Table Of ContentCurrent Topics in Pathology
Continuation of Ergebnisse der Pathologie
64
Editors
E. Grundmann W. H. Kirsten
Advisory Board
H.-W. Altmann, K. Benirschke, A. Bohle, H. Cottier,
M. Eder, P. Gedigk, Chr. Hedinger, S. Iijima,
J.
L. Van Lancker, K. Lennert, H. Meessen, B. Morson,
W. Sandritter, G. Seifert, S. Sell, H. C. Stoerk,
T. Takeuchi, H. U. Zollinger
Pulmonary Hypertension Related to
Aminorex Intake
DNA Injuries, Their Repair, and Carcinogenesis
Soft Tissue Tumors in the Rat
Visceral Candidosis
Contributors
J.
K. Küchemann, L. Van Lancker, D. Maas, E. L. Quiroga,
J. J.
U. N. Riede, K. Salfe1der, Schwarz, H. Steinhardt,
C. Thomas, K. Ueda, S. Widgren
With 107 Figures
Springer-Verlag Berlin Heidelberg New Y ork 1977
E Grundmann, Professor Dr., Pathologisches Institut der Universität, Westring 17,
D-4400 Münster/Westf., Germany
W.H. Kirsten, Professor Dr., Department of Pathology, The University of Chicago,
950 East 59th Street, Chicago, IL 60637, USA
ISBN-13: 978-3-642-66583-7 e-ISBN-13: 978-3-642-66581-3
DOI: 10.1007/978-3-642-66581-3
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Under § 54 of the German Copyright Law where coples are made for other than private use, a fee is
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©by Springer-Verlag Berlin-Heidelberg 1977.
Softcover reprint of the hardcover 1s t edition 1977
Library of Congress Catalog Card Number 5649162.
The use of registered names, trademarks, etc. m this publicatJon does not imply, even in the absence
of a specific statement, that such names are exempt from the relevant protective laws and regulations
and therefore free for general use.
Contents
Widgren, S. Pulmonary Hypertension Related to Aminorex Intake
(Histologie, Ultrastruetural, and Morphometrie Studies
of 37 Cases in Switzerland). With 33 Figures . . . . . . . . . . . 1
Van Lancker, I.L. DNA Injuries, Their Repair, and Carcinogenesis. With
14 Figures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 65
c.,
Thomas, Soft Tissue Tumors in the Rat. (Pathogenesis and
Steinhizrdt, H.I., Histopathology). With l3 Figures ................. 129
Küchemann, K.,
Maas, D., Riede, u.N.
Salfelder, K., Viseeral Candidosis (Anatomie Study of 34 Cases).
Ueda, K., With 47 Figures ............................. 177
Quiroga, E.L.,
Schwarz, I.
Subject Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 225
List of Contributors
Küchemann, Dr. K. Pathologisches Institut des Städt. Krankenhauses, Dhünberg 60,
D-5090 Leverkusen
Van Lancker, Prof. University ofCalifornia, Dept. ofPathology, School ofMedicine,
Dr.l.L. The Center for the Health Sciences, Los Angeles, CA 90024, USA
Maas,Dr. D. Abt. für klinische Immunpathologie an der Medizinischen
Universitätsklinik, Hugstetter Straße 55, D-7800 Freiburg
Quiroga, Dr. EL. Department of Pathology, University of Cincinnati, OH, USA
Riede, Dr. u.N. Pathologisches Institut der Universität, Albertstraße 19,
D-7800 Freiburg
Saltelder, Prof. Dr. K. Department ofPathology, Universidad de Los Andes,
Merida, Venezuela
Schwarz, Dr. I. Clinical Laboratories, Jewish Hospital, Cincinnati, OH 45229, USA
Steinhardt, Dr. H.1. Pathologisches Institut der Universität, Albertstraße 19,
D-7800 Freiburg
Thomas, Prof. Dr. C. Pathologisches Institut der Universität, Albertstraße 19
D-7800 Freiburg
Ueda, Dr. -K. Department ofPathology, University ofCincinnati, OH, USA
Widgren, Dr. S. Institut de Pathologie de l'Universite, 40, Bvd. de la Cluse,
CH-1211 Geneve 4
Pulmonary Hypertension Related to Aminorex Intake
Histologie, Ultrastruetural, and Morphometrie Studies of 37 Cases in Switzerland
S. WIDGREN
Introduetion ............................................. 2
I. Aminorex: First Pharmaeologie and Clinical Tests; Acute Toxicity 3
1. Pharmaeology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
2. Clinieal Tests ....................................... 3
3. Aeute Toxicity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
11. Epidemiology; Clinieal and Pathologie Features of Pulmonary Hypertension
in Conneetion With Aminorex Intake ......................... 4
1. Epidemiology ..... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
2. Clinieal Features ........................... . . . . . . . . . . 5
3. Pathology ......................................... 7
III. New Clinical and Pharmaeologie Tests . . . . . . . . . . . . . . . . . . . . . . . . . 8
IV. Material and Methods ................................... 10
1. Material . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
2. Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
V. Prineipa1 Cliniea1 and Anatomie Data ......................... 13
VI. Histologie Findings ..................................... 13
1. Personal Observations ................................. 13
2. Review of the Literature and Diseussion ..................... 29
VII. Ultrastrueture of Normal Museular Pulmonary Arteries ............. 31
1. Personal Observations ................................. 31
2. Review of the Literature and Diseussion . . . . . . . . . . . . . . . . . . . .. 33
VIII. Ultrastrueture of Lesions of Museular Pulmonary Arteries in Pulmonary
Hypertensive Disease. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 34
1. Personal Observations ................................. 34
2. Review of the Literature and Diseussion ..................... 42
IX. Numeneal Evaluation of Arterial Lesions . . . . . . . . . . . . . . . . . . . . . .. 45
1. Personal Observations ................................. 45
2. Review of the Literature and Diseussion ..................... 48
X. Morphometric Examinations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49
1. Personal Results ..................................... 49
2. Review of the Literature and Diseussion ..................... 51
XI. General Diseussion ..................................... 52
XII. Summary ........................................... 56
XIII. Zusammenfassung ..................................... 57
Referenees . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58
2
Introduction
In 1967 cardiologists in Switzerland were struck by the sudden increase in the number
of cases of so-called primary pulmonary hypertensive disease (PPHD). Up untill966, the
cardiology centers in Switzerland had not seen more than one or two cases a year, but this
number suddenly multiplied by ten or twenty times. At the June 1968 meeting ofthe
Swiss Society of Cardiology, Gurtner et al. (1968b) presented a paper which raised the
question whether the vascular types of cor pulmonale had increased. They also raised the
question about the possible responsibility of environmental factors, such as toxins or drugs,
in causing this increase.
Krrihenbühl et al. (1968) first suggested the possible responsibility of anorexigenic drugs,
but no proof was provided. Soon after this, the cardiology team in Bem (Gurtner et al.,
1968a) published their report, which resumed and completed the above-mentioned prelim
inary communication; 31 cases of PPHD, among which 17 had taken an anorexigenic drug,
aminorex fumarate (Menocil, Cilag), were reported. The importance of this work was soon
recognized and it was followed by several meetings (in Vienna, Hannover, and Bürgenstock)
and two round tables sponsored by the Swiss Society of Cardiology (in Montreux and
Basel).
Following the publication of a paper by Jomod et al. (1970) we were asked with Pro
fessor Kapanci by the Swiss Society of Cardiology-with the support of Cilag AG-to under
take a pathologie study of PHD cases deceased in Switzerland. A preliminary report was
given to the Swiss Society of Pathology in the fall of 1969 (Widgren and Kapanci, 1969),
in order to inform members of this Society of the problems and aims of the work which
had been undertaken. Material was provided by most of the pathology departments in
Switzerland. Thus it was possible to study the lungs taken at the necropsy of 37 patients
deceased from PHD related to the absorption of aminorex, and of 5 persons who had suf
fered from PPHD with no history of drug intake. Preceeding papers (Kapanci and Widgren,
1970; Widgren and Kapanci, 1970a, b, 1972) have given the preliminary results obtained
by optical and electron microscopy, numerical evaluation ofthe lesions ofpulmonary
arteries according to the classification established by Heath andEdwards (1958), and by
morphometric studies based on the principles of Weibel (Weibel, 1963, 1970; Weibel and
Gomez, 1962; Weibel et al., 1966). The purpose ofthe present workis to resurne and com
plete these various preliminary studies.
It must be emphasized that the lesions of pulmonary muscular arteries observed in this
study, did not differ, in any way, from those codified by Heath andEdwards (1958) in
cases of PHD secondary to cardiac malformations. Although it was not possible to provide
anatomie proof of the responsibility of aminorex in the development ofPHD, some of
the fmdings allow for the suggestion of a hypothesis regarding the action of the drug.
Our studies have shown, in fact, that muscularization of the intima often seen under the
light microseope, was revealed by the electron microscope to be constituted by myo-intimal
cells as described by Buck (1961) in experimental arteriosclerosis. The evolution of thele
sions toward dilatation and fibrosis is characterized by a thickening of the constituents of
the arterial wall, the consequence of which is a segmental obliteration of the lumen, which
contributes to the fixing or even the worsening of the muscular spasm induced by the direct
or indirect action of the drug.
3
I. Aminorex: First Pharmacologic and Clinical Tests; Acute Toxicity
I. Pharmacology
Aminorex (2-amino-5-phenyl-2-oxazoline) was synthesized by Poos et al. (1963). Its ehem
ical stroeture has some similarities to that of amphetamine, norepinephrine, and ephedrine
(Fig. 1). Like other anorexigens it is a sympathomimetie drog with which it shares eertain
vasomotor effeets. Introdueed by the MeNeil Corporation, it was eommercialized in 1965
by Cilag Chemie, Sehaffhausen, as a fumarate (Menoeil) in tablets eontaining 14 mg of the
produet. The reeommended daily dose was 1-2 tablets.
1-Phenyl-2 amIno-propan -sulfat
D-Arnphelarnin-sulfat
H2SO,
------------------------------
[O
2 -Amno-5 -phenyl-oxazohn -fumarat
_CH_CH]
Arninorex-Furnarat
_ I I
0, N HOOC-CHH< ji-eOOH Flg. 1. Chemical structure of amino
e' rex fumarate, compared to that of
amphetamine sulfate (with the kind
I
NH2 permission of Stepanekand Zolliker)
I
The first published experimental tests of aminorex were made by Yelnosky (1966) on dogs
under phenobarbital anesthesia. The eontraetile strength of the right heart measured with
open-ehest, the systemic arterial pressure, and the heart rate were transitorily inereased;
the injeetion of a ß-bloeking agent abolished or strongly redueed this eardiae effeet, sug
gesting that aminorex stimulates ß-reeptors; the injeetion of an a-bloeking drug was found
to suppress or reduee the effeet on the systemic arterial pressure. Prior treatment with
reserpine, which depletes eateeholamines, was found to signifieantly deerease the effeet
of aminorex, suggesting that the sympathomimetie effeet of aminorex might be due to a
liberation of eatecholamines. The effeet on the lesser cireulation was not studied in this
paper.
2. Clinical Tests
Clinical tests were generally ron on small groups ofpatients (Hadler, 1967;Hotz, 1967;
Kew, 1970; Krueger, 1968;Roos et al., 1970;Sandoval et al., 1971; Wood and Owen, 1965);
4
they showed that aminorex, administered as a base or as fumarate, had the advantage of
producing a regular weight loss. Unlike amphetamine, it was found to have no excessively
stimulating effect but did have a euphorizing one (Gadd and Gunne, 1970). It has been
tested on obese people without any other known health problems (Kew, 1970; Raas et
al., 1970;Sandoval et al., 1971) as weIl as on obese patients suffering from other diseases
(arte rial hypertension, cardiac failure, arteriosclerosis, diabetes), and no severe side-effects
were reported. Sandoval et al. (1971), however, noted that one case complained of dizziness
and another of fatigue. Hadler (1967), after testing two groups of patients taking aminorex
and comparing its effects with those of either amphetamine sulfate or phenmetrazine, ob
served 3 cases in one group and 2 in the other with cardiovascular side-effects. Precise
details were not given.
3. Acute Toxicity
Acute intoxication with aminorex (accidental or suicidal) has been reported in three pa
pers. Among 48 cases of intoxication due to the ingestion of various types of anorexigens
(Pasi, 1967),25 had taken aminorex. Borbely et al. (1970) studied 30 cases of acute in
toxication due to aminorex. This intoxication begins with astate of psychomotor restless
ness accompanied by mydriasis, redness of the skin, tachycardia, rise in blood pressure,
and hyperpnea. In severe cases, convulsions and a central respiratory depression may be
noted. No fatal case was reported. Late sequellae were not mentioned. The case reported
by Schuster et al. showed the same symptoms. Repeated check-ups, and in particular
cardiac catheterization could not objectivate any pulmonary vascular consequences.
11. Epidemiology; Clinical and Pathologie Features of Pulmonary Hypertension
in Connection with Aminorex Intake
1. Epidemiology
As stated in the introduction, an increase in the number of cases of so-called primary pul
monary hypertensive disease (PPHD) was noted by Swiss cardiologists in 1967. Following
the report by Gurtner et al. (1968a), a possible causal relationship with the intake of an
anorexigenic drug, aminorex fumarate (Menocil, Cilag) put on the market during the fall
of 1965 in Switzerland, was suggested. An increase in the incidence of this disease was ob
served in the Federal Republic of Germany and in Austria, where this drug was also sold.
Results of cooperative studies published in these three countries (Germany: Loogen, 1970;
Austria: Kaindl, 1969, 1971; Switzerland: Wirz andArbenz, 1970) indicated the approxi
mate number of patients affected with PHD in connection with the intake of aminorex,
as weIl as the number offatalities (see chart Fig. 2):
Germany: 35 deaths out of215 cases = 16.2%
Austria: 16 deaths out of 134 cases = 11.9%
Switzerland: ca. 44 deaths out of 244 cases = 18%.
5
Ax t
215 35 1.66-m.72
2104 -40 165-Ii.70
134 16 166-? 70
Fig. 2. GeographIe distribution of eases of PHD in eonneetion with aminorex intake.
Number of patients (Ax) and of deceased eases (+) according to Loogen (BRD = German
Federal Republic), Wirz and Arbenz (eH = Switzerland), and Kaindl (A = Austria) and
the duration of the studies are indicated
The mortality rate is thus somewhere between 12 and 18% of the number of patients
registered in the larger eardiology centers of these three countries, but it is quite possible
that the aetual figure is mueh higher, since, for various reasons, many cases may not have
been included in the surveys. Bass and Gurtner (1973) indicate a mortality rate of 20%.
On the other hand, in the countries where aminorex was sold, the incidence of PHD did
not change during these years, according to the inquiry of Fe"ero (1970). Outside these
three countries, only two papers have reported PHD related to aminorex intake, one case
in France (Berthou, 1972) and the other in Denmark (Norder~ and Müller, 1970).
The studies undertaken in Switzerland, Germany, and Austria (Loogen, 1972;Rivier
et al., 1972; Kaindl, 1969, 1971) showed that the incidence of illness in proportion to the
total number of persons who had taken the drug, was between 1 and 2%0. It is evident,
therefore, that other factors, as yet unknown, must be involved (Blankart, 1970). No evi
dence, however, of risk factors such as varicose veins, phlebitis, pulmonary embolism, ab
dominal, gynecological or varicosis operations, was found in the course of an extensive
epidemiologie study (Blankart, 1974). After the drug was withdrawn from the market in
1968, the frequency ofPHD suddenly diminished, and since 1969 (Loogen, 1972) it has
again become as rare as it was before 1967 (Rivier, personal communication).
2. Clinical Features
The clinical features of PHD related to the intake of anorexigens, especially aminorex
fumarate, are not fundamentally different from those of primary or secondary PHD.
