Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Phosphorus containing other than solely as part of an...
Reexamination Certificate
1999-04-19
2001-04-10
Henley, III, Raymond (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Phosphorus containing other than solely as part of an...
C514S137000, C514S247000, C514S821000
Reexamination Certificate
active
06214810
ABSTRACT:
BACKGROUND OF THE INVENTION
This application discloses a method of treating or preventing atrial arrhythmias which utilizes compounds which are blockers of the ultra-rapidly-activating delayed rectifier K
+
current (I
Kur
) of the human atrium in a use-dependent and/or rate-dependent manner, and which preferentially block at fast heart rates so that the effect is realized or maximized when required.
Atrial flutter and/or atrial fibrillation (AF) are the most commonly sustained cardiac arrhythmias in clinical practice and are likely to increase in prevalence with the aging of the population. Currently, AF affects more than 1 million Americans annually, represents over 5% of all admissions for cardiovascular diseases and causes more than 80,000 strokes each year in the United States. While AF is rarely a lethal arrhythmia, it is responsible for substantial morbidity and can lead to complications such as the development of congestive heart failure or thromboembolism. Currently available Class I and Class III antiarrhythmic drugs reduce the rate of recurrence of AF, but are of limited use because of a variety of potentially adverse effects including ventricular proarrhythmia. Because current therapy is inadequate and fraught with side effects, there is a clear need to develop new therapeutic approaches.
Although various antiarrythmic agents are now available on the market, those having both satisfactory efficacy and a high margin of safety have not been obtained. For example, antiarrhythmic agents of Class I, according to the classification scheme of Vaughan-Williams (“Classification of antiarrhythmic drugs”,
Cardiac Arrhythmias
, edited by: E. Sandoe, E. Flensted-Jensen, K. Olesen; Sweden, Astra, Sodertalje, pp 449-472, 1981) which cause a selective inhibition of the maxnmum velocity of the upstroke of the action potential (V
max
) are inadequate for preventing ventricular fibrillation. In addition, they have problems regarding safety, namely, they cause a depression of myocardial contractility and have a tendency to induce arrnythmias due to an inhibition of impulse conduction. &bgr;-adrenergenic receptor blockers and calcium channel (I
Ca
) antagonists which belong to Class II and IV, respectively, have a defect in that their effects are either limited to a certain type of arrhythmia or are contraindicated because of their cardiac depressant properties in certain patients with cardiovascular disease. Their safety, however, is higher than that of the antiarrhythmic agents of Class I.
Antiarrhythmic agents of Class III are drugs that cause a selective prolongation of the action potential duration (APD) without a significant depression of the maximum upstroke velocity (V
max
). Available drugs in this class are limited in number. Examples such as sotalol and amiodarone have been shown to possess interesting Class III properties (Singh B. N., Vaughan Williams E. M., “A third class of anti-arrhythmic action: effects on atrial and ventricular intracellular potentials and other pharmacological actions on cardiac muscle of MJ 1999 and AH 3747
”, Br. J. Pharmacol
1970; 39:675-689, and Singh B. N., Vaughan Williams E. M., “The effect of amiodarone, a new anti-anginal drug, on cardiac muscle”,
Br. J. Pharmacol
1970; 39:657-667), but these are not selective Class III agents. Sotalol also possesses Class II (&bgr;-adrenergic blocking) effects which may cause cardiac depression and is contraindicated in certain susceptible patients. Amiodarone also is not a selective Class III antiarrhythmic agent because it possesses multiple electrophysiological actions and is severely limited by side effects (Nademanee, K., “The Amiodarone Odessey”,
J. Am. Coll. Cardiol
. 1992; 20:1063-1065.) Drugs of this class are expected to be effective in preventing ventricular fibrillation. Selective Class III agents, by definition, are not considered to cause myocardial depression or an induction of arrhythmias due to inhibition of conduction of the action potential as seen with Class I antiarrhythmic agents.
Class III agents increase myocardial refractoriness via a prolongation of cardiac action potential duration (APD). Theoretically, prolongation of the cardiac action potential can be achieved by enhancing inward currents (i.e. Na
+
or Ca
2+
currents; hereinafter I
Na
and I
Ca
, respectively) or by reducing outward repolarizing potassium K
+
currents. The delayed rectifier (I
K
) K
+
current is the main outward current involved in the overall repolarization process during the action potential plateau, whereas the transient outward (I
to
) and inward rectifier (I
K1
) K
+
currents are responsible for the rapid initial and terminal phases of repolarization, respectively. Cellular electrophysiologic studies have demonstrated that I
K
consists of two pharmacologically and kinetically distinct K
+
current subtypes, I
Kr
(rapidly activating and deactivating) and I
Ks
(slowly activating and deactivating). (Sanguinetti and Jurkiewicz, “Two components of cardiac delayed rectifier K
+
current. Differential sensitivity to block by Class III antiarrhythmic agents”,
J Gen Physiol
1990, 96:195-215).
Class III antiarrhythmic agents currently in development, including d-sotalol, dofetilide (UK-68,798), almokalant (H234/09), E-4031 and methanesulfonamide-N-[1′-6-cyano-1,2,3,4-tetrahydro-2-naphthalenyl)-3,4-dihydro-4-hydroxyspiro[2H-1-benzopyran-2,4′-piperidin]-6yl], (+)-, monochloride (MK-499) predominantly, if not exclusively, block I
Kr
. Although, amiodarone is a blocker of I
Ks
(Balser J. R. Bennett, P. B., Hondeghem, L. M. and Roden, D. M. “Suppression of time-dependent outward current in guinea pig ventricular myocytes: Actions of quinidine and amiodarone”,
Circ. Res
. 1991, 69:519-529), it also blocks I
Na
and I
Ca
, effects thyroid function, is as a nonspecific adrenergic blocker, and acts as an inhibitor of the enzyme phospholipase (Nademanee, K. “The Amiodarone Odessey”.
J. Am. Coll. Cardiol
. 1992; 20:1063-1065). Therefore, its method of treating arrhythmia is uncertain.
Reentrant excitation (reentry) has been shown to be a prominent mechanism underlying supraventricular arrhythmias in man. Reentrant excitation requires a critical balance between slow conduction velocity and sufficiently brief refractory periods to allow for the initiation and maintenance of multiple reentry circuits to coexist simultaneously and sustain AF. Increasing myocardial refractoriness by prolonging APD, prevents and/or terminates reentrant arrhythmias. Most selective Class III antiarrhythmic agents currently in development, such as d-sotalol and dofetilide predominantly, if not exclusively, block I
Kr
, the rapidly activating component of I
K
found both in atrium and ventricle in man.
Since these I
Kr
blockers increase APD and refractoriness both in atria and ventricle without affecting conduction per se, theoretically they represent potential useful agents for the treatment of arrhythmias like AF. These agents have a liability in that they have an enhanced risk of proarrhythmia at slow heart rates. For example, torsades de pointes, a specific type of polymorphic ventricular tachycardia which is commonly associated with excessive prolongation of the electrocardigraphic QT interval, hence termed “acquired long QT syndrome”, has been observed when these compounds are utilized (Roden, D. M. “Current Status of Class III Antiarrhythmic Drug Therapy”,
Am J. Cardiol
, 1993; 72:44B-49B). This exaggerated effect at slow heart rates has been termed “reverse frequency-dependence” and is in contrast to frequency-independent or frequency-dependent actions. (Hondeghem, L. M., “Development of Class III Antiarrhythmic Agents”,
J. Cardiovasc. Cardiol
. 20 (Suppl. 2):S17-S22).
The slowly activating component of the delayed rectifier (I
Ks
) potentially overcomes some of the limitations of I
Kr
blockers associated with ventricular arrhythmias. Because of its slow activation kinetics however, the role of I
Ks
in atrial repolarization may be limited due to
Fermini Bernard
Lynch, Jr. Joseph J.
Salata Joseph J.
Swanson Richard J.
Camara Valerie J.
Daniel Mark R.
Henley III Raymond
Jang Soonhee
Merck & Co. , Inc.
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