Antiarrhythmic effects of a benzothiazine derivative (SD-3211) and its stereoisomer (SA3212) in anaesthetized rats and isolated perfused rat hearts compared with bepridil

Fukuchi, Miho; Nagashima, Satoru; Nakashima, Mitsuvoshi

doi:10.1007/bf00171737

Cited by 17 publications

(25 citation statements)

References 30 publications

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“…The antiarrhythmic action of the drug has been attributed to its sodium and calcium channel blocking properties from the profiles of the antiarrhythmic effect (Miyawaki et al, 1991;Nagashima et al, 1992;Hirasawa et al, 1992). SD-3212 was shown to be effective against various experimental arrhythmias such as those induced by ouabain-, chlorform, two-stage coronary ligation, and halothane plus adrenaline (Fukuchi et al, 1990;Miyawaki et al, 1991;Nagashima et al, 1992). In terms of the class I effect of SD-3212, two reports have indicated that SD-3212 inhibits P.,.…”

Section: Resultsmentioning

confidence: 99%

“…SD-3212 ((-) -(S) -2 -[5 methoxy -2 - [3-[methyl[2-[3,4(methylenedioxy) phenoxy] ethyl] amino] propoxy] phenyl]-4-methyl-2H-1,4-benzothiazine-3(4H)-one hydrogen fumarate) is a stereoisomer of semotiadil fumarate (SD-321 1), a recently developed non-dihydropyridine type calcium antagonist (Miyawaki et al, 1990;Fukuchi et al, 1990;Teramoto, 1993). This agent is reported to possess antiarrhythmic properties with vasodilator action (Miyawaki et al, 1991;Nagashima et al, 1992;Hirasawa et al, 1992).…”

Section: Introductionmentioning

confidence: 99%

“…This agent is reported to possess antiarrhythmic properties with vasodilator action (Miyawaki et al, 1991;Nagashima et al, 1992;Hirasawa et al, 1992). In experimental animals, SD-3212 exerted a potent and long-lasting inhibitory action against ventricular tachyarrhythmias induced by chloroform, ouabain, adrenaline and ischaemia/reperfusion (Fukuchi et al, 1990;Miyawaki et al, 1991;Nagashima et al, 1992). In vascular smooth muscle, SD-3212 exerted a calcium antagonistic vasodilator action (Nakayama et al, 1992).…”

Section: Introductionmentioning

confidence: 99%

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SD‐3212, a new class I and IV antiarrhythmic drug: a potent inhibitor of the muscarinic acetylcholine‐receptor‐operated potassium current in guinea‐pig atrial cells

Hara

Nakaya

1995

British J Pharmacology

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1 By use of patch-clamp techniques, the effects of SD-3212, a novel antiarrhythmic drug, on the calcium current (ICa), the sodium current (INa) shortened action potential duration. Both SD-3212 (0.1-lyM) and bepridil (1-10 pM) reversed the action potential shortening in a concentration-dependent manner. The antagonizing effect of SD-3212 on the carbachol-induced action potential shortening was more potent than that of bepridil. 5These results suggest that SD-3212 inhibits IK.ACh by depressing the function of the potassium channel itself and/or associated GTP-binding proteins. SD-3212 is a unique antiarrhythmic drug, which potently inhibits IK.ACh in addition to its class I and IV effects. SD-3212 and bepridil may be useful for the termination and prevention of vagally-induced atrial flutter and fibrillation.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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SD‐3212, a new class I and IV antiarrhythmic drug: a potent inhibitor of the muscarinic acetylcholine‐receptor‐operated potassium current in guinea‐pig atrial cells

Hara

Nakaya

1995

British J Pharmacology

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“…This compound is a stereoisomer of semotiadil fumarate (SD-3211), a recently developed non-dihydropyridine type calcium antagonist (Miyawaki et al, 1990;Fukuchi et al, 1990;Teramoto, 1993). In vitro and in vivo experiments on rats, guinea-pigs, and dogs, showed that SD-3212 had a potent and long lasting inhibitory or protective action against ventricular tachyarrhythmias induced by chloroform, ouabain, adrenaline, coronary occlusion and reperfusion (Fukuchi et al, 1990;Miyawaki et al, 1991;Nagashima et al, 1992). The antiarrhythmic potency of SD-3212 in these animal models is appreciably higher than that of SD-3211.…”

mentioning

confidence: 99%

Electrophysiological effects of SD‐3212, a new antiarrhythmic agent with vasodilator action, on guinea‐pig ventricular cells

Kodama

Suzuki

Maruyama

et al. 1995

British J Pharmacology

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“…Semotiadil (R-isomer) is a new calcium antagonist with a non-dihydropyridine structure [25][26][27][28][29] , and shows antihypertensive 30,31 and antianginal activities. 32,33 Levosemotiadil (S-isomer) is an antiar-rhythmic drug with sodium and calcium channel-blocking action [34][35][36][37][38][39] , as well as potassium-blocking activity. 40 Both enantiomers are highly bound to plasma proteins, and their unbound concentrations could not be determined precisely using any conventional methods.…”

Section: -3mentioning

confidence: 99%

Binding Study of Semotiadil and Levosemotiadil with Human Serum Albumin Using High-Performance Frontal Analysis

et al. 1999

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A drug in plasma is bound to plasma proteins, and the bound and unbound drug concentrations reach a rapid and reversible binding equilibrium. It has been known that the unbound drug concentration in plasma is more closely related to the pharmaceutical activity and side effects than to the total (bound+unbound) drug concentration. Several important pharmacokinetic properties, such as the hepatic metabolism rate, renal excretion rate, biomembrane permeation rate and steady state distribution volume, are functions of the unbound drug fraction. [1][2][3] Albumin is the major protein in plasma responsible for protein binding of many kinds of drugs. Human serum albumin (HSA) has two major binding sites: warfarin site (site I) and benzodiazepin site (site II); three additional specific binding sites are also proposed in the case of digitoxin, bilirubin and fatty acids.4,5 Coadministration of drugs which share the same binding site can cause an increase in the unbound drug concentrations due to binding competition, and may result in undesirable side-effects or unexpected changes in drug disposition. Qualitative and quantitative binding studies to estimate the binding parameters and to identify the binding site on a protein molecule are essential for effective drug development and safety in clinical use. In addition, the protein binding of a chiral drug is potentially different between the enantiomers 6,7 because of the intrinsic chirality of proteins, which may cause enantioselectivity in the drug disposition.So far, equilibrium dialysis and ultrafiltration methods have been widely used to determine unbound drug concentrations. However, these conventional methods have problems, such as drug adsorption onto the membrane and leakage of bound drug through the membrane, which often make it difficult, or even impossible, to determine the unbound concentrations in the case of hydrophobic and strongly bound drugs. To overcome these problems, we proposed a novel chromatographic method, named high-performance frontal analysis (HPFA). [8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24] HPFA has several unique features. Since HPFA does not use any membrane, this method is free from undesirable drug adsorption onto the membrane, or leakage of the bound drug. During the frontal analysis, bound drug is transformed into the unbound form, and all drug molecules are eluted as a single zonal peak of unbound drug. If the zonal drug peak is completely separated from the protein peak, both unbound and total drug concentrations are determined simultaneously from the plateau height and peak area, respectively. In addition, HPFA can be easily incorporated into an on-line HPLC system. The detectability can be improved by on-line preconcentration of the unbound drug in the plateau zone. The unbound concentrations of a racemic drug can be determined enantioselectively by the on-line coupling of a HPFA column with a chiral HPLC column.Semotiadil and levosemotiadil (chemical structure, see Fig. 1) are an enantiomeric pair of drugs wh...

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Antiarrhythmic effects of a benzothiazine derivative (SD-3211) and its stereoisomer (SA3212) in anaesthetized rats and isolated perfused rat hearts compared with bepridil

Cited by 17 publications

References 30 publications

SD‐3212, a new class I and IV antiarrhythmic drug: a potent inhibitor of the muscarinic acetylcholine‐receptor‐operated potassium current in guinea‐pig atrial cells

SD‐3212, a new class I and IV antiarrhythmic drug: a potent inhibitor of the muscarinic acetylcholine‐receptor‐operated potassium current in guinea‐pig atrial cells

Electrophysiological effects of SD‐3212, a new antiarrhythmic agent with vasodilator action, on guinea‐pig ventricular cells

Binding Study of Semotiadil and Levosemotiadil with Human Serum Albumin Using High-Performance Frontal Analysis

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