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Atromid in high cholesterol states
580
JOURNAL OF ATHEROSCLEROSIS RESEARCH
ATROMID IN H I G H C H O L E S T E R O L STATES T. B. C O U N I H A N AND P. K E E L A N
Medical Unit, Mater M~sericordiae Hospital, Dublin (Eire)
MATERIAL
Eighteen patients were given Atromid for periods varying from 3 to 9 months (average 6 months). The trial lasted from August 1969. to April 1963. There were 10 males and 8 females in the series. The ages of the males ranged from 32 to 62 (average 51) years and of the females from 45 to 62 (average 53) years. The clinical diagnosis in 16 was ischaemic heart disease. Six of these had essential hypertension also; 1 had diabetes mellitus and 1 aortic valve disease. Of the remaining 2, diabetes mellitus was the diagnosis in one and familial hypercholesterolaemia in the other. Initial cholesterol levels were elevated in 17 cases and normal in 1. Ten patients were on moderate restriction of animal fat (60 g) whilst 13 were taking an anticoagulant, warfarin. METHOD
Serum cholesterol levels were estimated in the I.C.I. laboratories by a modified ABELL technique. Concurrent analyses carried out at random on 17 of these patients in our own hospital laboratory using the SACKETT method 1 showed good correlation. One patient on repeated estimation of serum cholesterol by the FERRO AND HAM technique 2 in another hospital, had consistently elevated values; yet his initial cholesterol levels on I.C.I. readings were both well within the normal range. The daily dose of Atromid varied from 5 to 8 (average 7) 250 mg-capsules taken in divided doses. At least 2 readings were taken in all patients prior to starting Atromid. Thereafter, readings were taken at 2 weeks, 4 weeks and then at monthly intervals. Some patients occasionally defaulted. SGOT readings were taken on 8 patients prior to commencing Atromid and again at the end of the trial period. RESULTS
The results are summarized in Figs. 1 and 2. These illustrate the response in the 17 with elevated serum cholesterol levels. The most striking falls were seen in those with the highest initial readings (e.g., a fall from 756 to 290 mg/100 ml and from 480 to 245 mg/100 ml both within the space of 3 months). In those whose initial level was lower the response was less. One patient with an initial level of 265 mg/100 ml J. Atheroscler. Res., 3 (1963) 580-583
ATROMID IN HIGH CHOLESTEROL STATES
581
showed no alteration after 8 months, whilst another with an initial figure of 250 mg/100ml showed a fall of only 25 mg/100 ml after 7 months. Apart from these two, the fall was at least 50 mg/100 ml in the other patients. As mentioned previously, there was one patient (the 18th case) with normal serum cholesterol on I.C.I. readings, who was given Atromid. He showed a paradoxical
o
~,oo 1
-] Months
Fig. 1. Cholesterol values in 17 patients before and during Atromid treatment, and at the end of the trial period (3-9 months).
response, the cholesterol level climbing to 290 mg/100 ml over a period of 4 months. I t has since fallen to 240 mg/100 ml at which level it has remained. Hospital readings with the FERRO AND HAM technique were elevated before Atromid was given. They have remained so since. We estimated SGOT in 8 cases; 7 gave normal results. One was elevated to 144 units after the patient had taken Atromid for 3 months. Though the drug was not withdrawn, the value returned to normal 3 weeks later. The rise in transaminase was associated with a fall in serum cholesterol from 756 to 290 rag/100 ml. Since 1958 this patient was subject to recurrent attacks of gout. Immediately prior to starting Atromid his blood uric acid was 4.2 rag/100 ml; 9 weeks later he had a mild attack of gout. Questioning did not reveal any precipitating factor for this. The blood uric acid level one month after the attack was 4.7 rag/100 ml. The patient with diabetes mellitus showed an initial improvement in glucose tolerance; the urine became sugar-free and fasting and postprandial blood sugars fell to normal. This was temporary, lasting 5 weeks only; it then became necessary to prescribe chlorpropamide. Xanthomata, which were present initially in two patients regressed on therapy, but, as yet, have not quite d i s a p p e a r e d . J. Atheroscler. Res., 3 (1963) 580-583
582
T . B . COUNIHAN, P. KEELAN
All 13 patients taking warfarin required a reduction in dosage of about one-third when Atromid was added. Before this synergism became known, 3 had bled. There was no mortality in the series. The only morbidity was bleeding in patients who were also taking warfarin. Six patients felt better whilst taking Atromid, their cardiac pain occurring less frequently and being of diminished severity. In 3 of these, the ECG tracing showed improvement. E O O
<, 45O v
4OO
E
?
t~
250 200.
*(D
ISO
Months
Fig. 2. Mean values of s e r u m cholesterol before and during t r e a t m e n t w i t h Atromid, and at t h e end of the trial period. 0 : m e a n values of s e r u m cholesterol; O : n u m b e r of p a t i e n t s tested on each occasion; I: s t a n d a r d deviations ± 1.
ACKNOWLEDGEMENTS
Our thanks are due to DRS. S. BLAKE AND M. I. DRURY for permission to study two patients. SUMMARY
Atromid was given to 17 patients with hypercholesterolaemia and in all the serum cholesterol was reduced; in 1 patient, the initial serum cholesterol level was normal and Atromid led to a paradoxical response. Thirteen patients were receiving warfarin sodium and all required a reduction in anticoagulant dose when Atromid was administered. RI~SUMI~
L'Atromide fut donn6 ~t 17 sujets avec hypercholest6rol6mie. Chez tousle cholest6rol s6rique fut r6duit, chez un sujet le cholest6rol s6rique de d@part 6tait normal et l'Atrornide donna une r@ponse paradoxale. L'administration d'Atromide a abaiss6 le besoin d'anticoagulants chez 13 sujets ayant re~u du. sodium warfarin. J. Atheroscler. Res., 3 (1963) 580--583
ATROMID IN HIGH CHOLESTEROL STATES
583
ZUSAMMENFASSUNG
A t r o m i d w u r d e 17 P a t i e n t e n m i t H y p e r c h o l e s t e r i n / i m i e gegeben. Bei allen w u r d e das S e r u m c h o l e s t e r i n h e r a b g e s e t z t ; bei einem P a t i e n t e n w a r d e r A u s g a n g s w e r t des S e r u m cholesterins n o r m a l u n d fiihrte A t r o m i d zu einer p a r a d o x a l e n R e a k t i o n . Dreizehn P a t i e n t e n erhielten W a r f a r i n - N a t r i u m u n d bei allen w a r die b e n 6 t i g t e Dosis der A n t i k o a g u l a n t i e n niedriger als A t r o m i d gegeben wurde. REFERENCES
1 G. E. SACKETT,J. Biol. Chem., 64 (1925) 203. 2 p. V. FERRO AND A. B. HAM, Am. J. Clin. Pathol., 33 (1960) 545. J. Atheroscler. Res., 3 (1963) 580-583
JOURNAL OF ATHEROSCLEROSIS RESEARCH
ATROMID IN H I G H C H O L E S T E R O L STATES T. B. C O U N I H A N AND P. K E E L A N
Medical Unit, Mater M~sericordiae Hospital, Dublin (Eire)
MATERIAL
Eighteen patients were given Atromid for periods varying from 3 to 9 months (average 6 months). The trial lasted from August 1969. to April 1963. There were 10 males and 8 females in the series. The ages of the males ranged from 32 to 62 (average 51) years and of the females from 45 to 62 (average 53) years. The clinical diagnosis in 16 was ischaemic heart disease. Six of these had essential hypertension also; 1 had diabetes mellitus and 1 aortic valve disease. Of the remaining 2, diabetes mellitus was the diagnosis in one and familial hypercholesterolaemia in the other. Initial cholesterol levels were elevated in 17 cases and normal in 1. Ten patients were on moderate restriction of animal fat (60 g) whilst 13 were taking an anticoagulant, warfarin. METHOD
Serum cholesterol levels were estimated in the I.C.I. laboratories by a modified ABELL technique. Concurrent analyses carried out at random on 17 of these patients in our own hospital laboratory using the SACKETT method 1 showed good correlation. One patient on repeated estimation of serum cholesterol by the FERRO AND HAM technique 2 in another hospital, had consistently elevated values; yet his initial cholesterol levels on I.C.I. readings were both well within the normal range. The daily dose of Atromid varied from 5 to 8 (average 7) 250 mg-capsules taken in divided doses. At least 2 readings were taken in all patients prior to starting Atromid. Thereafter, readings were taken at 2 weeks, 4 weeks and then at monthly intervals. Some patients occasionally defaulted. SGOT readings were taken on 8 patients prior to commencing Atromid and again at the end of the trial period. RESULTS
The results are summarized in Figs. 1 and 2. These illustrate the response in the 17 with elevated serum cholesterol levels. The most striking falls were seen in those with the highest initial readings (e.g., a fall from 756 to 290 mg/100 ml and from 480 to 245 mg/100 ml both within the space of 3 months). In those whose initial level was lower the response was less. One patient with an initial level of 265 mg/100 ml J. Atheroscler. Res., 3 (1963) 580-583
ATROMID IN HIGH CHOLESTEROL STATES
581
showed no alteration after 8 months, whilst another with an initial figure of 250 mg/100ml showed a fall of only 25 mg/100 ml after 7 months. Apart from these two, the fall was at least 50 mg/100 ml in the other patients. As mentioned previously, there was one patient (the 18th case) with normal serum cholesterol on I.C.I. readings, who was given Atromid. He showed a paradoxical
o
~,oo 1
-] Months
Fig. 1. Cholesterol values in 17 patients before and during Atromid treatment, and at the end of the trial period (3-9 months).
response, the cholesterol level climbing to 290 mg/100 ml over a period of 4 months. I t has since fallen to 240 mg/100 ml at which level it has remained. Hospital readings with the FERRO AND HAM technique were elevated before Atromid was given. They have remained so since. We estimated SGOT in 8 cases; 7 gave normal results. One was elevated to 144 units after the patient had taken Atromid for 3 months. Though the drug was not withdrawn, the value returned to normal 3 weeks later. The rise in transaminase was associated with a fall in serum cholesterol from 756 to 290 rag/100 ml. Since 1958 this patient was subject to recurrent attacks of gout. Immediately prior to starting Atromid his blood uric acid was 4.2 rag/100 ml; 9 weeks later he had a mild attack of gout. Questioning did not reveal any precipitating factor for this. The blood uric acid level one month after the attack was 4.7 rag/100 ml. The patient with diabetes mellitus showed an initial improvement in glucose tolerance; the urine became sugar-free and fasting and postprandial blood sugars fell to normal. This was temporary, lasting 5 weeks only; it then became necessary to prescribe chlorpropamide. Xanthomata, which were present initially in two patients regressed on therapy, but, as yet, have not quite d i s a p p e a r e d . J. Atheroscler. Res., 3 (1963) 580-583
582
T . B . COUNIHAN, P. KEELAN
All 13 patients taking warfarin required a reduction in dosage of about one-third when Atromid was added. Before this synergism became known, 3 had bled. There was no mortality in the series. The only morbidity was bleeding in patients who were also taking warfarin. Six patients felt better whilst taking Atromid, their cardiac pain occurring less frequently and being of diminished severity. In 3 of these, the ECG tracing showed improvement. E O O
<, 45O v
4OO
E
?
t~
250 200.
*(D
ISO
Months
Fig. 2. Mean values of s e r u m cholesterol before and during t r e a t m e n t w i t h Atromid, and at t h e end of the trial period. 0 : m e a n values of s e r u m cholesterol; O : n u m b e r of p a t i e n t s tested on each occasion; I: s t a n d a r d deviations ± 1.
ACKNOWLEDGEMENTS
Our thanks are due to DRS. S. BLAKE AND M. I. DRURY for permission to study two patients. SUMMARY
Atromid was given to 17 patients with hypercholesterolaemia and in all the serum cholesterol was reduced; in 1 patient, the initial serum cholesterol level was normal and Atromid led to a paradoxical response. Thirteen patients were receiving warfarin sodium and all required a reduction in anticoagulant dose when Atromid was administered. RI~SUMI~
L'Atromide fut donn6 ~t 17 sujets avec hypercholest6rol6mie. Chez tousle cholest6rol s6rique fut r6duit, chez un sujet le cholest6rol s6rique de d@part 6tait normal et l'Atrornide donna une r@ponse paradoxale. L'administration d'Atromide a abaiss6 le besoin d'anticoagulants chez 13 sujets ayant re~u du. sodium warfarin. J. Atheroscler. Res., 3 (1963) 580--583
ATROMID IN HIGH CHOLESTEROL STATES
583
ZUSAMMENFASSUNG
A t r o m i d w u r d e 17 P a t i e n t e n m i t H y p e r c h o l e s t e r i n / i m i e gegeben. Bei allen w u r d e das S e r u m c h o l e s t e r i n h e r a b g e s e t z t ; bei einem P a t i e n t e n w a r d e r A u s g a n g s w e r t des S e r u m cholesterins n o r m a l u n d fiihrte A t r o m i d zu einer p a r a d o x a l e n R e a k t i o n . Dreizehn P a t i e n t e n erhielten W a r f a r i n - N a t r i u m u n d bei allen w a r die b e n 6 t i g t e Dosis der A n t i k o a g u l a n t i e n niedriger als A t r o m i d gegeben wurde. REFERENCES
1 G. E. SACKETT,J. Biol. Chem., 64 (1925) 203. 2 p. V. FERRO AND A. B. HAM, Am. J. Clin. Pathol., 33 (1960) 545. J. Atheroscler. Res., 3 (1963) 580-583