JPH01294622A - Adhesion of leukopenia or agent for suppressing aggregation of leukopenia - Google Patents

Abstract

PURPOSE:To obtain an aggregation suppressing agent containing 2-phenyl-1,2- benzoisoselenazole-3(2H)-one and salt thereof as active ingredients, having adhesion and aggregation suppressing action for leukopenia and high safeness and useful in prevention and remedy for intravascular slight circulation disorder, etc. CONSTITUTION:2-Phenyl-1,2-benzoisoselenazole-3(2H)-one (hereinunder referred to as the compound A) and salt thereof are used as active ingredients. The compound A and salt thereof can be prepared in form of tablet, capsule, inhalant, granule, etc., and can be administered normally in oral, hypodermic, intramuscular or subcutaneous application. The dose ia normally 20-200mg/adult.day, preferably 200-1000mg/adult.day in case of oral administration.

Description

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.

<Prior art> Under normal conditions, white blood cells may adhere to vascular endothelial cells, but only for a very short time.

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)).

<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.

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
).

However, such action is not linked to the action of inhibiting leukocyte adhesion or aggregation.

<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.

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.

Specific prescription examples of 0 tablets administered subcutaneously, intramuscularly, or intravenously are shown below.

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.

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.

The dose is preferably 200 to 1000 mg/day, and may be increased or decreased as appropriate depending on the patient's symptoms.

The present invention will be further explained below with reference to Examples.

The present invention is not limited thereby.

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.

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.

The results are shown in Table 2.

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.

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)

[Claims] 2-phenyl-1,2-benziisoselenazole-3 (
Leukocyte adhesion or aggregation inhibitor containing 2H)-one or its physiologically acceptable salt as an active ingredient