JPH0378364B2 - - Google Patents
Info
- Publication number
- JPH0378364B2 JPH0378364B2 JP57225752A JP22575282A JPH0378364B2 JP H0378364 B2 JPH0378364 B2 JP H0378364B2 JP 57225752 A JP57225752 A JP 57225752A JP 22575282 A JP22575282 A JP 22575282A JP H0378364 B2 JPH0378364 B2 JP H0378364B2
- Authority
- JP
- Japan
- Prior art keywords
- dogs
- calcium
- dobesylate
- lymph
- calcium dobesylate
- 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.)
- Expired - Lifetime
Links
- 208000010125 myocardial infarction Diseases 0.000 claims description 5
- 150000001875 compounds Chemical class 0.000 claims description 4
- 239000003814 drug Substances 0.000 claims description 3
- 229940124597 therapeutic agent Drugs 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims 1
- 241000282472 Canis lupus familiaris Species 0.000 description 13
- 239000011575 calcium Substances 0.000 description 13
- 229910052791 calcium Inorganic materials 0.000 description 13
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 12
- 210000002751 lymph Anatomy 0.000 description 8
- 241001465754 Metazoa Species 0.000 description 7
- 206010011086 Coronary artery occlusion Diseases 0.000 description 3
- 230000000747 cardiac effect Effects 0.000 description 3
- 238000011282 treatment Methods 0.000 description 3
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108010003272 Hyaluronate lyase Proteins 0.000 description 2
- 102000001974 Hyaluronidases Human genes 0.000 description 2
- SNIOPGDIGTZGOP-UHFFFAOYSA-N Nitroglycerin Chemical compound [O-][N+](=O)OCC(O[N+]([O-])=O)CO[N+]([O-])=O SNIOPGDIGTZGOP-UHFFFAOYSA-N 0.000 description 2
- 239000000006 Nitroglycerin Substances 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- 206010003119 arrhythmia Diseases 0.000 description 2
- 230000004064 dysfunction Effects 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 229940088598 enzyme Drugs 0.000 description 2
- 229960003711 glyceryl trinitrate Drugs 0.000 description 2
- 229960002773 hyaluronidase Drugs 0.000 description 2
- 238000011221 initial treatment Methods 0.000 description 2
- 238000002587 lymphangiography Methods 0.000 description 2
- 210000001365 lymphatic vessel Anatomy 0.000 description 2
- 230000000638 stimulation Effects 0.000 description 2
- 230000002861 ventricular Effects 0.000 description 2
- CTLTUPWEUCZSIP-UHFFFAOYSA-N 1,4-dihydroxycyclohexa-2,4-diene-1-sulfonic acid Chemical compound OC1=CCC(O)(S(O)(=O)=O)C=C1 CTLTUPWEUCZSIP-UHFFFAOYSA-N 0.000 description 1
- 108010082126 Alanine transaminase Proteins 0.000 description 1
- 108010003415 Aspartate Aminotransferases Proteins 0.000 description 1
- 102000004625 Aspartate Aminotransferases Human genes 0.000 description 1
- 208000031229 Cardiomyopathies Diseases 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
- 206010061216 Infarction Diseases 0.000 description 1
- 101100462505 Mus musculus Pik3c2a gene Proteins 0.000 description 1
- 206010064966 Myocardial oedema Diseases 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 208000001871 Tachycardia Diseases 0.000 description 1
- 208000009729 Ventricular Premature Complexes Diseases 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 229940035676 analgesics Drugs 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 230000006793 arrhythmia Effects 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- 230000036765 blood level Effects 0.000 description 1
- 150000001669 calcium Chemical class 0.000 description 1
- QGNBTYAQAPLTMX-UHFFFAOYSA-L calcium dobesilate Chemical compound [Ca+2].OC1=CC=C(O)C(S([O-])(=O)=O)=C1.OC1=CC=C(O)C(S([O-])(=O)=O)=C1 QGNBTYAQAPLTMX-UHFFFAOYSA-L 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 230000004087 circulation Effects 0.000 description 1
- 210000004351 coronary vessel Anatomy 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 210000005069 ears Anatomy 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- -1 for example Chemical class 0.000 description 1
- 238000010562 histological examination Methods 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 230000007574 infarction Effects 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 230000032630 lymph circulation Effects 0.000 description 1
- 210000001165 lymph node Anatomy 0.000 description 1
- 230000001926 lymphatic effect Effects 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 230000004089 microcirculation Effects 0.000 description 1
- 230000003680 myocardial damage Effects 0.000 description 1
- 230000002107 myocardial effect Effects 0.000 description 1
- 210000004165 myocardium Anatomy 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 230000010412 perfusion Effects 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 230000033764 rhythmic process Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 230000006794 tachycardia Effects 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 239000003440 toxic substance Substances 0.000 description 1
Landscapes
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
本発明は心筋梗塞治療剤に関するものである。
２，５−ジヒドロキシベンゼンスルホン酸カルシ
ウムは次式：
で表わされる。
この化合物の一般的な国際的慣用的名称はカル
シウムドベシレート（calcium dobesilate）で、
この化合物はロスカム（Roskam）法によるウサ
ギの耳の平均出血時間（bleeding time）を短縮
することが知られている（米国特許第3509207号
参照）。
本発明においては、驚くべきことには、このカ
ルシウムドベシレートが心臓のリンパ循環に大き
な影響を与えることを見い出した。
第１の研究では、18匹のいずれかの性の健康な
雑種の犬を６匹づつの３個の群に分けた。第１群
の犬には全く処置を行わず、これを対照群とし
た。第２群の犬にはヒアルロニダーゼ（500I.
U.／Kg）を静脈内注射し、第３群の犬にはカル
シウムドベシレート（25mg／Kg）を静脈内注射し
た。対照の動物はすぐに剖検したが、他の二つの
群の動物はそれぞれの物質を投与してから４時間
後に剖検した。
その後直ちに各動物について死後の心臓のリン
パ管造影法を行つた。格子をリンパ管写真（lym
−phangiogram）上に載せ、格子の１cm2単位中
にリンパ管が認められた時には必ず定量的指標と
して点を行つた。
第１表に与えた結果は１cm2当りのリンパ管の数
およびその心室表面に相当する値（its equi−
valence to ventricular surface）（％）を両者の
群について対照群と比較して示す。
The present invention relates to a therapeutic agent for myocardial infarction.
Calcium 2,5-dihydroxybenzenesulfonate has the following formula: It is expressed as The common international customary name for this compound is calcium dobesylate;
This compound is known to reduce the mean bleeding time of rabbit ears by the Roskam method (see US Pat. No. 3,509,207). In the present invention, it has surprisingly been found that this calcium dobesylate has a significant effect on the lymphatic circulation of the heart. In the first study, 18 healthy mixed-breed dogs of either sex were divided into three groups of six dogs each. The first group of dogs received no treatment and served as a control group. Group 2 dogs received hyaluronidase (500I.
Dogs in group 3 received calcium dobesylate (25 mg/Kg) intravenously. Control animals were necropsied immediately, while animals in the other two groups were necropsied 4 hours after administration of their respective substances. Immediately thereafter, postmortem cardiac lymphangiography was performed on each animal. Lymph vessel photo with lattice (lym
-phangiogram), and whenever a lymphatic vessel was observed within 1 cm 2 of the grid, a dot was added as a quantitative indicator. The results given in Table 1 show the number of lymph vessels per cm 2 and their equivalent value on the ventricular surface (its equi-
The valence to ventricular surface (%) is shown for both groups compared to the control group.
【表】
正常な心臓では目に見えたリンパ管の数はヒア
ルロニダーゼで処置した群におけるよりカルシウ
ムドベシレートで処置した犬における方が多かつ
た。
第２の研究では、24匹の雑種の犬において左冠
状動脈の前室間枝を閉塞することにより心筋梗塞
（M.I.）を誘発させた。13匹の犬には冠状動脈閉
塞直後に50mg／Kgのカルシウムドベシレートを投
与し、他方残りの11匹の犬には処置を行わなかつ
た。動物の死亡直後にリンパ管造影法を行つて心
臓の梗塞区域と非梗塞区域とにおけるリンパ管の
数を目に見えるようにした。７匹の正常な犬（冠
状動脈閉塞症は認められない）を対照として使用
した。この結果を第２表に示す。Table: In normal hearts, the number of visible lymph vessels was greater in dogs treated with calcium dobesylate than in the hyaluronidase treated group. In a second study, myocardial infarction (MI) was induced in 24 mongrel dogs by occluding the anterior interventricular branch of the left coronary artery. Thirteen dogs received 50 mg/Kg of calcium dobesylate immediately after coronary artery occlusion, while the remaining 11 dogs received no treatment. Immediately after the animals died, lymphangiography was performed to visualize the number of lymph vessels in the infarcted and non-infarcted areas of the heart. Seven normal dogs (no coronary artery occlusion) were used as controls. The results are shown in Table 2.
【表】
この動物実験から、カルシウムドベシレート
が、破壊された心筋組織の区域中のリンパ管の数
を統計的に有意に増大することができることが分
る。かかるリンパ管数の増大は心電図の軌跡
（trac−ing）における明白な変化（ST部の上昇
程度の減少）を伴う。また組織学的検査からカル
シウムドベシレート投与後に心筋浮腫が減少する
ことが分つた。カルシウムドベシレートは、活性
リンパ管の数を増加することにより、冠状動脈閉
塞後の心筋の破壊から生ずる毒性物質の排出を助
けることができ、また梗塞の程度を小さくするこ
とができる。既知のように、リンパ幹管およびリ
ンパ節を結紮して犬におけるリンパ液の流れを実
験的にそこなうことにより、間隙性浮腫、心臓の
微小循環の障害、心筋の損傷および心電図の変化
が生ずる。かかる状態はリンパうつ滞心筋症とし
て知られている。これらの所見はヒトにおける洞
機能不全症候群の所見と極めて類似している。
第３の研究では、心臓を電気的に刺激すること
により誘発した心臓不整脈に対するカルシウムド
ベシレートの作用を６匹の雑種の犬について調べ
た。これらの犬のうち３匹には50〜75mg／Kgのカ
ルシウムドベシレートを静脈内投与した。心電図
は、未処置の動物の場合には、不整脈頻拍の突
発、ならびに異形（heterotopic）および心室性
の期外収縮を包含するリズムの異常性を示した。
カルシウムドベシレートを投与した動物の場合に
は、心電図の軌跡は実際上正常であつた。この実
験は、カルシウムドベシレートが、心臓の電気的
刺激により生ずる心臓リンパ液の循環の動的不全
を軽減することを示すものである。
新たに６時間未満の期間心筋梗塞を起した100
個の症例について臨床試験を行つた。50個の症例
では従来の治療を行い（対照）、他の50個の症例
ではさらにカルシウムドベシレートを投与した。
評価基準は病歴（苦痛、ニトログリセリンの消費
量、鎮痛剤および可動化）、血清酵素および心電
図の変化に基づいて行つた。
薬剤は潅流により最初の３時間の間では毎時50
〜100mg／Kgの用量で投与し、次いで入院後少く
とも３日目までは６時間毎に25mg／Kgの用量で投
与した。その後は経口投与を行つた。予備的な結
果から、徴候および症状の改善、ニトログリセリ
ン消費量の減少、迅速な可動化、ある酵素
（CPK、SGOT、SGPT、LDH、HBDH）の血
液レベルの低下、および心電図の軌跡の顕著な正
常化が分つた。
有用な用量範囲：日用量は５〜50ｇで、初期治
療には比較的多量の用量が好ましい。前記化合物
は錠剤、カプセル剤のような任意の適当な形態で
投与できるが、初期の処置には注射できる溶液が
好ましい。ｐ−ジヒドロキシベンゼンスルホン酸
カルシウム塩の代りに、例えばナトリウム、カリ
ウム、マグネシウム塩、あるいは例えばジエチル
アミン、エタノールアミン、ピペラジン等のよう
な有機塩基とのような他の塩を使用することがで
きる。[Table] This animal study shows that calcium dobesylate can statistically significantly increase the number of lymph vessels in areas of destroyed myocardial tissue. This increase in the number of lymph vessels is accompanied by obvious changes in the electrocardiogram trac-ing (reduced degree of ST segment elevation). Furthermore, histological examination revealed that myocardial edema decreased after administration of calcium dobesylate. By increasing the number of active lymph vessels, calcium dobesylate can aid in the elimination of toxic substances resulting from destruction of the myocardium after coronary artery occlusion and can reduce the extent of infarction. As is known, experimental disruption of lymph flow in dogs by ligating lymphatic vessels and lymph nodes results in interstitial edema, impaired cardiac microcirculation, myocardial damage, and electrocardiographic changes. Such a condition is known as lymphodepressive cardiomyopathy. These findings are very similar to those of sinus dysfunction syndrome in humans. In a third study, the effects of calcium dobesylate on cardiac arrhythmias induced by electrical stimulation of the heart were investigated in six mongrel dogs. Three of these dogs received 50-75 mg/Kg of calcium dobesylate intravenously. Electrocardiograms showed rhythm abnormalities including bursts of arrhythmia tachycardia and heterotopic and ventricular extrasystole in untreated animals.
In animals receiving calcium dobesylate, the electrocardiogram trajectory was virtually normal. This experiment shows that calcium dobesylate alleviates the dynamic dysfunction of cardiac lymph circulation caused by electrical stimulation of the heart. 100 new myocardial infarctions lasting less than 6 hours
A clinical trial was conducted on individual cases. Fifty cases received conventional treatment (control), and the other 50 cases additionally received calcium dobesylate.
Evaluation criteria were based on medical history (pain, nitroglycerin consumption, analgesics and mobilization), serum enzymes and electrocardiogram changes. The drug is administered at a rate of 50 per hour during the first 3 hours by perfusion.
A dose of ~100 mg/Kg was administered, followed by a dose of 25 mg/Kg every 6 hours until at least 3 days after admission. After that, oral administration was performed. Preliminary results show improvement in signs and symptoms, reduced nitroglycerin consumption, rapid mobilization, lower blood levels of certain enzymes (CPK, SGOT, SGPT, LDH, HBDH), and a marked ECG trajectory. I know things have returned to normal. Useful dose range: Daily doses are 5-50 g, with larger doses being preferred for initial treatment. Although the compounds can be administered in any suitable form such as tablets or capsules, injectable solutions are preferred for initial treatment. Instead of the calcium salt of p-dihydroxybenzenesulfonic acid, other salts can be used, such as, for example, the sodium, potassium, magnesium salts, or with organic bases, such as, for example, diethylamine, ethanolamine, piperazine, and the like.
Claims (1)
有させてなる心筋梗塞治療剤。[Claims] 1. The following formula for the pharmaceutically effective amount: A therapeutic agent for myocardial infarction, which comprises a compound represented by the following formula contained in a pharmaceutically acceptable carrier.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US33367181A | 1981-12-23 | 1981-12-23 | |
| US333671 | 1981-12-23 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS58116416A JPS58116416A (en) | 1983-07-11 |
| JPH0378364B2 true JPH0378364B2 (en) | 1991-12-13 |
Family
ID=23303775
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP22575282A Granted JPS58116416A (en) | 1981-12-23 | 1982-12-22 | Cardiac disease therapy |
Country Status (2)
| Country | Link |
|---|---|
| JP (1) | JPS58116416A (en) |
| IT (1) | IT1212555B (en) |
-
1982
- 1982-12-21 IT IT8249714A patent/IT1212555B/en active
- 1982-12-22 JP JP22575282A patent/JPS58116416A/en active Granted
Non-Patent Citations (1)
| Title |
|---|
| CHEM.ABSTR=1972 * |
Also Published As
| Publication number | Publication date |
|---|---|
| IT8249714A0 (en) | 1982-12-21 |
| IT1212555B (en) | 1989-11-30 |
| JPS58116416A (en) | 1983-07-11 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP1744739B1 (en) | Use of treprostinil to treat neuropathic diabetic foot ulcers | |
| Fredlund et al. | Long QT interval and ventricular tachycardia of “torsade de pointe” type in hypothyroidism | |
| Rowland et al. | Electrophysiological assessment of amiodarone in treatment of resistant supraventricular arrhythmias. | |
| Gaffney et al. | Study of the relationship between the neurotransmitter store and adrenergic nerve block induced by reserpine and guanethidine | |
| KR20110026422A (en) | Dronedarone for the Prevention of Permanent Atrial Fibrillation | |
| JPH0717502B2 (en) | Baclofen for the treatment of angina | |
| KR20110026421A (en) | Dronedarone for Prevention of Cardioversion | |
| JPH0378364B2 (en) | ||
| Holt et al. | Intravenous amiodarone; An effective anti-arrhythmic agent | |
| Hooqenhuvze et al. | Acute effects of intravenous amiodarone in patients with complex ventricular dysrhythmias | |
| Kim et al. | Large dose sublingual nitroglycerin in acute myocardial infarction: relief of chest pain and reduction of Q wave evolution | |
| JP2769217B2 (en) | Long-acting compositions of propafenone and quinidine for the treatment of cardiac conditions | |
| Waldman | The treatment of angina pectoris with testosterone propionate | |
| RU1812991C (en) | Method of stenocardia stress treatment | |
| Conrad et al. | Transvenous pacing in two patients with repetitive ventricular arrhythmias | |
| CN115634243A (en) | Application of Shuanghuanglian in preparing medicine for treating arrhythmia caused by aconitine poisoning | |
| RU2320328C2 (en) | Method for treating persisting form of atrial fibrillation | |
| Shector et al. | Ventricular arrhythmia induced by methoxamine hydrochloride | |
| Lüderitz | Historical perspectives on cardioversion and defibrillation | |
| Hood Jr et al. | Treatment of refractory ventricular tachysystole with hyperbaric oxygenation | |
| CN118742307A (en) | Use of bupivacaine multivesicular liposomes as stellate ganglion blockers | |
| Kubik et al. | Practolol and Dextro-Propranolol in Prophylaxis of Post Infarction Arrhythmias | |
| Dear | Spontaneous reversion of complete A‐V block to sinus rhythm in the dog | |
| Mah | Cardioversion in the treatment of atrial flutter | |
| McAllen | Experiences of coronary intensive care in a district hospital. |