moderate Moderate Moderate Moderate
7-10 6-24 7-7 7-15 7-23
__---
Bedridden
8-14
I
Bedridden
1 8-7
IMinimal but ambulatory Bedridden
Minimal
7-3
7-24 LSHD, HCVD, EH, CS, SR with PVC’S, compensated, Class III-D; previous myo- I 7-31 cardial infarction
Minimal Minimal
6-18 6-26
46
4SHD, HCVD, CS, NSR, compensated, Class III-C; previous myocardial infarction
J.R. 8 yr.
Moderate
8-29
UHD, CS, NSR, compensated Class II-C; previous myocardial infarction
Moderate
8-22
til
Moderate
5-26
L.H. 3 yr.
Moderate Moderate
ACTIVITY*
3-26 5-13
56
ASHD, EH, CS, NSR, compensated, Class II-C; previous myocardial infarction
I
DATE
W.R. 1% yr.
I
DIAGNOSIS
33
AGE
J.C.B. 3 yr.
PATIENT AND DURATION OF ANGINAL SYMPTOMS
TABLE
II.
After 2 weeks of IV heparin daily
After 1 week of IV heparin daily
After 1 week of saline placebo
Initial study
Initial study After 1 week of saline placebo After 1 week of IV heparin daily After 2 weeks of IV heparin daily
Initial study After 1 week of IV heparin After 2 weeks at home s Rx After 1 week of saline placebo After 1 week of IV heparin daily -Initial study After 1 week of saline placebo After 1 week of IV heparin daily After 2 weeks of IV heparin daily
THERAPEUTIC STATUS
SODIUM HEPARIN:
i-
Severe
3 11
---Moderate to severe
Severe
Severe
14 8
Severe
19
6
12
9
10
__-
15
__14
15
None 12
I-
Pos.
PO%
Pos.
Pos.
Pos.
Pos.
Pos. Pos.
(Recent myocardial
--
TEST
.494
,503
,482
,502 ,442
Q-T INDEX1
-’I
/
-
II-III II-III
IV
:: ’
III
i II-III
1 II-III
I
/ I
III
BCG GRADE1
’ -
1
I
III-11 Q-T not measurable III-IV Q-T not measurable III-IV (2-T not meas- 1 urable ~ III-IV Q-T not measurable
,486
,546
,506 ,505
infarction)
test not done
Pos.
Pos.
Pos.
Pos. Neg.
ST-T CRITERIA
ANOXEMIA
Anoxemia
6
7
None
10 None
PAIN (MIN.)
0
14
I
I I )- I-
0
i
Moderate
i
----Mild
7 3
__--Moderate Moderate 3
10
Moderate
7 10
10
Moderate Moderate
7
4
7
AVERAGE NO. NITRC GLYCRRIP TABLETS, WK.
10
Moderate Moderate
DEGREE OF SEVERITY
4
10
AV. NO /WK.
ATTACKS
OF STUDY
ANGINAL
RESULTS
C.L.G. 3 yr.
76
-63
-
64
A.S. 4 yr.
W.M. 4 yr.
53
C.G. 2 mo.
ASHD, EH, CS, SR with PVC’s, compensated Class II-C
ASHD, HCVD, EH, CS, NSR, compensated, Class II-C; previous myocardial infarction
ASHD, HCVD, EH, CS, NSR, compensated, Class III-D
---
LHD, ASHD, EH, AI, CS, SR with PVC’S, compensated, Class II-C
--
--
--
--
Minimal Moderate Moderate Moderate Moderate Moderate Moderate
8-22 8-29 94 11-7 11-14 11-21 1 l-28
Bedridden
9-16 9-25
Moderate Moderate
IO-23 lo-31
9-26 10-2 lo-17
Moderate
z2
--Moderate Moderate
_--Moderate Moderate
9-9
__Minimal but ambulatory Minimal but ambulatory Bedridden
9-2
Minimal
8-11
study
study
Initial study After 1 week of saline placebo After 1 week of IV heparin daily After 2 weeks of IV heparin daily
Initial study After 1 week of saline placebo After 2 weeks of IV heparin daily
After 2 weeks of IV heparin daily
After 1 week of IV heparin daily
After 1 week of saline placebo
Initial
After 1 week of saline placebo After 1 week of IV heparin daily After 2 weeks of IV heparin daily Repeat study after 2 mo.s Rx After 1 week of IV heparin daily After 2 weeks of IV heparin daily After 3 weeks of IV heparin daily
Initial
Severe
7
Mild
Mild
7 7
Mid Mild ::
0
Pos. Pos.
None None
-__ Pos. Pos.
Pos.
-
i
Pos.
Pos.
Pos.
Pos.
Pos.
Neg.
-.
---
,538
,506
,480 ,504
,527
.492 .480
Q-T
not measurable
not?Zasurable
not measurable
Q-T
not measurable
Q-T
,525
,533
,446
,487
Pos. Neg.
.477
Neg.
,462
,550
Pos. Neg.
,530
Pos.
Pos. Pos.
15 None
5
5
5
5
None
0 _-
None
None
0
0
None
None
0 0
None
None
None
8
15
18
__-Moderate -
Severe
Severe
7
12
__-Severe
-
Moderate to severe Moderate to severe Mild to moderate -
4
0
0
0
0
0
8
15
14
_-
III
III III
III
III
A.I.5
A.1.B
A.1.Q
A.1.I
A.1.S
AI.%
2
3
P
z z $ 2
F ”
t:
3 2
and
Key
.I-
ASHD, CS, XSR, compensated, Class II-C
I.
I.
Table
TGrading of hallistocardiograms IV representing progressive $Aortic insufficit?nc$ imparts
I
Moderate Moderate i Moderate
3-3 1 4-7 4-14 I
Moderate
Moderate
12-5 I-
Moderate
11-29
3324
Moderate Moderate
I-
Moderate
lo-27 11-13 11-21
Moderate Moderate
-l- --~-~
inspect.ion
to the
of Brown
4
14 18
/WK.
ballistocardiogram
method
After 1 week of saline placebo After 1 week of IV heparin daily After 2 weeks of IV heparin daily
Initial study After 1 week of saline placebo After 10 days of IV heparin -___-__ Initial study After 1 week of saline placebo After 1 week of IV heparin daily After 2 weeks of IV heparin daily -----Initial study
(CONT'D) AVERAGE
and
which
with is deceptive
associates’”
the and
precludes
designation
10
5
16 16
15
14
16
16
Moderate __--Moderate to severe Moderate to severe Moderate to severe Moderate to severe
l;one
Moderate
Sane
10 Kane
PAIN (MIN.)
None 20
10
TABLETS/ I WK.
1k-0. NITRO ; IGLYCERD
Moderate Moderate
I--__-
Mild
Mild Mild
SEVERITY
I ANGINALATTACKS -- --__.I ‘TLV. NO. DEGREE OF
RESULTSOF~TUDY
THERAPEUTIC STATUS
SODIUMHEPARIN:
amplitude
ACTIVITY*
10-3 lo-16
DATE
II.
was done by t,he qualitative grades of ahnormality. normal appearing form and
CS, NSR, compensated, Class II-C; previous myocardial infarction
I-ASHD,
__~ I- ---__ ASHD, EH, CS, incomplete AV block, compensated, Class II-C
I-
see Table I. Table
58
AGE
*See footnote*, t&e footnotet,
For
C.Y. 5 yr.
R.G. 8 mo.
D.B.
PATIENT AND DURATIOX OFANGINAL SYMPTOMS -
TABLE
’
proper
grading.
I, II,
III
,486
and
III
II-III
III
III
III
III III
III
III III
III.
-
BCG :RADE$
,514
,484
,537
,471
,465
,536 526
,443
,512 ,487
Q-T
INDEXi
-----
0 as normal
Pos.
Pos.
Pos.
Pos.
Pos.
Pos.
Pos. Pos.
xeg.
:Borderli (me Neg.
ST-T CRITERI A
ANOXEMIATEST
z~
2
F =: 5 2 z 3 > z
i r
KORY
ET
AL.:
KHELLIN,
HEPARIN,
PERITRATE
IN
ANGINA
I’ECTORIS
313
MATERIAL
Eighteen male cardiac patients were selected from the wards of Thayier Veterans Administration Hospital. Each patient gave a typical clinical history of moderate to severe angina pectoris of from two months’ to twelve years’ duration. All of the patients had arteriosclerotic heart disease, six were hypertensive, and one patient in addition exhibited luetic aortic insufficiency. Ten patients gave histories of previous myocardial infarctions (Tables I, II, and 1 I I). All patients were hospitalized for the entire period of study. METHOD
OF
STUDY
The basic pattern of testing was the evaluation of the frequency and severity of angina1 attacks during control, placebo, and drug periods with anoxemia tests at the beginning and end of each period. Subjective evaluation was carried out in each patient by a daily record of each angina1 attack throughout the study period. This record included the time of onset, activity preceding the episode, type, location, and duration of the pain, and the number of nitroglycerin tablets taken for relief. Daily checks were made with each patient to assure the accuracy of these records. The anoxemia test was performed with the patient breathing a mixture of 10 per cent oxygen in nitrogen for a period of twenty minutes unless the electrocardiogram showed positive ST-T changes44 or angina1 pain occurred, in which case the test was terminated by the administration of 100 per cent oxygen. The technique and criteria for a positive test including the “Q-T Anoxemia Index” have been previously described.? Ballistocardiograms were graded qualitatively according to the criteria of Brown and associates.45 Initial ballistocardiograms were abnormal in all patients. In the khellin study (Table I) the initial anoxemia test was followed by a two-week period on an identically appearing oral placebo which in turn was followed by a second anoxemia test. Then after two weeks on 50 mg. khellin three times daily, a third anoxemia test was done. For the heparin study (Table II) the initial anoxemia test was followed by daily intravenous injections of 5 ml. of normal saline as a placebo for one week followed by a second anoxemia test. The patients were then given daily intravenous injections of 50 mg. of sodium heparin for 10 to 21 days with weekly anoxemia tests during this period. This change in medication was unknown both to the patient and to the nurses, and the placebo was entirely similar to the heparin in appearance. Anoxemia tests were performed between eighteen and twenty-four hours after the injections of heparin in order to eliminate the possibility cf acute effect of the drug.47 Serum cholesterol and cholesterol Serum turbidity esters were determined once or twice weekly during the study. was measured in five subjects before and after a standard fatty meal using direct readings of the Klett-Summerson photoelectric colorimeter21 before and after the period of heparin administration. The test was carried out eighteen hours after the last injection of heparin in order to preclude any acute effect. Pentaerythritol tetranitrate was employed in dosages of 30 to 90 mg. daily in three divided doses (Table III).
- -.
--_--
ASHD, HCS’D, CS, NSR, compensated, Class III-C; previous myocardial infarction
ASHD, HCVD, EH, CS, SR with PVC’s, compensated, Class III-D previous myocardial infarction
56
46
W.R. 1% v.
J.R. 8 yr.
--
DIAGNOSIS
AGE
PATIENT AND DURATION OF ANGINA L SYMPTOMS --
__--
-
III.
Moderate
Bedridden Bedridden Moderate Moderate
8-27
8-14 5-21 l&3 l&8
8-8
8-13
--
ACTIVITY*
I-
After 2 weeks on ziate, 20 mg. . . --____After 2 weeks on IV heparin daily After 1 week on Peritrate, 10 mg. t. i. d. After 5 weeks on p$ate, 20 mg. . . . After 5 days on pT;ate, 30 mg.
Initial evaluation After 5 days on Eeiripte, 10 mg.
THERAPEUTIC STATUS
__-
Moderate i I Moderate
4 4
.-
Severe
14
Severe
Mild
14
8
Mild
70 14
II Moderate
DEGREE OF SEVERITY
.-
63 18
AVERAGE NO. NITROGLYCERIN TABLETS/ WK.
RESULTSOFSTUDY
ANGINALATTACKS
AV. NO. /WK.
PEXTAERYTHRITOLTETRANITRATE(PERITRATE):
Bedridden Moderate
---
DATE
TABLE
= -
--
ANOXEMIA
TEST
Q-T INDEXt
_.-~
6
Pos.
,515
--
-63&iii-
,506
--
Pos.
Pos.
-
12
6
I Anodemia test not done 8 ,515
(MIN.)
PAIN
-.-
;
:I
1 -
! 1
II
IV
IV IV
BCG GRADE;
ASHD, HCVD, EH, CS, NSR, compensated, Class III-D
ASHD, HCVD, CS, NSR, compensated, Class II-C
ASHD, HCVD, EH, CS, NSR, compensated, Class II-C; previous myocardial infarction
ASHD, HCVD, CS, NSR, compensated, Class II-C; previous myocardial infarction
For Key see Table I. *See footnote*, Table I. tSee footnote?, Table I. JYee footnotef, Table II.
64
64
J.M. 3 yr.
-.
76
W.M. 4 Yi-.
A.S. 4 yr.
56
C.M. 4 yr.
Bedridden Bedridden
11-18 12-3
Moderate Moderate
Moderate
10-3
9-30 IO-9
Moderate
9-26
Moderate Moderate
-_
-_
-
After 2 weeks on feiri:ate, 20 mg. . .
After 2 weeks on IV heparin daily
Initial study After 1 week on Peritrate, 20 mg. t. i. d.
After 2 weeks on IV heparin daily After 1 week on Peritrate 10 mg. t. i. d.
Initial study After 2 weeks on Peritrate, 20 mg. t. i. d.
24
12
0
0
0 0
Severe
--Severe
Moderate Moderate -~
None
0
28
3
7 7
15
4 8
0
0 0
---
Pos.
Pos.
Pos. Pos.
Pos.
Pos.
Pos. Pos.
.444 ,451
not measurable
Q-T
Q-T not measurable
-__-
----
.528
,527
.439 .468 .-
316
AMERICAN
HEART
JOURNAL
RESULTS
A. Khdin: Six patients were tested with khellin (Table I). Only one patient (G.S.) reversed a previously positive anoxemia test after khellin, and this was unaccompanied by any subjective improvement. The other five patients either retained positive tests throughout or reverted to negative after the placebo period. No subjective benefit from khellin was evident in four of these five patients. However, one patient (S.G.) despite a persistent strongly positive anoxemia test exhibited striking and unmistakable subjective improvement following khellin administration. CASE l.-S.G.-This patient was a 52-year-old physician with progressive typical angina pectoris of 11 years’ duration and at least one previous myocardial infarction. Prior to admission the patient had required 30 to 40 nitroglycerin tablets a day in order to continue in his position in administrative medicine. Throughout the placebo period he had at least three angina1 attacks a day while on bedrest. If he attempted even minimal activity, the number of attacks would increase. After the second day on khellin, the angina decubitus disappeared, and the patient was able to engage in progressive activity with only rare attacks of very mild pain. Although mild nausea was a bothersome side effect, he was able to resume his job, requiring only three to four nitroglycerin tablets a week. He continued to do well during several months of follow-up on this regimen.
B . Heparin : Eleven patients were treated with heparin (Table II). There were no toxic symptoms and no bleeding manifestations in any of these patients. No consistent alteration of the serum cholesterol or cholesterol esters was demonstrated. No significant change in fasting serum turbidity or in the turbidity after a standard fatty meal could be shown in five patients tested before and after periods of heparin administration (Table IV). Only one patient (C.G.) showed striking clinical improvement, and this was accompanied by reversal of the anoxemia test after one week of heparin injections. CASE 2.-C.G.-This .56-year-old farmer with luetic aortic insufficiency and arteriosclerotic heart disease exhibited angina1 pain of severe degree but of only two months’ duration. Dramatic symptomatic improvement and reversal of a strongly positive anoxemia test followed one week of daily heparin injections. There had been no such subjective or objective improvement while he was receiving the placebo. At one- and two-month intervals after heparin was discontinued, this patient again showed positive anosemia tests, but reversal to negative occurred after the first week of a second trial of heparin. However, in spite of the continuance of daily heparin for three more weeks, the anoxemia test again became positive. Subjectively, the patient at no time demonstrated recurrence of symptoms after the first course of heparin.
Comment.-The degree of angina in this patient was out of proportion to the degree of cardiac enlargement and could not be attributed to cardiomegalq secondary to aortic insufficiency. Luetic ostial stenosis may indeed be a factor in this patient’s symptoms although his age, abnormal serum turbidity, and changes in the ocular fundi favor the additional diagnosis of arteriosclerotic heart disease. There are no reports on the favorable effect of heparin in either luetic aortic insufficiency or ostial stenosis. Since this patient represents the single, striking, favorable response to heparin, the consideration of the luetic Finally, even in this most favorable response heart disease deserves emphasis. to heparin, the anoxemia test reverted from negative to positive during the last three-week course on the drug.
KORY
ET
AL.:
KHELLIN,
HEPARIN,
PERITRATE
IN
ANGINA
317
PECTORIS
Improvement in the amplitude and form of the ballistocardiogram occurred in only one patient (C.L.G.). This patient showed neither symptomatic improvement nor change in the anoxemia test. In none of the five patients tested was the course of heparin associated with any significant decrease in either fasting or postprandial serum turbidity (Table IV). TABLE
IV.
SERUMTURBIDITY
BEFOREANDAFTERAFATTY
SERUM
TURBIDITY
MEAL
IN UNITS
OF OPTICAL
DENSITY*
THERAPY
PATIENT
S-HOUR LEVEL
~-HOUR LEVEL
FASTING ___-
IVERAGEOFAAND S-HOUR LEVELS
--__
J.C.B. C.G. W.M. J.R. W.R.
Placebo After 1 week
heparin
60 5.5
105 110
245 230
30 46
148 180
lzl
150
242.5 225
Placebo After 2 weeks
heparin
Saline After 2 weeks
heparin
210 150
275 300
Saline After 2 weeks
heparin
100 100
;Y
Saline After 2 weeks
heparin
*Normal values Normalvaluesfor
serum turbidity: of3and B-hour
100
104 120
60 25 to 45 units values range from
170 119.5
56
for fasting average
175
36to
95.5 95 108
119 unitszl
C. Peritrate: Of the six patients tested with Peritrate (Table III), there were no anoxemia test reversals, but a striking reduction in the number and severity of angina1 attacks occurred in two patients. CASE 3.-W.R.-This 56-year-old retired given at home prior to admission or to heparin patient had been bedridden for many weeks, up and about with only infrequent episodes of many months on this regimen. The anoxemia but two subsequent tests were strongly positive
railroad engineer had failed to respond to khellin given in the hospital as a part of this study. This but after two days on Peritrate he was able to be mild precordial pain. He continued to do well for test was not carried out on this patient initially, despite the symptomatic improvement.
CASE 4.-J.R.-This 46-year-old laborer had been bedridden for two months during which time he showed no improvement whatsoever on daily heparin. He also failed to improve with 30 mg. of Peritrate daily, but on 60 and 90 mg. a day his angina1 attacks became fewer and milder and permitted ambulation. The anoxemia test, however, remained strongly positive throughout.
Two patients (W.M. and C.Mc.) gave classical histories for true angina pectoris together with positive anoxemia tests and abnormal ballistocardiograms but became completely free of angina1 attacks during the hospital stay prior to the beginning of the study. Neither patient had any pain during either the placebo or the Peritrate trial but both retained positive Levy tests throughout. The remaining two patients (A.S. and J.M.) showed no improvement of any kind with Peritrate.
318
AMERICAN
HEART
JOURNAL
DISCUSSION
A. KheZZin.-The use of khellin in the treatment of angina pectoris has been the subject of numerous studies4-I9 with results varying from those reporting 80 and 90 per cent improvement 4- 6~17to those suggesting that it was no better than a placebo. 8 The six cases here reported indicate that khellin is not routinely effective in the treatment of angina pectoris. The actual percentage of favorable response in this small series is lower than most other reports. However, the dramatic and sustained improvement of patient S.G. on khellin therapy cannot be disputed by statistical data. Even more impressive was the response of Case 14 of Rosenman and co-workers ‘j; he repeatedly improved on khellin and relapsed on placebos. It would thus appear that khellin is an effective therapeutic agent in a limited but definite percentage of patients with angina pectoris, but the relatively high incidence of unpleasant side effects restricts its general usefulness. B. He@%-In only three of the eleven patients was there any subjective improvement whatsoever and in only one of these was this improvement striking and accompanied by reversal of the anoxemia test. This objective improvement, however, was not sustained despite continued heparin therapy. The results of this study support the view of several other workers30z31133-35 that sodium heparin is not a generally useful agent in the treatment of angina pectoris, at least in daily intraveneous 50 mg. doses. Certainly, these findings do not at all agree with the statement of Graham and co-workers2g that “ . . 5.5 of 59 patients with moderate or severe angina pectoris reported marked relief from this symptom with a drastic decrease in nitroglycerin requirement soon after the period of initiating heparin injections,” or the report of Engelberg3? that ‘I . . heparin reduced the incidence of angina1 attacks of 55 per cent of cases with severe coronary atherosclerosis.” The improvement in the ballistocardiogram in patient C.L.G. is probably of no significance since this has previously been found to occur on placebo medication alone.42 The failure of heparin to induce changes in serum turbidity after a standard fatty meal suggests that the abolition of alimentary lipemia by heparin is an acute effect and that chronic reduction of alimentary lipemia cannot be accomplished with heparin. C. Per&ate.-Only two of the six patients obtained subjective improvement, and none showed reversal of the previously positive anoxemia test. However, the degree and persistence of the subjective improvement obtained by. these two patients were impressive particularly since neither had shown any These response to a course of heparin given just prior to the trial with Peritrate. findings though small in number do lend support to those40s43 who have reported Peritrate effective in lessening the frequency of angina1 attacks in some patients. The data presented here in connection with all three drugs suggest that the reversal of a positive anoxemia test to negative is too rigid a test for general usefulness in evaluating the effectiveness of drugs in angina pectoris. The difficulty is that no drugs thus far studied have been able to reverse this test to negative in any appreciable number of patients.
KORY
ET
AL.
:
KHELLIN,
HEPARIN,
PERITRATE
IN
ANGINA
PECTORIS
319
Russek and his co-workers consider the electrocardiographic response to exercise quite valuable in drug evaluation.43 However, these investigators Certainly the found khellin completely ineffective as tested by these criteria. fact that ten separate groups of investigators in tests on 548 patients5-7sg,11-1Y have reported favorable responsesto khellin in 60 to 90 per cent of the patients would suggest that this drug does have some therapeutic effect in angina pectoris. two data and test,
In evaluating the therapeutic effectiveness of drugs in angina pectoris, principal methods have been advocated: (A) Statistical compilation of obtained by the “double blind” placebo method as described by Greiner his co-workers;* and (B) the use of objective tests such as the anoxemia exercise-electrocardiographic tests, and the ballistocardiogram.
Both methods are of value in assessingthe general usefulness of a particular therapeutic agent. However, if the drug in question is repeatedly alternated with a placebo in a single patient with improvement following use of the drug and relapse following substitution of the placebo, and if this improvement recurs over a period of months or years, no statistical compilation or objective test could negate the efficacy of such a drug in the particular patient. Since angina pectoris itself may vary greatly from patient to patient, it seemsquite plausible that a drug might be quite effective in a limited number of patients but when averaged over a whole series of patients may appear ineffective. It would seem, therefore, that certain drugs, though of little general usefulnessin angina pectoris, may be highly effective in an occasional patient.
SUMMARY
1. Three drugs, khellin, heparin, and pentaerythritol tetranitrate (Peritrate), have been investigated for therapeutic efficacy in angina pectoris. Subjective evaluation with a “daily record” was supplemented by objective evaluation by means of the anoxemia test. 2. Khellin though of definite therapeutic value in a limited number of patients with angina pectoris is not generally useful because of the high incidence of side reactions. 3.
Fifty milligrams of heparin daily produced subjective and objective in only one of eleven patients, and this benefit was not sustained. This drug appears virtually ineffective in angina pectoris. benefit
4. Peritrate provided impressive and sustained subjective improvement in two of six patients but failed to alter the anoxemia test in any way. 5. Although the general usefulness of therapeutic agents in angina pectoris can best be established by statistical compilation of “double-blind placebo” subjective data and by objective testing, the therapeutic value in an individual may be amply demonstrated by alternate long periods on drug and placebo with a favorable response following the drug and failure of response following the placebo.
320
AMERICAN
HEART
SUMMARIO
IN
JOURNAL
INTERLINGUA
Tres drogas-khellina, heparina, e Peritrato-esseva investigate in re lor efficacia therapeutic in angina de pectore. Evaluation subjective per medio de1 “notas clinic diurne” esseva supplementate per le method0 plus objective de1 “reaction a anoxemia.” Khellina esseva clarmente de valor in alicun patientes, sed a causa de1 alte frequentia de su effectos sccessori illo non pote esser considerate coma de valor general. Cinquanta milligrammas de intravenose heparina a natrium per die se monstrava practicamente inefficace in angina de pectore. Petritrato resultava in bon responsas secundo le evalutation subjective in duo inter sex patientes, sed illo non alterava le reaction a anoxemia. Ben que le melior method0 pro determinar le valor general de agentes therapeutic in angina de pectore consiste in le compilation statistic de datos subjective secundo le method0 (describite per Greiner e su associates) de “simulacros a duple camouflage” e in le execution de reactiones objective, le valor de un tal agente in un case individual es amplemente demonstrabile per lealternation de longe periodos a droga e a simulacro, si le prime es sequite per responsas favorabile e le secunde per le absentia de tal responsas. REFERENCES
1. 2. .z .
9. 10.
11. 12. 13. 14. 15. 16.
Roehm,
D. C., Kory, R. C., and Meneely, G. R.: Studies on an Electrocardiographic Manifestation of Hypoxemia, Am. J. Med. 13:904, 1952. Roehm, D. C., Kory, R. C., Mabe, R. E., Townes, A. S., and Meneely, G. R.: Duration of the Q-T Interval During the Anoxemia Test, AM. HEART J. 47:204, 1954. Samaan. K.: The Pharmacological Action of Khellin, Quart. I. Pharm. & Pharmacol. ._ 5~5, 1932. Anrep, G. V., Barsaum, G. S., Kenawy, M. R., and Misrahy, G.: Ammi Visnaga in the Treatment of the Angina1 Syndrome, Brit. Heart J. 8:171, 1946. Anrep, G. V., Kenawy, M. R., and Barsaum, G. S.: The Coronary Vasodilator Action of Khellin, AM. HEART J. 37531, 1949. Rosenman, R. H., Fishman, A. P., Kaplan, S. R., Levin, H. G., and Katz, L. N.: Observations on the Clinical Use of Visammin (Khellin), J.A.M.A. 143:160, 1950. Armbrust, C. A., Jr., and Levine, S. A.: The Treatment of Angina Pectoris With a Preparation of Khellin (Ammi Visnaga), Am. J. M. SC. 220:127, 1950. Greiner, T., Gold, H., Cattell, MC., Travell, J., Bakyst, H., Rinzler, S. H., Benjamin, Z. H., Warshaw, L. J., Bobb, A. L., Kwit, N. T., Modell, W., Rothendler, H. H., Messeloff, A Method for the Evaluation of the Effects of Drugs C. R., and Kramer, M. L.: on Cardiac Pain in Patients With Angina of Effort. A Study of Khellin (Visammin), Am. J. Med. 9:143, 1950. Effect of Khellin on Coronary Artery Insufficiency as EvalBest, M. M., and Coe, W. S.: uated by Electrocardiographic Tests, Circulation 2:344, 1950. Scott, R. C., Iglauer, A., Green, R. S., Kaufman, J. W., Berman, B., and McGuire, J.: Studies on the Effect of Oral and Parenteral Administration of Visammin (Khellin) in Patients With Angina Pectoris, Circulation 3:80, 1951. Hultgren, H. N., Robertson, H. S., and Stevens, L. E.: Clinical and Experimental Study of Use of Khellin in Treatment of Angina Pectoris, J.A.M.A. 148:465, 19.52. Scott, R. C., and Seiwert, V. J.: The Treatment of Angina Pectoris With Pure Crystalline Khellin, Ann. Int. Med. 36:1190, 1952. Kleiber, E. E.: Parenteral Administration of Ammivin (Khellin) in the Treatment of Coronary Disease, Ann. Int. Med. 36:1179, 1952. Corm, J. J., Kissane, R. W., Koons, R. A., and Clark, T. E.: The Treatment of Angina Pectoris With Khellin, Ann. Int. Med. 36:1173, 1952. Conn, J. J., Kissane, R. W., Koons, R. .A., and Clark, T. E.: The Treatment of Angina Pectoris With Khellin, Ann. Int. Med. 38:23, 1953. Button, W. H., Jr., and Foote, C. C.: Evaluation of the Effects of Khellin on the Human Electrocardiogram, Am. J. M. SC. 223:663, 19.52.
KORY
17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 3.5. 36. 37. 38. 39. ‘IO. 41. 42. 43. 44. 45.
46.
ET
AL.:
KHELLIN,
HEPARIN,
PERITRATE
IN
ANGINA
PECTORIS
321
The Use of Crystallin Visammin in the L. A., Rudy, W. B., and Gilbert, N. C.: Treatment of Angina Pectoris, Circulation 5:851, 1952. Best, M. M.: Management of Khellin Toxicity; Effects of Dosage and Purification, Am. J. M. SC. 224:308, 1952. Hejtmancik, M. R., Futch, E. D., and Herrmann, G. R.: Clinical Effects of Khelltron in Angina Pectoris, Texas J. Med. 49:679, 1953. Hahn, P. F.: Abolishment of Alimentary Lipemia Following Injections of Heparin, Science 98:19, 1943. Weld, C. B.: Alimentary Lipemia and Heparin, Canad. M. A. J. 51:578, 1944. Anderson. N. G.. and Fawcett. B.: An Antichvlomicronemic Substance Produced b\ Heparin Injections, Proc. Sot. Exper. Biol. & Med. 74:768, 1950. Anfinsen, C. B:, Boyle, E., and Brown, R. K.: The Role of Heparin in Lipoprotein Metabolism, Scrence 115:583, 1952. Block, W. J., Jr., Barker, N. W., and Mann, F. D.: Effect of Small Doses of Heparin iu Increasing the Translucence of Plasma During Alimentary Lipemia. Studies in Normal Individuals and Patients With Atherosclerosis, Circulation 4:674, 1951. Utz, J. P., Mann, F. D., and Barker, N. W.: Clearing of Lipemic Plasma by Heparin. Duration of Effect and Other Studies, Proc. Staff Meet., Mayo Clin. 28:531, 1953. Gofman, J. W., Lindgren, F. T., Elliott, H., Mantz, W., Hewitt, J., Strisower, B., Herring, V.. and Lvon. T. P.: The Role of Lipids and Lioooroteins in Atherosclerosis. Science . I lli:166, i95h. Gofman, J. W., Jones, H. B., Lindgren, F. T., Lyon, T. P., Elliott, H. A., and Strisower, B.: Blood Lipids and Human Atherosclerosis, Circulation 2:161, 1950. Gofman, J. W., Lindgren, F. T., Jones, H. B., Lyon, T. P., and Strisower, B.: Lipoproteins and Atherosclerosis. I. Gerontol. 6:lOS. 1951. Graham, D. M., Lyon, T: P, Gofman, J. W.; Jones, H. B:, Yankley, A., Simonton, J., and White, S.: Blood Lrplds and Human Atherosclerosrs. II. The Influence of Heparin Upon Lipoprotein Metabolism, Circulation 4:666, 1951. Rinzler, S. H., Travell, J., Bakyst, H., Benjamin, 2. H., Rosenthal, R. L., Rosenfeld, D., and Hrrsch, B. B.: Effect of Heparin in Effort Angina, Am. J. Med. 14:438, 1953. Russek, H. I., Urbach, K. F., and Doerner, A. A.: Effect of Heparin in Cases of Coronary Insufficiency. Evaluation by Electrocardiographic Tests, J.A.M.A. 149:1008, 1952. Engelberg, H.: Heparin Therapy of Severe Coronary Atherosclerosis With Observations of Its Effect on Angina Pectoris, the Two-Step Electrocardiogram and the Ballistocardiogram, Am. J. M. SC. 224:487, 1952. Binder, M. J., Kalmanson, G. M., Dremck, E. J., and Rosove, L.: Clinical Evaluation of Heparin in the Treatment of Angina Pectoris, J.A.M.A. 151:967, 1953. Gruner, A., Hilden, T., Raaschou, F., and Vogelius, H.: Heparin Treatment of Angina Pectoris, Am. J. Med. 14:433, 1953. Port, M., Katz, A., Hellman, E., and Enselberg, C. D.: The Heparin Treatment of Angina Pectoris, AM. HEART J. 45:769, 1953. Von Oettingen, W. F., Donahue, D. D., Lawton, A. H., Monaco, A. R., Yagoda, H.! and Valaer, P. J.: Toxicity and Potential Dangers of Penta-Erythritol-Tetramtrate (PETN). Fed. Sec. Agency, U. S. Public Health Service Bulletin No. 282, 1944. Balatre, P., Merlen, J. F., and Grandjean, L.: Les Esters Nitres des Polyalcools en Therapeutique Cardiovasculaire, Presse m&d. 57:1067, 1949. Dailheu-Geoffroy, P.: Action Comparee de la Pentanitrine et des autres Vaso-Dilatateurs Coronariens dans L’Angine de Poitrine, from an extract of the l’ouest-Medical, 3:37, 1950. Marche, J.: Le Traitement des Coronarites Chroniques par les Esters Mitres des Polyalcools, Fiches Medicales 144:1, 1950. Winsor, T., and Humphreys, P.: Influence of Pentaerythritol Tetranitrate (Peritrate) on Acute and Chronic Coronary Insufficiency, Angiology 3:1, 1952. Perlman, A.: A Study of the Therapeutic Action and Toxicity of Pentaerythritol Tetranitrate, Angiology 3:16, 1952. Talley, R. W., Beard, 0. W., and Doherty, J. E.: Use of Pentaerythritol Tetranitrate (Peritrate) in Treatment of Angina Pectoris, AM. HEART J. 44:866, 1952. Russek, H. I., Urbach, K. F., Doerner, A. A., and Zohman, B. L.: Choice of a Coronary Vasodilator Drug in Clinical Practice. Evaluation of Effects by Electrocardiographic Tests, J.A.M.A. 153:207, 1953. Patterson, J. E., Clark, T. W., and Levy, R. L.: A Comparison of Electrocardiographic Changes Observed During the “Anoxemia Test” on Normal Persons and on Patients With Coronary Sclerosis, AM. HEART J. 23:837, 1942. Brown., H. R., Jr., Hoffman, M. J., and de Lalla, V., Jr.: Ballistocardiographic Findings m Patients With Symptoms of Angina Pectoris, Circulation 1:132, 1950. Gilbert, N. C., and Nalefski, L. A.: The Effect of Heparin and Dicumarol in Increasing Coronary Flow Volume, J. Lab. & Clin. Med. 34:797, 1949. Nalefski,
Ross C.
EVALUATION
IN ANGINA PECTORIS: HEPARIN, PERITRATE
KHELLIN,
M.D.,* ALEXANDER S. TOWNES, M.D., ROBERT EVA R. DORRIS, B.S.,* AND GEORGE R. MENEELY,
KORY,
NASHVILLE,
E. MABE, M.D.
M.D.,**
TENN.
T
HE present study is a subjective and an objective evaluation of three agents, khellin, sodium heparin, and pentaerythritol tetranitrate (Peritrate) as therapeutic agents in patients with angina pectoris. For the past several years the Levy anoxemia test has been employed in this laboratory both as a diagThe nostic aid and in connection with an investigation of the Q-T interval.‘J anoxemia test is both highly reproducible and objective. Any drug which brings about both subjective improvement and reversal of a previously positive test should be considered as an effective therapeutic agent in anginapectoris. Khellin (5, 8-dimethoxy-2-methyl-6, ‘I-furanochromone), one of the substances isolated from the plant, Ammi visnaga, has been found to be a smooth muscle relaxant3 and a coronary artery dilator.4-1” Heparin was found to affect serum lipids in early studies20-25and later was reported by Gofman and his co-workers to induce a return toward normal of abnormal serum lipoproteins?-“” and to effect clinical improvement in patients with angina pectoris.2g Several other investigators3n-35 have reassessed the clinical efficacy of sodium heparin in angina pectoris, but only one32could confirm Gofman’s results. Pentaerythritol tetranitrate (Peritrate) is a nitric acid ester of a tetrahydric alcohol, pentaerythritol, and pharmacologically is a slowly absorbed, long-acting nitrate.35-37 Clinical trial of this drug in patients with angina pectoris was reported first by French workers in 1950,3*J9 and later by Winsor and Humphreys*Q who reported ” satisfactory improvement in the precordial pain” in 78.4 per cent of 125 patients with angina pectoris. Perlman41 found Peritrate relatively nontoxic in clinical use, and only moderately effective in angina. Talley and his co-workers4? found Peritrate ineffective in fourteen patients, but Russek and associates43consider Peritrate “ . the most effective drug currently available for prolonged prophylactic therapy in angina pectoris.” From the Research Laboratory and Medical Service, Thayer Veterans and the Department of Medicine, Vanderbilt University School of Medicine, Received for publication Jan. 13. 1955. Veterans Administration Hospital, Wood, Wis *Present address: **Present address: Newell Hospital, Chattanooga. Term. 308
Administration Hospital, Nashville. Teoo.
P.M. 2 yr.
S.G. 11 yr.
coronary numerals
Key:
*All tThe index
-___T.N. 1 yr.
_--__
this
i
I-
ASHD, CS, NSR, eompensated, Class II-B
57
l-
8-25
s-1 1
7-25
---
6-21 7-8 7-18
_!I 4-30 5-18 6-1
3-8 3-24 4-7
were on limited ambulation except those “Q-T Anosemia Index” relates t.he initial correct,ed of 0.480 and above are considered abnormal. ASHD = arteriosclerotic heart disease: HCVD sclerosis; AI = aortic insufficiency: NSR = normal II and III refer to the functional capacity classification
patients
--
ASHD, CS, NSR, compensated, Class III-C; previous myocardial infarction
--
ASHD, CS, NSR, compensated, Class II-B, osteoarthritis of cervical and dorsal spine
ASHD, EH, CS, SR with PVC’S, compensated, Class II-B; previous myocardial infarction
52
52
--
l-9 l-25 2-6
HCVD, ASHD, EH, CS, NSR, compensated, Class II-B
W.T. 12 yr.
-___-G.S. 2 mo.
_-----
_~--
DATE
l-6 I-20 2-7
--
DIAGNOSIS
ASHD, CS, NSR, compensated, Class II-B; previous myocardial infarction
AGE
W.H. 5 yr.
AND DURATION OF ANGINAL SYMPTOMS
PATIENT
-
.-
= hypertensive sinus rhythm; and letters
increase
2 1
18
27 24 4
42 15 13
4 1
7
Q-T
1 1
Pos. Pos. Neg.
Neg. Neg. Neg.
Pos. Pos. Pos.
Pos. Neg. Neg.
I-
test.
Pos. Neg. Neg.
Pos. Pos. Pos.
I-
I-
I
I-
I
ANOXEMIA
anosemia
17 None
16
14
2
14
8
17
None None None
18 None None
21
11
the
---
15
11
12 13 7
28
18 16
42
i
7
during
--__
14 1 4
0 0
14
LYERAGE NO. NITRO/ GLYCERIN 1
ip
= luetic heart, disease; EH = enlarged with premature ventricular contractions. classification of the American Heart
in corrected
Moderate Moderate Moderate
Severe Moderate Very mild
Moderate Mild Moderate
Moderate Mild Very mild
Moderate Moderate Moderate
Mild Mild None
DEGREE OF SEVERITY
ATT.4CKS
I-
cardiovascular disease; LHD SR with PVC’s = Sinus rhythm I$ and (’ and D to the therapeut,ic
maximum
Initial study After 2 weeks on placebo After 2 weeks on khellin 50 mg.-t.i.d.
Initial study After 2 weeks on placebo After 2 weeks on khellii 50 mg.-t.i.d.
Initial study After 2 weeks on placebo After 2 weeks on khellin 50 mg.-t.i.d.
designated as “bedridden.” Q-T interval with the
Bedrest Bedrest Moderate
--Bedridden Bedridden Moderate
Moderate Moderate Moderate
Initial study After 2 weeks on placebo After 2 weeks on khellin 50 mg.- t.i.d.
Moderate Moderate Moderate
Initial study After 2 weeks on placebo After 2 weeks on khellin
ANGINAL
\V. NO. /WK.
OF STUDY
STATUS
RESULTS
THER.4PEUTIC
EHELLIN:
Initial study After 2 weeks on placebo After 2 weeks on khellin 50 mg.-t.i.d.
I.
Moderate Moderate Moderate
Moderate Moderate Moderate
ACTIVITY*
TAELE
Q-T
,487 ,461 ,482
,562 ,488
,499
,505 ,503 470
,526 ,481 .466
.549 492
,464
441 ,453 ,522
INDEXt
for CS = Roman Association.
Falues heart;
IA
TEST
Bedridden Moderate Moderate Moderate Moderate
7-10 6-24 7-7 7-15 7-23
__---
Bedridden
8-14
I
Bedridden
1 8-7
IMinimal but ambulatory Bedridden
Minimal
7-3
7-24 LSHD, HCVD, EH, CS, SR with PVC’S, compensated, Class III-D; previous myo- I 7-31 cardial infarction
Minimal Minimal
6-18 6-26
46
4SHD, HCVD, CS, NSR, compensated, Class III-C; previous myocardial infarction
J.R. 8 yr.
Moderate
8-29
UHD, CS, NSR, compensated Class II-C; previous myocardial infarction
Moderate
8-22
til
Moderate
5-26
L.H. 3 yr.
Moderate Moderate
ACTIVITY*
3-26 5-13
56
ASHD, EH, CS, NSR, compensated, Class II-C; previous myocardial infarction
I
DATE
W.R. 1% yr.
I
DIAGNOSIS
33
AGE
J.C.B. 3 yr.
PATIENT AND DURATION OF ANGINAL SYMPTOMS
TABLE
II.
After 2 weeks of IV heparin daily
After 1 week of IV heparin daily
After 1 week of saline placebo
Initial study
Initial study After 1 week of saline placebo After 1 week of IV heparin daily After 2 weeks of IV heparin daily
Initial study After 1 week of IV heparin After 2 weeks at home s Rx After 1 week of saline placebo After 1 week of IV heparin daily -Initial study After 1 week of saline placebo After 1 week of IV heparin daily After 2 weeks of IV heparin daily
THERAPEUTIC STATUS
SODIUM HEPARIN:
i-
Severe
3 11
---Moderate to severe
Severe
Severe
14 8
Severe
19
6
12
9
10
__-
15
__14
15
None 12
I-
Pos.
PO%
Pos.
Pos.
Pos.
Pos.
Pos. Pos.
(Recent myocardial
--
TEST
.494
,503
,482
,502 ,442
Q-T INDEX1
-’I
/
-
II-III II-III
IV
:: ’
III
i II-III
1 II-III
I
/ I
III
BCG GRADE1
’ -
1
I
III-11 Q-T not measurable III-IV Q-T not measurable III-IV (2-T not meas- 1 urable ~ III-IV Q-T not measurable
,486
,546
,506 ,505
infarction)
test not done
Pos.
Pos.
Pos.
Pos. Neg.
ST-T CRITERIA
ANOXEMIA
Anoxemia
6
7
None
10 None
PAIN (MIN.)
0
14
I
I I )- I-
0
i
Moderate
i
----Mild
7 3
__--Moderate Moderate 3
10
Moderate
7 10
10
Moderate Moderate
7
4
7
AVERAGE NO. NITRC GLYCRRIP TABLETS, WK.
10
Moderate Moderate
DEGREE OF SEVERITY
4
10
AV. NO /WK.
ATTACKS
OF STUDY
ANGINAL
RESULTS
C.L.G. 3 yr.
76
-63
-
64
A.S. 4 yr.
W.M. 4 yr.
53
C.G. 2 mo.
ASHD, EH, CS, SR with PVC’s, compensated Class II-C
ASHD, HCVD, EH, CS, NSR, compensated, Class II-C; previous myocardial infarction
ASHD, HCVD, EH, CS, NSR, compensated, Class III-D
---
LHD, ASHD, EH, AI, CS, SR with PVC’S, compensated, Class II-C
--
--
--
--
Minimal Moderate Moderate Moderate Moderate Moderate Moderate
8-22 8-29 94 11-7 11-14 11-21 1 l-28
Bedridden
9-16 9-25
Moderate Moderate
IO-23 lo-31
9-26 10-2 lo-17
Moderate
z2
--Moderate Moderate
_--Moderate Moderate
9-9
__Minimal but ambulatory Minimal but ambulatory Bedridden
9-2
Minimal
8-11
study
study
Initial study After 1 week of saline placebo After 1 week of IV heparin daily After 2 weeks of IV heparin daily
Initial study After 1 week of saline placebo After 2 weeks of IV heparin daily
After 2 weeks of IV heparin daily
After 1 week of IV heparin daily
After 1 week of saline placebo
Initial
After 1 week of saline placebo After 1 week of IV heparin daily After 2 weeks of IV heparin daily Repeat study after 2 mo.s Rx After 1 week of IV heparin daily After 2 weeks of IV heparin daily After 3 weeks of IV heparin daily
Initial
Severe
7
Mild
Mild
7 7
Mid Mild ::
0
Pos. Pos.
None None
-__ Pos. Pos.
Pos.
-
i
Pos.
Pos.
Pos.
Pos.
Pos.
Neg.
-.
---
,538
,506
,480 ,504
,527
.492 .480
Q-T
not measurable
not?Zasurable
not measurable
Q-T
not measurable
Q-T
,525
,533
,446
,487
Pos. Neg.
.477
Neg.
,462
,550
Pos. Neg.
,530
Pos.
Pos. Pos.
15 None
5
5
5
5
None
0 _-
None
None
0
0
None
None
0 0
None
None
None
8
15
18
__-Moderate -
Severe
Severe
7
12
__-Severe
-
Moderate to severe Moderate to severe Mild to moderate -
4
0
0
0
0
0
8
15
14
_-
III
III III
III
III
A.I.5
A.1.B
A.1.Q
A.1.I
A.1.S
AI.%
2
3
P
z z $ 2
F ”
t:
3 2
and
Key
.I-
ASHD, CS, XSR, compensated, Class II-C
I.
I.
Table
TGrading of hallistocardiograms IV representing progressive $Aortic insufficit?nc$ imparts
I
Moderate Moderate i Moderate
3-3 1 4-7 4-14 I
Moderate
Moderate
12-5 I-
Moderate
11-29
3324
Moderate Moderate
I-
Moderate
lo-27 11-13 11-21
Moderate Moderate
-l- --~-~
inspect.ion
to the
of Brown
4
14 18
/WK.
ballistocardiogram
method
After 1 week of saline placebo After 1 week of IV heparin daily After 2 weeks of IV heparin daily
Initial study After 1 week of saline placebo After 10 days of IV heparin -___-__ Initial study After 1 week of saline placebo After 1 week of IV heparin daily After 2 weeks of IV heparin daily -----Initial study
(CONT'D) AVERAGE
and
which
with is deceptive
associates’”
the and
precludes
designation
10
5
16 16
15
14
16
16
Moderate __--Moderate to severe Moderate to severe Moderate to severe Moderate to severe
l;one
Moderate
Sane
10 Kane
PAIN (MIN.)
None 20
10
TABLETS/ I WK.
1k-0. NITRO ; IGLYCERD
Moderate Moderate
I--__-
Mild
Mild Mild
SEVERITY
I ANGINALATTACKS -- --__.I ‘TLV. NO. DEGREE OF
RESULTSOF~TUDY
THERAPEUTIC STATUS
SODIUMHEPARIN:
amplitude
ACTIVITY*
10-3 lo-16
DATE
II.
was done by t,he qualitative grades of ahnormality. normal appearing form and
CS, NSR, compensated, Class II-C; previous myocardial infarction
I-ASHD,
__~ I- ---__ ASHD, EH, CS, incomplete AV block, compensated, Class II-C
I-
see Table I. Table
58
AGE
*See footnote*, t&e footnotet,
For
C.Y. 5 yr.
R.G. 8 mo.
D.B.
PATIENT AND DURATIOX OFANGINAL SYMPTOMS -
TABLE
’
proper
grading.
I, II,
III
,486
and
III
II-III
III
III
III
III III
III
III III
III.
-
BCG :RADE$
,514
,484
,537
,471
,465
,536 526
,443
,512 ,487
Q-T
INDEXi
-----
0 as normal
Pos.
Pos.
Pos.
Pos.
Pos.
Pos.
Pos. Pos.
xeg.
:Borderli (me Neg.
ST-T CRITERI A
ANOXEMIATEST
z~
2
F =: 5 2 z 3 > z
i r
KORY
ET
AL.:
KHELLIN,
HEPARIN,
PERITRATE
IN
ANGINA
I’ECTORIS
313
MATERIAL
Eighteen male cardiac patients were selected from the wards of Thayier Veterans Administration Hospital. Each patient gave a typical clinical history of moderate to severe angina pectoris of from two months’ to twelve years’ duration. All of the patients had arteriosclerotic heart disease, six were hypertensive, and one patient in addition exhibited luetic aortic insufficiency. Ten patients gave histories of previous myocardial infarctions (Tables I, II, and 1 I I). All patients were hospitalized for the entire period of study. METHOD
OF
STUDY
The basic pattern of testing was the evaluation of the frequency and severity of angina1 attacks during control, placebo, and drug periods with anoxemia tests at the beginning and end of each period. Subjective evaluation was carried out in each patient by a daily record of each angina1 attack throughout the study period. This record included the time of onset, activity preceding the episode, type, location, and duration of the pain, and the number of nitroglycerin tablets taken for relief. Daily checks were made with each patient to assure the accuracy of these records. The anoxemia test was performed with the patient breathing a mixture of 10 per cent oxygen in nitrogen for a period of twenty minutes unless the electrocardiogram showed positive ST-T changes44 or angina1 pain occurred, in which case the test was terminated by the administration of 100 per cent oxygen. The technique and criteria for a positive test including the “Q-T Anoxemia Index” have been previously described.? Ballistocardiograms were graded qualitatively according to the criteria of Brown and associates.45 Initial ballistocardiograms were abnormal in all patients. In the khellin study (Table I) the initial anoxemia test was followed by a two-week period on an identically appearing oral placebo which in turn was followed by a second anoxemia test. Then after two weeks on 50 mg. khellin three times daily, a third anoxemia test was done. For the heparin study (Table II) the initial anoxemia test was followed by daily intravenous injections of 5 ml. of normal saline as a placebo for one week followed by a second anoxemia test. The patients were then given daily intravenous injections of 50 mg. of sodium heparin for 10 to 21 days with weekly anoxemia tests during this period. This change in medication was unknown both to the patient and to the nurses, and the placebo was entirely similar to the heparin in appearance. Anoxemia tests were performed between eighteen and twenty-four hours after the injections of heparin in order to eliminate the possibility cf acute effect of the drug.47 Serum cholesterol and cholesterol Serum turbidity esters were determined once or twice weekly during the study. was measured in five subjects before and after a standard fatty meal using direct readings of the Klett-Summerson photoelectric colorimeter21 before and after the period of heparin administration. The test was carried out eighteen hours after the last injection of heparin in order to preclude any acute effect. Pentaerythritol tetranitrate was employed in dosages of 30 to 90 mg. daily in three divided doses (Table III).
- -.
--_--
ASHD, HCS’D, CS, NSR, compensated, Class III-C; previous myocardial infarction
ASHD, HCVD, EH, CS, SR with PVC’s, compensated, Class III-D previous myocardial infarction
56
46
W.R. 1% v.
J.R. 8 yr.
--
DIAGNOSIS
AGE
PATIENT AND DURATION OF ANGINA L SYMPTOMS --
__--
-
III.
Moderate
Bedridden Bedridden Moderate Moderate
8-27
8-14 5-21 l&3 l&8
8-8
8-13
--
ACTIVITY*
I-
After 2 weeks on ziate, 20 mg. . . --____After 2 weeks on IV heparin daily After 1 week on Peritrate, 10 mg. t. i. d. After 5 weeks on p$ate, 20 mg. . . . After 5 days on pT;ate, 30 mg.
Initial evaluation After 5 days on Eeiripte, 10 mg.
THERAPEUTIC STATUS
__-
Moderate i I Moderate
4 4
.-
Severe
14
Severe
Mild
14
8
Mild
70 14
II Moderate
DEGREE OF SEVERITY
.-
63 18
AVERAGE NO. NITROGLYCERIN TABLETS/ WK.
RESULTSOFSTUDY
ANGINALATTACKS
AV. NO. /WK.
PEXTAERYTHRITOLTETRANITRATE(PERITRATE):
Bedridden Moderate
---
DATE
TABLE
= -
--
ANOXEMIA
TEST
Q-T INDEXt
_.-~
6
Pos.
,515
--
-63&iii-
,506
--
Pos.
Pos.
-
12
6
I Anodemia test not done 8 ,515
(MIN.)
PAIN
-.-
;
:I
1 -
! 1
II
IV
IV IV
BCG GRADE;
ASHD, HCVD, EH, CS, NSR, compensated, Class III-D
ASHD, HCVD, CS, NSR, compensated, Class II-C
ASHD, HCVD, EH, CS, NSR, compensated, Class II-C; previous myocardial infarction
ASHD, HCVD, CS, NSR, compensated, Class II-C; previous myocardial infarction
For Key see Table I. *See footnote*, Table I. tSee footnote?, Table I. JYee footnotef, Table II.
64
64
J.M. 3 yr.
-.
76
W.M. 4 Yi-.
A.S. 4 yr.
56
C.M. 4 yr.
Bedridden Bedridden
11-18 12-3
Moderate Moderate
Moderate
10-3
9-30 IO-9
Moderate
9-26
Moderate Moderate
-_
-_
-
After 2 weeks on feiri:ate, 20 mg. . .
After 2 weeks on IV heparin daily
Initial study After 1 week on Peritrate, 20 mg. t. i. d.
After 2 weeks on IV heparin daily After 1 week on Peritrate 10 mg. t. i. d.
Initial study After 2 weeks on Peritrate, 20 mg. t. i. d.
24
12
0
0
0 0
Severe
--Severe
Moderate Moderate -~
None
0
28
3
7 7
15
4 8
0
0 0
---
Pos.
Pos.
Pos. Pos.
Pos.
Pos.
Pos. Pos.
.444 ,451
not measurable
Q-T
Q-T not measurable
-__-
----
.528
,527
.439 .468 .-
316
AMERICAN
HEART
JOURNAL
RESULTS
A. Khdin: Six patients were tested with khellin (Table I). Only one patient (G.S.) reversed a previously positive anoxemia test after khellin, and this was unaccompanied by any subjective improvement. The other five patients either retained positive tests throughout or reverted to negative after the placebo period. No subjective benefit from khellin was evident in four of these five patients. However, one patient (S.G.) despite a persistent strongly positive anoxemia test exhibited striking and unmistakable subjective improvement following khellin administration. CASE l.-S.G.-This patient was a 52-year-old physician with progressive typical angina pectoris of 11 years’ duration and at least one previous myocardial infarction. Prior to admission the patient had required 30 to 40 nitroglycerin tablets a day in order to continue in his position in administrative medicine. Throughout the placebo period he had at least three angina1 attacks a day while on bedrest. If he attempted even minimal activity, the number of attacks would increase. After the second day on khellin, the angina decubitus disappeared, and the patient was able to engage in progressive activity with only rare attacks of very mild pain. Although mild nausea was a bothersome side effect, he was able to resume his job, requiring only three to four nitroglycerin tablets a week. He continued to do well during several months of follow-up on this regimen.
B . Heparin : Eleven patients were treated with heparin (Table II). There were no toxic symptoms and no bleeding manifestations in any of these patients. No consistent alteration of the serum cholesterol or cholesterol esters was demonstrated. No significant change in fasting serum turbidity or in the turbidity after a standard fatty meal could be shown in five patients tested before and after periods of heparin administration (Table IV). Only one patient (C.G.) showed striking clinical improvement, and this was accompanied by reversal of the anoxemia test after one week of heparin injections. CASE 2.-C.G.-This .56-year-old farmer with luetic aortic insufficiency and arteriosclerotic heart disease exhibited angina1 pain of severe degree but of only two months’ duration. Dramatic symptomatic improvement and reversal of a strongly positive anoxemia test followed one week of daily heparin injections. There had been no such subjective or objective improvement while he was receiving the placebo. At one- and two-month intervals after heparin was discontinued, this patient again showed positive anosemia tests, but reversal to negative occurred after the first week of a second trial of heparin. However, in spite of the continuance of daily heparin for three more weeks, the anoxemia test again became positive. Subjectively, the patient at no time demonstrated recurrence of symptoms after the first course of heparin.
Comment.-The degree of angina in this patient was out of proportion to the degree of cardiac enlargement and could not be attributed to cardiomegalq secondary to aortic insufficiency. Luetic ostial stenosis may indeed be a factor in this patient’s symptoms although his age, abnormal serum turbidity, and changes in the ocular fundi favor the additional diagnosis of arteriosclerotic heart disease. There are no reports on the favorable effect of heparin in either luetic aortic insufficiency or ostial stenosis. Since this patient represents the single, striking, favorable response to heparin, the consideration of the luetic Finally, even in this most favorable response heart disease deserves emphasis. to heparin, the anoxemia test reverted from negative to positive during the last three-week course on the drug.
KORY
ET
AL.:
KHELLIN,
HEPARIN,
PERITRATE
IN
ANGINA
317
PECTORIS
Improvement in the amplitude and form of the ballistocardiogram occurred in only one patient (C.L.G.). This patient showed neither symptomatic improvement nor change in the anoxemia test. In none of the five patients tested was the course of heparin associated with any significant decrease in either fasting or postprandial serum turbidity (Table IV). TABLE
IV.
SERUMTURBIDITY
BEFOREANDAFTERAFATTY
SERUM
TURBIDITY
MEAL
IN UNITS
OF OPTICAL
DENSITY*
THERAPY
PATIENT
S-HOUR LEVEL
~-HOUR LEVEL
FASTING ___-
IVERAGEOFAAND S-HOUR LEVELS
--__
J.C.B. C.G. W.M. J.R. W.R.
Placebo After 1 week
heparin
60 5.5
105 110
245 230
30 46
148 180
lzl
150
242.5 225
Placebo After 2 weeks
heparin
Saline After 2 weeks
heparin
210 150
275 300
Saline After 2 weeks
heparin
100 100
;Y
Saline After 2 weeks
heparin
*Normal values Normalvaluesfor
serum turbidity: of3and B-hour
100
104 120
60 25 to 45 units values range from
170 119.5
56
for fasting average
175
36to
95.5 95 108
119 unitszl
C. Peritrate: Of the six patients tested with Peritrate (Table III), there were no anoxemia test reversals, but a striking reduction in the number and severity of angina1 attacks occurred in two patients. CASE 3.-W.R.-This 56-year-old retired given at home prior to admission or to heparin patient had been bedridden for many weeks, up and about with only infrequent episodes of many months on this regimen. The anoxemia but two subsequent tests were strongly positive
railroad engineer had failed to respond to khellin given in the hospital as a part of this study. This but after two days on Peritrate he was able to be mild precordial pain. He continued to do well for test was not carried out on this patient initially, despite the symptomatic improvement.
CASE 4.-J.R.-This 46-year-old laborer had been bedridden for two months during which time he showed no improvement whatsoever on daily heparin. He also failed to improve with 30 mg. of Peritrate daily, but on 60 and 90 mg. a day his angina1 attacks became fewer and milder and permitted ambulation. The anoxemia test, however, remained strongly positive throughout.
Two patients (W.M. and C.Mc.) gave classical histories for true angina pectoris together with positive anoxemia tests and abnormal ballistocardiograms but became completely free of angina1 attacks during the hospital stay prior to the beginning of the study. Neither patient had any pain during either the placebo or the Peritrate trial but both retained positive Levy tests throughout. The remaining two patients (A.S. and J.M.) showed no improvement of any kind with Peritrate.
318
AMERICAN
HEART
JOURNAL
DISCUSSION
A. KheZZin.-The use of khellin in the treatment of angina pectoris has been the subject of numerous studies4-I9 with results varying from those reporting 80 and 90 per cent improvement 4- 6~17to those suggesting that it was no better than a placebo. 8 The six cases here reported indicate that khellin is not routinely effective in the treatment of angina pectoris. The actual percentage of favorable response in this small series is lower than most other reports. However, the dramatic and sustained improvement of patient S.G. on khellin therapy cannot be disputed by statistical data. Even more impressive was the response of Case 14 of Rosenman and co-workers ‘j; he repeatedly improved on khellin and relapsed on placebos. It would thus appear that khellin is an effective therapeutic agent in a limited but definite percentage of patients with angina pectoris, but the relatively high incidence of unpleasant side effects restricts its general usefulness. B. He@%-In only three of the eleven patients was there any subjective improvement whatsoever and in only one of these was this improvement striking and accompanied by reversal of the anoxemia test. This objective improvement, however, was not sustained despite continued heparin therapy. The results of this study support the view of several other workers30z31133-35 that sodium heparin is not a generally useful agent in the treatment of angina pectoris, at least in daily intraveneous 50 mg. doses. Certainly, these findings do not at all agree with the statement of Graham and co-workers2g that “ . . 5.5 of 59 patients with moderate or severe angina pectoris reported marked relief from this symptom with a drastic decrease in nitroglycerin requirement soon after the period of initiating heparin injections,” or the report of Engelberg3? that ‘I . . heparin reduced the incidence of angina1 attacks of 55 per cent of cases with severe coronary atherosclerosis.” The improvement in the ballistocardiogram in patient C.L.G. is probably of no significance since this has previously been found to occur on placebo medication alone.42 The failure of heparin to induce changes in serum turbidity after a standard fatty meal suggests that the abolition of alimentary lipemia by heparin is an acute effect and that chronic reduction of alimentary lipemia cannot be accomplished with heparin. C. Per&ate.-Only two of the six patients obtained subjective improvement, and none showed reversal of the previously positive anoxemia test. However, the degree and persistence of the subjective improvement obtained by. these two patients were impressive particularly since neither had shown any These response to a course of heparin given just prior to the trial with Peritrate. findings though small in number do lend support to those40s43 who have reported Peritrate effective in lessening the frequency of angina1 attacks in some patients. The data presented here in connection with all three drugs suggest that the reversal of a positive anoxemia test to negative is too rigid a test for general usefulness in evaluating the effectiveness of drugs in angina pectoris. The difficulty is that no drugs thus far studied have been able to reverse this test to negative in any appreciable number of patients.
KORY
ET
AL.
:
KHELLIN,
HEPARIN,
PERITRATE
IN
ANGINA
PECTORIS
319
Russek and his co-workers consider the electrocardiographic response to exercise quite valuable in drug evaluation.43 However, these investigators Certainly the found khellin completely ineffective as tested by these criteria. fact that ten separate groups of investigators in tests on 548 patients5-7sg,11-1Y have reported favorable responsesto khellin in 60 to 90 per cent of the patients would suggest that this drug does have some therapeutic effect in angina pectoris. two data and test,
In evaluating the therapeutic effectiveness of drugs in angina pectoris, principal methods have been advocated: (A) Statistical compilation of obtained by the “double blind” placebo method as described by Greiner his co-workers;* and (B) the use of objective tests such as the anoxemia exercise-electrocardiographic tests, and the ballistocardiogram.
Both methods are of value in assessingthe general usefulness of a particular therapeutic agent. However, if the drug in question is repeatedly alternated with a placebo in a single patient with improvement following use of the drug and relapse following substitution of the placebo, and if this improvement recurs over a period of months or years, no statistical compilation or objective test could negate the efficacy of such a drug in the particular patient. Since angina pectoris itself may vary greatly from patient to patient, it seemsquite plausible that a drug might be quite effective in a limited number of patients but when averaged over a whole series of patients may appear ineffective. It would seem, therefore, that certain drugs, though of little general usefulnessin angina pectoris, may be highly effective in an occasional patient.
SUMMARY
1. Three drugs, khellin, heparin, and pentaerythritol tetranitrate (Peritrate), have been investigated for therapeutic efficacy in angina pectoris. Subjective evaluation with a “daily record” was supplemented by objective evaluation by means of the anoxemia test. 2. Khellin though of definite therapeutic value in a limited number of patients with angina pectoris is not generally useful because of the high incidence of side reactions. 3.
Fifty milligrams of heparin daily produced subjective and objective in only one of eleven patients, and this benefit was not sustained. This drug appears virtually ineffective in angina pectoris. benefit
4. Peritrate provided impressive and sustained subjective improvement in two of six patients but failed to alter the anoxemia test in any way. 5. Although the general usefulness of therapeutic agents in angina pectoris can best be established by statistical compilation of “double-blind placebo” subjective data and by objective testing, the therapeutic value in an individual may be amply demonstrated by alternate long periods on drug and placebo with a favorable response following the drug and failure of response following the placebo.
320
AMERICAN
HEART
SUMMARIO
IN
JOURNAL
INTERLINGUA
Tres drogas-khellina, heparina, e Peritrato-esseva investigate in re lor efficacia therapeutic in angina de pectore. Evaluation subjective per medio de1 “notas clinic diurne” esseva supplementate per le method0 plus objective de1 “reaction a anoxemia.” Khellina esseva clarmente de valor in alicun patientes, sed a causa de1 alte frequentia de su effectos sccessori illo non pote esser considerate coma de valor general. Cinquanta milligrammas de intravenose heparina a natrium per die se monstrava practicamente inefficace in angina de pectore. Petritrato resultava in bon responsas secundo le evalutation subjective in duo inter sex patientes, sed illo non alterava le reaction a anoxemia. Ben que le melior method0 pro determinar le valor general de agentes therapeutic in angina de pectore consiste in le compilation statistic de datos subjective secundo le method0 (describite per Greiner e su associates) de “simulacros a duple camouflage” e in le execution de reactiones objective, le valor de un tal agente in un case individual es amplemente demonstrabile per lealternation de longe periodos a droga e a simulacro, si le prime es sequite per responsas favorabile e le secunde per le absentia de tal responsas. REFERENCES
1. 2. .z .
9. 10.
11. 12. 13. 14. 15. 16.
Roehm,
D. C., Kory, R. C., and Meneely, G. R.: Studies on an Electrocardiographic Manifestation of Hypoxemia, Am. J. Med. 13:904, 1952. Roehm, D. C., Kory, R. C., Mabe, R. E., Townes, A. S., and Meneely, G. R.: Duration of the Q-T Interval During the Anoxemia Test, AM. HEART J. 47:204, 1954. Samaan. K.: The Pharmacological Action of Khellin, Quart. I. Pharm. & Pharmacol. ._ 5~5, 1932. Anrep, G. V., Barsaum, G. S., Kenawy, M. R., and Misrahy, G.: Ammi Visnaga in the Treatment of the Angina1 Syndrome, Brit. Heart J. 8:171, 1946. Anrep, G. V., Kenawy, M. R., and Barsaum, G. S.: The Coronary Vasodilator Action of Khellin, AM. HEART J. 37531, 1949. Rosenman, R. H., Fishman, A. P., Kaplan, S. R., Levin, H. G., and Katz, L. N.: Observations on the Clinical Use of Visammin (Khellin), J.A.M.A. 143:160, 1950. Armbrust, C. A., Jr., and Levine, S. A.: The Treatment of Angina Pectoris With a Preparation of Khellin (Ammi Visnaga), Am. J. M. SC. 220:127, 1950. Greiner, T., Gold, H., Cattell, MC., Travell, J., Bakyst, H., Rinzler, S. H., Benjamin, Z. H., Warshaw, L. J., Bobb, A. L., Kwit, N. T., Modell, W., Rothendler, H. H., Messeloff, A Method for the Evaluation of the Effects of Drugs C. R., and Kramer, M. L.: on Cardiac Pain in Patients With Angina of Effort. A Study of Khellin (Visammin), Am. J. Med. 9:143, 1950. Effect of Khellin on Coronary Artery Insufficiency as EvalBest, M. M., and Coe, W. S.: uated by Electrocardiographic Tests, Circulation 2:344, 1950. Scott, R. C., Iglauer, A., Green, R. S., Kaufman, J. W., Berman, B., and McGuire, J.: Studies on the Effect of Oral and Parenteral Administration of Visammin (Khellin) in Patients With Angina Pectoris, Circulation 3:80, 1951. Hultgren, H. N., Robertson, H. S., and Stevens, L. E.: Clinical and Experimental Study of Use of Khellin in Treatment of Angina Pectoris, J.A.M.A. 148:465, 19.52. Scott, R. C., and Seiwert, V. J.: The Treatment of Angina Pectoris With Pure Crystalline Khellin, Ann. Int. Med. 36:1190, 1952. Kleiber, E. E.: Parenteral Administration of Ammivin (Khellin) in the Treatment of Coronary Disease, Ann. Int. Med. 36:1179, 1952. Corm, J. J., Kissane, R. W., Koons, R. A., and Clark, T. E.: The Treatment of Angina Pectoris With Khellin, Ann. Int. Med. 36:1173, 1952. Conn, J. J., Kissane, R. W., Koons, R. .A., and Clark, T. E.: The Treatment of Angina Pectoris With Khellin, Ann. Int. Med. 38:23, 1953. Button, W. H., Jr., and Foote, C. C.: Evaluation of the Effects of Khellin on the Human Electrocardiogram, Am. J. M. SC. 223:663, 19.52.
KORY
17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 3.5. 36. 37. 38. 39. ‘IO. 41. 42. 43. 44. 45.
46.
ET
AL.:
KHELLIN,
HEPARIN,
PERITRATE
IN
ANGINA
PECTORIS
321
The Use of Crystallin Visammin in the L. A., Rudy, W. B., and Gilbert, N. C.: Treatment of Angina Pectoris, Circulation 5:851, 1952. Best, M. M.: Management of Khellin Toxicity; Effects of Dosage and Purification, Am. J. M. SC. 224:308, 1952. Hejtmancik, M. R., Futch, E. D., and Herrmann, G. R.: Clinical Effects of Khelltron in Angina Pectoris, Texas J. Med. 49:679, 1953. Hahn, P. F.: Abolishment of Alimentary Lipemia Following Injections of Heparin, Science 98:19, 1943. Weld, C. B.: Alimentary Lipemia and Heparin, Canad. M. A. J. 51:578, 1944. Anderson. N. G.. and Fawcett. B.: An Antichvlomicronemic Substance Produced b\ Heparin Injections, Proc. Sot. Exper. Biol. & Med. 74:768, 1950. Anfinsen, C. B:, Boyle, E., and Brown, R. K.: The Role of Heparin in Lipoprotein Metabolism, Scrence 115:583, 1952. Block, W. J., Jr., Barker, N. W., and Mann, F. D.: Effect of Small Doses of Heparin iu Increasing the Translucence of Plasma During Alimentary Lipemia. Studies in Normal Individuals and Patients With Atherosclerosis, Circulation 4:674, 1951. Utz, J. P., Mann, F. D., and Barker, N. W.: Clearing of Lipemic Plasma by Heparin. Duration of Effect and Other Studies, Proc. Staff Meet., Mayo Clin. 28:531, 1953. Gofman, J. W., Lindgren, F. T., Elliott, H., Mantz, W., Hewitt, J., Strisower, B., Herring, V.. and Lvon. T. P.: The Role of Lipids and Lioooroteins in Atherosclerosis. Science . I lli:166, i95h. Gofman, J. W., Jones, H. B., Lindgren, F. T., Lyon, T. P., Elliott, H. A., and Strisower, B.: Blood Lipids and Human Atherosclerosis, Circulation 2:161, 1950. Gofman, J. W., Lindgren, F. T., Jones, H. B., Lyon, T. P., and Strisower, B.: Lipoproteins and Atherosclerosis. I. Gerontol. 6:lOS. 1951. Graham, D. M., Lyon, T: P, Gofman, J. W.; Jones, H. B:, Yankley, A., Simonton, J., and White, S.: Blood Lrplds and Human Atherosclerosrs. II. The Influence of Heparin Upon Lipoprotein Metabolism, Circulation 4:666, 1951. Rinzler, S. H., Travell, J., Bakyst, H., Benjamin, 2. H., Rosenthal, R. L., Rosenfeld, D., and Hrrsch, B. B.: Effect of Heparin in Effort Angina, Am. J. Med. 14:438, 1953. Russek, H. I., Urbach, K. F., and Doerner, A. A.: Effect of Heparin in Cases of Coronary Insufficiency. Evaluation by Electrocardiographic Tests, J.A.M.A. 149:1008, 1952. Engelberg, H.: Heparin Therapy of Severe Coronary Atherosclerosis With Observations of Its Effect on Angina Pectoris, the Two-Step Electrocardiogram and the Ballistocardiogram, Am. J. M. SC. 224:487, 1952. Binder, M. J., Kalmanson, G. M., Dremck, E. J., and Rosove, L.: Clinical Evaluation of Heparin in the Treatment of Angina Pectoris, J.A.M.A. 151:967, 1953. Gruner, A., Hilden, T., Raaschou, F., and Vogelius, H.: Heparin Treatment of Angina Pectoris, Am. J. Med. 14:433, 1953. Port, M., Katz, A., Hellman, E., and Enselberg, C. D.: The Heparin Treatment of Angina Pectoris, AM. HEART J. 45:769, 1953. Von Oettingen, W. F., Donahue, D. D., Lawton, A. H., Monaco, A. R., Yagoda, H.! and Valaer, P. J.: Toxicity and Potential Dangers of Penta-Erythritol-Tetramtrate (PETN). Fed. Sec. Agency, U. S. Public Health Service Bulletin No. 282, 1944. Balatre, P., Merlen, J. F., and Grandjean, L.: Les Esters Nitres des Polyalcools en Therapeutique Cardiovasculaire, Presse m&d. 57:1067, 1949. Dailheu-Geoffroy, P.: Action Comparee de la Pentanitrine et des autres Vaso-Dilatateurs Coronariens dans L’Angine de Poitrine, from an extract of the l’ouest-Medical, 3:37, 1950. Marche, J.: Le Traitement des Coronarites Chroniques par les Esters Mitres des Polyalcools, Fiches Medicales 144:1, 1950. Winsor, T., and Humphreys, P.: Influence of Pentaerythritol Tetranitrate (Peritrate) on Acute and Chronic Coronary Insufficiency, Angiology 3:1, 1952. Perlman, A.: A Study of the Therapeutic Action and Toxicity of Pentaerythritol Tetranitrate, Angiology 3:16, 1952. Talley, R. W., Beard, 0. W., and Doherty, J. E.: Use of Pentaerythritol Tetranitrate (Peritrate) in Treatment of Angina Pectoris, AM. HEART J. 44:866, 1952. Russek, H. I., Urbach, K. F., Doerner, A. A., and Zohman, B. L.: Choice of a Coronary Vasodilator Drug in Clinical Practice. Evaluation of Effects by Electrocardiographic Tests, J.A.M.A. 153:207, 1953. Patterson, J. E., Clark, T. W., and Levy, R. L.: A Comparison of Electrocardiographic Changes Observed During the “Anoxemia Test” on Normal Persons and on Patients With Coronary Sclerosis, AM. HEART J. 23:837, 1942. Brown., H. R., Jr., Hoffman, M. J., and de Lalla, V., Jr.: Ballistocardiographic Findings m Patients With Symptoms of Angina Pectoris, Circulation 1:132, 1950. Gilbert, N. C., and Nalefski, L. A.: The Effect of Heparin and Dicumarol in Increasing Coronary Flow Volume, J. Lab. & Clin. Med. 34:797, 1949. Nalefski,