Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1996-11-12
1998-12-01
Henley, III, Raymond
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
A61K 3144
Patent
active
058439692
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/JP96/00924 filed Apr. 4, 1996.
TECHNICAL FIELD
This invention relates to a therapeutic agent or preventing agent for various kinds of diseases associated with an injury caused by active oxygen generated after ischemia-reperfusion.
TECHNICAL BACKGROUND
In recent years, it has been found that large amount of active oxygen is generated in an ischemic state and subsequent reperfusion of blood in various kinds of organs including heart, and this is one of the factors to induce various kinds of diseases. That is, when blood flow is blocked in a blood vessel by a thrombus, etc., the ischemic state occurs in the controlling region of the blood vessel. In this case, the oxygen supply to the tissue in the region is intercepted and accordingly the tissue falls in a dangerous state. When this state lasts for a certain length, the tissue runs into a necrotic state. Once this occurs, the recovery is impossible. Therefore, it is important that the reperfusion of blood is achieved at the earliest opportunity to save the tissue before it is suffered from permanent damage.
However, even the reperfusion is started before the necrosis of the tissue, the reperfusion itself has harmful effects on the tissue in a hypoxia state. This phenomenon is called ischemia-reperfusion injury.
In a normal state, xanthine and hypoxanthine, metabolites of nucleic acids, exist each in cells at a low concentration and are converted into nucleic acid with xanthine hydrogenase. However, in an ischemic state, the synthesis of ATP is lowered. Accordingly, ADP and AMP are accumulated and, the contents of xanthine and hypoxanthine, metabolites of nucleic acid, increase significantly. Further, when the reperfusion of blood is initiated, the xanthine hydrogenase is converted into xanthine oxidase. The produced xanthine oxidase metabolizes the xanthine and hypoxanthine to uric acid with oxygen which works as an electron receptor. This process produces a large amount of oxygen-anion radicals (O.sup.2-) as by-product. The oxygen-anion radical is the active oxygen, which carries one of the factors causing the ischemia-reperfusion injury. Further, it is considered that other active oxygen species such as hydrogen peroxide and hydroxy radical are secondarily produced and the injury is aggravated.
On the other hand, it is known that the active oxygen is generated from leukocyte through other path besides this. That is, in an ischemic state, the leukocyte is activated by a chemical mediator such as leukotriene, accumulates at the ischemic sites and generates active oxygen there. Accordingly, it plays an important role on the ischemia-reperfusion injury.
The generation of active oxygen is considered to affect aggravation of prognosis in various kinds of ischemic diseases including myocardial infarction and others such as cerebral infarction, pulmonary thromboembolism, thrombosis in other various organs, etc. Similarly, it is pointed out that the generation of active oxygen is affecting aggravation of prognosis in various kinds of operations such as coronary artery bypass operation which need to block blood flow temporarily, percutaneous transluminal coronary angioplasty, injuries during the application of a thrombolytic agent, various kinds of operations and treatments during organ transplantation, etc. Therefore, a substance suppressing the generation of active oxygen is considered to be useful for the prevention of these injuries.
Until now, as substances suppressing the generation of active oxygen, allopurinol, which is an inhibitor of xanthine oxidase and used as a therapeutic agent for gout and a xanthine oxidase inhibitor disclosed in Japanese Unexamined Patent Publication (Kokai) No. 3-157385 have been studied from the view point of suppressing effect against organ injuries caused by ischemia-reperfusion. However, the results of the animal experiments using an ischemia-reperfusion injury model are divided into two groups: an effective group (Journal of Clinical Investigation, 1984, 74, 1156-1164 and European Journal
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Horiuchi Hideki
Kitahara Shigehisa
Kondo Shiro
Ota Mikio
Takano Yasuhiro
Henley III Raymond
Teijin Limited
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