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
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/415—1,2-Diazoles
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • 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
• • 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
  • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure

Definitions

• the present invention relates to a method of treating heart failure. More particularly, the present invention relates to a method of treating heart failure using a positive inotrope and a ⁇ -adrenergic receptor antagonist.
• Heart failure is a pathophysiological condition in which the heart fails to pump blood at a rate commensurate with the requirements of the metabolizing tissues of the body.
• physiological mechanisms for modulating the function of the heart are utilized to increase heart rate and contractility.
• adrenergic pathways The most important of the mechanisms that are responsible for modulating cardiac function are the adrenergic pathways. In a normal heart, these pathways are largely responsible for allowing cardiac pumping performance to meet the circulatory demands of increased activity by rapidly increasing or decreasing cardiac function according to circulatory demands. The cellular actions of these pathways are mediated through a family of receptors, called adrenergic receptors. There are two ⁇ - adrenergic receptor subtypes, ⁇ i and ⁇ 2 , which, when stimulated, initiate a G-protein coupled signaling cascade, resulting in immediate stimulation of pump performance. See Figure 1.
• adrenergic activity is stimulated by increased sympathetic nerve activity, presynaptic facilitation of norepinephrine release and eventually, decreased neuronal norepinephrine reuptake.
• Increased circulating epinephrine also stimulates cardiac ⁇ -adrenergic receptors, particularly in the initial phase of heart failure.
• the immediate stimulation of pump performance by ⁇ -adrenergic mechanisms is subsequently aided by two additional means of stabilizing or increasing cardiac function. These are an increase in plasma volume, which in turn increases preload, and hypertrophy of the cardiac myocytes, which results in more contractile elements.
• the subcellular mechanisms mediating these additional cardiac functions include both the ⁇ -adrenergic receptor pathways and the oti-adrenergic receptor pathway, among other myocellular pathways.
• the exposure to elevated levels of cognate agonists causes the adrenergic receptors to undergo regulatory changes.
• the ⁇ i-adrenergic receptor exhibits down-regulation or loss of receptor protein and may also be partially uncoupled from the signaling response.
• ⁇ 2 -adrenergic receptors are not down-regulated, but are weakly uncoupled from the signaling response.
• the o ⁇ -adrenergic receptors are slightly up-regulated and are partially uncoupled from the signaling response.
• the increased agonist exposure continues to chronically stimulate the remaining adrenergic signaling function, resulting in the compromise of the modulatory effects of the adrenergic system. Therefore, the prime functional capabilities of the adrenergic system, to rapidly and substantially increase or decrease cardiac function according to demand, are compromised, while the adverse effects of chronic stimulation of cardiac function remain.
• ⁇ -adrenergic receptor antagonists ⁇ -adrenergic receptor antagonists
• ⁇ -adrenergic antagonists ⁇ -blockers
• One ⁇ - adrenergic antagonist can differ from another in a variety of ways, including by receptor subtype specificity, effect on expression of the adrenergic receptor, and effect on adrenergic receptor signaling.
• ⁇ -adrenergic antagonists are important therapeutic tools for use in patients experiencing heart failure, these drugs often cause adverse side effects, such as bradycardia, myocardial depression, dyspnea, easy fatigability, fluid retention and worsening of heart failure.
• the characteristics which contribute to the undesirable side effects of ⁇ -adrenergic antagonists are controversial and not well understood. See Kelly and Smith, in Heart Disease : A Textbook Of Cardiovascular Medicine, Chapter 16 at page 488 (5th ed., Braunwald ed., 1997) .
• Positive inotropic agents strengthen heart muscle contractility, and they exert their effects through the second messengers of the signal transduction pathways involved in modulating contractile function (illustrated in Figure 1) .
• Table 1 lists the second messengers involved in mediating a positive inotropic response for various inotropic agents.
• positive inotropic agents use only a limited number of second messengers to mediate their cellular effects, and some use more than one second messenger.
• Table 2 lists the three most commonly observed second messengers and their effects on important processes in the heart and vascular smooth muscle, including increases in the heart rate, contractility and vasodilation.
• cyclic adenosine monophosphate cyclic adenosine monophosphate (cAMP) is capable of producing vasodilation and a positive inotropic effect. Cyclic AMP also produces an increase in heart rate, a very counterproductive property for a heart failure medication. In addition, all positively inotropic second messengers carry an arrhythmogenic risk that is usually dose-related.
• Ca 2+ channel agonists Ca 2+ o ⁇ -adrenergic receptor Inositol triphosphate/DAG agonists
• G s stimulatory G protein
• DAG diacylglycerol
• AMP adenosine monophosphate
• IP 3 inositol triphosphate
• ⁇ -adrenergic antagonists cannot be used, and often the only therapy available is intravenous positive inotropic agents. Although patients receiving intravenous inotropic agents usually feel better and improve hemodynamically for a short time, this treatment is expensive and has the potential to increase mortality. Other uses of positive inotropic therapy, including oral forms of positive inotropes, have been abandoned because of the above-mentioned increase in mortality.
• Chronic heart failure is a progressive disease syndrome which is associated with high degrees of morbidity and mortality despite medical therapy.
• heart transplantation can improve outcomes, a limited organ donor supply confines this treatment to fewer than 5% of subjects who could benefit from it.
• the effects of medical therapy on chronic heart failure are largely confined to modest effects (15-20% reductions in mortality) observed with ACE inhibitors in subjects with mild or moderate heart failure-.
• ACE inhibitors in subjects with mild or moderate heart failure-.
• the invention provides a method of treating heart failure.
• the method comprises administering an effective amount of a positive inotropic agent to a patient suffering from heart failure until the patient is hemodynamically and clinically stable.
• a ⁇ -adrenergic receptor antagonist is administered to the patient, beginning with a low dose which is gradually increased to an effective dose.
• the administration of effective doses of both the positive inotropic agent and the ⁇ -adrenergic receptor antagonist can be continued indefinitely.
• the dose of the positive inotropic agent is gradually reduced to the lowest possible dose that does not reduce the hemodynamic and clinical stability of the patient and is, most preferably, discontinued altogether.
• Figure 1 is a diagram of a myocardial cell, showing signal transduction mechanisms involved in modulating contractile function.
• the diagram shows cyclic adenosine monophosphate (cAMP) -dependent and cAMP-independent pathways for various receptor agonists.
• G s stimulatory G protein
• G ⁇ inhibitory G protein
• C adenylyl cyclase
• PDE phosphodiesterase.
• G s mediates the stimulation of adenylyl cyclase and, thereby, causes a rise in intracellular cAMP which, in turn, stimulates Ca ++ influx into the myocyte through Ca ++ channels in the sarcolemma and accelerates the uptake of Ca ++ by the sarcoplasmic reticulum.
• G x mediates the inhibition of adenylyl cyclase and has the opposite effect on the movement of Ca ++ .
• Figure 2 shows a comparison of the survival function curves of patients treated with enoximone and metoprolol (this study) to New York Heart Association class IV placebo-treated patients in the PROMISE trial and to enalapril-treated patients in the CONSENSUS trial.
• Figure 3 Graph of time versus probability of survival for NYHA Class III-V heart failure patients treated with placebo, vesnarinone alone, or a combination of vesnarinone and metoprolol.
• the invention provides a method of treating heart failure.
• Methods of diagnosing heart failure are well known in the art. See Heart Disease : A Textbook Of
• Cardiovascular Medicine (Braunwald ed., 5th ed., 1997). Symptoms associated with heart failure include shortness of breath, an inability to work or exercise, swollen feet and ankles, cyanosis respiratory congestion, and persistent cough. Reduced left (or right) ventricular ejection fraction, a measure of the heart's pumping efficiency, is the most reliable diagnostic indicator of heart failure. Echo-cardiography is commonly employed to detect other diagnostic indications of heart failure including increased chamber dimensions and wall thickness, various motion abnormalities, left ventricle dilation and hypertrophy. The method of the invention has been found particularly useful for treating advanced, late-stage heart failure. Late-stage heart failure is characterized diagnostically by a severely reduced ventricular ejection fraction.
• NYHA New York Heart Association
• Symptoms of cardiac insufficiency or of angina may be present even at rest. If any physical activity is undertaken, discomfort is increased.
• Other NYHA heart failure classifications include: NYHA Class I asymptomatic; NYHA Class II symptomatic with routine exertion; and NYHA Class III symptomatic with less than routine exertion.
• Any positive inotropic agent may be used in the practice of the invention, except for cardiac glycosides and ⁇ -adrenergic receptor agonists. The ⁇ -agonists would compete with the ⁇ -adrenergic receptor antagonists used in the method of the invention.
• the partial ⁇ -agonist xamoterol was found to increase mortality by 148%. See Bristow and Lowes, Coronary Artery Disease, 5, 112-118 (1994) .
• the phosphodiesterease inhibitor milrinone produced only a 24% increase in mortality.
• the positive inotropic agent acts through the second messenger cAMP, since only cAMP produces vasodilation, as well as a positive inotropic effect (see Tables 1 and 2 above) .
• vasodilation is desirable, powerful vasodilation should be avoided.
• the main problem with agents acting through cAMP is their positive chronotropic effects.
• an increase in the heart rate can be negatively correlated with effects on survival across several classes of drugs, including angiotensin converting enzyme (ACE) inhibitors, vesnarinone, milrinone, flosequinan, and prostacyclin.
• ACE angiotensin converting enzyme
• the increase in heart rate is lessened or completely eliminated by the use of the ⁇ -adrenergic antagonist.
• a weaker versus a more powerful inotropic agent is preferred.
• a comparison of the maximum inotropic responses obtained with seven different agents in isolated right ventricular trabeculae removed from non-failing and failing human hearts shows that the quinolinone compounds OPC-8490 and OPC-18790 and the quinoline flosequinan are weak inotropic agents, while the sodium-channel agonist BDF-9148 and the phosphodiesterase inhibitors enoximone and milrinone are moderately powerful, and the full, non- selective agonist isoproterenol gives the most powerful inotropic response.
• Bristow and Lowes, Coronary Artery Disease, 5, 112-118 (1994) Bristow and Lowes, Coronary Artery Disease, 5, 112-118 (1994) .
• Effective dosage forms, modes of administration and dosage amounts of the positive inotropic agent may be determined empirically, and making such determinations is within the skill of the art. It is understood by those skilled in the art that the dosage amount will vary with the activity of the particular agent employed, the severity of the heart failure, the route of administration, the rate of excretion, the duration of the treatment, the identity of any other drugs being administered to the patient, the age and size of the patient, and like factors well known in the medical art.
• the "lowest effective dose" of an inotropic agent is the lowest dose effective in producing a beneficial therapeutic effect.
• the inotropic therapy should, preferably, produce a minimal or no effect at rest, and then a more vigorous positive inotropic response during periods of increased demand, such as during exercise.
• Phosphodiesterase inhibitors are uniquely capable of this function, since the increased level of cAMP generated by these agents with increased adrenergic signaling during exercise will produce a greater inotropic effect. Therefore, at the right dose, the phosphodiesterase inhibitor will have little or no inotropic effect at rest, but a clear-cut effect on exercise. This function will be heightened by the concurrent ⁇ -adrenergic receptor blockade.
• Suitable modes of administration of the positive inotropic agent can include, but are not limited to, oral, nasal, topical, transdermal, rectal, and parenteral routes.
• Preferred parenteral routes include, but are not limited to, subcutaneous, intradermal, intravenous, intramuscular and intraperitoneal routes.
• the positive inotropic agent is administered orally.
• advanced, late-stage heart failure patients are often treated with intravenous positive inotropes, typically the ⁇ -agonist dobutamine.
• intravenous positive inotropes typically the ⁇ -agonist dobutamine.
• the patient is preferably gradually withdrawn from the intravenous inotrope as the dose of an oral inotrope according to the invention is gradually increased to the effective dose.
• the positive inotropic agent is administered to a patient suffering from heart failure until the patient is hemodynamically and clinically stable.
• the time for a patient to become hemodynamically and clinically stable is typically about 2- 6 weeks.
• the positive inotropic agent and other heart failure medications such as diuretics, ACE inhibitors, and digoxin, are adjusted to optimal levels as the patient is progressively physically rehabilitated.
• the positive inotrope is preferably a phosphodiesterase inhibitor.
• Phosphodiesterase inhibitors are moderate inotropes which, at the right dose, produce a minimal or no effect at rest and a more vigorous positive inotropic response during periods of increased demand, such as during exercise. Since they act solely through cAMP, they provide vasodilation as well as inotropic effects.
• they give less increased mortality than other positive inotropes.
• the positive inotropic agent is the phosphodiesterase inhibitor enoximone.
• a suggested daily dosage of enoximone is about 1-3 mg/kg/day, preferably administered in 3 or 4 divided doses. However, the total daily dosage of the agent will be determined by an attending physician within the scope of sound medical judgment.
• a ⁇ -adrenergic receptor antagonist is used to overcome the adverse effects of the positive inotropic agent. For instance, since cAMP production is lessened by removing nonrepinephrine from adrenergic receptors, the action of positive inotropes which depend on the production of cAMP to exert their effects will be decreased. Increased availability of cAMP should occur only intermittently when the ⁇ -blocker is outcompeted for the receptor by high cardiac adrenergic drive, that is, when the cardiac myocyte needs the inotropic support.
• ⁇ -adrenergic receptor antagonist is a compound which blocks, at least partially, an effect of the endogenous ⁇ -adrenergic receptor agonists (e.g., epinephrine and norepinephrine) .
• ⁇ -adrenergic receptor antagonists include adrenergic receptor antagonists that can bind to ⁇ -, as well as ⁇ - adrenergic receptors.
• the two ⁇ -adrenergic receptor subtypes, ⁇ ⁇ and ⁇ 2 are coupled by the stimulatory guanine nucleotide-binding protein (G s ) to the effector enzyme, adenylyl cyclase, on the cell surface membrane of myocardial cells. See Figure 1.
• G s stimulatory guanine nucleotide-binding protein
• adenylyl cyclase adenylyl cyclase
• the ⁇ G s -GTP complex is a powerful stimulus for the activation of adenylyl cyclase, which generates cAMP from adenosine triphosphate (ATP) .
• Cyclic AMP typically exerts its effect in a cell by activating cAMP-dependent protein kinase A
• PKA phosphorylates various target proteins, thereby regulating the activity of the target protein.
• Cyclic AMP exerts positive inotropic and chronotropic activity by increasing the flux of calcium through sarcolemmal slow Ca 2+ channels and increasing Ca 2+ uptake and release by the cytoplasmic reticulum.
• ⁇ ⁇ -adrenergic receptors are coupled through G 3 to slow Ca 2+ channel influx by cAMP-independent pathways. Activation of these pathways leads to an increase in myosin ATPase activity, resulting in increased heart pump performance. Unoccupied adrenergic receptors appear to possess a low level of intrinsic activity.
• a small percentage of the total adrenergic receptors on a celir exist, at a given time, in an active conformation that is in equilibrium with a more abundant, inactive conformation.
• Receptors in an active conformation initiate signal transduction even in the absence of agonists.
• agonists bind to the active conformation of the receptor, stabilizing it and shifting the equilibrium toward the active signaling conformation.
• Adrenergic receptor antagonists exert their effect through a variety of mechanisms. Some adrenergic receptor antagonists act as neutral antagonists. Neutral antagonists bind equally to the active and inactive conformations of a receptor. Neutral antagonists, therefore, have no effect on the intrinsic activity of an adrenergic receptor.
• adrenergic receptor antagonists are negative antagonists, also called inverse agonists. Inverse agonists inhibit the intrinsic activity of the adrenergic receptor, presumably by binding preferentially to the inactive conformation, shifting the equilibrium toward the receptor conformation that does not initiate signaling.
• adrenergic receptor antagonists exhibit a characteristic known as intrinsic sympathomimetic activity.
• Antagonists having intrinsic sympathomimetic activity are partial or weak agonists. They shift the adrenergic receptor moderately toward an active conformation, but their binding blocks the action of the more potent endogenous agonists.
• Many adrenergic receptor antagonists are known (see, e.g.. Heart Disease : A Textbook Of Cardiovascular
• adrenergic receptor antagonists can be identified by a variety of methods well known in the art. For instance, to determine if a compound is a ⁇ adrenergic receptor antagonist, competitive binding experiments with 125 I-iodocyanopindolol (ICYP), a compound which binds selectively to ⁇ adrenergic receptors, can be employed. Suitable conditions are described in Bristow et al . , Circulation, 84, 1024-1039
• Binding to ⁇ j or ⁇ 2 adrenergic receptors can be differentiated in a number of ways, such as competitive binding experiments using known ⁇ : - or ⁇ 2 -specific ligands or, preferably, using recombinant cells transformed to express only ⁇ ⁇ or ⁇ 2 adrenergic receptors (see, e.g., Tate et al., Eur. J. Biochem. , 196,
• Preferred ⁇ -adrenergic receptor antagonists for use in the present invention are those with no or low intrinsic sympathomimetic activity and, preferably, low inverse agonist activity.
• an adrenergic receptor antagonist having low inverse agonist activity has less than about 50% inverse agonist activity, preferably less than about 40% inverse agonist activity, and even more preferably less than about 30% inverse agonist activity.
• An adrenergic receptor antagonist having low intrinsic sympathomimetic activity has less than about 30% intrinsic sympathomimetic activity, more preferably less than about 20% intrinsic sympathomimetic activity, and even more preferably less than about 10% intrinsic sympathomimetic activity.
• Adrenergic receptor antagonists having low intrinsic sympathomimetic activity and low inverse agonist activity may be identified as described in co-pending application number 09/047,755, entitled “Method For Identifying Adrenergic Receptor Antagonists Having Good Tolerability, " filed March 25, 1998, claiming benefit of provisional application number 60/043,906, filed April 3, 1997, the complete disclosures of which are incorporated herein by reference. Briefly, the basal adrenergic receptor signaling activity is measured.
• the basal signaling activity is the level of measurable intrinsic signaling activity of unoccupied adrenergic receptors) or any defined level of receptor signaling activity, such as the level of activity which is achieved upon stimulation of a particular receptor (e.g., a ⁇ i-adrenergic receptor) with a specific amount of a known agonist.
• Adrenergic receptor signaling activity can be quantitated by measuring any cellular response initiated by adrenergic receptor signal transduction. For instance, the adenylyl cyclase activity associated with the adrenergic receptor, the heart contractility support provided by the adrenergic receptor, or the level of phosphorylation of protein kinase A associated with the adrenergic receptor can be measured.
• An adrenergic receptor antagonist having inverse agonist activity can be identified, for example, by its ability to decrease adenylyl cyclase activity compared to basal adenylyl cyclase activity, to inhibit heart contractility support by the adrenergic receptor compared to the basal level ⁇ " f heart contractility support, and/or to decrease the level of phosphorylation of protein kinase A associated with the adrenergic receptor compared to the basal level of phosphorylation of protein kinase A.
• An adrenergic receptor antagonist having intrinsic sympathomimetic activity can be identified, for example, by its ability to increase adenylyl cyclase activity compared to basal adenylyl cyclase activity, to increase heart contractility support provided by the adrenergic receptor compared to the basal level of heart contractility support, and/or to increase the level of phosphorylation of protein kinase A associated with the adrenergic receptor compared to the basal level of phosphorylation of protein kinase A.
• the basal adrenergic receptor signaling activity, the inverse agonist activity and the intrinsic sympathomimetic activity can all conveniently be measured in a single assay.
• adenylyl cyclase activity could be measured.
• An adrenergic receptor antagonist useful in the present invention would produce no more than about a 50% reduction, and less than about a 30% increase, in adenylyl cyclase activity compared to basal adenylyl cyclase activity.
• Adrenergic receptor antagonists having low intrinsic sympathomimetic activity and low inverse agonist activity produce limited adverse side effects in a patient to whom the adrenergic receptor antagonist is administered (i.e., the adrenergic receptor antagonist is well tolerated by the patient) . The less the inverse agonist activity and the less the intrinsic sympathomimetic activity, the greater the decrease in adverse side effects.
• Adverse side effects are undesirable effects or conditions which are directly or indirectly caused by the pharmacological activity of an adrenergic receptor antagonist. These adverse side effects can include bradycardia, myocardial depression, dyspnea, hypotension, congestive heart failure, worsening of asthma ⁇ worsening of chronic obstructive pulmonary disease, intermittent claudication, Raynaud' s phenomenon, mental depression, increased risk of hypoglycemia (among insulin- dependent diabetic patients), easy fatigability, disturbingly vivid dreams, insomnia, impaired sexual function, or fluid retention.
• a decrease in such adverse side effects can refer to a decrease in the number of different side effects experienced by a patient, to a decrease in the severity of a particular side effect experienced by a patient, or to a decrease in the occurrence of a particular side effect experienced by a patient.
• the ⁇ -adrenergic antagonist used in the method of the invention is metoprolol, carvedilol or bucindolol. Most preferably, the ⁇ -adrenergic antagonist is metoprolol.
• Effective dosage forms, modes of administration and dosage amounts of the ⁇ -adrenergic antagonist may be determined empirically, and making such determinations is within the skill of the art. It is understood by those skilled in the art that the dosage amount will vary with the activity of the particular agent employed, the severity of the heart failure, the route of administration, the rate of excretion, the duration of the treatment, the identity of any other drugs being administered to the patient, the age and size of the patient, and like factors well known in the medical art.
• Suitable modes of administration can include, but are not limited to, oral, nasal, topical, transdermal, rectal, and parenteral routes. Preferred parenteral routes include, but are not limited to, subcutaneous, intradermal, intravenous, intramuscular and intraperitoneal routes. Preferred is oral administration.
• ⁇ a low dose of the ⁇ -adrenergic antagonist is begun after the patient receiving the positive inotropic agent is hemodynamically and clinically stable.
• the amount of the ⁇ -adrenergic antagonist is gradually increased until an effective dose is achieved.
• An effective daily dose of the ⁇ -adrenergic antagonist will be that amount of the agent which is the lowest dose effective to produce a therapeutic effect and which maintains the hemodynamic and clinical stability of the patient.
• a suggested daily dosage of metoprolol is about 100 to 200 mg/day
• a suggested daily dosage of carvedilol is about 50 mg/day
• a suggested daily dosage of bucindolol is about 100 mg/day.
• the total daily dosage of these or other ⁇ -adrenergic antagonists will be determined by an attending physician within the scope of sound medical judgment.
• the effective daily dose may be administered as two, three, four, five, six or more sub-doses, administered separately at appropriate intervals throughout the day.
• the "low dose" for beginning administration of the ⁇ -adrenergic receptor will be about 5-10% of expected final effective dose.
• a suggested low dose of metoprolol is about 5-20 mg/day
• a suggested low dose of carvedilol is about 2.5-5.0 mg/day
• a suggested low dose of bucindolol is about 5-10 mg/day.
• Treatment with the combination of full effective doses of ⁇ -blocker and positive inotrope can be continued indefinitely.
• the dose of the positive inotropic agent is gradually reduced to the lowest possible dose that does not lessen the hemodynamic and clinical stability of the patient. If possible, the administration of the positive inotrope is discontinued altogether.
• An attempt to reduce the dose of the positive inotrope should not be begun until the patient is stable and, preferably, also exhibits improved myocardial function as assessed by an improved left ventricular ejection fraction.
• the positive inotrope and the ⁇ -adrenergic antagonist should be administered in combination for at least two months before attempting to reduce the dose of the positive inotrope.
• Withdrawal of the positive inotrope is preferably accomplished by decreasing the positive inotropic dose by 50% weekly until the subject is off the drug. If clinical deterioration occurs, which is common, the positive inotropic agent should be returned to the previous dose that was associated with clinical stability.
• Phase 1 Stabilization on an oral dose of a positive inotropic a ⁇ ent .
• Enoximone a positive inotropic agent
• a positive inotropic agent was administered orally, beginning at doses of 1.0- 2.0 mg/kg/day given in 3 or 4 divided doses (e.g. 0.25 mg/kg q.i.d.).
• the subject was withdrawn from i.v. inotropic support, if any.
• the i.v. inotrope was typically the ⁇ -adrenergic receptor agonist dobutamine.
• Phase 2 Adjustment of oral heart failure medication in an outpatient setting. For the next 2-6 " weeks oral heart failure medication including diuretics, ACE inhibitors, digoxin and enoximone were adjusted to optimal levels as the patient was progressively physically rehabilitated.
• Phase 3 Institution of oral ⁇ -adrenergic receptor antagonist ( ⁇ -blocker ⁇ therapy. Once the patient was stable, oral administration was begun at a low dose (6.25 mg/day) of the ⁇ -adrenergic receptor antagonist metoprolol given in addition to the enoximone. The metoprolol was then up-titrated to a standard effective dose (typically 100-200 mg/day in one, two or three doses per day) . Treatment with the combination of full doses of metoprolol and enoximone was continued for 2-4 months.
• ⁇ -adrenergic receptor antagonist ⁇ -blocker ⁇ therapy.
• Phase 4 Attempted withdrawal o_f thfi positive inotropic a ⁇ ent .
• LVEF improvement > 5 EF units an attempt was made to withdraw the enoximone and continue treatment with metoprolol alone. This was done by decreasing the enoximone dose by 50% weekly until the subject was off the drug. If clinical deterioration occurred, which was common, the enoximone was returned to the previous dose which was associated with clinical stability. The majority of subjects did better on the combination of enoximone and metoprolol, but approximately one-third were weaned from the enoximone.
• Phase 5 Long term treatment. Treatment with metoprolol alone or the combination of enoximone and metoprolol was continued indefinitely or until cardiac transplantation was possible.
• the average dose of enoximone used in these subjects was 189 ⁇ 13 mg/day, and the average dose of metroprolol was 113 ⁇ 9 mg/day.
• Clinical outcome The clinical outcome at the time of last follow-up (mean 20.9 ⁇ 3.9 months) for the 30 treated subjects is shown in Table 6.
• Rates for patients in the Packer et al. and Cowley et al. studies also improved. No rates were given for the other two studies.
• EXAMPLE 2 Treatment of Heart Failure with a
• Vesnarinone is another positive inotrope, but it has a different mechanism of action than enoximone. In addition to mild phosphodiesterates inhibition, vesnarinone also produces a decrease in potassium currents and increases intracellular sodium by prolonging the opening of sodium channels . See Feldman et al . , New Eng. J. Med.
• NYHA Class III-IV heart failure patients were treated with vesnarinone and metoprolol essentially as described in Example 1.
• Other NYHA Class III-IV heart failure patients from a clinical trial receiving placebo or vesnarinone alone (the VEST trial) were used as controls.
• the final doses were 60 mg/day placebo (VEST trial), 60 mg/day vesnarinone (VEST trial), and a combination of 60 mg/day vesnarinone and 100 mg/day metoprolol (this study) .

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