Treatment of ejection fraction retention heart failure with guanethidine and guanidinol

Abstract

The present invention relates to methods of treating a patient diagnosed with or having ejection fraction retention heart failure (HFpEF) by administering an effective amount of a peripherally acting antihypertensive agent that reduces excessive vein contraction, such as guanethidine, guanidinol, or a pharmaceutically acceptable salt thereof, alone or in combination with other agents.

Description

[0001] This application claims priority to U.S. Provisional Application No. 63 / 376,121, filed on September 19, 2022, which is hereby incorporated by reference. Technical Field

[0002] The present invention relates to methods of treating patients diagnosed with or suffering from heart failure with preserved ejection fraction (HFpEF) by administering an effective amount of guanethidine, guanadil, or a pharmaceutically acceptable salt thereof, alone or in combination with other agents. Background Art

[0003] Although age-adjusted mortality rates for coronary heart disease and hypertensive cardiovascular disease have gradually declined, the incidence and prevalence of heart failure are increasing and are expected to continue to rise into the 21st century (Tsao et al., Heart Disease and Stroke Statistics-2022 Update: A Report From the American Heart Association, Circulation 145(8): e153-e639, 2022). The incidence and prevalence of heart failure are significantly associated with age, with a prevalence of nearly 10% in adults over 80 years of age, and mortality rates increase exponentially with age in all major demographic subgroups of the U.S. population. Although several factors contribute to the rise in heart failure, the main one is the progressive aging of the population. The exponential increase in the prevalence of heart failure is attributed to the increasing prevalence and cumulative duration of systemic hypertension and coronary artery disease with age and age-related changes in cardiac structure and function, even in the absence of overt clinically defined cardiovascular disease (Lakatta et al., Circulation, 107(1):139-46, 2003; Lakatta et al., Circulation, 107(2):346-54). Consistent with the high prevalence and significant mortality associated with this condition, heart failure is currently the leading indication for cardiovascular hospitalization in adults over the age of 65 years. It is not only the most common diagnosis-related group in the Medicare population, but also the most expensive group, with estimated annual inpatient expenditures in the United States exceeding $40 billion (Tsao et al. 2022).

[0004] Although heart failure currently affects more than 7 million Americans, more than half have normal left ventricular systolic function, commonly referred to as HFpEF (e.g., heart failure with preserved ejection fraction). Heart failure in the United States causes more than 280,000 deaths, more than one million hospitalizations, 1.8 million office visits, and nearly 700,000 emergency room visits each year (Benjamin et al., Circulation, 2018, 137: e67-e492). HF hospitalizations account for more than 6.5 million hospital days and are a large portion of the billions of dollars spent on HF in the United States each year (Gheorghiade et al., J Am Coll Cardiol, 2013, 61: 391-403), which is expected to rise to $53.1 billion by 2030 (Ziaeian et al., Nat Rev Cardiol, 2016, 13: 368-78). There are an estimated 30 million individuals with HFpEF worldwide.

[0005] Heart failure with preserved ejection fraction is the most common form of heart failure and is a heterogeneous clinical syndrome that has proven difficult to treat. Heart failure is defined as the inability of the heart to pump blood to the body at a rate commensurate with its needs, or the ability to pump blood to the body only at the expense of high filling pressures. HFpEF is characterized by an abnormal increase in left ventricular filling pressures at rest or during exertion in the setting of preserved stroke volume to end-diastolic volume ratio (e.g., ejection fraction).

[0006] There remains a need for more effective treatments for HFpEF. Summary of the invention

[0007] The present invention relates to the use of peripherally acting antihypertensive agents to reduce excessive venous constriction in patients for the treatment of HFpEF. Such peripherally acting antihypertensive agents include guanethidine, guanadil, and pharmaceutically acceptable salts thereof. In one embodiment, these peripherally acting antihypertensive agents include those that reduce the release of catecholamines (such as norepinephrine), deplete peripheral catecholamines, reduce peripheral vascular resistance, or any combination of any of the foregoing.

[0008] One embodiment is a method of treating a patient diagnosed with or suffering from HFpEF, the method comprising administering to the patient an effective amount of guanethidine, guanadil, or a pharmaceutically acceptable salt thereof.

[0009] Another embodiment is a method of reducing the risk of cardiovascular hospitalization in a patient diagnosed with or suffering from HFpEF, the method comprising administering to the patient an effective amount of guanethidine, guanadil, or a pharmaceutically acceptable salt thereof.

[0010] Yet another embodiment is a method of enhancing exercise capacity or fitness, or both, in a patient with HFpEF, the method comprising administering to the patient an effective amount of guanethidine, guanadril, or a pharmaceutically acceptable salt thereof.

[0011] Yet another embodiment is a method of treating a patient diagnosed with or suffering from HFpEF, the method comprising administering to the patient an effective amount of (a) guanethidine, guanadrenaline, or a pharmaceutically acceptable salt thereof and (b) one or more second therapeutic agents selected from a diuretic (such as a thiazide diuretic or a loop diuretic), angiotensin converting enzyme (ACE) inhibitor, angiotensin receptor antagonist (alone or in combination with a neutral endopeptidase inhibitor), a mineralocorticoid antagonist (MRA), a calcium channel blocker, a beta blocker, a neprilysin inhibitor, angiotensin receptor-neprilysin inhibitor, angiotensin II receptor blocker (ARB), an aldosterone antagonist, a sodium-glucose cotransporter-2 (SGLT-2) inhibitor, or any combination of any of the foregoing.

[0012] Yet another embodiment is a method of reducing the risk of cardiovascular hospitalization in a patient diagnosed with or suffering from HFpEF, the method comprising administering to the patient an effective amount of (a) guanethidine, guanadrene, or a pharmaceutically acceptable salt thereof and (b) one or more second therapeutic agents selected from a diuretic (such as a thiazide diuretic or a loop diuretic), angiotensin converting enzyme (ACE) inhibitor, angiotensin receptor antagonist (alone or in combination with a neutral endopeptidase inhibitor), a mineralocorticoid antagonist (MRA), a calcium channel blocker, a beta blocker, a neprilysin inhibitor, angiotensin receptor-neprilysin inhibitor, angiotensin II receptor blocker (ARB), an aldosterone antagonist, a sodium-glucose cotransporter-2 (SGLT-2) inhibitor, or any combination of any of the foregoing.

[0013] Yet another embodiment is a method of enhancing exercise capacity or fitness, or both, in a patient with HFpEF, the method comprising administering to the patient an effective amount of (a) guanethidine or a pharmaceutically acceptable salt thereof and (b) one or more second therapeutic agents selected from a diuretic (such as a thiazide diuretic or a loop diuretic), an angiotensin converting enzyme (ACE) inhibitor, angiotensin receptor antagonist (alone or in combination with a neutral endopeptidase inhibitor), a mineralocorticoid antagonist (MRA), a calcium channel blocker, a beta blocker, a neprilysin inhibitor, angiotensin receptor-neprilysin inhibitor, angiotensin II receptor blocker, an aldosterone antagonist, a sodium-glucose cotransporter-2 (SGLT-2) inhibitor, or any combination of any of the foregoing.

[0014] The patient's exercise capacity can be assessed by measuring the patient's maximal exercise capacity or submaximal exercise capacity (e.g., 6-minute walk test (6MWT)). In one embodiment, patients with HFpEF have a subnormal or poor maximal exercise capacity. In another embodiment, patients with HFpEF have a subnormal or poor submaximal exercise capacity (e.g., as measured by 6MWT). Normal exercise capacity is the exercise capacity of an average healthy patient of similar age. In another embodiment, the patient's exercise capacity is assessed by measuring peak oxygen consumption or by the duration of a treadmill exercise test.

[0015] In one embodiment, the second therapeutic agent in the methods described herein is selected from a beta blocker, an ACE inhibitor, an angiotensin receptor blocker, a diuretic, an aldosterone antagonist, or any combination of any of the foregoing.

[0016] In one embodiment, the patient has been diagnosed with HFpEF prior to administration of guanethidine or a pharmaceutically acceptable salt thereof.

[0017] In another embodiment, the patient has HFpEF and has a LVEF greater than 40%, 45%, 50%, or 55%. For example, the patient may have a LVEF greater than 55%. In yet another embodiment, the patient has HFpEF and has a LVEF between 40% and 50% or between 40% and 55%.

[0018] In yet another embodiment, patients with HFpEF exhibit (i) an LVEF greater than 50% and (ii) evidence of spontaneous (at rest) or provocable (e.g., during exercise or fluid challenge) increased left ventricular filling pressures (e.g., elevated natriuretic peptides, non-invasive and / or invasive hemodynamic measurements).

[0019] Yet another embodiment is a pharmaceutical composition comprising (a) guanethidine, guanadol or a pharmaceutically acceptable salt thereof and (b) one or more second therapeutic agents selected from diuretics (such as thiazide diuretics or loop diuretics), angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor antagonists (alone or in combination with neutral endopeptidase inhibitors), mineralocorticoid antagonists (MRAs), calcium channel blockers, beta blockers, enkephalinase inhibitors, angiotensin receptor-enkephalinase inhibitors, angiotensin II receptor blockers, aldosterone antagonists, sodium-glucose cotransporter-2 (SGLT-2) inhibitors, or any combination of any of the foregoing. In any of the methods described herein, guanethidine, guanadol or a combination thereof with or without a second therapeutic agent can be administered in the form of a pharmaceutical composition described herein. The pharmaceutical composition can be in the form of an oral dosage form and can be administered orally. DETAILED DESCRIPTION

[0020] Subjects with HFpEF are characterized by elevated ventricular filling pressures at rest or during exercise in order to maintain cardiac output sufficient to meet the body's needs. Without being bound by any particular theory, the inventors speculate that a targetable explanation for the high filling pressures is an increase in stress volume mediated by structural changes in the veins and / or secondary to excessive venous constriction. Excessive venous constriction can be addressed by guanethidine or guanadol.

[0021] It is clear that extreme peripheral vascular abnormalities are an integral part of the syndrome of hypertension and heart failure. Zelis et al., Cardiovasc Dis. 1982, 24(6):437-59; Arnold et al., Circulation. 1991, 84(6):2418-25. Systemic vasoconstriction exists in part because of activation of the sympathetic nervous system and the renin angiotensin system. Francis et al., Circulation, 1990, 82(5):1724-9. Vasoconstriction has been demonstrated in both arteries and veins, although the main emphasis in the past few decades has been placed on the study of the arterial system.

[0022] Veins have an important, often overlooked, variable blood storage function. Based on data from non-human species, the large capacity of these vessels allows this low-pressure reservoir to contain more than 70% of the total body blood volume. Rothe, Physiol Rev. 1983, 63: 1281-1342. In normal subjects, more than half of the total blood volume is contained in the extrathoracic veins. The capacity of the extrathoracic veins is primarily controlled by the adrenergic nervous system. Aellig, Br J Clin Pharmacol, 1994, 38(4): 289-305. As a result, reflex changes in venous vasomotor tone provide a rapid-acting mechanism for compensatory redistribution of blood volume. For example, venous constriction serves to partially restore normal cardiac preload during assumption of the upright posture. In addition, Guyton (Banet and Guyton, Am J Physiol, 1971, 220: 662-666) has shown that an intact cardiovascular reflex mediated by venous vasoconstriction prevents the pooling of blood in the peripheral circulation, which is essential for the development of a total cardiac output response to metabolic increases. The increase in central blood volume from venous constriction and the concomitant decrease in peripheral venous capacity can lead to increased preload and provide an explanation for the higher filling pressures characteristic of heart failure or heart failure with preserved ejection fraction in the context of normal systolic function. Theoretical analysis (Burkhoff et al., Am J Physiol, 1993, 265(5 Pt. 2): H1819-28) suggests that the increase in pulmonary venous pressure that occurs in the context of acute pulmonary edema does not simply occur as a direct hemodynamic consequence of left ventricular systolic or diastolic dysfunction, but is more determined by sympathetic control of venous capacity.

[0023] Most patients with heart failure and normal systolic function are elderly. Physiological differences in venous capacity, venous tone, and possibly venous responses to sympathetic stimulation have been described with age and support a role for the venous system in the development of HFpEF. Elderly patients exhibit reduced limb venous compliance and capacity compared with younger subjects. Olsen et al., Am J Physiol. 1998; 275(3 Pt 2): H878-H886; Olsen et al., Am J Physiol. 2000; 278: H222-H232. Autonomic control of the cardiovascular system, regulated by α- and β-adrenergic receptors, changes with age. Although the density of β receptors does not appear to change with age, the response of the cardiovascular system to β adrenergic stimulation decreases significantly with age. Mechanisms include downregulation of β1 receptors and reduced agonist binding, uncoupling of β2 receptors, and altered signal transduction. O'Malley et al., J Hypertension, 1988;6(Suppl 1):S59-S62. In contrast, alpha 1 receptor-mediated contraction is maintained with age until at least the seventh decade of life. Klein et al., Clin Pharmacol Ther. 1990;47:535-539. For example, the ability of phenylephrine (an alpha 1-agonist) to increase blood pressure does not change with aging in human subjects. Shigemi et al., Am J Physiol. 1994;267:H210-H210. The combination of reduced vasodilatory beta-2 receptors and preserved contractile alpha 1 receptors can cause an increase in resting venous tone. This, combined with a decrease in peripheral venous capacity, will lead to an increase in capacity in the central compartment. One study showed an increase in venous tone in healthy elderly subjects. Gascho et al., Am J Cardiol. 1989;63:1267-1270.

[0024] In subjects with hypertension who did not report heart failure, effective compliance (a measure of the effect of blood volume on central venous pressure) was lower than in controls. Walsh et al., Cardiovasc Res 1969, 3:338. Since the arterial system is an insignificant contributor to effective compliance (Guyton et al., Am J Physiol 1959;5:1008-1014; Echt et al., Circ Res 1974;33:61), the compliance of the total circulation is primarily related to the properties of the venous side of the circulation. Therefore, reduced effective compliance in hypertensive patients indicates reduced venous distensibility, which may be a result of sympathetic stimulation. Indeed, the compensatory increase in preload caused by venous constriction in essential hypertension could explain why these patients have high cardiac output (Liu et al., 1993, Circulation, 88(4 Pt 1): 1893-906) and normalized effective arterial elasticity (as demonstrated by our data) despite very high arteriolar resistance (Maurer et al., J Am Coll Cardiol, 2007 Mar, 49(9): 972-81).

[0025] In summary, the venous system is not only an understudied and underappreciated regulator of cardiovascular function, but based on classic physiological principles, it may play an important mechanistic role in the development of the syndrome of heart failure with preserved ejection fraction (HFpEF). Without being bound by any particular theory, the inventors speculate that the reduction in peripheral venous capacity from sympathetic stimulation leads to an increase in central capacity and is one of the major pathophysiological mechanisms behind the morbidity associated with HFpEF.

[0026] Although studies have focused on abnormalities in left or right ventricular structure or function as the primary cause of high filling pressures, classical Guytonian physiology (Guyton et al., Annu Rev Physiol. 1972, 34: 13-46; Guyton et al., Clin Anesth. 1964, 3: 1-34) suggests that ventricular filling pressures are primarily determined by changes in loading conditions (preload greater than afterload) and less by cardiac chamber properties. In mammals, 70% of blood volume is stored in the venous system (Rothe, Physiol Rev. 1983, 63: 1281-1342), and the compliance of the venous system is approximately 30 times that of the arterial system (Gelman, Anesthesiology, 2008, 108 (4): 735-748). Simulations of the cardiovascular system (Burkhoff et al., Am J Physiology, 1993, 265(5Pt 2): H1819-28) and physiological experiments (Tyberg, Pflugers Arch. 2002, 445(1): 10-7; Tyberg et al., Adv Exp Med Biol. 1993, 346: 313-7) have demonstrated that changes in venous volume (Fudim et al., J Am Coll Cardiol. 2022, 10; 79(18): 1858-1869) by modulating the relationship between stressed and unstressed volumes are an important factor contributing to excessive increases in left ventricular filling pressures during exercise or during acute decompensation in patients with HFpEF. In further support of a role for venous abnormalities in the development of HFpEF, a condition that predominantly occurs in older adults, venous properties change dramatically with human aging, primarily due to changes in beta receptor density and sensitivity and a significant decrease in venous dialysis capacity (Pan et al., J Pharmacol Exp Ther. 1986, 239(3):802-7). Thus, an important and previously overlooked mechanism in HFpEF underlying the development of exercise intolerance and acute pulmonary edema, as well as less severe forms of acute decompensated heart failure leading to hospitalization, may be altered venous properties. Thus, while many mechanisms may contribute to the limitation of exercise and the ability to perform activities of daily living in HFpEF, there is growing evidence that the hemodynamic response to exercise is extremely abnormal, characterized by rapid and significant increases in right and left heart filling pressures that typically return to baseline values ​​during recovery (Bourlaug et al., Circ Heart Fail., 2010, 3(5):588-595). These rapid increases in filling pressures are probably mediated by a shift in blood volume from the major visceral beds into the central circulation caused by venous constriction.While device-based therapies to ablate the sympathetic control of the venous visceral bed are being evaluated as a therapy for HFpEF (see, e.g., Clinicaltrials.gov identifier: NCT04592445), there are currently no approved pharmacological therapies to address these venous abnormalities in HFpEF. Previous studies of nitrates have failed to show clinical benefit in patients with HFpEF (Redfield et al., N Engl J Med, 2015, 373(24):2314-24). However, nitrates have complex effects on both venous and arterial properties and the potential for rapid tolerance exists.

[0027] Guanethidine is a peripherally acting antihypertensive agent that reduces the release of catecholamines such as norepinephrine. Guanethidine is transported across sympathetic nerve membranes by the same mechanism that transports norepinephrine itself (NET, uptake 1), and uptake is essential for the drug's action. Once guanethidine enters the nerve, it concentrates in transmitter vesicles, where it replaces norepinephrine. It can also inhibit the release of granules by reducing norepinephrine. Guanethidine blocks normal sympathetic reflexes and lowers blood pressure by reducing venous return and cardiac output and attenuating the responsiveness of resistance and capacitance vessels to sympathetic stimulation (Woosley et al., N Eng J Med, 1976, 295: 1053-57). Without being bound by any particular theory, the inventors hypothesize that guanethidine is an effective therapy for patients with HFpEF by attenuating the sympathetic stimulation that causes venous constriction and drives blood volume distribution to the central circulation.

[0028] Guanethidine has the unique effect of targeting the peripheral sympathetic nervous system and relaxing the peripheral venous system. Its selective action is a result of the fact that the drug is a substrate for the pump that transports norepinephrine to nerve endings. Guanethidine is actively transported into neurons by this "norepinephrine pump"; inhibition of the norepinephrine pump also inhibits the uptake and action of guanethidine. Once in the adrenergic neuron, guanethidine binds to the norepinephrine storage vesicles and releases norepinephrine from the nerve endings. In addition to depleting norepinephrine, guanethidine also blocks the release of catecholamines that are normally produced by nerve stimulation.

[0029] Other peripherally acting antihypertensive agents that reduce excessive venous constriction in patients may be used in place of guanethidine or guanadrenaline. Such agents include agents that reduce the release of catecholamines (such as norepinephrine), agents that deplete peripheral catecholamines, agents that reduce peripheral vascular resistance, or any combination of any of the foregoing.

[0030] Unless otherwise stated or obvious from the context, as used herein, the term "or / or" should be understood to be inclusive.

[0031] As used herein, the terms "a", "an" and "the" shall be construed as meaning in the singular or plural, unless specifically stated or clear from the context.

[0032] Ranges provided herein should be understood as shorthand for all of the values ​​within the range.

[0033] Unless otherwise specified or apparent from the context, as used herein, the term "about" is understood to be within the normal tolerance range of the art, such as within 2 standard deviations of the mean. Approximately can be understood to be within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05% or 0.01% of the value. Unless otherwise clear from the context, all numerical values ​​provided herein can be modified by the term about.

[0034] The term "treat," in the context of administering a therapy to a patient, refers to the reduction or inhibition of the progression and / or duration of a disease or condition, the reduction or amelioration of the severity of the disease or condition, and / or the amelioration of one or more symptoms thereof resulting from the administration of one or more therapies.

[0035] The term "administer" includes, but is not limited to, oral administration, administration as a suppository, topical contact, intravenous, transdermal, parenteral, intraperitoneal, intramuscular, intralesional, intrathecal, intranasal, rectal, transdermal or subcutaneous administration, or implantation of a sustained release device (e.g., a miniature osmotic pump) to a subject. Administered by any route, these routes include parenteral and transmucosal (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal or transdermal). Parenteral administration includes, for example, intravenous, intramuscular, intraarteriole, intradermal, subcutaneous, intraperitoneal, intraventricular and intracranial. In an embodiment, administration does not include administration of any activating agent other than the listed activating agent. A preferred route of administration is an oral route.

[0036] The term "combination" refers to a collection of agents (e.g., active ingredients or drugs) for therapy delivered by simultaneous, concurrent or fixed-dose combination delivery. Simultaneous delivery refers to a mixture of drugs delivered (whether a true mixture, suspension, emulsion or other physical combination). In this case, the combination can be a mixture or a separate container of guanethidine (or its pharmaceutically acceptable salt) and a second agent combined immediately before delivery. Concurrent delivery refers to the simultaneous delivery of guanethidine (or its pharmaceutically acceptable salt) and a second agent, or a separate delivery at a sufficiently close time, so that the addition or preferably synergistic activity relative to the activity of a separate guanethidine (or its pharmaceutically acceptable salt) or cardiovascular drug is observed. Fixed-dose combination delivery refers to the delivery of two or more drugs contained in a single dosage form (such as a capsule or tablet) for oral administration.

[0037] "Effective amount" is an amount relative to the absence of the compound that is sufficient for the compound to achieve the purpose (e.g., to achieve the effect of administering the compound, to treat a disease, to reduce enzyme activity, to increase enzyme activity, to reduce a signal transduction pathway, or to alleviate one or more symptoms of a disease or condition). An example of an "effective amount" is an amount sufficient to help treat, prevent, delay, inhibit, stop or alleviate one or more symptoms of a disease or condition, which may also be referred to as a "therapeutically effective amount". "Relief" of one or more symptoms (and grammatical equivalents of the phrase) means a reduction in the severity or frequency of one or more symptoms, or the elimination of symptoms. An "effective amount" of a drug may be an amount of drug that, when administered to a subject, will have an expected preventive effect (e.g., to prevent or delay the onset (or recurrence) of damage, disease, pathology or condition, or to reduce the likelihood of onset (or recurrence) of damage, disease, pathology or condition, or to alleviate its symptoms). A complete preventive effect does not necessarily occur due to the administration of a single dose, but may only occur after a series of doses are administered. Therefore, a preventive effective amount may be administered once or multiple times. The exact amount depends on the purpose of the treatment and can be determined by those skilled in the art using known techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms (Volumes 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th edition, 2003, Gennaro ed., Lippincott, Williams & Wilkins). The dosage can vary depending on the needs of the patient and the compound used. In the context of the present disclosure, the dose administered to the patient should be sufficient to produce a beneficial therapeutic response in the patient over time. The size of the dose can also be determined based on the presence, nature, and extent of any adverse side effects. Determination of the appropriate dosage for a particular situation is within the skill of the practitioner.

[0038] As used herein, the terms "subject" and "patient" are used interchangeably and, unless otherwise indicated, refer to a human or mammal patient. Suitable mammals include, but are not limited to, livestock (such as cats and dogs), horses, sheep, goats, and pigs. In a preferred embodiment, the patient is a human patient. In one embodiment, the patient is at least 40 years old. In another embodiment, the patient is at least 50 years old. In yet another embodiment, the patient is at least 60 to 65 years old.

[0039] "HFpEF" or "heart failure with preserved ejection fraction (also called diastolic heart failure)" is typically diagnosed upon identification of heart failure and a preserved ejection fraction. The ejection fraction can be assessed by two-dimensional transthoracic echocardiography (TTE). HFpEF can be diagnosed based on the 2022 AHA / ACC / HFSA Guideline for the Management of Heart Failure (Circulation, 2022, 145(18): e895-e1032) (see Sections 2.2 and 2.3), which are hereby incorporated by reference in their entirety. Common symptoms of HFpEF include, but are not limited to, fatigue, weakness, dyspnea, orthopnea, paroxysmal nocturnal dyspnea, and edema. HFpEF may be characterized by a decrease in left ventricular compliance or, as we hypothesize, changes in loading conditions leading to increased pressure in the left ventricle. Increased left atrial size is often seen in HFpEF due to chronic or intermittent high left ventricular end-diastolic pressure and, therefore, high left atrial pressure. HFpEF corresponds to the diagnosis code I50.3 in the 2022 ICD-10-CM (ICD-10 Clinical Modification).

[0040] In one embodiment, a patient with HFpEF exhibits an LVEF greater than 40%. In another embodiment, a patient with HFpEF exhibits an LVEF of at least 45% (e.g., the patient exhibits an LVEF of at least 45% within 6 months of initiating treatment by the methods herein). In yet another embodiment, a patient with HFpEF exhibits an LVEF greater than 50%.

[0041] In another embodiment, patients with HFpEF exhibit (i) an LVEF greater than 50% and (ii) evidence of spontaneous (at rest) or provocable (e.g., during exercise or fluid challenge) increased left ventricular filling pressures (e.g., elevated natriuretic peptides, non-invasive and / or invasive hemodynamic measurements).

[0042] In yet another embodiment, patients with HFpEF exhibit (i) an LVEF greater than 50% and (ii) evidence of spontaneous (at rest) or provocable (e.g., during exercise or fluid challenge) increased left ventricular filling pressures (e.g., elevated natriuretic peptides, non-invasive and / or invasive hemodynamic measurements).

[0043] In one embodiment, the patient has HFpEF and exercise-induced left atrial hypertension (EILAH). In one embodiment, EILAH is defined as a pulmonary capillary wedge pressure (PCWP) of no more than 15 mm Hg measured supine at rest, but an exercise-induced PCWP of at least 25 mm Hg. In another embodiment, the patient has been diagnosed with HFpEF and EILAH.

[0044] In another embodiment, a patient with HFpEF exhibits (i) an LVEF of at least 45% (e.g., an LVEF of at least 45% within 6 months prior to initiation of treatment by the methods described herein), (ii) chronic heart failure, (iii) a PCWP of no more than 15 mmHg when measured supine at rest, but an exercise-induced PCWP of at least 25 mmHg. In one embodiment, the patient is over 40 years of age. Chronic heart failure can be defined as one or more of the following: (a) symptoms of heart failure requiring treatment with diuretics (intermittent or continuous) for at least 30 days, (b) a history of heart failure associated with the New York Heart Association (NYHA) or a history of heart failure associated with the New York Heart Association (NYHA). (c) at least one of the following: (i) at least one HF hospitalization (heart failure as primary or secondary) within 12 months of treatment initiation; (ii) at least one HF hospitalization (heart failure as primary or secondary) within 12 months of treatment initiation; (iii) at least one HF hospitalization (heart failure as primary or secondary) within 12 months of treatment initiation; (iv) at least one HF hospitalization (heart failure as primary or secondary) within 12 months of treatment initiation; (v) at least one HF hospitalization (heart failure as primary or secondary) within 12 months of treatment initiation; (vi) at least one HF hospitalization (heart failure as primary or secondary) within 12 months of treatment initiation; diagnosis), (ii) treatment with intravenous (IV) diuretics or augmentation of oral diuretics for heart failure within 12 months of initiation of treatment, (iii) N-terminal pro-B-type natriuretic peptide (NT-proBNP) value greater than 150 pg / ml in normal sinus rhythm and / or greater than 450 pg / ml in atrial fibrillation within the past 6 months, or (iv) B-type natriuretic peptide (BNP) value greater than 50 pg / ml in normal sinus rhythm and / or greater than 150 pg / ml in atrial fibrillation within the past 6 months.

[0045] In patients with HFpEF, there is an increased risk of congestive heart failure, atrial fibrillation, and pulmonary hypertension. Risk factors are high blood pressure, hyperlipidemia, diabetes, obesity, smoking, and obstructive sleep apnea. In this type of heart failure, the heart muscle contracts well, but the ventricles do not fill well with blood during the diastolic phase.

[0046] Guanethidine

[0047] Guanethidine has the chemical name guanidine, [2-(hexahydro-1(2H)-azocinyl)ethyl]-, and can be in the form of its sulfate salt, guanethidine sulfate or guanethidine monosulfate (CAS 645-43-2), which has the chemical name guanidine, [2-(hexahydro-1(2H)-azocinyl)ethyl]-, sulfate (1:1). Guanethidine has been sold under the trade name Ismelin (U.S. Food and Drug Administration New Drug Application No. 012329). Pharmaceutically acceptable salts of guanethidine include, but are not limited to, guanethidine sulfate.

[0048] Guanethidine or a pharmaceutically acceptable salt thereof can be administered in a dosage form containing one or more pharmaceutically acceptable excipients, such as an oral dosage form (e.g., tablets, capsules, granules, or oral liquids). Guanethidine or a pharmaceutically acceptable salt thereof can be administered once a day, twice a day, or more frequently. In a preferred embodiment, guanethidine or a pharmaceutically acceptable salt thereof is administered once a day, such as in an immediate release or sustained release oral dosage form. Preferably, guanethidine or a pharmaceutically acceptable salt thereof is administered orally.

[0049] The total daily dose of guanethidine or its pharmaceutically acceptable salt can be about 0.5mg or 1mg to about 100mg scope (based on guanethidine free alkali). In one embodiment, the total daily dose of guanethidine or its pharmaceutically acceptable salt can be about 25mg to about 50mg or about 50mg to about 100mg scope. In a preferred embodiment, the total daily dose of guanethidine or its pharmaceutically acceptable salt is about 0.5mg, 2mg or 5mg to about 25mg scope. In one embodiment, about 1mg, 2mg, 3mg, 4mg, 5mg, 7.5mg or 10mg of guanethidine or its pharmaceutically acceptable salt (based on guanethidine free alkali) is applied every day. In another embodiment, about 5mg, 6mg, 7mg, 8mg, 9mg, 10mg, 11mg, 12mg, 13mg, 14mg, 15mg, 16mg, 17mg, 18mg, 19mg or 20mg of guanethidine or its pharmaceutically acceptable salt (based on guanethidine free alkali) is applied every day. In yet another embodiment, about 0.5 mg, 1 mg, 2.5 mg, 5 mg, 10 mg or 25 mg of guanethidine or a pharmaceutically acceptable salt thereof (based on guanethidine free base) is administered daily. In another embodiment, about 1 mg to about 3 mg (e.g., 1 mg, 2 mg or 3 mg) of guanethidine or a pharmaceutically acceptable salt thereof (based on guanethidine free base) is administered daily. For example, the total daily dose of guanethidine or a pharmaceutically acceptable salt thereof can be 10 mg (based on guanethidine free base). In addition, in a preferred embodiment, guanethidine or a pharmaceutically acceptable salt thereof is administered once a day.

[0050] In one embodiment, 10 mg of guanethidine is orally administered to the patient once daily.

[0051] Guanethidine therapy can be initiated without a loading dose.

[0052] Guanadre

[0053] Guanadil's chemical name is 2-(1,4-dioxaspiro[4.5]dec-2-ylmethyl)guanidine, and it is also available in the form of a sulfate salt, which is 2-(1,4-dioxaspiro[4.5]dec-3-ylmethyl)guanidine sulfate. Guanadil has been sold under the trade name Hylorel (FDA New Drug Application No. 018104). Pharmaceutically acceptable salts of guanadil include, but are not limited to, guanadil sulfate. Guanadil and its pharmaceutically acceptable salts can be prepared as described in U.S. Pat. No. 3,547,951.

[0054] Guanadil or a pharmaceutically acceptable salt thereof can be administered in a dosage form containing one or more pharmaceutically acceptable excipients, such as an oral dosage form (e.g., tablets, capsules, granules, or oral liquids). Guanadil or a pharmaceutically acceptable salt thereof can be administered once a day, twice a day, or more frequently. In a preferred embodiment, guanadil or a pharmaceutically acceptable salt thereof is administered once a day, such as in an immediate release dosage form. Preferably, guanadil or a pharmaceutically acceptable salt thereof is administered orally.

[0055] The total daily dose of guanadil or its pharmaceutically acceptable salt may range from about 1 mg to about 100 mg (based on guanadil free base) and preferably from about 10 mg to about 75 mg or from about 20 mg to about 75 mg. Preferably, guanadil or its pharmaceutically acceptable salt is orally administered once a day.

[0056] Guanadol therapy can be initiated without a loading dose.

[0057] Other medicines

[0058] Patients may be treated with a combination (e.g., a fixed dose combination) of guanethidine or guanadrenolide (or a pharmaceutically acceptable salt thereof) and another cardiovascular agent. Suitable cardiovascular agents that may be administered with guanethidine (or a pharmaceutically acceptable salt thereof) include, but are not limited to, diuretics (such as thiazide diuretics or loop diuretics), angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor antagonists (alone or in combination with neutral endopeptidase inhibitors), mineralocorticoid antagonists (MRAs), calcium channel blockers, beta blockers (beta adrenergic receptor blockers), enkephalinase inhibitors, angiotensin receptor-enkephalinase inhibitors (ARNIs) (e.g., a combination of sacubitril and valsartan, such as ), angiotensin II receptor blockers (ARBs), aldosterone antagonists, sodium-glucose cotransporter-2 (SGLT-2) inhibitors, and any combination of any of the foregoing. In a preferred embodiment, the cardiovascular agent is selected from beta blockers, ACE inhibitors, ARBs, diuretics, aldosterone antagonists, and any combination of any of the foregoing.

[0059] Suitable thiazide diuretics for use in the methods and compositions described herein include chlorothiazide, hydrochlorothiazide, chlorthalidone, indapamide, and metolazone.

[0060] Suitable loop diuretics for use in the methods and compositions described herein include furosemide, torsemide, bumetanide, and ethacrynic acid.

[0061] Suitable ACE inhibitors for use in the methods and compositions described herein include benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, perindopril, quinapril, ramipril, and trandolapril.

[0062] Suitable MRAs for use in the methods and compositions described herein include spironolactone and eplerenone.

[0063] Suitable calcium channel blockers for use in the methods and compositions described herein include amlodipine, aranidipine, azelnidipine, barnidipine, benidipine, cilnidipine, clevidipine, efonidipine, felodipine, isradipine, lacidipine, lercanidipine, manidipine, nicardipine, nifedipine, nilvadipine, nimodipine, nisoldipine, nitrendipine and pranidipine.

[0064] Suitable beta blockers for use in the methods and compositions described herein include epinephrine, cebulol, atenolol, betaxolol, bisoprolol, carteolol, carvedilol, esmolol, labetalol, metoprolol, nadolol, oxprenolol, penbutolol, pindolol, propranolol, sotalol, and timolol.

[0065] Suitable neprilysin inhibitors for use in the methods and compositions described herein include thiophene, candoxatril, and candoxatrilat.

[0066] Suitable ARNIs for use in the methods and compositions described herein include combinations of sacubitril and valsartan, such as

[0067] Suitable angiotensin II receptor blockers (ARBs) for use in the methods and compositions described herein include eprosartan, olmesartan, valsartan, telmisartan, losartan, azilsartan medoxomil, candesartan, and irbesartan.

[0068] Suitable sodium-glucose co-transporter-2 (SGLT-2) inhibitors for use in the methods and compositions described herein include apagliflozin, bepagliflozin, canagliflozin, dapagliflozin, empagliflozin, erpagliflozin, hengagliflozin, ipagliptin, rupagliflozin, repagliflozin, soglipflozin, and togliflozin.

[0069] In one embodiment, the patient is treated with a combination (e.g., a fixed dose combination) of guanethidine or guanadrenolide (or a pharmaceutically acceptable salt thereof) and one or more of a diuretic, an MRA, an ACE inhibitor, an ARB, an ARNI, and an SGLT-2 inhibitor.

[0070] The recommended starting dose and schedule is 49 mg / 51 mg (49 mg sacubitril and 51 mg valsartan) taken orally twice a day. The dose is doubled to a target maintenance dose of 97 mg / 103 mg after two to four weeks, twice a day. Sacubitril / valsartan compositions are described in U.S. Patent Nos. 7,468,390, 8,101,659, 8,404,744, 8,796,331, 8,877,938, and 9,388,134, the entire contents of which are incorporated by reference. Preferably, sacubitril / valsartan is administered with an ARB.

[0071] The recommended dosage and schedule of hydralazine is 10 mg orally 4 times a day for the first 2 to 4 days, increasing to 25 mg orally 4 times a day for the remainder of the first week. For week 2 and subsequent weeks, the dose is increased to 50 mg orally 4 times a day. The hydralazine compositions described above are described in U.S. Pat. Nos. 6,465,463 and 6,784,177, the entire contents of which are incorporated by reference.

[0072] Each drug may be administered at the dosage and schedule as described above.

[0073] Pharmaceutical composition

[0074] Yet another embodiment is a pharmaceutical composition comprising (a) guanethidine, guanadrenaline, or a pharmaceutically acceptable salt thereof and (b) one or more second therapeutic agents selected from a diuretic (such as a thiazide diuretic or a loop diuretic), angiotensin converting enzyme (ACE) inhibitor, angiotensin receptor antagonist (alone or in combination with a neutral endopeptidase inhibitor), a mineralocorticoid antagonist (MRA), a calcium channel blocker, a beta blocker, a neprilysin inhibitor, angiotensin receptor-neprilysin inhibitor, angiotensin II receptor blocker, an aldosterone antagonist, a sodium-glucose cotransporter-2 (SGLT-2) inhibitor, or any combination of any of the foregoing.

[0075] One embodiment is a pharmaceutical composition comprising (a) guanethidine or a pharmaceutically acceptable salt thereof and (b) one or more second therapeutic agents selected from diuretics (such as thiazide diuretics or loop diuretics), angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor antagonists (alone or in combination with neutral endopeptidase inhibitors), mineralocorticoid antagonists (MRA), calcium channel blockers, beta blockers, enkephalinase inhibitors, angiotensin receptor-enkephalinase inhibitors, angiotensin II receptor blockers, aldosterone antagonists, sodium-glucose cotransporter-2 (SGLT-2) inhibitors, or any combination of any of the foregoing. For example, the second therapeutic agent can be a diuretic, an MRA, an ACE inhibitor, an ARB, an ARNI, an SGLT-2 inhibitor, or any combination of any of the foregoing.

[0076] The pharmaceutical composition may be in an oral dosage form, such as a tablet or solution. The pharmaceutical composition may be administered according to the methods described herein.

[0077] The following examples are provided in order to more fully illustrate some embodiments of the present invention. However, they should in no way be construed as limiting the broad scope of the present invention.

[0078] Foreseen embodiments

[0079] Clinical trials evaluating the safety and efficacy of guanethidine or guanadrenolide will enroll patients with HFpEF and reduced exercise capacity as demonstrated by treadmill testing, cardiopulmonary exercise testing, or submaximal testing with a six-minute hall walk duration, or patients with reduced health status. A more careful phenotyping of the subjects may involve exercise hemodynamic studies demonstrating a significant rise in pulmonary capillary wedge pressure during exercise. Such subjects may then be randomly assigned an active agent (e.g., guanethidine (e.g., guanethidine sulfate) or guanadrenolide (e.g., guanadrenolide sulfate)) or a matching placebo. Repeating the testing after several weeks of therapy can assess the effects of guanethidine or guanadrenolide on central hemodynamics, maximal or submaximal exercise capacity, or health status.

[0080] All patent and non-patent documents cited herein are incorporated by reference in their entirety.

Claims

1. A method for treating a patient diagnosed with heart failure with preserved ejection fraction (HFpEF), the method comprising administering to the patient an effective amount of guanethidine, guanadil, or a pharmaceutically acceptable salt thereof.

2. A method for reducing the risk of cardiovascular hospitalization in a patient diagnosed with heart failure with preserved ejection fraction (HFpEF), the method comprising administering to the patient an effective amount of guanethidine, guanadil, or a pharmaceutically acceptable salt thereof.

3. A method of enhancing exercise capacity, health status, or both in a patient diagnosed with heart failure with preserved ejection fraction (HFpEF), the method comprising administering to the patient an effective amount of guanethidine, guanadril, or a pharmaceutically acceptable salt thereof.

4. A method of treating a patient diagnosed with heart failure with preserved ejection fraction (HFpEF), the method comprising administering to the patient an effective amount of (a) guanethidine, guanadrenolide, or a pharmaceutically acceptable salt thereof and (b) one or more second therapeutic agents selected from a diuretic, angiotensin converting enzyme (ACE) inhibitor, angiotensin receptor antagonist, a mineralocorticoid antagonist (MRA), a calcium channel blocker, a beta blocker, a neprilysin inhibitor, angiotensin receptor-neprilysin inhibitor, angiotensin II receptor blocker, an aldosterone antagonist, a sodium-glucose cotransporter-2 (SGLT-2) inhibitor, or any combination of any of the foregoing.

5. A method of reducing the risk of cardiovascular hospitalization in a patient diagnosed with heart failure with preserved ejection fraction (HFpEF), the method comprising administering to the patient an effective amount of (a) guanethidine, guanadrenolide, or a pharmaceutically acceptable salt thereof and (b) one or more second therapeutic agents selected from a diuretic, angiotensin converting enzyme (ACE) inhibitor, angiotensin receptor antagonist, a mineralocorticoid antagonist (MRA), a calcium channel blocker, a beta blocker, a neprilysin inhibitor, angiotensin receptor-neprilysin inhibitor, angiotensin II receptor blocker (ARB), an aldosterone antagonist, a sodium-glucose cotransporter-2 (SGLT-2) inhibitor, or any combination of any of the foregoing.

6. A method of enhancing exercise capacity, health status, or both in a patient diagnosed with heart failure with preserved ejection fraction (HFpEF), the method comprising administering to the patient an effective amount of (a) guanethidine, guanadrenolide, or a pharmaceutically acceptable salt thereof and (b) one or more second therapeutic agents selected from a diuretic, angiotensin converting enzyme (ACE) inhibitor, angiotensin receptor antagonist, a mineralocorticoid antagonist (MRA), a calcium channel blocker, a beta blocker, a neprilysin inhibitor, angiotensin receptor-neprilysin inhibitor, angiotensin II receptor blocker (ARB), an aldosterone antagonist, a sodium-glucose cotransporter-2 (SGLT-2) inhibitor, or any combination of any of the foregoing.

7. The method of any one of claims 4-6, wherein the second therapeutic agent is selected from a beta blocker, an ACE inhibitor, an angiotensin receptor blocker, a diuretic, an aldosterone antagonist, an SGLT-2 inhibitor, or any combination of any of the foregoing.

8. The method of any one of the preceding claims, wherein the patient has been diagnosed with HFpEF prior to administration of the guanethidine, guanadrenolide, or a pharmaceutically acceptable salt thereof.

9. The method of any of the preceding claims, wherein the patient has been diagnosed with HFpEF and has a LVEF greater than 45%.

10. The method of any of the preceding claims, wherein the patient has been diagnosed with HFpEF and has a LVEF greater than 50%.

11. The method of any of the preceding claims, wherein the patient has been diagnosed with HFpEF and exercise-induced left atrial hypertension.

12. The method of any one of the preceding claims, wherein the method comprises orally administering from about 0.5 mg to about 100 mg of guanethidine or a pharmaceutically acceptable salt thereof (based on guanethidine free base).

13. The method of any one of the preceding claims, wherein the method comprises oral administration of about 0.5 mg to about 25 mg of guanethidine or a pharmaceutically acceptable salt thereof (based on guanethidine free base) per day.

14. The method of any one of the preceding claims, wherein the method comprises oral administration of about 0.5 mg to about 10 mg of guanethidine or a pharmaceutically acceptable salt thereof (based on guanethidine free base) per day.

15. The method of any one of the preceding claims, wherein the method comprises oral administration of about 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 7.5 mg or 10 mg of guanethidine or a pharmaceutically acceptable salt thereof (based on guanethidine free base) per day.

16. The method of any one of the preceding claims, wherein the method comprises oral administration of about 0.5 mg, 1 mg, 2.5 mg, 5 mg, 10 mg or 25 mg of guanethidine or a pharmaceutically acceptable salt thereof (based on guanethidine free base) per day.

17. The method of any one of the preceding claims, wherein the method comprises orally administering about 10 mg of guanethidine or a pharmaceutically acceptable salt thereof (based on guanethidine free base).

18. The method of any one of the preceding claims, wherein the method comprises administering guanethidine free base.

19. The method of any one of claims 1-18, wherein the method comprises administering guanethidine sulfate.

20. The method of any one of claims 1-11, wherein the method comprises oral administration of guanadol or a pharmaceutically acceptable salt thereof.

21. The method of any one of claims 1-11 and 20, wherein the method comprises administering guanadil sulfate.

22. A method of treating a patient diagnosed with heart failure with preserved ejection fraction (HFpEF), the method comprising administering to the patient an effective amount of a peripherally acting antihypertensive agent that reduces excessive venous constriction in the patient.

23. The method of claim 22, wherein the peripherally acting antihypertensive agent reduces the release of catecholamines, depletes peripheral catecholamines, reduces vascular resistance, or any combination of any of the foregoing.

24. A pharmaceutical composition comprising (a) guanethidine, guanadrenolide or a pharmaceutically acceptable salt thereof and (b) one or more second therapeutic agents selected from diuretics, angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor antagonists, mineralocorticoid antagonists (MRA), calcium channel blockers, beta blockers, enkephalinase inhibitors, angiotensin receptor-enkephalinase inhibitors, angiotensin II receptor blockers, aldosterone antagonists, sodium-glucose cotransporter-2 (SGLT-2) inhibitors, and any combination of any of the foregoing.