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Pharmacokinetics and pharmacodynamics of the ACAT inhibitor DuP128 in man
250
Wednesday 12 October 1994: Poster Abstracts Treatment II
and p~~a~tatin (P), a hydrophilic HMG-CoA reductase inhibitor, in 45 (28 men) patients with severe refractory familial combined hyperlipidemia (FCH), mean age 49 f 9 years. Monotherapy with a statin or a fibrate for at least 6 months in the past had failed to control their lipidemia. CHD was documented in 22 patients. In addition to a hypolipidemic diet the patients received G (two daily doses of 600 mg) and P (one bedtime dose of 40 mg) for a period of 52 weeks. Plasma lipoproteins and apoproteins were measured every month. Serum ALT, AST, yGT, alkaline phosphatase, creatinine kinase (CK), BUN and creatinine were monitored. The pm-treatment mean values (*SD) in mg/dl were: total cholesterol (TC) 316 f 33, triglycerides (TG) 312 f45, LDL-C 223 f 26, VLDL-C53f9,HDL-C36rt5,apoB173fI5andapoA-I118 * 9. At the 12th week the maximum modification of values was recorded: TC -35%, LDL-C -42%. VLDL-C -52%. HDLC +21%, TG -48%, apo B -33%, apo A-I +13%. All changes were highly significant (P < 0.001) and maintained for the rest of 40 treatment weeks. The treatment met intervention criteria for the 22 CHD-positive patients (LDL-C levels < 130 mg/dl) and the 23 primary prevention patients (CHD risk reduction 59%). No patient exhibited myopathy, liver or renal dysfunction, major gastrointestinal disturbances, insomnia, persistent headache or ocular problems. A moderate transient elevation of CK in five patients and of transaminase in four was recorded. In conclusion, the combined administration of P and G is an efficient and safe therapeutic choice for patients with severe FCH, but its routine use needs to be supported by mom extensive studies. Effectiveness of a system of LDL-apheresis using a cascade filtration method in the treatment of homozygous familial hypercholesterolemia Barbagallo, Avema MR*, Di Marco T, Spano L, Traina G, Marino G, Notarbartolo A, Dept. of Int. Med. and Geriatrics,
12711
Univ. of Palermo; Catania, Italy
*Chair of Applied Physiopathol., Univ. of
Hypercholesterolemia has been recognized as a primary risk factor for coronary heart disease. Reduction of plasma levels of TC and LDL-C has been shown to decrease coronary atherosclerosis. LDL-apheresis represents useful non-pharmacological tool to treat severe hypercholesterolemias. We have evaluated the effectiveness of a system of LDLapheresis using a cascade filtration method (DIDECO BT 985, Mirandola, Italy) in two young male subjects (I5 and 25 years) with homozygous familial hypercholesterolemia. Both showed severe coronary atherosclerosis as determined by angiography. Procedures were performed at intervals of 7 days in each case. We observed a mean reduction of plasma levels of TC by 57.8% (range 40.2-69.9%), LDL-C by 60.0% (range 40.771.9%) TG by 43.5%, HDL-C by 26.946, apo A-I by 29.5% and apo B by 54.3%. We have also noted a reduction of other parameters such as fibrinogen (50%) and Lp(a) (55.9%). At the end of each procedure a mean of about 8 g of cholesterol was removed from the total body pool. A decrease of total proteins (24.9%) and albumin (18.1%) was also observed, but this was completely restored before tbe following apheresis (1 week). These data achieve results not inferior to more selective methods (and with a reduction of LDL-C of up to 70%). The lack of selectivity, far from being a problem, actually leads to the simultaneous reduction of other risk parameters such as Lp(a) and fibrinogen. Pharmacokinetics and pharmacodynamics of the ACAT inhibitor DuP128 in man Lai CM, Brogdon BL, Pieniaszek HJ, Quon CY, Zyruk H, Connell JM, Benedek IH, w Terry JG, Grouse III JR, The
12721
DuPont Merck Pharmaceutical Co’mpany, Wilmington, DE, USA
We assessed phannacokinetics (doses 900 mg to 15 g/day) and pharmacodynamics (doses 900 mg to 3600 mg/day) of the ACAT inhibitor DuP128 (N’-(2,4-diflurophenyl)-N-[5-(4,5-diphenyl-lHimidazol-2-ylthio)pentyl]-N-heptyhuea) in males with mild hypercholesterolemia, with neomycin and placebo controls. Assays for DuP128, its sulfoxide (XC164) and sulfone (XB277) metabolites used HPLC. Cholesterol absorption was determined by a continuous-feeding, [14C]cbolesteroll[3H]beta sitosterol method. DuP128 plasma level (C,,,& and ama under concentrationtime curve (AUC) increased with dose. C,, and AUC values at Day 13 exceeded those of Day 0 both for DuP128 and metabolites. DuP128 oral plasma clearance (CL@) increased with dose, but was lower at Day 13 than Day 0. Oral volume of distribution (V/F) was dose-independent. DuP128 terminal half-life (tin) ranged from 17.9 to 47.6 h at Dav 0. All were loneer at Dav 13. ’ Neither DuP128 nor metabolites were detectable in itine. DuP128 (pooled 900-36OOmg/day doses) induced a 14.4+ 11.4% reduction in cholesterol absorption (P < 0.05 vs placebo). Neomycin induced 26.4 f 10.7% reduction (P c 0.01). After 6 weeks, neomycin reduced serum TC and LDL-C by 22.4 f9.28 and 24.0f 11.62, respectively (P < 0.01 vs placebo). DuP128 induced reductions of 3.9 rt 11% (ns) and 4.9 rt 14.3% (P = 0.05). Plasma DuP128 levels did not correlate with change in cholesterol absorption or LDL-C. DuP128 is poorly absorbed with a long t1/2that increases with multiple dosing resulting in an increase in AUC after once daily dosing. ACAT inhibitors impede cholesterol absorption in humans; however, the magnitude, as exemplified by DuP128, is small. Monotherapy with HMG-CoA reductase inhibitors does not induce muscle damage in hypercholesterolemic patients &nit TWA, Contermans J, Erkelens DW, B&r P, Univ. Hospital
12731
Utrecht, PO Box 85500, Utrecht, The Netherlands
Treatment with inhibitors of HMG-CoA reductase is associated with high serum creatine kinase (CK) levels and myopathy (Gnmdy et al N Engl J Med 1988; 319: 24-33). To assess muscle damage, we studied CK and myoglobin (Mb) release after a 45min ergometer test, 2 W/kg lean body mass (Bar P et al Muscle Nerve 1986: 9(5S): 200-201). in two erotms of 11 oatients with primary hyperchoiesterolaemia (group I, age 50 k-7, maleslfemales (m/f) 7/4, LDL-C 6.0 f 0.9 mmoV1; group II, age 54 + 9, m/f 9/2, LDL-C 6.1 f 1.1) before and after 18 weeks of treatment with equipotent doses of pravastatin (group I) resp simvastatin (group II), 35.5 resp 28.3 mg/day. Biopsies were taken 48 h after exercise from the quadriceps muscle and stained with H&E. LDL-C after treatment was 4.0 f 0.9 in group I and 3.3 f 0.5 in group II. Peak CK and Mb levels occurred 8 h resp 1 h after exercise in all cases. Pm-exercise CK (CKo) before and after treatment did not differ in group I (64 f 30 U/l vs 86 f 72, P > 0.05 Wilcoxon) nor did CK rise (peak CK minus CK,$: 20 f 7vs15f10.Mbo(28f9ng/lmsp33rt6)andMbrise(5f7vs 18 f 18) before and after treatment also did not differ between groups I and II. In group II, CKo before and after treatment did not differ (89 + 49 vs 82 f 61) nor did CK rise: 40 f 50 vs 28 f 25. Mbo (33 + 15 vs 35 + 8) and Mb rise (31 f 59 vs 16 f 23) did not differ either. Treatment did not affect muscle histology as judged by light microscopy in group I (3 abnormal at baseline resp 4 after treatment) and II (0 resp 0) (x2. P > 0.05). Conclusion: 18 weeks of monotherapy with pravastatin or simvastatin does not give rise to muscle damage in hypercholesterolemic patients. 12741
Effects of long-term alcohol consumption on fluvaatatin pharmacokinetics, efficacy and safety in patients with hypercholesterolemia
Atherosclerosis X, Montreal, October 1994
Wednesday 12 October 1994: Poster Abstracts Treatment II
and p~~a~tatin (P), a hydrophilic HMG-CoA reductase inhibitor, in 45 (28 men) patients with severe refractory familial combined hyperlipidemia (FCH), mean age 49 f 9 years. Monotherapy with a statin or a fibrate for at least 6 months in the past had failed to control their lipidemia. CHD was documented in 22 patients. In addition to a hypolipidemic diet the patients received G (two daily doses of 600 mg) and P (one bedtime dose of 40 mg) for a period of 52 weeks. Plasma lipoproteins and apoproteins were measured every month. Serum ALT, AST, yGT, alkaline phosphatase, creatinine kinase (CK), BUN and creatinine were monitored. The pm-treatment mean values (*SD) in mg/dl were: total cholesterol (TC) 316 f 33, triglycerides (TG) 312 f45, LDL-C 223 f 26, VLDL-C53f9,HDL-C36rt5,apoB173fI5andapoA-I118 * 9. At the 12th week the maximum modification of values was recorded: TC -35%, LDL-C -42%. VLDL-C -52%. HDLC +21%, TG -48%, apo B -33%, apo A-I +13%. All changes were highly significant (P < 0.001) and maintained for the rest of 40 treatment weeks. The treatment met intervention criteria for the 22 CHD-positive patients (LDL-C levels < 130 mg/dl) and the 23 primary prevention patients (CHD risk reduction 59%). No patient exhibited myopathy, liver or renal dysfunction, major gastrointestinal disturbances, insomnia, persistent headache or ocular problems. A moderate transient elevation of CK in five patients and of transaminase in four was recorded. In conclusion, the combined administration of P and G is an efficient and safe therapeutic choice for patients with severe FCH, but its routine use needs to be supported by mom extensive studies. Effectiveness of a system of LDL-apheresis using a cascade filtration method in the treatment of homozygous familial hypercholesterolemia Barbagallo, Avema MR*, Di Marco T, Spano L, Traina G, Marino G, Notarbartolo A, Dept. of Int. Med. and Geriatrics,
12711
Univ. of Palermo; Catania, Italy
*Chair of Applied Physiopathol., Univ. of
Hypercholesterolemia has been recognized as a primary risk factor for coronary heart disease. Reduction of plasma levels of TC and LDL-C has been shown to decrease coronary atherosclerosis. LDL-apheresis represents useful non-pharmacological tool to treat severe hypercholesterolemias. We have evaluated the effectiveness of a system of LDLapheresis using a cascade filtration method (DIDECO BT 985, Mirandola, Italy) in two young male subjects (I5 and 25 years) with homozygous familial hypercholesterolemia. Both showed severe coronary atherosclerosis as determined by angiography. Procedures were performed at intervals of 7 days in each case. We observed a mean reduction of plasma levels of TC by 57.8% (range 40.2-69.9%), LDL-C by 60.0% (range 40.771.9%) TG by 43.5%, HDL-C by 26.946, apo A-I by 29.5% and apo B by 54.3%. We have also noted a reduction of other parameters such as fibrinogen (50%) and Lp(a) (55.9%). At the end of each procedure a mean of about 8 g of cholesterol was removed from the total body pool. A decrease of total proteins (24.9%) and albumin (18.1%) was also observed, but this was completely restored before tbe following apheresis (1 week). These data achieve results not inferior to more selective methods (and with a reduction of LDL-C of up to 70%). The lack of selectivity, far from being a problem, actually leads to the simultaneous reduction of other risk parameters such as Lp(a) and fibrinogen. Pharmacokinetics and pharmacodynamics of the ACAT inhibitor DuP128 in man Lai CM, Brogdon BL, Pieniaszek HJ, Quon CY, Zyruk H, Connell JM, Benedek IH, w Terry JG, Grouse III JR, The
12721
DuPont Merck Pharmaceutical Co’mpany, Wilmington, DE, USA
We assessed phannacokinetics (doses 900 mg to 15 g/day) and pharmacodynamics (doses 900 mg to 3600 mg/day) of the ACAT inhibitor DuP128 (N’-(2,4-diflurophenyl)-N-[5-(4,5-diphenyl-lHimidazol-2-ylthio)pentyl]-N-heptyhuea) in males with mild hypercholesterolemia, with neomycin and placebo controls. Assays for DuP128, its sulfoxide (XC164) and sulfone (XB277) metabolites used HPLC. Cholesterol absorption was determined by a continuous-feeding, [14C]cbolesteroll[3H]beta sitosterol method. DuP128 plasma level (C,,,& and ama under concentrationtime curve (AUC) increased with dose. C,, and AUC values at Day 13 exceeded those of Day 0 both for DuP128 and metabolites. DuP128 oral plasma clearance (CL@) increased with dose, but was lower at Day 13 than Day 0. Oral volume of distribution (V/F) was dose-independent. DuP128 terminal half-life (tin) ranged from 17.9 to 47.6 h at Dav 0. All were loneer at Dav 13. ’ Neither DuP128 nor metabolites were detectable in itine. DuP128 (pooled 900-36OOmg/day doses) induced a 14.4+ 11.4% reduction in cholesterol absorption (P < 0.05 vs placebo). Neomycin induced 26.4 f 10.7% reduction (P c 0.01). After 6 weeks, neomycin reduced serum TC and LDL-C by 22.4 f9.28 and 24.0f 11.62, respectively (P < 0.01 vs placebo). DuP128 induced reductions of 3.9 rt 11% (ns) and 4.9 rt 14.3% (P = 0.05). Plasma DuP128 levels did not correlate with change in cholesterol absorption or LDL-C. DuP128 is poorly absorbed with a long t1/2that increases with multiple dosing resulting in an increase in AUC after once daily dosing. ACAT inhibitors impede cholesterol absorption in humans; however, the magnitude, as exemplified by DuP128, is small. Monotherapy with HMG-CoA reductase inhibitors does not induce muscle damage in hypercholesterolemic patients &nit TWA, Contermans J, Erkelens DW, B&r P, Univ. Hospital
12731
Utrecht, PO Box 85500, Utrecht, The Netherlands
Treatment with inhibitors of HMG-CoA reductase is associated with high serum creatine kinase (CK) levels and myopathy (Gnmdy et al N Engl J Med 1988; 319: 24-33). To assess muscle damage, we studied CK and myoglobin (Mb) release after a 45min ergometer test, 2 W/kg lean body mass (Bar P et al Muscle Nerve 1986: 9(5S): 200-201). in two erotms of 11 oatients with primary hyperchoiesterolaemia (group I, age 50 k-7, maleslfemales (m/f) 7/4, LDL-C 6.0 f 0.9 mmoV1; group II, age 54 + 9, m/f 9/2, LDL-C 6.1 f 1.1) before and after 18 weeks of treatment with equipotent doses of pravastatin (group I) resp simvastatin (group II), 35.5 resp 28.3 mg/day. Biopsies were taken 48 h after exercise from the quadriceps muscle and stained with H&E. LDL-C after treatment was 4.0 f 0.9 in group I and 3.3 f 0.5 in group II. Peak CK and Mb levels occurred 8 h resp 1 h after exercise in all cases. Pm-exercise CK (CKo) before and after treatment did not differ in group I (64 f 30 U/l vs 86 f 72, P > 0.05 Wilcoxon) nor did CK rise (peak CK minus CK,$: 20 f 7vs15f10.Mbo(28f9ng/lmsp33rt6)andMbrise(5f7vs 18 f 18) before and after treatment also did not differ between groups I and II. In group II, CKo before and after treatment did not differ (89 + 49 vs 82 f 61) nor did CK rise: 40 f 50 vs 28 f 25. Mbo (33 + 15 vs 35 + 8) and Mb rise (31 f 59 vs 16 f 23) did not differ either. Treatment did not affect muscle histology as judged by light microscopy in group I (3 abnormal at baseline resp 4 after treatment) and II (0 resp 0) (x2. P > 0.05). Conclusion: 18 weeks of monotherapy with pravastatin or simvastatin does not give rise to muscle damage in hypercholesterolemic patients. 12741
Effects of long-term alcohol consumption on fluvaatatin pharmacokinetics, efficacy and safety in patients with hypercholesterolemia
Atherosclerosis X, Montreal, October 1994