Diss. (sammanfattning) Uppsala : Univ., 2001. / Härtill 5 uppsatser.

Quinacainol, 1-[2-(1,1-dimethylethyl)-4-quinolyl]-3-(4-piperidyl)-1-propanol is a class I antiarrhythmic agent provisionally subclassified as Ic. Studies were carried out in order to (1) determine the actions of quinacainol in acute myocardial ischæmia, (2) ascertain the mechanism(s) responsible for these actions, and (3) ascertain the appropriateness of its subclassification. Toxicological, hæmodynamic, and ECG effects in chronically prepared conscious rats were determined following administration of 1, 2, 4, or 8 mg/kg of quinacainol given i.v. over 10 minutes on alternate days. Toxicity referable to the heart was seen at doses of 8 mg/kg and above. In rats given 8 or 16 mgkg, arrhythmias occurred. Quinacainol had no major effects on blood pressure, unlike most class I antiarrhythmics, but lowered heart rate (not statistically significantly) and prolonged P-R interval and QRS duration. In an attempt to protect against ischæmic arrhythmias, doses of 2 mg/kg and 4 mg/kg were given. The high dose gave the best protection. It reduced the incidence of ventricular tachycardia (VT) from a control value of 80% to 30%, and reduced the incidence of ventricular fibrillation (VF) from a control value of 60% to 10%. An increase in the incidence of premature ventricular contractions was seen at both doses. Blood pressure was not adversely effected although slight bradycardic effects as well as prolongation of the P-R interval were seen at both doses. Both doses reduced S-T segment and delayed onset of elevation of S-T segment and R-wave which were induced by coronary occlusion. Sensitivity to electrical stimulation was tested in pentobarbital anæsthetised rats using ventricular electrodes. Doses of 0.5, 1, 2, and 4 mg/kg were given cumulatively as a 10 min infusion every 25 min. Quinacainol did not affect QRS duration or the Q-Tc interval but dose-dependently widened P-R interval when compared to pretreatment. Quinacainol dose-dependently increased threshold current, threshold duration, and ventricular fibrillation threshold. In addition, quinacainol elevated effective refractory period while decreasing maximum following frequency. Open-chest rats under pentobarbital anæsthesia were used to record the effects of quinacainol on epicardial intracellular potentials. Recordings were made by conventional microelectrode techniques before and after cumulative doses of 0.5, 1, 2, 4, and 8 mg/kg i.v. Quinacainol dose-dependently reduced phase zero of the action potential (AP) and AP height but did not influence other phases of the AP (with the exception of prolonging repolarization at the highest dose); actions indicative of class Ic. Effects of quinacainol on isolated rat hearts were assessed using a modified Langendorff heart preparation and were compared with those of tetrodotoxin (TTX). Quinacainol widened the P-R interval and QRS duration without having major effect on the Q-Tc interval. In addition it slowed the sinus beating rate. Quinacainol was more potent than TTX. All findings indicated that quinacainol is a potent antiarrhythmic agent with Na⁺channel blocking properties. / Medicine, Faculty of / Anesthesiology, Pharmacology and Therapeutics, Department of / Graduate

The antiarrhythmic actions of prostaglandins were first investigated using arrhythmias associated with cardiac ischemia in the dog and the rat. These studies were followed by investigations of the possible mechanisms of action, using rat heart tissue in intact, isolated, and cell culture preparations. Preliminary experiments in the dog revealed that prostaglandins E₂ and F₁α markedly reduced the number of premature ventricular contractions occurring within the first 25 minutes following coronary artery ligation. Prostaglandin E₂ or F₁α did not markedly alter the cardiovascular response to occlusion, making it unlikely that modulation of autonomic reflexes is a central factor in their antiarrhythmic action. Coronary ligation in the rat was used to compare the antiarrhythmic effectiveness of prostaglandins, lidocaine, and quinidine. Prostaglandins E₂, F₂β and quinidine were found to be the most effective against arrhythmias occurring within the first 25 minutes following occlusion, reducing the number of PVCs by 40 to 50 per cent. The number of flutter episodes and the number of animals dying from arrhythmias was also markedly decreased by prostaglandins E₂ and F₂β and by quinidine. Prostaglandins F₁α and A₂, and lidocaine had lesser effects. Prostaglandins had only minor effects on blood pressure or heart rate, which were not related to their antiarrhythmic activity. No significant differences were found in the infarct size with prostaglandin treatment. The effects of prostaglandins E₂, A₂ and F₂β, quinidine, and lidocaine were tested in in situ rat heart on electrically-induced flutter threshold and maximum following frequency. Flutter threshold was not changed by any of the prostaglandins tested, although lidocaine increased and quinidine decreased it. Prostaglandins caused a dose-dependent change in maximum following frequency which was usually less than 10 per cent of control. Lidocaine produced a marked increase and quinidine a marked decrease in maximum following frequency. The slight depressive action of prostaglandins does not correlate with their antidysrhythmic actions. Prostaglandins of the E, A, and F series were found to have only minimal effects on rate and force in isolated rat hearts. However, both PGE₂ and PGF₂β, delayed the loss of contractile force with time at 10⁻⁷ M. All prostaglandins tested markedly increased coronary flow rate at 10⁻⁵ M. The effects on the beating behavior of cultured rat heart cells of fourteen prostaglandins of the A, B, D., E, and F series were investigated in cultured rat heart cells. With the exception of PGF₂α, which produced a chronotropic response, prostaglandins had limited direct action in cultured rat heart cells. The effects of ouabain, calcium, potassium, dinitrophenol, and Cyanea toxin, together with prostaglandins, lidocaine, and quinidine on cultured rat heart cells were also investigated. Ouabain and calcium increased rate and fibrillatory movements, while potassium and dinitrophenol slowed rate and decreased rhythmic beating. Cyanea toxin produced a characteristic series of arrhythmogenic changes which were also used to test for antiarrhythmic activity in cultured heart cells. Lidocaine and quinidine were effective only against cellular arrhythmias caused by high calcium concentration, and prostaglandins were effective only against dinitrophenol-induced arrhythmias, indicating that there is no over-all "protective" effect of prostaglandins in cell culture. / Medicine, Faculty of / Anesthesiology, Pharmacology and Therapeutics, Department of / Unknown

The structural and functional consequences of the interaction of various antiarrhythmics with human erythrocyte membranes, guinea pig brain synap-tosomes and myocardial sarcolemmal membranes were studied at drug concentrations affecting the stability of intact erythrocytes to hypotonic lysis. It was assumed that such stabilization might bear some molecular resemblance to the electrical stabilizing properties of these drugs in excitable tissues. Membrane perturbational actions of these drugs were measured in terms of the specific incorporation of the chromophoric probes, 5,51-dithio-bis-(2-nitrobenzoic acid) (DTNB) and trinitrobenzenesulfonic acid (TNBS) into membrane sulfhydryl and amino groups respectively. Most drugs tested, including lidocaine, quinidine, the verapamil analogue D-600 and the quaternary analogues QX 572 and pranolium, exhibited a concentration-dependent stimulation of DTNB and TNBS incorporation. At drug concentrations producing erythrocyte stabilization, the protein perturbational properties of quinidine, lidocaine, D-600 and QX 572 as viewed in terms of DTNB labelling were equivalent while differences were apparent with quinidine, D-600 and lidocaine at high concentrations in the destabilizing range. Most agents, with the exception of pranolium, showed a similar pattern of DTNB incorporation in brain synaptic membranes as in erythrocytes. Studies of the incorporation of TNBS into erythrocyte membranes indicated that antiarrhythmics induce greater structural alterations in membrane phospholipids as compared with membrane proteins. Bretylium and practolol, two substances with minimal direct cardiodepressant properties, did not enhance DTNB or TNBS incorporations into erythrocyte membranes, although both agents, especially practolol, possessed marked antihemolytic properties. It appeared, therefore, that the membrane perturbational actions of antiarrhythmics as analyzed here by means of group-specific chemical probes are a better index of their direct myocardial membrane actions than erythrocyte stabilization. The functional consequences of drug-membrane interaction as reflected in the inhibition of membrane-associated enzymes by antiarrhythmics were shown to be critically dependent on the drug and membrane in question. The activity of erythrocyte membrane ouabain-sensitive K+-stimulated p-nitrophenyl-phosphatase (K+-NPPase) was more readily inhibited than that of Mg++-independent and Mg++-stimulated NPPase by most drugs examined. In myocardial sarcolemmal membranes, lidocaine was stimulatory to the K+-NPPase whereas all other agents exhibited stimulatory actions only at the lowest drug concentrations. The Ca++-ATPase system in the erythrocyte membrane was also inhibited by antiarrhythmics with propranolol, pranolium and lidocaine showing a relatively higher degree of inhibition of the high Ca++ affinity component while quinidine and D-600 exerted equal inhibitory actions on both high and low Ca++ affinity components of the enzyme. A comparison of the perturbational actions of antiarrhythmics in isolated erythrocyte membranes, in the membranes of the intact erythrocyte and in brain synaptic membranes was made by analyzing the effects of drugs on the activity of the membrane acetylcholinesterase present in these preparations. Inhibitory actions of all drugs tested were comparable in both intact and isolated erythrocyte membranes but differed in the excitable tissue membrane. The nature of the inhibition exerted by the antiarrhythmics on acetylcholinesterase of intact erythrocytes was of a mixed type for most drugs except practolol which inhibited non-competitively. The transmembrane chloride gradient had no influence on the inhibition by bretylium, lidocaine and D-600 of the acetylcholinesterase activity of the intact cells but the inhibition produced by quinidine and propranolol was enhanced when erythrocytes were suspended in a low chloride medium. The foregoing results, therefore, indicate that the membrane perturbational actions of antiarrhythmics vary with the agent in question and with the particular membrane system. It is suggested that the molecular mechanisms by which these drugs alter cardiac automaticity may not be identical and may differ in various regions of the myocardium. This in turn may underlie the differing spectra of clinical effectiveness exhibited by these pharmacological agents. / Medicine, Faculty of / Anesthesiology, Pharmacology and Therapeutics, Department of / Graduate

This document only includes an excerpt of the corresponding thesis or dissertation. To request a digital scan of the full text, please contact the Ruth Lilly Medical Library's Interlibrary Loan Department (rlmlill@iu.edu).

Tocainide carbamoyl ester glucuronlde (TOCG) (R-NHCO.O-GA) is a major metabolite of tocainide (TonocardR). The structure of TOCG was first proposed by Elvin (35) based on the structure of 3-(2,6-xylyl)-5-methylhydantoln, a base hydrolyzed product of TOCG in urine. Due to the presence of two carbonyl groups on the hydantoin ring, TOCG was proposed to arrive from a novel metabolic pathway involving the addition of carbon dioxide to the terminal nitrogen of tocainlde followed by glucuronic acid conjugation. With the initial intention of carrying out a bioavailability study of tocainide using a deuterated pseudoracemic sample, the stereospecific synthesis of R(-)- and S(+)-trideuterated tocainide was attempted through two synthetic approaches. This thesis describes a chemical reaction between tocainide and urea, a second pathway which leads to the formation of 3-(2,6-xylyl)-5-methylhydantoin through a tocainide ureide intermediate. With this observation, a tocainide N-ureide glucuronide structure (R-NHCO.NH-GA) was proposed for TOCG in support of the theory that an in vivo reaction between tocainide and urea may have resulted a tocainide N-ureide which can be further conjugated with glucuronic acid. Attempts were made to assign the correct structure of TOCG by identification of the theoretical tocainide carbamic acid (based on Elvln's proposed structure) or the tocainide N-ureide intermediate in urine. This thesis also describes the preparative HPLC isolation and the structural characterization of this novel glucuronic acid conjugate. Evidence obtained as proof for the identity of TOCG as a conjugate was obtained from acid hydrolysis, basic hydrolysis, beta-glucuronidase hydrolysis, with or without the presence of sacchro-1,4-lactone, and a naphthoresorcinol color test. Structural evidence for the carbamoyl ester linkage of TOCG was obtained from proton-NMR and FAB analysis. The 400-MHz proton NMR data of the isolated glucuronide provided partial evidence for the intact structure of TOCG. In FAB analysis, the [M+1] ion adduct at m/z 413, [M+Na] at m/z 435, and [M-H+2Na] at m/z 457 have provided positive evidence for the molecular ion of TOCG at m/z 412 in favor of the carbamoyl ester structure. In addition to the hydrolysis of TOCG at pH > 12 to the hydantoin, this hydantoin was found to also undergo spontaneous first-order hydrolysis at pH > 12. To assay the levels of TOCG in urine as the hydantoin, a set of accurately timed calibration samples were employed in an assay protocol to take Into account the spontaneous hydrolysis of the hydantoin. Based on this analytical approach, the levels of TOCG were determined in three subjects both after an IV and oral dose of 200 mg tocainide HC1. The urinary excretion half-lives of TOCG of 13.86 hours and 13.33 hours, after an IV and oral dose respectively, were found to agree with literature values. / Pharmaceutical Sciences, Faculty of / Graduate

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2006. / Härtill 4 uppsatser.

Class III antiarrhythmic drugs share the common mechanism of widening the cardiac action potential without affecting conduction velocity. This thesis reports on the actions of newly developed putative Class III antiarrhythmic drugs, tedisamil, KC 8851, RP 62719, UK 68798, and risotilide, as well as an ATP-sensitive K⁺ channel blocker, glibenclamide. Studies were performed to examine the actions of these drugs in acute myocardial ischaemia and possible mechanisms responsible for these actions. The hypothesis tested was that drug treatment prevented arrhythmias induced by acute myocardial ischaemia. Species dependent actions of these drugs on ECG and blood pressure were examined in rats, guinea pigs, pigs and primates. The five putative class III drugs listed above were assessed for antiarrhythmic activity in a conscious rat model of myocardial ischaemia. It was found that only tedisamil and KC 8851, which widened the Q-T[formula omitted] interval of the ECG (by up to 65%) , were effective at suppressing fibrillation in this species. None of the drug treatments decreased the incidence of ventricular premature beats. Tedisamil, but not glibenclamide, prevented tachycardias in a rat model of myocardial ischaemia- and reperfusion-induced arrhythmias. In an anaesthetized pig model of acute myocardial ischaemia, tedisamil and UK 68,798 were shown to mildly prolong the Q-T[formula omitted] interval by less than 20%, but protection against arrhythmias was equivocal. In further studies, tedisamil and UK 68,798 were compared to each other for effects on ventricular epicardial action potential morphology using intracellular recording in vivo, and effects on ventricular effective refractory period using electrical stimulation in vivo in both rats and guinea pigs. Tedisamil (4 mg/kg, i.v.) prolonged rat ventricular epicardial action potential duration fourfold in vivo, while UK68,798 (up to 1 mg/kg, i.v.) was ineffective in this species. Tedisamil (4 mg/kg, i.v.) widened guinea pig ventricular epicardial potentials by 80%, while UK 68,798 (25 μg/kg, i.v.) increased these by 30%. Action potential widening paralleled increases in ventricular refractoriness to electrical induction of premature beats. It was found that the species selective actions of these drugs was most likely related to differences in selectivity for K⁺ channels which contribute to repolarization in myocardium. / Medicine, Faculty of / Anesthesiology, Pharmacology and Therapeutics, Department of / Graduate

No description available.

Moricizine is a novel phenothiazine antiarrhythmic agent that depresses the activity of ectopic foci, has a low incidence of adverse effects relative to other agents, and is useful in treating pediatric atrial ectopic tachycardia. A study was conducted to determine the pharmacokinetics of moricizine in children after oral administration. Moricizine was isolated from frozen serum obtained from four male patients (ages 7, 8, 9, and 18 years) receiving the drug for supraventricular tachycardia and analyzed by high-performance liquid chromatography with ultraviolet detection according to an established protocol. Peak serum levels were between 400 and 2000 ng/mL. Elimination of moricizine did not follow simple single-compartment pharmacokinetics. In three patients we observed an increase or slower decline in blood level occurring after 4 hours. Because of the paroxysmal nature of the tachycardias, decreases in patient heart rate could not be correlated with moricizine blood level. These results suggest that the pediatric pharmacokinetics of moricizine excretion are complex and may differ from those seen in adults.