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J A Barrett - One of the best experts on this subject based on the ideXlab platform.

  • Preclinical pharmacology of celiprolol: a cardioselective beta-adrenergic antagonist and mild vasodilator.
    American heart journal, 1991
    Co-Authors: M H Perrone, J A Barrett
    Abstract:

    Celiprolol is a new antihypertensive agent that represents a new generation of beta-blockers. It combines cardioselective beta-adrenergic antagonism (beta 1) with a mild vasodilation via vasoselective beta-adrenergic agonism (beta 2). Results of animal studies show that celiprolol has beta 1-antagonist potency similar to that of propranolol and atenolol, and Cardioselectivity slightly greater than that of atenolol. Celiprolol does not produce bronchoconstriction but has mild propranolol-resistant bronchodilatory properties in cats. The compound also relaxes vascular smooth muscle in a propranolol-sensitive fashion, suggesting a mechanism of beta 2-agonism. The beta 2-agonism results in a selective downregulation in beta 2-receptor number and response in tissue culture, as well as in peripheral tissue from celiprolol-treated volunteers. The decreases in beta 2-receptors are blocked by concomitant treatment with propranolol. Celiprolol is devoid of cardiac depressant activity and in fact has mild cardiostimulatory actions. The cardiostimulation is not via beta 1-stimulation, since it is not abolished by beta-blocking doses of propranolol. In a model of severe myocardial ischemia, celiprolol attenuates the ischemia-induced myocardial acidosis and improves the regional segment function. These results are suggestive of myocardial protection. In summary, celiprolol distinguishes itself from other beta-blockers by virtue of its Cardioselectivity, vasorelaxation via beta 2-agonism, and the lack of bronchoconstriction and cardiodepression. These properties observed in animal studies have also been documented in clinical trials.

  • Preclinical pharmacology of celiprolol : a cardioselective β-adrenergic antagonist and mild vasodilator
    American Heart Journal, 1991
    Co-Authors: M H Perrone, J A Barrett
    Abstract:

    Abstract Celiprolol is a new antihypertensive agent that represents a new generation of β-blockers. It combines cardioselective β-adrenergic antagonism ( β 1 ) with a mild vasodilation via vasoselective β-adrenergic agonism ( β 2 ). Results of animal studies show that celiprolol has β 1 -antagonist potency similar to that of propranolol and atenolol, and Cardioselectivity slightly greater than that of atenolol. Celiprolol does not produce bronchoconstriction but has mild propranolol-resistant bronchodilatory properties in cats. The compound also relaxes vascular smooth muscle in a propranolol-sensitive fashion, suggesting a mechanism of β 2 -agonism. The β 2 -agonism results in a selective downregulation in β 2 -receptor number and response in tissue culture, as well as in peripheral tissue from celiprolol-treated volunteers. The decreases in β 2 -receptors are blocked by concomitant treatment with propranolol. Celiprolol is devoid of cardiac depressant activity and in fact has mild cardiostimulatory actions. The cardiostimulation is not via β 1 -stimulation, since it is not abolished by β-blocking doses of propranolol. In a model of severe myocardial ischemia, celiprolol attenuates the ischemia-induced myocardial acidosis and improves the regional segment function. These results are suggestive of myocardial protection. In summary, celiprolol distinguishes itself from other β-blockers by virtue of its Cardioselectivity, vasorelaxation via β 2 -agonism, and the lack of bronchoconstriction and cardiodepression. These properties observed in animal studies have also been documented in clinical trials.

E R Wagner - One of the best experts on this subject based on the ideXlab platform.

  • cardioselective ammonium phosphonium and sulfonium analogues of alpha tocopherol and ascorbic acid that inhibit in vitro and ex vivo lipid peroxidation and scavenge superoxide radicals
    Journal of Medicinal Chemistry, 1995
    Co-Authors: J M Grisar, G Marciniak, F N Bolkenius, J Vernemismer, E R Wagner
    Abstract:

    Analogues of alpha-tocopherol and ascorbic acid with permanently cationic substituents, i.e., phosphonium (8, 9), sulfonium (11), acylhydrazinium (13, 14), and ammonium (1, 16, 21), were synthesized, and the 2R and 2S enantiomers of the alpha-tocopherol analogues 1, 8, 11, and 13 were separated. The compounds were found to scavenge lipoperoxyl and superoxide radicals in vitro and accumulate in heart tissue (Cardioselectivity) as demonstrated by measurement of ex vivo inhibition of lipid peroxidation in mouse heart homogenates and confirmed by HPLC determination of drug concentrations for 1 and 11. The 2R and 2S enantiomers of 1 inhibited ex vivo lipid peroxidation to an equal extent. Thus the in vivo uptake into myocytes (Cardioselectivity) is independent of the geometry at the chiral center and common to permanently cationic compounds.

  • Cardioselectivity of alpha tocopherol analogues with free radical scavenger activity in the rat
    Drug Metabolism and Disposition, 1991
    Co-Authors: J Dow, J M Grisar, E R Wagner, Margaret A Petty, K D Haegele
    Abstract:

    MDL74270 (6-acetyloxy-3,4-dihydro-N,N,N,2,5,7, 8-heptamethyl-2H-1-benzopyran-2-ethanaminium, 4-methylbenzenesulfonate) is a quaternary amine analogue of alpha-tocopherol with free radical scavenger properties. Rats were injected iv with [14C]MDL74270 (0.91 mg/kg), and whole blood and heart tissue were sampled. Five min after drug, the heart tissue/blood ratio (T/B) of radioactivity was 3.5, whereas at 1 hr it was 20.1 and remained at this value up to at least 6 hr. After iv administration the t 1/2 of radioactivity in blood was 6.3 hr, but po blood levels could not be quantified. The 0- to 96-hr urinary elimination of radioactivity was 39.9 +/- 5.7% of the dose after iv and only 1.2 +/- 0.4% after po administration, conversely, 44.7 +/- 5.2% was excreted in feces after iv and 79.1 +/- 17.4% after po administration. These results confirmed poor oral absorption of the compound. Tissue distribution of [14C]MDL74270 was compared with that of its tertiary amine analogue [14C]MDL74366 in rat heart, skeletal muscle, brain, and whole blood, after iv administration (1 mg/kg). The heart T/B was above 20, 1-6 hr after [14C]MDL74270, whereas it was less than 2 after [14C]MDL74366. Over the 1- to 6-hr time interval, skeletal muscle T/B varied from 1.8 to 5 compared with 1.5 to 0.6 for [14C] MDL74366. Brain T/B was higher after the tertiary amine compound. Results showed marked Cardioselectivity of radioactivity after [14C] MDL74270. Differential centrifugation of heart homogenates showed that radioactivity was equally distributed between the major subcellular fractions studied.(ABSTRACT TRUNCATED AT 250 WORDS)

Peter E. Light - One of the best experts on this subject based on the ideXlab platform.

  • Cardioselectivity of the sulphonylurea HMR 1098: studies on native and recombinant cardiac and pancreatic KATP channels
    British journal of pharmacology, 2002
    Co-Authors: Jocelyn E. Manning Fox, Hussein D. Kanji, Robert J. French, Peter E. Light
    Abstract:

    In this study we investigated the effects of the putative cardioselective sulphonylurea derivative HMR 1098 on ATP-sensitive potassium (KATP) channels from cardiac ventricular myocytes, the INS-1 β-cell line and from recombinant KATP channels composed of SUR2A/Kir6.2, SUR1/Kir6.2, SUR1/Kir6.1 an Kir6.2,ΔC26. Recombinant channels were expressed in tsA201 or COS-1 cells. The effects of HMR 1098 on single channel and whole-cell currents were recorded using the patch-clamp technique. At the single channel level, using excised inside-out membrane patches, HMR 1098 inhibited KATP channels from ventricular cells and INS-1 cells with IC50s of 0.88 and 720 μM respectively. Similar results to those in cardiac cells were obtained using recombinant SUR2A/Kir6.2 KATP channels. HMR 1098 inhibition of SUR2A/Kir6.2 KATP channels was unaffected by the presence of internal ADP. In whole-cell recordings, HMR 1098 inhibited SUR2A/Kir6.2 and SUR1/Kir6.2 currents with IC50s of 2.1 and 860 μM respectively. HMR 1098 was without effect on currents either from the Kir6.2,ΔC26 truncation mutant or from Kir2.1. Our results demonstrate that HMR 1098 is a selective inhibitor of cardiac KATP channels, showing a 400–800-fold selectivity over β-cell KATP channels. The non-aromatic substitutions in the sulphonylurea moiety greatly increase the Cardioselectivity of this compound while reducing the overall blocking potency of this sulphonylurea derivative. British Journal of Pharmacology (2002) 135, 480–488; doi:10.1038/sj.bjp.0704455

M H Perrone - One of the best experts on this subject based on the ideXlab platform.

  • Preclinical pharmacology of celiprolol: a cardioselective beta-adrenergic antagonist and mild vasodilator.
    American heart journal, 1991
    Co-Authors: M H Perrone, J A Barrett
    Abstract:

    Celiprolol is a new antihypertensive agent that represents a new generation of beta-blockers. It combines cardioselective beta-adrenergic antagonism (beta 1) with a mild vasodilation via vasoselective beta-adrenergic agonism (beta 2). Results of animal studies show that celiprolol has beta 1-antagonist potency similar to that of propranolol and atenolol, and Cardioselectivity slightly greater than that of atenolol. Celiprolol does not produce bronchoconstriction but has mild propranolol-resistant bronchodilatory properties in cats. The compound also relaxes vascular smooth muscle in a propranolol-sensitive fashion, suggesting a mechanism of beta 2-agonism. The beta 2-agonism results in a selective downregulation in beta 2-receptor number and response in tissue culture, as well as in peripheral tissue from celiprolol-treated volunteers. The decreases in beta 2-receptors are blocked by concomitant treatment with propranolol. Celiprolol is devoid of cardiac depressant activity and in fact has mild cardiostimulatory actions. The cardiostimulation is not via beta 1-stimulation, since it is not abolished by beta-blocking doses of propranolol. In a model of severe myocardial ischemia, celiprolol attenuates the ischemia-induced myocardial acidosis and improves the regional segment function. These results are suggestive of myocardial protection. In summary, celiprolol distinguishes itself from other beta-blockers by virtue of its Cardioselectivity, vasorelaxation via beta 2-agonism, and the lack of bronchoconstriction and cardiodepression. These properties observed in animal studies have also been documented in clinical trials.

  • Preclinical pharmacology of celiprolol : a cardioselective β-adrenergic antagonist and mild vasodilator
    American Heart Journal, 1991
    Co-Authors: M H Perrone, J A Barrett
    Abstract:

    Abstract Celiprolol is a new antihypertensive agent that represents a new generation of β-blockers. It combines cardioselective β-adrenergic antagonism ( β 1 ) with a mild vasodilation via vasoselective β-adrenergic agonism ( β 2 ). Results of animal studies show that celiprolol has β 1 -antagonist potency similar to that of propranolol and atenolol, and Cardioselectivity slightly greater than that of atenolol. Celiprolol does not produce bronchoconstriction but has mild propranolol-resistant bronchodilatory properties in cats. The compound also relaxes vascular smooth muscle in a propranolol-sensitive fashion, suggesting a mechanism of β 2 -agonism. The β 2 -agonism results in a selective downregulation in β 2 -receptor number and response in tissue culture, as well as in peripheral tissue from celiprolol-treated volunteers. The decreases in β 2 -receptors are blocked by concomitant treatment with propranolol. Celiprolol is devoid of cardiac depressant activity and in fact has mild cardiostimulatory actions. The cardiostimulation is not via β 1 -stimulation, since it is not abolished by β-blocking doses of propranolol. In a model of severe myocardial ischemia, celiprolol attenuates the ischemia-induced myocardial acidosis and improves the regional segment function. These results are suggestive of myocardial protection. In summary, celiprolol distinguishes itself from other β-blockers by virtue of its Cardioselectivity, vasorelaxation via β 2 -agonism, and the lack of bronchoconstriction and cardiodepression. These properties observed in animal studies have also been documented in clinical trials.

J M Grisar - One of the best experts on this subject based on the ideXlab platform.

  • cardioselective ammonium phosphonium and sulfonium analogues of alpha tocopherol and ascorbic acid that inhibit in vitro and ex vivo lipid peroxidation and scavenge superoxide radicals
    Journal of Medicinal Chemistry, 1995
    Co-Authors: J M Grisar, G Marciniak, F N Bolkenius, J Vernemismer, E R Wagner
    Abstract:

    Analogues of alpha-tocopherol and ascorbic acid with permanently cationic substituents, i.e., phosphonium (8, 9), sulfonium (11), acylhydrazinium (13, 14), and ammonium (1, 16, 21), were synthesized, and the 2R and 2S enantiomers of the alpha-tocopherol analogues 1, 8, 11, and 13 were separated. The compounds were found to scavenge lipoperoxyl and superoxide radicals in vitro and accumulate in heart tissue (Cardioselectivity) as demonstrated by measurement of ex vivo inhibition of lipid peroxidation in mouse heart homogenates and confirmed by HPLC determination of drug concentrations for 1 and 11. The 2R and 2S enantiomers of 1 inhibited ex vivo lipid peroxidation to an equal extent. Thus the in vivo uptake into myocytes (Cardioselectivity) is independent of the geometry at the chiral center and common to permanently cationic compounds.

  • Cardioselectivity of alpha tocopherol analogues with free radical scavenger activity in the rat
    Drug Metabolism and Disposition, 1991
    Co-Authors: J Dow, J M Grisar, E R Wagner, Margaret A Petty, K D Haegele
    Abstract:

    MDL74270 (6-acetyloxy-3,4-dihydro-N,N,N,2,5,7, 8-heptamethyl-2H-1-benzopyran-2-ethanaminium, 4-methylbenzenesulfonate) is a quaternary amine analogue of alpha-tocopherol with free radical scavenger properties. Rats were injected iv with [14C]MDL74270 (0.91 mg/kg), and whole blood and heart tissue were sampled. Five min after drug, the heart tissue/blood ratio (T/B) of radioactivity was 3.5, whereas at 1 hr it was 20.1 and remained at this value up to at least 6 hr. After iv administration the t 1/2 of radioactivity in blood was 6.3 hr, but po blood levels could not be quantified. The 0- to 96-hr urinary elimination of radioactivity was 39.9 +/- 5.7% of the dose after iv and only 1.2 +/- 0.4% after po administration, conversely, 44.7 +/- 5.2% was excreted in feces after iv and 79.1 +/- 17.4% after po administration. These results confirmed poor oral absorption of the compound. Tissue distribution of [14C]MDL74270 was compared with that of its tertiary amine analogue [14C]MDL74366 in rat heart, skeletal muscle, brain, and whole blood, after iv administration (1 mg/kg). The heart T/B was above 20, 1-6 hr after [14C]MDL74270, whereas it was less than 2 after [14C]MDL74366. Over the 1- to 6-hr time interval, skeletal muscle T/B varied from 1.8 to 5 compared with 1.5 to 0.6 for [14C] MDL74366. Brain T/B was higher after the tertiary amine compound. Results showed marked Cardioselectivity of radioactivity after [14C] MDL74270. Differential centrifugation of heart homogenates showed that radioactivity was equally distributed between the major subcellular fractions studied.(ABSTRACT TRUNCATED AT 250 WORDS)