Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

• an “effective amount” of udenafil or a pharmaceutically acceptable salt thereof in accordance with the present invention includes an oral dosage amount that includes, but is not limited to, a single dosage amount administered daily, including a single dosage amount of about 75 mg or 87.5 mg administered once or twice a day and a single dosage amount of about 125 mg administered once daily.
• the improvement can be about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24, about 25, about 26, about 27, about 28, about 29, or about 30% or greater, as compared to VO2 at VAT in the absence of the methods of the present invention (e.g., in the absence of daily udenafil administration).
• the method comprises administering, preferably daily, an effective amount of an effective PDE5 inhibitor to the SVHD patient, including a Fontan patient, where the PDE5 inhibitor is preferably udenafil or a pharmaceutically acceptable salt thereof.
• the udenafil or a pharmaceutically acceptable salt thereof is in a solid or semi-solid oral dosage form selected from a group consisting of a tablet, a capsule, a gel, a liquid, a liquid dispersion, a pill, a powder, and a suspension.
• the method according to claim 1 wherein the udenafil or a pharmaceutically acceptable salt thereof is in a solid oral dosage form.
• the method according to claim 7, wherein the solid oral dosage form is a solid or semisolid oral dosage form selected from a group consisting of a tablet, a capsule, a gel, a liquid, a liquid dispersion, a pill, a powder, and a suspension.
• the effective amount is a total daily dosage of udenafil or a pharmaceutically acceptable salt thereof is in an amount of between about 125 mg and 175 mg.
• FIG. 5 is a schematic drawing of an exemplary Norwood procedure (Stage 1) of a reconstructed SVHD heart with Hypoplastic Left Heart Syndrome (HLHS);
• Ventricular performance and cardiac contractility are important measurements that can reveal impairment of cardiovascular health before overt heart failure is present.
• Ventricular performance can be assessed using echocardiographic methods and quantified via a myocardial performance index or MPI.
• MPI is an index that combines systolic and diastolic function.
• the disclosed methods and compositions of the present invention may result in about a 1, about 2, about 5, about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, or about 50% or more improvement in ventricular performance, as measured by any known technique, including but not limited to myocardial performance index (MPI), blood pool MPI, tissue doppler MPI, average isovolumetric contraction and relaxation, and other known ventricular performance indices.
• MPI myocardial performance index
• blood pool MPI blood pool MPI
• tissue doppler MPI tissue doppler MPI
• average isovolumetric contraction and relaxation and other known ventricular performance indices.
• the methods of the present invention increase and/or maximize oxygen consumption at the ventilatory anaerobic threshold (VAT) and at maximum effort or max VO2 to improve exercise capacity, and increase and/or maximize work rate at VAT and VE/VCO2 at VAT in SVHD patients, including Fontan patients.
• VAT ventilatory anaerobic threshold
• VO2 maximum effort or max VO2
• udenafil or a pharmaceutically acceptable salt thereof can be administered at a total daily dose of about 37.5 mg, about 75 mg, about 87.5 mg, 125 mg, or about 175 mg.
• udenafil or a pharmaceutically acceptable salt thereof can be administered at a total daily dose range of from about 37.5 mg to about 175 mg, preferably, a total daily dose range of from 75 mg to about 175 mg, more preferably, a total daily dose range of from about 87.5 mg to about 175 mg and, most preferably, a total daily dose range of from 125 mg to about 175 mg.
• the udenafil or a pharmaceutically acceptable salt thereof can be administered as a pharmaceutical composition.
• the pharmaceutical composition comprising udenafil or a pharmaceutically acceptable salt thereof can be formulated in a wide variety of oral or parenteral dosage forms on clinical application.
• Each of the dosage forms can contain various disintegrating agents, surfactants, fillers, thickeners, binders, diluents such as wetting agents or other pharmaceutically acceptable excipients.
• the pharmaceutical preparation is preferably in unit dosage form.
• the preparation is subdivided into unit doses containing appropriate quantities of the udenafil or any acceptable pharmaceutical salt thereof.
• the unit dosage form can be a packaged preparation, such as a sachet, the package containing discrete quantities of preparation, such as packeted tablets, caplets, capsules, orally-disintegrating dosage forms, sublingual dosage forms, buccal dosage forms and powders in vials or ampoules.
• the unit dosage form can be a capsule, tablet, caplets, pills, orally-disintegrating dosage forms, sublingual dosage forms, buccal dosage forms, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.
• the paired echocardiographic data, the paired PAT-derived vascular function data, and the paired measure of serum BNP level is provided in Table 3. Table 3: Secondary Outcomes with Comparison Based on Treatment Arm
• the primary aim was to determine the effect of udenafil on exercise capacity in adolescents with Fontan physiology over a six-month period.
• the primary outcome was the between group difference in the change in oxygen consumption at peak exercise (peak VO2) from baseline to the 26-week visit.
• Secondary exercise outcomes included between group differences in change in additional measures at maximal exertion, as well as change in measures of submaximal exercise at the ventilatory anaerobic threshold (VAT). All measurement of values for exercise testing were initially made by the exercise physiologists and physicians at the individual participating sites. These were subsequently reviewed for accuracy in a blinded fashion at each site by one of two trained reviewers (MGM, SMP) in conjunction with the sites’ exercise teams prior to finalization.
• MGM two trained reviewers
• Udenafil and placebo were well tolerated by study participants. There were no deaths in the study cohort. A total of 24 participants (6%) experienced a serious adverse event; 14 in the udenafil group and 10 in the placebo group. There were 3 events in the udenafil group and 2 events in the placebo group that were thought to have a possible, probable, or definite relationship to study drug. Those that occurred in the udenafil group included unilateral retinal artery and vein thrombosis, transient lower extremity diplegia, and transient dyspnea. Frequent non-serious adverse events thought to have a possible, probable, or definite relationship to study drug are listed in Table 4. Headache, facial flushing, abdominal pain, epistaxis, and erection (male participants) were more common in the udenafil group. There were no reported episodes of priapism. All other adverse events occurred with similar frequency between the groups.
• VO2 at VAT sets the limits within which an individual patient will have to function on a daily basis. These limits dictate capacity for routine activities including work, school, and recreation. Any improvement in VO2 at VAT will necessarily result in an improvement in tolerance of these routine activities.

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Citations (2)

• 2022
  • 2022-12-20 CN CN202280092060.3A patent/CN119072312A/zh active Pending
  • 2022-12-20 US US17/803,841 patent/US20240285630A1/en active Pending
  • 2022-12-20 JP JP2024537409A patent/JP2025504706A/ja active Pending
  • 2022-12-20 EP EP22862347.6A patent/EP4452273A1/en active Pending
  • 2022-12-20 AU AU2022419178A patent/AU2022419178A1/en active Pending
  • 2022-12-20 WO PCT/US2022/000033 patent/WO2023121689A1/en not_active Ceased
  • 2022-12-20 CA CA3243958A patent/CA3243958A1/en active Pending
• 2024
  • 2024-06-20 MX MX2024007796A patent/MX2024007796A/es unknown

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