Methods and compositions for improving exercise performance, single ventricular performance, cardiac output and myocardial performance index (mpi) in single ventricular heart disease, using udenafil compositions

A method of treating a Fontan patient's exercise capacity, comprising:

• administering 87.5 mg of udenafil or a pharmaceutically acceptable salt thereof twice daily to the patient to increase oxygen consumption at VAT to improve the Fontan patient's exercise capacity.

A daily method of increasing venous capacitance in a patient, who has a single functioning ventricle in which the patient's systemic venous return is connected directly to the pulmonary arteries without the interposition of a second functioning ventricle, to increase oxygen consumption at ventilatory anaerobic threshold (VAT) to improve daily the patient's exercise capacity at VAT, said method comprising:

• administering to the Fontan patient daily an effective daily dose of a phosphodiesterase type 5 inhibitor (PDE5i) to increase the Fontan patient's venous capacitance to increase the Fontan patient's oxygen consumption at VAT to improve daily the Fontan patient's exercise capacity at VAT.

A daily method of inducing venous vasodilation in a patient, who has a single functioning ventricle in which the patient's systemic venous return is connected directly to the pulmonary arteries without the interposition of a second functioning ventricle, to increase the patient's venous capacitance to enable the patient to increase oxygen consumption at the patient's ventilatory anaerobic threshold (VAT) to improve daily the patient's exercise capacity at VAT, said method comprising:

• inducing daily the patient's venous vasodilation to increase the patient's venous capacitance to increase oxygen consumption by the patient at the patient's VAT to improve daily the patient's exercise capacity at VAT.

A daily method of interfering with the conversion of cyclic guanosine monophosphate (cGMP) to 5′-guanosine monophosphate (5′-GMP) in a patient, who has a single functioning ventricle in which the patient's systemic venous return is connected directly to the pulmonary arteries without the interposition of a second functioning ventricle, to induce venous vasodilation in the patient to increase the patient's venous capacitance to enable the patient to increase oxygen consumption at the patient's ventilatory anaerobic threshold (VAT) to improve daily the patient's exercise capacity at VAT, said method comprising:

• interfering daily with the conversion of cGMP to 5′-GMP in the patient to induce venous vasodilation to increase the patient's venous capacitance to increase oxygen consumption by the patient at the patient's VAT to improve daily the patient's exercise capacity at VAT.

A daily method of potentiating the nitric oxide-stimulated cyclic guanosine monophosphate (cGMP) signal in a patient, who has a single functioning ventricle in which the patient's systemic venous return is connected directly to the pulmonary arteries without the interposition of a second functioning ventricle, to induce venous vasodilation in the patient to increase the patient's venous capacitance to enable the patient to increase oxygen consumption at the patient's ventilatory anaerobic threshold (VAT) to daily improve the patient's exercise capacity at VAT, said method comprising:

• potentiating daily the cGMP signal in a patient to increase the patient's venous capacitance to increase oxygen consumption by the patient at the patient's VAT to daily improve the patient's exercise capacity at VAT.

A daily method of inhibiting cyclic guanosine monophosphate (cGMP) degradation in a patient, who has a single functioning ventricle in which the patient's systemic venous return is connected directly to the pulmonary arteries without the interposition of a second functioning ventricle, to induce venous vasodilation in the patient to increase the patient's venous capacitance to enable the patient to increase oxygen consumption at the patient's ventilatory anaerobic threshold (VAT) to daily improve the patient's exercise capacity at VAT, said method comprising:

• inhibiting daily cGMP degradation in a patient to increase the patient's venous capacitance to increase oxygen consumption by the patient at the patient's VAT to daily improve the patient's exercise capacity at VAT.

A daily method of achieving peak venous capacitance in a patient, who has a single functioning ventricle in which the patient's systemic venous return is connected directly to the pulmonary arteries without the interposition of a second functioning ventricle (Fontan patient), to enable the Fontan patient to achieve daily peak oxygen consumption at ventilatory anaerobic threshold (VAT) to further enable the Fontan patient to achieve peak exercise capacity at VAT daily, said method comprising:

• administering to the Fontan patient daily an effective daily dose of a phosphodiesterase type 5 inhibitor (PDE5i) to achieve peak venous capacitance in the Fontan patient to enable the Fontan patient to achieve peak oxygen consumption at VAT daily, so that the Fontan patient can achieve peak exercise capacity at VAT on a daily basis.

A daily method of inducing peak venous vasodilation in a patient, who has a single functioning ventricle in which the patient's systemic venous return is connected directly to the pulmonary arteries without the interposition of a second functioning ventricle (Fontan patient), to enable the Fontan patient to achieve peak venous capacitance daily to further enable the Fontan patient to achieve peak oxygen consumption at the patient's ventilatory anaerobic threshold (VAT) to enable the Fontan patient to achieve daily peak exercise capacity at VAT, said method comprising:

• inducing daily peak venous vasodilation in the Fontan patient to achieve peak venous capacitance in the Fontan patient to enable the Fontan patient to achieve daily peak oxygen consumption at the Fontan patient's VAT, so that peak exercise capacity at VAT is achieved daily by the Fontan patient.

A daily method of interfering with the conversion of cyclic guanosine monophosphate (cGMP) to guanosine 5′-monophosphate (5′-GMP) in a patient, who has a single functioning ventricle in which the patient's systemic venous return is connected directly to the pulmonary arteries without the interposition of a second functioning ventricle (Fontan patient), to induce daily peak venous vasodilation to achieve peak venous capacitance in the Fontan patient to enable the Fontan patient to achieve peak oxygen consumption at the Fontan patient's ventilatory anaerobic threshold (VAT) so that the Fontan patient can achieve daily peak exercise capacity at VAT, said method comprising:

• interfering daily with the conversion of cGMP to 5′-GMP in the Fontan patient to induce daily peak venous vasodilation to achieve daily peak venous capacitance in the Fontan patient to achieve daily peak oxygen consumption by the Fontan patient so that, whenever the Fontan patient exercises, the Fontan patient can achieve peak oxygen consumption and exercise capacity at VAT.

A daily method of potentiating the nitric oxide-stimulated cyclic guanosine monophosphate (cGMP) signal in a patient, who has a single functioning ventricle in which the patient's systemic venous return is connected directly to the pulmonary arteries without the interposition of a second functioning ventricle (Fontan patient), to induce venous vasodilation in the patient to increase the patient's venous capacitance to enable the patient to increase oxygen consumption at the patient's ventilatory anaerobic threshold (VAT) to daily improve the patient's exercise capacity at VAT, said method comprising:

• potentiating daily the cGMP signal in a patient to increase the patient's venous capacitance to increase oxygen consumption by the patient at the patient's VAT to daily improve the patient's exercise capacity at VAT.

A daily method of inhibiting cyclic guanosine monophosphate (cGMP) degradation in a patient, who has a single functioning ventricle in which the patient's systemic venous return is connected directly to the pulmonary arteries without the interposition of a second functioning ventricle (Fontan patient), to induce venous vasodilation in the patient to increase the patient's venous capacitance to enable the patient to increase oxygen consumption at the patient's ventilatory anaerobic threshold (VAT) to daily improve the patient's exercise capacity at VAT, said method comprising:

• inhibiting daily cGMP degradation in a patient to increase the patient's venous capacitance to increase oxygen consumption by the patient at the patient's VAT to daily improve the patient's exercise capacity at VAT.

A daily method for providing increased on demand oxygen to a patient, who is in need of oxygen and who has a single functioning ventricle in which the patient's systemic venous return is connected directly to the pulmonary arteries without the interposition of a second functioning ventricle and whose venous, atrial, ventricular and arterial shunts are inoperative, so that the patient in need of oxygen has increased oxygen available to achieve on demand improved exercise capacity, as measured at ventilatory anaerobic threshold (VAT), said method comprising:

• enabling daily in the patient increased venous capacitance to provide daily increased transpulmonary blood flow, in which the patient's increased transpulmonary blood flow through the patient's lungs is assisted by the patient's central venous pressure, to enable the patient to achieve daily increased oxygen uptake by the patient's increased transpulmonary blood flow to provide increased on demand oxygen in the patient, so that the patient in need of oxygen has increased on demand oxygen available to achieve on demand increased exercise capacity, as measured at VAT.

A daily method for providing increased on demand oxygen to a patient, who has a single functioning ventricle in which the patient's systemic venous return is connected directly to the pulmonary arteries without the interposition of a second functioning ventricle and whose venous, atrial, ventricular and arterial shunts are inoperative, so that the patient, when in need of increased oxygen for exercise, has sufficient oxygen to achieve on demand increased work rate at ventilatory anaerobic threshold (VAT), said method comprising:

• inducing daily in the patient increased venous capacitance to provide daily increased transpulmonary blood flow in the patient, assisted by the patient's central venous pressure, to enable the patient to achieve increased oxygen uptake by the patient's lungs to provide sufficient on demand oxygen in the patient, so that the patient, when in need of oxygen for exercise, has sufficient on demand oxygen available to achieve increased work rate at the patient's VAT.

A daily method for providing increased on demand oxygen to a patient who has a single functioning ventricle in which the patient's systemic venous return is connected directly to the pulmonary arteries without the interposition of a second functioning ventricle and whose venous, atrial, ventricular and arterial shunts are inoperative, so that the patient, when in need of oxygen, has sufficient oxygen to achieve on demand increased ventilator efficiency during exercise (VE/CO2 slope) at ventilatory anaerobic threshold (VAT), said method comprising:

• inducing daily in the patient increased venous capacitance to provide daily increased transpulmonary blood flow in the patient, assisted by the patient's central venous pressure, to enable the patient to achieve increased oxygen uptake by the patient's lungs to provide sufficient on demand oxygen in the patient, so that the patient, when in need of oxygen for exercise, has sufficient on demand oxygen available to achieve increased VE/CO2 slope at the patient's VAT.

A method of increasing or to increase the likelihood of increasing venous capacitance in a patient, who has a single functioning ventricle in which the patient's systemic venous return is connected directly to the pulmonary arteries without the interposition of a second functioning ventricle (Fontan patient), to increase or to increase the likelihood of increasing the Fontan patient's oxygen consumption at ventilatory anaerobic threshold (VAT), said method comprising:

• administering to the Fontan patient an effective daily dose of a phosphodiesterase type 5 inhibitor (PDE5i) to increase or to increase the likelihood of increasing the Fontan patient's venous capacitance to increase or to increase the likelihood of increasing the Fontan patient's oxygen consumption at VAT.

A method of increasing oxygen availability in a Fontan patient by both increasing peak VO2 to or near its physiological ceiling and increasing VO2 at VAT by a statistically significant amount comprising administration of an effective PDE5 inhibitor (PDE5i).

A method of treating SVHD in a patient who has had a Fontan procedure by improving exercise capacity at both VAT and peak VO2 comprising administering an effective amount of an effective PDE5 inhibitor (PDE5i).

A method of improving exercise capacity in a Fontan patient by both increasing peak VO2 to or near its physiological ceiling and increasing VO2 at VAT by a statistically significant amount comprising administering an effective PDE5 inhibitor (PDE5i).

A pharmaceutical composition comprising the composition of Table 11.

A method of treating a single ventricular heart disease (SVHD) patient who has a single functioning ventricle to improve ventricular performance of the SVHD patient's single functioning ventricle, wherein the SVHD patient is in need of the treatment to improve ventricular performance of the SVHD patient's single functioning ventricle, comprising:

• administering daily an effective amount of udenafil or a pharmaceutically acceptable salt thereof to the SVHD patient to improve the ventricular performance of the SVHD patient's single functioning ventricle.

A method of improving myocardial performance index (MPI) in a single ventricular heart disease (SVHD) patient who has a single functioning ventricle, wherein the SVHD patient is in need of improvement in the MPI, comprising:

• administering daily an effective amount of udenafil or a pharmaceutically acceptable salt thereof to the SVHD patient to improve the SVHD patient's MPI.

A method of improving cardiac output in a single ventricular heart disease (SVHD) patient who has a single functioning ventricle, wherein the SVHD patient is in need of improvement in cardiac output, comprising:

• administering daily an effective amount of udenafil or a pharmaceutically acceptable salt thereof to the SVHD patient to improve the SVHD patient's cardiac output.

A method of treating a single ventricular heart disease (SVHD) patient who has a single functioning ventricle to improve ventricular performance of the SVHD patient's single functioning ventricle, wherein the SVHD patient is in need of the treatment to improve ventricular performance of the SVHD patient's single functioning ventricle, comprising:

• administering daily an effective amount of udenafil or a pharmaceutically acceptable salt thereof to the SVHD patient to improve the ventricular performance of the SVHD patient's single functioning ventricle, wherein the effective amount produces an udenafil Cmax pharmacokinetic blood plasma profile in the SVHD patient of between 300 and 700 ng/ml.

A method of improving myocardial performance index (MPI) in a single ventricular heart disease (SVHD) patient who has a single functioning ventricle, wherein the SVHD patient is in need of improvement in the MPI, comprising:

• administering daily an effective amount of udenafil or a pharmaceutically acceptable salt thereof to the SVHD patient to improve the SVHD patient's MPI, wherein, the effective amount produces an udenafil Cmax pharmacokinetic blood plasma profile in the SVHD patient of between 300 and 700 ng/ml.

A method of improving cardiac output in a single ventricular heart disease (SVHD) patient who has a single functioning ventricle, wherein the SVHD patient is in need of improvement in cardiac output, comprising:

• administering daily an effective amount of udenafil or a pharmaceutically acceptable salt thereof to the SVHD patient to improve the SVHD patient's cardiac output, wherein, the effective amount produces an udenafil Cmax pharmacokinetic blood plasma profile in the SVHD patient of between 300 and 700 ng/ml.

The method of treating a single ventricular heart disease (SVHD) patient who has undergone Fontan surgery (Fontan patient), to increase ventricular performance comprising administering, preferably daily, an effective amount of an effective PDE5 inhibitor to the patient.

A pharmaceutical composition for oral administration for treating a single ventricular heart disease (SVHD) patient who has a single functioning ventricle for improving the SVHD patient's myocardial performance index (MPI), wherein the SVHD patient is in need of treatment with the oral pharmaceutical composition to improve the SVHD patient's MPI, said pharmaceutical composition comprising:

• an effective amount of udenafil or a pharmaceutically acceptable salt thereof, whereby, when said oral pharmaceutical composition is orally administered to the SVHD patient daily to improve the SVHD patient's MPI, the effective amount of udenafil produces in the SVHD patient a udenafil pharmacokinetic plasma profile, wherein the udenafil pharmacokinetic plasma profile is selected from a group of udenafil pharmacokinetic plasma profiles consisting of a Cmax between 300 and 700 ng/ml, a Tmax between 1 and 1.6 hr, an AUCt between 2550 and 4150 ng·hr/ml or more, and an AUC0-24 between 5110 and 8290 ng·hr/ml, individually, collectively or in any combination thereof.

A method of treating a single ventricular heart disease (SVHD) patient who has undergone Fontan surgery (Fontan patient), to improve ventricular performance, maintain ventricular performance, or decrease the rate of decline of ventricular performance, comprising administering, preferably daily, an effective amount of an effective PDE5 inhibitor to the patient.

A pharmaceutical composition for oral administration for treating a single ventricular heart disease (SVHD) patient who has a single functioning ventricle for improving certain markers of the SVHD patient's, wherein the markers include myocardial performance index (MPI), exercise capacity as measured by oxygen consumption at anaerobic threshold (VAT), work rate at VAT and VE/VCO2 at VAT, wherein the SVHD patient is in need of treatment with the oral pharmaceutical composition to improve the SVHD patient's markers, said pharmaceutical composition comprising:

• an effective amount of udenafil or a pharmaceutically acceptable salt thereof, whereby, when said oral pharmaceutical composition is orally administered to the SVHD patient daily to improve the SVHD patient's markers, the effective amount of udenafil produces in the SVHD patient a udenafil pharmacokinetic plasma profile, wherein the udenafil pharmacokinetic plasma profile is selected from a group of udenafil pharmacokinetic plasma profiles consisting of a Cmax between 300 and 700 ng/ml, a Tmax between 1 and 1.6 hr, an AUCt between 2550 and 4150 ng·hr/ml or more, and an AUC0-24 between 5110 and 8290 ng·hr/ml, individually, collectively or in any combination thereof.

Use of an effective dose of udenafil, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the treatment of a patient with single ventricle heart disease, who has had a Fontan procedure, for improving the patient's exercise capacity and cardiac output, whose exercise capacity and cardiac output are adversely affected due to a decline in the patient's heart function after the Fontan procedure, wherein the medicament is formulated to be administered to the patient in a total daily dose of udenafil or a pharmaceutically acceptable salt thereof, wherein the total daily dose is from about 125 mg to about 175 mg, wherein the patient is in need of treatment to improve the patient's exercise capacity and cardiac output, and wherein the patient is at least about 12 years of age or older.

Use of udenafil or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating a patient with single ventricle heart defect, who has had Fontan procedure, for improving the patient's exercise capacity and cardiac output, whose exercise capacity and cardiac output are adversely affected due to a decline in the patient's heart function after the Fontan procedure, wherein the medicament is formulated to be administered to the patient in a dose of 87.5 mg, wherein the patient is in need of treatment to improve the patient's exercise capacity and cardiac output, wherein the medicament is administered at least once or twice daily, and wherein the patient is at least about 12 years of age or older.

The dosage of udenafil, or a pharmaceutically acceptable salt thereof, is 87.5 mg, and a composition comprising the 87.5 mg udenafil dosage is administered once or twice per day to a patient with single ventricle heart disease, who has undergone a Fontan procedure and who has Fontan physiology, for improving the patient's exercise capacity and cardiac output, wherein the patient is at least 12 years of age or older.