JPH07304689A - Fulminant hepatitis and acute liver failure therapeutic agent - Google Patents

Abstract

(57) [Summary] [Purpose] To provide a drug for treating widespread liver necrosis and acute liver failure due to fulminant hepatitis. [Composition] A therapeutic agent for fulminant hepatitis and a therapeutic agent for acute liver failure containing a platelet activating factor antagonist.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a drug for treating widespread liver necrosis and acute liver failure due to fulminant hepatitis. More specifically, the present invention relates to platelet activating factor (pl
ateleacting factor,
Hereinafter, a therapeutic agent for fulminant hepatitis and a therapeutic agent for acute liver failure containing an antagonist.

[0002]

Fulminant hepatitis is a disease with a very high mortality rate that results in high fever, severe abdominal pain, and systemic jaundice, and then death due to consciousness disorder / coma due to hepatic encephalopathy. In this disease, hepatocytes are rapidly attacked and destroyed, resulting in rapid liver failure. One of the mechanisms of fulminant hepatitis is the tumor necrosis factor (TN) in hepatic macrophages triggered by hyperendotoxemia caused by hypofunction of the reticuloendothelial system.
F) Increased production occurs, and this TNF activates the arachidonic acid cascade of Kupffer cells, especially the lipoxygenase pathway, and the liberated metabolites damage hepatocytes and endothelial cells.
A link that causes necrosis is considered. Other mediators are also considered to be involved, but no report showing the involvement of PAF has been made to date.

As a drug treatment, a corticosteroid such as prednisolone or an immunosuppressant such as cyclosporine is used for the purpose of anti-inflammatory or prevention of hepatocyte necrosis, and glucagon insulin (GI), which is expected to promote liver regeneration, is used. Therapy, special composition amino acid therapy for the purpose of nutritional supplementation and treatment of hepatic encephalopathy, and interferon therapy for the purpose of suppressing the viral growth that causes hepatitis. However, even if plasma exchange and complications (cerebral edema, bleeding tendency, DIC (disseminated intravascular blood coagulation syndrome), renal failure, heart failure, infectious disease, etc.) are taken in addition to these drug therapies, the survival rate is still low. It is about 30%. Further, focusing on the mechanism of fulminant hepatitis mentioned above, 5-lipoxygenase inhibitor, leukotriene D ₄ (LTD ₄ ) antagonist, LTB
₄ Potential as therapeutic agents such as antagonists have also been investigated, but there has been no report that sufficient effects were obtained clinically. Therefore, development of a new therapeutic agent that further improves the lifesaving rate is desired.

[0004]

DISCLOSURE OF THE INVENTION An object of the present invention is to prevent hepatic failure by suppressing widespread hepatocyte necrosis in fulminant hepatitis, thereby preventing fulminant hepatitis which has not been sufficiently effective by conventional drugs. To find a drug that enables treatment of acute liver failure.

[0005]

As a result of intensive studies, the present inventors have found that a PAF antagonist exhibits remarkable efficacy in animal models of fulminant hepatitis and acute liver failure, and completed the present invention. Came to. That is, PA in galactosamine liver injury in mice, which is one of the models of fulminant hepatitis,
F-antagonist improves survival rate of mice, serum aspartate aminotransferase (GOT) in partially hepatectomized liver injury in rat, which is one of the models of acute liver failure,
Increased activity of alanine aminotransferase (GPT),
It was found that a PAF antagonist markedly suppressed the increase of serum bilirubin level and lethal reaction. Furthermore, it was found by a histopathological examination that the PAF antagonist also suppresses hepatocyte necrosis. It was also found that administration of PAF to rats induces hepatitis-like pathology. These facts are considered to indicate that PAF is involved in the mechanism of fulminant hepatitis and acute liver failure resulting from hepatocyte necrosis, and that PAF antagonists are suitable for the treatment of these diseases. To be

The PAF antagonist used in the present invention is PAF
Any compound may be used as long as it suppresses the action of the above. Examples of such PAF antagonists include the compounds described in the following documents. (i) Braquet, P., Touqui, L., Shen, TY, and Vargafti
g, BB Pharmacol. Rev. 39 , 97-145 (1987) (ii) Ichiro Kudo, Keizo Inoue Inflammation 7 , 309-325 (1987) (iii) Keizo Waku, Keizo Inoue Platelet activating factor (modern chemistry, special issue 17) [Tokyo Kagaku Dojin] (iv) San-Bao Hwang J. Lipid Mediators 2 , 123-158
(1990) More specifically, it has one or two heteroatoms selected from the group consisting of derivatives having the following basic skeleton.
It is a heterocyclic monocyclic or polycyclic or condensed ring compound containing three or three, and includes the compounds listed as examples.

1) Thiazolidine Derivatives Examples of thiazolidine derivatives include, for example, JP-A-1-279.
No. 882, specifically, compounds of the general formula

[Chemical 1] (In the formula, R1 and R2 may be the same or different and may be represented by the general formula -A-R4 (wherein A is a single bond, C1 -C8 alkylene, C2 -C).
8 alkenylene, or C2-C8 alkynylene group,
R4 represents a hydrogen atom, C1 -C12 alkyl, C2 -C8 alkenyl, C3 -C8 cycloalkyl, or C1 -C6 alkyl substituted with a halogen atom. ) Or a general formula-[(CH2) n-O] m-[(CH2) n'-O] m'-
B-R5 (wherein B is a single bond or a C1 -C6 alkylene group,
R5 is a hydrogen atom, C1-C6 alkyl, C2-C8 alkenyl, C3-C8 cycloalkyl, substituted silyl group,
Alternatively, it represents a substituted or unsubstituted aryl group, and n is 2 to 4
, M is an integer of 1 to 3, n ′ is an integer of 2-4, and m ′ is 0 or an integer of 1-2. ), A group represented by

R3 is a hydrogen atom, C1 -C2 alkyl,
Allyl, propargyl or the general formula-(CH2) j --R6 (wherein R6 represents a halogen atom, an aryl group optionally substituted by one or more hydroxyl groups or a C1 -C4 alkoxy group, Or a group represented by the general formula -D-R7 (wherein D represents an oxygen atom or a sulfur atom, R7 represents a hydrogen atom, a C1 -C4 alkyl or a C1 -C4 alkanoyl group), j is 2-4
Represents the integer. ) Or a general formula-(CH2) k CO--E--R8 (wherein E is an oxygen atom, a sulfur atom, imino or C1).
--C4 alkylimino group, R8 is hydrogen atom or C1
A -C4 alkyl group or ER8 represents a 5- to 7-membered cyclic amino group which may contain another hetero atom in the ring,
k represents an integer of 1-3. Or a general formula -F-R9 (wherein F represents a C2-C6 alkylene group, R9 represents a nitrogen atom-containing aromatic heterocyclic group or a general formula,

[0009]

[Chemical 2] (In the formula, R10 is a hydrogen atom, C1 -C4 alkyl or C
1-C4 represents an alkanoyl group, R11 represents a hydrogen atom or C
5 represents a 1-C4 alkyl group, or R10 and R11 may together form another hetero atom in the ring.
Represents a 7-membered cyclic amino group. ) Represents an amino group. ) Represents a group represented by. ) Represented by a thiazolidin-4-one derivative and an acid addition salt thereof,
Preferably (+)-cis-3,5-dimethyl-2- (3
-Pyridyl) thiazolidin-4-one hydrochloride.

Other than the above, 1- (3-methyl-3-phenylbutyl) -4- [2- (3-pyridyl)
Thiazolidin-4-ylcarbonyl] piperazine fumarate (YM-264) [Arch. Int. Pha
rmacodyn. 308, 123-136 (199
0)], 1- (3-phenylpropyl) -4- [2-
(3-Pyridyl) -thiazolidin-4-ylcarbonyl] piperazine fumarate (YM-461) [Lip
ids 26 , 1179-1183 (1991)].

2) Thienotriazolodiazepine (heterazepine) Derivatives Examples of the thienotriazolodiazepine derivative include compounds described in JP-A No. 61-176591, specifically the general formula

[Chemical 3] (Wherein R12 is hydrogen, a linear or branched alkyl group having 1 to 4 carbon atoms which may be optionally substituted by halogen or hydroxy, cyclopropyl, 1 to 3 carbons Represents an alkoxy having an atom, halogen; R13 and R14 may be the same or different and each is hydrogen, a linear or branched alkyl or hydroxyalkyl group having 1 to 4 carbon atoms, or two The radicals R @ 13 and R @ 14 together with the nitrogen atom may optionally contain nitrogen, oxygen or sulfur atoms as well as heteroatoms 5-, 6-
Or represents a 7-membered ring and the second nitrogen atom may be optionally substituted by an alkyl group having 1 to 4 carbon atoms; R15 represents a phenyl group, provided that the phenyl group is 2 Optionally substituted by methyl, halogen, nitro or trifluoromethyl at position 2 or 6 or R4 is α-
Represents pyridyl, and n is 0, 1, 2, 3, 4, 5,
Represents any one of 6, 7 or 8. ).

Of these, 4- (2-chlorophenyl) -9-methyl-2- [3- (4-morpholinyl) -3-propan-1-yl] -6H-thieno [3,2-f] [is preferred. 1,2,4] triazolo [4,3-
a] [1,4] diazepine (WEB-2086)
[J. Pharmacol. Exp. Ther. 24
1, 974-981 (1987)]. Compounds other than the above include 6- (2-chlorophenyl)-
8,9-Dihydro-1-methyl-8-[(4-morpholinyl) -carbonyl] -4H, 7H-cyclopenta [4,5] thieno [3,2-f] [1,2,4] triazolo [4 , 3-a] [1,4] diazepine (WEB-2
170), 6- (2-chlorophenyl) -8,9-dihydro-1-methyl-8-dipropylaminocarbonyl-
4H, 7H-cyclopenta [4,5] thieno [3,2-
f] [1,2,4] triazolo [4,3-a] [1,
4] Diazepine (WEB-2347) [Japanese Patent Application Laid-Open No. 2-24
No. 3691],

(S)-(+)-6- (2-chlorophenyl) -3-cyclopropanecarbonyl-8,11-dimethyl-2,3,4,5-tetrahydro-8H-pyrido [4 ', 3'] : 4,5] Thieno [3,2-f] [1,
2,4] triazolo [4,3-a] [1,4] diazepine (E6123) [Arzneim. Forsch. /
Drug Res. 40, 1201-1205
(1990)], 4- (2-chlorophenyl) -9-methyl-2- [2- [4- (2-methylpropyl) -phenyl] ethyl] -6H-thieno [3,2-f] [1,
2,4] triazolo [4,3-a] [1,4] diazepine (Y-24180) [Prostalandins
40, 553-569 (1990)], tetrahydro -4,7,8,10- methyl - (chloro-2-phenyl) -6 - [(dimethoxy-3,4-phenyl) thio]
Methylthiocarbonyl-9-pyrido [4 ', 3': 4,
5] Thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepine (BN-5073
9) [J. Lipid Mediators 3,13
-26 (1991)], 5- [3- [4- (2-chlorophenyl) -9-methyl-6H-thieno [3,2-
f] [1,2,4] triazolo [4,3-a] [1,
4] diazepin-2-yl] -2-propynyl] phenanthridin-6 (5H) -one (Ro24-4736)
[J. Pharmacol. Exp. Ther. 25
9, 78-85 (1991)]

3) Pyrrolothiazole Derivatives As the pyrrolothiazole derivative, for example, JP-A-59-
The compounds described in Japanese Patent No. 134798, specifically the general formula

[Chemical 4] Wherein R16 and R17 are the same or different and represent a hydrogen atom or an alkyl group, and a) R20 represents cyano or alkylcarbonyl,
Or b) R20 is a formula

[Chemical 5] R18 represents a hydrogen atom and R19 represents an amino, alkylamino, dialkylamino, phenylamino or diphenylamino group, or R18
And R19 are the same or different and each represents a hydrogen atom, an alkyl group having 1 to 5 carbon atoms or an unsubstituted or substituted phenyl group, or R18 represents a hydrogen atom and R19 is a pyridyl group or 1 Represents an alkyl group of up to 5 carbon atoms, wherein said alkyl group is carboxyl, amino, alkylamino, dialkylamino, morpholino, piperidino, pyrrolidin-1-yl,
Piperazin-1-yl (alkyl, pyridyl, optionally substituted at the 4-position by an unsubstituted or substituted phenyl group or an unsubstituted or substituted benzyl group), unsubstituted or substituted phenyl, pyridyl or imidazolyl Or R18 and R19 together with the nitrogen atom to which they are attached form an imidazolyl group or a 5- or 6-membered heterocycle, said heterocycle being such as an oxygen atom, a sulfur atom or a nitrogen atom. By an alkyl, alkoxycarbonyl, hydroxyalkyl, dialkylaminoalkyl, dialkylaminoalkyl, pyridyl, pyridinyl, pyrazinyl, unsubstituted or substituted phenyl or unsubstituted or substituted benzyl group Replaced Or

C) R20 is the formula

[Chemical 6] Or

[Chemical 7] Where R ′ and R ″ are the same or different alkyl groups. (However, the alkyl group and the alkyl moiety in the present definition are linear or branched and contain 1 to 4 carbon atoms unless otherwise specified, and the possible substituents on the phenyl and benzyl groups are halogen, An alkyl, alkoxy, alkylthio, trifluoromethyl, or dialkylamino group))), a 1H, 2H-pyrrolo [1,2-c] thiazole derivative represented by the formula (a) or formula (b). Mention may be made of tautomers of the compounds of the formula A when representing groups and acids and their addition salts and, if present, their metal salts and their addition salts with nitrogen bases.

Among them, 3- (3-pyridinyl) -1H, 3H-pyrrolo- [1,2-c] thiazole-7-carboxamide (RP-48740) is preferable.
[Prostalandins 30 , 668
(1985)]. In addition, (+)-N-
[3- (Benzoyl) phenyl] -3- (3-pyridinyl) -1H, 3H-pyrrolo- [1,2-c] thiazole-7-carboxamide (RP-59227). 4) Tetrahydrofuran derivative and tetrahydrothiophene derivative trans-2,5-bis (3,4,5-trimethoxyphenyl) tetrahydrofuran (L-652,731)
[J. Biol. Chem. 260,15639-15
645 (1985)],

Trans- (±) -tetrahydro-2-
[3-Methoxy-5-methylsulfonyl-4-propoxyphenyl] -5- (3,4,5-trimethoxyphenyl) -furan (L-659,989) [Bioch
em. Biophys. Res. Commun. 15
0,1213-1220 (1988)], cis
(±) -1- [2- [hydroxy [tetrahydro-5-
[(Octadecylaminocarbonyl) oxy] methyl]
Furan-2-yl] methoxyphosphinyloxyethyl] quinolinium hydroxide (SRI 63-44
1) [Annu. Rev. Pharmacol. Tox
icol. 27 , 237-255 (1987)], cis (±) -1- [2- [hydroxy [tetrahydro-
2,5-Dimethyl-5-[(octadecylaminocarbonyl) oxy] methyl] furan-2-yl] methoxyphosphinyloxyethyl] quinolinium hydroxide (SRI 63-675), trans-2,5-bis (3 , 4,5-Trimethoxyphenyl) tetrahydrothiophene (L-653,150),

5) Gingoleide derivative 3-t-butyl-hexahydro-4,7b-dihydroxy-8-methyl-9H-1,7a-epoxymethano-1
H, 6aH-cyclopenta [c] furo [2,3-b]
Flo [3 ', 2': 3,4] cyclopenta [1,2-
d] Furan-5,9,12- (4H) trione (BN
52020, ginkgolide A), 3-t-butyl-hexahydro-4,7b, 11-trihydroxy-8.
-Methyl-9H-1,7a-epoxymethano-1H, 6
aH-cyclopenta [c] furo [2,3-b] furo [3 ′, 2 ′: 3,4] cyclopenta [1,2-d]
Furan-5,9,12- (4H) trione (BN 5
2021, Gingolid B) [Blood Ves
sels 16 , 559-572 (1985)], 3
-T-Butyl-hexahydro-2,4,7b, 11-tetrahydroxy-8-methyl-9H-1,7a-epoxymethano-1H, 6aH-cyclopenta [c] furo [2,3-b] furo [3 ', 2': 3,4] Cyclopenta [1,2-d] furan-5,9,12- (4H)
Trion (BN 52022, Ginkgolide C)

6) Imidazoisoquinoline derivative 5- [4 '-(3,4,5-trimethoxyphenylethyl) phenyl] -2,3-dihydro-imidazo [2,2]
1-a] isoquinoline hydrochloride (SDZ 6
4-412) [J. Pharmacol. Exp. Th
er. 247, 617-623 (1988)].

7) Dihydropyridine derivative 2- (phenylthio) ethyl-5-ethoxycarbonyl-2,4,6-trimethyl-1,4-dihydropyridine-3-carboxylate (PCA-4233) [J. P
armacol. Exp. Ther. 255, 28-
33 (1990)], 2- (phenylthio) ethyl-5.
-Methoxycarbonyl-2,4,6-trimethyl-1,
4-dihydropyridine-3-carboxylate (PCA
-4248) [J. Pharmacol. Exp. Th
er. 255, 34-39 (1990)], 4- (2-
Chlorophenyl) -1,4-dihydro-3- (ethoxycarbonyl) -6-methyl-2- [4- (2-methylimidazo [4,5-c] pyrid-1-yl) phenyl]-
5- [N- (2-pyridyl) carbamoyl] pyridine (UK-74505) [Agent Actions
Suppl. 34, 221-227 (1991)]

8) Glycerol derivative (RS) -2-methoxy-3- (octadecylcarbamoyloxy) propyl-2- (3-thiazolio) ethyl phosphate (CV-3988) [Life Sc
i. 32, 1975-1982 (1983)], 3-
[4-[(R) -2- (methoxycarbonyloxy)-
3- (octadecylcarbamoyloxy) propoxy]
Butyl] thiazolium iodide (Ro19-370
4) [Prostalandins 30 , 694
(1985)], 1-O-hexadecyl- (2R,
S) -O-Ethyl-3-O- (7-thiazolioheptyl) glycerol chloride (ONO 6240) [P
rosta glandins 31 , 271-281
(1986)], 1-O-octadecyl-2-acetyl-sn-glycero-3-phosphoric acid 6'-.
Trimethylammonium hexyl ether (U-66
985) [J. Biol. Chem. 260,1271
0-12714 (1985)],

2- (2-acetyl-6-methoxy-3,
9-Dioxo-4,8-dioxa-2,10-diazaoctacos-1-yl) -1-ethyl-pyridinium chloride (CV-6209) [J. Pharmaco
l. Exp. Ther. 242, 263-268 (1
987), 1-Ethyl-2- [N- (2-methoxy) benzoyl-N-[(2R) -2-methoxy-3- (4-
Octadecylcarbamoyloxy) piperidinocarbonyloxypropyloxy] carbonyl] aminomethylpyridinium chloride (E5880) [Arzne
im. -Forsch. / Drug Res. 41 , 7
19-724 (1991)], 1-O-hexadecyl-
2-O-ethyl-rac-glycero-3-phosphoric acid 4- (N, N-dimethylamino) pyridinium butyl ester (KO-286011) [Arc
h. Pharmacol. 342, 713-718 (1
990)]

In addition, 3-bromo-5- [N-phenyl-N- [2-] described in JP-A No. 02-76854.
[2- (1,2,3,4-tetrahydro-2-isoquinolylcarbonyloxy) ethyl] carbamoyl] ethyl] carbamoyl] -1-propylpyridinium nitrate (TCV-309), J.P. Pharmacol.
Exp. Ther. 252, 1090-1096 (1
990) 1-acetyl-4- (8-chloro-
5,6-Dihydro-11H-benzo [5,6] cyclohepta [1,2-b] pyridine-11-yridine) piperidine (Sch-37370), J. Mol. Pharmaco
l. Exp. Ther. 259, 44-51 (199
N- (2-dimethylaminoethyl) -N described in 1).
-(3-Pyridinylmethyl) [4- (2,4,6-triisopropylphenyl) thiazol-2-yl] amine (SR-27417), Proc. Natl. Ac
ad. Sci. USA 82 , 672-676.
Kadsureno described in (1985).
ne), Chem. Pharm. Bull. 34 , 34
0 (1986) and FR-49175 and J. Ant
FR-900452 and the like described in ibiotics,
It can be used as a PAF antagonist.

[0024]

[Examples] It will be specifically described below by showing experimental examples that PAF antagonists are effective therapeutic agents for fulminant hepatitis and acute liver failure. The following compounds were used in the experiment. Compound [I]: (+)-cis-3,5-dimethyl-
2- (3-pyridyl) thiazolin-4-one hydrochloride compound [II]: 4- (2-chlorophenyl) -9
-Methyl-2- [3- (4-morpholinyl-3-propan-1-yl] -6H-thieno [3,2-f]
[1,2,4] triazolo [4,3-a]-[1,
4] Diazepine compound [III]: 3- (3-pyridinyl) -1
H, 3H-pyrrolo- [1,2-c] thiazole-7-
Carboxamide

Experimental Example 1 Treatment of Endotoxin-Induced Acute Liver Failure in Partial Hepatectomy Rats
Action (experimental method) Gastroenterology (Gastroe
nterol. ) It was tested according to the method described in Vol. 99, p. 771 (1990). That is, about 2/3 of the liver
2 days after the partial hepatectomy, Compound [I] (dissolved in physiological saline) or Compound [II] (dissolved in physiological saline containing 10% Nikkor) was intravenously administered to the Wistar male rat from which the liver had been excised. . After 5 minutes, endotoxin (E.
coli 055: B5, 0.1 mg / kg body weight) was dissolved in physiological saline and intravenously administered, and 5 hours later, serum total bilirubin concentration, GOT activity, and G, which are indicators of liver function, were measured.
PT activity was measured. Further, life and death after 24 hours were observed.

(Experimental Results) The results are shown in Table 1-1 and Table 1 below.
-2, Table 1-3, and Table 1-4 were as shown.

[Table 1] Table 1-1 Effect of PAF Antagonist on Increased Serum Total Bilirubin Level in Endotoxin-induced Liver Injury in Partial Hepatectomy Rats * Is statistically significant with a risk rate of less than 5%

[0027]

[Table 2] Table 1-2 P for elevation of serum GOT activity in endotoxin-induced liver injury in partially hepatectomized rats
Effect of AF antagonist * Is statistically significant with a risk rate of less than 5%

[0028]

[Table 3] Tables 1-3 P for serum GPT activity increase in endotoxin-induced liver injury in partially hepatectomized rats
Effect of AF antagonist * Is statistically significant with a risk rate of less than 5%

[0029]

[Table 4] Tables 1-4 Effects of PAF antagonists on lethal reaction in endotoxin-induced liver injury in partially hepatectomized rats Administration of endotoxin to rats with partial hepatectomy, which is a model of acute liver failure, resulted in serum total bilirubin, GOT and
The GPT was markedly increased, and there was a high probability that the rats were killed. Compound [I] and compound [I] which are PAF antagonists
I] was found to suppress the increase in serum total bilirubin, GOT, and GPT. It was also revealed that the mortality rate was reduced.

Experimental Example 2 Effect of galactosamine on liver injury in mice (experimental method) This test is basically based on Chris Galan.
Os et al. (Proc. Natl. Acad. Sci. USA 76 , 5939-5
943). That is, D-galactosamine hydrochloride (750 mg / kg body weight) and endotoxin (E. coli 011) were administered to a group of 10 5-week-old balb / c female mice.
1: B4, 1.0 μg / kg body weight) was dissolved in physiological saline and administered via the tail vein. Immediately after that, compound [I] (dissolved in physiological saline) or compound [III] (dissolved in physiological saline) was administered through the tail vein, and life or death was observed for 7 days. (Experimental Results) The results are shown in Table 2-1 below.

[Table 5] Table 2-1 Effect of PAF antagonist on lethal reaction in galactosamine liver injury in mice It was revealed that Compound [I] and Compound [III] suppress the lethality of galactosamine liver injury in mice, which is a fulminant hepatitis model.

When a PAF antagonist is administered as a therapeutic agent for fulminant hepatitis and acute liver failure, its administration method and dose vary depending on the type of PAF antagonist, administration subject, symptoms and the like. The dosage form may be in the form of tablets, capsules, powders, granules, powders, solutions, injections, suppositories, etc., but if treatment is required as quickly as possible,
It is desirable to use an injection. PAF for prescription
The antagonist may be used alone or in combination with other pharmaceutically active ingredients. For orally administered preparations, as it is or with suitable additives, for example, conventional excipients such as lactose, mannitol, corn starch, potato starch, etc., and binders such as crystalline cellulose, cellulose derivatives, gum arabic, corn starch, gelatin etc. , Corn starch, potato starch, disintegrants such as carboxymethylcellulose calcium, talc, lubricants such as magnesium stearate, other extenders, wetting agents, buffers, preservatives, tablets, powders, etc. It can be a granule or a capsule.

As the injection, an aqueous solvent such as distilled water for injection, physiological saline, 5 to 20% glucose injection, or a solution of a non-aqueous solvent such as vegetable oil, synthetic fatty acid glyceride, higher fatty acid ester, propylene glycol, etc., It may be a suspension or an emulsion, and if necessary, commonly used additives such as a solubilizing agent, a tonicity agent, a suspending agent, an emulsifying agent, a stabilizer, and a preservative may be appropriately added. . Alternatively, it can be used as a freeze-dried preparation by putting it in a vial bottle or the like and appropriately dissolving it in the above solvent at the time of use. Further, the PAF antagonist can be mixed with various bases such as an emulsion base or a water-soluble base to give a suppository, or can be formulated into an inhalant or an aerosol. The dose of the PAF antagonist required to obtain the new activity of the present invention is generally 5 to 100 m per adult for oral administration.
It is suitable to administer g, preferably 10 to 50 mg orally, and in the case of intravenous or intramuscular administration, 1 to 75 mg, preferably 1 to 25 mg per dose is suitable and ~ 4 doses. On the other hand, a dose corresponding to 1/4 to 1/2 of the above dose is administered to children depending on their age.

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Claims (2)

[Claims] 1. A therapeutic agent for fulminant hepatitis containing a platelet activating factor antagonist. 2. A therapeutic agent for acute liver failure containing a platelet activating factor antagonist.