Since corneal nerve is severed by corneal surgeries such as laser photorefractive keratectomy (PRK), laser-assisted-in-situ keratomileusis (LASIK), laser epithelial keratomileusis (LASEK) and keratoplasty, the corneal sensitivity does not recover generally for about 3 weeks to 1 year. It has been reported, for example, that after LASIK, the corneal nerve is apparently severed (Non-patent Document 1), and that corneal sensitivity decreases in a corneal region where, after LASIK, neurogram is not observed or the nerve bundle is too short to create connection (Non-patent Document 2).
It has been demonstrated that the corneal hyposensitivity after PRK and LASIK causes lower lacrimal gland responses and decreased lacrimal fluid (Non-patent Document 3). As a result of the functional decrease of corneal sensitivity, patients after a corneal surgery blink less number of times, problematically showing the symptoms of dry eye. In dry eye patients, lacrimal hypofunction gives rise to pathological changes in the corneal epithelium and decreased corneal sensitivity (Non-patent Document 4). Specifically, it is problematic that decreased corneal sensitivity diminishes lacrimation and makes corneal surface symptoms severe. Other reports state that corneal wound cure is hampered due to dry eyes caused by PRK and LASIK (Non-patent Document 3), and that recurrent corneal erosions were observed after LASIK surgery (Non-patent Document 5).
At present, however, recovery of corneal sensitivity that has decreased after a corneal surgery is left to spontaneous recovery, and no active treatment is provided to recover corneal sensitivity in the treatment of dry eyes. In addition, corneal hyposensitivity is caused by the diseases accompanying corneal neurodegeneration, such as neuroparalytic keratopathy, corneal ulcer, and diabetic keratopathy, but no appropriate therapies are available. Regarding corneal nerves, it has been reported that the nerves derived from the first branch (ophthalmic branch) that bifurcates at the trigeminal ganglion are mostly distributed in the cornea and profoundly involved in postoperative restoration of corneal sensation, repair of corneal epithelium, and the like (Non-patent Document 4).
Retinal ganglion cells are the output cells of the retina; the neurites thereof, also called as optic nerve fibers, run in the retinal inner layer and nerve fiber layer (the side closest to the vitreous body) and assemble in the optic disc, then leave the eyeball and form optic nerves, thus playing a role in transmitting visual information to the cerebral cortex. It is known that various retinal diseases, increased intraocular pressure (glaucoma) and the like cause optic nerve atrophy and degeneration, resulting in visual dysfunctions. Drugs that allow the function of the visual information transmission pathway in the retina to be restored, particularly drugs capable of neogenesis and promoted elongation of retinal nerve cell neurites, are possibly useful against these visual dysfunctions.
N-(1-acetylpiperidin-4-yl)-4-fluorobenzamide is a compound exhibiting an enhancing action of the cholinergic activity (Patent Document 1). This amide compound is a compound expected to be useful for treating disorders in mammalian central nervous systems, more specifically of amnesia, dementia and the like. It has also been demonstrated that this amide compound may enhance the release of somatostatin in experiments using rat hippocampal slices, inhibit the calcium influx suppression induced by somatostatin in the rat hippocampal neuron, and improve cognitive dysfunctions via activation of the somatostatin neurotransmission system (Non-patent Document 6, Patent Document 2). It is also known that N-(1-acetylpiperazin-4-yl)-4-fluorobenzamide is used as a promoter for producing a neurotrophic factor (Patent Document 3).
Somatostatin is known to promote neuritogenesis of rabbit trigeminal nerve cell in in vitro experiments, and administration of somatostatin by instillation is known to improve corneal sensitivity function in in vivo tests using rabbits (Patent Document 4, particularly Test Example 2 and Test Example 3). However, N-(1-acetylpiperidin-4-yl)-4-fluorobenzamide is not known to enhance the release of somatostatin in ocular tissue nerve cells, nor to promote neuritogenesis.    patent reference 1: WO2000/042011    patent reference 2: WO2000/072834    patent reference 3: WO2003/084542    patent reference 4: WO2004/039403    non-patent reference 1: Tuuli, U. L. et al., Experimental Eye Research 1998, 66, pp. 755-763    non-patent reference 2: Tuuli, U. L. et al., Investigative Opthalmology & Visual Science 2000, 41, pp. 393-397    non-patent reference 3: Ang, R. T. et al., Current Opinion in Opthalmology 2001, 12, pp. 318-322    non-patent reference 4: Xu, K.-T. et al., Cornea 1996, 15, pp. 235-239    non-patent reference 5: Solomon, R. et al., The Ocular Surface 2004, 2, pp. 34-42    non-patent reference 6: Tokita, K. et al., European Journal of Pharmacology 2005, 527, pp. 111-120
USPTO Backgrounds
USPTO Backgrounds