JPH02262519A - Diabetic nerve disorder agent - Google Patents
Diabetic nerve disorder agentInfo
- Publication number
- JPH02262519A JPH02262519A JP1083069A JP8306989A JPH02262519A JP H02262519 A JPH02262519 A JP H02262519A JP 1083069 A JP1083069 A JP 1083069A JP 8306989 A JP8306989 A JP 8306989A JP H02262519 A JPH02262519 A JP H02262519A
- Authority
- JP
- Japan
- Prior art keywords
- beraprost
- diabetic
- nerve disorder
- active ingredient
- diabetic nerve
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 206010012601 diabetes mellitus Diseases 0.000 title abstract description 13
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 title abstract description 6
- 210000005036 nerve Anatomy 0.000 title abstract 3
- 239000004480 active ingredient Substances 0.000 claims abstract description 9
- 150000003839 salts Chemical class 0.000 claims abstract description 7
- 239000003814 drug Substances 0.000 claims description 16
- 208000032131 Diabetic Neuropathies Diseases 0.000 claims description 14
- 229940124597 therapeutic agent Drugs 0.000 claims description 6
- XYGDXKXDLNMDFG-UHFFFAOYSA-N 4-(1h-cyclopenta[b][1]benzofuran-5-yl)butanoic acid Chemical compound OC(=O)CCCC1=CC=CC2=C1OC1=C2CC=C1 XYGDXKXDLNMDFG-UHFFFAOYSA-N 0.000 claims 1
- 229960002890 beraprost Drugs 0.000 abstract description 13
- CTPOHARTNNSRSR-APJZLKAGSA-N beraprost Chemical compound O([C@H]1C[C@@H](O)[C@@H]([C@@H]21)/C=C/[C@@H](O)C(C)CC#CC)C1=C2C=CC=C1CCCC(O)=O CTPOHARTNNSRSR-APJZLKAGSA-N 0.000 abstract description 13
- 150000001875 compounds Chemical class 0.000 abstract description 6
- 150000003180 prostaglandins Chemical class 0.000 abstract description 2
- 239000003795 chemical substances by application Substances 0.000 abstract 2
- 229940094443 oxytocics prostaglandins Drugs 0.000 abstract 1
- 229940079593 drug Drugs 0.000 description 8
- 230000000694 effects Effects 0.000 description 7
- 241000700159 Rattus Species 0.000 description 6
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 6
- 208000007536 Thrombosis Diseases 0.000 description 4
- -1 alkali metal salts Chemical class 0.000 description 4
- 230000007830 nerve conduction Effects 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 201000001119 neuropathy Diseases 0.000 description 3
- 230000007823 neuropathy Effects 0.000 description 3
- 208000033808 peripheral neuropathy Diseases 0.000 description 3
- 159000000000 sodium salts Chemical class 0.000 description 3
- 238000011282 treatment Methods 0.000 description 3
- 208000019553 vascular disease Diseases 0.000 description 3
- 208000012902 Nervous system disease Diseases 0.000 description 2
- 231100000215 acute (single dose) toxicity testing Toxicity 0.000 description 2
- 238000011047 acute toxicity test Methods 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 238000001802 infusion Methods 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 230000001766 physiological effect Effects 0.000 description 2
- YIBNHAJFJUQSRA-YNNPMVKQSA-N prostaglandin H2 Chemical compound C1[C@@H]2OO[C@H]1[C@H](/C=C/[C@@H](O)CCCCC)[C@H]2C\C=C/CCCC(O)=O YIBNHAJFJUQSRA-YNNPMVKQSA-N 0.000 description 2
- DZUXGQBLFALXCR-UHFFFAOYSA-N (+)-(9alpha,11alpha,13E,15S)-9,11,15-trihydroxyprost-13-en-1-oic acid Natural products CCCCCC(O)C=CC1C(O)CC(O)C1CCCCCCC(O)=O DZUXGQBLFALXCR-UHFFFAOYSA-N 0.000 description 1
- XBYGDAGWXPBGNY-UHFFFAOYSA-N 4-(1-benzofuran-5-yl)butanoic acid Chemical compound OC(=O)CCCC1=CC=C2OC=CC2=C1 XBYGDAGWXPBGNY-UHFFFAOYSA-N 0.000 description 1
- 206010059245 Angiopathy Diseases 0.000 description 1
- 206010003210 Arteriosclerosis Diseases 0.000 description 1
- 208000000412 Avitaminosis Diseases 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- 206010021135 Hypovitaminosis Diseases 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 208000025966 Neurological disease Diseases 0.000 description 1
- 206010029333 Neurosis Diseases 0.000 description 1
- 208000003782 Raynaud disease Diseases 0.000 description 1
- 208000012322 Raynaud phenomenon Diseases 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 208000007107 Stomach Ulcer Diseases 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 230000001430 anti-depressive effect Effects 0.000 description 1
- 230000001315 anti-hyperlipaemic effect Effects 0.000 description 1
- 230000000702 anti-platelet effect Effects 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 239000000935 antidepressant agent Substances 0.000 description 1
- 229940005513 antidepressants Drugs 0.000 description 1
- 208000011775 arteriosclerosis disease Diseases 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- 230000004531 blood pressure lowering effect Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000000812 cholinergic antagonist Substances 0.000 description 1
- 230000004087 circulation Effects 0.000 description 1
- 230000006866 deterioration Effects 0.000 description 1
- XEYBRNLFEZDVAW-ARSRFYASSA-N dinoprostone Chemical compound CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1C\C=C/CCCC(O)=O XEYBRNLFEZDVAW-ARSRFYASSA-N 0.000 description 1
- 229960001123 epoprostenol Drugs 0.000 description 1
- KAQKFAOMNZTLHT-VVUHWYTRSA-N epoprostenol Chemical compound O1C(=CCCCC(O)=O)C[C@@H]2[C@@H](/C=C/[C@@H](O)CCCCC)[C@H](O)C[C@@H]21 KAQKFAOMNZTLHT-VVUHWYTRSA-N 0.000 description 1
- 125000001033 ether group Chemical group 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 210000004051 gastric juice Anatomy 0.000 description 1
- 230000000762 glandular Effects 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 201000001421 hyperglycemia Diseases 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 229960000367 inositol Drugs 0.000 description 1
- CDAISMWEOUEBRE-GPIVLXJGSA-N inositol Chemical compound O[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@H](O)[C@@H]1O CDAISMWEOUEBRE-GPIVLXJGSA-N 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 235000021174 kaiseki Nutrition 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 201000009240 nasopharyngitis Diseases 0.000 description 1
- 208000015238 neurotic disease Diseases 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 1
- NOOLISFMXDJSKH-UHFFFAOYSA-N p-menthan-3-ol Chemical compound CC(C)C1CCC(C)CC1O NOOLISFMXDJSKH-UHFFFAOYSA-N 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 208000001297 phlebitis Diseases 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- DZUXGQBLFALXCR-CDIPTNKSSA-N prostaglandin F1alpha Chemical compound CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)C[C@H](O)[C@@H]1CCCCCCC(O)=O DZUXGQBLFALXCR-CDIPTNKSSA-N 0.000 description 1
- 150000003174 prostaglandin I2 derivatives Chemical class 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 230000004088 pulmonary circulation Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- CDAISMWEOUEBRE-UHFFFAOYSA-N scyllo-inosotol Natural products OC1C(O)C(O)C(O)C(O)C1O CDAISMWEOUEBRE-UHFFFAOYSA-N 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000002636 symptomatic treatment Methods 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000007916 tablet composition Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 201000010875 transient cerebral ischemia Diseases 0.000 description 1
- 230000000304 vasodilatating effect Effects 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 208000030401 vitamin deficiency disease Diseases 0.000 description 1
Landscapes
- Furan Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
【発明の詳細な説明】
［産業上の利用分野］
本発明はプロスタグランジン Ｉ２誘導体の一種である
ベラプロストを有効成分とする糖尿病性神経障害治療剤
に関する。DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to a therapeutic agent for diabetic neuropathy containing beraprost, a type of prostaglandin I2 derivative, as an active ingredient.
［従来の技術］
プロスタグランジン ＋２（ＰＣｌ３ 、プロスタサイ
クリン）自体は、１９７０年にジエイ・アール・ヴエイ
ン（Ｊ、 Ｒ，ＶａｎＯ）らによって発見された化合物
であり、アラキドン酸からエンドパーオキシド（ｐｃｃ
２またはＰＧＨ２）を経由して動脈壁にて生合成され、
強力な血小板凝集抑制作用および末梢血管拡張作用を有
する物質と［７て注目されている［ネイチ＋ −（Ｎａ
ｔｕｒｅ）、２６８巻、６８８頁（１９７８年）参照］
。[Prior Art] Prostaglandin +2 (PCl3, prostacyclin) itself is a compound discovered in 1970 by J.R. VanO et al.
It is biosynthesized in the arterial wall via PGH2 or PGH2),
[7] [Natural + -(Na
ture), vol. 268, p. 688 (1978)]
.
ＰＣｌ３は不安定なエキソエノール構造を有しているた
め、中性の水溶液中でも極めて不安定で、生理的に活性
のほとんどない６−ケドーＰＧＦ１αへと変換する。ｐ
ｃ＋ｚのこの不安定性はこの化合物を医薬として利用し
ようとするばあいに大きな欠点になる。さらにＰＣｌ３
は生体内で不安定で、その生理作用には持続性がないと
いう欠点を有している。Since PCl3 has an unstable exoenol structure, it is extremely unstable even in a neutral aqueous solution, and is converted into 6-kedo PGF1α, which has almost no physiological activity. p
This instability of c+z is a major drawback when attempting to use this compound as a medicine. Furthermore, PCl3
has the disadvantage that it is unstable in vivo and its physiological effects are not sustainable.
ＰＣｌ３のこれらの欠点が大幅に改善された化合物とし
て、ＰＣｌ３の特徴的構造であるエキソエノールエーテ
ル部分の構造をインターｍ−フ二二しン型に変換した骨
格を有するＰＣＩ２誘導体が、特開昭５７−３２２７７
号公報、特開昭５７−１４４２７８号公報、特開昭５８
−１２４７７８号公報などに記載されている。As a compound in which these drawbacks of PCl3 have been significantly improved, a PCI2 derivative having a skeleton in which the structure of the exoenol ether moiety, which is a characteristic structure of PCl3, is converted to an inter-m-funinicine type has been proposed in Japanese Patent Application Laid-open No. 57-32277
No. 57-144278, Japanese Patent Application Laid-Open No. 1983
-124778, etc.
本発明の糖尿病性神経障害治療剤の有効成分は前記公報
に記載されている安定な構造を有するｐｃ＋ｚ誘導体の
一種である、（±） −（ＩＲ’２Ｒ，３ａＳ 、８
ｂＳ ）−２，３，３ａ、８ｂ−テトラヒドロ−２ヒ
ドロキシ−１−［（Ｈ）−（３Ｓ ）−３−ヒドロキ
シ４−メチル−１−オクテン−６−イニル］ −１ｌ＋
−シクロペンタ［ｂｌベンゾフラン−５−ブチリックア
シッド［以下、ベラプロスト（ｂｃｒａｐｒｏｓｔ）と
いう］である。The active ingredient of the therapeutic agent for diabetic neuropathy of the present invention is (±) -(IR'2R,3aS,8
bS )-2,3,3a,8b-tetrahydro-2hydroxy-1-[(H)-(3S )-3-hydroxy4-methyl-1-octen-6-ynyl] -1l+
-cyclopenta[bl benzofuran-5-butyric acid [hereinafter referred to as bcraprost].
前記公報にはベラプロストが強力な血小板凝集抑制作用
および血管拡張作用に基づく血圧降下作用を有しており
、それゆえ体外循環への応用、バーシャー病、レイノー
病、心筋梗塞、一過性脳虚血発作（ＴＩＡ） 、糖尿病
性血栓症、動脈硬化症への応用が考えられている。また
、ベラプロストの胃粘膜保護作用あるいは胃液分泌抑制
作用に基づく胃潰瘍への応用が前記公報で述べられてい
るし、さらには抗高脂血症作用をも有することが特開昭
１３２−２８６９２４号公報に記載されている。そのう
ち、特開昭５８−１２４７７８号公報に応用例の一つと
して記載されている糖尿病性血栓症とは糖尿病性懐石の
ように明らかに血栓形成をともない血管閉塞によって引
き起こされる糖尿病の疾患をさす。The publication states that beraprost has a strong anti-platelet aggregation effect and a blood pressure lowering effect based on a vasodilatory effect, and is therefore suitable for use in extracorporeal circulation, Bersher's disease, Raynaud's disease, myocardial infarction, and transient cerebral ischemia. Applications are being considered for stroke (TIA), diabetic thrombosis, and arteriosclerosis. Furthermore, the above publication describes the application of beraprost to gastric ulcers based on its gastric mucosal protective action or gastric juice secretion suppressing action, and it is also reported in JP-A No. 132-286924 that it also has an antihyperlipidemic action. It is described in. Among them, diabetic thrombosis, which is described as one of the applied examples in JP-A No. 58-124778, refers to a diabetic disease caused by blood vessel occlusion that clearly involves thrombus formation, as in diabetic kaiseki.
一方、糖尿病性神経障害の病因にはこれまでビタミン欠
乏説、ソルビトール蓄積とミオイノシトール減少説、血
管障害説などが報告されているが、いまだ決定的な結論
はえられておらず［治療学、１６巻、３５１−３５４頁
（１９８６年）参照コ抗血栓作用を存しないアルドース
還元酵素阻害剤がこの疾患に有効なことが数多く報告さ
れていることから分かるように、近年では高血糖に基づ
く代謝異常が神経障害の発症に主要な役割を果たしてい
ると一般に認められている［メディカル・ブラクテイス
（Ｍｅｄｉｃａｌ Ｐｒａｃｔｉｃｃ）、２巻、５０〜
５３頁（１９８５年）参照］。このように糖尿病性神経
障害は血管障害がその成因に関与していると考えられる
ものの、糖尿病性血栓症とは明確に異なるものであり、
ベラプロストが糖尿病性神経障害に対して改善作用を有
することは知られていない。On the other hand, the etiology of diabetic neuropathy has been reported to include vitamin deficiency theory, sorbitol accumulation and myo-inositol reduction theory, and vascular disorder theory, but no definitive conclusion has been reached yet. 16, pp. 351-354 (1986).In recent years, hyperglycemia-induced metabolic It is generally accepted that abnormalities play a major role in the development of neurological disorders [Medical Practic, Vol. 2, 50-
53 (1985)]. Although vascular disorders are thought to be involved in the pathogenesis of diabetic neuropathy, it is clearly different from diabetic thrombosis.
It is not known that beraprost has an ameliorating effect on diabetic neuropathy.
［発明が解決しようとする課題］
糖尿病性神経障害は糖尿病の合併症の中でも最も頻度が
高く、患者数が最大の疾患である。[Problems to be Solved by the Invention] Diabetic neuropathy is the most frequent complication of diabetes and is the disease with the largest number of patients.
治療薬としては対症療法的に消炎鎮痛剤、ビタミン剤、
抗痙学割、抗うつ剤などが用いられているが、効果につ
いては一定の見解がなく、有効な治療薬の開発が広く望
まれている。As a symptomatic treatment, anti-inflammatory analgesics, vitamins,
Anti-spasmodic drugs and anti-depressants have been used, but there is no consensus on their effectiveness, and the development of effective treatments is widely desired.
近年、プロスタグランジンＥ＋ （ＰＧＥ＋ ）がこの
種の神経症にを効なことが見出され、臨床上も一部使用
され始めているが、ＰＧＥ＋は一回の肺循環で大部分失
活するため点滴静注を必要とする。このため、治療上煩
雑である。しかも、点滴時穿刺部に静脈炎が生じたり、
血管病が現れ、患者にとって好ましいものではない［総
合臨床、３７巻、２３９２〜２３９４頁（１９８８年）
参照］。In recent years, prostaglandin E+ (PGE+) has been found to be effective against this type of neurosis, and has begun to be used clinically in some cases, but PGE+ is largely inactivated after a single pulmonary circulation, so it is not recommended for intravenous infusion. Requires intravenous injection. Therefore, the treatment is complicated. Moreover, phlebitis may occur at the puncture site during infusion,
Vascular disease appears and is not favorable for the patient [General Clinical Research, Vol. 37, pp. 2392-2394 (1988)
reference].
糖尿病性神経障害に対するＰＣｌ３の効果も検討された
が、化学的に不安定なため、製剤化が困難であった。The effect of PCl3 on diabetic neuropathy was also investigated, but it was difficult to formulate it because it was chemically unstable.
本発明者らは永年にわたり、経口投与可能で安定な糖尿
病性神経障害治療薬の検索を続けてきた結果、ベラブロ
スｉ・が顕著に糖尿病性神経障害を改善することを見出
し、本発明を完成するに至った。The present inventors have continued to search for an orally administrable and stable drug for the treatment of diabetic neuropathy for many years, and as a result, they have discovered that Bellabros i. significantly improves diabetic neuropathy, and have completed the present invention. reached.
［課題を解決するための手段］
本発明は、（±） −（１Ｒ＊，２Ｒ＊，３ａＳ 、
８ｂＳ ）−２，３，３ａ、８ｂ−テトラヒドロ−２
−ヒドロキシ−１＝［（Ｅ）−（３Ｓ ）−３−ヒド
ロキシ−４−メチル−１−オクテン−Ｂ−イニル］−１
＋＋−シクロペンタ［ｂ］ベンゾフラン−５−ブチリッ
クアシッドまたはその塩を有効成分とする糖尿病性神経
障害治療剤に関する。[Means for solving the problem] The present invention provides (±) −(1R*, 2R*, 3aS,
8bS)-2,3,3a,8b-tetrahydro-2
-Hydroxy-1=[(E)-(3S)-3-hydroxy-4-methyl-1-octen-B-ynyl]-1
The present invention relates to a therapeutic agent for diabetic neuropathy containing ++-cyclopenta[b]benzofuran-5-butyric acid or a salt thereof as an active ingredient.
ここで、前記化合物はセラミ体はもとより６体およびｇ
体を包含するものである。Here, the above compound includes not only ceramiform but also 6-form and g
It encompasses the body.
［実施例コ
本発明の薬剤の有効成分であるベラプロストは、たとえ
ば前述の特開昭５８−１２４７７８号公報に記載されて
いる方法により製造することができる。ベラプロストの
塩としては、たとえばナトリウム塩、カリウム塩などの
アルカリ金属塩、マグネシウム塩、カルシウム塩などの
アルカリ土類金属塩、アンモニウム塩、第１級、第２級
または第３級アミン塩、さらには塩基性アミノ酸塩など
薬理学的に許容しうる塩があげられる。[Example Beraprost, which is the active ingredient of the drug of the present invention, can be produced, for example, by the method described in JP-A-58-124778. Salts of beraprost include, for example, alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as magnesium salts and calcium salts, ammonium salts, primary, secondary or tertiary amine salts, and even salts of beraprost. Examples include pharmacologically acceptable salts such as basic amino acid salts.
本発明の糖尿病性神経障害治療剤としては、ベラプロス
トまたはその塩をそのまま用いてもよいが、通常は普通
の補助剤、たとえば賦形剤その他と一緒に、錠剤、カプ
セル剤、散剤、顆粒剤、液剤などの内服可能な一般的な
医薬製剤の形態で用いられる。これらの製剤は常坊によ
り製造できる。たとえば錠剤を製造するばあいの賦形剤
としては、澱粉、乳糖、結晶セルロースなどが用いられ
る。製剤例としてベラプロストを２０μｇ含有する錠剤
の処方の１例を第１表に示す。この錠剤は通常成人１人
当り、３錠／回、３回／日経口投与するものである。As the therapeutic agent for diabetic neuropathy of the present invention, beraprost or its salt may be used as it is, but it is usually used in tablets, capsules, powders, granules, etc. together with common adjuvants, such as excipients. It is used in the form of general pharmaceutical preparations that can be taken orally, such as liquid preparations. These formulations can be manufactured by Tokibo. For example, when manufacturing tablets, excipients include starch, lactose, and crystalline cellulose. Table 1 shows an example of a tablet formulation containing 20 μg of beraprost. This tablet is usually orally administered 3 tablets/time, 3 times/day per adult.
本発明の薬剤は経口投与でそのすぐれた治療効果を発揮
するが、化学構造上安定性を有しているため製剤上の難
点はなく、その他注射剤、小割など中広い投与が可能で
ある。経口投与のばあいの投与量は通常成人１人あたり
１〜５００μｇ１日、好ましくは１０〜２００μｇ７日
（いずれも有効成分基準）である。The drug of the present invention exhibits excellent therapeutic effects when administered orally, but because it has a stable chemical structure, there are no difficulties in formulation, and it can be administered in a wide range of ways such as injections and small portions. . In the case of oral administration, the dosage is usually 1 to 500 μg per adult per day, preferably 10 to 200 μg per 7 days (all based on active ingredients).
Ｅ以下余白］ λＪ 表 つぎに試験例をもって本発明を説明する。Margin below E] λJ table Next, the present invention will be explained using test examples.
試験例１
［ストレプトシトシン誘発糖尿病ラットの神経障害に対
する効果］
（本ｍ ２００ｇ （１０週退部後） ０：）Ｓ、Ｄ、
’ｆ−、雄性ラ雄性ラット肝７匹）を−晩絶食させたの
ち、ストレプトシトシン（シグマ社）を体重１ ｋｇ当
り４５Ｂ静脈内投与して糖尿病を発症させた。Test Example 1 [Effect on streptocytosine-induced neuropathy in diabetic rats] (200 g (10 weeks after withdrawal) 0:) S, D,
After fasting overnight, streptocytosine (Sigma) (45B/kg body weight) was administered intravenously to induce diabetes.
発症直後よりベラプロストのナトリウム塩の水溶液を該
ナトリウム塩換算で０ 、２ ｍ ｇ ／ ｋｇ体重ず
つ１０１回４週間に４つたり連続的に経口投与した。投
与開始時、２週間後および４週間後に尾部の神経伝導速
度（ＩＩｌ／５ｅｃ）をシグナルプロセッサーを用いて
測定した。その結果を第１図に示す。Immediately after the onset of symptoms, an aqueous solution of the sodium salt of beraprost was orally administered continuously at a dose of 0.2 mg/kg body weight (calculated as the sodium salt) 101 times, 4 times every 4 weeks. At the start of administration, 2 weeks later, and 4 weeks later, nerve conduction velocity (IIl/5ec) in the caudal region was measured using a signal processor. The results are shown in FIG.
第１図に示されるように正常ラットでは成長に伴って神
経伝導速度が増加したが、糖尿病を発症したラットでは
明らかに神経伝導速度の増加が抑制され、神経障害を示
した。これに対して糖尿病ラットに本発明の薬剤を連続
投与した場合、２週間で約５５％の改訃がみられ、４週
間では正常ラットの神経伝導速度と同程度の値を示し、
明確に神経障害を改善した。As shown in FIG. 1, in normal rats, the nerve conduction velocity increased with growth, but in the rats that developed diabetes, the increase in nerve conduction velocity was clearly suppressed, indicating neuropathy. On the other hand, when the drug of the present invention was continuously administered to diabetic rats, approximately 55% deterioration was observed in 2 weeks, and the nerve conduction velocity showed a value similar to that of normal rats in 4 weeks.
Neuropathy was clearly improved.
試験例２
［急性毒性試験］
ラットを用いて急性毒性試験を行なった。投与経路およ
び性別のしＤ５ｏ値を第２表に示す。Test Example 2 [Acute toxicity test] An acute toxicity test was conducted using rats. D5o values by route of administration and gender are shown in Table 2.
［以下余白］
第
表
＊リッチフィールド・ウィルコキソン
（Ｌｉｔｃｈｆ’１ｃｌｄ−Ｗｉｌｃｏｘｏｎ ）法［
ジャーナル・オブ・ファーマコロジー・アンド・イクス
ベリメンタル・セラビューティクス（Ｊ。[Left below] Table * Litchfield-Wilcoxon method [
Journal of Pharmacology and Experimental Therapeutics (J.
Ｐｈａｍａｃｏｌ、Ｅｘｐｌ、 Ｔｈｏｒａｐ、 、
９［ｆ巻、９９頁（１９４９）参照］
０内は９５％信頼限界
病理所見としては、ラットの雄雌および各段ｌ）経路に
共通した主要所見として、死亡例では肺の軽度ないし中
程度のうっ血、腺胃部の軽度ないし中程度の出血、軽度
小腸カタルが認められた。Pharmacol, Expl, Thorap, ,
9 [Refer to Vol. Congestion, mild to moderate bleeding in the glandular stomach area, and mild small intestinal catarrh were observed.
このように、極めて高用量では副作用が認められるが、
薬理試験の使用例（０，２ｍｇ／ｋｇの経口役Ｌｊ、
）と同じ投与経路である経口投与のＬＤ５ｏ値と比較す
ると、６０〜７５倍のひらきかあり、このこと、から本
発明の薬剤は安全域の広い化合物であることがわかる。Although side effects are observed at extremely high doses,
Example of use in pharmacological testing (0.2 mg/kg oral Lj,
), the LD5o value is 60 to 75 times higher than that obtained by oral administration, which is the same route of administration.This shows that the drug of the present invention is a compound with a wide safety margin.
［発明の効果］
本発明のベラプロストを有効成分とする薬剤は糖尿病性
神経障害を顕著に改善し、かつ安全な薬剤であり、さら
に従来のＰＣ系薬剤にくらべて化学的に安定で経口投与
できるため、糖尿病性神経障害治療剤として有用である
。[Effect of the invention] The drug containing beraprost as an active ingredient of the present invention significantly improves diabetic neuropathy, is a safe drug, and is chemically more stable than conventional PC drugs and can be administered orally. Therefore, it is useful as a therapeutic agent for diabetic neuropathy.
による神経障害改善効果を示すグラフである。It is a graph showing the neurological disorder improving effect of.
Claims (1)
Ｓ＾＊）−２，３，３ａ，８ｂ−テトラヒドロ−２−ヒ
ドロキシ−１−［（Ｅ）−（３Ｓ＾＊）−３−ヒドロキ
シ−４−メチル−１−オクテン−６−イニル］−１Ｈ−
シクロペンタ［ｂ］ベンゾフラン−５−ブチリックアシ
ッドまたはその塩を有効成分とする糖尿病性神経障害治
療剤。1 (±) - (1R^*, 2R^*, 3aS^*, 8b
S^*)-2,3,3a,8b-tetrahydro-2-hydroxy-1-[(E)-(3S^*)-3-hydroxy-4-methyl-1-octen-6-ynyl]-1H −
A therapeutic agent for diabetic neuropathy containing cyclopenta[b]benzofuran-5-butyric acid or a salt thereof as an active ingredient.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP1083069A JP2608135B2 (en) | 1989-03-31 | 1989-03-31 | Diabetic neuropathy treatment |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP1083069A JP2608135B2 (en) | 1989-03-31 | 1989-03-31 | Diabetic neuropathy treatment |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH02262519A true JPH02262519A (en) | 1990-10-25 |
| JP2608135B2 JP2608135B2 (en) | 1997-05-07 |
Family
ID=13791891
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP1083069A Expired - Fee Related JP2608135B2 (en) | 1989-03-31 | 1989-03-31 | Diabetic neuropathy treatment |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP2608135B2 (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1998041209A1 (en) * | 1997-03-14 | 1998-09-24 | Toray Industries, Inc. | Protective agents for cells constituting nervous system |
| WO1999039714A1 (en) * | 1998-02-06 | 1999-08-12 | Teijin Limited | Remedies for neurological disorders |
| US6919372B1 (en) * | 1997-12-26 | 2005-07-19 | Yamanouchi Pharmaceutical Co., Ltd. | Sustained release pharmaceutical compositions |
| US7071359B1 (en) | 1999-08-05 | 2006-07-04 | Teijin Limited | Neuropathy improvers containing nitrogenous compounds as the active ingredient |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS58124778A (en) * | 1982-01-20 | 1983-07-25 | Toray Ind Inc | 5,6,7-trinor-4,8-inter-m-phenylene pgi2 derivative |
| JPS62286924A (en) * | 1986-06-05 | 1987-12-12 | Kaken Pharmaceut Co Ltd | Anti-hyperlipemia agent |
-
1989
- 1989-03-31 JP JP1083069A patent/JP2608135B2/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS58124778A (en) * | 1982-01-20 | 1983-07-25 | Toray Ind Inc | 5,6,7-trinor-4,8-inter-m-phenylene pgi2 derivative |
| JPS62286924A (en) * | 1986-06-05 | 1987-12-12 | Kaken Pharmaceut Co Ltd | Anti-hyperlipemia agent |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1998041209A1 (en) * | 1997-03-14 | 1998-09-24 | Toray Industries, Inc. | Protective agents for cells constituting nervous system |
| EP0947195A1 (en) * | 1997-03-14 | 1999-10-06 | Toray Industries, Inc. | Protective agents for cells constituting nervous system |
| US6340693B1 (en) | 1997-03-14 | 2002-01-22 | Toray Industries, Inc. | Protective agent for nervous system structural cells |
| US6919372B1 (en) * | 1997-12-26 | 2005-07-19 | Yamanouchi Pharmaceutical Co., Ltd. | Sustained release pharmaceutical compositions |
| WO1999039714A1 (en) * | 1998-02-06 | 1999-08-12 | Teijin Limited | Remedies for neurological disorders |
| AU753080B2 (en) * | 1998-02-06 | 2002-10-10 | Teijin Limited | Remedies for neurological disorders |
| US7071359B1 (en) | 1999-08-05 | 2006-07-04 | Teijin Limited | Neuropathy improvers containing nitrogenous compounds as the active ingredient |
Also Published As
| Publication number | Publication date |
|---|---|
| JP2608135B2 (en) | 1997-05-07 |
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