Novel use of PDE5 inhibitor combinations to promote neurite outgrowth

Abstract

This disclosure relates to the pharmaceutical technology. In particular, this disclosure provides a pharmaceutical combination / composition comprising a phosphodiesterase type 5 (PDE5) inhibitor, arginine, and N-acetylcysteine, and its applications in treating cardiovascular disease and erectile dysfunction. In one embodiment, this disclosure relates to a method for promoting neurite outgrowth, the method comprising the step of exposing a neuron to an effective amount of a pharmaceutical combination or composition comprising a phosphodiesterase type 5 (PDE5) inhibitor or a pharmaceutically acceptable salt thereof, arginine, and N-acetylcysteine, thereby promoting neurite outgrowth.

Description

[Technical Field]

[0001] (Field) The present disclosure relates to the technical field of medicaments. In particular, the present disclosure provides a pharmaceutical combination / pharmaceutical composition comprising a phosphodiesterase type 5 (PDE5) inhibitor, arginine and N-acetylcysteine, and the use thereof in promoting neurite outgrowth and / or treating and / or preventing neurological disorders. [Background Art]

[0002] (Background of the Invention) Phosphodiesterase type 5 inhibitors (PDE5 inhibitors) are vasodilatory drugs that act by blocking the degradation of cyclic GMP by cGMP-specific phosphodiesterase type 5 (PDE5) in smooth muscle cells that line the blood vessels supplying various tissues. Part of the physiological process of vasodilation involves the release of nitric oxide (NO) by vascular endothelial cells, which then diffuse to nearby vascular smooth muscle cells. There, NO activates soluble guanylate cyclase, which converts guanosine triphosphate (GTP) to cyclic guanosine monophosphate (cGMP) (the main effector of this system). PDE5 inhibitors prolong the action of cGMP by inhibiting its breakdown by the enzyme PDE5 (which is found throughout the body) (Goldstein I, Lue TF, Padma-Nathan H, Rosen RC, Steers WD, Wicker PA (May 1998). "Oral sildenafil in the treatment of erectile dysfunction. Sildenafil Study Group," The New England Journal of Medicine. 338(20):1397-404). PDE5 inhibitors are contraindicated with alpha-blockers, soluble guanylate cyclase-stimulating agents, or nitrate drugs (which can cause blood pressure to drop very low). PDE5 inhibitors may cause headache, stomach ache, diarrhea, flushing, dizziness, weakness, pruritus, and erythema after administration. [Prior art documents] [Non-patent literature]

[0003] [Non-Patent Document 1] Goldstein I, Lue TF, Padma-Nathan H, Rosen RC, Steers WD, Wicker PA (May 1998). "Oral sildenafil in the treatment of erectile dysfunction.Sildenafil Study Group", The New England Journal of Medicine.338(20):1397-404) [Overview of the project] [Means for solving the problem]

[0004] (Summary of the invention) This disclosure relates to a PDE5 inhibitor or a pharmaceutically acceptable salt thereof in combination with arginine and / or N-acetylcysteine ​​(NAC), which, surprisingly, promotes neurite outgrowth and treats and / or prevents neuropathy. In one embodiment, the disclosure relates to a method for promoting neurite outgrowth, the method comprising the step of exposing a neuron to an effective amount of a pharmaceutically appropriate combination or pharmaceutically appropriate composition comprising a phosphodiesterase type 5 (PDE5) inhibitor or a pharmaceutically acceptable salt thereof, arginine, and N-acetylcysteine, thereby promoting neurite outgrowth. In particular, the pharmaceutically appropriate combination or pharmaceutically appropriate composition may promote axonal and dendrite elongation. Alternatively, the disclosure relates to a pharmaceutically appropriate composition or pharmaceutically appropriate combination disclosed herein for use in a method for promoting neurite outgrowth. Alternatively, the present invention discloses the use of a pharmaceutically appropriate composition or pharmaceutically appropriate combination disclosed herein in the preparation of a pharmaceutically appropriate composition for promoting neurite outgrowth.

[0005] In another embodiment, the Disclosure relates to a method for treating and / or preventing neuropathy or nerve injury by promoting neurite outgrowth, the method comprising the step of administering an effective amount of a pharmaceutically acceptable combination or pharmaceutically acceptable composition comprising a phosphodiesterase type 5 (PDE5) inhibitor or a pharmaceutically acceptable salt thereof, arginine, and N-acetylcysteine ​​to a subject requiring such treatment or composition. Alternatively, the Disclosure relates to a pharmaceutically acceptable composition or pharmaceutically acceptable combination disclosed herein for use in a method for treating and / or preventing neuropathy or nerve injury by promoting neurite outgrowth. Alternatively, the Invention discloses the use of a pharmaceutically acceptable composition or pharmaceutically acceptable combination disclosed herein in the preparation of a pharmaceutically for treating and / or preventing neuropathy or nerve injury by promoting neurite outgrowth.

[0006] In one embodiment, neurological disorders or injuries mediated by the promotion of neurite outgrowth include, but are not limited to, epilepsy, Alzheimer's disease and other dementias, cerebrovascular diseases (including stroke, migraine and other headache disorders), multiple sclerosis, Parkinson's disease, neuroinfections, brain tumors, traumatic injuries of the nervous system resulting from head trauma, Huntington's disease, ALS, multiple sclerosis, ischemia associated with stroke, neuroparopathy, motor neuron disease, sciatic crush, peripheral neuropathy, diabetes-related neuropathy, spinal cord injury and facial nerve crush of the nervous system caused by physical, mechanical or chemical trauma, memory loss or mental disorders, intracranial hemorrhage, spinal cord injury, and neurological symptoms resulting from infection or immune response.

[0007] In some other embodiments, the methods of the present invention may be used in the treatment of peripheral nerve damage caused by bodily injury (e.g., burns, wounds, surgery, and accident-related injuries), ischemia, prolonged exposure to cold (e.g., frostbite), central nervous system damage resulting from, for example, stroke or intracranial hemorrhage (e.g., cerebral hemorrhage), dementia, Alzheimer's disease, Huntington's disease, or Parkinson's disease.

[0008] In one embodiment, the PDE5 inhibitor in this disclosure is selected from sildenafil, tadalafil, and vardenafil, and / or pharmaceutically acceptable salts thereof.

[0009] In one embodiment, the amount of PDE5 inhibitor in the pharmaceutical combination or pharmaceutical composition described herein is in the range of about 0.1% (w / w) to about 50% (w / w). Specific embodiments of the amount of PDE5 inhibitor include about 0.1% (w / w) to about 45% (w / w), about 0.1% (w / w) to about 40% (w / w), about 0.1% (w / w) to about 35% (w / w), about 0.1% (w / w) to about 30% (w / w), about 0.1% (w / w) to about 25% (w / w), about 0.1% (w / w) to about 20% (w / w), about 0.1% (w / w) to about 15% (w / w), and about 0. 1%(w / w) to approximately 10%(w / w), approximately 0.1%(w / w) to approximately 5%(w / w), approximately 0.1%(w / w) to approximately 2.5%(w / w), approximately 0.1%(w / w) to approximately 1%(w / w), approximately 0.5%(w / w) to approximately 50%(w / w), approximately 0.5%(w / w) to approximately 45%(w / w), approximately 0.5%(w / w) to approximately 40%(w / w), approximately 0.5%(w / w) to approximately 35%(w / w), approximately 0.5%(w / w) ~30%(w / w), 0.5%(w / w)~25%(w / w), 0.5%(w / w)~20%(w / w), 0.5%(w / w)~15%(w / w), 0.5%(w / w)~10%(w / w), 0.5%(w / w)~5%(w / w), 0.5%(w / w)~2.5%(w / w), 0.5%(w / w)~1%(w / w), 1.0%(w / w)~50%(w / w), approximately 1.0%(w / w) to approximately 45%(w / w), approximately 1.0%(w / w) to approximately 40%(w / w), approximately 1.0%(w / w) to approximately 35%(w / w), approximately 1.0%(w / w) to approximately 30%(w / w), approximately 1.0%(w / w) to approximately 25%(w / w), approximately 1.0%(w / w) to approximately 20%(w / w), approximately 1.0%(w / w) to approximately 15%(w / w), approximately 1.0%(w / w) to approximately 10%(w / w), approximately 1.0%(w / w) to approximately 5%(w / w), approximately 5%(w / w) to approximately 50%(w / w), approximately 5%(w / w) to approximately 45%(w / w), approximately 5%(w / w) to approximately 40%(w / w), approximately 5%(w / w) to approximately 35%(w / w), approximately 5%(w / w) to approximately 30%(w / w), approximately 5%(w / w) to approximately 25%(w / w), approximately 5%(w / w) to approximately 20%(w / w), approximately 5%(w / w) to approximately 15%(w / w), approximately 5%(w / w) to approximately 10%(w / w), approximately 10%(w / w) to approximately 50% (w / w), approximately 10%(w / w)~approximately 45%(w / w), approximately 10%(w / w)~approximately 40%(w / w), approximately 10%(w / w)~approximately 35%(w / w), approximately 10%(w / w)~approximately 30%(w / w), approximately 10%(w / w)~approximately 25%(w / w), approximately 10%(w / w)~approximately 20%(w / w), approximately 15%(w / w)~approximately 50%(w / w), approximately 15%(w / w)~approximately 45%(w / w), approximately 15%(w / w)~approximately 40%(w / w), approximately 15%(w / w)~approximately 35%(w / w), approximately 15%(w / w) to approximately 30%(w / w), approximately 15%(w / w) to approximately 25%(w / w), approximately 20%(w / w) to approximately 50%(w / w), approximately 20%(w / w) to approximately 45%(w / w), approximately 20%(w / w) to approximately 40%(w / w), approximately 20%(w / w) to approximately 35%(w / w), approximately 20%(w / w) to approximately 30%(w / w), approximately 20%(w / w) to approximately 25%(w / w), approximately 25%(w / w) to approximately 50%(w / w), approximately 25%(w / w) to approximately 45%(w / w) Examples include, but are not limited to, approximately 25%(w / w) to 40%(w / w), approximately 25%(w / w) to 35%(w / w), approximately 30%(w / w) to 50%(w / w), approximately 30%(w / w) to 45%(w / w), approximately 30%(w / w) to 40%(w / w), approximately 35%(w / w) to 50%(w / w), approximately 35%(w / w) to 45%(w / w), approximately 40%(w / w) to 50%(w / w), and approximately 40%(w / w) to 45%(w / w).

[0010] In one embodiment, the amount of arginine in the pharmaceutical combination or pharmaceutical composition described herein is in the range of about 4.0% (w / w) to about 80% (w / w). Specific embodiments of the amount of arginine include approximately 4.0% (w / w) to 75% (w / w), approximately 4.0% (w / w) to 70% (w / w), approximately 4.0% (w / w) to 65% (w / w), approximately 4.0% (w / w) to 60% (w / w), approximately 4.0% (w / w) to 55% (w / w), approximately 4.0% (w / w) to 50% (w / w), approximately 4.0% (w / w) to 45% (w / w), approximately 4.0% (w / w) to 40% (w / w), approximately 4.0% (w / w) to 35% (w / w), and approximately 4.0% (w / w) to 30% (w / w). ), approximately 4.0%(w / w) to approximately 25%(w / w), approximately 4.0%(w / w) to approximately 20%(w / w), approximately 4.0%(w / w) to approximately 15%(w / w), approximately 4.0%(w / w) to approximately 10%(w / w), approximately 10.0%(w / w) to approximately 80%(w / w), approximately 10.0%(w / w) to approximately 75%(w / w), approximately 10.0%(w / w) to approximately 70%(w / w), approximately 10.0%(w / w) to approximately 65%(w / w), approximately 10.0%(w / w) to approximately 60%(w / w), approximately 10.0%(w / w) to approximately 55%(w / w), approximately 10.0%(w / w) )~approximately 50% (w / w), approximately 10.0% (w / w)~approximately 45% (w / w), approximately 10.0% (w / w)~approximately 40% (w / w), approximately 10.0% (w / w)~approximately 35% (w / w), approximately 10.0% (w / w)~approximately 30% (w / w), approximately 10.0% (w / w)~approximately 25% (w / w), approximately 10.0% (w / w)~approximately 20% (w / w), approximately 10.0% (w / w)~approximately 15% (w / w), approximately 15.0% (w / w)~approximately 80% (w / w), approximately 15.0% (w / w)~approximately 75% (w / w), approximately 15.0% (w / w)~approximately 70% (w / w), approximately 15.0%(w / w) to approximately 65%(w / w), approximately 15.0%(w / w) to approximately 60%(w / w), approximately 15.0%(w / w) to approximately 55%(w / w), approximately 15.0%(w / w) to approximately 50%(w / w), approximately 15.0%(w / w) to approximately 45%(w / w), approximately 15.0%(w / w) to approximately 40%(w / w), approximately 15.0%(w / w) to approximately 35%(w / w), approximately 15.0%(w / w) to approximately 30%(w / w), approximately 15.0%(w / w) to approximately 25%(w / w), approximately 15.0%(w / w) to approximately 20%(w / w), approximately 20.0%(w / w) to approximately 80%(w / w), approximately 20.0%(w / w) to approximately 75%(w / w), approximately 20.0%(w / w) to approximately 70%(w / w), approximately 20.0%(w / w) to approximately 65%(w / w), approximately 20.0%(w / w) to approximately 60%(w / w), approximately 20.0%(w / w) to approximately 55%( w / w), approximately 20.0%(w / w) to approximately 50%(w / w), approximately 20.0%(w / w) to approximately 45%(w / w), approximately 20.0%(w / w) to approximately 40%(w / w), approximately 20.0%(w / w) to approximately 35%(w / w), approximately 20.0%(w / w) to approximately 30%(w / w), approximately 20.0%(w / w) ~ approximately 25% (w / w), approximately 25.0% (w / w) ~ approximately 80% (w / w), approximately 25.0% (w / w) ~ approximately 75% (w / w), approximately 25.0% (w / w) ~ approximately 70% (w / w), approximately 25.0% (w / w) ~ approximately 65% ​​(w / w), approximately 25.0% (w / w) ~ approximately 60% (w / w), approximately 25.0% (w / w) to approximately 55% (w / w), approximately 25.0% (w / w) to approximately 50% (w / w), approximately 25.0% (w / w) to approximately 45% (w / w), approximately 25.0% (w / w) to approximately 40% (w / w), approximately 25.0% (w / w) to approximately 35% (w / w), approximately 25.0% (w / w) to approximately 30% %(w / w), approximately 30.0%(w / w) to approximately 80%(w / w), approximately 30.0%(w / w) to approximately 75%(w / w), approximately 30.0%(w / w) to approximately 70%(w / w), approximately 30.0%(w / w) to approximately 65%(w / w), approximately 30.0%(w / w) to approximately 60%(w / w), approximately 30.0% (w / w) ~ approximately 55% (w / w), approximately 30.0% (w / w) ~ approximately 50% (w / w), approximately 30.0% (w / w) ~ approximately 45% (w / w), approximately 30.0% (w / w) ~ approximately 40% (w / w), approximately 30.0% (w / w) ~ approximately 35% (w / w), approximately 35.0% (w / w) ~ approximately 80% (w / w) ), approximately 35.0% (w / w) to approximately 75% (w / w), approximately 35.0% (w / w) to approximately 70% (w / w), approximately 35.0% (w / w) to approximately 65% ​​(w / w), approximately 35.0% (w / w) to approximately 60% (w / w), approximately 35.0% (w / w) to approximately 55% (w / w), approximately 35.0% (w / w) to Approximately 50% (w / w), approximately 35.0% (w / w) to approximately 45% (w / w), approximately 35.0% (w / w) to approximately 40% (w / w), approximately 40.0% (w / w) to approximately 80% (w / w), approximately 40.0% (w / w) to approximately 75% (w / w), approximately 40.0% (w / w) to approximately 70% (w / w), approximately 40.0%(w / w) to approximately 65%(w / w), approximately 40.0%(w / w) to approximately 60%(w / w), approximately 40.0%(w / w) to approximately 55%(w / w), approximately 40.0%(w / w) to approximately 50%(w / w), approximately 40.0%(w / w) to approximately 45%(w / w), approximately 45.0%(w / w) to approximately 80%(w / w), approximately 45.0%(w / w) to approximately 75%(w / w), approximately 45.0%(w / w) to approximately 70%(w / w), approximately 45.0%(w / w) to approximately 65% (w / w), approximately 45.0% (w / w) to approximately 60% (w / w), approximately 45.0% (w / w) to approximately 55% (w / w), approximately 45.0% (w / w) to approximately 50% (w / w), approximately 50.0% (w / w) to approximately 80% (w / w), approximately 50.0% (w / w) to approximately 75% (w / w), approximately 50.0% (w / w) to approximately 70% (w / w), approximately 50.0% (w / w) to approximately 65% ​​(w / w), approximately 50.0% (w / w) to approximately 60% (w / w), approximately 50.0% (w / w) to approximately 55% (w / w), approximately 55.0% (w / w) to approximately 80% (w / w), approximately 55.0% (w / w) to approximately 75% (w / w), approximately 55.0% (w / w) to approximately 70% (w / w), approximately 55.0% (w / w) to approximately 65% ​​(w / w), approximately 55.0% (w / w) to approximately 60% (w / w), approximately 60.0% (w / w) to approximately 80% (w / w), approximately 60.0% (w / w) to approximately 75% (w / w), approximately 60.0% (w / w) Examples include, but are not limited to, approximately 70% (w / w), 60.0% (w / w) to 65% (w / w), 65.0% (w / w) to 80% (w / w), 65.0% (w / w) to 75% (w / w), 65.0% (w / w) to 70% (w / w), 70.0% (w / w) to 80% (w / w), 70.0% (w / w) to 75% (w / w), or approximately 75.0% (w / w) to 80% (w / w).

[0011] In one embodiment, the amount of N-acetylcysteine ​​in the pharmaceutical combination or pharmaceutical composition described herein is in the range of about 4% (w / w) to about 80% (w / w). Specific embodiments of the amount of arginine include approximately 4.0% (w / w) to 75% (w / w), approximately 4.0% (w / w) to 70% (w / w), approximately 4.0% (w / w) to 65% (w / w), approximately 4.0% (w / w) to 60% (w / w), approximately 4.0% (w / w) to 55% (w / w), approximately 4.0% (w / w) to 50% (w / w), approximately 4.0% (w / w) to 45% (w / w), approximately 4.0% (w / w) to 40% (w / w), approximately 4.0% (w / w) to 35% (w / w), and approximately 4.0% (w / w) to 30% (w / w). ), approximately 4.0%(w / w) to approximately 25%(w / w), approximately 4.0%(w / w) to approximately 20%(w / w), approximately 4.0%(w / w) to approximately 15%(w / w), approximately 4.0%(w / w) to approximately 10%(w / w), approximately 10.0%(w / w) to approximately 80%(w / w), approximately 10.0%(w / w) to approximately 75%(w / w), approximately 10.0%(w / w) to approximately 70%(w / w), approximately 10.0%(w / w) to approximately 65%(w / w), approximately 10.0%(w / w) to approximately 60%(w / w), approximately 10.0%(w / w) to approximately 55%(w / w), approximately 10.0%(w / w) )~approximately 50% (w / w), approximately 10.0% (w / w)~approximately 45% (w / w), approximately 10.0% (w / w)~approximately 40% (w / w), approximately 10.0% (w / w)~approximately 35% (w / w), approximately 10.0% (w / w)~approximately 30% (w / w), approximately 10.0% (w / w)~approximately 25% (w / w), approximately 10.0% (w / w)~approximately 20% (w / w), approximately 10.0% (w / w)~approximately 15% (w / w), approximately 15.0% (w / w)~approximately 80% (w / w), approximately 15.0% (w / w)~approximately 75% (w / w), approximately 15.0% (w / w)~approximately 70% (w / w), approximately 15.0%(w / w) to approximately 65%(w / w), approximately 15.0%(w / w) to approximately 60%(w / w), approximately 15.0%(w / w) to approximately 55%(w / w), approximately 15.0%(w / w) to approximately 50%(w / w), approximately 15.0%(w / w) to approximately 45%(w / w), approximately 15.0%(w / w) to approximately 40%(w / w), approximately 15.0%(w / w) to approximately 35%(w / w), approximately 15.0%(w / w) to approximately 30%(w / w), approximately 15.0%(w / w) to approximately 25%(w / w), approximately 15.0%(w / w) to approximately 20%(w / w), approximately 20.0%(w / w) to approximately 80%(w / w), approximately 20.0%(w / w) to approximately 75%(w / w), approximately 20.0%(w / w) to approximately 70%(w / w), approximately 20.0%(w / w) to approximately 65%(w / w), approximately 20.0%(w / w) to approximately 60%(w / w), approximately 20.0%(w / w) to approximately 55%( w / w), approximately 20.0%(w / w) to approximately 50%(w / w), approximately 20.0%(w / w) to approximately 45%(w / w), approximately 20.0%(w / w) to approximately 40%(w / w), approximately 20.0%(w / w) to approximately 35%(w / w), approximately 20.0%(w / w) to approximately 30%(w / w), approximately 20.0%(w / w) ~ approximately 25% (w / w), approximately 25.0% (w / w) ~ approximately 80% (w / w), approximately 25.0% (w / w) ~ approximately 75% (w / w), approximately 25.0% (w / w) ~ approximately 70% (w / w), approximately 25.0% (w / w) ~ approximately 65% ​​(w / w), approximately 25.0% (w / w) ~ approximately 60% (w / w), approximately 25.0% (w / w) to approximately 55% (w / w), approximately 25.0% (w / w) to approximately 50% (w / w), approximately 25.0% (w / w) to approximately 45% (w / w), approximately 25.0% (w / w) to approximately 40% (w / w), approximately 25.0% (w / w) to approximately 35% (w / w), approximately 25.0% (w / w) to approximately 30% %(w / w), approximately 30.0%(w / w) to approximately 80%(w / w), approximately 30.0%(w / w) to approximately 75%(w / w), approximately 30.0%(w / w) to approximately 70%(w / w), approximately 30.0%(w / w) to approximately 65%(w / w), approximately 30.0%(w / w) to approximately 60%(w / w), approximately 30.0% (w / w) ~ approximately 55% (w / w), approximately 30.0% (w / w) ~ approximately 50% (w / w), approximately 30.0% (w / w) ~ approximately 45% (w / w), approximately 30.0% (w / w) ~ approximately 40% (w / w), approximately 30.0% (w / w) ~ approximately 35% (w / w), approximately 35.0% (w / w) ~ approximately 80% (w / w) ), approximately 35.0% (w / w) to approximately 75% (w / w), approximately 35.0% (w / w) to approximately 70% (w / w), approximately 35.0% (w / w) to approximately 65% ​​(w / w), approximately 35.0% (w / w) to approximately 60% (w / w), approximately 35.0% (w / w) to approximately 55% (w / w), approximately 35.0% (w / w) to Approximately 50% (w / w), approximately 35.0% (w / w) to approximately 45% (w / w), approximately 35.0% (w / w) to approximately 40% (w / w), approximately 40.0% (w / w) to approximately 80% (w / w), approximately 40.0% (w / w) to approximately 75% (w / w), approximately 40.0% (w / w) to approximately 70% (w / w), approximately 40.0%(w / w) to approximately 65%(w / w), approximately 40.0%(w / w) to approximately 60%(w / w), approximately 40.0%(w / w) to approximately 55%(w / w), approximately 40.0%(w / w) to approximately 50%(w / w), approximately 40.0%(w / w) to approximately 45%(w / w), approximately 45.0%(w / w) to approximately 80%(w / w), approximately 45.0%(w / w) to approximately 75%(w / w), approximately 45.0%(w / w) to approximately 70%(w / w), approximately 45.0%(w / w) to approximately 65% (w / w), approximately 45.0% (w / w) to approximately 60% (w / w), approximately 45.0% (w / w) to approximately 55% (w / w), approximately 45.0% (w / w) to approximately 50% (w / w), approximately 50.0% (w / w) to approximately 80% (w / w), approximately 50.0% (w / w) to approximately 75% (w / w), approximately 50.0% (w / w) to approximately 70% (w / w), approximately 50.0% (w / w) to approximately 65% ​​(w / w), approximately 50.0% (w / w) to approximately 60% (w / w), approximately 50.0% (w / w) to approximately 55% (w / w), approximately 55.0% (w / w) to approximately 80% (w / w), approximately 55.0% (w / w) to approximately 75% (w / w), approximately 55.0% (w / w) to approximately 70% (w / w), approximately 55.0% (w / w) to approximately 65% ​​(w / w), approximately 55.0% (w / w) to approximately 60% (w / w), approximately 60.0% (w / w) to approximately 80% (w / w), approximately 60.0% (w / w) to approximately 75% (w / w), approximately 60.0% (w / w) Examples include, but are not limited to, approximately 70% (w / w), 60.0% (w / w) to 65% (w / w), 65.0% (w / w) to 80% (w / w), 65.0% (w / w) to 75% (w / w), 65.0% (w / w) to 70% (w / w), 70.0% (w / w) to 80% (w / w), 70.0% (w / w) to 75% (w / w), or approximately 75.0% (w / w) to 80% (w / w).

[0012] In one embodiment, the amount of the PDE5 inhibitor is in the range of approximately 0.1% (w / w) to approximately 50% (w / w), the amount of arginine is in the range of approximately 4.0% (w / w) to approximately 80% (w / w), and the amount of N-acetylcysteine ​​is in the range of approximately 4% (w / w) to approximately 80% (w / w). Specific embodiments of the amounts of the PDE5 inhibitor, arginine, and N-acetylcysteine ​​are within the ranges described herein.

[0013] In one embodiment, the amount of PDE5 inhibitor in the pharmaceutical combination or pharmaceutical composition described herein is in the range of about 0.5 mg to about 250 mg. Specific embodiments of the amount of PDE5 inhibitor include about 0.5 mg to about 250 mg, about 0.5 mg to about 240 mg, about 0.5 mg to about 230 mg, about 0.5 mg to about 220 mg, about 0.5 mg to about 210 mg, about 0.5 mg to about 200 mg, about 0.5 mg to about 190 mg, about 0.5 mg to about 180 mg, about 0.5 mg to about 170 mg, about 0.5 mg to about 160 mg, about 0.5 mg to about 150 mg, about 0.5 mg to about 140 mg, about 0.5 mg to about 130 mg, about 0.5 mg to about 120 mg, and about 0.5 mg to about 110 mg. , about 0.5 mg to about 100 mg, about 0.5 mg to about 90 mg, about 0.5 mg to about 80 mg, about 0.5 mg to about 70 mg, about 0.5 mg to about 60 mg, about 0.5 mg to about 50 mg, about 0.5 mg to about 40 mg, about 0.5 mg to about 30 mg, about 0.5 mg to about 2 0mg, about 0.5mg to about 10mg, about 0.5mg to about 5mg, about 0.5mg to about 1mg, about 1mg to about 250mg, about 1mg to about 240mg, about 1mg to about 230mg, about 1mg to about 220mg, about 1mg to about 210mg, about 1mg to about 200mg, about 1m g ~ approx. 190 mg, approx. 1 mg ~ approx. 180 mg, approx. 1 mg ~ approx. 170 mg, approx. 1 mg ~ approx. 160 mg, approx. 1 mg ~ approx. 150 mg, approx. 1 mg ~ approx. g, approx. 1mg to approx. 90mg, approx. 1mg to approx. 80mg, approx. 1mg to approx. 70mg, approx. 1mg to approx. 60mg, approx. 1mg to approx. 50mg, approx. 1mg to approx. 40mg, approx. Approx. 250 mg, approx. 5 mg to approx. 240 mg, approx. 5 mg to approx. 230 mg, approx. 5 mg to approx. 220 mg, approx. 5 mg to approx. 210 mg, approx. 5 mg to approx. 200 mg, approx. About 5 mg to about 150 mg, about 5 mg to about 140 mg, about 5 mg to about 130 mg, about 5 mg to about 120 mg, about 5 mg to about 110 mg, about 5 mg to about 100 mg, about 5 mg to about 90 mg, about 5 mg to about 80 mg, about 5 mg to about 70 mg, about 5 mg to about 60 mg,Approximately 5mg to 50mg, approximately 5mg to 40mg, approximately 5mg to 30mg, approximately 5mg to 20mg, approximately 5mg to 10mg, approximately 10mg to 250mg, approximately 10mg to 240mg, approximately 10mg to 230mg, approximately 10mg to 220mg, approximately 10mg to 210mg, approximately 10mg to 200mg, approximately 10mg to 190mg, approximately 10mg to 180mg, approximately 10mg to 170mg, approximately 10mg to 160mg, approximately 10mg to 150mg, approximately 10mg to 140mg, approximately 10mg to 130mg, approximately 10mg to 120mg, approximately 10mg to 110mg g, approximately 10mg to approximately 100mg, approximately 10mg to approximately 90mg, approximately 10mg to approximately 80mg, approximately 10mg to approximately 70mg, approximately 10mg to approximately 60mg, approximately 10mg to approximately 50mg, approximately 10mg to approximately 40mg, approximately 10mg to approximately 30mg, approximately 10mg to approximately 20mg, approximately 20mg to approximately 250mg, approximately 20mg to approximately 240mg, approximately 20mg to approximately 230mg, approximately 20mg to approximately 220mg, approximately 20mg to approximately 210mg, approximately 20mg to approximately 200mg, approximately 20mg to approximately 190mg, approximately 20mg to approximately 180mg, approximately 20mg to approximately 170mg, approximately 20mg to approximately 160mg, approximately 20mg to approximately 150mg, approximately 20mg~140mg, approximately 20mg~130mg, approximately 20mg~120mg, approximately 20mg~110mg, approximately 20mg~100mg, approximately 20mg~90mg, approximately 20mg~80mg, approximately 20mg~70mg, approximately 20mg~60mg, approximately 20mg~50mg, approximately 20mg~40mg, approximately 20mg~30mg, approximately 30mg~250mg, 30mg~240mg, 30mg~230mg, 30mg~220mg, 30mg~210mg, approximately 30mg~200mg, approximately 30mg~190mg, approximately 30mg~ Approximately 180mg, approximately 30mg~170mg, approximately 30mg~160mg, approximately 30mg~150mg, approximately 30mg~140mg, approximately 30mg~130mg, approximately 30mg~120mg, approximately 30mg~110mg, approximately 30mg~100mg, approximately 30mg~90mg, approximately 30mg~80mg, approximately 30mg~70mg, approximately 30mg~60mg, approximately 30mg~50mg, approximately 30mg~40mg, approximately 40mg~250mg, approximately 40mg~240mg, approximately 40mg~230mg, approximately 40mg~220mg, approximately 40mg~210mgApproximately 40mg~200mg, approximately 40mg~190mg, approximately 40mg~180mg, approximately 40mg~170mg, approximately 40mg~160mg, approximately 40mg~150mg, approximately 40mg~130mg, approximately 40mg~120mg, approximately 40mg~110mg, approximately 40mg~100mg, approximately 40mg~90mg, approximately 40mg~80mg, approximately 40mg~70mg, approximately 40mg~60mg, approximately 40mg~50mg, approximately 50mg~250mg, approximately 50mg~240mg, approximately 50mg~230mg, approximately 50mg~ Approximately 220mg, approximately 50mg~approximately 210mg, approximately 50mg~approximately 200mg, approximately 50mg~approximately 190mg, approximately 50mg~approximately 180mg, approximately 50mg~approximately 170mg, approximately 50mg~approximately 160mg, approximately 50mg~approximately 140mg, approximately 50mg~approximately 130mg, approximately 50mg~approximately 120mg, approximately 50mg~approximately 110mg, approximately 50mg~approximately 100mg, approximately 50mg~approximately 90mg, approximately 50mg~approximately 80mg, approximately 50mg~approximately 70mg, approximately 50mg~approximately 60mg, approximately 60mg~approximately 250mg, approximately 60mg~approximately 240mg, approximately 60mg~approximately 230mg Approximately 60mg to 220mg, approximately 60mg to 210mg, approximately 60mg to 200mg, approximately 60mg to 190mg, approximately 60mg to 180mg, approximately 60mg to 170mg, approximately 60mg to 160mg, approximately 60mg to 150mg, approximately 60mg to 140mg, approximately 60mg to 130mg, approximately 60mg to 120mg, approximately 60mg to 110mg, approximately 60mg to 100mg, approximately 60mg to 90mg, approximately 60mg to 80mg, approximately 60mg to 70mg, approximately 70mg to 250mg, approximately 70mg to 240mg, approximately 70mg to 230mg, approximately 70mg... g ~ approx. 220mg, approx. 70mg ~ approx. 210mg, approx. 70mg ~ approx. 200mg, approx. 70mg ~ approx. 190mg, approx. 70mg ~ approx. 180mg, approx. 70mg ~ approx. 160mg, approx. 70mg ~ approx. 150mg, approx. 70mg ~ approx. 140mg, approx. 70mg ~ approx. 130mg, approx. 70mg ~ approx. 120mg, approx. 70mg ~ approx. 110mg, approx. 70mg ~ approx. 100mg, approx. 70mg ~ approx. 90mg, approx. 70mg ~ approx. 80mg, approx. 80mg ~ approx. 250mg, approx. 80mg ~ approx. 240mg, approx. 80mg ~ approx. 230mg, approx. 80mg ~ approx. 220mgApproximately 80mg~210mg, approximately 80mg~200mg, approximately 80mg~190mg, approximately 80mg~170mg, approximately 160mg, approximately 150mg, approximately 140mg, approximately 130mg, approximately 120mg, approximately 110mg, approximately 100mg, approximately 90mg, approximately 250mg, approximately 240mg, approximately 230mg, approximately 220mg, approximately 210mg, 9 0mg~approx. 200mg, 90mg~approx. 190mg, 90mg~approx. 180mg, approx. 90mg~approx. 170mg, approx. 90mg~approx. 160mg, approx. 90mg~approx. 150mg, approx. 90mg~approx. 140mg, approx. 90mg~approx. 130mg, approx. 90mg~approx. 120mg, approx. 90mg~approx. 110mg, approx. 90mg~approx. 100mg, approx. 100mg~approx. 250mg, approx. 100mg~approx. 240mg, approx. 100mg~approx. 230mg, approx. 100mg~approx. 220mg, approx. 100mg~approx. 210mg, approx. 100mg~approx. 200mg, approx. 100mg~approx. 190mg, approx. 100mg~approx. 180mg, approx. 100mg g ~ approx. 170mg, approx. 100mg ~ approx. 160mg, approx. 100mg ~ approx. 150mg, approx. 100mg ~ approx. 140mg, approx. 100mg ~ approx. 130mg, approx. 100mg ~ approx. 120mg, approx. 100mg ~ approx. 110mg, approx. 110mg ~ approx. 250mg, approx. 110mg ~ approx. 240mg, approx. 110mg ~ approx. 230mg, approx. 110mg ~ approx. 220mg, approx. 110mg ~ approx. 210mg, approx. 110mg ~ approx. 200mg, approx. 110mg ~ approx. 190mg, approx. 110mg ~ approx. 180mg, approx. 110mg ~ approx. 170mg, approx. 110mg ~ approx. 160mg, approx. 110mg ~ approx. 150mg, approx. 110mg ~ approx. 1 40mg, approximately 110mg~130mg, approximately 110mg~120mg, approximately 120mg~250mg, approximately 120mg~240mg, approximately 120mg~230mg, approximately 120mg~220mg, approximately 120mg~210mg, approximately 120mg~200mg, approximately 120mg~190mg, approximately 120mg~180mg, approximately 120mg~170mg, approximately 120mg~160mg, approximately 120mg~150mg, approximately 120mg~140mg, approximately 120mg~130mg, approximately 130mg~250mg, 130mg~240mg, approximately 130mg~230mgApproximately 130mg to 220mg, approximately 130mg to 210mg, approximately 130mg to 200mg, approximately 130mg to 190mg, approximately 130mg to 180mg, approximately 130mg to 170mg, approximately 130mg to 160mg, approximately 130mg to 150mg, approximately 130mg to 140mg, approximately 130mg to 250mg, approximately 130mg to 240mg, approximately 130mg to 230mg, approximately 130mg to about 220mg, about 130mg to about 210mg, about 130mg to about 200mg, about 130mg to about 190mg, about 130mg to about 180mg, about 130mg to about 170mg, about 130mg to about 160mg, about 130mg to about 150mg, about 130mg to about 140mg, about 140mg to about 250mg, about 140mg to about 240mg, about 140mg to about 230mg, about 1 40mg to about 220mg, about 140mg to about 210mg, about 140mg to about 200mg, about 140mg to about 190mg, about 140mg to about 180mg, about 140mg to about 170mg, about 1 40mg to about 160mg, about 140mg to about 150mg, about 150mg to about 250mg, about 150mg to about 240mg, about 150mg to about 230mg, about 150mg to about 220mg, about 15 Examples of dosage ranges include 0mg to approximately 210mg, approximately 150mg to approximately 200mg, approximately 150mg to approximately 190mg, approximately 150mg to approximately 180mg, approximately 150mg to approximately 170mg, approximately 150mg to approximately 160mg, approximately 200mg to approximately 250mg, approximately 200mg to approximately 240mg, approximately 200mg to approximately 230mg, approximately 200mg to approximately 220mg, and approximately 200mg to approximately 210mg, but are not limited to these.

[0014] In one embodiment, the amount of arginine or N-acetylcysteine ​​in the pharmaceutical combination or pharmaceutical composition described herein is in the range of about 25 mg to about 400 mg. Specific embodiments of the amount of arginine or N-acetylcysteine ​​include about 25 mg to about 400 mg, about 25 mg to about 390 mg, about 25 mg to about 380 mg, about 25 mg to about 370 mg, about 25 mg to about 360 mg, about 25 mg to about 350 mg, about 25 mg to about 340 mg, about 25 mg to about 330 mg, about 25 mg to about 320 mg, about 25 mg to about 310 mg, about 25 mg to about 300 mg, about 25 mg to about 290 mg, about 25 mg to about 280 mg, about 25 mg to about 270 mg, and about 25 mg to about 260 mg. mg, about 25 mg to about 250 mg, about 25 mg to about 240 mg, about 25 mg to about 230 mg, about 25 mg to about 220 mg, about 25 mg to about 210 mg, about 25 mg to about 200 mg, about 25 mg to about 190 mg, about 25 mg to about 180 mg, about 25 mg to about 170mg, about 25mg to about 160mg, about 25mg to about 150mg, about 25mg to about 140mg, about 25mg to about 130mg, about 25mg to about 120mg, about 25mg to about 110mg, about 25mg to about 100mg, about 25mg to about 90mg, about 25mg ~80mg, 25mg~70mg, 25mg~60mg, 25mg~50mg, 25mg~40mg, 25mg~30mg, 30mg~400mg, 30mg~390mg, 30mg~380mg, 30mg~3 70mg, about 30mg to about 360mg, about 30mg to about 350mg, about 30mg to about 340mg, about 30mg to about 330mg, about 30mg to about 320mg, about 30mg to about 310mg, about 30mg to about 300mg, about 30mg to about 290mg, about 30mg ~280mg, 30mg~270mg, 30mg~260mg, 30mg~300mg, 30mg~240mg, 30mg~230mg, 30mg~220mg, 30mg~210mg, 30mg~200mg, 3 0mg to about 190mg, about 30mg to about 180mg, about 30mg to about 170mg, about 30mg to about 160mg, about 30mg to about 150mg, about 30mg to about 140mg, about 30mg to about 130mg, about 30mg to about 120mg, about 30mg to about 110mg,Approximately 30mg to 100mg, approximately 30mg to 90mg, approximately 30mg to 80mg, approximately 30mg to 70mg, approximately 30mg to 60mg, approximately 30mg to 50mg, approximately 30mg to 40mg, approximately 40mg to 400mg, approximately 40mg to 390mg, approximately 40mg to 380mg, approximately 40mg to 370mg, approximately 40mg to 360mg, approximately 40mg to 350mg, approximately 40mg to 340mg, approximately 40mg to 330mg, approximately 40mg to 320mg, approximately 40mg to 310mg, approximately 40mg to 300mg, approximately 40mg to 290mg, approximately 40mg to approximately 2 80mg, approximately 40mg~270mg, approximately 40mg~260mg, approximately 40mg~400mg, approximately 40mg~240mg, approximately 40mg~230mg, approximately 40mg~220mg, approximately 40mg~210mg, approximately 40mg~200mg, approximately 40mg~190mg, approximately 40mg~180mg, approximately 40mg~170mg, approximately 40mg~160mg, approximately 40mg~150mg, approximately 40mg~140mg, approximately 40mg~130mg, approximately 40mg~120mg, approximately 40mg~110mg, approximately 40mg~100mg, approximately 40mg~90mg Approximately 40mg to 80mg, approximately 40mg to 70mg, approximately 40mg to 60mg, approximately 40mg to 50mg, approximately 50mg to 400mg, approximately 50mg to 390mg, approximately 50mg to 380mg, approximately 50mg to 370mg, approximately 50mg to 360mg, approximately 50mg to 350mg, approximately 50mg to 340mg, approximately 50mg to 330mg, approximately 50mg to 320mg, approximately 50mg to 310mg, approximately 50mg to 300mg, approximately 50mg to 290mg, approximately 50mg to 280mg, approximately 50mg to 270mg, approximately 50mg to 260mg, approximately 50mg~ Approximately 500mg, approximately 50mg~approximately 240mg, approximately 50mg~approximately 230mg, approximately 50mg~approximately 220mg, approximately 50mg~approximately 210mg, approximately 50mg~approximately 200mg, approximately 50mg~approximately 190mg, approximately 50mg~approximately 180mg, approximately 50mg~approximately 170mg, approximately 50mg~approximately 160mg, approximately 50mg~approximately 150mg, approximately 50mg~approximately 140mg, approximately 50mg~approximately 130mg, approximately 50mg~approximately 120mg, approximately 50mg~approximately 110mg, approximately 50mg~approximately 100mg, approximately 50mg~approximately 90mg, approximately 50mg~approximately 80mg, approximately 50mg~approximately 70mg, approximately 50mg~approximately 60mg,Approximately 75mg to 400mg, approximately 75mg to 390mg, approximately 75mg to 380mg, approximately 75mg to 370mg, approximately 75mg to 360mg, approximately 75mg to 350mg, approximately 75mg to 340mg, approximately 75mg to 330mg, approximately 75mg to 320mg, approximately 75mg to 310mg, approximately 75mg to 300mg, approximately 75mg to 290mg, approximately 75mg to 280mg, approximately 75mg to 270mg, approximately 75mg to 260mg, approximately 75mg to 750mg, approximately 75mg to 240mg, approximately 75mg to 230mg, approximately 75mg to 220mg. Approximately 75mg to approximately 210mg, approximately 75mg to approximately 200mg, approximately 75mg to approximately 190mg, approximately 75mg to approximately 180mg, approximately 75mg to approximately 170mg, approximately 75mg to approximately 160mg, approximately 75mg to approximately 150mg, approximately 75mg to approximately 140mg, approximately 75mg to approximately 130mg, approximately 75mg to approximately 120mg, approximately 75mg to approximately 110mg, approximately 75mg to approximately 100mg, approximately 75mg to approximately 90mg, approximately 75mg to approximately 80mg, approximately 100mg to approximately 400mg, approximately 100mg to approximately 390mg, approximately 100mg to approximately 380mg, approximately 100mg to approximately 370mg, approximately 100mg to approximately 360mg. mg, approximately 100mg to approximately 350mg, approximately 100mg to approximately 340mg, approximately 100mg to approximately 330mg, approximately 100mg to approximately 320mg, approximately 100mg to approximately 310mg, approximately 100mg to approximately 300mg, approximately 100mg to approximately 290mg, approximately 100mg to approximately 280mg, approximately 100mg to approximately 270mg, approximately 100mg to approximately 260mg, approximately 100mg to approximately 1000mg, approximately 100mg to approximately 240mg, approximately 100mg to approximately 230mg, approximately 100mg to approximately 220mg, approximately 100mg to approximately 210mg, approximately 100mg to approximately 200mg, approximately 100mg to approximately 190mg, approximately 100mg g ~ approx. 180mg, approx. 100mg ~ approx. 170mg, approx. 100mg ~ approx. 160mg, approx. 100mg ~ approx. 150mg, approx. 100mg ~ approx. 140mg, approx. 100mg ~ approx. 130mg, approx. 100mg ~ approx. 120mg, approx. 100mg ~ approx. 110mg, approx. 125mg ~ approx. 400mg, approx. 125mg ~ approx. 390mg, approx. 125mg ~ approx. 380mg, approx. 125mg ~ approx. 370mg, approx. 125mg ~ approx. 360mg, approx. 125mg ~ approx. 350mg, approx. 125mg ~ approx. 340mg, approx. 125mg ~ approx. 330mg, approx. 125mg ~ approx. 320mg, approx. 125mg ~ approx. 310mgApproximately 125mg to approximately 300mg, approximately 125mg to approximately 290mg, approximately 125mg to approximately 280mg, approximately 125mg to approximately 270mg, approximately 125mg to approximately 260mg, approximately 125mg to approximately 1250mg, approximately 125mg to approximately 240mg, approximately 125mg to approximately 230mg, approximately 125mg to approximately 220mg, approximately 125mg to approximately 210mg, approximately 125mg to approximately 200mg, approximately 125mg to approximately 190mg, approximately 125mg to approximately 180mg, approximately 125mg to approximately 170mg, approximately 125mg to approximately 160mg, approximately 125mg to approximately 150mg, approximately 125mg to approximately 140mg, approximately 125mg to approximately 1... 30mg, approximately 150mg to approximately 400mg, approximately 150mg to approximately 390mg, approximately 150mg to approximately 380mg, approximately 150mg to approximately 370mg, approximately 150mg to approximately 360mg, approximately 150mg to approximately 350mg, approximately 150mg to approximately 340mg, approximately 150mg to approximately 330mg, approximately 150mg to approximately 320mg, approximately 150mg to approximately 310mg, approximately 150mg to approximately 300mg, approximately 150mg to approximately 290mg, approximately 150mg to approximately 280mg, approximately 150mg to approximately 270mg, approximately 150mg to approximately 260mg, approximately 150mg to approximately 250mg, approximately 150mg to approximately 240mg, approximately 150mg ~approx. 230mg, approx. 150mg~approx. 220mg, approx. 150mg~approx. 210mg, approx. 150mg~approx. 200mg, approx. 150mg~approx. 190mg, approx. 150mg~approx. 180mg, approx. 150mg~approx. 170mg, approx. 150mg~approx. 160mg, approx. 175mg~approx. 400mg, approx. 175mg~approx. 390mg, approx. 175mg~approx. 380mg, approx. 175mg~approx. 370mg, approx. 175mg~approx. 360mg, approx. 175mg~approx. 350mg, approx. 175mg~approx. 340mg, approx. 175mg~approx. 330mg, approx. 175mg~approx. 320mg, approx. 175mg~approx. 310mg, approx. 17 5mg~approx. 300mg, approx. 175mg~approx. 290mg, approx. 175mg~approx. 280mg, approx. 175mg~approx. 270mg, approx. 175mg~approx. 260mg, approx. 175mg~approx. 250mg, approx. 175mg~approx. 240mg, approx. 175mg~approx. 230mg, approx. 175mg~approx. 220mg, approx. 175mg~approx. 210mg, approx. 175mg~approx. 200mg, approx. 190mg, approx. 175mg~approx. 180mg, approx. 200mg~approx. 400mg, approx. 200mg~approx. 390mg, approx. 200mg~approx. 380mg, approx. 200mg~approx. 370mg, approx. 200mg~approx. 360mgApproximately 200mg~350mg, approximately 200mg~340mg, approximately 200mg~330mg, approximately 200mg~320mg, approximately 200mg~310mg, approximately 200mg~300mg, approximately 200mg~290mg, approximately 200mg~280mg, approximately 200mg~270mg, approximately 200mg~260mg, approximately 200mg~2000mg, approximately 200mg~240mg, approximately 200mg~230mg, approximately 200mg~220mg, approximately 200mg~210mg, approximately 225mg~400mg, approximately 225mg~390mg, approximately 225mg~3 80mg, approximately 225mg~370mg, approximately 225mg~360mg, approximately 225mg~350mg, approximately 225mg~340mg, approximately 225mg~330mg, approximately 225mg~320mg, approximately 225mg~310mg, approximately 225mg~300mg, approximately 225mg~290mg, approximately 225mg~280mg, approximately 225mg~270mg, approximately 225mg~260mg, approximately 225mg~250mg, approximately 225mg~240mg, approximately 225mg~230mg, approximately 225mg~220mg, approximately 225mg~210mg, approximately 225mg Approximately 200mg, approximately 250mg to approximately 400mg, approximately 250mg to approximately 390mg, approximately 250mg to approximately 380mg, approximately 250mg to approximately 370mg, approximately 250mg to approximately 360mg, approximately 250mg to approximately 350mg, approximately 250mg to approximately 340mg, approximately 250mg to approximately 330mg, approximately 250mg to approximately 320mg, approximately 250mg to approximately 310mg, approximately 250mg to approximately 300mg, approximately 250mg to approximately 290mg, approximately 250mg to approximately 280mg, approximately 250mg to approximately 270mg, approximately 250mg to approximately 260mg, approximately 275mg to approximately 400mg, approximately 275mg to approximately 390mg, approximately 27 5mg~approx. 380mg, approx. 275mg~approx. 370mg, approx. 275mg~approx. 360mg, approx. 275mg~approx. 350mg, approx. 275mg~approx. 340mg, approx. 275mg~approx. 330mg, approx. 275mg~approx. 320mg, approx. 275mg~approx. 310mg, approx. 275mg~approx. 300mg, approx. 275mg~approx. 290mg, approx. 275mg~approx. 280mg, approx. 300mg~approx. 400mg, approx. 300mg~approx. 390mg, approx. 300mg~approx. 380mg, approx. 300mg~approx. 370mg, approx. 300mg~approx. 360mg, approx. 300mg~approx. 350mg, approx. 300mg~approx. 340mgApproximately 300mg to approximately 330mg, approximately 300mg to approximately 320mg, approximately 300mg to approximately 310mg, approximately 325mg to approximately 400mg, approximately 325mg to approximately 390mg, approximately 325mg to about 380mg, about 325mg to about 370mg, about 325mg to about 360mg, about 350mg to about 350mg, about 325mg to about 340mg, about 3, Examples of dosages include 25mg to approximately 330mg, approximately 350mg to approximately 400mg, approximately 350mg to approximately 390mg, approximately 350mg to approximately 380mg, approximately 350mg to approximately 370mg, approximately 350mg to approximately 360mg, approximately 375mg to approximately 400mg, approximately 375mg to approximately 390mg, and approximately 375mg to approximately 380mg, but are not limited to these.

[0015] In one embodiment, the pharmaceutical combination or composition described herein comprises about 0.5 mg to about 250 mg of a PDE5 inhibitor, about 25 mg to about 400 mg of arginine, and about 25 mg to about 400 mg of N-acetylcysteine. Specific embodiments of the pharmaceutical combination or composition described herein have the amounts of the PDE5 inhibitor, N-acetylcysteine, and arginine disclosed herein.

[0016] In some embodiments, the amount of PDE5 inhibitor in the pharmaceutical combination or pharmaceutical composition described herein is approximately 1 mg, approximately 2 mg, approximately 3 mg, approximately 4 mg, approximately 5 mg, approximately 6 mg, approximately 7 mg, approximately 8 mg, approximately 9 mg, approximately 10 mg, approximately 11 mg, approximately 12 mg, approximately 13 mg, approximately 14 mg, approximately 15 mg, approximately 16 mg, approximately 17 mg, approximately 18 mg, approximately 19 mg, approximately 20 mg, approximately 21 mg, approximately 22 mg, approximately 23 mg, approximately 24 mg, approximately 25 mg, approximately 26 mg, approximately 27 mg, approximately 28 mg, approximately 29 mg, approximately 30 mg, approximately 31 mg, approximately 32 mg, approximately 33 mg, approximately The amounts are approximately 34mg, 35mg, 36mg, 37mg, 38mg, 39mg, 40mg, 41mg, 42mg, 43mg, 44mg, 45mg, 46mg, 47mg, 48mg, 49mg, or 50mg, and the amounts of arginine are approximately 225mg, 226mg, 227mg, 228mg, 229mg, 230mg, 231mg, 232mg, 233mg, 234mg, 235mg, 236mg, 237mg, 238mg, 239mg, 240mg, 241mg, 242mg, or 243mg. , approximately 244 mg, approximately 245 mg, approximately 246 mg, approximately 247 mg, approximately 248 mg, approximately 249 mg, approximately 250 mg, approximately 251 mg, approximately 252 mg, approximately 253 mg, approximately 254 mg, approximately 255 mg, approximately 256 mg, approximately 257 mg, approximately 258 mg, approximately 259 mg, approximately 260 mg, approximately 261 mg, approximately 262 mg, approximately 263 mg, approximately 264 mg, approximately 265 mg, approximately 266 mg, approximately 267 mg, approximately 268 mg, approximately 269 mg, approximately 270 mg, approximately 271 mg, approximately 272 mg, approximately 273 mg, approximately 274 mg, or approximately 275 mg, and / or N-acetylcysteine The amounts are approximately 225mg, 226mg, 227mg, 228mg, 229mg, 230mg, 231mg, 232mg, 233mg, 234mg, 235mg, 236mg, 237mg, 238mg, 239mg, 240mg, 241mg, 242mg, 243mg, 244mg, 245mg, 246mg, 247mg, 248mg, 249mg, 250mg, 251mg, 252mg, 253mg, 254mg, 255mg, 256mg, 257mg, 258mg, 259mg,The amounts are approximately 260 mg, 261 mg, 262 mg, 263 mg, 264 mg, 265 mg, 266 mg, 267 mg, 268 mg, 269 mg, 270 mg, 271 mg, 272 mg, 273 mg, 274 mg, or 275 mg. In certain embodiments, the amount of the PDE5 inhibitor is approximately 20 mg, the amount of arginine is approximately 250 mg, and / or the amount of N-acetylcysteine ​​is approximately 250 mg.

[0017] In one embodiment, the daily dose of the pharmaceutical combination or pharmaceutical composition is twice the dose of the PDE5 inhibitor, arginine, and / or N-acetylcysteine ​​described herein. In one embodiment, the pharmaceutical combination or pharmaceutical composition disclosed herein is administered twice daily, and as a result, the daily dose of the pharmaceutical combination or pharmaceutical composition is twice the dose of the PDE5 inhibitor, arginine, and / or N-acetylcysteine ​​described herein.

[0018] In some embodiments, the daily dose of the PDE5 inhibitor in the pharmaceutical combination or composition disclosed herein is about 4 mg to about 100 mg. In some embodiments, the daily dose of arginine in the pharmaceutical combination or composition disclosed herein is about 20 mg to about 1000 mg. In some embodiments, the daily dose of N-acetylcysteine ​​in the pharmaceutical combination or composition disclosed herein is about 20 mg to about 1000 mg. A particular embodiment of the pharmaceutical combination or composition disclosed herein has a daily dose of PDE5 inhibitor of about 40 mg. A particular embodiment of the pharmaceutical combination or composition disclosed herein has a daily dose of arginine of about 500 mg. A particular embodiment of the pharmaceutical combination or composition disclosed herein has a daily dose of N-acetylcysteine ​​of about 500 mg. Certain embodiments of the pharmaceutical combinations or compositions disclosed herein have a daily dose of approximately 40 mg of a PDE5 inhibitor, a daily dose of approximately 500 mg of arginine, and / or a daily dose of approximately 500 mg of N-acetylcysteine.

[0019] In one embodiment, the pharmaceutical combination or pharmaceutical composition disclosed herein is in a liquid formulation, wherein the concentration of sildenafil disclosed herein is about 1 nM to about 1000 nM, the concentration of arginine is 1 μM to 1000 μM, and / or the concentration of N-acetylcysteine ​​is 0.1 mM to 100 mM.

[0020] In one embodiment, the combination or composition disclosed herein is in the form of a solid or liquid formulation (particularly a capsule or tablet or solution for injection or oral administration).

[0021] In one embodiment, the PDE5 inhibitor disclosed herein, or a pharmaceutically acceptable salt thereof, arginine, and N-acetylcysteine are administered simultaneously, sequentially or separately.

[0022] In one embodiment, the PDE5 inhibitor disclosed herein, or a pharmaceutically acceptable salt thereof, is administered simultaneously with N-acetylcysteine.

[0023] In a further embodiment, the PDE5 inhibitor is sildenafil or sildenafil citrate.

[0024] In one embodiment, the combination or composition disclosed herein produces a synergistic effect compared to the PDE5 inhibitor or a pharmaceutically acceptable salt thereof (e.g., sildenafil or sildenafil citrate) alone.

[0025] In one embodiment, the combination or composition disclosed herein is for oral administration.

[0026] In one embodiment, the combination or composition disclosed herein is a unit dosage formulation comprising a fixed dose of 20 mg of the PDE5 inhibitor, 250 mg of arginine and 250 mg of NAC. In a further embodiment, the PDE5 inhibitor is sildenafil. In a further embodiment, the combination or composition disclosed herein is a tablet or a pill.

[0027] In one embodiment, the combination or composition disclosed herein is administered once daily, twice daily, or three times daily; or once weekly, twice weekly, three times weekly, four times weekly, five times weekly, six times weekly, or seven times weekly. In a specific embodiment, the pharmaceutical combination or pharmaceutical composition disclosed herein is administered twice daily.

[0028] In one embodiment, the agents (PDE5 inhibitors, arginine, and NAC) in the combinations or compositions disclosed herein are derivatives of those agents (including, but not limited to, salts, pharmaceutically acceptable salts, solvates, hydrates, esters, tautomers, stereoisomers, enantiomers, or diastereomers thereof). Unless otherwise specified, the agents in the combinations or compositions disclosed herein encompass the above derivatives.

[0029] In further embodiments, the Disclosure provides a fixed-dose formulation comprising a PDE5 inhibitor, arginine, and NAC in a ratio of about 2:about 25:about 25. In one embodiment, the formulation comprises a fixed dose of 20 mg of a PDE5 inhibitor, a fixed dose of 250 mg of arginine, and a fixed dose of 250 mg of NAC. In further embodiments, the PDE5 inhibitor is sildenafil. In further embodiments, the combination or composition disclosed herein is in the form of a tablet or pill. [Brief explanation of the drawing]

[0030] [Figure 1-1] Figures 1A to 1D. Neurite extension by SAN treatment. Figure 1A: After 24 hours of traumatic injury, the blank group showed no effect on neurite extension. In the S-administered group, A-administered group, N-administered group, and SAN-administered group, neurite regeneration in the S-only group was similar to the blank group (see Figure 1B), while the SAN group showed a significant increase in both neurite length and number (see Figures 1C and 1D). Compared to the A+N group, neurites in the SAN group could regenerate up to 50% in number at 1 μg / ml (Figure 1C) and up to 30% in length at 0.5 μg / ml (Figure 1D). [Figure 1-2] Same as above. [Figure 1-3] Same as above. [Figure 1-4] Same as above.

[0031] [Figure 2]Figure 2. SAN restores memory loss. Rats underwent brain injury surgery. After the surgery, these rats were either administered SAN for 28 days or not.

[0032] [Figure 3] Figure 3. Neurite regeneration. The efficacy of the SAN group is favorable compared to the sham group. Neurite regeneration was possible up to 28% in the SAN group, which is 4.5 times higher than the 6% in the sham group.

[0033] [Figure 4] Figure 4. SAN restores memory in rats. Memory function after brain injury was evaluated using the Morris Water Maze (MWM) task. TBI rats were trained for the MWM task at 4 weeks post-injury and tested at 5 weeks post-injury. A total of 18 rats were randomly assigned to the following three groups: 1) Siamese group (N=6): The animals underwent the same surgical procedure to induce brain injury except for the induction of trauma; 2) Injury group (N=6): The animals underwent traumatic brain injury surgery; 3) Injury + SAN group (N=6): Rats with TBI were given oral gavage of SAN daily from day 1 to day 28 post-injury. The average time to return to the floating platform was 12 seconds for the shamese group, 30 seconds for the trauma group (*<0.05), and 18 seconds for the group given SAN after trauma (*<0.05), indicating that the SAN group clearly has the function of restoring memory.

[0034] [Figure 5]Figures 5A and 5B. Recovery of neurite BDNF in rats. Figure 5A: Western blotting analysis. Rats were euthanized by CO2 asphyxiation and their brains were removed. The tissue was homogenized in TEE buffer containing PMSF, and the cell membranes were lysed using Triton® X-100. The lysates were centrifuged for 10 minutes (13000 rpm at 4°C), and the supernatant was collected. Protein concentrations were determined by a BCA assay kit. Proteins were loaded at 80 μg / well onto a 12% SDS-polyacrylamide gel and transferred to a PVDF membrane. Nonspecific reactivity was blocked at room temperature for 1 hour, and primary anti-BDNF and anti-α-tubulin were incubated overnight at 4°C. The membrane was then washed three times for 20 minutes each. A secondary antibody conjugated to horseradish peroxidase (HRP) was used at a 1:10000 dilution. Immunoreactive bands were detected using an ECL system. The total intensity of the bands was analyzed by ImageJ. Figure 5B: Immunohistochemistry. Rats were anesthetized with Zoletil 50 (35 mg / kg) and Rompun (7.5 mg / kg), perfused with PBS (pH 7.4), and then perfused with 4% PFA in PBS. Brains were removed and fixed overnight in 4% PFA at 4°C. The brains were then embedded in OCT (optimal cutting temperature compound) and immersed in liquid nitrogen. Frozen sections were prepared to a thickness of 10 μm and fixed with 4% PFA. Heat-induced antigen retrieval using an autoclave was applied. The sections were immersed in 2N HCl for 30 minutes and placed in 0.1 M borate buffer for 10 minutes. The sections were blocked at 4°C for 24 hours. The sections were incubated with anti-BDNF for 24 hours, and then rinsed three times over 20 minutes each. The sections were incubated with Alexa 488-conjugated goat anti-mouse IgG for 1 hour. The sections were then mounted using DAPI-Fluoromount-G. [Figure 6]Figures 6A and 6B. SAN restores CD68 expression. Figure 6A: Western blotting analysis. Rats were euthanized by CO2 asphyxiation and their brains were removed. The tissue was homogenized in TEE buffer containing PMSF, and the cell membrane was lysed using Triton® X-100. The lysate was centrifuged for 10 minutes (13000 rpm at 4°C), and the supernatant was collected. Protein concentration was determined by a BCA assay kit. Protein was loaded at 80 μg / well onto a 12% SDS-polyacrylamide gel and transferred to a PVDF membrane. Nonspecific reactivity was blocked at room temperature for 1 hour, and primary anti-CD68 and anti-α-tubulin were incubated overnight at 4°C. The membrane was then washed three times for 20 minutes each. A secondary antibody conjugated to horseradish peroxidase (HRP) was used at a 1:10000 dilution. Immunoreactive bands were detected using an ECL system. The total intensity of the bands was analyzed by ImageJ. Figure 6B: Immunohistochemistry. Rats were anesthetized with Zoletil 50 (35 mg / kg) and Rompun (7.5 mg / kg), perfused with PBS (pH 7.4), and then perfused with 4% PFA in PBS. Brains were removed and fixed overnight in 4% PFA at 4°C. The brains were then embedded in OCT (Optimal Cutting Temperature Compound) and immersed in liquid nitrogen. Frozen sections were prepared to a thickness of 10 μm and fixed with 4% PFA. Heat-induced antigen retrieval was performed using an autoclave. The sections were immersed in 2N HCl for 30 minutes and placed in 0.1 M borate buffer for 10 minutes. The sections were blocked at 4°C for 24 hours. The sections were incubated with anti-CD68 for 24 hours, and then rinsed three times for 20 minutes each. The sections were incubated with Alexa 488-conjugated goat anti-mouse IgG for 1 hour. The sections were then mounted using DAPI-Fluoromount-G.

[0035] [Figure 7]Figure 7. SAN induces SOD-1 expression (Western osmosis). Rats were euthanized by CO2 asphyxiation, and their brains were removed. The tissue was homogenized in TEE buffer containing PMSF, and the cell membrane was lysed using Triton® X-100. The lysate was centrifuged for 10 minutes (13000 rpm at 4°C), and the supernatant was collected. Protein concentration was determined by a BCA assay kit. Protein was loaded at 80 μg / well onto a 12% SDS-polyacrylamide gel and transferred to a PVDF membrane. Nonspecific reactivity was blocked at room temperature for 1 hour, and primary anti-SOD-1 and anti-α-tubulin were incubated overnight at 4°C. The membrane was then washed three times over 20 minutes. A secondary antibody conjugated to horseradish peroxidase (HRP) was used at a 1:10000 dilution. Immunoreactive bands were detected using an ECL system. The total intensity of the bands was analyzed by ImageJ. [Modes for carrying out the invention]

[0036] (Details of the invention) Where used herein, “treatment” means a clinical intervention that attempts to alter the natural course of the individual or cell being treated, and which may be performed either preventively or in the course of a clinicopathological condition. Desired treatment effects include prevention of disease onset or recurrence, reduction of symptoms, reduction of any direct or indirect pathological consequences of the disease, prevention or reduction of tissue / organ damage, reduction of disease incidence, improvement or mitigation of disease symptoms, and remission or improved prognosis.

[0037] As used herein as an adjective, the terms “pharmaceutical” or “pharmaceutically acceptable” mean substantially non-toxic and substantially harmless to the recipient. “Pharmaceutical composition” further intends that the carrier, solvent, additives, and salts must be compatible with the active ingredient of the composition (e.g., the compounds of the present invention). It will be understood by those skilled in the art that the terms “pharmaceutical formulation” and “pharmaceutical composition” are generally interchangeable and are used in this manner for the purposes of this application.

[0038] The “individual” or “subject” disclosed herein is a vertebrate. In certain embodiments, the vertebrate is a mammal. Mammals include, but are not limited to, livestock (e.g., cattle), sport animals, pets (e.g., cats, dogs, and horses), primates, mice, and rats. In certain embodiments, the vertebrate is a human.

[0039] As disclosed herein, “effective dose” means an amount that is effective in achieving the desired therapeutic or preventive outcome over the required period of time at a particular dosage. In one embodiment, the PDE5 inhibitor, arginine, and / or NAC in the combination or composition disclosed herein are present in an effective dose.

[0040] The “therapeutic effective dose” of a substance / molecule in this disclosure may vary depending on factors such as the individual’s medical condition, age, sex, and weight, as well as the substance / molecule’s ability to elicit the desired response in that individual. The therapeutic effective dose is also the amount in which the therapeutically beneficial effect outweighs any toxic or adverse effects of the substance / molecule. The “preventive effective dose” refers to the amount that is effective in achieving the desired preventive outcome over the required period of time at a particular dose. Typically, but not always, the preventive effective dose will be smaller than the therapeutic effective dose, as the preventive dose is used in a subject before or at an earlier stage of the disease. In one embodiment, the PDE5 inhibitor, arginine, and / or NAC in the combination or composition disclosed herein are present in a therapeutic effective dose.

[0041] The “combined” administrations disclosed herein include concurrent administrations and sequential administrations in any order. Where used herein, “combination therapy” or “combination” includes the administration of a PDE5 inhibitor, arginine, and NAC as part of a specific treatment regimen intended to provide a beneficial effect from the synergistic action of these agents.

[0042] As used herein, “additives” include pharmaceutically acceptable carriers or stabilizers that are nontoxic to cells or mammals to which they are exposed at the doses and concentrations used. In one embodiment, the physiologically acceptable carrier is a pH-buffered aqueous solution.

[0043] As used in this specification, the term "approximately" refers to a variation of approximately ±1%, ±2%, ±3%, ±4%, ±5%, ±6%, ±7%, ±8%, ±9%, or ±10%.

[0044] As used herein, the term "fixed dose" refers to the presence of two or more distinct components in a single composition in a specific (fixed) ratio with respect to each other.

[0045] Neurological diseases are associated with the death or damage of nerve cells. The loss of dopaminergic neurons in the substantia nigra is the etiology of Parkinson's disease. Although the molecular mechanisms of neurodegeneration in Alzheimer's disease are not yet established, it is clear that brain inflammation, as well as the deposition of β-amyloid protein and other such agents, can inhibit neuronal survival and reduce the growth of neurites used for communication between neurons. Extensive neuronal cell death is observed in patients suffering from cerebral ischemia or spinal cord injury. Currently, there are no satisfactory treatments for these diseases.

[0046] This disclosure has surprisingly found that a combination or composition of a PDE5 inhibitor (preferably sildenafil), arginine, and N-acetylcysteine ​​can promote neurite outgrowth, particularly compared to the administration of the PDE5 inhibitor alone. Accordingly, this disclosure provides a method or use for promoting neurite outgrowth or for treating and / or preventing neuropathy by administering a pharmaceutical combination comprising a PDE5 inhibitor (preferably sildenafil), arginine, and N-acetylcysteine.

[0047] Several phosphodiesterase type 5 (PDE5) inhibitors or pharmaceutically acceptable salts thereof (e.g., sildenafil (SLID), tadalafil, and vardenafil) are approved by health authorities to treat erectile dysfunction. The mechanism by which penile erection occurs is that nitric oxide (NO) diffuses from vascular endothelial cells into the smooth muscle cells of the penis, activating guanylate cyclase (GC), thereby increasing the production of cyclic guanosine monophosphate (cGMP) and inhibiting the influx of calcium ions. This reduces the concentration of calcium ions in the cells, relaxing the smooth muscle of the corpus cavernosum; the corpus cavernosum then becomes congested with a large amount of blood, resulting in an erection, as has been found in previous experiments. For example, sildenafil plays a role in inhibiting the hydrolysis of cGMP, and as a result, its cGMP can continuously act to achieve the effects of congestion and erection. According to the sildenafil package insert, sildenafil does not have a direct relaxant effect on isolated human corpus cavernosum, but enhances the action of nitric oxide (NO) by inhibiting phosphodiesterase type 5 (PDE5), which is responsible for the breakdown of cGMP in the corpus cavernosum. However, sildenafil also has several side effects. It can cause headache, stomach ache, diarrhea, flushing, dizziness, weakness, itching, and erythema after administration. Most of these side effects occur within minutes of ingesting sildenafil. If sildenafil is taken for a long period, severe hypertension may occur, and problems such as transient vision loss and coronary artery sclerosis may increase. These side effects are generally thought to be caused by vasodilation; rapid vasodilation can cause vascular endothelial cells to withstand the pressure from high blood flow, which in turn causes vascular endothelial cells to release endogenous free radicals, thereby causing damage to the vascular cells by these free radicals.

[0048] Arginine is a drug that can be used as an oral tablet or oral capsule. During the erection process, L-arginine can be catalyzed by endothelial nitric oxide synthase to produce nitric oxide, which can be rapidly released into the spaces between cavernous tissues. As a result, the amount of divalent calcium ions in the smooth muscle cells of the cavernous arteries decreases, causing smooth muscle relaxation and increasing blood flow.

[0049] N-acetylcysteine ​​(NAC) has antioxidant properties and can promote the conversion of glutathione disulfide (GSSG) to glutathione (GSH) in cells, and GSH is an essential component for synthesizing the most effective antioxidant enzymes throughout the body. Furthermore, it has been reported that NAC has inhibitory effects on inducible nitric oxide synthase (NOS) protein and NO production (Araki et al., N-acetylcysteine ​​inhibits induction of nitric oxide synthase in 3T3-L1 adipocytes, J UOEH 29(4):417-429(2007); Bergamini et al., N-acetylcysteine ​​inhibits in vivo nitric oxide production by inducible nitric oxide synthase, NITRIC OXIDE: Biology and Chemistry Vol.5, No.4, pp.349-360(2001); Rota et al., N-acetylcysteine ​​negatively modulates nitric oxide production in endotoxin-treated rats through inhibition of NF-κB activation; Antioxidants & Redox Signaling, Vol.4, No.1(2004)). Therefore, NAC causes adverse effects in NO production, which is the opposite of the effect induced by arginine.

[0050] However, this disclosure unexpectedly found that a combination of a PDE5 inhibitor, NAC, and arginine may promote neurite outgrowth or treat and / or prevent neuropathy.

[0051] Examples of the amount or dose of the PDE5 inhibitor used herein in this pharmaceutical combination include approximately 1 mg to approximately 500 mg, approximately 5 mg to approximately 490 mg, approximately 5 mg to approximately 450 mg, approximately 5 mg to approximately 400 mg, approximately 5 mg to approximately 350 mg, approximately 5 mg to approximately 300 mg, approximately 5 mg to approximately 250 mg, approximately 5 mg to approximately 200 mg, approximately 5 mg to approximately 175 mg, approximately 5 mg to approximately 150 mg, approximately 5 mg to approximately 125 mg, approximately 5 mg to approximately 100 mg, approximately 5 mg to approximately 90 mg, approximately 5 mg to approximately 80 mg, approximately 5 mg to approximately 70 mg, approximately 5 mg to approximately 60 mg, approximately 5 mg to approximately 50 mg, and approximately 5mg to about 40mg, about 5mg to about 30mg, about 5mg to about 20mg, about 5mg to about 10mg, about 10mg to about 480mg, about 10mg to about 470mg, about 10mg to about 460mg, about 10mg to about 450mg, about 10mg to about 440mg, about 10mg to about 430mg, about 10m g ~ about 420 mg, about 10 mg - about 410 mg, about 10 mg - about 400 mg, about 10 mg - about 390 mg, about 10 mg - about 380 mg, about 10 mg - about 370 mg, about 10 mg - about 360 mg, about 10 mg - about 350 mg, about 10 mg - about 340 mg, about 10 mg - about 330 mg , about 10mg to about 320mg, about 10mg to about 310mg, about 10mg to about 300mg, about 10mg to about 290mg, about 10mg to about 280mg, about 10mg to about 270mg, about 10mg to about 260mg, about 10mg to about 250mg, about 10mg to about 240mg, about 10mg to about 230mg, about 10mg to about 220mg, about 10mg to about 210mg, about 10mg to about 200mg, about 10mg to about 190mg, about 10mg to about 180mg, about 10mg to about 170mg, about 10mg to about 160mg, about 10mg to about 150mg, about 10mg to about 140mg, about 1 0mg to about 130mg, about 10mg to about 120mg, about 10mg to about 110mg, about 10mg to about 100mg, about 10mg to about 90mg, about 10mg to about 80mg, about 10mg to about 70mg, about 10mg to about 60mg, about 10mg to about 50mg, about 10mg to about 40mg, about 10 mg ~ about 30mg, about 10mg - about 20mg, about 20mg - about 450mg, about 20mg - about 400mg, about 20mg - about 350mg, about 20mg - about 300mg, about 20mg - about 250mg, about 20mg - about 200mg, about 20mg - about 175mg, about 20mg - about 150mg,Approximately 20mg to approximately 125mg, approximately 20mg to approximately 100mg, approximately 20mg to approximately 90mg, approximately 20mg to approximately 80mg, approximately 20mg to approximately 70mg, approximately 20mg to approximately 60mg, Approximately 20mg to approximately 50mg, approximately 20mg to approximately 40mg, approximately 20mg to approximately 30mg, approximately 50mg to approximately 450mg, approximately 50mg to approximately 400mg, approximately 50mg to approximately 350mg, Approximately 50mg to approximately 300mg, approximately 50mg to approximately 250mg, approximately 50mg to approximately 200mg, approximately 50mg to approximately 175mg, approximately 50mg to approximately 150mg, approximately 50mg to approximately 125 mg, about 50mg to about 100mg, about 50mg to about 90mg, about 50mg to about 80mg, about 50mg to about 70mg, about 50mg to about 60mg, about 100mg to about 450 Examples include, but are not limited to, mg, approximately 100mg to 400mg, approximately 100mg to 350mg, approximately 100mg to 300mg, approximately 100mg to 250mg, approximately 100mg to 200mg, approximately 100mg to 175mg, approximately 100mg to 150mg, approximately 100mg to 125mg, or approximately 1mg, 2mg, 3mg, 4mg, 5mg, 6mg, 7mg, 8mg, 9mg, 10mg, 15mg, 20mg, 25mg, 30mg, 35mg, 40mg, 45mg, 50mg, 55mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, or approximately 100mg.

[0052] Examples of the amounts or doses of arginine or N-acetylcysteine ​​used in this pharmaceutical combination as described herein include approximately 10 mg to 2 g, approximately 10 mg to 1.9 g, approximately 10 mg to 1.8 g, approximately 10 mg to 1.7 g, approximately 10 mg to 1.6 g, approximately 10 mg to 1.5 g, approximately 10 mg to 1.4 g, approximately 10 mg to 1.3 g, approximately 10 mg to 1.2 g, approximately 10 mg to 1.1 g, approximately 10 mg to 1.0 g, and approximately 10 mg to 900 mg. Approximately 10mg to approximately 800mg, approximately 10mg to approximately 700mg, approximately 10mg to approximately 600mg, approximately 10mg to approximately 500mg, approximately 10mg to approximately 400mg, approximately 10mg to approximately 300mg, approximately 10mg to approximately 200mg, approximately 10mg to approximately 100mg , about 10mg to about 50mg, about 10mg to about 25mg, about 100mg to about 2g, about 100mg to about 1.9g, about 100mg to about 1.8g, about 100mg to about 1.7g, about 100mg to about 1.6g, about 100mg to about 1.5g, about 1 00mg~about 1.4g, about 100mg~about 1.3g, about 100mg~about 1.2g, about 100mg~about 1.1g, about 100mg~about 1.0g, about 100mg~about 900mg, about 100mg~about 800mg, about 100mg~about 700m g, about 100mg to about 600mg, about 100mg to about 500mg, about 100mg to about 400mg, about 100mg to about 300mg, about 100mg to about 200mg, or about 2g, about 1.9g, about 1.8g, about 1.7g, about 1.6g, Examples include, but are not limited to, approximately 1.5g, 1.4g, 1.3g, 1.2g, 1.1g, or 1.0g, or approximately 950mg, 900mg, 850mg, 800mg, 750mg, 700mg, 650mg, 600mg, 550mg, 500mg, 450mg, 400mg, 350mg, 300mg, 250mg, 200mg, 150mg, 100mg, 50mg, 25mg, or 10mg.

[0053] The combinations or compositions disclosed herein generally include one or more pharmaceutically acceptable additives, carriers, or diluents. The specific carrier, diluent, or additive used depends on the meaning and purpose to which the active ingredient is applied. Generally, tablet formulations include substances such as diluents, binders, lubricants, disintegrants, and mixtures thereof. Suitable diluents include various types of starch, lactose, mannitol, kaolin, calcium phosphate or calcium sulfate, inorganic salts (e.g., sodium chloride), powdered sugar, and powdered cellulose derivatives. More specifically, examples of diluents or fillers include lactose, mannitol, xylitol, dextrose, sucrose, sorbitol, compressed sugar, microcrystalline cellulose, powdered cellulose, starch, pregelatinized starch, dextrate, dextran, dextrin, dextrose, maltodextrin, calcium carbonate, calcium hydrogen phosphate, tricalcium phosphate, calcium sulfate, magnesium carbonate, magnesium oxide, poloxamer, and, for example, polyethylene oxide and hydroxypropyl methylcellulose. A binder may be added if desired. Suitable binders include celluloses (e.g., cellulose, methylcellulose, ethylcellulose, and hydroxymethylcellulose), polypropylpyrrolidone, polyvinylpyrrolidone, gelatin, gum arabic, polyethylene glycol, starch, sugars (e.g., lactose, sucrose, fructose, and glucose), natural and synthetic gums (e.g., acacia gum, alginates, and gum arabic), and waxes. Lubricants are typically used in tablet formulations to prevent tablets and punches from sticking together in the die.Suitable lubricants include calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated vegetable oil, light mineral oil, magnesium stearate, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc, and zinc stearate. Disintegrants may also be added to the combination or composition to disintegrate the dosage form and release the compound. Suitable disintegrants include sodium starch glycolate, sodium carboxymethylcellulose, calcium carboxymethylcellulose, sodium croscarmellose, polyvinylpyrrolidone, methylcellulose, microcrystalline cellulose, powdered cellulose, lower alkyl-substituted hydroxypropyl cellulose, potassium polaritrin, starch, pregelatinized starch, and sodium alginate.

[0054] Combinations or compositions of PDE5 inhibitors, such as those combining arginine and NAC, are useful in promoting neurite outgrowth or in treating and / or preventing neuropathy. Surprisingly, combinations or compositions of NAC and arginine may enhance the effects of PDE5 inhibitors while simultaneously reducing their adverse effects.

[0055] Neurological disorders are diseases of the central nervous system and the peripheral nervous system. In other words, they affect the brain, spinal cord, cranial nerves, peripheral nerves, nerve roots, autonomic nervous system, neuromuscular junctions, and muscles. These disorders include epilepsy, Alzheimer's disease and other dementias, cerebrovascular diseases (including stroke, migraines and other headache disorders), multiple sclerosis, Parkinson's disease, neuroinfections, brain tumors, traumatic injuries to the nervous system resulting from head injuries, and neurological disorders resulting from malnutrition.

[0056] Many bacterial infections (i.e., Mycobacterial tuberculosis, Neisseria meningitides), viral infections (i.e., human immunodeficiency virus (HIV), enterovirus, West Nile virus, Zika virus), fungal infections (i.e., Cryptococcus, Aspergillus), and parasitic infections (i.e., malaria, Chagas disease) can affect the nervous system. Neurological symptoms can result from the infection itself or from the immune response.

[0057] The biological effects of this combination include, but are not limited to, the pharmacokinetic and / or pharmacodynamic synergies resulting from the combination of the above-mentioned drugs. Administration of these combined drugs is typically carried out over a prescribed period (usually minutes, hours, days, or weeks, depending on the selected combination). Combination therapy is intended to encompass the administration of the indicated therapeutic agents in a contemporaneous, sequential, or separate manner. For example, each therapeutic agent may be administered at separate time points, and moreover, the administration of these therapeutic agents may be substantially simultaneous. Sequential, contemporaneous, or separate administration of each therapeutic agent may be carried out by any appropriate route (including, but not limited to, oral, intravenous, intramuscular, and direct absorption through mucosal tissue).

[0058] Administration can be achieved, for example, by administering to a subject a single oral dosage form having each drug in a fixed ratio, or a plurality of single oral dosage forms for each of those therapeutic agents. In one embodiment of a fixed-dose formulation, the PDE5 inhibitor, arginine, and NAC are contained in a ratio of about 2:about 25:about 25. In particular, the formulation contains a fixed dose of 20 mg of the PDE5 inhibitor, a fixed dose of 250 mg of arginine, and a fixed dose of 250 mg of NAC. In a further embodiment, the PDE5 inhibitor is sildenafil. In a further embodiment, the composition, combination, or formulation disclosed herein is a tablet or pill.

[0059] In another embodiment, the combinations and compositions of the present disclosure may be administered parenterally (e.g., by intramuscular, intrathecal, intravenous, and intraarterial routes), preferably intravenously. Typically, the compounds and compositions of the present invention for intravenous administration are solutions in a sterile isotonic aqueous vehicle (e.g., water, saline, Ringer's solution, or dextrose solution). If necessary, the composition may also include a solubilizer. The combinations and compositions for intravenous administration may optionally include a local anesthetic (e.g., lignocaine) to relieve pain at the injection site. For intravenous administration, the combinations and compositions of the present disclosure may be supplied as sterile lyophilized powder or water-free concentrate in a sealed container (e.g., an ampoule or sachet), the container indicating the amount of the active agent. Such powder or concentrate is then diluted with a suitable aqueous medium before intravenous administration. One ampoule of sterile water, saline solution, or other suitable aqueous medium may be supplied with the powder or concentrate for dilution before administration. Alternatively, the combinations and compositions of the present disclosure may be supplied in a pre-mixed form, ready for administration. Where the combinations and compositions of the present disclosure are to be administered by intravenous infusion, they may be dispensed in an infusion bottle containing, for example, sterile pharmaceutical-grade water, saline, or another suitable medium. Rectal administration may be performed through the use of suppositories formulated from conventional carriers (e.g., cocoa butter, modified vegetable oils, and other fatty acid bases). Suppositories may be formulated by known methods using known formulations; see, for example, Remington: The Science and Practice of Pharmacy, Alfonso R. Gennaro ed., Mack Publishing Co. Easton, Pa., 19th ed., 1995, pp. 1591–1597 (incorporated herein by reference).

[0060] A therapeutically effective dosing regimen for treating a particular disorder or condition depends on its nature and severity and can be determined by standard clinical techniques according to the judgment of a healthcare professional. Furthermore, in vitro or in vivo assays may be used to assist in identifying the optimal dosage. Naturally, the amount of the compound of the present invention constituting a therapeutically effective dose also depends on the route of administration.

[0061] The following embodiments are provided for illustrative purposes only and are not intended to limit the scope of the present invention. [Examples]

[0062] (Experimental method)

[0063] (Preparation of drugs)

[0064] Sildenafil (S), arginine (A), N-acetylcysteine ​​(N), and S-nitroso-N-acetylpenicillamine (SNAP) were dissolved and diluted in phosphate-buffered saline (PBS). In particular, the following solutions are prepared for cell culture: a solution containing 100 nM sildenafil (hereinafter referred to herein as SILD or "S"); a mixed solution of 100 nM sildenafil and 10 mM N-acetylcysteine ​​(hereinafter referred to herein as "SN"); a mixed solution of 100 nM sildenafil, 150 μM arginine and 10 mM N-acetylcysteine ​​(hereinafter referred to herein as "SAN"); a mixed solution of 100 nM sildenafil and 100 μM S-nitroso-N-acetylpenicillamine (SNAP) (hereinafter referred to herein as "SS"); and a mixed solution of 100 nM sildenafil, 100 μM SNAP and 10 mM N-acetylcysteine ​​(hereinafter referred to herein as "SSN"). For animal models, SANs are a mixture of sildenafil (0.33 mg / kg) + arginine (60 mg / kg) + N-acetylcysteine ​​(60 mg / kg), a mixture of sildenafil (3.3 mg / kg) + arginine (60 mg / kg) + N-acetylcysteine ​​(60 mg / kg), and a mixture of sildenafil (33 mg / kg) + arginine (60 mg / kg) + N-acetylcysteine ​​(60 mg / kg). These solutions are stored at 4°C. For clinical and human studies, a combination of SANs containing 20 mg of sildenafil, 250 mg of arginine, and 250 mg of NAC is used and applied to the subjects.

[0065] (cell culture)

[0066] Primary cortical cells were isolated from 18-day-old (E18) Sprague-Dawley rats and placed on a 24-well plate in a 2×10⁶ arrangement. 5 Cell density per well, or 6 × 10 on a 6-well plate. 5 Cells / well density, or 6 × 10 in a 35 mm glass-bottomed Petri dish coated with 0.1 mg / mL poly-D-lysine (Sigma-Aldrich). 5Cells were seeded at a cell / dish density. Neurons were cultured in Neurobasal medium (Invitrogen) containing B27 supplement (Invitrogen), GlutaMax reagent (Invitrogen), and penicillin / streptomycin (P / S, Sigma-Aldrich). Cells were incubated in a 5% CO2 atmosphere for 37 minutes. o It was propagated using C.

[0067] (In vitro model of traumatic injury)

[0068] In DIV16, cells were pre-treated for 48 hours with various concentrations of SAN (0, 0.01 μM sildenafil + 150 μM arginine and 10 mM N-acetylcysteine, 0.1 μM sildenafil + 150 μM arginine and 10 mM N-acetylcysteine, 0.5 μM sildenafil + 150 μM arginine and 10 mM N-acetylcysteine, 1 μM sildenafil + 150 μM arginine and 10 mM N-acetylcysteine). In DIV17, cell-free areas were created by gently scratching the cell monolayer with a sterile 200 μL Gilson pipette tip. After 10 minutes, the cells were returned to recovery medium containing the same concentrations of SAN as above for a further 24 hours. Nerve outgrowth was observed using a microscope 24 hours after neurite injury. The number and length of neurite extensions were measured using ImageJ.

[0069] (Fluorescence image)

[0070] After treatment with SAN, fixed neurons were stained with mouse anti-MAP2 (1:500, Abcam), followed by secondary antibody staining. Cell nuclei were stained with 300 nM 4',6-diamidino-2-phenylindole (DAPI) (Sigma-Aldrich). Stained neurons were observed at 200× magnification on an Olympus IX51 microscope.

[0071] (Animal model of traumatic brain injury)

[0072] The animals were deeply anesthetized using an intraperitoneal injection of a combination of Zoletil 50 (35 mg / kg) and Rompun (7.5 mg / kg). Once deep anesthesia was achieved, each animal was fixed in a stereotactic frame (World Precision Instruments (WPI)). Using aseptic procedures, a midline scalp incision was made, and its skin and fascia were reflected backward to expose the skull. Using a WPI surgical drill, a hole was carefully drilled through the skull, above the CA1 region of the hippocampus. A syringe (25 gauge, SGE Analytical Science) was inserted into the hole using the following coordinates: AP -3.6 mm from the bregma; ML ±1.5 mm from the midline; DV -4 mm from the dura mater. After 10 minutes, the syringe was slowly removed and the hole was filled with gelfoam. The skin was then pulled back over the skull and held together with two staples. The animals were randomly divided into eight groups: 1) Siamese (n=6); the same surgical procedure to induce brain injury was performed on the animals, except for the induction of trauma. 2) Injured (n=6); the animals underwent traumatic brain injury surgery. 3) Injured + Post-treatment SAN (n=6); TBI animals that received SAN via oral gastric tube daily for 28 days after the trauma.

[0073] (immunohistochemistry)

[0074] Under anesthesia with Zoletil 50 (35 mg / kg) and Rompun (7.5 mg / kg), rats were perfused with PBS (pH 7.4), followed by perfusion with 4% PFA in PBS. The brains were removed and fixed overnight in 4% PFA at 4°C. The brains were then embedded in OCT (Optimal Cutting Temperature Compound) and immersed in liquid nitrogen. Frozen sections were prepared to a thickness of 10 μm and fixed with 4% PFA. Heat-induced antigen retrieval using an autoclave was applied. The sections were immersed in 2N HCl for 30 minutes and placed in 0.1 M borate buffer for 10 minutes. The sections were blocked at 4°C for 24 hours. The sections were incubated with antibody (anti-MAP-2) for 24 hours, followed by rinsing the sections three times for 20 minutes each. The sections were incubated with secondary antibody for 1 hour. Before using a microscope, the sections were mounted using DAPI-Fluoromount-G.

[0075] (Morris water maze challenge)

[0076] The Morris Water Maze (MWM) was initiated on the fourth day after injury. The water maze consisted of a black circular pool (160 cm in diameter, 45 cm deep). This pool was divided into four equally spaced quadrants. The pool was filled with water (25±2°C) to a depth of 27 cm. A circular platform (12 cm in diameter, 25 cm deep) was submerged 2 cm below the water surface and positioned in a fixed location (50.8 cm from the wall) within quadrant III. A camera was mounted above the center of the pool and analyzed using Ethovision XT v 10.0 software. Acquisition trials were conducted over four consecutive days. Rats underwent four consecutive training trials on each training day. Each trial used a different starting position and consisted of swimming followed by remaining on the platform for at least 20 seconds. If a rat failed to reach the platform within 60 seconds, it was guided to the platform. The time to reach the platform (latency in seconds) and the length of the path were measured. After the imaging trials, the platform was removed from the pool. The rats were allowed to swim for 60 seconds. The frequency of reaching the platform, the time to the first arrival at the platform (latency), and the swimming path were measured.

[0077] (Hematoxylin-eosin staining)

[0078] Under anesthesia with Zoletil 50 (35 mg / kg) and Rompun (7.5 mg / kg), rats were perfused with PBS (pH 7.4), followed by perfusion with 4% PFA in PBS. The brains were removed and fixed overnight in 4% PFA at 4°C. The brains were then embedded in OCT (Optimal Cutting Temperature Compound) and immersed in liquid nitrogen. Frozen sections were prepared to a thickness of 10 μm and fixed with 4% PFA. These sections were immersed in hematoxylin for 10 minutes, followed by rinsing with ddH2O for 1 minute. These sections were stained with eosin for 5 minutes and dehydrated with ethanol. These sections were immersed twice in xylene for 1 minute each and mounted with Entellan.

[0079] (Western analysis)

[0080] Rats were euthanized by CO2 asphyxiation, and their brains were removed. The tissue was homogenized in TEE buffer containing PMSF, and the cell membranes were lysed using Triton® X-100. The lysates were centrifuged for 10 minutes (13000 rpm at 4°C), and the supernatant was collected. Protein concentrations were determined by a BCA assay kit. Proteins were loaded at 80 μg / well onto a 12% SDS-polyacrylamide gel and transferred to a PVDF membrane. Nonspecific reactivity was blocked at room temperature for 1 hour, and primary anti-BDNF, anti-CD68, and anti-α-tubulin were incubated overnight at 4°C. The membrane was then washed three times for 20 minutes each. Secondary antibodies conjugated to horseradish peroxidase (HRP) were used at a 1:10000 dilution. Immunoreactive bands were detected using an ECL system. The total intensity of the bands was analyzed by ImageJ.

[0081] (immunohistochemistry)

[0082] Rats were anesthetized with Zoletil 50 (35 mg / kg) and Rompun (7.5 mg / kg), perfused with PBS (pH 7.4), and then perfused with 4% PFA in PBS. The brains were removed and fixed overnight in 4% PFA at 4°C. The brains were then embedded in OCT (Optimal Cutting Temperature Compound) and immersed in liquid nitrogen. Frozen sections were prepared to a thickness of 10 μm and fixed with 4% PFA. Heat-induced antigen retrieval using an autoclave was applied. The sections were immersed in 2N HCl for 30 minutes and placed in 0.1 M borate buffer for 10 minutes. The sections were blocked at 4°C for 24 hours. The sections were incubated with antibodies (anti-BDNF, anti-CD68) for 24 hours, and then the sections were rinsed three times for 20 minutes each. The sections were incubated with Alexa 488-conjugated goat anti-mouse IgG for 1 hour. Before microscopy, the sections were mounted using DAPI-Fluoromount-G.

[0083] (Experimental results)

[0084] (Example 1. In vitro neurite regeneration assay)

[0085] To test neurite regeneration in vitro, a traumatic injury assay was performed. This assay has been used in previous reports to test cell migration and neurite extension (Loh SH, Francescut L, Lingor P, Bahr M, Nicotera P (2008), Cell Death Differ 15:283-298; Wu CL, Chou YH, Chan Tseng CY, Firestein BL (2011) J Neurosci 31:15468-15480g; YJ, Teng NY, Hsu HL, Chen L (2012) PLoS One 7:e34999). As shown in Figure 1A, after 24 hours of traumatic injury, the blank group showed no effect on neurite extension. In the S-administered, A-administered, N-administered, and SAN-administered groups, neurite regeneration in the S-only group was similar to that of the blank group (see Figure 1B), while the SAN group showed a significant increase in both neurite length and number (see Figures 1C and 1D). Compared to the A+N group, neurites in the SAN group could regenerate up to 50% in number at 1 μg / ml (Figure 1C) and up to 30% in length at 0.5 μg / ml (Figure 1D).

[0086] (Example 2. SAN restores memory loss)

[0087] Rats were subjected to brain injury surgery. After the surgery, these rats were either administered SAN for 28 days or not. As shown in Figure 2, the efficacy of the treatment in the SAN group was favorable compared to the sham group. Neurite regeneration in the SAN group was up to 28%, which is 4.5 times higher than the 6% in the sham group (Figure 3).

[0088] Twenty-eight days after brain injury, the inventors tested the memory capacity of rats using the MWM water maze method. It was found that the speed at which rats returned to the floating platform was fastest in the sham group, followed by the post-traumatic SAN group, and slowest in the trauma group. As shown in Figure 4, the average time to return to the floating platform was 12 seconds for the sham group and 30 seconds for the trauma group. * (<0.05) For the group that received SAN after trauma, the time was 18 seconds ( * <0.05), the SAN group clearly possesses the function of recovering memories.

[0089] (Example 3. Restoration of neurites in rats)

[0090] In the process of repairing the nervous system, the nerve growth factor BDNF plays a crucial role, and BDNF secretion can support the repair of the nervous system. From the protein expression in whole brain tissue in Figure 5A, we can see that there are no significant differences in BDNF expression across all groups. However, in post-treatment, BDNF secretion tended to gradually increase with the dose of SAN. In Figure 5B, we measured BDNF using fluorescence and analyzed its expression location. We found that while BDNF is uniformly distributed throughout the whole brain, in injured brains, BDNF secretion is concentrated in the injured area, which may explain the absence of significant differences in BDNF expression in the whole brain alone.

[0091] In the process of nerve injury and repair, the quality of wound repair depends on the activity of astrocytes. The inventors used CD68, a biological indicator of astrocytes, to determine its activity. Based on the expression response of CD68, a whole-brain tissue protein, in Figure 6A, the inventors found that CD68 levels were significantly increased in the trauma group, pre-treatment (0.33 mg / kg, 33 mg / kg), and post-treatment (33 mg / kg) compared to the blank group (Ψ<0.05); after SAN, both pre-treatment (0.33 mg / kg, 3.3 mg / kg) and post-treatment (0.33 mg / kg, 3.3 mg / kg) levels were significantly decreased. *The inventors found that the pre-treatment (3.3 mg / kg) group, the post-treatment (3.3 mg / kg) group, and the sham group were not significantly different (#>0.05). In Figure 6B, the inventors measured CD68 using a fluorescent marker and analyzed its expression location. They found that CD68 secretion was not high in the uninjured brain, but in the traumatized brain, a large amount of CD68 was secreted, and its location was also concentrated in the traumatized area.

[0092] Regarding the antioxidant effects in the wound area, the inventors analyzed SOD-1, an antioxidant protein in the brain, to determine whether SAN administration could help the rat brain perform antioxidant action against unnecessary oxidative stress. As shown in Figure 7, SOD-1 protein expression in whole brain tissue was significantly improved in the medium-dose and high-dose pre-treatment and post-treatment groups, specifically at 3.3 mg / kg. * It was found that the value was <0.05.

[0093] The above description and examples are merely illustrative of preferred embodiments of the present invention. Those skilled in the art can carry out modifications in accordance with the general knowledge and the invention herein, but these modifications still remain within the scope of the invention herein in terms of the spirit of the invention.

Claims

1. A method for promoting neurite outgrowth, A process of exposing neurons to an effective amount of a pharmaceutical combination comprising a phosphodiesterase type 5 (PDE5) inhibitor or a pharmaceutically acceptable salt thereof, arginine, and N-acetylcysteine. Methods that include...

2. A method for treating and / or preventing neuropathy or nerve injury by promoting neurite outgrowth, A process of administering an effective amount of a pharmaceutical combination containing a phosphodiesterase type 5 (PDE5) inhibitor or a pharmaceutically acceptable salt thereof, arginine, and N-acetylcysteine ​​to a subject in need thereof. Methods that include...

3. The method according to claim 2, wherein the neurological disorder or injury mediated by the promotion of neurite outgrowth is epilepsy, Alzheimer's disease and other dementias, cerebrovascular diseases including stroke, migraine and other headache disorders, multiple sclerosis, Parkinson's disease, neuroinfections, brain tumors, traumatic injuries of the nervous system resulting from head trauma, Huntington's disease, ALS, multiple sclerosis, ischemia associated with stroke, neuroparopathy, motor neuron disease, sciatic nerve contusion, peripheral neuropathy, diabetes-related neuropathy, spinal cord injury and facial nerve contusion to the nervous system caused by physical, mechanical or chemical trauma, memory loss, or mental disorders, intracranial hemorrhage, spinal cord injury, or neurological symptoms resulting from infection or immune response.

4. The method according to claim 2, wherein the nerve disorder or nerve injury is a central nervous system (CNS) disorder or central nervous system (CNS) injury, which is a peripheral nerve injury caused by bodily injury (e.g., related to burns, wounds, surgery, and accidents), ischemia, prolonged exposure to cold (e.g., frostbite), damage to the central nervous system resulting from, for example, stroke or intracranial hemorrhage (e.g., cerebral hemorrhage), dementia, Alzheimer's disease, Huntington's disease, or Parkinson's disease.

5. The method according to claim 3, wherein the nerve disorder or nerve injury is a stroke or intracranial hemorrhage.

6. The method according to any one of the preceding claims, wherein the PDE5 inhibitor is selected from sildenafil, tadalafil, and vardenafil.

7. The amount of the PDE5 inhibitor is in the range of approximately 0.1% (w / w) to approximately 50% (w / w), the amount of arginine is in the range of approximately 4.0% (w / w) to approximately 80% (w / w), and the amount of N-acetylcysteine ​​is in the range of approximately 4% (w / w) to approximately 80% (w / w); or The aforementioned pharmaceutical combination comprises approximately 0.5 mg to approximately 250 mg of the PDE5 inhibitor, approximately 25 mg to approximately 400 mg of arginine, and approximately 25 mg to approximately 400 mg of N-acetylcysteine. The method according to any of the prior claims.

8. The method according to any of the preceding claims, wherein the pharmaceutical combination is in the form of a solid or liquid formulation.

9. The method according to any of the preceding claims, wherein the pharmaceutical combination is a capsule or a tablet.

10. The method according to any one of the preceding claims, wherein the PDE5 inhibitor or a pharmaceutically acceptable salt, arginine, and N-acetylcysteine ​​are administered simultaneously, sequentially, or separately.

11. The method according to any one of the preceding claims, wherein the PDE5 inhibitor is sildenafil or sildenafil citrate.

12. The method according to any of the preceding claims, wherein the pharmaceutical combination is administered twice a day.

13. The method according to any of the preceding claims, wherein the pharmaceutical combination is a fixed-dose formulation.

14. The method according to claim 13, wherein the formulation comprises a fixed dose of 20 mg of a PDE5 inhibitor, a fixed dose of 250 mg of arginine, and a fixed dose of 250 mg of NAC.

15. The method according to claim 14, wherein the PDE5 inhibitor is sildenafil.

16. The method according to claim 15, wherein the preparation is a tablet or a pill.

17. A fixed-dose formulation containing a PDE5 inhibitor, arginine, and NAC in a ratio of approximately 2:25:

25.

18. The fixed-dose formulation according to claim 17, wherein the PDE5 inhibitor is sildenafil.

19. A fixed-dose formulation according to claim 17, in the form of a tablet or pill.

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