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Atorvastatin is a powerful and safe agent for lowering plasma cholesterol concentration in heterozygous familial hypercholesterolemia
Thursday 13 October 1994: Poster Abstracts Treatment Ill
316
responses following injury to the vessel after angioplasty. It is considered that several growth factors produced at the site of injury mediate SMC proliferation. These growth factors act via distinct receptors and exhibit significant differences in their signal transduction mechanisms. Thus, the strategies for the development of effective agents to inhibit SMC proliferation include finding agents that inhibit proliferation to many different growth factors and act on regulatory mechanisms that control cell growth rather than produce general cellular cytotoxicity. In this study, we report the activity of a compound from a novel naphthopyran series, 29018 1, on SMC proliferation in vitro and arterial thickening in vivo. 290181 produced a dose-dependent inhibition of vascular SMC proliferation (It& = 20 nM) in response to serum or individual growth factors such as PDGF-bb, bFGF and EGF. Cell growth inhibition by 290181 was not due to cell death, as demonstrated by intracellular lactate dehydrogenase release (LDH), reversibility upon washing, and the stereospecific action of 290181. In the rat carotid artery balloon injury model, oral administration of 290181 over the experimental period produced a dose-dependent inhibition of intimal thickening (48% inhibition at 98 mg/kg/day, P < 0.005). These studies demonstrate that the novel pyran 290181 is a potent inhibitor of SMC proliferation in vitro and intimal thickening in vivo, and may have utility in the prevention of proliferative responses associated with vascular disease including restenosis and atherosclerosis. 1226(
Atorvastatin is a powerful and safe agent for lowering plasma cholesterol concentration in heterozygous familial hypercholesterolemia Firth JC, Bateman M, Jones J, Mountney J, Martens
m C, ht. Med., Univ. of Cape Town Med. Sch., Observatory 7925, South Africa
The safety and efficacy of 80 mg/day of atorvastatin, a hydroxymethylglutaryl coenzyme A teductase inhibitor, was investigated in subjects with heteroxygous familial hypercholesterolemia (FH) diagnosed by PCR assay for local LDL receptor mutations or by excluding binding-defective apo B in primary hypercholesterolemia with xanthomata. Subjects underwent a 4-week drug washout and dietary stabilization phase. Secondary dyslipoproteinemia and significant organ dysfunction were excluded and consenting adults with a calculated LDL-C >6.4 mmohl were included. 22 were entered into the open-label, randomized parallel-arm design, testing treatment in divided and single doses. Clinical as well as lipid, liver, renal and muscle safety parameters were monitored at weeks 2,4 and 6. The average lipid parameters at weeks -2, -1 and 0 were used to derive the lipid modulating effects, One patient withdrew for personal reasons. No serious adverse events were experienced. No differences of response were noted between the regimens (single dose n = 10). After 6 weeks the LDLC was lowered by 57% from (mean, SD) 8.16 f 1.15 to 3.53 kO.99 mmol/l (P
(2271
Univ. Sch. of Med., Kusunoki-cho, Chuo-ku, Kobe 650; Med., Sanraku Hosp.; 2Res. Inst., Sankyo Co Ltd, Japan
lint.
We have examined changes of lesion composition in established atherosclerosis in WHHL rabbits when serum TC levels were reduced by administration of pravastatin sodium, given to mature (10 months) WHHL rabbits at 50 mg/kg for 1 year. We estimated 8 surface lesion area and intimal thickening in aortic lesions and degree of coronary stenosis. Atherosclerotic lesions were immunohistochemically and conventionally stained, and each component area was measured using a color image analyzer. Serum TC and LDL-C levels were about 20% lower in pravastatin-treated rabbits tban in controls, the surface lesion area and intimal thickening of abdominal ateas were 26% and 30% lower respectively and coronary stenosis was 50% lower at circumflex arteries and 29% lower as an average of all arteries. Within the lesions, the % ama of macrophages plus extracellular lipid deposits was significantly lower in aortic (-38%) and coronary (-36%) lesions in the treated group. These results suggest that pravastatin treatment suppresses the progression of established atherosclerosis by reducing the number of macrophages and extracellular lipid deposits in the lesions. Lipid-apheresis reduces plasma cholesterol but not apolipoproteins A-I and B j&&t&& Mahon MG, Dwivedy AK, Fang N, Iannuzzi C, Cham BE, Dept. of Med., Univ. of Qld, Australia
)228)
We report here that lipid-apheresis (LA), an extracorporeal lipid extraction procedure, rapidly reduces plasma cholesterol but not apolipoproteins in a mammalian animal model. Because of good blood access, hypercholesterolemic calves were used in this study. Between 5 and 12 LA treatments were performed on each calf and 25-7596 of their blood volume was treated per LA. LA consisted of separation of red blood cells from plasma, delipidation of the plasma with a mixture of butanol and diisopropyl ether, removal of traces of solvents, and remixing of the delipidated plasma with the red blood cells and reintroduction into the animals. All steps were continuous. Blood samples were taken before, during and up to 24 h after LA. Hematological and biochemical parameters were unaffected. Plasma cholesterol was rapidly reduced by up to 40%, but returned to pretreatment values after 16-20 h. Apolipoprotein A-i and B levels did not change during and after each LA tmatment. The rapid increase of cholesterol after LA may indicate mobilization of cholesterol from various fat deposits. The use of other animal models has already shown that LA is safe and can cause regression of atherosclerosis by accelerating reverse cholesterol transport. In the near future we would like to apply this novel procedure for the treatment of atherosclerosis to humans. )2291
Use of response surface analysis to determine the dose of a reductase inhibitor and bile acid resin regimen for optimal LDL-cholesterol lowering Wm. Johnson M, Samuels J, Elswick RK,
vJM. Schs. of Pharmacy and Med., Virginia Commonwealth Univ., 401 North 12th St., Richmond, VA 23298, USA
Hypercholesterolemic patients with coronary heart disease or multiple risk factors may need to lower their LDLC 30% or more to achieve recommended goals. A large dose of a single agent with its associated increased cost and side effects is often required. Alternatively, combined therapy with low doses of a mductase inhibitor and a bile acid resin may be more effective with less cost and fewer side effects. To determine the most effective combination regimen, graded doses of pravastatin (PRAVA) and colestipol (COL) were studied in patients with LDL-C between 140 and 200 mg/dl using response surface methodology. After a 6-week single-blind, diet-stabilization period, patients underwent a randomly assigned study regimen for 8 weeks. Using a 3X3 factorial design, all possible combinations of the following daily doses were studied: placebo, COL 5 g, COL 10 g, PRAVA 10 mg,
Atherosclerosis X, Montreal, October 1994
316
responses following injury to the vessel after angioplasty. It is considered that several growth factors produced at the site of injury mediate SMC proliferation. These growth factors act via distinct receptors and exhibit significant differences in their signal transduction mechanisms. Thus, the strategies for the development of effective agents to inhibit SMC proliferation include finding agents that inhibit proliferation to many different growth factors and act on regulatory mechanisms that control cell growth rather than produce general cellular cytotoxicity. In this study, we report the activity of a compound from a novel naphthopyran series, 29018 1, on SMC proliferation in vitro and arterial thickening in vivo. 290181 produced a dose-dependent inhibition of vascular SMC proliferation (It& = 20 nM) in response to serum or individual growth factors such as PDGF-bb, bFGF and EGF. Cell growth inhibition by 290181 was not due to cell death, as demonstrated by intracellular lactate dehydrogenase release (LDH), reversibility upon washing, and the stereospecific action of 290181. In the rat carotid artery balloon injury model, oral administration of 290181 over the experimental period produced a dose-dependent inhibition of intimal thickening (48% inhibition at 98 mg/kg/day, P < 0.005). These studies demonstrate that the novel pyran 290181 is a potent inhibitor of SMC proliferation in vitro and intimal thickening in vivo, and may have utility in the prevention of proliferative responses associated with vascular disease including restenosis and atherosclerosis. 1226(
Atorvastatin is a powerful and safe agent for lowering plasma cholesterol concentration in heterozygous familial hypercholesterolemia Firth JC, Bateman M, Jones J, Mountney J, Martens
m C, ht. Med., Univ. of Cape Town Med. Sch., Observatory 7925, South Africa
The safety and efficacy of 80 mg/day of atorvastatin, a hydroxymethylglutaryl coenzyme A teductase inhibitor, was investigated in subjects with heteroxygous familial hypercholesterolemia (FH) diagnosed by PCR assay for local LDL receptor mutations or by excluding binding-defective apo B in primary hypercholesterolemia with xanthomata. Subjects underwent a 4-week drug washout and dietary stabilization phase. Secondary dyslipoproteinemia and significant organ dysfunction were excluded and consenting adults with a calculated LDL-C >6.4 mmohl were included. 22 were entered into the open-label, randomized parallel-arm design, testing treatment in divided and single doses. Clinical as well as lipid, liver, renal and muscle safety parameters were monitored at weeks 2,4 and 6. The average lipid parameters at weeks -2, -1 and 0 were used to derive the lipid modulating effects, One patient withdrew for personal reasons. No serious adverse events were experienced. No differences of response were noted between the regimens (single dose n = 10). After 6 weeks the LDLC was lowered by 57% from (mean, SD) 8.16 f 1.15 to 3.53 kO.99 mmol/l (P
(2271
Univ. Sch. of Med., Kusunoki-cho, Chuo-ku, Kobe 650; Med., Sanraku Hosp.; 2Res. Inst., Sankyo Co Ltd, Japan
lint.
We have examined changes of lesion composition in established atherosclerosis in WHHL rabbits when serum TC levels were reduced by administration of pravastatin sodium, given to mature (10 months) WHHL rabbits at 50 mg/kg for 1 year. We estimated 8 surface lesion area and intimal thickening in aortic lesions and degree of coronary stenosis. Atherosclerotic lesions were immunohistochemically and conventionally stained, and each component area was measured using a color image analyzer. Serum TC and LDL-C levels were about 20% lower in pravastatin-treated rabbits tban in controls, the surface lesion area and intimal thickening of abdominal ateas were 26% and 30% lower respectively and coronary stenosis was 50% lower at circumflex arteries and 29% lower as an average of all arteries. Within the lesions, the % ama of macrophages plus extracellular lipid deposits was significantly lower in aortic (-38%) and coronary (-36%) lesions in the treated group. These results suggest that pravastatin treatment suppresses the progression of established atherosclerosis by reducing the number of macrophages and extracellular lipid deposits in the lesions. Lipid-apheresis reduces plasma cholesterol but not apolipoproteins A-I and B j&&t&& Mahon MG, Dwivedy AK, Fang N, Iannuzzi C, Cham BE, Dept. of Med., Univ. of Qld, Australia
)228)
We report here that lipid-apheresis (LA), an extracorporeal lipid extraction procedure, rapidly reduces plasma cholesterol but not apolipoproteins in a mammalian animal model. Because of good blood access, hypercholesterolemic calves were used in this study. Between 5 and 12 LA treatments were performed on each calf and 25-7596 of their blood volume was treated per LA. LA consisted of separation of red blood cells from plasma, delipidation of the plasma with a mixture of butanol and diisopropyl ether, removal of traces of solvents, and remixing of the delipidated plasma with the red blood cells and reintroduction into the animals. All steps were continuous. Blood samples were taken before, during and up to 24 h after LA. Hematological and biochemical parameters were unaffected. Plasma cholesterol was rapidly reduced by up to 40%, but returned to pretreatment values after 16-20 h. Apolipoprotein A-i and B levels did not change during and after each LA tmatment. The rapid increase of cholesterol after LA may indicate mobilization of cholesterol from various fat deposits. The use of other animal models has already shown that LA is safe and can cause regression of atherosclerosis by accelerating reverse cholesterol transport. In the near future we would like to apply this novel procedure for the treatment of atherosclerosis to humans. )2291
Use of response surface analysis to determine the dose of a reductase inhibitor and bile acid resin regimen for optimal LDL-cholesterol lowering Wm. Johnson M, Samuels J, Elswick RK,
vJM. Schs. of Pharmacy and Med., Virginia Commonwealth Univ., 401 North 12th St., Richmond, VA 23298, USA
Hypercholesterolemic patients with coronary heart disease or multiple risk factors may need to lower their LDLC 30% or more to achieve recommended goals. A large dose of a single agent with its associated increased cost and side effects is often required. Alternatively, combined therapy with low doses of a mductase inhibitor and a bile acid resin may be more effective with less cost and fewer side effects. To determine the most effective combination regimen, graded doses of pravastatin (PRAVA) and colestipol (COL) were studied in patients with LDL-C between 140 and 200 mg/dl using response surface methodology. After a 6-week single-blind, diet-stabilization period, patients underwent a randomly assigned study regimen for 8 weeks. Using a 3X3 factorial design, all possible combinations of the following daily doses were studied: placebo, COL 5 g, COL 10 g, PRAVA 10 mg,
Atherosclerosis X, Montreal, October 1994