JP4568385B2 - Intermittent claudication - Google Patents
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Description
【０００１】
【発明の属する技術分野】
本発明は、アミノアルコキシビベンジル類を有効成分とする間歇性跛行、特に末梢循環障害に基づく間歇性跛行の改善薬に関するものである。
【０００２】
【従来の技術及び発明が解決しようとする課題】
末梢循環障害の中でも間歇性跛行を訴える患者は多く、年々患者数は増加している。間歇性跛行はおもに四肢主幹動脈の慢性閉塞（閉塞性動脈硬化症、閉塞性血栓血管炎など）に伴う症状で、労作に伴って四肢の筋肉の虚血がもたらされ、筋虚血に起因する鈍痛・しびれなどで運動の持続が困難となるが、安静により再度運動が可能になる状態をいう。その主な原因は、動脈硬化でのコレステロールの内腔への蓄積、血栓の生成であると考えられている（須階二郎ら 現代医療２０，２８０−２８４，１９８８）。
【０００３】
間歇性跛行症状の従来の評価法は、患者の主観的訴えに基づいた跛行距離の長短で行われているが、これは客観性や再現性に乏しい欠点がある。また足関節部圧測定法は、安静時の値で運動時の病態を推測するという点で問題がある。このように間歇性跛行については適切な客観的評価法が確立されていないので、有効な薬剤も開発されていない。臨床的には、保存的手術適応外治療として、抗血小板剤、血管拡張剤などが主に用いられている。
【０００４】
近年、近赤外線分光による運動負荷中の下肢筋肉内酸素動態の測定が、非侵襲かつ簡便な客観的評価法として注目されており（小見山高士ら 医学のあゆみ，１６６，８０７−８，１９９４、市来正隆ら 脈管学３５（１），５３−５９，１９９５、重松宏 ＭＥＤＩＣＡＬ ＤＩＧＥＳＴ，４４（３），１１−１４，１９９５）、この客観的評価法で有効性を示す間歇性跛行の改善薬が切望されている。しかし、間歇性跛行の動物モデルは現在までにまったく報告されておらず、治療薬も開発されていない。
【０００５】
一方、アミノアルコキシビベンジル類は抗血小板作用・抗セロトニン作用を有することが開示されており（特開昭５８−０３２８４７、特開平０２−３０４０２２）、血栓症・微小循環障害に効果が期待できる。しかし、これらが間歇性跛行改善作用を有することは知られていない。
【０００６】
【課題を解決するための手段】
本発明者らは、独自に間歇性跛行の動物モデルを作成し、これを用いて検討した結果、下記一般式（１）で表わされるアミノアルコキシビベンジル類が間歇性跛行に対し有効であることを見出した。
【０００７】
【化３】
（ただし、式中Ｒ1 は水素原子、ハロゲン原子、Ｃ1 〜Ｃ5 のアルコキシ基、またはＣ2 〜Ｃ6 のジアルキルアミノ基を表わし、Ｒ2 は水素原子、ハロゲン原子またはＣ1 〜Ｃ5 のアルコキシ基を表わし、Ｒ3 は水素原子、ヒドロキシル基、−Ｏ−（ＣＨ2 ）n −ＣＯＯＨ（式中、ｎは１〜５の整数を表わす。）、または−Ｏ−ＣＯ−（ＣＨ2 ）l −ＣＯＯＨ（式中、ｌは１〜３の整数を表わす。）を表わし、Ｒ4 は
【０００９】
【化４】
（式中、Ａはカルボキシル基で置換されていてもよいＣ３ 〜Ｃ５ のアルキレン基を表わす）を表わし、ｍは０〜５の整数を表わす。）
その他、本発明の要旨として以下が挙げられる。
（２）（±）−１−［０−［２−（ｍ−メトキシフェニル）エチル］フェノキシ］−３−（ジメチルアミノ）−２−プロピル水素スクシナート塩酸塩を有効成分とすることを特徴とする前記の間歇性跛行改善薬。
（３）末梢循環障害に基づく間歇性跛行に対する改善薬であることを特徴とする前記の間歇性跛行改善薬。
（４）末梢循環障害が末梢動脈硬化症又は末梢動脈閉塞症であることを特徴とする前記の間歇性跛行改善薬。
（５）運動負荷時の筋肉内酸素動態を改善することを特徴とする前記の間歇性跛行改善薬。
（６）下肢筋肉内の酸素動態を改善することを特徴とする前記の間歇性跛行改善薬。
（７）近赤外線分光を用いて測定することを特徴とする前記の間歇性跛行改善薬。
（８）間歇性跛行に対する客観的評価モデルを用いることを特徴とする間歇性跛行改善薬の評価方法。
（９）筋肉内酸素動態を近赤外線分光により定量測定することを特徴とする前記の評価方法。
（１０）前記の評価方法により得られることを特徴とする間歇性跛行改善薬。
（１１）一般式（１）で表わされるアミノアルコキシビベンジル類、薬学上許容し得るその塩、エステル及びそれらの溶媒和物から選ばれる化合物を有効成分とすることを特徴とする前記の間歇性跛行改善薬。
（１２）（±）−１−［０−［２−（ｍ−メトキシフェニル）エチル］フェノキシ］−３−（ジメチルアミノ）−２−プロピル水素スクシナート塩酸塩を有効成分とすることを特徴とする前記の間歇性跛行改善薬。
【００１１】
【発明の実施の形態】
本発明について詳細に説明すると、本発明で使用する一般式（１）で表わされるアミノアルコキシビベンジル類において、Ｒ1 は水素原子；塩素原子、弗素原子等のハロゲン原子；メトキシ基、エトキシ基、ブトキシ基等のＣ1 〜Ｃ5 のアルコキシ基：ジメチルアミノ基、ジエチルアミノ基、メチルエチルアミノ基等のＣ2 〜Ｃ6 のジアルキルアミノ基を表わす。Ｒ2 は水素原子；塩素原子、弗素原子等のハロゲン原子：メトキシ基、エトキシ基、ブトキシ基等のＣ1 〜Ｃ5 のアルコキシ基を表わす。Ｒ3 は水素原子：ヒドロキシル基；−Ｏ−（ＣＨ2 ）2 −ＣＯＯＨ，−Ｏ−（ＣＨ2 ）3 −ＣＯＯＨ等の−Ｏ−（ＣＨ2 ）n −ＣＯＯＨ（ｎは１〜５の整数を表わす）；−Ｏ−ＣＯ−（ＣＨ2 ）2 −ＣＯＯＨ，−Ｏ−ＣＯ−（ＣＨ2 ）3 −ＣＯＯＨ等の−Ｏ−ＣＯ−（ＣＨ2 ）l −ＣＯＯＨ（ｌは１〜３の整数を表わす）を表わす。Ｒ4 はアミノ基、メチルアミノ基、エチルアミノ基、ブチルアミノ基、ヘキシルアミノ基、ヘプチルアミノ基、ジメチルアミノ基、ジエチルアミノ基、メチルエチルアミノ基等を表わすか、又はトリメチレンアミノ基、ペンタメチレンアミノ基、ポリメチレン鎖の中央にカルボキシル基が置換した３−カルボキシペンタメチレンアミノ基等の環にカルボキシル基が置換していてもよい４〜６員のポリメチレンアミノ基を表わす。
本発明で用いる一般式（１）で表わされるアミノアルコキシビベンジル類において、アミノアルコキシ基
【００１２】
【化５】
はフェニル基の２−位に結合しているのが好ましい。また、一般式（１）において、Ｒ1 は水素原子、Ｃ1 〜Ｃ5 のアルコキシ基、又はＣ2 〜Ｃ6 のジアルキルアミノ基が好ましく、Ｒ2 は水素原子が好ましく、Ｒ4 は少くとも１個のＣ1 〜Ｃ8 のアルキル基を有するアミノ基又はトリメチレン基ないしはペンタメチル基を有する４〜６員のポリメチレンアミノ基であるのが好ましく、ｍは０〜２の整数であるのが好ましい。
【００１４】
本発明では、一般式（１）で表わされる化合物の薬学的に許容される塩やエステルも用いることができる。このような塩やエステルを形成する酸としては、例えば塩化水素酸、臭化水素酸、硫酸、リン酸、硝酸、酢酸、コハク酸、アジピン酸、プロピオン酸、酒石酸、マレイン酸、蓚酸、クエン酸、安息香酸、トルエンスルホン酸、メタンスルホン酸等が用いられる。また、一般式（１）で表わされる化合物、その塩やエステルの溶媒和物、例えば水和物も用いることができる。
これらのうちで特に好ましいのは、下記（２）式で表わされる（±）−１−〔０−〔２−（ｍ−メトキシフェニル）エチル〕フェノキシ〕−３−（ジメチルアミノ）−２−プロピル水素スクシナートの塩酸塩である。
【００１５】
【化６】
本発明で用いる一般式（１）で表わされるアミノアルコキシビベンジル類は公知化合物であり、例えば特開昭５８−３２８４７号公報に記載の方法により容易に合成することができる。
本発明に係る間歇性跛行改善薬の投与方法は任意である。
即ち、皮下注射、静脈内注射、筋肉注射、腹腔内注射等の非経口投与も、また経口投与も可能である。
【００１７】
投与量は患者の年齢、健康状態、体重、同時処理があるならばその種類、処置頻度、所望の効果の性質等により決定される。
一般的に有効成分の１日投与量は０．５〜５０ｍｇ／ｋｇ体重、通常１〜３０ｍｇ／ｋｇ体重であり、１回あるいはそれ以上投与される。
本発明化合物を経口投与する場合は、錠剤、カプセル剤、粉剤、液剤、エリキシル剤等の形態で、また、非経口投与の場合は、液剤あるいは懸濁化剤等の殺菌した液状の形態で用いられる。上述の様な形態で用いられる場合、固体あるいは液体の毒性のない製剤的担体が組成に含まれ得る。
【００１８】
固体担体の例としては通常のゼラチンタイプのカプセルが用いられる。また、有効成分を補助薬とともに、あるいはそれなしに錠剤化、粉末包装される。
これらのカプセル、錠剤、粉末は一般的に５〜９５％、好ましくは２５〜９０％重量の有効成分を含む。
即ち、これらの投与形式では１回の投与につき５〜５００ｍｇ、好ましくは２５〜２５０ｍｇの有効成分を含有するのがよい。
【００１９】
液状担体としては水あるいは石油、ピーナツ油、大豆油、ミネラル油、ゴマ油等の動植物起源の、または合成の油が用いられる。
また、一般に生理食塩水、デキストロールあるいは類似のショ糖溶液、エチレングリコール、プロピレングリコール、ポリエチレングリコール等のグリコール類が液状担体として好ましく、特に生理食塩水を用いた注射液の場合には通常０．５〜２０％、好ましくは１〜１０％重量の有効成分を含むようにする。
【００２０】
【実施例】
以下に実施例により、本発明をさらに具体的に説明するが、本発明はこの実施例に限定されるものではない。
間歇性跛行モデルの作成
雄性Ｎｅｗ Ｚｅａｌａｎｄ Ｗｈｉｔｅ Ｒａｂｂｉｔ １４羽を第１群（９羽）と第２群（５羽）とに無作意に分けた。
両群ともペントバルビタール麻酔下にて、鼠蹊部で右大腿動脈を露出し、カテーテルを７ｃｍ挿入し、右腸骨動脈内で直径３ｍｍに膨張させたまま引き抜くバルーン障害を３回施行した後、大腿動脈を結索した。カテーテルとしてはバクスター社のＦｏｇａｒｔｙ（サイズ：２フレンチ）を用いた。手術１週間後に第１群、２週間後に第２群を、それぞれペントバルビタール麻酔下、仰臥位にて下肢後面を切開した。右ひ腹筋内側部に直接近赤外線分光のプローブを装着し、運動負荷として右坐骨神経に１Ｈｚ、２分間の電気刺激を加えた。負荷後安静状態において運動中低下していたオキシヘモグロビンが回復してデオキシヘモグロビンと交差するまでの時間（回復時間）を測定した。近赤外線分光の測定にはＯＭ−１００（島津製作所）を用い、近赤外光の送受光間距離は５ｍｍとした。結果を表１に示す。
【００２１】
また、大腿動脈を結索しない場合、結索直後及び結索１週間後の下肢筋肉内の酸素動態パターンを模式的に図１〜図３に示す。
本モデルは、臨床での間歇性跛行患者と同じパターン（小見山高士ら 医学のあゆみ，１６６，８０７−８，１９９４、市来正隆ら 脈管学３５（１），５３−５９，１９９５）を示しており、本モデルにより運動筋酸素動態を客観的に定量測定することができる。即ち、本モデルは、間歇性跛行に対する客観的動物モデルである。
【００２２】
【表１】
間歇性跛行の重症度の指標である回復時間が経時的に短縮したのは、時間がたつに従って、側副血行路が発達し、筋肉内の酸素動態が改善されたものと考えられる。
【００２４】
実施例
雄性Ｎｅｗ Ｚｅａｌａｎｄ Ｗｈｉｔｅ Ｒａｂｂｉｔ １６羽を、薬剤投与群（７羽）と対照群（９羽）とに無作意に分け、モデルと同じ処置を行った。
薬剤投与群には、手術当日から近赤外線分光測定日まで、特開昭５８−３２８４７号公報に記載の方法により得られた（±）−１−〔０−〔２−（ｍ−メトキシフェニル）エチル〕フェノキシ〕−３−ジメチルアミノ−２−プロピル水素スクシナート塩酸塩を１００ｍｇ／ｋｇとなるように、１％トラガント溶液に懸濁して、１日１回経口投与した。対照群にはトラガント溶液を１日１回経口投与した。手術１週間後に近赤外線分光で回復時間を測定した。結果を表２に示す。
【００２５】
【表２】
表２に示したとおり、手術１週間後の回復時間は、対照群に対し、投薬群において有意に短縮し、下肢筋肉酸素動態の改善が見られた。いずれの動物も下肢の虚血壊死はみられなかった。この実験結果から、本発明に係るアミノアルコキシビベンジル類を有効成分とする薬剤は、側副血行路の発達促進あるいは側副血行路の血流維持によって下肢筋肉内の酸素動態を改善し、間歇性跛行改善作用を有することが明らかである。
【００２７】
【発明の効果】
本発明に係るアミノアルコキシビベンジル類を有効成分とする薬剤は、間歇性跛行、およびその病因と考えられる末梢動脈硬化症、末梢動脈閉塞症などの末梢循環障害において、間歇性跛行の改善および予防効果を有することが期待される。
【図面の簡単な説明】
【図１】間歇性跛行モデルにおける下肢筋肉内の酸素動態パターンを近赤外線分光法により測定した場合の模式図。大腿動脈を結索しない場合の図で、正常パターンを示す。
【図２】間歇性跛行モデルにおける下肢筋肉内の酸素動態パターンを近赤外線分光法により測定した場合の模式図。大腿動脈を結索した直後の図で、重症パターンを示す。
【図３】間歇性跛行モデルにおける下肢筋肉内の酸素動態パターンを近赤外線分光法により測定した場合の模式図。大腿動脈を結索後１週間経過した時点の図で、図２よりも軽症パターンを示す。
【符号の説明】
Ｏｘｙ Ｈｂ ： オキシヘモグロビン
Ｄｅｏ Ｈｂ ： デオキシヘモグロビン[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a drug for improving intermittent claudication, particularly intermittent claudication based on peripheral circulatory disturbance, comprising aminoalkoxybibenzyls as an active ingredient.
[0002]
[Prior art and problems to be solved by the invention]
Many patients complain of intermittent claudication among peripheral circulatory disorders, and the number of patients is increasing year by year. Intermittent claudication is a symptom mainly associated with chronic occlusion of the main limb arteries (occlusive arteriosclerosis, obstructive thromboangiitis, etc.). It means that it is difficult to continue exercise due to dull pain, numbness, etc., but it becomes possible to exercise again by resting. It is thought that the main cause is accumulation of cholesterol in the lumen due to arteriosclerosis and generation of a thrombus (Jiro Sukiya et al., Contemporary Medicine 20, 280-284, 1988).
[0003]
Conventional evaluation methods for intermittent claudication are performed with the length of the lameness based on the patient's subjective complaints, but this has a drawback of poor objectivity and reproducibility. In addition, the ankle joint pressure measurement method has a problem in that a pathological condition during exercise is estimated from a value at rest. Thus, since an appropriate objective evaluation method has not been established for intermittent claudication, an effective drug has not been developed. Clinically, antiplatelet agents, vasodilators and the like are mainly used as conservative off-label treatments.
[0004]
In recent years, the measurement of oxygen dynamics in the lower limb muscles during exercise load by near infrared spectroscopy has attracted attention as a non-invasive and simple objective evaluation method (Takashi Komiyama et al., Ayumi, 166, 807-8, 1994, City Masataka Kurusu, Angiology 35 (1), 53-59, 1995, Hiroshi Shigematsu MEDICAL DIGEEST, 44 (3), 11-14, 1995), an agent for improving intermittent claudication that is effective in this objective evaluation method Is anxious. However, no animal model of intermittent claudication has been reported to date and no therapeutic drug has been developed.
[0005]
On the other hand, aminoalkoxybibenzyls have been disclosed to have antiplatelet action and antiserotonin action (Japanese Patent Laid-Open No. 58-032847, Japanese Patent Laid-Open No. 02-304002), and can be expected to be effective for thrombosis and microcirculatory disturbance. However, it is not known that these have an effect of improving intermittent claudication.
[0006]
[Means for Solving the Problems]
The inventors of the present invention independently created an animal model of intermittent claudication, and as a result of studying it, the aminoalkoxybibenzyls represented by the following general formula (1) are effective against intermittent claudication. I found.
[0007]
[Chemical 3]
(Wherein, R 1 represents a hydrogen atom, a halogen atom, a C 1 -C 5 alkoxy group, or a C 2 -C 6 dialkylamino group, and R 2 represents a hydrogen atom, a halogen atom, or C 1 -C 5. R 3 represents a hydrogen atom, a hydroxyl group, —O— (CH 2 ) n —COOH (wherein n represents an integer of 1 to 5), or —O—CO— (CH 2 ) L -COOH (wherein l represents an integer of 1 to 3), and R 4 represents
[Formula 4]
(Wherein, A represents a C3 to C5 alkylene group which may be substituted with a carboxyl group), and m represents an integer of 0 to 5. )
In addition, the gist of the present invention is as follows.
(2) (±) -1- [0- [2- (m-methoxyphenyl) ethyl] phenoxy] -3- (dimethylamino) -2-propyl hydrogen succinate hydrochloride as an active ingredient The above-mentioned intermittent claudication drug.
(3) The above-mentioned intermittent claudication improving drug, which is an improvement drug for intermittent claudication based on peripheral circulation disorder.
(4) The above-mentioned intermittent claudication improving agent, wherein the peripheral circulation disorder is peripheral arteriosclerosis or peripheral arterial occlusion.
(5) The above-mentioned intermittent claudication improver characterized by improving intramuscular oxygen dynamics during exercise load.
(6) The intermittent claudication improver characterized by improving oxygen dynamics in lower limb muscles.
(7) The said intermittent claudication improving agent characterized by measuring using near-infrared spectroscopy.
(8) A method for evaluating an intermittent claudication drug, characterized by using an objective assessment model for intermittent claudication.
(9) The evaluation method described above, wherein the intramuscular oxygen dynamics are quantitatively measured by near infrared spectroscopy.
(10) An intermittent claudication improver obtained by the evaluation method described above.
(11) The above-mentioned intermittentness characterized by comprising as an active ingredient a compound selected from aminoalkoxybibenzyls represented by the general formula (1), pharmaceutically acceptable salts, esters and solvates thereof. Lameness improving drug.
(12) (±) -1- [0- [2- (m-methoxyphenyl) ethyl] phenoxy] -3- (dimethylamino) -2-propyl hydrogen succinate hydrochloride is an active ingredient. The above-mentioned intermittent claudication drug.
[0011]
DETAILED DESCRIPTION OF THE INVENTION
The present invention will be described in detail. In the aminoalkoxybibenzyls represented by the general formula (1) used in the present invention, R 1 is a hydrogen atom; a halogen atom such as a chlorine atom or a fluorine atom; a methoxy group, an ethoxy group, alkoxy C 1 -C 5 or a butoxy group: dimethylamino group, diethylamino group, represents a dialkylamino group of C 2 -C 6 such as a methyl ethylamino group. R 2 represents a hydrogen atom; a halogen atom such as a chlorine atom or a fluorine atom: a C 1 -C 5 alkoxy group such as a methoxy group, an ethoxy group, or a butoxy group. R 3 is a hydrogen atom: a hydroxyl group; -O- (CH 2) 2 -COOH , -O- (CH 2) 3 -O- (CH 2) a -COOH such as n -COOH (n is an integer of from 1 to 5 the expressed); - O-CO- (CH 2) 2 -COOH, -O-CO- ( in CH 2) 3 -COOH, etc. -O-CO- (CH 2) l -COOH (l is 1 to 3 Represents an integer). R 4 represents an amino group, a methylamino group, an ethylamino group, a butylamino group, a hexylamino group, a heptylamino group, a dimethylamino group, a diethylamino group, a methylethylamino group or the like, or a trimethyleneamino group, pentamethylene It represents a 4- to 6-membered polymethyleneamino group in which a carboxyl group may be substituted on a ring such as an amino group and a 3-carboxypentamethyleneamino group substituted with a carboxyl group at the center of the polymethylene chain.
In the aminoalkoxybibenzyls represented by the general formula (1) used in the present invention, an aminoalkoxy group
[Chemical formula 5]
Is preferably bonded to the 2-position of the phenyl group. In general formula (1), R 1 is preferably a hydrogen atom, a C 1 -C 5 alkoxy group, or a C 2 -C 6 dialkylamino group, R 2 is preferably a hydrogen atom, and R 4 is at least It is preferably an amino group having one C 1 -C 8 alkyl group or a trimethylene group or a 4-6 membered polymethyleneamino group having a pentamethyl group, and m is preferably an integer of 0-2. .
[0014]
In the present invention, pharmaceutically acceptable salts and esters of the compound represented by the general formula (1) can also be used. Examples of acids that form such salts and esters include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, succinic acid, adipic acid, propionic acid, tartaric acid, maleic acid, succinic acid, and citric acid. Benzoic acid, toluenesulfonic acid, methanesulfonic acid and the like are used. Moreover, the solvate of the compound represented by General formula (1), its salt, and ester, for example, a hydrate, can also be used.
Among these, (±) -1- [0- [2- (m-methoxyphenyl) ethyl] phenoxy] -3- (dimethylamino) -2-propyl represented by the following formula (2) is particularly preferable. Hydrogen succinate hydrochloride.
[0015]
[Chemical 6]
The aminoalkoxybibenzyls represented by the general formula (1) used in the present invention are known compounds and can be easily synthesized, for example, by the method described in JP-A-58-32847.
The method for administering the intermittent claudication drug according to the present invention is arbitrary.
That is, parenteral administration such as subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection, or the like is also possible.
[0017]
The dosage is determined by the patient's age, health status, weight, type of treatment, if any, the nature of the desired effect, etc.
In general, the daily dose of the active ingredient is 0.5 to 50 mg / kg body weight, usually 1 to 30 mg / kg body weight, and is administered once or more.
When the compound of the present invention is administered orally, it is used in the form of tablets, capsules, powders, solutions, elixirs, etc. In the case of parenteral administration, it is used in a sterilized liquid form such as solutions or suspending agents. It is done. When used in such a form as described above, a solid or liquid non-toxic pharmaceutical carrier may be included in the composition.
[0018]
As an example of the solid carrier, a normal gelatin type capsule is used. In addition, the active ingredients are tableted and powdered with or without adjuvants.
These capsules, tablets and powders generally contain 5 to 95%, preferably 25 to 90% by weight of active ingredient.
That is, these dosage forms should contain 5 to 500 mg, preferably 25 to 250 mg of active ingredient per administration.
[0019]
As the liquid carrier, water or oil of animal or plant origin such as petroleum, peanut oil, soybean oil, mineral oil, sesame oil, or synthetic oil is used.
In general, physiological saline, dextrol or similar sucrose solution, glycols such as ethylene glycol, propylene glycol, polyethylene glycol and the like are preferable as the liquid carrier, and in the case of an injection solution using physiological saline, it is usually 0.00. It contains 5 to 20%, preferably 1 to 10% by weight of the active ingredient.
[0020]
【Example】
The present invention will be described more specifically with reference to the following examples, but the present invention is not limited to these examples.
Creation of intermittent claudication model 14 male New Zealand White Rabbits were randomly divided into a first group (9) and a second group (5).
In both groups, under pentobarbital anesthesia, the right femoral artery was exposed at the buttocks, the catheter was inserted 7 cm, and the balloon was withdrawn while being inflated to a diameter of 3 mm within the right iliac artery. The artery was connected. Baxter Fogarty (size: 2 French) was used as the catheter. One week after the surgery, the first group and the second group after 2 weeks were incised in the supine position under pentobarbital anesthesia, respectively. A near-infrared spectroscopic probe was directly attached to the inside of the right gastrocnemius muscle, and 1 Hz, 2 minutes of electrical stimulation was applied to the right sciatic nerve as an exercise load. The time (recovery time) until oxyhemoglobin, which had decreased during exercise in a resting state after loading, recovered and crossed with deoxyhemoglobin was measured. For measurement of near infrared spectroscopy, OM-100 (Shimadzu Corporation) was used, and the distance between near infrared light transmission and reception was 5 mm. The results are shown in Table 1.
[0021]
Moreover, in the case where the femoral artery is not tied, FIGS. 1 to 3 schematically show oxygen dynamic patterns in the lower limb muscles immediately after ligation and one week after ligation.
This model shows the same pattern as that of patients with intermittent claudication in clinical practice (Takashi Omiyama et al., Ayumi of Medicine, 166, 807-8, 1994, Masataka Ichiki et al., Angiology 35 (1), 53-59, 1995). This model enables objective and quantitative measurement of exercise muscle oxygen dynamics. That is, this model is an objective animal model for intermittent claudication.
[0022]
[Table 1]
The recovery time, which is an index of the severity of intermittent claudication, has been reduced over time. It is thought that as time passed, the collateral circulation developed and the intramuscular oxygen dynamics improved.
[0024]
EXAMPLE 16 Male New Zealand White Rabbits were randomly divided into a drug administration group (7 birds) and a control group (9 birds), and the same treatment as the model was performed.
In the drug administration group, (±) -1- [0- [2- (m-methoxyphenyl)] obtained by the method described in JP-A-58-32847 from the day of surgery to the day of near infrared spectroscopy measurement. [Ethyl] phenoxy] -3-dimethylamino-2-propyl hydrogen succinate hydrochloride was suspended in a 1% tragacanth solution so as to be 100 mg / kg and orally administered once a day. To the control group, tragacanth solution was orally administered once a day. The recovery time was measured by near infrared spectroscopy one week after the operation. The results are shown in Table 2.
[0025]
[Table 2]
As shown in Table 2, the recovery time one week after the operation was significantly shortened in the dosing group compared with the control group, and improvement in lower limb muscle oxygen dynamics was observed. None of the animals had ischemic necrosis of the lower limbs. From these experimental results, the drug comprising the aminoalkoxybibenzyls according to the present invention as an active ingredient improves oxygen dynamics in the lower limb muscles by promoting the development of the collateral circulation or maintaining the blood flow in the collateral circulation. It is clear that it has the effect of improving sexual claudication.
[0027]
【The invention's effect】
The drug containing aminoalkoxybibenzyls according to the present invention as an active ingredient improves and prevents intermittent claudication in intermittent claudication and peripheral circulation disorders such as peripheral arteriosclerosis and peripheral arterial occlusion considered to be the etiology thereof. Expected to have an effect.
[Brief description of the drawings]
FIG. 1 is a schematic diagram in a case where an oxygen dynamic pattern in a lower limb muscle in an intermittent claudication model is measured by near infrared spectroscopy. A normal pattern is shown in the figure when the femoral artery is not tied.
FIG. 2 is a schematic diagram in a case where an oxygen dynamic pattern in a lower limb muscle in an intermittent claudication model is measured by near infrared spectroscopy. A severe pattern is shown in the figure immediately after the femoral artery is tied.
FIG. 3 is a schematic diagram when the oxygen dynamic pattern in the lower limb muscle in the intermittent claudication model is measured by near infrared spectroscopy. It is a figure at the time when 1 week has passed after the femoral artery is tied, and shows a milder pattern than FIG.
[Explanation of symbols]
Oxy Hb: Oxyhemoglobin Deo Hb: Deoxyhemoglobin
Claims (5)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP09657796A JP4568385B2 (en) | 1996-04-18 | 1996-04-18 | Intermittent claudication |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP09657796A JP4568385B2 (en) | 1996-04-18 | 1996-04-18 | Intermittent claudication |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2007285289A Division JP2008074864A (en) | 2007-11-01 | 2007-11-01 | Intermittent claudication ameliorating agent |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH09286722A JPH09286722A (en) | 1997-11-04 |
| JP4568385B2 true JP4568385B2 (en) | 2010-10-27 |
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| Application Number | Title | Priority Date | Filing Date |
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| JP09657796A Expired - Fee Related JP4568385B2 (en) | 1996-04-18 | 1996-04-18 | Intermittent claudication |
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| US6998121B2 (en) * | 2003-01-23 | 2006-02-14 | Milkhaus Laboratory, Inc. | Method of treatment of connective tissue disorders by administration of streptolysin O |
| CA2460777A1 (en) * | 2001-09-26 | 2003-04-03 | Mitsubishi Pharma Corporation | Thrombus/thrombogenesis inhibitors |
| CN1913881A (en) * | 2004-02-02 | 2007-02-14 | 三菱制药株式会社 | Preventive and/or therapeutic agent for chronic cerebral circulatory failure |
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