WO1994007482A1 - Prophylactic and remedy for cerebral edema - Google Patents
Prophylactic and remedy for cerebral edema Download PDFInfo
- Publication number
- WO1994007482A1 WO1994007482A1 PCT/JP1993/001372 JP9301372W WO9407482A1 WO 1994007482 A1 WO1994007482 A1 WO 1994007482A1 JP 9301372 W JP9301372 W JP 9301372W WO 9407482 A1 WO9407482 A1 WO 9407482A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- cerebral edema
- nna
- cerebral
- mca
- prophylactic
- Prior art date
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
Definitions
- the present invention relates to a prophylactic or therapeutic agent for ischemic cerebral edema, which comprises ⁇ "-nitro-L-arginine (P, abbreviated as L-NNA) or a salt thereof as an active ingredient.
- a prophylactic or therapeutic agent for ischemic cerebral edema which comprises ⁇ "-nitro-L-arginine (P, abbreviated as L-NNA) or a salt thereof as an active ingredient.
- nitric oxide is involved in vascular relaxation, platelet aggregation, adhesion suppression, and maintenance of biological functions as an intercellular messenger ( Trends Pharmacol. 10, 428-431, 1989; Trends
- L-NNA known as an inhibitor of NO synthase (hereinafter abbreviated as NOS)
- NOS NO synthase
- Cerebral edema is a condition defined as an increase in brain water volume resulting in an increase in brain volume (see J. Neuropath. Exp. Neurol. 26, III-.14 1967).
- the pathology that causes cerebral edema can vary. The consequences are death from brain incarceration. It is known that ischemic cerebral edema occurs experimentally and clinically, very early before the appearance of infarct lesions (see Handbook of Stroke Experiments 1990).
- L-NNA has a preventive or therapeutic effect on ischemic serum cerebral edema, leading to the present invention.
- the L-NNA used in the present invention is a known substance and can be easily obtained.However, for example, L-NNA can also be obtained by laying down by the method described in J. Am. Cem. So 78.238 (1956). it can.
- the salt of L-NNA is not particularly limited as long as it is a pharmaceutically acceptable salt.
- the L-NNA or a salt thereof according to the present invention is prepared by adding suitable excipients, auxiliaries, lubricants, preservatives, stabilizers, wetting agents, emulsifiers, coloring agents, flavoring agents, fragrances, etc. Orally or parenterally, preferably in the form of tablets, granules, fine granules, powders, capsules, syrups, elixirs, drops, solutions, suspensions, emulsions, etc. It can be administered in the form of intravenous administration.
- the carrier for the formulation may be, for example, lactose, sucrose, sorbitol, mannite, starch such as potato starch or corn starch, a starch derivative, a cellulose derivative or gelatin.
- Suitable auxiliaries which can be usually used are suitable, and at the same time, lubricants such as magnesium stearate, carbowax or polyethylene glycol can be added. It can be made into capsules and the like.
- an injection in the case of aqueous preparations, for example, an effective amount of the main component is dissolved in distilled water for injection, and if necessary, isooxidants, stabilizers, and local anesthetics After adding a preservative and the like, and completely dissolving, an injection can be prepared by filtration, filling, sealing, and steam sterilization by a conventional method.
- an aqueous solution containing the main component dissolved in distilled water for injection may be lyophilized by a conventional method.
- saccharides such as mannitol, inositol, lactose, maltose, and sucrose, sugar alcohols, glycine, and the like can be added, and lyophilized as usual.
- the dose of L-NNA or a salt thereof of the present invention can be appropriately selected depending on the patient's body type, age, physical condition, degree of disease, and the like, but is preferably 5 to 100 mg / body per day. is there.
- the L--NNA or a salt thereof according to the present invention has a therapeutic effect on cerebral edema formed 2-3 times after the onset of ischemic cerebrovascular disease. Pre-administration prior to the onset of cerebral edema can also be expected to have a protective effect on brain adenoma.
- a control solvent physiological saline 1 ml / kg
- L-NNA Sigma, 1 mg / kg
- the water content in the left cerebral hemisphere was measured by the dry weight method. That is, rats were decapitated and sacrificed 48 hours after MCA closure, and the wet weight (W) of the left cerebral hemisphere taken out within 90 seconds was measured. Then, it was dried in an oven at 105 ° C for 5 days, and the dry weight (D) was measured. The water content was obtained from the calculation formula of [(W—D) ZW] ⁇ 100%. Next, using the dried tissue, the sodium and potassium contents were quantified using an atomic absorption spectrophotometer. That is, a certain amount of concentrated nitric acid was added to the dried brain tissue, and the mixture was incubated at 45 ° C for 90 minutes.
- Number is the number of specimens, Number is the average number of specimens S. E. M
- Magnesium stearate 0.5 mg l O OmgZl tablets were added and mixed well, and the mixture was directly tabletted with a tableting machine to a diameter of 7 mm and a weight of 10 Omg to obtain tablets.
Abstract
A prophylactic or remedy for ischemic cerebral edema containing Nφ-nitro-L-arginine or a salt thereof as the active ingredient.
Description
明 細 書 Specification
脳浮腫の予防および治療剤 Prevention and treatment of brain edema
技術分野 Technical field
本発明は Ν" ·-ニトロ— L一アルギニン （P下、 L一 N N Aと略す） または その塩を有効成分として含有することを特徴とする虚血脳浮腫の予防または治 療剤に関する。 背景枝術 The present invention relates to a prophylactic or therapeutic agent for ischemic cerebral edema, which comprises Ν "-nitro-L-arginine (P, abbreviated as L-NNA) or a salt thereof as an active ingredient.
脳血管障害による死亡率は、 最近、 低下の傾向を示してはいるが、 それによ る後遺症、 あるいは精神、 知能障害によって社会復帰が坊げられている患者数 は必ずしも減少していないのが実態である。 今後、 老齢化がさらに進めば、 高 齢者の脳血管障害の発症はふえ、 血管性痴呆との絡みもあり、 脳浮腫との取り 組みはまさに重要な問題になつてくると考えられている。 Although the mortality rate due to cerebrovascular disease has recently been on a downward trend, the number of patients who are rehabilitated due to sequelae or mental or intellectual impairment has not necessarily decreased. It is. If aging progresses in the future, the onset of cerebrovascular disease in the elderly will increase, and the involvement of vascular dementia will make the approach to cerebral edema a very important issue. .
脳浮腫による頭蓋内圧亢進に対して現在の臨床上では、 マンニト--ル等の高 張利尿剤による対症療法が行われてきたが、 患者の生命および機能的予後は必 ずしも満足すべき結果は得られておらず、 少しでも病因に即した薬剤が切望さ れている。 In the current clinical setting, symptomatic treatment with hypertonic diuretics such as mannitol has been performed for increased intracranial pressure due to cerebral edema, but the patient's life and functional prognosis must always be satisfied No results have been obtained, and there is an eager need for a drug that is at least as appropriate to the etiology.
近年、 一酸化窒素 （N O) が、 血管弛緩作用、 血小板凝集、 粘着抑制作用の ほか、 細胞間の情報伝達物質として生体の機能維持に関与していることが明ら かになつてきており （Trends Pharmacol. 10， 428-431， 1989 ； Trends In recent years, it has been clarified that nitric oxide (NO) is involved in vascular relaxation, platelet aggregation, adhesion suppression, and maintenance of biological functions as an intercellular messenger ( Trends Pharmacol. 10, 428-431, 1989; Trends
Neurosci. 14, 29-39, 1987 ； Trends Bioc em. 16, 81-83， 1991 Treads Neurosci. 13, 1-6， 1992 ； Trends Pharmacol. 12. 130-131, 1991 ； Trends Pharmacol. 12, 87-88. 1991 ； Treads Pharmacol. 12, 125-128, 199Γ参照） ， なかでも NO synthase (以下、 N O Sと略す） の inhibitorとして知られる L— N N Aが、 虚血清脳梗塞に効果があることが示された （Eur. J. Pharni. 204, 339-340, 1991) 。 この文献には、 中大脳動脈 （M C A ) 閉塞マウスに、 し-- N Aを投与することにより、 脳梗塞部位を縮小させるデ一タが記載されてい
脳浮腫は脳内の水分量が増加して脳容量の増大をきした状態として定義され る病態である （J. Neuropath. Exp. Neurol. 26, 丄 -.14 1967参照） 。 脳浮腫を 弓 Iき起こす病態は多様である力《、 その結果はいずれも脳陥頓による死を招く。 このうち実験的にも臨床的にも虚血清脳浮腫は、 梗塞巣出現以前のごく初期に 発生することが知られている （脳卒中実験ハンドブック 1990参照） 。 Neurosci. 14, 29-39, 1987; Trends Biochem. 16, 81-83, 1991 Treads Neurosci. 13, 1-6, 1992; Trends Pharmacol. 12. 130-131, 1991; Trends Pharmacol. 12, 87- 88. 1991; Treads Pharmacol. 12, 125-128, 199Γ), among which L-NNA, known as an inhibitor of NO synthase (hereinafter abbreviated as NOS), has been shown to be effective in ischemic cerebral infarction. (Eur. J. Pharni. 204, 339-340, 1991). This document describes data on the reduction of the cerebral infarction site by administering SH-NA to middle cerebral artery (MCA) occluded mice. Cerebral edema is a condition defined as an increase in brain water volume resulting in an increase in brain volume (see J. Neuropath. Exp. Neurol. 26, III-.14 1967). The pathology that causes cerebral edema can vary. The consequences are death from brain incarceration. It is known that ischemic cerebral edema occurs experimentally and clinically, very early before the appearance of infarct lesions (see Handbook of Stroke Experiments 1990).
梗塞巣出現以前に発生する虚血清脳浮腫を予防または治療することは、 脳血 管障害の発症を抑える意味で、 臨床上極めて重要なことであると理解されてい る。 発明の開示 It is understood that preventing or treating ischemic cerebral edema that occurs before the appearance of an infarct focus is of crucial clinical significance in reducing the occurrence of cerebral vascular disorders. Disclosure of the invention
本発明者等は、 これらの課題に鑑み、 鋭意研究を重ねた結果、 L一 N N Aに 虚血清脳浮腫の予防または治療効果があることを見出し、 本発明に至つた。 本発明で用いられる L - N N Aは、 公知物質であり、 容易に入手可能である が、 例えば J. Am. C em. So 78. 238 (1956) 記載の方法により台成して得 ることもできる。 In view of these problems, the present inventors have conducted intensive studies and, as a result, have found that L-NNA has a preventive or therapeutic effect on ischemic serum cerebral edema, leading to the present invention. The L-NNA used in the present invention is a known substance and can be easily obtained.However, for example, L-NNA can also be obtained by laying down by the method described in J. Am. Cem. So 78.238 (1956). it can.
また、 L一 N N Aの塩としては、 医薬上許容しうる塩であれば特に制限はな いが例えば、 塩酸、 硫酸、 硝酸等との無機酸塩、 酢酸、 シユウ酸、 酒石酸、 p ―トルエンスルホン酸等との有機酸塩、 ナトリゥム、 力リゥム等とのアル力リ 金属塩、 カルシウム、 マグネシウム等とのアルカリ土類金属塩等が挙げられる。 The salt of L-NNA is not particularly limited as long as it is a pharmaceutically acceptable salt.For example, inorganic salts with hydrochloric acid, sulfuric acid, nitric acid, etc., acetic acid, oxalic acid, tartaric acid, p-toluene sulfone Organic acid salts with acids and the like, alkaline metal salts with sodium and potassium, alkaline earth metal salts with calcium, magnesium and the like.
[発明を実施するための最良の形態] [Best Mode for Carrying Out the Invention]
本発明による L—N N Aまたはその塩は、 適当な賦形剤、 補助剤、 滑沢剤、 防腐剤、 安定剤、 湿潤剤、 乳化剤、 着色剤、 風味剤また芳香剤等を加え、 錠剤、 被覆錠剤、 顆粒剤、 細粒剤、 粉末剤、 カプセル剤、 シロップ剤、 エリキシル剤、 滴下剤、 溶液、 懸濁液、 乳濁液等の形態にして、 経口または非経口的に、 好ま しくは、 静脈内投与の形で投与することができる。 The L-NNA or a salt thereof according to the present invention is prepared by adding suitable excipients, auxiliaries, lubricants, preservatives, stabilizers, wetting agents, emulsifiers, coloring agents, flavoring agents, fragrances, etc. Orally or parenterally, preferably in the form of tablets, granules, fine granules, powders, capsules, syrups, elixirs, drops, solutions, suspensions, emulsions, etc. It can be administered in the form of intravenous administration.
例えば、 内服剤として製剤化する場合は、 製剤用担体としては、 例えば乳糖、 ショ糖、 ソルビッ ト、 マンニッ ト、 ジャガイモデンプンまたはトウモロコシデ ンプン等のデンプンまたはデンプン誘導体、 セルロース誘導体もしくはゼラチ ンのような通常使用し得る助剤が適当で、 同時に例えばステアリン酸マグネシ ゥム、 カルボワックスまたはポリエチレングリコールのような滑沢剤を添加す ることができ、 これらの混合物を常法により、 顆粒剤、 錠剤、 カプセル剤等に することができる。
また注射剤の場台の製剤用担体としては水性製剤の場合には、 例えば注射用 蒸留水に有効量の主成分を溶解し、 必要に応じて、 等酸化剤、 安定化剤、 局所 麻酔剤、 保存剤等を加え、 完全に溶解した後、 常法により濾過、 充填、 密封し、 蒸気滅菌して注射剤を調整することができる。 For example, when formulated as an internal preparation, the carrier for the formulation may be, for example, lactose, sucrose, sorbitol, mannite, starch such as potato starch or corn starch, a starch derivative, a cellulose derivative or gelatin. Suitable auxiliaries which can be usually used are suitable, and at the same time, lubricants such as magnesium stearate, carbowax or polyethylene glycol can be added. It can be made into capsules and the like. In the case of aqueous preparations, as a carrier for preparations for injection preparations, for example, an effective amount of the main component is dissolved in distilled water for injection, and if necessary, isooxidants, stabilizers, and local anesthetics After adding a preservative and the like, and completely dissolving, an injection can be prepared by filtration, filling, sealing, and steam sterilization by a conventional method.
凍結乾燥製剤として製剤化する場台には、 注射用蒸留水に主成分を溶解した 水溶液を常法により凍結乾燥してもよく、 また必要に応じて、 凍結乾燥の行な いやすぃ陚形剤として、 マンニトール、 イノシトール、 ラク トース、 マルトー ス、 スクロースなどの糖または糖アルコール類あるいはグリシン等を添加して 常法通り凍結乾燥することができる。 When preparing a lyophilized formulation, an aqueous solution containing the main component dissolved in distilled water for injection may be lyophilized by a conventional method. As described above, saccharides such as mannitol, inositol, lactose, maltose, and sucrose, sugar alcohols, glycine, and the like can be added, and lyophilized as usual.
本発明の L - NN Aまたはその塩の投与量は、 患者の体型、 年令、 体調、 疾 患の度合い等により、 適宜選択することができるが、 好ましくは、 1日当たり 5〜100mg/b o d yである。 The dose of L-NNA or a salt thereof of the present invention can be appropriately selected depending on the patient's body type, age, physical condition, degree of disease, and the like, but is preferably 5 to 100 mg / body per day. is there.
本発明による L- - NNAまたはその塩は、 虚血清脳血管障害発症後、 2〜3 曰後に形成される脳浮腫に対し、 治療効果を有する。 また、 脳浮腫発生前に予 め投与することにより、 脳淳腫予防効果も期待できる。 実施例 The L--NNA or a salt thereof according to the present invention has a therapeutic effect on cerebral edema formed 2-3 times after the onset of ischemic cerebrovascular disease. Pre-administration prior to the onset of cerebral edema can also be expected to have a protective effect on brain adenoma. Example
次に実施例を挙げて、 本発明をさらに詳細に説明するが、 本発明はこれらの みに限定されるものではない。 参考例 Next, the present invention will be described in more detail with reference to examples, but the present invention is not limited to only these examples. Reference example
中大脳動脈 (MCA) 閉塞モデルラッ 卜の作製 Preparation of middle cerebral artery (MCA) occlusion model rat
雄性 Sp r a gue— Dawl e yラッ ト （体重 297 385 g) を 3% ハロセン （70%NO2 、 30%O2 で希釈） 吸収にて麻酔導入、 1%ハロセ ン吸入にて維持し、 手術台に側臥位に固定した。 左外耳孔と左外眼孔の中間に 線状皮膚切開をおき、 左側頭筋の前縁に沿って、 下方は娣骨弓まで切開した。 眼窩内脂肪組織および眼球を摘出し、 眼窩の奥は出血するので電気凝固し切断 した。 側頭筋は頭蓋骨から剥離し、 後下方へ圧排した。 手術用顕微鏡下で側頭 骨底部の奥に認められ、 側頭筋内側を走行する三叉神経第三枝がでる卵円孔と 眼窩裂の中間に電気ドリルで径 2 mm位の小孔を開けた。 薄い骨を一層残し、 これを眼科用ビンセッ 卜で除去した。 硬膜を透かして左 MC Aを確認し、 注意 しながら硬膜を切開した。 クモ膜を 6]り、 横走する嗅索の上を横切る M A本 幹を電気凝固し切断した。 閉塞時に麻酔を切り、 摘出した眼窩内容物を術内に
充填して創を閉じた。 偽手術群では、 MCAを電気凝固切断すること以外の外 科的処置をすベて同様に行なつた。 実施例 Male Sprague-Dawley rat (body weight 297 385 g) was anesthetized by absorption of 3% halothane (diluted with 70% NO 2 and 30% O 2 ), and maintained by inhalation of 1% halothane. In a lateral position. A linear skin incision was made between the left external ear canal and the left external eye opening, and along the anterior edge of the left temporal muscle, down to the 娣 arch. The orbital adipose tissue and eyes were removed, and the interior of the orbit was bleeding and electrocoagulated and cut. The temporalis muscle was detached from the skull and pumped down posteriorly. A small hole about 2 mm in diameter was drilled between the oval hole and the orbital fissure in the third branch of the trigeminal nerve running inside the temporal muscle under the surgical microscope. Was. One thin bone was left and removed with an ophthalmic bin. The left MCA was confirmed through the dura, and the dura was incised carefully. The MA trunk that crossed the arachnoid membrane and crossed over the transverse olfactory tract was electrocoagulated and cut. Anesthesia is cut off at the time of occlusion, and the extracted orbital contents are injected The wound was closed by filling. In the sham-operated group, all medical procedures other than electrocoagulation of MCA were performed similarly. Example
L-NNAの脳浮腫予防および治療効果 L-NNA Prevents and Treats Brain Edema
参考例で作製したモデルを用いて、 L--NNAの脳浮腫予防および治療効果 を調べた。 Using the model prepared in Reference Example, the preventive and therapeutic effects of L-NNA on cerebral edema were examined.
対照溶媒 （生理食塩水 1 m 1 k g ) と L - NNA (シグマ社製、 1 m g ./ k g) は、 それぞれのラッ 卜に台計 4回投与した。 すなわち、 MCA閉塞前か らの投与群では、 MCA閉塞前 5分、 続いて MCA閉塞後 3、 6、 24時間後 に、 また MC A閉塞後からの投与群では、 MC A閉塞 5分、 3、 6、 24時間 後にそれぞれ腹腔内投与した。 A control solvent (physiological saline 1 ml / kg) and L-NNA (Sigma, 1 mg / kg) were administered to each rat 4 times in total. That is, in the administration group before MCA occlusion, 5 minutes before MCA occlusion, and then 3, 6, and 24 hours after MCA occlusion, and in the administration group after MCA occlusion, 5 minutes and 3 minutes after MCA occlusion. The animals were intraperitoneally administered 6, 24 hours later.
左大脳半球内水分量の測定は、 乾燥重量法で行なった。 すなわち、 MCA閉 塞後 48時間後にラッ トを断頭屠殺し、 90秒以内に取り出した左大脳半球の 湿重量 （W) をそれぞれ測定した。 その後、 105°Cのオーブン中で 5日間乾 燥させ、 乾燥重量 （D) を測定した。 水分含量は、 [ (W— D) ZW] X 10 0 %の計算式より得た。 次にこの乾燥組織を用いてナトリウムと力リウム含量 を原子吸光光度計を用いて定量した。 すなわち、 乾燥脳組織に一定の濃硝酸を 加え、 45°Cで 90分間ィンキュベ一卜した。 95°Cで一旦乾燥させた後、 再 び少量の濃硝酸を加え、 完全に脳組織を可溶化させ測定試料とした。 それぞれ のイオン濃度は、 mE qZk g乾燥組織重量で表示した。 結果を第 1表に示す。
The water content in the left cerebral hemisphere was measured by the dry weight method. That is, rats were decapitated and sacrificed 48 hours after MCA closure, and the wet weight (W) of the left cerebral hemisphere taken out within 90 seconds was measured. Then, it was dried in an oven at 105 ° C for 5 days, and the dry weight (D) was measured. The water content was obtained from the calculation formula of [(W—D) ZW] × 100%. Next, using the dried tissue, the sodium and potassium contents were quantified using an atomic absorption spectrophotometer. That is, a certain amount of concentrated nitric acid was added to the dried brain tissue, and the mixture was incubated at 45 ° C for 90 minutes. After drying once at 95 ° C, a small amount of concentrated nitric acid was added again to completely solubilize the brain tissue and used as a measurement sample. Each ion concentration was expressed as mEqZkg dry tissue weight. The results are shown in Table 1.
【表 1】 処 理群 水分 （％) N a (niEq/kg) K (mEq/kg) 無 処 置 79.22+0.88(6) 353.6+ 3.9(6) 695.1+ 8.5(6) 偽手術群 80.71±0.34(6) 463.5+25.9(6) 633.5+ 8.7(6) tfCA閉塞 [Table 1] Treatment group Moisture (%) Na (niEq / kg) K (mEq / kg) No treatment 79.22 + 0.88 (6) 353.6+ 3.9 (6) 695.1+ 8.5 (6) Sham operation group 80.71 ± 0.34 (6) 463.5 + 25.9 (6) 633.5+ 8.7 (6) tfCA occlusion
** **
-生理食塩水 81.91+0.19(7) 571.5+16.5(6) 576.3+ 4.9(6) 前投与群- ## ## ## -Saline 81.91 + 0.19 (7) 571.5 + 16.5 (6) 576.3 + 4.9 (6) pre-treatment group-## ## ##
-L-NNA 80.95+0.24(7) 486.3^25.0(6) 624.8+11.0(6) -L-NNA 80.95 + 0.24 (7) 486.3 ^ 25.0 (6) 624.8 + 11.0 (6)
「生理食塩水 82.20+0.24(7) 616.9+17.8(6) 589.2+24.2(6) 後投与群- L -NNA 81.42±0.23(7) 543.1+27.9(6)' 631.8+15.3(6) `` Saline 82.20 + 0.24 (7) 616.9 + 17.8 (6) 589.2 + 24.2 (6) Post-treatment group-L-NNA 81.42 ± 0.23 (7) 543.1 + 27.9 (6) '631.8 + 15.3 (6)
( ) 数は供試数、 数値は供試数の平均値土 S. E. M () Number is the number of specimens, Number is the average number of specimens S. E. M
* P< 0. 05 (偽手術群に対して） * P <0.05 (for sham operation group)
** P < 0. 01 (偽手術群に対して） ** P <0.01 (for sham operation group)
if P< 0. 05 (M C A閉塞生理食塩水群に対して） if P <0.05 (for M C A occluded saline group)
P< o. 01 (MC A閉塞生理食塩水群に対して）
P <o. 01 (for MC A occluded saline group)
第 1表から明らかなように、 正常 （無処置） ラッ 卜の左大脳半球内水分、 ナ卜リ ゥムおよびカリウム含量と比較して、 偽手術群では、 これら 3つのパラメ - -夕に明 らかな変化が観察された。 このことは、 MC Aを閉塞すること以外の外科的処置に よって、 ある程度の浮腫を引き起こすことを示している。 As evident from Table 1, these three parameters were significantly lower in the sham-operated group compared to the water, sodium and potassium contents in the left cerebral hemisphere of normal (untreated) rats. A clear change was observed. This indicates that surgical procedures other than occlusion of the MCA cause some edema.
MC A閉塞 48時間後、 左大脳半球内水分およびナトリゥム含量は、 偽手術群に 比較して有意に増大した。 一方、 カリウム含量は逆に有意に減少した。 MCA.閉塞 前から、 あるいは MC A閉塞後から L一 NN Aを腹腔内投与すると、 これら水分と ナトリゥム含量の増大と力リゥム含量の減少は、 有意に抑制された。 48 hours after MCA occlusion, water and sodium content in the left cerebral hemisphere were significantly increased compared to the sham-operated group. On the other hand, the potassium content decreased significantly. Intraperitoneal administration of L-NNA before MCA occlusion or after MCA occlusion significantly reduced these increases in water and sodium content and decrease in liposome content.
[製剤例 1 ] [Formulation Example 1]
L—ΝΝΛ塩酸塩 5mg L-ΝΝΛhydrochloride 5mg
マンニトール 5 0m g Mannitol 50 mg
5 Srng/Ziバイアル これらを加えてよく混合し、 容器に充填し、常法により凍結乾燥し密封する。 .れを使用時に lmgの蒸留水に溶解し、 注射剤として用いる。 5 Srng / Zi vial Add these, mix well, fill into a container, freeze-dry and seal in a conventional manner. When used, dissolve in lmg of distilled water to use as an injection.
[製剤例 2 ] [Formulation Example 2]
L- NNA 1 Omg L- NNA 1 Omg
乳糖 44. omg Lactose 44.omg
トウモロコシデンプン 2 Omg Corn starch 2 Omg
結晶セルロース 25mg Microcrystalline cellulose 25mg
ステアリン酸マグネシウム 0. 5 m g l O OmgZl錠 これらを加えてよく混台し、 打錠機で直径 7mm、 重量 10 Omgに直接打錠し 錠剤とした。
Magnesium stearate 0.5 mg l O OmgZl tablets These were added and mixed well, and the mixture was directly tabletted with a tableting machine to a diameter of 7 mm and a weight of 10 Omg to obtain tablets.
Claims
1. N" —ニトロ一 L—アルギニンまたはその塩を有効成分として含有することを 特徴とする虚血性脳浮腫の予防または治療剤。 1. An agent for preventing or treating ischemic cerebral edema, comprising N "-nitro-L-arginine or a salt thereof as an active ingredient.
2 . Νω —ニトロ一 L—アルギニンを有効成分として含有することを特徴とす る請求項 1記載の虚血性脳浮腫の予防剤。
. 2 New omega - preventive agent for ischemic cerebral edema claim 1, wherein you characterized in that it contains a nitro one L- arginine as an active ingredient.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP4/297591 | 1992-09-25 | ||
| JP29759192 | 1992-09-25 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1994007482A1 true WO1994007482A1 (en) | 1994-04-14 |
Family
ID=17848542
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/JP1993/001372 WO1994007482A1 (en) | 1992-09-25 | 1993-09-27 | Prophylactic and remedy for cerebral edema |
Country Status (1)
| Country | Link |
|---|---|
| WO (1) | WO1994007482A1 (en) |
-
1993
- 1993-09-27 WO PCT/JP1993/001372 patent/WO1994007482A1/en active Application Filing
Non-Patent Citations (2)
| Title |
|---|
| CHEMICAL ABSTRACTS, Vol. 113, No. 15, Abstract No. 129875v. * |
| EUR. J. PHARM., 204, p. 339-340, (1991). * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| ES2386786T3 (en) | Method for treating skin blush using selective alpha-2-adrenergic receptor agonists. | |
| RU2290929C2 (en) | Pharmaceutical composition for treatment of interstitial cystitis | |
| US5489576A (en) | Therapeutic agent for hemorrhoidal diseases | |
| JP5680412B2 (en) | Use of Leonurine and compositions thereof | |
| ES2251095T3 (en) | THERAPEUTIC AGENTS FOR DIABETIC COMPLICATIONS. | |
| WO1996038173A1 (en) | Brain edema inhibitor | |
| KR20010101616A (en) | Cerebrovascular regeneration/reconstruction promoters and nerve tissue secondary degeneration inhibitors comprising ginsenoside Rb1 | |
| JP7404658B2 (en) | Tear film stabilizer and meibum secretion promoter | |
| CN108939052B (en) | Application of exenatide in preparation of medicine for preventing or treating atrial fibrillation | |
| WO2019161761A1 (en) | A pharmaceutical composition for treating malaria | |
| US6462021B1 (en) | Use of low molecular weight thrombin inhibitor | |
| US7635691B2 (en) | Use of CDP-choline for the prophylactic treatment of cerebral ischemia | |
| WO1994007482A1 (en) | Prophylactic and remedy for cerebral edema | |
| AU2001225625A1 (en) | Use of melagatran for manufacture of a medicament for the treatment of ischemic disorders | |
| WO2021052441A1 (en) | Uses of complex of angiotensin ii receptor antagonist metabolite and nep inhibitor in treating heart failure | |
| US6090823A (en) | Remedy for spinal injury | |
| CN115192597A (en) | Pharmaceutical composition for preventing and treating pulmonary hypertension, preparation method and application thereof | |
| WO1999040919A1 (en) | Remedies for cardiac dilastolic disorders | |
| JPH06192080A (en) | Preventing and therapeutic agent for cerebral edema | |
| KR100592792B1 (en) | Pharmaceutical Composition for Preventing and Treating Hepatitis Comprising Green Tea Catechins as an Active Ingredient | |
| CN111939158A (en) | Application of stephanine and derivatives thereof in preparation of medicines for treating neurodegenerative diseases | |
| EP3823622A1 (en) | Methods and compositions for promoting wound healing in a subject suffering from ectodermal dysplasias | |
| CN112915193B (en) | Application of KP-1 in preparation of medicine for treating chronic lung diseases | |
| WO2007100079A1 (en) | Prophylactic or therapeutic agent for allergic ophthalmic disease or allergic nasal disease comprising tricyclic triazolobenzoazepine derivative | |
| RU2664668C1 (en) | Antiarrhythmic drug |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| AK | Designated states |
Kind code of ref document: A1 Designated state(s): US |
|
| AL | Designated countries for regional patents |
Kind code of ref document: A1 Designated state(s): DE FR GB |
|
| DFPE | Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101) | ||
| 121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
| 122 | Ep: pct application non-entry in european phase |