JPH01294622A - Adhesion of leukopenia or agent for suppressing aggregation of leukopenia - Google Patents
Adhesion of leukopenia or agent for suppressing aggregation of leukopeniaInfo
- Publication number
- JPH01294622A JPH01294622A JP12547288A JP12547288A JPH01294622A JP H01294622 A JPH01294622 A JP H01294622A JP 12547288 A JP12547288 A JP 12547288A JP 12547288 A JP12547288 A JP 12547288A JP H01294622 A JPH01294622 A JP H01294622A
- Authority
- JP
- Japan
- Prior art keywords
- leukopenia
- adhesion
- compound
- aggregation
- salt
- 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
- 230000002776 aggregation Effects 0.000 title claims abstract description 17
- 238000004220 aggregation Methods 0.000 title claims abstract description 17
- 201000002364 leukopenia Diseases 0.000 title abstract 3
- 231100001022 leukopenia Toxicity 0.000 title abstract 3
- 150000003839 salts Chemical class 0.000 claims abstract description 7
- 239000004480 active ingredient Substances 0.000 claims abstract description 4
- 230000023404 leukocyte cell-cell adhesion Effects 0.000 claims description 7
- 239000003112 inhibitor Substances 0.000 claims description 2
- 229940126062 Compound A Drugs 0.000 abstract description 12
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 abstract description 12
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 9
- 239000003795 chemical substances by application Substances 0.000 abstract description 3
- 239000002775 capsule Substances 0.000 abstract description 2
- 239000008187 granular material Substances 0.000 abstract description 2
- 230000002265 prevention Effects 0.000 abstract description 2
- DYEFUKCXAQOFHX-UHFFFAOYSA-N Ebselen Chemical compound [se]1C2=CC=CC=C2C(=O)N1C1=CC=CC=C1 DYEFUKCXAQOFHX-UHFFFAOYSA-N 0.000 abstract 2
- 238000007918 intramuscular administration Methods 0.000 abstract 1
- 238000007920 subcutaneous administration Methods 0.000 abstract 1
- 210000000265 leukocyte Anatomy 0.000 description 11
- 210000004369 blood Anatomy 0.000 description 5
- 239000008280 blood Substances 0.000 description 5
- 208000035475 disorder Diseases 0.000 description 5
- 239000000243 solution Substances 0.000 description 4
- 241000700159 Rattus Species 0.000 description 3
- 210000004204 blood vessel Anatomy 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 description 2
- 229960002897 heparin Drugs 0.000 description 2
- 229920000669 heparin Polymers 0.000 description 2
- 230000001575 pathological effect Effects 0.000 description 2
- 230000001681 protective effect Effects 0.000 description 2
- 210000003556 vascular endothelial cell Anatomy 0.000 description 2
- 206010001052 Acute respiratory distress syndrome Diseases 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 208000031104 Arterial Occlusive disease Diseases 0.000 description 1
- 206010003210 Arteriosclerosis Diseases 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 108010024636 Glutathione Proteins 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 208000013616 Respiratory Distress Syndrome Diseases 0.000 description 1
- 206010038687 Respiratory distress Diseases 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 238000000692 Student's t-test Methods 0.000 description 1
- 208000026062 Tissue disease Diseases 0.000 description 1
- GBOGMAARMMDZGR-UHFFFAOYSA-N UNPD149280 Natural products N1C(=O)C23OC(=O)C=CC(O)CCCC(C)CC=CC3C(O)C(=C)C(C)C2C1CC1=CC=CC=C1 GBOGMAARMMDZGR-UHFFFAOYSA-N 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 201000000028 adult respiratory distress syndrome Diseases 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 208000021328 arterial occlusion Diseases 0.000 description 1
- 208000011775 arteriosclerosis disease Diseases 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 230000005779 cell damage Effects 0.000 description 1
- 208000037887 cell injury Diseases 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- GKTWGGQPFAXNFI-HNNXBMFYSA-N clopidogrel Chemical compound C1([C@H](N2CC=3C=CSC=3CC2)C(=O)OC)=CC=CC=C1Cl GKTWGGQPFAXNFI-HNNXBMFYSA-N 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- GBOGMAARMMDZGR-JREHFAHYSA-N cytochalasin B Natural products C[C@H]1CCC[C@@H](O)C=CC(=O)O[C@@]23[C@H](C=CC1)[C@H](O)C(=C)[C@@H](C)[C@@H]2[C@H](Cc4ccccc4)NC3=O GBOGMAARMMDZGR-JREHFAHYSA-N 0.000 description 1
- GBOGMAARMMDZGR-TYHYBEHESA-N cytochalasin B Chemical compound C([C@H]1[C@@H]2[C@@H](C([C@@H](O)[C@@H]3/C=C/C[C@H](C)CCC[C@@H](O)/C=C/C(=O)O[C@@]23C(=O)N1)=C)C)C1=CC=CC=C1 GBOGMAARMMDZGR-TYHYBEHESA-N 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 210000002889 endothelial cell Anatomy 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 229960003180 glutathione Drugs 0.000 description 1
- 239000000411 inducer Substances 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 208000028867 ischemia Diseases 0.000 description 1
- VNYSSYRCGWBHLG-AMOLWHMGSA-M leukotriene B4(1-) Chemical compound CCCCC\C=C/C[C@@H](O)\C=C\C=C\C=C/[C@@H](O)CCCC([O-])=O VNYSSYRCGWBHLG-AMOLWHMGSA-M 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 206010040560 shock Diseases 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000012353 t test Methods 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Landscapes
- 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、２−フェニル−１，２−ベンゾイソセレナゾ
ール−３（２Ｈ）−オン（以下、化合物Ａと称す）又は
その生理学的許容塩を有効成分とする白血球の粘着又は
凝集抑制剤に関する。Detailed Description of the Invention <Industrial Application Field> The present invention relates to 2-phenyl-1,2-benziisoselenazol-3(2H)-one (hereinafter referred to as compound A) or its physiologically acceptable The present invention relates to a leukocyte adhesion or aggregation inhibitor containing a salt as an active ingredient.
〈従来の技術〉
正常状態では白血球が血管内皮細胞に粘着することはあ
ってもそれはごく短時間にかぎられる。<Prior art> Under normal conditions, white blood cells may adhere to vascular endothelial cells, but only for a very short time.
しかし微小循環系に虚血あるいは炎症等の病的刺激が加
わると白血球は血管内皮細胞に粘着して局所性の微小循
環障害を惹起し、更に粘着した白血球は固有運動により
て内皮細胞間を通過して内皮下へ遊出し、そこで活性酸
素やりソゾーム酵素を放出して局所性の細胞障害を起こ
すことが解明されている（Ｓｈａｗ、Ｊ、Ｏ，、＾ｍ、
Ｊ、Ｐａｔｈｏ１．．１０１．２８３゜１９８０、Ｆａ
ｎｔｏｎｅ、Ｊ、Ｃ，、Ｗａｒｄ、Ｐ、Ａ、、＾ｓ、Ｊ
、Ｐａｔｈｏ１．，１０７３９７．１９８２） 、この
ことから、白血球の粘着を抑制する薬物には病的組織に
おける微小循環障害及び組織障害に対する防禦効果を期
待できると考えられ、検討した結果、これらの防禦効果
には全血系における白血球の粘着又は凝集抑制作用が強
く関与することが解明されるに至った（Ｔｈｒｏｍｂｏ
ｓｉｓａｎｄ Ｈａｅ園ｏｓｔａｓ１ｓ ｊＪ、１
，２００．ｐ−１１８３（１９８５））。However, when pathological stimuli such as ischemia or inflammation are applied to the microcirculatory system, leukocytes adhere to vascular endothelial cells and cause local microcirculatory disorders, and the adhered leukocytes further pass between endothelial cells due to their proper movement. It has been elucidated that the cells secrete into the subendothelium, where they release active oxygen and sosomal enzymes, causing local cell damage (Shaw, J.O., ^m,
J, Patho1. ．． 101.283゜1980, Fa
ntone, J, C,, Ward, P, A,, ^s, J
, Patho1. , 107397. 1982), it is thought that drugs that inhibit leukocyte adhesion can be expected to have a protective effect against microcirculatory disorders and tissue disorders in pathological tissues.As a result of our investigation, we found that these protective effects are not fully effective. It has now been clarified that the adhesion or aggregation inhibitory effect of leukocytes in the blood system is strongly involved (Thrombo
sisand Hae garden ostas1s jJ, 1
, 200. p-1183 (1985)).
〈発明が解決しようとする問題点〉
かかる背景のもとに本発明者等は全血系において白血球
の粘着又は凝集を抑制する作用を呈する薬物について鋭
意検討した結果本発明を完成した。<Problems to be Solved by the Invention> Against this background, the present inventors have completed the present invention as a result of intensive studies on drugs that exhibit the effect of inhibiting adhesion or aggregation of leukocytes in the whole blood system.
化合物Ａはグルタチオンペルオキシダーゼ様抗酸化作用
及び抗炎症作用を有することが知られている（バイオケ
ミカル ファーマコロジー、３３゜３２３５〜３２３９
．１９８４及び３３．３２４１〜３２４５．１９８４
） 。Compound A is known to have glutathione peroxidase-like antioxidant and anti-inflammatory effects (Biochemical Pharmacology, 33゜3235-3239
．． 1984 and 33.3241-3245.1984
).
しかしながら、かかる作用は白血球の粘着又は凝集抑制
作用と結びつくものではない。However, such action is not linked to the action of inhibiting leukocyte adhesion or aggregation.
〈発明の構成〉
白血球の粘着又は凝集により引き起される疾病としては
微小循環障害並びに血管壁及びその周辺組織の損傷をあ
げることができ、更に前記微小循環障害の具体例として
は成人型呼吸窮迫症、動脈硬化、ショック肺等のショッ
ク症々、末梢動脈閉塞症等をあげることができる。<Structure of the Invention> Diseases caused by adhesion or aggregation of leukocytes include microcirculatory disorders and damage to blood vessel walls and surrounding tissues, and specific examples of the microcirculatory disorders include adult-type respiratory distress. Shock symptoms such as arteriosclerosis, shock lung disease, and peripheral arterial occlusion disease can be cited.
化合物Ａ又はその生理学的許容塩は公知の製剤技術によ
り錠剤、カプセル剤、散剤、顆粒剤又は注射剤等の剤型
に製剤化可能であり９通常経口。Compound A or a physiologically acceptable salt thereof can be formulated into dosage forms such as tablets, capsules, powders, granules, or injections by known formulation techniques, and is usually administered orally.
皮下、筋肉内あるいは静脈内に投与される０錠剤の具体
的処方例を以下に示す。Specific prescription examples of 0 tablets administered subcutaneously, intramuscularly, or intravenously are shown below.
錠剤
化合物Ａ ５０ｍｇカルボキ
シメチルセルロース ２５５ｇでんぷん
５＋ｓｇ結晶セルロース
４０１ｇ計 １２２
１ｇ化合物Ａは安全性の高い化合物であり、そのマウス
及びラットに対する急性毒性値（ＬＤ、。）を以下の表
１に示す。Tablet Compound A 50mg Carboxymethylcellulose 255g Starch
5+sg crystalline cellulose
401g total 122
1g Compound A is a highly safe compound, and its acute toxicity values (LD, .) for mice and rats are shown in Table 1 below.
表１
化合物Ａ又はその生理学的許容塩の投与量は通常成人−
人当り経口投与の場合２０〜２０００ｍｇ／日。Table 1 The dosage of Compound A or its physiologically acceptable salt is usually for adults.
Oral administration per person is 20-2000 mg/day.
好ましくは２００〜１０００ｍｇ／日であり、患者の症
状に応じて適宜増減すればよい。The dose is preferably 200 to 1000 mg/day, and may be increased or decreased as appropriate depending on the patient's symptoms.
以下１本発明を更に実施例により説明するが。The present invention will be further explained below with reference to Examples.
本発明はこれによって限定されるものではない。The present invention is not limited thereby.
実施例
ラットの全血系における白血球の粘着又は凝集に対する
化合物Ａの作用を次の方法により測定した。即ち１体重
２６０〜２８３ｇのウィスター今道系雄性ラットを一夜
絶食させたのち、化合物Ａを０．５零ツイーン８０に溶
解して該溶液を１０ｍ１／ｋｇの容量で経口投与した。Example The effect of Compound A on adhesion or aggregation of leukocytes in the whole blood system of rats was measured by the following method. That is, after fasting overnight Wistar Kondo male rats weighing 260 to 283 g, Compound A was dissolved in 0.5 Zero Tween 80 and the solution was orally administered at a volume of 10 ml/kg.
１時間後にベントパルビタールナトリウム麻酔（４０ａ
＋ｇ／ｋｇ、腹腔内投与）下で抗ｗＩ固剤としてｌ／１
０容量のヘパリン溶液（生理食塩液中に４０単位／ｍｌ
のヘパリンを含有）を用い心臓より採血した。白血球の
粘着及び凝集はクロノログ・アブリボメータ−（５４０
型）（クロノログ社、アメリカ）を用いインピーダンス
法で測定した。即ち、セル内温度を３７℃に、スターラ
ーの回転速度を１１０００ｒｐに設定し、血液１ｍｌに
対して１ｍｇ／ｍｌのサイトカラシンＢ溶液、 ５μｌ
を添加し、 １分後に５μＭのロイコトリエンＢ４
溶液（白血球の粘着及び凝集誘導剤）を２０μｌ 加
えて白血球の粘着及び凝集を屈発した。ｉ導剤添加６分
後にインピーダンス変化（△Ω）を測定し、これを白血
球の粘着及び凝集の指標とした。測定値を平均値±標準
誤差で示し、統計的有意性をｔ−検定により判定した。After 1 hour, bentoparbital sodium anesthesia (40a
l/1 as anti-wI solid agent under +g/kg, i.p.
0 volume of heparin solution (40 units/ml in saline)
(containing heparin) was used to collect blood from the heart. Adhesion and aggregation of leukocytes were measured using Chronolog Alibometer (540).
It was measured by the impedance method using a model (Chronolog, USA). That is, the temperature inside the cell was set to 37°C, the rotation speed of the stirrer was set to 11000 rpm, and 5 μl of 1 mg/ml cytochalasin B solution was added to 1 ml of blood.
was added and 1 minute later, 5 μM leukotriene B4 was added.
20 μl of a solution (leukocyte adhesion and aggregation inducer) was added to induce leukocyte adhesion and aggregation. Impedance change (ΔΩ) was measured 6 minutes after addition of the i-conducting agent, and this was used as an index of leukocyte adhesion and aggregation. Measured values were expressed as mean value ± standard error, and statistical significance was determined by t-test.
結果を表２に示した。The results are shown in Table 2.
表２
傘◆ Ｐ＜０．０１ （対照群との比較）表２に示すご
とく化合物Ａはｏ、３ｍｇ／ｋｇの使用量で白血球の粘
着又は凝集の抑制傾向を示し、３ＩＩＩｇ／ｋｇ以上の
投与量では有為な抑制効果を示した。Table 2 Umbrella ◆ P<0.01 (Comparison with control group) As shown in Table 2, Compound A showed a tendency to inhibit adhesion or aggregation of leukocytes at a dose of 3 mg/kg, and when administered at a dose of 3IIIg/kg or more. The amount showed a significant suppressive effect.
したがって、化合物Ａは血管内における白血球の粘着又
は凝集によって引起こされる微小循環障害並びに粘着又
は凝集により活性化された白血球によって引起こされる
血管壁及び周辺組織の損傷の予防と治療に有用であるこ
とが確認された。Therefore, Compound A is useful for the prevention and treatment of microcirculatory disorders caused by adhesion or aggregation of leukocytes in blood vessels and damage to blood vessel walls and surrounding tissues caused by leukocytes activated by adhesion or aggregation. was confirmed.
Claims (1)
２Ｈ）−オン又はその生理学的許容塩を有効成分とする
白血球の粘着又は凝集抑制剤2-phenyl-1,2-benziisoselenazole-3 (
Leukocyte adhesion or aggregation inhibitor containing 2H)-one or its physiologically acceptable salt as an active ingredient
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP12547288A JP2596970B2 (en) | 1988-05-23 | 1988-05-23 | Leukocyte adhesion or aggregation inhibitor |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP12547288A JP2596970B2 (en) | 1988-05-23 | 1988-05-23 | Leukocyte adhesion or aggregation inhibitor |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH01294622A true JPH01294622A (en) | 1989-11-28 |
| JP2596970B2 JP2596970B2 (en) | 1997-04-02 |
Family
ID=14910933
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP12547288A Expired - Fee Related JP2596970B2 (en) | 1988-05-23 | 1988-05-23 | Leukocyte adhesion or aggregation inhibitor |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP2596970B2 (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0622076A1 (en) * | 1992-01-17 | 1994-11-02 | Daiichi Pharmaceutical Co., Ltd. | Inhibitor for restenosis after percutaneous coronary arterioplasty |
| US7671211B1 (en) | 1999-03-31 | 2010-03-02 | Arne Holmgren | Substrates for thioredoxin reductase |
| US10058542B1 (en) | 2014-09-12 | 2018-08-28 | Thioredoxin Systems Ab | Composition comprising selenazol or thiazolone derivatives and silver and method of treatment therewith |
-
1988
- 1988-05-23 JP JP12547288A patent/JP2596970B2/en not_active Expired - Fee Related
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0622076A1 (en) * | 1992-01-17 | 1994-11-02 | Daiichi Pharmaceutical Co., Ltd. | Inhibitor for restenosis after percutaneous coronary arterioplasty |
| EP0622076A4 (en) * | 1992-01-17 | 1994-12-21 | Daiichi Seiyaku Co | Inhibitor for restenosis after percutaneous coronary arterioplasty. |
| US7671211B1 (en) | 1999-03-31 | 2010-03-02 | Arne Holmgren | Substrates for thioredoxin reductase |
| US10058542B1 (en) | 2014-09-12 | 2018-08-28 | Thioredoxin Systems Ab | Composition comprising selenazol or thiazolone derivatives and silver and method of treatment therewith |
Also Published As
| Publication number | Publication date |
|---|---|
| JP2596970B2 (en) | 1997-04-02 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| LAPS | Cancellation because of no payment of annual fees |