- Email: [email protected]
2.P.59 Efficacy and safety of cerivastatin, a novel potent HMG-CoA reductase inhibitor, in primary hypercholesterolaemia: A comparative study
Tuesday 7 October Lipid-lowering
128
function and plaque stabilization and, to a lesser extent, to the regression of coronary atherosclerosis. 2.P.55
ACAT inhibition rats by enhancing
by CI-1011 lowers plasma the clearance of VLDL
triglycerides
Research,
CiproEbrate women with
in tbe treatment hypertipidaemia
and Cardiac Diseases, Warner-Lambert Company, Ann
of hypertensive IIa
Research
Centre,
3rd Chepepkovskaya
Russia
AI of this study was to investigate LDL-lowering efficacy of ciprofibrate (C) in the treatment of hypertensive postmenopausal women with hyperlipidaemia IIa. Methods: Fifteen postmenopausal women aged 61.9 & 6.7 with stable arterial hypertension while on low-fat diet and antihypertensive therapy were given C 100 mg once daily for 3 months. Lipid profile, AST, ALT, alkaline phosphotase (ALP), creatinphosphokinase (CK), bilirubin and creatinin were assessedat baseline and in 1 and 3 months of ciprofibrate therapy ResuIts: Changes in mean lipid parameters are given in the table below. Liptds, mmol/l TC TG HDL-C LDL-C ‘ICMDL
I & D, Parke-Davis,
Week 0 BXSliIK
I month c 1oomg
3 months cmomg
A%. 3 months vs. Baseline.*
1.63 1.90 1.24 5.41 6.30
5.94 1.32 I .48 3.78 4.13
5% 1.17 I .49 3.92 4.08
-21.9% -38.5 +16.8 -28.4 -35.3
‘p < 0.001.
There were no significant changes in AST, CK, bilirubin and creatinin levels over the study. There was significant reduction in ALP level after 1 month (-28%) and after 3 months (-42%) of C therapy. There was significant, but asymptomatic elevation in ALT levels (+26%), which has remained within normal range. One patient experienced slight nausea and continued therapy with ciprofibrate. Conclusion: Ciprofibrate possess a substantial LDL-lowering efficacy in the treatment of postmenopausal hypertensive women with hyperlipidaemia IIa phenotype. Therapy with Ciprofibrate is safe and well tolerable, there were no serious adverse events over the study.
1 lth International
Symposium
Barcelona,
Spain
Atorvastarin, a new hydroxymethylglutaryl coenzyme A reductase (HMGCoA RD) inhibitor decreases not only plasma cholesterol, but triglyceride levels, when administered to New Zealand White (NZW) rabbits fed a cholesterol (0.5% w/w)/coconut oil (148, w/w) diet (29% and 37% reduction, respectively). The comparative effect of atorvastatin (ATV), simvastatin @VT) and bezaflbrate (BIB) on enzyme activities involved in lipid metabolism was tested in NZW rabbits fed the hyperlipidemic diet or the same diet supplemented with the drugs (100 mg/kg/day for BFB and 3 m&g/day for SVT and ATV). The animals were fed the hyperlipemic diet for three weeks, and then assigned to four treatment groups: control (only hyperlipemic diet, n = 8) and the BIB (n = 8), SVT (n = 8), and ATV (n = 8) groups, during the remaining 4 weeks of the study. The feeding of the cholesterol/coconut oil diet increased the activities of diacylglycerol acyltransferase (DGAT) (3.1 fold, p = O.o003), CTP: Phosphocholine cytidyltransferase (CT) (1.65 fold, p = 0.0003), acyl coenzyme A: cholesterol acyl transferase (ACAT) (30 fold, p < O.OOOl),and cholesterol-7-cr-hydroxylase (C7o) (4.3 fold, p = 0.017) vs values obtained from rabbits fed a control chow. The activity of HMG-CoA RD decreased 37% (p < 0.1). while the activities of hepatic lipase (HL) and lipoprotein lipase (LPL) were unmodified by the dietary intervention. When these activities were assayed in samples from dyslipidemic rabbits treated with the three drugs, only the activity of C7o was decreased by BFB (60%), SVT (55%), and ATV (75%), although only ATV reached significance (p < 0.05). Given that BFB has a well known effect on C7a activity, the reduction induced by both vastatins must be driven indirectly by the inhibition of hepatic HMG-CoA RD elicited by these drugs. This work was supported partly by Parke Davis (project no 981-SPA-01) and the FPCNL. Lrl2 P 58
Effects of Atorvastatin on endothelium-dependent and contractions in dysIipidemIc rabbits
Dept of Physiology,
15a, Moscow,
oiI fed rabbit
relaxations
V. Lahera,, R. Maeso, R. Mufioz-Garcia, E. Rodrigo, J. Navarro-Cid, G. Hemandezt , C. Diaz’ , V. Cachofeiro. ‘R&D Dept Parke Davis, Barcelona;
postmenopausal
V. Kukharchuk, A. Sussekov,M. Tvorogova, V. Titov, G. Arabidze. Cardiology
EffectofatorvastatinonkeyenzymesregulatingIipII metabolism in tbe choIesterol/coconut
‘Departamento
CI-1011, sulfamic acid [[2,4,6-tris(l-methylethyl)phenyl]acetyl]-2,6-bis (1-methylethyl)phenyl ester, is an inhibitor of acyl-CoAcholesterol acyltransferase (ACAT), the enzyme that esterifies cholesterol to form cholesteryl esters (CE) in several tissues, including intestine, liver and arterial macrophages. Inhibition of ACAT by CI-1011 reduces the CE content in these tissues. However, we also found that CI-1011 potently reduces plasma triglyceride (TG) concentrations in normal, chow-fed and in sucrose-fed rats. We decided to determine if TG lowering was due to a decrease in VLDL-TG production. Rats fed a normal chow diet were fasted overnight and then given a single dose of CI-1011 (30 m&g, 6 AM). Four hours after dosing, Triton WR-1339 (600 m&g) was injected IV to block VLDL clearance. One additional drug dose was given 4 hours post-triton, and animals were sacrificed 20 hr post-T&on. Plasma TG increased after Triton blockade to approx. 3000 mg/dL in controls. This was blunted only slightly by CI-1011 (2500 mg/dL). However, CI-1011, decreased VLDL-CE output by 40%, and the relative amount of CE in VLDL (%CE) decreased from 32% to 23% with treatment. A similar experiment was performed after 4 weeks of drug treatment (10 mg/kg). Plasma cholesterol and VLDL-CE decreased 72% and 83%. respectively, and %-CE dropped from 41 to 19%, with no change in TG. Lastly, in sucrose-fed rats CE in post-T&on VLDL was undetectable after 2 weeks of CI-1011 treatment (10 mg/kg), without an inhibitory effect on TG production. These data suggest that decreasing CE availability in the liver affects TG clearance, not secretion. Tbis was confirmed in separate experiments by following the disappearance of tz51-labeled VLDL. From these data we hypothesize that hepatic CE availability not only determines the CE content of VLDL but also the rate of VLDL catabolism. I 2 P.56
12.p.571
J.C. Laauaa, J.C. Verd, M. Calvo, M. Alegret, C. Dfazt , G. Hernatrdez’ , R.M. Sanchez. Dept. Farmacologfa, Fat. Farmacia, Univ. Barcelona;
in
Brian R. Krause, Bruce J. Auerbach. Vascular Parke-Davis Pharmaceutical Arbor MI 48105, USA
1997: Posters drugs
School
of Medicine,
Vniv Complutense,
Madrid,
Spain
Dyslipidemia is associated with endothelial dysfunction mainly characterized by diminished endotbehum-dependent relaxations. The participation of endothelium-dependent and independent contracting factors in such a dysfunction is not well-known. In the present study we evaluated the effects of Atorvastatin treatment (ATV; 2.5 mg&#lay) on endothelium-dependent and -independent relaxations and contractions in aortic rings from rabbits fed a diet containing 0.5% cholesterol + 14% coconut oil for 10 weeks. Plasma cholesterol (Cho) and triglyceride (TG) concentrations were higher in rabbits fed the experimental diet (p c: 0.05) (Cho: 1902 & 110 mg/dl; TG: 408 f 42 mg/dl) than in controls (Cho: 57 f 4.2 mg/dl; TG: 108 f 20 mg/dl). ATV treatment reduced (p < 0.05) both Cho and TG (Cho: 1242 f 52 mg/dl; TG: 220 f 32 mg/dl) in dyslipidemic rabbits but not in controls. Concentration-related relaxing response to acetylcholine (Ach: 1O-9-1O-’ moUL) was reduced (p < 0.05) in dyslipidemic rabbits compared to controls. Treatment with ATV prevented this reduced response. The concentrationrelated constrictor response to Ach in presence of the NO synthase inhibitor LNAME ( 10m4 mol/L) was slightly higher in dyslipidemic rabbits than in controls. ATV treatment reduced this response in both groups. Responses to sodium nitroprusside (10-9-10-5 mol/L), phenylephrine (1O-9-1O-5 mol/L) and angiotensin II ( 10e7 mol/L) were comparable in all groups. In conclusion, ATV treatment improves endothelial dysfunction in dyslipidemic rabbits by acting on both NO and EDCF availability. I 2 P 59
Efficacy and safety of cerivastatin, a novd patent HMG-CoA reductase inhibitor, in primary hypercboIesterolaemiaz A comparative study
L.A. Leitar. The Canadian Toronto,
Cerivastatin
Study Group;
St Michael
s Hospital,
Canaa’a
Cerivastatin (CER) is a synthetic and highly selective HMG-CoA reductase inhibitor that effectively reduces cholesterol levels at very low doses. In a random&d, double-blind, dose titration study performed at 13 Canadian centres, the lipid-lowering effects of cerivastatin were studied in 387 adult
on Atherosc1ero.k
Paris,
October
1997
Tuesday 7 October Lipid-lowering
patients with primary hypercholesterolaemia (baseline LDL-C = 5.90 mmol/l). After a lo-week diet-controlled period, the last 6 weeks of which included a single-blind placebo run-in phase, 260 patients were randomised to receive CER (starting at a dose of 0.05 mg/day, which could be titrated according to a fixed schedule up to 0.3 mg!day with an aim to achieve a plasma LDL-C level of 13.36 mmol/l), and 127 received simvastatin (SIM) titrated in a similar fashion (5-40 mg/day) for 32 weeks. The mean dose at the end of the study for CER was 0.242 mg/day and for SIM was 21.7 mg/day. Intention-to-treat analysis of changes (96 from baseline) in lipid levels at endpoint were: CER sIh4
LDL-C-
Total-C’
HDLC
-27.17 -33.93
-19.99 -24.25
+9.90 +10.03
Triglytides -11.65 -9.94
(‘CER and SIM significantly different from each other [p < 0.051)
Changes from baseline were significant in both groups for all four lipid parameters (p < 0.05). CER was well tolerated: adverse events were generally mild. The percentage of patients discontinuing therapy due to adverse events was similar with CER (5.4%) and SIM (7.9%). Response rates (> 15% decrease in LDL-C) were high and not significantly different between both groups (88.9% CER, 93.2% SIM). The results of this study demonstrate that CER, at doses 100 times lower than SIM, effectively reduces LDL-C levels in patients with primary hypercholesterolaemia. This study was funded with a grant from Bayer, Canada.
I
2 P.60
Effect of fb~vastatin on small dense low density lipoproteins postmenopausal women with an atberogenic IipopFotein phenotype
in
W. M&z H. Scharnagl, C. Abletshauser, H. Wieland, M. Baumstark. ~tmkt Pharma,
of Medicine, Albert Niirnberg, Germany
Ludwigs-University,
Freiburg
and Novartis
Low density lipoproteins (LDL) represent a heterogeneous population of particles differing by size, density and composition. The predominance of small dense LDL is an important risk factor for coronary artery disease. Postmenopausal status promotes the development of an atherogenic lipoprotein profile also characterized by increases in the concentrations of small dense LDL. It appears that hormone replacement therapy only incompletely reverses this unfavourable lipoprotein profile. Lipid modifying drugs may therefore be needed to effectively prevent atherosclerosis in postmenopausal women. Varying results regarding the effect of HMG-CoA reductase inhibitors on small dense LDL have been reported. In a placebo controlled study, we examined the effects of fluvastatin (40 mg daily) on lipids, lipoproteins and the distribution of six LDL subfractions in n = 55 postmenopausal women. Patients were specifically selected for the presence of an atherogenic lipoprotein phenotype according to the following criteria: LDL cholesterol > 150 mg/dL and apo B in LDL-5 plus LDL-6 > 25 mg/dL. Lipoprotein subfractions were analysed at the beginning and at the end of a 12 weeks treatment period. Compared to placebo fluvastatin reduced total cholesterol, LDL cholesterol and triglycerides by 20, 25 and 15 percent. The concentration of small dense LDL (LDL-5 plus LDL-6) was reduced by 42 percent. We conclude that fluvastatin is effective in favourably modifying the lipoprotein profile in postmenopausal women and may therefore be a useful complement in the prevention of atherosclerosis in postmenopausal women. 2.P.61
Comparative study of policosanol, gem6brozil and combination therapy in tbe treatment of type II hypercboleaterolemia
R. M&s G. Castaiio’, J. Illnait’, I,. Femindez, J.C. Femfindez. Centro %&al de Investigaciones Cientificas; ‘Centro de Investigaciones A46dico-Quiru’rgicas, Cuba
This study compares the efficacy and tolerability of policosanol, gemfibrotil and the combination therapy with both drugs. Sixty hypercholesterolemic patients started a fitst step cholesterol-lowering diet for 12 weeks. After this period, 58 patients were included and randomly distributed in three groups: 1) a group receiving getibrozil (600 mg twice-a-day) for 6 weeks and firstly on a gemfibrozil tablet (600 mg) and one policosanol (5 mg) tablet for the next 6 weeks; a group 2 receiving firstly policosanol (5 mg twice-a-day) and one tablet of each drug in the next 6 weeks, meanwhile group 3 received all time the combination therapy. Gemfibrozil (group 1) significantly reduced cholesterol (12.4%). LDL-C (12.4%) and triglycerides (33.9%), while increased significantly HDL-C by 11%. After addition of policosanol significant reductions of cholesterol (18.9%) LDL-C (22.8%) and triglycerides (48.9%) 1 Ith International
Symposium
1997: Posters drugs
129
were obtained. In this period, HDL-C increased significantly by 33.5%. Policosanol (group 2) significantly reduced cholesterol by 25.4%, LDL-C by 30.6% and triglycerides by 26.61, while significantly raised HDL-C levels by 11.1%. Significant reductions of cholesterol (21.1%), LDL-C (24.7%) and triglycerides (43.5%) as increases of HDL-C (25.8%) were obtained in the step of combination therapy. Group 3 showed significant and similar reductions of cholesterol bv 18.5% and 20.1%. LDL-C bv 21.5% and 23.3% and triglycerides by 45.8% and 47% in each period, res&ctively. HDL-C levels raised significantly by 24.3% and 26.1%, respectively. No patient withdrew from the trial. Adverse experiences reported were mild: two patients reported headache and nauseas during gemfibrozil monotherapy (group 1); no adverse experiences were reported in the group 2 and two patients from group 3 reported rasb and asthenia, respectively. The results indicate that both drugs are effective and well tolerated in patients with type II hypercholesterolemia and that combination therapy shows some advantages compared with the independent therapies. L2.P.62
1 Effect of eicosapentaenoic acid in combination reductase inhibitor on lipid metabolism
with HMG-CoA
H. Mataki, I;. Watuji, S. Miwa, K. Matsushita, T. Miki, M. Go, K. Ishida, S. Okada’, M. Yokovama2. Deuartment of Internal Medicine, NiDuon Steel Corporation Hirohaia Works Hospital, Hiougo; ’ Departmenr of’iaarhology, Nippon Steel Corporation Hirohata Works Hospital, Hyougo; 2 First Department of Internal Medicine, Kobe Univ. School of Medicine, Hyougo, Japan
Eicosapentaenoic acid (EPA) has been noted to reduce plasma lipids in hyperlipidemia. However, few investigation has been reported concerning effect in combination with other drugs. We examined the effect of EPA in combination with HMG-CoA reductase inhibitor on lipid metabolism. We administered twelve weeks of 1.8 g/day EPA and 5 mg/day sinvastatin or 10 mg/day pravastatin, following weeks of only 5 mg/day sinvastatin or 10 mg/day pravastatin and no EPA to hyperlipidemic patients. The patients were measured plasma level of total cholesterol (TC), HDL cholesterol (HDL), triglyceride (TG), LDL cholesterol (HDL), LP(a), RLP, and other parameters before and after twelve and twenty-four weeks of treatment. Plasma level of TC decreased from 249 to 203 in twelve weeks, and 202 mgldl in twenty-four weeks. TG significantly decreased 163 to 101 in twelve weeks, and increased to 150 mg/dl in twenty-four weeks. HDL, LP(a), RLP shows of little change. Our findings suggest EPA in combination with HMG-CoA reductase significantly reduced TG level in comparison with HMG-CoA reductase alone. We would assessmore about other parameters. ( 2.P.63
( Tolerability
of pbytosterols
in apo E-deficient
mice
M.H. Moghadasian, B.M. McManus, J.J. Frohlich. St. Paul’s Hospital University
of British
Columbia,
and
Canada
Background: Several human and animal studies have shown the cholesterollowering effects of plant sterols. We described an anti-atherogenic effect of a mixture of plant sterols (FCP-3PI) in apo E-deficient mice (Moghadasian et al. 1997 Arterioscler Thromb Vast Biol 17: 119-126). The purpose of the current study was to assessthe longer-term tolerability of an anti-atherogenic dose of FCP-3PI. Materials and Methods: Young male apo E-deficient mice were fed a Western diet containing 9% (w/w) fat and 0.15% (w/w) cholesterol, supplemented with (n = 9) 2% (w/w) or without (n = 6) FCP 3PI for 18 weeks. Blood samples were collected for hematological and biochemical tests; tissues were fixed in 10% buffered formalin and used for histological examination. Results: Treatment with FCP-3PI caused a significant reduction in the susceptibility of red cells to hemolysis as determined by the percentage hemolysis at 0.05 mM NaCl (83.3 f 6.7 vs 95.5 & 2.3, p -Z 0.001) and a reduction in the number of platelets (681 f 118 vs 857 i 185, p < 0.05). Other hematological and histobgical parameters were comparable in the treated and control animals except for slight testicular atrophy in the treated group. Control animals had non-specific, ORO-negative vacuolation in their kidneys and liven,. This vacuolation was not observed in the treated groups. Urinalysis and plasma glucose levels were similar in both groups. Conclusion: In addition to having cholesterol-lowering and anti-atherogenie activities (as shown previously), the phytosterol mixture used appears to be safe for long-term use in this animal model.
on Atherosclerosis,
Paris,
October
1997
128
function and plaque stabilization and, to a lesser extent, to the regression of coronary atherosclerosis. 2.P.55
ACAT inhibition rats by enhancing
by CI-1011 lowers plasma the clearance of VLDL
triglycerides
Research,
CiproEbrate women with
in tbe treatment hypertipidaemia
and Cardiac Diseases, Warner-Lambert Company, Ann
of hypertensive IIa
Research
Centre,
3rd Chepepkovskaya
Russia
AI of this study was to investigate LDL-lowering efficacy of ciprofibrate (C) in the treatment of hypertensive postmenopausal women with hyperlipidaemia IIa. Methods: Fifteen postmenopausal women aged 61.9 & 6.7 with stable arterial hypertension while on low-fat diet and antihypertensive therapy were given C 100 mg once daily for 3 months. Lipid profile, AST, ALT, alkaline phosphotase (ALP), creatinphosphokinase (CK), bilirubin and creatinin were assessedat baseline and in 1 and 3 months of ciprofibrate therapy ResuIts: Changes in mean lipid parameters are given in the table below. Liptds, mmol/l TC TG HDL-C LDL-C ‘ICMDL
I & D, Parke-Davis,
Week 0 BXSliIK
I month c 1oomg
3 months cmomg
A%. 3 months vs. Baseline.*
1.63 1.90 1.24 5.41 6.30
5.94 1.32 I .48 3.78 4.13
5% 1.17 I .49 3.92 4.08
-21.9% -38.5 +16.8 -28.4 -35.3
‘p < 0.001.
There were no significant changes in AST, CK, bilirubin and creatinin levels over the study. There was significant reduction in ALP level after 1 month (-28%) and after 3 months (-42%) of C therapy. There was significant, but asymptomatic elevation in ALT levels (+26%), which has remained within normal range. One patient experienced slight nausea and continued therapy with ciprofibrate. Conclusion: Ciprofibrate possess a substantial LDL-lowering efficacy in the treatment of postmenopausal hypertensive women with hyperlipidaemia IIa phenotype. Therapy with Ciprofibrate is safe and well tolerable, there were no serious adverse events over the study.
1 lth International
Symposium
Barcelona,
Spain
Atorvastarin, a new hydroxymethylglutaryl coenzyme A reductase (HMGCoA RD) inhibitor decreases not only plasma cholesterol, but triglyceride levels, when administered to New Zealand White (NZW) rabbits fed a cholesterol (0.5% w/w)/coconut oil (148, w/w) diet (29% and 37% reduction, respectively). The comparative effect of atorvastatin (ATV), simvastatin @VT) and bezaflbrate (BIB) on enzyme activities involved in lipid metabolism was tested in NZW rabbits fed the hyperlipidemic diet or the same diet supplemented with the drugs (100 mg/kg/day for BFB and 3 m&g/day for SVT and ATV). The animals were fed the hyperlipemic diet for three weeks, and then assigned to four treatment groups: control (only hyperlipemic diet, n = 8) and the BIB (n = 8), SVT (n = 8), and ATV (n = 8) groups, during the remaining 4 weeks of the study. The feeding of the cholesterol/coconut oil diet increased the activities of diacylglycerol acyltransferase (DGAT) (3.1 fold, p = O.o003), CTP: Phosphocholine cytidyltransferase (CT) (1.65 fold, p = 0.0003), acyl coenzyme A: cholesterol acyl transferase (ACAT) (30 fold, p < O.OOOl),and cholesterol-7-cr-hydroxylase (C7o) (4.3 fold, p = 0.017) vs values obtained from rabbits fed a control chow. The activity of HMG-CoA RD decreased 37% (p < 0.1). while the activities of hepatic lipase (HL) and lipoprotein lipase (LPL) were unmodified by the dietary intervention. When these activities were assayed in samples from dyslipidemic rabbits treated with the three drugs, only the activity of C7o was decreased by BFB (60%), SVT (55%), and ATV (75%), although only ATV reached significance (p < 0.05). Given that BFB has a well known effect on C7a activity, the reduction induced by both vastatins must be driven indirectly by the inhibition of hepatic HMG-CoA RD elicited by these drugs. This work was supported partly by Parke Davis (project no 981-SPA-01) and the FPCNL. Lrl2 P 58
Effects of Atorvastatin on endothelium-dependent and contractions in dysIipidemIc rabbits
Dept of Physiology,
15a, Moscow,
oiI fed rabbit
relaxations
V. Lahera,, R. Maeso, R. Mufioz-Garcia, E. Rodrigo, J. Navarro-Cid, G. Hemandezt , C. Diaz’ , V. Cachofeiro. ‘R&D Dept Parke Davis, Barcelona;
postmenopausal
V. Kukharchuk, A. Sussekov,M. Tvorogova, V. Titov, G. Arabidze. Cardiology
EffectofatorvastatinonkeyenzymesregulatingIipII metabolism in tbe choIesterol/coconut
‘Departamento
CI-1011, sulfamic acid [[2,4,6-tris(l-methylethyl)phenyl]acetyl]-2,6-bis (1-methylethyl)phenyl ester, is an inhibitor of acyl-CoAcholesterol acyltransferase (ACAT), the enzyme that esterifies cholesterol to form cholesteryl esters (CE) in several tissues, including intestine, liver and arterial macrophages. Inhibition of ACAT by CI-1011 reduces the CE content in these tissues. However, we also found that CI-1011 potently reduces plasma triglyceride (TG) concentrations in normal, chow-fed and in sucrose-fed rats. We decided to determine if TG lowering was due to a decrease in VLDL-TG production. Rats fed a normal chow diet were fasted overnight and then given a single dose of CI-1011 (30 m&g, 6 AM). Four hours after dosing, Triton WR-1339 (600 m&g) was injected IV to block VLDL clearance. One additional drug dose was given 4 hours post-triton, and animals were sacrificed 20 hr post-T&on. Plasma TG increased after Triton blockade to approx. 3000 mg/dL in controls. This was blunted only slightly by CI-1011 (2500 mg/dL). However, CI-1011, decreased VLDL-CE output by 40%, and the relative amount of CE in VLDL (%CE) decreased from 32% to 23% with treatment. A similar experiment was performed after 4 weeks of drug treatment (10 mg/kg). Plasma cholesterol and VLDL-CE decreased 72% and 83%. respectively, and %-CE dropped from 41 to 19%, with no change in TG. Lastly, in sucrose-fed rats CE in post-T&on VLDL was undetectable after 2 weeks of CI-1011 treatment (10 mg/kg), without an inhibitory effect on TG production. These data suggest that decreasing CE availability in the liver affects TG clearance, not secretion. Tbis was confirmed in separate experiments by following the disappearance of tz51-labeled VLDL. From these data we hypothesize that hepatic CE availability not only determines the CE content of VLDL but also the rate of VLDL catabolism. I 2 P.56
12.p.571
J.C. Laauaa, J.C. Verd, M. Calvo, M. Alegret, C. Dfazt , G. Hernatrdez’ , R.M. Sanchez. Dept. Farmacologfa, Fat. Farmacia, Univ. Barcelona;
in
Brian R. Krause, Bruce J. Auerbach. Vascular Parke-Davis Pharmaceutical Arbor MI 48105, USA
1997: Posters drugs
School
of Medicine,
Vniv Complutense,
Madrid,
Spain
Dyslipidemia is associated with endothelial dysfunction mainly characterized by diminished endotbehum-dependent relaxations. The participation of endothelium-dependent and independent contracting factors in such a dysfunction is not well-known. In the present study we evaluated the effects of Atorvastatin treatment (ATV; 2.5 mg&#lay) on endothelium-dependent and -independent relaxations and contractions in aortic rings from rabbits fed a diet containing 0.5% cholesterol + 14% coconut oil for 10 weeks. Plasma cholesterol (Cho) and triglyceride (TG) concentrations were higher in rabbits fed the experimental diet (p c: 0.05) (Cho: 1902 & 110 mg/dl; TG: 408 f 42 mg/dl) than in controls (Cho: 57 f 4.2 mg/dl; TG: 108 f 20 mg/dl). ATV treatment reduced (p < 0.05) both Cho and TG (Cho: 1242 f 52 mg/dl; TG: 220 f 32 mg/dl) in dyslipidemic rabbits but not in controls. Concentration-related relaxing response to acetylcholine (Ach: 1O-9-1O-’ moUL) was reduced (p < 0.05) in dyslipidemic rabbits compared to controls. Treatment with ATV prevented this reduced response. The concentrationrelated constrictor response to Ach in presence of the NO synthase inhibitor LNAME ( 10m4 mol/L) was slightly higher in dyslipidemic rabbits than in controls. ATV treatment reduced this response in both groups. Responses to sodium nitroprusside (10-9-10-5 mol/L), phenylephrine (1O-9-1O-5 mol/L) and angiotensin II ( 10e7 mol/L) were comparable in all groups. In conclusion, ATV treatment improves endothelial dysfunction in dyslipidemic rabbits by acting on both NO and EDCF availability. I 2 P 59
Efficacy and safety of cerivastatin, a novd patent HMG-CoA reductase inhibitor, in primary hypercboIesterolaemiaz A comparative study
L.A. Leitar. The Canadian Toronto,
Cerivastatin
Study Group;
St Michael
s Hospital,
Canaa’a
Cerivastatin (CER) is a synthetic and highly selective HMG-CoA reductase inhibitor that effectively reduces cholesterol levels at very low doses. In a random&d, double-blind, dose titration study performed at 13 Canadian centres, the lipid-lowering effects of cerivastatin were studied in 387 adult
on Atherosc1ero.k
Paris,
October
1997
Tuesday 7 October Lipid-lowering
patients with primary hypercholesterolaemia (baseline LDL-C = 5.90 mmol/l). After a lo-week diet-controlled period, the last 6 weeks of which included a single-blind placebo run-in phase, 260 patients were randomised to receive CER (starting at a dose of 0.05 mg/day, which could be titrated according to a fixed schedule up to 0.3 mg!day with an aim to achieve a plasma LDL-C level of 13.36 mmol/l), and 127 received simvastatin (SIM) titrated in a similar fashion (5-40 mg/day) for 32 weeks. The mean dose at the end of the study for CER was 0.242 mg/day and for SIM was 21.7 mg/day. Intention-to-treat analysis of changes (96 from baseline) in lipid levels at endpoint were: CER sIh4
LDL-C-
Total-C’
HDLC
-27.17 -33.93
-19.99 -24.25
+9.90 +10.03
Triglytides -11.65 -9.94
(‘CER and SIM significantly different from each other [p < 0.051)
Changes from baseline were significant in both groups for all four lipid parameters (p < 0.05). CER was well tolerated: adverse events were generally mild. The percentage of patients discontinuing therapy due to adverse events was similar with CER (5.4%) and SIM (7.9%). Response rates (> 15% decrease in LDL-C) were high and not significantly different between both groups (88.9% CER, 93.2% SIM). The results of this study demonstrate that CER, at doses 100 times lower than SIM, effectively reduces LDL-C levels in patients with primary hypercholesterolaemia. This study was funded with a grant from Bayer, Canada.
I
2 P.60
Effect of fb~vastatin on small dense low density lipoproteins postmenopausal women with an atberogenic IipopFotein phenotype
in
W. M&z H. Scharnagl, C. Abletshauser, H. Wieland, M. Baumstark. ~tmkt Pharma,
of Medicine, Albert Niirnberg, Germany
Ludwigs-University,
Freiburg
and Novartis
Low density lipoproteins (LDL) represent a heterogeneous population of particles differing by size, density and composition. The predominance of small dense LDL is an important risk factor for coronary artery disease. Postmenopausal status promotes the development of an atherogenic lipoprotein profile also characterized by increases in the concentrations of small dense LDL. It appears that hormone replacement therapy only incompletely reverses this unfavourable lipoprotein profile. Lipid modifying drugs may therefore be needed to effectively prevent atherosclerosis in postmenopausal women. Varying results regarding the effect of HMG-CoA reductase inhibitors on small dense LDL have been reported. In a placebo controlled study, we examined the effects of fluvastatin (40 mg daily) on lipids, lipoproteins and the distribution of six LDL subfractions in n = 55 postmenopausal women. Patients were specifically selected for the presence of an atherogenic lipoprotein phenotype according to the following criteria: LDL cholesterol > 150 mg/dL and apo B in LDL-5 plus LDL-6 > 25 mg/dL. Lipoprotein subfractions were analysed at the beginning and at the end of a 12 weeks treatment period. Compared to placebo fluvastatin reduced total cholesterol, LDL cholesterol and triglycerides by 20, 25 and 15 percent. The concentration of small dense LDL (LDL-5 plus LDL-6) was reduced by 42 percent. We conclude that fluvastatin is effective in favourably modifying the lipoprotein profile in postmenopausal women and may therefore be a useful complement in the prevention of atherosclerosis in postmenopausal women. 2.P.61
Comparative study of policosanol, gem6brozil and combination therapy in tbe treatment of type II hypercboleaterolemia
R. M&s G. Castaiio’, J. Illnait’, I,. Femindez, J.C. Femfindez. Centro %&al de Investigaciones Cientificas; ‘Centro de Investigaciones A46dico-Quiru’rgicas, Cuba
This study compares the efficacy and tolerability of policosanol, gemfibrotil and the combination therapy with both drugs. Sixty hypercholesterolemic patients started a fitst step cholesterol-lowering diet for 12 weeks. After this period, 58 patients were included and randomly distributed in three groups: 1) a group receiving getibrozil (600 mg twice-a-day) for 6 weeks and firstly on a gemfibrozil tablet (600 mg) and one policosanol (5 mg) tablet for the next 6 weeks; a group 2 receiving firstly policosanol (5 mg twice-a-day) and one tablet of each drug in the next 6 weeks, meanwhile group 3 received all time the combination therapy. Gemfibrozil (group 1) significantly reduced cholesterol (12.4%). LDL-C (12.4%) and triglycerides (33.9%), while increased significantly HDL-C by 11%. After addition of policosanol significant reductions of cholesterol (18.9%) LDL-C (22.8%) and triglycerides (48.9%) 1 Ith International
Symposium
1997: Posters drugs
129
were obtained. In this period, HDL-C increased significantly by 33.5%. Policosanol (group 2) significantly reduced cholesterol by 25.4%, LDL-C by 30.6% and triglycerides by 26.61, while significantly raised HDL-C levels by 11.1%. Significant reductions of cholesterol (21.1%), LDL-C (24.7%) and triglycerides (43.5%) as increases of HDL-C (25.8%) were obtained in the step of combination therapy. Group 3 showed significant and similar reductions of cholesterol bv 18.5% and 20.1%. LDL-C bv 21.5% and 23.3% and triglycerides by 45.8% and 47% in each period, res&ctively. HDL-C levels raised significantly by 24.3% and 26.1%, respectively. No patient withdrew from the trial. Adverse experiences reported were mild: two patients reported headache and nauseas during gemfibrozil monotherapy (group 1); no adverse experiences were reported in the group 2 and two patients from group 3 reported rasb and asthenia, respectively. The results indicate that both drugs are effective and well tolerated in patients with type II hypercholesterolemia and that combination therapy shows some advantages compared with the independent therapies. L2.P.62
1 Effect of eicosapentaenoic acid in combination reductase inhibitor on lipid metabolism
with HMG-CoA
H. Mataki, I;. Watuji, S. Miwa, K. Matsushita, T. Miki, M. Go, K. Ishida, S. Okada’, M. Yokovama2. Deuartment of Internal Medicine, NiDuon Steel Corporation Hirohaia Works Hospital, Hiougo; ’ Departmenr of’iaarhology, Nippon Steel Corporation Hirohata Works Hospital, Hyougo; 2 First Department of Internal Medicine, Kobe Univ. School of Medicine, Hyougo, Japan
Eicosapentaenoic acid (EPA) has been noted to reduce plasma lipids in hyperlipidemia. However, few investigation has been reported concerning effect in combination with other drugs. We examined the effect of EPA in combination with HMG-CoA reductase inhibitor on lipid metabolism. We administered twelve weeks of 1.8 g/day EPA and 5 mg/day sinvastatin or 10 mg/day pravastatin, following weeks of only 5 mg/day sinvastatin or 10 mg/day pravastatin and no EPA to hyperlipidemic patients. The patients were measured plasma level of total cholesterol (TC), HDL cholesterol (HDL), triglyceride (TG), LDL cholesterol (HDL), LP(a), RLP, and other parameters before and after twelve and twenty-four weeks of treatment. Plasma level of TC decreased from 249 to 203 in twelve weeks, and 202 mgldl in twenty-four weeks. TG significantly decreased 163 to 101 in twelve weeks, and increased to 150 mg/dl in twenty-four weeks. HDL, LP(a), RLP shows of little change. Our findings suggest EPA in combination with HMG-CoA reductase significantly reduced TG level in comparison with HMG-CoA reductase alone. We would assessmore about other parameters. ( 2.P.63
( Tolerability
of pbytosterols
in apo E-deficient
mice
M.H. Moghadasian, B.M. McManus, J.J. Frohlich. St. Paul’s Hospital University
of British
Columbia,
and
Canada
Background: Several human and animal studies have shown the cholesterollowering effects of plant sterols. We described an anti-atherogenic effect of a mixture of plant sterols (FCP-3PI) in apo E-deficient mice (Moghadasian et al. 1997 Arterioscler Thromb Vast Biol 17: 119-126). The purpose of the current study was to assessthe longer-term tolerability of an anti-atherogenic dose of FCP-3PI. Materials and Methods: Young male apo E-deficient mice were fed a Western diet containing 9% (w/w) fat and 0.15% (w/w) cholesterol, supplemented with (n = 9) 2% (w/w) or without (n = 6) FCP 3PI for 18 weeks. Blood samples were collected for hematological and biochemical tests; tissues were fixed in 10% buffered formalin and used for histological examination. Results: Treatment with FCP-3PI caused a significant reduction in the susceptibility of red cells to hemolysis as determined by the percentage hemolysis at 0.05 mM NaCl (83.3 f 6.7 vs 95.5 & 2.3, p -Z 0.001) and a reduction in the number of platelets (681 f 118 vs 857 i 185, p < 0.05). Other hematological and histobgical parameters were comparable in the treated and control animals except for slight testicular atrophy in the treated group. Control animals had non-specific, ORO-negative vacuolation in their kidneys and liven,. This vacuolation was not observed in the treated groups. Urinalysis and plasma glucose levels were similar in both groups. Conclusion: In addition to having cholesterol-lowering and anti-atherogenie activities (as shown previously), the phytosterol mixture used appears to be safe for long-term use in this animal model.
on Atherosclerosis,
Paris,
October
1997