JPH09143094A - Preventive/therapeutic agent for fulminant hepatitis - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the above agent having activity to remedy the liver function failure due to fulminant hepatitis and presenting excellent preventive/therapeutic effect on fulminant hepatitis, containing, as active ingredient, an insulin-like growth factor 1 (derivative). SOLUTION: This preventive/therapeutic agent contains, as active ingredient, an insul-in-like growth factar 1 (derivative), and is obtained by subjecting the active ingredient to pharmaceutical manufacturing into formulations such as solid preparation like tablets, capsules, powder, granules, troches, pills, ointment or suppository, liquid preparations like suspension, solution, syrup or elixir, or liposome preparation. These pharmaceutical preparations can be administered orally or parenterally (intravenous, intramuscular, subcutaneous, intracutaneous, intraperitoneal, or enteral administration). It is preferable that the dose of the preparation be 0.1-10mg/kg b.w./adult a day in one to several portions in terms of the active ingredient.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel preventive or therapeutic agent for fulminant hepatitis and is useful in the field of medicine.

[0002]

Fulminant hepatitis is a disease with a high mortality rate in which hepatocytes undergo extensive and rapid necrosis due to the causes of hepatitis virus, drugs, etc., causing serious liver dysfunction. According to the diagnostic criteria, fulminant hepatitis refers to fulminant hepatitis that causes hepatic coma due to severe liver dysfunction within about 8 weeks after the onset of hepatitis symptoms and shows prothrombin time of 40% or less. I am trying. Further, there are an acute type that develops fulminant hepatitis within 10 days after the onset of hepatitis symptoms and a subacute type that develops after 11 days. Conventionally known treatments for fulminant hepatitis include plasma exchange, transfusion, assistance with artificial liver assisting device, and combined administration of glucagon and insulin, but improvement in mortality has not been observed. Since fulminant hepatitis has serious symptoms and a high mortality rate, more effective preventive or therapeutic agents are required.

[0003]

The object of the present invention is to provide a novel preventive or therapeutic agent for fulminant hepatitis.

[0004]

As a result of intensive studies to solve the above problems, the present inventors have found that insulin-like growth factor 1 (hereinafter referred to as IGF-1) or its derivative is fulminant hepatitis. It has been found to have an excellent preventive and therapeutic effect against. The present invention relates to a preventive or therapeutic agent for fulminant hepatitis, which contains IGF-1 or a derivative thereof.

IGF-1 is an insulin-like peptide existing in blood, which has a growth-promoting action on various cells, and its production and secretion depend on growth hormone. In recent years, this IGF-1 has been
Since it can be produced relatively easily and has a growth promoting action, it has a chondrocyte proliferative action as a therapeutic agent for pituitary dwarfism and a growth promoting agent for short stature. As a therapeutic agent, it is known to be used as a therapeutic agent for diabetes because it has an insulin-like action, and as a therapeutic agent for ulcers, trauma, burns, etc. because it has an anabolic action. However, the preventive and therapeutic effect of IGF-1 on fulminant hepatitis has not been known so far.

[0006]

BEST MODE FOR CARRYING OUT THE INVENTION As the IGF-1 used in the present invention, a gene recombination technique (for example, JP-A-61-139) is used.
6), IGF-derived from mammals such as humans and cows produced by peptide synthesis method, cell culture method and the like.
1 is included. The IGF-1 derivative is a mutant protein having an IGF-1 activity produced by gene recombination technology or the like, in which a part of the amino acid sequence of IGF-1 has amino acid insertion, substitution, substitution or deletion, And chemically modified products such as O-glucosylated IGF-1 (see WO90 / 02198). Preferable derivatives of IGF-1 include those in which 1 to 5 amino acids have been deleted from the N-terminus as described in WO89 / 5822. The preventive / therapeutic agent for fulminant hepatitis of the present invention can be used for the prevention and treatment of fulminant hepatitis in mammals such as humans, cows, sheep, pigs, etc. For example, human IGF-
Preferably, IGF-1 from a particular species such as bovine IGF-1 for bovine is used. In addition, the IGF-1 or its derivative of the present invention includes the above-mentioned IGF-1.
-1 or a derivative salt thereof (for example, acid addition salts such as hydrochloride and sulfate, and base addition salts such as sodium salt) are also included.

IGF-1 or its derivative can be prepared by using a conventional formulation method such as solid formulation such as tablets, capsules, powders, granules, fine granules, troches, pills, ointments and suppositories. Formulated in the form of conventional pharmaceutical preparations such as suspensions, solutions, syrups, elixirs and other liquid preparations, liposome preparations, and oral or parenteral administration (intravenous, intramuscular, subcutaneous, intradermal, intraperitoneal) , Enteral administration). The preparation is prepared by a conventional means using optionally required pharmaceutical carriers, excipients and other pharmaceutically acceptable additives.

Solid preparations such as tablets, capsules, powders, granules, fine granules, troches, pills, ointments and suppositories are bound by binders such as syrup, acacia, gelatin, sorbit, tragacanth, polyvinyl. Pyrrolidone and the like; Excipients such as lactose, corn starch, calcium phosphate, sorbit, glycine and the like; Lubricants such as magnesium stearate, talc, polyethylene glycol, silica and the like; Disintegrators such as potato starch and the like; or acceptable wetting agents , For example, sodium lauryl sulfate may be contained. The tablets may be coated with an enteric coating known per se in a manner well known in the art.

Liquid formulations may be aqueous or oily suspensions, solutions, syrups, elixirs and the like.
Such liquid formulations include commonly used additives such as suspending agents such as sorbit syrup, methyl cellulose, glucose / sugar syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminum stearate gel, hydrogenated edible fats and the like; emulsifiers. ,
For example, lecithin, sorbitan monooleate, gum arabic, etc .; aqueous vehicles such as water, saline;
Non-aqueous vehicles such as almond oil, coconut oil,
Oily ester, propylene glycol, ethanol and the like; preservatives such as methyl p-hydroxybenzoate, p
-Propyl hydroxybenzoate, sorbic acid, etc. may be contained. Further, the pharmaceutical preparation may be a solid preparation that is dissolved before use and is dissolved in water or other suitable vehicle before oral or parenteral administration.

Liposomes are closed vesicles having an inner aqueous phase portion surrounded by a lipid bilayer formed by dispersing lipids in water, and can take in physiologically active substances such as proteins. . Freeze-thaw method for liposomes,
It can be produced by a known method such as an ultrasonic treatment method, a surfactant treatment method, a reverse phase evaporation method, or an emulsifier method. Examples of lipids used in the production of liposomes include phospholipids, glycolipids and derivatized lipids. As the phospholipid, phosphatidylcholine, phosphatidylserine, phosphatidic acid, phosphatidylglycerin, phosphatidylethanolamine, phosphatidylinositol, sphingomyelin, dicetylphosphate,
Examples of these inclusions, soybean phospholipids, egg yolk phospholipids, glycolipids, cerebroside, sulfatide, ganglioside, etc., and induced lipids, cholic acid, deoxycholic acid, etc.

Specific examples of these preparations include freeze-dried preparations described in JP-A-4-208228 and JP-A-5-208228.
Examples include the nasal preparations described in JP-A-58877.

[0012] The amount of the active ingredient in the pharmaceutical preparation may be an amount sufficient to produce the desired prophylactic or therapeutic effect. I
The dose of GF-1 or its derivative varies depending on the age, symptoms and administration route of the patient, but is usually about 0.1 to 10 mg / kg, preferably about 0.2 as IGF-1 per adult per day. It is about 5 mg / kg, which can be administered once or in divided doses.

[0013]

【Example】

Experimental Example 1 (Effect of IGF-1 on rat fulminant hepatitis model) (Experimental method) Six 6-week-old SD male rats purchased from Japan Charles River KK (1 group 6) (normal group) or 9
The animals were divided into two groups (a disease state control group and an IGF-1 administration group) for use. A human IGF-1 administration group was subcutaneously administered with a physiological saline solution of human IGF-1 (0.5 mg / ml) at a volume of 2 ml / kg, and a normal group and a disease control group had the same volume of physiological saline. Was subcutaneously administered. After 1 hour, 40 mg / ml of D-galactosamine and lipopolysaccharide (Sigma, Catalog N) were added to the IGF-1 administration group and the disease control group.
o. L-6636, Salmonella abort
us equi strain TCA extraction method) 0.0032 mg /
A physiological saline mixed solution containing 1 ml was intravenously administered at a volume of 5 ml / kg. To the normal group, the same amount of physiological saline was intravenously administered. 18 hours later, blood was collected from the abdominal aorta under anesthesia and sacrificed. The animals were fasted for 18 hours before slaughter (drinking freely). BUN (blood urea nitrogen) in serum, creatinine, glucose, total bilirubin, GOT, and GPT were measured.

(Results) The results are shown in Table 1. In the disease control group, simultaneous administration of 200 mg / kg of D-galactosamine and 0.016 mg / kg of lipopolysaccharide simultaneously killed 4 out of 9 cases by 18 hours, and compared with the normal group in the surviving cases. As a result, an increase in serum BUN, creatinine, total bilirubin, GOP, GPT and a decrease in glucose were observed. IGF-1 1.0 mg / kg 1-hour subcutaneous administration significantly suppressed mortality and changes in the above serum parameters, namely, increase in BUN, creatinine, total bilirubin, GOP, GPT and decrease in glucose, or A suppression tendency was recognized. These results indicate that IGF-1 has an effect of improving liver dysfunction in fulminant hepatitis.

[0015]

[Table 1]

[0016]

EFFECT OF THE INVENTION IGF-1 or its derivative which is an active ingredient of the present invention has an action of improving liver dysfunction in fulminant hepatitis, and exhibits an excellent preventive and therapeutic effect on fulminant hepatitis. IGF-1 or its derivative is useful as a preventive or therapeutic agent for fulminant hepatitis.

Claims (1)

[Claims] 1. A preventive or therapeutic agent for fulminant hepatitis, which comprises insulin-like growth factor 1 or a derivative thereof.