JPH11246408A - Therapeutic agent for hepatic disorder - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject therapeutic agent useful for hepatic function disorders, such as acute/chronic hepatitis, cirrhosis and fatty liver, by including leucovorin as an active ingredient. SOLUTION: This therapeutic agent not only has yellow-decreasing effects on icteric symptoms, but also improves hepatic function values [plasma GOT (plasma AST), plasma GPT (plasma ALT)], by including, as an active ingredient, leucovorin [N- 4-[(2-amino-5-formyl-1,4,5,6,7,8-hexahydro-4-oxo-6-pteridinyl) methyl]amino}benzoyl-L-glutamic acid]. Leucovorin has also suppressive effects on hepatic fibrogenesis due to chronic hepatic disorders. The daily dose of leucovorin as the above therapeutic agent it generally 1-1,000 mg in terms of d1-leucovorin or 1-leucovorin.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD [0001] The present invention relates to a therapeutic agent for hepatic disorder, and more specifically, it contains leucovorin as an active ingredient,
In particular, the present invention relates to a therapeutic agent for hepatic disorder based on the action of leucovorin for improving liver function and inhibiting liver fibrosis.

[0002]

The liver, the central organ of metabolism, contains carbohydrates,
Actively metabolizes proteins, lipids, nucleic acids, vitamins, hormones, etc., and the liver detoxifies endogenous and exogenous substances by oxidation, reduction, conjugation, etc. It performs functions such as assisting excretion in the urine, and is one of the vital organs for the human body.

By the way, liver diseases such as acute / chronic hepatitis, cirrhosis, and fatty liver caused by viral infection, alcohol, drugs, autoimmune diseases, etc., impair the above-mentioned function of the liver. Furthermore, due to such liver dysfunction, the secretion of bile from the liver is suppressed, and various jaundice symptoms may sometimes appear. Such jaundice symptoms may lead to liver failure or renal failure if left unchecked. Improving and maintaining liver function is extremely important because of the risk of death.

[0004] Conventionally used drugs for improving liver dysfunction are intended to compensate for insufficient intake and utilization of nutrients caused by liver dysfunction, and to improve liver function such as anti-inflammatory and detoxification. Nutrient preparations such as carbohydrate preparations, lipid preparations, amino acid preparations, vitamin preparations, etc. which are dietary treatments, liver hydrolyzate, liver extract, liver protection agents such as herbal medicines, antiviral agents, corticosteroids, immunotherapy agents And diuretics.

[0005] Among them, dietary treatment involves administration of various nutrient preparations. On the contrary, attention must be paid to fatty liver due to overnutrition. Liver protectants are not expected to have remarkable effects, but have few side effects and have the advantage of being able to be administered for a long time, but they are used as symptomatic treatments.

[0006] Interferon preparations, steroid preparations, immunostimulants, antiviral agents, etc., which have recently begun to be used, are limited in the diseases to be treated, and have many side effects. There is a problem that is difficult to be effective. In addition, malotilate, which has an activating effect on liver function, has emerged as a therapeutic agent for liver damage, but its main indication is improvement of liver dysfunction in cirrhosis, and contraindications for patients with jaundice are observed. It is supposed to be.

[0007]

SUMMARY OF THE INVENTION Accordingly, in view of the above situation, an object of the present invention is to treat liver diseases such as acute / chronic hepatitis, cirrhosis, and fatty liver caused by viral infections, alcohol, drugs, autoimmune diseases and the like. It is an object of the present invention to provide a more effective drug that can be clinically applied to the accompanying liver dysfunction and further to the liver dysfunction with jaundice.

Under these circumstances, as a result of investigations to solve the above problems, the present inventors have found that leucovorin, which is known as an antifolate antimetabolite, has an effect of improving hepatic disorders, in particular, a liver function value. The present inventors have newly found that they have an effect of improving certain plasma GPT and GOT levels and an effect of suppressing liver fibrosis due to chronic liver injury, and have completed the present invention based on such findings.

[0009]

Accordingly, the present invention provides, as one aspect thereof, a therapeutic agent for liver injury containing leucovorin or a pharmacologically acceptable salt thereof as an active ingredient. The therapeutic agent for liver damage provided by the present invention is based on the liver function value improvement and liver fibrosis inhibitory effects of leucovorin, and therefore, the present invention provides, as another aspect thereof, leucovorin or a pharmacological agent thereof. The present invention also provides a hepatic function value improving agent and a hepatic fibrosis inhibitor containing a salt acceptable as an active ingredient. That is,
These therapeutic agents provided by the present invention can improve liver function test values such as plasma GPT and GOT which have deviated from the normal range due to liver damage, and suppress liver fibrosis due to chronic liver damage. In addition, it is characterized by being able to prevent cirrhosis, and is therefore a very clinically useful drug.

[0010]

BEST MODE FOR CARRYING OUT THE INVENTION Leucovorin, an active ingredient of the present invention, lowers serum total bilirubin level in patients with obstructive jaundice and has a remarkable yellowing effect. Therefore, a therapeutic agent for obstructive jaundice has already been proposed ( JP-A-7-291864)
Have been. However, leucovorin may exhibit undesirable side effects in liver disorders associated with liver diseases such as acute / chronic hepatitis, cirrhosis, and fatty liver caused by viral infections, alcohol, drugs, autoimmune diseases, etc., especially chronic liver disorders. No, plasma GPT and GOT
It has not been known to improve liver function values such as hepatic function and to suppress liver fibrosis. Therefore, the present invention is a clinically useful drug as a therapeutic agent for liver damage, and provides a great deal of light not only to patients exhibiting jaundice symptoms but also to patients with liver diseases such as chronic liver damage.

The leucovorin used as an active ingredient in the present invention has a chemical name of N- [4-[[(2-amino-5-
Formyl-1,4,5,6,7,8-hexahydro-4
-Oxo-6-pteridinyl) methyl] amino] benzoyl] -L-glutamic acid, but it can also be used in the present invention in the form of a pharmaceutically acceptable salt thereof. Such salts are conventional non-toxic salts, for example salts with bases, ie salts with inorganic bases, such as alkali metal salts (eg sodium salt,
Potassium salt) and alkaline earth metal salts (eg, calcium salt, magnesium salt, etc.). These pharmacologically acceptable salts include both anhydrous salts which are anhydrous and hydrates which are hydrates. Further, leucovorin, which is an active ingredient of the present invention, has d-form and l-form optical isomers, and both mixtures and l-forms are included in leucovorin of the present invention. However, a particularly preferred leucovorin is l-leucovorin.

The feature of the present invention is based on the action of leucovorin to improve liver function values. Examples of such improved liver function values include plasma GPT and GPT. Plasma GOT (also called plasma AST) is aspartate aminotransferase (common name: glutamate-oxaloacetate transaminase),
As a clinical test value of liver function, the reference range value of a healthy person is
7 to 40 U / L. However, due to inflammation and cell necrosis due to liver damage, GOT in cells flows out into the blood and increases its value. Plasma GPT (also referred to as plasma ALT) is alanine aminotransferase (common name: glutamic acid-pyruvate transaminase), and the reference value in a healthy person is 5-35 U / L.
In the case of hepatocellular injury, liver GPT decreases and activity in the blood increases.

The measurement of these plasma GOT and GPT values is as follows.
It is a clinical test that is essential for screening for occult liver disease, early diagnosis of acute hepatitis, and diagnosis of non-jaundice hepatitis.
Furthermore, it is useful for the course diagnosis of chronic liver disease, the diagnosis of recurrence, and the guidance of patients' lives.

Leucovorin, an active ingredient in the present invention, improves liver function test values such as GOT and GPT in rats with chronic liver injury. Therefore, the medicament of the present invention containing leucovorin as an active ingredient is useful as a liver function value improving agent.

A further feature of the present invention is based on the inhibitory action of leucovorin on liver fibrosis. Liver fibrosis refers to a state in which fibrous connective tissue in the liver is significantly increased, and liver dysfunction is caused by the liver fibrosis. Collagen is the main component of fibrous connective tissue that plays an important role in liver fibrosis, and when liver fibrosis occurs, collagen production is promoted. One of the amino acids constituting collagen is hydroxyproline, which is almost exclusively incorporated only into collagen. Therefore, reducing the content of hydroxyproline in the liver is an indicator of liver fibrosis suppression.

Prolyl hydroxylase, which is one of collagen synthases and serves as an indicator of hepatic fibrosis in the blood, is associated with an increase in the concentration of the enzyme in the blood. It is known to have. Leucovorin, an active ingredient of the present invention, was found to reduce hydroxyproline content in the liver and prolyl hydroxylase in plasma in rats with chronic liver injury accompanied by liver fibrosis. Therefore, the medicament of the present invention containing leucovorin as an active ingredient is also useful as a liver fibrosis inhibitor.

The dose of leucovorin as a therapeutic agent of the present invention is not particularly strictly limited, and varies depending on the administration method and the type and degree of hepatic dysfunction to be treated. l-Leucovorin can be appropriately selected within a range of 1 mg to 1,000 mg / day, preferably 5 mg to 800 mg / day.

The therapeutic agent of the present invention may be an inorganic or organic solid or liquid pharmaceutical carrier or diluent commonly used in pharmaceutical preparations, for example, starch, lactose, sucrose, crystalline cellulose, calcium hydrogen phosphate and the like. Forming agents; Binders such as acacia, hydroxypropylcellulose, alginic acid, gelatin, polyvinylpyrrolidone; Lubricants such as stearic acid, magnesium stearate, calcium stearate, hydrogenated vegetable oil; Modified starch, calcium carboxymethylcellulose, low-substituted hydroxypropyl Disintegrating agents such as cellulose; dissolving aids such as nonionic surfactants and anionic surfactants;
It can be formulated into a dosage form suitable for oral, parenteral or topical administration.

Suitable dosage forms for oral administration include solid preparations such as tablets, coatings, capsules, troches, powders, fine granules, granules and dry syrups, and liquid preparations such as syrups. Dosage forms suitable for parenteral administration include, for example, injections, drops, suppositories and the like. These preparations can be prepared using a method known per se in the field of pharmacology.

[0020]

EXAMPLES The usefulness of the therapeutic agent of the present invention will be described below by describing the results of pharmacological tests, safety and specific formulation examples.

[Pharmacological test] Hepatic function of leucovorin in rats with chronic liver injury
Improvement effect 1. Test Method Rats were given 0.5 ml / kg of carbon tetrachloride for 11 weeks.
Is administered subcutaneously twice a week (Monday and Thursday),
L-Leucovorin was intravenously administered 5 times a week (every day from Monday to Friday) for 2 weeks to cause chronic liver injury due to carbon tetrachloride, and the effect of 1-leucovorin on liver injury was examined.

There were two groups of leucovorin administration: a 1-leucovorin administration group at 4 mg / kg / day (n = 20) and a 10 mg / kg / day administration group (n = 20). In addition, a group to which only carbon tetrachloride was administered without simultaneous administration of l-leucovorin (n = 20) was set. In order to confirm the onset of chronic liver injury due to carbon tetrachloride administration in this test, untreated groups of normal rats (n =
5) and a group to which only olive oil (solvent of carbon tetrachloride) was subcutaneously administered (n = 5). Blood samples were collected from the test rats in each group on Wednesdays 2, 4, 6, 8 and 10 weeks after the start of the carbon tetrachloride treatment, and GOT (AS
T) and GPT (ALT) values were measured.

2. Results The time course of plasma GOT and GPT in each group is shown in FIG. 1 (GOT) and FIG. 2 (GPT). As is clear from the results in the figure, in the group to which only carbon tetrachloride was administered (vehicle control group), plasma GOT (plasma AST), which is a liver function test value, was caused by the onset of chronic liver injury.
And plasma GPT (plasma ALT) levels are increasing over time, whereas co-administration of 1-leucovorin
It turned out that the rise was suppressed. Therefore,
It has been shown that l-leucovorin, which is an active ingredient of the present invention, improves liver function values and is effective as a therapeutic agent for liver damage based thereon.

II. Leucovorin in rats with chronic liver injury
Inhibition of liver fibrosis Test Method In test I described above, rats were sacrificed on Friday, the 12th week, the liver hypertrophy was observed to determine the effect of leucovorin on hepatic fibrosis, and the liver hydroxyproline content was measured. The evaluation of the state of enlargement of the liver was performed based on the ratio of liver weight / body weight. In addition, 8 during the test period
On Wednesday of the week, blood was collected from the test rats in each group, and the plasma prolyl hydroxylase concentration, which is an indicator in the blood of liver fibrosis, was measured.

2. Results The liver hypertrophy state is shown in FIG. As is clear from the results in the figure, in the group to which only carbon tetrachloride was administered (control group), as compared to the untreated group to which carbon tetrachloride was not administered and the group to which olive oil was administered, chronic liver injury was caused. Liver hypertrophy was markedly observed. However,
It was found that when l-leucovorin was concurrently administered with carbon tetrachloride, liver hypertrophy was reduced as compared with the control group.

FIG. 4 shows the hydroxyproline content in the liver. From the results in the figure, the liver hydroxyproline content, which is an index of liver fibrosis, shows a higher value in the group administered with carbon tetrachloride alone than in the untreated group and the olive oil administration group, and the liver fibrosis due to chronic liver injury Was suggested,
The simultaneous administration of l-leucovorin reduced the hydroxyproline content in the liver, suggesting suppression of liver fibrosis.

FIG. 5 shows the concentrations of prolyl hydroxylase in plasma. From the results in the figure, the administration of l-leucovorin showed a decrease in plasma prolyl hydroxylase concentration, which is an indicator of liver fibrosis, with collagen synthase,
It was confirmed that 1-leucovorin inhibited the progression of liver fibrosis based on the inhibitory action of collagen synthase induction. From the above results, it was shown that l-leucovorin, which is an active ingredient of the present invention, significantly reduced hepatic fibrosis and was effective as a hepatic disorder improving agent.

[Safety] It is already known that leucovorin is a sufficiently safe drug when used as a medicine. Specifically, L for mouse
In the D ₅₀ value, 5,000 mg / kg in oral administration
That is, 500 to 800 mg / kg for intravenous administration.
It is.

[Formulation Example] Tablet Composition: 1-leucovorin 5 g lactose 120 g microcrystalline cellulose 25 g corn starch 25 g 5% hydroxypropylmethylcellulose aqueous solution 100 ml magnesium stearate 5 g The above ingredients are kneaded, granulated, dried and compressed into tablets by a conventional method. Then, a tablet weighing 180 mg containing 5 mg of l-leucovorin in one tablet was prepared.

Injection One vial is filled with 12.5 mg of l-leucovorin as a powder. At the time of use, about 3 to 4 ml of distilled water for injection is added and dissolved to prepare an injection.

[0031]

As described in detail above, leucovorin, which is an active ingredient of the present invention, contains plasma GOT and G, which are liver function values.
Improves PT value and suppresses liver fibrosis. Therefore, it is effective as a therapeutic agent for liver damage such as acute / chronic hepatitis, cirrhosis, and fatty liver caused by viral infection, alcohol, drugs, autoimmune diseases and the like. Judging from that point, the therapeutic agent of the present invention is extremely useful clinically as a therapeutic agent for hepatic disorders that improves liver function values and suppresses hepatic fibrosis, as well as a therapeutic agent that also reduces jaundice symptoms. And its safety is high, and its medical utility is remarkable.

[Brief description of the drawings]

FIG. 1. GOT (A in plasma) described in [Pharmacological test I]
3 is a graph showing the effect of l-leucovorin on the variation of ST).

FIG. 2 shows GPT (A) in plasma described in [Pharmacological Test I].
3 is a graph showing the effect of 1-leucovorin on the change in LT).

FIG. 3 is a diagram showing the effect of l-leucovorin on the state of liver hypertrophy associated with chronic liver injury, as described in [Pharmacological test II].

FIG. 4 is a diagram showing the content of hydroxyproline in the liver described in [Pharmacological Test II].

FIG. 5 is a diagram showing the concentration of prolyl hydroxylase in plasma described in [Pharmacological Test II].

Claims (5)

[Claims] 1. A therapeutic agent for hepatic disorder containing leucovorin or a pharmacologically acceptable salt thereof as an active ingredient. 2. The therapeutic agent for liver damage according to claim 1, which is based on the action of leucovorin for improving the liver function value. 3. The therapeutic agent for hepatic disorder according to claim 1, which is based on the inhibitory action of leucovorin on hepatic fibrosis. 4. A liver function improving agent containing leucovorin or a pharmacologically acceptable salt thereof as an active ingredient. 5. A hepatic fibrosis inhibitor comprising leucovorin or a pharmacologically acceptable salt thereof as an active ingredient.