Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
2000-06-07
2001-10-02
Jones, Dwayne C. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
C514S646000
Reexamination Certificate
active
06297287
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to novel anti-arrhythmic compositions and methods of treating cardiac arrhythmia wherein the active anti-arrhythmic agent is one of several classes of polyamines and certain derivatives thereof.
2. Description of the Prior Art
Cardiac arrhythmias are disorders involving the electrical impulse generating system of the heart. The disorders include premature contractions (extrasystoles) originating in abnormal foci in atria or ventricles, paroxysmal supraventricular tachycardia, atrial flutter, atrial fibrillation, ventricular fibrillation and ventricular tachycardia [Goodman et al, eds.,
The Pharmacological Basis of Therapeutics
, Sixth Edition, New York, MacMillan Publishing Co., pages 761-767 (1980)]. More particularly, cardiac arrhythmia is a disorder of rate, rhythm or conduction of electrical impulses within the heart. It is often associated with coronary artery diseases, e.g., myocardial infarction and atherosclerotic heart disease. Arrhythmia can eventually cause a decrease of mechanical efficiency of the heart, reducing cardiac output. As a result, arrhythmia can have life-threatening effects that require immediate intervention.
Anti-arrhythmic drugs are commonly divided into four classes according to their electro-physiological mode of action. See Edvardsson,
Current Therapeutic Research
, Vol. 28, No. 1 Supplement, pages 113S-118S (July 1980); and Keefe et al,
Drugs
, Vol. 22, pages 363-400 (1981) for background information of classification first proposed by Vaughn-Williams [Classification of Anti-Arrhythmic Drugs in Symposium of Cardiac Arrhythmias, pages 449-472, Sandoe et al, (eds.) A. B. Astra, Soederlalje, Sweden (1970)].
The classification of anti-arrhythmic drugs is as follows:
I. Local anesthetic effect
II. Beta-receptor blockade
III. Prolongation of action potential duration
IV. Calcium antagonism.
Class I agents usually have little or no effect on action potential duration and exert local anesthetic activity directly at cardiac cell membrane. Class II agents show little or no effect on the action potential and exert their effects through competitive inhibition of beta-adrenergic receptor sites, thereby reducing sympathetic excitation of the heart. Class III agents are characterized by their ability to lengthen the action potential duration, thereby preventing or ameliorating arrhythmias. Class IV agents are those which have an anti-arrhythmic effect due to their actions as calcium antagonists.
Class I
Sodium Channel Depressors
These agents are efficacious in repressing a sodium current. However, these agents have no or only minute effects on the retention time of the normal action potential and decrease the maximum rising velocity (V
max
) of the sodium current. They exert anti-arrhythmic activity but at the same time strongly repress cardiac functions. Careful consideration is required in administering to patients with cardiac failure or hypotension.
Class II
Beta-Blocking Agents
The agents in this class, represented by propranol-ol, are efficacious in the beta-blocking action and are useful in treating patients with arrhythmia in which the sympathetic nerve is involved. However, care must be taken in their use since these agents have side effects caused by the beta-blocking action, such as depression of cardiac functions, induction of bronchial asthmatic attack and hypoglycemic seizures.
Class III
Pharmaceutical Agents for Prolonging the Retention Time of the Action Current
These agents are efficacious in remarkably prolonging the retention time of the action current of the cardiac muscle and in prolonging an effective refractory period. Re-entry arrhythmia is considered to be suppressed by the action of the pharmaceutical agents of Class III. The medica-ments of this Class III include amiodarone and bretylium. However, all the agents have severe side effects; therefore, careful consideration is required for use.
Class IV
Calcium Antagonists
These agents control a calcium channel and suppress arrhythmia due to automatic sthenia of sinoatrial nodes and to ventricular tachycardia in which atrial nodes are contained in the re-entry cycle.
Although various anti-arrhythmic agents within the above classes are now available on the market, those having both satisfactory effects and high safety have not been obtained. For example, anti-arrhythmic agents of Class I which cause a selective inhibition of the maximum 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 the myocardial contractility and have a tendency to induce arrhythmias due to an inhibition of the impulse conduction. Beta-adrenoceptor blockers and calcium antagonists which belong to Classes II and IV, respectively, have the defect 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 anti-arrhythmic agents of Class I.
Anti-arrhythmic agents of Class III are drugs which cause a selective prolongation of the duration of the action potential without a significant depression of the V
max
. Drugs in this class are limited. Examples such as sotalol and amiodarone have been shown to possess Class III properties. Sotalol also possesses Class II effects which may cause cardiac depression and are contraindicated in certain susceptible patients. Also, amiodarone is severely limited by side effects. Drugs of this class are expected to be effective in preventing ventricular fibrillations. Pure Class III agents, by definition, are not considered to cause myocardial depression or an induction of arrhythmias due to the inhibition of the action potential conduction as seen with Class I anti-arrhythmic agents.
A number of anti-arrhythmic agents have been reported in the literature, such as those disclosed in EP 397,121; EP 300,908; EP 307,121; U.S. Pat. Nos. 4,629,739; 4,544,654; 4,788,196; EP application 88 302 597.5; EP application 88 302 598.3; EP application 88 302 270.9; EP application 88 302 600.7; EP application 88 302 599.1; EP application 88 300 962.3; EP application 235,752; DE 36 33 977; U.S. Pat. Nos. 4,804,662; 4,797,401; 4,806,555; and 4,806,536.
It is an object of the present invention to provide novel anti-arrhythmic pharmaceutical compositions and methods of treating cardiac arrhythmia wherein the effective anti-arrhythmic agent functions according to a mechanism substantively different from that of any of the above-described four classes of anti-arrhythmic agents. The compositions and methods of treatment of the present invention are not, therefore, subject to the above-noted disadvantages associated with the known four classes of anti-arrhythmic agents.
SUMMARY OF THE INVENTION
The present invention provides novel pharmaceutical compositions in unit dosage form for the treatment of cardiac arrhythmia comprising an effective anti-arrhythmic amount of at least one compound in association with a pharmaceutically acceptable, substantially non-toxic carrier or excipient; the compound having one of the formulae:
wherein:
R and R′ may be the same or different and are H, alkyl, fluoroalkyl or aralkyl having from 1 to 12 carbon atoms;
R
1
-R
4
may be the same or different and are H, R or R′;
m and n may be the same or different and are integers from 2 to 10, inclusive; and
x, y and z may be the same or different and are integers from 0 to 8, inclusive;
or (III) a salt of (I) or (II) with a pharmaceutically acceptable acid.
The invention also provides a novel method for the treatment of cardiac arrhythmia and related heart problems or effecting anti-arrhythmic action which comprises administering to a patient requiring anti-arrhythmic therapy an anti-arrhythmic effective amount of at least one of the above-described compounds.
DETAILED DESCRIPTION OF THE INVENTION
Clarke Dennis P.
Jones Dwayne C.
Miles & Stockbridge
University of Florida Research Foundation Inc.
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