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Subacute administration of pentaerythritoltetranicotinate (perycit®) to man A study of plasma lipids and level of free nicotinic acid
Atherosclerosis,
20 (1974) 65-68
65
0 Elsevier Scientific Publishing Company, Amsterdam - Printed in The Netherlands
SUBACUTE ADMINISTRATION ATE (PERYCIT@) TO MAN A STUDY
OF PLASMA
LENNART
HARTHON
LIPIDS
AND
OF PENTAERYTHRITOLTETRANICOTIN-
AND LEVEL OF FREE NICOTINIC
ACID
NILS SVEDMYR
Research Department, AB Bofors, Nobel-Pharma, Miilndal, and the Lung
Clinic, Renstriimska Sjukhuset,
Gothenburg (Sweden) (Revised, received September 20th, 1973)
SUMMARY
Pentaerythritoltetranicotinate (PETN) was administered to 8 healthy male volunteers in a dose of 1 g x 3 for 10 days. There was a gradual and significant reduction of the fasting plasma cholesterol level with about 25 % of the basal values when measured in the morning. The triglyceride level was also reduced; however, more variably, and most pronounced in subjects with an initially high level. The plasma FFA-level or blood glucose was not changed in the morning fasting samples. There was a gradual and significant increase in the total pyridine content of whole blood. The content of free nicotinic acid in plasma increased maximally with about 0.85 ,ug/ml 60-120 min after the administration of 1 g PETN but was not elevated in the morning samples taken 14 hr after the last dose. It may be concluded that a moderate but prolonged increase of the nicotinic acid content of plasma is as effective to decrease the plasma lipids as nicotinic acid producing high peak values but rapidly decreasing plasma levels.
Key words : Cholesterol nicotinate
- Hyperlipaenzia - Triglycerides
-
Nicotinic
acid - Pentaerythritoltetra-
INTRODUCTION
Studies in man have indicated that almost maximal pharmacological effects of nicotinic acid were obtained with relatively low concentrations (0.5-1.0 pg/ml) of the free drug in plasma. This independent of if nicotinic acid was administered by intravenous infusion or orally in the form of an ester, pentaerythritoltetranicotinate (PETN)l-a.
66
L. HARTHON,
N. SVEDMYR
With therapeutic effective doses of nicotinic acid, peak concentrations amounting to 15-30 pg/ml of free nicotinic acid are reached in plasmas and it might be that this high concentration is necessary for a therapeutic response. It was therefore of interest to study whether so high plasma levels of nicotinic acid are needed to reduce the plasma lipids or if the large doses of the compound mainly serve to maintain an effective plasma concentration for a sufficiently long time. The effect of nicotinic acid on plasma cholesterol appears usually after some days of medication and maximum effect is not reached until 2-3 week&‘. In the present investigation we have studied the action of a prolonged administration of PETN on the cholesterol and triglyceride levels of plasma in healthy volunteers as well as the plasma level of free nicotinic acid. METHODS
The experiments were performed on 10 healthy male volunteers, aged 25-40 years. The subjects were told to take 1 g x 3 PETN (Perycit@, Bofors) for 10 days. By determining the content of total pyridine compounds in whole blood it was possible to control if they followed the recommended dose schedule. In two subjects the expected increase of pyridine compounds did not occur. On interrogation they admitted that they had not taken the tablets as recommended and were therefore excluded from the study. There was no change in the diet of the subjects during the investigation. Fasting blood samples were taken from a cubital vein in the morning. A basal blood sample was first taken. Thereafter the subjects were told to take the tablets at about 8, 13 and 18 o’clock for 10 days. On the morning of day 3, 6 and 10 new blood samples were taken before the first tablet of PETN. The total pyridine compounds of whole blood reflecting the content of NAD+ and NADH in the erythrocytes were determined according to Harthon et aLa and free nicotinic acid in plasma according to Carlson 9. Total cholesterol in plasma was determined according to Grafnetter et ~1.10and triglycerides according to Eggstein and Kreutzll, FFA of plasma according to Trout et ~1.12,and glucose according to Bergmeyer and Berntrs. RESULTS
The subjects tolerated the medication well. Some of them showed a moderate flush after the first doses of PETN but there were no complaints of gastro-intestinal disturbances during the medication. From the third day there was a statistically significant decrease of the total cholesterol level of plasma, the effect increasing with the duration of the medication. On the 10th day a decrease of approximately 25 % of the basal level was recorded (Table 1). There was also an effect on the triglyceride level, but the decrease was statistically significant only after 10 days. The effect was rather variable and most pronounced in those subjects who had the highest basal triglyceride level. There was
SUBACUTE
TABLE
67
OF PERYCIT TO MAN
I
INFLUENCE
(PETN) 1 g X 3
OF PENTAERYTHRITOLTETRANICOTINATE
OF TOTAL WHOLE
ADMINISTRATION
CHOLESTEROL
AND
TRIGLYCERIDES
AND
THE
CONTENT
FOR
10
OF TOTAL
DAYS
ON PLASMA
PYRIDINE
LEVELS
COMPOUNDS
IN
BLOOD
Parameter
Cholesterol (mg/lOO ml & S.E.M.) Triglycerides (mg/lOOml h S.E.M.) Pyridine compounds (pug/ml & S.E.M.) & P < 0.05. b P < 0.01.
A6 days
Al0 days
* 4.5a
-34
+ 14”
-56
& 31
-46
= 33
--43 & 178
Basal value
A3 dQys
216 * 15
-14
134 C 50
-52
7.8 I 0.3
+6.0*
1.6”
-‘11.9 $ 1.6’
i
13h
10.8 & 2.Q
c P < 0.001.
a marked increase in the total pyridine compounds of whole blood (Table 1) but no change of the content of free nicotinic acid in plasma in the morning samples. This was not surprising as the sample was taken 14 hr after the last dose of PETN and 1 g of the drug causes a measurable increase of nicotinic acid in plasma only for 6-8 hr7. No significant changes of FFA level of plasma or blood glucose was observed in the morning samples. The time-concentration curve was analysed on the 10th day after the morning administration of 1 g PETN. This curve is represented in Fig. 1, showing a maximum increase of 0.64 & 0.25 lug/ml free nicotinic acid after 60 min. This corresponds well to an earlier report3. The individual maximum increase in the free nicotinic acid concentration during the period 60-120 min is amounting to 0.85 f 0.28 ,ug/ml (P i 0.01).
I
I
1
2
3
4
5
6
7 burs
Fig. 1. Increase in plasma concentration of free nicotinic acid in 8 healthy male volunteers (means 7t S.E.) as a function of time after ingestion of 1 g PETN at tirr.e 0 and 6 br ($1
68
L. HARTHON, N. SVEDMYR
DISCUSSION
The results indicated that the moderate increase in the plasma concentration of free nicotinic acid produced by administration during 10 days of the nicotinic acid ester, pentaerythritoltetranicotinate, significantly reduced the cholesterol and triglyceride level of plasma in healthy humans. The reduction of the cholesterol level was of the same magnitude as that reported by FrGberg et al.6 after administration of 1 g x 3 of nicotinic acid to healthy subjects. The peak concentration of nicotinic acid in plasma after administration of nicotinic acid in tablets is, however, much higher than after administration of the ester PETN, whereas the duration of an increased pharmacologically active concentration is about the same3 with the two drugs. It therefore seems more probable that it is the duration of a moderately increased but active nicotinic acid content in plasma and not a high peak concentration of the compound which is of pharmacotherapeutic importance for the treatment of hyperlipaemic conditions. It is also probable that the effectiveness of this type of drugs could be increased further with a still more longacting ester of nicotinic acid giving a plasma concentration of free nicotinic acid of about 0.5 ,ug/ml. REFERENCES 1 SVEDMYR, N., HARTHON, L. AND LLJNDHOLM,L., The relationship between the plasma con-
2 3
4
5
centration of free nicotinic acid and some of its pharmacological effects in man. Clin. Pharmacol. Therap., 10 (1969) 559. SVEDMYR,N., HARTHON, L. AND LUNDHOLM,L., A study of some acute pharmacodynamic effects of pentaerythritoltetranicotinate (Perycit) in man, PharmacoL Clin., 2 (1969) 13. SVEDMYR, N. AND HARTHON, L., Comparison between the absorption of nicotinic acid and pentaerythritoltetranicotinate (Perycit, Bofors) from ordinary and enterocoated tablets, Actu Pharmacol. Toxicol., 28 (1970) 66. EKSTR~~M-JODAL, B., HARTHON, L., HXGGENDAL,E., MahimRG, R. AND SVEDMYR,N., Influence of nicotinic acid and pentaerythritoltetranicotinate (Perycit, Bofors) on the cardiac output in man, Pharmacol. Clin., 2 (1970) 89. ALTSCHUL, B., Influence of nicotinic acid on hypercholesterolemia and on the course of atherosclerosis. In: R. ALTSCHUL (Ed.), Niacin in Vascular Disorders and Hyperlipemia, Thomas,
Springfield, Ill., 1964, p. 3. 6 FRBBERG, S. O., BOBERG,J., CARLSON,L. A. AND ERIKSSON,M., Effect of nicotinic acid on the
7 8 9
10 11 12
13
diurnal variation of plasma levels of glucose, free fatty acids, triglycerides and cholesterol and of urinary excretion of catecholamines. In: K. F. GEY AND L. A. CARLSON (Eds.), Metabolic E&cts of Nicotinic Acid and its Derivatives, Huber, Bern, ‘1971, p. 167. HARTHON, L.. AND SIGROTH, K., On the absorption, excretion and metabolism of pentaerythritoltetranicotinate (Perycit), Arzneimittel Forsch., (1974) In press. HARTHON, L., SIGROTH, K. AND SJ~~BOM,R. A., Ein Beitrag zur Klgrung der Resorption des HexanikotinsZureesters des meso-Inositols im Organismus, Arzneimittef Forsch., 14 (1964) 126. CARLSON,L. A., Determination of free nicotinic acid in blood plasma, Cfin. Chim. Acta, 13 (1966) 349. GRAPNETTER,A. L., FODOR, J.,TEPLY, V. AND ZACEK, K., The effect of storage on levels of cholesterol in serum as measured by simple, direct method, Clin. Chim. Acta, 16 (1967) 33. EGGSTEIN,M. AND KREUTZ, F. H., Eine neue Bestimmung der Neutralfette in Blutserum und Gewebe, Klin. Wschr., 44 (1966) 262, TROUT, D. L., ESTES,E. H. AND FRIEDBERG, S. J., Titration of free fatty acids in plasma. A study of current methods and a new modification, J. Lipid. Res., 1 (1960) 199. BERGMEYER, H. AND BERNT, E., D-Glucose Bestimmung mit Glucose-Oxidase und Peroxidase. In: H. BERGMEYER(Ed.), Methoden der enzymatischen Annlyse, Verlag Chemie, Weinheim,
1962, p. 123.
20 (1974) 65-68
65
0 Elsevier Scientific Publishing Company, Amsterdam - Printed in The Netherlands
SUBACUTE ADMINISTRATION ATE (PERYCIT@) TO MAN A STUDY
OF PLASMA
LENNART
HARTHON
LIPIDS
AND
OF PENTAERYTHRITOLTETRANICOTIN-
AND LEVEL OF FREE NICOTINIC
ACID
NILS SVEDMYR
Research Department, AB Bofors, Nobel-Pharma, Miilndal, and the Lung
Clinic, Renstriimska Sjukhuset,
Gothenburg (Sweden) (Revised, received September 20th, 1973)
SUMMARY
Pentaerythritoltetranicotinate (PETN) was administered to 8 healthy male volunteers in a dose of 1 g x 3 for 10 days. There was a gradual and significant reduction of the fasting plasma cholesterol level with about 25 % of the basal values when measured in the morning. The triglyceride level was also reduced; however, more variably, and most pronounced in subjects with an initially high level. The plasma FFA-level or blood glucose was not changed in the morning fasting samples. There was a gradual and significant increase in the total pyridine content of whole blood. The content of free nicotinic acid in plasma increased maximally with about 0.85 ,ug/ml 60-120 min after the administration of 1 g PETN but was not elevated in the morning samples taken 14 hr after the last dose. It may be concluded that a moderate but prolonged increase of the nicotinic acid content of plasma is as effective to decrease the plasma lipids as nicotinic acid producing high peak values but rapidly decreasing plasma levels.
Key words : Cholesterol nicotinate
- Hyperlipaenzia - Triglycerides
-
Nicotinic
acid - Pentaerythritoltetra-
INTRODUCTION
Studies in man have indicated that almost maximal pharmacological effects of nicotinic acid were obtained with relatively low concentrations (0.5-1.0 pg/ml) of the free drug in plasma. This independent of if nicotinic acid was administered by intravenous infusion or orally in the form of an ester, pentaerythritoltetranicotinate (PETN)l-a.
66
L. HARTHON,
N. SVEDMYR
With therapeutic effective doses of nicotinic acid, peak concentrations amounting to 15-30 pg/ml of free nicotinic acid are reached in plasmas and it might be that this high concentration is necessary for a therapeutic response. It was therefore of interest to study whether so high plasma levels of nicotinic acid are needed to reduce the plasma lipids or if the large doses of the compound mainly serve to maintain an effective plasma concentration for a sufficiently long time. The effect of nicotinic acid on plasma cholesterol appears usually after some days of medication and maximum effect is not reached until 2-3 week&‘. In the present investigation we have studied the action of a prolonged administration of PETN on the cholesterol and triglyceride levels of plasma in healthy volunteers as well as the plasma level of free nicotinic acid. METHODS
The experiments were performed on 10 healthy male volunteers, aged 25-40 years. The subjects were told to take 1 g x 3 PETN (Perycit@, Bofors) for 10 days. By determining the content of total pyridine compounds in whole blood it was possible to control if they followed the recommended dose schedule. In two subjects the expected increase of pyridine compounds did not occur. On interrogation they admitted that they had not taken the tablets as recommended and were therefore excluded from the study. There was no change in the diet of the subjects during the investigation. Fasting blood samples were taken from a cubital vein in the morning. A basal blood sample was first taken. Thereafter the subjects were told to take the tablets at about 8, 13 and 18 o’clock for 10 days. On the morning of day 3, 6 and 10 new blood samples were taken before the first tablet of PETN. The total pyridine compounds of whole blood reflecting the content of NAD+ and NADH in the erythrocytes were determined according to Harthon et aLa and free nicotinic acid in plasma according to Carlson 9. Total cholesterol in plasma was determined according to Grafnetter et ~1.10and triglycerides according to Eggstein and Kreutzll, FFA of plasma according to Trout et ~1.12,and glucose according to Bergmeyer and Berntrs. RESULTS
The subjects tolerated the medication well. Some of them showed a moderate flush after the first doses of PETN but there were no complaints of gastro-intestinal disturbances during the medication. From the third day there was a statistically significant decrease of the total cholesterol level of plasma, the effect increasing with the duration of the medication. On the 10th day a decrease of approximately 25 % of the basal level was recorded (Table 1). There was also an effect on the triglyceride level, but the decrease was statistically significant only after 10 days. The effect was rather variable and most pronounced in those subjects who had the highest basal triglyceride level. There was
SUBACUTE
TABLE
67
OF PERYCIT TO MAN
I
INFLUENCE
(PETN) 1 g X 3
OF PENTAERYTHRITOLTETRANICOTINATE
OF TOTAL WHOLE
ADMINISTRATION
CHOLESTEROL
AND
TRIGLYCERIDES
AND
THE
CONTENT
FOR
10
OF TOTAL
DAYS
ON PLASMA
PYRIDINE
LEVELS
COMPOUNDS
IN
BLOOD
Parameter
Cholesterol (mg/lOO ml & S.E.M.) Triglycerides (mg/lOOml h S.E.M.) Pyridine compounds (pug/ml & S.E.M.) & P < 0.05. b P < 0.01.
A6 days
Al0 days
* 4.5a
-34
+ 14”
-56
& 31
-46
= 33
--43 & 178
Basal value
A3 dQys
216 * 15
-14
134 C 50
-52
7.8 I 0.3
+6.0*
1.6”
-‘11.9 $ 1.6’
i
13h
10.8 & 2.Q
c P < 0.001.
a marked increase in the total pyridine compounds of whole blood (Table 1) but no change of the content of free nicotinic acid in plasma in the morning samples. This was not surprising as the sample was taken 14 hr after the last dose of PETN and 1 g of the drug causes a measurable increase of nicotinic acid in plasma only for 6-8 hr7. No significant changes of FFA level of plasma or blood glucose was observed in the morning samples. The time-concentration curve was analysed on the 10th day after the morning administration of 1 g PETN. This curve is represented in Fig. 1, showing a maximum increase of 0.64 & 0.25 lug/ml free nicotinic acid after 60 min. This corresponds well to an earlier report3. The individual maximum increase in the free nicotinic acid concentration during the period 60-120 min is amounting to 0.85 f 0.28 ,ug/ml (P i 0.01).
I
I
1
2
3
4
5
6
7 burs
Fig. 1. Increase in plasma concentration of free nicotinic acid in 8 healthy male volunteers (means 7t S.E.) as a function of time after ingestion of 1 g PETN at tirr.e 0 and 6 br ($1
68
L. HARTHON, N. SVEDMYR
DISCUSSION
The results indicated that the moderate increase in the plasma concentration of free nicotinic acid produced by administration during 10 days of the nicotinic acid ester, pentaerythritoltetranicotinate, significantly reduced the cholesterol and triglyceride level of plasma in healthy humans. The reduction of the cholesterol level was of the same magnitude as that reported by FrGberg et al.6 after administration of 1 g x 3 of nicotinic acid to healthy subjects. The peak concentration of nicotinic acid in plasma after administration of nicotinic acid in tablets is, however, much higher than after administration of the ester PETN, whereas the duration of an increased pharmacologically active concentration is about the same3 with the two drugs. It therefore seems more probable that it is the duration of a moderately increased but active nicotinic acid content in plasma and not a high peak concentration of the compound which is of pharmacotherapeutic importance for the treatment of hyperlipaemic conditions. It is also probable that the effectiveness of this type of drugs could be increased further with a still more longacting ester of nicotinic acid giving a plasma concentration of free nicotinic acid of about 0.5 ,ug/ml. REFERENCES 1 SVEDMYR, N., HARTHON, L. AND LLJNDHOLM,L., The relationship between the plasma con-
2 3
4
5
centration of free nicotinic acid and some of its pharmacological effects in man. Clin. Pharmacol. Therap., 10 (1969) 559. SVEDMYR,N., HARTHON, L. AND LUNDHOLM,L., A study of some acute pharmacodynamic effects of pentaerythritoltetranicotinate (Perycit) in man, PharmacoL Clin., 2 (1969) 13. SVEDMYR, N. AND HARTHON, L., Comparison between the absorption of nicotinic acid and pentaerythritoltetranicotinate (Perycit, Bofors) from ordinary and enterocoated tablets, Actu Pharmacol. Toxicol., 28 (1970) 66. EKSTR~~M-JODAL, B., HARTHON, L., HXGGENDAL,E., MahimRG, R. AND SVEDMYR,N., Influence of nicotinic acid and pentaerythritoltetranicotinate (Perycit, Bofors) on the cardiac output in man, Pharmacol. Clin., 2 (1970) 89. ALTSCHUL, B., Influence of nicotinic acid on hypercholesterolemia and on the course of atherosclerosis. In: R. ALTSCHUL (Ed.), Niacin in Vascular Disorders and Hyperlipemia, Thomas,
Springfield, Ill., 1964, p. 3. 6 FRBBERG, S. O., BOBERG,J., CARLSON,L. A. AND ERIKSSON,M., Effect of nicotinic acid on the
7 8 9
10 11 12
13
diurnal variation of plasma levels of glucose, free fatty acids, triglycerides and cholesterol and of urinary excretion of catecholamines. In: K. F. GEY AND L. A. CARLSON (Eds.), Metabolic E&cts of Nicotinic Acid and its Derivatives, Huber, Bern, ‘1971, p. 167. HARTHON, L.. AND SIGROTH, K., On the absorption, excretion and metabolism of pentaerythritoltetranicotinate (Perycit), Arzneimittel Forsch., (1974) In press. HARTHON, L., SIGROTH, K. AND SJ~~BOM,R. A., Ein Beitrag zur Klgrung der Resorption des HexanikotinsZureesters des meso-Inositols im Organismus, Arzneimittef Forsch., 14 (1964) 126. CARLSON,L. A., Determination of free nicotinic acid in blood plasma, Cfin. Chim. Acta, 13 (1966) 349. GRAPNETTER,A. L., FODOR, J.,TEPLY, V. AND ZACEK, K., The effect of storage on levels of cholesterol in serum as measured by simple, direct method, Clin. Chim. Acta, 16 (1967) 33. EGGSTEIN,M. AND KREUTZ, F. H., Eine neue Bestimmung der Neutralfette in Blutserum und Gewebe, Klin. Wschr., 44 (1966) 262, TROUT, D. L., ESTES,E. H. AND FRIEDBERG, S. J., Titration of free fatty acids in plasma. A study of current methods and a new modification, J. Lipid. Res., 1 (1960) 199. BERGMEYER, H. AND BERNT, E., D-Glucose Bestimmung mit Glucose-Oxidase und Peroxidase. In: H. BERGMEYER(Ed.), Methoden der enzymatischen Annlyse, Verlag Chemie, Weinheim,
1962, p. 123.