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Effect of verapamil and nifedipine on cholesteryl ester metabolism and LDL oxidation in macrophages
Thursday I3 October 1994: Poster Abstracts Treatment Ill
were not affected. Despite a lack of effect on fasting plasma TG CGS 26214 significantly accelerated the clearance of postprandial lipemia induced by an oral fat load. This effect was characterized by an earlier lipemia peak (2 vs 4 h) and faster return to baseline TG levels (8 vs 24 h) in test vs control animals. Cardiac safety was studied in isolated atrial preparation from rats treated with up to 25 mgikg of CGS 26214 (25 000x the MED on plasma TC) and compared to control as well & rats treated with lOO@kg of L-T3. Whereas atrial rate, atrial tension and heart weight were significantly increased by 37, 43 and 47% in T3-treated animals, CGS 26214 had no effect on any of these parameters. These results clearly indicate that the lipid-lowering activity and cardiovascular side effects of thyroid hormone can be significantly dissociated by major alterations of the original structure of L-T3.
323
of serum and HDL. The same concentrations of the drugs inhibited both LDL derived malonyldialdehyde-like products and nitroblue tetrazolium dye reduction in a dose-dependent fashion. The results suggest that verapamil and n&&pine exert their macrophage-mediated a&atherosclerotic effect via reduction of LDL oxidative modification, reduction of intracellular ChE synthesis, stimulation of ChE hydrolysis and of cholesterol excretion from the cells. Efftieacy of low doses of simvastatin and niacin used concomitantly in patients with combined byperlipidemia Dujovne CA, Hunninghake DB, Goldberg RB, m Stein EA. Knbpp RH, Illingworth DR, Miller VT, Frost PH, Tobert JA, Chicago Center for Clin. Res., 800 South Wells St,
12551
Suite M25, Chicago, IL 60607, USA
Marked reduction of LDL and Lp(a) by CGS 26214, 12531 a selective cardiac-sparing thyromimetic in cynomolgus monkeys a, Yurachek EC, Beil ME, Hintze TH, Dotson RA, Trapani AJ, Steele RE, Shwartzkopf C, Dardik BN, Rex Dept., Pharmaceuricals Div., Ciba-Geigy Corp., Summit, NJ 07901, USA
This study was designed to investigate the lipid-lowering profile of CGS 26214 in cynomolgus monkeys and to demonstrate the dissociation between its hypolipidemic (HL) activity and cardiovascular side effects. After oral treatment with 1-lO,@kg of CGS 26214 for 5 days, LDL-cholesterol was dose-dependently reduced with a minimum effective dose of 1 pg/kg (23% reduction, P < 0.05). Using the same animals instrumented chronically to measure cardiovascular parameters, CGS 26214 was given at 3O,@kg (30X minimum effective HL dose) p.0. for 7 days. At the end of the treatment period, CGS 26214 showed no effect on mean arterial pressure (MAP, A = -6 f 4 mmHg), heart rate (HR. A = 2* 8 bpm), left ventricular systolic (LVSP, A=-7* 7 mmHg) and end diastolic pressures (A = 0 + 1 mmHg) and LV dP/dt (A = -10 + 8%). However, in the same studies, plasma TC and Lp(a) were reduced by 20 and 428, respectively. In comparison, L-T3 which was given at lOOpg/kg, i.e. 4x its minimum effective hypolipidemic dose, had a similar effect on plasma lipid parameters as CGS 26214 but increased MAP (22 f 2 mmHg), HR (73 + 21 bpm), LVSP (47 * 10 mmHg) and LV dP/dt (33 * 5 %; P < 0.05 for all parameters). These studies clearly indicate that, in comparison to L-T3, CGS 26214 has a potent effect on plasma LDL and Lp(a), coupled with a lack of cardiovascular side effects in a non-human primate species. Effect of verapamil and nifedipine on cholesteryl ester metabolism and LDL oxidation in macrophages Dushkin MI, Schwartz Ysh*, Inst. of Int. Med., *Inst. of General
12541
Parho & Human Ecol., Siberian Div. of Russian Acad. Med. Sci., Vladimirovski Spusk st, 2a Novosibirsk: 630003 Russia
Using mouse macrophage cultures, we studied the effects of verapamil and nifedipine on cholesteryl ester and LDL metabolism, with special reference to the following parameters: (a) incorporation of [t4C]oleate into cholesteryl esters (ChE) b) contents of ?6 Cloleate from total and free cholesterol (FCh), (c) liberation of [’ ChE and incorporation of [3H]FCh into ChE, (d) excretion of [3H]Ch from the cells and (e) LDL oxidation. Verapamil and nifedipine (lO-100pM) were shown to decrease in a dosedependent manner the incorporation of [‘4C]oleate into ChE and to increase the concentration of FCh, but had no appreciable effect on the concentration of total Ch in macrophages cultured in the presence of acetylated LDL. The drugs stimulated the liberation of [14C]oleate from cellular ChE. The pharmacological concentration (25-75 PM) of verapamil and nifedipine increased the excretion of r3H]FCh from ChE of macrophages in the presence
After a 6-week dietary run-in period, 177 patients with combined hyperlipidemia were randomized to receive treatment with lowdose simvastatin, crystalline niacin (Nicols), or both together for 17 weeks. Simvastatin was given at 10 mg daily throughout; niacin was built up to 750 mg daily in the first week and taken at this dose for 8 weeks, then at 1.5 g daily for 8 weeks. Because of niacin-induced flushing, only simvastatin was blinded. The effects of low-dose simvastatin and niacin on lipoproteins were essentially additive, producing a near-optimal lipoprotein pattern. However, flushing was frequent even at 750 mg niacin. No safety problems emerged, but the study was too small and too short to assess safety adequately. It is not clear to what extent low-dose treatment diminishes the risk of the known interaction between inhibitors of HMG-CoA reductase and niacin to produce myopathy. Transport of different HMG-CoA reductase inhibitors across the blood-brain and intestinal epitheliil barriers Tamai 1, Tsuji A, Dept of Pharmaceutics, Fat. of Pharm. Sci.,
12561
Kanazawa Univ., 13-1 Takara-machi, Kanazawa 920, Japan
Certain HMG-CoA reductase inhibitors, lovastatin (L) and simvastatin (S), cause sleep disturbance whereas pravastatin (P) apparently does not, which suggest that the permeability of the blood-brain barrier (BBB) to these drugs is different. Since all three drugs are effective after oral administration, it seems that they all efficiently traverse the intestinal epithelial barrier (IEB), which in turn suggests that transport mechanisms for these drugs differ between BBB and IEB. In this study the permeability and transport mechanisms responsible for these drugs were evaluated using brain perfusion and primary cultures of brain capillary endothelial cells as surrogates for the BBB and intestinal brush-border membrane vesicles for the IEB. The lipid solubilities of L, P and S, and the acid forms of L and S (LA and SA respectively) differ greatly (octanol/water partition coefficients at pH 7.4 range from 0.59 to 48 400). The most water-soluble of the drugs, P, is transported across the IEB by the carrier-mediated mechanism specific to monocarboxylic acids (MCA), in a pH-dependent manner. LA and SA inhibited this transport of P, which suggests that they too are transported across the IEB by this carrier-mediated mechanism. It has been suggested that drugs are transported across the BBB by the same mechanism, but P was found to have too low an affinity for the MCA carrier to be effectively transported into brain. By contrast, lipophilic L and S showed very rapid permeability into brain by simple diffusion. These results explain the differential permeability through the brain and intestinal barriers. By utilizing the tissue-specific carrier-mediated transport mechanisms it may be possible to control
Atherosclerosis X, Montreal, October I994
were not affected. Despite a lack of effect on fasting plasma TG CGS 26214 significantly accelerated the clearance of postprandial lipemia induced by an oral fat load. This effect was characterized by an earlier lipemia peak (2 vs 4 h) and faster return to baseline TG levels (8 vs 24 h) in test vs control animals. Cardiac safety was studied in isolated atrial preparation from rats treated with up to 25 mgikg of CGS 26214 (25 000x the MED on plasma TC) and compared to control as well & rats treated with lOO@kg of L-T3. Whereas atrial rate, atrial tension and heart weight were significantly increased by 37, 43 and 47% in T3-treated animals, CGS 26214 had no effect on any of these parameters. These results clearly indicate that the lipid-lowering activity and cardiovascular side effects of thyroid hormone can be significantly dissociated by major alterations of the original structure of L-T3.
323
of serum and HDL. The same concentrations of the drugs inhibited both LDL derived malonyldialdehyde-like products and nitroblue tetrazolium dye reduction in a dose-dependent fashion. The results suggest that verapamil and n&&pine exert their macrophage-mediated a&atherosclerotic effect via reduction of LDL oxidative modification, reduction of intracellular ChE synthesis, stimulation of ChE hydrolysis and of cholesterol excretion from the cells. Efftieacy of low doses of simvastatin and niacin used concomitantly in patients with combined byperlipidemia Dujovne CA, Hunninghake DB, Goldberg RB, m Stein EA. Knbpp RH, Illingworth DR, Miller VT, Frost PH, Tobert JA, Chicago Center for Clin. Res., 800 South Wells St,
12551
Suite M25, Chicago, IL 60607, USA
Marked reduction of LDL and Lp(a) by CGS 26214, 12531 a selective cardiac-sparing thyromimetic in cynomolgus monkeys a, Yurachek EC, Beil ME, Hintze TH, Dotson RA, Trapani AJ, Steele RE, Shwartzkopf C, Dardik BN, Rex Dept., Pharmaceuricals Div., Ciba-Geigy Corp., Summit, NJ 07901, USA
This study was designed to investigate the lipid-lowering profile of CGS 26214 in cynomolgus monkeys and to demonstrate the dissociation between its hypolipidemic (HL) activity and cardiovascular side effects. After oral treatment with 1-lO,@kg of CGS 26214 for 5 days, LDL-cholesterol was dose-dependently reduced with a minimum effective dose of 1 pg/kg (23% reduction, P < 0.05). Using the same animals instrumented chronically to measure cardiovascular parameters, CGS 26214 was given at 3O,@kg (30X minimum effective HL dose) p.0. for 7 days. At the end of the treatment period, CGS 26214 showed no effect on mean arterial pressure (MAP, A = -6 f 4 mmHg), heart rate (HR. A = 2* 8 bpm), left ventricular systolic (LVSP, A=-7* 7 mmHg) and end diastolic pressures (A = 0 + 1 mmHg) and LV dP/dt (A = -10 + 8%). However, in the same studies, plasma TC and Lp(a) were reduced by 20 and 428, respectively. In comparison, L-T3 which was given at lOOpg/kg, i.e. 4x its minimum effective hypolipidemic dose, had a similar effect on plasma lipid parameters as CGS 26214 but increased MAP (22 f 2 mmHg), HR (73 + 21 bpm), LVSP (47 * 10 mmHg) and LV dP/dt (33 * 5 %; P < 0.05 for all parameters). These studies clearly indicate that, in comparison to L-T3, CGS 26214 has a potent effect on plasma LDL and Lp(a), coupled with a lack of cardiovascular side effects in a non-human primate species. Effect of verapamil and nifedipine on cholesteryl ester metabolism and LDL oxidation in macrophages Dushkin MI, Schwartz Ysh*, Inst. of Int. Med., *Inst. of General
12541
Parho & Human Ecol., Siberian Div. of Russian Acad. Med. Sci., Vladimirovski Spusk st, 2a Novosibirsk: 630003 Russia
Using mouse macrophage cultures, we studied the effects of verapamil and nifedipine on cholesteryl ester and LDL metabolism, with special reference to the following parameters: (a) incorporation of [t4C]oleate into cholesteryl esters (ChE) b) contents of ?6 Cloleate from total and free cholesterol (FCh), (c) liberation of [’ ChE and incorporation of [3H]FCh into ChE, (d) excretion of [3H]Ch from the cells and (e) LDL oxidation. Verapamil and nifedipine (lO-100pM) were shown to decrease in a dosedependent manner the incorporation of [‘4C]oleate into ChE and to increase the concentration of FCh, but had no appreciable effect on the concentration of total Ch in macrophages cultured in the presence of acetylated LDL. The drugs stimulated the liberation of [14C]oleate from cellular ChE. The pharmacological concentration (25-75 PM) of verapamil and nifedipine increased the excretion of r3H]FCh from ChE of macrophages in the presence
After a 6-week dietary run-in period, 177 patients with combined hyperlipidemia were randomized to receive treatment with lowdose simvastatin, crystalline niacin (Nicols), or both together for 17 weeks. Simvastatin was given at 10 mg daily throughout; niacin was built up to 750 mg daily in the first week and taken at this dose for 8 weeks, then at 1.5 g daily for 8 weeks. Because of niacin-induced flushing, only simvastatin was blinded. The effects of low-dose simvastatin and niacin on lipoproteins were essentially additive, producing a near-optimal lipoprotein pattern. However, flushing was frequent even at 750 mg niacin. No safety problems emerged, but the study was too small and too short to assess safety adequately. It is not clear to what extent low-dose treatment diminishes the risk of the known interaction between inhibitors of HMG-CoA reductase and niacin to produce myopathy. Transport of different HMG-CoA reductase inhibitors across the blood-brain and intestinal epitheliil barriers Tamai 1, Tsuji A, Dept of Pharmaceutics, Fat. of Pharm. Sci.,
12561
Kanazawa Univ., 13-1 Takara-machi, Kanazawa 920, Japan
Certain HMG-CoA reductase inhibitors, lovastatin (L) and simvastatin (S), cause sleep disturbance whereas pravastatin (P) apparently does not, which suggest that the permeability of the blood-brain barrier (BBB) to these drugs is different. Since all three drugs are effective after oral administration, it seems that they all efficiently traverse the intestinal epithelial barrier (IEB), which in turn suggests that transport mechanisms for these drugs differ between BBB and IEB. In this study the permeability and transport mechanisms responsible for these drugs were evaluated using brain perfusion and primary cultures of brain capillary endothelial cells as surrogates for the BBB and intestinal brush-border membrane vesicles for the IEB. The lipid solubilities of L, P and S, and the acid forms of L and S (LA and SA respectively) differ greatly (octanol/water partition coefficients at pH 7.4 range from 0.59 to 48 400). The most water-soluble of the drugs, P, is transported across the IEB by the carrier-mediated mechanism specific to monocarboxylic acids (MCA), in a pH-dependent manner. LA and SA inhibited this transport of P, which suggests that they too are transported across the IEB by this carrier-mediated mechanism. It has been suggested that drugs are transported across the BBB by the same mechanism, but P was found to have too low an affinity for the MCA carrier to be effectively transported into brain. By contrast, lipophilic L and S showed very rapid permeability into brain by simple diffusion. These results explain the differential permeability through the brain and intestinal barriers. By utilizing the tissue-specific carrier-mediated transport mechanisms it may be possible to control
Atherosclerosis X, Montreal, October I994