Methods of improving myocardial performance in fontan patients using udenafil compositions

Abstract

To provide a pharmaceutical composition for treating, preventing, and / or minimizing conditions, symptoms, and / or side effects associated with a subject who has previously had a Fontan procedure.SOLUTION: A pharmaceutical composition comprises udenafil or a pharmaceutically acceptable salt thereof for use in improving exercise capacity being determined by improvement in VO2 at maximal effort or ventilatory anaerobic threshold (VAT) in a patient having Fontan physiology, wherein a dosage of the udenafil or a pharmaceutically acceptable salt thereof is 87.5 mg, and the composition is administered twice a day.SELECTED DRAWING: None

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This invention relates to U.S. Provisional Patent Application No. 62,036,506, filed August 12, 2014. No. 62 / 186,132, filed June 29, 2015. This application claims priority from the provisional application filed on Dec. 13, 2003, the disclosure of which is specifically incorporated by reference.

[0002] The present invention generally relates to a method for treating phosphodiesterase E5 (PD-1)-related metabolic syndrome in patients undergoing the Fontan procedure. Specifically, the PDE5 inhibitor is udenafil or its derivatives. is a pharma- ceutically acceptable salt thereof. [Background technology]

[0003] I. Background on the Fontan Procedure The Fontan or Fontan / Kreutzer procedure is used to treat congenital heart disease with a functional single ventricle. The Fontan procedure is a palliative surgical procedure for children born with a right heart defect. Designed to provide continuous blood flow to the pulmonary and systemic circulation without the need for a pump chamber This operation allowed systemic venous blood to flow through the arteries, capillaries, and other organs based on the impingement of a single ventricle. pulmonary circulation through the systemic venous system, and directly through the pulmonary circulation. Compared with shunts, it has improved life expectancy for patients with a single ventricle and pulmonary outflow tract obstruction.

[0004] This surgery involves creating a cavopulmonary anastomosis, separating the systemic circulation from the pulmonary circulation, and preventing hypoxemia and ventricular However, after the Fontan procedure, the ventricle that pumps blood to the pulmonary artery There is no pump. Instead, blood returns to the lungs by passive flow from the systemic veins. Thus, a circulatory system characterized by high central venous pressure, abnormal pulmonary vascular resistance, and chronically low cardiac output is created. Over time, these distinctive features of Fontan physiology begin to recede after puberty. This results in a predictable and sustained decline in cardiovascular efficiency, characterized by a progressive decline in exercise capacity. This decline in exercise tolerance correlates with increased symptoms of cardiovascular dysfunction, hospitalization, and heart failure management. The need for reinforcement or transplantation may arise.

[0005] Those with Fontan circulation do not have "normal" cardiac physiology or function. The two main complications that can affect the downstream are due to its location (venous or arterial) and ) depending on the following effects on blood pressure, which increases ("hypertension") and decreases ("hypotension"). First, when the Fontan circulation is present, "systemic venous hypertension" exists, which is caused by the venous blood pressure (blood returning to the heart) is different from that of individuals with normal (non-Fontan) cardiac function. This is caused by systemic venous hypertension, which is basically related to the distribution of fluids in the body. There are many negative consequences that can result from this (congestive heart failure, edema or swelling, liver function, The second complication is "pulmonary arterial hypotension." where the blood pressure in the arteries to or within the lungs (i.e., the lungs) is increased by 100% without normal cardiac function. Again, pulmonary symptoms such as cyanosis (purple lips) or lack of exercise tolerance are There are many negative consequences associated with hypotension. Following the Fontan procedure (short-term or Subsequent medical morbidity and mortality (which may occur over the long term) are thought to result from changes in systemic and pulmonary blood pressure. It is being done.

[0006] The long-term effects of significant univentricular preload and inefficient oxygenation due to the arterial shunt are Forty years ago, it was uniformly fatal. But in 2010, newborns with single ventricle congenital heart disease now have a chance of survival. However, these children are expected to survive into adolescence and adulthood. As the pandemic continues to grow, it is clear that this approach has significant limitations. However, the Fontan / Kreutzer procedure results in serious complications with very serious consequences. Over time, this can lead to widespread abnormalities affecting multiple organ systems. Generally, patients can live into their 20s or 30s without any of the potentially life-threatening complications. The chances of survival are low. Therefore, the Fontan procedure may improve the dysfunctional state. There is a clear need to find a treatment, given the increasing prevalence of the Fontan procedure. This is especially true when considering the age of 2 and, notably, the Fontan procedure is used to treat congenital It has become the most common surgery for cardiac disease. Circulation,117:13-15(2008).

[0007] Several studies examining the outcomes of the Fontan procedure have shown decreased survival beyond 15 years after surgery. Regardless of the type of cavopulmonary bypass, there is a high rate of continued attrition and progression. There is a risk of death. Another study examining the morphology of single left ventricle after the Fontan procedure found that The results showed that the odds of dying before he or she reached his or her late 20s were 1 in 4. J. Rychik, "Forty Years of the Fontan O peration:A Failed Strategy,″Pediatric Ca rdiac Surgery Annual,96-100(2010).

[0008] Given that Fontan patients are living longer, the researchers We have been exploring medical therapies to address the side effects of surgery, particularly in children and young adults with single ventricle physiology. People with abnormal exercise tolerance after the Fontan operation have improved cardiac output and central venous pressure. Strategies targeted at reducing this adverse physiological effect could improve their overall health and This will soften the sound.

[0009] One study showed that the PDE5 inhibitor sildenafil improved ventilatory efficiency during maximal and submaximal exercise. The results showed that the anaerobic metabolic threshold was significantly improved in two subgroups. These findings suggest improved oxygen consumption in children and young adults with single ventricle physiology. Sildenafil may be an important drug for improving exercise capacity after the Fontan operation Goldberg et al,Circulation,123:1 185-1193(2011).

[0010] More recent studies have shown that sildenafil in patients palliated using the Fontan circulation Increases ventricular systolic elastance and improves ventricular-arterial coupling Short-term sildenafil was well tolerated by most patients, with mild side effects. Shabanian et al., Pediatr. Cardiol., 34 (1):129-34(2013). The structure of sildenafil is shown below.

[0011] [ka]

[0012] In addition, the hemodynamic response to exercise and exercise tolerance in patients with Fontan circulation was evaluated. The short-term effects of the PDE5 inhibitor tadalafil were evaluated in a pilot study. inicaltrials.gov / ct2 / show / record / NCT0129 Similar to the published results for sildenafil, tadalafil was Short-term once-daily treatment improves ventilatory efficiency and oxygen saturation in young Fontan subjects The results improved, but exercise tolerance remained unchanged. on, 128:A16024(2013). The chemical structure of tadalafil is shown below.

[0013] [ka]

[0014] For optimal effectiveness, the PDE5 inhibitors sildenafil or tadalafil should be used with Fontan It needs to be given to patients long term to delay or prevent the onset of Fontan circulatory failure. The Fontan procedure may result in chronic conditions, and the Fontan procedure may be When children reach adolescence or adulthood, short-term treatment is unlikely to address associated mortality. This is especially true when Fontan failure begins, leaving patients at increased risk of death or heart transplant. There is an inevitable deterioration in hemodynamics and function that follows. Early experience with Fontan transplants has been associated with high operative mortality and morbidity. The hypothesis that PVR is sufficiently low for the right ventricle of the transplanted tissue after heart transplantation is correct if the patient survives. This was not the case in the early Fontan transplant experience.

[0015] Both sildenafil and tadalafil are known to have undesirable side effects. However, pulmonary arterial hypertension (PAH) patients who switched from sildenafil to tadalafil Significantly different oxygen saturation, significantly different post-6-minute walk test oxygen saturation, and significantly different It has been found that PDE5 inhibitors can be used to treat heart or cardiovascular conditions. It has been shown that they are not interchangeable when iatr Cardiol,35(4):699-704(2014). II. Background on PDE5 Inhibitors and Udenafil

[0016] PDE5 reacts with the second messenger molecule (cGMP) and cyclic adenosine-3', It regulates various cellular functions by catalyzing the hydrolysis of cAMP 5'-monophosphate (cAMP). Cyclic guanosine-3',5'-monophosphate, a member of the phosphodiesterase family It is a cGMP-specific phosphodiesterase. Boolell et al., nt'l J. Impot. Res., 8:47(1996). PDE5 inhibits the function of the pulmonary arterial wall. Because it is present in smooth muscle, PDE5 inhibitors prevent pulmonary blood flow, which is usually the result of failure of the right ventricle of the heart. It has been investigated for the treatment of pulmonary hypertension, a condition in which the vascular system is overloaded with fluid.

[0017] Udenafil is a drug used in urology to treat erectile dysfunction. It belongs to a class of drugs called PDE5 inhibitors, which include sildenafil, tadalafil, Typical dosages are 100 and 200 mg. Udenafil is available in South Korea, Russia, and the Philippines. , and is not approved for use by the U.S. Food and Drug Administration.

[0018] The Fontan procedure is palliative, not curative. However, in many cases to promote normal or near-normal growth, development, exercise tolerance, and a good quality of life. can bring about. In 20 / 30% of cases, patients will eventually require a heart transplant.

[0019] Modifications to the Fontan surgical model were one of the early steps to improve outcomes. The use of nesting, multi-stage Fontan procedures, and better perioperative management are now This has led to a marked reduction in mortality rates in recent years. and rare clinical syndromes of protein-losing enteropathy (PLE) and plastic bronchitis. There is a delayed attrition of patients. Management of a worsening Fontan syndrome involves Detailed hemodynamic and imaging evaluation to treat any treatable lesions, such as stenosis, irregular Early control of pulse and maintenance of sinus rhythm, symptomatic treatment for PLE and plastic bronchitis, systemic vascular Arrhythmic procedures from manipulation of resistance and pulmonary vascular resistance, and the less preferred atrial-pulmonary artery connection. The Fontan conversion to extracardiac cavopulmonary bypass with heart transplantation is one of the most common options. This remains the only successful definitive palliation in Fontan patients who continue to deteriorate. , worsening liver or kidney function, etc. Fontan circulation has already destroyed the body, so the heart Transplantation is not a perfect solution, and patients with Fontan circulation remain dependent even after heart transplantation. However, sometimes I feel unwell.

[0020] There are currently no studies in the art that would extend the lifespan of Fontan patients and avoid or eliminate the need for heart transplants. For the purpose of delaying complications or side effects of the Fontan procedure, There is a need in the art for a method to delay the onset of heart failure or to prevent the Fontan procedure. There is a need for improved treatments to improve the quality of life of surgical patients. The present invention fulfills this need. Summary of the Invention

[0021] In one embodiment, the present invention relates to a condition, syndrome, or condition associated with a patient who has previously undergone the Fontan procedure. The present invention is directed to methods for treating, preventing, and / or minimizing symptoms and / or side effects of The methods of the present invention are directed to patients undergoing the Fontan procedure for the amelioration of associated acute and chronic symptom episodes. The use of udenafil or its pharmacologic acceptable salts in adolescent patients with a single ventricle The method comprises administering to a patient a therapeutically effective amount of a PDE5 inhibitor, The DE5 inhibitor is udenafil or a pharma- ceutically acceptable salt thereof.

[0022] In one embodiment, the present invention provides a method for improving cardiac output in a patient who has had the Fontan procedure. The method includes administering to a patient a therapeutically effective amount of a PDE5 inhibitor, The PDE5 inhibitor is udenafil or a pharma- ceutically acceptable salt thereof.

[0023] In another embodiment, the present invention provides a method for reducing pulmonary vascular resistance in a patient who has had the Fontan procedure. The method includes administering to a patient a therapeutically effective amount of a PDE5 inhibitor, The PDE5 inhibitor is udenafil or a pharma- ceutically acceptable salt thereof.

[0024] In yet another embodiment, the present invention relates to a method for improving exercise tolerance in patients who have had the Fontan procedure. The present invention is directed to a method for treating a patient suffering from atopic dermatitis, the method comprising administering to the patient a therapeutically effective amount of a PDE5 inhibitor. wherein the PDE5 inhibitor is udenafil or a pharma- ceutically acceptable salt thereof.

[0025] In one embodiment, the present invention relates to a method for improving myocardial performance in a patient who has had the Fontan procedure. The method includes administering to a patient a therapeutically effective amount of a PDE5 inhibitor, The PDE5 inhibitor is udenafil or a pharma- ceutically acceptable salt thereof.

[0026] In an exemplary embodiment, the method of the present invention provides a therapeutically effective dose of udenafil or its pharmaceutical equivalents. The method includes administering to the patient a once daily dose of a therapeutically acceptable salt thereof.

[0027] In another embodiment, the methods of the present invention provide a therapeutically effective dose of udenafil or a pharma- ceutical tolerable thereof. This involves administering an acceptable salt to the patient twice daily.

[0028] In another embodiment, the patient is a pediatric patient, the patient being between about 2 and about 18 years of age. Treatment is also encompassed by the methods of the invention.

[0029] In yet another embodiment, the present invention provides an improved method of treating a patient who has had a Fontan procedure. The method involves comparing patients who were prescribed udenafil or improving patient compliance with a dosing schedule for its pharma- ceutical acceptable salt; Shows.

[0030] In one embodiment, the present invention is directed to an improved method of treating a patient who has had a Fontan procedure. and the method of the present invention has less adverse effects compared to conventional methods of treating such patients. In another embodiment, the method of the present invention provides a method for treating Very few, if any, serious, moderate, or mild adverse events were reported. do.

[0031] In another embodiment, the method of the present invention is carried out without the use of the method of the present invention (e.g., Udenauer et al., Improvement in patients' maximal VO2 compared to maximal VO2 without drug administration For example, the improvement may be achieved without the use of the methods of the invention (e.g., administration of udenafil). 5, 6, 7, 8, 9, and 10 times the VO2 at maximum effort (without the use of , about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20 , about 21, about 22, about 23, about 24, about 25, about 26, about 27, about 28, about 29, or about It can be 30% or more.

[0032] In another embodiment, the method of the present invention is carried out without the use of the method of the present invention (e.g., Udenauer et al., The improvement in VO2 at the patient's anaerobic threshold compared to VO2 without administration of the drug For example, the improvement may be achieved without the use of the methods of the present invention (e.g., the use of udenafil). Compared to the maximum VO2 during the absence of administration, the 0, approx. 11, approx. 12, approx. 13, approx. 14, approx. 15, approx. 16, approx. 17, approx. 18, approx. 19, approx. 2 0, about 21, about 22, about 23, about 24, about 25, about 26, about 27, about 28, about 29, or It can be about 30% or more.

[0033] In another embodiment, the method of the present invention is carried out without the use of the method of the present invention (e.g., Udenauer et al., compared with blood pool MPI or other published measures of ventricular function (without drug administration) , resulting in an improvement in the patient's blood pool MPI or other disclosed measures of ventricular function. For example, The improvement may be compared to blood levels in the absence of the methods of the invention (e.g., in the absence of administration of udenafil). Compared to pooled MPI or other disclosed measures of ventricular function, 9, approx. 10, approx. 11, approx. 12, approx. 13, approx. 14, approx. 15, approx. 16, approx. 17, approx. 18, approx. 9, about 20, about 21, about 22, about 23, about 24, about 25, about 26, about 27, about 28, about 2 9, or about 30% or more.

[0034] In another embodiment, the method of the present invention is carried out without the use of the method of the present invention (e.g., Udenauer et al., 1. Compare the logarithm of reactive hyperemia index (in the absence of drug administration) or other published measures of vascular function. This results in an improvement in the patient's log reactive hyperemia index or other disclosed measure of vascular function. For example, improvement may occur in the absence of the methods of the invention (e.g., in the absence of administration of udenafil). ) or another disclosed measure of vascular function. 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, About 18, about 19, about 20, about 21, about 22, about 23, about 24, about 25, about 26, about 27, It can be about 28, about 29, or about 30% or more.

[0035] And finally, in yet another embodiment, the methods of the invention provide a method for determining a characteristic pharmacokinetic profile. The pharmacokinetic profile is consistent with a C of 300-700 ng / ml. max ,also More specifically, it is about 500 ng / ml; T of 1 to 1.6 hours max or more specifically, about 1.3 hours; AUCτ of 2550 to 4150 ng·h / ml, or more specifically, about 3 350 ng·h / ml; and AUC of 5110–8290 ng·h / ml 0-24 or More specifically, it may contain about 6701 ng·hr / ml.

[0036] The foregoing general description and the following detailed description are exemplary and explanatory only and are not intended to limit the invention as claimed. The following brief description of the drawings and the present invention are intended to provide a further description of the invention. Other objects, advantages, and novel features will become readily apparent to those skilled in the art from the detailed description of the invention. cormorant. [Brief description of the drawings]

[0037] [Figure 1] FIG. 1 shows the percentage of subjects reporting at least one, three, or five adverse events by treatment group.

[0038] [Diagram 2] Figure 2 shows the change in peak VO2 (ml / kg / min) at maximal effort from baseline (day 1) to the last visit (post-medication, day 5) by treatment group, with a positive change indicating improvement.

[0039] [Diagram 3] FIG. 3 shows peak VO2 at maximal effort at baseline (day 1) and at the final visit (post-medication, day 5) by treatment group, with a positive change indicating improvement.

[0040] [Figure 4] FIG. 4 shows the change in VO2 (ml / kg / min) at anaerobic threshold from baseline (day 1) to the final visit (post-medication, day 5) by treatment group, with a positive change indicating improvement.

[0041] [Diagram 5] FIG. 5 shows peak VO2 at anaerobic threshold at baseline (day 1) and the final visit (post-medication, day 5) by treatment group, with a positive change indicating improvement.

[0042] [Figure 6] Figure 6 shows the change in natural log of Reactive Hyperemia Index from baseline (day 1) to the last visit (post-medication, day 5) by treatment group. A positive change indicates improvement.

[0043] [Figure 7] Figure 7 shows the natural logarithm of the reactive hyperemia index (RHI) at baseline (day 1) and the last visit (post-medication, day 5) by treatment group. A positive change indicates an improvement.

[0044] [Figure 8] Figure 8 shows the change in blood pool MPI from baseline (day 1) to the last visit (post-medication, day 5) by treatment group. A negative change indicates improvement.

[0045] [Figure 9] Figure 9 shows blood pool MPI at baseline (day 1) and last visit (post-medication, day 5) by treatment group. A negative change indicates an improvement.

[0046] [Figure 10] Figure 10 shows the change in tissue Doppler MPI from baseline (day 1) to the last visit (post-medication, day 5) by treatment group. A negative change indicates improvement.

[0047] [Figure 11] Figure 11 shows tissue Doppler MPI at baseline (day 1) and the last visit (post-medication, day 5) by treatment group. A negative change indicates an improvement.

[0048] [Figure 12] Figure 12 shows the change in mean isovolumic contraction from baseline (day 1) to the last visit (post-medication, day 5) by treatment group. A negative change indicates improvement.

[0049] [Figure 13]Figure 13 shows the mean isovolumic contraction at baseline (day 1) and at the last visit (post-medication, day 5) by treatment group. A negative change indicates an improvement.

[0050] [Figure 14] Figure 14 shows the change in mean isovolumic relaxation from baseline (day 1) to the last visit (post-medication, day 5) by treatment group. A negative change indicates improvement.

[0051] [Figure 15] Figure 15 shows the mean isovolumic relaxation at baseline (day 1) and at the last visit (post-medication, day 5) by treatment group. A negative change indicates an improvement.

[0052] [Figure 16] FIG. 16 shows individual concentration-time curves stratified by dosing regimens: (A) 37.5 mg every 24 hours, (B) 37.5 mg every 12 hours, (C) 87.5 mg every 24 hours, (D) 87.5 mg every 12 hours, and (E) 125 mg every 24 hours.

[0053] [Figure 17] Figure 17 shows the concentration time concentration profile of udenafil in subjects. The solid line represents the actual data, and the dashed line represents the predicted data for the second day of the 12-hour dosing regimen. Data are expressed as the mean ± standard deviation.

[0054] [Figure 18]Figure 18 shows a comparison of Cmax between various dosing regimens. Box plots show the 10-90 percentile and range of observations, with the midline representing the median of the dosing regimens. Significant differences: 37.5mg q24h vs. 87.5mg q12h, p<0.001; 37.5mg q24h vs. 125mg q24h, p<0.001; 37.5mg q12h vs. 87.5mg q12h, p<0.001; 37.5mg q12h vs. 125mg q24h, p<0.01; 87.5mg q24h vs. 87.5mg q12h, p<0.05.

[0055] [Figure 19] 19 shows a comparison of (A) AUCτ and (B) AUC0-24 between various dosing regimens. Box plots show the 10-90th percentiles and range of observations, with the midline representing the median of the dosing regimens. Significant differences: A) 37.5mg q24h vs. 87.5mg q12h, p<0.001; 37.5mg q24h vs. 125mg q24h, p<0.001; 37.5mg q12h vs. 87.5mg q12h, p<0.01; 37.5mg q12h vs. 125mg q24h, p<0.01; B) 37.5mg q24h vs. 87.5mg q12h, p<0.001; 37.5mg q24h vs. 125mg q24h, p<0.01; 37.5mg q12h vs. 87.5mg q12h, p<0.001; 87.5mg q24h vs. 87.5mg 87.5 mg q12 h vs. 125 mg q24 h, p<0.001.

[0056] [Figure 20] Figure 20 shows a comparison of A) CL / F and B) V / F between various dosing regimens. Box plots show the 10-90th percentile and range of observations, with the midline representing the median of the dosing regimens. Significant differences: A) 37.5 mg q24h vs. 87.5 mg q12h, p<0.05; B) 37.5 mg q24h vs. 87.5 mg q12h, p<0.01.

[0057] [Figure 21]FIG. 21 shows DV (observed concentration) versus subject ID.

[0058] [Figure 22] FIG. 22 shows time (hours) versus subject ID.

[0059] [Figure 23] FIG. 23 shows DV (observed concentration) versus time after administration (TAD).

[0060] [Figure 24] FIG. 24 shows DV (observed concentration) versus time (hours).

[0061] [Diagram 25] FIG. 25 shows individual visual plots (SID1-12) including variability between observed concentration (DV) versus predicted concentration (PRED) and individual predicted (IPRED) error versus time (hr).

[0062] [Figure 26] FIG. 26 shows individual visual plots (SID13-24) including variability between observed concentration (DV) versus predicted concentration (PRED) and individual predicted (IPRED) error versus time (hr).

[0063] [Figure 27] Figure 27 shows individual visual plots (SID25-30) including variability between observed concentration (DV) versus predicted concentration (PRED) and individual predicted (IPRED) error versus time (hr).

[0064] [Figure 28] Figure 28 shows a summary of the mean plasma concentrations per time point of the pharmacokinetic study of udenafil in Fontan patients. Data are presented as mean ± standard deviation.

[0065] [Figure 29]Figure 29 shows a non-compartmental analysis of udenafil in Fontan patients stratified by dosing regimen. Data are presented as mean ± standard deviation.

[0066] [Diagram 30] FIG. 30 shows a goodness-of-fit plot of observed versus predicted data (DV vs. PRED).

[0067] [Diagram 31] FIG. 31 shows a goodness-of-fit plot of observed data versus individual predicted data (DV versus IPRED).

[0068] [Diagram 32] FIG. 32 shows a goodness-of-fit plot of the observed versus predicted data (DV vs. PRED) for the final model.

[0069] [Diagram 33] FIG. 33 shows a goodness-of-fit plot of the final model for observed versus individual predicted data (DV versus IPRED).

[0070] [Diagram 34] FIG. 34 shows characteristic Fontan physiology. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0071] I. Fontan physiology Fontan physiology is a class of congenital heart defects that share the common feature of a functional single ventricle. These include disorders that result in hypoplastic left or right ventricles. Typically, the systemic and pulmonary circulations are separated through a series of two or three operations to allow access to oxygen. This eliminates the mixing of oxygen-rich and oxygen-poor blood. This is accomplished by connecting the blood vessels directly to the heart. This allows the physiology to function as follows: (1) A single systemic ventricle pumps oxygen-rich blood from the aorta to the systemic vascular bed of the body. (2) Systemic venous blood then returns to the pulmonary vascular bed through the vena cava without the assistance of the subpulmonary ventricle. (3) Finally, oxygen-rich blood flows passively through the common systemic atrium, The cycle is repeated. This structure is illustrated in Figure 34.

[0072] The Fontan procedure involves creating an anastomosis of the superior and inferior vena cava and pulmonary arteries, separating the systemic circulation from the pulmonary circulation and preventing hypoxemia. However, after the Fontan procedure, blood is sent to the pulmonary artery. There is no ventricular pump that pumps blood out of the heart. Instead, blood is returned to the lungs by passive flow from the systemic veins. Thus, the primary physiological consequence of this type of relaxation is the diversion of pulmonary blood flow from the systemic venous bed to the atria. The main function of the pulmonary artery is to maintain the pressure gradient across the pulmonary bed. Normal circulatory flow is augmented by the increased pressure generated by the right ventricle. In subjects, this increases the pressure in the pulmonary artery at rest by approximately 20-25 mmHg and increases the pressure during exercise. With Fontan physiology, there is no subpulmonary ventricle, and therefore no blood flow. There is no pressure increase as fluid enters the pulmonary artery. At rest, the pressure gradient across the pulmonary vascular bed is extremely small. The ability to increase this pressure gradient with exercise depends on the body's ability to tolerate gradually increasing central venous pressure. is extremely limited.

[0073] The unique outcome is that the Fontan procedure relies entirely on passive reduction in venous pressure to drive pulmonary blood flow. The pulmonary vascular resistance is significantly affected by changes in pulmonary vascular resistance. Even elevations within the range would have adverse effects on Fontan physiology. Any reduction in resistance may increase pulmonary blood flow, even if the value is already normal. Therefore, the use of udenafil is not considered to be a potential side effect specific to this type of palliated congenital heart defect. Unlike other uses of PDE-5 inhibitors, this treatment does not affect pulmonary vascular resistance or This would result in lower tolerance in populations without elevated vascular pressure. in normal cardiovascular and pulmonary vascular disease or palliated with biventricular repair (thus pulmonary artery In comparison with the very rare patient with congenital heart disease (subvalvular ventricle) and associated pulmonary vascular disease, This is a clearly different use of the same drug. II. Clinical measurements relevant to Fontan patients

[0074] The Fontan procedure is currently performed for children born with functional single ventricle congenital heart disease. The Fontan procedure has significantly increased survival in pediatric subjects but is not curative. The procedure is palliative rather than definitive, and it also reduces arrhythmias, ventricular dysfunction, proteinuria, and other heart problems. Complications such as rare clinical syndromes such as white-leaking enteropathy (PLE) and plastic bronchitis, as well as hepatic A series of adverse events may lead to delayed attrition in patients with cardiac and renal complications. This can result in side effects and complications.

[0075] In one embodiment, the disclosed invention provides a clinically relevant indicator of patient health status following the Fontan procedure. The aim of the present invention is to improve or prevent the deterioration of specific measurements associated with such measurements. These include exercise stress testing, vascular function testing, and echocardiographic assessment of ventricular function. But not limited to these. Exercise stress testing

[0076] Exercise testing should include assessment of VO2 values ​​during maximal effort or at the anaerobic threshold. VO2max, or the maximum amount of oxygen an individual can use during intense exercise. This measurement is generally used as a measure of cardiovascular fitness and aerobic endurance confidence. Theoretically, it could be used by humans during high levels of exercise. The more oxygen available, the more energy a person can produce. requires oxygen for prolonged (aerobic) exercise, and blood carries oxygen to the muscles and meets the demands of aerobic exercise. This test is cardiopulmonary bypass because the heart must pump enough blood to fill the lungs. It is the most reliable measure of a person's health.

[0077] VO2 is often measured by wearing a mask on the subject and measuring the inhaled and exhaled volumes and gas concentrations. This measurement is used in both clinical practice and research. The test is usually performed at an exhausting level with increasing intensity. The subjects' maximum effort and and / or designed to provide a reading at the subject's anaerobic threshold. .

[0078] Patients who have had a previous Fontan procedure typically experience a decline in VO2 measurements over time. The patient will be treated with the method of the present invention, resulting in a VO2 measurement for the patient. maintains the same level, indicating no further decline in VO2 function, or The improvement of cardiovascular function through treatment indicates that the treatment is clinically beneficial and improves cardiovascular function. This indicates that the condition can be improved or prevented.

[0079] In one embodiment, the present invention provides a method for determining VO2 measurements in subjects who have previously undergone the Fontan procedure. The present invention is directed to a method for improving or maintaining the level of vasopressin in a patient, the method comprising administering a therapeutically effective amount of a PDE5 inhibitor to a patient. wherein the PDE5 inhibitor is udenafil or a pharma- ceutical acceptable salt thereof. In some embodiments, VO2 is measured during maximal effort, while in other embodiments, In this condition, VO2 is measured at the subject's anaerobic threshold.

[0080] In some embodiments, the disclosed methods and compositions are administered to a Fontan patient and administered over time. As the exercise progresses, exercise tolerance does not decrease or decreases minimally. The disclosed methods and compositions provide a reduction in blood glucose levels over time of less than about 40, less than about 35, less than about 30, or less than about 35 a decrease in exercise tolerance of less than about 20%, less than about 15%, less than about 10%, or less than about 5% The time between the first and second measurements used to calculate the decline in exercise tolerance may be For example, the interval is about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 1 1 or about 12 months; about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, About 10, about 11, about 12, about 13, about 14, or about 15 years, or any combination thereof In total, the total can be, for example, 1 year and 3 months; 4 years and 7 months, etc.

[0081] In some embodiments, the disclosed methods and compositions are administered to a Fontan patient to improve exercise tolerance. More specifically, the methods and compositions disclosed herein may improve maximal effort VO 1, 2, 5, 10, 15, 20, 25, 30, 35, 40, 45, or 50% or more of 2 Alternatively, the disclosed methods and compositions may improve the V at the anaerobic threshold of a patient. O2 1, 2, 5, 10, 15, 20, 25, 30, 35, 40, 45, or 50% or more It can be improved. Vascular function tests

[0082] Endothelial dysfunction is an important endpoint for assessing vascular health in intervention studies. Currently, endothelial dysfunction is positively associated with traditional cardiovascular disease (CVD) risk factors. and independently predict cardiovascular events over a 1- to 6-year interval. is well established.

[0083] Pulse amplitude tonometry (PAT) is an FDA approved method for assessing vascular function. This method evaluates endothelium-dependent hyperemia in response to reactive hyperemia and flow-mediated dilation (FMD). PAT devices are increasingly being used as an alternative measure of augmentation. Digital pulse wave amplitude (PWA) was recorded using cardiography. The measurements were taken continuously during three stages: the break in the blood flow, the 5-minute forearm occlusion, and the reactive hyperemia after cuff release. Unlike FMD, PAT testing does not depend on highly skilled laboratory technicians and can be easily analyzed after testing. The analysis is largely automated. More importantly, at least one long-term study Study finds that PAT measures of endothelial function predict CVD events over a 6-year follow-up period These major advantages are expected to be realized when prognostic significance and reliability can be confirmed. This may make AT testing more suitable for clinical practice.

[0084] Patients who have had a previous Fontan procedure typically experience a decline in vascular function over time. By treating patients, the patient's vascular function improves or decreases. Preventing further decline is important because it ensures that treatment is clinically beneficial and improves patients' quality of life. This suggests that it may be possible to improve cardiovascular health and prevent a decline in cardiovascular function.

[0085] In one embodiment, the present invention provides a method for improving vascular function in a subject who has previously undergone the Fontan procedure. The present invention is directed to a method of improving or maintaining the quality of life of a patient by administering a therapeutically effective amount of a PDE5 inhibitor to a patient. wherein the PDE5 inhibitor is udenafil or a pharma- ceutical acceptable salt thereof. In some embodiments, vascular function is measured using the PAT index.

[0086] In some embodiments, the disclosed methods and compositions are administered to a Fontan patient and administered over time. Vascular function does not decrease or decreases minimally with age. Vascular function is limited. However, pulse amplitude tonometry, the natural logarithm of the reactive hyperemia index, the reactive hyperemia index, and the Lamingham RHI, area under the curve for maximum occlusion / control, mean up to maximum occlusion / control and other known EndoPAT indicators, can be measured using any conventional known technique. In some embodiments, vascular function is measured using the PAT index. More specifically, The disclosed methods and compositions have the potential to reduce or eliminate inflammatory bowel disease over time, such as by reducing or eliminating inflammatory bowel disease, such as by reducing or eliminating inflammatory bowel disease over time ... A decrease in vascular function of less than 35%, less than about 20%, less than about 15%, less than about 10%, or less than about 5%. The time between the first and second measurements used to calculate the decrease in vascular function For example, the interval is about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 1 1 or about 12 months; about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, About 10, about 11, about 12, about 13, about 14, or about 15 years, or any combination thereof In total, the total can be, for example, 1 year and 3 months; 4 years and 7 months, etc.

[0087] In some embodiments, the disclosed methods and compositions are administered to a Fontan patient to improve vascular function. Vascular function may be measured using a number of methods, including but not limited to pulse amplitude tonometry, Natural logarithm of reactive hyperemia index, reactive hyperemia index, Framingham RHI, maximum occlusion / control Area under the curve, mean maximum occlusion / control, and other known EndoPAT indices In some embodiments, vascular function can be measured using any conventional technique known in the art, including The PAT index is used to measure the PAT index. More specifically, the methods and compositions of the present disclosure include, but are not limited to, However, pulse amplitude tonometry, the natural logarithm of the reactive hyperemia index, the reactive hyperemia index, and the flow Mingham RHI, area under the curve for maximum occlusion / control, mean up to maximum occlusion / control, and about 1, about 2, or about 3 times the mean of one or more measurements of vascular function, including other known EndoPAT indices. , about 5, about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, or about 5 It can result in an improvement of more than 0%. Echocardiographic assessment of ventricular function

[0088] Ventricular function, or cardiac contractility, can indicate impairment of cardiovascular health before overt heart failure is detected. Ventricular function can be assessed using echocardiography, which is an important measurement to clarify myocardial function. This can be quantified via the Functional Performance Index, or MPI. MPI is an index that combines systolic and diastolic function. Specifically, MPI is the sum of isovolumic contraction time and isovolumic relaxation time divided by ejection time. It is defined as:

[0089] Various versions of MPI are known in the art, and each version of MPI is MPI indices can be used to assess ventricular function. For example, MPI indices include blood pool MPI, These may include tissue Doppler MPI, mean isovolumic contraction, and mean isovolumic relaxation. Not limited to.

[0090] Patients who have had a previous Fontan procedure typically experience a decline in ventricular function over time. Treating patients so that their ventricular function is maintained and minimized over time. A reduction or increase in IL-16 indicates that treatment is clinically beneficial and improves the patient's quality of life. These results suggest that it may be possible to increase blood flow and prevent decline in cardiovascular function.

[0091] In one embodiment, the present invention provides a method for maintaining ventricular function in subjects who have previously undergone the Fontan procedure. The present invention relates to a method for maintaining, causing a minimal decrease in, or increasing, ventricular function. The method includes administering to the patient a therapeutically effective amount of a PDE5 inhibitor, In some embodiments, the PDE5 inhibitor is udenafil or a pharma- ceutically acceptable salt thereof. In some embodiments, ventricular performance is measured using the myocardial performance index (MPI). In some embodiments, the MPI may be a blood pool MPI, while in other embodiments, the MPI may be a tissue pool MPI. It may be a large MPI.

[0092] In some embodiments, the disclosed methods and compositions are administered to a Fontan patient and administered over time. With the passage of time, there is minimal or no decrease in ventricular function. Features include, but are not limited to, Myocardial Performance Index (MPI), Blood Pool MPI, Tissue Doppler Any conventional publicly available indices of ventricular function, including MPI, mean isovolumic contraction and relaxation, and other known indices of ventricular function, may be used. More specifically, the methods and compositions of the present disclosure provide a method for measuring the amount of oxidative stress that can be measured over time using known techniques. Less than about 40, Less than about 35, Less than about 30, Less than about 35, Less than about 20, Less than about 15, Less than about 1 This may result in a reduction in ventricular function of less than 0 or less than about 5%. The time between the first and second measurements used in the method may be, for example, about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, or about 12 months; about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, or about 15 years, or any combination thereof, e.g., 1 year and 3 months; 4 years and 7 months, etc. etc.

[0093] In some embodiments, the disclosed methods and compositions are administered to a Fontan patient and administered over time. Ventricular function is measured using, but not limited to, myocardial performance index (M PI), blood pool MPI, tissue Doppler MPI, average isovolumic contraction and relaxation, and other Any conventional technique, including known indices of ventricular function, may be used to measure the ventricular function. The disclosed methods and compositions include, but are not limited to, Myocardial Performance Index (MPI), Blood Pool MPI, These include tissue Doppler MPI, mean isovolumic contraction and relaxation, and other known ventricular function indices. about 1, about 2, about 5, about 10, about 15, about 20, about 30, about 40, about 50, about 60, about 70, about 80, about 90, about 100, about 150, about 200, about 300, about 400, about 500, about 600, about 700, about 800, about 900, about 100 about 20, about 25, about 30, about 35, about 40, about 45, or about 50% improvement or more Ugh. III. Method according to the invention

[0094] In one embodiment, the present invention relates to a condition associated with a subject who has previously undergone the Fontan procedure. The present invention is directed to methods of treating, preventing, and / or minimizing the symptoms, symptoms, or side effects of administering to the patient a therapeutically effective amount of a PDE5 inhibitor, wherein the PDE5 inhibitor is Udenafil or a pharma- ceutically acceptable salt thereof.

[0095] In the Fontan circulation, pulmonary blood flow is passive and depends on the pressure difference between the systemic venous circulation and the ventricular end-diastolic pressure. Agents that can enable more efficient transport of blood through the pulmonary vascular bed are known as cardiac preload agents. This allows for improved cardiac output.

[0096] PDE5 inhibitors reduce pulmonary vascular resistance in patients with pulmonary hypertension and myocardial dysfunction. It is a class of drugs that improves ventricular function.

[0097] Several studies have demonstrated the efficacy of sildenafil alone in children and young adults undergoing the Fontan procedure. Single-use or long-term use has been evaluated. However, sildenafil has a short half-life and typically It is administered 3-4 times a day. Such a dosing schedule is not convenient and increases patient compliance. In addition, administration of drugs with short half-lives may reduce the therapeutic effect of the drug. This results in large fluctuations in therapeutic levels, with blood levels of PDE5 inhibitors reaching therapeutic levels for parts of the day. The inventors of the present invention have found that the longer the Administration of PDE5 inhibitors with short half-lives to patients undergoing the Fontan operation It is hypothesized that this will prevent or improve the subsequent decline in aerobic fitness in patients.

[0098] Patient compliance is essential for optimal treatment effectiveness, especially when administered daily for extended periods of time, such as several years or more. This is especially true for Fontan patients. In particular, individuals who have had the Fontan procedure are most likely to develop heart failure, stroke (thrombosis), or sudden death from some unknown cause. Of note, the risk of death from heart failure The incidence rate was very low within 10 years after the Fontan procedure, but increased over time from 10 years after the Fontan procedure. http: / / bendantzer.wordpress. s.com / 2013 / 03 / 13 / fontan-circulation-succ ess-or-failure / .

[0099] Of course, the risk of death or cardiac arrest increases with time from the date of the Fontan procedure. Increased need for organ transplants. This may be due to sudden death or heart failure, but it is also due to a gradual decline in heart function. As the years pass after the Fontan procedure, heart function may decline. This is reflected in a reduced ability to perform aerobic exercise. For patients who received treatment at a young age, exercise tolerance was significantly reduced (44%) compared with normal patients. This ability tends to decline linearly each year (2.6% decline per year). Patients with ontonic circulation have a significantly decreased exercise tolerance (<55% of normal) at age 30 years. The number of health problems and hospitalization rates increase dramatically. This is perhaps not surprising, since the heart does 20 minutes of work each day, so heart function changes over time. The present invention can eliminate or significantly reduce the decrease in the amount of oxygen that occurs over time. A procedure using this technique would be highly desirable for Fontan patients. The key to the success of such a procedure is The primary objective of this study was to determine patient compliance with the desired dosing schedule.

[0100] Patient compliance with prescribed medication schedules, or lack thereof is known to be a critical factor in the success of any treatment. Healthcare outcomes are measured by the patient's adherence to recommended treatment plans. Patient non-adherence is a factor in health and well-being. It is a pervasive threat to the wellbeing of people and can also pose a significant economic burden. In some conditions, over 40% of patients are There are great risks involved in misunderstanding, forgetting, or ignoring the Prevention or treatment programs are highly complex and / or involve lifestyle changes and modification of existing habits When patients require correction, nonadherence can be as high as 70%. Martin et al. al.,Ther.Clin.Risk Manag.,1(3):189-199( 2005) ("However, a major barrier to effective drug treatment is the or failing to follow the recommendations of another healthcare provider. Therefore, it is recommended that you take sildenafil or other drugs at least 4 to 6 hours apart. A preferred once daily or multiple daily dose, e.g., 3 to 6 times daily, is preferred compared to the multiple daily doses required. Two doses are administered to produce the desired results (e.g., improved cardiac output, reduced pulmonary vascular resistance, improved exercise tolerance). treatments that can result in improved functioning, improved myocardial performance, and prevention or improvement of decline in aerobic exercise capacity Such a more simplified administration regimen would improve patient compliance. This is likely to lead to a significant increase in the number of patients with pulmonary embolism and, at the same time, improved treatment outcomes.

[0101] In one embodiment, the present invention provides a method for improving cardiac output in patients who have had the Fontan procedure. The present invention relates to a method for administering a therapeutically effective amount of the PDE5 inhibitor udenafil or its pharmaceutical equivalent. For example, the methods of the present invention include administering udenafil to a patient in the form of a therapeutically acceptable salt thereof. Compared to untreated subjects, the results were approximately 5%, 8%, 10%, 15%, 20%, and 25%, about 30%, about 35%, about 40%, about 45%, or about 50% improvement in cardiac output. It can be achieved.

[0102] In another embodiment, the present invention reduces pulmonary vascular resistance in patients who have had the Fontan procedure. The present invention relates to a method for administering a therapeutically effective amount of the PDE5 inhibitor udenafil or a pharmaceutical For example, the methods of the present invention include administering udenafil to a patient. Compared to subjects who did not receive the treatment, the results were approximately 5%, 8%, 10%, 15%, 20%, and 2%. A decrease in pulmonary vascular resistance of 5%, about 30%, about 35%, about 40%, about 45%, or about 50%. It can be achieved.

[0103] In yet another embodiment, the present invention provides a method for evaluating exercise tolerance in patients who have had the Fontan procedure. The present invention relates to a method for improving the efficacy of a therapeutically effective amount of the PDE5 inhibitor udenafil or its For example, the methods of the present invention include administering to a patient a pharma- ceutical acceptable salt of Udenaf. Compared to subjects not receiving the drug, the %, 25%, 30%, 35%, 40%, 45%, or 50% of your VO2 max. This can result in an increase in measured exercise capacity.

[0104] In one embodiment, the present invention provides a method for improving myocardial performance in patients who have undergone the Fontan procedure. The present invention relates to a method for treating a patient having a pulmonary circulation disorder, the method comprising administering to the patient a therapeutically effective amount of a PDE5 inhibitor. For example, the method of the present invention may reduce the urinary incontinence rate by about 5%, compared to subjects not receiving udenafil. About 8%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about This can result in an improvement in myocardial performance of 45%, or about 50%.

[0105] In one embodiment, the present invention provides a method for evaluating aerobic exercise capacity in patients who have had the Fontan procedure. The present invention relates to a method for preventing or ameliorating the decline of cerebral hepatic endothelial function, the method comprising administering a therapeutically effective amount of the PDE5 inhibitor Udena For example, the method of the present invention includes administering to a patient a medicament for the treatment of a disease comprising administering to the patient a medicament for the treatment of a disease, such as ... The study showed that the effects of udenafil on the morbidity and mortality rates were approximately 5%, 8%, 10%, and 60%, respectively, compared with subjects not receiving udenafil. 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, or about 50% can result in the amelioration of the decline in aerobic exercise capacity as measured by VO2 max .

[0106] In yet another embodiment, the present invention relates to an improved method for treating a patient who has had a Fontan procedure. The method is to compare patients who were prescribed udenafil or and improving patient compliance with a dosing schedule for said pharma- ceutical acceptable salts. .

[0107] Udenafil has a half-life of 7.3 to 12.1 hours and is more effective than sildenafil or tadalafil. It is thought to possibly have a better safety profile than Udena. Phil has unique properties and max is 1.0-1.5 hours, and T1 / 2 is 11 ~13 hours (relatively fast onset and long duration of action). Both as-needed and once-daily use of udenafil has been reported. The efficacy and tolerability have been evaluated in several studies, and recent and ongoing studies have shown Currently, tadalafil is administered in the FD A, but udenafil inhibits phosphodiesterase subtypes. Once-daily administration to patients with erectile dysfunction who cannot tolerate tadalafil due to type selectivity Gu Kang et al., Ther. Adv. Urol., 5(2):101-110(2013). Udenafil administered once a day is effective in treating erectile dysfunction (ED). ) and the results were reported in 12 When administered weekly, udenafil significantly improved erectile function in men with ED. hao et al.,Eur.J.of Urology,60:380-387(2 011) These reports suggest that udenafil is effective as a once-daily treatment for a variety of conditions. While other reports have suggested that PDE5 inhibitors may be useful in preventing Fontan surgery, Sabri et al., Ped iatr.Cardiol.,35(4):699-704(2014).

[0108] Therefore, the use of fontanel, which includes administering udenafil or a pharma- ceutical acceptable salt thereof, is This document is directed to methods of treating, minimizing and / or preventing symptoms associated with cancer surgery. It is surprising that the invention shows desirable results, preferably with administration once or twice daily. The "favorable outcomes" were improved cardiac output, decreased pulmonary vascular resistance, and exercise tolerance. improvement of myocardial performance; prevention and improvement of decline in aerobic exercise capacity; and / or patient comfort. Benefits of using the technology include, but are not limited to, improved compliance.

[0109] In one embodiment of the invention, a therapeutically effective dose of udenafil or a pharma- ceutical acceptable salt thereof is administered. A once-daily dose of the active salt provides therapeutic levels of udenafil, which can reach the patient's bloodstream for up to approximately 8 hours. In another embodiment of the present invention, a therapeutically effective dose of udenafil or its pharmaceutical equivalent is A single daily dose of a salt acceptable to 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, or about 24 resulting in therapeutic levels being present in the patient's bloodstream over time.

[0110] In one embodiment of the invention, a therapeutically effective dose of udenafil or a pharma- ceutical acceptable salt thereof is administered. Twice-daily administration of soluble salts provides therapeutic levels of soluble salts for at least approximately 16 hours of any 24-hour administration period. In other embodiments, a therapeutically effective dose of udenafil or its equivalent is provided. The twice daily administration of a pharma- ceutical acceptable salt of , about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours Hours, Approx. 17 hours, Approx. 18 hours, Approx. 19 hours, Approx. 20 hours, Approx. 21 hours, Approx. 22 hours, Approx. It provides therapeutic levels of udenafil for 23 hours or about 24 hours.

[0111] In another embodiment, the methods of the present invention further comprise administering to a subject a non-medicament such as sildenafil or tadalafil. The results are surprising as they show improved results compared to prior art treatments using PDE5 inhibitors. In yet another embodiment, the method of the present invention comprises administering to the patient sildenafil or tacrolimus. Compared to prior art treatments using non-udenafil PDE5 inhibitors such as darafil, It was surprising to see no and / or less severe side effects.

[0112] In one embodiment, administration of udenafil or a pharma- ceutical acceptable salt thereof twice daily is , fewer side effects compared to once-daily administration of udenafil or its pharma- ceutical acceptable salts. In another embodiment, twice-daily udenafi or a pharma- ceutical acceptable salt thereof is therapeutically effective at a total daily dose that is less than once a day It is surprising that such levels of udenafil can be achieved.

[0113] In one embodiment, the patient who has undergone the Fontan procedure is a human patient. In one embodiment, the patient is an adult human patient over 18 years of age. In another embodiment, the patient is a pediatric patient between about 2 and about 18 years of age. The patient is a pediatric patient between about 12 and about 16 years of age. IV. Pediatric patients

[0114] Treating pediatric patients poses unique challenges because pediatric physiology is not simply a miniature version of adult physiology. Size is only one of many differences. Children's body surface area, maturity and function of organs and systems, and cognitive and emotional development, which in turn influences disease, diagnosis, treatment, and response to medications. Due to the unique anatomy and physiology of children, there may be differences in the It is even possible that the diseases being treated behave differently in children. Because humans process drugs differently than adults, the effects and dosage of drugs may be different than those observed in adults. Children differ from adults in many ways besides body size. So simply adjusting the dose of a drug for a smaller person doesn't necessarily produce the same response. This is not necessarily the case for treating adult conditions and may result in adverse drug reactions. The efficacy of a drug used in does not predict successful treatment of pediatric patients with the same drug.

[0115] Thus, the present invention also provides that pediatric Fontan patients can be successfully treated with the methods of the present invention. The present invention is also directed to the surprising discovery that the method comprises administering a therapeutically effective amount of a PDE5 inhibitor to a pediatric patient. wherein the PDE5 inhibitor is udenafil or a pharma- ceutical acceptable salt thereof. be.

[0116] The structure of udenafil is shown below:

[0117] [ka] V. Dosage and Formulation

[0118] In one embodiment, udenafil or a pharma- ceutically acceptable salt thereof is present in an amount of from about 0.01 to about In another embodiment, udenafil or its equivalent is administered at a total daily dose of 150 mg / kg. The pharma- ceutical acceptable salts of the compound may be administered in a total daily dose of from about 0.01 mg / kg up to about 30 mg / kg. In another embodiment, udenafil or a pharma- ceutically acceptable salt thereof is administered in a dose of , about 5mg, about 10mg, about 15mg, about 20mg, about 25mg, about 27.5mg, about 3 0mg, about 32.5, about 35mg, about 37.5mg, about 40mg, about 42.5mg, about 4 5mg, about 47.5mg, about 50 mg, about 55mg, about 60mg, about 65mg, about 70 mg, about 75mg, about 80mg, about 85mg, about 87.5mg, about 90mg, about 95mg , about 100mg, about 125mg, about 150mg, about 175mg, about 200mg, about 225 In one embodiment, the compound is administered in a total daily dose of about 250 mg, about 250 mg, or about 275 mg. The amount of udenafil or a pharma- ceutical acceptable salt thereof is about 25 mg, about 37.5 mg, about 5 0 mg, about 75 mg, about 87.5 mg, 125 mg, about 175 mg, about 200 mg, about 225mg, about 250mg, about 275mg, about 300mg, about 325mg, about 350mg , about 375mg, about 400mg, about 425mg, about 450mg, about 475mg, about 500 mg, about 525mg, about 550mg, about 575mg, about 600mg, about 625mg, about 6 The drug is administered in a total daily dose of about 50 mg, about 675 mg, or about 700 mg. In embodiments, udenafil or a pharma- ceutically acceptable salt thereof is about 37.5 mg, about 75 mg, g, about 87.5 mg, 125 mg, or about 175 mg total daily dose.

[0119] In one embodiment, udenafil or a pharma- ceutically acceptable salt thereof is administered once daily. do.

[0120] In another embodiment, udenafil or a pharma- ceutical acceptable salt thereof is administered twice daily. In one embodiment, udenafil or a pharma- ceutically acceptable salt thereof is administered twice daily. and a therapeutically effective blood level is maintained for at least about 18, 19, or 20 minutes during the 24-hour administration period. In some embodiments, the dose is maintained for about 21, about 22, about 23, or about 24 hours per day. The total daily dose of udenafil or a pharma- ceutical acceptable salt administered once daily is The total daily dose of udenafil or a pharma- ceutical acceptable salt thereof is less than the total daily dose of udenafil or a pharma- ceutical acceptable salt thereof. In this embodiment, the total daily dose of udenafil or a pharma- ceutical acceptable salt administered twice daily is When udenafil or its pharma- ceutical acceptable salt is administered once a day during a 24-hour period In other embodiments, the therapeutically effective blood levels are maintained for the same period of time as a higher dose of The total daily dose of udenafil or a pharma- ceutical acceptable salt administered twice daily is 24 The same time period when udenafil or its pharma- ceutical acceptable salts are administered once daily The therapeutically effective blood levels are maintained for a longer period of time compared to the same dose.

[0121] In some embodiments, udenafil or a pharma- ceutical acceptable salt thereof is administered twice daily. The salts were compared with once-daily administered udenafil or its pharma- ceutical acceptable salts. A greater reduction in conditions, symptoms, or side effects associated with subjects who had previously undergone pulmonary surgery produce.

[0122] In some embodiments, the pharma- ceutically 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, a sulfuric acid addition salt, or a benzoic acid addition salt. In another embodiment, the acid addition salt is a salt of quercetin, Phosphate, tartrate, acetate, lactate, maleate, fumarate, gluconate, methane Sulfonate (mesylate), glycolate, succinate, p-toluenesulfonate (Tosylate), Galacturonate, Embonate, Glutamate, Aspartate , oxalates, benzenesulfonates, camphorsulfonates, cinnamates, adipic acids In certain embodiments, udenafiin is an organic acid addition salt, such as a cyclamate salt, or a cyclamate salt. Pharmaceutically acceptable salts of benzoyl include oxalates, benzenesulfonates, camphorsulfonates, The salts are salts of the following formula: acid salts, cinnamates, adipates, or cyclamates.

[0123] In one embodiment, udenafil or a pharma- ceutical acceptable salt thereof is administered as a pharmaceutical composition. In one embodiment, a pharmaceutical composition comprising udenafil or a pharma- ceutical acceptable salt thereof is administered. The pharmaceutical composition can be formulated into a wide variety of oral or parenteral dosage forms for clinical application. The formulation may contain a variety of disintegrants, surfactants, fillers, thickeners, binders, wetting agents, or other diluents. may contain other pharmacologically acceptable excipients.

[0124] Udenafil compositions can be administered intranasally, bucally, sublingually, orally, rectally, ophthalmically, parenterally (intravenously, dermally) orally. intramuscular, subcutaneous, intracisternal, intraperitoneal, pulmonary, vaginal, locally administered nistered, topically administered, Topical administration by tampon, mucosal administration, via aerosol, or buccal or nasal spray Administration can be by any pharmacologically acceptable method, such as via a pharmaceutical formulation.

[0125] Additionally, the udenafil composition can be administered in solid dosage forms, tablets, pills, lozenges, capsules, liquid Liquid dispersion, gel, aerosol, lung aerosol, nasal aerosol Any pharmacologically acceptable formulation, such as a sol, ointment, cream, semisolid dosage form, and suspension, may be used. Further, the compositions can be formulated in controlled release, sustained release, immediate release, or other suitable formulations. Any combination of these may also be used. Additionally, the composition may be a transdermal delivery system. .

[0126] In another embodiment, a pharmaceutical composition comprising udenafil or a pharma- ceutical acceptable salt thereof is administered orally. The solid dosage form may be a powder, granule, capsule, tablet, or pill. In yet another embodiment, the solid dosage form is made of calcium carbonate, starch, sugar, etc. It may contain one or more excipients such as sugar, lactose, microcrystalline cellulose, or gelatin. In addition, solid dosage forms may contain, in addition to excipients, additives such as talc or magnesium stearate. In some embodiments, the oral dosage form is an immediate release or modified release form. Modified release dosage forms include controlled release, sustained release, enteric release, and the like. Excipients used in modified release dosage forms are well known to those skilled in the art.

[0127] In a further embodiment, a pharmaceutical composition comprising udenafil or a pharma- ceutical acceptable salt thereof. The drug may be formulated as a sublingual or buccal dosage form. Such dosage forms are administered sublingually. These include sublingual tablets or solution compositions that are placed in the mouth and buccal tablets that are placed between the cheek and gums.

[0128] In yet a further embodiment, a pharmaceutical composition comprising udenafil or a pharma- ceutical acceptable salt thereof is The pharmaceutical composition can be formulated as a nasal dosage form. Such dosage forms of the present invention are suitable for nasal delivery. Includes solution, suspension, and gel compositions.

[0129] In one embodiment, the pharmaceutical composition is an oral formulation such as a suspension, emulsion, or syrup. In other embodiments, the liquid dosage form can be formulated into a liquid dosage form for administration. In addition to simple diluents such as water and liquid paraffin, wetting agents, sweeteners, flavorings, or preservatives In certain embodiments, udenafil or its derivatives may be included in the formulation. Compositions containing pharma- ceutically acceptable salts of can be formulated so as to be suitable for administration to pediatric patients.

[0130] In one embodiment, the pharmaceutical composition is a sterile aqueous solution, suspension, emulsion, non-aqueous solution, In other embodiments, the solution may be formulated into a non-aqueous solution or suspension for parenteral administration, such as a suppository. The turbidity liquid may be propylene glycol, polyethylene glycol, vegetable oil such as olive oil, or The suppository may contain an injectable ester such as ethyl oleate. Tepsol, Macrogol, Tween 61, Cacao butter, Laurin oil oil), or glycerol gelatin can be used.

[0131] The dosage of the pharmaceutical composition is determined based on the patient's body weight, age, sex, administration time and method, excretion rate, and disease. It can vary depending on the severity of the disease. VI. Adverse events

[0132] Adverse events should be considered, especially when treating susceptible populations such as pediatric patients with Fontan physiology. It is important to consider that PDE-5 inhibitors have been shown to cause adverse events, including eye and / or hearing problems. Therefore, PD-1 inhibitors such as udenafil or its pharma- ceutical acceptable salts may cause One aspect of the present invention is to develop methods by which E5 inhibitors can be safely administered to pediatric patients. be.

[0133] In some embodiments, a pediatric patient with Fontan physiology is administered a PDE5 inhibitor. , may treat, minimize, and / or prevent the deleterious effects of Fontan physiology. In one embodiment, a PDE5 inhibitor, specifically udenafil or a pharma- ceutical acceptable salt thereof, Administration of 5-HT21 has been associated with minimal, if any, serious adverse events. In an embodiment, a PDE-5 inhibitor, specifically udenafil or a pharma- ceutical acceptable salt thereof, is Administration results in minimal, if any, unexpected adverse events.

[0134] In some embodiments, the patient is administered udenafil or a pharma- ceutical acceptable salt thereof. Pediatric patients with Fontan physiology may experience only mild drug-related adverse events. and in other embodiments, patients may experience only moderate drug-related adverse events. In some embodiments, the patient is administered udenafil or a pharma- ceutical acceptable salt thereof. Pediatric patients with Fontan physiology are Fontan patients receiving other PDE5 inhibitors. may experience fewer, less frequent, or less severe adverse events compared to VII. Pharmacokinetic parameters

[0135] Pharmacokinetics refers to the absorption, distribution, metabolism, and excretion of a drug after it is administered to a subject. Drug kinetics influences the efficacy and toxicity of a drug. The kinetic profile of a given drug is In addition to the composition itself, dosages and modes of administration and how the drug is formulated and administered are also included. Pharmacokinetic parameters that may be useful in determining clinical utility The meter measures plasma concentration, plasma concentration over time, and maximum plasma concentration (C max ), the best Time to reach concentration (T max ), area under the concentration-time curve during the dosing interval (AUCτ), Daily area under the concentration-time curve (AUC 0-24 );CL / F, apparent clearance; V / F, apparent volume of distribution; ke, elimination rate constant; T1 / 2, terminal half-life But not limited to these.

[0136] In some embodiments, the disclosed invention provides udenafil or a pharma- ceutical acceptable salt thereof. The study focuses on the administration of 1,2,3-trifluoroethylene (1,2,4-trifluoroethylene) to patients with Fontan physiology, with specific pharmacokinetic profiles. For example, in some embodiments, the methods of the present disclosure provide a 00ng / ml, about 50 to about 650ng / ml, about 100 to about 600ng / ml, about 15 Udenafil blood levels in the range of 0 to about 550 ng / ml, or about 200 to about 500 ng / ml In other words, the administration method of the present disclosure can produce plasma concentrations of 50, 75, 100, 125, 150, 175, 200, 225, 250, 275, 30 0, 325, 350, 375, 400, 425, 450, 475, 500, 525, 55 More than 0, 575, 600, 625, 650, 675, or 700 ng / ml, Udena In some embodiments, the plasma concentration is about Maintained above 140ng / ml.

[0137] In some embodiments, the method of the present disclosure comprises: max However, about 25, about 50, about 75, about 1 00, approx. 125, approx. 150, approx. 175, approx. 200, approx. 225, approx. 250, approx. 275, approx. 3 00, approx. 325, approx. 350, approx. 375, approx. 400, approx. 425, approx. 450, approx. 475, approx. 5 00, 525, 550, 575, 600, 625, 650, 675, or In some embodiments, the pharmacokinetic profile is about 700 ng / ml. is C max is approximately 506.

[0138] In some embodiments, the methods of the present disclosure include max But about 0.1, 0.2, 0.3, 0 .4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1 .4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2 Features that are 0.4, 2.5, 2.6, 2.7, 2.8, 2.9, or 3.0 hours (hours) In some embodiments, the T max It takes about 1.3 hours. do.

[0139] In some embodiments, the methods of the present disclosure provide a method for determining whether an area under the curve (AUC) is in a Fontan patient. The study included a characteristic pharmacokinetic profile specific to udenafil at therapeutically effective doses in For example, AUCτ is 750-4500ng·h / ml and 800-4000ng·h / ml. ml, or 850 to 3500 ng·h / ml. More specifically, the AUCτ is about 75 0, approx. 800, approx. 850, approx. 900, approx. 950, approx. 1000, approx. 1050, approx. 1100, Approx. 1150, Approx. 1200, Approx. 1250, Approx. 1300, Approx. 1400, Approx. 1500, Approx. 160 0, approx. 1700, approx. 1800, approx. 1900, approx. 2000, approx. 2100, approx. 2200, approx. 2 300, approx. 2400, approx. 2500, approx. 2600, approx. 2700, approx. 2800, approx. 2900, Approx. 3000, Approx. 3100, Approx. 3200, Approx. 3300, Approx. 3400, Approx. 3500, Approx. 360 0, approx. 3700, approx. 3800, approx. 3900, approx. 4000, approx. 4100, approx. 4200, approx. 4 In some embodiments, the A UCτ is approximately 3350.

[0140] In some embodiments, the AUC 0-24 750-8500ng·h / ml, 800 ~8000ng·h / ml, or 850-7500ng·h / ml. , AUC 0-24 is about 750, about 800, about 850, about 900, about 950, about 1000 , about 1050, about 1100, about 1150, about 1200, about 1250, about 1300, about 14 00, approx. 1500, approx. 1600, approx. 1700, approx. 1800, approx. 1900, approx. 2000, approx. 2100, approx. 2200, approx. 2300, approx. 2400, approx. 2500, approx. 2600, approx. 2700 , approx. 2800, approx. 2900, approx. 3000, approx. 3100, approx. 3200, approx. 3300, approx. 34 00, approx. 3500, approx. 3600, approx. 3700, approx. 3800, approx. 3900, approx. 4000, approx. 4100, approx. 4200, approx. 4300, approx. 4400, approx. 4500, approx. 4600, approx. 4700 , 4800, 4900, 5000, 5100, 5200, 5300, 54 00, 5500, 5600, 5700, 5800, 5900, 6000, approx. 6100, 6200, 6300, 6400, 6500, 6600, 6700 , 6800, 6900, 7000, 7100, 7200, 7300, 74 00, approx. 7500, approx. 7600, approx. 7700, approx. 7800, approx. 7900, approx. 8000, approx. 8100, about 8200, about 8300, about 8400, or about 8500 ng·hr / ml In some embodiments, the AUC 0-24 is about 6700.

[0141] In some embodiments, the pharmacodynamics of administration of udenafil to patients with Fontan physiology The results can be attributed to the characteristic pharmacokinetic profile of the drug administration or dosing regimen. VIII. definition

[0142] As used herein, the term "about" will be understood by those of ordinary skill in the art and To some extent, this will depend on the context in which the term is used. Unless otherwise clear to a person of ordinary skill in the art given the context in which it is used, "about" shall mean up to and including the particular term. That would mean minus 10%.

[0143] "Treatment" means targeting and combating a pathological condition, i.e., improving or preventing the condition. Thus, a particular treatment may be tailored to the target condition and current or future medical therapies and treatment methods. will depend on future status. Treatment may have associated toxicities.

[0144] The terms "administration of" or "administering" an active agent refer to a therapeutically useful form and method. Providing an active agent of the present invention to a subject in need of treatment in a form that can be introduced into the individual's body in an effective amount. It should be understood that this means that

[0145] The term "therapeutically effective amount" refers to a therapeutically effective amount that is used to treat symptoms, progression, or other adverse events seen in patients who have had the Fontan procedure. The present invention provides an active ingredient in a suitable composition and a suitable dosage form for treating or preventing the onset of complications. A therapeutically effective amount refers to a sufficient amount of a drug to be administered to a patient depending on the state or severity of the patient's condition and the target of treatment. The therapeutically effective amount will vary depending on, for example, the route of administration, the subject, etc. The degree of toxicity will depend on any of a number of factors, including the condition of the individual, as well as other factors that will be appreciated by those of skill in the art. can be changed.

[0146] The term "treatment" or "treating" generally refers to the natural history of the subject being treated. It refers to an intervention that alters the course of clinical pathology and can be performed for prevention or during clinical pathology. Desirable effects include preventing the onset or recurrence of disease, alleviating symptoms, Suppressing, reducing, or inhibiting any direct or indirect pathological consequence of a disease; These include improving or alleviating the symptoms of the disease, and inducing remission or improved prognosis. The present invention is not limited to these.

[0147] The terms "individual," "host," "subject," and "patient" are used interchangeably herein. It is used.

[0148] As used herein, "improving cardiac output" refers to the amount of blood pumped by the heart. Cardiac output is measured as a function of oxygen consumption.

[0149] As used herein, the term "exercise capacity" refers to the maximum amount of exertion a patient can sustain. Exercise tolerance can be measured by a number of different clinical techniques, including interviews or direct measurements. The method of the present invention can be measured by, but is not limited to, riding a bicycle ergometer or The literature includes a variety of methods to measure exercise tolerance, including walking on a treadmill. Therefore, the term "improving exercise tolerance" refers to any level of exertion or exercise. This means that the patient's ability to perform the activity is increased.

[0150] As used herein, the term "reducing pulmonary vascular resistance" refers to the reduction in pulmonary vascular resistance by the pulmonary vasculature. "Reduction" refers to the reduction or lowering of the resistance offered to blood flow by the

[0151] As used herein, "improving myocardial performance" may be used without limitation. However, there are specific electrocardiogram readings, echocardiogram readings, cardiac output measurements, heart rate, yield, Specific cardiac measurements including systolic or diastolic blood pressure, forced vital capacity, oxygen saturation, and respiratory rate Refers to an increase or decrease in a result.

[0152] As used herein, "aerobic fitness" refers to a patient's ability to perform a specified aerobic activity. Refers to ability.

[0153] As used herein, "child" refers to subjects ranging in age from newborn to about 18 years of age. Pediatric subjects are a population of subjects of any age, even if the subject continues treatment beyond approximately age 18. The subject begins a course of treatment with a composition or according to a method of the present disclosure before reaching about 18 years of age. More specifically, within the population of "pediatric" subjects, neonates may be included within the age range of 1 week. Ages range from one week to one month, infants are between one and two years old, and toddlers are between two and six years old. Children can refer to subjects between 6 and 18 years of age.

[0154] The following examples are given to illustrate the invention. However, it should be understood that the invention is not limited to the above examples. It should be understood that the present invention is not intended to be limited to the specific conditions or details set forth herein. All referenced printed publications are specifically incorporated by reference. EXAMPLES

[0155] Example 1 - Phase I / II Pharmacokinetic and Pharmacodynamic Study Udenafil in adolescents with single ventricle physiology after Fontan palliation Phase I / II dose escalation study

[0156] The trial will last for 5 months, with an additional 3 months of follow-up for adverse events (AEs). The 36 subjects enrolled in this study were divided into six cohorts, as shown in Table 1. It was done.

[0157] [Table 1]

[0158] The objective of this study was to evaluate the safety, efficacy and safety of udenafil at multiple dose levels over a 5-day period. Pharmacokinetic profile of udenafil in adolescents with menstrual periods and exercise The short-term effects of udenafil on pharmacodynamic measures of tolerance, ventricular function, and vascular function The purpose was to evaluate.

[0159] Multiple doses of udenafil or its pharma- tically acceptable salts were administered to males aged 14 to 18 years. The study was administered to male and female Fontan patients.

[0160] The inclusion criteria for this clinical trial include the following: Men and women aged 14-18 years with Fontan physiology Return visits to the center to collect blood samples and perform tests as specified in the clinical trial protocol Willingness to Patients are prohibited from drinking alcohol, caffeinated beverages, and grapefruit juice for the duration of the study. must agree to withhold news from Informed consent by subjects and, where appropriate, by parents / legal guardians Informed consent

[0161] Exclusion criteria for this study included the following: Preventing the successful completion of a planned test or invalidating its results; Possible non-cardiac medical, psychiatric, and / or social disorders Height <132cm (minimum height requirement for exercise stress test) - Known foci that result in a mean gradient of >4mmHg between the regions proximal and distal to the occlusion Pulmonary artery branch stenosis, or pulmonary vein stenosis Physiology of one lung Severe ventricular dysfunction as determined by echocardiographic review immediately prior to study enrollment or Valve regurgitation (systemic atrioventricular valve or semilunar valve) Significant renal impairment based on laboratory tests at the screening visit (serum creatinine > 2.0), liver dysfunction (serum AST and / or ALT >3x upper limit of normal), Gastrointestinal or biliary disorders that may impair the absorption, metabolism, or excretion of the administered drug - Hospitalization for acute decompensated heart failure within 12 months prior to study screening Diagnosis of active protein-losing enteropathy or plastic bronchitis Active evaluation or listing for heart transplant It is listed in History of use of PDE5 inhibitors within 3 months of study screening Intercurrent illnesses that, in the opinion of the investigator, preclude participation Current treatment with alpha blockers or nitrates - Pregnant at the time of enrollment Latex allergy

[0162] Table 2 shows the overall data for the 36 enrolled subjects (column 2) and for each of the six individual cohorts. Baseline characteristics are shown. The median age of enrolled subjects was 16 years (range 14-18 years). 58% were male, 78% were white, and 6% were Hispanic. There were no significant differences in line characteristics (right column).

[0163] [Table 2]

[0164] Example 2 - Safety and Adverse Events The purpose of this example is to document the safety of the udenafil compositions administered in the study described in Example 1. The objective of this study was to record and evaluate the results.

[0165] Tables 3-6 show the number of subjects who reported at least one AE. Data are broken down by treatment group. Counts are presented by AE category (Table 3) and preferred term (Table 6). Tables 3 to 6 show the results of all AEs (Table 3), serious AEs (Table 4), and non-AEs by category. Serious AEs (Table 5) and all AEs by preferred term (Table 6) should be reported. It was not done.

[0166] [Table 3]

[0167] [Table 4]

[0168] [Table 5]

[0169] [Table 6]

[0170] Table 7 shows all adverse events classified by cohort, subject, AE term, and preferred term. A narrative description is provided (limited to non-serious conditions at the time of writing).

[0171] [Table 7-1]

[0172] [Table 7-2]

[0173] [Table 7-3]

[0174] [Table 7-4] [Table 7-5] Agent statement number: 107984-0107

[0175] Table 8 shows the number of subjects with AEs ≥ n, where n = 1, 2, ..., 6, by treatment group. Indicates a number. [Table 8]

[0176] Tables 9–12 show AEs by preferred term (similar to Table 6), but in addition show the number of subjects with AEs and Number of AEs and AEs (Table 9), by treatment group and related to study drug (possibly or probably related). associated vs. unassociated (Table 10), mild vs. moderate / severe (Table 11), and unexpected Report number of AE events / subject grouped by expected vs unexpected AEs (Table 12) do. [Table 9] [Table 10] [Table 11] [Table 12]

[0177] Table 13 shows that AEs occurred more than once in at least one cohort (one patient). ≥ 2 AEs for any subject or ≥ 2 subjects for at least 1 AE) We focus on a limited subset of Table 7. [Table 13]

[0178] Figure 1 shows the results for at least one, three, or five (numbers taken from Table 6) by treatment group. The percentage of subjects reporting adverse events is shown. The horizontal axis indicates the cohorts on the left with the lowest daily dose. (exercise only group; zero dose, not placebo) to the right of the highest single dose (125mg g). The percentage varies from 100% to 0% (exercise only group). As expected, The exercise-only group was characterized by the lowest % rate. Plots report dose and AEs. There is no clear association between the percentages of subjects.

[0179] Example 3 - Exercise stress test The purpose of this example is to compare the efficacy of the treatment described in Example 1 using various exercise testing parameters. The objective of this study was to evaluate the efficacy of the protocol.

[0180] The primary outcome for this treatment arm of the study was maximum VO2 as determined by exercise stress testing. Table 14 shows the important outcomes of exercise stress testing by treatment group - peak VO2 (maximum The results of the study (limited to subjects who achieved maximum effort) are summarized below for the 36 subjects enrolled in the study. Of these, 33 subjects achieved maximum effort in the exercise stress test at each time point, and 31 subjects achieved maximum effort at both times. The first two lines show the data from baseline and follow-up measurements, Meanwhile, the third line shows the difference between the two measures (the change score, the outcome for this treatment group). Analysis of variance suggests that there were no differences between the change scores (p=0.85). [Table 14]

[0181] Figures 2 and 3 visually show the change score results (positive changes indicate improvement). Figure 2 shows the paired Individual change scores for each subject with measurements (circles) are shown, and the two lines are the mean and median values. The plot does not suggest that the change scores increase with dose. The maximum VO2 values ​​before and after treatment for each cohort are shown.

[0182] As expected, baseline and follow-up measurements were strongly correlated, with correlation coefficients >0.8. .

[0183] An additional outcome, VO2 at anaerobic threshold, was also measured. The results are shown in Table 15 and Figures 4 and 5. The overall results were Similar to VO2. [Table 15]

[0184] Of note, both exercise outcomes (peak VO2 and V at anaerobic threshold) O2) were strongly correlated (correlation coefficients at each visit were greater than 0.7), and the trend lines in Figures 2 and 4 This may explain the similarity.

[0185] Example 4 - Vascular Function Test The primary outcome of vascular function was assessed using the EndoPAT® device (Itamar Medica Endothelial pulse amplitude tonometry (PATO) is determined by endothelial pulse amplitude tonometry (PATO) (Panasonics, Inc., Caesarea, Israel). T) was determined according to the index.

[0186] Table 16 shows the critical outcome of vascular function tests - the natural logarithm of reactive hyperemia index (ln Results for the RHI are summarized by treatment group. Thirty subjects enrolled in the treatment group of the clinical trial Of these, 27 subjects had acceptable quality pairs (QC score of 3 (best) or equal to 2). The structure of the table is the same as that of the exercise variables. [Table 16]

[0187] Figures 6 and 7 visually show the change score results (positive changes indicate improvement). Individual change scores for each subject with measurements (circles) are shown, and the two lines are the mean and median values. The plot does not suggest that the change scores increase with dose. The lnRHI values ​​before and after treatment for each cohort are shown.

[0188] Baseline and follow-up measurements were moderately correlated, with an overall correlation coefficient of 0.4.

[0189] Notably, both the mean baseline and follow-up measurements were normal (lnRH as the threshold between abnormal (defined as lnRHI ≤ 0.51) and abnormal (defined as lnRHI ≤ 0.51) values. This is close to the cutoff value of 0.51 suggested by the EndoPAT literature. Analysis shows that some patients saw as much as a 9.75% improvement on this measure.

[0190] Table 17 shows the secondary EndoPAT outcomes (RHI, Framingham RHI, etc.; upper panel Change scores are reported only for EndoPAT (Patient Control) and other EndoPAT indices. In this case, positive changes indicate possible improvement. [Table 17]

[0191] Example 5 - Echocardiographic assessment of ventricular function The primary outcome of ventricular function was assessed using echocardiographic methods and was the myocardial performance index (MP I) was measured. MPI is a function of the ventricular shape, which is the sum of systolic and diastolic ventricular function. It is an evaluation criterion that does not depend on the state (Charles S. Kleinman et al., 2008-Health and Fitness). MPI is the isovolumic index for ejection time. It is obtained by using the sum of the sexual contraction period and the relaxation period as an index.

[0192] Table 18 shows the results for the critical outcome of echocardiographic assessment of ventricular function - blood pool MPI. The results are summarized below. Of the 30 subjects enrolled in the treatment arm of the clinical trial, 27 were The structure of the table is the same as that of the exercise variables. The data was analyzed based on these evaluation criteria. The results showed that some patients showed improvement of as much as 21.5%. [Table 18]

[0193] Figures 8 and 9 visually show the change score results (negative changes indicate improvement). Figure 8 shows the results for the pair Individual change scores for each subject with measurements (circles) are shown, and the two lines are the mean and median values. The plot does not suggest that the change scores increase with dose. The blood pool MPI index values ​​before and after treatment for each cohort are shown.

[0194] Baseline and follow-up measurements were strongly correlated, with an overall correlation coefficient of 0.7 (last (two lines). Notably, both the mean baseline and follow-up measurements were in the elevated range ( elevated area (>0.4).

[0195] Tables 19-21 and Figures 9-15 show three other versions of MPI: Tissue Doppler MPI Similar results for I and mean isovolumic contraction and relaxation are reported. [Table 19] [Table 20] [Table 21]

[0196] For these three further MPI versions, the negative changes are still possible. The overall conclusions are similar to those of blood pool MPI.

[0197] In addition, positive outcomes were observed during the short-term studies described in Examples 1-5. Therefore, Fontan patients may be administered udenafil or a pharmacologic salt thereof for a longer period of time. This may result in more favorable pharmacodynamic outcomes.

[0198] Example 6 - Pharmacokinetic studies NONMEM version 7.2, R, PDxPOP® 5, Xpose, and and Phoenix WinNonlin were used for pharmacokinetic analysis.

[0199] A pharmacokinetic analysis was performed on Fontan patients who received udenafil. The results of the data evaluation for individual subjects by cohort are shown in Figure 17. The nafil concentration profile is shown. Plasma concentrations were measured at various time points in patients. Noncompartmental analysis was performed and stratified by administration regimen.

[0200] Figures 18-20 show various comparisons between the medication cohorts. Based on the data, 87.5 mg was administered compared with 37.5 mg every 12 hours or every 24 hours cohorts. In the 12-hourly and 125-mg 24-hourly cohorts, max has increased significantly (Figure 18).

[0201] The 87.5 mg q12h cohort had a C max (Figure 18) showed an increase in ≥37.5 mg q12h or q24h cohorts. In the 87.5 mg every 12 hours cohort and the 125 mg every 24 hours cohort, AUCτ was significantly increased in the 125 mg q24 h cohort compared to the 37.5 mg q24 h cohort (Figure 19). In the 24-hour cohort, AUC 0-24 87.5 mg every 12 hours The cohort had the highest AUC among all dosing regimens tested. 0-24 The increase in 9) With the exception of a significant difference between 37.5 mg every 24 hours and 87.5 mg every 12 hours, No significant differences were observed in CL / F or V / F between the methods (Figure 20). Among the test administration methods, k e , T1 / 2, and T max There was no statistically significant difference between the two groups.

[0202] Population Pharmacokinetic Model Development

[0203] A population pharmacokinetic analysis was performed using a nonlinear mixed-effects model. The subjects are assumed to be in a steady state (SS). Dose (D) is given at time tD after repeated administration of dose D given at intervals τ Time (t) (t≧t DPK samples / udenafil concentrations were collected on study day 6.

[0204] Only the sixth day of drug administration was provided, allowing subjects to take the drug at home at regular intervals. Due to this, the steady-state flag is expected to be tested for doses that are not available. As mentioned above, udenafil maintains a steady state of 5 It has previously been reported that the α-amyloid ion concentration was reached in 10 days, with little or no further accumulation apparently occurring after 7 days of treatment. As described in the study, steady state is assumed to be reached by day 6. If a dose was missed during the study period prior to collection, this could result in a steady-state pharmacokinetic profile. This may affect the ability to determine whether a PK sample can be expected to be If two or more additional drug administration dates and times were available prior to the visit, A good dosing profile would have been used for the analysis.

[0205] Structural Model

[0206] One- and two-compartment models were examined (based on the literature and available data). The equation for the drug input model describes oral absorption: For the one-compartment model the following equation can be applied:

number

[0207] Considering that CL=k10*V, the following equation can also be applied:

number

[0208] The two-compartment model can be described by the following differential equation:

number

[0209] The amount of drug in the body after oral administration can be described by the following differential equation:

number

[0210] The robustness of the final model was verified by bootstrap resampling (n = 1000) with P The minimization was evaluated using DxPOP® 5. Bootstrap (minimization was successful for all runs) Values ​​obtained using the row-based method were compared with parameter estimates from the final model. To assess the accuracy of model predictions, we performed the normalized prediction distribution error (NPDE).

[0211] Certain a priori information was used to guide the development of the model.

[0212] One- and two-compartment models including oral absorption inputs were obtained from the literature cited above. Initial estimates were used and then explored to determine possible model structures. During the model building process, feature values, statistical significance levels, goodness-of-fit plots, and standard errors are used The model was evaluated.

[0213] The only covariate available for analysis was current body weight. Body weight was a predictor of clearance and volume of distribution. were tested as a fixed effect on representativeness (e.g., weight was a “fixed effect” on clearance). The median weight in the dataset was 65.3 kg.

[0214] The "representative" clearance was determined for a 70 kg patient using the weight (WT) in the data set. The estimated THETA(1) and THETA(2) for subjects with known WT are CL and V values ​​can be directly compared with those of subjects of "normal" weight, e.g., WTs=70 kg.

[0215] A concern sometimes expressed is that the estimated weight of a child in terms of an adult size standard of 70 kg The scale parameter value chosen may have biased the estimate or affected the precision of the estimate. This concern is unfounded. It is subject to reorganization and Allometric scaling is simply a constant determined by whatever body weight is chosen for standardization. The precision of the parameter estimates can be seen by inspection of the covariate model. The parameter values ​​are not changed by multiplying them by ad hoc constants. The criterion for weight covariate equation selection in the model was statistical significance.

[0216] 21 to 29 show the results of the pharmacokinetic data analysis.

[0217] During the model building process, a number of residual error models were evaluated. The models could not be run and they were terminated every time. The additive error models could be run but the GOF process The lot did not fit well to the one-compartment model, but was better fitted to the two-compartment model. The model showed a better fit. Despite the high CV% of the residual variability, The overall error model provided good estimates of the other parameters with 95% CI and the GOF plot Visual inspection showed a good fit, The choice was made to use this model as the base model (Figures 30-31). All doses were collected from each subject, before dosing on Day 6, when samples were collected, before and after dosing, and after and after If the data set had been included, it may have been possible to control the high CV%. There is no need to do this since the model fit is so good, but this will further reduce the %CV. It can.

[0218] After comparing the actual data with the predicted data, the final model was created. The F plots can be found in Figures 32 and 33.

[0219] We engaged in bootstrap resampling to rescale the parameter estimates of the final model by 10 The results were compared to those determined after 00 bootstrap runs. Visual predictive check (95% prediction interval (plot comparing the measured data) and the normalized predictive distribution error (NPDE) method were used to finalize the model. We also performed a visual posterior prediction performance evaluation.

[0220] The pharmacokinetics of udenafil was modeled using a two-compartment model with additive and proportional error. The apparent clearance (CL / F) is based on the standard adult weight of 70 kg. The respiratory rate constant was 0.28 h-1 (95% CI 0. 16~0.39), and the apparent clearance (CL / F / 70kg) was 36L / h (95% CI 28.5-43.1), and the median volume of distribution (V2 / F) was 74 L (95% CI 36 .2–112), and the intercompartmental clearance (Q / F) was 21.1 L (95% CI 10.4-31.8), and the peripheral volume of distribution (V3 / F) was 181 L (95% CI 14 The final model was estimated using bootstrap resampling and normalized prediction. The methods were evaluated using the measured distribution error and visual posterior predictive performance assessment methods. It was shown that the variance model fits the data well.

[0221] A two-compartment model including an absorption rate constant is used to describe single ventricle physiology after Fontan palliation. To successfully describe the pharmacokinetics of udenafil in adolescents with was included in the final model, CL / FL / hr / 70kg, normalized to adult weight of 70kg There was a statistically significant effect on apparent clearance (CL / F) when

[0222] Example 7 - Phase III study of udenafil in Fontan patients A Phase III study of udenafil in Fontan patients with palliative care following the Fontan procedure Udenafil (87.5 mg, 1 hr) in a population of adolescents with single ventricle congenital heart disease The study will determine the safety of the drug (twice daily). The study will continue for at least six months and up to one year. The study will evaluate the pharmacodynamic profile of udenafil over a range of time periods. Clinical outcomes were exercise tolerance, echocardiographic measures of ventricular function, endothelial function, and serum biomarkers. These will include clinical markers, as well as functional health status / quality of life measures. Udenafil (87.5 mg twice daily) is safe and has been shown to improve exercise tolerance and cardiovascular health. It is believed that this study will be effective in improving other evaluation items of the condition and quality of life. It is expected.

[0223] Clinical trial method: 300 participants aged 12 to 19 years who had undergone the Fontan procedure before the age of 5. Randomized, double-blind, randomized, randomized, randomized, double-blind study of subjects receiving 87.5 mg twice daily for 6 months to 1 year of treatment. placebo-controlled clinical trial

[0224] Inclusion criteria for this study include the following: Male or female aged 12-19 Fontan procedure before age 5

[0225] Exclusion criteria for this study included the following: Height < 132cm Hospitalization for acute decompensated heart failure within the last 12 months Current intravenous inotropes Being evaluated for or listed for a heart transplant Diagnosis of protein-losing enteropathy, plastic bronchitis, and liver cirrhosis Areas proximal and distal to the obstruction, as measured by catheterization or echocardiography A known Fontan tunnel obstruction resulting in a mean gradient of >4 mmHg between the pulmonary artery Branch stenosis, or pulmonary vein stenosis Physiology of one lung Critical ventricular function assessed qualitatively by clinical echocardiography within 6 months prior to enrollment Insufficiency - Significant valvular regurgitation or ventricular flow as assessed by clinical echocardiography within 6 months prior to enrollment Outlet stenosis or aortic arch obstruction - Significant kidney, liver, or digestive disorders that may impair the absorption, metabolism, or excretion of orally administered drugs. Gastric or bile duct disorders Inability to complete exercise stress testing at baseline screening - History of use of PDE5 inhibitors within 3 months prior to the start of the study Use of other medications to treat pulmonary hypertension within 3 months prior to the start of the study Known intolerance to oral udenafil Frequent use of drugs or other substances that inhibit or induce CYP3A4 Current use of alpha-blockers or nitrates Preventing the successful completion of a planned test or invalidating its results; Participating or planning another research protocol that may be Preventing the successful completion of a planned test or invalidating its results; Possible non-cardiac medical, psychiatric, and / or social disorders Ongoing or planned cardiac disease outside the trial site that would prevent completion of the study treatment For women: Pregnant at screening, planning pregnancy before completing the study or refusing to use an acceptable method of contraception for the duration of the study. You may not refrain from or limit your intake of grapefruit juice for the duration of this study. stomach Refusal to provide written informed consent / assent According to the primary care physician , subjects are more likely to be less compliant with the clinical trial protocol

[0226] The study will include baseline measurements of proposed pharmacodynamic (PD) endpoints and quality of life outcomes. - Life studies will include: For example, EndoPAT vascular assessment has gained consent This will be the first PD test performed after the test. After the vascular assessment, subjects were asked to A short break will be required after the vascular evaluation or echocardiogram to assess ventricular function. A light snack will be provided. Vascular evaluation, echocardiogram, and rest period will be performed. After the break, safety labs will be conducted. Serum creatinine and liver enzymes (aspartate aminotransferase and alavirase) were measured in participants. Blood samples were collected to assess cytochrome P450 (K-ATPase) levels and urine samples were collected from female participants. If the pregnancy test is positive, all further testing will be discontinued. The patient will not be enrolled in the study. The results will be reported according to local IRB procedures. This will be communicated to the subject and / or legal guardian by the site investigator. After safety testing, exercise testing was performed according to the previously published PHN Fontan cross-sectional study. Successful results were obtained using a braked bicycle ergometer following a linear progression protocol. After the exercise stress test, subjects will complete a baseline test. In addition, The Peds QL, cardiac specific Peds QL, and PCQLI were This will be administered during the Sline testing visit.

[0227] The study coordinator contacted each subject weekly for 4 weeks and monthly thereafter to report any adverse events. Collect and answer exam related questions.

[0228] At the end of the study, subjects were fasted and caffeine-free and were first asked to complete a baseline The patients underwent a vascular function assessment, including repeating the in-test and quality of life surveys. Follow-up interviews with subjects will be conducted 30 and 90 days after the end-of-study examination to determine the outcome of the study. Any adverse events that may be related to or occur within 90 days after completion of the study Any further adverse events possibly related to the product may be recorded.

[0229] Udenafil over a 6- to 12-month period in adolescents with Fontan physiology (87.5 mg twice daily) was safe and well tolerated, with no significant adverse events associated with udenafil. Very few, if any, serious adverse events are expected. The severity is based on the Common Terminology Criteria for Adverse Events. a for Adverse Events)(CTCAE)Version 4.0 Med Determined according to DRA 12.1 (http: / / ctep.cancer.gov) Similarly, exercise tolerance, echocardiographic measures of ventricular function, endothelial function, and heart failure-related The effects of udenafil on pharmacodynamic outcomes, including biomarkers of The efficacy of udenafil in this patient population is expected to improve over time. The outcomes to be measured for this purpose include: Exercise: Exercise from baseline to end of study test, measured using a standard exercise stress test. Change in maximal oxygen intake in; Echo: From baseline to end of study, as measured by pulsed Doppler echocardiography Change in myocardial performance index from time to test; Endothelial function: log-transformed reactive filling rate obtained from the EndoPAT® device Changes in blood indices; and Biomarkers: Change in serum BNP levels from baseline to end of study

[0230] In addition, Exercise: Submaximal measures of exercise tolerance will be collected and evaluated. Echo: Systolic and diastolic function measurements are collected from targeted echocardiograms. become.

[0231] This study also assessed outcomes related to ventricular cavity size, flatness, and mass; tissue droplet size, The mean dP / dt and peak systolic annular velocity during the isovolumic contraction phase (dP / dtic) of the LA Systolic function estimated using the S' function; diastolic function and MPI tissue Doppler-based estimates values; as well as qualitative and quantitative estimates of AV valve insufficiency.

[0232] It is also expected that functional health status will improve following administration of udenafil. Changes in functional health status from admission to the end of the study were assessed using a full-scale Pedometer. s QL, Peds QL physical function score, Peds QL psychosocial function score, Pe ds QL Cardiac Specific Module Quality of Life Score and / or Pediatric Cardiac Quality of Life Inventory (PCQLI) score It can be measured using

[0233] Additionally, the response to udenafil after the Fontan procedure in individuals with single ventricle disease has been Genetic material will be collected during the study to identify genetic determinants. Whether certain subgroups of people have a stronger positive response to udenafil than others For example, the response to udenafil is This may be influenced by variants involved in the vascular response to endothelial nitric oxide synthase. Variants in the male hormone may affect how men with erectile dysfunction respond to sildenafil This has not been studied with udenafil. Variation in genes regulating inotropic and chronotropic responses may affect exercise tolerance in patients after the Fontan procedure. This can affect the ability of the body to tolerate udenafil and its response to the drug. Future genotyping studies will be performed to analyze the genetic contribution to the response.

[0234] Additional covariate measures included age, sex, race / ethnicity, height / weight, ventricular morphology, and stability. These included resting oxygen saturation, baseline pharmacodynamic test results, and current medication use. These variables include, but are not limited to, the following: The associations between factors and safety and PD outcomes will be identified.

[0235] Data collection included demographic information, including age, sex, race, and ethnicity, cardiac anatomy, and phonocardiogram. Date of Tanning surgery, presence or absence of fenestration, degree of atrioventricular regurgitation, and grade of ventricular function This will include recording all patient status, concomitant medications, and significant comorbidities. Safety data will be collected from each These events will be reviewed with each subject during study visits and telephone consultations. and graded according to severity and relationship to the study drug based on established criteria. Two additional telephone visits will be conducted 30 and 90 days after the end-of-study test. , which may or may possibly be related to the study drug during the period following completion of the study procedures Evaluate adverse events occurring during treatment.

[0236] Other data collection will include: Exercise stress test - Braked cycle ergometer exercise stress test These data were collected according to a protocol established by the PHN Fontan Cross-Sectional Study 3. It will be collected. Assessment of ventricular function - each study echocardiogram was de-identified and stored for data analysis. The measurements are sent to a core laboratory that performs the test and submits the measurements to the PHN Data Coordinating Centre (DCC). It becomes. Vascular Function Testing - De-identified data from the EndoPAT® study These data will be collected according to a standardized protocol. The vascular core laboratory will submit the measurements to the PHN DCC. will be sent to ab). Biomarkers - Serum for measurement of BNP levels was collected from the core clinical laboratory. The results will be sent directly to the PHN DCC. This will be the case. Quality of Life Survey - The results of the Quality of Life Survey are It will be submitted to the N DCC. Biorepository samples - Samples collected for the biorepository will be The samples will then be sent directly to a biorepository for further analysis.

[0237] Subjects will be treated with other medications at the physician's discretion. Patients will be recorded on the study form. If open-label use of any of the study drugs is initiated, discontinuation of study drug will be required.

[0238] When an individual subject completed the study, the subject's cardiologist was notified and Medication will be discontinued. There is no need to take subjects off the study medication. Individual subjects The decision to continue off-label use of PDE5 inhibitors is made by the subject and his / her cardiologist. This will be decided by a specialist.

[0239] Although certain preferred embodiments of the present invention have been described and specifically exemplified above, It is not intended that the invention be limited to such embodiments. Various modifications may be made to the embodiments without departing from the scope of the invention.

Claims

1. In patients with Fontan physiology, maximal effort or ventilatory anaerobic threshold (VAT) or udenafil for use in improving exercise capacity as determined by improvement in VO2 in A pharmaceutical composition containing udenafil or its pharma- ceutical acceptable salt. and the dosage of said composition is 87.5 mg of a therapeutically acceptable salt thereof, said composition being administered twice daily. composition.

2. The udenafil or a pharma- ceutical acceptable salt thereof is in the form of a solid dosage form for oral administration. A pharmaceutical composition for the use described in claim 1.

3. 3. The pharmaceutical composition for use according to claim 2, wherein said solid dosage form for oral administration is a tablet.

4. 3. The pharmaceutical composition for use according to claim 2, wherein said solid dosage form for oral administration is a capsule.

5. Udenafil or a pharma- ceutical acceptable salt thereof may be administered in the form of a tablet, capsule, gel, liquid, or liquid dispersion. in a solid or semi-solid oral dosage form selected from the group consisting of a pill, a powder, and a suspension; A pharmaceutical composition for the use according to claim 1.

6. The twice daily administration of the pharmaceutical composition results in the patient's bloodstream receiving at least 100 mg of the compound for at least 24 hours during the 24 hour administration period. For the use according to claim 1, a therapeutic level of udenafil is obtained which lasts for at least 16 hours. A pharmaceutical composition for the treatment of

7. 13. Any of the preceding claims, wherein the pharma- ceutically acceptable salt of udenafil is an acid addition salt. A pharmaceutical composition for the use described in claim 1.

8. In subjects with Fontan physiology, the maximal effort or ventilatory anaerobic threshold (VAT) udenafil for use in improving exercise capacity as determined by improved VO2 in or a pharma- ceutical composition comprising udenafil or its medicament, Pharmaceutically acceptable salts are available as udenafil in a total daily dose of 125 mg to 175 mg. The pharmaceutical composition to be administered.

9. The pharmaceutical composition for use according to claim 8, wherein the pharmaceutical composition is in the form of a solid dosage form for oral administration. Pharmaceutical composition.

10. The solid dosage form for oral administration is a capsule, gel, liquid, liquid dispersion, pill, powder, or suspension.

10. The pharmaceutical composition for use according to claim 9,

11. 10. The pharmaceutical composition for use according to claim 9, wherein said solid dosage form for oral administration is a tablet.

12. 10. The pharmaceutical composition for use according to claim 9, wherein the solid dosage form for oral administration is a capsule. 。

13. Exercise capacity, work volume, equivalent ventilation of carbon dioxide (VE / VCO2), and / or ventricular function Oral administration medication containing udenafil or a pharma- ceutical acceptable salt thereof for improving A pharmaceutical composition comprising udenafil or a pharma- ceutical acceptable salt thereof at a dosage of 87.5 mg. wherein said composition is administered twice daily.

14. Improvements in exercise capacity, work output, and carbon dioxide equivalent ventilation (VE / VCO2) improve the patient's ventilation.

14. A pharmaceutical composition for use according to claim 13, determined at the anaerobic threshold.

15. Improvement in ventricular function is determined using standard echocardiography techniques, 14. The pharmaceutical composition for use according to claim 13, wherein the myocardial examination technique is myocardial performance index.

16. The udenafil or a pharma- ceutical acceptable salt thereof is in the form of a solid dosage form for oral administration. A pharmaceutical composition for the use described in claim 13.

17. 17. The pharmaceutical composition for use according to claim 16, wherein said solid dosage form for oral administration is a tablet.

18. 17. The pharmaceutical composition for use according to claim 16, wherein the solid dosage form for oral administration is a capsule. thing.

19. Udenafil or a pharma- ceutical acceptable salt thereof may be administered in the form of a tablet, capsule, gel, liquid, or liquid dispersion. in a solid or semi-solid oral dosage form selected from the group consisting of a pill, a powder, and a suspension; A pharmaceutical composition for the use according to claim 16.

20. 13. Any of the preceding claims, wherein the pharma- ceutically acceptable salt of udenafil is an acid addition salt. A pharmaceutical composition for the use described in claim 1.

21. The twice daily administration of the pharmaceutical composition results in the patient's bloodstream receiving at least 100 mg of the compound for at least 24 hours during the 24 hour administration period. The use according to claim 13, which provides a therapeutic level of udenafil that lasts for at least 16 hours. A pharmaceutical composition for use in treating

22. 22. The pharmaceutical composition for use according to claim 21, wherein the patient has renal impairment.

Images