JP2003081874A - Optic nerve protecting agent containing alpha 1-receptor blocking drug as active ingredient - Google Patents

Abstract

PROBLEM TO BE SOLVED: To find a new pharmacological effect of an alpha 1-receptor blocking drug. SOLUTION: Alpha 1-receptor blocking drugs was studied for their new pharmacological effects, and it was found that they have an optical nerve protecting effect. Accordingly, an alpha 1-receptor blocking drug is useful as an optical nerve protecting agent for treating normal intraocular pressure glaucoma, and retinal diseases represented by retinal vascular occlusion, diabetic retinopathy, ischemic optic neuropathy, macular degeneration, retinal pigmentary degeneration and Leber's disease.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to an optic nerve protecting agent containing an α ₁ receptor blocker as an active ingredient.

[0002]

2. Description of the Related Art The human optic nerve consists of about 1 million optic nerve fibers, and if 30% of the optic nerve fibers are damaged, an abnormality can be detected by a static perimeter, and if 50% of them are damaged by a dynamic perimeter, It is said that the visual field will be affected. Optic nerve fibers consist of axons of optic ganglion cells and reach the lateral geniculate body. Optic ganglion cells can be classified into several types anatomically and physiologically, and axons originating from them have different morphologies and possess functions. The disorder of the optic nerve is basically that the axon flow is invaded, and the axon flow disorder site is the lamina cribrosa. Impairment of axon flow means death of optic nerve cells, and it has been suggested that apoptosis is involved in this (New Ophthalmology, 16 (6) 833-84).
1). When optic nerve cells are damaged, visual field damage and various retinal disorders may occur, which may ultimately lead to blindness. Therefore, development of an optic nerve protective agent that protects optic nerve cells and prevents their death is desired.

The α ₁ receptor blocker binds to the adrenergic α ₁ receptor to suppress neurotransmission, and is mainly used as an antihypertensive drug. Bunazosin, an α ₁ receptor blocker, is marketed as a blood pressure lowering agent. In addition, it has been reported in Japanese Patent No. 2610619 that bunazosin has an intraocular pressure lowering action and is useful for treating ocular hypertension. Furthermore, the formulation for applying bunazosin to eye drops is Japanese Patent Publication 7-
23302. In addition, terazosin (WO95 / 31200), which is an α ₁ receptor blocker,
It has been reported that prazosin (US Pat. No. 4,197,301) and dapiprazole (JP-A-54-157576) have an intraocular pressure-lowering effect.

[0004] In general, glaucoma is a disease in which optic nerve fibers are organically impaired in the optic papilla due to an increase in intraocular pressure, resulting in papilla depression and retinal nerve fiber loss, which eventually causes visual field impairment. Has been done. Therefore, finding a method of indirectly preventing visual field damage by suppressing an increase in intraocular pressure has become the mainstream of glaucoma research.

If a drug capable of actively protecting optic nerve cells is found, it is expected that the visual field disorder can be directly prevented.

Recently, a disease which causes a change in the nipple and a change in the visual field despite the fact that the intraocular pressure does not rise has been noted, and this disease is called normal tension glaucoma. Normal-tension glaucoma, while the intraocular pressure is always within the normal range (21 mmHg or less),
It is a disease in which the optic nerve is damaged and the visual field is lost. In the treatment of this normal-tension glaucoma, it is also necessary to lower the intraocular pressure, and intraocular pressure-lowering agents have been administered, but if a drug that can protect the optic nerve is found, the visual field disorder can be directly treated. Since it can be prevented or can be a more useful drug, it is desired to develop a drug having such an effect.

In retinal diseases, retinal blood flow circulatory disorders occupy a particularly important position in retinal diseases. Due to this impaired blood flow in the retina, the supply of oxygen and nutrients becomes insufficient,
Retinal ganglion cells die. Typical examples of symptoms associated with impaired retinal blood circulation are retinal vascular occlusions in which retinal veins and arteries are occluded or narrowed, diabetic retinopathy that contributes to retinal detachment, and ischemic dysfunction that causes visual impairment. If you have optic neuropathy. In other retinal diseases such as macular degeneration, retinitis pigmentosa, and Leber's disease, it is considered that this ganglion cell death is deeply involved in the onset or pathological condition.

As can be seen from the above, protecting optic nerve cells enables direct treatment or prevention of visual field disorders and is a very useful means for the prevention or treatment of various retinal diseases.

[0009] As described above, alpha ₁ receptor blockers are known to have intraocular pressure lowering action, but there is no report about the optic nerve protective effect of alpha ₁ receptor blockers, also alpha ₁ receptor About how blockers affect retinal diseases such as normal tension glaucoma, retinal vascular occlusion, diabetic retinopathy, ischemic optic neuropathy, macular degeneration, retinitis pigmentosa, and Leber's disease There is no report.

[0010]

For optic nerve protective action of alpha ₁ receptor blockers as described above THE INVENTION An object you try solving] is not yet known, Studies on the neuroprotective effect of alpha ₁ receptor blockers are very interesting It was a challenge.

[0011]

Therefore, the present inventors have proposed that α
As a result of intensive studies on the relationship between the ₁ receptor blocker and the optic nerve protecting effect, it was found that the α ₁ receptor blocker has an excellent optic nerve cell protecting effect.

[0012]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention relates to a optic nerve cell protective agent comprising an α ₁ receptor blocker as an active ingredient.

Examples of the compound having an α ₁ receptor blocking action in the present invention include bunazosin, prazosin, terazosin, naphthopidil, doxazosin, trimazosin, dapiprazole, alfuzosin, tamsulosin, KRG-33.
32 and the like.

[0014] Among the alpha ₁ receptor blockers, alpha ₁ receptor blockers having a basic heterocyclic rings in its chemical structure are preferred.
The basic heterocycle refers to a heterocycle which contains a nitrogen atom in the ring and exhibits basicity. Further, among the basic heterocycles, a saturated heterocycle containing two nitrogen atoms is preferable. Specific examples include imidazolidine, piperazine, homopiperazine and the like.
Examples of the α ₁ receptor blocker having a basic heterocycle in the chemical structure include bunazosin, prazosin, terazosin, naphthopidil, doxazosin, trimazosin, dapiprazole and the like.

These drugs may be in the form of a salt with an inorganic acid or an organic acid. Examples of the salt include hydrochloride,
Examples thereof include sulfates, phosphates, oxalates and the like.

[0016] The present inventors in the course of research and development as a glaucoma therapeutic agent for alpha ₁ receptor blockers, surprisingly, found that the alpha ₁ receptor blockers have the optic nerve cell protective action, the present invention Completed Details will be explained in the later section of pharmacological test, but Kashii et al. (IOVS. 1994, vol.35, no.2 685-695)
The effects on rat fetal retinal nerve cultured cell death caused by addition of glutamate and rat fetal retinal nerve cultured cell death caused by serum removal were examined in accordance with the method described in _1. , and α ₁ receptor blocker exerted an effect on nerve cell death. It has been found that it can be effectively suppressed and become an excellent optic nerve protecting drug.

In the present invention, the α ₁ receptor blocker can be administered orally or parenterally. Examples of the dosage form include tablets, capsules, granules, powders, eye drops, injections and the like, with eye drops and injections being particularly preferable. These can be formulated using a commonly used technique.

Concretely, for example, Japanese Patent Publication No. 7-23302
No., WO95 / 31200, and commercially available formulations can be used.

Taking eye drops as an example, to explain in more detail, isotonic agents such as sodium chloride and concentrated glycerin, buffering agents such as boric acid, borax, sodium phosphate, sodium acetate, polyoxyethylene sorbitan monooleate, Polyoxyl stearate 40, polyoxyethylene hydrogenated castor oil and other surfactants, sodium citrate, sodium edetate and other stabilizers, benzalkonium chloride, parabens and other preservatives are used as necessary, and eye drops Can be prepared. The pH may be in the range acceptable for ophthalmic preparations, but is preferably in the range of 4-8. Further, the eye ointment can be prepared by using a widely used base such as white petrolatum and liquid paraffin.

The dose can be appropriately selected according to the symptoms, age and the like, but in the case of oral administration, it is 0.1 to 100 m per day.
g can be administered once or in several divided doses. If it is an eye drop, 0.0001 to 1% (w / v), preferably 0.001 to 0.1% (w / v) may be applied once to several times a day.

The α ₁ receptor blocker according to the present invention can also be used in combination with other intraocular pressure-lowering agents.

The results of pharmacological tests are shown below as examples. This example is intended to provide a better understanding of the invention and is not intended to limit the scope of the invention.

[0023]

Examples [Pharmacological test] In order to examine the protective effect of α ₁ receptor blocker on optic nerve cells, (1) action on rat fetal retinal nerve cell death induced by addition of glutamate and (2) serum removal were induced. The effect on rat fetal retinal nerve culture cell death was tested by the following method.

(1) Effect of α ₁ Receptor Blocker on Rat Fetal Retinal Nerve Culture Cell Death Induced by Glutamic Acid Retinal cells were isolated and isolated from a rat fetus (18 days old),
7 days cultured on plastic coverslips polyethyleneimine coated with 10% fetal bovine serum-containing Eagle's basal medium _{(37 ℃, 5% CO 2} /95% air) it was. From the 8th day, cells were cultured in Eagle basal medium containing 10% horse serum. On day 6 of culture, cytosine arabinoside (10 μM) was added to suppress the growth of non-neuronal cells. On day 11 of culture, cells were cultured for 10 minutes in a medium containing glutamate (1 mM) and an α ₁ receptor blocker in Eagle's basal medium without serum. Subsequently, the cells were transferred to a serum-free Eagle basal medium containing neither glutamate nor an α ₁ receptor blocker and cultured for 1 hour. Then, the toxicity was determined by the trypan blue dye removal method. That is, the cells were stained with 1.5% trypan blue solution for 10 minutes, fixed with a 10% neutral formalin solution, washed with physiological saline, and then counted under a phase contrast microscope. At that time, the cells stained with trypan blue were regarded as dead cells and the unstained cells were regarded as viable cells, and the survival rate of the cultured cells was calculated from the ratio of the number of viable cells to the total number of counted cells (200 or more). A group to which 1 mM glutamic acid was added alone and a group to which both ₁ mM glutamic acid and an α ₁ receptor blocker were added were referred to as a “1 mM glutamic acid single addition group” and a “1 mM glutamic acid + α ₁ receptor blocker addition group”, respectively. These results were compared with the corresponding calculated values for the "untreated group", which received no treatment. α ₁
As a receptor blocker, bunazosin hydrochloride, prazosin hydrochloride,
The results of the experiments using terazosin hydrochloride and naphthopidil hydrochloride are shown in Tables 1 to 4, respectively. The values in the table are average values.

[0025]

[Table 1]

[0026]

[Table 2]

[0027]

[Table 3]

[0028]

[Table 4]

(2) Effect of α ₁ Receptor Blocker on Rat Fetal Retinal Neuronal Culture Cell Death Induced by Serum Removal Retinal cells were isolated and isolated from rat fetuses (18 days old),
The cells were cultured on a polylysine-coated glass coverslip in Eagle basal medium containing 10% fetal bovine serum for 7 days (37 ° C., 5% CO ₂ /95% air). From the 8th day, cells were cultured in Eagle basal medium containing 10% horse serum. On the 6th day of culture, cytosine arabinoside (10
μM) was added to suppress the proliferation of non-neuronal cells. On day 10 of culture, cells were cultured for 24 hours in serum-free Eagle basal medium or in medium containing 10 μM bunazosin hydrochloride in serum-free Eagle basal medium. Then, the toxicity was determined by the trypan blue dye removal method. That is, the cells were diluted with 1.5% trypan blue solution to 1
After staining for 0 minutes, the cells were fixed with a 10% neutral formalin solution and washed with physiological saline, and then the cells were counted under a phase contrast microscope. At that time, cells stained with trypan blue were regarded as dead cells and unstained cells were regarded as viable cells, and the total number of counted cells (20
The survival rate of the cultured cells was calculated from the ratio of the number of living cells to 0 or more). In addition, using the Tanel assay method, the number of Tanel-positive cells (apoptotic cells) and that of Tanel-negative cells (viable cells) increased by serum removal were counted, and the ratio of the Tanel-positive cells to the total number of counted cells (200 or more) was determined. "Serum-depleted group" and "serum-depleted + α ₁ receptor blocker-added" were used for the group cultured in Eagle basal medium without serum and the group in which α ₁ receptor blocker was added to Eagle basal medium without serum, respectively. Group ". These results were taken as the corresponding calculated values for the "untreated group" which had not been treated at all. Table 5 shows the results of the experiment using bunazosin hydrochloride as an α ₁ receptor blocker. The values in the table are average values.

[0030]

[Table 5]

As can be seen from the results shown in Tables 1 to 5 above, the α ₁ receptor blocker has an effect of remarkably suppressing retinal nerve cultured cell death (apoptosis). Therefore, α ₁ receptor blockers are used as protective agents for optic nerve cells such as retinal ganglion cells, for example, normal tension glaucoma and retinal vascular occlusion, diabetic retinopathy, ischemic optic neuropathy, macular degeneration, retinitis pigmentosa. It is useful as a prophylactic or therapeutic agent for retinal diseases represented by infectious diseases and Leber's disease.

[0032]

EFFECTS OF THE INVENTION From the results of pharmacological tests, α such as bunazosin
_1- receptor blockers have optic nerve protective action and are represented by normal tension glaucoma and retinal vascular occlusion, diabetic retinopathy, ischemic optic neuropathy, macular degeneration, retinitis pigmentosa, Leber's disease, etc. It is useful as a therapeutic agent for retinal diseases. Therefore, the present invention provides an optic nerve protecting agent containing an α ₁ receptor blocker as an active ingredient.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61P 3/10 A61P 3/10 9/10 9/10 27/02 27/02 27/06 27/06 43 / 00 111 43/00 111 // C07D 239/95 C07D 239/95 249/16 249/16 295/08 295/08 A 405/12 405/12 (72) Inventor Hideaki Hara 8916 Takayama-cho, Ikoma-shi, Nara −16 Santen Pharmaceutical Co., Ltd. Research Laboratories (72) Inventor Wakana Goto 8916 Takayamacho, Ikoma City, Nara Prefecture 1616 Santen Pharmaceutical Co., Ltd. Research Laboratories F Term (reference) 4C063 AA01 BB09 CC73 CC75 CC82 DD31 EE01 4C084 AA02 AA17 DC50 MA35 MA37 MA41 MA52 MA58 MA66 NA14 ZA331 ZA361 ZC202 ZC351 ZC412 4C086 AA01 AA02 BC50 BC54 BC61 GA02 GA07 GA12 MA01 MA04 NA14 ZA33 ZA36 ZC20 ZC35 ZC41

Claims (10)

[Claims] 1. A optic nerve cell protective agent comprising an α ₁ receptor blocker as an active ingredient. Wherein alpha ₁ receptor blockers, optic nerve cell protective agent according to claim 1, wherein the alpha ₁ receptor blocker with basic heterocyclic rings in the chemical structure. 3. The optic nerve cell protecting agent according to claim 1, wherein the α ₁ receptor blocker is bunazosin, prazosin, terazosin, naphthopidil, doxazosin, trimazosin or dapiprazole. 4. The optic nerve cell protective agent according to claim 1, wherein the optic nerve cells are retinal ganglion cells. 5. The optic nerve cell protective agent according to claim 1, which is used for prevention or treatment of eye diseases. 6. The protective agent for optic nerve cells according to claim 5, wherein the eye disease is normal tension glaucoma. 7. The eye disease is retinal vascular occlusion, diabetic retinopathy,
The optic nerve cell protective agent according to claim 5, which is ischemic optic neuropathy, macular degeneration, retinitis pigmentosa or Leber's disease. 8. A therapeutic or prophylactic agent for visual field disorders based on the action of protecting optic nerve cells, which comprises an α ₁ receptor blocker as an active ingredient. 9. alpha ₁ receptor blockers, therapeutic or prophylactic agent for visual field loss in claim 8, wherein the alpha ₁ receptor blocker with basic heterocyclic rings in the chemical structure. 10. The therapeutic or prophylactic agent for visual field disorders according to claim 8, wherein the α ₁ receptor blocker is bunazosin, prazosin, terazosin, naphthopidil, doxazosin, trimazosin or dapiprazole.