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Studies on the mode of action of cardioactive drugs in animals and manCampbell, Terry J. January 1982 (has links)
No description available.
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Simultaneous high performance liquid chromatographic determination of procainamide, N-acetylprocainamide, disopyramide, mono-N-dealkyldisopramide, quinidine, and propranolol in serum /Wesley, James F. January 1981 (has links)
Thesis (M.S.)--Rochester Institute of Technology, 1981. / Typescript. Includes bibliographical references (leaves 83-84).
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Pharmacological and antiarrhythmic properties of quinacainol : a new sodium channel blocker?Howard, Paisley Gail January 1990 (has links)
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
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Membrane actions of antiarrhythmic drugsAu, Tony Long Sang January 1978 (has links)
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
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Studies on the metabolism of tocainide in humansKwok, David W. K. January 1987 (has links)
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
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Antifibrillatory actions of K+ channel blocking drugsBeatch, Gregory N. January 1991 (has links)
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
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Amelioration of oxidative lung injury by antiarrhythmic agentsDas, Kumuda C. 13 October 2005 (has links)
Class I antiarrhythmic drugs, such as lidocaine, quinidine and procainamide, are known to be effective membrane stabilizers. However, the mechanism of such "membrane stabilization" has not been elucidated. In the present study we found that all three drugs are powerful scavengers of hydroxyl! radical. In addition, lidocaine was found to be a quencher of singlet oxygen. These drugs are also found to inhibit NADPH-dependent lipid peroxidation in bovine lung microsomes in a dose dependent manner. Since oxyradicals are implicated in the lipid peroxidation process and antiarrhythmic drugs were found to scavenge/quench reactive oxygen species, we proposed that the membrane Stabilizing effects of antiarrhythmic drugs may, in part, be due to their antioxidant properties.
Ischemia-reperfusion injury has been studied in many organs. Despite the evidence of functional, metabolic and structural abnormalities during reperfusion, the precise mechanism of reperfusion lung injury remains obscure. Data from the organ models suggest that toxic oxygen metabolites play an important role in the mechanism of reperfusion tissue injury. Lidocaine has also been shown to be clinically valuable for the treatment and prevention of ventricular arrhythmia occurring after surgical correction of myocardial infraction. We found that the class I antiarrhythmic drugs are effective in ameliorating post-ischemic lung reperfusion injury in an ex vivo perfused rat lung model exposed to both normoxic and hyperoxic conditions.
Since phagocytes are known to generate reactive oxygen species and play an important role in causing irreversible oxidative tissue injury during reperfusion of organs, we examined the role of antiarrhythmic agents on macrophage function. We found that these drugs inhibit superoxide and hydrogen peroxide production in stimulated macrophages in a dose dependent manner. The diminished production of superoxide was found to be not due to the inactivation of superoxide generating NADPH-oxidase enzyme but by inhibition of the phagocytosis process by these drugs
The results of these studies indicate that the antiarrhythmic drugs, such as, lidocaine, quinidine and procainamide, are effective antioxidants and can protect biomembranes against lipid peroxidation injury and post-ischemic reperfusion injury of the lung. We have investigated the mechanism(s) of action of these drugs in ameliorating oxidative tissue injury and found that these drugs are not only effective in removing reactive oxygen species but also cause inactivation of pulmonary macrophage from inappropriately generating reactive species of oxygen. The fundamental knowledge derived from these Studies could lead to enhanced functional improvement of patients following cardiopulmonary bypass, pulmonary arterial embolectomy and acute respiratory distress syndrome, all of which undergo a period of elective/induced ischemia and reperfusion or oxidative stress. / Ph. D.
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