WO2009084732A1

WO2009084732A1 - Agent for alleviating adverse side effects produced in interferon/ribavirin combination therapy

Info

Publication number: WO2009084732A1
Application number: PCT/JP2008/073969
Authority: WO
Inventors: Sumio Kawata
Original assignee: Nippon Chemiphar Co., Ltd.
Priority date: 2007-12-28
Filing date: 2008-12-26
Publication date: 2009-07-09
Also published as: TW200940075A

Abstract

An acidosis-ameliorating agent such as a preparation containing potassium citrate and sodium citrate (Uralyt-U, Uralyt Tablets (registered trade names)) is used as a prophylactic or therapeutic agent for anemia which is an adverse side effect produced in the interferon/ribavirin combination therapy. The interferon may be interferon α-2a, interferon α-2b, pegylated interferon α-2a, pegylated interferon α-2b, consensus interferon or purified interferon α.

Description

Side-effect reducing agent in interferon / ribabilin combination therapy

The present invention relates to an agent for reducing side effects in an interferon / ribavirin combination therapy comprising an alkenyl arsenic acid metal salt as an active ingredient. Light

Background art

The number of people infected with hepatitis C virus in Japan is currently estimated to be about 2 million.

Infection with hepatitis C virus causes acute hepatitis after a certain incubation period, but subjective symptoms are relatively poor, and it is easy to shift to chronic hepatitis.

Chronic hepatitis also has few subjective symptoms, and if left untreated, it can cause cirrhosis and even liver cancer.

The annual number of deaths from liver cancer is 30,000 to 35,000, of which about 80% are caused by hepatitis C virus.

Therefore, the country is currently striving for early detection of potential patients with chronic hepatitis C through screening, and it is important to treat hepatitis before cirrhosis or liver cancer.

As a treatment for chronic hepatitis C, maintenance therapy (liver protection therapy) and drugs with drugs such as darsitylittin and ursodeoxycholic acid, which are aimed at suppressing hepatitis and improving liver function Antiviral therapy using interferon for the purpose of this is known. As for the pile wi / res therapy, it is known that the interferon mouth is monotherapy and these are combined with ribavirin.

By the way, as the type of hepatitis C virus found in Japan, genotype lb type is the most common, followed by 2a and 2b types, and the rest. That's it. Interferon monotherapy is effective for the 2a and 2b types, but it is known that interferon monotherapy is not very effective for the lb type.

Another problem is that interferon monotherapy is not effective when the viral load increases.

For example, the effect or effect of Intron A Injection 300 (manufactured by Ceiling 'Blau) is described as follows.

Efficacy or effect

Improvement of viremia in chronic hepatitis C

(1) In the case of this drug alone

1) Patients whose blood HCV RN A level is not high

(2) When combined with revivin

1) Patients with high blood HCV RNA levels

2) Patients who are ineffective with monotherapy of interferon mouth products or patients who have relapsed after interferon mouth monotherapy

• Improvement of viral blood in chronic active hepatitis B positive for HB e antigen and DNA polymerase

• Renal cancer, chronic myelogenous leukemia, multiple myeloma Therefore, combination therapy with ribavirin is considered to be a more appropriate treatment method than interferon monotherapy, but in this ribavirin combination therapy, interferon alone is administered. In addition to side effects such as fever, malaise, depression, thyroid and other autoimmune diseases, and interstitial pneumonia, the incidence of anemia is high and has become a serious therapeutic problem.

In other words, when the hemoglobin concentration decreases, the ribavirin dose is reduced, or the administration of ribavirin is discontinued, and further, the interferon dose is reduced, withdrawn, or discontinued.

The complete cure rate and the effect of discontinuation of peginterferon and ribavirin combination therapy in patients with refractory treatment (HCV type 1) The rate has been reported to decrease to 50.8% in the weight-reduced case compared to 62.5%, and further to 19.2% in the discontinued case.

Therefore, it is extremely important that interferon and ribavirin combination therapy do not lead to weight loss or discontinuation. By the way, as a method of reducing anemia, which is a side effect in the combination therapy of interferon and ribavirin, the use of antioxidants (Patent Document 1: Special Table 2 0 0 2-54 2 2 0 2) and the use of icosapentate (ethyl pentylate) (EPA) (Patent Document 2: WO 2 0 04/0 7 3 7 0 6), Use of Ellis Mouth Poetin (EP 0) (Patent Document 3: Special Table 2 0 04— 5 0 5 1 1 4) Yes.

However, to date, there has been no report that these drugs have been used clinically as effective drugs for reducing the occurrence of anemia, which is a side effect of interferon and ribavirin combination therapy. In pyruvate kinase deficiency, an enzyme dysfunction, ATP production is reduced because pyruvate kinase, an enzyme that produces ATP in the glycolytic pathway, is inherently dysfunctional. It is known that potassium and water flow out of the cell and then turn into spiny erythrocytes by dehydration in erythrocytes, causing extravascular hemolysis in the spleen and leading to anemia.

It is also known that ribavirin consumes ATP due to phosphorylation in erythrocytes during (Peg) interferon / ribavirin combination therapy in chronic hepatitis C. It has been reported that erythrocytes fall into ene rg cy s i s and lyse in erythrocytes due to the death of ATP by rivapirin. (Non-patent literature l: De Franceschi Leta 1., Hepatology, 2 00 00 Ar, 3 1 (4), 9 97- 1 0 04, Non-patent document 2: 4th Japanese liver Abstract of the Annual Meeting of the Society Liver 4 7 卷 supp 1. (1), (2 0 0 6), A 2 1 4)

In addition, accumulation of ribavirin phosphorylated substance decreases the ATP concentration in the red blood cells, and the original disk-shaped red blood cells change into a spherical shape, thereby increasing the red blood cell fragility and dissolving the red blood cells. It has also been suggested to cause bloody anemia. (Non-patent Document 3: Liver, No. 40–1, 6-1 3 (2008)) Therefore, a drug that can suppress the decrease in ATP production is anemia, which is a side effect of ribavirin combination therapy. It is expected as a preventive or therapeutic agent. “Uralit I U (Registered Trademark)” and “Uralit Tablets (Registered Trademark)”, which are formulations containing potassium citrate and sodium citrate, are used to improve acid urine in gout and hyperuricemia, and It is widely known that it is useful for “improvement”. (Non-patent literature 4: Yasushi Ueda, clinical evaluation 9, 4 2 1 pages, 1 9 8 1 year, Non-patent literature 5 _: Teruo Kitagawa, Clinical pediatrics, 3 9, 2 2 5 7 pages, 1 9 86 years) However, to the best of the inventors' knowledge, no report has been made that a combined citrate-strength and sodium taenoate combination product is effective as a prophylactic or therapeutic agent for anemia. Therefore, in interferon / ribavirin combination therapy, there is a need to provide an effective drug that can reduce anemia, which is a frequently occurring side effect. Disclosure of the invention

The object of the present invention is to reduce the side effects seen during interferon and ribavirin combination therapy for chronic hepatitis C, thereby enabling drug treatment without reducing or discontinuing revivin and Z or interferon. It is to provide a side effect reducing agent (preventive and therapeutic agent). That is, the present invention relates to a preventive and therapeutic agent for anemia containing an acidosis improving agent as an active ingredient.

The present invention also relates to a preventive and therapeutic agent for side effects caused by administration of ribavirin containing an acidosis improving agent as an active ingredient.

The present invention also relates to a preventive and therapeutic agent for side effects caused by interferon / ribavirin combination therapy comprising an acidosis improving agent as an active ingredient. The present invention also relates to a pharmaceutical comprising an acidosis improving agent and revivin. Furthermore, the present invention relates to a pharmaceutical comprising interferon, an acidosis improving agent and ribavirin. BEST MODE FOR CARRYING OUT THE INVENTION

Next, the present invention will be described in detail.

As used herein, anemia refers to a state in which the number of red blood cells or the amount of hemoglobin in the blood has decreased below a normal value. According to the International Anemia Criteria (WHO), the amount of hemoglobin is 13.0 gZd L for adult boys and 1 2. O gZd L for girls.

Side effects that may be associated with ribavirin in combination therapy with ribavirin and interferon (hereinafter abbreviated as IFN) or peginterferon (PEGylated IFN) include, According to the package insert (manufactured by Co., Ltd.), serious side effects include anemia (red blood cell decrease, hemoglobin decrease), agranulocytosis, leukopenia, granulocytopenia, thrombocytopenia, aplastic anemia, depression, suicide Intention, stupor, hearing loss, consciousness disorder, convulsions, disorientation, delirium, hallucination, fainting, mania, delusion, confusion, aggressive behavior, schizophrenia-like symptoms, dementia-like symptoms, excitement, liver dysfunction , Shock, gastrointestinal bleeding, peptic ulcer, small intestine ulcer, ischemic colitis, dyspnea, increased hemorrhoids, cerebral hemorrhage, cerebral infarction, interstitial pneumonia, lung line Disease, pulmonary edema, diabetes mellitus, renal disorder, cardiomyopathy, heart failure, myocardial infarction, angina pectoris, arrhythmia, sepsis, retinopathy, autoimmune disease, hemolytic uremic syndrome, thrombotic thrombocytopenic purpura, skin mucosa Eye syndrome, rhabdomyolysis, and other side effects include systemic symptoms (fever, malaise, chills, flu-like symptoms), mental nervous system (headache, insomnia, abnormal sensation, partial discomfort, super-extremeness, etc. ), Blood (leukopenia, neutropenia, lymphocyte reduction, hemoglobin reduction, thrombocytopenia, erythrocyte reduction, hematocrit reduction, anemia, lymphocyte increase, neutrophil increase, erythrocyte increase, etc.), liver (AS T) GOT) Rise, ALT

(GPT) rise, γ—GTP rise, LDH rise, bilirubin rise, jaundice etc., kidney (tachyuremia, hematuria etc.), circulatory organ (tachycardia etc.), digestive system (anorexia etc.), skin (hair loss etc.) ), Nerve / muscle (joint pain, etc.), respiratory (cough, bronchospasm, etc.), eye (cornea / conjunctiva) Inflammation, eye itching, visual field stenosis, etc.) and administration site (injection site reaction). The side effects referred to herein include, but are not limited to, the above side effects, and other side effects that have been reported so far in combination therapy with revivin / (peg) interfernone. It is not a thing.

Among the above-mentioned side effects, the side effects to be the target of the preventive or therapeutic agent referred to in the present specification are preferably anemia (red blood cell decrease, hemoglobin decrease), white blood cell decrease, granulocyte decrease, thrombocytopenia, aplastic anemia. There are blood system side effects, but anemia is more preferable. As revivin preparations, Rebetol capsules (trade name, manufactured by Schering 'Blau Co., Ltd.) and Pico Pegas tablets (trade name, manufactured by Chugai Pharmaceutical Co., Ltd.) are commercially available. When using Rebetol capsules, the dosage should be 40 00 to 1600 mg, preferably 6 00 to 1 00 mg daily, divided into 2 doses daily, 24 Oral administration is performed weekly, after dinner in the morning, but the number of administrations per day and administration period may be changed as appropriate depending on the degree of symptoms, body weight, age, etc. In this specification, the interferon is not particularly limited as long as it is an interferon used for the treatment of viral hepatitis in chronic hepatitis C. Natural type IFN, IFN α-2a I FNa-2 b, PEGylated natural IF Ν α, PEGylated IFN a _ 2 a, PEGylated IFN CK — 2 b, natural IFN j3, PEGylated natural IFN j3, natural IFN γ, consensus IFN, PEGylated consensus

IFN, and combinations thereof, preferably natural IFN, IFNa-2b, PEGylated IFN α_2a, PEGylated IFN-2b, natural IFN0 More preferably PEGylated IFN 1 2 a, PEGylated

I F N a-2 b.

The (peg) interferon dosage, administration period, administration schedule, and administration route in this specification are not particularly limited as long as they are within the scope of treatment for the treatment of viremia in chronic hepatitis C. . For example, interferon alfa-2b (genetical recombination) is usually given intramuscularly 6 to 300,000 international units daily 6 or 3 times a week for adults. Peguinterferon 1 alpha 2b (Genetical Recombination) is usually given subcutaneously at 1.5 g / kg once a week for adults. Recently, in order to enhance the effect of the combination therapy of peginterferon + ribavirin, a combination of three drugs with NS 3 protease inhibitor (VX- 9 50, S CH 500 300) has been proposed.

However, in this case as well, side effects such as anemia caused by ribavirin are expected, and the preventive and therapeutic agents of the present invention can be used. Acidosis refers to an acid-base relationship in which the relationship between acid and base in the blood is in an acid-dominant state, but the acidose improving agent, which is an active ingredient of the preventive and therapeutic agent of the present invention, is set to a normal value. It refers to a drug having a reverting action, and examples thereof include alkali metal succinate, sodium hydrogen carbonate, and the like, and more preferably, a formulation containing sodium citrate's sodium citrate. Next, the results of clinical trials are shown.

As described in Example 1 result 5 (4) below, the difference between the amount of ATP in red blood cells at the start of administration and the amount of ATP at 4 weeks is the difference between the amount of hemoglobin at the start of administration and the amount of ATP at 4 weeks. It was confirmed that there was a positive correlation with the difference in the amount of hemoglobin. In addition, in result 5 (5), there was no significant difference in the amount of ATP in red blood cells at the start of administration between the group with or without the ULARIT tablet (registered trademark). As is clear from the results 1 and 2, the uralite tablet (registered trademark) combination group and the non-ularit tablet (registered trademark) non-combination group, which are anti-acidic cis-improving agents, are defined as ATP in erythrocytes at 4 weeks after administration. There was a significant difference between the two in terms of quantity. (Table 2 and Table 3)

Therefore, the combination of citrate-strength and sodium taenoate, which is an acidosis-improving agent, suppresses the decrease in the production of ATP in red blood cells, reducing the amount of hemoglobin, which is a side effect of ribavirin and interferon Suppresses the poor Expected to be a prophylactic or therapeutic agent for blood. In addition, as shown in the results 3 and 4 of Example 1 below, an acidosis improving agent combined with sodium citrate and sodium citrate was used in the ribavirin / pegylated interferon combination therapy for the non-combination group. It was confirmed that weight loss was significantly suppressed. (Tables 4 and 5) In the combination therapy of revivin and interferon, if the hemoglobin concentration decreases, the dose of revivin is decreased, the administration of revivin is discontinued, and further, the amount of interferon is decreased. 'Drug withdrawal' will be discontinued.

For example, in the case of Levetol Capsenore (manufactured by Schering-Blur Co., Ltd.), if the hemoglobin concentration is less than 10 g Z d L, the amount of ribavirin is reduced, and if less than 8.5 g / d L, Discontinuation of administration.

About the complete cure rate and the effect of discontinuation of peginterferon and ribavirin combination therapy in refractory cases (HCV type 1) from a clinical study in Japan, the complete cure rate was 62.5% when there was no dose change. It has been reported to decrease to 50.8% and further to 19.2% in cases of discontinuation.

In other words, with interferon and ribavirin combination therapy, it is extremely important not to reduce or discontinue, so a drug that can suppress even a slight decrease in the amount of hemoglobin is extremely useful clinically. Therefore, the acidosis ameliorating agent is expected to have an effect of suppressing the loss of ribavirin. Therefore, the acidose ameliorating agent is expected as a prophylactic or therapeutic agent for anemia, which is a side effect of ribavirin / interferon combination therapy. The preventive and therapeutic agent of the present invention comprises an acidosis improving agent as an active ingredient as an excipient, a binder, a lubricant, a coloring agent, a flavoring agent, sterile water, an isotonic agent, a PH adjuster, and a stabilizer. It can be prepared in an appropriate pharmaceutical preparation by appropriately combining with a soothing agent and the like. The dosage form of the formulation is tablet, force pusher, micro force pusher, granule, fine granule Agents, powders, oral liquid preparations, syrups, and injections. The administration method is oral, intravenous or intraarterial, and oral administration is particularly preferable.

In addition, it is preferable to use URALIT® u (registered trademark) or URALIT tablet (registered trademark), which is marketed as a safe acidosis improving agent with few side effects.

The dose of the prophylactic and therapeutic agent of the present invention can be appropriately increased or decreased depending on the dosage form, administration method, number of administrations per day, symptom level, body weight, age and the like.

For example, when URALIT® u (registered trademark) or URALIT tablet (registered trademark) is administered orally, the total amount of the active ingredients citrate strength rum and citrate sodium is: -12 g / day, preferably 3-12 g / day, divided into 3 or 4 doses per day, but the total dose may be administered once or in several doses as needed Good. The administration period and administration schedule of the prophylactic and therapeutic agent of the present invention can be any period from the administration of revivin and / or interferon in standard revivin / interferon combination therapy to the end of administration of revivin / interferon. Administration period · Can be administered according to the administration schedule.

From the viewpoint of prevention of side effects, it is preferable to start administration of prophylactic and therapeutic agents at the stage when the administration of revivin / interferon is decided.

In addition, from the viewpoint of reducing the side effects of the expressed ribavirin Zinterfen mouth, it is preferable to administer it after the administration of ribavirin Zinterphe mouth. Therefore, the present invention is as follows.

(1) A preventive and therapeutic agent for anemia containing an acidosis improving agent as an active ingredient.

(2) A preventive and therapeutic agent for side effects caused by the administration of ribapirin, which contains an acidosis improving agent as an active ingredient.

(3) A preventive and therapeutic agent for side effects caused by an interferon / ribavirin combination therapy comprising an acidosis improving agent as an active ingredient.

(4) The side effect is a disease associated with a decrease in ATP. (2) or (3) Prophylactic and therapeutic agents.

(5) The preventive and therapeutic agent according to (2) or (3), wherein the side effect is a decrease in hemoglobin.

(6) The preventive and therapeutic agent according to (2) or (3), wherein the side effect is hemolysis.

(7) The preventive and therapeutic agent according to (2) or (3), wherein the side effect is anemia.

(8) A pharmaceutical product comprising an acidosis improving agent and revivin.

(9) A pharmaceutical product consisting of interferon, acidosis improving agent and revivin.

(10) The preventive and therapeutic agent according to any one of (1) to (9), wherein the acidosis improving agent is an alkali metal citrate.

(1 1) The preventive and therapeutic agent according to (1 0), wherein the acidosis-improving agent is a formulation containing potassium citrate and sodium citrate.

(1 2) The preventive and therapeutic agent according to any one of (1) to (9), wherein the acidosis improving agent is sodium hydrogen carbonate.

(1 3) The preventive and therapeutic agent according to any one of (3) to (7) and (9) to (12), wherein the interferon is interferon α.

(1 4) Interferon is selected from interferon a-2a, interferon hi-2b, PEG 匕 interferon ii 2a, PEG 匕 interferon α-2b, consensus interferon or purified interferon α (1) The preventive and therapeutic agent according to (1). Examples of the present invention are shown below, but the present invention is not limited thereto. Example 1 Clinical trial 1

Patients with hepatitis C who receive peginterferon and ribavirin (11 people: 5 men, 6 women), peginterferon and ribavirin combined with potassium titanate and sodium taenate Divided into groups (5: 2 males, 3 females), and the amount of AT sputum and hemoglobin in red blood cells before and 4 weeks after drug administration The amount of bottles, the number of reduced doses of ribaprine 4 weeks after administration, and the total dose were confirmed. In addition, the reduction of the revivin based on the hemoglobin concentration was stopped according to the criteria described in Table 1 below.

Target patient-Moglobin concentration Revivin amount

Person

Heart disease 0 g / d <1

Or (60 0 mg Z day 40 0 mg day) Already 800 mg / day 6 00 mg / day Day of travel l OO Omg Z day 6 0 0 mg Z day No disease 8.5 / d Less than 1 stop heart Disease Less than 10 g / d 1

Or during the administration period, the pre-dose value (600 mg Z 曰 400 mg Z days 2 g / dL or more compared to the previous value 800 mg Z days 6 00 mg Z days L 0 0 0 mg Z day 6 00 mg Z day Yes 8.5 gd Less than L Cancel

4 weeks after the weight loss

1 2 gZ d L less than Bae Guin Tar Ferron also is, for Bae Guintoron subcutaneous Note: using the (Schering 'Blau Co., Ltd. Bae Guin Tar interferon alpha _ 2 b (gene recombination)), once _1. 5 μ g / kg was administered subcutaneously once a week.

Rebabiline used Rebetol capsule (manufactured by Schering Plow Co., Ltd.), and was administered at a dose of 60 mg to lOOOOg per day after breakfast and after dinner according to the weight of the patient.

Potassium citrate 'is a combination of sodium citrate (registered trademark) ), 1 g was administered 3 times a day.

The amount of ATP in erythrocytes was measured based on the following measurement principle described in Japanese Clinical Practice No. 53/1993, page 24, 3rd issue.

Hexokinase

(1) Glucose + AT P G 6 P + AD P

Mg ^{2 +}

G 6 P D

(2) G 6 P + NAD P 1.6 P GA + NAD PH + H + And the amount of hemoglobin was measured using JE N_S manufactured by Beckman Coulter. Clinical trial 2

(1) Patients with chronic hepatitis C who receive pegylated interferon and ribavirin (13 people: 4 men, 9 women), peginterferon and ribavirin, It is divided into the group (6 persons: 4 males, 2 females) who receive the combination of sodium and citrate sodium, and the amount of ATP and hemoglobin in red blood cells before and 4 weeks after drug administration, and administration Four weeks later, the number of rivapirin doses reduced and the total dose were confirmed.

(2) For peginterferon, use pegintron subcutaneous injection (Siering Plow Co., Ltd .: peginterflon alpha 1 b (genetical recombination)) 1.5 times. μgZkg was administered subcutaneously once a week.

Revivin used Rebetol capsule (manufactured by Schering-Plough Co., Ltd.) and was administered at a dose of 600 mg to lOOOOmg per day after breakfast and after dinner according to the weight of the patient.

A combination of sodium citrate and sodium taenoate is registered in the form of Ularit Tablets (registered trademark). ), 2 g at a time was administered 3 times a day (4 people: 3 men, 1 woman) and 1 g at a time 3 times a day (2 people: 1 male and 1 female each). Clinical trial 3

In the same way as in Clinical Trial 2, the Ularit Tablets (registered trademark) combination group (2 g at a time, 3 times a day, total of 3 people: 1 male, 2 females), Ulalit Tablets (registered trademark) Tests were conducted on the combined use group (3 people in total: 1 male and 2 female), and the amount of hemoglobin in erythrocytes before and 4 weeks after drug administration, as well as the reduction in ribavirin 4 weeks after administration Number and total dose were confirmed. Test results Results 1 Examination of the amount of ATP in red blood cells in patients with chronic hepatitis C

Table 2 shows the amount of ATP in red blood cells before and 4 weeks after drug administration in clinical trial 1. Table 2

Uralit I: Peginterferon + Ribavirin group

Ularit +: Peguinterferon + Ribapilin + Potassium oxalate sodium

ATP (R B C): ATP content in red blood cells

p r e: Before drug administration

post: 4 weeks after drug administration Regarding the amount of ATP in erythrocytes at 4 weeks after administration, the decrease in ATP tended to be suppressed in the combination group of ULARIT Tablet (registered trademark) compared to the non-combination group.

(P = 0. 0 5 9 9) Result 2 Examination of the amount of ATP in the amount of red blood cells in patients with chronic hepatitis C

Table 3 shows the amount of ATP in erythrocytes at 4 weeks after administration. (Aggregated data from clinical trials 1 and 2) Table 3

Ularito: Peguinterferon + Ribavirin group

Ularit +: Peguinterferon + ribavirin + potassium citrate / natrium taenate

AT P (RB C): ATP content in red blood cells

Regarding the ATP level in red blood cells at 4 weeks, there was a significant difference between the two groups in the group with or without the ULARIT tablet (registered trademark). (P <0. 0 1) Results 3 Examination of the number of cases of rivapirin weight loss in patients with chronic hepatitis C

Table 4 shows the number of cases of rivapirin reduction and the ratio of rivapirin dose (the initial dose is 100% when administered for 4 weeks). (Data collected from clinical trials 1 to 3) Table 4

Uralit I: Peguinterferon + Ribapilin group

Ularit +: Peguinterferon + ribavirin + potassium citrate-sodium citrate combination drug administration group As shown in Table 4, the number of cases of weight loss at 4 weeks in the non-Uralit® (registered trademark) non-administration group The number of weight loss in the combination group was 0%, compared with 19%.

There was also a significant difference in the total dose of ribavirin between the non-Uralit® (registered trademark) combination group and the combined use group. (P <0. 0 5) Results 4 Examination of the number of ribavirin reduction cases in patients with chronic hepatitis C who are anemic (H b <14 g / d 1) before the start of treatment

In clinical trials 1 to 3, for patients with hepatitis C who are anemic (Hb <14 g / dl) and are likely to lose ribavirin, the group receiving peginterferon and ribavirin (1 3 patients) ) And peginterferon and ribavirin were combined with a combination of potassium citrate and sodium taenate (10 patients), and the number of ribavirin reduced and the total dose after 4 weeks of administration were analyzed.

The results are shown in Table 5. Table 5

Ularitto: Peguinterferon + Ribavirin administration group

Uralit +: Peguinterferon + ribavirin + potassium taenate / sodium citrate combination drug administration group As is clear from Table 5, the number of cases of weight loss at 4 weeks in the non-Uralit® (non-registered trademark) group 3 1%, whereas in the combination group with ULARIT Tablet (registered trademark), the number of cases of weight loss was 0%.

In addition, the total dose of ribavirin was also significantly different between the non-Uralit® (registered trademark) combination group and the combined use group. (P <0. 0 5) Result 5

(1) As a result of summing up data from the above clinical trials 1 to 3, the amount of hemoglobin at 4 weeks was compared with that at the start of administration in the Uralit Tablets (registered trademark) non-combination group (2 7 patients) and the combination group (1 4 Both names were found to decrease significantly. (P ku 0. 0 1)

(2) As a result of collecting data from clinical trials 1 and 2, the amount of ATP in erythrocytes at 4 weeks was compared with that at the start of administration. Both names were found to decrease significantly. (P ku 0. 0 1)

(3) As a result of collecting data from clinical trials 1 and 2, the difference between the amount of ATP in red blood cells at the start of administration and the amount of ATP at 4 weeks is positively correlated with the amount of hemoglobin at 4 weeks It has been found. (35 people, correlation function of Pear r son r = 0. 3 0 5 3)

(4) As a result of summing up data from clinical trials 1 and 2, the difference between the amount of ATP in red blood cells at the start of administration and the amount of ATP at 4 weeks is the difference between the amount of hemoglobin at the start of administration and the amount of ATP at 4 weeks. It was found that there was a positive correlation with the difference in the amount of moglobin. (Correlation function r = 0, 3 6 3 2 for 3 5 persons, Pear s o n)

(5) As a result of totaling data from clinical trials 1 to 3, the amount of hemoglobin at the start of administration was determined between the ularit tablets (registered trademark) non-combination group (2 7 patients) and the combination group (1 4 patients). There was no significant difference, and as a result of collecting data from clinical trials 1 and 2, the amount of ATP in erythrocytes at the start of administration was also confirmed in the ULARIT Tablet (registered trademark) non-combination group (24 patients) and the combination group ( 1 1) There was no significant difference between them. Example 2

Ularitsu I U (registered trademark)

1 g contains the following ingredients (as dry weight).

Lithium citrate

(Department of office) Sodium Quenate

Contains yellow No. 5, citrate anhydride, lemon oil as additives. Example 3

Ularit lock (registered trademark)

Each tablet contains the following ingredients (as dry weight).

'Calcium taenoate 2 3 1. 5 mg

(JP) Sodium citrate 1 9 5. 0 mg

Additives include magnesium stearate, crystalline cellulose, hydroxycellulose, partial alpha or starch, and anhydrous citrate.

Claims

The scope of the claims

1 An agent for preventing and treating anemia containing an acidosis ameliorating agent as an active ingredient.

2 A preventive and therapeutic agent for side effects caused by administration of ribavirin, which contains an acidosis ameliorating agent as an active ingredient.

3 A preventive and therapeutic agent for side effects of interferon and ribapirin combination therapy containing an acidosis ameliorating agent as an active ingredient.

4. The preventive and therapeutic agent according to claim 2 or 3, wherein the side effect is a disease associated with a decrease in ATP.

5. The preventive and therapeutic agent according to claim 2 or 3, wherein the side effect is a decrease in hemoglobin.

6. The preventive and therapeutic agent according to claim 2 or 3, wherein the side effect is hemolysis. 7. The preventive and therapeutic agent according to claim 2 or 3, wherein the side effect is anemia. 8 A drug consisting of an acidosis ameliorating agent and revivin.

9 A pharmaceutical product consisting of interferon, acidosis improving agent and revivin.

The acidosis ameliorating agent is an alkali metal citrate salt.

The prophylactic and therapeutic agent according to any one of items 9.

11. The preventive and therapeutic agent according to claim 10, wherein the acidosis-improving agent is a potassium kennate 'sodium citrate combination preparation.

The preventive and therapeutic agent according to any one of claims 1 to 9, wherein the acidosis improving agent is sodium hydrogen carbonate.

13. The prophylactic and therapeutic agent according to any one of claims 3 to 7 and claims 9 to 12, wherein the 3 3 interferon is interferon α.

1 4 Interferon is interferon α-2a, interferon α-2b, PEG interferon 1a, PEEG interferon α-2b

The prophylactic and therapeutic agent according to claim 1.3, which is selected from the group consisting of a consensus interferon and a purified interferon.