A method for improving myocardial performance in Fontan patients using an udenafil composition.

Abstract

The present invention provides a pharmaceutical composition used in a method for treating patients with single ventricle heart disease (SVHD) who have undergone the Fontan procedure. [Solution] A pharmaceutical composition for use in a method of treating a patient with SVHD to improve exercise capacity determined by improvement in the patient's VO2max and VO2 at the anaerobic threshold, wherein the SVHD patient has undergone Fontan surgery, and the method comprises administering to the SVHD patient an effective daily dose of the udenafil or a pharmaceutically acceptable salt thereof to treat the SVHD patient to improve exercise capacity determined by improvement in the patient's VO2max and VO2 at the anaerobic threshold, wherein the udenafil or a pharmaceutically acceptable salt thereof is administered in a total daily dose of about 175 mg.

Description

[Technical Field]

[0001] Cross-reference of related applications This invention relates to U.S. Provisional Patent Application No. 62,036,506, filed on August 12, 2014. Based on the and U.S. Provisional Patent Application No. 62 / 186,132 filed on June 29, 2015. Priority is claimed accordingly, and the disclosure of the said provisional application is specifically incorporated by reference.

[0002] In general, this invention relates to phosphodiesterase E5 (PD) in patients who have undergone the Fontan procedure. E5) Regarding the field of use of inhibitors. Specifically, PDE5 inhibitors include udenafil or so It is a pharmaceutically acceptable salt. [Background technology]

[0003] I. Background of the Fontan procedure The Fontan procedure or Fontan / Kreutzer procedure is used to treat functional single-ventricle congenital heart disease. This is a palliative surgical procedure for children born with heart disease. The Fontan procedure involves right heart pocket Designed to continuously supply blood flow to the pulmonary and systemic circulation without requiring a separate pump chamber. The surgery was performed, and systemic venous blood was discharged from the arteries and capillaries based on the impetus of the single ventricle. , and can flow directly into the pulmonary circulation through the systemic venous system. This arrangement is the former artery. Compared to shunts, it has improved the average life expectancy of patients with single ventricle and pulmonary outflow tract obstruction.

[0004] This surgery creates a superior-subspecies vena cava-pulmonary artery anastomosis, separating the systemic and pulmonary circulation to treat hypoxemia and ventricular problems. Both relieve the volume overload. However, after the Fontan procedure, the ventricles that pump blood into the pulmonary artery... There is no pump. Instead, blood returns to the lungs from the systemic veins by passive flow. Therefore, the cardiovascular system is characterized by high central venous pressure, abnormal pulmonary vascular resistance, and chronically low cardiac output. A ring forms. Over time, these unique characteristics of Fontan physiology begin after puberty. This results in a predictable, sustained decline in cardiovascular efficiency, characterized by a progressive decline in exercise capacity. This decreased exercise tolerance correlates with an increase in symptoms of cardiovascular dysfunction, leading to hospitalization and heart failure management. The need for strengthening or transplantation may arise.

[0005] Those with Fontan circulation do not have "normal" cardiac physiology or function. Many "downstream" Two main complications that can affect the "downstream" are its location (vein or artery). The following effects on blood pressure, which rises ("high blood pressure") and falls ("low blood pressure") depending on the following factors: Yes, it exists. First, if Fontan circulation is present, then "systemic venous hypertension" exists, which is a condition where the veins in the body are affected. The blood pressure (blood returning to the heart) is different for individuals with normal (non-Fontan circulation) cardiac function compared to individuals with normal cardiac function. It means that it is higher in comparison. Basically, it is related to the distribution of fluids in the body, such as systemic venous hypertension. This can lead to many negative consequences (congestive heart failure, edema or swelling, liver dysfunction). A disorder (possibly protein-losing enteropathy) is present. The second complication is "pulmonary hypotension." Therefore, in this case, the blood pressure in the arteries leading to or within the lungs (i.e., the lungs) is not indicative of normal cardiac function. It is lower compared to the individual. This is likely due to pulmonary symptoms such as cyanosis (purple lips) or lack of exercise tolerance. There are many negative outcomes associated with pulse hypotension. Following Fontan surgery (short-term or The secondary medical conditions and deaths that occur over a long period are thought to be caused by changes in systemic and pulmonary blood pressure. It is being done.

[0006] Due to the long-term effects of significant single ventricular preload and inefficient oxygenation caused by arterial shunts, 10 Surviving beyond the teenage or twenties is rare. It was uniformly fatal 40 years ago. However, neonates with single ventricle congenital heart disease in 2010 now have a chance of survival and are expected to survive. However, as these children grow into adolescence and adulthood it becomes clear that there are significant limitations to this approach. Although life-saving is possible, the Fontan / Creutzer operation results in profound physiological injury with very serious consequences. Over time, widespread abnormalities in multiple organ systems have an impact. Realistically, it is unlikely that patients will survive into their twenties or thirties without some life-threatening complications. Therefore, there is a clear need to find a treatment that can improve the dysfunctional state of the Fontan operation. This is especially true considering the increasing prevalence of the Fontan operation, and notably, the Fontan operation has become the most frequently performed operation for congenital heart disease after the age of 2. W.M. Gersony,

[0007] Multiple studies examining the outcomes of the Fontan operation have shown a decrease in survival beyond 15 years after surgery. Regardless of the type of veno-pulmonary anastomosis, there is a high and ongoing risk of death with natural attrition. Another study morphologically examining the single left ventricle after Fontan surgery showed that the likelihood of him or her dying before reaching the late twenties was 1 in 4. J. Rychik, ″Forty Years of the Fontan O peration: A Failed Strategy,″ Pediatric Ca

[0008] Considering that the lifespan of Fontan patients has been increasing, researchers have been exploring medical therapies to address the side effects of the Fontan procedure. In particular, children and young adults with single-ventricle physiology have abnormal exercise tolerance after Fontan surgery. Strategies targeting to improve cardiac output and reduce central venous pressure would improve their overall health and mitigate the impact of this harmful physiology. In one study, the PDE5 inhibitor sildenafil was found to significantly improve ventilation efficiency between maximal exercise and maximal submaximal exercise. Also, improvement in oxygen consumption at the anaerobic metabolic threshold was suggested in two small groups. These findings suggest that sildenafil may be an important agent to improve exercise capacity after Fontan surgery in children and young adults with single-ventricle physiology. Goldberg et al, Circulation, 123:1 185 - 1193 (2011).

[0009] In a more recent study, sildenafil was confirmed to increase ventricular systolic elastance and improve ventricular-arterial coupling in patients with a Fontan circulation who were sedated. Short-term sildenafil showed good tolerance in most patients, with mild side effects. Shabanian et al., Pediatr. Cardiol., 34 (1):129 - 34 (2013). The structure of sildenafil is shown below.

[0010]

[0011]

Chemical formula

[0012] In addition, regarding the hemokinetic response to exercise and exercise tolerance in patients with Fontan circulation The short-term effects of the PDE5 inhibitor tadalafil were evaluated in a preliminary study. http: / / cl inicaltrials.gov / ct2 / show / record / NCT0129 See 1069. Similar to the published sildenafil results, tadalafil Short-term treatment administered once daily improved ventilation efficiency and oxygen saturation in young Fontan subjects. Although the condition improved, exercise tolerance remained unchanged. Menon et al., Circulati on, 128:A16024 (2013). The chemical structure of tadalafil is shown below.

[0013] [ka]

[0014] For optimal results, use the PDE5 inhibitor sildenafil or tadalafil in Fontan. It is necessary to administer it to patients over a long period of time to delay or prevent the onset of Fontan circulatory insufficiency. There may be. The Fontan procedure can cause chronic conditions, and children who have undergone the Fontan procedure may develop chronic conditions. When children reach adolescence or adulthood, short-term treatment is unlikely to address mortality associated with the condition. This is especially true when Fontan insufficiency begins, and the patient faces death or a heart transplant. There is an unavoidable decline in hemodynamics and function. In patients with Fontan circulation... Early experience with transplantation showed high surgical mortality and morbidity rates. Patients with Fontan circulation If the person survives, the hypothesis that PVR is sufficiently low relative to the right ventricle of the transplanted tissue after heart transplantation is correct. Early Fontan transplant experiences revealed that this is not ideal.

[0015] Both sildenafil and tadalafil are known to have undesirable side effects. However, in patients with pulmonary hypertension (PAH) who switched from sildenafil to tadalafil, Significantly different oxygen saturation, significantly different oxygen saturation after a 6-minute walk test, and significantly different It has been found that it indicates walking distance, and PDE5 inhibitors are used to treat cardiac or cardiovascular conditions. In that case, they have been shown to be incompatible. (Sabri et al., Ped) iatr Cardiol,35(4):699-704(2014). II. Background on PDE5 inhibitors and udenafil

[0016] PDE5 is a secondary signaling molecule (cGMP) and cyclic adenosine-3', By catalyzing the hydrolysis of 5'-monophosphate (cAMP), various cellular functions are regulated. Cyclic guanosine-3',5'-monophosphorus, which belongs to the phosphodiesterase class, is a related enzyme. It is an acid (cGMP) specific phosphodiesterase. Boolell et al., I nt'l J.Impot.Res.,8:47(1996). PDE5 is found in the arterial walls within the lungs. Because it is present in smooth muscle, PDE5 inhibitors are usually used to treat pulmonary blood loss resulting from damage to the right ventricle of the heart. It has been studied for the treatment of pulmonary hypertension, a disease in which excessive fluid load is placed on the tubules.

[0017] Udenafil is a drug used in urology to treat erectile dysfunction. This drug belongs to a class of drugs called PDE5 inhibitors, which includes sildenafil and tadalaf. This also includes yl and vardenafil. Typical doses are 100 and 200 mg. Udenafil is available in South Korea, Russia, and the Philippines. In the United States... Its use is not approved by the U.S. Food and Drug Administration.

[0018] The Fontan procedure provides temporary relief, but it is not curative. However, in many cases... To ensure normal or near-normal growth, development, exercise tolerance, and a good quality of life. It can bring about. In 20-30% of cases, patients will eventually require a heart transplant.

[0019] Modifications in the Fontan surgical model were one of the initial steps to improving outcomes. The use of nesting, multi-stage Fontan surgery, and better perioperative management are now This has led to a significant decrease in daily mortality rates. Nevertheless, arrhythmias, ventricular dysfunction, and Furthermore, it may have complications such as protein-losing enteropathy (PLE) and rare clinical syndromes of cast bronchitis. There is a delayed spontaneous decrease in the patient's condition. For managing worsening Fontan, within the Fontan circuit... Detailed hemodynamic and imaging evaluations for treating any treatable lesions such as stenosis, and irregularities. Early control of pulse and maintenance of sinus rhythm, symptomatic treatment for PLE and cast bronchitis, systemic vascular Manipulation of resistance and pulmonary vascular resistance, as well as arrhythmia treatment from the less desirable atrial-pulmonary artery linkage method. One example is Fontan conversion to superior and inferior vena cava pulmonary artery anastomosis, which involves surgery. However, this is the only successful final relief in Fontan patients whose condition is worsening. The Fontan circulation, which causes worsening liver or kidney function, has already destroyed the body, so the heart Transplantation is not a perfect solution, and therefore patients with Fontan circulation still have to rely on heart transplants. However, sometimes I feel unwell.

[0020] In this technical field, extending the lifespan of Fontan patients and avoiding the need for heart transplants or For the purpose of delaying the improvement of treatments related to complications or side effects of the Fontan procedure There is a need. Also, in this technological field, there is a need to delay the onset of heart failure and Fontan technique. There is a need for improved treatment methods that enhance the quality of life of patients who have undergone surgery. Yes, this invention meets this need. [Overview of the project]

[0021] In one embodiment, the present invention relates to conditions and symptoms associated with patients who have previously undergone the Fontan procedure. This covers methods for treating, preventing, and / or minimizing symptoms and / or side effects. In particular, The present invention relates to the Fontan procedure for the remission of associated acute and chronic symptoms. The use of udenafil or its pharmacoacceptable salts in adolescent patients with single ventricle The method comprises administering a therapeutically effective dose of a PDE5 inhibitor to a patient, and the P DE5 inhibitors are udenafil or its pharmaceutically acceptable salts.

[0022] In one embodiment, the present invention provides a method for improving cardiac output in patients who have undergone the Fontan procedure. The method involves administering a therapeutically effective dose of a PDE5 inhibitor to the patient, The PDE5 inhibitor is udenafil or a pharmaceutically acceptable salt thereof.

[0023] In another embodiment, the present invention is a method for reducing pulmonary vascular resistance in patients who have undergone Fontan surgery. The method involves administering a therapeutically effective dose of a PDE5 inhibitor to the patient, The PDE5 inhibitor is udenafil or a pharmaceutically acceptable salt thereof.

[0024] In yet another embodiment, the present invention improves the exercise tolerance of patients who have undergone Fontan surgery. The method in question involves administering a therapeutically effective dose of a PDE5 inhibitor to a patient. The PDE5 inhibitor is udenafil or a pharmaceutically acceptable salt thereof.

[0025] In one embodiment, the present invention provides a method for improving myocardial performance in patients who have undergone Fontan surgery. The method involves administering a therapeutically effective dose of a PDE5 inhibitor to the patient, The PDE5 inhibitor is udenafil or a pharmaceutically acceptable salt thereof.

[0026] In exemplary embodiments, the method of the present invention involves a therapeutically effective dose of udenafil or its pharmaceutically effective This includes administering an acceptable salt to the patient once daily.

[0027] In another embodiment, the method of the present invention involves a therapeutically effective dose of udenafil or a pharmaceutically effective dose thereof. This includes administering a tolerable salt to the patient twice a day.

[0028] In another embodiment, the patient is a pediatric patient aged approximately 2 to 18 years. Also, adult patients Treatment is also included in the method of the present invention.

[0029] In yet another embodiment, the present invention provides an improved method for treating patients who have undergone Fontan surgery. The target group was patients prescribed udenafil drugs, and the method involved comparing them to patients prescribed non-udenafil drugs. This improves patient compliance with the medication schedule for the pharmacoagulated salt. This indicates.

[0030] In one embodiment, the present invention relates to an improved method for treating patients who have undergone the Fontan procedure. Therefore, the method of the present invention has less than conventional methods for treating such patients. It causes an adverse event or a less severe adverse event. In another embodiment, the method of the present invention is Even if such adverse events occur, they are very rare, resulting in only a small number of serious, moderate, or mild adverse events. ru.

[0031] In another embodiment, the method of the present invention is used when the method of the present invention is not used (for example, Udenaf Improvement in the patient's maximal effort VO2 compared to maximal effort VO2 (without injection administration). This brings about improvements, for example, when the method of the present invention is not used (for example, the administration of udenafil). Compared to VO2 at maximum effort (without the given conditions), approximately 5, 6, 7, 8, 9, and 10. , approximately 11, approximately 12, approximately 13, approximately 14, approximately 15, approximately 16, approximately 17, approximately 18, approximately 19, approximately 20 , approximately 21, approximately 22, approximately 23, approximately 24, approximately 25, approximately 26, approximately 27, approximately 28, approximately 29, or approximately It can be 30% or more.

[0032] In another embodiment, the method of the present invention is used when the method of the present invention is not used (for example, Udenaf Compared to VO2 without injection, the improvement in the patient's VO2 at the anaerobics threshold. It brings good. For example, the improvement is not achieved by using the method of the present invention (for example, udenafil Compared to the maximum effort VO2 (without administration), it was approximately 5, 6, 7, 8, 9, and 1. 0, approximately 11, approximately 12, approximately 13, approximately 14, approximately 15, approximately 16, approximately 17, approximately 18, approximately 19, approximately 2 0, approximately 21, approximately 22, approximately 23, approximately 24, approximately 25, approximately 26, approximately 27, approximately 28, approximately 29, or It can be approximately 30% or more.

[0033] In another embodiment, the method of the present invention is used when the method of the present invention is not used (for example, Udenaf Compared to blood pool MPI or other disclosure criteria for ventricular function (in the absence of IV administration) This leads to improvements in the patient's blood pool MPI or other disclosure assessment criteria for ventricular function. For example, The improvement is in the blood when the method of the present invention is not used (for example, when udenafil is not administered). Compared to pooled MPI or other disclosure criteria for ventricular function, approximately 5, 6, 7, 8, and 8. 9, approximately 10, approximately 11, approximately 12, approximately 13, approximately 14, approximately 15, approximately 16, approximately 17, approximately 18, approximately 1 9, approximately 20, approximately 21, approximately 22, approximately 23, approximately 24, approximately 25, approximately 26, approximately 27, approximately 28, approximately 2 9%, or approximately 30% or more.

[0034] In another embodiment, the method of the present invention is used when the method of the present invention is not used (for example, Udenaf Compare the logarithmic reactive hyperemia index (in the absence of IV administration) with other disclosure criteria for vascular function. This results in an improvement in the logarithmic reactive hyperemia index of the patient or other disclosure criteria for vascular function. For example, the improvement is achieved when the method of the present invention is not used (for example, when udenafil is not administered). Compared to the logarithm of the reactive hyperemia index or another disclosure assessment criterion for vascular function, it is approximately 5, approximately 6, approximately 7, approximately 8, approximately 9, approximately 10, approximately 11, approximately 12, approximately 13, approximately 14, approximately 15, approximately 16, approximately 17, Approximately 18, approximately 19, approximately 20, approximately 21, approximately 22, approximately 23, approximately 24, approximately 25, approximately 26, approximately 27, It can be approximately 28%, approximately 29%, or approximately 30% or more.

[0035] And finally, in yet another embodiment, the method of the present invention is characterized by a pharmacokinetic profile It can lead to [unclear]. The pharmacokinetic profile is 300-700 ng / ml C max ,also More specifically, approximately 500 ng / ml; 1-1.6 hours T max , or more specifically, Approximately 1.3 hours; AUCτ of 2550-4150 ng·hours / ml, or more specifically, approximately 3 AUC of 350 ng·h / ml and 5110 to 8290 ng·h / ml 0-24 , or More specifically, it can contain approximately 6701 ng·h / ml.

[0036] The general statements above and the detailed statements below are for illustrative and explanatory purposes only and are not claimed. This invention is intended to provide a further description of the present invention, along with a brief description of the drawings below. From the detailed description of the invention, other purposes, advantages, and novel features will be readily apparent to those skilled in the art. cormorant. [Brief explanation of the drawing]

[0037] [Figure 1] Figure 1 shows the percentage of subjects who reported at least one, three, or five adverse events in each treatment group.

[0038] [Figure 2] Figure 2 shows the change in peak VO2 (ml / kg / min) during maximum effort from baseline (day 1) to the final visit (day 5 after medication) for each treatment group, with a positive change indicating improvement.

[0039] [Figure 3] Figure 3 shows the peak VO2 at maximum effort for each treatment group at baseline (day 1) and at the final visit (day 5 after medication), with positive changes indicating improvement.

[0040] [Figure 4] Figure 4 shows the change in VO2 (ml / kg / min) at the anaerobic metabolic threshold from baseline (day 1) to the final visit (day 5 after medication), with positive changes indicating improvement.

[0041] [Figure 5] Figure 5 shows the peak VO2 at the anaerobic threshold for each treatment group at baseline (day 1) and at the final visit (day 5 after medication), with positive changes indicating improvement.

[0042] [Figure 6] Figure 6 shows the change in the natural logarithm of the reactive hyperemia index from baseline (day 1) to the final visit (day 5 after medication) for each treatment group. A positive change indicates improvement.

[0043] [Figure 7] Figure 7 shows the natural logarithm (RHI) of the reactive hyperemia index at baseline (day 1) and at the final visit (day 5 after medication) for each treatment group. A positive change indicates improvement.

[0044] [Figure 8] Figure 8 shows the change in blood pool MPI from baseline (day 1) to the final visit (day 5 after medication) for each treatment group. A negative change indicates improvement.

[0045] [Figure 9] Figure 9 shows the baseline (day 1) and final visit (day 5 after medication) blood pool MPI for each treatment group. A negative change indicates improvement.

[0046] [Figure 10] Figure 10 shows the change in tissue Doppler MPI from baseline (day 1) to the final visit (day 5 after medication) for each treatment group. A negative change indicates improvement.

[0047] [Figure 11] Figure 11 shows the tissue Doppler MPI at baseline (day 1) and at the final visit (day 5 after medication) for each treatment group. A negative change indicates improvement.

[0048] [Figure 12] Figure 12 shows the change in mean isovolumetric contraction from baseline (day 1) to the final visit (day 5 after medication) for each treatment group. A negative change indicates improvement.

[0049] [Figure 13]Figure 13 shows the mean isovoluted contractions at baseline (day 1) and at the final visit (day 5 after medication) for each treatment group. Negative changes indicate improvement.

[0050] [Figure 14] Figure 14 shows the change in mean isovoluted relaxation from baseline (day 1) to the final visit (day 5 after medication) for each treatment group. A negative change indicates improvement.

[0051] [Figure 15] Figure 15 shows the mean isovoluted relaxation at baseline (day 1) and at the final visit (day 5 after medication) for each treatment group. Negative changes indicate improvement.

[0052] [Figure 16] Figure 16 shows individual concentration-time curves stratified by the following administration methods: (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 the subjects. The solid line represents the measured data, and the dashed line represents the predicted data for the second dose of the day under a 12-hour dosing regimen. The data is expressed as mean ± standard deviation.

[0054] [Figure 18]Figure 18 shows a comparison of Cmax among various dosing regimens. The box plots show the 10th to 90th percentiles and ranges of the observations, and the median line represents the median for each dosing regimen. Significant differences: 37.5 mg every 24 hours vs. 87.5 mg every 12 hours, p<0.001; 37.5 mg every 24 hours vs. 125 mg every 24 hours, p<0.001; 37.5 mg every 12 hours vs. 87.5 mg every 12 hours, p<0.001; 37.5 mg every 12 hours vs. 125 mg every 24 hours, p<0.01; 87.5 mg every 24 hours vs. 87.5 mg every 12 hours, p<0.05.

[0055] [Figure 19] Figure 19 shows a comparison of (A) AUCτ and (B) AUC0-24 among various administration methods. The box plots show the 10th to 90th percentiles and ranges of the observed results, and the median line represents the median for each administration method. Significant difference: A) 37.5 mg every 24 hours vs. 87.5 mg every 12 hours, p<0.001; 37.5 mg every 24 hours vs. 125 mg every 24 hours, p<0.001; 37.5 mg every 12 hours vs. 87.5 mg every 12 hours, p<0.01; 37.5 mg every 12 hours vs. 125 mg every 24 hours, p<0.01; B) 37.5 mg every 24 hours vs. 87.5 mg every 12 hours, p<0.001; 37.5 mg every 24 hours vs. 125 mg every 24 hours, p<0.01; 37.5 mg every 12 hours vs. 87.5 mg every 12 hours, p<0.001; 87.5 mg every 24 hours vs. 87.5 mg Every 12 hours, p<0.001; 87.5 mg every 12 hours vs. 125 mg every 24 hours, p<0.001.

[0056] [Figure 20] Figure 20 shows a comparison of A) CL / F and B) V / F between different dosing regimens. Box plots show the 10th to 90th percentiles and ranges of the observations, and the median line represents the median for each dosing regimen. Significant differences: A) 37.5 mg every 24 hours vs. 87.5 mg every 12 hours, p<0.05; B) 37.5 mg every 24 hours vs. 87.5 mg every 12 hours, p<0.01.

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

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

[0059] [Figure 23] Figure 23 shows the difference between DV (measured concentration) and time after administration (TAD).

[0060] [Figure 24] Figure 24 shows DV (measured concentration) versus time (time).

[0061] [Figure 25] Figure 25 shows individual visual plots (SID1-12) including variability between measured concentration (DV) vs. predicted concentration (PRED) and individual prediction (IPRED) error vs. time (time).

[0062] [Figure 26] Figure 26 shows individual visual plots (SID13-24) including variability between measured concentration (DV) vs. predicted concentration (PRED) and individual prediction (IPRED) error vs. time (time).

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

[0064] [Figure 28] Figure 28 summarizes the mean plasma concentrations per time point in the pharmacokinetic study of udenafil in Fontan patients. The data are shown as mean ± standard deviation.

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

[0066] [Figure 30] Figure 30 shows the goodness-of-fit plot of measured data versus predicted data (DV vs. PRED).

[0067] [Figure 31] Figure 31 shows the goodness-of-fit plot of measured data versus individual predicted data (DV versus IPRED).

[0068] [Figure 32] Figure 32 shows the goodness-of-fit plot of the final model, comparing measured data with predicted data (DV vs. PRED).

[0069] [Figure 33] Figure 33 shows the goodness-of-fit plot of the final model between measured data and individual predicted data (DV vs. IPRED).

[0070] [Figure 34] Figure 34 shows the characteristic Fontan physiology. [Modes for carrying out the invention]

[0071] I. Fontan physiology Fontan physiology is a type of congenital heart defect that shares the common characteristic of a functional single ventricle. This is a limited mitigation of the condition. These include disorders that result in a malformed left or right ventricle. Typically, the systemic and pulmonary circulations are separated through a series of two or three surgeries, and oxygen is supplied to the body. This eliminates the mixing of oxygen-rich blood and oxygen-poor blood. This is because the superior and inferior vena cava are affected by the pulmonary artery. This is achieved by directly connecting to the pulse. This allows the following physiological processes to occur: (1) A single systemic ventricle pumps oxygen-rich blood from the aorta to the body's vascular bed. (2) Next, systemic venous blood returns through the vena cava and into the pulmonary vascular bed without assistance from the subpulmonary ventricles. It flows passively through. (3) And finally, oxygen-rich blood returns to the common body atrium. This cycle repeats. This structure is illustrated in Figure 34.

[0072] The Fontan procedure creates an anastomosis between the superior and inferior vena cava and the pulmonary artery, separating the systemic and pulmonary circulation and reducing hypoxemia. This also relieves ventricular volume overload. However, after the Fontan procedure, blood is pumped into the pulmonary artery. There is no ventricular pump to generate blood. Instead, blood is returned to the lungs by a passive flow from the systemic veins. Therefore, the main physiological consequence of this type of relief is that pulmonary blood flow is reduced from the systemic venous bed to the atria. It is entirely dependent on the pressure gradient to pass through the pulmonary bed. Normal circulatory flow is increased by the increased pressure generated by the right ventricle. In some individuals, this increases the pressure present in the pulmonary artery at rest by approximately 20-25 mmHg, and during exercise... If accompanied by this, it can double. If Fontan physiology is present, there is no subpulmonary valve ventricle, and therefore blood There is no pressure increase when the fluid enters the pulmonary artery. At rest, the pressure gradient in the pulmonary vascular bed is remarkably small. The ability to increase this pressure gradient through exercise is due to the body's ability to withstand the gradually rising central venous pressure. It becomes extremely restricted.

[0073] The unique outcome is that pulmonary blood flow is entirely dependent on a passive decrease in venous pressure, thus Fontan The principle is greatly influenced by changes in pulmonary vascular resistance. In normal physiological conditions, pulmonary vascular resistance is sufficiently normal. Even an increase within the range can have adverse effects on Fontan physiology. Even if the value is already normal, any decrease in resistance may increase pulmonary blood flow. Therefore, the use of udenafil is potentially specific to this type of mild congenital heart defect. It provides a treatment that, unlike other uses of PDE-5 inhibitors, does not affect pulmonary vascular resistance or lung In populations where vascular pressure is not elevated, tolerance will likely be lower. This is structural. Normal cardiovascular disease and pulmonary vascular disease or palliative care using biventricular repair (therefore pulmonary artery Compared to the very rare patients with congenital heart disease (with a subvalvular ventricle) and related pulmonary vascular disease, this This is a clearly different use of the same type of drug. II. Clinical measurements related to Fontan patients

[0074] For children born with functional single ventricle congenital heart disease, the Fontan procedure is currently It is the current standard of treatment. The Fontan procedure has greatly increased the survival rate of pediatric subjects, but the cure Rather than being a permanent solution, it is a temporary relief, and the surgery also treats arrhythmias, ventricular dysfunction, and protein Complications such as rare clinical syndromes like white-lipping enteropathy (PLE) and cast bronchitis, as well as liver A series of side effects that may lead to delayed spontaneous death in patients with visceral and renal complications. It causes effects and complications.

[0075] In one embodiment, the invention of the present disclosure clinically demonstrates the patient's health status after the Fontan procedure. Regarding improving or preventing declines in specific measurement results. These include exercise stress tests, vascular function tests, and evaluation of ventricular function using echocardiography. However, it is not limited to these. Exercise stress test

[0076] Exercise stress testing includes the assessment of VO2 values ​​during maximal effort or at the anaerobic threshold. This is possible. VO2max, or maximum oxygen uptake, can be used by an individual during strenuous exercise. This refers to the maximum amount of oxygen available. This measurement is generally used to assess cardiovascular health and aerobic endurance. It is considered a reliable indicator. Theoretically, it can be used by a person during high-level exercise. The more oxygen available, the more energy a person can produce. Long-term (aerobic) exercise requires oxygen, and blood carries oxygen to the muscles, meeting the demands of aerobic exercise. The heart must pump out a sufficient amount of blood to fill the volume, so this test is cardiopulmonary This is the most reliable standard for assessing health status.

[0077] VO2 is often measured by having the subject wear a mask and by the volume and concentration of inhaled and exhaled air. It is measured by measuring [a specific parameter]. These measurement results are used in both clinical settings and research. This is often the case and is considered the most accurate method. The test usually involves gradually increasing the intensity until exhaustion occurs. This includes exercising on a treadmill or riding a bicycle until the subject has made the maximum effort to do so. It is designed to provide a reading of the subject's anaerobic metabolic threshold. .

[0078] Patients who have previously undergone Fontan surgery generally experience a decrease in VO2 levels over time. The experiment will be conducted. The patient will be treated by the method according to the present invention, and as a result, the patient's VO2 measurement will be measured. This indicates that the same level is maintained and there is no further decline in VO2 function, or VO2 measurement values. If the condition improves with treatment, it indicates that the treatment is clinically beneficial and corrects the decline in cardiovascular function. To indicate that something can be prevented or avoided.

[0079] In one embodiment, the present invention relates to VO2 measurements of subjects who have previously undergone Fontan surgery. The method concerns improving or maintaining the condition. The method involves administering a therapeutically effective dose of a PDE5 inhibitor to the patient. This includes administering, where the PDE5 inhibitor is udenafil or a pharmaceutically acceptable equivalent thereof. It is a salt. In some embodiments, VO2 is measured at maximum effort, while in other embodiments In this scenario, VO2 is measured at the subject's anaerobic metabolic threshold.

[0080] In some embodiments, the methods and compositions disclosed herein are administered to Fontan patients over time. With continued use, exercise tolerance does not decrease, or only decreases minimally. More specifically, The method and composition shown increase over time to less than 40, less than 35, less than 35, and less than 35. A decrease in exercise tolerance of less than, approximately less than 20, approximately less than 15, approximately less than 10, or approximately less than 5% It is possible. The time between the first and second measurements used to calculate the decrease in exercise tolerance. The intervals are, for example, approximately 1, approximately 2, approximately 3, approximately 4, approximately 5, approximately 6, approximately 7, approximately 8, approximately 9, approximately 10, approximately 1 1, or about 12 months; about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, Approximately 10, 11, 12, 13, 14, or 15 years, or any combination thereof Combined, for example, it could be 1 year and 3 months; 4 years and 7 months, etc.

[0081] In some embodiments, the methods and compositions disclosed herein are administered to Fontan patients, and exercise tolerance This may result in improved performance. More specifically, the methods and compositions disclosed herein have a maximum effort VO2 2, 1, 2, 5, 10, 15, 20, 25, 30, 35, 40, 45, or 50% or more It can be improved. Alternatively, the methods and compositions of this disclosure may improve the patient's anaerobic metabolic threshold. O2 of 1, 2, 5, 10, 15, 20, 25, 30, 35, 40, 45, or 50% or less It can be improved. Vascular function tests

[0082] Endothelial dysfunction is an important indicator for assessing vascular health in intervention studies. It is a cam. Currently, vascular endothelial dysfunction is considered a traditional risk factor for cardiovascular disease (CVD) and is correct. To demonstrate the relationship and to independently predict cardiovascular events over a 1-6 year interval. It is well established.

[0083] Pulse amplitude tonometry (PAT) is an FDA-approved method for evaluating vascular function. This method is rated and is endothelial-dependent in response to reactive hyperemia and flow-dependent vasodilation (FMD). It is increasingly being used as an alternative evaluation criterion for expansion. The PAT device is a fingertip plethysm. Digital pulse wave amplitude (PWA) is recorded using radiography. PWA is measured at rest. Measurements are taken continuously during three stages: the sline period, 5 minutes of forearm occlusion, and reactive hyperemia after cuff release. It can be determined. Unlike FMD, the PAT test does not rely on highly skilled technicians, and post-test resolution can be determined. Analysis is largely automated. More importantly, at least one long-term research project is underway. The study found that the PAT evaluation criteria for endothelial function predict CVD events over a 6-year follow-up period. This demonstrated that these significant advantages, when their prognostic importance and reliability can be confirmed, are P The AT test can be made more suitable for clinical practice.

[0084] Patients who have previously undergone Fontan surgery generally experience a decline in vascular function over time. This will result in treating the patient, and as a result, improving the patient's vascular function, or improving vascular function. Preventing further decline ensures that treatment is clinically beneficial and improves the patient's quality of life. This would demonstrate that it can improve blood pressure and prevent the decline of cardiovascular function.

[0085] In one embodiment, the present invention improves the vascular function of a subject who has previously undergone the Fontan procedure. This method focuses on improving or maintaining the condition. The method involves administering a therapeutically effective dose of a PDE5 inhibitor to the patient. This includes, where the PDE5 inhibitor is udenafil or a pharmaceutically acceptable salt thereof. In some embodiments, vascular function is measured using the PAT index.

[0086] In some embodiments, the methods and compositions disclosed herein are administered to Fontan patients over time. Vascular function does not decrease or decreases only minimally with age. Vascular function is limited. However, pulse amplitude tonometry measurement, natural logarithm of reactive hyperemia index, reactive hyperemia index, Lammingham RHI, area under the concentration curve relative to maximum occlusion / control, mean up to maximum occlusion / control , and can be measured using any conventional known technique, including other known EndoPAT metrics. In some embodiments, vascular function is measured using the PAT index. More specifically, The methods and compositions disclosed herein have a time interval of approximately 40, approximately 35, approximately 30, and approximately A decrease in vascular function of less than 35, less than approximately 20, less than approximately 15, less than approximately 10, or less than approximately 5% It can be caused by the time between the first and second measurements used to calculate the decrease in vascular function. The intervals are, for example, approximately 1, approximately 2, approximately 3, approximately 4, approximately 5, approximately 6, approximately 7, approximately 8, approximately 9, approximately 10, approximately 1 1, or about 12 months; about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, Approximately 10, 11, 12, 13, 14, or 15 years, or any combination thereof Combined, for example, it could be 1 year and 3 months; 4 years and 7 months, etc.

[0087] In some embodiments, the methods and compositions disclosed herein are administered to Fontan patients, and the vascular mechanism It may lead to improved function. Vascular function is not limited, but pulse amplitude tonometry measurement, Natural logarithm of the reactive hyperemia index, reactive hyperemia index, Framingham RHI, maximum occlusion / control The area under the concentration curve, the mean up to maximum occlusion / control, and other known EndoPAT metrics are used. It can be measured using any of the conventional known techniques, including, in some embodiments, vascular function. It is measured using the PAT index. More specifically, the methods and compositions of this disclosure are not limited to However, pulse amplitude tonometry measurement, natural logarithm of reactive hyperemia index, reactive hyperemia index, flare Mingham RHI, area under the concentration curve relative to maximum occlusion / control, mean up to maximum occlusion / control, and about 1, about 2 of one or more vascular function measurement results, including other known EndoPAT indices. , approximately 5, approximately 10, approximately 15, approximately 20, approximately 25, approximately 30, approximately 35, approximately 40, approximately 45, or approximately 5 It can result in an improvement of 0% or more. Echocardiographic evaluation of ventricular function

[0088] Ventricular function or myocardial contractility indicates impaired cardiovascular health before overt heart failure is discovered. This is an important measurement result to clarify. Ventricular function can be evaluated using echocardiography, and myocardial function It can be quantified via the Efficiency Index or MPI. The MPI is an index that combines contractile and vasoconstrictive functions. Specifically, MPI is the sum of isovolumetric contraction time and isovolumetric relaxation time divided by ejection time. It is defined as follows.

[0089] Various versions of MPI are publicly known in the art, and each version of MPI is mind It can be used to assess ventricular function. For example, the MPI index is the blood pool MPI. These include tissue Doppler MPI, mean isovoluted contraction, and mean isovoluted relaxation, but these Not limited to this.

[0090] Patients who have previously undergone the Fontan procedure generally experience a decline in ventricular function over time. This will result in treating the patient, maintaining the patient's ventricular function, and minimizing the risk over time. A decrease or increase indicates that the treatment is clinically beneficial and improves the patient's quality of life. This suggests that it may raise IF levels and prevent a decline in cardiovascular function.

[0091] In one embodiment, the present invention restores ventricular function in a subject who has previously undergone Fontan surgery. To maintain, cause a minimal reduction in said ventricular function, or increase said ventricular function The method comprises administering a therapeutically effective dose of a PDE5 inhibitor to a patient, where PDE5 inhibitors are udenafil or its pharmaceutically acceptable salts. Several implementations In some embodiments, ventricular function is measured using the Myocardial Performance Index (MPI). In one embodiment, the MPI may be a blood pool MPI. In another embodiment, the MPI may be a tissue dop It could be Ra MPI.

[0092] In some embodiments, the methods and compositions disclosed herein are administered to Fontan patients over time. This may result in a minimal or no decrease in ventricular function. The functions are not limited to, but include Myocardial Performance Index (MPI), Blood Pool MPI, and Tissue Doppler. Any conventional public ventricular function index, including MPI, mean isovoluted contraction and relaxation, and other known public It can be measured using the technology of knowledge. More specifically, the methods and compositions of this disclosure are measured over time and Also, less than approximately 40, less than approximately 35, less than approximately 30, less than approximately 35, less than approximately 20, less than approximately 15, approximately 1 This can result in a decrease in ventricular function of less than 0 or less than approximately 5%. Calculating the decrease in ventricular function... The time between the first measurement and the second measurement used is, for example, approximately 1, approximately 2, approximately 3, approximately 4. Approximately 5, 6, 7, 8, 9, 10, 11, or 12 months; approximately 1, 2, 3, approximately 4, approximately 5, approximately 6, approximately 7, approximately 8, approximately 9, approximately 10, approximately 11, approximately 12, approximately 13, approximately 14, Or approximately 15 years, or any combination thereof, for example, 1 year and 3 months; 4 years and 7 months. It can be any way.

[0093] In some embodiments, the methods and compositions disclosed herein are administered to Fontan patients over time. It leads to improved ventricular function. Ventricular function is not limited to the Myocardial Performance Index (M PI), blood pool MPI, tissue Doppler MPI, mean isovolumetric contraction and relaxation, and other It can be measured using any conventional known technique, including known ventricular function indices. For example, The methods and compositions shown are not limited to, but include, the Myocardial Performance Index (MPI), blood pool MPI, This includes tissue Doppler MPI, mean isovolumetric contraction and relaxation, and other known ventricular function indices. Ventricular function of approximately 1, 2, 5, 10, and 15 degrees, as measured by known techniques for deviation. It brings about improvements of approximately 20, 25, 30, 35, 40, 45, or 50% or more. Shut up. III. The method according to the present invention

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

[0095] In Fontan circulation, pulmonary blood flow is passive and depends on the pressure difference between systemic venous circulation and ventricular end-diastolic pressure. Therefore, it is delivered. Drugs that can make it possible to transport blood more efficiently through the pulmonary vascular bed are used for precardia. This allows for improvement, thus improving cardiac output.

[0096] PDE5 inhibitors reduce pulmonary vascular resistance in patients with pulmonary hypertension and myocardial insufficiency. Furthermore, it is a type of drug that improves ventricular function.

[0097] Several studies have investigated the effects of sildenafil monotherapy on children and young adults who underwent the Fontan procedure. We have evaluated single-use and long-term use. However, sildenafil has a short half-life and is typically It is administered 3-4 times a day. Such a dosing schedule is inconvenient and does not improve patient compatibility. It may reduce the efficacy of the drug. In addition, administering drugs with a short half-life may reduce the efficacy of the drug. This can cause significant fluctuations in therapeutic levels, and the blood levels of PDE5 inhibitors may be elevated for part of the day. The risk of dropping below a therapeutically effective level increases. The inventors of this invention have found that longer Administration of PDE5 inhibitors with a long half-life to patients who have undergone Fontan surgery is considered a risk factor for Fontan surgery. We hypothesize that this will later prevent or improve the decline in the patient's aerobic exercise capacity.

[0098] Patient compliance is crucial for optimal treatment effectiveness, especially when administering daily vaccinations over long periods, such as several years or more. This is extremely important for medications that must be taken. This is especially true for Fontan patients. In particular, individuals who undergo Fontan surgery are almost always at risk of heart failure, stroke (thrombosis), Or death from several unexplained sudden deaths. Of particular note is the risk of death from heart failure. The risk is very low within 10 years of the Fontan procedure, but increases over time from 10 years after the Fontan procedure. This means it will increase. http: / / bendantzer.wordpres s.com / 2013 / 03 / 13 / fontan-circulation-succ ess-or-failure / .

[0099] Naturally, as time passes from the date of the Fontan procedure, the risk of death or heart disease increases. The need for organ transplantation increases. This can be due to sudden death or heart failure, but the heart function gradually deteriorates. It can also be due to a decline. After Fontan surgery, as the years go by, cardiac function This deteriorates, which is reflected in a decrease in the ability to perform aerobic exercise. For example, Fontan In patients who received the treatment at an early stage, exercise tolerance was significantly reduced (44%) compared to normal patients. This can occur, and this motor ability tends to decline linearly each year (a decrease of 2.6% per year). Patients with Fontan circulation experience a significant decrease in exercise tolerance at age 30 (less than 55% of normal). The number of health problems and hospitalization rates increase dramatically. To reiterate, one ventricle becomes two Since it is doing work for minutes, this is probably not surprising. Therefore, cardiac function over time This invention can eliminate the decrease that occurs with excess or significantly reduce that decrease. This method is highly desirable for Fontan patients. The key to the success of such a method is Patient compliance with a reasonable medication schedule is crucial.

[0100] Patient compliance with prescribed medication schedule or lack thereof It is known to be a critically important factor in the success of any treatment. In particular, a good quality medical Healthcare outcomes include patient adherence to recommended treatment plans. It depends on the patient's non-adherence. This is a widespread threat to ellbeing and could potentially impose a significant economic burden. Yes. In some conditions, more than 40% of patients receive medical guidance (healthcare a Misunderstanding, forgetting, or ignoring the dvice carries significant risks. Furthermore, The prevention or treatment plan is very complex and / or involves lifestyle changes and modifications to existing habits. When positive results are required, non-adherence rates can be as high as 70%. (Martin et al.) al.,Ther.Clin.Risk Manag.,1(3):189-199( 2005) ("However, a major obstacle to effective drug treatment is that the patient is able to consult his or her doctor.") or failing to follow the recommendations of other healthcare providers. Therefore, sildenafil and other medications should be taken at least 4 to 6 hours apart. Compared to the need for multiple doses per day, for example, 3 to 6 doses per day, a preferred once-daily dose is preferable. The desired results (e.g., improved cardiac output, reduced pulmonary vascular resistance, improved exercise tolerance) can be achieved with two doses. Treatment that can bring about improvement (improvement of myocardial performance, prevention or improvement of decline in aerobic exercise capacity) Treatment is highly desirable. Such a simplified administration method is more patient-compliant. This is likely to lead to a significant increase in [the number of cases] and, at the same time, an improvement in treatment outcomes.

[0101] In one embodiment, the present invention improves cardiac output in patients who have undergone the Fontan procedure. The method in question involves a therapeutically effective dose of the PDE5 inhibitor udenafil or its pharmacological effects. The method of the present invention involves administering an acceptable salt to the patient. For example, the method of the present invention involves udenafil Compared to subjects who did not receive the treatment, approximately 5%, approximately 8%, approximately 10%, approximately 15%, approximately 20%, approximately An improvement in cardiac output of 25%, approximately 30%, approximately 35%, approximately 40%, approximately 45%, or approximately 50%. It can be done.

[0102] In another embodiment, the present invention reduces pulmonary vascular resistance in patients who have undergone the Fontan procedure. The method targets a therapeutically effective dose of the PDE5 inhibitor udenafil or its pharmacologically This includes administering an acceptable salt to the patient. For example, the method of the present invention involves administering udenafil. Compared to subjects who did not receive the treatment, the percentages were approximately 5%, 8%, 10%, 15%, 20%, and 2%. A reduction in pulmonary vascular resistance of 5%, approximately 30%, approximately 35%, approximately 40%, approximately 45%, or approximately 50% It can be done.

[0103] In yet another embodiment, the present invention relates to exercise tolerance in patients who have undergone Fontan surgery. The method of improvement is to use a therapeutically effective dose of the PDE5 inhibitor udenafil or The method of the present invention involves administering a pharmaceutically acceptable salt to the patient. For example, the method of the present invention involves udenaf Compared to subjects who did not receive the drug, approximately 5%, 8%, 10%, 15%, and 20% of those subjects did not receive the drug. To % of maximum VO2, approximately 25%, 30%, 35%, 40%, 45%, or 50% Therefore, it can lead to an increase in the measured exercise tolerance.

[0104] In one embodiment, the present invention improves myocardial performance in patients who have undergone the Fontan procedure. The method involves administering a therapeutically effective dose of a PDE5 inhibitor to a patient. For example, the method of the present invention shows approximately 5% improvement compared to subjects who were not administered udenafil. Approximately 8%, approximately 10%, approximately 15%, approximately 20%, approximately 25%, approximately 30%, approximately 35%, approximately 40%, approximately This can result in a 45% or approximately 50% improvement in myocardial performance.

[0105] In one embodiment, the present invention relates to the aerobic exercise capacity of patients who have undergone Fontan surgery. The method focuses on preventing or improving the decline, and the method is to use a therapeutically effective dose of the PDE5 inhibitor Udena This includes administering fil or a pharmaceutically acceptable salt thereof to the patient. For example, the present invention The law showed approximately 5%, approximately 8%, approximately 10%, and approximately compared to subjects who did not receive udenafil. 15%, approximately 20%, approximately 25%, approximately 30%, approximately 35%, approximately 40%, approximately 45%, or approximately 50% This can lead to remission of the decline in aerobic exercise capacity, as measured by maximum VO2. .

[0106] In yet another embodiment, the present invention relates to an improved method for treating patients who have undergone Fontan surgery. The method involves comparing patients prescribed udenafil or non-udenafil drugs with patients prescribed udenafil or This demonstrates improved patient compliance with the medication schedule for the pharmacoagulated salt. .

[0107] Udenafil has a half-life of 7.3 to 12.1 hours, and sildenafil or tadalafil Compared to the Udena, it is thought to have a potentially better safety profile. Phil has unique characteristics, T max The interval is 1.0 to 1.5 hours, and T1 / 2 is 11 It takes approximately 13 hours (relatively fast onset and long-lasting effect). Therefore, Udenaphy Both on-demand use and once-daily use have been reported. Sex and tolerability have been evaluated in several studies, and recent and ongoing studies have indicated that either This also shows that udenafil is promising in terms of administration method. Currently, tadalafil is FD Although it is the only daily-administered drug approved for Category A, udenafil is a phosphodiesterase sub-subscription drug. For erectile dysfunction patients who cannot tolerate tadalafil due to type selectivity, administer once daily. It can be used as a given. Gu Kang et al., Ther.Adv.Urol., 5(2):101-110(2013). Once-daily administration of udenafil is used to treat erectile dysfunction (ED). The treatment was evaluated, and the results were for 50 mg or 75 mg once daily at 12 The study showed that udenafil significantly improved erectile function in ED patients when administered for a week. hao et al.,Eur.J.of Urology,60:380-387(2 011). These reports suggest that udenafil is effective as once-daily treatment for various conditions. While suggesting that it may be useful, other reports indicate that PDE5 inhibitors are associated with Fontan surgery. This demonstrates various effectiveness in treating the symptoms. Sabri et al., Ped iatr.Cardiol.,35(4):699-704(2014).

[0108] Therefore, Fonta, which includes administering udenafil or a pharmaceutically acceptable salt thereof, This book covers methods for treating, minimizing, and / or preventing symptoms associated with surgery. It is surprising that the invention shows desirable results with preferably once or twice-daily administration. The "desired outcomes" included improved cardiac output, reduced pulmonary vascular resistance, and improved exercise tolerance. Improvement of the patient's condition, improvement of myocardial performance, prevention and improvement of the decline in aerobic exercise capacity, and / or the patient's condition Improvements in compliance are one example, but they are not limited to these.

[0109] In one embodiment of the present invention, a therapeutically effective dose of udenafil or a pharmaceutically acceptable dose thereof is used. A once-daily dose of this salt delivers therapeutic levels of udenafil, increasing the patient's bloodstream to approximately 8 hours. It exists in between. In other embodiments of the present invention, a therapeutically effective dose of udenafil or its pharmaceutically effective A once-daily dose of an acceptable salt is approximately 10, 11, 12, 13, 14, or 14 times the normal dose. 15, approximately 16, approximately 17, approximately 18, approximately 19, approximately 20, approximately 21, approximately 22, approximately 23, or approximately 24 Over time, this brings about a therapeutic level present in the patient's bloodstream.

[0110] In one embodiment of the present invention, a therapeutically effective dose of udenafil or a pharmaceutically acceptable dose thereof is used. The twice-daily administration of active salts ensures that at least approximately 16 hours of the 24-hour administration period are at a therapeutic level. This provides udenafil. In other embodiments, a therapeutically effective dose of udenafil or so The pharmacoagulably acceptable twice-daily administration of the salt should be at least approximately 9 hours within a 24-hour administration period. Approximately 10 hours, approximately 11 hours, approximately 12 hours, approximately 13 hours, approximately 14 hours, approximately 15 hours, approximately 16 hours Time: approximately 17 hours, approximately 18 hours, approximately 19 hours, approximately 20 hours, approximately 21 hours, approximately 22 hours, approximately It delivers therapeutic levels of udenafil for 23 hours, or approximately 24 hours.

[0111] In another embodiment, the method of the present invention involves a non-Udenafil such as sildenafil or tadalafil. It is surprising that it shows improved results compared to prior art treatments using fil-PDE5 inhibitors. It should have been done. In yet another embodiment, the method of the present invention involves sildenafil or ta Compared to prior technologies using non-udenafil PDE5 inhibitors such as darafil, The absence of side effects and / or mild side effects was surprising.

[0112] In one embodiment, administration of udenafil or a pharmaceutically acceptable salt thereof twice daily is Compared to once-daily administration of udenafil or a pharmacoagulably acceptable salt thereof, it has fewer side effects. It is surprising that this causes. In another embodiment, Udenafi administered twice daily Lu or a pharmaceutically acceptable salt thereof is therapeutically effective at a total daily dose less than once daily. It is remarkable that such a level of Udenafil can be achieved.

[0113] In one embodiment, the patient undergoing the Fontan procedure is a human patient. In this embodiment, the patient is an adult human patient aged 18 years or older. In another embodiment, the patient is aged In one embodiment, the patient is a child aged approximately 2 to 18 years. The patient is either 18 years old or a child aged approximately 12 to 16 years. IV. Pediatric patients

[0114] Since pediatric physiology is not simply a scaled-down version of adult physiology, treating pediatric patients presents unique challenges. Body size is just one of many differences. Children's body surface area, the maturity and function of organs and systems, Furthermore, cognitive and emotional development, as a result, the response to illness, diagnosis, treatment, and medication. Differences can occur. Due to the unique biological structure and physiology of children, differences seen in adults may occur. Diseases that are commonly treated can even manifest differently in children. Moreover, pediatric patients Because they process medication differently than adults, the effects and dosage of the medication should be observed in humans. There can be a lot of variation. Children differ from adults in many ways besides their body size. Merely adjusting the dosage of a drug for a person with a small build does not necessarily produce the same reaction and may even cause drug adverse reactions. Therefore, the efficacy of a drug used to treat adult conditions does not predict the success of treating pediatric patients with the same drug.

[0115] Therefore, the present invention also targets the surprising discovery that pediatric Fontan patients can be successfully treated by the method of the present invention. The method includes administering a therapeutically effective amount of a PDE5 inhibitor to a pediatric patient where the PDE5 inhibitor is udenafil or a pharmaceutically acceptable salt thereof.

[0116] The structure of udenafil is shown below.

[0117]

Chemical formula

[0118] In one embodiment, udenafil or a pharmaceutically acceptable salt thereof is administered at a total daily dosage of about 0.01 to about 150 mg / kg. In another embodiment, udenafil or a pharmaceutically acceptable salt thereof is administered at a total daily dosage of about 0.01 mg / kg up to about 30 mg / kg In another embodiment, udenafil or a pharmaceutically acceptable salt thereof is administered at a total daily dosage of about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 27.5 mg, about 3 0 mg, about 32.5, about 35 mg, about 37.5 mg, about 40 mg, about 42.5 mg, about 4 5 mg, about 47.5 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 87.5 mg, about 90 mg, about 95 mg ​​​, about 100mg, about 125mg, about 150mg, about 175mg, about 200mg, about 225 It is administered in a total daily dose of mg, approximately 250 mg, or approximately 275 mg. In one embodiment Udenafil or its pharmaceutically acceptable salts are approximately 25 mg, approximately 37.5 mg, and approximately 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 Approximately 375mg, 400mg, 425mg, 450mg, 475mg, 500mg mg, about 525mg, about 550mg, about 575mg, about 600mg, about 625mg, about 6 It is administered in a total daily dose of 50 mg, approximately 675 mg, or approximately 700 mg. In terms of administration, udenafil or its pharmaceutically acceptable salt is administered in approximately 37.5 mg, approximately 75 mg. It is administered in a total daily dose of approximately 87.5 mg, 125 mg, or 175 mg.

[0119] In one embodiment, udenafil or a pharmaceutically acceptable salt thereof is administered once daily. ru.

[0120] In another embodiment, udenafil or a pharmaceutically acceptable salt thereof is administered twice daily. In one embodiment, udenafil or a pharmaceutically acceptable salt thereof is administered twice daily. Therapeutically effective blood levels were at least approximately 18, 19, and 20 hours during the 24-hour administration period. It is maintained for approximately 21, 22, 23, or 24 hours. In some embodiments, 2 hours per day The total daily dose of udenafil or a pharmacoagulable salt administered once daily is equal to the total daily dose of udenafil administered once daily. Less than the total daily dose of udenafil or a pharmacoagulably acceptable salt. Several implementations In this state, the total daily dosage of udenafil or a pharmaceutically acceptable salt administered twice a day is such that within 24 hours, when udenafil or a pharmaceutically acceptable salt thereof is administered once a day it maintains a therapeutically effective blood level for the same amount of time as a higher dosage. In other embodiments the total daily dosage of udenafil or a pharmaceutically acceptable salt administered twice a day is 24 hours and maintains a therapeutically effective blood level for a longer time compared to the same dosage when udenafil or a pharmaceutically acceptable salt thereof is administered once a day.

[0121] In some embodiments, udenafil or a pharmaceutically acceptable salt thereof administered twice a day produces a greater reduction in conditions, symptoms, or side effects associated with subjects who have previously undergone a Fontan procedure compared to udenafil or a pharmaceutically acceptable salt thereof administered once a day.

[0122] In some embodiments, the pharmaceutically acceptable salt of udenafil is an acid addition salt. In one embodiment, the acid addition salt of udenafil is an inorganic acid addition salt such as a hydrochloride addition salt, hydrobromide addition salt, sulfate addition salt, or phosphate addition salt. In another embodiment, the acid addition salt is an organic acid addition salt such as citrate, tartrate, acetate, lactate, maleate, fumarate, gluconate, methanesulfonate (mesylate), glycolate, succinate, p-toluenesulfonate (tosylate), galacturonate, embonate, glutamate, aspartate , oxalate, benzenesulfonate, camphorsulfonate, cinnamate, adipate , or cyclamate. In a particular embodiment, the pharmaceutically acceptable salt of udenafil is oxalate, benzenesulfonate, camphorsulfonate These are salts, cinnamates, adipines, or cyclamates.

[0123] In one embodiment, udenafil or a pharmaceutically acceptable salt thereof is used as a pharmaceutical composition. It is administered. In one embodiment, a medicine comprising udenafil or a pharmaceutically acceptable salt thereof. The drug composition can be formulated into a wide variety of oral or parenteral dosage forms for clinical use. These include various disintegrants, surfactants, fillers, thickeners, binders, wetting agents, and other diluents, It may contain other pharmacologically acceptable excipients.

[0124] Udenafil composition can be administered intranasally, orally, sublingually, orally, rectally, ophthalmally, orally (intravenously, orally). (Internal, intramuscular, subcutaneous, intracisional, intraperitoneal), lung, vaginal, local administration (locally administered) (nistered), topically administered, It can be administered via tampe-type topical application, mucosal administration, aerosol, or buccal or nasal spray. It can be administered by any pharmacologically acceptable method, such as via a formulation.

[0125] Furthermore, udenafil compositions are available in solid dosage forms, tablets, pills, lozenges, capsules, and liquid forms. Liquid dispersion, gel, aerosol, pulmonary aerosol, nasal air Any pharmacologically acceptable form, such as rosol, ointment, cream, semi-solid dosage form, and suspension. It can be formulated into dosage forms. Furthermore, the composition can be a controlled-release formulation, a sustained-release formulation, a rapid-release formulation, or a so-called Any combination of these may be used. Furthermore, the composition may be delivered via a transdermal system. .

[0126] In another embodiment, a pharmaceutical composition comprising udenafil or a pharmaceutically acceptable salt thereof is used It can be formulated into solid dosage forms for oral administration, and the solid dosage forms are powder, granules, capsules, tablets, or pills. It is possible. In yet another embodiment, the solid dosage form is calcium carbonate, starch, sucrose It may contain one or more excipients such as sugar, lactose, microcrystalline cellulose, or gelatin. In addition, the solid dosage form contains talc or magnesium stearate, in addition to the excipient. It may contain a lubricant. In some embodiments, the oral dosage form is immediate-release or modified-release. It can be in a specific state. Modified release formulations include controlled release, sustained release, and enteric-coated release. Excipients used in modified release formulations are widely known to those skilled in the art.

[0127] In further embodiments, a pharmaceutical composition comprising udenafil or a pharmaceutically acceptable salt thereof. It can be formulated as a sublingual or buccal dosage form. Such dosage forms are administered sublingually. The present invention includes a sublingual tablet or solution composition and a buccal tablet that is placed between the cheek and gums.

[0128] In a further embodiment, a medicine comprising udenafil or a pharmaceutically acceptable salt thereof The drug composition can be formulated as a nasal administration dosage form. Such dosage forms of the present invention are for nasal delivery. The present invention includes solutions, suspensions, and gel compositions.

[0129] In one embodiment, the pharmaceutical composition is an oral suspension, emulsion, or syrup. It can be formulated into a liquid dosage form for administration. In other embodiments, the liquid dosage form is widely used. In addition to water and simple diluents such as liquid paraffin, humectants, sweeteners, flavorings, or preservatives are also used. It may contain various excipients such as udenafil or so Compositions containing pharmaceutically acceptable salts of can be formulated 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, Alternatively, it can be formulated into parenteral administration systems such as suppositories. In other embodiments, it can be an aqueous solution or a suspension. The turbid liquid contains propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and It may contain injectable esters such as ethyl oleate. As a base for suppositories, Tepzole, macrogol, Tween 61, cocoa butter, laurin oil Oil or glycerol gelatin can be used.

[0131] The dosage of the pharmaceutical composition depends on the patient's weight, age, sex, administration time and method, excretion rate, and disease. It can be changed depending on the severity of the illness. VI. Adverse events

[0132] Adverse events should be considered, especially when treating susceptible populations such as pediatric patients with Fontan physiology. This is an important consideration. PDE-5 inhibitors have adverse events including eye and / or hearing problems. This can cause PD. Therefore, udenafil or its pharmaceutically acceptable salts, etc. In one aspect of the present invention, developing a method for safely administering E5 inhibitors to pediatric patients is necessary. be.

[0133] In some embodiments, pediatric patients with Fontan physiology are administered PDE5 inhibitors. The harmful effects of Fontan physiology can be treated, minimized, and / or prevented. In this embodiment, a PDE5 inhibitor, specifically udenafil or a pharmaceutically acceptable salt thereof, is used. Administering this drug will result in minimal serious adverse events, if any. In terms of administration, PDE-5 inhibitors, specifically udenafil or a pharmaceutically acceptable salt thereof, are used. Administering the drug will result in minimal, if any, unexpected adverse events.

[0134] In some embodiments, udenafil or a pharmaceutically acceptable salt thereof is administered. Pediatric patients with Fontan physiology may only experience mild adverse events related to medication. In other embodiments, patients may experience only moderate adverse events related to the drug. In some embodiments, udenafil or a pharmaceutically acceptable salt thereof is administered. Pediatric patients with Fontan physiology are Fontan patients who are receiving another PDE5 inhibitor. Compared to other conditions, adverse events may be experienced less frequently, less often, or less severely. VII. Pharmacokinetic parameters

[0135] Pharmacokinetics refers to the absorption, distribution, metabolism, and excretion of a drug after it has been administered to a subject. Pharmacokinetics affect the efficacy and toxicity of a drug. Given the pharmacokinetic profile, This includes not only the composition itself, but also the dosage and method of administration, and how the drug is formulated and administered. It may depend on the amount. Pharmacokinetic parameters that may be useful in determining clinical utility The meters include plasma concentration, plasma concentration over time, and peak plasma concentration (C). max ), the best Time to reach concentration (T max ), area under the concentration-time curve within the dosing interval (AUCτ), steady state Area under the daily concentration-time curve (AUC) 0-24 );CL / F, apparent clearance; Examples include V / F (apparent volume of distribution), ke (disappearance rate constant), and T1 / 2 (terminal phase half-life). However, it is not limited to these.

[0136] In some embodiments, the invention of the present disclosure is directed to a method of administering udenafil or a pharmaceutically acceptable salt thereof to a patient with Fontan physiology, and the administration results in a distinct pharmacokinetic profile. For example, in some embodiments, the method of the present disclosure can produce a plasma concentration of udenafil in the range of about 10 to about 7 00 ng / ml, about 50 to about 650 ng / ml, about 100 to about 600 ng / ml, about 15 0 to about 550 ng / ml, or about 200 to about 500 ng / ml. In other words, the dosing regimen of the method of the present disclosure can result in a sustained plasma concentration of udenafil that exceeds 25, 50, 75, 100, 125, 150, 175, 200, 225, 250, 275, 30 0, 325, 350, 375, 400, 425, 450, 475, 500, 525, 55 0, 575, 600, 625, 650, 675, or 700 ng / ml. In some embodiments, the plasma concentration is maintained above about 140 ng / ml. In some embodiments, the method of the present disclosure includes a characteristic pharmacokinetic profile in which C is about 25, about 50, about 75, about 1 00, about 125, about 150, about 175, about 200, about 225, about 250, about 275, about 3

[0137] 00, about 325, about 350, about 375, about 400, about 425, about 450, about 475, about 5 max 00, about 525, about 550, about 575, about 600, about 625, about 650, about 675, or about 700 ng / ml. In some embodiments C is about 506. In some embodiments, the method of the present disclosure includes a characteristic pharmacokinetic profile in which T is about 0.1, 0.2, 0.3, 0 max In some embodiments

[0138] In some embodiments, the method of the present disclosure includes a characteristic pharmacokinetic profile in which T max is about 0.1, 0.2, 0.3, 0 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1 0.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2 Characteristics of being 0.4, 2.5, 2.6, 2.7, 2.8, 2.9, or 3.0 hours (hours). Includes a typical pharmacokinetic profile. In some embodiments, T max It takes about 1.3 hours. ru.

[0139] In some embodiments, the method disclosed herein is such that the area under the concentration curve (AUC) is such that the Fontan patient Includes a characteristic pharmacokinetic profile specific to udenafil at therapeutically effective doses in this context. Hmm. For example, AUCτ is 750-4500 ng·hours / ml, 800-4000 ng·hours / It is ml, or 850-3500 ng·hours / ml. More specifically, AUCτ is approximately 75 0, approximately 800, approximately 850, approximately 900, approximately 950, approximately 1000, approximately 1050, approximately 1100, Approximately 1150, approximately 1200, approximately 1250, approximately 1300, approximately 1400, approximately 1500, approximately 160 0, approximately 1700, approximately 1800, approximately 1900, approximately 2000, approximately 2100, approximately 2200, approximately 2 300, approximately 2400, approximately 2500, approximately 2600, approximately 2700, approximately 2800, approximately 2900, Approximately 3000, approximately 3100, approximately 3200, approximately 3300, approximately 3400, approximately 3500, approximately 360 0, approximately 3700, approximately 3800, approximately 3900, approximately 4000, approximately 4100, approximately 4200, approximately 4 The values ​​are 300, approximately 4400, or approximately 4500 ng·h / ml. In some embodiments, A UCτ is approximately 3350.

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

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

[0142] Where used herein, the term “about” will be understood by those skilled in the art, and It will vary to some extent depending on the context in which it is used. If it is not clear to a person skilled in the art considering the context in which it is being used, then "about" is the maximum of the specific term plus This would mean a decrease of 10%.

[0143] "Treatment" targets a disease state and fights against it, that is, it improves or prevents the disease state. This is intended to be the case. Therefore, specific treatments are based on the current state of the target disease state, medical therapies and treatment methods. The outcome will depend on the future condition. Treatment may involve associated toxicity.

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

[0145] The term "therapeutic effective dose" refers to the symptoms, progression, and other factors observed in patients who have undergone the Fontan procedure. The present invention provides a suitable composition and dosage form for treating or preventing the onset of complications. This refers to a sufficient amount of medication. The therapeutically effective dose depends on the patient's condition or its severity, and the treatment being administered. The effective therapeutic dose will vary depending on the elephant's age, weight, etc. For example, the route of administration and the subject's test results will also be considered. It depends on one of many factors, including the condition of the person, as well as other factors that would be understood by those skilled in the art. It can be changed.

[0146] The terms "treatment" or "the act of treating" generally refer to the natural history of the subject receiving treatment. This refers to interventions aimed at changing something, and can be carried out for preventative purposes or in the course of clinicopathology. The desired effects include preventing the onset or recurrence of the disease, and alleviating symptoms. To suppress, reduce, or inhibit any direct or indirect pathological outcome of a disease; pathological state This includes improving or alleviating the condition, and causing remission or an improvement in prognosis. These are not the only options.

[0147] The terms “individual,” “host,” “subject,” and “patient” are used interchangeably in this specification. It is used.

[0148] As used herein, “improving cardiac output” means the amount of cardiac output that is pumped out by the heart. This means an increase in the volume of blood being pumped. Cardiac output is measured as a function of oxygen consumption.

[0149] As used herein, the term “exercise tolerance” refers to the maximum amount of exertion a patient can sustain. It refers to a high value. Exercise tolerance is measured using many different clinical techniques, including interviews or direct measurements. This can be measured. The method of the present invention is not limited to riding a bicycle ergometer or This includes various methods for measuring exercise tolerance, including walking on a treadmill. Therefore, the term "improving exercise tolerance" applies to any level of exertion or exercise. This means that patients who perform physical activity will see an improvement in their abilities.

[0150] As used herein, the term "reducing pulmonary vascular resistance" means reducing the pulmonary vascular system This refers to reducing or decreasing the resistance provided to blood flow.

[0151] As used herein, “improving myocardial performance” is, depending on the context, limited to: However, it does not include specific electrocardiogram reading, echocardiogram reading, cardiac output measurement, heart rate, and Specific cardiac function measurements including systolic or diastolic blood pressure, forced vital capacity, oxygen saturation, and respiratory rate. This refers to an increase or decrease in the result.

[0152] As used herein, “aerobic exercise capacity” refers to the patient’s ability to perform specific aerobic exercises. It refers to ability.

[0153] As used herein, “child” refers to subjects ranging in age from newborns to approximately 18 years of age. This refers to a group of people. Child subjects are considered to be in a group even if they continue treatment after the age of approximately 18. If a person begins a series of treatments using the compositions of this disclosure or in accordance with the methods of this disclosure before reaching approximately 18 years of age This can include subjects who are 1 week old. More specifically, within the group of "child" subjects, newborns are those who are 1 week old. Infants are defined as children from weeks to one month old, toddlers as children from one year old to under two years old, and toddlers as children from two years old to under six years old. This can be defined as "fully grown." "Children" may refer to subjects aged 6 to 18 years.

[0154] The following examples are given to illustrate the present invention. However, the present invention is not described in these examples. It should be understood that this should not be limited to specific conditions or details. All referenced printed publications are specifically incorporated by reference. [Examples]

[0155] Example 1 - Phase I / II pharmacokinetic and pharmacodynamic studies After Fontan relaxation, udenafil in adolescents with single ventricle physiology Phase I / II dose escalation trial

[0156] The clinical trial lasted five months, with an additional three-month follow-up period for adverse events (AEs). The study was conducted over a period of time. The 36 subjects enrolled in the trial were comprised of the six cohorts listed in Table 1. It was done.

[0157] [Table 1]

[0158] The purpose of this clinical trial is to assess the safety of udenafil at a multi-dose level over a 5-day period. Pharmacokinetic profile of udenafil in adolescents with tannins, and exercise The short-term effects of udenafil on pharmacodynamic evaluation criteria for tolerance, ventricular function, and vascular function. The task was to evaluate.

[0159] Multiple doses of udenafil or a pharmacoagulable salt thereof for males aged 14-18 years. It was administered to female Fontan patients.

[0160] The inclusion criteria for this clinical trial are as follows: • Males and females aged 14-18 with Fontan physiology • Return visit to the center to perform blood collection and testing as described in the clinical trial protocol. A willingness to do so • Patients were not permitted to consume alcohol, caffeinated beverages, or grapefruit juice during the trial period. They must agree to refrain from broadcasting. • Informed assent by the subject, and, if necessary, by the parent / legal guardian. Informed consent

[0161] The following are the exclusion criteria for this examination. If the planned test is prevented from being successfully completed or the results are invalidated... Other medical disorders, mental disorders, and / or social disorders that may be suspected to be related to the heart. • Height < 132cm (minimum height requirement for exercise stress testing) • Known for causing an average difference of >4 mmHg between the proximal and distal regions of occlusion. Intracardiac tunnel occlusion, pulmonary artery branch stenosis, or pulmonary vein stenosis • Physiology of a single lung • Severe ventricular dysfunction or Valve regurgitation (atrioventricular valve or semilunar valve) • Severe kidney impairment based on clinical tests performed during screening visits (serum creatinine > 2.0) Liver impairment (serum AST and / or ALT > 3 times the upper limit of normal), oral administration Gastrointestinal or biliary tract disorders that may impair the absorption, metabolism, or excretion of the drug. • Hospitalization for acute decompensated heart failure within 12 months prior to the trial screening. • Diagnosis of active protein-losing enteropathy or cast bronchitis • Active evaluation or list for heart transplantation It is listed in • History of PDE5 inhibitor use within 3 months of trial screening • The principal investigator's opinion is that pre-existing conditions would prevent participation. • Current treatment with alpha-blockers or nitrates • Pregnant at the time of registration • Latex allergy

[0162] Table 2 shows the overall data (second column) for the 36 enrolled subjects and for each of the six individual cohorts. Baseline characteristics are shown. The median age of registered subjects was 16 years (ranging from 14 to 18 years). The group consisted of 58% male, 78% white, and 6% Hispanic. The baseline data was collected between cohorts. 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 composition administered in the test described in Example 1. The task was to include and evaluate the information.

[0165] Tables 3-6 show the number of subjects who reported at least one adverse event (AE). Data are available for each treatment group. The counts are shown for each AE category (Table 3) and for each basic word (Table 6). Tables 3-6 show all AEs (Table 3), serious AEs (Table 4), and non- Report all serious AEs (Table 5) and all AEs for each basic word (Table 6). Report serious AEs. It wasn't done.

[0166] [Table 3]

[0167] [Table 4]

[0168] [Table 5]

[0169] [Table 6]

[0170] Table 7 shows all adverse events categorized by cohort, subject, AE term, and basic term. This describes the narrative format (limited to non-serious cases 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 data for subjects where the number of AEs in each treatment group is ≥n, where n=1, 2, ..., 6. To indicate a number. [Table 8]

[0176] Tables 9-12 show AEs for each basic word (same as Table 6), but also show the number of subjects with AEs. The number of AEs (Table 9), by treatment group and related to the study drug (possibly related or likely related). (Including related) vs. unrelated (Table 10), mild vs. moderate / severe (Table 11), and expected Report the number of AE events per subject, grouped into expected AEs and unexpected AEs (Table 12). do. [Table 9] [Table 10] [Table 11] [Table 12]

[0177] Table 13 shows that at least one cohort experienced more than one AE (1 patient). Regarding the test subject, ≥2 AEs or ≥2 subjects for at least 1 AE) Basic term We will focus on a limited subset of Table 7. [Table 13]

[0178] Figure 1 shows at least one, three, or five (numbers taken from Table 6) for each treatment group. This shows the percentage of subjects who reported adverse events. The horizontal axis represents the cohort, with the minimum daily dose on the left. (Exercise-only group; dose zero, not placebo) to the right: maximum single dose (125mg) It is classified as g). The percentage fluctuates between 100% and 0% (exercise-only group). As expected. The exercise-only group is characterized by the lowest percentage. The plot reports dose and adverse events. The results do not suggest any clear correlation between the percentages of subjects.

[0179] Example 3 - Exercise Stress Test The purpose of this example is to treat the treatment described in Example 1 using various exercise stress test parameters. The objective was to evaluate the effectiveness of the protocol.

[0180] The primary outcome for this treatment group in this study was maximal VO2 as determined by exercise stress testing. Yes. Table 14 shows the key outcomes of the exercise stress test for each treatment group - peak VO2 (most This summarizes the results (limited to subjects who achieved great effort). The results are based on the 36 subjects enrolled in the clinical trial. Of the participants, 33 reached maximum effort in the exercise stress test at each time point, and 31 subjects reached both maximum effort and maximum effort. This was reached at that point in time. The first two lines show baseline and follow-up measurement data. On the other hand, the third line shows the difference between the two measurement results (change score, the outcome for this treatment group). Analysis of variance suggests no significant difference between the change scores (p=0.85). [Table 14]

[0181] Figures 2 and 3 visually show the change score results (positive change indicates improvement). Figure 2 shows pairs. The individual change scores for each subject with a measurement (circle) are shown, and the two lines represent the mean and median. The plot does not suggest that the change score increases with dose. Figure 3 shows the results for each subject and 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 a correlation coefficient of >0.8. .

[0183] Further outcomes, including VO2 at the anaerobic threshold, were also measured. A similar analysis was performed on the following. The results are shown in Table 15 and Figures 4 and 5. The overall result is maximum It is similar to VO2. [Table 15]

[0184] Notably, both exercise outcomes (peak VO2 and anaerobic threshold) O2) showed a strong correlation (correlation coefficient exceeding 0.7 for each visit), similar to the trend lines in Figures 2 and 4. This could explain the similarity.

[0185] Example 4 - Vascular function test The primary outcome of vascular function is measured using the EndoPAT® device (Itamer Medica). Endothelial pulse amplitude tonometry (PA) determined by (Lu Co., Ltd., Caesarea, Israel) The decision was made according to the T) indicator.

[0186] Table 16 shows the natural logarithm (ln) of the reactive hyperemia index, a crucial outcome of vascular function testing. Results regarding RHI (Reduced Risk Intake) will be summarized for each treatment group. The study included 30 subjects enrolled in the clinical trial's treatment groups. Of these, 27 subjects had acceptable quality pairs (QC score equal to 3 (best) or 2). Measurements were taken. The table structure is the same as that of the motion variables. [Table 16]

[0187] Figures 6 and 7 visually show the change score results (positive change indicates improvement). Figure 6 shows pairs The individual change scores for each subject with a measurement (circle) are shown, and the two lines represent the mean and median. The plot does not suggest that the change score increases with dose. Figure 7 shows the results for each subject and The lnRHI values ​​before and after treatment for each cohort are shown.

[0188] Baseline and follow-up measurements showed moderate correlation, with an overall correlation coefficient of 0.4.

[0189] Notably, both the mean baseline and follow-up measurements were normal (lnRH). As a threshold between values ​​of I > 0.51 and abnormal values ​​(lnRHI ≤ 0.51) The data solution is close to 0.51, which is the cutoff value proposed by the EndoPAT literature. The analysis shows that some patients showed improvement of as much as 9.75% according to these evaluation criteria.

[0190] Table 17 shows secondary EndoPAT outcomes (RHI, Framingham RHI, etc.; see panel above) Change scores will only be reported for (L) and other EndoPAT metrics. Positive changes suggest the possibility of improvement. [Table 17]

[0191] Example 5 - Echocardiographic evaluation of ventricular function The primary outcome of ventricular function was evaluated using echocardiography, and the myocardial performance index (MP) was determined. I) was measured according to the following. MPI is the ventricular function of the systolic and diastolic combined, ventricular shape It is an evaluation criterion that is independent of the state (Charles S. Kleinman et al, (2008 - Health and Fitness). MPI is equivalent to ejection time. This is obtained by using the sum of the systolic and diastolic phases as an indicator.

[0192] Table 18 shows the crucial outcome of echocardiographic assessment of ventricular function—related to blood pool MPI. The results are summarized below. Of the 30 subjects enrolled in the clinical trial's treatment group, 27 subjects received a positive result. Measurements were taken. The table structure is the same as that of the motion variables. Data analysis was performed using this evaluation criterion. The study 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 change indicates improvement). Figure 8 shows pairs The individual change scores for each subject with a measurement (circle) are shown, and the two lines represent the mean and median. The plot does not suggest that the change score increases with dose. Figure 9 shows the results for each subject and The blood pool MPI index values ​​before and after treatment for each cohort are shown.

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

[0195] Tables 19-21 and Figures 9-15 show three other versions of MPI: Tissue Doppler MP I, as well as similar results regarding mean isovoluted contraction and relaxation, are reported. [Table 19] [Table 20] [Table 21]

[0196] For these three further versions of MPI, negative changes are still possible. It suggests a sex, and the overall conclusion is the same as that of the blood pool MPI.

[0197] In addition, positive outcomes were observed during the short-term trials described in Examples 1-5. Therefore, administer udenafil or a pharmacoagulably acceptable salt thereof to Fontan patients for a longer period of time. This could lead to even more beneficial pharmacodynamic outcomes.

[0198] Example 6 - Pharmacokinetic Study NONMEM version 7.2, R, PDxPOP(registered trademark) 5, Xpose, and Phoenix WinNonlin was used for pharmacokinetic analysis.

[0199] Pharmacokinetic analysis was performed on Fontan patients who received udenafil. Figure 16 shows the drug administration. Figure 17 shows the results of data assessment for individual subjects in each cohort, and the subjects' arm size The Nafil concentration profile is shown. Plasma concentrations were measured at various time points in the patient. Non-compartmental analysis was performed to stratify the data by administration method.

[0200] Figures 18-20 show various comparisons between medication cohorts. Non-compartmental analysis is used. Based on this, the 87.5 mg dose was compared to the 37.5 mg dose every 12 hours or every 24 hours cohort. In the 12-hour interval cohort and the 125 mg 24-hour interval cohort, C max The number increased significantly. (Figure 18).

[0201] The 87.5mg every 12-hour cohort showed a higher C5% compared to the corresponding cohort receiving the dose every 24 hours. max This showed an increase (Figure 18). Compared to the 37.5 mg every 12 hours or every 24 hours cohort. In the 87.5 mg every 12 hours cohort and the 125 mg every 24 hours cohort, AUCτ The number of cases increased significantly (Figure 19). 125 mg compared to 37.5 mg every 24 hours cohort. In the 24-hour cohort, AUC 0-24 The number of cases increased significantly. 87.5 mg every 12 hours The cohort had the highest AUC among all drug delivery methods tested. 0-24 This showed an increase (Figure 1) 9) Except for a significant difference between 37.5 mg every 24 hours and 87.5 mg every 12 hours, the administration No significant difference was observed in CL / F or V / F between the methods (Figure 20). Five trials Among the experimental administration methods, k e , T1 / 2, also T max There was no statistically significant difference.

[0202] Development of population pharmacokinetic models

[0203] Population pharmacokinetic analysis was performed using a nonlinear mixed-effects model analysis method. This method involves parameters Estimate the representative values ​​of the subjects and their variances. It is assumed that the subjects are in a steady state (SS). The dose (D) was given at intervals τ, and after repeated administrations of dose D, time tD was given. Time (t) (t≧t) DPK samples / udenafil concentrations were collected on day 6 of the experiment.

[0204] Since only the drug administration on day 6 is provided, subjects are required to take the medication at home at regular intervals. It is expected that this will occur, and consequently, the steady-state flag will not be tested for the available dosage. This will explain the following. As mentioned above, the steady state of udenafil is 5 during multiple doses. It is reached in days, and further accumulation appears to be almost nonexistent after 7 days of administration, as previously reported. As described in the study, we assume that a steady state is reached by day 6. PK sample If a dose was missed during the trial period prior to sampling, this will affect the steady state pharmacokinetic profile. Conversely, this may affect the ability to determine whether or not it is conceivable. PK samples are collected. If two or more additional days and times of drug administration were available prior to the visit, A favorable medication profile would likely have been used for the analysis.

[0205] Structural model

[0206] We investigated 1- and 2-compartment models (based on literature and available data). The equation for the drug's 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 determined by bootstrap resampling (n=1000) P Evaluated with DxPOP(registered trademark) 5. Bootstrap (all actual minimizations that were successful) The values ​​obtained using row-based bases were compared with the parameter estimates from the final model. To evaluate the accuracy of the model predictions, we performed normalized predictive distribution error (NPDE).

[0211] We used certain a priori information to guide the development of the model.

[0212] One- and two-compartment models, including oral absorption input, were obtained from the above literature. We evaluated the model using initial estimates and investigated in detail to determine the possible structure of the model. Using functional values, statistical significance levels, goodness-of-fit plots, and standard errors during the model building process The model was evaluated.

[0213] The only covariate available for the analysis was current body weight. Body weight was used for clearance and distribution volume. Tested as a fixed effect on representative values ​​(for example, weight is a "fixed" effect on clearance). (There is an "effect"). The median weight in the dataset was 65.3 kg.

[0214] The "typical value" for clearance is calculated using weight (WT) in the dataset for a 70kg patient. As predicted, estimated THETA(1) and THETA(2) for subjects with known WT were: The CL and V values ​​can be directly compared to those of a "standard" weight, for example, a subject with WTs = 70 kg.

[0215] A concern sometimes expressed is that, in terms of the adult size standard of 70 kg, the estimated size in children is... The scale parameter values ​​used may have biased the estimates or affected the accuracy of the estimates. This could happen. This concern is unfounded. This can be reorganized, and Relative growth scale is simply a constant determined by any weight chosen for standardization. This can be seen in the examination of the covariate model. The accuracy of the parameter estimates is Multiplying the meter value by a limiting (ad hoc) constant will ensure it remains unchanged. The criterion for selecting the covariate equation for the model's weights was statistical significance.

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

[0217] During the model building process, we evaluated many residual error models, including proportional error models and exponential error models. The models could not be run, and they terminated each time. The additional error model could be run, but the GOF model... The lot does not fit well for the 1-compartment model, but not for the 2-compartment model. The mixed model showed a better fit. Despite the high CV% of residual variability, The combined error model gives good estimates of other parameters at 95% CI, and the GOF plot Since it showed a good fit in visual inspection, The choice was made to use this model as the base model (Figures 30-31). (Pitches on days 1-5) All doses were taken from each subject, both before administration on day 6 when samples were collected and before and after sample collection. If it was included in the dataset, it may be possible to control the high CV%. Although this is unnecessary because the model fit is good, this further reduces the %CV. Seu.

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

[0219] We worked on bootstrap resampling and estimated the parameters of the final model by 10 This was compared to what was determined after performing the bootstrap for 00. In addition, visual aspects Post-predictive performance evaluation (visual predictive check) (95% prediction interval) (A plot comparing this with actual measured data) and the normalized predictive distribution error (NPDE) method are used for the final model. The evaluation was applied. Furthermore, a visual post-event prediction performance evaluation was conducted.

[0220] The pharmacokinetics of udenafil are measured using a two-compartment model that includes mixed addition and proportional errors. Therefore, it was well explained. The apparent clearance (CL / F) is standard for an adult weight of 70 kg. The scale was evaluated using the actual body weight. The respiratory rate constant was 0.28°-1 (95% CI 0.0). 16~0.39), apparent clearance (CL / F / 70kg) is 36L / h (95%) (CI 28.5~43.1), median volume of distribution (V2 / F) is 74 L (95% CI 36 (0.2~112), Compartment clearance (Q / F) is 21.1L (95% CI) 10.4~31.8), and peripheral distribution volume (V3 / F) was 181 L (95% CI 14 It was estimated to be 1-221). The final model used bootstrap resampling and normalization. The measurement distribution error and visual post-hoc prediction performance were evaluated using these methods. We demonstrated that the random model fits the data well.

[0221] A two-compartment model including the absorption rate constant describes single ventricle physiology after Fontan relaxation. This paper successfully describes the pharmacokinetics of udenafil in adolescents. (Subject weight) The final model, CL / FL / Hour / 70kg, was standardized to an adult weight of 70kg. This had a statistically significant effect on the apparent clearance (CL / F).

[0222] Example 7 - Phase III trial of udenafil in Fontan patients Phase III trials of udenafil in Fontan patients showed relief from Fontan surgery. Udenafil (87.5 mg, 1) in a group of young people with single ventricle congenital heart disease This will determine the safety of (twice a day). Furthermore, this study will last at least 6 months to a maximum of 1 year. The pharmacodynamic profile of udenafil will be evaluated over a period of time within this range. The academic outcomes include exercise tolerance, echocardiographic results of ventricular function, endothelial function, and serum biometrics. This will include omarkers, as well as measurement results for functional health status / quality of life. Udenafil (87.5 mg, twice daily) is safe and improves exercise tolerance and cardiovascular health. This may be effective in improving other evaluation items of the state, as well as improving the quality of life. It is expected.

[0223] Clinical trial method - 300 children aged 12-19 who underwent Fontan surgery before the age of 5. A randomized, double-blind study was conducted in subjects receiving 87.5 mg twice daily for 6 months to 1 year of treatment. Test, placebo-controlled clinical trial

[0224] The following are the criteria for inclusion in this study. • Male or female between the ages of 12 and 19 • Fontan surgery performed before the age of 5

[0225] The following are the exclusion criteria for this examination. • Height < 132cm • Hospitalization for acute decompensated heart failure within the last 12 months • Current intravenous inotropic drugs • Being evaluated for or on a list for a heart transplant • Diagnosis of protein-losing enteropathy, cast bronchitis, and cirrhosis of the liver • The area proximal and distal to the occlusion, as measured by catheter insertion or echocardiography. Known Fontan intracardiac tunnel occlusion and pulmonary artery occlusion result in an average difference of >4 mmHg between these two conditions. Branch stenosis, or pulmonary vein stenosis • Physiology of a single lung • Significant ventricular function qualitatively assessed by clinical echocardiography within 6 months prior to registration. Insufficiency • Severe valvular regurgitation or ventricular flow evaluated by clinical echocardiography within 6 months prior to registration. Outlet stenosis, or aortic arch occlusion • Severe renal impairment, hepatic impairment, or gastrointestinal impairment that may impair the absorption, metabolism, or excretion of orally administered drugs. Bile duct disorders or bile duct disorders • Unable to complete the exercise stress test at baseline screening. • History of PDE5 inhibitor use within 3 months prior to the start of the trial • Use of other medications to treat pulmonary hypertension within 3 months prior to the start of the trial. • Known intolerances to oral udenafil • Frequent use of drugs or other substances that inhibit or induce CYP3A4 • Current use of alpha-blockers or nitrates If the planned test is prevented from being successfully completed or the results are invalidated... Currently participating in or planning another research protocol. If the planned test is prevented from being successfully completed or the results are invalidated... Other medical disorders, mental disorders, and / or social disorders that may be suspected to be related to the heart. • Ongoing or planned cardiac disease studies conducted outside of the clinical trial center that are likely to hinder the completion of the trial. treatment • Regarding women: If pregnant at the time of screening, or planning to become pregnant before the completion of the test. Refusing to use an acceptable method of contraception during or after the trial period. • During this clinical trial, you may not refrain from or limit your intake of grapefruit juice. stomach • Refusal to provide written informed consent / ascent According to the opinion of the primary care physician: The subjects are likely to have low compliance with the clinical trial protocol.

[0226] The study will assess the baseline measurement and quality of the proposed pharmacodynamic (PD) endpoints. This will include a life survey. For example, EndoPAT vascular assessment will be conducted with consent. Next, this will be performed as the first PD test. This involves fasting (from midnight until after the test). The procedure must be performed in a caffeine-free state. After vascular assessment, the subject will undergo target cardiac examination. A co-graph will be used to assess ventricular function. A short rest will be taken after the vascular assessment or echocardiogram. This will be provided. Light refreshments will be offered. Vascular evaluation, echocardiogram, and rest After the break, safety labs will be conducted. Regarding the participants, serum creatinine and liver enzymes (aspartate aminotransferase and ara) Blood samples were taken to assess ninaminotransferase levels, and urine samples were taken from female participants to assess pregnancy test results. Tests will be included. If the pregnancy test is positive, all subsequent tests will be stopped. This means the patient will not be enrolled in the clinical trial. The results will be processed according to the procedures of the local IRB. This information will then be communicated to the subject and / or their legal guardian by the principal investigator at the clinical trial site. After safety checks, an exercise stress test was performed, as previously published in the PHN Fontan cross-sectional study. Successfully performed using a brake-type bicycle ergometer according to a linear incremental load protocol. This will result in the subject completing the baseline test after the exercise stress test. In addition, The Peds QL, cardiac-specific Peds QL, and PCQLI are based on The procedure will be performed during your Sline trial visit.

[0227] The clinical trial coordinator will call each subject weekly for four weeks, and then monthly, to report any adverse events. Collect information and answer questions related to the exam.

[0228] At the end of the trial, subjects came to the clinic fasting and caffeine-free, and first, baseline Undergo a vascular function assessment, including repeating the in-test and quality of life survey. Follow-up surveys with subjects were conducted 30 and 90 days after the end of the trial, and the clinical trial implementation plan was implemented. Any event that may occur within 90 days after the completion of the artwork, possibly related to the test drug or the test drug Any further adverse events possibly related to the product may be recorded.

[0229] Udenafil over a period of 6-12 months in adolescents with Fontan physiology (87.5 mg, twice daily) is safe and well-tolerated, and is associated with severe udenafil side effects. Severe adverse events are expected to be very rare, even if they occur. The degree is defined by the Common Terminology Criteria for Adverse Events. a for Adverse Events (CTCAE) version 4.0 Med Determined in accordance with DRA 12.1 (http: / / ctep.cancer.gov) Similarly, exercise tolerance, echocardiographic results of ventricular function, endothelial function, and factors related to heart failure were also considered. The effects of udenafil on pharmacodynamic outcomes, including biomarkers, are compared to a series of treatments. Improvement is expected in between. The effectiveness of udenafil in this patient population will be assessed. The outcomes to be measured for this purpose include the following: • Exercise: Measured using a standard exercise stress test, from baseline to the end of the clinical trial. Changes in maximum oxygen uptake; • Echocardiography: Measured by pulsed Doppler echocardiography, from baseline to the end of the clinical trial. Changes in myocardial performance index up to the time of the test; • Endothelial function: Logarithmically converted reactive charge obtained from the EndoPAT(registered trademark) device Changes in blood index; and • Biomarkers: Changes in serum BNP levels from baseline to the end of the study.

[0230] In addition, • Exercise: Measurement results of the submaximal exercise tolerance will be collected and evaluated. • Echocardiography: Measurement results of systolic and diastolic function are collected from target echocardiography. Yes.

[0231] Furthermore, this study included outcomes related to ventricular chamber size, flatness, and mass; tissue dopamine. Rah's mean dP / dt and peak systolic annular velocity during isovolumetric systole (dP / dtic) ( Contractile function estimated using S'; Expanded function and MPI estimated based on tissue Doppler. Values; as well as qualitative and quantitative estimates of AV valve regurgitation, can be examined.

[0232] Furthermore, an improvement in functional health is expected after administration of udenafil. Changes in functional health from inception to the end of the study were measured on a full scale. 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 [this method].

[0233] Furthermore, the response to udenafil after Fontan surgery in people with single ventricle lesions Genetic material will be collected during this study to identify genetic determinants. Whether a particular subgroup has a stronger positive response to udenafil compared to others This will provide an indicator. For example, the response to udenafil is the response to udenafil. It can be influenced by variants involved in vascular responses. Endothelial nitric oxide synthase genetics This variant may affect the response to sildenafil in patients with erectile dysfunction. This has been reported. This has not been studied for udenafil. Vascular effects on exercise The diversity of genes that regulate inotropic and chronotropic responses is related to the exercise tolerance of patients after Fontan surgery. It can affect brain function and the response to udenafil. DNA is preserved and the response to udenafil In the future, we will conduct genotyping research to analyze the genetic involvement in these reactions.

[0234] Further covariate measures include age, sex, race / ethnicity, height / weight, ventricular morphology, and safety. These include static oxygen saturation, baseline pharmacodynamic test results, and current drug use. However, it is not limited to these. By observing these variables, various clinical conditions can be identified. This will allow us to identify the relationship between the cause and safety and PD outcomes.

[0235] Data collection includes demographic information such as age, sex, race, and ethnicity, as well as cardiac structure and phone numbers. Date of the tanning surgery, whether or not fenestration was performed, degree of atrioventricular valve regurgitation, and grade of ventricular function. This will include recording concomitant medications and serious comorbidities. Safety data will be collected by each This will be confirmed with each participant during their visit to the clinical trial facility and during their telephone consultation. These events will be recorded. The severity and the relationship with the test drug are then graded according to established standards. Two further telephone consultations will be conducted 30 and 90 days after the end of the clinical trial. , during the period after the completion of the test procedure, which may be related to or likely related to the test drug. Evaluate the adverse events that occur.

[0236] Other data collection methods include the following: • Exercise stress test - Exercise strength measurement using a brake-type cycle ergometer. The data were collected according to the protocol established by the PHN Fontan Cross-Sectional Study 3. They will be gathered together. • Assessment of ventricular function - Each test echocardiogram is stored in an anonymized format for data analysis. The measurements are then sent to the core laboratory that submits them to the PHN Data Adjustment Center (DCC). It will become that. • Vascular function tests - De-specific data from the EndoPAT® trial The data will be collected according to a standardized protocol. This data will be analyzed. The vascular core laboratory submits the measurement data to PHN DCC. It will be sent to ab). • Biomarkers - Serum for measuring BNP levels is available in the core clinical laboratory. It will be sent to the clinical lab. The results will be sent directly to PHN DCC. That will happen. • Quality of Life Survey - The results of the Quality of Life Survey are available at PH It will be submitted to N DCC. • Samples for biorepository - Samples collected for biorepository will It will be sent directly to the biorepository for further analysis.

[0237] Participants will be treated with other medications at the physician's discretion. The current medication will be tested upon arrival at the trial clinic. This will be recorded in the trial form. At any point during the trial, any other PDE5 inhibitors If any open-label use is initiated, the use of the test drug must be discontinued.

[0238] When each subject completes the trial, their attending cardiologist will be notified. The medication will be discontinued. There is no need to make the subjects stop taking the study drug. Each subject is insured. The decision of whether or not to continue off-label use of PDE5 inhibitors rests with the subject and their cardiac care provider. The decision will be made by a specialist.

[0239] Several preferred embodiments of the present invention have been described and specifically illustrated above, The present invention is not intended to be limited to such embodiments. The scope and gist of the present invention are as follows: Various modifications can be made to the embodiment without deviation. The present invention also includes the following embodiments. [1] A pharmaceutical composition comprising udenafil or a pharmaceutically acceptable salt thereof, used in a method of treating a patient with single ventricle heart disease (SVHD) to improve exercise capacity determined by improvement in the patient's VO2max and VO2 at the anaerobic threshold, wherein the SVHD patient has undergone Fontan surgery. The method involves administering an effective daily dose of udenafil or a pharmaceutically acceptable salt thereof to the SVHD patient, and the VO2 of the SVHD patient. 2 This includes treating the SVHD patient to improve exercise capacity as determined by improvement in VO2 at max and anaerobic threshold, Herein, the udenafil or a pharmaceutically acceptable salt thereof is administered in a total daily dose of approximately 175 mg in a pharmaceutical composition. [2] The pharmaceutical composition according to [1], wherein udenafil or a pharmaceutically acceptable salt thereof is formulated into a solid dosage form for oral administration. [3] The pharmaceutical composition according to [2], wherein the oral solid dosage form is a solid or semi-solid oral dosage form selected from the group consisting of tablets, capsules, gels, liquid dispersions, pills, powders, and suspensions. [4] A pharmaceutical composition for the use described in [2], wherein the oral solid dosage form is a tablet. [5] The pharmaceutical composition according to [2], wherein the oral dosage form contains about 87.5 mg of udenafil or a pharmaceutically acceptable salt thereof, and the method involves orally administering the oral dosage form to the SVHD patient twice daily. [6] The pharmaceutical composition according to [1], wherein the SVHD patient is approximately 12 to 18 years old. [7] The pharmaceutical composition according to [6], wherein the udenafil or a pharmaceutically acceptable salt thereof is formulated as an oral dosage form. [8] The pharmaceutical composition according to [7], wherein the oral dosage form is a solid or semi-solid oral dosage form selected from the group consisting of tablets, capsules, gels, liquid dispersions, pills, powders, and suspensions. [9] The pharmaceutical composition according to [7], wherein the oral administration form is a tablet.

[10] The pharmaceutical composition according to [7], wherein the oral dosage form contains about 87.5 mg of udenafil or a pharmaceutically acceptable salt thereof, and the method comprises orally administering the oral dosage form to the SVHD patient twice daily.

Claims

[Claim 1] The invention described in the present specification.

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