Methods of improving exercise performance, single ventricular performance, and myocardial performance index (MPI) in single ventricle heart disease, using udenafil compositions

Abstract

To provide a method for treating a patient who has undergone Fontan surgery (Fontan patient) or a patient with single ventricle heart disease (SVHD) having a functional single ventricle, in order to improve exercise capacity of the patient.SOLUTION: A method comprising administering daily an effective amount of udenafil, which is a PDE5 inhibitor, or a pharmaceutically acceptable salt thereof to a Fontan patient or to a patient with single ventricle heart disease (SVHD) having a functional single ventricle, to improve exercise capacity of the Fontan patient or the SVHD patient by increasing oxygen consumption at ventilatory anaerobic threshold (VAT).SELECTED DRAWING: Figure 1A

Description

[Technical Field]

[0001] Government Interest Statement This study was supported, at least in part, by funding from the National Heart, Lung, and Blood Institute (NHLB) of the National Institutes of Health. Funding was provided by a grant from the New England Research Institute. New England Research Institute utes, Inc.) under NHLBI grant U24 HL135691 and / or or U01 HL068270. Pediatric Heart Network (Pedia tric Heart Network) Clinical Site Grant (UG1 HL13568 5, UG1 HL135680, UG1 HL135683, UG1 HL135689 , UG1 HL135682, UG1 HL135665, UG1 HL135646, The Government has granted all rights to the invention disclosed herein. You may have certain rights in your data and inventions.

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS This application is a continuation of U.S. Provisional Patent Application No. 62 / 905,350, filed September 24, 2019. No. 62 / 936,497, filed November 16, 2019; and and U.S. Provisional Patent Application No. 63,023,070, filed May 11, 2020. The above provisional application is incorporated herein by reference in its entirety. It shall be possible.

[0003] Udenafil compositions are used to treat patients with single ventricle heart disease (SVHD), including those after the Fontan procedure. To improve exercise capacity, single ventricle performance, and myocardial performance index (MPI) in patients provide. [Background technology]

[0004] The heart is a muscular organ that pumps blood through the blood vessels of the circulatory system. In humans, the heart The left heart is located between the lungs and the chest, and is divided into a left and a right heart. It has four chambers: the atrium and left ventricle on the left side, and the right atrium and right ventricle on the right side. The blood with less oxygen ("blue blood") enters the right side through the right atrium and is filled with fresh oxygen. Blood ("red blood") exits the left side through the left ventricle. The heart has three valves: the tricuspid valve, the pulmonary valve, and the mitral valve. The heart has four valves: the mitral valve, the aortic valve, and the pulmonary valve. These valves prevent the backflow of blood within the heart. prevents blood from flowing forward to the lungs and body.

[0005] The human heart beats (expands and contracts) approximately 100,000 times per day, at 5-6 quarks per minute. It is the heart's main pumping chamber and pumps 1000 gallons of blood, or about 2,000 gallons per day. The left ventricle pumps fresh, oxygenated blood (red blood) through the aortic valve to the body. This blood then circulates through arteries and arterioles to all parts of the body, providing oxygen and As blood circulates, it carries oxygen and nutrients with it, along with carbon dioxide and In this process, blood changes from oxygen-rich blood (red blood) to This oxygen-poor blood then becomes oxygen-poor blood (blue blood). The blue blood flows through each vein and returns to the right atrium. This blue blood flows from the right atrium through the tricuspid valve to the right Passes into the ventricle and is then pumped by the right ventricle to the lungs to exchange carbon dioxide for oxygen This new, fresh, oxygenated blood (red blood) returns from the lungs to the left atrium via the pulmonary veins. This blood passes from the left atrium to the left ventricle through the mitral valve before being sent to the body. is released and begins a new cycle.

[0006] Thus, the normal human cardiovascular system consists of the pulmonary circulation and the systemic circulation connected in series, with the right It is driven by the pumping action of the left and right ventricles. Gewillig M.:Congen ital heart disease.The FONTAN CIRCULATIO N. Heart, 91:839-846 (2005).

[0007] Single ventricle heart disease (SVHD) is the presence of only one functioning ventricle (pumping chamber). It is a rare pediatric disorder that encompasses a group of cardiac malformations, each of which results in a different form of the normal heart. Unlike babies born with a normal heart (four chambers, two ventricles), babies with SVHD have a functional They are born with only one ventricle (one pumping chamber), i.e., a single-ventricle heart. A non-functioning or missing ventricle (pumping chamber) is too weak to function properly. The single ventricle may be smaller than the normal ventricle, may be absent altogether, or may not properly move blood through the circulation. They may be configured to prevent the blood from contributing to the flow at all times. These include hypoplastic left heart syndrome, tricuspid atresia, and bilateral atrioventricular valve left ventricular insertion.

[0008] Typically, newborns with SVHD have a high blood density, with oxygen-poor blood (blue blood) and oxygen-rich blood ( The mixture of red blood and cyanotic blue blood is mixed in a single ventricle. The oxygen content of the blood mixture leaving the heart varies depending on the type and severity of SVHD heart defect. It is highly dependent on severity and location. Some newborns with SVHD have mild cyanosis. However, in others, cyanosis becomes severe and the body needs oxygen early to survive. Unfortunately, without surgical intervention, newborns born with SVHD Most live births do not survive.

[0009] SVHD can be considered to have two main subtypes. In this condition, the left ventricle and aorta (the main artery leading to the body) are underdeveloped, and the heart cannot function without intervention. In the second subtype, the right ventricle and pulmonary artery ( The aorta (the main artery leading to the lungs) is underdeveloped, and the heart cannot pump blood to the lungs.

[0010] In the first subtype, infants born with an underdeveloped left ventricle and aorta, Urgent intervention is required within the first few days or weeks of life to stabilize blood flow to the The procedure is called the Norwood procedure (see Figure 5), and involves the use of a patch of material along with the pulmonary valve and pulmonary artery. The Norwood procedure involves the reconstruction of the aorta (the main artery that supplies blood to the body). Since the pulmonary artery is used for this purpose, it is necessary to include the path by which blood gets to the lungs. This is accomplished by including a "shunt" of blood from the aortic circulation to the pulmonary circulation. This shunt usually runs between the right subclavian artery (which supplies blood to the right arm) and the right pulmonary artery. The Norwood procedure is a tubular graft placed in the anterior vein of the rectum, allowing newborns to survive infancy. This temporary measure is designed to reduce the risk of heart failure, but is not a permanent solution. This puts the two pumping chambers under stress, forcing them to pump blood both to the body and to the lungs. To relieve this stress, two additional surgeries will be performed. The first of these is , Glenn anastomosis or hemi-Fontan procedure (see Figure 6), performed at 4 to 6 months. This involves directly connecting the superior vena cava (the large vein in the upper body) to the pulmonary artery. This allows blue blood from the upper body to return to the lungs and become oxygenated without the need for a ventricular pump. The final surgical procedure is the Fontan procedure (see Figure 1A and Figure 7). , usually performed between 18 and 48 months of age, involves directly connecting the inferior vena cava (the large vein in the lower body) to the pulmonary artery This involves pumping blue blood from the lower body to the ventricles, specifically to the lungs. The fluid returns to the lungs and fills with oxygen without the need for pumping. After surgery, all the blue blood returns to the lungs, and all the red blood returns from the lungs to the heart. ventricles dedicated to pumping blood through the lungs to the heart, as in a normal four-chamber heart This is achieved without the aid of a pump.

[0011] In the second subtype, infants born with an underdeveloped right ventricle and pulmonary arteries, Acute neonatal intervention is often unnecessary. This group of infants may have too little blood flow to the lungs. Is there too much blood flow to the lungs, or enough blood to allow growth and development? It requires close monitoring to determine if there is too little blood flow to the lungs. If a shunt is placed, as is done as part of the Norwood procedure, If there is too much blood flow to the lungs, the blood flow to the lungs must be reduced to avoid the onset of congestive heart failure. A restrictor may be placed around the pulmonary artery to reduce flow. Infants born with an underdeveloped right ventricle and pulmonary arteries may require surgical intervention if adequate blood flow is not available. Some babies survive the first few months of life without the need for a replacement. Whether or not adequate cardiac support is available, infants born with this type of SVHD may experience increased cardiac stress. To reduce the risk of infection and separate blue and red blood, a Glenn anastomosis was performed at 4-6 months of age. Those still requiring surgery or hemi-Fontan surgery and Fontan surgery at 18-48 months of age do.

[0012] After the Fontan procedure, the subtype of single ventricle heart disease becomes less important because In all patients, (i) passive blood flow bypasses the heart and goes directly to the lungs from the superior and inferior vena cava; and (ii) a single ventricle pumping blood to the body. Over the past 40 to 50 years, this "Fontan circulation" "Contan circulation" has enabled thousands of patients to survive. However, this is far from normal. The ventricles pump blood through the lungs and back to the heart. Due to the absence of a pump, the Fontan circulation relies on the body's veins to accomplish this task. This greatly increases the "blood pressure" in the veins and It also causes a restriction in the amount of blood that can circulate through the body in a given time, known as reduced cardiac output.

[0013] In the long term, the combination of increased intravenous pressure and decreased cardiac output can lead to a series of long-term complications. Complications become predictable and ultimately result in significantly reduced survival. Complications related to the urinary circulation include damage to the kidneys and liver, lungs, and gastrointestinal tract. Lymphatic overload leading to protein loss, bleeding and blood clotting, including risk of stroke These include damage to the heart, as well as progressive impairment of the heart's own pumping ability.

[0014] The ability to perform exercise is used as a marker of circulatory health in many forms of heart disease. In patients with Fontan circulation, exercise is also an important indicator of health and prognosis. Exercise capacity is a significant predictor of Fontan circulation in childhood. is often maintained but typically begins to decline during adolescence and early adulthood This deterioration correlates with increased prevalence of heart failure symptoms, hospitalization, and mortality, and is often These may be due to complications of the Fontan circulation itself. Transplantation may remain a treatment option, but heart transplantation carries its own set of complications. At risk, Fontan patients are at risk for chronic and progressive dysfunction of many organ systems. The disorder often makes them poor candidates for heart transplants.

[0015] Despite the long-standing existence of this very serious congenital heart defect, to this day, it remains a staple in the American diet. Neither the Food and Drug Administration (FDA) nor any other equivalent agency worldwide has any regulatory authority, including for Fontan patients. No medical therapy is approved to treat patients with SVHD, including those with Fontan surgery. Extending the lifespan of SVHD patients, including those with heart failure, and preventing disease progression and the need for heart transplants associated with SVHD and Fontan circulation complications, with the aim of avoiding or delaying There is a real need for novel drug therapies for SVHD patients, including those after the Fontan procedure. There is demand for it.

[0016] Also, (i) improved myocardial performance index ("MPI"), (ii) improved single ventricle performance, i) Ventilatory anaerobic threshold hold) (VAT) and / or maximal aerobic capacity (VO2 max or VO2 max) (iv) improvement in exercise tolerance during VAT; (v) improvement in diacid tolerance during VAT; (vi) improvement of univentricular function; New drug therapies for SVHD patients, including those after the Fontan procedure, are also truly needed to improve outcomes. It is essential and in demand. Summary of the Invention

[0017] The present invention aims to develop a novel method for treating SVHD patients, including those after the Fontan procedure. The above-mentioned shortcomings and disadvantages associated with the current treatment of SVHD patients, including those after the Fontan procedure, It overcomes the points.

[0018] Generally, the methods of the invention provide a method for treating SVHD patients, including post-Fontan patients, comprising: The present invention is directed to the use of udenafil or a pharmaceutically acceptable salt thereof. The method involves administering an effective amount of udenafil or its derivatives to patients with SVHD, including those after the Fontan procedure. The administration, preferably daily, of a pharmaceutically acceptable salt of and improving exercise tolerance or performance.

[0019] Generally, the methods of the present invention involve administering an effective amount of udenafil or a pharmaceutically acceptable salt thereof to a subject Daily administration to SVHD patients, including those undergoing Fontane surgery, (a) Ventricular performance of functional single ventricle in patients with SVHD assessed by MPI; (b) exercise tolerance assessed by oxygen consumption during VAT; (c) Exercise tolerance assessed by oxygen consumption at submaximal exercise or VO2 max. Noh; (d) work rate at time of VAT; (e) VE / VCO2 at time of VAT; (f) resting diastolic blood pressure; and (g) oxygen saturation at rest (%); individually, collectively, or in any combination.

[0020] Preferably, the method of the present invention improves the above (a) to (g), and each of the following measures is taken: Preferably, the method of the present invention includes improving At least the combination of (a) to (e) above is improved. In the present invention, an effective amount of udenafil is administered to SVHD patients, including patients after the Fontan operation. or a pharmaceutically acceptable salt thereof daily, the above (a) to (g) are improved. "improved" includes improvements individually, collectively, or in any combination.

[0021] The improvement in single ventricle performance in the methods of the present invention includes improvement in both systolic and diastolic function. These include improved blood pool MPI, improved tissue Doppler MPI, and improved cardiac output (Doppler method). Improvement in univentricular function (assessed by the product of the integral under the stroke volume curve and heart rate) The improvement of the present invention can be demonstrated by, but is not limited to, improvements in other measures. Improvements in exercise tolerance or capacity include exercise at the anaerobic threshold ("VAT"). Improved tolerance or exercise capacity and / or submaximal or maximum VO2 These include, but are not limited to, improved exercise tolerance or exercise capacity during exercise. In the present invention, the method of the present invention is implemented for SVHD patients, including patients after the Fontan operation. When applied, improved power output during VAT, carbon dioxide ventilation during VAT (VE / VCO2) Improvement in resting diastolic blood pressure and / or oxygen saturation (%) at rest Improvement can be achieved.

[0022] Generally, an "effective amount" is an amount that exerts a therapeutic effect or efficacy without causing treatment-limiting side effects. is sufficient to elicit or induce a pharmacological effect, The term "amount of salt" is used herein to mean the amount of salt tolerated.

[0023] More specifically, "effective amount" refers to an amount of a compound that is effective in inhibiting PDE6 and / or PDE11. treatment-limiting toxicities, treatment-limiting side effects, and / or inability to tolerate any other treatments in patients with SVHD, including those after the Fontan procedure, without causing any limiting side effects udenafil or urea sufficient to elicit or induce a therapeutic or pharmacological effect is used herein to mean the amount of a pharmaceutically acceptable salt thereof.

[0024] An example of the "effective amount" of udenafil or a pharmaceutically acceptable salt thereof in the present invention is Examples of total daily doses include, but are not limited to, about 87.5 mg to about 175 mg. More preferably, udenafil or a pharmaceutically acceptable salt thereof according to the present invention An "effective amount" encompasses a total daily dose in the range of about 125 mg to about 175 mg. Preferably, the "effective amount" of udenafil or a pharmaceutically acceptable salt thereof in the present invention is and oral doses, including but not limited to single doses administered daily. A single dose of approximately 75 mg or 87.5 mg administered once or twice daily and once daily This involves administering a single dose of approximately 125 mg.

[0025] The present invention also provides a method for treating visual disturbances, back pain, muscle pain, sperm concentration, or without causing treatment-limiting side effects such as quality, particularly MPI, ventricular performance, and heart rate. output, exercise tolerance or exercise capacity at VAT, submaximal exercise load or VO2 max Exercise tolerance or exercise capacity, work rate at VAT, VE / VCO2 at VAT, and resting dilation diastolic blood pressure, and resting oxygen saturation (%), individually, together, or in any combination. To improve the overall survival rate, patients with SVHD, including those after the Fontan procedure, were given an effective dose of udenafi or a pharmaceutically acceptable salt thereof, In other words, the present invention contemplates the use of phosphodiesterase-6 ("PDE6") and and / or limiting treatments related to inhibition of phosphodiesterase-11 ("PDE11") an effective amount of an effective PDE5 inhibitor, preferably Udena, without causing side effects that The efficacy of Fil or its pharmaceutically acceptable salts in patients with SVHD, including those after the Fontan procedure As used herein, PDE6 refers to: Any isozyme or variant of PDE6, PDE6α, PDE6β, PDE6γ, Catalytic and / or inhibitory subunits such as PDE6R and / or PDE6C As used herein, the term "unit" encompasses units individually, collectively, or in any combination. When PDE11 is used, it is a phosphodiesterase-11A (PDE11A) and P Any isozyme or variant of DE11, PDE11A1, PDE11A2, PD catalytic subunits such as PDE11A, including PDE11A3, and / or PDE11A4 and / or inhibitory subunits, individually, collectively, or in any combination. do.

[0026] In one embodiment, the present invention provides a method for the treatment of MP in SVHD patients, including post-Fontan patients. As used herein, MPI refers to a method for improving overall cardiac function. The method provides a measure of both systolic and diastolic function for assessing the patient's administering, preferably daily, an effective amount of an effective PDE5 inhibitor to said PD The E5 inhibitor is preferably udenafil or a pharmaceutically acceptable salt thereof.

[0027] In the present invention, the term "improve, improving, improving, or improved" in relation to MPI is used interchangeably with "improve, improving, improving, or improved" in relation to MPI. "Improved" as used herein means improving single ventricle performance, i.e., functional single ventricle. It should be understood that this means improving the diastolic and systolic function of the ventricle. The ventricles are throttled better or more efficiently with each heartbeat. SVHD, including post-Fontan patients undergoing or treated in the methods of the present invention The patient's cardiac output and the amount of blood that can circulate throughout the body in a given amount of time are increased or improved. and SVHD patients, particularly including post-Fontan patients who have not been treated with the methods of the present invention. That is, the method of the present invention is increased or improved compared to not performing the method of the present invention. MPI in the absence of udenafil administration, or other disclosed single M in patients with SVHD, including those after the Fontan procedure, when compared with measures of ventricular performance PI, or other disclosed measures of ventricular performance. For example, the improvements When the method of the present invention is not performed (for example, when daily administration of udenafil is not performed), , approximately 5% when compared with blood pool MPI, or other disclosed measures of single ventricle performance. or more, about 6% or more, about 7% or more, about 8% or more, about 9% or more, about 10% or more, about 11% or more , about 12% or more, about 13% or more, about 14% or more, about 15% or more, about 16% or more, about 17% or more, about 18% or more, about 19% or more, about 20% or more, about 21% or more, about 22% or more, about 2 3% or more, approximately 24% or more, approximately 25% or more, approximately 26% or more, approximately 27% or more, approximately 28% or more, The method may comprise administering to the patient an effective amount of the active ingredient. The method includes administering, preferably daily, an effective PDE5 inhibitor, Preferred is udenafil or a pharmaceutically acceptable salt thereof.

[0028] In one embodiment, the present invention provides a method for the treatment of functionally single-heart disease in patients with SVHD, including post-Fontan patients. The present invention relates to a method for improving ventricular systolic function, the method comprising administering to a patient with SVHD an effective amount of an effective PD administering, preferably daily, an E5 inhibitor or a pharmaceutically acceptable salt thereof; The PDE5 inhibitor is preferably udenafil or a pharmaceutically acceptable salt thereof.

[0029] In one embodiment, the present invention provides a method for the treatment of functionally single-heart disease in patients with SVHD, including post-Fontan patients. The present invention relates to a method for improving ventricular diastolic function, the method comprising administering an effective amount of an effective PD administering, preferably daily, an E5 inhibitor or a pharmaceutically acceptable salt thereof; The PDE5 inhibitor is preferably udenafil or a pharmaceutically acceptable salt thereof.

[0030] In one embodiment, the present invention provides a method for the treatment of functionally single-heart disease in patients with SVHD, including post-Fontan patients. The present invention relates to a method for improving cardiac output in a patient with SVHD, the method comprising administering an effective amount of an effective PD administering, preferably daily, an E5 inhibitor or a pharmaceutically acceptable salt thereof; The PDE5 inhibitor is preferably udenafil or a pharmaceutically acceptable salt thereof.

[0031] In one embodiment, the present invention provides a method for the treatment of functionally single-heart disease in patients with SVHD, including post-Fontan patients. The present invention relates to a method for improving the expressibility of a ventricle in patients with SVH, including those after the Fontan procedure. D. administering to the patient an effective amount of an effective PDE5 inhibitor or a pharmaceutically acceptable salt thereof, preferably The method includes daily administration, and the PDE5 inhibitor is preferably udenafil or a preparation thereof. It is a pharmaceutically acceptable salt.

[0032] In another embodiment, the present invention provides a method for the treatment of venous pressure in SVHD patients, including post-Fontan patients. The method includes the steps of: Patients with SVHD, including post-operative patients, are administered an effective amount of an effective PDE5 inhibitor, preferably daily. The PDE5 inhibitor is preferably udenafil or a pharmaceutically acceptable salt thereof. It is a salt that is used.

[0033] In one embodiment, the present invention provides a method for treating SVHD patients, including post-Fontan patients, over a period of time. The present invention relates to a method for improving the amount of blood that can circulate throughout the body of a patient after a Fontan procedure. and administering an effective amount of an effective PDE5 inhibitor or a pharmaceutically acceptable salt thereof to a patient with SVHD, including The PDE5 inhibitor is preferably udenafil. or a pharmaceutically acceptable salt thereof.

[0034] That is, the present invention provides a method for the treatment of SVHD patients, including those who have undergone the Fontan procedure, with a complete diagnosis of functional single ventricle. The present invention relates to a method for improving single ventricle performance in a patient with SVHD, the method comprising administering an effective amount of an effective The method includes administering, preferably daily, a PDE5 inhibitor or a pharmaceutically acceptable salt thereof. The PDE5 inhibitor is preferably udenafil or a pharmaceutically acceptable salt thereof. .

[0035] In yet another embodiment, the present invention provides a method for the treatment of SVHD in patients with SVHD, including post-Fontan patients. By improving resting diastolic blood pressure, including resting diastolic blood pressure in patients after the Fontan operation, The present invention relates to a method for significantly lowering resting diastolic blood pressure in patients with SVHD. Patients with SVHD, including those after tanning, are administered an effective amount of an effective PDE5 inhibitor, preferably every 2 weeks. The PDE5 inhibitor is preferably udenafil or a pharmaceutical equivalent thereof. It is an acceptable salt.

[0036] In yet another embodiment, the present invention provides a method for the treatment of SVHD in patients with SVHD, including post-Fontan patients. This invention relates to a method for improving resting oxygen saturation (%) in patients after the Fontan procedure. administering, preferably daily, an effective amount of an effective PDE5 inhibitor to a patient with SVHD, including The PDE5 inhibitor is preferably udenafil or a pharmaceutically acceptable salt thereof. be.

[0037] In yet another embodiment, the present invention provides a method for the treatment of SVHD in patients with SVHD, including post-Fontan patients. The present invention relates to a method for improving exercise capacity or exercise tolerance in patients after the Fontan procedure. administering, preferably daily, an effective amount of an effective PDE5 inhibitor to a patient with SVHD, including The PDE5 inhibitor is preferably udenafil or a pharmaceutically acceptable salt thereof. be.

[0038] In another embodiment, the present invention provides a method for determining ventilatory status in SVHD patients, including post-Fontan patients. Methods for improving exercise capacity or exercise tolerance at anaerobic threshold ("VAT") The methods of the present invention may be used in patients who have not been treated with or undergone the methods of the present invention. Fontaine that has not (e.g., has not been administered daily with udenafil in accordance with the method of the present invention) VO2 during VAT in SVHD patients, including those after Fontan surgery, was significantly higher in patients after Fontan surgery than in those after Fontan surgery. It improves VO2 during VAT in SVHD patients, including those with The improvement occurs when the method of the present invention is not performed (e.g., when daily administration of udenafil is not performed). Compared to VO2 at VAT, the following were observed: % or more, approximately 5% or more, approximately 6% or more, approximately 7% or more, approximately 8% or more, approximately 9% or more, approximately 10% or more , about 11% or more, about 12% or more, about 13% or more, about 14% or more, about 15% or more, about 16% or more, about 17% or more, about 18% or more, about 19% or more, about 20% or more, about 21% or more, about 2 2% or more, approximately 23% or more, approximately 24% or more, approximately 25% or more, approximately 26% or more, approximately 27% or more, The concentration can be about 28% or more, about 29% or more, or about 30% or more. SVHD patients, including those after Fontane surgery, are administered an effective amount of an effective PDE5 inhibitor, preferably The method includes daily administration, and the PDE5 inhibitor is preferably udenafil or a preparation thereof. It is a pharmaceutically acceptable salt.

[0039] In another embodiment, the present invention provides a method for treating submaximal SVHD in patients with SVHD, including post-Fontan patients. This document relates to a method for improving exercise capacity or exercise tolerance during exercise load or maximum VO2. The method of the invention is not limited to cases where the method of the invention is not performed (e.g., where daily administration of udenafil is not performed). Compared with submaximal exercise VO2 in patients without Fontan surgery, SVHD patients This improves the patient's VO2 during submaximal exercise. For example, the improvement can be achieved by If this method is not implemented (for example, if udenafil is not administered daily), Compared to VO2 during active load, approximately 1% or more, approximately 2% or more, approximately 3% or more, approximately 4% or more , about 5% or more, about 6% or more, about 7% or more, about 8% or more, about 9% or more, about 10% or more, about 1 1% or more, approximately 12% or more, approximately 13% or more, approximately 14% or more, approximately 15% or more, approximately 16% or more, About 17% or more, about 18% or more, about 19% or more, about 20% or more, about 21% or more, about 22% or more Above, about 23% or more, about 24% or more, about 25% or more, about 26% or more, about 27% or more, about 28% % or more, about 29% or more, or about 30% or more. Patients with SVHD, including those after cancer surgery, are administered an effective amount of an effective PDE5 inhibitor, preferably daily. The PDE5 inhibitor is preferably udenafil or a pharmaceutically acceptable salt thereof. It is an acceptable salt.

[0040] In another embodiment, the present invention provides a method for the treatment of VAT in SVHD patients, including post-Fontan patients. The method of the present invention relates to a method for improving the power output when the method of the present invention is not carried out ( For example, compared with the work rate at VAT when udenafil is not administered daily, It improves the work rate during VAT in SVHD patients, including those after venous surgery. For example, The above improvement does not occur when the method of the present invention is not performed (e.g., when daily administration of udenafil is not performed). VO2 at VAT (without VAT) of approximately 1%, 2%, and 3% or more , about 4% or more, about 5% or more, about 6% or more, about 7% or more, about 8% or more, about 9% or more, about 10 % or more, about 11% or more, about 12% or more, about 13% or more, about 14% or more, about 15% or more, about 16% or more, approximately 17% or more, approximately 18% or more, approximately 19% or more, approximately 20% or more, approximately 21% or more , about 22% or more, about 23% or more, about 24% or more, about 25% or more, about 26% or more, about 27% The method may be about 28% or more, about 29% or more, or about 30% or more. We administered effective doses of effective PDE5 inhibitors to patients with SVHD, including those after the Fontan procedure, and Preferably, the PDE5 inhibitor is administered daily, and the PDE5 inhibitor is preferably udenafil or and pharmaceutically acceptable salts thereof.

[0041] In another embodiment, the present invention provides a method for the treatment of VAT in SVHD patients, including post-Fontan patients. This paper describes a method for improving the carbon dioxide ventilation equivalent (VE / VCO2) during VAT. The method of the invention is not limited to cases where the method of the invention is not performed (e.g., where daily administration of udenafil is not performed). VE / VCO2 at VAT in patients with SVHD including those after the Fontan procedure compared with patients without VAT This improves the VE / VCO2 during VAT in patients. For example, the above improvement can be achieved by the present invention. VAT when the above method is not implemented (for example, when daily administration of udenafil is not implemented) Compared to VO2, the following are approximately 1% or more, approximately 2% or more, approximately 3% or more, approximately 4% or more, and approximately 5% or more, about 6% or more, about 7% or more, about 8% or more, about 9% or more, about 10% or more, about 11% or more , about 12% or more, about 13% or more, about 14% or more, about 15% or more, about 16% or more, about 17% or more, about 18% or more, about 19% or more, about 20% or more, about 21% or more, about 22% or more, about 2 3% or more, approximately 24% or more, approximately 25% or more, approximately 26% or more, approximately 27% or more, approximately 28% or more, The method may be for a patient after a Fontan operation, in which the percentage of the total blood volume is about 29% or more, or about 30% or more. and administering an effective amount of an effective PDE5 inhibitor, preferably daily, to patients with SVHD, including those with The PDE5 inhibitor is preferably udenafil or a pharmaceutically acceptable salt thereof. It's salt.

[0042] In one embodiment, the present invention relates to a Fontan heart transplant recipient who underwent cardiac reconstruction of an abnormal SVHD heart. Improved methods for treating SVHD patients, including post-surgical patients, include the daily method of the present invention. This has been shown to reduce adverse events compared with conventional methods of treating SVHD patients, including those after the Fontan procedure. This invention relates to a method for reducing the incidence or severity of elephantiasis.

[0043] In another embodiment, the methods of the present invention provide a method for treating a serious adverse event, a moderate adverse event, or a mild adverse event. The method reduces adverse events, if any, in patients with S, including those after the Fontan procedure. administering to a VHD patient an effective amount of an effective PDE5 inhibitor, preferably administered daily. Preferably, the PDE5 inhibitor is udenafil or a pharmaceutically acceptable salt thereof.

[0044] In one embodiment, the present invention provides a method for treating SVHD patients who have undergone the Fontan procedure. In one such embodiment, a post-Fontan patient is The patient was diagnosed with hypoplastic left heart syndrome (HLHS), but first, a Norwood procedure (e.g. , see Figure 5 ) followed by a hemi-Fontan or bidirectional Glenn procedure (e.g., see Figure 6 ). (see Figure 1A and Figure 7) and subsequently underwent the Fontan procedure. In such embodiments, post-Fontan patients are first treated with a hemi-Fontan procedure or both He underwent a retrograde Glenn procedure and then a Fontan procedure. Patients with SVHD, including those with SVHD, are administered an effective amount of an effective PDE5 inhibitor, preferably daily. The PDE5 inhibitor is preferably udenafil or a pharmaceutically acceptable salt thereof. It is a salt that can be used.

[0045] In one embodiment, the present invention provides a method for treating SVHD patients, including post-Fontan patients. The improved method for SVHD is provided, wherein the SVHD is a patient with atrioventricular canal defect (AV Canal), Patients with dilated atrioventricular valves (DILV), double outlet right ventricle (DORV), Ebstei Patients with malformations, HLHS patients, mitral atresia (usually associated with HLHS), and pure pulmonary atresia Patients with PA / IVS, single left ventricle, tricuspid atresia, and tricuspid stenosis The method further comprises administering to a patient selected from the group consisting of SVHD patients with cusp atresia, valvular atresia, and phononib. Patients with SVHD, including those after tanning, are administered an effective amount of an effective PDE5 inhibitor, preferably every 2 weeks. The PDE5 inhibitor is preferably udenafil or a pharmaceutical equivalent thereof. In an exemplary embodiment, the method of the present invention preferably comprises the steps of: an effective amount of an effective PDE5 inhibitor or a compound thereof, which is a pharmaceutically acceptable salt thereof; Administer a pharmaceutically acceptable salt once daily to patients with SVHD, including those after the Fontan procedure. Includes:

[0046] In another embodiment, the methods of the present invention preferably comprise administering udenafil or a pharmaceutically acceptable salt thereof. an effective amount of an active PDE5 inhibitor or a pharmaceutically acceptable salt thereof, administered twice a day; This includes administering it to patients with SVHD, including those after the Fontan procedure.

[0047] In another embodiment, the method of the present invention preferably comprises administering udenafil or a pharmaceutically acceptable salt thereof. an effective amount of an active PDE5 inhibitor or a pharmaceutically acceptable salt thereof, This includes administering the drug at least three times daily to patients with SVHD, including those after the Fontan procedure.

[0048] In another embodiment, SVHD patients, including post-Fontan patients, are children between about 2 and about 18 years of age. Treatment of adult patients is also contemplated by the methods of the present invention.

[0049] In yet another embodiment, the present invention provides a method for treating patients with SVHD, including post-Fontan patients. and an improved method for administering luteinizing agents to post-Fontan patients prescribed non-udenafil medications. Compared with patients with SVHD, including those after the Fontan procedure, udenafil or a pharmaceutically acceptable salt thereof, Regarding the law.

[0050] Finally, in yet another embodiment, the methods of the present invention provide pharmacokinetic profiles that exhibit unique characteristics. The pharmacokinetic profile described above is 300-700 ng / ml, or more specifically about 500 ng / ml, Cmax; 1 hour to 1.6 hours; Or, more specifically, about 1.3 hours, Tmax; 2550-4150 ng / ml; Or, more specifically, an AUC of approximately 3350 ng / ml τ ; and, 5110~82 90 ng / ml, or more specifically, about 6701 ng / ml, AUC 0-24 It can include:

[0051] It is understood that the present invention does not include udenafil formulations that are therapeutically equivalent to the udenafil formulations of the present invention. In other words, the present invention contemplates the use of pharmaceutical formulations that are (i) therapeutically equivalent to each other; (ii) bioequivalent; (iii) interchangeable; and (iv) a compound of the present invention. When administered to SVHD patients, including patients after the Fontan procedure, in the method, the object of the present invention can be achieved. The present invention contemplates the development of an udenafil formulation with effective bioavailability for the administration or practice of do.

[0052] That is, in one embodiment of the present invention, the present invention provides a method for determining the pharmacokinetic profile of a compound of formula (I) or (II). The ratio of the mean values is within the range of approximately 0.8 to approximately 1.25 in the 90% confidence interval (CI). In another embodiment of the present invention, the present invention contemplates a formulation in which the pharmacokinetic profile In the 90% confidence interval (90% CI) of the file, the ratio of the mean values is approximately 0.8 to approximately 1.2. The present invention contemplates alternative formulations of udenafil that fall within the scope of the present invention. S, including post-Fontan patients, treated with the disclosed method or practicing the method of the present invention. In patients with VHD, the pharmacokinetic profile of the patient, such as Cmax, Tmax, and AUC, Udenafil plasma concentrations can fluctuate by up to approximately 45% (i.e., -20 to +25%). More preferably, the present invention contemplates a patient having the following: SVHD patients, including post-Fontan patients, practicing the methods of the present invention, max, Tmax, AUC t、 and AUC 0-24 Maximum pharmacokinetic profile such as Udenafil plasma concentrations can vary by approximately 40% (i.e., -20 to +20%) By way of example, the present invention contemplates a patient who is to be treated with the methods of the present invention or who is to undergo the methods of the present invention. SVHD patients, including those after the Fontan operation, who are taking the following udenafil drugs Kinetic profile: (a) a Cmax plasma concentration that is about -20% to about +25% of about 500 ng / ml, Preferably, the udenafil Cmax is about -20% to about +20% of about 500 ng / ml. plasma concentration; (b) a Tmax of about -20% to about +25% of about 1.3 hours, more preferably 1. Udenafil Tmax, which is approximately -20% to approximately +20% over 3 hours; (c) AUC of about -20% to about +25% of about 3350 ng / ml t , more preferred The udenafil AUC is approximately -20% to +20% of approximately 3350 ng / ml. t ; (d) AUC of about -20% to about +25% of about 6701 ng / ml 0-24 ,twist Preferably, udenafil AU is about -20% to about +20% of about 6701 ng / ml. C 0-24 , Individually, collectively, or in any combination, patients with:

[0053] That is, the present invention provides bioequivalent and alternative compounds for use in the methods of the present invention. The present invention further contemplates possible formulations of udenafil. When administered to patients with SVHD, including those after the Fontan procedure, The above Cmax, Tmax, and AUC in VHD patients t , and / or AUC 0-2 The company is considering a formulation of udenafil that will provide 4.

[0054] The above Summary of the Invention is not intended to describe each disclosed embodiment or every implementation of the present invention. It should be understood that the above description is not intended to be a complete description of the exemplary embodiments. It is intended to provide an illustration of the invention as claimed. By the way, examples are provided for guidance, but these examples can be used in various combinations. In each case, the above examples serve only as illustrative and should be considered as limiting examples. It shouldn't be. [Brief explanation of the drawings]

[0055] These and other objects, advantages, and features of the present invention, and the manner in which they are accomplished, are: The following Brief Description of the Drawings, Detailed Description, and Examples of the Preferred Embodiments are provided for illustrative purposes only. From the examples, those skilled in the art will readily understand.

[0056] [Figure 1A] FIG. 1A is a schematic diagram of an exemplary Fontan physiology. [Figure 1B] Figure 1B shows the screening method (subject randomization and treatment) used in the Fontan Udenafil Exercise Longitudinal (FUEL) study, as described in Examples 1-2. Peak VO2 (VO2 max) represents oxygen consumption during peak exercise. RER represents respiratory exchange ratio. [Figure 2A] Figure 2A shows the difference in change in mean peak or max VO2 from baseline to week 26 by treatment group, along with standard deviations. [Figure 2B] FIG. 2B shows the percentage of subjects (y-axis) who demonstrated an improvement in peak VO2 (x-axis) greater than or equal to the baseline percentage. [Figure 3A] Figure 3A shows the difference in change in mean VO2 during VAT from baseline to week 26 by treatment group, along with standard deviations. [Figure 3B]FIG. 3B shows the percentage of subjects (y-axis) who demonstrated an improvement in VO2 at VAT (x-axis) greater than or equal to the baseline percentage. [Figure 4A] Figure 4A shows the difference in the change in mean work rate during VAT from baseline to week 26 by treatment group, along with standard deviations. [Figure 4B] FIG. 4B shows the percentage of subjects (y-axis) who demonstrated an improvement in power output (x-axis) greater than or equal to baseline percent. [Figure 5] FIG. 5 is a schematic diagram of an exemplary Norwood procedure (stage 1) for a reconstructed SVHD heart with hypoplastic left heart syndrome (HLHS). [Figure 6] FIG. 6 is a schematic diagram of an exemplary bidirectional Glenn procedure (stage 2) of a reconstructed SVHD heart with hypoplastic left heart syndrome (HLHS). [Figure 7] FIG. 7 is a schematic diagram of an exemplary Fontan procedure (stage 3), which is an extracardiac fenestrated Fontan procedure for a reconstructed SVHD heart with hypoplastic left heart syndrome (HLHS). DETAILED DESCRIPTION OF THE INVENTION

[0057] I. Fontan physiology Fontan physiology is a common concept of a functionally single ventricle. It is the ultimate palliative treatment for a class of congenital heart diseases that share the same characteristics. The class includes defects that result in a hypoplastic (dysfunctional) left or right ventricle. Typically, a series of two or three surgeries is performed to separate the systemic and pulmonary circulation, achieving the above-mentioned A mixture of oxygenated and deoxygenated blood caused by congenital heart disease This is because the superior and inferior vena cava are directly attached to the pulmonary artery, i.e., both vena cavae are directly attached to the pulmonary artery. This is achieved by a pulmonary artery / pulmonary artery anastomosis, which allows the Fontan physiology to function as follows: (1) Single systemic ventricle e) sends oxygenated blood (red blood) from the aorta to the systemic arterial vascular beds throughout the body, (2) Systemic venous blood (blue blood) returns through the vena cava, and this blue blood enters the pulmonary artery. Oxygen in the lungs without the help of the sub-pulmonary ventricle Passively passing through the pulmonary vascular bed for uptake, oxygenating the blue blood, and (3) this new oxygen The blood containing the protein (red blood) then passes through the normal functioning systemic atria to the functional The red blood-blue blood circulation cycle repeats as it returns to the systemic single-ventricular pump. Its anatomy is shown in Figures 1A and 7.

[0058] The Fontan procedure involves creating a bicaval pulmonary anastomosis, connecting the systemic and pulmonary circulations. This isolates the ventricles and relieves both hypoxemia and ventricular volume overload. However, after the Fontan procedure, The ventricular pump that would propel blue blood into the pulmonary arteries is gone. The blue blood returns to the lungs via passive flow from the systemic veins. The primary physiological consequence of palliative care is that pulmonary blood flow is reduced by a pressure gradient from the systemic venous bed to the atrium. Normal circulation through the pulmonary vascular bed is generated by the right ventricle. In healthy young adults, this is the same as that present in the pulmonary artery at rest. This results in an increase in pressure of approximately 20-25 mmHg, which can double with exercise. In the case of the pulmonary artery, there is no subpulmonary ventricle, so the pressure of the blue blood entering the pulmonary artery is At rest, the pressure gradient in the pulmonary vascular bed is significantly reduced. The ability to increase blood pressure with exercise depends on the body's tolerance to sustained increases in central venous pressure. It is very limited depending on the Noh.

[0059] as a result of the complete reliance on passive reduction in venous pressure to drive pulmonary blood flow Fontan physiology is extremely sensitive to changes in pulmonary vascular resistance. Even increases well within the normal range may have a detrimental effect on Fontan physiology The use of udenafil has unique and effective benefits for patients with congenital heart disease who have undergone this type of palliative surgery. Unlike other uses of PDE-5 inhibitors, this treatment also reduces pulmonary vascular resistance. It is intended to reduce pulmonary vascular resistance in a population in which pulmonary vascular pressure is not also elevated. These include (i) structurally normal hearts and those with pulmonary arterial hypertension (PAH) and chronic obstructive pulmonary disease (COPD) (ii) patients with pulmonary vascular disease such as COPD, and (iii) patients with heart failure such as congestive heart disease. or (iii) underwent palliative surgery with biventricular repair (which resulted in pulmonary valve replacement). Very rare patients with congenital heart disease (with inferior ventricles) and associated pulmonary vascular disease, compared with This is a distinctly different use of this class of drug.

[0060] II. Clinical Measurements Related to Post-Fontan Patients In children born with functional single ventricle or single ventricle congenital heart disease, the Fontan procedure The Fontan procedure is currently the standard treatment. While this procedure has significantly increased survival in children with functional single ventricle heart disease, It also brings a series of side effects and complications that can lead to patient attrition, including arrhythmias, ventricular Functional impairment and rare clinical manifestations such as protein-losing enteropathy (PLE) and bronchitis plastica It is associated with complications such as cerebrospinal fluid (CSF) and liver and kidney complications.

[0061] In one embodiment, the disclosed invention provides a method for determining the risk of developing a Fontan syndrome, particularly a type of steroid hormone, that is an indicator of patient health after the Fontan procedure. Improving or preventing the decline of certain clinically meaningful physiological measures Such measurements include exercise stress testing, vascular function testing, and cardiac evaluation of ventricular performance. These include, but are not limited to, criterion evaluation.

[0062] III. Exercise stress test Exercise stress tests include submaximal exercise stress or ventilatory anaerobic threshold (VAT) stress. VO2 max, or maximum oxygen consumption, is the rate at which a person This measurement is the maximum amount of oxygen an individual can utilize during strenuous exercise. It is generally considered a reliable indicator of fitness and aerobic endurance in people. The more oxygen available during exercise, the more energy a person can produce. requires oxygen for prolonged (aerobic) exercise, blood carries oxygen to muscles, and the heart This test is performed because the heart must pump enough blood to meet the demands of the body. It is a measure of lung strength.

[0063] VO2 is measured by having the subject wear a mask and measuring the volume of inhaled and exhaled air and gas concentrations. This measurement is often used in both clinical practice and research. The test is usually conducted at increasing intensity until exhaustion. The submaximal exercise of the subject was performed either on a dorm or on a bicycle ergometer. It is designed to take readings at stress and / or at the subject's anaerobic threshold.

[0064] In patients with SVHD, including those who have had the Fontan procedure, V usually progresses over time. However, when performing the method of the present invention, or When treating SVHD patients, including those after the Fontan procedure, VO2 measurements were: (i) VO 2. The measurement remains at a similar level, indicating that no further decline has occurred; or (ii) an increase in VO2 and / or a decrease in the rate of decline in VO2 measurements. and improved with treatment, each of which is consistent with the treatment of the present invention. or the method is clinically beneficial. Treatment in this setting may significantly slow or reduce the decline in VO2 measured during exercise .

[0065] In one embodiment, the present invention provides a method for the treatment of VD in patients with SVHD or subjects who have undergone the Fontan procedure. The present invention relates to a method for improving or maintaining O2 measurements in patients after the Fontan procedure. administering, preferably daily, an effective amount of an effective PDE5 inhibitor to a patient with SVHD, including The PDE5 inhibitor is preferably udenafil or a pharmaceutically acceptable salt thereof. In some embodiments of the present invention, VO2 is measured during submaximal exercise, while in others In this embodiment, VO2 is measured at the subject's anaerobic threshold (VAT).

[0066] In some embodiments, the disclosed methods and compositions of the present invention are administered to patients after the Fontan procedure. When administered to SVHD patients, including those with idiopathic steroid use, exercise tolerance may decrease over time. More specifically, the disclosed methods and compositions of the present invention provide Over time, it goes from about 40% to about 35% to about 30% to about 35% to about 20%. results in a reduction in exercise tolerance of less than about 15%, less than about 10%, or less than about 5% The period between the first and second measurements used to calculate the decline in exercise tolerance is: For example, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, Approximately 7 months, approximately 8 months, approximately 9 months, approximately 10 months, approximately 11 months, or approximately 12 months Months; about 1 year, about 2 years, about 3 years, about 4 years, about 5 years, about 6 years, about 7 years, about 8 years Years, about 9 years, about 10 years, about 11 years, about 12 years, about 13 years, about 14 years, if or about 15 years, or any combination thereof, e.g., 1 year 3 months; 4 years 7 months, etc. It can be said that...

[0067] In some embodiments, the disclosed methods and compositions of the present invention are used in post-Fontan patients. Administration of this drug to patients with SVHD, including those with idiopathic pulmonary hypertension, may improve exercise tolerance. In particular, the disclosed methods and compositions of the present invention provide a VO2 reduction of 1. % or more, 2% or more, 5% or more, 10% or more, 15% or more, 20% or more, 25% or more, 30 % or more, 35% or more, 40% or more, 45% or more, or 50% or more improvement Alternatively, the disclosed methods and compositions of the present invention may be used in patients with SVH, including post-Fontan patients. D) VO2 at the patient's ventilatory anaerobic threshold (VAT) is 1% or more, 2% or more, 5% or more, 10% or more, 15% or more, 20% or more, 25% or more, 30% or more, 35% or more , may result in an improvement of 40% or more, 45% or more, or 50% or more.

[0068] IV. Vascular Function Test Endothelial dysfunction is an important outcome for assessing vascular health in intervention studies Endothelial dysfunction is clearly associated with traditional cardiovascular disease (CVD) risk factors, It is now well established that CI is an independent predictor of cardiovascular events over a 1- to 6-year interval. It is established.

[0069] Pulse amplitude tonometry, an FDA-approved method for measuring vascular function, Amplitude tonometry (PAT) is a method for measuring the endothelial response to reactive hyperemia. It can be used as a surrogate measure of flow-mediated dilation and flow-mediated vasodilation (FMD). PAT devices are increasingly being used to measure the blood pressure using fingertip plethysmography. Pulse wave amplitude (PWA) was recorded during a resting baseline period followed by a 5-minute forearm occlusion. It can be measured continuously during three periods: occlusion, reactive hyperemia after cuff release, and reactive hyperemia after cuff release. Therefore, PAT testing does not depend on highly skilled technicians, and post-test analysis can be largely automated. Most importantly, the PAT measure of endothelial function was At least one longitudinal study has shown that CVD predicts CVD events over time. These significant advantages have led to the development of PAT testing, which has demonstrated its significance and reliability as a prognostic predictor. If its reliability can be confirmed, it may be suitable for clinical implementation.

[0070] Patients with SVHD, including those with a prior Fontan procedure, usually experience a progressive decline over time. As the disease progresses, vascular function declines. SVHD, including post-Fontan patients, to improve or prevent further decline in function. Treating patients is considered to be clinically beneficial, including those after the Fontan procedure. To demonstrate that it can improve the quality of life of SVHD patients or prevent the decline in cardiovascular function. It will be.

[0071] In one embodiment, the present invention provides a method for treating SVHD, including SVHD patients who have previously undergone the Fontan procedure. The present invention relates to a method for improving or maintaining vascular function in a patient with VHD, the method comprising administering the method to the patient after the Fontan procedure. and administering an effective amount of an effective PDE5 inhibitor, preferably daily, to SVHD patients, including patients with SVHD. The PDE5 inhibitor is preferably udenafil or a pharmaceutically acceptable salt thereof. In some embodiments, vascular function is measured using the PAT index.

[0072] In some embodiments, the disclosed methods and compositions of the present invention are administered to patients after the Fontan procedure. When administered to SVHD patients, including those with cerebrospinal fluid (CSF), vascular function is not reduced or even reduced over time. The vascular function can be measured using any conventionally known method, For example, pulse amplitude tonometry, natural logarithm of reactive hyperemia index, reactive hyperemia index, flamin Gum (RHI), area under the curve for maximum occlusion / control, mean value up to maximum occlusion / control, and and other known Endo-PAT indices. In some embodiments, vascular function is measured using the PAT index. The disclosed methods and compositions of the invention reduce the risk of aging by less than about 40%, less than about 35%, or , less than about 30%, less than about 35%, less than about 20%, less than about 15%, less than about 10%, or about It may result in a reduction in vascular function of less than 5%. The period between the first and second measurements can be, for example, about 1 month, about 2 months, about 3 months, or about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months 11 months, or 12 months; 1 year, 2 years, 3 years, or 4 years; About 5 years, about 6 years, about 7 years, about 8 years, about 9 years, about 10 years, about 11 years, about 12 years 1 year, approximately 13 years, approximately 14 years, or approximately 15 years, or any combination thereof , for example, 1 year 3 months; 4 years 7 months, etc.

[0073] In some embodiments, the disclosed methods and compositions of the present invention are used in post-Fontan patients. Administration of vasculitis to SVHD patients, including those with vasculitis, can improve vascular function. Measurement can be performed using any conventionally known method, for example, pulse amplitude tonometry, reaction Natural logarithm of the reactive hyperemia index, reactive hyperemia index, Framingham RHI, maximum occlusion / control Area under the curve, mean value to maximum occlusion / control, and other known endo-PAT indices. In some embodiments of the present invention, vascular function can be measured using PAT. More specifically, the methods and compositions of the present disclosure provide a method for measuring one of the vascular functions. Or in multiple measurements, about 1% or more, about 2% or more, about 5% or more, about 10% or more, about 15% or more, approximately 20% or more, approximately 25% or more, approximately 30% or more, approximately 35% or more, approximately 40% or more , which may result in an improvement of about 45% or more, or about 50% or more, as measured above. are pulse amplitude tonometry, natural logarithm of reactive hyperemia index, reactive hyperemia index, Framingham RHI, area under the curve for maximum occlusion / control, mean value up to maximum occlusion / control, and other Examples include, but are not limited to, the well-known Endo PAT index.

[0074] V. Echocardiographic Assessment of Ventricular Performance Ventricular performance and myocardial contractility reveal impaired cardiovascular health before overt heart failure appears. Ventricular performance is assessed using echocardiography and is an important measure of cardiac function. It can be quantified through the muscle performance index or MPI. MPI is a measure of contractile and diastolic function. Specifically, the MPI is a combination of isovolumic contraction time and isovolumic relaxation time. It is defined as the sum of the heart rate and heart rate divided by the ejection time.

[0075] Various versions of MPI are known in the art, and each version of MPI For example, the MPI index may be blood pool MPI and tissue MPI. Examples of MPI include, but are not limited to, pulsed tissue Doppler MPI. It can be measured by transcardial echocardiography (TDE). To calculate PI, the isovolumic contraction time (IVCT) and isovolumic relaxation time ( IVRT) and ejection time (ET). Then, IVCT and IVRT are added together to calculate the The MPI is calculated by dividing the sum by ET.

[0076] Patients who have had a previous Fontan procedure typically experience a decline in ventricular performance over time. The patient's ventricular performance is maintained and shows only a minimal decline over time. Treatment of a patient with a disease that is clinically beneficial and / or increases the risk of death from the disease. It has been shown that it can improve the quality of life of patients or prevent the decline of cardiovascular function. do.

[0077] In one embodiment, the present invention provides a method for assessing ventricular performance in subjects who have previously undergone the Fontan procedure, by: The methods of the present invention relate to methods for maintaining, minimizing the decrease in, or increasing the level of a patient's administering, preferably daily, an effective amount of an effective PDE5 inhibitor to a subject, The DE5 inhibitor is preferably udenafil or a pharmaceutically acceptable salt thereof. In some embodiments, ventricular performance is assessed using the Myocardial Performance Index (MPI). In some embodiments, the MPI may be a blood pool MPI, and in other embodiments, The PI may be tissue Doppler MPI.

[0078] In some embodiments, the disclosed methods and compositions of the present invention are used in post-Fontan patients. administration to patients minimizes or eliminates the decline in ventricular performance over time. Ventricular performance can be measured using any conventionally known method, for example, myocardial Performance index (MPI), blood pool MPI, tissue Doppler MPI, mean isovolumic contraction and relaxation, etc. Known ventricular performance indices include, but are not limited to, those of the present invention. The disclosed methods and compositions reduce the reduction in ventricular performance over time by less than about 40%, about Less than 35%, Less than about 30%, Less than about 35%, Less than about 20%, Less than about 15%, Less than about 10% or less than about 5%. The period between the first and second measurements can be, for example, about 1 month, about 2 months, about 3 months, or about 4 months. 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months or approximately 12 months; approximately 1 year, approximately 2 years, approximately 3 years, approximately 4 years, approximately 5 years 6 years, 7 years, 8 years, 9 years, 10 years, 11 years, 12 years, Approximately 13 years, approximately 14 years, or approximately 15 years, or any combination thereof, e.g. For example, it could be 1 year 3 months; 4 years 7 months, etc.

[0079] In some embodiments, the disclosed methods and compositions of the present invention are used in post-Fontan patients. When administered to patients with SVHD, including those with pulmonary embolism, ventricular function can be improved over time. Ventricular performance can be measured using any conventionally known method, for example, myocardial Performance index (MPI), blood pool MPI, tissue Doppler MPI, mean isovolumic contraction and relaxation, etc. Known ventricular performance indices include, but are not limited to, those of the present invention. The methods and compositions are intended to improve ventricular performance by at least about 1% and at least about 2% as measured by any known method. % or more, about 5% or more, about 10% or more, about 15% or more, about 20% or more, about 25% or more, about 3 Improve by 0% or more, approximately 35% or more, approximately 40% or more, approximately 45% or more, or approximately 50% or more These methods include myocardial performance index (MPI), blood pool MPI, tissue doppler MPI, and Well-known ventricular performance indices include, but are not limited to, pla-MPI, mean isovolumic contraction and relaxation, etc. It will not be done.

[0080] VI. Methods of the Invention The disclosed methods of the present invention involve improving exercise tolerance and / or ventricular performance, Improve exercise capacity and ventricular performance in patients with SVHD, including those after the Fontan procedure Generally, the method is preferably used in SVHD patients, including post-Fontan patients. an effective amount of an active PDE5 inhibitor, such as udenafil or a pharmaceutically acceptable salt thereof; or a pharmaceutically acceptable salt thereof, (a) Ventricular performance of functional single ventricle in patients with SVHD assessed by MPI; (b) exercise tolerance assessed by oxygen consumption during VAT; (c) Exercise tolerance assessed by oxygen consumption at submaximal exercise or VO2 max. Noh; (d) work rate at time of VAT; (e) VE / VCO2 at time of VAT; improving each individually or in any combination; (f) resting diastolic blood pressure; and (g) oxygen saturation at rest (%); individually, collectively, or in any combination.

[0081] Preferably, the method of the present invention improves the above (a) to (g), and each of the following measures is taken: More preferably, the present invention In this case, an effective amount of udenafil or its pharmaceutical preparations is administered to patients with SVHD, including those after the Fontan operation. By administering a suitable salt daily, the above (a) to (g) are improved, and the individual , together or in any combination.

[0082] As previously mentioned and as used herein, an effective PDE5 inhibitor is one that inhibits the growth of various tissues. c in response to cyclic GMP in smooth muscle cells lining the blood vessels supplying the It inhibits the decomposition action of GMP-specific phosphodiesterase 5 (PDE5).

[0083] As previously mentioned and as used herein, MPI refers to focused ) is a measure of ventricular contraction and diastolic function determined by echocardiography, and is also used in various heart diseases. This value is a prognostic and progression marker of isovolumic contraction time (ICT) and isovolumic relaxation time (ICT). It is defined as the sum of the intermittent heart rate (IRT) divided by the ejection time (ET) and is calculated for a single ventricle. Changes in myocardial performance index can be assessed by blood pool Doppler assessment of the outflow and inflow tract of a functional single ventricle. In other words, MPI is a measure of global cardiac dysfunction and It is a measure of global systolic and diastolic time intervals to assess ventricular performance. Furthermore, since MPI is a Doppler index, it is independent of ventricular geometry and is not associated with either SVHD or SVHD. Applies to both left and right ventricular function, depending on whether the ventricle is functionally single. It is possible.

[0084] More specifically, the method comprises administering an effective amount of an effective PDE5 inhibitor or a pharmaceutically acceptable salt thereof to a patient. by daily administration of a medicament containing denafenifide or a pharmaceutically acceptable salt thereof, preferably udenafil or a pharmaceutically acceptable salt thereof. , blindness or visual loss due to inhibition of the photoreceptor phosphodiesterase enzyme (PDE6), Back pain and / or muscle pain due to inhibition of PDE11, such as 11A1 (PDE11A1) and / or sperm concentration by inhibiting PDE11, such as 11A3 (PDE11A3) without causing treatment-limiting side effects, including but not limited to, a decrease in This includes achieving one or more of the above improvements. Kayik, G. et al.: Invest igation of PDE5 / PDE6 and PDE5 / PDE11 sele active potent tadalafil-like PDE5 inhibit ors using combination of molecular model ing approaches, molecular fingerprint-ba sed virtual screening protocols and stru cture-based pharmacophore development., J ournal of Enzyme Inhibition and Medicina l Chemistry, Volume 32 (Issue 1): Pages 311-330 (2017); Poma ra G. and Morelli G.: Inhibition of phospho diesterase 11 (PDE11) impacts on sperm q uality., Int J Impot Res, vol. 17: pp. 385-386 (200 5 years), and Huang SA and Lie, JD: Phosphodie sterase-5 (PDE5) Inhibitors.In the Manag ment of Erectile Dysfunction., Pharmacy and Therapeutics, Volume 38 (No. 7): Pages 407-419 (July 2013 month).

[0085] Quite uniquely and surprisingly, the methods of the present invention are useful in patients with S. elegans, including post-Fontan patients. Oxygen consumption at ventilatory anaerobic threshold (VAT) and submaximal exercise in patients with VHD Increase and / or maximize oxygen consumption during stress or VO2 max to improve exercise tolerance Improves performance and increases VAT work rate and VAT VE / VCO2 and / or is what is maximized.

[0086] Also, quite uniquely and surprisingly, the method of the present invention is useful for SVHD patients, i.e. In other words, the method of the present invention improves MPI in patients after the Fontan procedure. It improves both the systolic and diastolic function of the functional single ventricle and overall cardiac function. The method of the present invention provides a fill-and-drain property, i.e., fresh oxygen to meet the demands of peripheral tissues. function of the SVHD patient, including those after the Fontan operation, to pump blood containing improves pumping capacity of the primary single ventricle and overall performance of reconstructed abnormal SVHD hearts is.

[0087] The clinical value of MPI improvement was demonstrated in placebo-treated SVHD patients in the FUEL study. Patients treated with the method of the present invention compared to those who underwent Fontan surgery. Statistically significant improvement in MPI in SVHD patients, especially those after the Fontan procedure , is proven.

[0088] The clinical value of improving MPI was measured using the TDE, as mentioned above, to measure the isovolumic contraction time and isovolumic relaxation time. This is also evidenced by improved single ventricle performance as assessed by duration and ejection time.

[0089] "Isovolumic contraction time" (IVCT) is used herein to refer to the time during which a single ventricle contracts during early systole. This refers to an event during which the ventricle contracts isovolumically without any change in volume. This period of the cardiac cycle, the squeeze-out event, occurs with all heart valves closed.

[0090] "Isovolumic relaxation time" (IVRT) is used herein to refer to the time from the second heart sound (S2) emanating from the closure of the valve. The cardiac cycle, i.e., the period from the onset of cardiac contraction to the initiation of filling of the functional single ventricle following the opening of the valve. IVRT is the interval between contraction and relaxation of a functional single ventricle. It may be an indicator of a disorder.

[0091] "Ejection time" (ET) is used herein to measure the pressure difference across the valve when the valve is open and closed. This means the single ventricular ejection time (UVET) of the reconstructed abnormal heart, which is calculated by

[0092] "Stroke volume" as used herein refers to the amount of blood pumped into the circulatory system by a functional single ventricle in one contraction. This refers to the amount of fresh oxygenated blood available.

[0093] "Cardiac output" as used herein refers to the functional unit of cardiac output in SVHD patients, including post-Fontan patients. It refers to the amount of blood that the ventricles can pump into the circulatory system in one minute. The cardiac output is calculated by

[0094] The methods of the present invention provide improvements in the treatment of SVHD patients, including post-Fontan patients. Each is unique and surprising, but they are key to the treatment of SVHD patients, including those after the Fontan procedure. The combination of improvements in treatment is particularly unique and surprising.

[0095] In another embodiment, surprisingly, urea, such as sildenafil or tadalafil, Compared with previous, very limited studies with PDE5 inhibitors other than PHE, Udenaf In yet another embodiment, the method of the present invention has shown improved results when a medicament for treating a pulmonary edema is administered. Surprisingly, PDEs other than udenafil, such as sildenafil or tadalafil, Compared to other previous treatments using 5 inhibitors, the method of the present invention The method has been shown to have fewer and / or less severe side effects.

[0096] In some embodiments, the post-Fontan patient can be an adult human, while In other embodiments, the post-Fontan patient may be an adolescent human. In some embodiments, the Fontan patient may be between about 12 and about 19 years of age, while other In this embodiment, the post-Fontan patient can be between about 12 and 18 years of age. In this embodiment, the post-Fontan patient can be between about 12 and about 16 years of age. In other embodiments, the post-Fontan patient can be between about 6 years of age and adulthood. In some cases, post-Fontan patients can be under 18 years of age.

[0097] VII. Dosage and Formulation The structure of udenafil is shown below:

[0098] [ka]

[0099] In some embodiments, the udenafil or pharmaceutically acceptable salt thereof is about 0.01 In another embodiment, Udenaf may be administered in a total daily dose of about 150 mg / kg. The amount of the benzodiazepine or a pharmaceutically acceptable salt thereof is from about 0.01 mg / kg to a maximum of about 30 mg / kg. In another embodiment, udenafil or its pharmaceutical equivalents can be administered in a total daily dose of 100 mg / kg or more. Acceptable salts are about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, and about 12.5 mg , about 15mg, about 17.5mg, about 20mg, about 22.5mg, about 25mg, about 27.5 mg, about 30mg, about 32.5, about 35mg, about 37.5mg, about 40mg, about 42.5 mg, approx. 45 mg, approx. 47.5 mg, approx. 50 mg, approx. 52.5 mg, approx. 55 mg, approx. 57 .5mg, about 60mg, about 62.5mg, about 65mg, about 67.5mg, about 70mg, about 72.5mg, about 75mg, about 77.5mg, about 80mg, about 82.5mg, about 85mg , about 87.5mg, about 90mg, about 92.5mg, about 95mg, about 97.5mg, about 10 0mg, approx. 102.5mg, approx. 105mg, approx. 107.5mg, approx. 110mg, approx. 112 .5mg, about 115mg, about (bout)117.5mg, about 120mg, about 122.5 mg, approx. 125mg, approx. 127.5mg, approx. 130mg, approx. 132.5mg, approx. 135m g, approx. 137.5mg, approx. 140mg, approx. 142.5mg, approx. 145mg, approx. 147.5 mg, approx. 150mg, approx. 152.5mg, approx. 155mg, approx. 157.5mg, approx. 160m g, approx. 162.5mg, approx. 165mg, approx. 167.5g, approx. 170mg, approx. 172.5m g, about 175mg, about 180mg, about 182.5mg, about 185mg, about 187.5mg , about 190mg, about 192.5mg, about 195mg, about 197.5mg, about 200mg, Approx. 202.5mg, approx. 205mg, approx. 207.5mg, approx. 210mg, approx. 212.5mg , about 215mg, about 217.5mg, about 220mg, about 222.5mg, about 225mg, Approx. 227.5mg, approx. 230mg, approx. 232.5mg, approx. 235mg, approx. 237.5mg , about 240mg, about 242.5mg, about 245mg, about 247.5mg, about 250mg, Approx. 252.5mg, approx. 255mg, approx. 257.5mg, approx. 260mg, approx. 262.5mg , about 265 mg, about 267.5 mg, about 270 mg, about 272.5 mg, or about 275 The drug may be administered at a dose of about 2.5 mg to about 275 mg, for example, No individual dose has treatment-limiting toxicity that would prevent the product from being approved for marketing. In yet another embodiment, Udenaf The amount of the benzodiazepine or a pharmaceutically acceptable salt thereof is about 5 mg, about 10 mg, about 15 mg, about 20 mg , about 25mg, about 27.5mg, about 30mg, about 32.5, about 35mg, about 37.5mg , about 40mg, about 42.5mg, about 45mg, about 47.5mg, about 50mg, about 55mg , about 60mg, about 65mg, about 70mg, about 75mg, about 80mg, about 85mg, about 87 .5mg, about 90mg, about 95mg, about 100mg, about 125mg, about 150mg, about 1 About 5 mg, such as 75 mg, about 200 mg, about 225 mg, about 250 mg, or about 275 mg The total daily dose of the compound can be between 275 mg and about 275 mg, provided that the individual total daily doses are However, the total daily dose may not be approved for marketing due to treatment-limiting toxicities or side effects. It does not cause any effect.

[0100] In yet another embodiment, the udenafil or a pharmaceutically acceptable salt thereof is administered in an amount of about 25 ml g, approx. 37.5 mg, approx. 50 mg, approx. 75 mg, approx. 87.5 mg, 125 mg, approx. 175 mg, about 200mg, about 225mg, about 250mg, about 275mg, about 300mg, about 3 25mg, about 350mg, about 375mg, about 400mg, about 425mg, about 450mg, Approximately 475mg, approximately 500mg, approximately 525mg, approximately 550mg, approximately 575mg, approximately 600mg g, about 625 mg, about 650 mg, about 675 mg, or about 700 mg, etc., about 25 mg A total daily dose of about 700 mg to about 700 mg may be administered, provided that such individual total daily dose is However, if the total daily dose is not approved for marketing, there are treatment-limiting toxicities and treatment-limiting side effects. It does not cause any use.

[0101] In another embodiment, the udenafil or a pharmaceutically acceptable salt thereof is about 37.5 mg, May be administered at a total daily dose of about 75 mg, about 87.5 mg, 125 mg, or about 175 mg. In another embodiment, the udenafil or a pharmaceutically acceptable salt thereof is about 37 The total daily dose ranges from 0.5 mg to about 175 mg, preferably from 75 mg to about 175 mg. A total daily dose range of about 175 mg, more preferably about 87.5 mg to about 175 mg. The dose range is preferably 125 mg to about 175 mg, and most preferably 125 mg to about 175 mg. In a preferred embodiment, udenafil or any pharmaceutically acceptable salt thereof is Any dose or total daily dose can be administered to post-Fontan patients, but However, any of the selected individual doses and any of the selected individual total daily amounts Daily doses cause such treatment-limiting toxicities and side effects that they would not be approved for marketing. It is something that does not rub.

[0102] That is, the present invention provides any dosage, any total daily amount, any treatment regimen, any agent. In this form, udenafil or its pharmaceutically acceptable salts are administered to patients with SVHD, including those after the Fontan procedure. The present invention contemplates the administration of salts containing benzodiazepines, provided that any such doses, total daily doses, therapeutic levels, Treatment-limiting toxicity that would preclude marketing approval for Zymen, or any formulation selected. In particular, the present invention is applicable to patients, including those after the Fontan procedure. By administering an effective amount of udenafil or a pharmaceutically acceptable salt thereof to a patient with SVHD, MPI, single ventricle performance, systolic and / or diastolic function compared with untreated SVHD patients , ventricular pumping capacity, cardiac output, exercise tolerance at VAT and / or VO2 max, or Exercise capacity, work rate at VAT, VE / CO2 at VAT, diastolic blood pressure at rest, Improve oxygen saturation (%) and / or reduce the rate of decline in SVHD progression. The therapeutically effective amount is intended to inhibit the activity of PDE6 and / or PD There are no treatment-limiting toxicities or side effects associated with E11 inhibition and / or or does not cause treatment-limiting side effects that would preclude marketing of the drug product. is.

[0103] In one embodiment, udenafil or a pharmaceutically acceptable salt thereof is administered once daily. It is possible.

[0104] In another embodiment, udenafil or a pharmaceutically acceptable salt thereof is administered once daily. Alternatively, the dose can be divided into multiple doses, for example, twice a day, once a day, or It can also be administered three times a day, four times a day, or more times a day.

[0105] In yet another embodiment, udenafil or a pharmaceutically acceptable salt thereof is therapeutically effective The blood level is maintained for at least about 1.5 hours to about 24 hours during the 24-hour administration period. More specifically, at least about 1.5 hours, at least about 2 hours ...2 hours, at least about 2 hours, at least about 2 hours, at least about 2 hours, at least about 3 hours, at least about 4 hours, at least about 5 hours, at least about 6 hours, at least about 7 hours, at least about 8 hours, at least about 9 hours, at least about 10 hours, Approximately 11 hours, at least approximately 12 hours, at least approximately 13 hours, at least approximately 14 hours , at least about 15 hours, at least about 16 hours, at least about 17 hours, at least about 18 hours, at least about 19 hours, at least about 20 hours, at least about 21 hours, at least at least about 22 hours, at least about 23 hours, or at least about 24 hours. That is, the present invention provides udenafil and / or A 24-hour administration period with any active metabolite of udenafil, such as the active metabolite of DA8164 The present invention contemplates maintaining effective blood levels for any period within the period.

[0106] In some embodiments, udenafil or a pharmaceutically acceptable salt thereof when administered twice daily. The total daily dose of udenafil or its pharmaceutically acceptable salts when administered once daily is The total daily amount of salt consumed can be less than the recommended daily amount.

[0107] In some embodiments, udenafil or a pharmaceutically acceptable salt thereof when administered twice daily. The total daily dose of udenafil or its pharmaceutically acceptable salts is 100 mg / kg / day. Maintain therapeutically effective blood levels for the same number of hours in a 24-hour period as when administered once daily In other embodiments, udenafil or a pharmaceutically acceptable salt thereof when administered twice daily may be used. The total daily dose of udenafil or its pharmaceutically acceptable salts is the same as that of udenafil or its pharmaceutically acceptable salts. Maintain therapeutically effective blood levels for more hours over a 24-hour period than with a single dose That is, the present invention provides any total daily dose of udenafil or any of its acceptable doses. Tolerable salts can be taken once a day or in divided doses multiple times a day, e.g., twice a day, three times a day, or Dosing four times a day or more frequently daily can achieve therapeutically effective blood levels. It is intended to be maintained 24 hours a day.

[0108] In one embodiment, surprisingly, udenafil or a pharmaceutically acceptable salt thereof When administered twice daily, udenafil or its pharmaceutically acceptable salt is administered once daily. In another embodiment, surprisingly, udenafil or its derivatives have fewer side effects than Twice-daily administration of a pharmaceutically acceptable salt of Therapeutically effective levels of udenafil can be achieved.

[0109] In some embodiments, the pharmaceutically acceptable salt of udenafil is an acid addition salt. In one embodiment, the acid addition salt of udenafil is a hydrochloric acid addition salt, a hydrobromic acid addition salt, or an acid addition salt of udenafil. The salts may be inorganic acid addition salts such as salts, sulfate addition salts, or phosphoric acid addition salts. In embodiments, the acid addition salts include citrate, tartrate, acetate, lactate, maleate, fumarole, and the like. Salt, gluconate, methanesulfonate (mesylate), glycolate, succinate Salt, p-toluenesulfonate (tosylate), galacturonate, embonate, glutamate Salt, aspartate, oxalate, benzenesulfonate, camphorsulfonate Organic acid addition salts such as phosphates, cinnamates, adipates, or cyclamates In certain embodiments, the pharmaceutically acceptable salt of udenafil is an oxalate, a benzyl oxalate, or a benzoate. benzosulfonates, camphorsulfonates, cinnamates, adipates, or cyclamates It can be a amine salt.

[0110] In some embodiments, udenafil or a pharmaceutically acceptable salt thereof is used in pharmaceutical compositions In one embodiment, udenafil or a pharmaceutically acceptable salt thereof may be administered. Pharmaceutical compositions containing the salts can be used in a variety of oral or parenteral dosage forms for clinical applications. Each dosage form contains various disintegrants, surfactants, excipients, and It may contain diluents such as thickeners, binders, wetting agents, or other pharmaceutically acceptable excipients. It is possible.

[0111] The udenafil composition can be administered using any pharmaceutically acceptable method, e.g., For example, via an aerosol formulation or in a buccal or nasal gel or spray formulation. Through the formulation, it can be administered intranasally, bucally, sublingually, orally, rectally, or ophthalmically (ocu lar) administration, parenteral administration (intravenous administration, intradermal administration, intramuscular administration, subcutaneous administration, intracisternal administration) , intraperitoneal administration), intrapulmonary administration, intravaginal administration, topical administration, topical administration after scarification, mucosal administration It is possible.

[0112] Additionally, the udenafil composition can be formulated into any pharmaceutically acceptable dosage form, such as a solid dosage form. The formulation can be, for example, a tablet, pill, lozenge, capsule, caplet, buccal Disintegrating dosage forms, sublingual dosage forms, buccal dosage forms, liquids, liquid dispersions, liquid suspensions, solutions, aerosols ointments, pulmonary aerosols, nasal aerosols, and semisolid formulations, i.e., ointments, creams, etc. These include adhesives such as gums, thin films, and gels, as well as patches such as transdermal patches. Furthermore, the compositions may be in the form of controlled release formulations, sustained release formulations, immediate release formulations, or In addition, the composition may be an oral formulation, an oral administration formulation, an oral administration controlled formulation, or any combination thereof. It may also be a dermal delivery system.

[0113] In another embodiment, the pharmaceutical composition comprising udenafil or a pharmaceutically acceptable salt thereof is It can be formulated into a solid dosage form for oral administration, such as a powder, granules, or capsule. tablets, caplets, caches, orally disintegrating dosage forms, sublingual dosage forms, It may be a buccal dosage form, a lozenge, or a pill. Solid dosage forms include calcium carbonate, starch, sucrose, lactose, and microcrystalline cellulose. The composition may contain one or more excipients such as cellulose, cellulose acetate, or gelatin. In addition to the above excipients, the solid dosage form may contain lubricants such as talc or magnesium stearate. In some embodiments, the oral dosage form may be an immediate release formulation. The modified release dosage form may be a controlled release dosage form, a sustained release dosage form, or a modified release dosage form. Modified release dosage forms include modified release or sustained release dosage forms, and enteric release dosage forms. The excipients that can be used are those commonly known to those skilled in the art.

[0114] For example, solid carriers may serve as diluents, flavoring agents, binders, preservatives, oral dosage form disintegration agents, or encapsulating agents. It may be one or more substances that act as an injector. , capsules, tablets, caplets, caches, lozenges, or pills Oral dosage forms such as the above preferably contain 5% to 70% udenafil. Carriers include magnesium carbonate, magnesium stearate, talc, sugar, lactose (e.g., lactose monohydrate), pectin, dextrin, starch (e.g., corn starch), (H), gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose cellulose, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, dioxide These include silicon (e.g., colloidal silicon dioxide), low-melting waxes, and cocoa butter. The term "preparation" refers to any solid, liquid, or pharmaceutical preparation of udenafil, with or without encapsulating material. is intended to encompass semi-solid matrix formulations.

[0115] Liquid formulations include solutions, suspensions, and emulsions, for example, water or water / pro For parenteral injection, liquid preparations are typically in polyethylene glycol solution. For example, an aqueous solution suitable for oral use can be prepared by dissolving the drug in an aqueous solution of Nafil is dissolved in water and, if desired, suitable colorants, flavoring agents, stabilizers, and thickeners are added. In another example, aqueous suspensions suitable for oral use can be prepared by adding Powdered udenafil is mixed with natural or synthetic rubber, resin, methylcellulose, carboxyl Disperse the mixture in water containing a viscous substance such as a well-known suspending agent, such as sodium methylcellulose. It can be prepared by

[0116] Also, solid preparations that are intended to be converted, shortly before use, into liquid preparations for oral administration. Such liquid forms include solutions, suspensions, and emulsions. In one embodiment, the pharmaceutical composition is administered orally, such as in a suspension, emulsion, or syrup. It can be formulated into a liquid dosage form for use, and in addition to udenafil, it can also contain coloring agents, flavoring agents, stabilizers, Buffers (salts of inorganic acids such as phosphates, borates, and sulfates) are used to adjust the pH for intravenous administration. buffers to adjust to desired ranges), artificial and natural sweeteners, dispersants, thickeners, solvents In another embodiment, the liquid dosage form may contain water and liquid paraffin. In addition to the commonly used simple diluents such as ethanol, humectants, sweeteners, aromatic compounds, or Various excipients, such as preservatives, may be included. In certain embodiments, udenafi Compositions containing benzodiazepine or a pharmaceutically acceptable salt thereof are suitable for administration to pediatric patients. It can be formulated.

[0117] In one embodiment, the pharmaceutical composition is a sterile aqueous solution, suspension, emulsion, or In other embodiments, the compound can be formulated into a dosage form for parenteral administration, such as a non-aqueous solution. The non-aqueous solution or suspension may contain propylene glycol, polyethylene glycol, oleic acid, Vegetable oils such as corn oil, or injectable esters such as ethyl oleate may be included. Alternatively, the pharmaceutical composition may be formulated into a dosage form for rectal or vaginal administration. The suppository bases are Witepsol, Macrogol, Tween 61, and cocoa. Fats, lauric oils, or glycerinated gelatin can be used.

[0118] The pharmaceutical formulations may require the addition of suitable co-solvents such as surfactants in the formulation. Cosolvents such as polysorbate 20, polysorbate 60, and polysorbate Pluronic F-68, Pluronic F-84, and Pluronic P-103 cyclodextrin; and polyoxyl 35 castor oil. The solvent is typically used at a level of about 0.01% to about 2% by weight. To reduce the variability of the formulation, the physical separation of the components of the suspension or emulsion is minimized. To reduce the viscosity and / or improve formulation, a viscosity greater than that of a simple aqueous solution may be used. Such viscosity-increasing agents may be, for example, polyvinyl alcohol. , polyvinylpyrrolidone, methylcellulose, hydroxypropylmethylcellulose, Hydroxyethyl cellulose, carboxymethyl cellulose, hydroxypropyl cellulose chondroitin sulfate and its salts, hyaluronic acid and its salts, and combinations thereof Such agents are typically present at a level of about 0.01% to about 2% by weight. Used.

[0119] The pharmaceutical preparation is preferably in unit dose form. In such form, the preparation may be administered in a suitable and divided into unit doses containing a quantity of udenafil or any acceptable pharmaceutical salt thereof. The unit dosage form may be a packaged preparation such as a packet, and the package The pack contains individual doses of the drug product and is packaged in a vial or ampoule. Available in pellets, capsules, orally disintegrating dosage forms, sublingual dosage forms, buccal dosage forms, and powders. The unit dosage form may also be a capsule, tablet, caplet, pill, orally disintegrating agent. It may be in the form of a tablet, sublingual dosage form, buccal dosage form, cachet, or lozenge tablet itself. Alternatively, any of these may be packaged in an appropriate number. .

[0120] The pharmaceutical compositions may be immediate release, sustained release, extended release, modified release, convenient, and / or comfortable. Such ingredients may include high molecular weight anionic viscosity enhancers. Membrane-mimetic polymers, gelling polysaccharides, and micronized drug carrier matrices Examples include:

[0121] In another embodiment, the pharmaceutical composition comprising udenafil or a pharmaceutically acceptable salt thereof is They can be formulated as orally disintegrating, sublingual, or buccal dosage forms. Such dosage forms include sublingual tablet or solution compositions that are administered under the tongue, and pacifiers that are placed between the cheek and gum. It consists of a steroid tablet.

[0122] The pharmaceutical preparation may be prepared by further containing a coating agent, for example, ultraviolet light. sunscreens, metal oxides such as titanium oxide, etc., which can generate free radicals by As a free radical scavenger, for example, a coating of an organic acid such as benzoic acid In addition, the coating agent may contain a water-soluble polymer (e.g., hypromethane). cellulose or hydroxypropyl cellulose), polyethylene glycol, tricitric acid Ethyl, cellulose acetate phthalate, hydroxypropyl methylcellulose acetate succinate, Polyvinyl acetate phthalate, methyl methacrylate-methacrylic acid copolymer, shell Lac, cellulose acetate succinate, cellulose acetate trimellitate, hydroxy phthalate Contains propyl methylcellulose, zein, sodium alginate, and mannitol and / or an enteric coating layer containing ethyl cellulose, medium chain triglycerides, Enteric coating solution containing leic acid, sodium alginate, stearic acid, etc. These include, but are not limited to:

[0123] In yet another embodiment, a pharmaceutical composition comprising udenafil or a pharmaceutically acceptable salt thereof. The product can be formulated as a nasal dosage form. Such dosage forms of the present invention are suitable for nasal delivery. These include solution compositions, suspension compositions, emulsion compositions, and gel compositions.

[0124] In one embodiment, the pharmaceutical composition is a liquid such as a solution, suspension, emulsion, or syrup. In another embodiment, the liquid dosage form can be formulated as follows: In addition to the commonly used simple diluents such as water and liquid paraffin, It may contain various excipients such as cereals, spices, aromatic compounds, or preservatives. In an embodiment, a composition comprising udenafil or a pharmaceutically acceptable salt thereof is administered to a pediatric patient. It can be formulated to be suitable for administration.

[0125] The dosage of the pharmaceutical composition is determined based on the patient's weight, age, sex, administration time, administration method, excretion rate, and may vary depending on the severity of the disease.

[0126] VIII. Exercise stress testing Exercise stress tests include submaximal exercise stress or ventilatory anaerobic threshold (VAT) stress. The VO2 value of the VO2 max ("maximum VO2"), or maximum ("Maximum") oxygen consumption is the maximum oxygen available to an individual during strenuous exercise. This measurement is considered a reliable indicator of cardiovascular fitness and aerobic endurance. Theoretically, the more oxygen available during exercise, the better a person can produce. Muscles require oxygen for prolonged (aerobic) exercise, and blood is needed to The heart must pump enough blood to carry oxygen to the muscles and meet the demands of aerobic exercise. This test is often used to measure cardiorespiratory fitness. Although peak VO2 may be useful as a surrogate for many cardiovascular disease states, In this unique physiology, the right Central venous pressure, or cardiac output, rather than ventricular contraction (pumping), is the primary driver of transpulmonary blood flow. Driving factors. Gewillig M and Goldberg DJ. Failur e of the fontan circulation.Heart Fail C lin., Vol. 10(Issue 1): pp. 105-116(January 2014); Egbe AC, C onnolly HM, Miranda WR, Ammash NM, Hagler D J, Veldtman GR, and Borlaug BA., Hemodynamic s of Fontan Failure: The Role of Pulmona ry Vascular Disease., Circ Heart Fail., 10 Volume (12): e004515 (September 2017); Gewillig M, Brown SC, Eyskens B, Heying R, Ganame J, Budts W; La Gerche A., and Gorenflo M., The Fontan ci. rculation: who controls cardiac output? Interact Cardiovasc Thorac Surg., Vol. 10(Issue 3) : pages 428-433 (March 2010); and Goldberg DJ, Avita bile CM, McBride MG, and Paridon SM., Exerci se capacity in the Fontan circulation., C ardiol Young., Volume 23 (No. 6): Pages 824-830 (December 2013) With the increase in cardiac output due to strenuous exercise, the central venous pressure in the Fontan circulation must rise to meet the demands of the Navaratnam D, Fitzsim mons S, Grocott M, Rossiter HB, Emmanuel Y, Diller GP, Gordon-Walker T, Jack S, Sheron. N, Pappachan J, Pratap JN, Vettukattil JJ, O. and Veldtman G., Exercise-Induced Systemic Venous Hypertension in the Fontan Circul ation., Am J Cardiol., Volume 117 (No. 10): Pages 1667-167. 1 (May 15, 2016). During submaximal exercise, the increase in central venous pressure is due to this physiological Because the limit of exercise is not reached, outcomes at this exercise level are not comparable to the response of pharmacological manipulation of the pulmonary vasculature. may be more susceptible to

[0127] VO2 is measured by having the subject wear a mask and measuring the volume of inhaled and exhaled air and gas concentrations. This measurement is often used in both clinical practice and research. The test is usually conducted at increasing intensity until exhaustion. The submaximal exercise of the subject was performed either on a dorm or on a bicycle ergometer. It is designed to take readings at stress and / or at the subject's anaerobic threshold.

[0128] Patients who have had a previous Fontan procedure typically experience a decrease in VO2 measurements over time. A patient may be treated with the methods disclosed herein to achieve a consistent VO2 reading. If the VO2 function was maintained at a similar level, it would indicate that no further decline in VO2 function occurred. If the treatment improves the cardiovascular function, the treatment is clinically beneficial. may improve cardiovascular function, prevent cardiovascular decline, or slow the rate of cardiovascular decline. This indicates that there is something. IX. Myocardial Performance Index (MPI)

[0129] Generally speaking, the MPI (also called the Doppler-derived index or Tei index) is A measure of ventricular systolic and diastolic function determined by focused echocardiography. MPI evaluates cardiac function by combining the time intervals between systole and diastole. More specifically, MPI is a ventricular function expressed numerically using cardiac time intervals. This value can be used to evaluate isovolumic contraction time (ICT) and isovolumic relaxation time. It is equal to the sum of the inter-ventricular time (IRT) divided by the ejection time (ET) and is used for either the left or right ventricle. Pellett, AA et al.: The Tei I ndex:Methodology and Disease.State Value s., Echocardiography: A Jrnl.of CV Ultras Sound & Allied Tech., Vol. 21(No. 7): pp. 669-672(200 4 years); and Ulucay, A., Tatli E.: Myocardial per formance index., Anadolu Kardiyol Derg., 8 Vol. (No. 2): pp. 143-8 (April 2008) (both of which are incorporated herein by reference in their entireties). In the FUEL study, the performance of functional single ventricles was assessed by MPI. That is, the MPI results from the FUEL study were compared with the outflow and inflow blood pool Doppler images of a functional single ventricle. In other words, the MPI of the FUEL test is , cardiac time intervals using pulsed Doppler velocity spectra of ventricular inflow and outflow in a functional single ventricle. It was determined by measurement.

[0130] X. Echocardiography Echocardiography was performed by sonographers specially trained for this protocol. The primary outcome was MPI using Doppler-based outflow and inflow duration measurements. The duration of inflow into the main ventricle and the duration of outflow through the main semilunar valves were measured and calculated using standard formulas. Tei C, Ling LH, Hodge DO, et al.: New index of combined systolic and diastolic c myocardial performance: a simple and re producible measure of cardiac function-a study in normals and dilated cardiomyop athy., J Cardiol, Vol. 26 (No. 6): pp. 357-66 (1995); Pellet AA et al.: The Tei Index: Methodology and Disease State Values., Echocardiograp hy:A Jrnl Of CV Ultrasound & Allied Tech , Vol. 21 (No. 7): pp. 669-672 (2004). Further tissue Doppler images were obtained. This was used to calculate MPI based on the tissue Doppler method mentioned above. Harada K, Tamura M, Toyono M, et al: Comparison of the right ve ntricular Tei index by tissue Doppler im aging to that obtained by pulsed Doppler in children without heart disease., Am J Cardiol, Vol. 90 (No. 5): pp. 566-9 (2002). Measurements were taken and the average duration was used in the calculations.

[0131] These methods can be further understood from the following non-limiting examples. [Example]

[0132] Example 1 Fontan-Udenafil Exercise Longitudinal (FUEL) Study The FUEL trial was conducted at 30 centers around the world. A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of Udenafil in Adolescents with SVHD This was a controlled trial. (Mezzion Pharma Co., Ltd.) The Pediatric Heart Network, funded by the National Heart, Lung, and Blood Institute, with funding from the National Heart and Blood Institute. Conducted by ClinicalTrials.gov number: NCT027411 15).

[0133] The primary objective was to evaluate the effect of Fontan physiology on exercise tolerance over a 6-month period in adolescents. The primary outcome was a 2-month increase from baseline in urinary tract infections (URI) and urinary tract infections (URI). Change in oxygen consumption at peak exercise (maximum or VO2 max) by the 6-week visit Secondary exercise outcomes were changes in additional measures at maximal exercise load and Changes in submaximal exercise measures at ventilatory anaerobic threshold (VAT) were clinical outcomes. The secondary primary outcomes were echocardiographic measures of systolic and diastolic ventricular function. Changes in myocardial performance index (MPI), which is the degree of myocardial ischemia, and changes in peripheral vascular function obtained by the PAT method. The change in the log-transformed reactive hyperemia index (lnRHI), a measure of hyperemia, and the change in the log-transformed hyperemia index (lnH1) were The change in serum BNP levels was the endpoint. Safety was monitored through adverse event reporting. ,Adverse event reporting will follow a pre-specified protocol from the Study Coordinator Outreach. Information was collected through ad hoc patient and family interactions with study team members at each site. .

[0134] Study population Those aged 12 to 18 years, who have had the Fontan operation, and who are taking PDE5 inhibitors not receiving treatment with steroids, weighing more than 40 kg, and meeting the minimum height requirement for bicycle ergometry Those who met the required height (132 cm or more) were eligible for inclusion. To isolate the effects of vasodilator therapy on the ventricular function, we performed a randomized controlled trial in patients with severe ventricular dysfunction and severe atrioventricular regurgitation. Patients with a peak oxygen consumption of 50% of the predicted value for age and sex in a preclinical exercise test Patients with a mean age of 18 or older were excluded. A complete list of inclusion and exclusion criteria is shown in Table 1.

[0135] [Table 1]

[0136] Randomization and study procedures After enrollment, subjects were randomized to udenafil or placebo using permuted block randomization. Patients were randomized 1:1 and stratified by ventricular morphology (left ventricular, right ventricular, or mixed). After confirmation of study eligibility and consent, participants were selected by an internet-based algorithm. were randomly assigned.

[0137] Baseline laboratory tests completed before starting treatment showed brain natriuretic peptide (BNP) levels Blood samples were taken to measure NP (non-peptide) levels, and cardiac activity was assessed using a standard cycle ergometer training protocol. Pulmonary exercise testing (CPET), standard echocardiogram, and finger cuff (Endo PAT: Itamar Medical, Israel Peripheral vascular function was evaluated using peripheral arterial tonometry (PAT), which is measured by During CPET, a respiratory exchange ratio (RER) of 1.10 or greater at peak exercise was defined as Subjects who achieved submaximal exercise load were eligible for randomization and initiation of study medication. Subjects who did not achieve a submaximal exercise load were asked to complete the exercise at a subsequent opportunity within 2 weeks of their first attempt. The exercise stress test was repeated. Clinical examinations at the end of the study included repeated measurements of serum BNP, CPE, and T, echocardiogram, and PAT were performed.

[0138] statistical analysis With a type I error rate of 0.05, the mean change in VO2 peak from baseline to week 26 of the study was To allow for 90% power to detect a mean treatment difference of 10% of change, 20 A sample size of 0 subjects was chosen, given the following: baseline standard deviation The correlation between the maximum VO2 measurements was 0.33, and the dropout rate was 7.235 ml / kg / min. The rate of non-completion and failure to complete the study was 10%, and 15% of subjects had a maximum score of 0.001 on the 26-week exercise stress test. These assumptions are based on historical data and may not be intersubject specific. This reflects a conservative approach to assessing correlations and the failure to achieve submaximal exercise load. do.

[0139] The primary analysis used the intention-to-treat population to examine the variation in the primary outcome between treatment groups. The difference in ventricular morphology (single left ventricle vs. single right ventricle, or The covariates were defined as: 1) VO2 max (or VO2 max) and treatment group as fixed factors, and 2) VO2 max (or VO2 max) as a continuous covariate. Analysis of variance (ANCOVA) was used. For subjects who did not have data at the 26th week visit, This value was imputed as the same as the baseline value (no change). Subjects who completed the protocol with measurable secondary endpoints were included. Analyses of secondary outcomes that are continuous data points are described in the case of the primary outcome. To assess the generalizability of the findings at the ventilatory anaerobic threshold, a human Comparison of demographic and clinical characteristics was performed in subjects without matched VAT VO2 data. and the remainder of the cohort.

[0140] Test results Between July 2016 and May 2018, 1,376 patients were screened at 30 institutions. Figure 1B. Of these, 200 patients received udenafil and 200 received placebo. At the time of randomization, the mean age was 15.5 years and the mean height was 163 cm. The mean diameter was 6 cm and the mean weight was 58.1 kg. Sixty percent of the subjects were male, and 81% described his racial identity as Caucasian. were taller than subjects in the control group, but otherwise baseline characteristics were similar between groups. .

[0141] Primary purpose: Measure of movement Maximal exercise data (VO2 max) were available for all subjects during baseline testing. At the 26-week trial, 379 subjects (189 in the udenafil group and 190 in the placebo group) were enrolled. The lack of data from the 26-week study was due to the patient's withdrawal. The reasons for this were: omissions, data collection errors (n=14), and subjects' inability to achieve an RER of 1.10 or greater ( n=7). There were no significant differences between the udenafil and placebo groups in resting heart rate, respiratory rate, There was no difference in the change in systolic blood pressure from baseline to the 26-week study. There was a small but statistically significant increase in resting oxygen saturation in the denafil group, and also a small However, there was a statistically significant reduction in diastolic blood pressure.

[0142] Resting data and exercise performance results are shown in Table 2.

[0143] [Table 2]

[0144] Resting diastolic blood pressure analysis showed an increase of +0.2 compared with the placebo group (no improvement). There was a statistically significant change (a decrease indicates an improvement) in diastolic blood pressure in the udenafil group (-2.9 A significant difference (reduction, improvement) was observed (p=0.003).

[0145] Analysis of resting oxygen saturation (%) showed a decrease of -0.3 compared with the placebo group (no improvement). There was a statistically significant change (an increase indicates an improvement) in oxygen saturation (%) in the udenafil group compared to the control group. (+0.5 increase, improvement) was shown (p=0.002).

[0146] Analysis of maximal exercise showed a decrease of 3.7 mL / min (-0.2%) in the placebo group. In the udenafil group, VO2 max increased by 44 mL / min (2.8%). However, the difference did not reach statistical significance (p=0.071).

[0147] Furthermore, metabolic data for calculating VO2 during VAT were collected from 3 Data were available from 17 subjects, 170 in the udenafil group and 181 in the placebo group. Compared with the larger cohort, baseline demographics in this subgroup were No differences were observed in characteristics or clinical features. The udenafil group experienced a 30 mL / min decrease compared to a 8 mL / min decrease (-0.7%) in the placebo group. There was a statistically significant (p=0.023) improvement of 1.92% L / min. The measured carbon dioxide ventilation equivalent (VE / VCO2) was 0.05 (0.2 %) in the udenafil group compared with 0.8 (2.1%) in the udenafil group (p=0.011). The results showed a significant decrease (improvement in ventilatory efficiency), while the power output was 0.31 watts ( 0.78%) in the udenafil group compared with 3.5 wt (5.5%) in the udenafil group (p Therefore, after the Fontan procedure, 87.5 mg twice daily was shown to improve the efficacy of the drug. Treatment of patients was statistically significant on multiple measures of exercise capacity at the ventilatory anaerobic threshold. showed a significant improvement.

[0148] Secondary Objective Scale Paired echocardiographic data for MPI measurements were available for 250 (63%) subjects. There were 122 patients in the udenafil group and 128 in the placebo group. Table 3. Placebo group There was a statistically significant difference in MPI in the udenafil treatment group compared with the control group (+0.01 increase, no improvement). There was a significant (p=0.028) change (decrease indicates improvement) (decrease of -0.02, improvement). Ta.

[0149] Paired PAT-derived vascular function data were available for 328 (81%) subjects. The udenafil group had 163 patients and the placebo group had 165 patients. In both the placebo and lnRHI groups, the improvement was not significant (0.07, 0. 05, p=0.59). Paired serum BNP measurements were performed in 378 (95%) subjects. The logarithmic serum B The change in NP values did not differ between groups (p=0.18). The vascular function data obtained from the corresponding PAT and the corresponding serum BNP level scale are presented. Shown in 3.

[0150] [Table 3]

[0151] [Table 4]

[0152] Safety and Tolerability

[0153] [Table 5]

[0154] Udenafil and placebo were well tolerated by subjects. No deaths occurred in the study cohort. A total of 24 subjects (6%) experienced serious adverse events, 14 of which were arm-related. 10 were in the nafil group and 10 in the placebo group. There were three events considered probable or definite in the udenafil group and one in the pram group. There were two cases in the Sebo group. Events occurring in the udenafil group included unilateral retinal artery thrombosis, unilateral retinal artery thrombosis, and These include intravenous thrombosis, transient paraplegia, and transient dyspnea. Occurred in at least 5% of subjects and may be related to the study drug Common non-serious adverse events considered to be of high or definite incidence are shown in Table 4. Headache, Facial flushing, abdominal pain, nosebleeds, and erections (male subjects) were more common in the udenafil group. All other adverse events occurred with similar frequency between groups.

[0155] Example 2 Further FUEL test results The following example is based on Goldberg, DJ, which is incorporated herein by reference in its entirety. et al:Results of the Fontan Udenafil Exercis e Longitudinal (FUEL) Trial.Circulation; The above-mentioned F mentioned in Vol. 141 (No. 8): 141: pp. 641-651 (2020) This provides further explanation of the UEL test.

[0156] The Fontan procedure involves the creation of a total cavopulmonary anastomosis, a circulation in which pulmonary vascular resistance is of great importance. Over time, this circulation can lead to cardiovascular problems associated with reduced exercise capacity. This leads to a decrease in efficiency. There is a lack of clinical trials.

[0157] The FUEL trial was a Phase III clinical trial conducted at 30 centers. Participants received 2 doses of 100mg of cefotaxime twice daily. Patients were randomly assigned in a 1:1 ratio to receive 87.5 mg of udenafil or placebo. The outcome was the between-group difference in change in peak exercise oxygen consumption. Secondary outcomes included: Intergroup differences in changes during submaximal exercise at ventilatory anaerobic threshold (VAT), myocardial performance index (MPI), the natural logarithm of the reactive hyperemia index (lnRHI), and serum cerebral sodium tolerance. Urinary peptides (BNP) were included.

[0158] Between 2017 and 2019, 30 clinical sites in North America and South Korea conducted 400 subjects with Fontan physiology were randomized. Mean age at randomization was 18.2 years. The age range was 15.5 ± 2 years, 60% of the subjects were male, and 81% were white. subjects were included in the primary analysis, and 21 subjects (11 with udenafil) had missing data. 10 randomized to placebo) were included in the 26-week assessment. Among randomized subjects, peak oxygen consumption was 44 ± 245 mL / min in the udenafil group. (2.8%), and in the placebo group, it decreased by 3.7 ± 228 mL / min (-0.2%) ( p=0.071). VAT analysis showed that the udenafil group and the placebo group showed significantly improved oxygen consumption. Consumption (+33±185(3.2%)mL / min vs. -9±193(-0.9%)mL / min , p=0.012), carbon dioxide ventilation equivalent (-0.8 vs. -0.06, p=0.014 ), and power (+3.8 watts vs. +0.34 watts, p=0.021). The MPI analysis also showed a statistically significant improvement compared to the placebo group over the same period. Compared with the control group, the udenafil treatment group showed a statistically significant improvement (p=0.028). There was no difference in the changes in RHI and serum BNP levels.

[0159] In the FUEL study, treatment with udenafil (87.5 mg twice daily) Improvement in oxygen consumption during exercise (p=0.071) and (i) ventilatory anaerobic threshold (VA (ii) multiple measures of exercise capacity at rest, (iii) MPI, and (iv) resting diastolic blood pressure. and (iv) there was a statistically significant improvement in resting oxygen saturation (%).

[0160] The FUEL trial was funded by Medione Pharma and funded by the National Heart, Lung, and Blood Institute. This study was conducted by the Pediatric Heart Network, which supports the study. ClinicalTrials.g ov number: NCT02741115 (incorporated herein by reference in its entirety).

[0161] Clinical perspective New phase Publication in Circulation: Largest Medical Intervention Trial in Congenital Heart Disease The authors describe the results of the Fontan-Udenafil Exercise Longitudinal (FUEL) trial. dberg DJ et al.: Results of the FUEL Trial.Ci rculation, vol. 141(no. 8):141: pp. 641-651 (2020) Goldberg DJ et al.: Results of Experiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, f the FUEL Trial., Circulation, Vol. 141(No. 8):1 Circulation 41: pp. 641-651 (2020) errata has been added. The adjusted MPI results for the EL study are presented. Treatment with udenafil did not statistically significantly increase peak oxygen consumption, but This resulted in a noticeable increase in peak oxygen consumption. Treatment with udenafil improved exercise capacity at ventilatory anaerobic threshold (VAT), a measure of exercise capacity. Power at VAT, carbon dioxide ventilation equivalent (VE / VCO2) at VAT, MPI, resting state The study resulted in statistically significant improvements in diastolic blood pressure and oxygen saturation at rest. Udenafil was well tolerated by FUEL study subjects, with side effects reported as phosphodiesterase inhibitors. The findings were limited to those previously known to be associated with enzyme 5 inhibitors.

[0162] clinical implications Udenafil has been evaluated in a large Phase III clinical trial to evaluate its efficacy in patients with pulmonary embolism after Fontan surgery. It is the first drug to show quantifiable benefits on measures of athletic performance in adolescents. These findings suggest that udenafil treatment may be beneficial for patients undergoing total cavopulmonary bypass. Hort's physiological function, exercise capacity, work rate, VE / VCO 2、 MPI, cardiac output, milking Squeezing performance, the ability to circulate throughout the body within a certain period of time Improved flow, resting diastolic blood pressure and / or oxygen saturation, and functional single ventricle performance. This suggests that it can be improved. Ongoing research is investigating the long-term clinical course of people living with single ventricle congenital heart disease. There is a need to determine the impact of chronic treatment with udenafil on

[0163] Children born with single ventricle congenital heart disease (SVHD) require a defective A series of staged surgical procedures is required to reconstruct the damaged heart. The final planned palliative surgery in this series of staged surgical procedures to reconstruct the heart The Fontan procedure, which is a surgical procedure for the treatment of pulmonary artery disease, connects the systemic and pulmonary circulations by creating a total cavopulmonary anastomosis. Fontan F and Baudet E., Surgical repair of tricuspid atresia.Thorax., Volume 26 ( 3, pp. 240-248 (May 1971); and Kreutzer G, Gal indez E, Bono H, De Palma C, and Laura JP., A n operation for the correction of tricus pid atresia.The Journal of thoracic and Cardiovascular Surgery., Vol. 66(4): pp. 613-621 (October 1973).

[0164] However, due to the absence of a subpulmonary pump, the resulting Fontan circulation is It is passive and characterized by chronically elevated central venous pressure and low cardiac output. Gewillig M and Goldberg DJ. Failure of t he fontan circulation.Heart Fail Clin., 1 Volume 0 (Issue 1): Pages 105-116 (January 2014); Egbe AC, Connol ly HM, Miranda WR, Ammash NM, Hagler DJ, Vel. dtman GR, and Borlaug BA., Hemodynamics of Fontan Failure: The Role of Pulmonary Va Scular Disease., Circ Heart Fail., Vol. 10 (Issue 12 ):e004515(September 2017); Gewillig M, Brown SC, Eyskens B, Heying R, Ganame J, Budts W, La G. erche A., and Gorenflo M., The Fontan circul ation: who controls cardiac output?, Inte ract Cardiovasc Thorac Surg., Volume 10 (Issue 3): Page 42 8~433 (March 2010); and Goldberg DJ, Avitabile CM, McBride MG, and Paridon SM., Exercise c apacity in the Fontan circulation., Cardi ol Young., Vol. 23(No. 6): pp. 824-830 (December 2013). Although vasodilators are well tolerated in childhood, cardiovascular efficiency declines throughout adolescence. Descending into adulthood. Dennis M, Zannino D, du Pless is K, Bullock A, Disney PJS, Radford DJ, Hor nung T, Grigg L, Cordina R, d'Udekem Y, and C. elermajer DS., Clinical Outcomes in Adole scents and adults After the Fontan Proce dure., J Am Coll Cardiol., Vol. 71 (No. 9): pp. 1009~1. 017 (March 6, 2018);Fernandes SM, McElhinney D B, Khairy P, Graham DA, Landzberg MJ, and Rho des J., Serial cardiopulmonary exercise t esting in patients with previous Fontan surgery., Pediatr Cardiol., Volume 31 (No. 2): pp. 175-1 80 (February 2010); Giardini A, Hager A, Pace Napo leone C, and Picchio FM., Natural history o f exercise capacity after the Fontan ope ration: a longitudinal study., Ann Thorac Surg., Volume 85 (No. 3): Pages 818-21 (March 2008); Jenkins PC, Chinnock RE, Jenkins KJ, Mahle WT, Mulla. N, Sharkey AM, and Flanagan MF., Decreased exercise performance with age in childre n with hypoplastic left heart syndrome. J Pediatr., vol. 152(4): pp. 507-512(April 2008);Pa ridon SM, Mitchell PD, Colan SD, Williams R V, Blaufox A, Li JS, Margossian R, Mittal S,R. ussell J, Rhodes J, and Pediatric Heart Network Investigators, A cr oss-sectional study of exercise performance nce during the first 2 decades of life a fter the Fontan operation., J Am Coll Car diol., Vol. 52(No. 2): pp. 99-107 (July 8, 2008); and Atz AM, Zak V, Mahony L, Uzark K, D'Agincourt N. , Goldberg DJ, Williams RV, Breitbart RE, Co lan SD, Burns KM, Margossian R, Henderson H T, Korsin R, Marino BS, Daniels K, McCrindle. BW, and Pediatric Heart Network investigators, Longitudinal Outco mes of Patients With Single Ventricle Af ter the Fontan Procedure., J Am Coll Card iol., Vol. 69 (No. 22): pp. 2735-2744 (June 6, 2017). is associated with decreased exercise tolerance, decreased overall cardiac function, decreased single ventricle performance, and heart failure symptoms. This correlates with increased prevalence of HIV, increased hospitalization, and increased mortality. , Dimopoulos K, Okonko D, Li W, Babu-Narayan. SV, Broberg CS, Johansson B, Bouzas B, Mull. en MJ, Poole-Wilson PA, Francis DP, and Gatz. oulis MA., Exercise intolerance in adults congenital heart disease: comparative se verity, correlates, and prognostic impli cation., Circulation., Vol. 112(No. 6): pp. 828-35(20 August 9, 2005); Diller GP, Giardini A, Dimopoulos K, Gargiulo G, Muller J, Derrick G, Giannak. oulas G, Khambadkone S, Lammers AE, Picchio F.M., Gatzoulis M.A., and Hager A., Predictors of morbidity and mortality in contempora ry Fontan patients: results from a multi center study including cardiopulmonary xercise testing in 321 patients., Eur Hea rt J., Volume 31 (No. 24): Pages 3073-3083 (December 2010);Down ing TE, Allen KY, Glatz AC, Rogers LS, Ravis hankar C, Rychik J, Faerber JA, Fuller S, Mo ntenegro LM, Steven JM, Spray TL, Nicolson SC, Gaynor JW, and Goldberg DJ., Long-term s urvival after the Fontan operation: Twen ty years of experience at a single cente r., The Journal of thoracic and cardiovas cular surgery., 154 volumes (1 issue): pages 243 - 253 e2 (2017 July); Khairy P, Fernandes SM, Mayer JE, Jr. ., Triedman JK, Walsh EP, Lock JE, and Landzbe rg MJ., Long-term survival, modes of deat h, and predictors of mortality in patien ts with Fontan surgery., Circulation., 117 volumes (1 issue): pages 85 - 92 (January 1, 2008); Pundi KN, Johnson JN, Dearani JA, Pundi KN, Li Z, Hinck CA, Da hl SH, Cannon BC, O’Leary PW, Driscoll DJ, and Cetta F., 40-Year Follow-Up After the F ontan Operation: Long-Term Outcomes of 1 ,052 Patients., J Am Coll Cardiol., Vol. 66 (15 Issue): pages 1700-1710 (October 13, 2015); Cunningham JW , Nathan AS, Rhodes J, Shafer K, Landzberg M J, and Opotowsky AR., Decline in peak oxygen n consumption over time predicts death o r transplantation in adults with a Fonta n circulation., Am Heart J., vol. 189: pp. 184-192 (July 2017); Udholm S, Aldweib N, Hjortda l VE, and Veldtman GR., Prognostic power of cardiopulmonary exercise testing in Fon tan patients: a systematic review., Open Heart., Volume 5(Issue 1):e000812 (July 2018).

[0165] After the Fontan procedure, pulmonary blood flow is determined by the central venous pressure, pulmonary vascular resistance, and systemic atrial pressure. This construction depends on the relationship between the The role of pulmonary vascular resistance as a regulator of pulmonary blood flow and univentricular preload has been expanded in This is crucial for circulation efficiency. Gewillig M and Goldberg DJ.、Failure of the fontan circulation.He Art Fail Clin., Vol. 10(1): pp. 105-116 (January 2014) ;Egbe AC, Connolly HM, Miranda WR, Ammash N M., Hagler DJ, Veldtman GR., and Borlaug BA., H. emodynamics of Fontan Failure: The Role of Pulmonary Vascular Disease., Circ Hear t Fail., Vol. 10(Issue 12):e004515(September 2017);Gewill ig M, Brown SC, Eyskens B, Heying R, Ganame. J., Budts W., La Gerche A., and Gorenflo M., The Fontan circulation: who controls cardia c output?, Interact Cardiovasc Thorac Sur g., Vol. 10(3): pp. 428-433 (March 2010); and Goldber g DJ, Avitabile CM, McBride MG, and Paridon SM., Exercise capacity in the Fontan circ ulation., Cardiol Young., Volume 23 (No. 6): pp. 824-830 (December 2013). In a previous report, phosphodiesterase 5 (PDE5) inhibition Administration of pulmonary vasodilators, including Agnol, has been investigated with mixed results. etti G, Gala S, Ferroni F, Bordese R, Append ini L., Pace Napoleone C., and Bergamasco L.; Endothelin inhibitors lower pulmonary va scular resistance and improve functionality Fontan循环患者的容量 ation.、《胸心血管外科杂志》。 153卷(6期):第1468 - 1475页(2 017年6月);Goldberg DJ、French B、McBride MG、 Marino BS、Mirarchi N、Hanna BD、Wernovsky G、Paridon SM、以及Rychik J.、口服西地那非对Fontan手术后儿童和年轻人运动能力的影响:一项随机、双盲、 安慰剂对照、交叉试验。、《循环》。 123卷(11期):第1185 - 1193页(2011年5月2 2日);Hebert A、Mikkelsen UR、Thilen U、Idorn L、Jensen AS、Nagy E、Hanseus K、Sorensen K E、以及Sondergaard L.、波生坦改善Fontan手术后青少年和成年人的运动能力:TEMPO(Fontan患者内皮素受体拮抗剂治疗,一项随机、 安慰剂对照、双盲研究测量 ​​​​​​​uring Peak Oxygen Consumption) study.、Ci rculation.、130巻(23号):頁2021~2030(2014年12月 2日);Mori H、Park IS、Yamagishi H、Nakamura M、Ishikawa S、Takigiku K、Yasukochi S、Naka yama T、Saji T、およびNakanishi T.、Sildenafil reduces pulmonary vascular resistance i n single ventricular physiology.、Int J C ardiol.、221巻:頁122~127(2016年10月15日);Rhode s J、Ubeda-Tikkanen A、Clair M、Fernandes S M、Graham DA、Milliren CE、Daly KP、Mullen M P、およびLandzberg MJ.、Effect of inhaled ilo prost on the exercise function of Fontan patients: a demonstration of concept.、I nt J Cardiol.、168巻(3号):頁2435~2440(2013年1 0月3日);Schuuring MJ、Vis JC、van Dijk AP、va n Melle JP、Vliegen HW、Pieper PG、Sieswerd a GT、de Bruin-Bon RH、Mulder BJ、およびBouma BJ.、Impact of bosentan on exercise capac ity in adults after the Fontan procedure : a randomized controlled trial., Eur JH eart Fail., Vol. 15(No. 6): pp. 690-698(June 2013);Tun ks RD, Barker PC, Benjamin DK, Jr., Cohen-W. olkowiez M, Fleming GA, Laughon M, Li JS, and and Hill KD. Sildenafil exposure and hemody namic effect after Fontan surgery., Pedia tr Crit Care Med., Volume 15 (No. 1): Pages 28-34 (January 2014 );Van De Bruaene A, La Gerche A, Claessen G, De Meester P, Devroe S, Gillijns H, Bogae. rt J, Claus P, Heidbuchel H, Gewillig M, and Budts W., Sildenafil improves exercise he modynamics in Fontan patients., Circ Card iovasc Imaging., Volume 7 (No. 2): Pages 265-273 (March 2014) ;Goldberg DJ, French B, Szwast AL, McBride MG, Marino BS, Mirachi N, Hanna BD, Wernovs. ky G, Paridon SM, and Rychik J., Impact of s ildenafil on echocardiographic indices o f myocardial performance after the Fonta n operation., Pediatr Cardiol., Volume 33 (No. 5): Page 6 89~696 (June 2012); and Giardini A, Balducci A, Specchia S, Gargiulo G, Bonvicini M, and P icchio FM., Effect of sildenafil on haemo dynamic response to exercise and exercise e capacity in Fontan patients., Eur Heart J., Vol. 29 (Issue 13): pp. 1681-1687 (July 2008).

[0166] A Phase I / II Study of Udenafil, a Long-Acting PDE5 Inhibitor (Medione-Fa (Seoul, Republic of Korea) has completed a study in adolescent patients with Fontan physiology. and was well tolerated at all dosing regimens tested. Goldberg DJ, Zak V, Goldstein BH, Chen S, Hamstra MS, Radojew. ski EA, Maunsell E, Mittal S, Menon SC, Schum acher KR, Payne RM, Stylianou M, Kaltman JR. , deVries TM, Yeager JL, Paridon SM, and Pediatric Heart Network researcher, Results of a phase I / II multi -center investigation of udenafil in ado lescents after fontan palliation., Am Hea rt J., Vol. 188: pp. 42-52 (June 2017). 87.5 mg twice daily. The mean serum concentrations were highest in this group, and no dose-limiting adverse events occurred. Fontan Ude (PHN) longitudinal study Nafil Exercise Longitudinal (FUEL) Trial (NCT 02741115) in adolescent patients undergoing Fontan palliative care over a 6-month period. To evaluate the effects of udenafil on exercise capacity and other cardiovascular and functional outcomes. Ta.

[0167] method The FUEL study was conducted in adolescent patients with SVHD who had previously undergone Fontan palliative care. This was an international, multicenter, randomized, double-blind, placebo-controlled trial of udenafil in addition to standard treatment. The study was funded by the National Heart, Lung, and Blood Institute (NHLBI) and is supported by regulatory approval. The study was initiated in collaboration with Medione Pharma, the sponsor of the study, and is approved by the Food and Drug Administration. The above FUEL protocol and consent form, as well as subsequent All amendments to the Guidelines will be reviewed by the DSMB, each study center's Institutional Review Board or equivalent, and It has been approved by regulatory authorities in the United States, Canada, and the Republic of Korea. If the participant was under 18 years of age, consent was obtained from their legal guardian. The study design was previously published. rg DJ, Zak V, Goldstein BH, McCrindle BW, Me non SC, Schumacher KR, Payne RM, Rhodes J,M. cHugh KE, Penny DJ, Trachtenberg F, Hamstra MS, Richmond ME, Frommelt PC, Files MD, Yea ger JL, Pemberton VL, Stylianou MP, Pearson. GD, Paridon SM, and researchers from the Pediatric Heart Network, Design and rationale of the Fontan Udenafil Exe rcise Longitudinal (FUEL) trial., Am Hear t J., Volume 201: Pages 1-8 (July 2018).

[0168] Study population Those aged 12 to 18 years, who have had the Fontan operation, and who are taking PDE5 inhibitors not undergoing treatment with steroids, weighing more than 40 kg, and having completed at least one cycle ergometer Those who met the required height (132 cm or more) were eligible for inclusion. To isolate the effects of vasodilators on patients with severe ventricular dysfunction and severe atrioventricular regurgitation, Patients with a peak oxygen consumption of 50% or less than the predicted value for age and sex in a preclinical exercise test Patients with < % of the CI were excluded. A complete list is provided in Table 1 above.

[0169] Randomization and study procedures After enrollment, subjects were randomized in a double-blind, permuted block randomization design to receive either udenafil or were randomized to placebo in a 1:1 ratio, and ventricular morphology (left ventricular, right ventricular, or mixed) After confirmation of study eligibility and consent, participants were randomly selected via internet access. Randomization was performed by algorithm.

[0170] Baseline laboratory tests completed before starting treatment showed brain natriuretic peptide (BNP) levels Blood samples were taken to measure NP (non-peptide) levels, and cardiac activity was assessed using a standard cycle ergometer training protocol. Pulmonary exercise testing (CPET) (previously reported in children and adolescents with Fontan physiology) Announcement, Sleeper LA, Anderson P, Hsu DT, Mahony L, McCrindle BW, Roth SJ, Saul JP, Williams RV. , Geva T, Colan SD, Clark BJ, and Pediatric Heart Network Researcher, Design of a large cross-sectional st udy to facilitate future clinical trials in children with the Fontan palliation. Am Heart J., Volume 152 (No. 3): Pages 427-433 (September 2006), Standard echocardiograms and finger cuff echocardiograms (EndoPAT; Itamar Medical) were performed. Peripheral arterial tonometry (PAT) was used to measure the peripheral arterial pressure (PAP) of the ventricle. Vascular function was evaluated. During CPET, the respiratory exchange ratio (RER) was 1.1 at peak exercise. Subjects who achieved submaximal exercise stress, defined as a score of 0 or greater, were considered for randomization and study drug administration. Subjects who did not achieve submaximal exercise load were initially eligible for the study within 2 weeks of the first attempt. The exercise stress test was repeated at the next opportunity within 14 days. Clinical examination at the end of the test showed serum BN Repeated measurements of P, CPET, echocardiogram, and PAT were performed.

[0171] Primary and secondary endpoints The primary objective was to evaluate the effect of Fontan physiology on exercise tolerance over a 6-month period in adolescents. The primary outcome was a 2-month increase from baseline in urinary tract infections (URI) and urinary tract infections (URI). Between-group differences in change in oxygen consumption at peak exercise (VO2 max) by the 6-week visit Secondary exercise outcomes included changes in additional measures at maximal exercise load and The difference between groups was the change in a measure of submaximal exercise at the aerobic anaerobic threshold (VAT). All dynamic stress test measurements were initially performed by exercise physiologists and physicians at each participating institution. These were then reviewed by two trained reviewers (MGM, SMP) at each facility. The results were reviewed for accuracy by one of the researchers in collaboration with the athletic team at each facility in a blinded manner. The final decision was made after the examination. Both the maximum VO2 and the VO2 at VAT were determined by the physical habits (b To avoid introducing confounding based on short-term changes in body habits, Unindexed oxygen consumption was assessed. The analysis of oxygen consumption is shown in Table 5.

[0172] [Table 6]

[0173] The imputation was performed as follows: Subjects who were confirmed alive but discontinued the study (and whose VO2 peak was missing at 26 weeks) is the most recent value available (e.g., the value at the end of the study visit if available, otherwise If so, the value at the baseline visit was assigned. Completed 26 weeks and was physically unable to reach maximal effort in a cardiopulmonary exercise test after two attempts Subjects who were unable to achieve the maximum effort in the baseline exercise test were Upon reaching force, subjects were assigned a baseline value. One exception was subject 330011, who was selected for inclusion because he had an RER of 1.10. It was rejected.

[0174] The primary clinical secondary outcome was systolic and diastolic cardiac rhythms obtained by echocardiography. Between-group differences in the change in myocardial performance index (MPI), a measure of ventricular function, obtained by the PAT method Changes in the log-transformed reactive hyperemia index (lnRHI), a measure of peripheral vascular function The between-group differences and the between-group differences in the change in log-transformed serum BNP levels were used as secondary outcomes. Each measurement of the OUTCOME was performed in a core laboratory. Safety was monitored through adverse event reporting. Reporting of adverse events will be conducted through a pre-specified protocol for study coordinator outreach. Through ad hoc patient and family information exchanges with study team members at each site, in accordance with the guidelines. were collected.

[0175] statistical analysis With a type I error rate of 0.05, the mean change in peak VO2 from baseline to week 26 of the study was To allow for 90% power to detect a mean treatment difference of 10% of change, 20 A sample size of 0 subjects was chosen. The baseline standard deviation was 7.235 ml / kg / min, and the correlation between peak VO2 measurements was 0.33, with dropout rates and study incompletion The rate was 10%, and 15% of subjects achieved submaximal exercise stress during the 26-week exercise test. These assumptions are based on historical data and are not intersubject correlations. This reflects a conservative approach to assessing the effect of exercise and the failure to achieve submaximal exercise load. Analysis was performed using independent two-sample mean t-tests. The population was used to assess the difference in change in the primary outcome between treatment groups. The ventricular morphology (single left ventricle, single right ventricle, or mixed) and treatment group were used as fixed factors. Analysis of covariance (ANCOVA) was performed with baseline peak VO2 as a continuous covariate. For subjects without data at the 26-week visit, this value was the same as the baseline value. The α value was set at 0.05 using two-sided tests. All statistical analyses were The analysis was performed using SAS statistical software 9.4 (SAS Institute Inc.). The analysis was performed using a 3D printer (ITUTE, Inc., Cary, North Carolina). The analysis included subjects who completed the protocol with measurable values for each secondary endpoint. The analysis of secondary outcomes that were continuous data points was performed in the same manner as for the primary outcome. To assess the generalizability of findings at the ventilatory anaerobic threshold, Demographic characteristics were assessed using Student's t-test and Fisher's exact test. Comparison of clinical characteristics was performed between subjects without matched VAT VO2 data and the cohort. The remaining subjects were divided into two groups: the udenafil cohort and the placebo cohort. Fisher's exact test was used to compare adverse events between the groups.

[0176] result Subjects: Between July 2016 and May 2018, 1376 patients were screened at 30 centers. Figure 1B. Of these, 200 were treated with udenafil and 200 with pla. At randomization, the mean age was 15.5 years and the mean height was 1.5 cm. The average height was 63.6 cm and the average weight was 58.1 kg. Sixty percent of the subjects were male. 81% described their racial identity as White. Subjects were taller than subjects in the udenafil group, but other baseline characteristics were was similar between groups.

[0177] [Table 7]

[0178] Measures of Movement The resting, submaximal, and maximal exercise measures are shown in Table 2. The maximal exercise data were Available for all subjects at baseline and 379 subjects at 26 weeks (189 in the udenafil group and 190 in the placebo group) were available. Reasons for missing data during the study included patient dropouts, data collection errors (n=14), and subject The main reasons for the failure to achieve an RER of 1.10 or higher were: There were no significant differences between the placebo and baseline in resting heart rate, respiratory rate, and systolic blood pressure. There was no difference in the change from baseline to the 26-week study. Although the placebo group had a higher airway volume, there was no difference in the change in minute ventilation between the groups. The fill group had a small but statistically significant increase in resting oxygen saturation and a small but statistically significant increase in There was a statistically significant reduction in diastolic blood pressure.

[0179] Analysis of maximal exercise showed a decrease of 3.7 mL / min (-0.2%) in the placebo group. In the udenafil group, peak VO2 increased by 44 mL / min (2.8%), The difference did not reach statistical significance (Figures 2A-B, p=0.071). Metabolic data for calculating T VO2 were available for 351 subjects. There were 170 patients in the steroid group and 181 in the placebo group. No differences were observed in baseline demographic or clinical characteristics between the subgroups Table 7. With paired VAT VO2 data, the udenafil group had a VO2 of 29.7 m There was a statistically significant improvement of 2.85% in the placebo group compared with 9.5% in the placebo group. A decrease in mL / min (-0.8%) occurred during VAT (Figures 3A-B, p=0.023). The measured ventilatory carbon dioxide equivalent (VE / VCO2) was 0.05 compared with 0.05 in the placebo group. In the udenafil group, there was a significant decrease of 0.8 (p=0.0114) (improvement in ventilatory efficiency) while the power output was 0.31 watts (0.5%) compared with 0.31 watts (0.5%) in the placebo group. The denafil group showed a significant improvement of 3.5 watts (5.2%). Figures 4A-4B , p=0.029.

[0180] [Table 8]

[0181] Secondary Objectives Paired echocardiographic data for MPI measurements were available for 250 (63%) subjects. The number of patients was 122 in the udenafil group and 128 in the placebo group. Table 3. Placebo group There was a statistically significant difference in MPI in the udenafil treatment group compared with the control group (+0.01 increase, no improvement). There was a significant change (decrease indicates improvement) in (-0.02 decrease, improvement) (p=0.02 8) Vascular function data obtained from matched PAT were available for 328 subjects (81%). The data were available from the udenafil group (163 patients) and the placebo group (165 patients). The improvement in lnRHI was not significant in either the placebo or the control group (0.07, 0.05, p=0.59). Paired serum BNP levels were measured in 378 (95%) patients. Log blood pressure was available from 187 participants in the udenafil group and 191 in the placebo group. Changes in serum BNP levels did not differ between groups (p=0.18).

[0182] Safety and Tolerability Udenafil and placebo were well tolerated by subjects. No deaths occurred in the study cohort. A total of 24 subjects (6%) experienced serious adverse events, 14 of which were arm-related. 10 were in the nafil group and 10 in the placebo group. There were three events considered probable or definite in the udenafil group and one in the pram group. There were two cases in the Sebo group. Events occurring in the udenafil group included unilateral retinal artery thrombosis, unilateral retinal artery thrombosis, and These include venous thrombosis, transient paraplegia, and transient dyspnea. High frequency non-serious events that are considered possible, likely, or definite Serious adverse events are shown in Table 4. Headache, hot flush, abdominal pain, epistaxis, and erection (male subjects) were reported. The incidence of priapism was higher in the udenafil group. No cases of priapism were reported. Other adverse events were All occurred with similar frequency between groups.

[0183] Consideration The FUEL trial evaluated udenafi in children with SVHD who underwent the Fontan procedure. A Phase III clinical trial of udenafil was conducted. Although the relative improvement in VO2 did not reach statistical significance, treatment with udenafil significantly improved submaximal Udenafi demonstrated statistically significant improvements in the prespecified secondary endpoint of exercise. Subjects randomized to the IV-1000 group were evaluated for oxygen consumption, work rate, and ventilation at anaerobic threshold. PAT-induced reactive hyperemia showed a greater increase in myocardial efficiency and myocardial performance index. No relative improvement was observed in the index. Overall, udenafil was associated with few serious adverse events. Side effects are generally limited to those known to be associated with PDE5 inhibitor therapy. Goldberg DJ, French B, McBr ide MG, Marino BS, Mirachi N, Hanna BD, Wer. novsky G, Paridon SM, and Rychik J., Impact of oral sildenafil on exercise performan ce in children and young adults after th e fontan operation: a randomized, double -blind, placebo-controlled, crossover tr ial., Circulation., Vol. 123(No. 11): pp. 1185-1193(2 May 22, 011);Goldberg DJ, Zak V, Goldstein B H, McCrindle BW, Menon SC, Schumacher KR, Pa. yne RM, Rhodes J, McHugh KE, Penny DJ, Trach. tenberg F, Hamstra MS, Richmond ME, Frommel. t PC, Files MD, Yeager JL, Pemberton VL, Sty. Ianou MP, Pearson GD, Paridon SM, and Pediatric Cardiac Nephrology Pediatric Heart Network I., De sign and rationale of the Fontan Udenafi l Exercise Longitudinal (FUEL) trial., Am Heart J., vol. 201: pp. 1-8 (July 2018); and Chang H J, Song S, Chang SA, Kim HK, Jung HO, Choi JH. , Lee JS, Kim KH, Jeong JO, Lee JH, and Kim DK. .,Efficacy and Safety of Udenafil for th e Treatment of Pulmonary Arterial Hypert ension: a Placebo-controlled, Double-bli nd, Phase IIb Clinical Trial., Clin Ther. , Volume 41 (No. 8): Pages 1499-1507 (August 2019).

[0184] The Fontan procedure and its modifications have saved a generation of patients with SVHD who would otherwise have died. However, the circulation created by this surgery has been chronically elevated central venous pressure and heart rate. They have an inherent physiological defect that results in a chronically reduced output. M and Goldberg DJ., Failure of the fontan c Irrigation. Heart Fail Clin., Vol. 10(1): pp. 105 ~116(January 2014);Egbe AC, Connolly HM, Mirand a WR, Ammash NM, Hagler DJ, Veldtman GR, and Borlaug BA., Hemodynamics of Fontan Failu re: The Role of Pulmonary Vascular Disease se., Circ Heart Fail., Vol. 10(Issue 12): e004515(20 September 2017); Gewillig M, Brown SC, Eyskens B , Heying R, Ganame J, Budts W, La Gerche A, O. Yo and Gorenflo M., The Fontan circulation: wh o controls cardiac output?, Interact Card iovasc Thorac Surg., Volume 10 (No. 3): Pages 428-433 (201 (March 2010). The fundamental limitations to cardiovascular efficiency in the Fontan circulation are numerous and generally , abnormalities in pulmonary vascular resistance, abnormalities in single ventricle diastolic function, endothelial damage in systemic and pulmonary vessels, pathological blood Examples include tube remodeling. Egbe AC, Connolly HM, Mira nda WR, Ammash NM, Hagler DJ, Veldtman GR, and Borlaug BA., Hemodynamics of Fontan Fai lure: The Role of Pulmonary Vascular Dis ease., Circ Heart Fail., Vol. 10 (Issue 12): e004515( September 2017);Averin K, Hirsch R, Seckeler MD, W hiteside W, Beekman RH, 3rd, and Goldstein BH., Diagnosis of occult diastolic dysfun ction late after the Fontan procedure us ing a rapid volume expansion technique. Heart., Volume 102 (Issue 14): Pages 1109–1114 (July 15, 2016); Goldstein BH, Connor CE, Gooding L, and Rocc hini AP., Relation of systemic venous ret urn, pulmonary vascular resistance, and diastolic dysfunction to exercise capaci ty in patients with single ventricle rec eiving fontan palliation., Am J Cardiol. Volume 105 (No. 8): Pages 1169-1175 (April 15, 2010); Hays BS, Baker M, Laib A, Tan W, Udholm S, Goldstein. BH, Sanders SP, Opotowsky AR, and Veldtman G. R., Histopathological abnormalities in th e central arteries and veins of Fontan s Subjects., Heart., Vol. 104 (No. 4): pp. 324-331 (February 2018) Khambadkone S, Li J, de Leval MR, Cullen S, Deanfield JE, and Redington AN., Basal p. ulmonary vascular resistance and nitric oxide responsiveness late after Fontan-t type operation., Circulation., Vol. 107(No. 25): pp. 3 204~3208 (July 1, 2003); Mitchell MB, Campbell DN, Ivy D, Boucek MM, Sondheimer HM, Pietra. B, Das BB, and Coll JR., Evidence of pulmon ary vascular disease after heart transpl antation for Fontan circulation failure. , J Thorac Cardiovasc Surg., Volume 128 (No. 5): Page 693 ~702 (November 2004); and Sarkola T, Jaeggi E, Sl orach C, Hui W, Bradley T, and Redington AN. ,Assessment of vascular remodeling after the Fontan procedure using a very novel high resolution ultrasound method: arte rial wall thinning and venous thickening in late follow-up., Heart Vessels., Volume 28 (1 Issue: pp. 66-75 (January 2013). Each of the above pathological features of circulation is a promising therapeutic target. Regarding pharmacotherapy with drugs designed to reduce pulmonary vascular resistance, which may be effective These agents have been evaluated for their broad range of tolerability, efficacy in treating pulmonary hypertension, and efficacy in treating pulmonary hypertension. Insights are gained from the unique role of pulmonary vascular resistance as a regulator of cardiac output after pulmonary resistance surgery. . Egbe AC, Connolly HM, Miranda WR, Ammash N M., Hagler DJ, Veldtman GR., and Borlaug BA., H. emodynamics of Fontan Failure: The Role of Pulmonary Vascular Disease., Circ Hear t Fail., Volume 10(Issue 12):e004515(September 2017).

[0185] Previous studies using other pulmonary vasodilators in patients with Fontan circulation have been equivocal. Agnoletti G, Gala S, Ferroni F, Bord ese R, Appendini L, Pace Napoleone C, and Be. rgamasco L., Endothelin inhibitors lower pulmonary vascular resistance and improv e functional capacity in patients with F ontan circulation., J Thorac Cardiovasc S urg., Volume 153 (No. 6): Pages 1468-1475 (June 2017); Goldbe rg DJ, French B, McBride MG, Marino BS, Mira rchi N, Hanna BD, Wernovsky G, Paridon SM, and Rychik J., Impact of oral sildenafil on exercise performance in children and yo ung adults after the fontan operation: a randomized, double-blind, placebo-contr olled, crossover trial., Circulation., 123 Volume (issue 11): pages 1185 - 1193 (May 22, 2011); Hebert A, M ikkelsen UR, Thilen U, Idorn L, Jensen AS, N agy E, Hanseus K, Sorensen KE, and Sondergaa rd L., Bosentan improves exercise capacit y in adolescents and adults after Fontan operation: the TEMPO (Treatment With En dothelin Receptor Antagonist in Fontan P atients, a Randomized, Placebo - Controlle d, Double - Blind Study Measuring Peak Oxy gen Consumption) study., Circulation., 130 Volume (issue 23): pages 2021 - 2030 (December 2, 2014); Mori H, Par k IS, Yamagishi H, Nakamura M, Ishikawa S, T akigiku K, Yasukochi S, Nakayama T, Saji T, and Nakanishi T., Sildenafil reduces pulmo nary vascular resistance in single ventr icular physiology., Int J Cardiol., 221 Volume: pages 122 - 127 (October 15, 2016); Rhodes J, Ubeda - Tikk anen A, Clair M, Fernandes SM, Graham DA, Mi lliren CE, Daly KP, Mullen MP, and Landzberg MJ., Effect of inhaled iloprost on the e xercise function of Fontan patients: a d emonstration of concept.、Int J Cardiol.、 Vol. 168(No. 3): pp. 2435 - 2440 (October 3, 2013); Schuurin g MJ, Vis JC, van Dijk AP, van Melle JP, Vli egen HW, Pieper PG, Sieswerda GT, de Bruin- Bon RH, Mulder BJ, and Bouma BJ.、Impact of bosentan on exercise capacity in adults after the Fontan procedure: a randomized controlled trial.、Eur J Heart Fail.、Vol. 15 (No. 6): pp. 690 - 698 (June 2013); Tunks RD, Barker P C, Benjamin DK, Jr., Cohen-Wolkowiez M, Fle ming GA, Laughon M, Li JS, and Hill KD.、Sild enafil exposure and hemodynamic effect a fter Fontan surgery.、Pediatr Crit Care M ed.、Vol. 15(No. 1): pp. 28 - 34 (January 2014); Van De Bruae ne A, La Gerche A, Claessen G, De Meester P 、Devroe S, Gillijns H, Bogaert J, Claus P, H eidbuchel H, Gewillig M, and Budts W.、Silde nafil improves exercise hemodynamics in Fontan patients., Circ Cardiovasc Imaging ., Volume 7 (Issue 2): Pages 265-273 (March 2014); Goldberg DJ, F rench B, Szwast AL, McBride MG, Marino BS, M irarchi N, Hanna BD, Wernovsky G, Paridon S M, and Rychik J., Impact of sildenafil on e chocardiographic indices of myocardial p performance after the Fontan operation.,P ediatr Cardiol., Volume 33 (No. 5): Pages 689-696 (June 2012 ); and Giardini A, Balducci A, Specchia S, G argiulo G, Bonvicini M, and Picchio FM., Eff. ect of sildenafil on haemodynamic response se to exercise and exercise capacity in Fontan patients., Eur Heart J., vol. 29 (issue 13): p. 1681-1687 (July 2008). Several small studies across a range of pulmonary vasodilator classes. Large single-center trials have shown that acute improvement occurs after a single dose, but these trials The study did not examine sustained effects or long-term use. Rhodes J , Ubeda-Tikkanen A, Clair M, Fernandes SM, G Raham DA, Milliren CE, Daly KP, Mullen MP, and Landzberg MJ., Effect of inhaled ilopro st on the exercise function of Fontan pa tients: a demonstration of concept., Int J Cardiol., 168(3):2435 - 2440(October 3, 2013); Tunks RD, Barker PC, Benjamin DK, Jr., C ohen - Wolkowiez M, Fleming GA, Laughon M, Li JS, and Hill KD., Sildenafil exposure and hemodynamic effect after Fontan surgery. , Pediatr Crit Care Med., 15(1):28 - 34(January 2014); Van De Bruaene A, La Gerche A, Cla essen G, De Meester P, Devroe S, Gillijns H , Bogaert J, Claus P, Heidbuchel H, Gewillig M, and Budts W., Sildenafil improves exerc ise hemodynamics in Fontan patients., Cir c Cardiovasc Imaging., 7(2):265 - 273(March 2014); and Giardini A, Balducci A, Specchi a S, Gargiulo G, Bonvicini M, and Picchio FM . Effect of sildenafil on haemodynamic r esponse to exercise and exercise capacitance y in Fontan patients., Eur Heart J., Vol. 29(1 3, pp. 1681-1687 (July 2008). Adolescent and adult patients after the Fontan procedure. Two medium-sized trials evaluated the use of endothelin receptor antagonists in human patients. These two studies showed conflicting results, and a phase I study in this cohort was not conducted. Hebert A, Mikkelsen UR, Thilen U, I dorn L, Jensen AS, Nagy E, Hanseus K, Sorens en K.E., and Sondergaard L., Bosentan improves s exercise capacity in adolescents and a dults after Fontan operation: the TEMPO (Treatment With Endothelin Receptor Anta gonist in Fontan Patients, a Randomized, Placebo-Controlled, Double-Blind Study Measuring Peak Oxygen Consumption) study ., Circulation., Vol. 130 (No. 23): pp. 2021-2030 (2014 December 2, 2014); and Schuuring MJ, Vis JC, van Dijk AP, van Melle JP, Vliegen HW, Pieper PG, Si eswerda GT, de Bruin-Bon RH, Mulder BJ, and Bouma BJ., Impact of bosentan on exercise capacity in adults after the Fontan pro cedure: a randomized controlled trial. ur J Heart Fail., Volume 15 (No. 6): pp. 690-698 (June 2013 Furthermore, even in studies where benefit was suggested, this benefit was not due to the putative efficacy of the drug. It was accompanied by a drop in hemoglobin levels, a side effect that likely offset any benefit. t A, Mikkelsen UR, Thilen U, Idorn L, Jensen. AS, Nagy E, Hanseus K, Sorensen KE, and Sond ergaard L., Bosentan improves exercise ca pacity in adolescents and adults after F ontan operation: the TEMPO (Treatment Wi th Endothelin Receptor Antagonist in Fon tan Patients, a Randomized, Placebo-Cont rolled, Double-Blind Study Measuring Pea k Oxygen Consumption) study., Circulation ., Vol. 130 (No. 23): pp. 2021-2030 (December 2, 2014). This FUE The L study is a phase I clinical trial in adolescent patients with SVHD after Fontan palliative care. The first large-scale study to suggest physiological benefits associated with the use of specific pulmonary vasodilators at controlled doses. This is a mock multi-center study.

[0186] The challenges of living with Fontan physiology are well illustrated by assessments of exercise capacity. Adolescents with Fontan physiology have a reduced exercise tolerance compared to healthy individuals, This difference becomes more pronounced over time and is associated with increased rates of hospitalization and heart failure symptoms. . Fernandes SM, McElhinney DB, Khairy P, Gra ham DA, Landzberg MJ, and Rhodes J., Serial cardiopulmonary exercise testing in pati ents with previous Fontan surgery., Pedia tr Cardiol., Volume 31 (No. 2): Pages 175-180 (February 2010); Gi ardini A, Hager A, Pace Napoleone C, and Pic chio FM., Natural history of exercise cap acity after the Fontan operation: a long itudinal study., Ann Thorac Surg., Vol. 85(No. 3). : pages 818~21 (March 2008); Jenkins PC, Chinnock RE , Jenkins KJ, Mahle WT, Mulla N, Sharkey AM, and Flanagan, M.F., Decreased exercise performance. rmance with age in children with hypoplasia stic left heart syndrome., J Pediatr., 152 Vol. (4): pp. 507-512 (April 2008); Paridon SM, Mitch ell PD, Colan SD, Williams RV, Blaufox A, Li JS, Margossian R, Mittal S, Russell J, Rhode. s J, and Pediatric Cardiac Network researchers, A cross-sectional study of exercise performance during the first 2 decades of life after the Fonta n operation., J Am Coll Cardiol., Vol. 52(No. 2): pp. 99-107 (July 8, 2008); Atz AM, Zak V, Mahony L , Uzark K, D'Agincourt N, Goldberg DJ, Willi ams RV, Breitbart RE, Colan SD, Burns KM, Ma. rgossian R, Henderson HT, Korsin R, Marino. BS, Daniels K, McCrindle BW, and Pediatric Heart Network Researcher, Longitudinal Outcomes of Patients Wi th Single Ventricle After the Fontan Pro cedure., J Am Coll Cardiol., Volume 69 (No. 22): Page 273 5~2744 (June 6, 2017); Diller GP, Dimopoulos K , Okonko D, Li W, Babu-Narayan SV, Broberg C S, Johansson B, Bouzas B, Mullen MJ, Poole-W. ilson PA, Francis DP, and Gatzoulis MA., Exe. rcise intolerance in adult congenital he art disease: comparative severity, corre lates, and prognostic implication.、Circu lation.、112th volume (issue 6): pages 828 - 35 (August 9, 2005); Dill er GP, Giardini A, Dimopoulos K, Gargiulo G 、Muller J, Derrick G, Giannakoulas G, Khamb adkone S, Lammers AE, Picchio FM, Gatzoulis MA, and Hager A., Predictors of morbidity and mortality in contemporary Fontan pat ients: results from a multicenter study including cardiopulmonary exercise testi ng in 321 patients.、Eur Heart J., 31st volume (issue 24 ): pages 3073 - 3083 (December 2010); Cunningham JW, Nat han AS, Rhodes J, Shafer K, Landzberg MJ, and Opotowsky AR., Decline in peak oxygen co nsumption over time predicts death or tr ansplantation in adults with a Fontan ci rculation.、Am Heart J., 189th volume: pages 184 - 192 (July 201 7); as well as, Udholm S, Aldweib N, Hjortdal VE 、and Veldtman GR., Prognostic power of car diopulmonary exercise testing in Fontan patients: a systematic review., Open Hear t., Vol. 5 (No. 1): e000812 (July 2018). Predicted by age and gender. Exercise tolerance should be below 50% of the normal range, and if it is exceeded, circulatory-related pathological conditions are likely to occur. This is the approximate threshold at which a person becomes depressed, typically during their 20s, but may occur earlier. Diller GP, Giardini A, Dimopoulos K , Gargiulo G, Muller J, Derrick G, Giannakou las G, Khambadkone S, Lammers AE, Picchio F M, Gatzoulis M.A., and Hager A., Predictors of morbidity and mortality in contemporary Fontan patients: results from a multice ter study including cardiopulmonary exe rcise testing in 321 patients. J., Volume 31 (No. 24): Pages 3073-3083 (December 2010). exercise tolerance The ability to improve is a marker of improved circulatory function and, more generally, of patients undergoing the Fontan procedure. This study is likely to have significant implications for the long-term health of patients who have had udenafil. Improved key measures of exercise tolerance after pharmacological intervention in Fontan patients It suggests that it may be useful.

[0187] In the FUEL test, maximum VO2 is relatively easy to measure, and in previous tests, It has been used as an approved surrogate for elephants to detect changes in peak VO2. Power was set. Dallaire F, Wald RM, and Marelli A., The Role of Cardiopulmonary Exercise Testing for Decision Making in Patients with Repaired Tetralogy of Fallot., Pedia tr Cardiol., Volume 38 (No. 6): Pages 1097-1105 (August 2017); Mancini D., LeJemtel T., and Aaronson K., Peak. VO (2): a simple yet enduring standard. Circulation., Vol. 101 (No. 10): pp. 1080-1082 (2000) March);Okonko DO, Grzeslo A, Witkowski T, Mand. al AK, Slater RM, Roughton M, Foldes G, Thum. T, Majda J, Banasiak W, Missouri CG, Poole. -Wilson PA, Anker SD, and Ponikowski P., Eff ect of intravenous iron sucrose on exerc ise tolerance in anemic and nonanemic pa tients with symptomatic chronic heart fa illure and iron deficiency FERRIC-HF: ar andomized, controlled, observer-blinded trial., J Am Coll Cardiol., Volume 51 (No. 2): pp. 103-1. 12 (January 15, 2008); and Redfield MM, Chen HH, B orlaug BA, Semigran MJ, Lee KL, Lewis G, LeW. inter MM, Rouleau JL, Bull DA, Mann DL, Desw. al A, Stevenson LW, Givertz MM, Ofili EO, O' Connor CM, Felker GM, Goldsmith SR, Bart BA , McNulty SE, Ibarra JC, Lin G, Oh JK, Patel. MR, Kim RJ, Tracy RP, Velazquez EJ, Anstrom. KJ, Hernandez AF, Mascette AM, Braunwald E, and Trial R., Effect of phosphodiesterase- 5 inhibition on exercise capacity and cl inical status in heart failure with pres erved ejection fraction: a randomized cl inical trial., JAMA., Vol. 309(12): pp. 1268-1277 (March 27, 2013). However, peak VO2 is a surrogate for many cardiovascular disease states. However, it may not be as appropriate as an endpoint after the Fontan procedure. In this unique physiology, the contraction of the right ventricle is not controlled by the central venous pressure, i.e., the cardiac Stroke volume is the primary driver of transpulmonary blood flow. Gewillig M and Goldber g DJ., Failure of the fontan circulation. Heart Fail Clin., Vol. 10(1): pp. 105-116 (2014) Mon); Egbe AC, Connolly HM, Miranda WR, Ammas h NM, Hagler DJ, Veldtman GR, and Borlaug BA. ., Hemodynamics of Fontan Failure: The Ro le of Pulmonary Vascular Disease., Circ H eart Fail., Vol. 10(Issue 12):e004515(September 2017);Gew illig M, Brown SC, Eyskens B, Heying R, Gana. me J, Budts W, La Gerche A, and Gorenflo M, T. he Fontan circulation: who controls card iac output?, Interact Cardiovasc Thorac S urg., Vol. 10(3): pp. 428-433 (March 2010); and Goldb erg DJ, Avitabile CM, McBride MG, and Parido n SM., Exercise capacity in the Fontan ci rculation., Cardiol Young., Vol. 23(No. 6): pp. 824-8 30 (December 2013). Increased cardiac output due to strenuous exercise may lead to Fontan circulation problems. Central venous pressure in the annulus must rise to meet that demand, but ultimately , reaching a definitive upper limit beyond which it can no longer rise. am D, Fitzsimmons S, Grocott M, Rossiter HB. , Emmanuel Y, Diller GP, Gordon-Walker T, Ja ck S, Sheron N, Pappachan J, Pratap JN, Vett. ukattil JJ, and Veldtman G., Exercise-Induc ed Systemic Venous Hypertension in the F ontan Circulation., Am J Cardiol., vol. 117 (10 Issue: pp. 1667-1671 (May 15, 2016). During submaximal exercise, Because the increase in pulse pressure does not reach the physiological upper limit, the outcome at this exercise level is related to the pulmonary vasculature. This suggests that the serotonin receptors in the blood may be more sensitive to pharmacological treatment during exercise compared with peak exercise. In this case, both oxygen consumption and power at the anaerobic threshold were relatively high. This was proven by the fact that there was almost no change in central venous pressure during exercise, and The tendency for improvement or decline in VO2 at peak VO2 is similar for subpulmonary ventricles. The physiology of patients with

[0188] Although the findings reported here are important, this study is limited. To minimize the burden on subjects, the study design included cardiac magnetic resonance imaging and immersion imaging. Detailed hemodynamic measurements such as those obtained by in-situ catheterization were not included. Furthermore, evaluation of PAT outcomes did not demonstrate any advantage of udenafil over placebo. [?] Further investigation of the multiple measures obtained in these studies is warranted in this initial analysis. This was not done, but will be the subject of future analysis. Finally, the duration of the FUEL test This hindered assessment of long-term safety, but is being addressed in the ongoing FUEL open-label extension study. is.

[0189] When udenafil (87.5 mg, twice daily) was administered in addition to standard treatment, the maximum exercise There was no statistically significant improvement in oxygen consumption at the ventilatory anaerobic threshold. Statistically significant improvements were observed in multiple measures of exercise capacity. First large-scale, multicenter, placebo-controlled, randomized trial demonstrating measurable physiological benefit in post-treatment patients This is a milestone in the approximately 50-year history of Fontan Circulation, and is a valuable tool for treating congenital heart disease. This will be a model for public-private partnerships that will enable scientific advances in the field. To determine whether there is selective benefit in subpopulations within a large cohort with Further studies are needed to assess long-term tolerability and safety.

[0190] The disclosures cited in this Example 2 are incorporated herein by reference in their entirety as if fully set forth herein. is incorporated herein by reference.

[0191] Example 3 Formulation of udenafil tablets An example of a tablet formulation containing 87.5 mg of udenafil is detailed in Table 11. udenafil formulations as reported in Example 1 were used in combination with the FU This was used in patients after the Fontan procedure who were enrolled in the EL trial.

[0192] [Table 9]

[0193] Example 4 Arm echocardiographic indices of myocardial performance in SVHD subjects undergoing Fontan palliative care The effects of Nafil The goal of the FUEL trial is to evaluate patients approximately 12 to 18 years old with functional single ventricle physiology after the Fontan procedure. To determine the effect of udenafil on echocardiographic measures of myocardial performance in adolescents aged 18 years The FUEL trial was a randomized, double-blind, placebo-controlled study conducted in the United States (26 patients), At 30 different centers in Canada (2 patients) and South Korea (2 patients), patients after the Fontan procedure The study was conducted in adolescents aged approximately 12 to 18 years. Patients after the Fontan procedure were randomly assigned to receive either placebo or They were randomized to receive denafil (87.5 mg twice daily) for 26 weeks.

[0194] Each subject underwent echocardiography at the beginning and end of the 26-week period. Echocardiographic data were available for 250 subjects (63%), with 12 in the udenafil group. There were 2 patients in the serotonin-dependent group and 128 in the placebo group. Table 3. Placebo group (+0.01 increase, no improvement) There was a statistically significant change in MPI in the udenafil treatment group (a decrease of -0.02) compared with The change in MPI was related to the blood flow in the outflow tract of the functional single ventricle. Velocity was determined by fluid pool Doppler evaluation. All measurements were performed at the Wisconsin The study was conducted in the echocardiography core laboratory at Children's Hospital. Subjects treated with udenafil were treated with purine for the same period. There was a statistically significant difference in myocardial performance index (MPI) compared with placebo-treated subjects (p =0.028) (a decrease indicates an improvement).

[0195] These data demonstrated an improvement in MPI in the udenafil group compared with the placebo group. Myocardial performance was significantly improved by the von It is an important factor in the long-term health of patients with SVHD, including those with SVHD who have undergone tanning surgery. This physiological improvement complements the improvements noted in athletic performance, This suggests that the benefits of steroid therapy may be multifactorial.

[0196] All patents, patent documents, articles, abstracts, errata, and other information referenced or cited herein The entire disclosure, including all publications and references thereto, is incorporated herein by reference in its entirety. 2019 / 0030037, U.S. Patent No. 10,137,128, U.S. Patent Application No. 5 / 887,523, U.S. Patent Publication No. 2018 / 0169103, and U.S. Pat. Nos. 0,653,698, as if each were individually incorporated in its entirety. No. 6,029,139, which is incorporated herein by reference in its entirety.

[0197] In the event of a conflict with any related prior application cited under "Related Applications," this application shall prevail, including definitions. Priority will be given to the following:

[0198] Various modifications and alterations to the present invention may be made by those skilled in the art without departing from the spirit and scope of the present invention. It will be apparent that the illustrated embodiments and examples are given by way of example only and are not intended to be limiting of the invention. The scope of the present invention is defined by the following claims. is limited only by

Claims

1. To improve exercise tolerance in patients who have undergone the Fontan procedure (post-Fontan patients), 1. A method of treating a patient, comprising: Daily administration of an effective amount of udenafil or a pharmaceutically acceptable salt thereof to patients after the Fontan procedure. By increasing the oxygen consumption at the ventilatory anaerobic threshold (VAT), To improve exercise tolerance in patients after Tanning surgery, A method comprising:

2. Carbon dioxide ventilation equivalent (VE / VCO ２ ) after the Fontan procedure 10. The method of claim 1, wherein the method improves exercise tolerance in a patient.

3. Increasing work rate during VAT improves exercise tolerance in patients after the Fontan operation. The method of claim 1.

4. Increasing work rate during VAT improves exercise tolerance in patients after the Fontan operation. The method of claim 2.

5. Increasing oxygen consumption at peak exercise capacity may improve exercise capacity in patients after the Fontan procedure. The method of claim 1 , wherein

6. Carbon dioxide ventilation equivalent (VE / VCO ２ ) after the Fontan procedure 6. The method of claim 5, wherein the method improves exercise tolerance in a patient.

7. Increasing work rate during VAT improves exercise tolerance in patients after the Fontan operation. The method of claim 5.

8. Increasing work rate during VAT improves exercise tolerance in patients after the Fontan operation. The method of claim 6.

9. The method of claim 1 , wherein the patient is an adolescent patient.

10. 10. The method of claim 1, wherein the patient is about 12 to about 19 years old.

11. 10. The method of claim 1, wherein the patient is about 12 to about 18 years old.

12. 1. A method of treating exercise tolerance in a post-Fontan patient, comprising: 87.5 mg of udenafil or a pharmaceutically acceptable salt thereof was administered to the patient, and VA Increasing oxygen consumption at T improves exercise tolerance in patients after the Fontan procedure. thing, A method comprising:

13. Carbon dioxide ventilation equivalent (VE / VCO ２ ) after the Fontan procedure 13. The method of claim 12, wherein the method improves exercise tolerance in a patient.

14. Increasing work rate during VAT improves exercise tolerance in patients after the Fontan operation. The method of claim 12.

15. Increasing work rate during VAT improves exercise tolerance in patients after the Fontan operation. The method of claim 13.

16. Increasing oxygen consumption at peak exercise capacity may improve exercise capacity in patients after the Fontan procedure. The method of claim 12, wherein

17. Carbon dioxide ventilation equivalent (VE / VCO ２ ) after the Fontan procedure 17. The method of claim 16, wherein the method improves exercise tolerance in a patient.

18. Increasing work rate during VAT improves exercise tolerance in patients after the Fontan operation.

17. The method of claim 16.

19. Increasing work rate during VAT improves exercise tolerance in patients after the Fontan operation.

18. The method of claim 17.

20. Any of claims 1 to 11, wherein the side effects caused in patients after the Fontan procedure are minimal or non-existent. The method according to any one of claims 1 to 4.

21. The method of any one of claims 12 to 19, wherein the side effects caused in patients after the Fontan procedure are minimal or non-existent.

10. The method according to any one of claims 1 to 9.

22. It is believed to have beneficial effects, including a reduced rate of physiological decline, in patients after the Fontan procedure. The method according to any one of claims 1 to 11.

23. for patients after the Fontan procedure, including extending disease-free survival in these patients.

12. The method according to any one of claims 1 to 11, which has a beneficial effect on

24. The benefits of Fontan surgery for patients include a reduction in the rate of physiological decline in patients after the Fontan procedure. The method according to any one of claims 12 to 19, which has a beneficial effect on

25. for patients after the Fontan procedure, including extending disease-free survival in these patients. The method according to any one of claims 12 to 19, which has a beneficial effect on

26. The patient's systemic venous return is directly connected to the pulmonary artery without the intervening second functional ventricle. It increases venous capacity and lowers the ventilatory anaerobic threshold (VAT) in patients with a functional single ventricle. Increase oxygen consumption during VAT and improve the patient's exercise tolerance during VAT daily. It is a daily law, Administration of an effective daily dose of phosphodiesterase type 5 inhibitor (PDE5i) to patients after the Fontan operation Daily administration of IVF increases venous capacity in patients after the Fontan procedure and improves the Fontan function during VAT. Increased oxygen consumption in postoperative patients and improved exercise tolerance during VAT in Fontan patients Do this every day, A method comprising:

27. The patient's systemic venous return is directly connected to the pulmonary artery without the intervening second functional ventricle. Inducing vasodilation in patients with a functional single ventricle increases the patient's venous capacity. This allows the patient to increase their oxygen consumption at their ventilatory anaerobic threshold (VAT). In this way, the patient's exercise tolerance during VAT is improved every day. By inducing vasodilation in patients daily, the patient's venous capacity is increased, and the patient's VAT is improved. Increased oxygen consumption by the patient and improved exercise tolerance during VAT daily and, A method comprising:

28. The patient's systemic venous return is directly connected to the pulmonary artery without the intervening second functional ventricle. 5'-cyclic guanosine monophosphate (cGMP) in patients with a functional single ventricle It induces vasodilation in patients by blocking the conversion of guanosine monophosphate (5'-GMP) to guanosine monophosphate (5'-GMP). , increasing the patient's venous capacity and allowing the patient to receive oxygen at the patient's ventilatory anaerobic threshold (VAT). Daily method to improve the patient's exercise tolerance during VAT by increasing consumption And, Daily blocking of the conversion of cGMP to 5'-GMP in patients resulted in vasodilation. Induce and increase the patient's venous capacity, increasing oxygen consumption by the patient in the patient's VAT. To improve the patient's exercise tolerance during VAT daily. A method comprising:

29. The patient's systemic venous return is directly connected to the pulmonary artery without the intervening second functional ventricle. Nitric oxide-induced cyclic guanosine monophosphate (CGMP)-induced vasoconstriction in patients with a functional single ventricle Induce vasodilation in a patient by enhancing cGMP (cGMP) signaling, thereby increasing venous capacity in the patient. Increased oxygen consumption at the patient's ventilatory anaerobic threshold (VAT) In this way, the patient's exercise tolerance during VAT is improved every day. enhancing cGMP signaling in a patient daily to increase the patient's venous capacity; Increased oxygen consumption by patients during VAT and improved exercise tolerance during VAT Daily improvements to A method comprising:

30. The patient's systemic venous return is directly connected to the pulmonary artery without the intervening second functional ventricle. inhibits cyclic guanosine monophosphate (cGMP) breakdown in patients with a functional single ventricle Inducing vasodilation in the patient, increasing the venous capacity of the patient, and By increasing the oxygen consumption at the ventilatory anaerobic threshold (VAT), A daily method for improving the exercise tolerance of a patient, Daily inhibition of cGMP degradation in a patient increases the patient's venous capacity and Increased oxygen consumption by patients during VAT and improved exercise tolerance during VAT Doing good every day A method comprising:

31. The patient's systemic venous return is directly connected to the pulmonary artery without the intervening second functional ventricle. In patients with a functional single ventricle (post-Fontan patients), the highest venous capacity was achieved. By doing so, patients after the Fontan procedure can achieve the maximum oxygen consumption at the ventilatory anaerobic threshold (VAT). Furthermore, the Fontan operation patients were able to achieve the maximum exercise tolerance during VAT. It is a daily law that allows you to achieve the above every day. Administration of an effective daily dose of phosphodiesterase type 5 inhibitor (PDE5i) to patients after the Fontan operation Daily administration of IV fluids can achieve maximum venous capacity in post-Fontan patients, and To enable postoperative patients to achieve their maximum oxygen consumption during VAT every day, and to enable post-Fontan patients To be able to achieve maximum exercise tolerance during VAT every day, A method comprising:

32. The patient's systemic venous return is directly connected to the pulmonary artery without the intervening second functional ventricle. In patients with a functional single ventricle (post-Fontan patients), This allows post-Fontan patients to achieve maximum venous capacity daily and Postoperative patients can achieve the maximum oxygen consumption at their ventilatory anaerobic threshold (VAT). This will enable patients after the Fontan procedure to achieve their maximum exercise tolerance during VAT every day. It is a daily law, Daily induction of maximum venous dilation in Fontan patients The maximum venous capacity was achieved in patients with Fontan surgery, and the VAT of Fontan patients was improved. The maximum oxygen consumption during VAT was achieved daily, and the maximum exercise tolerance during VAT was achieved by Fontan. To be achieved daily by postoperative patients, A method comprising:

33. The patient's systemic venous return is directly connected to the pulmonary artery without the intervening second functional ventricle. In patients with a functional single ventricle (post-Fontan operation patients), cyclic guanosine monophosphate (CGMP) by preventing the conversion of cGMP to guanosine 5'-monophosphate (5'-GMP) Induce maximum venous dilation daily and achieve maximum venous capacity in patients after Fontan operation. The maximum oxygen saturation at the ventilatory anaerobic threshold (VAT) in patients after the Fontan operation was This allows patients after the Fontan procedure to achieve their maximum exercise tolerance during VAT daily. It is a daily law that allows you to achieve Daily prevention of cGMP to 5'-GMP conversion in post-Fontan patients Induce maximum venous dilation daily and achieve maximum venous capacity daily in post-Fontan patients. To achieve peak oxygen consumption daily by Fontan patients and to encourage exercise in Fontan patients. Whenever possible, Fontan patients can achieve peak oxygen consumption and exercise tolerance during VAT. To make it so that A method comprising:

34. The patient's systemic venous return is directly connected to the pulmonary artery without the intervening second functional ventricle. Nitric oxide-induced circulatory dysfunction in patients with a functional single ventricle (post-Fontan patients) By enhancing cGMP signaling, vasodilation is induced in patients. Induce and increase the patient's venous capacity so that the patient is able to perform a ventilatory anaerobic threshold (VAT) exercise. improve the patient's exercise tolerance during VAT by increasing the patient's oxygen consumption daily; It is a daily law, enhancing cGMP signaling in a patient daily to increase the patient's venous capacity; Increased oxygen consumption by patients during VAT and improved exercise tolerance during VAT Daily improvements to A method comprising:

35. The patient's systemic venous return is directly connected to the pulmonary artery without the intervening second functional ventricle. In patients with a functional single ventricle (post-Fontan operation patients), Inhibiting cGMP degradation induces vasodilation in patients, increasing venous capacity in patients Increased oxygen consumption at the patient's ventilatory anaerobic threshold (VAT) In this way, the patient's exercise tolerance during VAT is improved every day. Daily inhibition of cGMP degradation in a patient increases the patient's venous capacity and Increased oxygen consumption by patients during VAT and improved exercise tolerance during VAT Doing good every day A method comprising:

36. The patient's systemic venous return is oxygenated without the intervention of a second functional ventricle. A functional single ventricle with a direct connection to the pulmonary artery and a venous shunt, For patients with inoperable shunts, ventricular shunts, and arterial shunts, increased Increased oxygen availability for patients who need it through on-demand oxygen delivery Improve exercise tolerance on demand as measured at ventilatory anaerobic threshold (VAT) It is a daily law that In patients, increased venous capacity allows for increased transpulmonary blood flow daily. and allowing the patient's central venous pressure to assist in the patient's increased transpulmonary blood flow through the patient's lungs. This allows the patient to achieve increased oxygen intake daily due to increased transpulmonary blood flow. This allows for increased oxygen delivery to patients on demand and reduces the need for oxygen. Increased oxygen availability to patients on demand and improved exercise tolerance as measured by VAT. To be increased on demand, A method comprising:

37. The patient's maximum oxygen consumption rate (VO2 max) measured while increasing the patient's exercise intensity is: The patient's maximum VO2 is improved compared to that without the increase in oxygen demand. Item 37. Daily method according to item 36.

38. The patient's systemic venous return is directly connected to the pulmonary artery without the intervening second functional ventricle. A patient with functional single ventricle and its venous shunt, atrial shunt, ventricular shunt, and and arterial shunts are inoperable, providing increased oxygen on demand. This allows for ventilatory anaerobic response when patients require increased oxygen for exercise. Has enough oxygen to achieve increased power output on demand at the work threshold (VAT) It is a daily law that Increased venous volume is induced in patients daily, which is compensated for by the patient's central venous pressure. Provides enhanced transpulmonary blood flow to the patient daily, allowing the patient to receive increased blood flow from the patient's lungs. This allows the patient to achieve adequate oxygen intake and provides sufficient oxygen to meet their needs. This allows for increased oxygen intake during the patient's VAT if the patient requires oxygen for exercise. Having enough oxygen on demand to achieve the power output; A method comprising:

39. The patient's maximum oxygen consumption rate (VO2 max) measured while increasing the patient's exercise intensity improved.

39. The daily method of claim 38, wherein

40. The patient's systemic venous return is directly connected to the pulmonary artery without the intervening second functional ventricle. A patient with functional single ventricle and its venous shunt, atrial shunt, ventricular shunt, and and arterial shunts are inoperable, providing increased oxygen on demand. This allows the patient to achieve oxygen at the ventilatory anaerobic threshold (VAT) when oxygen is needed. Sufficient oxygen to achieve increased exercise ventilatory efficiency (VE / CO2 gradient) on demand The Mainichi Law provides that Increased venous volume is induced in patients daily, which is compensated for by the patient's central venous pressure. The assisted transpulmonary blood flow is increased daily in the patient, allowing the patient to receive increased oxygen uptake by the patient's lungs. By enabling the patient to achieve adequate oxygen supply on demand, If the patient requires acid for exercise, the increased VE / CO2 gradient during the patient's VAT is having enough oxygen on demand to achieve A method comprising:

41. 41. The daily method of claim 40, wherein the patient's oxygen consumption at peak exercise capacity is increased.

42. The patient's systemic venous return is directly connected to the pulmonary artery without the intervening second functional ventricle. Increase venous capacity in patients with a functional single ventricle (post-Fontan patients) Increased likelihood of or increase in the ventilatory anaerobic threshold (VAT) 1. A method of increasing or increasing the likelihood of increasing oxygen consumption in a post-operative patient, comprising: Patients after the Fontan operation were given an effective daily dose of a phosphodiesterase type 5 inhibitor (PDE5i). By providing venous fluid, it is possible to increase or potentially increase venous capacity in patients after the Fontan procedure. Increases or increases the likelihood of increased oxygen consumption during VAT in patients after the Fontan procedure To do so, A method comprising:

43. Increase the maximum VO2 to or near its physiological upper limit and Increased oxygen utilization in Fontan patients by a statistically significant amount A method of increasing the level of erythrocyte proliferation, comprising the administration of an effective PDE5 inhibitor (PDE5i).

44. 44. The method according to claim 43, wherein the PDE5i is udenafil or a pharmaceutically acceptable salt thereof. How to post.

45. VAT and maximum VO ２ By improving exercise tolerance both at the time of A method for treating SVHD in patients who have undergone Tanning surgery, comprising administering an effective amount of an effective PDE.

20. A method comprising administering a PDE5i inhibitor.

46. 46. The method according to claim 45, wherein the PDE5i is udenafil or a pharmaceutically acceptable salt thereof. How to post.

47. Increase the maximum VO2 to or near its physiological upper limit and Increase exercise capacity in Fontan patients by a statistically significant amount A method for improving the condition, comprising administering an effective PDE5 inhibitor (PDE5i). Law.

48. 48. The method according to claim 47, wherein the PDE5i is udenafil or a pharmaceutically acceptable salt thereof. How to post.

49. The method according to any one of claims 1 to 19, which increases oxygen saturation in patients after the Fontan procedure. How to do it.

50. The method according to any one of claims 1 to 19, which reduces diastolic blood pressure in patients after the Fontan procedure. How to do it.

51. Fontan therapy, including reducing the rate of decline in cardiovascular efficiency in patients after the Fontan procedure The method according to any one of claims 1 to 19, which has a beneficial effect on postoperative patients. 。

52. udenafil or its pharmaceutically acceptable salt is 87.5 mg of udenafil or its 20. The method of claim 1, wherein the compound is administered in a daily dose including twice daily administration of a pharmaceutically acceptable salt of The method according to any one of claims 1 to 5.

53. A pharmaceutical composition comprising a composition described in Table 11.

54. A single-ventricle heart with a functional single ventricle for improving ventricular performance in patients with SVHD A method of treating a patient with ventricular heart disease (SVHD), comprising: Patients with a functional single ventricle who require treatment to improve ventricular performance, Daily administration of an effective amount of udenafil or a pharmaceutically acceptable salt thereof to a patient with SVHD. and improve ventricular performance in functional single ventricle patients with SVHD. A method comprising:

55. The ventricular performance of the SVHD patient is evaluated by the myocardial performance index (MPI) of the SVHD patient.

55. The method of claim 54,

56. the administering step 87.5 mg of udenafil or its pharmaceutically acceptable salt administered twice daily administering the effective amount of udenafil to a patient with SVHD; 56. The method of claim 55, comprising:

57. 57. The method of claim 56, which causes minimal or no side effects in SVHD patients.

58. Udenafil or a pharmaceutically acceptable salt thereof. An effective amount of udenafil is about 125 mg to about 175 mg.

55. The method of claim 54, wherein the range is

59. 5. The effective amount of udenafil or a pharmaceutically acceptable salt thereof is about 175 mg.

4. The method according to claim 4.

60. Not receiving daily treatment with an effective amount of udenafil or its pharmaceutically acceptable salts Ventricular performance in patients with SVHD compared with functional single ventricle in patients with SVHD 55. The method of claim 54, wherein the performance improvement is increased.

61. 61. Any one of claims 54 to 60, wherein the effective amount does not cause treatment-limiting side effects. The method described in paragraph .

62. The treatment-limiting side effects are associated with inhibition of PDE6 and / or PDE11 62. The method of claim 61 .

63. 54 to 56, wherein the SVHD patient is a post-Fontan patient who has undergone the Fontan operation.

62. The method of any one of claims 62 to 62.

64. Any of claims 54 to 62, wherein the SVHD patient has undergone the Norwood procedure.

10. The method according to claim 1.

65. Any of claims 54 to 62, wherein the SVHD patient has undergone bidirectional Glenn procedure. The method according to any one of claims 1 to 5.

66. 63. The method of any one of claims 54 to 62, wherein the SVHD patient is at least 6 years old. method.

67. 63. The method of any one of claims 54 to 62, wherein the SVHD patient is at least 8 years old. method.

68. 63. The method of any one of claims 54 to 62, wherein the SVHD patient is at least 10 years old. How to do it.

69. 63. The method of any one of claims 54 to 62, wherein the SVHD patient is at least 12 years old. How to do it.

70. 63. The method of any one of claims 54 to 62, wherein the SVHD patient is an adolescent patient.

71. The method of any one of claims 54 to 62, wherein the SVHD patient is an adult patient.

72. 66. The method of any one of claims 63 to 65, wherein the SVHD patient is at least 8 years old. method.

73. 66. The method of any one of claims 63 to 65, wherein the SVHD patient is at least 10 years old. How to do it.

74. 66. The method of any one of claims 63 to 65, wherein the SVHD patient is at least 12 years old. How to do it.

75. 66. The method of any one of claims 63 to 65, wherein the SVHD patient is an adolescent patient.

76. 66. The method of any one of claims 63 to 65, wherein the SVHD patient is an adult patient.

77. 1. A method of treating a patient with single ventricle heart disease (SVHD) having a functional single ventricle, comprising: VHD patients had functional single ventricle ventricular performance assessed by myocardial performance index (MPI), ventilation, and Exercise tolerance assessed by oxygen consumption at the anaerobic threshold (VAT), submaximal exercise Dynamic load or maximum VO ２ Exercise tolerance assessed by oxygen consumption at time of VAT Power, carbon dioxide ventilation equivalent (VE / VCO ２ ), resting diastolic blood pressure, and / or Requiring treatment to improve resting oxygen saturation (%), An effective amount of udenafil or a pharmaceutically acceptable salt thereof is administered daily to the SVHDn patient. By doing so, the SVHD patient, (a) Ventricular performance of functional single ventricle in SVHD patients assessed by MPI; (b) exercise tolerance assessed by oxygen consumption during VAT; (c) Submaximal exercise or maximum VO ２ Exercise tolerance assessed by oxygen consumption during exercise Noh; (d) Work rate at time of VAT; (e) VE / VCO at time of VAT ２ ; (f) resting diastolic blood pressure; and (g) oxygen saturation at rest (%); improving each individually, collectively, or in any combination; A method comprising:

78. 78. The method of claim 77, wherein (a), (b), (d), (e), and (f) are improved. How to do it.

79. 78. The method of claim 77, wherein (a), (b), (d), (e), and (g) are improved. How to do it.

80. 7. The improvement of (a), (b), (d), (e), (f), and (g).

7. The method according to claim 7.

81. 70 to 75, wherein the SVHD patient is a post-Fontan patient who has undergone the Fontan operation.

81. The method of any one of claims 81 to 81.

82. Any of claims 70 to 81, wherein the SVHD patient has undergone the Norwood procedure.

10. The method according to claim 1.

83. Any of claims 70 to 81, wherein the SVHD patient has undergone bidirectional Glenn procedure. The method according to any one of claims 1 to 5.

84. Functional single ventricle ventricular performance assessed by myocardial performance index (MPI), ventilatory anaerobic Exercise tolerance assessed by oxygen consumption at the maximal exercise threshold (VAT), including submaximal exercise load Or maximum VO ２ Exercise tolerance assessed by oxygen consumption during exercise, work rate during VAT, and and carbon dioxide ventilation equivalent (VE / VCO ２ functional impairments requiring treatment to improve 1. A method of treating a patient with single ventricle heart disease (SVHD) having a single ventricle, comprising: an effective amount of udenafil or a pharmaceutically acceptable salt thereof is administered daily to the patient after the Fontan procedure. By administering, the SVHD patient (a) Ventricular performance of functional single ventricle in SVHD patients assessed by MPI; (b) exercise tolerance assessed by oxygen consumption during VAT; (c) Submaximal exercise or maximum VO ２ Exercise tolerance assessed by oxygen consumption during exercise Noh; (d) Work rate at time of VAT; and (e) VE / VCO at time of VAT ２ , improving each individually, collectively, or in any combination; A method comprising:

85. 85. The method of claim 84, wherein the SVHD patient is a post-Fontan patient who has undergone the Fontan procedure. The method described.

86. 85. The method of claim 84, wherein the SVHD patient is a post-Fontan patient who has undergone the Norwood procedure. The method described.

87. 9. The method of claim 8, wherein the SVHD patient is a post-Fontan patient who underwent a bidirectional Glenn procedure.

4. The method according to claim 4.

88. Functional single ventricle ventricular performance assessed by myocardial performance index (MPI), ventilatory anaerobic Exercise tolerance assessed by oxygen consumption at threshold exertion (VAT), work rate at VAT, and carbon dioxide ventilation equivalent (VE / VCO ２ ) requiring treatment to improve function 1. A method of treating a patient with single ventricle heart disease (SVHD) having a single ventricle, comprising: An effective amount of udenafil or a pharmaceutically acceptable salt thereof is administered daily to the SVHD patient. By doing so, the SVHD patient (a) Ventricular performance of functional single ventricle in SVDHD patients assessed by MPI; (b) exercise tolerance assessed by oxygen consumption during VAT; (c) Work rate at time of VAT; and (d) VE / VCO at time of VAT ２ , improving each individually, collectively, or in any combination; A method comprising:

89. 89. The method of claim 88, wherein the SVHD patient is a post-Fontan patient who has undergone the Fontan procedure. The method described.

90. 89. The method of claim 88, wherein the SVHD patient is a patient who has undergone the Norwood procedure.

91. 85. The method of claim 84, wherein the SVHD patient has undergone a bidirectional Glenn procedure. 。

92. Myocardial performance index (MPI) in patients with single ventricle heart disease (SVHD) who have a functional single ventricle wherein the SVHD patient is a patient in need of improvement in MPI, An effective amount of udenafil or a pharmaceutically acceptable salt thereof is administered daily to the SVHD patient. thereby improving MPI in the SVHD patient; A method comprising:

93. 93. The method of claim 92, wherein the SVHD patient is a post-Fontan patient who has undergone the Fontan procedure. The method described.

94. 93. The method of claim 92, wherein the SVHD patient is a patient who has undergone the Norwood procedure.

95. 93. The method of claim 92, wherein the SVHD patient has undergone a bidirectional Glenn procedure. 。

96. Claims 92-9, wherein MPI is measured by pulsed tissue Doppler echocardiography (TDE).

6. The method according to any one of claims 5 to 5.

97. Measure MPI using pulsed tissue Doppler echocardiography (TDE); 96. The method of any one of claims 92 to 95, comprising a further step.

98. Methods for improving cardiac output in patients with single ventricle heart disease (SVHD) who have a functional single ventricle wherein the SVHD patient is a patient in need of improved cardiac output; An effective amount of udenafil or a pharmaceutically acceptable salt thereof is administered daily to the SVHD patient. improving cardiac output in the SVHD patient; A method comprising:

99. 10. The method of claim 9, wherein the cardiac output of the SVHD patient is assessed by a myocardial performance index (MPI).

8. The method according to claim 8.

100. 100. The method of claim 99, wherein the MPI is measured by pulsed tissue Doppler echocardiography (TDE). How to post.

101. Measure MPI using pulsed tissue Doppler echocardiography (TDE); 99. The method of claim 98, comprising the further step.

102. 99 to 100, wherein the SVHD patient is a post-Fontan patient who has undergone the Fontan operation.

101. The method of any one of claims 101 to 103.

103. Any of claims 99 to 101, wherein the SVHD patient is a patient who has undergone the Norwood procedure.

1. The method according to claim 1.

104. Any of claims 99 to 101, wherein the SVHD patient has undergone bidirectional Glenn procedure. The method according to any one of claims 1 to 4.

105. A single-ventricle heart with a functional single ventricle for improving ventricular performance in patients with SVHD A method of treating a patient with ventricular heart disease (SVHD), comprising: Patients with a functional single ventricle who require treatment to improve ventricular performance, Daily administration of an effective amount of udenafil or a pharmaceutically acceptable salt thereof to a patient with SVHD. and improving ventricular performance of a functional single ventricle in a patient with SVHD, Udenafil Cmax pharmacokinetics in SVHD patients resulting from the effective dose a plasma profile of 300-700 ng / ml; method.

106. The udenafil Cmax pharmacokinetic plasma profile in the SVHD patient is about 5 about -20% to about +25% of about 500 ng / ml, more preferably about -20% to about +25% of about 500 ng / ml 106. The method of claim 105, wherein the saturation is from 20% to about +20%.

107. The udenafil Cmax pharmacokinetic plasma profile in the SVHD patient is about 5 106. The method of claim 105, wherein the concentration is about -20% to about +20% of 000 ng / ml.

108. The effective dose of udenafil Tmax in SVHD patients further provides 106. The method of claim 105, wherein the pharmacokinetic plasma profile is about 1 hour to 1.6 hours.

109. Claim 1: The udenafil Tmax is about -20% to about +25% of about 1.3 hours. The method described in 08.

110. Claim 1: The udenafil Tmax is about -20% to about +20% of about 1.3 hours. The method described in 08.

111. Udenafil AUC in SVHD patients achieved by the effective dose τ Pharmacokinetics 10. The method of claim 1, wherein the plasma profile is from about 2550 ng-h / ml to about 4150 ng-h / ml. The method described in 05.

112. The udenafil AUC in the SVHD patients τ Pharmacokinetic plasma profile of approximately 3 112. The method of claim 111, wherein the concentration is about -20% to about +25% of 350 ngh / ml.

113. The udenafil AUC in the SVHD patients τ Pharmacokinetic plasma profile of approximately 3 112. The method of claim 111, wherein the concentration is about -20% to about +20% of 350 ngh / ml.

114. Pharmacokinetics of udenafil AUCτ in SVHD patients resulting from the effective dose 10. The method of claim 1, wherein the plasma profile is from about 5110 ng-h / ml to about 8290 ng-h / ml. The method described in 05.

115. The udenafil AUC in the SVHD patients ０－２４ Pharmacokinetic plasma profile is about -20% to about +25% of about 6701 nghr / ml 。

116. The udenafil AUC in the SVHD patients ０－２４ Pharmacokinetic plasma profile is about -20% to about +20% of about 6701 nghr / ml 。

117. Claim 105: The SVHD patient is a post-Fontan patient who has undergone the Fontan procedure.

117. The method of any one of claims 1 to 116.

118. Any of claims 105 to 116, wherein the SVHD patient is a patient who has undergone the Norwood procedure. The method according to any one of claims 1 to 5.

119. The method of any one of claims 105 to 116, wherein the SVHD patient has undergone bidirectional Glenn procedure.

10. The method according to any one of claims 1 to 9.

120. 1. A method of treating a patient with single ventricle heart disease (SVHD) having a functional single ventricle, comprising: VHD patients had functional single ventricle ventricular performance assessed by myocardial performance index (MPI), ventilation, and Exercise tolerance assessed by oxygen consumption at the anaerobic threshold (VAT), submaximal exercise Dynamic load or maximum VO ２ Exercise tolerance assessed by oxygen consumption at time of VAT Power, carbon dioxide ventilation equivalent (VE / VCO ２ ), resting diastolic blood pressure, and / or Requiring treatment to improve resting oxygen saturation (%), An effective amount of udenafil or a pharmaceutically acceptable salt thereof is administered daily to the SVHDn patient. By doing so, the SVHD patient, (b) ventricular performance of functional single ventricle in SVHD patients assessed by MPI; (b) exercise tolerance assessed by oxygen consumption during VAT; (c) Submaximal exercise or maximum VO ２ Exercise tolerance assessed by oxygen consumption during exercise Noh; (d) Work rate at time of VAT; (e) VE / VCO at time of VAT ２ ; (f) resting diastolic blood pressure; and (g) oxygen saturation at rest (%); each individually, collectively, or in any combination; Udenafil Cmax pharmacokinetics in SVHD patients resulting from the effective dose a plasma profile of 300-700 ng / ml; method.

121. The udenafil Cmax pharmacokinetic plasma profile in the SVHD patient is about 5 about -20% to about +25% of about 500 ng / ml, more preferably about -20% to about +25% of about 500 ng / ml 121. The method of claim 120, wherein the saturation is from 20% to about +20%.

122. The udenafil Cmax pharmacokinetic plasma profile in the SVHD patient is about 5 121. The method of claim 120, wherein the concentration is about -20% to about +20% of 000 ng / ml.

123. The effective dose of udenafil Tmax in SVHD patients further provides 121. The method of claim 120, wherein the pharmacokinetic plasma profile is about 1 hour to 1.6 hours.

124. Claim 1: The udenafil Tmax is about -20% to about +25% of about 1.3 hours.

23. The method according to claim 23.

125. Claim 1: The udenafil Tmax is about -20% to about +20% of about 1.3 hours.

23. The method according to claim 23.

126. Udenafil AUC in SVHD patients achieved by the effective dose τ Pharmacokinetics 10. The method of claim 1, wherein the plasma profile is from about 2550 ng-h / ml to about 4150 ng-h / ml.

20. The method according to claim 20.

127. The udenafil AUC in the SVHD patients τ Pharmacokinetic plasma profile of approximately 3 127. The method of claim 126, wherein the concentration is about -20% to about +25% of 350 ngh / ml.

128. The udenafil AUC in the SVHD patients τ Pharmacokinetic plasma profile of approximately 3 127. The method of claim 126, wherein the concentration is about -20% to about +20% of 350 ngh / ml.

129. Udenafil AUC in SVHD patients achieved by the effective dose τ Pharmacokinetics 10. The method of claim 1, wherein the plasma profile is from about 5110 ng-h / ml to about 8290 ng-h / ml.

20. The method according to claim 20.

130. The udenafil AUC in the SVHD patients ０－２４ Pharmacokinetic plasma profile is about -20% to about +25% of about 6701 nghr / ml 。

131. The udenafil AUC in the SVHD patients ０－２４ Pharmacokinetic plasma profile is about -20% to about +20% of about 6701 ngh / ml 。

132. 120. The method of claim 120, wherein the SVHD patient is a post-Fontan patient who has undergone the Fontan procedure.

132. The method of any one of claims 1 to 131.

133. Any of claims 120 to 131, wherein the SVHD patient has undergone the Norwood procedure. The method according to any one of claims 1 to 5.

134. The method of any one of claims 120 to 131, wherein the SVHD patient has undergone bidirectional Glenn procedure.

10. The method according to any one of claims 1 to 9.

135. Myocardial performance index (MPI) was evaluated in patients with single ventricle heart disease (SVHD) who had a functional single ventricle. a method for improving MPI, wherein the SVHD patient is a patient in need of improvement of MPI, Daily administration of an effective amount of udenafil or a pharmaceutically acceptable salt thereof to a patient with SVHD. and improving MPI in SVHD patients, Udenafil Cmax pharmacokinetics in SVHD patients resulting from the effective dose a plasma profile of 300-700 ng / ml; method.

136. The udenafil Cmax pharmacokinetic plasma profile in the SVHD patient is about 5 about -20% to about +25% of about 500 ng / ml, more preferably about -20% to about +25% of about 500 ng / ml 136. The method of claim 135, wherein the saturation is from 20% to about +20%.

137. The udenafil Cmax pharmacokinetic plasma profile in the SVHD patient is about 5 136. The method of claim 135, wherein the concentration is about -20% to about +20% of 000 ng / ml.

138. The effective dose of udenafil Tmax in SVHD patients further provides 136. The method of claim 135, wherein the pharmacokinetic plasma profile is about 1 hour to 1.6 hours.

139. Claim 1: The udenafil Tmax is about -20% to about +25% of about 1.3 hours.

38. The method according to claim 38.

140. Claim 1: The udenafil Tmax is about -20% to about +20% of about 1.3 hours.

38. The method according to claim 38.

141. Udenafil AUC in SVHD patients achieved by the effective dose τ Pharmacokinetics 10. The method of claim 1, wherein the plasma profile is from about 2550 ng-h / ml to about 4150 ng-h / ml.

35. The method according to claim 35.

142. The udenafil AUC in the SVHD patients τ Pharmacokinetic plasma profile of approximately 3 142. The method of claim 141, wherein the concentration is about -20% to about +25% of 350 ngh / ml.

143. The udenafil AUC in the SVHD patients τ Pharmacokinetic plasma profile of approximately 3 142. The method of claim 141, wherein the concentration is about -20% to about +20% of 350 ngh / ml.

144. Udenafil AUC in SVHD patients achieved by the effective dose τ Pharmacokinetics 10. The method of claim 1, wherein the plasma profile is from about 5110 ng-h / ml to about 8290 ng-h / ml.

35. The method according to claim 35.

145. The udenafil AUC in the SVHD patients ０－２４ Pharmacokinetic plasma profile is about -20% to about +25% of about 6701 nghr / ml 。

146. The udenafil AUC in the SVHD patients ０－２４ Pharmacokinetic plasma profile is about -20% to about +20% of about 6701 ngh / ml 。

147. Claim 135: The SVHD patient is a post-Fontan patient who has undergone the Fontan procedure.

147. The method of any one of claims 1 to 146.

148. Any of claims 135 to 146, wherein the SVHD patient is a patient who has undergone the Norwood procedure. The method according to any one of claims 1 to 5.

149. The method of claims 145 to 146, wherein the SVHD patient has undergone bidirectional Glenn procedure.

10. The method according to any one of claims 1 to 9.

150. Methods for improving cardiac output in patients with single ventricle heart disease (SVHD) who have a functional single ventricle wherein the SVHD patient is a patient in need of improved cardiac output; Daily administration of an effective amount of udenafil or a pharmaceutically acceptable salt thereof to a patient with SVHD. and improving cardiac output in SVHD patients, Udenafil Cmax pharmacokinetics in SVHD patients resulting from the effective dose a plasma profile of 300-700 ng / ml; method.

151. The udenafil Cmax pharmacokinetic plasma profile in the SVHD patient is about 5 about -20% to about +25% of about 500 ng / ml, more preferably about -20% to about +25% of about 500 ng / ml 151. The method of claim 150, wherein the ratio is from 20% to about +20%.

152. The udenafil Cmax pharmacokinetic plasma profile in the SVHD patient is about 5 151. The method of claim 150, wherein the concentration is about -20% to about +20% of 000 ng / ml.

153. The effective dose of udenafil Tmax in SVHD patients further provides 151. The method of claim 150, wherein the pharmacokinetic plasma profile is about 1 hour to 1.6 hours.

154. Claim 1: The udenafil Tmax is about -20% to about +25% of about 1.3 hours.

53. The method according to claim 53.

155. 15. The udenafil Tmax is about -20% to about +20% of about 1.3 hours.

3. The method according to claim 3.

156. Udenafil AUC in SVHD patients achieved by the effective dose τ Pharmacokinetics 10. The method of claim 1, wherein the plasma profile is from about 2550 ng-h / ml to about 4150 ng-h / ml.

50. The method according to claim 50.

157. The udenafil AUC in the SVHD patients τ Pharmacokinetic plasma profile of approximately 3 157. The method of claim 156, wherein the concentration is about -20% to about +25% of 350 ngh / ml.

158. The udenafil AUC in the SVHD patients τ Pharmacokinetic plasma profile of approximately 3 157. The method of claim 156, wherein the concentration is about -20% to about +20% of 350 ngh / ml.

159. Udenafil AUC in SVHD patients achieved by the effective dose τ Pharmacokinetics 10. The method of claim 1, wherein the plasma profile is from about 5110 ng-h / ml to about 8290 ng-h / ml.

50. The method according to claim 50.

160. The udenafil AUC in the SVHD patients ０－２４ Pharmacokinetic plasma profile is about -20% to about +25% of about 6701 nghr / ml 。

161. The udenafil AUC in the SVHD patients ０－２４ Pharmacokinetic plasma profile is about -20% to about +20% of about 6701 ngh / ml 。

162. Claim 150. The SVHD patient is a post-Fontan patient who has undergone the Fontan procedure.

162. The method of any one of claims 1 to 161.

163. Any of claims 150 to 161, wherein the SVHD patient has undergone the Norwood procedure. The method according to any one of claims 1 to 5.

164. The method of any one of claims 150 to 161, wherein the SVHD patient has undergone bidirectional Glenn procedure.

10. The method according to any one of claims 1 to 9.

165. Orally administered medicament for treating patients with single ventricle heart disease (SVHD) who have a functional single ventricle 1. A composition comprising: The SVHD patient has a functional single ventricle as assessed by the myocardial performance index (MPI). Performance, exercise tolerance assessed by oxygen consumption at ventilatory anaerobic threshold (VAT) , exercise tolerance assessed by oxygen consumption at submaximal exercise load or maximum VO2; Power at VAT, carbon dioxide ventilation equivalent (VE / VCO ２ ), resting diastolic blood pressure, and Patients who require treatment to improve their oxygen saturation (%) at rest and / or The pharmaceutical composition comprises: containing an effective amount of udenafil or a pharmaceutically acceptable salt thereof, As a result, when the oral pharmaceutical composition is orally administered daily to an SVHD patient, Effective doses of udenafil in SVHD patients The Cmax pharmacokinetic plasma profile was 300 ng / ml to 700 ng / ml; And the following in SVHD patients: (a) Ventricular performance of functional single ventricle in SVHD patients assessed by MPI; (b) exercise tolerance assessed by oxygen consumption during VAT; (c) Submaximal exercise or maximum VO ２ Exercise tolerance assessed by oxygen consumption during exercise Noh; (d) Work rate at time of VAT; (e) VE / VCO at time of VAT ２ ; (f) resting diastolic blood pressure; and (g) oxygen saturation at rest (%); The pharmaceutical composition improves at least one or more of the following:

166. The udenafil Cmax pharmacokinetic plasma profile in the SVHD patient is about 5 166. The oral pharmaceutical composition of claim 165, wherein the concentration is 0.000 ng / ml.

167. The udenafil Cmax pharmacokinetic plasma profile in the SVHD patient is about 5 167. The oral pharmaceutical composition of claim 166, wherein the solubility is about -20% to about +25% of 000 ng / ml. thing.

168. The udenafil Cmax pharmacokinetic plasma profile in the SVHD patient is about 5 167. The oral pharmaceutical composition of claim 166, wherein the saturation of the composition is about -20% to about +20% of 000 ng / ml. thing.

169. The effective dose of udenafil Tmax in SVHD patients further provides 166. The oral medication of claim 165, wherein the pharmacokinetic plasma profile is about 1 hour to 1.6 hours. Pharmaceutical composition.

170. The oral pharmaceutical composition of claim 169, wherein the udenafil Tmax is about 1.3 hours. Finished product.

171. Claim 1: The udenafil Tmax is about -20% to about +25% of about 1.3 hours.

70. An oral pharmaceutical composition according to claim 70.

172. Claim 1: The udenafil Tmax is about -20% to about +20% of about 1.3 hours.

70. An oral pharmaceutical composition according to claim 70.

173. Udenafil AUC in SVHD patients achieved by the effective dose τ Pharmacokinetics 10. The method of claim 1, wherein the plasma profile is from about 2550 ng-h / ml to about 4150 ng-h / ml.

65. An oral pharmaceutical composition according to claim 65.

174. The udenafil AUC in the SVHD patients τ Pharmacokinetic plasma profile of approximately 3 The oral pharmaceutical composition of claim 173, wherein the concentration is 350 ng / ml.

175. The udenafil AUC in the SVHD patients τ Pharmacokinetic plasma profile of approximately 3 The oral pharmaceutical composition according to claim 174, which is about -20 to about +25% of 350 ng / ml. Finished product.

176. The udenafil AUC in the SVHD patients τ Pharmacokinetic plasma profile of approximately 3 The oral pharmaceutical composition according to claim 174, which is about -20 to about +25% of 350 ng / ml. Finished product.

177. Udenafil AUC in SVHD patients achieved by the effective dose ０－２４ medicine The pharmacokinetic plasma profile is from about 5110 ng-h / ml to about 8290 ng-h / ml. An oral pharmaceutical composition according to claim 165.

178. The udenafil AUC in the SVHD patients ０－２４ Pharmacokinetic plasma profile The oral pharmaceutical composition of claim 177, wherein the .alpha.-tocopherol concentration is about 6701 ng / ml.

179. The udenafil AUC in the SVHD patients ０－２４ Pharmacokinetic plasma profile is about -20% to about +25% of about 6701 ngh / ml Pharmaceutical composition for use.

180. The udenafil AUC in the SVHD patients ０－２４ Pharmacokinetic plasma profile is about -20% to about +20% of about 6701 ngh / ml Pharmaceutical composition for use.

181. Claim 165: The SVHD patient is a post-Fontan patient who has undergone the Fontan procedure.

181. An oral pharmaceutical composition according to any one of claims 1 to 180.

182. Any of claims 165 to 180, wherein the SVHD patient is a patient who has undergone the Norwood procedure. The oral pharmaceutical composition according to any one of claims 1 to 4.

183. The SVHD patient is a patient who has undergone bidirectional Glenn procedure. An oral pharmaceutical composition described in any one of claims 1 to 4.

184. 181. The method of any one of claims 165 to 180, wherein the SVHD patient is at least 6 years old. The above-mentioned oral pharmaceutical composition.

185. 181. The method of any one of claims 165 to 180, wherein the SVHD patient is at least 8 years old. The above-mentioned oral pharmaceutical composition.

186. 181. The method of any one of claims 165 to 180, wherein the SVHD patient is at least 10 years old. The oral pharmaceutical composition described above.

187. 181. The method of any one of claims 165 to 180, wherein the SVHD patient is at least 12 years old. The oral pharmaceutical composition described above.

188. The method of any one of claims 165 to 180, wherein the SVHD patient is an adolescent patient. Oral pharmaceutical composition.

189. The method according to any one of claims 165 to 180, wherein the SVHD patient is an adult patient. Oral pharmaceutical composition.

190. The oral pharmaceutical composition of claim 181, wherein the SVHD patient is at least 6 years old.

191. The oral pharmaceutical composition of claim 181, wherein the SVHD patient is at least 8 years old.

192. 182. The oral pharmaceutical composition of claim 181, wherein the SVHD patient is at least 10 years old. 。

193. 182. The oral pharmaceutical composition of claim 181, wherein the SVHD patient is at least 12 years old. 。

194. The oral pharmaceutical composition of claim 181, wherein the SVHD patient is an adolescent patient.

195. The oral pharmaceutical composition of claim 181, wherein the SVHD patient is an adult patient.

196. The oral pharmaceutical composition of claim 182, wherein the SVHD patient is at least 6 years old.

197. The oral pharmaceutical composition of claim 182, wherein the SVHD patient is at least 8 years old.

198. 183. The oral pharmaceutical composition of claim 182, wherein the SVHD patient is at least 10 years old. 。

199. 183. The oral pharmaceutical composition of claim 182, wherein the SVHD patient is at least 12 years old. 。

200. The oral pharmaceutical composition of claim 182, wherein the SVHD patient is an adolescent patient.

201. The oral pharmaceutical composition of claim 182, wherein the SVHD patient is an adult patient.

202. The oral pharmaceutical composition of claim 183, wherein the SVHD patient is at least 6 years old.

203. The oral pharmaceutical composition of claim 183, wherein the SVHD patient is at least 8 years old.

204. 184. The oral pharmaceutical composition of claim 183, wherein the SVHD patient is at least 10 years old. 。

205. 184. The oral pharmaceutical composition of claim 183, wherein the SVHD patient is at least 12 years old. 。

206. The oral pharmaceutical composition of claim 183, wherein the SVHD patient is an adolescent patient.

207. The oral pharmaceutical composition of claim 183, wherein the SVHD patient is an adult patient.

208. To maintain, minimize the decline in, or increase ventricular performance In this study, we treated patients with single ventricle heart disease (SVHD) who underwent the Fontan procedure (post-Fontan patients). a method for treating a patient, the method comprising administering to said patient, preferably daily, an effective amount of an effective PDE5 inhibitor. The method comprising administering.

209. To minimize or prevent deterioration of ventricular performance in the long term 209. The method of claim 208, comprising:

210. The PDE5 inhibitor is preferably udenafil or a pharmaceutically acceptable salt thereof. The method of claim 208.

211. Any of claims 1 to 19, which improves myocardial performance index (MPI) in patients after the Fontan procedure.

10. The method according to claim 1.

212. Single-ventricle heart with functional single ventricle for improving myocardial performance index (MPI) in patients with SVHD 1. A pharmaceutical composition for oral administration for treating a patient with ventricular heart disease (SVHD), comprising: The SVHD patient is administered the oral pharmaceutical composition to improve MPI of the SVHD patient. Patients who require treatment with The pharmaceutical composition comprises: containing an effective amount of udenafil or a pharmaceutically acceptable salt thereof, Therefore, the oral pharmaceutical composition can be used to improve MPI in SVHD patients. When administered orally daily to HD patients, the effective amount of udenafil is This resulted in a udenafil pharmacokinetic plasma profile, The udenafil pharmacokinetic plasma profile may be measured individually, collectively, or in any combination. Combined, Cmax of 300-700 ng / ml, Tmax of 1-1.6 hours, 2550 AUC of 4150 ng / ml or more τ , and 5110-8290ng / h AUC in ml ０－２４ selected from a group of udenafil pharmacokinetic plasma profiles consisting of 、 Pharmaceutical compositions.

213. The oral pharmaceutical composition of claim 212, wherein the Cmax is about 500 ng / ml.

214. The udenafil Cmax pharmacokinetic plasma profile in the SVHD patient is about 5 214. The oral pharmaceutical composition of claim 213, wherein the solubility is about -20% to about +25% of 000 ng / ml. thing.

215. The udenafil Cmax pharmacokinetic plasma profile in the SVHD patient is about 5 214. The oral pharmaceutical composition of claim 213, wherein the solubility is about -20% to about +20% of 000 ng / ml. thing.

216. The pharmaceutical composition of claim 2128, wherein the Tmax is about 1.3 hours.

217. Claim 2: The udenafil Tmax is about -20% to about +25% of about 1.3 hours.

17. An oral pharmaceutical composition according to 16.

218. Claim 2: The udenafil Tmax is about -20% to about +20% of about 1.3 hours.

17. An oral pharmaceutical composition according to 16.

219. The udenafil AUC in the SVHD patients τ Pharmacokinetic plasma profile of 33 The oral pharmaceutical composition of claim 212, wherein the concentration is 50 ng / ml.

220. The udenafil AUC in the SVHD patients τ Pharmacokinetic plasma profile of approximately 3 The oral medicament according to claim 219, which is about -20% to about +25% of 350 ng / ml. composition.

221. The udenafil AUCτ pharmacokinetic plasma profile in the SVHD patient is about 3 The oral medicament according to claim 219, which is about -20% to about +20% of 350 ng / ml. composition.

222. The AUC ０－２４ is about 6701 ngh / ml thing.

223. The udenafil AUC in the SVHD patients τ Pharmacokinetic plasma profile of approximately 6 The oral medicament according to claim 222, which is about -20% to about +25% of 701 ng / ml. composition.

224. The udenafil AUC in the SVHD patients τ Pharmacokinetic plasma profile of approximately 6 The oral medicament according to claim 222, which is about -20% to about +20% of 701 ng / ml. composition.

225. Claim 212: The SVHD patient is a post-Fontan patient who has undergone the Fontan procedure.

225. An oral pharmaceutical composition according to any one of claims 1 to 224.

226. to improve ventricular performance, maintain ventricular performance, or reduce the rate of decline in ventricular performance To this end, we investigated patients with single ventricle heart disease (SVHD) who underwent the Fontan procedure (post-Fontan patients). A method of treating a patient comprising administering to said patient an effective amount of an effective PDE5 inhibitor, preferably or daily administration.

227. Treating patients with single ventricle heart disease (SVHD) who underwent the Fontan procedure (post-Fontan patients) A method of an effective amount of udenafil or a pharmaceutically acceptable salt thereof is administered daily to the patient after the Fontan procedure. By administering, the SVHD patient (a) Ventricular performance of single ventricle in SVHD patients assessed by MPI; (b) exercise capacity assessed by oxygen consumption at anaerobic threshold (VAT); (c) Submaximal exercise or maximum VO ２ Exercise tolerance assessed by oxygen consumption during exercise Noh; (d) Work rate at time of VAT; (e) Carbon dioxide ventilation equivalent (VE / VCO ２ ); (f) resting diastolic blood pressure; and / or (g) Oxygen saturation (%) at rest for (a) to (g) individually, collectively, and or any combination thereof, Improving, including, a method.

228. Single ventricle with functional single ventricle for improving certain markers in SVHD patients A pharmaceutical composition for oral administration for treating patients with SVHD, comprising the marker is assessed by myocardial performance index (MPI) and oxygen consumption at anaerobic threshold (VAT). Exercise tolerance, work rate at VAT, and VE / VCO at VAT ２ and The SVHD patient is administered the oral pharmaceutical composition to improve the markers of the SVHD patient. a patient in need of treatment with the pharmaceutical composition, containing an effective amount of udenafil or a pharmaceutically acceptable salt thereof, Thereby, the oral pharmaceutical composition is effective in improving the markers of SVHD patients. When administered orally daily to a patient with VHD, the effective amount of udenafil provides udenafil pharmacokinetic plasma profile in The udenafil pharmacokinetic plasma profile may be measured individually, collectively, or in any combination. Combined, Cmax of 300-700 ng / ml, Tmax of 1-1.6 hours, 2550 AUC of 4150 ng / ml or more τ , and 5110-8290ng / h AUC in ml ０－２４ selected from a group of udenafil pharmacokinetic plasma profiles consisting of 、 A pharmaceutical composition for oral administration.

229. The oral pharmaceutical composition of claim 228, wherein the Cmax is about 500 ng / ml.

230. The udenafil Cmax pharmacokinetic plasma profile in the SVHD patient is about 5 230. The oral pharmaceutical composition of claim 229, wherein the saturation concentration is about -20% to about +25% of 000 ng / ml. thing.

231. The udenafil Cmax pharmacokinetic plasma profile in the SVHD patient is about 5 230. The oral pharmaceutical composition of claim 229, wherein the solubility is about -20% to about +20% of 0.00 ng / ml. thing.

232. The pharmaceutical composition of claim 228, wherein the Tmax is about 1.3 hours.

233. Claim 2: The udenafil Tmax is about -20% to about +25% of about 1.3 hours.

33. An oral pharmaceutical composition according to claim 32.

234. Claim 2: The udenafil Tmax is about -20% to about +20% of about 1.3 hours.

33. An oral pharmaceutical composition according to claim 32.

235. The udenafil AUC in the SVHD patients τ Pharmacokinetic plasma profile of 33 The oral pharmaceutical composition of claim 228, wherein the concentration is 50 ng / ml.

236. The udenafil AUC in the SVHD patients τ Pharmacokinetic plasma profile of approximately 3 The oral medicament according to claim 235, which is about -20% to about +25% of 350 ng / ml. composition.

237. The udenafil AUC in the SVHD patients τ Pharmacokinetic plasma profile of approximately 3 The oral medicament according to claim 235, which is about -20% to about +20% of 350 ng / ml. composition.

238. The AUC ０－２４ is about 6701 nghr / ml thing.

239. The udenafil AUC in the SVHD patients τ Pharmacokinetic plasma profile of approximately 6 The oral medicament according to claim 238, which is about -20% to about +25% of 701 ng / ml. composition.

240. The udenafil AUC in the SVHD patients τ Pharmacokinetic plasma profile of approximately 6 The oral medicament according to claim 238, which is about -20% to about +20% of 701 ng / ml. composition.

241. Claim 228, wherein the SVHD patient is a post-Fontan patient who has undergone the Fontan procedure.

240. An oral pharmaceutical composition according to any one of claims 1 to 240.

242. Markers in SVHD patients are submaximal or maximum VO ２ Depending on the amount of oxygen consumed at the time The method according to any one of claims 228 to 240, further comprising assessing exercise tolerance. Oral pharmaceutical composition.

243. Markers in SVHD patients are submaximal or maximum VO ２ Depending on the amount of oxygen consumed at the time The method further comprises assessing exercise tolerance using a method for evaluating exercise tolerance in a patient with SVHD who has undergone the Fontan procedure. The oral pharmaceutical composition according to any one of claims 228 to 240, for postoperative patients. 。

244. Any one of claims 228 to 240, wherein the markers for SVHD patients further comprise MPI. The oral pharmaceutical composition according to claim 1.

245. The marker for SVHD patients further comprises MPI, and the SVHD patient has undergone the Fontan procedure. The oral administration method according to any one of claims 228 to 240, wherein the patient is a patient who has undergone the Fontan procedure. Pharmaceutical compositions.

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