Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/275—Nitriles; Isonitriles
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/445—Non condensed piperidines, e.g. piperocaine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/06—Antiarrhythmics

Definitions

• This invention relates to a novel pharmaceutical composition and in particular the use of a combination of antiarrhythmic agents in the treatment of arrhythmic disorders in mammals, including humans, in order to achieve a synergistic effect.
• Antiarrhythmic drugs have been grouped according to the pattern of electrophysiological effects they produce and/or their presumed mechanism of action. A classification in four groups has been originally proposed by Vaughan Williams in 1970. At the molecular level, class I compounds act on Na + currents; class II compounds possess ⁇ -adrenoceptor blocking activity; class III drugs prolong cardiac action potential such as potassium channel Mockers; and class IV drugs target Ca ++ channels.
• E-4031 (Eisai), whose chemical name is methanesulfonamide, N-[4-[[l-[2-(6- methyl-2-pyridinyl)ethyl]-4-piperidinyl]carbonyl]phenyl]-, dihydrochloride is a known potassium channel blocking agent i.e. a class III drug.
• Verapamil (5-[(3,4- dimethoxyphenethyl)methylamino]-2-(3,4-dimethoxyphenyl)-2- isopropylvaleronitrile) is a known class IV agent having calcium channel blocking activity.
• a combination of a class HI and class IV antiarrhythmic agents provides an effect which is more fundamental than a mere enhancement of the antiarrhythmic effect of each compound: It is now considered that the combined effect of the two anti arrhythmia agents leads to a beneficial modification of the mode of antiarrythmic effect for the combination. In particular the combination provides an improved antiarrhythmic activity in conjunction with a reduced adverse effect profile.
• the present invention provides a pharmaceutical composition, which composition comprises a class III antiarrhythmic agent and a class IV antiarrhythmic agent, providing that the composition is not a combination of lO ⁇ g/kg E4031 and 0. Img/kg verapamil, and optionally a pharmaceutically acceptable carrier therefor.
• the present invention also provides the use of a combination of a class III and a class IV antiarrhythmic agent in the manufacture of a medicament for use in treating cardiac arrhythmia, providing that the medicament is not a combination of lO ⁇ g/kg E403 and 0. Img/kg verapamil.
• the class III agent will normally be a potassium channel blocking agent, and any such agent known in the art would be suitable.
• Class III agents include the compounds of EP 235752, EP 245997, EP 322390, USP 4544654 and DE 3419067.
• a favoured potassium channel blocking agent is an inhibitor of the delayed rectifier potassium current.
• a particular example of such an agent is the compound E4031.
• Further examples include sematilide, dofetilide, almokalant and d-sotalol.
• the class IV agent will be a compound having calcium channel blocking activity, suitably having an L-type calcium blocking effect.
• Class IV agents include the compounds of USP 3261859, DE 2117571, ZA 6801482 and DE 2549568.
• a particular example of a class IV agent is verapamil.
• Further examples include the dihydropyridines such as nitrendipine, nifedipine and nisoldipine.
• the calcium blocking effect in the combination is not too great. It is considered that the upper limit for the calcium blocking effect is suitably met if the class IV agent is present in an amount lower than that which provides a substantial calcium blocking effect.
• a 'substantial calcium blocking effect' in this context is present when the class IV agent decreases action potential duration, increases PR interval, reduces arterial blood pressure and/or decreases cardiac contractile force. This is to be contrasted with 'a calcium blocking effect' which is considered to be present when the class IV agent decreases action potential duration and/or increases PR interval but has no significant effect upon arterial blood pressure and/or cardiac contractile force.
• composition which composition comprises a class III and a class IV antiarrhythmic agent, characterised in that the class HI reagent is present in an antiarrhythmic effective amount and the class IV antiarrhythmic agent is present in an amount lower than that which provides a substantial calcium blocking effect, and optionally a pharmaceutically acceptable carrier therefor.
• the class IV antiarrhythmic agent is present in the composition in an amount which exhibits a threshold calcium blocking effect, that is an amount which only just provides an electrophysiological effect due to a calcium antagonist effect.
• a lower limit for the amount of class IV antiarrhythmic agent in the composition is considered to be an amount which is below the threshold calcium blocking effect in that it is ineffective on action potential duration and on the PR interval.
• the class III and IV agents can be used in a wide variety of weight ratios to achieve the above mentioned synergistic effect.
• the ratio of class III to class IV agent may be from 1:1 to 10:1, preferably from 1:1 to 5:1, with a particular ratio of around 3:1.
• the dosage of class III agent may be within wide ranges, for example from 0.1 to 2.0 mg/kg, and the class IV agent may be within 0.01 to 1.0 mg/kg.
• the invention also provides a method for the treatment and/or prophylaxis of cardiac arrhythmias in mammals, particularly humans, which comprises administering to the mammal in need of such treatment and/or prophylaxis an effective amount of a combination of a class III antiarrhythmic agent and class IV antiarrhythmic agent, providing that the combination is not a combination of lO ⁇ g/kg E4031 and 0.1 mg/kg verapamil.
• the invention further provides a method for the treatment and/or prophylaxis of cardiac arrhythmias in mammals, particularly humans, which comprises administering to the mammal in need of such treatment and/or prophylaxis an amount of a combination of a class III antiarrhythmic agent and class IV antiarrhythmic agent, wherein the class III antiarrhythmic agent is administered in an antiarrhythmic effective amount and the class IV antiarrhythmic agent is administered in an amount lower than that which provides a substantial calcium blocking action.
• the invention also provides the use of a combination of a class IH and a class IV antiarrhythmic agent in the manufacture of a medicament for use in treating cardiac arrhythmia, wherein the class III antiarrhythmic agent is present in the medicament in an antiarrhythmic effective amount and the class IV antiarrhythmic agent is present in an amount lower than that which provides a substantial calcium blocking action
• the class III antiarrhythmic agent and class IV antiarrhythmic agent are administered together, preferably in a pharmaceutical composition.
• class III antia ⁇ hythmic agent and class IV antiarrhythmic agents are prepared according to conventional procedures depending upon the nature of the agent.
• the above mentioned agents are prepared according to methods disclosed in the following publications: Class III: E-4031 (EP235752 ), sematilide (USP4544654 ), dofetilide
• Class IV Verapamil (USP3261859 ), nitrendipine (DE2117571 ), nifedipine (ZA6801482 ), and nisoldipine (DE2549568 ).
• composition of the invention may be prepared using known techniques.
• the invention provides a process for the preparation of a composition, the composition comprising a class III antiarrhythmic agent, a class IV antiarrhythmic agent and, optionally, a pharmaceutically acceptable carrier, which process comprises the admixture of a class III antiarrhythmic agent, a class IV antiarrhythmic agent and, optionally, a pharmaceutically acceptable carrier, providing that said admixture does not give a combination of lO ⁇ g/kg E4031 and 0. Img/kg verapamil.
• the invention also particularly provides a process for the preparation of a pharmaceutical composition, the composition comprising a class III and a class IV antiarrhythmic agent, in which the class III reagent is present in an antiarrhythmic effective amount and the class IV antiarrhythmic agent is present in an amount lower than that which provides a substantial calcium blocking effect, and optionally a pharmaceutically acceptable carrier therefor, which process comprises admixing the antiarrhythmic effective amount of the class III antiarrhythmic agent, the class IV antiarrhythmic agent in an amount which is lower than that which provides a substantial calcium blocking effect and, optionally, the pharmaceutically acceptable carrier.
• an antiarrhythmic agent and includes the pharmaceutically acceptable salts and solvates of any particular agent including the class HI antiarrhythmic agent and class IV antiarrhythmic agents specifically mentioned herein.
• Such compounds are prepared according to known methods.
• An antiarrhythmic effective amount of a class III antiarrhythmic agent is that amount which would be considered by those skilled in the art to provide such as effect depending upon such factors as the efficacy of the particular agent, the nature of the pharmaceutically acceptable salt or pharmaceutically acceptable solvate chosen and the nature and severity of the disorders being treated and the weight of the mammal.
• a unit dose will normally contain 0.1 to 500 mg for example 2 to 50 mg, of the compound of the invention.
• Unit doses will normally be administered once or more than once a day, for example 2,3,4,5 or 6 times a day, more usually 2 to 4 times a day, such that the total daily dose is normally in the range, for a 70 kg adult of 0.1 to 2500 mg, more usually 50 to 2000 mg, for example 10 to 75mg, that is in the range of approximately 0.002 to 35 mg/kg/day, more usually 1 to 30 mg/kg/day, for example 0.15 to 1 mg/kg/day.
• the active compounds may be administered by any suitable route, e.g. by the oral, parenteral or topical routes.
• the compounds will normally be employed in the form of a pharmaceutical composition in association with a human or veterinary pharmaceutical carrier, diluent and/or excipient, although the exact form of the composition will naturally depend on the mode of administration.
• Active compounds or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof is normally administered in unit dosage form.
• compositions are prepared by admixture and are suitably adapted for oral, parenteral or topical administration, and as such may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, pastilles, reconstitutable powders, injectable and infusable solutions or suspensions, suppositories and transdermal devices.
• Orally administrable compositions are preferred, in particular shaped oral compositions, since they are more convenient for general use.
• Tablets and capsules for oral administration are usually presented in a unit dose, and contain conventional excipients such as binding agents, fillers, diluents, tabletting agents, lubricants, disintegrants, colourants, flavourings, and wetting agents.
• the tablets may be coated according to well known methods in the art.
• Suitable fillers for use include cellulose, mannitol, lactose and other similar agents.
• Suitable disintegrants include starch, polyvinylpyrrolidone and starch derivatives such as sodium starch glycollate.
• Suitable lubricants include, for example, magnesium stearate.
• Suitable pharmaceutically acceptable wetting agents include sodium lauryl sulphate.
• solid oral compositions may be prepared by conventional methods of blending, filling, tabletting or the like. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers. Such operations are, of course, conventional in the art.
• Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use.
• Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example, almond oil, fractionated coconut oil, oily esters such as esters of glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl rj-hydroxybenzoate or sorbic acid, and if desired conventional flavouring or colouring agents.
• suspending agents for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monoole
• fluid unit dose forms are prepared containing a compound of the present invention and a sterile vehicle.
• the compound depending on the vehicle and the concentration, can be either suspended or dissolved.
• Parenteral solutions are normally prepared by dissolving the compound in a vehicle and filter sterilising before filling into a suitable vial or ampoule and sealing.
• adjuvants such as a local anaesthetic, preservatives and buffering agents are also dissolved in the vehicle.
• the composition can be frozen after filling into the vial and the water removed under vacuum.
• Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilised by exposure to ethylene oxide before suspending in the sterile vehicle.
• a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the active compound.
• the composition may be in the form of a transdermal ointment or patch for systemic delivery of the active compound and may be prepared in a conventional manner, for example, as described in the standard textbooks such as 'Dermatological Formulations' - B.W. Barry (Drugs and the
• compositions may contain further active agents such as anti-hypertensive agents and diuretics.
• compositions will usually be accompanied by written or printed directions for use in the medical treatment concerned. No toxicological effects are indicated when an active compound is administered in the above mentioned dosage ranges.
• E-4031 a class III antiarrhythmic agent
• verapamil a calcium channel blocking drug
• a combination of both E-4031 and verapamil on ventricular fibrillation were evaluated in anesthetized dogs 3 days following myocardial infarction. Ventricular arrhythmias were induced by programmed electrical stimulation protocols. In dogs with myocardial infarction E-4031 (0.1 to 1.0 mg/kg) significantly increased QT intervals and ventricular effective refractory periods in both the normal in the infarcted areas. Verapamil reduced heart rate, mean arterial pressure, pressure-rate product and to a lesser extent dP/dtmax.
• verapamil did not change QT intervals and ventricular effective refractory periods but increased PR interval.
• high doses of verapamil induced more pronounced cardiodepressive effects than given alone.
• the incidence of ventricular arrhythmias was changed neither by cumulative administration of vehicle nor by increasing doses of verapamil.
• E-4031 (0.1 to 3.0 mg/kg) reduced the severity of ventricular arrhythmias from ventricular fibrillation to non sustained ventricular tachycardia.
• a combination of verapamil with E-4031 was able to suppress completely the occurrence of arrhythmias induced by programmed electrical stimulation (i.e. rendered these non-inducible) in several dogs, an effect which was never observed with E-4031 alone.
• class III antiarrhythmic agents such as dofetilide (UK-68,798), E-4031 and sematilide, that selectively prolong action potential duration and refractoriness in ventricular preparations, have been shown to reduce the incidence of ventricular fibrillation in canine models of sudden coronary death (3-6).
• Experiments were performed in anesthetized dogs with a previous myocardial infarction to determine the effects of the pure class III agent E-4031 on the ventricular effective refractory period (ERP) and on the inducibility of ventricular tachycardia or ventricular fibrillatio n.
• EEP ventricular effective refractory period
• verapamil and a combination verapamil with E-4031 were tested in order to evaluate the benefit of a combination of the two mechanisms, potassium and calcium blocking activities.
• Dogs were anesthetized using 30 mg/kg i.v. sodium pentobarbital.
• Subcutaneous needle electrodes were installed to monitor a lead II electrocardiogram (ECG).
• ECG electrocardiogram
• tracheal intubation for artificial respiration Harmonic 613 ventilator, South Natick, MA, U.S.A.
• a left thoracotomy was performed at the fourth intercostal space and the heart was exposed in a pericardial cradle.
• the left anterior descending (LAD) coronary artery was isolated close to its origin, a silk suture was placed around the artery and a two stage coronary artery occlusion was performed.
• LAD left anterior descending
• Reperfusion was performed in the presence of a critical stenosis for 30 min then complete reflow of the occluded zone was achieved.
• the pericardium was closed and the surgical incision was repaired.
• animals received amoxicillin (1.0 g, i.m., SmithKline-Beecham, Paris, France).
• Buprenorphine 0.3 mg, i.m., Schering-Plough, Kenilworth, NJ, U.S.A.
• droperidol 1.5 mg/kg, i.m., Janssen Pharmaceutica, Beerse, Belgium
• a CV5RL precordial lead of ECG was measured as previously described (7).
• the heart was re-exposed by thoracotomy through the left fifth intercostal space.
• One pair of stainless steel electrodes was attached to the left atrium for subsequent pacing.
• Two pairs of teflon coated needle electrodes were sutured respectively in the normal zone (NZ) and the infarcted zone (IZ) of the left ventricle to measure the effective refractory period (ERP) and for induction of trains of stimulation by PES testing.
• the ventricular ERP was determined in both NZ and IZ during atrial pacing at 300 msec.
• the ERP was calculated from the longest (S1-S2) interval which did not induce a propagated response in the tissue. To determine the actual ERP duration, the ventricular conduction time (time from the S 1 stimulus to the ventricular response) was substracted from the (S 1-S2) duration.
• the pacing protocol for programmed ventricular stimulation was adapted from Katoh et al. (4).
• animals were subjected to ventricular stimulation by delivering a triple-pulse train (S2-S3-S4) in the ventricular IZ using a Grass S8800 stimulator and SIU-5 isolation unit (Grass Instruments, Quincy, MA, USA).
• the (S1-S2) coupling interval of the train of stimuli was 10 msec longer than the measured refractoriness.
• the (S2-S3) and (S3-S4) train intervals were tested in the range of 125 to 200 msec to determine the susceptibility of the ventricle.
• NI non-inducible animals
• nsVT non-sustained ventricular tachycardia
• sVT sustained ventricular tachycardia
• VT/VF ventricular tachycardia-ventricular fibrillation
• E-4031 was given at 0.1, 0.3 and 1.0 mg/kg, i.v. Verapamil was administered at 0.03, 0.1 and 0.3 mg/kg.
• E-4031 + Verapamil E- 4031 (0.1 mg/kg) was given with increasing doses of verapamil.
• Electrocardiographic parameters, PR interval, QT interval and QTc were not changed by cumulative administration of vehicle.
• E-4031 induced a dose dependent increase in QT and QTc intervals, with no change in PR interval.
• Verapamil given alone only increased PR interval without any effect on QT intervals.
• verapamil markedly increased QT intervals, with limited effect on PR interval suggesting a potentiation of the action of the class III antiarrhythmic agent.
• verapamil given at 0.3 mg/kg alone or in presence of 0.1 mg/kg of E-4031 produced frequent atrio-ventricular blocks. Such conduction disturbances were never observed in presence of saline, or E-4031.
• Ventricular effective refractory periods were measured in both the normal and the infarcted areas. The vehicle did not significantly change VERP in both zones. E- 4031 increased effective refractory periods in both the normal and the infarcted zones (Table 2). In presence of E-4031, increasing doses of verapamil (0.03, 0.1 and 0.3 mg/kg) induced a marked increase in VERP. Effective refractory periods which were 158 ⁇ 7 and 152 ⁇ 6 msec in the normal and infarcted zones before the combination were increased to 202 ⁇ 9 and 200 ⁇ 11 msec respectively in presence of 0.1 mg kg (p ⁇ 0.001) and to 219 ⁇ 16 and 223 ⁇ 13 msec with 0.3 mg/kg (p ⁇ 0.001).
• pretreatment responses to PES was represented by VT/VF in 6 out of 8 dogs (figure 1).
• a steady response was obtained during the whole experiment in 5 dogs while one dog dropped toward nsVT during the third PES test.
• Two dogs responding with nsVT to pretreatment PES did not change throughout the experimental period.
• E-4031 administered at 0.1 mg/kg suppressed the incidence of VT/VF and sVT in 5 out of 7 dogs.
• Ventricular arrhythmias induced by PES are known to be generated by a re-entrant mechanism (9).
• class III antiarrhythmic agents may convert PES induced ventricular fibrillation to non-sustained ventricular tachycardia (4, 10).
• E-4031 typical class III antiarrhythmic compound
• verapamil was able to cause a greater protection of canine hearts since several animals given 0.01 or 0.03 mg/kg of verapamil (in the presence of 0.1 mg/kg of E-4031) were in a non-inducible state.
• verapamil alone did not change the incidence of ventricular arrhythmias induced by PES, an adjusted combination of a potassium and calcium blocking effect may represent a potent and safe therapeutic approach for cardiac arrhythmias.
• E-4031 and the combination of E-4031 and verapamil are associated with a dose dependent increase in ventricular effective refractory period. This suggest that the protection of PES induced arrhythmias may be related to a prolongation of the cardiac action potential.
• verapamil neither prevented PES -induced arrhythmias nor prolonged ventricular effective refractory period reinforces the hypothesis that action potential prolongation may represent an effective antifibrillatory mechanism.
• E-4031 did not change left ventricular pressure or (+)dP/dtmax but reduced heart rate. This effect was essentially responsible for the slight reduction in pressure-rate product, an index of cardiac work. Except at the high dose of 0.3 mg/kg, verapamil either in the absence or in the presence of E-4031 (0.1 mg/kg) did not markedly change cardiac function. However, the higher dose used in this study, induced a marked cardiodepressive effect with the occurrence of atrio-ventricular conduction disturbances suggesting a limitation in the beneficial effect of this combination.
• Singh BN Nademanee K. Control of cardiac arrhythmias by selective lengthening of repolarization: Theoretic considerations and clinical observations. Am Heart J 1985;109:421-430. 2. Colatsky TJ, Follmer CH, Starmer CF. Channel specificity in antiarrhythmic drug action. Mechanism of potassium channel block and its role in suppressing and aggravating cardiac arrhythmias. Circulation 1990;82:2235-2242.
• FIG. 1 Programmed electrical stimulation (PES) in anesthetized dogs, 3 days after anterior wall myocardial infarction. Effects of PES before drug dosing (0) and after cumulative administration of each drug. Each line represents one animal with the nature of the response to PES indicated on the ordinate (see text for inducibility criteria of animals to the stimulation).
• PES Programmed electrical stimulation
• mice Male Hartley guinea-pigs (250-300g) were anaesthetised with intraperitoneal injection of sodium pentobarbital (120 mg/kg). The heart was quickly excised and dissected in an oxygenated Tyrode solution (95% 02 / 5% C02). A thin papillary muscle was removed from either right or left ventricle and pinned onto the silastic floor of a tissue bath superfused with oxygenated Tyrode solution maintained at 37°C and at pH 7.35.
• the modified Tyrode solution contained (mM) : NaCl 125, KC1 4.0, CaCl 2 1.8, MgCl 2 1.0, NaHC0 3 24, NaH 2 P0 4 0.9, glucose 11.
• E-4031 and verapamil solutions were prepared daily as stock solutions in water (2 mM).
• transmembrane action potentials were recorded with conventional microelectrodes (10-30 Mohms) connected to a high input impedance amplifier (BIOLOGIC VF180).
• External stimuli (1Hz, 2msec, twice threshold) were delivered by a stimulator (PULSAR 6i) through bipolar platinum electrodes placed at the base of the preparation.
• PALSAR 6i External stimuli (1Hz, 2msec, twice threshold) were delivered by a stimulator (PULSAR 6i) through bipolar platinum electrodes placed at the base of the preparation.
• Signals were monitored on a storage 20 MHz oscilloscope (GOULD 1604) and simultaneously recorded on a digital tape recorder (BIOLOGIC DTR1204).
• Action potentials were digitalized for subsequent analysis (Software Clovis, CLOD sari) on a personal microcomputer equipped with a 12 bit analog-digit DAS50 converter.
• Protocol Papillary muscles were superfused with increasing doses of verapamil (from 0.3 to 10 ⁇ M) or E-4031 (from 0.01 to 0.3 ⁇ M). E-4031 was tested either in the absence or in the presence of 0.3 ⁇ M of verapamil. In the latter case, verapamil was added to the superfusion medium 30 minutes prior administration of the first dose of E-4031 and was present during the whole experiment. Each concentration was applied for 30 minutes which can be considered as the time necessary to reach steady state. Experiments were conducted at two cycle lengths (300 (CL300) and 1000 (CL1000) msec). Only fibres in which the same impalement was maintained throughout the whole experiment were used for analysis. Statistical analysis :
• Results are presented as mean ⁇ sem. Statistical analysis was performed using repeated measures analysis of variance followed by multiple comparisons using the Sidak procedure. For comparisons with equal group sizes the Greenhouse- Geisser adjustment was used to calculate p value, and for comparisons with unequal group sizes, the Geisser-Greenhouse conservative adjustment was taken into consideration (Ludbrook, 1994). All statistical analyses were performed by means of the microcomputer statistical program, CRUNCH 4.0 (Crunch Software Corporation, Oakland, CA). A p value of less than 0.05 was considered as statistically significant.
• JT Action potential amplitude, resting membrane potential and Vmax were not significantly modified by E-4031 whereas this compound induced a dose- dependent increase in action potential duration either at CL 1000 or 300 msec.
• CARMELIET E.E. Voltage- and time-dependent block of the delayed K+ current in cardiac myocytes by dofetilide. J. Pharmacol. Exp. Ther. 262: 809-817, 1992.
• HONDEGHEM L.M. AND SNYDERS D.J. Class III antiarrhythmic agents have a lot of potential but a long way to go. Reduced effectiveness and dangers of reverse use dependence. Circulation 81: 686-690, 1990. JURKIEWICZ N.K. AND SANGUINETTI M.C: Rate-dependent prolongation of cardiac action potentials by a methanesulfonanilide class III antiarrhythmic agent. Specific block of rapidly activating delayed rectifier K+ current by dofetilide. Circ Res 72: 75-83, 1993.
• VAUGHAN- WILLIAMS, E. M. Classification of antiarrhythmic drugs.
• E. Sandoe E. Flensted- Jensen and K. H. Olsen, pp. 449-472, Astra, Sodertalje, Sweden, 1970.

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