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Inefficiency of cynarin as therapeutic regimen in familial type ii hyperlipoproteinaemia
249
Atherosclerosis, 26 (1977) 249-253 0 Elsevier/North-Holland Biomedical Press
Short Communication __-_-
____~
INEFFICIENCY OF CYNARIN AS THERAPEUTIC FAMILIAL TYPE II HYPERLIPOPROTEINAEMIA
H. HECKERS, K. DITTMAR,
REGIMEN
IN
F.W. SCHMAHL and K. HUTH
Zentrum fiir Innere Medizin (Direktoren: Prof. Dr. H.G. Lasch and Prof. Dr. G. Schiitterle) der Uniuersitiit Giessen; Institut fiir Humangenetik (Direktor: Prof. Dr. W. Fuhrmann) der Uniuersittit Giessen; Diakonissenhaus Frankfurt (Leitender Arzt: Prof. Dr. K. Huth), Frankfurt/Main (West-Germany)
(Received 12th August, 1976) (Accepted 14th September, 1976)
Summary Seventeen ambulant outpatients with familial Type IIa or Type IIb hyperlipoproteinaemia were treated with Cynarin, the 1,5dicaffeyl ester of quinic acid, the constituent of the artichoke (Cynaru scolymus). The dose tested was 250 mg and 750 mg daily. The mean serum cholesterol and triglyceride concentrations were not significantly changed within 3 months. Cynarin, administered per OS, has no hypolipidaemic effect in familial Type II hyperlipoproteinaemia. Key words:
Cynarin
-Serum
lipids -
Type
II hyperlipoproteinaemia
Introduction In the treatment of Type II hyperlipoproteinaemia, which is associated with an accelerated incidence of coronary heart disease, many therapeutic regimens have been explored. No treatment regimen can be said to be completely acceptable, to have no side effects, and to be effective in lowering serum cholesterol levels to below 250 mg/dl in all patients. In the search for new effective hypolipidaemic drugs, we conducted a study of the effect of Cynarin * in patients whose blood lipid levels were well established with dietary treatment alone. Preliminary data support the assumption that Cynarin, the 1,4dicaffeyl ester of quinic acid [lo], the active constituent of the artichoke (Cynaru scolymus), should be an important agent in lowering * Cyn&n
was kindly supplied by Pharma-Schwarz GmbH, Monheim. originating from Farmitalia, Correspondence to: Dr. H. Heckers, Zentrum fiir Innere Medizin des Justus Liebig-Universitiit Klinikstrasse
36. D-6300
Giessen. West-Germany.
Milan. Giessen,
250
cholesterol levels without undesirable side effects [4,8,15,17]. The most effective decrease was found with a 59% mean reduction of serum cholesterol levels in Type IIa patients within a mean period of 7 months [ 71. Patients
and Methods
Seventeen ambulant outpatients with Type IIa (15 persons) or Type IIb (2 persons) hyperlipoproteinaemia were studied. Diagnosis of the condition was based upon determination of the fasting (12-16 h) total serum cholesterol [1] and triglyceride [ 51 levels and electrophoresis of lipoproteins [ 61. Studies of the patients’ families were performed to determine hereditary conduction. All but one fulfilled the criteria for familial hypercholesterolaemia. All patients had no obvious secondary disorders. Age, sex, clinical features and the initial lipid values of Type II hyperlipoproteinaemia are shown in Tables 1 and 2. Additionally, all patients were on a standardized basic fat-modified diet which had been started more than 6 months previously. Relative body weight was calculated using the Broca Index, which ranged from -15% to +5% within the tested groups. The weight of all patients was maintained the range of +l kg at the beginning of the test. Cynarin was administered per OS 15 min before the meals. The dose tested was 250 mg (Table 1) and 750 mg (Table 2) (3 times 250 mg) daily. All patients returned to the clinic once in a month. Adherence to the drug regimen was evaluated according to the patients’ request for more of the drug. Serum cholesterol and triglyceride levels and lipoprotein electrophoresis were obtained on at least two occasions during a 4- to 6-week period and had to be on a constant level before the administration of Cynarin was started. Other regularly monitored parameters were: serum protein electrophoresis, bilirubin, potassium, sodium, calcium, alkaline phosphatase, y-glutamyl transpeptidase (T-GT), glutamate dehydrogenase (GLDH), transaminases (GPT, GOT), creatine phosphatase (CPK) enzymes, urea, uric acid, and creatinine. Haemoglobin determination and leukocyte and platelet counts were carried out simultaneously. Results and Discussion As shown in Tables 1 and 2, the mean serum cholesterol and triglyceride concentrations in patients with Type II hyperlipoproteinaemia had not significantly changed within 3 months, neither with 250 mg nor with 750 mg Cynarin daily. In 4 patients, a further increase of the Cynarin dose to 1.5 g daily for another 3 months at the end of this study did not change the negative over-all response. Our results are in good agreement with the findings of Pommeranze and Chessin [ll] but in contrast to those of other authors who found Cynarin very effective in decreasing cholesterol [2,3,8,14,16] and triglyceride [9] levels in humans and in animals [4,12,13] at a dosage of 60 mg [7] to 1.5 g daily. We are unable to explain our negative findings, which diverge from those of others. The 250 mg Cynarin tablets tested were completely soluble in 0.7 M phospate buffer (500 ml) at pH 6.5 and 37°C within 5 min (X = 298 nm), supposing complete intestinal solubility. Measurements of Cynarin blood levels and further pharmacokinetic data after oral administration of the drug to animals
1
AMP AXTP A A
AXTP ATMP AMP ATMP
49 39 47 55 36 52 54 25 15
~0 CYNARIN
Clinical features =
LIPIDS
Age (years)
OF SERUM
(250 mg DAILY)
IN PATIENTS
461 533 290 478 268 295 500 416 279 391 -+36
381 _+33
I
On C~narin
448 463 298 514 282 286 496 357 288
entry
On
379 _+39
450 488 245 513 264 287 540 354 273
2
therapy
154 +17
265 470 272 281 520 350 259 375 k38
Oil entry
198 179 188 234 107 151 151 113 66
461 496
3 months
TYPE 11~HYPERLIPOPROTEINAEMIA
174 t20
186 96 100 154 +18
2 201 273 217 192 198 130 198 81 73
264 188 122 179 141 111
1
On Cynarin therapy
156 +16
192 122 70
141 188 183 229 145 137
3 months
Serum triglyceride concentrations (mg/dl)
WITH FAMILIAL
Serum cholesterol concentrations (mg/dl)
THERAPY
a A = arcus cornealis; X = xanthelasmas: M = myocardial infarction: P = angina pectoris; T = tendon xanthomas.
r SD
MeaIl
Patient No.
RESPONSE
TABLE
2
LIPIDS
TO
368
AP
AT
55
24
34
3
4
infarction;
IN
Cynarin
374
96
i32 T = tendon
382
t46
?21 xanthomas.
188 167
+-36
188
126
t91
232
64
137 141
279
91
164
120
391
73
137 100
94
328
431
151
848 94
198
364
179
292
3 months
(mg/dl)
IIb HYPERLIPOPROTEI-
153
420
140
107
315
2
therapy
226
Cynarin
134
364
1
On
TYPE
concentrations
Ha AND
triglyceride
TYPE
230
66
166
254
entry
On
Serum
FAMILIAL
160
564
293
394
*25 pectoris;
WITH
3 months
379
294
422
325
404
522
356
350
360
2
therapy
(mg/dl)
PATIENTS
concentrations
DAILY)
P = angina
+21
a A = arcus
365
296
439
+-29
298
8 372
388
AP
AX
54
34
7
326
* SD
328
Mean
455
AP
A
58
51
446
331
333
327
1
On
424
5
corneaIfs;
mg
cholesterol
(750
518
6
M = myocardial
320 300
AXMP
63
2
entry
On
1
Serum
features
a
THERAPY
(years)
CIinicaI
CYNARIN
Age
X = xanthelasmas;
SERUM
NO.
OF
Patient
NAEMIA
RESPONSE
TABLE
253
and humans are hitherto unknown because a reliable microscale method for the determination of Cynarin is not available. The Cynarin therapy was well tolerated by all patients without any undesired side-effects. All additionally monitored parameters, as listed under methods, remained within normal ranges. We can state that Cynarin, administered per OS, has no hypolipidaemic effect in familial Type II hyperlipoproteinaemia. References 1 Boehringer Biochemica Test Combination. 2 Caruzzo, C.. Carnaghi, R., Enrico-Bena, L. and De Marco, G.. Considerazioni sull’ attivita dell’ acido 1.4-dicaffellchinico sulle frazioni lipidiche de1 siero well’ aterosclerosi, Minerva Med., 60 (1969) 4514. 3 Eberhardt, G., Untersuchungen iiber die Wirkung van Cynarin bei Leberzellverfettung. Z. Gastroenterol.. 11 (1973) 183. 4 Eck, M. and Desbordes. F., Sur le taux de la cholestixine et le pouvoir cholesterolytique du serum de vieillard - Sur l’hypercholesterinemie, exogene et endogene du lapin. Influence de la stimulation hepatique, C.R.Soc. Biol., 117 (1934) 428,681. 5 Eggstein, M. and Kreutz, K.H., Eine neue Bestimmung der Neutralfette im Blutserum und Gewebe. I. Mitteilung (Prinzip. Durchfiihrung und Besprechung der Methode). Klin. Wschr., 44 (1966) 262. 6 Greten, H.. Seidel, D.. Walters, B. and Kolbe, J.. Die Lipoproteinelektrophorese zur Diagnose van Hyperlipoproteiniimien. Dtsch. Med. Wschr., 95 (1970) 1716. 7 Hammerl, H., Kindler. K.. Kriinzl, Ch.. Nebois, G.. Pichler, 0. and Studlar, M., Uber den Einfluss van Cynarin auf Hyperlipidamien unter besonderer Beriicksichtigung des Typs II (Hypercholesteriniimie). Wien. Med. Wschr., 41 (1973) 601. 8 Mancini. M.. Oriente, P. and D’Andrea, L.. Hypocholesterolemic effects of quinic acid 1,4-dicaffeate in atherosclerotic patients. In: S. Garattini and R. Paoletti (Ed%), Drugs Affecting Lipid Metabolism (Proceedings of the Symposium on Drugs Affecting Lipid Metabolism, Milan, 1960), Elsevier Publishing Company. Amsterdam, 1961. pp. 633-537. 9 Mars. G. and Brambllla. G., Wirkung van l.S-Dicaffeylchinasiiure (Cynarin) auf die Hypertriglyceridiimie im fortgewhrlttenen Alter, Med. Welt, 26 (1974) 1572. 10 Panizzi, L. and Scarpati, M., Constitution of cynarine, the active principle of the artichoke, Nature (Lond.), 174 (1954) 1062. 11 Pommeranze, J. and Cressin. M., Decholesterolizing agents, Amer. Heart J., 49 (1955) 262. 12 Preciosi, P. and Loscalzo, B., Valutazione sperimentale dell ac. 1,4-dicaffeilchinico principio attivo de1 carciofo, Arch. It. Sci. Farmacol., 7 (1957) 50. 13 Preziosi, P. and Loscalzo. B.. Pharmacological properties of 1.4-dicaffeylquinic acid, the active principle of Cynaro seolimus. Arch. Int. Pharmacodyn.. 117 (1958) 63. 14 Prlstautz. H., Cynarjn in der modernen Hyperllpiimiebehandlung. Wien. Med. Wschr.. 125 (1975) 705. 15 SchGnholzer, G.. Uber die Beeinflussung des Cholesterinstoffwechsels durch das aktive Prinzip der Artischokke und seine Anwendung in der Therapie der Arteriosklerose, Schweiz, Med. Wschr.. 69 (1939) 1288. 16 Siedek. H., Hammerl, H. and Pichler. 0.. Arterioskleroseprophylaxe und -therapie. Wien. Med. Wschr.. 107 (1957) 788. 17 Tixier, L., Les actions physiologiques et therapeutiques de Cynaro scolymus (artichaut). Presse Med., 47 (1939) 880.
Atherosclerosis, 26 (1977) 249-253 0 Elsevier/North-Holland Biomedical Press
Short Communication __-_-
____~
INEFFICIENCY OF CYNARIN AS THERAPEUTIC FAMILIAL TYPE II HYPERLIPOPROTEINAEMIA
H. HECKERS, K. DITTMAR,
REGIMEN
IN
F.W. SCHMAHL and K. HUTH
Zentrum fiir Innere Medizin (Direktoren: Prof. Dr. H.G. Lasch and Prof. Dr. G. Schiitterle) der Uniuersitiit Giessen; Institut fiir Humangenetik (Direktor: Prof. Dr. W. Fuhrmann) der Uniuersittit Giessen; Diakonissenhaus Frankfurt (Leitender Arzt: Prof. Dr. K. Huth), Frankfurt/Main (West-Germany)
(Received 12th August, 1976) (Accepted 14th September, 1976)
Summary Seventeen ambulant outpatients with familial Type IIa or Type IIb hyperlipoproteinaemia were treated with Cynarin, the 1,5dicaffeyl ester of quinic acid, the constituent of the artichoke (Cynaru scolymus). The dose tested was 250 mg and 750 mg daily. The mean serum cholesterol and triglyceride concentrations were not significantly changed within 3 months. Cynarin, administered per OS, has no hypolipidaemic effect in familial Type II hyperlipoproteinaemia. Key words:
Cynarin
-Serum
lipids -
Type
II hyperlipoproteinaemia
Introduction In the treatment of Type II hyperlipoproteinaemia, which is associated with an accelerated incidence of coronary heart disease, many therapeutic regimens have been explored. No treatment regimen can be said to be completely acceptable, to have no side effects, and to be effective in lowering serum cholesterol levels to below 250 mg/dl in all patients. In the search for new effective hypolipidaemic drugs, we conducted a study of the effect of Cynarin * in patients whose blood lipid levels were well established with dietary treatment alone. Preliminary data support the assumption that Cynarin, the 1,4dicaffeyl ester of quinic acid [lo], the active constituent of the artichoke (Cynaru scolymus), should be an important agent in lowering * Cyn&n
was kindly supplied by Pharma-Schwarz GmbH, Monheim. originating from Farmitalia, Correspondence to: Dr. H. Heckers, Zentrum fiir Innere Medizin des Justus Liebig-Universitiit Klinikstrasse
36. D-6300
Giessen. West-Germany.
Milan. Giessen,
250
cholesterol levels without undesirable side effects [4,8,15,17]. The most effective decrease was found with a 59% mean reduction of serum cholesterol levels in Type IIa patients within a mean period of 7 months [ 71. Patients
and Methods
Seventeen ambulant outpatients with Type IIa (15 persons) or Type IIb (2 persons) hyperlipoproteinaemia were studied. Diagnosis of the condition was based upon determination of the fasting (12-16 h) total serum cholesterol [1] and triglyceride [ 51 levels and electrophoresis of lipoproteins [ 61. Studies of the patients’ families were performed to determine hereditary conduction. All but one fulfilled the criteria for familial hypercholesterolaemia. All patients had no obvious secondary disorders. Age, sex, clinical features and the initial lipid values of Type II hyperlipoproteinaemia are shown in Tables 1 and 2. Additionally, all patients were on a standardized basic fat-modified diet which had been started more than 6 months previously. Relative body weight was calculated using the Broca Index, which ranged from -15% to +5% within the tested groups. The weight of all patients was maintained the range of +l kg at the beginning of the test. Cynarin was administered per OS 15 min before the meals. The dose tested was 250 mg (Table 1) and 750 mg (Table 2) (3 times 250 mg) daily. All patients returned to the clinic once in a month. Adherence to the drug regimen was evaluated according to the patients’ request for more of the drug. Serum cholesterol and triglyceride levels and lipoprotein electrophoresis were obtained on at least two occasions during a 4- to 6-week period and had to be on a constant level before the administration of Cynarin was started. Other regularly monitored parameters were: serum protein electrophoresis, bilirubin, potassium, sodium, calcium, alkaline phosphatase, y-glutamyl transpeptidase (T-GT), glutamate dehydrogenase (GLDH), transaminases (GPT, GOT), creatine phosphatase (CPK) enzymes, urea, uric acid, and creatinine. Haemoglobin determination and leukocyte and platelet counts were carried out simultaneously. Results and Discussion As shown in Tables 1 and 2, the mean serum cholesterol and triglyceride concentrations in patients with Type II hyperlipoproteinaemia had not significantly changed within 3 months, neither with 250 mg nor with 750 mg Cynarin daily. In 4 patients, a further increase of the Cynarin dose to 1.5 g daily for another 3 months at the end of this study did not change the negative over-all response. Our results are in good agreement with the findings of Pommeranze and Chessin [ll] but in contrast to those of other authors who found Cynarin very effective in decreasing cholesterol [2,3,8,14,16] and triglyceride [9] levels in humans and in animals [4,12,13] at a dosage of 60 mg [7] to 1.5 g daily. We are unable to explain our negative findings, which diverge from those of others. The 250 mg Cynarin tablets tested were completely soluble in 0.7 M phospate buffer (500 ml) at pH 6.5 and 37°C within 5 min (X = 298 nm), supposing complete intestinal solubility. Measurements of Cynarin blood levels and further pharmacokinetic data after oral administration of the drug to animals
1
AMP AXTP A A
AXTP ATMP AMP ATMP
49 39 47 55 36 52 54 25 15
~0 CYNARIN
Clinical features =
LIPIDS
Age (years)
OF SERUM
(250 mg DAILY)
IN PATIENTS
461 533 290 478 268 295 500 416 279 391 -+36
381 _+33
I
On C~narin
448 463 298 514 282 286 496 357 288
entry
On
379 _+39
450 488 245 513 264 287 540 354 273
2
therapy
154 +17
265 470 272 281 520 350 259 375 k38
Oil entry
198 179 188 234 107 151 151 113 66
461 496
3 months
TYPE 11~HYPERLIPOPROTEINAEMIA
174 t20
186 96 100 154 +18
2 201 273 217 192 198 130 198 81 73
264 188 122 179 141 111
1
On Cynarin therapy
156 +16
192 122 70
141 188 183 229 145 137
3 months
Serum triglyceride concentrations (mg/dl)
WITH FAMILIAL
Serum cholesterol concentrations (mg/dl)
THERAPY
a A = arcus cornealis; X = xanthelasmas: M = myocardial infarction: P = angina pectoris; T = tendon xanthomas.
r SD
MeaIl
Patient No.
RESPONSE
TABLE
2
LIPIDS
TO
368
AP
AT
55
24
34
3
4
infarction;
IN
Cynarin
374
96
i32 T = tendon
382
t46
?21 xanthomas.
188 167
+-36
188
126
t91
232
64
137 141
279
91
164
120
391
73
137 100
94
328
431
151
848 94
198
364
179
292
3 months
(mg/dl)
IIb HYPERLIPOPROTEI-
153
420
140
107
315
2
therapy
226
Cynarin
134
364
1
On
TYPE
concentrations
Ha AND
triglyceride
TYPE
230
66
166
254
entry
On
Serum
FAMILIAL
160
564
293
394
*25 pectoris;
WITH
3 months
379
294
422
325
404
522
356
350
360
2
therapy
(mg/dl)
PATIENTS
concentrations
DAILY)
P = angina
+21
a A = arcus
365
296
439
+-29
298
8 372
388
AP
AX
54
34
7
326
* SD
328
Mean
455
AP
A
58
51
446
331
333
327
1
On
424
5
corneaIfs;
mg
cholesterol
(750
518
6
M = myocardial
320 300
AXMP
63
2
entry
On
1
Serum
features
a
THERAPY
(years)
CIinicaI
CYNARIN
Age
X = xanthelasmas;
SERUM
NO.
OF
Patient
NAEMIA
RESPONSE
TABLE
253
and humans are hitherto unknown because a reliable microscale method for the determination of Cynarin is not available. The Cynarin therapy was well tolerated by all patients without any undesired side-effects. All additionally monitored parameters, as listed under methods, remained within normal ranges. We can state that Cynarin, administered per OS, has no hypolipidaemic effect in familial Type II hyperlipoproteinaemia. References 1 Boehringer Biochemica Test Combination. 2 Caruzzo, C.. Carnaghi, R., Enrico-Bena, L. and De Marco, G.. Considerazioni sull’ attivita dell’ acido 1.4-dicaffellchinico sulle frazioni lipidiche de1 siero well’ aterosclerosi, Minerva Med., 60 (1969) 4514. 3 Eberhardt, G., Untersuchungen iiber die Wirkung van Cynarin bei Leberzellverfettung. Z. Gastroenterol.. 11 (1973) 183. 4 Eck, M. and Desbordes. F., Sur le taux de la cholestixine et le pouvoir cholesterolytique du serum de vieillard - Sur l’hypercholesterinemie, exogene et endogene du lapin. Influence de la stimulation hepatique, C.R.Soc. Biol., 117 (1934) 428,681. 5 Eggstein, M. and Kreutz, K.H., Eine neue Bestimmung der Neutralfette im Blutserum und Gewebe. I. Mitteilung (Prinzip. Durchfiihrung und Besprechung der Methode). Klin. Wschr., 44 (1966) 262. 6 Greten, H.. Seidel, D.. Walters, B. and Kolbe, J.. Die Lipoproteinelektrophorese zur Diagnose van Hyperlipoproteiniimien. Dtsch. Med. Wschr., 95 (1970) 1716. 7 Hammerl, H., Kindler. K.. Kriinzl, Ch.. Nebois, G.. Pichler, 0. and Studlar, M., Uber den Einfluss van Cynarin auf Hyperlipidamien unter besonderer Beriicksichtigung des Typs II (Hypercholesteriniimie). Wien. Med. Wschr., 41 (1973) 601. 8 Mancini. M.. Oriente, P. and D’Andrea, L.. Hypocholesterolemic effects of quinic acid 1,4-dicaffeate in atherosclerotic patients. In: S. Garattini and R. Paoletti (Ed%), Drugs Affecting Lipid Metabolism (Proceedings of the Symposium on Drugs Affecting Lipid Metabolism, Milan, 1960), Elsevier Publishing Company. Amsterdam, 1961. pp. 633-537. 9 Mars. G. and Brambllla. G., Wirkung van l.S-Dicaffeylchinasiiure (Cynarin) auf die Hypertriglyceridiimie im fortgewhrlttenen Alter, Med. Welt, 26 (1974) 1572. 10 Panizzi, L. and Scarpati, M., Constitution of cynarine, the active principle of the artichoke, Nature (Lond.), 174 (1954) 1062. 11 Pommeranze, J. and Cressin. M., Decholesterolizing agents, Amer. Heart J., 49 (1955) 262. 12 Preciosi, P. and Loscalzo, B., Valutazione sperimentale dell ac. 1,4-dicaffeilchinico principio attivo de1 carciofo, Arch. It. Sci. Farmacol., 7 (1957) 50. 13 Preziosi, P. and Loscalzo. B.. Pharmacological properties of 1.4-dicaffeylquinic acid, the active principle of Cynaro seolimus. Arch. Int. Pharmacodyn.. 117 (1958) 63. 14 Prlstautz. H., Cynarjn in der modernen Hyperllpiimiebehandlung. Wien. Med. Wschr.. 125 (1975) 705. 15 SchGnholzer, G.. Uber die Beeinflussung des Cholesterinstoffwechsels durch das aktive Prinzip der Artischokke und seine Anwendung in der Therapie der Arteriosklerose, Schweiz, Med. Wschr.. 69 (1939) 1288. 16 Siedek. H., Hammerl, H. and Pichler. 0.. Arterioskleroseprophylaxe und -therapie. Wien. Med. Wschr.. 107 (1957) 788. 17 Tixier, L., Les actions physiologiques et therapeutiques de Cynaro scolymus (artichaut). Presse Med., 47 (1939) 880.