JP2006321765A - Preventive and therapeutic agent for rejection symptom in liver transplantation and therapeutic agent for liver dysfunction unpredicable of rejection symptom - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an effective agent low in side effect which agent is used in prevention and therapy of rejection symptom in liver transplantation or of liver dysfunction unpredicable of rejection symptom. <P>SOLUTION: The preventive and therapeutic agent for rejection symptom in liver transplantation and the therapeutic agent for liver dysfunction unpredicable of rejection comprises mizoribine as an active ingredient. Further, the agent comprising mizoribine as an active ingredient and characterized by used for decreasing or suspending steroid drugs and/or calcineurin inhibitors is provided. There is also provided a preventive and therapeutic agent comprising mizoribine and for rejection symptom and liver dysfunction caused by ABO incompatible liver transplantation. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

  The present invention relates to an effective medicament with few side effects in the prevention or treatment of rejection in liver transplantation or the treatment of abnormal liver function that cannot be determined as rejection. Specifically, the present invention relates to a preventive or therapeutic agent for rejection in liver transplantation containing mizoribine as an active ingredient, or a therapeutic agent for abnormal liver function that cannot be determined as rejection. Furthermore, the present invention relates to a drug containing mizoribine as an active ingredient characterized by being used in combination with a calcineurin inhibitor and / or a steroid agent, and in particular, for the purpose of reducing or suspending the steroid agent and / or reducing the calcineurin inhibitor. The present invention relates to a medicine containing mizoribine as an active ingredient. In another aspect, the present invention relates to a medicament containing mizoribine as an active ingredient, which is used for the prevention or treatment of rejection or abnormal liver function in ABO blood group incompatible liver transplantation.

  Organ transplantation is a treatment used for diseases that cannot be dealt with by other medical or surgical therapies. Liver transplantation includes living liver transplantation and brain death liver transplantation. In Japan, the brain death organ transplantation method was enacted in June 1999 and was enforced in October. However, living donor liver transplantation is frequently performed due to an absolute shortage of donors. Liver transplantation is an acute or chronic process that leads to liver failure, a congenital disorder in the liver, a lack of substances essential for life support, or an increase in harmful substances. Applicable in cases where a loss occurs.

  One of the major problems in transplanted patients is rejection, and several immunosuppressive drugs are used to suppress their occurrence. There are two main types of rejection: acute rejection and chronic rejection. The frequency of acute rejection is very high at 40 to 60%, and the most common occurrence is from 2 to 3 weeks to 2 months after the operation, and most often occurs within one year. There are many non-specific clinical symptoms such as fever and malaise. Laboratory findings indicate liver dysfunction such as elevated transaminase and elevated bilirubin. Chronic rejection, on the other hand, occurs in patients with repeated acute rejection or after a long period of time without any liver function abnormalities, clinically prolonged or progressive jaundice, and hepatic failure at the end . In kidney transplantation, there is a treatment called dialysis, so loss of function of the transplanted organ due to rejection does not immediately lead to the death of the patient, but in liver transplantation, if the transplanted organ loses its function, other than re-transplantation There is no way to save the patient. In Japan, there are very few chances of re-transplantation due to lack of brain-dead donors and fewer donor candidates in living liver transplantation, so strict control over rejection and the like is required more than renal transplantation.

  Immunosuppressants are always used in the context of side effects, and must be administered within a narrow therapeutic window to prevent side effects, rejection, and excessive immunosuppression. . In the case of liver transplantation, a combination of a calcineurin inhibitor and a steroid is generally used, but azathioprine or mycophenolate mofetil may be used in combination.

  4-carbamoyl-1-β-D-ribofuranosyl-imidazolium-5-oleate (hereinafter referred to as mizoribine) was discovered from the culture solution of Eupenicillium brefeldinum M-2166 strain (FERMP-1104) belonging to the genus Eupenicillium It is a weakly acidic substance that dissolves easily in water and decomposes by brown foaming at around 200 ° C., and its production method includes various methods such as fermentation and chemical synthesis using the above strains Are known (Non-patent Document 1, Patent Document 1, Patent Document 2, Patent Document 3, Patent Document 4, and the like).

Mizoribine is an already commercially available immunosuppressive agent, which has been found useful for suppressing rejection in, for example, kidney transplantation, and is usually equivalent to 2 to 3 mg of mizoribine as an initial amount per kg of body weight, and 1 to 3 as a maintenance amount. An anhydrous crystal is used as a bledinin (registered trademark name: manufactured by Asahi Kasei Co., Ltd.) tablet that is orally administered in an amount equivalent to 2 mg per day.
JP-A-48-56894 JP-A-50-121275 JP-A-50-121276 Japanese Patent Laid-Open No. 51-1693 Lai et al., Symposium to the 9th Biennlal Scientific Meeting Asian Pacific Association for the Study of the Liver (1994).

  An object of the present invention is to provide an effective medicine with few side effects in the prevention or treatment of rejection in liver transplantation or in the treatment of abnormal liver function that cannot be determined as rejection.

In order to solve the above-mentioned problems, the present inventor has found that immunosuppressive agents in liver transplantation are difficult to use drugs that are stronger in liver damage than those in other organ transplants, and that have a high frequency of occurrence of liver damage. We paid attention to the need for careful administration of drugs activated or inactivated in the liver due to large changes in liver function during the onset or rejection.
Prevention or treatment of rejection associated with liver transplantation, or treatment of liver dysfunction that cannot be determined to be rejection usually involves administration of a steroid agent alone, a calcineurin inhibitor alone, or a combination of a steroid agent and a calcineurin inhibitor. .
Steroids have many side effects, and the main ones are cataracts, diabetes, femoral head necrosis, psychiatric symptoms, full moon-like facial appearance, peptic ulcers, and growth disorders in children.
On the other hand, calcineurin inhibitors generally have nephrotoxicity. Furthermore, as side effects other than nephrotoxicity in tacrolimus, tremor, consciousness disorder, headache, insomnia, hyperglycemia, increased serum potassium level, diarrhea, hair loss, etc. have been reported, and in cyclosporine as side effects other than nephrotoxicity, Side effects such as hepatotoxicity, pancreatic toxicity, hypertension, hirsutism, and gingival swelling have been reported.
In contrast, mizoribine has been used in combination with multiple drugs such as corticosteroids, immunosuppressants, and anti-rheumatic agents in clinical practice, but there have been no reports of interactions so far. The incidence of side effects in the follow-up survey was low at 14.65% (719/4909 cases), mainly consisting of 4.95% (243 cases) of digestive system disorders such as abdominal pain and loss of appetite, leukopenia, etc. Blood system disorders 2.46% (121 cases), hypersensitivity such as rash 2.42% (119 cases), of which anemia is 0.63% (31 cases) (Bredinin tablets: Product information summary, Asahi Kasei) Corporation (created in December 2001)). In addition, there is a report of mizoribine administration equivalent to 500 mg or more per day in renal transplant patients (Today's transplant, 14, (6), 832 (2001), Therapeutic Research, 23, (5), 969 (2002)). However, the incidence of side effects such as anemia was almost the same as the approved dose (1 to 3 mg / kg).

In order to solve the above-mentioned problems, the present inventor has conducted extensive studies on mizoribine having low toxicity as described above, and as a result, found that mizoribine has particularly low hepatotoxicity, and further, the mizoribine and calcineurin inhibitor and / or Alternatively, the inventors have found that prevention or treatment using a steroid agent can be adapted to the purpose, and have made the present invention based on this finding.
That is, the present invention
(1) It contains mizoribine or a pharmaceutically acceptable salt thereof as an active ingredient, and the daily dose of the active ingredient is 0.5 mg / kg to 30 mg / kg, for liver transplantation, Preventive or therapeutic drugs associated with rejection, or drugs for abnormal liver function that cannot be determined as rejection;
(2) The preventive or therapeutic agent according to (1) above, which further comprises a calcineurin inhibitor as an active ingredient;
(3) The preventive or therapeutic agent according to (1) above, which further comprises a steroid as an active ingredient;
(4) The preventive or therapeutic agent according to (1) above, which further comprises a calcineurin inhibitor and a steroid as an active ingredient;
(5) The above-mentioned (1) to (4), characterized by being used for the prevention or treatment of abnormal liver function that cannot be determined as acute rejection or chronic rejection or rejection that occurs with liver transplantation and has a chronic course A preventive or therapeutic agent according to any one of
(6) The prophylactic or therapeutic agent according to any one of (1) to (5) above, which is used for the prevention or treatment of rejection or abnormal liver function in ABO blood type incompatible liver transplantation;
(7) To prevent or treat mizoribine or a pharmaceutically acceptable salt thereof as an active ingredient in the prevention or treatment of rejection or liver dysfunction caused by liver transplantation for the purpose of reducing or discontinuing steroids and / or reducing calcineurin inhibitors Or a prophylactic or therapeutic agent according to any one of (2) to (6) above,
(8) The prophylactic or therapeutic agent according to (7) above, wherein mizoribine or a pharmaceutically acceptable salt thereof is used in combination as an active ingredient for the purpose of reducing or discontinuing steroids;
(9) The prophylactic or therapeutic agent according to (7) above, wherein mizoribine or a pharmaceutically acceptable salt thereof is used in combination as an active ingredient for the purpose of reducing calcineurin inhibitor;
(10) The preventive or therapeutic agent according to (6), which is used in combination as a post-treatment after cyclophosphamide treatment in the prevention or treatment of rejection or abnormal liver function in ABO blood type incompatible liver transplantation;
(11) The preventive or therapeutic agent according to any one of (1) to (10) above, which is used for a patient who has developed renal disorder and / or neurological symptoms after liver transplantation;
(12) The preventive or therapeutic agent according to any one of (1) to (10) above, wherein the liver transplantation is liver transplantation for a patient with diabetes.
(13) A preventive or therapeutic agent for intractable acute rejection associated with liver transplantation, characterized by using mizoribine in combination with a steroid and / or calcineurin inhibitor;
(14) A preventive or therapeutic agent for humoral rejection in an ABO blood group-incompatible transplant, characterized by using mizoribine in combination with a steroid and / or calcineurin inhibitor;
(15) A method for preventing or treating rejection associated with liver transplantation, or a method for treating abnormal liver function that cannot be determined as rejection, characterized by using mizoribine in combination with a steroid and / or calcineurin inhibitor;
(16) Prevention or treatment of intractable acute rejection associated with liver transplantation, or prevention of humoral rejection in ABO blood type incompatible transplantation, characterized by using mizoribine in combination with a steroid and / or calcineurin inhibitor Or treatment method;
(17) Mizoribine or a pharmaceutically acceptable salt thereof as an active ingredient is administered at a dose of 0.5 mg / kg to 30 mg / kg per day, or a method for preventing or treating rejection associated with liver transplantation, or Treatment of abnormal liver function that cannot be determined as rejection;
About.

  The pharmaceutical comprising mizoribine of the present invention as an active ingredient provides effective treatment and prevention with few side effects in the prevention or treatment of rejection associated with liver transplantation, or in the treatment of abnormal liver function that cannot be determined as rejection. Can do. It is particularly useful when administered in combination with a calcineurin inhibitor and / or a steroid. Compared with calcineurin inhibitor alone administration or calcineurin inhibitor and steroid agent combination administration, side effects can be reduced, and further, steroid agent can be reduced or discontinued and / or calcineurin inhibitor can be reduced.

Hereinafter, the present invention will be specifically described.
The chemical name of mizoribine that can be used in the present invention is 4-carbamoyl-1-β-D-ribofuranosyl-imidazolium-5-oleate. Mizoribine is a nucleic acid-related substance found in the culture solution of Eupenicillium brefeldinum M-2166 (FERMP-1104) belonging to the genus Eupenicillium. It is easily soluble in water and weakly decomposes into brown foam at around 200 ° C. Various methods such as fermentation methods and chemical synthesis methods using the above-mentioned strains are known as production methods of acidic substances (JP-A 48-56894, JP-A 50-121275). (See, for example, Japanese Patent Laid-Open No. 50-121276, Japanese Patent Laid-Open No. 51-1693, or Lai et al .: Symposium to the 9th Biennlal Scientific Meeting Asian Pacific Association for the Study of the Liver (1994)).

  Mizoribine is an immunosuppressant already on the market, and has been found to be useful for suppressing rejection reactions in, for example, kidney transplantation. Usually, 1 kg of mizoribine is equivalent to 2 mg of mizoribine as an initial amount per kg of body weight, and 1 to An anhydrous crystal is used as a bledinin (registered trademark name: manufactured by Asahi Kasei Co., Ltd.) tablet that is orally administered in an amount equivalent to 2 mg per day.

  The “calcineurin inhibitor” referred to in the present specification may be any drug that inhibits calcineurin, and preferred examples include tacrolimus (FK506) or a pharmaceutically acceptable salt thereof as an active ingredient. Examples of the preparation include a preparation containing cyclosporine or a pharmaceutically acceptable salt thereof as an active ingredient. As typical examples of these, the former includes, for example, Prograf available from Fujisawa Pharmaceutical Co., Ltd., and the latter includes, for example, Sandy Mune or Neoral available from Novartis Pharma Co., Ltd. A drug containing an equivalent active ingredient is also a suitable example.

  In addition, as the “steroid agent” in the present specification, any steroidal drug may be used. However, as a preferable example, a preparation containing prednisolone or methylprednisolone as an active ingredient, or those pharmaceutically acceptable. And the like, and the like. Typical examples thereof include predonin tablets available from Shionogi Pharmaceutical Co., Ltd., medrol tablets available from Nippon Upjohn Co., Ltd., or drugs containing an active ingredient clearly equivalent to these.

  There are two types of rejection associated with liver transplantation: acute rejection and chronic rejection. The frequency of acute rejection is very high at 40 to 60%, and the most common occurrence is between 2 and 3 weeks to 2 months after surgery, and most often occurs within 1 year. There are many non-specific clinical symptoms such as fever and fatigue. Laboratory findings include elevated transaminase (aspartate aminotransferase (AST), alanine aminotransferase (ALT), etc.), increased bilirubin (total bilirubin, indirect bilirubin, direct bilirubin), and γ-glutamyltranspeptidase (γ-GTP). Liver dysfunction is observed. Among these, test values of AST, ALT, total bilirubin, and γ-GTP are particularly important. Among acute rejections, refractory acute rejection is mentioned as a particularly poor therapeutic outcome.

  On the other hand, there are cases of chronic rejection that repeat acute rejection and those that do not have liver function abnormalities for a long time and occur without notice, clinically prolonged or progressive jaundice, and liver failure at the end come. Laboratory findings include elevated transaminases (AST, ALT, etc.), elevated bilirubin (total bilirubin, indirect bilirubin, direct bilirubin) and liver dysfunction such as γ-GTP. Among these, test values of AST, ALT, total bilirubin, and γ-GTP are particularly important. Among chronic rejections, intractable chronic rejection is mentioned as a particularly poor therapeutic outcome.

  In addition, liver function abnormalities that cannot be determined as rejection associated with liver transplantation cannot be identified as rejection because biopsy has not been performed. However, laboratory findings indicate an increase in transaminase (AST, ALT, etc.), bilirubin (total bilirubin) Indirect bilirubin, direct bilirubin) and liver dysfunction such as γ-GTP are observed. Of these, test values for AST, ALT, total bilirubin, and γ-GTP are particularly important.

Rejection associated with liver transplantation, or liver function abnormality that cannot be determined as rejection, for example,
(1) Acute rejection or chronic rejection that occurs following liver transplantation (2) Intractable acute rejection associated with liver transplantation (3) Intractable chronic rejection associated with liver transplantation (4) For liver transplantation Hepatic function abnormalities that cannot be determined as a rejection that follows a chronic course (5) Rejection in ABO blood type incompatible liver transplantation (6) Liquid rejection in ABO blood type incompatible liver transplantation (7) ABO blood type incompatible liver Cellular rejection in transplantation (8) Abnormal liver function that cannot be determined as rejection in ABO blood group incompatible liver transplantation.

  Since the rejection in the ABO blood group incompatible liver transplantation of (5) to (8) has a risk of falling into a fatal transplant liver dysfunction in the short term or in the long term due to rejection, more strict management is required. Necessary.

  The effectiveness of the prophylactic or therapeutic agent of the present invention in such patients can be determined, for example, by the improvement in the test values of AST, ALT, total bilirubin, and γ-GTP. For example, a case where one or more of these four items are improved is determined to be effective, a case where two or more items are improved is determined to be more effective, and a case where three or more items are improved further It can be determined that it is effective and a case in which all four items are improved is particularly effective.

  The preventive or therapeutic agent for rejection associated with liver transplantation according to the present invention, or the therapeutic agent for abnormal liver function that cannot be determined to be a rejection, prevents or treats rejection associated with liver transplantation, or an abnormal liver function that cannot be determined to be a rejection. (1) Prevention or treatment of acute rejection or chronic rejection that occurs with liver transplantation and follows a chronic course, (2) Prevention or treatment of intractable acute rejection associated with liver transplantation, ( 4) Treatment of liver dysfunction that cannot be determined as rejection following the chronic course of liver transplantation, (5) Prevention or treatment of rejection in ABO blood type incompatible liver transplantation, (6) ABO blood type incompatible liver transplantation (8) It is effective in the treatment of abnormal liver function that cannot be determined as rejection in ABO blood group incompatible liver transplantation. Refractory acute rejection prevention or treatment due to planting, a feature to act effectively in the prevention or treatment of humoral rejection in (6) ABO blood type incompatibility liver transplantation.

  In practicing the present invention, a patient having the above signs or symptoms, mizoribine alone or mizoribine and a calcineurin inhibitor and / or steroid agent in an amount sufficient to eliminate or reduce the signs or symptoms. To administer.

  In the preventive or therapeutic agent for rejection associated with liver transplantation of the present invention or a therapeutic agent for abnormal liver function that cannot be determined as rejection, the daily dose of mizoribine or a pharmaceutically acceptable salt thereof as an active ingredient The lower limit is preferably 0.5 mg / kg or more, more preferably 0.9 mg / kg or more, further preferably 1 mg / kg, particularly preferably 1.1 mg / kg or more, and particularly preferably 1.4 mg / kg or more. Particularly, 1.5 mg / kg or more is more preferable, 2 mg / kg or more is very preferable, and 3 mg / kg or more is most preferable. Further, the upper limit is preferably 30 mg / kg or less, more preferably 20 mg / kg or less, still more preferably 12 mg / kg, particularly preferably 10 mg / kg, particularly preferably 9 mg / kg or less, particularly 8.5 mg / kg. The following is more preferable, 6 mg / kg or less is very preferable, particularly 3.6 mg / kg or less is very preferable, and 3.5 mg / kg is most preferable, and it may be divided into 1 to 3 times a day.

The dosage form of mizoribine includes a preparation for oral administration or a preparation for parenteral administration, and a preparation for oral administration is preferred. For example, mizoribine in an amount of 250 mg is administered to a patient adult weighing 50-60 kg twice a day using a 25 mg or 50 mg tablet for oral administration of mizoribine. The number of doses of mizoribine per day can be adjusted as appropriate, but the preferred number of doses is no more than 3 times a day, more preferably no more than 2 times a day, and most preferably once a day.
Mizoribine is easy to use as an orally-administered preparation (registered trademark name: bledinin tablet), and can be appropriately made into an orally-administered preparation such as a capsule or granule by a conventional method. Specifically, preparations for oral administration include, for example, anhydrous lactose, crystalline cellulose, dextran, and starch as excipients, sodium carboxymethylcellulose, methylcellulose, and ethylcellulose as binders, and carboxymethylcellulose, calcium carbonate, and methylcellulose as disintegrants. As a lubricant, stearic acid, magnesium stearate, talc and the like can be appropriately selected and combined, and can be made into an orally administered preparation such as a tablet or a capsule by a conventional method.

As a preparation for parenteral administration, it can be formulated as a suppository, a preparation by aerosol inhalation, a transdermal absorbable preparation or an injection by a conventional formulation technique.
Specifically, aerosol solutions and injections can be produced by dissolving mizoribine in an aqueous solvent. For example, the concentration of mizoribine in the liquid preparation is adjusted to 0.1 to 10 w / v%, preferably about 1 to 10 w / v% with respect to the aqueous solvent. What is necessary is just to process and make a formulation. Examples of the aqueous solvent include distilled water for injection and sterilized purified water. Furthermore, additives that are appropriately selected and used as usual liquid agents, for example, pH adjusting buffers (for example, phosphate buffer, borate buffer, citrate buffer, tartrate buffer, acetate buffer, etc.), Isotonic agents (eg, sorbitol, glycerin, polyethylene glycol, propylene glycol, glucose, sodium chloride, etc.), stabilizers (eg, sulfites, bisulfites, metabisulfites, etc.), antiseptic fungicides (eg, Benzalkonium chloride, paraoxybenzoates, benzyl alcohol, parachloromethaxinol, chlorcresol, phenethyl alcohol, sorbic acid or salts thereof, thimerosal, chlorobutanol, etc.), chelating agents (eg, sodium edetate, citric acid) Sodium, condensed sodium phosphate, etc.), thickeners (eg, poly Nirupiroridon, methylcellulose, sodium carboxymethylcellulose, hydroxypropylcellulose, polyvinyl alcohol, sodium polyacrylate, etc.) and the like can be added to and blended in the usual amount to be employed.

In the present invention, a preventive or therapeutic agent for rejection associated with liver transplantation characterized by using a steroid agent in combination, or a therapeutic agent for abnormal liver function that cannot be determined as rejection, the steroid agent is once a week, three times a week. The dose can be administered every other day or every day, and the dose is preferably 1 mg / kg / day or less, and more preferably 0.3 mg / kg / day or less. In this case, a reduction in side effects of the steroid can be expected due to a decrease in administration dose or administration period. When the administration interval becomes long, the dosage of the steroid can be adjusted within the preferred range as appropriate. Common side effects of steroids are mainly cataracts, diabetes, femoral head necrosis, psychiatric symptoms, full moon-like facial appearance, gastrointestinal ulcers, and growth disorders in children.
The administration form of the steroid is administered orally, but can also be administered by other parenteral methods (for example, by nasal spray, transdermal, suppository, etc.).

  The amount of mizoribine used in combination with steroid administration is preferably, for example, 0.5 mg / kg or more as the lower limit of the daily dose of mizoribine as an active ingredient or a pharmaceutically acceptable salt thereof. 0.9 mg / kg or more is more preferable, 1 mg / kg is more preferable, 1.1 mg / kg or more is particularly preferable, particularly 1.4 mg / kg or more is more preferable, particularly 1.5 mg / kg or more is more preferable, 2 mg / kg or more is very preferable, and 3 mg / kg or more is most preferable. Further, the upper limit is preferably 30 mg / kg or less, more preferably 20 mg / kg or less, still more preferably 12 mg / kg, particularly preferably 10 mg / kg, particularly preferably 9 mg / kg or less, particularly 8.5 mg / kg. The following is more preferable, 6 mg / kg or less is very preferable, particularly 3.6 mg / kg or less is very preferable, and 3.5 mg / kg is most preferable, and it may be divided into 1 to 3 times a day.

  In addition, in the preventive or therapeutic agent for rejection associated with liver transplantation characterized by the combined use of the calcineurin inhibitor of the present invention, or a therapeutic agent for abnormal liver function that cannot be determined as rejection, the calcineurin inhibitor is basically used every day. In the case of tacrolimus, it is desirable that the blood concentration as a trough is 20 ng / ml or less. In the case of cyclosporine, the blood concentration as a trough is preferably 350 ng / ml or less. In addition to nephrotoxicity, side effects of calcineurin inhibitors have been reported such as hyperglycemia, elevated serum potassium, chest pain, tremor, etc. for tacrolimus, and hepatotoxicity, pancreatic toxicity, hypertension, hirsutism, etc. for cyclosporine.

  The administration form of the calcineurin inhibitor is orally administered, but can be administered by other parenteral methods (for example, injection, nasal spray, transdermal, suppository, etc.).

  The amount of mizoribine used in combination with calcineurin inhibitor administration is, for example, the lower limit of the daily dose of mizoribine as an active ingredient or a pharmaceutically acceptable salt thereof is 0.5 mg / kg or more. Preferably, 0.9 mg / kg or more is more preferable, 1 mg / kg is more preferable, 1.1 mg / kg or more is particularly preferable, 1.4 mg / kg or more is particularly preferable, and 1.5 mg / kg or more is particularly preferable. 2 mg / kg or more is very preferable, and 3 mg / kg or more is most preferable. Further, the upper limit is preferably 30 mg / kg or less, more preferably 20 mg / kg or less, still more preferably 12 mg / kg, particularly preferably 10 mg / kg, particularly preferably 9 mg / kg or less, particularly 8.5 mg / kg. The following is more preferable, 6 mg / kg or less is very preferable, particularly 3.6 mg / kg or less is very preferable, and 3.5 mg / kg is most preferable, and it may be divided into 1 to 3 times a day.

  In establishing appropriate doses and intervals between mizoribine and steroids and / or calcineurin inhibitors, they should be determined by controlled clinical trials. For example, steroids are administered once a week, It can be administered three times, every other day, or every day, and the dosage is preferably 1 mg / kg / day or less, more preferably 0.3 mg / kg / day or less. In addition, calcineurin inhibitors are basically administered every day, and in the case of tacrolimus, it is desirable that the blood concentration as a trough is 20 ng / ml or less. In the case of cyclosporine, the blood concentration as a trough is preferably 350 ng / ml or less.

  In the present invention, a preventive or therapeutic agent for rejection associated with liver transplantation characterized by using a calcineurin inhibitor and a steroid in combination, or a therapeutic agent for abnormal liver function that cannot be determined to be rejection, mizoribine as an active ingredient The lower limit of the daily dose of the pharmaceutically acceptable salt thereof is preferably 0.5 mg / kg or more, more preferably 0.9 mg / kg or more, further preferably 1 mg / kg, 1.1 mg / kg. The above is particularly preferable, particularly 1.4 mg / kg or more is more preferable, particularly 1.5 mg / kg or more is further preferable, 2 mg / kg or more is very preferable, and 3 mg / kg or more is most preferable. Further, the upper limit is preferably 30 mg / kg or less, more preferably 20 mg / kg or less, still more preferably 12 mg / kg, particularly preferably 10 mg / kg, particularly preferably 9 mg / kg or less, particularly 8.5 mg / kg. The following is more preferable, 6 mg / kg or less is very preferable, particularly 3.6 mg / kg or less is very preferable, and 3.5 mg / kg is most preferable, and it may be divided into 1 to 3 times a day.

  In addition, the usefulness and safety of the combination administration of mizoribine with a steroid and / or calcineurin inhibitor is described in “combination of mizoribine with a steroid and / or calcineurin inhibitor” vs. “mycophenolate mofetil with a steroid and / or `` Combination of calcineurin inhibitors '' or `` Combination of mizoribine with steroids and / or calcineurin inhibitors '' vs. `` Steroids and / or calcineurin inhibitors '' should be determined by controlled clinical trials, but reference examples From the data shown in 1 and 2 and the results of Examples 1 to 6, the usefulness of mizoribine as a preventive or therapeutic agent for rejection associated with liver transplantation, or a therapeutic agent for abnormal liver function that cannot be determined as rejection, and Safety is considered extremely excellent.

  In the treatment of liver function abnormalities that cannot be determined as rejection or rejection associated with liver transplantation by using mizoribine in the present invention in combination with a steroid and / or calcineurin inhibitor, mizoribine and a steroid and / or In addition to administering the calcineurin inhibitor in separate preparations, there may be a method of administering it at once as a combination drug.

  From these, prevention or treatment of rejection associated with liver transplantation, or treatment of liver dysfunction that cannot be determined as rejection, mizoribine administration, or combination administration of mizoribine and calcineurin inhibitor and / or steroid agent, It can be expected to reduce side effects such as hyperglycemia and diabetes that can be seen by the combined administration of calcineurin inhibitors and steroids. Therefore, for patients who have developed renal disorder after liver transplantation or liver transplanters who have diabetes, the rejection inhibitor associated with liver transplantation of the present invention or a preventive or therapeutic agent for liver function abnormalities that cannot be identified as rejection Is particularly useful.

  The present invention is also useful for the treatment of rejection associated with liver transplantation that is not improved by the combined administration of a calcineurin inhibitor and a steroid, or for treatment of abnormal liver function that cannot be determined as rejection.

Next, examples of the preventive or therapeutic agent for rejection associated with liver transplantation of the present invention, or a therapeutic agent for abnormal liver function that cannot be determined as rejection will be described. The present invention is not limited to the following examples, but the effects of the present invention are sufficiently described by the following examples.
[Reference Example 1] Examination of inhibitory action on hepatic drug-metabolizing enzymes
Using human pooled microsomes obtained from the HAB Council, the effects of mizoribine on human liver CYP activity shown below were examined in vitro, and the possibility of drug interaction was examined. 7-Ethoxyresorufin deethylation activity (CYP1A1 / 2 activity), Bufuralol 1'-OH activity (CYP2D6 activity), Tolbutamide metabolic activity (CYP2C9 activity), S-Mephenytoin metabolic activity (CYP2C19 activity), Chlorzoxazone metabolic activity (CYP2E1 activity), Testosterone metabolic activity (CPY3A4 activity).
As a result, mizoribine showed no inhibitory action against any CYP studied (1A1 / 2, 2D6, 2C9, 2C19, 2E1, 3A4) (Ki;> 100 μM). Based on this, it is considered that this drug does not cause drug metabolism interaction involving CPY.

[Reference Example 2] Examination of hepatic drug-metabolizing enzyme induction effect Mizoribine was administered to rats for 10 consecutive days, and the effect on hepatic drug-metabolizing enzyme activity was examined using aminopyrine demethylase and aniline hydroxylase activities as an index. In both the 2.5 mg / kg administration group and the 5 mg / kg administration group, there was no significant change compared to the control group. Based on this, it is considered that this drug does not show liver drug metabolizing enzyme inducing action.

[Formulation Example 1]
Commercially available mizoribine 25 mg tablets or 50 mg tablets were used. For infants, this product was crushed and used.

[Example 1]
In 26 cases of acute rejection, mizoribine 0.9-6.0 mg / kg was administered for an average of 13 months per day, and the AST standard value before the start of mizoribine administration and six months later (2 times the normal value as the standard value) The transition of the number of cases within the standard value was judged to be effective) 7.69% was 61.54%, the standard value of total bilirubin (double the normal value as the standard value, The number of cases within the standard value was judged to be effective) (38.46% increased to 76.92%) (FIG. 1). Of these, 17 patients with refractory acute rejection who required multiple steroid pulse therapies showed a change in the number of cases within the AST standard value before the start of mizoribine administration and 6 months later. 9% increased to 64.7%, and the transition of the number of cases within the standard value of total bilirubin increased from 47.1% to 70.6% (FIG. 2). Mizoribine 1.5 to 3.5 mg / kg was administered daily for 15 months on average to 38 patients with abnormal liver function that cannot be determined to be a rejection, and the AST reference value before starting mizoribine, 6 months, and 12 months The number of cases within 21.1%, 63.2%, and 57.9%, and the number of cases within the total bilirubin reference value was 44.7%, 78.9%, and 84.2%. (FIG. 3). For the purpose of reducing tacrolimus, mizoribine 0.8-3.0 mg / kg was administered to 12 patients a day for an average of 9 months, and the mean blood trough level of tacrolimus before and 6 months after the start of mizoribine was 9.4 ng The patient's average serum creatinine level decreased from 1.31 mg / dl to 1.15 mg / dl, showing a tendency to improve renal function (FIG. 4). Mizoribine 1.1-3.6 mg / kg was administered on an average of 13 months per day for 9 patients for the purpose of steroid dose reduction or discontinuation, and 5 out of 6 cases within 3 months compared with before starting mizoribine administration I was able to stop steroids. In 3 cases, immunosuppressive therapy was started only with tacrolimus and mizoribine without using oral steroids after transplantation, and in 2 of these cases, immunosuppressive therapy could be continued without using steroids. . As post-therapy for cyclophosphamide in ABO blood group incompatible transplantation, mizoribine 1.4-8.5 mg / kg was administered daily for an average of 9 months to 8 patients, and AST criteria before and 6 months after the start of mizoribine administration The transition of the number of cases within the value increased from 25.0% to 50.0%, and the transition of the number of cases within the reference value of total bilirubin increased from 25.0% to 62.5% (FIG. 5). In FIGS. 1, 2 and 5, the ratio of cases within the reference values of AST and total bilirubin immediately before the start of mizoribine administration and 6 months after the start was expressed as a percentage. In FIG. 3, the ratio of cases within the standard values of AST and total bilirubin immediately before the start of mizoribine administration, 6 months after the start and 12 months after the start was expressed as a percentage. In FIG. 4, the right figure shows the trough value of tacrolimus immediately before the start of mizoribine administration and 6 months after the start, and the left figure shows the serum creatinine value immediately before the start of mizoribine administration and 6 months after the start.

[Example 2]
A female (44 years old) with primary sclerosing cholangitis was treated with ABO blood group-matched living donor liver transplantation using his brother as a donor. Although immunosuppressive therapy was performed with tacrolimus and prednisolone, liver function was not stable, and mizoribine 150 mg was used together from one year later. At the start of combination, AST 222IU / ml, ALT 486IU / ml, and γ-GTP 277IU / ml were all high, and total bilirubin was 0.8mg / dl, but after 9 months prednisolone was started to be used together The liver function was improved and stabilized with AST 20 IU / ml, ALT 17 IU / ml, γ-GTP 27 IU / ml, and total bilirubin 0.4 mg / dl.
From the above, it was found that mizoribine is effective as a therapeutic agent for abnormal liver function that cannot be determined as a rejection that occurs with liver transplantation and has a chronic course. Furthermore, a mizoribine-containing therapeutic agent, which is used in combination with a calcineurin inhibitor and a steroid agent, for treatment of liver dysfunction that is not stable even when immunosuppressive therapy with a combination of a calcineurin inhibitor and a steroid agent is performed. It was found that the therapeutic agent was very effective and that the therapeutic agent was effective in reducing the amount of steroid while controlling the liver function value. Specifically, for treatment of liver dysfunction that is not stable even when immunosuppressive therapy is performed with tacrolimus and prednisolone, a mizoribine-containing therapeutic agent characterized by being used in combination with tacrolimus and prednisolone is very effective, The therapeutic agent was found to be effective in reducing prednisolone while controlling liver function values.

[Example 3]
A male (51 years old) whose primary disease is fulminant hepatic failure due to hepatitis B was subjected to ABO blood group-matched living donor liver transplantation using his brother as a donor. Although immunosuppressive therapy was performed with tacrolimus and prednisolone, renal damage due to tacrolimus occurred 5 days after transplantation, so tacrolimus was reduced and 100 mg of mizoribine was additionally used. Steroids were discontinued after 4 months, and thereafter there was no abnormality in liver function, and the serum creatinine level was improved from 2.7 mg / dl to 1.8 mg / dl and stabilized.
From the above, it was found that mizoribine is effective as an agent for preventing or treating rejection associated with liver transplantation. Furthermore, when immunosuppressive therapy using a combination of a calcineurin inhibitor and a steroid is performed, a low-dose calcineurin inhibitor is used for the purpose of reducing the calcineurin inhibitor in patients with side effects caused by the calcineurin inhibitor, and It was found that a mizoribine-containing therapeutic agent characterized by being used in combination with a steroid agent is very effective, and that the therapeutic agent has an effect of stopping the steroid agent while controlling the blood biochemical value. Specifically, for the purpose of reducing tacrolimus, a mizoribine-containing therapeutic agent characterized by being used in combination with low-dose tacrolimus and prednisolone is very effective, and the therapeutic agent controls blood biochemical values. However, it was found that prednisolone can be stopped.

[Example 4]
A one-year-old girl with cholestasis due to biliary atresia was transplanted with an ABO blood type incompatible liver transplantation using her father as a donor. Immunosuppressive therapy was started with tacrolimus, prednisolone, and cyclophosphamide. A moderate acute rejection occurred 14 days after the transplantation, but it was recovered by a steroid pulse of methylprednisolone. Administration of mizoribine 2 mg / kg instead of cyclophosphamide was started 1 and a half months after the operation, and then liver function was stabilized, and tacrolimus and mizoribine alone showed no particular problems.
From the above, it has been found that mizoribine is effective as a preventive or therapeutic agent for rejection or abnormal liver function in ABO blood group incompatible liver transplantation. More specifically, a mizoribine-containing therapeutic agent characterized by being used in combination with a calcineurin inhibitor and a steroid after immunosuppressive therapy using a combination of a calcineurin inhibitor, a steroid and a cyclophosphamide is an ABO blood group It has been found that it is very effective for maintenance therapy after use of cyclophosphamide in incompatible transplantation, and that the therapeutic agent has an effect of stopping steroids while controlling liver function. Specifically, a mizoribine-containing therapeutic agent characterized by being used in combination with tacrolimus and prednisolone after performing immunosuppressive therapy with a combination of tacrolimus, prednisolone, and cyclophosphamide is a cyclophosphine in ABO blood group incompatible transplantation. It has been found that it is very effective for maintenance therapy after the use of famide and that the therapeutic agent has the effect of stopping prednisolone while controlling liver function.

[Example 5]
For a man (50 years old) whose liver disease due to hepatitis C is the primary disease, ABO blood group-matched living donor liver transplantation was performed using his wife as a donor. Since the primary disease was liver cancer caused by hepatitis C, postoperative immunosuppressive therapy was started with tacrolimus and steroid pulse, and the combination use of 100 mg of mizoribine was started on the 16th day after the operation without using oral steroids. At the start of the combination, tacrolimus caused kidney damage and neurological symptoms. However, tacrolimus was not reduced, both symptoms improved, no particular problems occurred, and liver function remained stable.
From the above, it was found that mizoribine is effective as an agent for preventing or treating rejection associated with liver transplantation. Furthermore, in patients who do not receive oral steroid therapy, a mizoribine-containing therapeutic agent, which is characterized by being used in combination with a calcineurin inhibitor, is effective. In this case, if a side effect caused by the calcineurin inhibitor occurs, the calcineurin inhibitor I found it possible to lose weight. Specifically, in patients who do not receive oral steroid therapy, a mizoribine-containing therapeutic agent characterized by being used in combination with tacrolimus is effective, and if side effects are caused by tacrolimus, tacrolimus may be reduced. I found it possible.

[Example 6]
A female (34 years old) with autoimmune liver disease as the primary disease was transplanted with an ABO blood group-matched living liver transplant using the father as a donor. Immunosuppressive therapy was started after transplantation with tacrolimus and prednisolone, but acute rejection occurred 3 months later and recovered with a steroid pulse of methylprednisolone. Nine months after the operation, prednisolone 5 mg was reduced to 2.5 mg and combined use of mizoribine 100 mg was started for the purpose of steroid weight reduction for long-term use of steroids. Liver function remained stable, prednisolone was discontinued after half a month, and remained unchanged after that.
From the above, it was found that mizoribine is effective as a preventive or therapeutic agent for rejection associated with liver transplantation. Furthermore, mizoribine treatment administered for the purpose of reducing the dose of steroid and discontinuing it in patients who have been combined with calcineurin inhibitors and steroids for a long time after liver transplantation is effective. I understand. Specifically, it was found that mizoribine treatment administered for the purpose of reducing or even stopping prednisolone is effective in patients who have been combined with tacrolimus and prednisolone for a long time after liver transplantation. .

  The present invention has few side effects and is effective for prevention or treatment of rejection in liver transplantation or treatment of abnormal liver function that cannot be determined as rejection, and is suitable for pharmaceutical use.

It is a figure which shows the effect of mizoribine with respect to the acute rejection reaction of Example 1. It is a figure which shows the effect of mizoribine with respect to the intractable acute rejection reaction of Example 1. It is a figure which shows the effect of mizoribine with respect to the liver function abnormality which cannot be determined with the rejection reaction of Example 1. It is a figure which shows the recovery | restoration of the renal function by the mizoribine administration in the patient with a renal disorder of Example 1, and the trough (trough) value of the calcineurin inhibitor before the start of mizoribine administration and 6 months after the start. It is a figure which shows the effect of the mizoribine with respect to the ABO blood group mismatched transplant of Example 1.

Claims (17)

  Rejection associated with liver transplantation, comprising mizoribine or a pharmaceutically acceptable salt thereof as an active ingredient, and the daily dose of the active ingredient is 0.5 mg / kg to 30 mg / kg Prophylactic or therapeutic drugs, or therapeutic drugs for abnormal liver function that cannot be determined as rejection.   The prophylactic or therapeutic agent according to claim 1, wherein a calcineurin inhibitor is further used in combination as an active ingredient.   The prophylactic or therapeutic agent according to claim 1, further comprising a steroid agent in combination as an active ingredient.   The prophylactic or therapeutic agent according to claim 1, wherein a calcineurin inhibitor and a steroid agent are used in combination as active ingredients.   The acute rejection that accompanies liver transplantation, or the chronic rejection or rejection, which is used for the prevention or treatment of abnormal liver function, which cannot be determined as the rejection, according to any one of claims 1 to 4 The preventive or therapeutic agent described.   The preventive or therapeutic agent according to any one of claims 1 to 5, which is used for the prevention or treatment of rejection or abnormal liver function in ABO blood group incompatible liver transplantation.   Mizoribine or a pharmaceutically acceptable salt thereof as an active ingredient is used in combination with the purpose of reducing or stopping steroids and / or reducing calcineurin inhibitors in the prevention or treatment of rejection or liver dysfunction caused by liver transplantation. The preventive or therapeutic agent according to any one of claims 2 to 6.   The prophylactic or therapeutic agent according to claim 7, wherein mizoribine or a pharmaceutically acceptable salt thereof is used in combination as an active ingredient for the purpose of reducing or suspending the steroid agent.   The prophylactic or therapeutic agent according to claim 7, wherein mizoribine or a pharmaceutically acceptable salt thereof is used in combination as an active ingredient for the purpose of reducing the amount of calcineurin inhibitor.   The preventive or therapeutic agent according to claim 6, which is used in combination as post-treatment after cyclophosphamide treatment in the prevention or treatment of rejection or liver function abnormality in ABO blood group-incompatible liver transplantation.   The prophylactic or therapeutic agent according to any one of claims 1 to 10, which is used for a patient who has developed renal disorder and / or neurological symptoms after liver transplantation.   The prophylactic or therapeutic agent according to any one of claims 1 to 10, wherein the liver transplantation is a liver transplantation for a patient with diabetes.   A prophylactic or therapeutic drug for intractable acute rejection associated with liver transplantation, characterized by using mizoribine in combination with a steroid and / or calcineurin inhibitor.   A preventive or therapeutic agent for humoral rejection in ABO blood group-incompatible transplants, characterized by using mizoribine in combination with a steroid and / or calcineurin inhibitor.   A method for preventing or treating rejection associated with liver transplantation, or a method for treating abnormal liver function that cannot be determined as rejection, characterized by using mizoribine in combination with a steroid and / or calcineurin inhibitor.   A method for preventing or treating intractable acute rejection associated with liver transplantation, or a method for preventing or treating humoral rejection in an ABO blood type incompatible transplant, characterized by using mizoribine in combination with a steroid and / or calcineurin inhibitor .   Mizoribine or a pharmaceutically acceptable salt thereof as an active ingredient is administered at a dose of 0.5 mg / kg to 30 mg / kg per day, or a method for preventing or treating rejection associated with liver transplantation, or rejection Is a treatment method for liver function abnormalities that cannot be determined.