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PubMedDate not supplied

Physiological pharmacokinetics of a new muscle-relaxant, inaperisone, combined with its pharmacological effect on blood flow rate.

This study was designed to develop a physiologically-based pharmacokinetic/pharmacodynamic model for drugs whose pharmacokinetics are influenced by their dose-dependent pharmacological effects. Since blood flow rate is one of the important factors that determine the distribution and elimination processes of drugs, we used inaperisone [IPS, (+/-)-4'-ethyl-2-methyl-3-(1-pyrrolidinyl)-propiophenone hydrochloride], a novel centrally acting muscle relaxant that has been found by us to significantly alter muscle and fat blood flow rates in a dose-dependent manner, as a model compound. With regard to the changes in muscle blood flow rate exhibited by IPS, the brain was shown to be the major site of action based on changes in the observed blood flow rates, determined by the 51Cr-labeled microsphere method, in rats injected iv and intracerebroventricularly with various doses of IPS. Consequently, the blood flow rates in the muscle and fat were well correlated with the concentration of IPS in the brain using Hill's equation. Moreover, hepatic and renal intrinsic clearances of IPS at steady-state were determined by the constant iv infusion method. The saturation of in vivo hepatic and renal metabolisms of IPS was found at venous plasma concentrations higher than 1 microgram/ml. Taken all together, we developed a physiologically-based pharmacokinetic model of IPS combined with its pharmacological effect in rats, which could simulate the concentration-dependent changes in blood flow rates based on the drug concentrations at the site of action.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

[A neuropharmacological study of a hydroxazine derivative].

Neuropharmacological studies with the compound 2-methyl, 3-phenyl, 3-methyltransxydroxasino-propiophenon hydrochloride with cipher PS1, were carried out on rats as well as follow-up of development of drug dependence after continuous usage of the substance. The obtained showed that the compound S1 had stimulating influence on the central nervous system of amphetamine-like type. After prolonged administration of amphetamine and the compound PS1 it was established in rats that amphetamine induced development of tolerance and occurrence of hypersensitivity during withdrawal. The compound PS1 did not cause similar changes in rats after its chronic administration.

Amphetamines↗
PubMed1986

Studies on the metabolism of propafenone. 3rd Comm.: Isolation of the conjugated metabolites in the dog and identification using fast atom bombardment mass spectrometry.

The metabolism and urinary and biliary excretion of propafenone (2-(2'-hydroxy-3'-propylamino-propoxy)-omega-phenyl-propiophenone hydrochloride) were studied in the dog. Approximately 20% of the dose was excreted in 24 h with the urine and about 65% with the bile. Propafenone was extensively metabolized. Less than 4% of the dose was recovered unchanged in urine and bile. The metabolites were mainly excreted as conjugates. Free metabolites accounted for less than 20% of the dose. Separation methods were developed to isolate and purify the conjugated metabolites. Fractionation on an Al2O3-column yielded a sulphate and a glucuronide fraction, further separation and purification was done by TLC and HPLC. Positive and negative ion fast atom bombardment mass spectra (FAB/MS) were obtained of the purified glucuronides. The structures of two hydroxylated propafenone derivatives and two O-methylated catechol-like derivatives were definitely proven by FAB/MS, the glucuronic acid moiety being conjugated to the hydroxyl function in the different aromatic rings. Two isomeric propafenone glucuronides were found in the bile, probably diastereomeric forms of the O-glucuronide. Thus FAB/MS proved to be a complementary method to electron impact ionization mass spectrometry (EI/MS) for studying drug metabolism. The structures of free and conjugated metabolites can be defined from the combination of both mass spectrometric techniques.

Administration, Oral↗
PubMed1984

Studies on the metabolism of propafenone. 1st Comm.: synthesis and chromatographic/mass spectrometric properties of the labelled compound and of the reference substances.

The synthesis of 14C-propafenone and 2H-propafenone (propafenone: 2-(2'-hydroxy-3'-propylamino-propoxy)-omega-phenyl-propiophenone hydrochloride) and some reference compounds is described. The thin-layer chromatographic, high-performance liquid and gas chromatographic properties of the substances are described. Propafenone and the reference substances were studied by mass spectrometry and compared with each other, with respect to structural elucidation of the metabolites. The chromatographic and mass spectrometric data (key ions) enables the metabolites of propafenone to be identified in biological material.

Adrenergic beta-Antagonists↗
PubMed1984

Studies on the metabolism of propafenone. 2nd comm.: studies on the biotransformation in the dog.

Following administration of 14C- and 2H-labelled propafenone hydrochloride (2-(2'-hydroxy-3'-propylaminopropoxy)-omega-phenyl-propiophenone hydrochloride) to beagle dogs, the metabolites were isolated from urine and bile and analysed by mass spectrometry. Reference substances were synthesized on the basis of the structures postulated from the mass spectra and compared with the substances isolated from the biological material. Propafenone was absorbed completely following i.d. administration and eliminated mainly with the bile. Within 28 h 10% of the dose was excreted with the urine and 87% with the bile. Propafenone was extensively metabolized. Less than 1% of the dose was recovered as unchanged substance in urine and bile. The urinary and biliary metabolites were almost exclusively conjugated. The main metabolite, accounting for more than 30% of the dose, was propafenone glucuronide, followed by conjugates of hydroxylated propafenone derivatives with glucuronic acid and sulphuric acid. 5-Hydroxy-propafenone, a propafenone derivative hydroxylated in the middle aromatic ring, and a derivative hydroxylated in the omega-phenyl ring each accounted for about 15% of the dose. Besides these monohydroxy metabolites, two other O-methylated catechol-like derivatives, substituted in the different aromatic rings were recovered. The remainder of the metabolic products identified were mainly substances resulting from degradation of the propoxyamine side chain.

Adrenergic beta-Antagonists↗
PubMed1981

[Effects of muscle relaxant E.M.P.P. on afferent discharges of muscle spindle in man--an microneurographic analysis (author's transl)].

Effects of a new muscle relaxant E.M.P.P.(4'-ethyl-2-methyl-3-piperidino-propiophenone . hydrochloride) on afferent discharges of muscle spindle were studied in 10 healthy volunteer subjects. Single unit afferent discharges of muscle spindle were recorded microneurographically from the median or tibial nerve using a tungsten microelectrode with a tip diameter of about 1 micrometer (impedence: about 10 M omega). Effects of an oral administration of 150--300 mg of E.M.P.P. on spontaneous afferent discharges as well as dynamic and static responses of muscle spindle were analysed in the present study. 1. E.M.P.P. suppressed remarkably the frequency of spontaneous afferent discharges of muscle spindle. Meanwhile, mental activations such as speech of mental arithmetic recovered temporarily the frequency of afferent discharges to that before E.M.P.P. administration. 2. E.M.P.P. suppressed the dynamic and static responses of muscle spindle to stretch. It also suppressed the dynamic responses of muscle spindle in the decontraction phase of electrically-induced twitch contractions of the receptor-bearing muscle. Based on these results, it is concluded that E.M.P.P. suppresses the static and dynamic activities of muscle spindle in man. These effects seem to be due to modifications of descending influences from central structures on the static and dynamic gamma motoneurons which innervate the muscle spindle.

Adult↗
PubMed1980

Testing propafenone hydrochloride in the Ames Salmonella microsome system and in mammalian cytogenetic systems (bone marrow, spermatogonia).

2'-(2-Hydroxy-3-propylaminopropoxy)-3-phenyl-propiophenone-hydrochloride (propafenone-HCl, Rytmonorm) was tested for mutagenic activity in the Salmonella microsome system (Ames test) and in mammalian cell systems. Neither in the Ames test (62.5-1000 microgram/plate) nor in the bone marrow cells and spermatogonia of Chinese hamster (injected doses: 1.57, 3.13, 6.27 mg/kg) there is any evidence for an enhancement of mutation frequencies or chromosome aberration rates. Also, the micronucleus rates were in the control range. Under the experimental conditions of this investigations propafenone-HCl was not mutagenic.

Animals↗
PubMed1999

Enantioseparation of amfepramone (rac-diethylpropion): preparative separation of the enantiomers and enantioselective analysis.

The enantiomers of the anorectic drug amfepramone [rac-diethylpropion, rac-2-(diethylamino)-1-phenyl-1-propanone; rac-DEP] were separated in the preparative scale by crystallization. With enantiopure di-O-benzoyltartaric acid as salt-forming chiral selector, diastereoisomeric salts of DEP enantiomers with a final purity of more than 97.5% were obtained. Analytical liquid chromatographic and electrophoretic methods for the control of the enantiomeric purity and the stoichiometry of the salts were developed. The enantioseparation of rac-DEP by capillary electrophoresis (CE) using hydroxypropyl-beta-cyclodextrin (HP-beta-CD) as chiral discriminator and phosphate buffer (pH 3.3) as run buffer led to good separations. HPLC methods were developed using polysaccharide chiral stationary phases (CSP). The separation of the two enantiomers and the two main degradation products (1-phenyl-1,2-propanedione and propiophenone), known from solid and liquid pharmaceutical preparations, was attained in one run on the silica-based CSP cellulose tris(3,5-dimethylphenylcarbamate) (Chiralcel OD). The conditions which might affect the enantioselectivity and the quality of the enantiomeric separation were investigated for Chiralcel OD and the related CSP amylose tris(3,5-dimethylphenylcarbamate) (Chiralpak AD). Both CSPs showed very similar chromatographic properties. The separation factors could be influenced significantly by varying the polar organic modifier added to the mobile phase.

Appetite Depressants↗
PubMed2002

A hybrid microdevice for electrophoresis and electrochromatography using UV detection.

We have designed a new class of microdevices composed of a supporting plastic (polyvinyl chloride, PVC) plate integrated with a groove for a piece of fused silica capillary (the separation channel), a slit for on-tube detection, an "islet" for the application of sample, electrode vessels and platinum electrodes. The design permits electrophoretic, electrochromatographic and chromatographic separations with on-tube UV detection. The efficient heat dissipation allows relatively high field strengths. This article is the first one dealing with microdevices where polymer solutions are replaced by homogeneous gels. A new type of gels synthesized from acrylamide and 2-hydroxy-3-allyloxy-propyl-beta-cyclodextrin (allyl-beta-CD) as a cross-linker was employed for electrophoresis and electrochromatography. 2-Acrylamido-2-methylpropanesulfonic acid was added to the monomer solution to create a high electroendosmotic flow in electrochromatographic runs. These gels have excellent electrochromatographic and electrophoretic properties for low-molecular-weight compounds and DNA, as shown previously, namely high resolution combined with high stability. The unique cross-linker can be used for specific interaction with the alkyl and phenyl groups. The tripeptide glutathione (gamma-L-glutamyl-L-cysteinyl-glycine) and its benzyl conjugates were selected as model compounds to study the resolving power of the gel because they are difficult to separate by free zone electrophoresis. The limit of detection (LOD) for S-benzyl-glutathione was determined (ca. 7 microM). Run-by-run reproducibility was high (the separation factor of glutathione in the gel was 0.3 with 2.5% coefficient of variation, CV). Neutral compounds (acetone, acetophenone, propiophenone and butyrophenone) were separated electrochromatographically in the gel. The influence of organic solvent (acetonitrile) on the electroendosmotic mobility was similar to that in reversed-phase separations, although the separation mechanism is different. ATP, ADP and AMP were separated in less than 10 s by free-zone electrophoresis.

Chromatography, Micellar Electrokinetic Capillary↗
PubMed2005

Dynamic structural change of the self-assembled lanthanum complex induced by lithium triflate for direct catalytic asymmetric aldol-Tishchenko reaction.

The development of a direct catalytic asymmetric aldol-Tishchenko reaction and the nature of its catalyst are described. An aldol-Tishchenko reaction of various propiophenone derivatives with aromatic aldehydes was promoted by [LaLi3(binol)3] (LLB), and reactivity and enantioselectivity were dramatically enhanced by the addition of lithium trifluoromethanesulfonate (LiOTf). First, we observed a dynamic structural change of LLB by the addition of LiOTf using 13C NMR spectroscopy, electronspray ionization mass spectrometry (ESI-MS), and cold-spray ionization mass spectrometry (CSI-MS). X-ray crystallography revealed that the structure of the newly generated self-assembled complex was a binuclear [La2Li4(binaphthoxide)5] complex 6. A reverse structural change of complex 6 to LLB by the addition of one equivalent of Li2(binol) was also confirmed by ESI-MS and experimental results. The drastic concentration effects on the direct catalytic asymmetric aldol-Tishchenko reaction suggested that the addition of LiOTf to LLB generated an active oligomeric catalyst species.

Catalysis↗
PubMed2006

Lewis base catalyzed Mannich-type reactions between trimethylsilyl enol ethers and aldimines.

Lewis base catalyzed Mannich-type reaction between trimethylsilyl enol ethers and N-tosylaldimines is described. Nitrogen anions generated from amides or imides such as lithium benzamide or potassium phthalimide are found to be effective Lewis base catalysts in DMF at room temperature to afford the corresponding beta-amino carbonyl compounds in good to high yields; the oxygen anion generated from carboxylic acids such as lithium acetate was also found to be effective in dry DMF. The above-mentioned lithium acetate-catalyzed Mannich-type reaction between aldimines and various trimethylsilyl (TMS) enol ethers such as silyl ketene acetal proceeded smoothly even in water-containing DMF. Then, Lewis base catalyzed three-component Mannich-type reactions of TMS enol ether, tosylamide, and aromatic aldehyde having electron-withdrawing group such as p-nitrobenzaldehyde were investigated. The reaction proceeded smoothly to afford the corresponding beta-amino ester in good yield. Further, ammonium carboxylates such as tetrabutyl ammonium acetate or tetrabutyl ammonium benzoate were found to be more effective Lewis base catalysts in the above-mentioned Mannich-type reaction. The synthesis proceeded in various solvents at lower temperatures. The reaction between aldimines and TMS enol ethers generated from thioester and various ketones such as propiophenone or cyclohexanone also proceeded smoothly to afford the corresponding beta-amino carbonyl compounds in high yields with good to high anti-selectivities.

Acetates↗
PubMed2003

Characterization of surfactant and phospholipid vesicles for use as pseudostationary phases in electrokinetic chromatography.

The physical, electrophoretic and chromatographic properties (mean diameter, electroosmotic flow, electrophoretic mobility, elution range, efficiency, retention, and hydrophobic, shape, and chemical selectivity) of three surfactant vesicles and one phospholipid vesicle were investigated and compared to a conventional micellar pseudostationary phase comprised of sodium dodecyl sulfate (SDS). Chemical selectivity (solute-pseudostationary phase interactions) was discussed from the perspective of linear solvation energy relationship (LSER) analysis. Two of the surfactant vesicles were formulated from nonstoichiometric aqueous mixtures of oppositely charged, single-tailed surfactants, either cetyltrimethylammonium bromide (CTAB) and sodium octyl sulfate (SOS) in a 3:7 mole ratio or octyltrimethylammonium bromide (OTAB) and SDS in a 7:3 mole ratio. The remaining surfactant vesicle was comprised solely of bis(2-ethylhexyl)sodium sulfosuccinate (AOT) in 10% v/v methanol, and the phospholipid vesicle consisted of 1-palmitoyl-2-oleyl-sn-glycero-3-phosphocholine (POPC) and phosphatidyl serine (PS) in 8:2 mole ratio. The mean diameters of the vesicles were 76.3 nm (AOT), 86.9 nm (CTAB/SOS), 90.1 nm (OTAB/SDS), and 108 nm (POPC/PS). Whereas the coefficient of electroosmotic flow (10(-4) cm2 V(-1) s(-1)) varied considerably (1.72 (OTAB/SDS), 3.77 (CTAB/SOS), 4.05 (AOT), 5.26 (POPC/PS), 5.31 (SDS)), the electrophoretic mobility was fairly consistent (-3.33 to -3.87 x 10(-4) cm2 V(-1) s(-1)), except for the OTAB/SDS vesicles (-1.68). This resulted in elution ranges that were slightly to significantly larger than that observed for SDS (3.12): 3.85 (POPC/PS), 8.6 (CTAB/SOS), 10.1 (AOT), 15.2 (OTAB/SDS). Significant differences were also noted in the efficiency (using propiophenone) and hydrophobic selectivity; the plate counts were lower with the OTAB/SDS and POPC/PS vesicles than the other pseudostationary phases (< or = 75,000/m vs. > 105,000/m), and the methylene selectivity was considerably higher with the CTAB/SOS and OTAB/SDS vesicles compared to the others (ca. 3.10 vs. < or = 2.6). In terms of shape selectivity, only the CTAB/SOS vesicles were able to separate all three positional isomers of nitrotoluene with near-baseline resolution. Finally, through LSER analysis, it was determined that the cohesiveness and hydrogen bond acidity of these pseudostationary phases have the greatest effect on solute retention and selectivity.

Chromatography, Micellar Electrokinetic Capillary↗
PubMed1981

Simultaneous determination of tetracaine and its degradation product, p-n-butylaminobenzoic acid, by high-performance liquid chromatography.

A high-performance liquid chromatographic method was developed for the simultaneous determination of tetracaine hydrochloride and its hydrolytic degradation product, p-n-butylaminobenzoic acid. Separation was achieved using a mu Bondapak C18 column and the eluent, water-acetonitrile-methanol (60:20:20), containing 0.06% (v/v) sulfuric acid, 0.5% (w/v) sodium sulfate, and 0.02% (w/v) sodium heptanesulfonate, at a flow rate of 2 ml/min Salicylic acid and propiophenone were used as internal standards. The UV detector response at 305 nm was linear for tetracaine hydrochloride in the 0.4--2.0-mg/ml range and for p-n-butylaminobenzoic acid in the 0.003--0.02-mg/ml range. The method is simple and precise.

4-Aminobenzoic Acid↗
PubMed1982

Stereospecific metabolic reduction of ketones.

The stereospecificity of the metabolic reduction of arylalkylketones was investigated. The ketones, propiophenone (I), phenyl-acetone (III), and 1-phenyl-1,2-propanedione (V) were reduced in vitro and in vivo in rats and rabbits to the corresponding alcohols, 1-phenyl-1-propanol (II), 1-phenyl-2-propanol (IV), and 1-phenyl-1,2-propanediol (VIII), respectively. For the analysis, a capillary GLC method employing chiral derivatizing reagents for the resolution of these optically active alcohols was utilized. This study revealed that the metabolic reduction of each ketone produced the corresponding alcohol as a mixture of its enantiomers. With one exception, the mixtures obtained from all in vivo and in vitro reactions were shown to contain at least 70% of one isomer [S(-)-II, S(+)-IV, and erythro-VIII, respectively], with in vitro reduction showing the highest degree of stereospecificity (90-98%). The in vivo reduction of I by the rat was exceptional in that both optical isomers of II were recovered in equal proportions.

Alcohols↗
PubMed2005

Alkylthiol gold nanoparticles in sol-gel-based open tubular capillary electrochromatography.

A novel open-tubular capillary electrochromatography (OTCEC) column was prepared by immobilizing dodecanethiol gold nanoparticles on prederivatised fused-silica capillary columns with sol-gel technology. 3-Mercaptopropyl-trimethoxysilane (MPTMS) was selected as sol-gel precursor to develop a sol-gel layer on the inner wall of the capillary, prior to assembly of dodecanethiol gold nanoparticles onto the generated sol-gel layer through specific interaction between the gold nanoparticles and surface terminating thiol groups. The electrochromatographic behaviour of the sol-gel gold nanoparticle capillary was compared with a gold nanoparticle capillary prepared via MPTMS surface functionalisation, through variation of the percentage of the organic modifier, pH, and separation voltage. Efficient separation for a "reversed-phase" test mixture of thiourea, naphthalene, and biphenyl and for selected polycyclic aromatic hydrocarbons (PAHs) was obtained on the sol-gel based gold nanoparticle capillaries. OTCEC separations of three selected drug substances (propiophenone, benzoin, and warfarin) were also demonstrated. Scanning electron microscopy was used for the characterization of the sol-gel gold nanoparticle capillary surface. The results confirm that dodecanethiol gold nanoparticles, bound on the sol-gel-based inner layer of fused-silica capillary, can provide sufficient solute-bonded phase interactions for OTCEC with reproducible retention as well as characteristic reversed-phase behaviour.

Journal Article↗
PubMedDate not supplied

Inward transport of 3H-MPP+ in freshly isolated rat hepatocytes: evidence for interaction with catecholamines.

1-Methyl-4-phenylpyridinium (MPP+), the neurotoxic metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), is efficiently taken up and accumulated by rat hepatocytes. However, the nature of the mechanism(s) involved in the hepatic uptake of MPP+ remains partially unknown. The aim of the present study was to further characterize the hepatic uptake of 3H-MPP+, namely by investigating the interactions of catecholamines (which are also efficiently taken up by rat hepatocytes) with MPP+ transport. The accumulation of 3H-MPP+ in isolated rat hepatocytes occurred through saturable and non-saturable mechanisms. The kinetics of the saturable component of 3H-MPP+ uptake was as follows: Vmax = 181.3 +/- 11.1 pmol mg protein-1 min-1 and Km = 47.1 microM (27.9, 66.3) (n = 5). The diffusion constant (in ml mg protein-1 min-1) for the non-saturable uptake of 3H-MPP+ was 0.00068 (0.00052, 0.00083) (n = 5). From the analysis of the time course of 3H-MPP+ accumulation at a substrate concentration of 100 nM 3H-MPP+, it was found that the rate constant of inward transport of 3H-MPP+ into hepatocytes (k(in)) was 15.7 +/- 3.8 microliters mg protein-1 min-1, the rate constant of outward transport of 3H-MPP+ from hepatocytes (kout) was 0.077 +/- 0.023 min-1 and the equilibrium accumulation (Amax) of 3H-MPP+ was 20.2 +/- 2.0 pmol mg protein-1 (n = 36). Decynium22 (1,1'-diethyl-2,2'-cyanide; 1 microM) significantly reduced kin to 6.1 +/- 1.8 microliters mg protein-1 min-1 (P < 0.05) and the equilibrium accumulation (Amax) of 3H-MPP+ to 9.6 +/- 1.3 pmol mg protein-1 (P < 0.005) (n = 36). 3H-MPP+ accumulation (in cells incubated with 200 nM 3H-MPP+) was sensitive to (-)-adrenaline, (-)-isoprenaline, (-)-dopamine, (+/-)-adrenaline and (-)-noradrenaline. The most potent catecholamine in inhibiting 3H-MPP+ uptake was (-)-adrenaline, with an IC50 of 99 (22, 449) microM (n = 6). (-)-Adrenaline competitively inhibited 3H-MPP+ uptake, as it significantly increased the Km value of 3H-MPP+ uptake (to 125.4 microM (63.6; 187.1); P < 0.02; n = 3) but did not change the Vmax value. The cyanine-derivatives decynium22 and cyanine863 (1-ethyl-2-([1,4-dimethyl-2-phenyl-6-pyrimidinylidene] methyl)quinolinium), which inhibit uptake2 as well as the apical type of the renal transporter for organic cations, potently inhibited 3H-MPP+ uptake with IC50's of 1.4 (0.4-5.3) (n = 6) and 6.5 (2.6-16) (n = 4) microM, respectively. Under conditions of monoamine oxidase (MAO) and catechol-O-methyl transferase (COMT) inhibition (with either pargyline (500 microM) + Ro01-2812 (3,5-dinitropyrocatechol; 2 microM) or pargyline (500 microM) + U-0521 (3,4-dihidroxy-2-methyl-propiophenone; 12 microM)), (-)-adrenaline (up to 1 mM) had no inhibitory effect on the uptake of 3H-MPP+. Moreover, the uptake of 3H-MPP+ in the presence of pargyline + Ro 01-2812 was significantly lower (66.9 +/- 30.4%; P < 0.05; n = 4) than in the absence of these compounds. Therefore, the effect of these MAO and COMT inhibitors on 3H-MPP+ uptake was examined. Interestingly enough, pargyline, Ro 01-2812 and U-0521 were found to inhibit the uptake of 3H-MPP+ (in cells incubated with 200 nM 3H-MPP+): 500 microM pargyline, 2 microM Ro 01-2812 and 100 microM U-0521 decreased the accumulation of 3H-MPP+ to 38.1 +/- 6.8 (n = 5), 60.5 +/- 10.1 (n = 7) and 71.3 +/- 14.5 (n = 7) % of control, respectively. It is concluded that 3H-MPP+ is efficiently taken up by rat hepatocytes by a carrier-mediated mechanism sensitive to catecholamines, decynium22 and cyanane863, and to the enzyme inhibitors pargyline, Ro 01-2812 and U-0521.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1992

LG 6-101 and LG 6-102, two new propafenone-related antiarrhythmic agents with good oral activity in rats.

LG 6-101 (1-[3-(2-methoxy-3-(2-methylpropylamino)-propoxy)-4-methyl- 2-thienyl]-3-phenyl-1-propanon hydrochloride; MW: 426.02) and LG 6-102 (2-(2-methoxy-3-propylamino-propoxy)-3-phenyl-propiophenon hydrochloride; MW: 391.92) are two new antiarrhythmic substances. They are structurally related to propafenone which is a widely used class Ic-antiarrhythmic drug. In man the oral bioavailability of propafenone is only about 5-40%. Therefore the development of compounds with similar mode of action but higher oral bioavailability seems to be meaningful. Both, LG 6-101 and LG 6-102 proved to be effective in isolated auricles and in experimental animals after intravenous administration. In the present study we tested the antiarrhythmic effects of LG 6-101 and LG 6-102 in rats after oral administration. Animals were treated with LG 6-101 (16, 32, 64, 128, 256 mg kg-1 bodyweight), LG 6-102 (4, 8, 16, 32, 64 mg kg-1 bodyweight) and propafenone (32, 64, 128, 256 mg kg-1 bodyweight) by gavage twice daily during 4 days. Both, LG 6-101 and LG 6-102 showed strong antiarrhythmic effects against arrhythmias induced on the fifth day by infusion of aconitine (10 micrograms kg-1 min-1). LG 6-102 was significantly more effective against cardiac arrest caused by infusion of aconitine (P less than or equal to 0.05) than LG 6-101. Both substances had good effects on the delay of ventricular premature beats.(ABSTRACT TRUNCATED AT 250 WORDS)

Aconitine↗