JP2001064183A - Ischemia and reperfusion damage inhibitor - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an ischemia and reperfusion damage inhibitor that can protect the tissues from an ischemia and reperfusion damage, for example, a prophylactic and/or therapeutic agent for hepatic ischemia and reperfusion damage (for example, shock, septicemia, hepatic resection, hepatic trauma and liver transplantation and the like). SOLUTION: This damage inhibitory agent includes, as an active ingredient, (-)-6-amino-2-(1-octynyl)-9-β-D-ribofuranosyl-9H-purine (2-octynyladenosine) or its pharmacologically acceptable salt.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to ischemia / reperfusion injury of living tissue accompanying ischemia and / or reperfusion injury of living tissue accompanying reperfusion after ischemia (hereinafter these injuries are referred to as ischemia / reperfusion). More specifically, it relates to an agent for suppressing tissue injury induced by hepatic ischemia and / or reperfusion.

[0002]

2. Description of the Related Art Conventionally, 2-alkynyl adenosine and its derivatives have a strong antihypertensive effect and may be useful as antihypertensive agents, therapeutic agents for ischemic diseases of the heart or brain, or antiatherosclerotic agents. It has already been reported (Tokuhei 1-3)
No. 3577, Japanese Patent Publication No. 17526/1995, Patent 27741
No. 69, and JP-A-3-2877537).

[0003] Such 2-alkynyl adenosine and its derivatives, rather than A ₁ receptor of adenosine from having a strong affinity for A ₂ receptor (Abiru T., European
J.Pharmacol., 196, 69, 1991 ), its development as a small pharmaceuticals having inhibitory effect on the heart or central are to occur via the A ₁ receptor is expected.

Recently, adenosine or adenosine derivatives have been reported to be effective in ischemic reperfusion injury in the heart (Cargnoni A., J. Cardiovasc. Pharmacol., 33,
883, 1999, JP-A-4-124143).

[0005] As one of the mechanisms of ischemia-reperfusion injury, production of cytotoxic free radicals, damage of endothelial cells via neutrophils, and the like are considered. In particular, adenosine is regarded as an endogenous substance involved in neutrophil regulation (Sc
hrier DJ, J. Immunol., 137 , 3284, 1986), acting through the action and adenosine A ₂ receptor mediated adenosine A ₁ receptors on neutrophils has been reported to differ. Act through the A Denoshin A ₂ receptor on neutrophils is the favored against ischemia-reperfusion injury, as its effect, inhibition of cytotoxic reactive oxygen generation, suppress phagocytosis Action and adhesion inhibitory action (Cronstein BN, J. Clin. Invest., 85, 1150, 1
990).

With respect to vascular endothelial cell injury, conventionally, even if neutrophil elastase is released into the blood under normal conditions, it is quickly inactivated by forming a complex with α ₁ -protease inhibitor, which is a physiological inhibitor. is the, while, ischemia reperfusion time active oxygen species alpha ₁ in - a protease inhibitor to inactivate (Wiess SJ, J.Immunol,.
136, 636, 1986), it has been thought that a field where neutrophil elastase can act around neutrophils where reactive oxygen species are accumulated is formed, resulting in vascular endothelial cell injury.
However, at present, neutrophil elastase is not inhibited by neutrophil and endothelial cell adhesion space at the time of ischemia / reperfusion, and neutrophil elastase is not inhibited. Thus, it is thought that the interaction between neutrophils and vascular endothelial cells via the adhesion molecule is the largest factor for the occurrence of vascular endothelial cell injury. Vascular endothelial cells play an important role in controlling blood flow, inflammation, blood coagulation, etc., and maintaining microcirculation smoothly. In recent years, the same has been found during ischemia-reperfusion in the liver, and endothelial cell injury by neutrophil elastase is followed by a decrease in blood flow and microthrombus formation, resulting in a decrease in hepatic tissue blood flow, It has become clear that the action of neutrophil elastase released from neutrophils migrating extravascularly causes hepatocellular injury. In fact, cytokines such as interleukin-8 (Harada N., Blood, 93, 157, 1999) and neutrophil elastase (Kushimoto S., Crit. Care Med., 24, 190)
8, 1996) have been reported to be significantly involved in hepatic ischemia-reperfusion injury.

On the other hand, adenosine and adenosine A ₂ receptor agonists, tumor destruction factor from activated monocytes (Tumo
r necrosis factor: hereinafter referred to as “TNF” -α release (Bouma MG, J. Immunol., 153, 4159, 1994), release of reactive oxygen species (DelaHarpe J., J. Immunol., 143, 59)
6, 1989) and leukocyte adhesion factor (CD11b / CD18: MAC-1, Woll
ner A., Am. J. Respir. Cell. Mol. Biol., 9, 179, 1
It has been reported that the expression of 993) is suppressed. Also,
Adenosine, adenosine A ₁ through receptors inhibit adenylate cyclase adenosine 3 ', and the effect of suppressing the production of 5'-cyclic phosphate (hereinafter referred to as "cAMP"), adenosine A ₂ receptor Has the effect of activating adenylate cyclase and promoting the production of cAMP (Stiles GL, Trends in Pharmacol. Sci.,
7, 486, 1986). In fact, represented by the following formula (1) having a selective adenosine A ₂ receptor agonist activity (-) -
6-amino-2- (1-octynyl) -9-β-D-
Ribofuranosyl-9H-purine (hereinafter “2-octynyl adenosine”) increases cAMP (Abiru
T., European J. Pharmacol., 196, 69, 1991).

Embedded image

[0008] By the way, it has been reported that cAMP derivatives have cytoprotective effects on ischemic lung, liver, kidney, heart and the like in therapeutic agents for acute diseases caused by ischemia-reperfusion injury. ing. These are all expected to be effective by immersing the removed organ in a preparation solution of the cAMP derivative (JP-A-11-130).
No. 792), it is inevitable that extreme hemodynamic changes occur when reperfusion is performed after transplantation, and individual differences occur due to differences in the amount of drug that has penetrated into the tissues and blood vessels of the removed organs. The reality is poor. Furthermore, adenosine A ₂ receptor agonists have been reported to inhibit experimentally increased drug induced the GOT and GPT created mice ischemia-compounds having the above formula [1]
No effect on reperfusion injury is described (WO98 / 52)
611).

[0009] Note that the current adenosine _{A 2} receptors, the presence of _{A 2A} and _{A 2B} is known as a subtype. The _A2B receptor is likely to have low affinity,
The difference from the A _{2 A} receptor is not yet clear.
Research on adenosine A ₂ receptors to date would mainly be based on the action of the adenosine A _2A receptor,
It is believed that.

Heretofore, for the purpose of treating ischemia-reperfusion injury,
Xanthine oxidase inhibitors such as allopurinol (Ilea
rse DJ, Acta Physiol. Scand., Supply 548, 65, 1
986) and superoxide dismutase (Jolly S.
R., Circ. Res., 54, 227, 1984), and the administration of various drugs has been attempted, but no effective treatment has yet been established. Furthermore, no studies have been made on the usefulness of conventionally known 2-alkynyl adenosine derivatives for ischemia / reperfusion injury.

[0011]

An effective ischemia that can be used to avoid injuries to living tissues due to cessation of blood flow (ischemia) and resumption of blood flow (reperfusion), particularly hepatic ischemia / reperfusion injury.・
No reperfusion injury inhibitor has yet been discovered,
The development of therapeutic agents is expected.

[0012]

Means for Solving the Problems The present inventors have conducted intensive studies in order to solve the above-mentioned problems, and as a result, 2-octynyl adenosine having selective adenosine A _2A receptor agonistic action has been added to this compound. The present inventors have found that the present invention has an effect of suppressing tissue damage of ischemia / reperfusion, particularly hepatic ischemia / reperfusion injury, which has not been found at all, and completed the present invention. That is, the confirming an increase inhibitory effect of TNF-alpha of the expected cytotoxic cytokines from knowledge of inhibition and the adenosine A ₂ agonists known in which transaminase activity increased as a function of 2-octynyl adenosine, 2- octylphenyl New effects of nyladenosine include neutrophil elastase activity suppression, cytokine-induced neutrophil chemotaxis (or activation)
Substance (cytokine-induced neutrophil chemoattractan
t: hereinafter referred to as “CINC”), an increase in hepatic tissue blood flow and an increase in hepatic myelopeoxidase (hereinafter “MPO”) activity. As a result, ischemia / reperfusion tissue An improvement in a set of parameters indicative of injury, especially liver ischemia-reperfusion injury, has been realized. Therefore, the present invention provides an agent for suppressing ischemia / reperfusion injury, which comprises 2-octynyladenosine or a pharmacologically acceptable salt thereof as an active ingredient. That is, the present invention enables administration of a drug according to the hemodynamics of a patient by administering the inhibitor of the present invention from outside the body before, during or after ischemia reperfusion of the liver. I got it.

[0013]

Embodiments of the present invention will be described below in detail. The present invention provides an ischemic / reperfusion injury inhibitor characterized by containing 2-octynyladenosine or a pharmacologically acceptable salt thereof as an active ingredient (hereinafter, also simply referred to as the composition of the present invention). It is about.

In the present invention, 2-octynyl adenosine may be in the form of either a free base or an acid addition salt. Examples of the acid addition salt include hydrochloride, sulfate and hydrobromic acid. Inorganic salts such as salts, and oxalates,
Organic salts such as maleate, fumarate, citrate and malate can be exemplified.

Such 2-octynyl adenosine is a known compound and can be easily produced by a known method which has already been reported (Japanese Patent Publication No. 1-3347).
7, JP-A-5-194579).

[0016] The composition of the present invention can be prepared in any form of oral administration or parenteral administration depending on the administration method. The dose as the therapeutic pharmaceutical composition is desirably set in consideration of the patient's condition such as age and weight, the administration route, the nature and extent of the disease, and the like. Usually, the daily dose of the active ingredient of 2-octynyl adenosine for an adult may be about 0.01 to 1000 mg, preferably 0.01 to 500 mg. In some cases,
Lower component doses may be required, and conversely, higher doses may be required. The number of administrations is desirably single or multiple.

For example, examples of the oral preparation include solid preparations such as tablets, granules, powders and capsules and liquid preparations such as syrups and elixirs.
Parenteral preparations include injections, rectal preparations, skin external preparations, inhalants and the like.

When a solid preparation for oral administration is prepared, for example, 2-octynyladenosine may be added, if necessary, to excipients such as lactose, starch, crystalline cellulose, calcium calcium lactate, and calcium hydrogen phosphate. According to white sugar,
A binder such as hydroxypropylcellulose and polyvinylpyrrolidone, a disintegrant such as carboxymethylcellulose and calcium carboxymethylcellulose, a lubricant such as magnesium stearate and talc, and the like may be blended and formulated by a conventional method. Further, to produce capsules, powders or granules are filled in soft capsules, or 2-octynyladenosine is dissolved in glycerin, polyethylene glycol, sesame oil, olive oil, etc., and then coated with a gelatin film to form hard capsules. The agent can be taken. To prepare a liquid preparation for oral administration, 2-octynyladenosine and a sweetener such as sucrose, sorbitol, or glycerin are dissolved in water to give a clear syrup, or essential oil, ethanol, etc. are added. Elixir or gum arabic, tragacanth, polysorbate 8
0 or sodium carboxymethylcellulose may be added to form an emulsion or suspension. If desired, flavoring agents, coloring agents, preservatives, and the like may be added to these liquid preparations.

When preparing an injection, for example, 2-octynyl adenosine may be adjusted, if necessary, to pH adjustment with hydrochloric acid, sodium hydroxide, lactic acid, sodium lactate, sodium monohydrogen phosphate, sodium dihydrogen phosphate and the like. Agent, sodium chloride, dissolved in distilled water for injection together with an isotonic agent such as glucose, aseptically filtered and filled into ampoules, or mannitol, dextrin, cyclodextrin, gelatin, etc., and freeze-dried under vacuum, A ready-to-use injection may be used. Alternatively, lecithin, polysorbate 80, polyoxyethylene hydrogenated castor oil, or the like may be added to 2-octynyladenosine to solubilize or emulsify in water.

To prepare a rectal preparation, 2-octynyladenosine is heated and melted together with a suppository base such as cocoa butter, fatty acid tri, di or monoglyceride, or polyethylene glycol, and poured into a mold. Or by dissolving 2-octynyl adenosine in polyethylene glycol, soybean oil, or the like, and then coating with a gelatin film.

To prepare an external preparation for skin, 2-octynyladenosine is added to white petrolatum, beeswax, liquid paraffin, polyethylene glycol and the like, and if necessary, heated and kneaded to form an ointment or rosin. After kneading with an adhesive such as alkyl acrylate polymer,
What is necessary is just to spread on a nonwoven fabric, such as polyethylene, and to use it as a tape agent.

To prepare an inhalant, 2-octynyladenosine may be dissolved or dispersed in a propellant such as Freon gas and filled in a pressure-resistant container to form an aerosol.

[0023]

EXAMPLES The present invention will be described in more detail with reference to Production Examples, Test Examples and Examples. Production Example 2 Octinyl adenosine was produced as follows by the methods disclosed in Japanese Patent Publication No. 33377/1993 and JP-A-5-194579.

393 mg of 2-iodoadenosine (1 mm
ole) was dissolved in dimethylformamide (10 mL) -triethylamine (3 mL), and 21 mg of bis (triphenylphosphine) palladium dichloride and 12 mg of cuprous iodide were added. Under an argon stream, 122 mg (1.1 mmole) of 1-octyne was added. The mixture was stirred at 80 ° C. for 1 hour under heating. The reaction solution is concentrated under reduced pressure, the residue is dissolved in methanol, hydrogen sulfide is passed for 1 minute, and the deposited precipitate is removed by filtration. The filtrate is concentrated to dryness under reduced pressure, and the residue is subjected to silica gel column chromatography (elution solvent). : Chloroform: methanol = 10 to 5: 1, v / v), and recrystallized from methanol-water. The obtained product was dried under reduced pressure at 80 ° C and 5 mmHg in the presence of phosphorus pentoxide. Thus, 2-octynyladenosine having a water content of 1.56% was obtained (yield: about 85%). Melting point: 110-114
° C

Test Examples Test Example 1. Inhibition of neutrophil elastase release of activated neutrophils
Examination of the effect of 2-octynyl adenosine to be added 5 mL of 6% dextran physiological saline was added to 20 mL of heparinized venous blood collected from a healthy person, and the mixture was allowed to stand at room temperature for 20 minutes to precipitate red blood cells. 10 mL of the supernatant was layered on 3 mL of Nycoprep 1.077 (Nycomed Pharma AS), and centrifuged at 1000 rpm for 30 minutes to separate neutrophils. This was washed once with a phosphate buffer (pH 7.4), lysed with distilled water to remove mixed red blood cells, and then 1.8% saline was added. In addition, 150
After neutrophils were separated by centrifugation at 0 rpm for 5 minutes, the number of cells was adjusted to 5000 cells / μL with a phosphate buffer. To 105 μL of the neutrophil suspension, 2-octynyladenosine in a saline solution (dimethylsulfoxide (hereinafter referred to as “DM
SO ”) to a final concentration of 0.05% or less), 15 μL of cytochalasin B phosphate buffer (50 μg / mL) and N-formyl-methionyl-leucyl-phenylalanine phosphate buffer. (1
(0 μM: containing 1% DMSO for lysis) 15 μL was added to obtain a culture solution. The final concentration of 2-octynyl adenosine in the culture was 0.1, 1 or 10 μM.
A control to which only a solvent containing no 2-octynyladenosine was added was prepared in the same manner. Next, the culture solution is cultured at 37 ° C. for 30 minutes, and at 10,000 rpm for 10 minutes (under 4 ° C.).
Centrifuge. Take 50 μL of this supernatant, and add Tris-HCl buffer (0.1 M Tris-HCl (pH 8.5), 0.
15M NaCl) 150 μL and S2 as fluorescent substrate
After adding 50 μL of a 484 (Chromogenix AB: 2 mM) solution and culturing at 37 ° C. for 150 minutes, 100 μL of a 50% acetic acid aqueous solution was added, and neutrophil elastase activity was measured at a fluorescence intensity of 405 nm.

Result: 2-octynyl adenosine was 0.1%
From μM, the increase in neutrophil elastase release was suppressed in a concentration-dependent manner.

Test Example 2 For TNF-α Production of Activated Monocytes
Examination of the effect of 2-octynyladenosine on 5 ml of 6% dextran physiological saline was added to 20 ml of heparinized venous blood collected from a healthy person, and the mixture was allowed to stand at room temperature for 20 minutes to precipitate erythrocytes. 10 mL of the supernatant was layered on 3 mL of Nycoprep 1.077 (Nycomed Pharma AS), and centrifuged at 1000 rpm for 30 minutes to separate lymphocytes and monocytes. These lymphocytes and monocytes were added to an RPMI 1640 medium (G) containing 10% fetal bovine serum (Gibco).
ibco), transferred to a Petri dish (Falcon 1058, Becton Dickinson), and cultured at 37 ° C. in a 5% carbon dioxide atmosphere for 2 hours. Further serum free R
Lymphocytes were washed away using PMI 1640 medium and stained with Turk's solution (Turk's solution) to confirm that monocytes were separated by 90% or more.
The number of cells was adjusted to 1000 cells / μL using I 1640 medium. This was added to a 24-well culture microplate (Falc
on 3047, Becton Dickinson) in a volume of 0.4 mL per well. To this was added a solution of 2-octynyladenosine in RPMI 1640 medium (D for dissolution).
After adding 50 μL of MSO to a final concentration of 0.05% or less and leaving the mixture at room temperature for 5 minutes, lipopolysaccharide (hereinafter referred to as “LPS”: Difco, Esc)
RPMI of hrichia coli, serotype 0.55: B5)
A culture medium was added by adding 50 μL of a medium solution (20 ng / mL). The final concentration of 2-octynyl adenosine in the culture was 0.1, 1 or 10 μM. A control to which only a solvent containing no 2-octynyladenosine was added was prepared in the same manner. Next, 37 ° C in a 5% carbon dioxide atmosphere
For 16 hours, and transferred to an Eppendorf tube for each well, and 10,000 rpm for 10 minutes (4 ° C.).
Bottom) Centrifuge and measure the TNF-α concentration in the culture supernatant
The measurement was performed using an F-α ELISA kit.

Result: 2-octynyl adenosine was 0.1%
From μM, LPS stimulation-induced increase in TNF-α production was suppressed in a concentration-dependent manner.

Test Example 3 2 in Liver Ischemia-Reperfusion Injury
-Investigation of the effect of octynyl adenosine Wistar male rats (body weight 220 to 280 g) were intraperitoneally administered with ketamine hydrochloride (Parke-Davis) at 100 mg / kg, and the abdomen was incised in the midline. The portal vein, hepatic artery, and biliary branch to the middle and left lobes of the liver were blocked with arterial clamp for 60 minutes. At the same time as removing the arterial cleansing, the portal vein, hepatic artery, and branch of the bile duct to the right lobe were ligated with 3-0 silk to remove the effects of shunting of portal venous blood. In the sham operation group, a midline abdominal incision was made, and only the right lobe was ligated 60 minutes later. The test solution was administered using a polyethylene-15 (1.1 mm outer diameter; Igarashi) tube inserted into the right carotid artery. This method shows (1)
Tests (4) to (4) were performed. In addition, the administered saline solution of 2-octynyladenosine contained DMSO as a dissolving agent.
, But the final concentration was adjusted to 0.05% or less. On the other hand, only a solvent was similarly administered as a control.

(1) Blood transaminase (GOT and
And GPT) activity against 2-octynyl adenosine
In this animal model, it was confirmed that blood transaminase activity showed a maximum value at 12 hours after reperfusion (Kushimoto S., Crit. Care. Med., 24, 1908, 199).
6) At that point, blood transaminase activity was measured. In the test, a saline solution of 2-octynyladenosine was supplied to a microsyringe pump (KDS 200: kd S
0.01, 0.1 or 1 mg /
The administration was performed at a rate of kg / hr (flow rate 1 mL / hr) from 30 minutes before the start of ischemia to 6 hours after reperfusion. At 12 hours of reperfusion, 4 mL of arterial blood was collected from the celiac artery under anesthesia, and
GOT and GPT in the serum separated at 0 rpm were measured using an automatic biochemical analyzer (HITACHI 7350: Hitachi, Ltd.).

Results: At 12 hours after reperfusion, blood transaminase activity was significantly increased in the control compared with the sham-operated group, but in the 2-octynyladenosine-administered group,
At doses of 0.1 and 1 mg / kg / hr, an increase in blood transaminase activity was suppressed in a dose-dependent manner.

(2) 2-E for changes in hepatic tissue blood flow
Effect of Cutinyl Adenosine 2-Octinyl adenosine in saline 0.1 mg /
It was administered at a rate of kg / hr (flow rate 1 mL / hr) 30 minutes before the start of ischemia. Hepatic tissue blood flow was reperfusion 3 before ischemia reperfusion.
Until the hour, the measurement was performed using a non-contact Doppler blood flow meter (ALF21N: Advance Co., Ltd.).

Results: In the control, hepatic tissue blood flow decreased to 30% or less due to ischemia and gradually recovered after reperfusion.
Administration of octynyl adenosine (0.1 mg / kg / h
According to r), a remarkable blood flow improving effect was recognized from 1 hour after reperfusion.

(3) Above liver TNF-α and CINC concentrations
Effect of 2 -octynyladenosine on elevation of saline 0.1 mg / kg of 2-octynyladenosine
It was administered at a rate of kg / hr (flow rate 1 mL / hr) 30 minutes before the start of ischemia. After completion of reperfusion, 1 g of the liver middle lobe was excised with time, placed in 5 mL of a phosphate buffer (pH 7.4) containing 0.05% sodium azide, homogenized, and treated with 350 g.
The mixture was centrifuged at 0 rpm for 10 minutes (at 5 ° C.) to obtain a supernatant. Hepatic TNF-α and CINC concentrations in the supernatant were measured using a rat TNF-α ELISA kit (Genzyme) and a rat CINC / gro-1 ELISA kit (Immunological Biology Laboratories), respectively.

Results: Liver TNF-α and CINC were used as controls.
The concentrations showed maximum values at 1 and 2 hours after reperfusion, respectively, but 2-octynyl adenosine significantly suppressed these increases.

(4) On liver myeloperoxidase activity
Effect of 2 -octynyladenosine on elevation of saline 0.1 mg / kg of 2-octynyladenosine
It was administered at a rate of kg / hr (flow rate 1 mL / hr) 30 minutes before the start of ischemia. After completion of reperfusion, 1 g of the liver middle lobe was removed with time, and 6 mL of a phosphate buffer (pH 6.0) containing hexadecyltrimeterammonium bromide (Sigma) was used.
And homogenized. This is kept at -80 ° C for 24 hours.
And thawed at 10,000 rpm for 10 minutes (4 ° C
Bottom) The supernatant was obtained by centrifugation. 0.1 mL of this supernatant was used for O-dianisidine dihydrochloride (Sigma: 0.167 mg / mL)
And 0.6 mL of a phosphate buffer (pH 6.0) of aqueous hydrogen peroxide (0.0005%) and left at room temperature for 10 minutes. The MPO activity was measured at 460 nm absorbance using a spectrophotometer.

Results: In controls, hepatic MPO activity was 6% after reperfusion.
Although the maximum value was shown at the time, 2-octynyl adenosine significantly suppressed this increase.

Test Example 4 Acute toxicity 2-octynyladenosine was orally administered at a dose of 1000 mg / kg to ICR mice of 7 to 8 weeks of age (n = 5 (animal)). As a result, no deaths were found.

Next, the present invention will be described in detail with reference to examples, but the present invention is not limited thereto.

[0040] 2-octynyl adenosine, lactose, potato starch, microcrystalline cellulose and light anhydrous silicic acid are mixed, and a 10% methanol solution of hydroxypropylcellulose is added, kneaded and granulated, and extruded through a 0.8 mm diameter screen to prepare granules. After drying, magnesium stearate was added and the mixture was compression-molded into tablets of 200 mg.

[0041] The above components were heated and dissolved at 60 ° C., returned to room temperature, sterile-filtered, and further filled into glass ampules at 10 mL each.

[0042] The above components were heated and melted at 60 ° C., mixed uniformly, poured into a plastic suppository mold, and cooled to obtain 1 g of suppositories.

[0043]

According to the present invention, ischemia / reperfusion for protecting a tissue from ischemia / reperfusion injury, which comprises 2-octynyladenosine or a pharmacologically acceptable salt thereof as an active ingredient. A perfusion injury inhibitor is provided. These compounds improve a series of parameters such as cytokine production and neutrophil activation, which are indicators of liver ischemia-reperfusion injury, and also have a blood flow increasing effect. In particular, hepatic ischemia-reperfusion injury (eg, shock,
Sepsis, liver resection, liver trauma, liver transplantation, etc.).

Claims (2)

[Claims] (1) The (-)-6-amino- represented by the formula (1)
Ischemia characterized by containing 2- (1-octynyl) -9-β-D-ribofuranosyl-9H-purine (2-octynyladenosine) or a pharmaceutically acceptable salt thereof as an active ingredient. Reperfusion injury inhibitor. Embedded image 2. A hepatic ischemia-reperfusion injury inhibitor comprising the 2-octynyl adenosine according to claim 1 as an active ingredient.