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The effects of atromid on serum cholesterol, serum triglycerides, and radioactive fat tolerance in patients with hyperlipidemia. a preliminary report
538
JOURNAL OF ATHEROSCLEROSIS RESEARCH
T H E E F F E C T S OF ATROMID ON SERUM C H O L E S T E R O L , SERUM T R I G L Y C E R I D E S , AND R A D I O A C T I V E FAT T O L E R A N C E IN P A T I E N T S W I T H H Y P E R L I P I D E M I A . A PRELIMINARY REPORT
D. BERKOWITZ Hahnemann Medical College and Hospital and the Albert Einstein and Sidney H, llman Medical Centers, Phdadelphia, Pa. (U.S.A .)
INTRODUCTION Although m a n y of the various blood lipid fractions have been incriminated in the genesis of atherosclerosis, more recent data have suggested that hypertriglyceridemia and abnormal radioactive fat tolerance correlate still better with this condition 1-5. Accordingly, in the treatment of such patients with any pharmacological agent, the normalization of these abnormalities would appear to be a more rational objective than one directed solely towards lowering of the serum cholesterol. Currently, Atromid, a combination of ethyl-a-p-chlorophenoxy-isobutyrate with androsterone, is undergoing extensive clinical trials in the treatment of hyperlipidemia, and appears to be effective in this respect and without significant side effects. The present report describes our preliminary results of treatment with this preparation on serum cholesterol and triglyceride levels and radioactive fat tolerance. SUBJECTS AND METHODS The group under study comprised 25 patients whose cholesterol levels during a 6 month control period were consistently greater than 275 mg/100 ml. Twelve were female and 13 male. Their ages ranged from 35 to 63. None had hypothyroidism or nephrosis. The cholesterol was determined b y the method of ZAK6 and the triglycerides by the method of VAN HANDEL AND ZILVERSMIT7. Fat tolerance following an oral test meal of 181I-triolein was measured in accordance with our previously described technique s. Normal values in our laboratory are less than 125 rag/100 ml for the triglycerides and whole blood radioactivity levels of less than 15 % (maximum postprandial) and 5 % (24 h) of the initially ingested labeled fat. No dietary restrictions were imposed in any case. The dosage of Atromid was 2 g daily. Supported in part by a grant from the U.S. Public Health Service (H-3976). ]. Atheroscler. Res., 3 (1963) 538-541
EFFECTS
OF
ATROMID
IN
HYPERLIPIDEMIC
539
PATIENTS
0
Z N
N N
~¢TaCq
t"~ ~3'~ ~
~
It~ e,~ ,...~ t , D , ~ O'~ O0 t'~Cq ~'~ ¢xl t¢~ t",. tt'~ ~
t'~ t ~
Z
O N
W M
¢,1 ¢'-I'~ ¢q ¢ ~ ¢ q
¢q ~
¢q ¢qCq
¢q ¢~¢,1 ~
¢-1 ¢q ¢'q ¢ , 1 ~ 1 ¢ q
¢--1 ¢q ¢,1
N Z N
N
~
~ ~ ~ ~1~_~ ~ 7
~
~°~' ~ ~
g
o
N M ©
W
j . Atheroscler. Res.,
3 (1963)
538-541
540
D. BERKOWITZ
RESULTS
Abnormal fat tolerance was present in 14 (64 %) of the group before treatment. In each of these the initial triglyceride levels were also increased (Table I). After 3 months treatment, the cholesterol was decreased 15 or more per cent in 19 patients (76 %), the average for the group being 23 %. The triglycerides were likewise significantly reduced in 20 patients (80 %), in many instances to a much greater degree than the cholesterol. Fat tolerance became normal in 4 patients with a lesser degree of improvement occurring in 6 additional subjects (Table I).
DISCUSSION
Our original observations of the frequency of impaired radioactive fat tolerance in patients with ischaemic heart disease 9 have now been confirmed through increased experience by us and others. Results obtained from over S00 such studies indicate that abnormal radioactive fat tolerance is the most frequent lipid metabolic alteration present in this disease and constitutes a much more reliable indication of it than the cholesterol level. Accordingly, we have been interested in assessing the effects of numerous hypocholesterolemic preparations on this parameter with the belief that a rational pharmacological approach to the problem of hyperlipemia and/or ischaemic heart disease must be aimed at the restoration of normal fat tolerance over and above the reduction of any or all of the serum lipidsl0,11. The present data indicate that Atromid treatment may significantly improve abnormal fat tolerance and even revert it to normal. The results closely paralleled the changes produced in the triglyceride levels and bore no direct relation to the course of the cholesterol values. This ability, together with its cholesterol lowering potential already reportedl2,13, would appear to satisfy the minimal basic requirements of a suitable hypolipemic agent. If further studies can confirm these preliminary favorable impressions, Atromid may prove a most valuable aid in the treatment of atherosclerotic vascular disease.
SUMMARY
The effects of Atromid on the serum cholesterol, serum triglycerides, and radioactive fat tolerance were studied after a 3 months course of therapy in 25 patients with hyperlipidemia. Significant decreases in the cholesterol occurred in 76 % and in the triglycerides in 80 % of the group. Reductions in the hypertriglyceridemia were concomitantly associated with improvement in the fat tolerance, and in 4 patients with reversion to normal levels. Atromid appears to be a potentially important hypolipemic agent by virtue of its wide spectrum of activity, which embraces not only the various serum lipids but also the fat tolerance as well. J. Atheroscler. Res., 3 (1963) 538-541
EFFECTS OF ATROMID IN HYPERLIPIDEMIC PATIENTS
541
RESUME
Les effets de l ' A t r o m i d e sur le cholesterol s6rique, les triglyc~rides s~riques et la tolerance ~ la graisse r a d i o a c t i v e o n t 6t6 6tudi~s chez 25 sujets avec h y p e r l i p i d 6 m i e au b o u t d ' u n e th6rapie prolong6e p e n d a n t 3 tools. I1 est not6 dans 7 6 % des cas une baisse significative d u cholestfirol et d a n s 80 % des cas une baisse des triglyc6rides. Des r6ductions d ' h y p e r t r i g l y c 6 r i d 6 m i e ont s u r v e n u c o n c o m i t a m m e n t avec une am61ioration de la tol6rance A la graisse et, chez 4 malades, avec r e t o u r a u x n i v e a u x n o r m a u x . I1 a p p a r a i t que l ' A t r o m i d e est un i m p o r t a n t agent h y p o l i p ~ m i a n t grace ~ sa large g a m m e d ' a c t i v i t 6 s laquelle embrasse non seulement les divers lipides s6riques mais aussi la tol~rance ~ la graisse. ZUSAMMENFASSUNG Die W i r k u n g von A t r o m i d auf das Cholesterin, die Triglyzeride u n d die r a d i o a k t i v e F e t t - T o l e r a n z wurde nach einer 3 - m o n a t l i c h e n T h e r a p i e bei 25 P a t i e n t e n m i t H y p e r lipid~imie untersucht. Signifikante V e r m i n d e r u n g e n im Cholesterin k a m e n bei 76% u n d in den Triglyzeriden bei 8 0 % der G r u p p e vor. Niedrigere W e r t e der Hypertriglyzerid~imie waren i m m e r vergesellschaftet von einer Verbesserung der F e t t - T o l e r a n z , u n d bei 4 P a t i e n t e n von einer R t i c k k e h r zu n o r m a l e n W e r t e n . A t r o m i d scheint k r a f t seines breiten Aktivit~itsbereichs ein p o t e n t i e l l wichtiger hypolip~imischer Agens zu sein, dessen W i r k u n g nicht nur die verschiedenen S e r u m lipoide a b e r auch die F e t t - T o l e r a n z umschliesst. REFERENCES 1 R. H. SELLER, J. BRACHFELD, A. SANDBERGAND S. BELLET, Am. J. Med., 27 (1959) 231. 2 L. A. CARLSON, Acta Med. Scan&, 167 (1960) 399. 3 A. ANTONIS AND I. BERSOHN, Lancet, i (1960) 998. 4 M. J. ALBRINK, J. W. MEIGS AND E. B. MAN, Am. J. ]~led., 31 (1961) 4. 5 D. BERKOWITZ, Coronary Heart D,sease, Grune and Stratton, New York, 1962, p. 304. 6 B. ZAK, Am. J. Clin. Pathol., 27 (1957) 583. 7 E. VAN HANDEL AND D. B. ZILVERSMIT, J. Lab Clin. Med., 50 (1957) 152. s D. BERKOWITZ,Am. J. Chn. Nutr., 8 (1960) 327. 9 W. LIKOFF, D. BERKOWITZ, A. WOLDOW, A. G. JACOBS AND D. SKLAROFF, Czrculation, 18 (1958) 1118. 10 D. BERKOWITZ, M. W. CROLL AND W. LIKOFF, Am. J. Clin. Nutr., 10 (1962) 107. 11 D. BERKOWITZ, J. J. SPITZER AND W. LIKOFF, Am. J. Cardiol., 10 (1962) 198. 12 M. F. OLlVER, Lancet, i (1962) 1321. 13 L. HELLMAN, B. ZUMOFT, G. KESSLER, R. S. ROSENFELD AND T. F. GALLAGHER, J. Clin. Invest., 41 (1962) 1364. j . Atheroscler. Res , 3 (1963) 538-541
JOURNAL OF ATHEROSCLEROSIS RESEARCH
T H E E F F E C T S OF ATROMID ON SERUM C H O L E S T E R O L , SERUM T R I G L Y C E R I D E S , AND R A D I O A C T I V E FAT T O L E R A N C E IN P A T I E N T S W I T H H Y P E R L I P I D E M I A . A PRELIMINARY REPORT
D. BERKOWITZ Hahnemann Medical College and Hospital and the Albert Einstein and Sidney H, llman Medical Centers, Phdadelphia, Pa. (U.S.A .)
INTRODUCTION Although m a n y of the various blood lipid fractions have been incriminated in the genesis of atherosclerosis, more recent data have suggested that hypertriglyceridemia and abnormal radioactive fat tolerance correlate still better with this condition 1-5. Accordingly, in the treatment of such patients with any pharmacological agent, the normalization of these abnormalities would appear to be a more rational objective than one directed solely towards lowering of the serum cholesterol. Currently, Atromid, a combination of ethyl-a-p-chlorophenoxy-isobutyrate with androsterone, is undergoing extensive clinical trials in the treatment of hyperlipidemia, and appears to be effective in this respect and without significant side effects. The present report describes our preliminary results of treatment with this preparation on serum cholesterol and triglyceride levels and radioactive fat tolerance. SUBJECTS AND METHODS The group under study comprised 25 patients whose cholesterol levels during a 6 month control period were consistently greater than 275 mg/100 ml. Twelve were female and 13 male. Their ages ranged from 35 to 63. None had hypothyroidism or nephrosis. The cholesterol was determined b y the method of ZAK6 and the triglycerides by the method of VAN HANDEL AND ZILVERSMIT7. Fat tolerance following an oral test meal of 181I-triolein was measured in accordance with our previously described technique s. Normal values in our laboratory are less than 125 rag/100 ml for the triglycerides and whole blood radioactivity levels of less than 15 % (maximum postprandial) and 5 % (24 h) of the initially ingested labeled fat. No dietary restrictions were imposed in any case. The dosage of Atromid was 2 g daily. Supported in part by a grant from the U.S. Public Health Service (H-3976). ]. Atheroscler. Res., 3 (1963) 538-541
EFFECTS
OF
ATROMID
IN
HYPERLIPIDEMIC
539
PATIENTS
0
Z N
N N
~¢TaCq
t"~ ~3'~ ~
~
It~ e,~ ,...~ t , D , ~ O'~ O0 t'~Cq ~'~ ¢xl t¢~ t",. tt'~ ~
t'~ t ~
Z
O N
W M
¢,1 ¢'-I'~ ¢q ¢ ~ ¢ q
¢q ~
¢q ¢qCq
¢q ¢~¢,1 ~
¢-1 ¢q ¢'q ¢ , 1 ~ 1 ¢ q
¢--1 ¢q ¢,1
N Z N
N
~
~ ~ ~ ~1~_~ ~ 7
~
~°~' ~ ~
g
o
N M ©
W
j . Atheroscler. Res.,
3 (1963)
538-541
540
D. BERKOWITZ
RESULTS
Abnormal fat tolerance was present in 14 (64 %) of the group before treatment. In each of these the initial triglyceride levels were also increased (Table I). After 3 months treatment, the cholesterol was decreased 15 or more per cent in 19 patients (76 %), the average for the group being 23 %. The triglycerides were likewise significantly reduced in 20 patients (80 %), in many instances to a much greater degree than the cholesterol. Fat tolerance became normal in 4 patients with a lesser degree of improvement occurring in 6 additional subjects (Table I).
DISCUSSION
Our original observations of the frequency of impaired radioactive fat tolerance in patients with ischaemic heart disease 9 have now been confirmed through increased experience by us and others. Results obtained from over S00 such studies indicate that abnormal radioactive fat tolerance is the most frequent lipid metabolic alteration present in this disease and constitutes a much more reliable indication of it than the cholesterol level. Accordingly, we have been interested in assessing the effects of numerous hypocholesterolemic preparations on this parameter with the belief that a rational pharmacological approach to the problem of hyperlipemia and/or ischaemic heart disease must be aimed at the restoration of normal fat tolerance over and above the reduction of any or all of the serum lipidsl0,11. The present data indicate that Atromid treatment may significantly improve abnormal fat tolerance and even revert it to normal. The results closely paralleled the changes produced in the triglyceride levels and bore no direct relation to the course of the cholesterol values. This ability, together with its cholesterol lowering potential already reportedl2,13, would appear to satisfy the minimal basic requirements of a suitable hypolipemic agent. If further studies can confirm these preliminary favorable impressions, Atromid may prove a most valuable aid in the treatment of atherosclerotic vascular disease.
SUMMARY
The effects of Atromid on the serum cholesterol, serum triglycerides, and radioactive fat tolerance were studied after a 3 months course of therapy in 25 patients with hyperlipidemia. Significant decreases in the cholesterol occurred in 76 % and in the triglycerides in 80 % of the group. Reductions in the hypertriglyceridemia were concomitantly associated with improvement in the fat tolerance, and in 4 patients with reversion to normal levels. Atromid appears to be a potentially important hypolipemic agent by virtue of its wide spectrum of activity, which embraces not only the various serum lipids but also the fat tolerance as well. J. Atheroscler. Res., 3 (1963) 538-541
EFFECTS OF ATROMID IN HYPERLIPIDEMIC PATIENTS
541
RESUME
Les effets de l ' A t r o m i d e sur le cholesterol s6rique, les triglyc~rides s~riques et la tolerance ~ la graisse r a d i o a c t i v e o n t 6t6 6tudi~s chez 25 sujets avec h y p e r l i p i d 6 m i e au b o u t d ' u n e th6rapie prolong6e p e n d a n t 3 tools. I1 est not6 dans 7 6 % des cas une baisse significative d u cholestfirol et d a n s 80 % des cas une baisse des triglyc6rides. Des r6ductions d ' h y p e r t r i g l y c 6 r i d 6 m i e ont s u r v e n u c o n c o m i t a m m e n t avec une am61ioration de la tol6rance A la graisse et, chez 4 malades, avec r e t o u r a u x n i v e a u x n o r m a u x . I1 a p p a r a i t que l ' A t r o m i d e est un i m p o r t a n t agent h y p o l i p ~ m i a n t grace ~ sa large g a m m e d ' a c t i v i t 6 s laquelle embrasse non seulement les divers lipides s6riques mais aussi la tol~rance ~ la graisse. ZUSAMMENFASSUNG Die W i r k u n g von A t r o m i d auf das Cholesterin, die Triglyzeride u n d die r a d i o a k t i v e F e t t - T o l e r a n z wurde nach einer 3 - m o n a t l i c h e n T h e r a p i e bei 25 P a t i e n t e n m i t H y p e r lipid~imie untersucht. Signifikante V e r m i n d e r u n g e n im Cholesterin k a m e n bei 76% u n d in den Triglyzeriden bei 8 0 % der G r u p p e vor. Niedrigere W e r t e der Hypertriglyzerid~imie waren i m m e r vergesellschaftet von einer Verbesserung der F e t t - T o l e r a n z , u n d bei 4 P a t i e n t e n von einer R t i c k k e h r zu n o r m a l e n W e r t e n . A t r o m i d scheint k r a f t seines breiten Aktivit~itsbereichs ein p o t e n t i e l l wichtiger hypolip~imischer Agens zu sein, dessen W i r k u n g nicht nur die verschiedenen S e r u m lipoide a b e r auch die F e t t - T o l e r a n z umschliesst. REFERENCES 1 R. H. SELLER, J. BRACHFELD, A. SANDBERGAND S. BELLET, Am. J. Med., 27 (1959) 231. 2 L. A. CARLSON, Acta Med. Scan&, 167 (1960) 399. 3 A. ANTONIS AND I. BERSOHN, Lancet, i (1960) 998. 4 M. J. ALBRINK, J. W. MEIGS AND E. B. MAN, Am. J. ]~led., 31 (1961) 4. 5 D. BERKOWITZ, Coronary Heart D,sease, Grune and Stratton, New York, 1962, p. 304. 6 B. ZAK, Am. J. Clin. Pathol., 27 (1957) 583. 7 E. VAN HANDEL AND D. B. ZILVERSMIT, J. Lab Clin. Med., 50 (1957) 152. s D. BERKOWITZ,Am. J. Chn. Nutr., 8 (1960) 327. 9 W. LIKOFF, D. BERKOWITZ, A. WOLDOW, A. G. JACOBS AND D. SKLAROFF, Czrculation, 18 (1958) 1118. 10 D. BERKOWITZ, M. W. CROLL AND W. LIKOFF, Am. J. Clin. Nutr., 10 (1962) 107. 11 D. BERKOWITZ, J. J. SPITZER AND W. LIKOFF, Am. J. Cardiol., 10 (1962) 198. 12 M. F. OLlVER, Lancet, i (1962) 1321. 13 L. HELLMAN, B. ZUMOFT, G. KESSLER, R. S. ROSENFELD AND T. F. GALLAGHER, J. Clin. Invest., 41 (1962) 1364. j . Atheroscler. Res , 3 (1963) 538-541