Progress and prospects for optimum antiarrhythmic drug design

Courtney, Kenneth R.

doi:10.1007/bf02125464

Cited by 5 publications

(2 citation statements)

References 32 publications

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“…Thus, at 2 Hz the onset rate value of the frequency-dependent V, , block was 0.099 ? 0.01 AP-', a value which is similar to that for compounds which have been proposed as slow kinetics class I drugs (24,6,17). The recovery kinetics of V , , from the frequency-dependent block was studied in papillary muscles by applying a single test stimulus at various coupling intervals (300 msec-30 sec) after a stimulation train for 8 sec at 3 Hz (1 1,12,41).…”

Section: Frequency-dependent Effects Of Cre-1087mentioning

confidence: 98%

“…These results suggest that at frequencies higher than 2 Hz the V, , block apparently achieved a steadystate value. The time-constant (7,,*, sec) and the onset rate per action potential [K, (AP-')I at which V, , , decreased to a new steady-state level can be calculated from the regression lines in semilogarithmic plots (6,7,12,17,41). The onset rate of the frequencydependent V, , block, expressed as a fractional decrease per action potential (K), was dependent on the stimulation frequency, being always higher at lower stimulation frequencies at any drug concentrations tested (2,3,6,7,11,38,42).…”

Section: Frequency-dependent Effects Of Cre-1087mentioning

confidence: 99%

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Pharmacology of CRE‐1087, A New Antiarrhythmic Drug

Delpón

Valenzuela

Pérez

et al. 1992

Cardiovascular Drug Reviews

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CRE-1087, 1 -( 2-methoxy)-phenoxy-2,3 -bis[ 2-diethylamino-etox yI-propane dicitrate (Fig. l), is a new class Ic antiarrhythmic drug first synthetized in 1978 (1) in the Molecular Research Center of the Cermol Pharmaceutical Division. It can be administered either orally or intravenously. This agent was selected for clinical testing from a chemical series of related glycerol-aminoalkylethers on the basis of its superior antiarrhythmic activity and high safety ratio in both the parenteral and oral dosage forms.CRE-1087 crystallized as a white solid (molecular weight 780.80) with a melting point of 79-83'. It is soluble in water to the extent of about 35%, as a base it is soluble in ethanol, chloroform, dichloromethane, and in common organic solvents. PRECLINICAL STUDIES Electrophysiological Effects in Isolated Cardiac PreparationsMicroelectrode recordings have been used to study the effects of CRE-1087 on the transmembrane potentials of guinea pig atrial and ventricular muscle fibers under a variety of conditions (8,9,10,13,37). At concentrations between 0.1 and 100 pA4 CRE-1087 decreased in a concentration-dependent manner the amplitude, overshoot, and maximal rate of depolarization ( V , , , an index of the fast inward sodium current) of the atrial and ventricular action potentials, and slowed intraventricular conduction velocity. In microelectrode studies in guinea pig papillary muscles CRE-1087 was more potent than quinidine (43), propafenone (41), flecainide (12), or mexiletine (12,41,43) in inhibiting the V,,,. However, at all these concentrations CRE-1087 had no effect on either the resting membrane potential or the action potential duration measured at both 50% (APD,,) and

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Section: Frequency-dependent Effects Of Cre-1087mentioning

confidence: 98%

Section: Frequency-dependent Effects Of Cre-1087mentioning

confidence: 99%

Pharmacology of CRE‐1087, A New Antiarrhythmic Drug

Delpón

Valenzuela

Pérez

et al. 1992

Cardiovascular Drug Reviews

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Cardiovascular Agents

Cervoni¹,

Crandall²,

Chan³

2000

Kirk-Othmer Encyclopedia of Chemical Technology

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The six primary classes of cardiovascular drugs, ie, antiarrhythmic agents, antianginal agents, agents used in the treatment of congestive heart failure, antiatherosclerotic agents, antihypertensive agents, and thrombolytic agents, are reviewed. An overview of the physiology of the cardiovascular system is presented for each class together with the pathology of the system leading to specific cardiovascular disorders. The mechanism(s) of action of the cardiovascular agents are discussed when known, and the principal actions of the cardiovascular agents that contribute to amelioration of the underlying pathology of the cardiovascular disease are reviewed. Side effects and toxicities of the cardiovascular agents are also presented. Drugs clinically in use and some of those drugs under development are discussed. A brief review of the current and projected sales of ethical pharmaceuticals is presented in relation to the sales of cardiovascular agents which is the fastest growing segment of the ethical pharmaceutical market.

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Electrophysiological effects of flecainide enantiomers in canine Purkinje fibres

Smallwood

Robertson

Steinberg

1989

Naunyn-Schmiedeberg's Arch Pharmacol

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Since flecainide is a chiral class I antiarrhythmic agent, we examined the basic electrophysiological effects of its enantiomers (10-(6) - 3 x 10(-5) mol/l) in isolated canine Purkinje fibres using standard microelectrode techniques. Frequency-dependent block was studied by pacing at cycle lengths of 300 and 2000 ms. Both enantiomers produced a marked, concentration-dependent decrease in maximum upstroke velocity (Vmax), with greater depression occurring at a cycle length of 300 ms. The concentration causing a 50% decrease in Vmax (EC50) at this pacing rate were 5.0 +/- 0.6 x 10(-6) mol/l for (+)-flecainide and 6.2 +/- 0.8 x 10(-6) mol/l for (-)-flecainide, and were not significantly different. Both enantiomers also produced a concentration- and frequency-dependent decrease in action potential amplitude and an increase in conduction time with no significant differences between the enantiomers. However, at the highest concentration studied (3 x 10(-5) mol/l), none of the nine tissues exposed to (+)-flecainide could be paced at 300 ms cycle length while five of eight tissues exposed to (-)-flecainide could be paced, suggesting the possibility of a small difference between the effects of the enantiomers on membrane responsiveness. The effect of the enantiomers on action potential duration (APD) also depended on pacing rate. At the longer cycle length, ADP50 was shortened to a maximum of 61 +/- 7% and 67 +/- 7% from baseline by (+)- and (-)-flecainide, respectively, whereas APD95 was shortened by 30 +/- 6% and 32 +/- 3% from baseline by (+)- and (-)-flecainide, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

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Progress and prospects for optimum antiarrhythmic drug design

Cited by 5 publications

References 32 publications

Pharmacology of CRE‐1087, A New Antiarrhythmic Drug

Pharmacology of CRE‐1087, A New Antiarrhythmic Drug

Cardiovascular Agents

Electrophysiological effects of flecainide enantiomers in canine Purkinje fibres

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