tk - Frank Praetorius

frank.praetorius.gmxhome.de

tk - Frank Praetorius

1

Reprint

Editorial Board: F. Grosse-Brockhoff, Düsseldorf

· H. Krauss, Freiburg/Br. · R. H. Rosie,

Stuttgart · H. Köbcke, Munich

German Medical Monthly

Editor of the English Language Edition:

G. R. GRAHAM, LONDON

Board of Editorial Consultants: L. Heilmeyer

Ulm/Donau, Chairman

GEORG THIEME VERLAG – STUTTGART

Vol. XIII Stuttgart, March 1968 No. 3, page 111-116

The Thrombolytic Therapy of Recent Myocardial Infarction 1

Ill. Overall Assessment and Evaluation of Enzyme Studies

P. Körtge, F. Praetorius, B. Schneider, F. Heckner, J. van de Loo, F. A. Pezold,

H. Poliwoda, R. Schmutzler and D. Zekorn

From the First Medical Clinic (Director: Prof. H. Frh. v. Kress),

Free University, Berlin;

Institute of Biometry and Documentation (Director: Prof. B. Schneider),

College of Medicine, Hanover;

Division of Internal Medicine (Head: Prof. F. Heckner),

Zweckverband Hospital, Einbeck;

Medical Clinic and Policlinic (Director: Prof. E. Fritze),

Bergmannsheil Hospitals, Bochum;

Medical Clinic (Director: Prof. R. Gross),

University of Cologne;

Divisions of Internal Medicine and Infectious Diseases

(Director: Prof. F. A. Pezold), Behring City Hospital, Berlin;

Medical University Clinic (Former director: Prof. R. Schoen;

present director: Prof. W. Creutzfeldt), Gottingen;

Medical Clinic (Director: Prof. F. Hartmann),

College of Medicine, Hanover;

Medical University Clinic (Director: Prof. F. Koller),

Bürgerspital, Basle;

and the Medical-Scientific Research Division of Farbwerke Hoechst AG,

Frankfurt/Main-Hoechst

1 Translated from the Dtsch. med. Wschr. 92 (1967), 1546.


In earlier reports (18, 22) of this investigation

of the treatment of recent myocardial infarction

with streptokinase and anticoagulants, the

mortality, thromboembolic complications, risks of

haemorrhage and electrocardiographic findings

were compared in the two treatment groups. The

risks of treatment were equally small in the two

groups. The mortality rate (2nd-40th days) and the

electrocardiographic changes (ST-elevation, QRS

changes, T-wave inversion, formation of

rudimentary infarcts) were each significantly more

favourable in the group receiving thrombolytic

therapy. The timing of the commencement of

thrombolytic therapy within a twelve-hour period

after the onset of infarction was found to have no

definite effect on the parameters investigated.

The present report deals with the serum enzyme

findings in the two treatment groups.

Methods

1. Methods of enzyme estimation. Enzyme activity

was measured with reagent combinations produced by

Boehringer, Mannheim (12, 24). The serum levels of

glutamic-oxalacetic transaminase (GOT) and creatinine

phosphokinase (CPK) activity were measured. Other

enzymes such as GPT and LDH and its isoenzymes

were not estimated in every one of the participating

centres and were therefore excluded from this

assessment. Since the times of collection of the blood

samples reported in Part I sometimes entailed storage of

the samples for up to twelve hours before the tests were

performed, the interpretation of the curves of CPK

results is subject to some reservation.

The problem of the stability of CPK in vitro has

recently been re-emphasized (2, 6, 9, 20, 25). It should

be pointed out, however, that all groups investigated

(streptokinase early, late; anticoagulants alone) were

equally affected by this problem. Serum GOT, on the

other hand, only loses 4 % of its activity after 24 hours

(2, 6). The similarity of behaviour of the two enzyme

curves and the fact that any loss of CPK activity applied

equally to all groups justified the comparative

evaluation of the findings and tended to reduce doubts

about the absolute height of the CPK curves.

2

Tab. 1. Numbers, sex distribution and mean ages of

patients studied in Parts I - III of this report. a = all

patients (Part I), b = ECG studies (Part II), c = enzyme

studies (Part III). m = male; f = female

Streptokinase Anticoagulants alone

a 297 261

Number (n) b 134 100

c 94 24

Sex

Distribution:

a 235 (79.1 %) 215 (82.3 %)

m b 116 (86.5 %) 86 (86.0 %)

c 83 (88.3 %) 18 (75.0 %)

a 62 (20.9 %) 46 (17.7 %)

f b 18 (13.5 %) 14 (14.0 %)

c 11 (11.7 %) 6 (25.0 %)

Age of patients (years):

a 57.8 58.1

m + f b 58.0 60.8

c 57.8 62.0

a 56.9 57.2

m b 56.9 60.4

c 57.5 61.2 (51-77)

a 61.6 62.4

f b 61.9 62.9

c 61.4 64.2 (54-73)

2. Choice of patients. Table I lists the patients

studied in Parts I-III of this investigation according to

method of treatment, study group, sex and age. In the

group of patients treated with anticoagulants alone there

were only 24 with sufficiently detailed enzyme studies.

The group was thus too small as an adequate control

group for comparison with the streptokinase-treated

group. Our interpretation was therefore confined to a

comparison of enzyme activity in relation to the time of

commencement of thrombolytic therapy between the

early group (within three hours of infarction) and the

late group (between three and twelve hours of

infarction).

For this purpose the course of enzyme activities in

94 patients treated with streptokinase was available. The

age and sex distribution of these 94 patients was similar

to those of other treatment groups. They comprised 54

3


patients whose treatment commenced within three hours

of infarction ("streptokinase early") and 40 patients

whose treatment commenced from three hours to within

twelve hours after infarction ("streptokinase late"). The

mean ages of the two groups were 57.5 and 59.1 years

respectively. The site of infarction did not affect the

enzyme studies (4, 17). Re-infarction was not

considered.

To qualify for admission to the study programme

patients had to have at least two sets of enzyme estimations

during the first 24 hours after infarction. The

reduction in the total numbers of patients to 94 was

mainly due to the fact that the majority of patients did

not meet this requirement. Moreover, patients with

"rudimentary" infarcts, which were considered as a

special group in Part II, were omitted in the present

evaluation on account of their small numbers. As the

selection of patients in these circumstances could not be

held to be biased in favour of good risk patients, the

publication of the results of enzyme studies appeared

justified. Considerations involved in the interpretation

of enzyme kinetics in myocardial infarction also

appeared to be of general interest.

Altogether 838 enzyme estimations were assessed

(GOT: 534; CPK: 304). In a pilot study of patients

treated with streptokinase (n = 36) at one of the participating

centres, the mean levels of enzyme activity at

various points of time were calculated and a curve was

constructed (16) by geometric means (19). This showed

a higher level of enzyme activity in the ascending

portion of the curve in the "streptokinase early"

treatment group. The differences were significant

during the third to fourth hours (CPK) and the fifth to

sixth hours (GOT). In order to define these differences

more precisely the total material from the six

participating centres was analysed with the aid of an

electronic calculator at the Institute of Biometry and

Statistics of the College of Medicine at Hanover; this,

amongst other things, permitted the accurate calculation

of means for the individual treatment groups without the

need to segregate single values into time class intervals.

3. Method of interpretation. The purpose of the

evaluation was to define measures of the height of

serum enzyme activity in relation to time after

myocardial infarction. These parameters were chosen to

describe the course of the curves adequately and at the

same time to permit comparison of the curves in various

treatment groups so that the effect of treatment could be

assessed.

A study of the course of experimental enzyme

curves showed that this resembled the mathematical

function

4

y = A ⋅

−k1

⋅t

−k2

⋅t

( e − e )

In this formula y represents enzyme activity, t the time

(after the onset of infarction), and A1, k1, and k2 are the

indices of size describing the form of the curve. Of

these indices k1 describes the descending limb of the

curve, k2 the ascending limb and A the height of the

peak of the curve.

On the assumption of a 3-compartment model for

myocardial infarction (4), k1 may be taken as the

"elimination rate" of the enzyme from the blood serum

which is regarded as the distribution, k2 as the "infusion

rate" of the enzyme from the site of infarction into the

blood serum, and A as a measure of the total enzyme

activity liberated and hence proportional to the size of

the infarcted area as a whole. It must be obvious that

this interpretation is based on a greatly simplified

hypothetical model which only reflects an approximate

outline of the major relationships. The model cannot

take into account the finer points of this complicated

biological process. Great discrimination must therefore

be exercised in any interpretation of the parameters.

Notwithstanding this reservation, the descriptive

significance of the parameters A, k1 and k2 may be used

to describe and compare the course of the various

curves. In this context their application and

interpretation can be subjected to exact statistical

criteria. An objective basis for comparison is thus

assured.

The mathematical and biometric bases of this model

will be the subject of a separate report (Schneider and

colleagues: in preparation).

The method of least squares was used for purposes

of calculation (statistical evaluation) of the parameters

A, k1 and k2 from the observed points on the curves;

according to this the curves are constructed in such a

way that the sum of the squares of the deviations

between the points measured and the points on the

curves are as small as possible.

For reasons stated earlier, interpretation could not be

applied to each patient individually. Patients were

therefore grouped according to types of treatment

received. The curves of the patients in the

"streptokinase early" group and of patients in the

"streptokinase late" group were compared by the

method of least squares. This proved difficult because

of the wide scatter of values within each group and the

lack of any tendency to form smooth curves. This was

regarded as being due to individual differences between

the enzyme concentration curves of individual patients.

The result of this was that the scatter of points actually

measured about the calculated curve varied between

166 and 299 %.

5


In the classification of various patients into

treatment groups, the calculated parameters no longer

have any individual biological significance. Rather, they

should be regarded as a sort of "mean value" reflecting

something like the enzyme concentration over the

course of time of a group as a whole. This explains why

the peaks of the curves are substantially below the

peaks of the levels found in individual patients.

On the other hand, it may be expected that the height

and form of the curves will characterize the behaviour

of the enzymes in the various treatment groups. The

statistical evaluation of our results rests on this

interpretation.

Results

The course of the curves of enzyme activity of

GOT and CPK is illustrated in Figs. 1-3. Both enzymes

showed distinct differences in the ascending

Fig. 1. Levels of enzyme activities of GOT and CPK

in patients receiving early and late treatment of recent

myocardial infarcts with streptokinase (SK).

6

Fig. 2. Serum GOT activity during the first 48 hours after

the onset of infarction in patients receiving streptokinase

(SK). The constant k. is a measure of the steepness of

the rise in serum enzyme activity.

Fig. 3. Serum CPK activity during the first 48 hours after

the onset of infarction in patients receiving streptokinase

(SK). The constant k,, is a measure of the steepness of

the rise in serum enzyme activity.

7


limb of the curves between patients treated with

streptokinase early and those treated late. The

peaks of enzyme activity were also reached at

different points of time: the peak of CPK occurred

5.1 hours and the peak for GOT 4.3 hours earlier in

the patients who received early streptokinase

therapy. The differences in the heights of the peaks

were not significant: 2.7 mU/ml. for GOT and 0.63

mU/ml. for CPK.

Table 11 shows the parameters of the calculated

curves.

In addition to the peak, the constant k2 is important

in the interpretation. This constant exercises

its greatest influence over the ascending limb of

the curve of enzyme activity (first few hours after

the onset of infarction) and is to some extent a

measure of the steepness of rise in enzyme

activity. k2 was found to be greater for both

enzymes in the early streptokinase treatment group

than in the late group. This was interpreted as

evidence of a steeper rise in enzyme activity with

early streptokinase therapy (Figs. 2-3).

A statistical test could not be applied to the

parameters obtained since the parameters did not

follow a linear function and their distribution could

not be defined accurately. The results were

nevertheless statistically relevant since they were

obtained by the objective procedure of the method

of least squares. They thus possess practically all

the optimal statistical properties and, in particular,

they are true to expectation in that the mean of the

actual values coincides with the expected values,

and are efficient in the sense that they exhibit

minimal variance. These factors provided the

statistical basis for the interpretation of the results

obtained,

Discussion

The prevention of myocardial necrosis by

instant thrombolysis must be a very rare event in

coronary artery thrombosis. It must be assumed

that this optimal result of therapy is virtually

unattainable in practice and in fact cannot be

8

Tab. II. Parameters of the calculated curves * where E = the normal mean (6).

Relative

scatter*

Peak of curve

Time (hours) Height (mU/ml.)

k2

k1

A

Enzyme

178 %

60.6

28.8

1.11

0.60

237.0

GOT Streptokinase late

166 %

60.3

24.5

1.89

0.42

109.9

Streptokinase early

* −k1⋅t

−k

2⋅t

y = A⋅

( e − e )

299 %

2.48

20.8

2.51

0.40

3.69

CPK Streptokinase late

219 %

3.11

15.7

3.09

0.61

5.22

Streptokinase early

** Relative scatter of measured values about the calculated curve.

9


practice and in fact it cannot be demonstrated by

means of the methods available at the present time.

The rudimentary infarcts discussed in Part II (18)

of this report characteristically showed an

elevation in enzyme activity, but were excluded

from the analysis of enzyme activity because they

were not transmural infarcts. Since both optimal

possibilities (absence of necrosis, rudimentary

infarct) were excluded, only the findings in fully

developed myocardial infarcts will be discussed.

The following results were obtained:

1. The height of the peak of the curves was not

significantly different in the early and late

streptokinase treatment groups.

2. The curves of both enzymes (GOT, CPK)

showed a steeper rise in patients treated with

streptokinase early. With early treatment the peak

was thus attained more rapidly.

In Part I of this report (22) discussion of the

effects of thrombolytic therapy dealt with the

following possibilities: the re-opening of vessels

occluded by thrombus; the prevention of spread of

thrombosis to neighbouring vessels or its effective

treatment; and the restoration of the circulation in

the border zone adjoining the area of necrosis.

From these considerations the following

interpretations might be placed on the course of

enzyme activities:

a) According to current concepts it is assumed

that the total quantity of enzymes leaving a

myocardial infarct is proportional to the bulk of the

tissue destroyed (15, 21). The peak of the curve of

enzyme activity in the serum is regarded as

representative of the total enzyme release. Against

this is the fact that the influx of GOT into the

blood has a half-time of 42 hours (4) whereas the

peak of enzyme activity is attained much earlier.

At the time of the peak of the curve the rate of

influx of the enzyme into the blood is greater than

the rate of efflux of enzyme from the blood. After

the peak of the curve the "diffusion phase" first

predominates, that is, the distribution of the

10

enzyme throughout the vascular and extravascular

space (first exponential fall) (10). After this the

further fall in enzyme activity ("elimination

phase") (10) to normal levels - until equilibrium is

restored - is determined only by the turnover rate

of enzyme.

The assumption that the peak of enzyme

activity corresponds to the total quantity of

enzymes and hence to the size of the infarct can

really only be used for the comparison of series in

which the conditions for the loss of enzymes from

the infarcted area are constant as, for instance, in

infarcts of the same size due to permanent ligation

of a branch of the coronary artery. This is evident

from the model devised by Brüdigam and

colleagues (4) in which the peak of the curve was

shown to be equally affected by the total quantity

and the velocity constants of the influx and of the

efflux.

It is especially important for the circulatory

conditions through the area to be identical for

groups under comparison (10). This condition

cannot be fulfilled during the course of therapy

designed to improve the circulation through the

area by re-opening vessels. The re-opening of a

vessel supplying the region of the infarct could be

expected to result in the more rapid appearance of

the liberated enzymes in the general circulation

(5). This would result not only in an earlier

attainment of the peak but also in a greater height

of the peak itself since the injection of enzymes in

animal experiments has shown that an influx of

enzymes of this order cannot be compensated for

so rapidly by enzyme distribution and elimination.

Accordingly, in two groups of patients with

myocardial infarcts of similar size receiving

thrombolytic therapy, the more rapidly the vessels

were re-opened the sooner the peak of enzyme

activity would be attained and the higher it would

be. In these circumstances a higher peak, if

attained earlier, would not signify a larger area of

infarction.

11


) If it were assumed that the vessels in the

necrotic region remained patent at least during the

early phases of the process of infarction, the rate of

enzyme outflow would be dependent on the rate of

flow through the large afferent vessels (5). Other

factors which would affect the mechanism of

distribution of enzymes throughout the extracellular

tissue space and the entry of enzymes into

the plasma are not known at present (10).

In patients treated with streptokinase the GOT

and CPK levels rose more rapidly when treatment

was started earlier, that is, within three hours of the

onset of infarction. The peak of the enzyme curves

was also attained earlier.

From the foregoing discussion it might be

expected that the earlier peaks in the patients

receiving early streptokinase therapy would also

have been higher. This proved not to be so. The

differences of 2.7 mU/ml. for GOT and 0.6 mU/

ml. for CPK were small and not significant. It

could be argued that since the patients treated with

streptokinase early should have had not only

steeper rises but also higher peaks in enzyme

activity than those treated late if the infarcts were

of equal size in the two groups, the fact that they

did not have higher peaks could suggest that the

total quantity of enzymes and thus the average size

of the infarct was perhaps actually smaller in the

early treatment group.

An effect of streptokinase on the elimination

phase (from say the 4th to the 7th days) of the

enzymes is not to be expected since elimination

depends not on further happenings in the infarcted

area but on protein turnover rates (1, 10). In this

phase the curves of the early and late treatment

groups no longer showed any differences (Fig. 1).

In an investigation comparing streptokinase with

urokinase, Lippschutz and colleagues (14) found an

inverse correlation between the peak of enzyme activity

and the time required for enzyme levels to return to

normal: higher peaks led to a more rapid fall in the level

of enzyme activity. This finding is in line with the

12

interpretation we have discussed. A more rapid rise in

enzyme activity during streptokinase therapy was also

observed by Benda (3). Fletcher (8) obtained similar

curves for GOT activity. According to the in-vitro

investigations of Fletcher (7) there was no suggestion

that streptokinase influenced these enzymes directly.

Signs of Recanalization

According to the animal experiments of Hort

and colleagues (11), compared with permanent

occlusion, rapid re-opening of an occluded

coronary vessel produced a more rapid and more

extensive connective tissue reaction and scar

formation. The more rapid rise in CPK and GOT in

the serum of patients treated with streptokinase

early who attained the same peak level of enzyme

activity could be interpreted as being due to the

re-opening of a vessel occluded by thrombus.

From the findings we have presented that we are

not in a position to discuss in which particular

patients recanalization occurred or whether the

recanalization was complete. The possibility of

recanalization was mentioned also in Part II of this

report dealing with the electrocardiographic course

of myocardial infarction under thrombolytic

therapy (rapid onset of the so-called "regression

phenomena": regression of ST-elevation; reduction

of QRS changes; appearance and disappearance of

T-wave inversion).

Another consequence of rapid recanalization of

thrombotically occluded vessels could be an earlier

delineation of the necrotic area (11, 13), if it can be

assumed that not all the fibres have been subjected

to irreversible anoxic damage simultaneously

(incomplete occlusions; border areas). Two

findings in our material tend to support such an

effect: the relatively increased incidence of

rudimentary infarcts, that is infarcts which remain

small in the electrocardiogram, during

streptokinase therapy; and the presence of earlier

but not higher peaks of enzyme activity in patients

receiving early streptokinase therapy.

13


Treatment of an infarct with streptokinase involves

the patient in little risk. The nature and frequency of

the complications are acceptable in such a condition as

myocardial infarction. In no case was death due to

streptokinase and in only one patient was it necessary

to discontinue streptokinase therapy because of

haemorrhage in this case from a previously unsuspected

carcinoma of the stomach. Attention is drawn to

the most frequently encountered complication, because

it is usually avoidable: on six occasions bleeding

developed from the puncture sites after intramuscular

injections.

Overall Results and Conclusions

The purpose of this cooperative study from six

medical centres was to conduct a clinical and

therapeutic trial of the effects of thrombolytic

therapy with streptokinase in myocardial

infarction. The mortality, incidence of complications,

electrocardiographic findings and serum

enzyme curves were compared in numerically

large treatment groups of patients receiving

streptokinase and anticoagulant therapy.

1. The mortality during the first 24 hours was

the same in the two groups (5.38 % streptokinase;

5.36 % anticoagulants only). On the other hand,

the infarct mortality rate from the second to the

40th days was significantly lower in the streptokinase

group (8.7 %) than in the anticoagulant

group (16.1 %). The net result was a lower total

mortality (up to the 40th day) of 14.1 % (streptokinase)

compared with 21.7 % (anticoagulants

alone). There was no significant difference in the

incidence of cardiac rupture (2.7 % for streptokinase;

3.4 % for anticoagulants). Complications occurred

in 3.7 % of patients during streptokinase

therapy (among 558 patients; see Part I of this

report [22]).

2. On electrocardiography a significantly larger

number of patients belonging to the streptokinase

group showed rapid regression of ST-elevation,

changes in the QRS complex and T-wave

14

inversion. The proportion of rudimentary infarcts

was higher in the streptokinase treated group. At

the end of the 50-day observation period these

phenomena were again found in a higher

percentage of streptokinase patients. Rudimentary

infarcts were more frequently demonstrated in the

streptokinase group (among 234 patients; see Part

11 of this report [18]).

3. During streptokinase therapy a more rapid

rise in CPK and GOT activity occurred when

treatment was started during the first three hours

after infarction than when it was started later (3-12

hours). With early streptokinase therapy the peaks

of CPK and GOT activity were attained earlier.

There was no significant difference between the

heights of the peaks of the two streptokinase

treated groups. Statistical comparison with the

control group was omitted because of inadequate

numbers of estimations (among 94 patients; see

Part III of this report).

Strict randomization of treatment groups in the

present series was not attained. It was possible,

however, to show that there was no bias in selection

with regard to degree of severity in the various groups.

The findings of the present investigation have

confirmed the effect of thrombolytic therapy on

the course of recent myocardial infarction. The fall

in mortality rate from 21.7 % to 14.1 % suggests

that this effect may be significant for the patient.

In view of the statistically proved therapeutic

effect of streptokinase therapy in recent

myocardial infarction as assessed by various

methods of investigation (overall statistics,

electrocardiograms, enzymes) it seems reasonable

to suggest that patients with recent myocardial

infarction presenting within twelve hours of the

onset of the classical clinical features of infarction

should receive thrombolytic therapy, provided no

known contraindications to this exist.

15


Summary

A co-operative study was undertaken at six

medical centres to assess the effect of thrombolytic

therapy on the course of recent myocardial infarcts

in comparison with anticoagulant therapy alone.

The drop in mortality rate from 21.7 % to 14.1 %,

the more rapid regression of ECG changes and the

more rapid rise in serum enzyme activity were

evidence of the favourable effect of thrombolytic

therapy.

References (14) Lippschutz, E. J., J. L. Am

(1) Amelung, D.: Fermentdia- brus, C. M. Ambrus, J. Con-

gnostik interner Erkrankungen stant, A. C. Rekate, G. L. Col-

(Stuttgart 1964). lins, J. E. Sokal: Amer. J.

(2) Amelung, D., L. Hofmann, Cardiol. 16 (1955), 93.

L. Otto: Dtsch. med. Wschr. 91 (15) Nachlas, M. M., M. M.

(1966), 851. Friedman, S.P.Cohen: Surgery

(3) Benda, L.: In: Thromboly- 55 (1964), 700.

tische Therapie (Symposium), (16) Neuhaus, G., U. Humpert,

IV. Annual meeting of Dtsch. H Weller: Dtsch. Arch. klin.

Ges. für Angiologie, München Med. 210 (1965), 87.

1966 (in press). (17) Nissen, N. J., P. Ranlov,

(4) Brüdigam, B., K. W. Schnei- J , Weis-fogh: Brit, Heart J. 27

der: Dtsch. Arch, klin.Med.

206 (1960) 438.

(1965), 520

(18) Poliwoda, H., K. W. Die-

(1965), 520.

(5) Cain, H., W. Assmann: derich, B. Schneider, R. Roden-

Klin. Wschr. 38 (1960) , 433.

(6) Feissli, S., G. Forster, G.

Laudahn, E. Schmidt, F. W.

Schmidt: Klin.Wsdir.44 (1966),

390.

(7) Fletcher, A. P., N. Alkjaerburg,

F. Heckner, P. Körtge, J.

van de Loo, F. A. Pezold, F.

Praetorius, R. Schmutzler, D.

Zekorn: Dtsch. med. Wschr. 91

(1966), 978.

(19) Praetorius, F. 2 , P. Körtge:

sig, S. Sherry: J. clin. Invest. Angiology 17 (1966), 640

38 (1959), 1096.

(8) Fletcher, A. P.

(20) Rotthauwe, H. W., S. Ko-

1 1. R. Schmutzler, F. Heckner, P. Körtge, H. van de Loo,

F.A. Pezold, H. Poliwoda, F. Praetorius und D. Zekorn:

Zur thrombolytischen Therapie des frischen

Herzinfarktes. I. Einführung, Behandlungspläne,

allgemeine klinische Ergebnisse.

Dtsch. Med. Wschr. 91. 581 - 587 (1966)

English Language Edition:

Germ. Med. Mth., 11, 308 - 314 (1966)

, N. Alkjaersig,

S. Sherry, F. E. Smyrniotis,

S. Jick: J. clin. Invest. 38

(1959), 1111.

walewski: Klin. Wschr. 45

(1967), 387.

(21) Ruegsegger, P., J. Nydick,

A. Freiman, J. S. La Due: Cir

2. H. Poliwoda, K.W. Diederich, B. Schneider, R.

Rodenburg, F. Heckner, P. Körtge, J. van de Loo, F. A.

Pezold, F. Praetorius, R. Schmutzler, D. Zekorn: Zur

thrombolytischen Therapie des frischen Herzinfarktes.

(9) Forster, G.: Schweiz. med. culat. Res. 7 (1959), 4.

II. Ergebnisse der elektrokardiographischen

Wschr. 97 (1967), 329.

(10) Hess, B.: Enzyme im

Blutplasma (Stuttgart 1962).

(22) Schmutzler, R.,F. Heckner,

P. Körtge, J. van de Loo, F. A.

Pezold, H. Poliwoda, F. Prae-

Untersuchungen.

Dtsch. Med. Wschr. 91, 978 - 984 (1966)

(11) Hort, W., H. Poliwoda, S. torius, D. Zekorn: Dtsch. med.

da Canalis, J. Knigge: Klin.

Wschr. 44 (1966), 215.

(12) Karmen, A., F. Wroblewski,

J. La Due: J. clin. Invest.

34 (1955), 126, 131.

(13) Krug, A., A. Enderle, G.

Korb: Verb. dtsch. Ges. Kreisl.-

Forsch. 32 (1966), 279,

Wschr. 91 (1966), 581.

(23) Stein, E., M. Eggstein:

Dtsch, rned. Wschr. 90 (1965),

772.

(24) Tanzer, M., C. Gilvarg:

J. biol. Chem. 234 (1959), 3201.

(25) Vincent, W. R., E. Rapaport:

Amer, J. Cardiol. 15

(1965),17.

1

(8)http://www.pubmedcentral.nih.gov/pagerender.fcgi?artid=293258&p

ageindex=1#page

2

(19) http://www.frankpraetorius.gmxhome.de/download/Thrombolysis_Serum_Enzymes_1966

.pdf

Find more References:

http://www.frank-praetorius.gmxhome.de/Herzinfarkt_Enzyme.html

16

(Authors' addresses: Privatdozent Dr. P. Körtge; Dr. F.

Praetorius, I. Medizinische Universitätsklinik im Städtischen

Krankenhaus Westend, 1 Berlin 19, Spandauer

Damm 130; Prof. Dr. B. Schneider, Institut für Biometrie

und Dokumentation der Medizinischen Hochschule, 3

Hannover, Bischofsholer Damm 15; Prof. Dr. F, Heckner,

Innere Abteilung des Zweckverband-Krankenhauses

Einbeck, 3352 Einbeck, Deinerlindenweg; Dr. J. van de

Loo, Medizinische Universitätsklinik, 5 Köln-Lindenthal,

Lindenburg; Prof. Dr. F. A. Pezold, Städtisches Behring-

Krankenhaus, 1 Berlin-Zehlendorf, Gimpelsteig 3-5;

Privatdozent Dr. H. Poliwoda, Medizinische Klinik der

Medizinischen Hochschule Hannover im Krankenhaus

Oststadt, 3 Hannover, Podbielskistr. 380; Privatdozent

Dr. R. Schmutzler, Medizinische Universitätsklinik,

Bürgerspital, CH-4000 Basle; Dr. D. Zekorn, Medizinisch-Wissenschaftliche

Abteilung der Farbwerke

HoechstAG, 623 Frankfurt(M)-Hoechst,Germany)

The original text (Part I-III) in „Deutsche Medizinische

Wochenschrift“:

17

More magazines by this user
Similar magazines