JP2011051898A - Agent for alleviating adverse side effect produced in interferon/ribavirin combination therapy - Google Patents
Agent for alleviating adverse side effect produced in interferon/ribavirin combination therapy Download PDFInfo
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- JP2011051898A JP2011051898A JP2008205299A JP2008205299A JP2011051898A JP 2011051898 A JP2011051898 A JP 2011051898A JP 2008205299 A JP2008205299 A JP 2008205299A JP 2008205299 A JP2008205299 A JP 2008205299A JP 2011051898 A JP2011051898 A JP 2011051898A
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- interferon
- ribavirin
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- acidosis
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- 229960000329 ribavirin Drugs 0.000 title claims abstract description 63
- HZCAHMRRMINHDJ-DBRKOABJSA-N ribavirin Natural products O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1N=CN=C1 HZCAHMRRMINHDJ-DBRKOABJSA-N 0.000 title claims abstract description 63
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Abstract
Description
本発明はクエン酸アルカリ金属塩を有効成分として含有するインターフェロン・リバビリン併用療法における副作用軽減剤に関する。 The present invention relates to an agent for reducing side effects in an interferon / ribavirin combination therapy comprising an alkali metal citrate as an active ingredient.
我国におけるＣ型肝炎ウイルスの感染者数は、現在約２００万人と推定されている。
Ｃ型肝炎ウイルスに感染すると一定の潜伏期間を経て、急性肝炎にかかるが、自覚症状は比較的乏しく、慢性肝炎に移行しやすい。
そして、慢性肝炎も自覚症状は少なく、放置すれば、肝硬変を発病し、更には肝臓ガンに至ることもありうる。
肝臓ガンで死亡する患者は、年間３万〜３万５０００人で、そのうちの約８割が、Ｃ型肝炎ウイルスが原因とされている。
従って、国においても現在検診でＣ型慢性肝炎の潜在患者の早期発見に努めているところでもあり、肝硬変や肝臓ガンに至る前に、肝炎を治療することは重要である。
Ｃ型慢性肝炎の治療法としては、肝炎を抑え、肝機能を改善させる目的でなされるグリチルリチン製剤、ウルソデオキシコール酸等の薬物を用いた維持的療法（肝庇護療法）とウイルスを駆除することを目的としたインターフェロンを用いた抗ウイルス療法等が知られている。
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 may cause cirrhosis, and may lead to liver cancer.
The number of patients who die from liver cancer is 30,000 to 35,000 per year, 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 by screening, and it is important to treat hepatitis before cirrhosis or liver cancer.
Treatment of chronic hepatitis C includes the use of drugs such as glycyrrhizin preparations and ursodeoxycholic acid for the purpose of suppressing hepatitis and improving liver function, and eliminating viruses. Antiviral therapy using interferon for the purpose is known.
抗ウイルス療法にはインターフェロンやペグインターフェロンの単独療法とこれらとリバビリンとの併用療法が知られている。
ところで、我国で見られるＣ型肝炎ウイルスのタイプとしては、１ｂタイプが最も多く、次いで２ａ、２ｂタイプで、残りはまれである。２ａ、２ｂタイプについては、インターフェロン単独療法は効果的であるが、１ｂタイプについては、インターフェロン単独療法の効果はあまり高くないことが知られている。
またウイルス量が多くなるとインターフェロン単独療法は、治療効果が高くないことも問題視されている。
たとえばイントロンＡ注射用３００（シェリング・プラウ製）の効能又は効果の記載は以下のとおりである。
効能又は効果
・次のいずれかのＣ型慢性肝炎におけるウイルス血症の改善
（１）本剤単独の場合
１）血中ＨＣＶ ＲＮＡ量が高値ではない患者
（２）リバビリンとの併用の場合
１）血中ＨＣＶ ＲＮＡ量が高値の患者
２）インターフェロン製剤単独療法で無効の患者又はインターフェロン製剤単独療法後再燃した患者
・ＨＢｅ抗原陽性でかつＤＮＡポリメラーゼ陽性のＢ型慢性活動性肝炎のウイルス血症の改善
・腎癌、慢性骨髄性白血病、多発性骨髄腫
As antiviral therapy, interferon and peginterferon monotherapy and combination therapy with ribavirin are known.
By the way, as the type of hepatitis C virus found in Japan, the 1b type is the most common, followed by the 2a and 2b types, and the rest are rare. For the 2a and 2b types, interferon monotherapy is effective, but for the 1b type, it is known that the effect of interferon monotherapy is not so high.
In addition, when the amount of virus increases, interferon monotherapy is also regarded as a problem that the therapeutic effect is not high.
For example, the description of the effect or effect of Intron A 300 for injection (manufactured by Schering-Plough) is as follows.
Efficacy or effect ・ Improvement of viremia in any of the following chronic hepatitis C (1) In the case of this drug alone 1) Patients whose blood HCV RNA level is not high (2) In combination with ribavirin 1) Patients with high levels of blood HCV RNA 2) Patients who are ineffective with monotherapy of interferon preparation or patients who have relapsed after interferon preparation monotherapy ・ Improvement of viremia of chronic active hepatitis B positive for HBe antigen and DNA polymerase・ Renal cancer, chronic myelogenous leukemia, multiple myeloma
従ってインターフェロン単独療法よりもリバビリンとの併用療法の方がより適切な治療方法と考えられるが、しかしながらこのリバビリン併用療法においては、インターフェロン単独投与における副作用である発熱、倦怠感、うつ病、甲状腺などの自己免疫疾患、間質性肺炎などの副作用に加え、貧血の発生頻度が高く治療上の重大な問題となっている。
即ちヘモグロビン濃度が減少した場合は、リバビリンの用量を減量し、あるいはリバビリンの投与を中止したり、更にはインターフェロンの減量・休薬・中止することとなる。
治療難治例（ＨＣＶ１型）におけるペグインターフェロン・リバビリン併用療法の完治率と中止の影響について国内臨床試験から、用量変更なしの場合、完治率が６２．５％に対し、減量症例では５０．８％に低下し、さらに中止症例に至っては１９．２％に低下することが報告されている。
従って、インターフェロン・リバビリン併用療法では、減量や中止に至らないことが極めて重要となる。
Therefore, combination therapy with ribavirin is considered to be a more appropriate treatment method than interferon monotherapy.However, in this ribavirin combination therapy, side effects of interferon monotherapy such as fever, malaise, depression, thyroid, etc. In addition to side effects such as autoimmune diseases and interstitial pneumonia, the incidence of anemia is high and it has become a serious therapeutic problem.
That is, when the hemoglobin concentration decreases, the dose of ribavirin is reduced, or the administration of ribavirin is discontinued, and further, the interferon dose is reduced, withdrawn, or discontinued.
About the complete cure rate of pegylated interferon and ribavirin combination therapy in patients with refractory treatment (HCV type 1) and the effect of discontinuation from the Japanese clinical study, the complete cure rate was 62.5% without dose change, compared with 50.8% for patients with reduced weight It has been reported that it has decreased to 19.2% in cases of discontinuation.
Therefore, it is extremely important that interferon / ribavirin combination therapy does not lead to weight loss or discontinuation.
ところでインターフェロン・リバビリン併用療法における副作用である貧血の軽減方法として、抗酸化剤の使用（特許文献１）、イコサペント酸エチル（ＥＰＡ）の使用（特許文献２）、エリスロポエチン（ＥＰＯ）の使用（特許文献３）等が提案されている。
しかしながら、現在までのところインターフェロン・リバビリン併用療法における副作用である貧血の発生を軽減させる有効な薬物として、これらの薬物が臨床上用いられているとの報告はなされていない。
By the way, use of an antioxidant (Patent Document 1), use of ethyl icosapentate (EPA) (Patent Document 2), use of erythropoietin (EPO) (Patent Document) as a method for reducing anemia, which is a side effect in combined therapy of interferon and ribavirin. 3) etc. have been proposed.
However, to date, there has been no report that these drugs are clinically used as effective drugs for reducing the occurrence of anemia, which is a side effect of interferon / ribavirin combination therapy.
クエン酸カリウム・クエン酸ナトリウム配合製剤である「ウラリット−Ｕ（登録商標）」及び「ウラリット錠（登録商標）」は、「痛風ならびに高尿酸血症における酸性尿の改善、並びにアシドーシスの改善」に対して有用であることが広く知られている。（非特許文献１、２）
しかしながら、発明者らの知る限り、クエン酸カリウム・クエン酸ナトリウム配合製剤が、貧血の予防又は治療薬として有効である旨の報告はなされていない。
従って、インターフェロン・リバビリン併用療法において、高頻度に発生する副作用である貧血を軽減させる有効な薬物の提供が求められている。
“Uralit-U (registered trademark)” and “Uralit tablet (registered trademark)”, which are formulations containing potassium citrate and sodium citrate, are considered as “improvement of acidic urine and improvement of acidosis in gout and hyperuricemia” It is widely known that it is useful. (Non-Patent Documents 1 and 2)
However, as far as the inventors know, there has been no report that a combined preparation of potassium citrate / sodium citrate is effective as a prophylactic or therapeutic agent for anemia.
Therefore, in interferon / ribavirin combination therapy, provision of an effective drug that reduces anemia, which is a frequently occurring side effect, is demanded.
本発明の課題は、Ｃ型慢性肝炎のインターフェロン・リバビリン併用療法時に見られる副作用を軽減することにより、リバビリン及び／又はインターフェロンを減量又は中止することなく、薬物治療を可能にする副作用軽減剤（予防及び治療剤）を提供することにある。 An object of the present invention is to reduce a side effect seen during interferon / ribavirin combination therapy for chronic hepatitis C, thereby reducing a side effect of drug therapy without reducing or stopping ribavirin and / or interferon (prevention). And a therapeutic agent).
即ち、本発明は、アシドーシス改善剤を有効成分として含有する貧血の予防及び治療剤に関する。
また、本発明は、アシドーシス改善剤を有効成分として含有するリバビリン投与による副作用の予防及び治療剤に関する。
また、本発明は、アシドーシス改善剤を有効成分として含有するインターフェロン・リバビリン併用療法による副作用の予防及び治療剤に関する。
また、本発明は、アシドーシス改善剤とリバビリンからなる医薬品に関する。
さらにまた、本発明は、インターフェロンとアシドーシス改善剤とリバビリンからなる医薬品に関する。
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 ribavirin administration comprising an acidosis improving agent as an active ingredient.
The present invention also relates to an agent for preventing and treating 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 product comprising an acidosis improving agent and ribavirin.
Furthermore, the present invention relates to a pharmaceutical product comprising interferon, an acidosis improving agent and ribavirin.
次に本発明を詳細に説明する。
本明細書において、貧血とは、血液中の赤血球数または血色素量が正常値以下に減少した状態をいう。なお、国際的貧血判定基準（ＷＨＯ）によるとヘモグロビン量が、成人男子では１３．０ｇ／ｄＬ、女子では１２．０ｇ／ｄＬ以下とされている。
リバビリン（以下、ＲＩＢと略すこともある。）およびインターフェロン（以下、ＩＦＮと略すこともある。）又はペグインターフェロン（ＰＥＧ化ＩＦＮ）併用療法におけるＲＩＢが関与すると考えられる副作用としては、たとえばレベトールカプセル（シェーリング・プラウ（株）製）の添付文書によると、重大な副作用として、貧血（赤血球減少、ヘモグロビン減少）、無顆粒球症、白血球減少、顆粒球減少、血小板減少、再生不良性貧血、抑うつ、自殺企図、昏迷、難聴、意識障害、痙攣、見当識障害、せん妄、幻覚、失神、躁状態、妄想、錯乱、攻撃的行動、統合失調症様症状、痴呆様症状、興奮、肝機能障害、ショック、消化管出血、消化性潰瘍、小腸潰瘍、虚血性大腸炎、呼吸困難、喀痰増加、脳出血、脳梗塞、間質性肺炎、肺線維症、肺水腫、糖尿病、腎障害、心筋症、心不全、心筋梗塞、狭心症、不整脈、敗血症、網膜症、自己免疫疾患、溶血性尿毒症症候群、血栓性血小板減少性紫斑病、皮膚粘膜眼症候群、横紋筋融解症が挙げられ、そしてその他の副作用として全身症状（発熱、倦怠感、悪寒、インフルエンザ様症状）、精神神経系（頭痛、不眠、異常感、部分不快、激超他）、血液（白血球減少、好中球減少、リンパ球減少、ヘモグロビン減少、血小板減少、赤血球減少、ヘマトクリット減少、貧血、リンパ球増多、好中球増多、赤血球増加他）、肝臓（ＡＳＴ）ＧＯＴ）上昇、ＡＬＴ（ＧＰＴ）上昇、γ−ＧＴＰ上昇、ＬＤＨ上昇、ビルリルビン上昇、黄疸他）、腎臓（頻尿、血尿他）、循環器（頻脈他）、消化器（食欲不振他）、皮膚（脱毛他）、神経・筋（関節痛他），呼吸器（咳嗽、気管支痙攣他）、眼（角膜・結膜炎、眼そう痒症、視野狭窄他）、投与部位（注射部反応）等が挙げられている。
本明細書でいう副作用は、上記の副作用、並びにこれら以外にもリバビリン／（ペグ）インターフェロン併用療法においてこれまでに報告されているその他の副作用も含まれるが、これらに限定されるものではない。
上記の副作用の中で、本願明細書にいう予防又は治療剤の対象となる副作用としては好ましくは貧血（赤血球減少、ヘモグロビン減少）、白血球減少、顆粒球減少、血小板減少、再生不良性貧血、血液系の副作用が挙げられるが、さらに好ましくは貧血が挙げられる。
Next, the present invention will be described in detail.
In this specification, 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 g / dL for adult boys and 12.0 g / dL or less for girls.
Side effects that may be involved in RIB in combination therapy with ribavirin (hereinafter sometimes abbreviated as RIB) and interferon (hereinafter also abbreviated as IFN) or pegylated interferon (PEGylated IFN) include, for example, rebetol capsule ( According to the package insert of Schering-Plough, significant side effects include anemia (red blood cell reduction, hemoglobin reduction), agranulocytosis, leukopenia, granulocytopenia, thrombocytopenia, aplastic anemia, depression, Suicide attempt, stupor, hearing loss, consciousness disorder, convulsions, disorientation, delirium, hallucination, fainting, delusion, delusion, confusion, aggressive behavior, schizophrenia-like symptoms, dementia-like symptoms, excitement, liver dysfunction, shock , Gastrointestinal bleeding, peptic ulcer, small intestine ulcer, ischemic colitis, dyspnea, sputum increase, cerebral hemorrhage, cerebral infarction, interstitial pneumonia, Fibrosis, pulmonary edema, diabetes, kidney damage, cardiomyopathy, heart failure, myocardial infarction, angina, arrhythmia, sepsis, retinopathy, autoimmune disease, hemolytic uremic syndrome, thrombotic thrombocytopenic purpura, cutaneous mucosa Eye syndrome, rhabdomyolysis, and other side effects include systemic symptoms (fever, malaise, chills, flu-like symptoms), psychoneural system (headache, insomnia, abnormal feeling, partial discomfort, super-extreme, etc.) , Blood (leukopenia, neutropenia, lymphocyte reduction, hemoglobin reduction, thrombocytopenia, erythrocyte reduction, hematocrit reduction, anemia, lymphocytosis, neutrophilia, erythrocytosis, etc.), liver (AST) GOT ) Rise, ALT (GPT) rise, γ-GTP rise, LDH rise, bilirubin rise, jaundice etc., kidney (frequent urine, hematuria etc.), circulatory organ (tachycardia etc.), digestive organ (anorexia etc.), skin (Hair loss etc.), nerve -Muscles (joint pain etc.), respiratory organs (cough, bronchospasm etc.), eyes (cornea / conjunctivitis, itchy pruritus, visual field stenosis etc.), administration site (injection site reaction), etc. are mentioned.
The side effects referred to herein include, but are not limited to, the above-mentioned side effects and other side effects reported so far in the ribavirin / (peg) interferon combination therapy.
Among the above-mentioned side effects, the side effects targeted by the preventive or therapeutic agent referred to in the present specification are preferably anemia (red blood cell reduction, hemoglobin reduction), white blood cell reduction, granulocyte reduction, thrombocytopenia, aplastic anemia, blood Although there are side effects of the system, anemia is more preferable.
リバビリン製剤としては、レベトールカプセル（商品名、シェリング・プラウ（株）社製）及びコペガス錠（商品名、中外製薬（株）社製）が市販されている。
リバビリンの投与量は、レベトールカプセルを用いる場合、成人患者には、１日４００〜１６００ｍｇ、好ましくは６００〜１０００ｍｇを１日２回に分けて連日、２４週間、朝夕食後経口投与するものであるが、１日当たりの投与回数、投与期間は、症状の程度、体重、年齢等によって適宜変更される。
As ribavirin preparations, Rebetol capsules (trade name, manufactured by Schering-Plough Co., Ltd.) and Copegus tablets (trade name, manufactured by Chugai Pharmaceutical Co., Ltd.) are commercially available.
When using Rebetol capsules, ribavirin is administered to an adult patient by oral administration of 400-1600 mg, preferably 600-1000 mg, divided into 2 times a day, 24 days a week, after breakfast and dinner. The number of administrations per day and the administration period are appropriately changed depending on the degree of symptoms, body weight, age and the like.
本明細書において、インターフェロンとしては、Ｃ型慢性肝炎におけるウイルス血症の治療を目的として用られるインターフェロンであれば特に制限はなく、天然型ＩＦＮα、ＩＦＮα−２ａ、ＩＦＮα−２ｂ、ＰＥＧ化天然型ＩＦＮα、ＰＥＧ化ＩＦＮα−２ａ、ＰＥＧ化ＩＦＮα−２ｂ、天然型ＩＦＮβ、ＰＥＧ化天然型ＩＦＮβ、天然型ＩＦＮγ、コンセンサスＩＦＮ、ＰＥＧ化コンセンサスＩＦＮ、並びにこれらの組合せからなるものが挙げられ、好ましくは天然型ＩＦＮα、ＩＦＮα−２ｂ、ＰＥＧ化ＩＦＮα−２ａ、ＰＥＧ化ＩＦＮα−２ｂ、天然型ＩＦＮβが挙げられ、さらに好ましくはＰＥＧ化ＩＦＮα−２ａ、ＰＥＧ化ＩＦＮα−２ｂが挙げられる。
本明細書における（ペグ）インターフェロンの投与量、投与期間、投与スケジュール、投与経路は、Ｃ型慢性肝炎におけるウイルス血症の治療を目的として実施される範囲内であれば特に制限はない。
たとえばインターフェロンアルファ−２ｂ（遺伝子組換え）は、通常、成人には、１日６００万〜１０００万国際単位を週６回又は週３回筋肉内に投与する。
またペグインターフェロン−２ｂ（遺伝子組換え）は、通常、成人には、１回１．５μｇ／ｋｇを週１回皮下投与する。
In the present specification, the interferon is not particularly limited as long as it is an interferon used for the treatment of viremia in chronic hepatitis C. Natural type IFNα, IFNα-2a, IFNα-2b, PEGylated natural type IFNα PEGylated IFNα-2a, PEGylated IFNα-2b, natural IFNβ, PEGylated natural IFNβ, natural IFNγ, consensus IFN, PEGylated consensus IFN, and combinations thereof, preferably natural Examples include IFNα, IFNα-2b, PEGylated IFNα-2a, PEGylated IFNα-2b, and natural type IFNβ, and more preferably PEGylated IFNα-2a and PEGylated IFNα-2b.
The dose, administration period, administration schedule, and administration route of (peg) interferon in the present specification are not particularly limited as long as they are within a range that is implemented for the purpose of treating viremia in chronic hepatitis C.
For example, interferon alpha-2b (genetical recombination) is usually administered to adults 6 million to 10 million international units daily intramuscularly 6 or 3 times a week.
In addition, peginterferon-2b (genetical recombination) is usually subcutaneously administered to adults at a dose of 1.5 μg / kg once a week.
最近、ペグインターフェロン＋リバビリンの併用療法の効果を高める為、ＮＳ３プロテアーゼ阻害剤（ＶＸ−９５０，ＳＣＨ５０３０３４）との３剤併用が提案されている。
しかしながら、この場合もリバビリンに起因する貧血等の副作用の発生が予想され、本発明の予防及び治療剤を使用することができる。
Recently, in order to enhance the effect of a combination therapy of peginterferon and ribavirin, a triple combination with an NS3 protease inhibitor (VX-950, SCH503034) 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.
アシドーシスとは、血中の酸と塩基の関係が、酸優位の状態になったものをいうが、本発明の予防及び治療剤の有効成分であるアシドース改善剤は、これを正常値に戻す作用を有する薬物をいい、たとえば、クエン酸アルカリ金属塩、炭酸水素ナトリウム等が挙げられ、さらに好ましくはクエン酸カリウム・クエン酸ナトリウム配合製剤が挙げられる。 Acidosis means that the relationship between acid and base in 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, has the effect of returning it to a normal value. For example, an alkali metal citrate salt, sodium hydrogen carbonate and the like can be mentioned, and a combination preparation of potassium citrate / sodium citrate is more preferable.
次に臨床試験の試験結果を示す。
後記実施例１の表２で示すようにアシドーシス改善剤であるクエン酸カリウム・クエン酸ナトリウム配合製剤は、リバビリン・ペグインターフェロン併用療法において、リバビリンの減量を抑制する傾向を示した。
同じく表３で示すように治療開始前に貧血傾向にあるＣ型慢性肝炎患者についても、同様な結果が得られた。
従って、アシドーシス改善剤が、リバビリンの減量を抑制する効果が期待されることから、アシドース改善剤は、リバビリン・インターフェロン併用療法における副作用である貧血の予防又は治療剤として期待される。
リバビリン・インターフェロン併用療法において、ヘモグロビン濃度が減少した場合は、リバビリンの用量を減量し、あるいはリバビリンの投与を中止したり、更にはインターフェロンの減量・休薬・中止することとなる。
たとえばレベトールカプセル（シェーリング・プラウ（株）社製）の場合、ヘモグロビン濃度が１０ｇ／ｄＬ未満の場合、リバビリンを減量し、８．５ｇ／ｄＬ未満ではリバビリンの投与中止に至る。
治療難治例（ＨＣＶ１型）におけるペグインターフェロン・リバビリン併用療法の完治率と中止の影響について国内臨床試験から、用量変更なしの場合、完治率が６２．５％に対し、減量症例では５０．８％に低下し、さらに中止症例に至っては１９．２％に低下することが報告されている。
従って、インターフェロン・リバビリン併用療法では、減量や中止に至らないことが極めて重要となることから、わずかでもヘモグロビン量の減少を抑制できる薬物は臨床上、極めて有用となる。
Next, test results of clinical trials are shown.
As shown in Table 2 of Example 1 below, the combination preparation of potassium citrate / sodium citrate, which is an acidosis improving agent, showed a tendency to suppress the decrease in ribavirin in the ribavirin / peginterferon combination therapy.
Similarly, as shown in Table 3, similar results were obtained for patients with chronic hepatitis C who are anemic before the start of treatment.
Therefore, since the acidosis improving agent is expected to have an effect of suppressing ribavirin weight loss, the acidose improving agent is expected as an agent for preventing or treating anemia which is a side effect in the ribavirin / interferon combination therapy.
In the ribavirin / interferon combination therapy, if the hemoglobin concentration decreases, the dose of ribavirin is reduced, or the administration of ribavirin is discontinued, and further, the dose of interferon is reduced, withdrawn, or discontinued.
For example, in the case of Rebetol capsule (manufactured by Schering-Plough Co., Ltd.), if the hemoglobin concentration is less than 10 g / dL, the amount of ribavirin is decreased, and if it is less than 8.5 g / dL, the administration of ribavirin is discontinued.
About the complete cure rate of pegylated interferon and ribavirin combination therapy in patients with refractory treatment (HCV type 1) and the effect of discontinuation from the Japanese clinical study, the complete cure rate was 62.5% without dose change, compared with 50.8% for patients with reduced weight It has been reported that it has decreased to 19.2% in cases of discontinuation.
Therefore, in interferon / ribavirin combination therapy, it is extremely important not to lead to dose reduction or discontinuation. Therefore, a drug that can suppress even a slight decrease in the amount of hemoglobin is extremely useful clinically.
本発明の予防及び治療剤は、有効成分であるアシドーシス改善剤を賦形剤、結合剤、滑沢剤、着色剤、香味剤、滅菌水、等張化剤、ｐＨ調整剤、安定化剤、無痛化剤などと適宜組み合わせて適当な医薬用製剤に調製することができる。
製剤の剤形としては、錠剤、カプセル剤、マイクロカプセル剤、顆粒剤、細粒剤、散剤、経口用液体製剤、シロップ剤、注射剤が例示できる。投与方法は、経口および静脈内あるいは動脈内を問わず患者に投与されるが、とりわけ経口投与が好ましい。
なお、副作用の発現が少ない安全なアシドーシス改善剤として市販されているウラリット−Ｕ（登録商標）又はウラリット錠（登録商標）を使用することが好ましい。
本発明の予防及び治療剤の投与量は、その剤形、投与方法、１日当たりの投与回数、症状の程度、体重、年齢等によって適宜増減することができる。
例えばウラリット−Ｕ（登録商標）又はウラリット錠（登録商標）を経口投与する場合は、有効成分であるクエン酸カリウム及びクエン酸ナトリウムの合計量が１〜１２ｇ／日、好ましくは３〜１２ｇ／日を、１日３、４回に分けて投与するが、必要に応じて全量を１回あるいは数回に分けて投与してもよい。
The preventive and therapeutic agent of the present invention comprises an acidosis improving agent as an active ingredient as an excipient, binder, lubricant, coloring agent, flavoring agent, sterilized water, isotonic agent, pH adjuster, stabilizer, An appropriate pharmaceutical preparation can be prepared by appropriately combining with a soothing agent and the like.
Examples of the dosage form of the preparation include tablets, capsules, microcapsules, granules, fine granules, powders, oral liquid preparations, syrups, and injections. The method of administration is oral or intravenous or intraarterial, with oral administration being particularly preferred.
In addition, it is preferable to use URALIT-U (registered trademark) or URALIT tablet (registered trademark) which is commercially available as a safe acidosis improving agent with few side effects.
The dosage 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 orally administered, the total amount of the active ingredients potassium citrate and sodium citrate is 1 to 12 g / day, preferably 3 to 12 g / day. Is divided into three or four times a day, but the total amount may be divided into one or several times as needed.
本発明の予防及び治療剤の投与期間および投与スケジュールは、標準的なリバビリン・インターフェロン併用療法におけるリバビリンおよび／またはインターフェロンの投与前から、リバビリン／インターフェロン投与終了後まで、任意の投与期間・投与スケジュールで投与することができる。
副作用の予防の観点から、リバビリン／インターフェロンの投与を決定した段階で、予防及び治療剤の投与を開始することが好ましい。
また発現したリバビリン／インターフェロンの副作用を軽減する観点からは、リバビリン／インターフェロン投与後に投与することが好ましい。
The prophylactic and therapeutic agent administration period and administration schedule of the present invention can be any administration period / administration schedule from before administration of ribavirin and / or interferon in standard ribavirin / interferon combination therapy until after completion of ribavirin / interferon administration. Can be administered.
From the viewpoint of preventing side effects, it is preferable to start administration of the prophylactic and therapeutic agents at the stage when the administration of ribavirin / interferon is determined.
From the viewpoint of reducing the side effects of the expressed ribavirin / interferon, it is preferable to administer after administration of ribavirin / interferon.
従って、本発明は次のとおりである。
（１）アシドーシス改善剤を有効成分として含有する貧血の予防及び治療剤。
（２）アシドーシス改善剤を有効成分として含有するリバビリン投与による副作用の予防及び治療剤。
（３）アシドーシス改善剤を有効成分として含有するインターフェロン・リバビリン併用療法による副作用の予防及び治療剤。
（４）副作用が、ヘモグロビンの減少である（２）又は（３）記載の予防及び治療剤。
（５）副作用が、溶血である（２）又は（３）記載の予防及び治療剤。
（６）副作用が、貧血である（２）又は（３）記載の予防及び治療剤。
（７）アシドーシス改善剤とリバビリンからなる医薬品。
（８）インターフェロンとアシドーシス改善剤とリバビリンからなる医薬品。
（９）アシドーシス改善剤が、クエン酸アルカリ金属塩である（１）〜（８）の何れかの項に記載の予防及び治療剤。
（１０）アシドーシス改善剤が、クエン酸カリウム・クエン酸ナトリウム配合製剤である（９）記載の予防及び治療剤。
（１１）アシドーシス改善剤が、炭酸水素ナトリウムである（１）〜（８）の何れかの項に記載の予防及び治療剤。
（１２）インターフェロンがインターフェロンαである（３）〜（６）及び（８）〜（１１）の何れかの項に記載の予防及び治療剤。
（１３）インターフェロンがインターフェロンα−２ａ、インターフェロンα−２ｂ、ＰＥＧ化インターフェロンα−２ａ、ＰＥＧ化インターフェロンα−２ｂ、コンセンサスインターフェロン又は精製インターフェロンαから選ばれるものである（１２）記載の予防及び治療剤。
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 ribavirin administration comprising an acidosis improving agent as an active ingredient.
(3) A preventive and therapeutic agent for side effects caused by interferon / ribavirin combination therapy comprising an acidosis improving agent as an active ingredient.
(4) The preventive and therapeutic agent according to (2) or (3), wherein the side effect is a decrease in hemoglobin.
(5) The preventive and therapeutic agent according to (2) or (3), wherein the side effect is hemolysis.
(6) The preventive and therapeutic agent according to (2) or (3), wherein the side effect is anemia.
(7) A pharmaceutical comprising an acidosis improving agent and ribavirin.
(8) A pharmaceutical product comprising interferon, an acidosis improving agent and ribavirin.
(9) The preventive and therapeutic agent according to any one of (1) to (8), wherein the acidosis improving agent is an alkali metal citrate.
(10) The preventive and therapeutic agent according to (9), wherein the acidosis improving agent is a combined preparation of potassium citrate / sodium citrate.
(11) The preventive and therapeutic agent according to any one of (1) to (8), wherein the acidosis improving agent is sodium hydrogen carbonate.
(12) The preventive and therapeutic agent according to any one of (3) to (6) and (8) to (11), wherein the interferon is interferon α.
(13) The preventive and therapeutic agent according to (12), wherein the interferon is selected from interferon α-2a, interferon α-2b, PEGylated interferon α-2a, PEGylated interferon α-2b, consensus interferon, or purified interferon α. .
以下に、本発明の実施例を示すが、本発明はこれらに限定されるものではない。 Examples of the present invention are shown below, but the present invention is not limited thereto.
（試験方法）
（１）Ｃ型慢性肝炎を発症している患者をペグインターフェロンとリバビリンを投与する群（２２名）とペグインターフェロンとリバビリンにクエン酸カリウム・クエン酸ナトリウム配合製剤を投与する群（１１名）にわけ、投与４週間後のリバビリンの減量例数と総投与量を確認した。
（２）またリバビリンの減量の可能性が高いとされる貧血傾向（Ｈｂ＜１４ｇ／ｄｌ）にあるＣ型肝炎患者について、ペグインターフェロンとリバビリンを投与する群（９名）とペグインターフェロンとリバビリンにクエン酸カリウム・クエン酸ナトリウム配合製剤を投与する群（７名）にわけ、投与４週間後のリバビリンの減量例数と総投与量を確認した。
（３）ペグインターフェロンは、ペグイントロン皮下注用（シェーリング・プラウ（株）社製：ペグインターフェロン アルファ−２ｂ（遺伝子組換え））を用い、１回１．５μｇ／ｋｇを週１回皮下投与した。
リバビリンは、レベトールカプセル（シェーリング・プラウ（株）社製）を用い、患者の体重に応じて１日当たり６００ｍｇ〜１０００ｍｇを朝食後、夕食後に投与した。
クエン酸カリウム・クエン酸ナトリウム配合製剤は、ウラリット−Ｕ（登録商標）を用い、１回２ｇを１日３回投与した。なおヘモグロビン濃度に基づくリバビリンの減量・中止は表１記載の基準に従った。
(Test method)
(1) Patients with chronic hepatitis C in groups receiving peginterferon and ribavirin (22 patients) and groups receiving peginterferon and ribavirin combined with potassium citrate / sodium citrate (11 patients) It was confirmed that the number of ribavirin decreased 4 weeks after administration and the total dose.
(2) For hepatitis C patients with anemia tendency (Hb <14 g / dl) that is considered to have a high possibility of weight loss of ribavirin (9 patients), peginterferon and ribavirin It was divided into a group (7 persons) administered with a potassium citrate / sodium citrate combination preparation, and the number of ribavirin reduced cases and the total dose were confirmed 4 weeks after administration.
(3) As for peginterferon, 1.5 μg / kg was subcutaneously administered once a week using pegintron subcutaneous injection (manufactured by Schering-Plough Co., Ltd .: peginterferon alpha-2b (genetical recombination)).
Ribavirin was administered after breakfast and after dinner at 600 mg to 1000 mg per day, depending on the weight of the patient, using Rebetol capsule (manufactured by Schering-Plough Co., Ltd.).
The combined formulation of potassium citrate and sodium citrate was URALIT-U (registered trademark), and 2 g was administered 3 times a day. In addition, the reduction | decrease and cancellation of ribavirin based on hemoglobin concentration followed the standard of Table 1.
試験結果を表２および表３に示す。
（試験結果）
（１）Ｃ型慢性肝炎患者における検討
The test results are shown in Tables 2 and 3.
(Test results)
(1) Examination in patients with chronic hepatitis C
（２）治療開始前に貧血傾向（Ｈｂ＜１４ｇ／ｄｌ）にあるＣ型慢性肝炎患者における検討 (2) Examination in patients with chronic hepatitis C who are anemic (Hb <14 g / dl) before starting treatment
表２から明らかなようにウラリット−Ｕ（登録商標）（クエン酸カリウム・クエン酸ナトリウム配合製剤）は、リバビリン・ペグインターフェロン併用療法において、リバビリンの減量を抑制する傾向にあった。
表３から明らかなように、治療開始前に貧血傾向（Ｈｂ＜１４ｇ／ｄｌ）にあるＣ型慢性肝炎患者において、ウラリット−Ｕ（登録商標）（クエン酸カリウム・クエン酸ナトリウム配合製剤）のリバビリン減量抑制効果は優れている。
As is apparent from Table 2, URALIT-U (registered trademark) (potassium citrate / sodium citrate combination preparation) tended to suppress the reduction of ribavirin in the ribavirin / peginterferon combination therapy.
As is apparent from Table 3, ribavirin of URALIT-U (registered trademark containing potassium citrate / sodium citrate) in patients with chronic hepatitis C who tend to be anemic (Hb <14 g / dl) before the start of treatment. The weight loss suppression effect is excellent.
ウラリット−Ｕ（登録商標）
１ｇ中に下記成分を（乾燥重量として）含有する。
クエン酸カリウム
（日局）クエン酸ナトリウム
添加物として、黄色５号、無水クエン酸、レモン油を含有する。
Ularit-U (registered trademark)
1 g contains the following components (as dry weight).
Potassium citrate (JP) Contains sodium No. 5, anhydrous citric acid and lemon oil as sodium citrate additive.
ウラリット錠（登録商標）
１錠中に下記成分を（乾燥重量として）含有する。
クエン酸カリウム ２３１．５ｍｇ
（日局）クエン酸ナトリウム １９５．０ｍｇ
添加物として、ステアリン酸マグネシウム、結晶セルロース、ヒドロキシプロピルセルロース、部分アルファーかデンプン、無水クエン酸を含有する。
ULARIT Tablet (registered trademark)
One tablet contains the following ingredients (as dry weight).
Potassium citrate 231.5mg
(JP) Sodium citrate 195.0mg
Additives include magnesium stearate, crystalline cellulose, hydroxypropyl cellulose, partial alpha or starch, and anhydrous citric acid.
Claims (13)
Priority Applications (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2008205299A JP2011051898A (en) | 2008-08-08 | 2008-08-08 | Agent for alleviating adverse side effect produced in interferon/ribavirin combination therapy |
| PCT/JP2008/073969 WO2009084732A1 (en) | 2007-12-28 | 2008-12-26 | Agent for alleviating adverse side effects produced in interferon/ribavirin combination therapy |
| TW097151021A TW200940075A (en) | 2007-12-28 | 2008-12-26 | Agent for alleviating adverse side effects produced in interferon/ribavirin combination therapy |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2008205299A JP2011051898A (en) | 2008-08-08 | 2008-08-08 | Agent for alleviating adverse side effect produced in interferon/ribavirin combination therapy |
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| JP2008205299A Pending JP2011051898A (en) | 2007-12-28 | 2008-08-08 | Agent for alleviating adverse side effect produced in interferon/ribavirin combination therapy |
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