Clinical and metabolic effects of pentaerythritol tetranicotinate (perycit®) and a comparison with plain nicotinic acid

Atherosclerosis, 19 (1974) 61-73

0 Elsevier Scientific Publishing Company, Amsterdam - Printed in The Netherlands

61

CLINICAL AND METABOLIC EFFECTS OF PENTAERYTHRITOL TETRANICOTINATE (PERYCIT@) AND A COMPARISON WITH PLAIN NICOTINIC ACID

ANDERS

G. OLSSON,

LARS OR0

AND

STEPHAN

RdSSNER

Department of Internal Medicine, Karolinska Hospital and King Gustaf Vth Research Institute, Stockholm (Sweden) (Revised, received February

14th, 1973)

SUMMARY

a daily dose of 3 g lowers the cholesterol and triglyceride concentration in patients with different types of hyperlipidemia. Increasing the PerycitB dose up to 4.5 g causes a further decrease of the lipid levels. A comparison between Perytit@ and pure nicotinic acid showed that Perycit@ in doses up to 6 g is more effective in reducing elevated cholesterol levels. The reduction of the plasma triglyceride and cholesterol concentration is explained by a decrease of VLD triglyceride and cholesterol concentration. The cholesterol concentration also decreased in the LD fraction but increased in the HD fraction. The Ks of the i.v. fat tolerance was not significantly influenced by the Perycit@ treatment in the material studied and changes of the triglyceride concentration were not related to changes in Kz, suggesting that the mechanism of action of Perycit@ on the plasma lipids differs at least partly from that of pure nicotinic acid. As with nicotinic acid, elevated levels of transaminase and alkaline phosphatases were observed with Perycit@ but the increases were not related to the dose used or to the duration of the treatment. Perycit@, in contrast to pure nicotinic acid, did not elevate the uric acid concentration in plasma. Perycit

in

Key words: Intravenous fat tolerance - Nicotinic acid - Pentaerythritol tetranicotinate - Plasma cholesterol - Plasma triglycerides

INTRODUCTION

In 1955 Altschul et al. reported that nicotinic acid in gram doses reduced serum Supported by grants from the Karolinska Institute and King Gustaf Vth 80 Year Fund. Request for reprints should be sent to: Dr. L. Or@ Department of Internal Medicine, Karolinska Sjukhuset, 104 01 Stockholm 60 (Sweden)

62

A. G. OLSSON,

L. OR@ S. RiiSSNER

cholesterol concentrations in animals as well as in manrJ. It is now clearly demonstrated that plasma triglyceride levels are also markedly reduced by nicotinic acids+. From 1962 when we found that nicotinic acid inhibited the mobilization of free fatty acids7 we have been interested in this drug and have treated several hundreds of hyperlipidemic patients with it 314s. From that experience nicotinic acid in high doses seems to be an effective drug to reduce the increased lipoprotein levels seen in patients with different types of hyperlipoproteinemia. However, the value of nicotinic acid in clinical practice is limited to some extent because of its frequent side effects, mainly affecting the gastrointestinal tract. Various derivatives of nicotinic acid have therefore been tried. One of them, pentaerythritol tetranicotinate (Perycit@) also lowers cholesterol as well as triglyceride levels and has now been on the market for some years+is. The purpose of the present investigation was to study the lipid lowering effect of Perycit in more detail, such as dose response, and to make a direct comparison between Perycit and nicotinic acid. MATERIAL

AND METHODS

The subjects treated with Perycit@ had been admitted to the outpatient clinic, Department of Medicine, Karolinska Hospital, because of various ischemic manifestations, usually coronary heart disease. At least 6 months had elapsed since there had been any acute episode, such as a myocardial infarction. During a period of several months of ambulatory control they had been given general recommendations with regard to living and dietary habits. The plasma lipids were then followed until stable levels were seen. There were two groups of patients in this study. One consisted of 28 men and 4 women aged 24-10 years who had not been treated with nicotinic acid before (untreated group). The other group consisted of 28 men and 16 women, aged 46-70 years, and they had all had continuous treatment with nicotinic acid, 3-6 g daily for 3-8 years (nicotinic acid group). In the UIZtreated group there were some cases of asymptomatic hyperlipidemia and 2 patients were treated with diet and drugs for diabetes. However, no insulin-requiring diabetics were included in the study. With the exception of Perycit and nicotinic acid treatment all other treatments remained unchanged during the study. Pentaerythritol tetranicotinate was given in 0.5 g tablets as Perycit@ (Bofors). The nicotinic acid preparation used was Nicangin@ (Draco) which contains 1 g of nicotinic acid buffered with sodium bicarbonate. Both types of tablets were given after the meals to diminish the possible side effects. When starting with the drugs the dose was successively increased, usually from 0.5 g three times daily and after some days to 1 g three times daily. The untreated group was given Perycit in a dose of 3 g for 3 months followed by another 3 month period with 4.5 g. The treatment was then changed for 2-3 months to a corresponding dose of nicotinic acid, 4 g, given as 1 plus 1.5 plus 1.5 g daily. In the nicotinic acid treated group the nicotinic acid treatment was changed for

COMPARISON

2 months

OF PENTAERYTHRITOL

to Perycit

3 g Nicangin

in doses equivalent

corresponded

5.5 and 6.5 g of Perycit after. Lipoprotein

respectively.

WITH NICOTINIC

to the content

to 3 g of Perycit,

analysis

ultracentrifugation

TETRANICOTINATE

of nicotinic

blood

samples

before i*a. Serum

to 4.5, 5.0,

were taken each month

was made by paper electrophoresisi7

as described

acid as follows:

4, 4.5, 5 and 6 g of Nicangin

Venous

63

ACID

and by preparative

lipoproteins

were separated

into

very low, low and high density lipoproteins in the ultracentrifuge at d = 1.006 and d = 1.063. The cholesterol and triglyceride content of these three lipoprotein families were then analysedi@J~cJ. Classification of the type of hyperlipoproteinemia was done in the untreated patients as recommended in the WHO reportlg, with 1.24 mmol/l as the upper normal limit for triglycerides in the VLD and with 219 mg per 100 ml as the upper normal limit for cholesterol

in the LD lipoproteins.

Also other laboratory parameters, such as serum transaminases and alkaline phosphatases and uric acid were routinely followed with the same time interval as the plasma lipids. Intravenous

glucose tolerance

(i.v.g.t.) was performed

the study according to Ikkos and Luftao. The intravenous fat tolerance test (i.v.f.t.t.) detai121-2a. One ml of 10 % Intralipidm

emulsion

has previously

before and during been described

in

per kg body weight was given intra-

venously as a pulse injection and venous blood samples were taken every 5 min for 40 min. The samples were centrifuged and plasma turbidity was measured in a Thorp micronephelometer. A blank plasma sample was subtracted from each reading. The elimination

of the emulsion

of the emulsion

is eliminated

follows first order kinetics, every minute.

min. There is evidence

that the i.v.f.t.t.

tion and thus provides

information

No Perycit

was taken in the morning

Statistical

calculations

so that a constant

The elimination

reflects the endogenous

about changes in the plasma when the i.v.f.t.t.

were made as recommended

percentage

rate is expressed plasma

as Ka %/

TG elimina-

TG removal

system.

was performed. by Snedecorzl.

RESULTS

Clinical eflects Owing to side effects and for other reasons some patients were excluded from the study. In the untreated group 20 patients followed the scheme during treatment with Perycit and in the nicotinic acid group there were 35 patients who changed to Perycit for 2 months. In the untreated group 4 stopped the treatment with Perycit because of general fatigue, 2 because of flush and 1 developed a manifest diabetes which was then successfully treated with tablets. One patient got myocardial infarction, in one a cancer was diagnosed and 3 were not interested in continuing the treatment. When the 20 patients were then given nicotinic acid 5 had to stop because of gastrointestinal side effects and 1 stopped because of lack of interest. The nicotinic acid group consisted initially of 44 patients who had been treated with nicotinic acid for several years and who were willing to cooperate in this study. This group was thus already selected with regard to the side effects produced by nicotinic acid. In about

64

A. G. OLSSON, L. OR& S. RijSSNER

20 % of the cases this treatment could not be continued, usually due to gastrointestinal disturbances4**. When the treatment was changed to Perycit 9 of the 44 patients did not want to continue with Perycit, usually because of nausea. One of the patients got a myocardial infarction and was excluded from the last part of the study. No one stopped because of flush. Transaminases (Table 1) Untreated group. Before treatment with Perycit one GOT value was abnormal and 5 out of 19 determinations showed moderately elevated GPT levels. After 1 month’s treatment with 1 g x 3 of Perycit 7 out of 20 determinations were abnormal with respect to GPT but after 3 months only 3 values were abnormal. At the end of continued treatment with 4.5 g Perycit only 2 out of 18 determinations were abnormal. In a small number of patients there were transient elevations of the GOT levels. The change of the Perycit treatment to nicotinic acid was also without systematic effect on the transaminases. Nicotinic acid group. The patients for whom previous long term treatment with nicotinic acid was changed to Perycit were divided into two groups, those with 3 g and those with 4-6 g nicotinic acid. There were no significant changes of GOT and TABLE NUMBER

1 OF ABNORMAL

END OF PERIODS

(see

SERUM text)

0F

TRANSAMINASES, TREATMENT

WITH

GOT

AND

PERYCIT

GPT

AND

ALKALINE

AND NICOTINIC

PHOSPHATASES

AT THE

ACID

The table also gives the mean values of uric acid concentration. The last value during each treatment period was used. The P values give the statistical significance of the individual differences between the levels during the different periods. A. ph. = alkaline phosphatases; Per = Perycit; Nit = nicotinic acid. Untreatedgroup (patientsnot treatedpreviously with nicotinic acid)

Nicotinic acidgroup (patientstreated with nicotinic acid for 3-8

years)

Before Per 3g

Per 4sg

Nit 4g

Nit <3g

Per <3g

Nit <3g

Nit 24g

Per r,4g

Nit >4g

N

19

20

18&

15b

19

19

16c

16

16

16

GOT>20d GPT> 17d A.ph. > 40d Uric acid (mg/lOO ml) mean S.E.

1 5 1

2 3 1

1 2 1

1 1 1

4 2 5

1 1 6

1 1 2

3 3 4

2 2 4

6.38 0.58

6.24 0.40

6.27 7.14 0.51 0.61 P < 0.02

4 3 10

6.10 5.27 6.20 0.29 0.29 0.34 P < 0.01 P < 0.001

6.48 5.41 6.95 0.28 0.38 0.59 P < 0.01 P < 0.02

& Two patients remained on 3 g because of satisfactory effect. b Three patients did not tolerate nicotinic acid. c Two patients did not want to have nicotinic acid again. One patient stopped because of diabetes. d Normal range; GOT 4-20, GPT 2-17 and A.ph. lo-40 U/l.

COMPARISON

OF PENTAERYTHRITOL

TETRANICOTINATE

WITH NICOTINIC

ACID

65

GPT in either of the two groups. During all treatment periods a small number of patients with moderately elevated levels were seen. Alkaline phosphatases (Table I) Untreatedgroup.

In this group the Perycit treatment did not influence the phosphatase levels. Occasionally a moderate elevation was seen in 3 different patients during the study. During the continued treatment with nicotinic acid for 2 months there was I abnormal observation. Nicotinic acid group. In the group receiving 3 g the alkaline phosphatases were elevated in 5 out of 19 patients. After 2 months’ treatment with 3 g Perycit 10 out of 19 determinations were abnormal and 6 out of 16 after return to nicotinic acid. In the group with higher doses of nicotinic acid and Perycit the number of patients with elevated levels tended to be smaller. Uric acid (Table I) Untreated group. Before treatment

with Perycit the uric acid concentration was about 6.4 mg/lOO ml. This level remained quite unchanged during the whole period with Perycit in 3 as well as 4.5 g dose. However, after 1 month’s change to Nicangin the level had increased in 14 patients from 6.27 to 7.14 mg/lOO ml. In 10 patients who turned back to Perycit the uric acid concentration changed from 7.37 to 6.02 mg/lOO ml (P < 0.03). Nicotinic acid group. When 19 patients with 3 g of nicotinic acid daily changed the treatment to the corresponding dose of Perycit, the uric acid concentration fell from 6.10 to 5.27 mg/lOO ml. When they returned to Nicangin it increased to 6.20 mg/lOO ml. When the other group with 4 g of nicotinic acid daily changed to Perycit the uric acid concentration fell from 6.48 to 5.41 mg/lOO ml and increased to 6.95 mg/lOO ml when the patients started with nicotinic acid again. If both the 3 and 4 g groups are taken together the corresponding figures for uric acid concentration are 6.27 to 5.32 (P < 0.001) and 5.41 to 6.53 mg/lOO ml (P < 0.001). TABLE

2

UNTREATED

K-value

GROUP.

INTRAVENOUS

GLUCOSE

TOLERANCE

before and during treatment with Perycit,

4.5 g daily

Before

Dwing < 0.9 0.9-1.1

> 1.1

< 0.9

0.9-I.I

> I.1

5

1 1

6 1

1

4

66

A. G. OLSSON, L. OR& S. RijSSNER

Intravenous glucose tolerance test (Table 2) For 19 of the patients in the untreated group, the mean K value changed from

1.38 + 0.18 to 0.98 f 0.11 (P < 0.05) during treatment with Perycit. Before treatment there were 6 individuals with a K value below 0.9 and for 5 of them the values remained unchanged during treatment while one showed an increase. There were 2 patients with a K value between 0.9 and 1.1 and for one of them the value was unchanged while for the other the value decreased. Before treatment there were 11 patients with a K value above 1.1; for 7 of them the values decreased and for 4 these remained unchanged. Plasma lipids Untreated group (Tables 3A and 3B and Fig. 1). Perycit in a daily dose of 3 g caused a variable decrease of the plasma cholesterol and the triglyceride concentration.

TABLE 3A UNTREATED AND

GROUP.

TRIGLYCERIDES

EFFECT

OF PERYCIT

AND NICOTINIC

ACID

ON PLASMA

CHOLESTEROL

(mg

per

100 ml)

(IlXIlOl/~)

The figures give the mean values and S.E. of the mean&. Per = Perycit; Nit = nicotinic acid.

Cholesterol

Triglycerides

No. of patients

Before

20 18 15 10

304 308 313 309

& & * f

20 18 15 10

4.08 4.25 4.26 4.79

& f 5 5

Per3g 3 months

Per 4.5 g 3 months

Niclg 1-2 months

18 20 24 25

288 295 303 293

275 f 24 284 f 28 269 * 33

297 * 27 277 * 28

249 & 26

0.74 0.81 0.95 1.38

3.36 3.55 3.65 3.82

2.52 + 0.21 2.57 f 0.21 2.42 zk 0.25

2.91 5 0.50 3.14 + 0.71

3.07 f 0.66

f 20 i 21 & 25 f 28 + f * *

0.60 0.65 0.75 1.09

B For each subject the mean value from the different determinations was used.

Per 4.5g

I month

during the respective period

TABLE 3B UNTREATED

GROUP.

MEAN

VALUES

AND

S.E.M.

CALCULATED

ON INDIVIDUAL

DIFFERENCES

AND

LEVELS

OF SIGNIFICANCE

Periods of treatment

No. of patients

Cholesterol

(mg/lOO ml)

diff. & S.E.M.

Before vs. Per 3 g Per 3 g vs. Per 4.5 g Per 4.5 g VS.Nit 4 g

20 18 15

-16.2 -19.3 +13

* Calculated on logarithmic values.

level of sign.

* 6.01 P < 0.05 * 0.36 P < 0.01 * 5.05 P < 0.05

Triglycerides

(mmolll)

diff. * S.E.M.

level of sign.&

a.73 f 0.23 -1.03 & 0.53 +0.34 I_t0.41

P < 0.01 P < 0.05

Not significant

COMPARISON

OF PENTAERYTHRITOL

TETRANICOTINATE

WITH NICOTINIC

67

ACID

Fig. 1. Per cent changes of cholesterol and triglycerides during treatment with Perycit@, 1.5 g 3 times daily in 18 patients. Two patients (&I) received only 3 g daily.

In 2 of the patients the lipid levels were normalized with this dose. They had Type IV hyperlipoproteinemia. In the remaining 18 patients the dose was increased, and this had a significantly better effect on the plasma lipid concentrations. In 12 of the 18 patients the triglyceride decrease was more than 20% with the higher Perycit dose, and in 6 of them it was more than 40%. Five of the patients responded with a cholesterol decrease of more than 20%. Two of them had Type II, two Type IV and one had Type III hyperlipoproteinemia. When the Perycit treatment was changed to nicotinic acid in equivalent dose the mean cholesterol concentration increased slightly. The triglyceride level also tended to increase, but the difference was not statistically significant. TABLE 4 NICOTINIC (NICANGIN)

ACID

GROUP.

ON PLASMA

COMPARISON CHOLESTEROL

BETWEEN (lllg/lc@

THE l-d)

EFFECTS

OF

PERYCIT

AND TRIGLYCERIDE

AND

(TG)

PURE

(IllBlOl/l)

NICOTINIC

ACID

CONCENTRATION

The figures give the mean values & S.E.M. and the statistical significances are calculated on the individual differences. .-___. ___-__ _

Beforea Nicangin Perycit Diff. Per-Nit Level of sign.”

Dose < 3glday (N = 19)

Dose >

Chol.

TG

Chol.

TG

Chol.

TG

303 i 8.5 252 * 8.7 219 I 10.3

2.60 i 0.33 1.38 + 0.14 1.37 f 0.12

287 5 14.3 258 _C8.5 247 & 9.6

3.03 + 0.51 1.67 & 0.18 1.98 i_ 0.32

295 i 8.1 255 * 6.0 232 * 7.4

2.80 A: 0.30 1.51 *. 0.11 1.65 i_ 0.16

-32

1 6.7 -0.02

P C 0.001

* 0.08

Not sign.

a Several months or years. b For TG calculated on logarithmic values.

-11

4 g/day ( N = Id)

* 5.6

Not sign.

0.31 + 0.15 P < 0.05b

Total (N = 35)

-23

+ 4.8

P < 0.001

0.13 & 0.09 Not sign.

68

A. G. OLSSON, L. OR@ S. RiiSSNER

Nicotinic acid group (Table 4). When Perycit was given there was a further reduction of the cholesterol level from 255 to 232 mg/lOO ml. This reduction was statistically significant for the whole group and in the subgroup with 3 g of nicotinic acid. In patients with 4 g or more of nicotinic acid there were no statistically significant changes of the cholesterol concentration. The triglyceride concentration for the whole group and the subgroup with 3 g of nicotinic acid was unchanged during the Perycit treatment but increased in the group with the higher dose. This increase was statistically significant (P < 0.05) only when logarithmic values for the TG concentration were used. Lipoproteins Untreated group (Table 5 and Fig. 2). From the qualitative point of view there were similar changes of the lipoprotein patterns in the different types of hyperlipoproteinemia during treatment with Perycit, 4.5 g daily. In Type IIa and IIb both cholesterol and TG concentration tended to decrease in VLD lipoproteins, there was a significant fall of the cholesterol concentration in the LD and a significant rise of the cholesterol in the HD lipoproteins. A similar type of response was seen in the subject with Type III hyperlipoproteinemia with the pronounced fall of the cholesterol concentration in the VLD fraction. In Type IV only the TG and cholesterol fall in the VLD fraction and the cholesterol decrease in the LD fraction were statistically significant. Intravenous fat tolerance (Table 6)

This was performed in 15 of the patients. Although the triglyceride concentration decreased significantly in these 15 patients the KZvalue did not change significantly. Among the 15 patients there were 5 who had almost unchanged triglyceride concentration during treatment with Perycit. If these non-responders were excluded from the calculations there was still no significant change of the mean Kz. No relationship

PERYCIT”l.59.3 CHANGE OF LIPOPROTEIN PATTERNS DURING TREATMENT (n=20)

Fig. 2. Untreated group. Changes of lipoprotein patterns after Perycit@ treatment in 18 patients with 4.5 g daily and 2 patients (Type IV) with 3 g daily.

5

Before treatment During treatment P&

Before treatment During treatment

0.73

199.0 * 13.73 < 0.01

2.64 i 0.31 0.025 < P < 0.05

38.42

230.27 & 10.63

247

430

362.67 i < 0.05

406.67 & 35.27

0.49

3.85 i

3.79

6.58

1.69 & 0.22 0.05 < P < 0.1

3.18 i

Chol.

DURING

0.55

1.76 & 0.30 < 0.01

3.15 &- 0.48

3.03

5.50

0.83 f 0.16 0.05 < P < 0.1

1.87 i

TG

VLD

16.86

0.47 zk 0.06 0.43 f 0.03 ; 0.05

33.82 $ 4.74 < 0.01

0.46

0.36

0.61 xk 0.04 > 0.05

0.85 * 0.12

TG

59.64 * 7.21

90

228

19.67 & 4.18 0.05 < P < 0.01

54.67 f

Chol.

LD

11.14 109.36 + 10.11 < 0.01

137.18 i

73

115

269.33 rt 30.16 < 0.01

33.92

LOW

0.04 0.28 zk 0.04 > 0.05

0.28 i

0.38

0.32

0.23 i 0.03 > 0.05

f

3.84

AND

48.55 i > 0.05

46.45 i

58

45

5.56

7.11

59.33 zt 3.53 0.010 < P < 0.025

46.5

Chol.

DENSITY (LD)

0.21 h 0.04

TG

HD

DENSITY (VLD),

304.83 i

Chol.

(mgperlOOm1) AND VERYLOW WITH PERYCIT 1.5 g 3 TIMES DAILY

CHOLESTEROL

TREATMENT

PLASMA

& Statistical significance of individual changes, before and during.

IV n = 11

n=l

III

IIa + Ilb Before treatment n=2 During n=4 treatment P&

TG

Total

LIPOPROTEINS BEFORE AND

GROUP.TOTALTRIGLYCERIDES(~~~~~~O~/~)AND

HIGH DENSITY (HD)

UNTREATED

TABLE

5

z

g

g

%

5

8

A. G. OLSSON, L. ORij, S. RtiSSNER

70 TABLE

6

VALUES

FOR

(Kz)

BEFORE

FASTING

PLASMA

AND DURING

TRIGLYCERIDE

TREATMENT

WITH

CONCENTRATIONS PERYCIT

(l-1.5

AND g

X

3)

THE FOR

INTRAVENOUS

2-3

FAT

TOLERANCE

MONTHS

Triglyceride (TG) values are the means of samples obtained on 3 different days.

Before treatment

During treatment

TG

Kz + S.E.M.

TG

Kz * S.E.M.

BB LDa BE= ME& GE TG KH SJ BL EN KO KAO GS JS AS=

1.78 2.68 4.36 3.53 1.95 2.40 5.45 2.10 7.02 6.04 1.48 3.17 3.07 4.35 2.24

6.21 3.75 2.65 1.58 3.03 2.35 1.74 2.28 1.57 2.33 7.23 3.33 2.63 1.99 1.69

5 0.33 f 0.29 & 0.23 h 0.10 & 0.07 5 0.11 * 0.15 i 0.08 zk 0.16 f 0.10 & 0.72 i 0.42 i 0.08 & 0.08 zk 0.14

1.45 3.54 4.84 3.55 2.28 1.36 2.40 1.54 3.18 3.07 0.94 1.94 2.00 2.36 5.52

6.65 2.03 1.79 1.84 3.08 2.78 1.97 5.58 2.62 2.66 5.43 2.59 3.77 1.48 2.16

All subjects mean & S.E.M. (n = 15)

3.43 * 0.43

2.96

0.43

2.46 + 0.27

3.09

0.41

All responders mean & S.E.M. (n = 10)

3.67 & 0.61

3.17

0.62

2.02 & 0.23

3.55

0.55

Subject

* * f f + i i * zt + zt & & f &

0.32 0.05 0.25 1.11 0.21 0.04 0.09 0.37 0.17 0.06 0.25 0.11 0.24 0.31 0.14

* Non-responders.

between the TG changes and the changes of KZ could be demonstrated, neither in the whole material of 15 subjects, nor in the subgroup of 10 responders. The r-values (ATGlAKe) were r = 0.25 and r = 0.00. DISCUSSION

In agreement with previous studies Perycit in a daily dose of 3 g was found to lower the plasma cholesterol and triglyceride concentration. This dose is evidently not an optimal dose as the higher dose of 4.5 g daily produced a further decrease of the two lipid fractions. From the qualitative point of view the different types of hyperlipoproteinemia studied appeared to respond in a similar way to the Perycit treatment. The decrease of the triglyceride level was due mainly to a reduction of the TG in the VLD lipoproteins. A proportional decrease of the cholesterol concentration was seen in the VLD fraction but the cholesterol decrease in the LD fraction also contributed to the net cholesterol effect. In the patients with elevated cholesterol concentration, Types II, there was a small but significant increase of the cholesterol concentration in the HD fraction, which is considered not to be atherogenic. As is also seen with

COMPARISON

OF PENTAERYTHRITOL

TETRANICOTINATE

WITH NICOTINIC

nicotinic acid18 the only patient with type III had the most pronounced cholesterol concentration. The mechanism

of action

known, several mechanisms & of the i.v. fat tolerance increased removal

removal

material

acid on plasma

of fat from the blood lipoproteins

is of importance. could

but no such effect of similar

studied.

Effects

on for example

A similar

have explained order

concentration

With Perycit vation

transient

of plasma.

such high peak concentrations

is obtained,

When plain nicotinic

rise of the nicotinic

increase

lowering in the

of lipoproteins

may

acid and the nicostudies between acid in lowering

the the

acid is given by mouth

acid concentration

in the bloodz7.

are not seen but a more prolonged

which may be of importance

in the

with Perycit

the plain nicotinic

tinic ester Perycit may also be suggested by the comparative two drugs as Perycit was evidently more effective than nicotinic there is a pronounced

is not exactly

the lipid

was found

the liver synthesis

therefore be of greater importance. A difference with regard to action between

total cholesterol

lipids

decrease of

have been discussed3,22,25,26. The significant increase of test during nicotinic acid treatmentz2 suggests that an

of the endogenous

effect of Perycit,

of nicotinic

71

ACID

for the different

ele-

effects of the two

drugs. According to our previous experience 4,6ysJs, diabetes not requiring insulin is not a contraindication for using nicotinic acid to correct a coexisting hyperlipidemia. In this study there were two such patients

and they responded

to the Perycit

treat-

ment in the same way as the non-diabetic subjects. As many patients with atherosclerosis diseases are diabetics or prediabetics it is not surprising that one of the subjects got a manifest diabetes during the study. With regard to the i.v. glucose tolerance there were changes in all directions of similar magnitude as reported from studies on reproducibility with i.v.g.t. Thus Perycit appeAred similar to nicotinic acid with regard to diabetes and i.v. glucose tolerance. During treatment with nicotinic acid there is an increase of uric acid levels, an effect which seems to be explained

by a decreased

uric acid clearance

in the kidneysz8.

During treatment with Perycit no increase in serum uric acid levels was seen. Furthermore when changing from Nicangin to Perycit or Gee V~YSL~ serum uric acid levels were always higher with nicotinic acid. The reason for this is not known, but it is tempting to believe that with Perycit the critical concentration of nicotinic acid in the blood is never reached to produce a competitive inhibition of uric acid secretion in the kidneys, directly or indirectly. Like nicotinic acid, Perycit may also raise alkaline phosphatases and moderately elevated levels were seen during both types of treatment. However, this elevation did not appear to be related either to the duration of the treatment, or to the dose of the two drugs used. However, it must be pointed out that with nicotinic acid and also with Perycit marked increases of alkaline phosphatases and transaminases have been observed which has made it necessary to stop the treatment. The design of the present study does not permit a direct comparison to be made between Perycit and nicotinic acid as regards the subjective side effects. It is,

A. G. OLSSON, L. ORij, S. RijSSNER

72

however, clear that several of the patients preferred one of the two drugs which means that both the drugs could be tried even if the patient has had difficulties with one of them. Although Perycit like nicotinic acid is an effective drug to lower elevated plasma lipids only 7 out of 20 patients became normal with 3-4.5 g Perycit daily. With pure nicotinic acid higher doses are frequently used, up to doses of over 10 g especially in cases with Type IIA hyperlipidemias. It is therefore possible that also doses higher than 4.5 g of Perycit can be used, and in this study doses up to 6 g were given without any additional problems. Another possibility to increase the effectiveness of lowering the plasma lipids with drugs is to use different combinations and our experience of Perycit in combination with clofibrate and a similar substance will be reportedaa.

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lipoprotein lipase of Nicotiuic Acid

and its Derivatives, Hans Huber, Bern, 1971, p. 466. 23 CARLSON, L. A. AND R~~SSNER, S., A methodological study on an intravenous fat tolerance test with the Intralipid@ emulsion, Stand. J. Clin. Lab. Invest., 29 (1972) 271. 24 SNEDECOR,G. W., Statistical Methods, The Iowa State University Press, Ames, Iowa, 1961. 25 BRATTSAND,R., et al., Influence of nicotinic acid on postprandial hyperlipemia and lipoprotein lipase activity in the rat. In: K. F. GEY AND L. A. CARL~~N(Eds.), Metlbolic Effects of Nicotinic Acid and its Derivatives, Hans Huber, Bern, 1971, p. 525. 26 FKBBERG,S. O., BOBERG,J., CARLSON,L. A. AND ERICSON, M., Effect of nicotinic acid on the

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 Effects of Nicotinic Acid and its Derivatives, Huber, Bern, 1971, p. 167. 27 CARLSON, L. A. AND OR& L., Acute effect of a sustained release pyridyl carbinol preparation, Ronicol Retard@, on plasma free fatty acids, Acta Med. &and., 186 (1969) 337. H. M. AND THOMAS,G. B., Oral glucose tolerance, plasma 28 GAW, Z. N., POCELINKO,R., SOLOMON, insulin, and uric acid excretion in man during chronic administration of nicotinic acid, Metabolism, 20 (1971) 1031. 29 OLSSON, A. G., 0~6, L. AND R~~SSNER, S., Clinical and metabolic effects of pentaerythritoltetra-

nicotinate in combination

with cholesolvin or clofibrate, In manuscript.