WO2012018145A2 - Agent for improving quality of life - Google Patents
Agent for improving quality of life Download PDFInfo
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- WO2012018145A2 WO2012018145A2 PCT/JP2011/068339 JP2011068339W WO2012018145A2 WO 2012018145 A2 WO2012018145 A2 WO 2012018145A2 JP 2011068339 W JP2011068339 W JP 2011068339W WO 2012018145 A2 WO2012018145 A2 WO 2012018145A2
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- WO
- WIPO (PCT)
- Prior art keywords
- qol
- hepatocellular carcinoma
- improving
- patients
- liver function
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Definitions
- the present invention relates to a QOL (Quality of life) improving agent. More specifically, it contains human placenta extract (also called placenta hydrolyzate, placenta hydrolyzate, placenta extract, placenta hydrolyzate, etc.), is inexpensive, and provides QOL for patients with liver cancer (hepatocellular carcinoma).
- the present invention relates to a QOL improver that can be improved.
- hepatocellular carcinoma that arises from hepatocytes that are the liver's parenchyma and cholangiocellular carcinoma that arises from the bile duct in the liver, and about 90% of primary liver cancers are hepatocellular carcinoma.
- 80% to 90% of hepatocellular carcinoma occurs in association with cirrhosis or chronic hepatitis, which is the previous stage.
- treatment according to the cause (virus, alcohol, non-alcohol, drug, autoimmunity, etc.) is performed (for example, page 11 of Non-Patent Document 1, (See pages 18-19, 26, 36-37, etc.).
- Hepatocellular carcinoma in which hepatitis / cirrhosis has progressed is a disease with a high recurrence rate, not limited to viral, and metastatic hepatocellular carcinoma is a disease with a poor prognosis.
- various treatment methods have been tried (see pages 62 to 69 of Non-Patent Document 1).
- medical local treatment percutaneous ethanol local therapy, Cutaneous microwave coagulation therapy, radiofrequency ablation therapy, etc.
- TAE hepatic artery embolization therapy
- hepatic arterial infusion chemotherapy or the like
- Anti-hepatoma drugs for example, mitoxantrone, miriplatin hydrate, cisplatin, etc.
- molecular target drug sorafenib trade name: Nexavar, registered trademark
- Patent Document 1 describes an improvement in QOL of various cancer patients comprising administering a composition containing casein, peptone, RNA, and a serum albumin degradation product. It has not been revealed.
- the present invention has been made paying attention to the above problems. Its purpose is to reduce the economic burden on hepatocellular carcinoma patients, to suppress or reduce the growth of hepatocellular carcinoma, improve QOL, and consequently to increase the survival rate of hepatocellular carcinoma patients. Intensively studied and found that human placenta extract significantly improves QOL in patients with hepatocellular carcinoma. That is, this invention is providing the QOL improving agent for hepatocellular carcinoma patients which contains a placenta extract as an active ingredient.
- the gist of the present invention made to solve the above-mentioned problems is a QOL improving agent for hepatocellular carcinoma patients, comprising human placenta extract.
- the above-mentioned hepatocellular carcinoma patient may be a patient who has been administered a liver function improving agent including an interferon preparation and a nucleic acid related compound preparation.
- the liver function improving agent include glycyrrhizinate, ursodeoxycholic acid.
- Adenosine triphosphate flavin adenine dinucleotide, diisopropylamine dichloroacetate, glucuronolactone, glutathione, malotilate, methylmethionine sulfonium chloride, polyemphosphatidylcholine, protoporphyrin salt, branched chain amino acid preparation, liver hydrolyzate, interferon Examples include at least one selected from a preparation and a nucleic acid-related compound preparation. Furthermore, as a human placenta extract, Raeneck (trade name, registered trademark) is preferably used.
- the present invention also relates to a method for improving QOL, comprising a step of administering an effective amount of human placenta extract to a hepatocellular carcinoma patient, for preparing an agent for improving QOL of a hepatocellular carcinoma patient.
- a method for improving QOL comprising a step of administering an effective amount of human placenta extract to a hepatocellular carcinoma patient, for preparing an agent for improving QOL of a hepatocellular carcinoma patient.
- the use of human placenta extract comprising a step of administering an effective amount of human placenta extract to a hepatocellular carcinoma patient, for preparing an agent for improving QOL of a hepatocellular carcinoma patient.
- placenta extracts eg, Raeneck
- a liver function improving agent eg, monoammonium glycyrrhizinate
- the combined administration of the placenta extract and the liver function improving agent enables long-term administration.
- the cancer cells can be reduced, the subjective symptoms of the patient can be improved, and the QOL can be improved.
- the placenta extract can also reduce cancer cells by intravenous single continuous administration.
- placental extract can be used in combination with a liver function improving agent to allow longer-term administration of a liver function improving agent than with a liver function improving agent alone, improving liver function in patients with chronic liver disease.
- QOL is further improved.
- it has the feature that side effects caused by these administrations are few. Therefore, according to the present invention, taking into account the low drug price of Raeneck, it has a special effect in the treatment of hepatocellular carcinoma, including end-stage hepatocellular carcinoma.
- FIG. 1 is a graph showing the inhibitory effect of Raeneck on human hepatocellular carcinoma growth.
- (a), (b) and (c) show HepG2, HLE and Huh-7 cells, respectively.
- FIG. 2 is a graph showing the inhibitory effect on the growth of human hepatocellular carcinoma by the combined use of Raennek and monoammonium glycyrrhizinate.
- (a), (b) and (c) show HepG2, HLE and Huh-7 cells, respectively.
- ⁇ represents monoammonium glycyrrhizinate alone
- ⁇ represents monoammonium glycyrrhizinate + 10% raeneck
- ⁇ represents monoammonium glycyrrhizinate + 20% raeneck.
- the control (monoammonium glycyrrhizinate 0 ⁇ M) does not contain Raeneck.
- FIG. 3 is a graph showing that the GOT (AST) value and the GPT value were lowered when Laennec was used in combination with the patients (124 cases) whose GPT value did not fall by the third stage in Example 2. is there.
- FIG. 4 shows that as a result of combined use of pegylated interferon ⁇ and Laennec in hepatitis C patients who discontinued interferon therapy due to side effects, GOT and GPT values decreased and HCV (human hepatitis C virus) disappeared.
- shaft is IU / L.
- FIG. 5 is an abdominal dynamic CT image showing how the ascites of a hepatocellular carcinoma patient disappeared by treatment in Example 4 (part 1).
- FIG. 6 is an abdominal dynamic CT image showing how the ascites of a hepatocellular carcinoma patient disappeared by treatment in Example 4 (part 2).
- FIG. 7 is a graph showing the inhibitory effect on the growth of human hepatocellular carcinoma by the combined use of Raeneck and ursodeoxycholic acid.
- (a), (b) and (c) show HepG2, HLE and Huh-7 cells, respectively.
- ⁇ represents ursodeoxycholic acid alone
- ⁇ represents ursodeoxycholic acid + 10% raeneck
- ⁇ represents ursodeoxycholic acid + 20% raeneck.
- FIG. 8 is a graph showing the inhibitory effect on the growth of human hepatocellular carcinoma by the combined use of Raeneck and glucuronolactone.
- (a), (b) and (c) show HepG2, HLE and Huh-7 cells, respectively.
- ⁇ represents glucuronolactone alone
- ⁇ represents glucuronolactone + 10% raeneck
- ⁇ represents glucuronolactone + 20% raeneck.
- Significant difference tests were performed for glucuronolactone alone and Laennec alone.
- FIG. 9 is a diagram showing the inhibitory effect on human hepatocellular carcinoma growth by the combined use of Raeneck and glutathione.
- (a), (b) and (c) show HepG2, HLE and Huh-7 cells, respectively.
- ⁇ represents glutathione alone
- ⁇ represents glutathione + 10% raeneck
- ⁇ represents glutathione + 20% raeneck.
- FIG. 10 is a graph showing the inhibitory effect on the growth of human hepatocellular carcinoma by the combined use of Laennec and branched amino acids.
- (a), (b) and (c) show HepG2, HLE and Huh-7 cells, respectively.
- ⁇ represents a branched amino acid alone
- ⁇ represents a branched amino acid + 10% raeneck
- ⁇ represents a branched amino acid + 20% raeneck.
- FIG. 11 is a graph showing the inhibitory effect on the growth of human hepatocellular carcinoma by the combined use of Raenneck and methylmethioninesulfonium chloride.
- (a), (b) and (c) show HepG2, HLE and Huh-7 cells, respectively.
- ⁇ represents methylmethioninesulfonium chloride alone
- ⁇ represents methylmethioninesulfonium chloride + 10% raeneck
- ⁇ represents methylmethioninesulfonium chloride + 20% raeneck.
- the present invention is an agent for improving QOL for patients with hepatocellular carcinoma, comprising human placenta extract.
- the human placenta extract is not particularly limited in its extraction method, purification method, and treatment method.
- the human placenta extract is washed with water to remove blood, and if necessary, degreased, Examples thereof include those obtained by removing insoluble components after treatment by conventional methods such as pulverization, freeze-thawing, enzymatic degradation, and acid hydrolysis.
- the placenta extract is also referred to as placenta decomposition product, placenta hydrolyzate, placenta extract, placenta hydrolyzate and the like.
- Laennec is a preparation obtained by washing the placenta with water, removing blood, then degreasing with acetone, crushing, enzymatically decomposing with a protease, and further heat acid hydrolysis using hydrochloric acid to remove insoluble components.
- Laennec contains 112 mg of the above water-soluble substance of human placenta per tube (2 ml), and contains pepsin, lactose and pH adjuster as additives.
- the pH of Raeneck is 5.5 to 6.5, and the osmotic pressure ratio (ratio to physiological saline) is about 1.
- Raeneck contains nucleobases in addition to proteins and amino acids, not all the components have been identified.
- it has been studied for many years which of the contained components is involved in the efficacy effect it has not been elucidated.
- the effects of human placenta extract-containing products approved as pharmaceuticals are as described above, but it has been revealed that human placenta extract-containing products exhibit various other actions.
- Raeneck contains hepatocyte growth factor (HGF).
- HGF hepatocyte growth factor
- Laennec has been manufactured and sold as a liver function improving agent (intramuscular or subcutaneous administration) for chronic liver diseases since November 1984, but has never been applied to hepatocellular carcinoma.
- the main reasons are as follows.
- ⁇ Unlike the drugs listed above, which have the same efficacy and effect as Laenneq (improved liver function for chronic liver disease), the mechanism for improving liver function has not been elucidated;
- ⁇ There is no scientific basis (experimental data) for administering Raennec to patients with hepatocellular carcinoma; -Of the drugs listed above that have the same efficacy and effect as Laenneq (improved liver function for chronic liver disease), only a part of those drugs that have been studied for anti-hepatocellular carcinoma activity (ie, adenosine) Only sodium triphosphate, flavin adenine dinucleotide, monosodium glycyrrhizinate, ursodeoxycholic acid, etc.); ⁇ In addition, there are no reports
- the improvement of QOL means that the quality of life of a patient who has been lowered due to hepatocellular carcinoma is improved and then maintained to bring it closer to the normal human life.
- long-term treatment with anticancer drugs may conversely shorten the life of the patient, and even if the cancer is not completely cured, the life can be prolonged. Based on the idea that it is essential to have a comfortable life.
- Examples of QOL of patients who have decreased due to hepatocellular carcinoma include loss of appetite, weight loss, fatigue, general malaise, slight fever, abdominal distension, abdominal pain, ascites, jaundice and the like.
- the QOL improving agent of this invention contains a placenta extract
- content in a formulation will not be specifically limited, It can be set as a suitable quantity.
- conventional auxiliaries such as stabilizers, antioxidants, pH adjusters and soothing agents can be added.
- the dose of the placental extract to the hepatocellular carcinoma patient can be appropriately selected depending on the degree of disease, age, weight, etc. of the patient. (Containing 112 mg of placenta-derived component per ampoule) is administered once or divided into several times.
- As an administration method subcutaneous administration and intramuscular administration for which Raeneck is approved, and intravenous administration (use outside application) are also possible.
- the QOL improving agent of the present invention uses a liver function improving agent together with a placenta extract, they act synergistically to produce more excellent effects. That is, it is preferable that a hepatocellular carcinoma patient is administered a liver function improving agent together with the QOL improving agent of the present invention.
- the liver function improving agent means a drug that can suppress hepatitis, improve liver function, and suppress progression to liver cirrhosis or liver cancer regardless of disease-specific drugs and non-specific drugs.
- examples of such liver function improving agents include the following examples, including interferon preparations and nucleic acid related compound preparations which are disease-specific drugs.
- Glycyrrhizinate (monoammonium salt, monosodium salt): for example, strong minophagen P (intravenous injection) (trade name), strong neominophagen C (trade name) Adenosine triphosphate (sodium salt): For example, ATP Note 1 (trade name) Flavin adenine dinucleotide: eg Adelabin 9 Note (trade name) Ursodeoxycholic acid: For example, Urso tablet (trade name) Diisopropylamine dichloroacetate: for example Ribaol tablets (trade name) Glucuronolactone: Gronsan Injection (trade name), for example Glutathione: For example, Tachion Note (trade name) Malotilate: For example, Kandec Tablet (trade name) Methylmethionine sulfonium chloride: For example, Cavedin U Kowa (trade name) Polyenphosphatidylcholine: For example, Blobin capsule (trade
- liver function improving agent glycyrrhizinate, ursodeoxycholic acid, branched chain amino acid preparation, glucuronolactone, glutathione, and methylmethionine sulfonium chloride are preferable, and glycyrrhizinate and ursodeoxycholic acid are particularly preferable.
- Example 1 We investigated the growth inhibition effect of human hepatocarcinoma cells in vitro by the combined use of Raenneck and monoammonium glycyrrhizinate. [Materials and experimental methods] Reagent : Laeneck was used as the placenta extract. MTT assay was purchased from Nacalai.
- HepG2 liver cancer cell lines, differentiated, obtained from RIKEN
- HLE liver cancer cell lines, undifferentiated, obtained from JCRB (Japanese Collection of Research Bioresources) ) 10% serum-containing DMEM medium, Huh-7 (Hepatoma cell line, well-differentiated type, obtained from Tohoku University Research Institute for Aging) were each cultured in RPMI medium containing 10% serum.
- Example 2 This example shows that QOL of hepatitis patients affected by B virus, C virus, non-B non-C virus, and other causes is improved by administration of Raeneck. In the case of viral hepatitis, the goal is to eliminate the virus and lower the GPT value.
- liver function improving agent combination of ursodeoxycholic acid and monoammonium glycyrrhizinate
- the relationship between changes in GOT and GPT values and QOL improvement was examined.
- the following knowledge was obtained.
- Regimens for administration of liver function improving agents The total number of hepatitis patients (759 cases) treated for liver function improving agent administration, etc. is as shown in Table 1, but the patient's subjective findings and other objective findings (blood data, blood life Based on changes in chemical data, etc., the regimen for administration of liver function improving agents was as follows in principle.
- First stage Ursodeoxycholic acid (600 mg / day) orally administered
- Second stage Ursodeoxycholic acid and monoammonium glycyrrhizinate (40 ml to 60 ml three times a week) intravenously
- Third stage Ursodeoxycholic Increase the amount of monoammonium glycyrrhizinate used in combination with acid (60 ml to 100 ml 3 times a week)
- ii) Clinical effects
- Example 3 A man in his 50s who suffered from hepatitis C (genotype 2a), compensatory cirrhosis, and diffuse hepatocellular carcinoma. He was sentenced to one month of life in a hospital in Hiroshima Prefecture on April 9, 2007. I visited the hospital. He had subjective symptoms such as general malaise and loss of appetite, and his face was browned. April 20, 2007: With the consent of the patient, Laennek (one ampoule once every other day in the muscles) and monoammonium glycyrrhizinate (every other day, 3 ampoules intravenously) were started. UFT (Tegafur uracil, 2 tablets daily) was also prescribed. The results are shown over time.
- Example 4 The case was a man in his 50s who had a blood transfusion due to a traffic accident when he was 25 years old. I was working without any particular problems.
- Example 7 We investigated the growth inhibitory effect of human hepatocarcinoma cells in vitro by the combined use of Raennec and glucuronolactone. The determination of the presence of the material, the experimental method, and the combined effect is the same as in Example 5. The test results are shown in FIG. As shown in FIG.
- Example 7 We investigated the growth inhibitory effect of human hepatocarcinoma cells in vitro by the combined use of Laennec and glutathione. The determination of the presence of the material, the experimental method, and the combined effect is the same as in Example 5. The test results are shown in FIG. As shown in FIG. 9, when glutathione was used in combination with 10% Laennec, HepG2 and Huh-7 did not show a significant growth-inhibiting effect on cancer cells, but markedly suppressed against HLE.
- Example 8 We investigated the growth inhibitory effect of human hepatoma cells in vitro by the combined use of Laennec and branched amino acids. The determination of the presence of the material, the experimental method, and the combined effect is the same as in Example 5.
- the test results are shown in FIG.
- FIG. 10 when 10% Laennec was used in combination with a branched amino acid, HepG2 and Huh-7 did not show a significant growth inhibitory effect on cancer cells, but were prominent for HLE.
- Example 9 We investigated the growth-inhibitory effect of human hepatoma cells in vitro by the combined use of Raennec and methylmethioninesulfonium chloride. The determination of the presence of the material, the experimental method, and the combined effect is the same as in Example 5. The test results are shown in FIG. As shown in FIG. 11, when 10% Laeneck was used in combination with methylmethioninesulfonium chloride, HepG2 and Huh-7 did not show a significant growth inhibitory effect on cancer cells. A remarkable inhibitory effect was shown (see ⁇ in FIG. 11B).
- the QOL improving agent of the present invention hepatoma cells can be reduced, patient's subjective symptoms can be improved, and QOL can be improved, so that it is useful in the treatment of hepatocellular carcinoma including end-stage hepatocellular carcinoma.
- the QOL improving agent of the present invention when used in combination with a liver function improving agent, can significantly suppress the growth of hepatocellular carcinoma due to their synergistic effect, and thus is useful for the treatment of hepatocellular carcinoma.
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Abstract
Provided is an agent for improving the quality of life of hepatocellular carcinoma patients. The agent for improving the quality of life of hepatocellular carcinoma patients is characterized by including a human placenta extract, and is preferably used concomitantly with a liver function-improving agent (for example, a glycyrrhizinate). The agent for improving quality of life shrinks hepatoma cells, improves the subjective symptoms of patients and improves quality of life, and thus is particularly effective for the treatment of hepatocellular carcinoma, including end-stage hepatocellular carcinoma.
Description
本発明はＱＯＬ（Ｑｕａｌｉｔｙ ｏｆ ｌｉｆｅ：生活の質）改善剤に関する。より詳細には、ヒトの胎盤抽出物（胎盤分解物、胎盤水解物、胎盤エキス、胎盤加水分解物などとも称される）を含有し、安価で、肝臓癌（肝細胞癌）患者のＱＯＬを向上させることのできるＱＯＬ改善剤に関する。
The present invention relates to a QOL (Quality of life) improving agent. More specifically, it contains human placenta extract (also called placenta hydrolyzate, placenta hydrolyzate, placenta extract, placenta hydrolyzate, etc.), is inexpensive, and provides QOL for patients with liver cancer (hepatocellular carcinoma). The present invention relates to a QOL improver that can be improved.
原発性肝癌は、肝臓の実質である肝細胞から発生する肝細胞癌と、肝臓内の胆管から発生する胆管細胞癌に大別され、原発性肝癌の約９０％は肝細胞癌である。
肝細胞癌の８０％~９０％は、肝硬変あるいはその前段階である慢性肝炎に合併して発生する。肝細胞癌の前段階である慢性肝炎に対しては、その原因（ウイルス、アルコール、非アルコール、薬物、自己免疫性など）に応じた治療が行われる（例えば、非特許文献１の１１頁、１８~１９頁、２６頁、３６~３７頁など参照）。
Ｂ型慢性肝炎患者には、年齢、ウイルス量、ＧＰＴ（ＡＬＴ）値、炎症の程度、線維化の程度等の病態を考慮して、ペグインターフェロンを含むインターフェロン製剤、あるいはラミブジン等の核酸関連化合物、さらにはウルソデオキシコール酸、グリチルリチン酸モノアンモニウム等の肝機能改善剤（肝庇護剤）などの単独あるいは併用療法が多用されるが、ラミブジンは胎児への影響や長期投与による耐性ウイルスの出現などが知られている。
一方、Ｃ型慢性肝炎患者の場合も、年齢、ウイルス量、ＧＰＴ値等の病態を考慮して、ペグインターフェロン製剤、あるいはリバビリン（核酸関連化合物）、さらにはウルソデオキシコール酸、グリチルリチン酸モノアンモニウム等の肝機能改善剤などの単独あるいは併用療法が多用されるが、副作用により治療を断念する例も少なくない。
ちなみに、高ＨＣＶ−ＲＮＡ値のＣ型肝炎患者にリバビリン単独あるいはペグインターフェロンとリバビリンを併用投与した場合、副作用による脱落率は１７％（６５歳以上は２８％）にも達する。副作用による治療断念の理由は、貧血・ヘモグロビン減少が最も多い。貧血症状を来すと、リバビリン投与は不可能になる。その他、発疹・掻痒症、うつ状態を含む精神症状、肝発癌なども中止の理由となっている。
肝硬変に対しては、Ｂ型由来の場合は抗ウイルス療法を、Ｃ型由来の場合はインターフェロン療法を行うこともあるが、治療の基本は利尿剤の投与など対症的である。
上述した薬物療法によって慢性肝炎患者、肝硬変患者のＱＯＬが向上したという報告は多くない。ウイルス性肝炎の場合、ウイルスの消失、ＧＰＴ値の低下が目標である。そのためには、副作用を少なくし、標準的治療方法（例えば、ペグインターフェロンとリバビリンとの併用療法）をいかに持続させうるかがポイントになる。
肝炎・肝硬変が進展した肝細胞癌は、ウイルス性に限らず、再発率が高い疾患であり、転移性肝細胞癌は予後が悪い疾患である。現在、種々の治療法が試みられており（前掲非特許文献１の第６２~６９頁参照）、例えば早期癌に対しては、肝切除、内科的局所治療（経皮的エタノール局所療法、経皮的マイクロ波凝固療法、ラジオ波焼灼療法等）が根治的に行われるようになった。
進行癌に対しては、ＴＡＥ（肝動脈塞栓療法）、肝動注化学療法等による治療が行われている。
化学療法としては、抗肝癌剤（例えば、ミトキサントロン酸塩、ミリプラチン水和物、シスプラチンなど）が使用されており、最近、分子標的薬ソラフェニブ（商品名：ネクサバール、登録商標）が承認、製造販売されるなど、薬物療法にも進展はみられつつある。
肝細胞癌の発生機序について多くの知見が集積されているにもかかわらず、依然として不明な点が多いこともあって、治療法は確立されていない。このように、肝細胞癌を制圧することは極めて困難な状況であり、よって長年、入退院を繰り返しながら治療を受ける患者や、通院で治療を受ける患者に対しては、ＱＯＬの維持・改善をとくに考慮する必要がある。そのＱＯＬの維持・改善対策についても多面的な検討は行われているが、薬物療法の面では、前記抗肝細胞癌剤の副作用（例えば、ＧＯＴ値の上昇のような肝機能障害、白血球や血小板の減少のような血液障害、食欲不振のような消化器障害など）が高頻度に発生することに加え、高薬価であることが患者の経済的負担になっており、ＱＯＬの維持・改善対策推進の大きな障害になっている。
なお、特許文献１には、カゼイン、ペプトン、ＲＮＡ及び血清アルブミン分解生成物を含有する組成物を投与することからなる各種癌患者のＱＯＬの改善が記載されているが、肝細胞癌に対する効果は明らかにされていない。 Primary liver cancer is roughly classified into hepatocellular carcinoma that arises from hepatocytes that are the liver's parenchyma and cholangiocellular carcinoma that arises from the bile duct in the liver, and about 90% of primary liver cancers are hepatocellular carcinoma.
80% to 90% of hepatocellular carcinoma occurs in association with cirrhosis or chronic hepatitis, which is the previous stage. For chronic hepatitis, which is the previous stage of hepatocellular carcinoma, treatment according to the cause (virus, alcohol, non-alcohol, drug, autoimmunity, etc.) is performed (for example, page 11 of Non-PatentDocument 1, (See pages 18-19, 26, 36-37, etc.).
In patients with chronic hepatitis B, considering the pathology such as age, viral load, GPT (ALT) value, degree of inflammation, degree of fibrosis, interferon preparations containing peginterferon, or nucleic acid related compounds such as lamivudine, Furthermore, single or combination treatments such as ursodeoxycholic acid and monoammonium glycyrrhizinate are often used alone or in combination, but lamivudine has an effect on the fetus and the appearance of resistant viruses due to long-term administration. Are known.
On the other hand, in the case of patients with chronic hepatitis C, peginterferon preparations or ribavirin (nucleic acid-related compounds), ursodeoxycholic acid, monoammonium glycyrrhizinate, etc. in consideration of the pathological conditions such as age, viral load, GPT value, etc. However, there are many cases in which the treatment is abandoned due to side effects.
Incidentally, when ribavirin alone or a combination of peginterferon and ribavirin is administered to hepatitis C patients with high HCV-RNA levels, the dropout rate due to side effects reaches 17% (28% for those 65 years and older). The most common reason for abandoning treatment due to side effects is anemia / hemoglobin reduction. If anemia occurs, ribavirin administration becomes impossible. In addition, rash / pruritus, psychiatric symptoms including depression, and liver carcinogenesis are also reasons for discontinuation.
For cirrhosis, antiviral therapy may be performed if derived from type B, and interferon therapy may be performed if derived from type C, but the basic treatment is symptomatic such as administration of a diuretic.
There are not many reports that the QOL of patients with chronic hepatitis and cirrhosis has improved by the above-mentioned drug therapy. In the case of viral hepatitis, the goal is to eliminate the virus and lower the GPT value. To that end, it is important to reduce side effects and maintain a standard treatment method (for example, peginterferon and ribavirin combination therapy).
Hepatocellular carcinoma in which hepatitis / cirrhosis has progressed is a disease with a high recurrence rate, not limited to viral, and metastatic hepatocellular carcinoma is a disease with a poor prognosis. Currently, various treatment methods have been tried (see pages 62 to 69 of Non-Patent Document 1). For early cancer, for example, hepatectomy, medical local treatment (percutaneous ethanol local therapy, Cutaneous microwave coagulation therapy, radiofrequency ablation therapy, etc.) have been radically performed.
For advanced cancer, treatment with TAE (hepatic artery embolization therapy), hepatic arterial infusion chemotherapy, or the like is performed.
Anti-hepatoma drugs (for example, mitoxantrone, miriplatin hydrate, cisplatin, etc.) are used as chemotherapy, and recently molecular target drug sorafenib (trade name: Nexavar, registered trademark) has been approved and manufactured Progress is also being made in pharmacotherapy, such as being sold.
Despite the accumulated knowledge about the pathogenesis of hepatocellular carcinoma, there are still many unclear points, and no treatment has been established. In this way, it is extremely difficult to control hepatocellular carcinoma. Therefore, maintenance and improvement of QOL is especially important for patients who have been treated for many years and who have been repeatedly hospitalized or who are treated at hospital. It is necessary to consider. Although multifaceted studies have also been conducted on measures for maintaining and improving the QOL, in terms of pharmacotherapy, side effects of the anti-hepatocellular carcinoma agent (for example, liver dysfunction such as an increase in GOT value, leukocytes and In addition to the frequent occurrence of blood disorders such as decreased platelets and gastrointestinal disorders such as anorexia, high drug prices are an economic burden for patients, and maintenance and improvement of QOL This is a major obstacle to promoting measures.
In addition,Patent Document 1 describes an improvement in QOL of various cancer patients comprising administering a composition containing casein, peptone, RNA, and a serum albumin degradation product. It has not been revealed.
肝細胞癌の８０％~９０％は、肝硬変あるいはその前段階である慢性肝炎に合併して発生する。肝細胞癌の前段階である慢性肝炎に対しては、その原因（ウイルス、アルコール、非アルコール、薬物、自己免疫性など）に応じた治療が行われる（例えば、非特許文献１の１１頁、１８~１９頁、２６頁、３６~３７頁など参照）。
Ｂ型慢性肝炎患者には、年齢、ウイルス量、ＧＰＴ（ＡＬＴ）値、炎症の程度、線維化の程度等の病態を考慮して、ペグインターフェロンを含むインターフェロン製剤、あるいはラミブジン等の核酸関連化合物、さらにはウルソデオキシコール酸、グリチルリチン酸モノアンモニウム等の肝機能改善剤（肝庇護剤）などの単独あるいは併用療法が多用されるが、ラミブジンは胎児への影響や長期投与による耐性ウイルスの出現などが知られている。
一方、Ｃ型慢性肝炎患者の場合も、年齢、ウイルス量、ＧＰＴ値等の病態を考慮して、ペグインターフェロン製剤、あるいはリバビリン（核酸関連化合物）、さらにはウルソデオキシコール酸、グリチルリチン酸モノアンモニウム等の肝機能改善剤などの単独あるいは併用療法が多用されるが、副作用により治療を断念する例も少なくない。
ちなみに、高ＨＣＶ−ＲＮＡ値のＣ型肝炎患者にリバビリン単独あるいはペグインターフェロンとリバビリンを併用投与した場合、副作用による脱落率は１７％（６５歳以上は２８％）にも達する。副作用による治療断念の理由は、貧血・ヘモグロビン減少が最も多い。貧血症状を来すと、リバビリン投与は不可能になる。その他、発疹・掻痒症、うつ状態を含む精神症状、肝発癌なども中止の理由となっている。
肝硬変に対しては、Ｂ型由来の場合は抗ウイルス療法を、Ｃ型由来の場合はインターフェロン療法を行うこともあるが、治療の基本は利尿剤の投与など対症的である。
上述した薬物療法によって慢性肝炎患者、肝硬変患者のＱＯＬが向上したという報告は多くない。ウイルス性肝炎の場合、ウイルスの消失、ＧＰＴ値の低下が目標である。そのためには、副作用を少なくし、標準的治療方法（例えば、ペグインターフェロンとリバビリンとの併用療法）をいかに持続させうるかがポイントになる。
肝炎・肝硬変が進展した肝細胞癌は、ウイルス性に限らず、再発率が高い疾患であり、転移性肝細胞癌は予後が悪い疾患である。現在、種々の治療法が試みられており（前掲非特許文献１の第６２~６９頁参照）、例えば早期癌に対しては、肝切除、内科的局所治療（経皮的エタノール局所療法、経皮的マイクロ波凝固療法、ラジオ波焼灼療法等）が根治的に行われるようになった。
進行癌に対しては、ＴＡＥ（肝動脈塞栓療法）、肝動注化学療法等による治療が行われている。
化学療法としては、抗肝癌剤（例えば、ミトキサントロン酸塩、ミリプラチン水和物、シスプラチンなど）が使用されており、最近、分子標的薬ソラフェニブ（商品名：ネクサバール、登録商標）が承認、製造販売されるなど、薬物療法にも進展はみられつつある。
肝細胞癌の発生機序について多くの知見が集積されているにもかかわらず、依然として不明な点が多いこともあって、治療法は確立されていない。このように、肝細胞癌を制圧することは極めて困難な状況であり、よって長年、入退院を繰り返しながら治療を受ける患者や、通院で治療を受ける患者に対しては、ＱＯＬの維持・改善をとくに考慮する必要がある。そのＱＯＬの維持・改善対策についても多面的な検討は行われているが、薬物療法の面では、前記抗肝細胞癌剤の副作用（例えば、ＧＯＴ値の上昇のような肝機能障害、白血球や血小板の減少のような血液障害、食欲不振のような消化器障害など）が高頻度に発生することに加え、高薬価であることが患者の経済的負担になっており、ＱＯＬの維持・改善対策推進の大きな障害になっている。
なお、特許文献１には、カゼイン、ペプトン、ＲＮＡ及び血清アルブミン分解生成物を含有する組成物を投与することからなる各種癌患者のＱＯＬの改善が記載されているが、肝細胞癌に対する効果は明らかにされていない。 Primary liver cancer is roughly classified into hepatocellular carcinoma that arises from hepatocytes that are the liver's parenchyma and cholangiocellular carcinoma that arises from the bile duct in the liver, and about 90% of primary liver cancers are hepatocellular carcinoma.
80% to 90% of hepatocellular carcinoma occurs in association with cirrhosis or chronic hepatitis, which is the previous stage. For chronic hepatitis, which is the previous stage of hepatocellular carcinoma, treatment according to the cause (virus, alcohol, non-alcohol, drug, autoimmunity, etc.) is performed (for example, page 11 of Non-Patent
In patients with chronic hepatitis B, considering the pathology such as age, viral load, GPT (ALT) value, degree of inflammation, degree of fibrosis, interferon preparations containing peginterferon, or nucleic acid related compounds such as lamivudine, Furthermore, single or combination treatments such as ursodeoxycholic acid and monoammonium glycyrrhizinate are often used alone or in combination, but lamivudine has an effect on the fetus and the appearance of resistant viruses due to long-term administration. Are known.
On the other hand, in the case of patients with chronic hepatitis C, peginterferon preparations or ribavirin (nucleic acid-related compounds), ursodeoxycholic acid, monoammonium glycyrrhizinate, etc. in consideration of the pathological conditions such as age, viral load, GPT value, etc. However, there are many cases in which the treatment is abandoned due to side effects.
Incidentally, when ribavirin alone or a combination of peginterferon and ribavirin is administered to hepatitis C patients with high HCV-RNA levels, the dropout rate due to side effects reaches 17% (28% for those 65 years and older). The most common reason for abandoning treatment due to side effects is anemia / hemoglobin reduction. If anemia occurs, ribavirin administration becomes impossible. In addition, rash / pruritus, psychiatric symptoms including depression, and liver carcinogenesis are also reasons for discontinuation.
For cirrhosis, antiviral therapy may be performed if derived from type B, and interferon therapy may be performed if derived from type C, but the basic treatment is symptomatic such as administration of a diuretic.
There are not many reports that the QOL of patients with chronic hepatitis and cirrhosis has improved by the above-mentioned drug therapy. In the case of viral hepatitis, the goal is to eliminate the virus and lower the GPT value. To that end, it is important to reduce side effects and maintain a standard treatment method (for example, peginterferon and ribavirin combination therapy).
Hepatocellular carcinoma in which hepatitis / cirrhosis has progressed is a disease with a high recurrence rate, not limited to viral, and metastatic hepatocellular carcinoma is a disease with a poor prognosis. Currently, various treatment methods have been tried (see pages 62 to 69 of Non-Patent Document 1). For early cancer, for example, hepatectomy, medical local treatment (percutaneous ethanol local therapy, Cutaneous microwave coagulation therapy, radiofrequency ablation therapy, etc.) have been radically performed.
For advanced cancer, treatment with TAE (hepatic artery embolization therapy), hepatic arterial infusion chemotherapy, or the like is performed.
Anti-hepatoma drugs (for example, mitoxantrone, miriplatin hydrate, cisplatin, etc.) are used as chemotherapy, and recently molecular target drug sorafenib (trade name: Nexavar, registered trademark) has been approved and manufactured Progress is also being made in pharmacotherapy, such as being sold.
Despite the accumulated knowledge about the pathogenesis of hepatocellular carcinoma, there are still many unclear points, and no treatment has been established. In this way, it is extremely difficult to control hepatocellular carcinoma. Therefore, maintenance and improvement of QOL is especially important for patients who have been treated for many years and who have been repeatedly hospitalized or who are treated at hospital. It is necessary to consider. Although multifaceted studies have also been conducted on measures for maintaining and improving the QOL, in terms of pharmacotherapy, side effects of the anti-hepatocellular carcinoma agent (for example, liver dysfunction such as an increase in GOT value, leukocytes and In addition to the frequent occurrence of blood disorders such as decreased platelets and gastrointestinal disorders such as anorexia, high drug prices are an economic burden for patients, and maintenance and improvement of QOL This is a major obstacle to promoting measures.
In addition,
本発明は、上記の課題に着目して行われたものである。その目的は肝細胞癌患者の経済的負担が少なく、肝細胞癌の増殖を抑制あるいは縮小、ＱＯＬを向上させ、結果として、肝細胞癌患者の生存率を延長させることにあり、本発明者らが鋭意検討したところ、ヒト胎盤抽出物が肝細胞癌患者のＱＯＬを著しく改善することを見出した。即ち、本発明は胎盤抽出物を有効成分として含有する、肝細胞癌患者用のＱＯＬ改善剤を提供することにある。
The present invention has been made paying attention to the above problems. Its purpose is to reduce the economic burden on hepatocellular carcinoma patients, to suppress or reduce the growth of hepatocellular carcinoma, improve QOL, and consequently to increase the survival rate of hepatocellular carcinoma patients. Intensively studied and found that human placenta extract significantly improves QOL in patients with hepatocellular carcinoma. That is, this invention is providing the QOL improving agent for hepatocellular carcinoma patients which contains a placenta extract as an active ingredient.
上記の課題を解決するためになされた本発明の要旨は、ヒト胎盤抽出物を含有することからなる、肝細胞癌患者のＱＯＬ改善剤である。
上記の肝細胞癌患者は、インターフェロン製剤及び核酸関連化合物製剤を含めて肝機能改善剤を投与されている患者であってもよく、当該肝機能改善剤としては、グリチルリチン酸塩、ウルソデオキシコール酸、アデノシン三リン酸塩、フラビンアデニンジヌクレオチド、ジクロロ酢酸ジイソプロピルアミン、グルクロノラクトン、グルタチオン、マロチラート、メチルメチオニンスルホニウムクロリド、ポリエンフォスファチジルコリン、プロトポルフィリン塩、分岐鎖アミノ酸製剤、肝水解物、インターフェロン製剤及び核酸関連化合物製剤から選ばれた少なくとも１種が例示される。更に、ヒト胎盤抽出物としてはラエンネック（商品名、登録商標）が好適に使用される。
また、本発明は、ヒト胎盤抽出物の有効量を、肝細胞癌患者に投与する工程を含む、ＱＯＬの改善方法であり、肝細胞癌患者のＱＯＬを改善するための剤を調製するためのヒト胎盤抽出物の使用である。 The gist of the present invention made to solve the above-mentioned problems is a QOL improving agent for hepatocellular carcinoma patients, comprising human placenta extract.
The above-mentioned hepatocellular carcinoma patient may be a patient who has been administered a liver function improving agent including an interferon preparation and a nucleic acid related compound preparation. Examples of the liver function improving agent include glycyrrhizinate, ursodeoxycholic acid. , Adenosine triphosphate, flavin adenine dinucleotide, diisopropylamine dichloroacetate, glucuronolactone, glutathione, malotilate, methylmethionine sulfonium chloride, polyemphosphatidylcholine, protoporphyrin salt, branched chain amino acid preparation, liver hydrolyzate, interferon Examples include at least one selected from a preparation and a nucleic acid-related compound preparation. Furthermore, as a human placenta extract, Raeneck (trade name, registered trademark) is preferably used.
The present invention also relates to a method for improving QOL, comprising a step of administering an effective amount of human placenta extract to a hepatocellular carcinoma patient, for preparing an agent for improving QOL of a hepatocellular carcinoma patient. The use of human placenta extract.
上記の肝細胞癌患者は、インターフェロン製剤及び核酸関連化合物製剤を含めて肝機能改善剤を投与されている患者であってもよく、当該肝機能改善剤としては、グリチルリチン酸塩、ウルソデオキシコール酸、アデノシン三リン酸塩、フラビンアデニンジヌクレオチド、ジクロロ酢酸ジイソプロピルアミン、グルクロノラクトン、グルタチオン、マロチラート、メチルメチオニンスルホニウムクロリド、ポリエンフォスファチジルコリン、プロトポルフィリン塩、分岐鎖アミノ酸製剤、肝水解物、インターフェロン製剤及び核酸関連化合物製剤から選ばれた少なくとも１種が例示される。更に、ヒト胎盤抽出物としてはラエンネック（商品名、登録商標）が好適に使用される。
また、本発明は、ヒト胎盤抽出物の有効量を、肝細胞癌患者に投与する工程を含む、ＱＯＬの改善方法であり、肝細胞癌患者のＱＯＬを改善するための剤を調製するためのヒト胎盤抽出物の使用である。 The gist of the present invention made to solve the above-mentioned problems is a QOL improving agent for hepatocellular carcinoma patients, comprising human placenta extract.
The above-mentioned hepatocellular carcinoma patient may be a patient who has been administered a liver function improving agent including an interferon preparation and a nucleic acid related compound preparation. Examples of the liver function improving agent include glycyrrhizinate, ursodeoxycholic acid. , Adenosine triphosphate, flavin adenine dinucleotide, diisopropylamine dichloroacetate, glucuronolactone, glutathione, malotilate, methylmethionine sulfonium chloride, polyemphosphatidylcholine, protoporphyrin salt, branched chain amino acid preparation, liver hydrolyzate, interferon Examples include at least one selected from a preparation and a nucleic acid-related compound preparation. Furthermore, as a human placenta extract, Raeneck (trade name, registered trademark) is preferably used.
The present invention also relates to a method for improving QOL, comprising a step of administering an effective amount of human placenta extract to a hepatocellular carcinoma patient, for preparing an agent for improving QOL of a hepatocellular carcinoma patient. The use of human placenta extract.
後記実施例に示されるように、胎盤抽出物（例えばラエンネック）は肝細胞癌株の増殖を阻害する作用を有しており、特に肝機能改善剤（例えばグリチルリチン酸モノアンモニウム）と併用すると、それらの相乗効果により肝細胞癌株の増殖を顕著に抑制し得る。また、胎盤抽出物と肝機能改善剤との併用投与により、長期間の投与が可能になり、その結果、癌細胞を縮小させ、患者の自覚症状を改善し、ＱＯＬを向上させることができる。さらには、胎盤抽出物は、静脈内単独連続投与によっても、癌細胞を縮小させることができる。
また、胎盤抽出物は肝機能改善剤と併用することにより、肝機能改善剤の単独投与より、より長期間の肝機能改善剤の投与が可能になり、慢性肝疾患患者の肝機能が改善し、ＱＯＬが一層向上する。
しかも、これら投与によって発生する副作用は少ないという特長を有している。従って、本発明によれば、ラエンネックの薬価が低いことを考慮すると、末期の肝細胞癌も含め、肝細胞癌の治療において格別な効果をもたらす。 As shown in Examples below, placenta extracts (eg, Raeneck) have an action of inhibiting the growth of hepatocellular carcinoma strains, and particularly when used in combination with a liver function improving agent (eg, monoammonium glycyrrhizinate) This synergistic effect can significantly suppress the growth of hepatocellular carcinoma strains. Further, the combined administration of the placenta extract and the liver function improving agent enables long-term administration. As a result, the cancer cells can be reduced, the subjective symptoms of the patient can be improved, and the QOL can be improved. Furthermore, the placenta extract can also reduce cancer cells by intravenous single continuous administration.
In addition, placental extract can be used in combination with a liver function improving agent to allow longer-term administration of a liver function improving agent than with a liver function improving agent alone, improving liver function in patients with chronic liver disease. , QOL is further improved.
In addition, it has the feature that side effects caused by these administrations are few. Therefore, according to the present invention, taking into account the low drug price of Raeneck, it has a special effect in the treatment of hepatocellular carcinoma, including end-stage hepatocellular carcinoma.
また、胎盤抽出物は肝機能改善剤と併用することにより、肝機能改善剤の単独投与より、より長期間の肝機能改善剤の投与が可能になり、慢性肝疾患患者の肝機能が改善し、ＱＯＬが一層向上する。
しかも、これら投与によって発生する副作用は少ないという特長を有している。従って、本発明によれば、ラエンネックの薬価が低いことを考慮すると、末期の肝細胞癌も含め、肝細胞癌の治療において格別な効果をもたらす。 As shown in Examples below, placenta extracts (eg, Raeneck) have an action of inhibiting the growth of hepatocellular carcinoma strains, and particularly when used in combination with a liver function improving agent (eg, monoammonium glycyrrhizinate) This synergistic effect can significantly suppress the growth of hepatocellular carcinoma strains. Further, the combined administration of the placenta extract and the liver function improving agent enables long-term administration. As a result, the cancer cells can be reduced, the subjective symptoms of the patient can be improved, and the QOL can be improved. Furthermore, the placenta extract can also reduce cancer cells by intravenous single continuous administration.
In addition, placental extract can be used in combination with a liver function improving agent to allow longer-term administration of a liver function improving agent than with a liver function improving agent alone, improving liver function in patients with chronic liver disease. , QOL is further improved.
In addition, it has the feature that side effects caused by these administrations are few. Therefore, according to the present invention, taking into account the low drug price of Raeneck, it has a special effect in the treatment of hepatocellular carcinoma, including end-stage hepatocellular carcinoma.
図１はラエンネックのヒト肝細胞癌増殖への抑制効果を示す図である。図中、（ａ）、（ｂ）及び（ｃ）はそれぞれＨｅｐＧ２、ＨＬＥ及びＨｕｈ−７細胞を示す。
図２は、ラエンネックとグリチルリチン酸モノアンモニウムの併用によるヒト肝細胞癌増殖への抑制効果を示す図である。図中、（ａ）、（ｂ）及び（ｃ）はそれぞれＨｅｐＧ２、ＨＬＥ及びＨｕｈ−７細胞を示す。また、□はグリチルリチン酸モノアンモニウム単独、●はグリチルリチン酸モノアンモニウム＋１０％ラエンネック、○はグリチルリチン酸モノアンモニウム＋２０％ラエンネックを示す。コントロール（グリチルリチン酸モノアンモニウム ０μＭ）にはラエンネックは含まれていない。データは平均値±標準偏差（ｎ＝３）で示した。有意差検定はグリチルリチン酸モノアンモニウム単独に対して行った。＊ｐ＜０．０５、＊＊ｐ＜０．００５
図３は、実施例２において、第三段階までにＧＰＴ値が低下しなかった患者（１２４例）にラエンネックを併用したときに、ＧＯＴ（ＡＳＴ）値及びＧＰＴ値が低下したことを示す図である。
図４は、副作用のためインターフェロン療法を中止したＣ型肝炎患者に、ペグインターフェロンαとラエンネックを併用した結果、ＧＯＴ値及びＧＰＴ値が低下し、ＨＣＶ（ヒトＣ型肝炎ウイルス）が消失したことを示す図である。なお、ＧＯＴ値及びＧＰＴ値に関し、縦軸はＩＵ／Ｌである。
図５は、実施例４において、肝細胞癌患者の腹水が治療により消失していく経緯を示した腹部ダイナミックＣＴ画像である（その１）。
図６は、実施例４において、肝細胞癌患者の腹水が治療により消失していく経緯を示した腹部ダイナミックＣＴ画像である（その２）。
図７は、ラエンネックとウルソデオキシコール酸の併用によるヒト肝細胞癌増殖への抑制効果を示す図である。図中、（ａ）、（ｂ）及び（ｃ）はそれぞれＨｅｐＧ２、ＨＬＥ及びＨｕｈ−７細胞を示す。また、□はウルソデオキシコール酸単独、●はウルソデオキシコール酸＋１０％ラエンネック、○はウルソデオキシコール酸＋２０％ラエンネックを示す。データは平均値±標準偏差（ｎ＝３）で示した。有意差検定はウルソデオキシコール酸単独とラエンネック単独に対して行った。＊ｐ＜０．０５、＊＊ｐ＜０．００５
図８はラエンネックとグルクロノラクトンの併用によるヒト肝細胞癌増殖への抑制効果を示す図である。図中、（ａ）、（ｂ）及び（ｃ）はそれぞれＨｅｐＧ２、ＨＬＥ及びＨｕｈ−７細胞を示す。また、□はグルクロノラクトン単独、●はグルクロノラクトン＋１０％ラエンネック、○はグルクロノラクトン＋２０％ラエンネックを示す。データは平均値±標準偏差（ｎ＝３）で示した。有意差検定はグルクロノラクトン単独とラエンネック単独に対して行った。＊ｐ＜０．０５、＊＊ｐ＜０．００５
図９はラエンネックとグルタチオンの併用によるヒト肝細胞癌増殖への抑制効果を示す図である。図中、（ａ）、（ｂ）及び（ｃ）はそれぞれＨｅｐＧ２、ＨＬＥ及びＨｕｈ−７細胞を示す。また、□はグルタチオン単独、●はグルタチオン＋１０％ラエンネック、○はグルタチオン＋２０％ラエンネックを示す。データは平均値±標準偏差（ｎ＝３）で示した。有意差検定はグルタチオン単独とラエンネック単独に対して行った。＊ｐ＜０．０５、＊＊ｐ＜０．００５
図１０はラエンネックと分岐アミノ酸の併用によるヒト肝細胞癌増殖への抑制効果を示す図である。図中、（ａ）、（ｂ）及び（ｃ）はそれぞれＨｅｐＧ２、ＨＬＥ及びＨｕｈ−７細胞を示す。また、□は分岐アミノ酸単独、●は分岐アミノ酸＋１０％ラエンネック、○は分岐アミノ酸＋２０％ラエンネックを示す。データは平均値±標準偏差（ｎ＝３）で示した。有意差検定は分岐アミノ酸単独とラエンネック単独に対して行った。＊ｐ＜０．０５、＊＊ｐ＜０．００５
図１１はラエンネックとメチルメチオニンスルホニウムクロリドの併用によるヒト肝細胞癌増殖への抑制効果を示す図である。図中、（ａ）、（ｂ）及び（ｃ）はそれぞれＨｅｐＧ２、ＨＬＥ及びＨｕｈ−７細胞を示す。また、□はメチルメチオニンスルホニウムクロリド単独、●はメチルメチオニンスルホニウムクロリド＋１０％ラエンネック、○はメチルメチオニンスルホニウムクロリド＋２０％ラエンネックを示す。データは平均値±標準偏差（ｎ＝３）で示した。有意差検定はメチルメチオニンスルホニウムクロリド単独とラエンネック単独に対して行った。＊ｐ＜０．０５、＊＊ｐ＜０．００５ FIG. 1 is a graph showing the inhibitory effect of Raeneck on human hepatocellular carcinoma growth. In the figure, (a), (b) and (c) show HepG2, HLE and Huh-7 cells, respectively.
FIG. 2 is a graph showing the inhibitory effect on the growth of human hepatocellular carcinoma by the combined use of Raennek and monoammonium glycyrrhizinate. In the figure, (a), (b) and (c) show HepG2, HLE and Huh-7 cells, respectively. Further, □ represents monoammonium glycyrrhizinate alone, ● represents monoammonium glycyrrhizinate + 10% raeneck, and ◯ represents monoammonium glycyrrhizinate + 20% raeneck. The control (monoammonium glycyrrhizinate 0 μM) does not contain Raeneck. Data are shown as mean ± standard deviation (n = 3). A significant difference test was performed on monoammonium glycyrrhizinate alone. * P <0.05, ** p <0.005
FIG. 3 is a graph showing that the GOT (AST) value and the GPT value were lowered when Laennec was used in combination with the patients (124 cases) whose GPT value did not fall by the third stage in Example 2. is there.
FIG. 4 shows that as a result of combined use of pegylated interferon α and Laennec in hepatitis C patients who discontinued interferon therapy due to side effects, GOT and GPT values decreased and HCV (human hepatitis C virus) disappeared. FIG. In addition, regarding a GOT value and a GPT value, a vertical axis | shaft is IU / L.
FIG. 5 is an abdominal dynamic CT image showing how the ascites of a hepatocellular carcinoma patient disappeared by treatment in Example 4 (part 1).
FIG. 6 is an abdominal dynamic CT image showing how the ascites of a hepatocellular carcinoma patient disappeared by treatment in Example 4 (part 2).
FIG. 7 is a graph showing the inhibitory effect on the growth of human hepatocellular carcinoma by the combined use of Raeneck and ursodeoxycholic acid. In the figure, (a), (b) and (c) show HepG2, HLE and Huh-7 cells, respectively. Further, □ represents ursodeoxycholic acid alone, ● represents ursodeoxycholic acid + 10% raeneck, and ◯ represents ursodeoxycholic acid + 20% raeneck. Data are shown as mean ± standard deviation (n = 3). Significant difference tests were performed for ursodeoxycholic acid alone and Laennec alone. * P <0.05, ** p <0.005
FIG. 8 is a graph showing the inhibitory effect on the growth of human hepatocellular carcinoma by the combined use of Raeneck and glucuronolactone. In the figure, (a), (b) and (c) show HepG2, HLE and Huh-7 cells, respectively. Further, □ represents glucuronolactone alone, ● represents glucuronolactone + 10% raeneck, and ◯ represents glucuronolactone + 20% raeneck. Data are shown as mean ± standard deviation (n = 3). Significant difference tests were performed for glucuronolactone alone and Laennec alone. * P <0.05, ** p <0.005
FIG. 9 is a diagram showing the inhibitory effect on human hepatocellular carcinoma growth by the combined use of Raeneck and glutathione. In the figure, (a), (b) and (c) show HepG2, HLE and Huh-7 cells, respectively. Further, □ represents glutathione alone, ● represents glutathione + 10% raeneck, and ◯ represents glutathione + 20% raeneck. Data are shown as mean ± standard deviation (n = 3). Significant difference tests were performed for glutathione alone and Laennec alone. * P <0.05, ** p <0.005
FIG. 10 is a graph showing the inhibitory effect on the growth of human hepatocellular carcinoma by the combined use of Laennec and branched amino acids. In the figure, (a), (b) and (c) show HepG2, HLE and Huh-7 cells, respectively. Further, □ represents a branched amino acid alone, ● represents a branched amino acid + 10% raeneck, and ◯ represents a branched amino acid + 20% raeneck. Data are shown as mean ± standard deviation (n = 3). Significant difference tests were performed on branched amino acids alone and Laennec alone. * P <0.05, ** p <0.005
FIG. 11 is a graph showing the inhibitory effect on the growth of human hepatocellular carcinoma by the combined use of Raenneck and methylmethioninesulfonium chloride. In the figure, (a), (b) and (c) show HepG2, HLE and Huh-7 cells, respectively. Further, □ represents methylmethioninesulfonium chloride alone, ● represents methylmethioninesulfonium chloride + 10% raeneck, and ◯ represents methylmethioninesulfonium chloride + 20% raeneck. Data are shown as mean ± standard deviation (n = 3). Significant difference tests were performed for methylmethionine sulfonium chloride alone and Laennec alone. * P <0.05, ** p <0.005
図２は、ラエンネックとグリチルリチン酸モノアンモニウムの併用によるヒト肝細胞癌増殖への抑制効果を示す図である。図中、（ａ）、（ｂ）及び（ｃ）はそれぞれＨｅｐＧ２、ＨＬＥ及びＨｕｈ−７細胞を示す。また、□はグリチルリチン酸モノアンモニウム単独、●はグリチルリチン酸モノアンモニウム＋１０％ラエンネック、○はグリチルリチン酸モノアンモニウム＋２０％ラエンネックを示す。コントロール（グリチルリチン酸モノアンモニウム ０μＭ）にはラエンネックは含まれていない。データは平均値±標準偏差（ｎ＝３）で示した。有意差検定はグリチルリチン酸モノアンモニウム単独に対して行った。＊ｐ＜０．０５、＊＊ｐ＜０．００５
図３は、実施例２において、第三段階までにＧＰＴ値が低下しなかった患者（１２４例）にラエンネックを併用したときに、ＧＯＴ（ＡＳＴ）値及びＧＰＴ値が低下したことを示す図である。
図４は、副作用のためインターフェロン療法を中止したＣ型肝炎患者に、ペグインターフェロンαとラエンネックを併用した結果、ＧＯＴ値及びＧＰＴ値が低下し、ＨＣＶ（ヒトＣ型肝炎ウイルス）が消失したことを示す図である。なお、ＧＯＴ値及びＧＰＴ値に関し、縦軸はＩＵ／Ｌである。
図５は、実施例４において、肝細胞癌患者の腹水が治療により消失していく経緯を示した腹部ダイナミックＣＴ画像である（その１）。
図６は、実施例４において、肝細胞癌患者の腹水が治療により消失していく経緯を示した腹部ダイナミックＣＴ画像である（その２）。
図７は、ラエンネックとウルソデオキシコール酸の併用によるヒト肝細胞癌増殖への抑制効果を示す図である。図中、（ａ）、（ｂ）及び（ｃ）はそれぞれＨｅｐＧ２、ＨＬＥ及びＨｕｈ−７細胞を示す。また、□はウルソデオキシコール酸単独、●はウルソデオキシコール酸＋１０％ラエンネック、○はウルソデオキシコール酸＋２０％ラエンネックを示す。データは平均値±標準偏差（ｎ＝３）で示した。有意差検定はウルソデオキシコール酸単独とラエンネック単独に対して行った。＊ｐ＜０．０５、＊＊ｐ＜０．００５
図８はラエンネックとグルクロノラクトンの併用によるヒト肝細胞癌増殖への抑制効果を示す図である。図中、（ａ）、（ｂ）及び（ｃ）はそれぞれＨｅｐＧ２、ＨＬＥ及びＨｕｈ−７細胞を示す。また、□はグルクロノラクトン単独、●はグルクロノラクトン＋１０％ラエンネック、○はグルクロノラクトン＋２０％ラエンネックを示す。データは平均値±標準偏差（ｎ＝３）で示した。有意差検定はグルクロノラクトン単独とラエンネック単独に対して行った。＊ｐ＜０．０５、＊＊ｐ＜０．００５
図９はラエンネックとグルタチオンの併用によるヒト肝細胞癌増殖への抑制効果を示す図である。図中、（ａ）、（ｂ）及び（ｃ）はそれぞれＨｅｐＧ２、ＨＬＥ及びＨｕｈ−７細胞を示す。また、□はグルタチオン単独、●はグルタチオン＋１０％ラエンネック、○はグルタチオン＋２０％ラエンネックを示す。データは平均値±標準偏差（ｎ＝３）で示した。有意差検定はグルタチオン単独とラエンネック単独に対して行った。＊ｐ＜０．０５、＊＊ｐ＜０．００５
図１０はラエンネックと分岐アミノ酸の併用によるヒト肝細胞癌増殖への抑制効果を示す図である。図中、（ａ）、（ｂ）及び（ｃ）はそれぞれＨｅｐＧ２、ＨＬＥ及びＨｕｈ−７細胞を示す。また、□は分岐アミノ酸単独、●は分岐アミノ酸＋１０％ラエンネック、○は分岐アミノ酸＋２０％ラエンネックを示す。データは平均値±標準偏差（ｎ＝３）で示した。有意差検定は分岐アミノ酸単独とラエンネック単独に対して行った。＊ｐ＜０．０５、＊＊ｐ＜０．００５
図１１はラエンネックとメチルメチオニンスルホニウムクロリドの併用によるヒト肝細胞癌増殖への抑制効果を示す図である。図中、（ａ）、（ｂ）及び（ｃ）はそれぞれＨｅｐＧ２、ＨＬＥ及びＨｕｈ−７細胞を示す。また、□はメチルメチオニンスルホニウムクロリド単独、●はメチルメチオニンスルホニウムクロリド＋１０％ラエンネック、○はメチルメチオニンスルホニウムクロリド＋２０％ラエンネックを示す。データは平均値±標準偏差（ｎ＝３）で示した。有意差検定はメチルメチオニンスルホニウムクロリド単独とラエンネック単独に対して行った。＊ｐ＜０．０５、＊＊ｐ＜０．００５ FIG. 1 is a graph showing the inhibitory effect of Raeneck on human hepatocellular carcinoma growth. In the figure, (a), (b) and (c) show HepG2, HLE and Huh-7 cells, respectively.
FIG. 2 is a graph showing the inhibitory effect on the growth of human hepatocellular carcinoma by the combined use of Raennek and monoammonium glycyrrhizinate. In the figure, (a), (b) and (c) show HepG2, HLE and Huh-7 cells, respectively. Further, □ represents monoammonium glycyrrhizinate alone, ● represents monoammonium glycyrrhizinate + 10% raeneck, and ◯ represents monoammonium glycyrrhizinate + 20% raeneck. The control (
FIG. 3 is a graph showing that the GOT (AST) value and the GPT value were lowered when Laennec was used in combination with the patients (124 cases) whose GPT value did not fall by the third stage in Example 2. is there.
FIG. 4 shows that as a result of combined use of pegylated interferon α and Laennec in hepatitis C patients who discontinued interferon therapy due to side effects, GOT and GPT values decreased and HCV (human hepatitis C virus) disappeared. FIG. In addition, regarding a GOT value and a GPT value, a vertical axis | shaft is IU / L.
FIG. 5 is an abdominal dynamic CT image showing how the ascites of a hepatocellular carcinoma patient disappeared by treatment in Example 4 (part 1).
FIG. 6 is an abdominal dynamic CT image showing how the ascites of a hepatocellular carcinoma patient disappeared by treatment in Example 4 (part 2).
FIG. 7 is a graph showing the inhibitory effect on the growth of human hepatocellular carcinoma by the combined use of Raeneck and ursodeoxycholic acid. In the figure, (a), (b) and (c) show HepG2, HLE and Huh-7 cells, respectively. Further, □ represents ursodeoxycholic acid alone, ● represents ursodeoxycholic acid + 10% raeneck, and ◯ represents ursodeoxycholic acid + 20% raeneck. Data are shown as mean ± standard deviation (n = 3). Significant difference tests were performed for ursodeoxycholic acid alone and Laennec alone. * P <0.05, ** p <0.005
FIG. 8 is a graph showing the inhibitory effect on the growth of human hepatocellular carcinoma by the combined use of Raeneck and glucuronolactone. In the figure, (a), (b) and (c) show HepG2, HLE and Huh-7 cells, respectively. Further, □ represents glucuronolactone alone, ● represents glucuronolactone + 10% raeneck, and ◯ represents glucuronolactone + 20% raeneck. Data are shown as mean ± standard deviation (n = 3). Significant difference tests were performed for glucuronolactone alone and Laennec alone. * P <0.05, ** p <0.005
FIG. 9 is a diagram showing the inhibitory effect on human hepatocellular carcinoma growth by the combined use of Raeneck and glutathione. In the figure, (a), (b) and (c) show HepG2, HLE and Huh-7 cells, respectively. Further, □ represents glutathione alone, ● represents glutathione + 10% raeneck, and ◯ represents glutathione + 20% raeneck. Data are shown as mean ± standard deviation (n = 3). Significant difference tests were performed for glutathione alone and Laennec alone. * P <0.05, ** p <0.005
FIG. 10 is a graph showing the inhibitory effect on the growth of human hepatocellular carcinoma by the combined use of Laennec and branched amino acids. In the figure, (a), (b) and (c) show HepG2, HLE and Huh-7 cells, respectively. Further, □ represents a branched amino acid alone, ● represents a branched amino acid + 10% raeneck, and ◯ represents a branched amino acid + 20% raeneck. Data are shown as mean ± standard deviation (n = 3). Significant difference tests were performed on branched amino acids alone and Laennec alone. * P <0.05, ** p <0.005
FIG. 11 is a graph showing the inhibitory effect on the growth of human hepatocellular carcinoma by the combined use of Raenneck and methylmethioninesulfonium chloride. In the figure, (a), (b) and (c) show HepG2, HLE and Huh-7 cells, respectively. Further, □ represents methylmethioninesulfonium chloride alone, ● represents methylmethioninesulfonium chloride + 10% raeneck, and ◯ represents methylmethioninesulfonium chloride + 20% raeneck. Data are shown as mean ± standard deviation (n = 3). Significant difference tests were performed for methylmethionine sulfonium chloride alone and Laennec alone. * P <0.05, ** p <0.005
本発明は、ヒト胎盤抽出物を含有することからなる、肝細胞癌患者のＱＯＬ改善剤である。
本発明において、ヒト胎盤抽出物は、その抽出方法、精製法、処理方法が特に限定されるものではないが、例えば、ヒト胎盤を水洗して血液を除去し、必要に応じて脱脂した後、粉砕、凍結融解、酵素分解、酸加水分解などの常法により処理した後、不溶性成分を除去したものを挙げることができる。なお、胎盤抽出物は胎盤分解物、胎盤水解物、胎盤エキス、胎盤加水分解物などとも称される。
医療用医薬品として製造販売中のヒト胎盤抽出物含有製品は、慢性肝疾患に適用されるものと更年期障害・乳汁分泌不全に適用されるものに大別される。慢性肝疾患に適用される医薬品は、日本では（株）日本生物製剤がラエンネック（商品名、登録商標）として、更年期障害・乳汁分泌不全に適用される医薬品は、メルスモン製薬（株）がメルスモン（商品名、登録商標）として、製造販売している。両者は製造方法が異なるため、含有成分が同じではない。
ラエンネックは、胎盤を水洗して除血後、アセトン脱脂し、粉砕、プロテアーゼで酵素分解し、更に塩酸を使用した加熱酸加水分解し、不溶性成分を除去することにより得た製剤である。ラエンネックは、１管（２ｍｌ）当り、上記のヒト胎盤分解物の水溶性物質を１１２ｍｇ含有し、添加物としてペプシン、乳糖、ｐＨ調整剤を含有する。ラエンネックのｐＨは５．５~６．５であり、浸透圧比（生理食塩水に対する比）は約１である。ラエンネックには、蛋白質、アミノ酸の他に核酸塩基類などが含まれていること明らかになっているが、含有成分すべてが同定されているわけでない。また、含有成分のいずれが効能効果に関与しているのか、多年に亘って研究されているものの、解明されていない。
ヒト胎盤抽出物含有製品が、医薬品として承認されている効能効果は上記のとおりであるが、ヒト胎盤抽出物含有製品は、それ以外にも多様な作用を示すことが明らかになっている。
そのうち、癌治療に対しては、坂元らの報告１件のみである（坂元秀壮ら、第９４回日本消化器病学会九州支部例会／第８８回日本消化器内視鏡学会九州支部例会プログラム・抄録集、第１３２頁の１３３、平成２１年１１月２７日‐２８日）。当該報告では、末期の肝細胞癌患者へプラセンタ療法を行ったところ、肝細胞癌が著明に縮小したと報告している。しかし、プラセンタ療法の科学的根拠、使用した医薬品名と購入先、併用薬、用法用量、長期投与の可能性、予後、ＱＯＬ向上などを一切明らかにしていない。
癌治療に伴う随伴症状に関しては、メルスモンを試用した都築の報告とラエンネックを試用した品川らの報告の２件がある。
都築（都築靖、基礎と臨床１２巻１２号３４５頁、昭和５３年）は、メルスモンを胃癌（６例）、直腸癌（２例）、乳癌（１例）、前立腺癌（１例）らの患者に１日１回２ｍｌを２週間筋肉内投与したところ、胃癌患者の５例に食欲増進等の自覚症状が認められた。しかし、肝転移や全身悪液質の患者には効果は認められなかったと報告している。
品川ら（品川和子他、第８７回日本消化器病学会北陸支部例会講演要旨集、第２８頁の２９、平成１０年）は、ラエンネックが肝細胞増殖因子（ＨＧＦ）を含有していることから、肝切除後の患者の肝再生を期待してラエンネックを静脈内投与した。その結果、腹水が消失したと報告している。しかし、品川らは、肝細胞癌に対する効果、長期連続投与の可能性、ＱＯＬ向上については言及していない。なお、平成１０年当時、ラエンネックにはＨＧＦが含有されていると考えられていたが、その後の成分研究で、ラエンネックにはＨＧＦは微量しか含まれていないことが分かっている。
ラエンネックは、昭和５９年１１月以降、慢性肝疾患の肝機能改善剤（筋肉内あるいは皮下投与）として製造販売されてきたが、肝細胞癌へ適応されることは皆無であった。その主な理由は、以下のとおりである。
・ラエンネックと同じ効能効果（慢性肝疾患に対する肝機能改善）を有する、前掲の医薬品と異なり、肝機能改善作用の機序が解明されていないこと；
・ラエンネックを肝細胞癌患者に投与する際の科学的根拠（実験データ）がないこと；
・ラエンネックと同じ効能効果（慢性肝疾患に対する肝機能改善）を有する、前掲の医薬品のうち、抗肝細胞癌作用が研究されたことのある医薬品は、その一部にすぎないこと（即ち、アデノシン三リン酸ナトリウム、フラビンアデニンジヌクレオチド、グリチルリチン酸モノナトリウム、ウルソデオキシコール酸等のみであること）；
・しかも、これら医薬品が肝細胞癌患者を含む慢性肝疾患患者のＱＯＬを向上させるとする報告が見当たらないこと。
このような状況から、本発明者らは、
・ラエンネックを肝細胞癌患者へ適応する根拠を確立するために、ラエンネックによって癌細胞の増殖が抑制されるかを、ヒト肝癌細胞を用いて検証した。即ち、
・多くの慢性肝疾患患者に、肝機能改善剤とラエンネックを併用し、ＧＰＴ値、ＧＯＴ値等の変動を長期に亘って測定すると同時に、患者へのアンケート調査を実施し、ラエンネックの併用投与が肝機能を改善し、ＱＯＬを向上するかを検証した。
・肝細胞癌患者に、ラエンネックを筋肉内に肝機能改善剤（グリチルリチン酸モノアンモニウム）と長期に併用投与し、またラエンネックを静脈内に長期単独投与し、癌細胞の縮小、腹水の消失、自覚症状改善、ＱＯＬ向上を検査・調査した。
これらの結果に基づき、ラエンネックが、末期の肝細胞癌患者を含めて、肝細胞癌患者にも応用しうるかを検証したところ、ラエンネックの投与は所期の目的を達成し得ることが判明した。係る検証に基づいて、本発明は完成したものである。
本発明において、ＱＯＬの改善とは、肝細胞癌によって低下した患者の生活の質を向上させ、次いで維持させることにより、通常のヒトの生活状態により近づけることを意味する。前述のように、進行性の肝細胞癌の根治的治療が困難な状況では、抗癌剤による治療を長く続けることは逆に患者の寿命を縮めることがあり、癌が完治しなくとも延命ができ、快適な生活をおくれる方が肝要であるという発想に基づく。
肝細胞癌により低下した患者のＱＯＬの例としては、食欲不振、体重減少、疲労感、全身倦怠、微熱、腹部膨満、腹痛、腹水、黄疸などが挙げられる。
本発明のＱＯＬ改善剤は胎盤抽出物を含有すれば、製剤中の含有量は特に限定されず、適宜な量とすることができる。また、必要に応じて、安定化剤、酸化防止剤、ｐＨ調整剤、無痛化剤などの慣用の助剤を添加することもできる。
本発明において、胎盤抽出物の肝細胞癌患者への投与量は、患者の疾患の程度、年齢、体重などによって、適宜選択することができるが、ラエンネックに換算して、一日１~３アンプル（１アンプル当たり胎盤由来成分１１２ｍｇ含有）を１回又は数回に分けて投与する。投与方法としては、ラエンネックが認可されている皮下投与及び筋肉内投与の他、静脈内投与（適用外使用）も可能である。
本発明のＱＯＬ改善剤は、胎盤抽出物と共に肝機能改善剤を使用すると、それらが相乗的に作用しより優れた効果を奏する。即ち、肝細胞癌患者は、本発明のＱＯＬ改善剤と共に肝機能改善剤を投与されることが好ましい。本発明において、肝機能改善剤とは、疾患特異的な薬剤及び非特異的な薬剤を問わず、肝炎を抑え、肝機能を向上させ、肝硬変や肝癌への進行を抑制し得る薬剤を意味する。
係る肝機能改善剤としては、疾患特異的な薬剤であるインターフェロン製剤及び核酸関連化合物製剤を含めて、以下のような例を挙げることができる。
グリチルリチン酸塩（モノアンモニウム塩、モノナトリウム塩）：例えば強力ミノファーゲンＰ（静注）（商品名）、強力ネオミノファーゲンＣ（商品名）
アデノシン三リン酸塩（ナトリウム塩）：例えばＡＴＰ注第一（商品名）
フラビンアデニンジヌクレオチド：例えばアデラビン９号注（商品名）
ウルソデオキシコール酸：例えばウルソ錠（商品名）
ジクロロ酢酸ジイソプロピルアミン：例えばリバオール錠（商品名）
グルクロノラクトン：例えばグロンサン注（商品名）
グルタチオン：例えばタチオン注（商品名）
マロチラート：例えばカンデック錠（商品名）
メチルメチオニンスルホニウムクロリド：例えばキャベジンＵコーワ（商品名）
ポリエンフォスファチジルコリン：例えばブロビーンカプセル（商品名）
プロトポルフィリン塩（２ナトリウム塩）：例えばプロルモン錠（商品名）
分岐鎖アミノ酸製剤：例えばリーバクト（商品名）
肝水解物：例えばプロヘパール錠（商品名）
インターフェロン製剤（ペグインターフェロン製剤を含む）：例えばスミフェロン（商品名）
核酸関連化合物製剤：例えばリバビリン（商品名）
これらの肝機能改善剤は、添付文書に記載される用量用法で使用すればよい。
なお、上記の肝機能改善剤において、グリチルリチン酸塩、ウルソデオキシコール酸、分岐鎖アミノ酸製剤、グルクロノラクトン、グルタチオン、メチルメチオニンスルホニウムクロリドが好ましく、特にグリチルリチン酸塩、ウルソデオキシコール酸が好適である。 The present invention is an agent for improving QOL for patients with hepatocellular carcinoma, comprising human placenta extract.
In the present invention, the human placenta extract is not particularly limited in its extraction method, purification method, and treatment method.For example, the human placenta extract is washed with water to remove blood, and if necessary, degreased, Examples thereof include those obtained by removing insoluble components after treatment by conventional methods such as pulverization, freeze-thawing, enzymatic degradation, and acid hydrolysis. The placenta extract is also referred to as placenta decomposition product, placenta hydrolyzate, placenta extract, placenta hydrolyzate and the like.
Human placenta extract-containing products that are manufactured and sold as ethical drugs are broadly classified into those that are applied to chronic liver diseases and those that are applied to climacteric disorders and lactation insufficiency. In Japan, Japan Biopharmaceutical Co., Ltd. is called Raennek (trade name, registered trademark), and in Japan, Mercosmon Pharmaceuticals Co., Ltd. Manufactured and sold under the trade name (registered trademark). Since both are different in the production method, the contained components are not the same.
Laennec is a preparation obtained by washing the placenta with water, removing blood, then degreasing with acetone, crushing, enzymatically decomposing with a protease, and further heat acid hydrolysis using hydrochloric acid to remove insoluble components. Laennec contains 112 mg of the above water-soluble substance of human placenta per tube (2 ml), and contains pepsin, lactose and pH adjuster as additives. The pH of Raeneck is 5.5 to 6.5, and the osmotic pressure ratio (ratio to physiological saline) is about 1. Although it has been clarified that Raeneck contains nucleobases in addition to proteins and amino acids, not all the components have been identified. In addition, although it has been studied for many years which of the contained components is involved in the efficacy effect, it has not been elucidated.
The effects of human placenta extract-containing products approved as pharmaceuticals are as described above, but it has been revealed that human placenta extract-containing products exhibit various other actions.
Of these, only one report from Sakamoto et al. Is available for cancer treatment (Hideo Sakamoto et al., 94th Annual Meeting of the Japanese Gastroenterological Society Kyushu Branch / 88th Annual Meeting of the Japanese Gastroenterological Endoscopy Society Kyushu Branch)・ Abstract, page 132, 133, November 27-28, 2009). In this report, placental therapy was given to patients with end-stage hepatocellular carcinoma, and hepatocellular carcinoma was significantly reduced. However, the scientific grounds of placenta therapy, the names and suppliers of the drugs used, the concomitant drugs, the dosage regimen, the possibility of long-term administration, the prognosis, and the QOL improvement are not clarified at all.
Regarding the accompanying symptoms associated with cancer treatment, there are two reports: a report from Tsuzuki, who tried Mersmon, and a report from Shinagawa et al., Who tried Raennek.
Tsuzuki (Mr. Tsuzuki, Fundamental and Clinical 12, Vol. 12, 345, Showa 53) has introduced Mersmon into gastric cancer (6 cases), rectal cancer (2 cases), breast cancer (1 case), prostate cancer (1 case), etc. When patients were intramuscularly administered 2 ml once a day for 2 weeks, subjective symptoms such as increased appetite were observed in 5 patients with gastric cancer. However, they reported no effect in patients with liver metastasis or systemic cachexia.
Shinagawa et al. (Kazuko Shinagawa et al., Abstracts of the 87th Annual Meeting of the Japanese Gastroenterological Society Hokuriku Branch, page 28, 29, 1998) shows that Raeneck contains hepatocyte growth factor (HGF). Laenneck was administered intravenously in anticipation of liver regeneration in patients after hepatectomy. As a result, ascites is reported to have disappeared. However, Shinagawa et al. Do not mention the effects on hepatocellular carcinoma, the possibility of long-term continuous administration, and improvement in QOL. In addition, at the time of 1998, it was thought that Laennec contained HGF, but subsequent component studies have revealed that Laennec contains only trace amounts of HGF.
Laennec has been manufactured and sold as a liver function improving agent (intramuscular or subcutaneous administration) for chronic liver diseases since November 1984, but has never been applied to hepatocellular carcinoma. The main reasons are as follows.
・ Unlike the drugs listed above, which have the same efficacy and effect as Laenneq (improved liver function for chronic liver disease), the mechanism for improving liver function has not been elucidated;
・ There is no scientific basis (experimental data) for administering Raennec to patients with hepatocellular carcinoma;
-Of the drugs listed above that have the same efficacy and effect as Laenneq (improved liver function for chronic liver disease), only a part of those drugs that have been studied for anti-hepatocellular carcinoma activity (ie, adenosine) Only sodium triphosphate, flavin adenine dinucleotide, monosodium glycyrrhizinate, ursodeoxycholic acid, etc.);
・ In addition, there are no reports that these drugs improve QOL in patients with chronic liver disease including those with hepatocellular carcinoma.
From this situation, the inventors have
In order to establish the basis for adapting Raenneck to hepatocellular carcinoma patients, it was verified using human hepatoma cells whether the growth of cancer cells was suppressed by Raenneck. That is,
・ For many patients with chronic liver disease, liver function improver and Laennec are used in combination, and changes in GPT value, GOT value, etc. are measured over a long period of time. It was verified whether liver function was improved and QOL was improved.
・ In patients with hepatocellular carcinoma, Laenneck is administered intramuscularly with a liver function improving agent (monoammonium glycyrrhizinate) for a long period of time, and Laenneck is administered intravenously for a long period of time alone to reduce cancer cells, disappear ascites, and awareness We examined and investigated symptom improvement and QOL improvement.
Based on these results, it was proved that Raenneck can be applied to patients with hepatocellular carcinoma including those with end-stage hepatocellular carcinoma. As a result, it was found that administration of Raenneck can achieve the intended purpose. The present invention has been completed based on such verification.
In the present invention, the improvement of QOL means that the quality of life of a patient who has been lowered due to hepatocellular carcinoma is improved and then maintained to bring it closer to the normal human life. As mentioned above, in the situation where radical treatment of advanced hepatocellular carcinoma is difficult, long-term treatment with anticancer drugs may conversely shorten the life of the patient, and even if the cancer is not completely cured, the life can be prolonged. Based on the idea that it is essential to have a comfortable life.
Examples of QOL of patients who have decreased due to hepatocellular carcinoma include loss of appetite, weight loss, fatigue, general malaise, slight fever, abdominal distension, abdominal pain, ascites, jaundice and the like.
If the QOL improving agent of this invention contains a placenta extract, content in a formulation will not be specifically limited, It can be set as a suitable quantity. If necessary, conventional auxiliaries such as stabilizers, antioxidants, pH adjusters and soothing agents can be added.
In the present invention, the dose of the placental extract to the hepatocellular carcinoma patient can be appropriately selected depending on the degree of disease, age, weight, etc. of the patient. (Containing 112 mg of placenta-derived component per ampoule) is administered once or divided into several times. As an administration method, subcutaneous administration and intramuscular administration for which Raeneck is approved, and intravenous administration (use outside application) are also possible.
When the QOL improving agent of the present invention uses a liver function improving agent together with a placenta extract, they act synergistically to produce more excellent effects. That is, it is preferable that a hepatocellular carcinoma patient is administered a liver function improving agent together with the QOL improving agent of the present invention. In the present invention, the liver function improving agent means a drug that can suppress hepatitis, improve liver function, and suppress progression to liver cirrhosis or liver cancer regardless of disease-specific drugs and non-specific drugs. .
Examples of such liver function improving agents include the following examples, including interferon preparations and nucleic acid related compound preparations which are disease-specific drugs.
Glycyrrhizinate (monoammonium salt, monosodium salt): for example, strong minophagen P (intravenous injection) (trade name), strong neominophagen C (trade name)
Adenosine triphosphate (sodium salt): For example, ATP Note 1 (trade name)
Flavin adenine dinucleotide: eg Adelabin 9 Note (trade name)
Ursodeoxycholic acid: For example, Urso tablet (trade name)
Diisopropylamine dichloroacetate: for example Ribaol tablets (trade name)
Glucuronolactone: Gronsan Injection (trade name), for example
Glutathione: For example, Tachion Note (trade name)
Malotilate: For example, Kandec Tablet (trade name)
Methylmethionine sulfonium chloride: For example, Cavedin U Kowa (trade name)
Polyenphosphatidylcholine: For example, Blobin capsule (trade name)
Protoporphyrin salt (disodium salt): for example, prolumon tablet (trade name)
Branched-chain amino acid preparation: For example, Leveract (trade name)
Liver hydrolyzate: Prohepal tablet (trade name)
Interferon preparations (including pegylated interferon preparations): For example, Sumiferon (trade name)
Nucleic acid-related compound preparations: for example ribavirin (trade name)
These liver function improving agents may be used in the dosage regime described in the package insert.
In the above liver function improving agent, glycyrrhizinate, ursodeoxycholic acid, branched chain amino acid preparation, glucuronolactone, glutathione, and methylmethionine sulfonium chloride are preferable, and glycyrrhizinate and ursodeoxycholic acid are particularly preferable. .
本発明において、ヒト胎盤抽出物は、その抽出方法、精製法、処理方法が特に限定されるものではないが、例えば、ヒト胎盤を水洗して血液を除去し、必要に応じて脱脂した後、粉砕、凍結融解、酵素分解、酸加水分解などの常法により処理した後、不溶性成分を除去したものを挙げることができる。なお、胎盤抽出物は胎盤分解物、胎盤水解物、胎盤エキス、胎盤加水分解物などとも称される。
医療用医薬品として製造販売中のヒト胎盤抽出物含有製品は、慢性肝疾患に適用されるものと更年期障害・乳汁分泌不全に適用されるものに大別される。慢性肝疾患に適用される医薬品は、日本では（株）日本生物製剤がラエンネック（商品名、登録商標）として、更年期障害・乳汁分泌不全に適用される医薬品は、メルスモン製薬（株）がメルスモン（商品名、登録商標）として、製造販売している。両者は製造方法が異なるため、含有成分が同じではない。
ラエンネックは、胎盤を水洗して除血後、アセトン脱脂し、粉砕、プロテアーゼで酵素分解し、更に塩酸を使用した加熱酸加水分解し、不溶性成分を除去することにより得た製剤である。ラエンネックは、１管（２ｍｌ）当り、上記のヒト胎盤分解物の水溶性物質を１１２ｍｇ含有し、添加物としてペプシン、乳糖、ｐＨ調整剤を含有する。ラエンネックのｐＨは５．５~６．５であり、浸透圧比（生理食塩水に対する比）は約１である。ラエンネックには、蛋白質、アミノ酸の他に核酸塩基類などが含まれていること明らかになっているが、含有成分すべてが同定されているわけでない。また、含有成分のいずれが効能効果に関与しているのか、多年に亘って研究されているものの、解明されていない。
ヒト胎盤抽出物含有製品が、医薬品として承認されている効能効果は上記のとおりであるが、ヒト胎盤抽出物含有製品は、それ以外にも多様な作用を示すことが明らかになっている。
そのうち、癌治療に対しては、坂元らの報告１件のみである（坂元秀壮ら、第９４回日本消化器病学会九州支部例会／第８８回日本消化器内視鏡学会九州支部例会プログラム・抄録集、第１３２頁の１３３、平成２１年１１月２７日‐２８日）。当該報告では、末期の肝細胞癌患者へプラセンタ療法を行ったところ、肝細胞癌が著明に縮小したと報告している。しかし、プラセンタ療法の科学的根拠、使用した医薬品名と購入先、併用薬、用法用量、長期投与の可能性、予後、ＱＯＬ向上などを一切明らかにしていない。
癌治療に伴う随伴症状に関しては、メルスモンを試用した都築の報告とラエンネックを試用した品川らの報告の２件がある。
都築（都築靖、基礎と臨床１２巻１２号３４５頁、昭和５３年）は、メルスモンを胃癌（６例）、直腸癌（２例）、乳癌（１例）、前立腺癌（１例）らの患者に１日１回２ｍｌを２週間筋肉内投与したところ、胃癌患者の５例に食欲増進等の自覚症状が認められた。しかし、肝転移や全身悪液質の患者には効果は認められなかったと報告している。
品川ら（品川和子他、第８７回日本消化器病学会北陸支部例会講演要旨集、第２８頁の２９、平成１０年）は、ラエンネックが肝細胞増殖因子（ＨＧＦ）を含有していることから、肝切除後の患者の肝再生を期待してラエンネックを静脈内投与した。その結果、腹水が消失したと報告している。しかし、品川らは、肝細胞癌に対する効果、長期連続投与の可能性、ＱＯＬ向上については言及していない。なお、平成１０年当時、ラエンネックにはＨＧＦが含有されていると考えられていたが、その後の成分研究で、ラエンネックにはＨＧＦは微量しか含まれていないことが分かっている。
ラエンネックは、昭和５９年１１月以降、慢性肝疾患の肝機能改善剤（筋肉内あるいは皮下投与）として製造販売されてきたが、肝細胞癌へ適応されることは皆無であった。その主な理由は、以下のとおりである。
・ラエンネックと同じ効能効果（慢性肝疾患に対する肝機能改善）を有する、前掲の医薬品と異なり、肝機能改善作用の機序が解明されていないこと；
・ラエンネックを肝細胞癌患者に投与する際の科学的根拠（実験データ）がないこと；
・ラエンネックと同じ効能効果（慢性肝疾患に対する肝機能改善）を有する、前掲の医薬品のうち、抗肝細胞癌作用が研究されたことのある医薬品は、その一部にすぎないこと（即ち、アデノシン三リン酸ナトリウム、フラビンアデニンジヌクレオチド、グリチルリチン酸モノナトリウム、ウルソデオキシコール酸等のみであること）；
・しかも、これら医薬品が肝細胞癌患者を含む慢性肝疾患患者のＱＯＬを向上させるとする報告が見当たらないこと。
このような状況から、本発明者らは、
・ラエンネックを肝細胞癌患者へ適応する根拠を確立するために、ラエンネックによって癌細胞の増殖が抑制されるかを、ヒト肝癌細胞を用いて検証した。即ち、
・多くの慢性肝疾患患者に、肝機能改善剤とラエンネックを併用し、ＧＰＴ値、ＧＯＴ値等の変動を長期に亘って測定すると同時に、患者へのアンケート調査を実施し、ラエンネックの併用投与が肝機能を改善し、ＱＯＬを向上するかを検証した。
・肝細胞癌患者に、ラエンネックを筋肉内に肝機能改善剤（グリチルリチン酸モノアンモニウム）と長期に併用投与し、またラエンネックを静脈内に長期単独投与し、癌細胞の縮小、腹水の消失、自覚症状改善、ＱＯＬ向上を検査・調査した。
これらの結果に基づき、ラエンネックが、末期の肝細胞癌患者を含めて、肝細胞癌患者にも応用しうるかを検証したところ、ラエンネックの投与は所期の目的を達成し得ることが判明した。係る検証に基づいて、本発明は完成したものである。
本発明において、ＱＯＬの改善とは、肝細胞癌によって低下した患者の生活の質を向上させ、次いで維持させることにより、通常のヒトの生活状態により近づけることを意味する。前述のように、進行性の肝細胞癌の根治的治療が困難な状況では、抗癌剤による治療を長く続けることは逆に患者の寿命を縮めることがあり、癌が完治しなくとも延命ができ、快適な生活をおくれる方が肝要であるという発想に基づく。
肝細胞癌により低下した患者のＱＯＬの例としては、食欲不振、体重減少、疲労感、全身倦怠、微熱、腹部膨満、腹痛、腹水、黄疸などが挙げられる。
本発明のＱＯＬ改善剤は胎盤抽出物を含有すれば、製剤中の含有量は特に限定されず、適宜な量とすることができる。また、必要に応じて、安定化剤、酸化防止剤、ｐＨ調整剤、無痛化剤などの慣用の助剤を添加することもできる。
本発明において、胎盤抽出物の肝細胞癌患者への投与量は、患者の疾患の程度、年齢、体重などによって、適宜選択することができるが、ラエンネックに換算して、一日１~３アンプル（１アンプル当たり胎盤由来成分１１２ｍｇ含有）を１回又は数回に分けて投与する。投与方法としては、ラエンネックが認可されている皮下投与及び筋肉内投与の他、静脈内投与（適用外使用）も可能である。
本発明のＱＯＬ改善剤は、胎盤抽出物と共に肝機能改善剤を使用すると、それらが相乗的に作用しより優れた効果を奏する。即ち、肝細胞癌患者は、本発明のＱＯＬ改善剤と共に肝機能改善剤を投与されることが好ましい。本発明において、肝機能改善剤とは、疾患特異的な薬剤及び非特異的な薬剤を問わず、肝炎を抑え、肝機能を向上させ、肝硬変や肝癌への進行を抑制し得る薬剤を意味する。
係る肝機能改善剤としては、疾患特異的な薬剤であるインターフェロン製剤及び核酸関連化合物製剤を含めて、以下のような例を挙げることができる。
グリチルリチン酸塩（モノアンモニウム塩、モノナトリウム塩）：例えば強力ミノファーゲンＰ（静注）（商品名）、強力ネオミノファーゲンＣ（商品名）
アデノシン三リン酸塩（ナトリウム塩）：例えばＡＴＰ注第一（商品名）
フラビンアデニンジヌクレオチド：例えばアデラビン９号注（商品名）
ウルソデオキシコール酸：例えばウルソ錠（商品名）
ジクロロ酢酸ジイソプロピルアミン：例えばリバオール錠（商品名）
グルクロノラクトン：例えばグロンサン注（商品名）
グルタチオン：例えばタチオン注（商品名）
マロチラート：例えばカンデック錠（商品名）
メチルメチオニンスルホニウムクロリド：例えばキャベジンＵコーワ（商品名）
ポリエンフォスファチジルコリン：例えばブロビーンカプセル（商品名）
プロトポルフィリン塩（２ナトリウム塩）：例えばプロルモン錠（商品名）
分岐鎖アミノ酸製剤：例えばリーバクト（商品名）
肝水解物：例えばプロヘパール錠（商品名）
インターフェロン製剤（ペグインターフェロン製剤を含む）：例えばスミフェロン（商品名）
核酸関連化合物製剤：例えばリバビリン（商品名）
これらの肝機能改善剤は、添付文書に記載される用量用法で使用すればよい。
なお、上記の肝機能改善剤において、グリチルリチン酸塩、ウルソデオキシコール酸、分岐鎖アミノ酸製剤、グルクロノラクトン、グルタチオン、メチルメチオニンスルホニウムクロリドが好ましく、特にグリチルリチン酸塩、ウルソデオキシコール酸が好適である。 The present invention is an agent for improving QOL for patients with hepatocellular carcinoma, comprising human placenta extract.
In the present invention, the human placenta extract is not particularly limited in its extraction method, purification method, and treatment method.For example, the human placenta extract is washed with water to remove blood, and if necessary, degreased, Examples thereof include those obtained by removing insoluble components after treatment by conventional methods such as pulverization, freeze-thawing, enzymatic degradation, and acid hydrolysis. The placenta extract is also referred to as placenta decomposition product, placenta hydrolyzate, placenta extract, placenta hydrolyzate and the like.
Human placenta extract-containing products that are manufactured and sold as ethical drugs are broadly classified into those that are applied to chronic liver diseases and those that are applied to climacteric disorders and lactation insufficiency. In Japan, Japan Biopharmaceutical Co., Ltd. is called Raennek (trade name, registered trademark), and in Japan, Mercosmon Pharmaceuticals Co., Ltd. Manufactured and sold under the trade name (registered trademark). Since both are different in the production method, the contained components are not the same.
Laennec is a preparation obtained by washing the placenta with water, removing blood, then degreasing with acetone, crushing, enzymatically decomposing with a protease, and further heat acid hydrolysis using hydrochloric acid to remove insoluble components. Laennec contains 112 mg of the above water-soluble substance of human placenta per tube (2 ml), and contains pepsin, lactose and pH adjuster as additives. The pH of Raeneck is 5.5 to 6.5, and the osmotic pressure ratio (ratio to physiological saline) is about 1. Although it has been clarified that Raeneck contains nucleobases in addition to proteins and amino acids, not all the components have been identified. In addition, although it has been studied for many years which of the contained components is involved in the efficacy effect, it has not been elucidated.
The effects of human placenta extract-containing products approved as pharmaceuticals are as described above, but it has been revealed that human placenta extract-containing products exhibit various other actions.
Of these, only one report from Sakamoto et al. Is available for cancer treatment (Hideo Sakamoto et al., 94th Annual Meeting of the Japanese Gastroenterological Society Kyushu Branch / 88th Annual Meeting of the Japanese Gastroenterological Endoscopy Society Kyushu Branch)・ Abstract, page 132, 133, November 27-28, 2009). In this report, placental therapy was given to patients with end-stage hepatocellular carcinoma, and hepatocellular carcinoma was significantly reduced. However, the scientific grounds of placenta therapy, the names and suppliers of the drugs used, the concomitant drugs, the dosage regimen, the possibility of long-term administration, the prognosis, and the QOL improvement are not clarified at all.
Regarding the accompanying symptoms associated with cancer treatment, there are two reports: a report from Tsuzuki, who tried Mersmon, and a report from Shinagawa et al., Who tried Raennek.
Tsuzuki (Mr. Tsuzuki, Fundamental and Clinical 12, Vol. 12, 345, Showa 53) has introduced Mersmon into gastric cancer (6 cases), rectal cancer (2 cases), breast cancer (1 case), prostate cancer (1 case), etc. When patients were intramuscularly administered 2 ml once a day for 2 weeks, subjective symptoms such as increased appetite were observed in 5 patients with gastric cancer. However, they reported no effect in patients with liver metastasis or systemic cachexia.
Shinagawa et al. (Kazuko Shinagawa et al., Abstracts of the 87th Annual Meeting of the Japanese Gastroenterological Society Hokuriku Branch, page 28, 29, 1998) shows that Raeneck contains hepatocyte growth factor (HGF). Laenneck was administered intravenously in anticipation of liver regeneration in patients after hepatectomy. As a result, ascites is reported to have disappeared. However, Shinagawa et al. Do not mention the effects on hepatocellular carcinoma, the possibility of long-term continuous administration, and improvement in QOL. In addition, at the time of 1998, it was thought that Laennec contained HGF, but subsequent component studies have revealed that Laennec contains only trace amounts of HGF.
Laennec has been manufactured and sold as a liver function improving agent (intramuscular or subcutaneous administration) for chronic liver diseases since November 1984, but has never been applied to hepatocellular carcinoma. The main reasons are as follows.
・ Unlike the drugs listed above, which have the same efficacy and effect as Laenneq (improved liver function for chronic liver disease), the mechanism for improving liver function has not been elucidated;
・ There is no scientific basis (experimental data) for administering Raennec to patients with hepatocellular carcinoma;
-Of the drugs listed above that have the same efficacy and effect as Laenneq (improved liver function for chronic liver disease), only a part of those drugs that have been studied for anti-hepatocellular carcinoma activity (ie, adenosine) Only sodium triphosphate, flavin adenine dinucleotide, monosodium glycyrrhizinate, ursodeoxycholic acid, etc.);
・ In addition, there are no reports that these drugs improve QOL in patients with chronic liver disease including those with hepatocellular carcinoma.
From this situation, the inventors have
In order to establish the basis for adapting Raenneck to hepatocellular carcinoma patients, it was verified using human hepatoma cells whether the growth of cancer cells was suppressed by Raenneck. That is,
・ For many patients with chronic liver disease, liver function improver and Laennec are used in combination, and changes in GPT value, GOT value, etc. are measured over a long period of time. It was verified whether liver function was improved and QOL was improved.
・ In patients with hepatocellular carcinoma, Laenneck is administered intramuscularly with a liver function improving agent (monoammonium glycyrrhizinate) for a long period of time, and Laenneck is administered intravenously for a long period of time alone to reduce cancer cells, disappear ascites, and awareness We examined and investigated symptom improvement and QOL improvement.
Based on these results, it was proved that Raenneck can be applied to patients with hepatocellular carcinoma including those with end-stage hepatocellular carcinoma. As a result, it was found that administration of Raenneck can achieve the intended purpose. The present invention has been completed based on such verification.
In the present invention, the improvement of QOL means that the quality of life of a patient who has been lowered due to hepatocellular carcinoma is improved and then maintained to bring it closer to the normal human life. As mentioned above, in the situation where radical treatment of advanced hepatocellular carcinoma is difficult, long-term treatment with anticancer drugs may conversely shorten the life of the patient, and even if the cancer is not completely cured, the life can be prolonged. Based on the idea that it is essential to have a comfortable life.
Examples of QOL of patients who have decreased due to hepatocellular carcinoma include loss of appetite, weight loss, fatigue, general malaise, slight fever, abdominal distension, abdominal pain, ascites, jaundice and the like.
If the QOL improving agent of this invention contains a placenta extract, content in a formulation will not be specifically limited, It can be set as a suitable quantity. If necessary, conventional auxiliaries such as stabilizers, antioxidants, pH adjusters and soothing agents can be added.
In the present invention, the dose of the placental extract to the hepatocellular carcinoma patient can be appropriately selected depending on the degree of disease, age, weight, etc. of the patient. (Containing 112 mg of placenta-derived component per ampoule) is administered once or divided into several times. As an administration method, subcutaneous administration and intramuscular administration for which Raeneck is approved, and intravenous administration (use outside application) are also possible.
When the QOL improving agent of the present invention uses a liver function improving agent together with a placenta extract, they act synergistically to produce more excellent effects. That is, it is preferable that a hepatocellular carcinoma patient is administered a liver function improving agent together with the QOL improving agent of the present invention. In the present invention, the liver function improving agent means a drug that can suppress hepatitis, improve liver function, and suppress progression to liver cirrhosis or liver cancer regardless of disease-specific drugs and non-specific drugs. .
Examples of such liver function improving agents include the following examples, including interferon preparations and nucleic acid related compound preparations which are disease-specific drugs.
Glycyrrhizinate (monoammonium salt, monosodium salt): for example, strong minophagen P (intravenous injection) (trade name), strong neominophagen C (trade name)
Adenosine triphosphate (sodium salt): For example, ATP Note 1 (trade name)
Flavin adenine dinucleotide: eg Adelabin 9 Note (trade name)
Ursodeoxycholic acid: For example, Urso tablet (trade name)
Diisopropylamine dichloroacetate: for example Ribaol tablets (trade name)
Glucuronolactone: Gronsan Injection (trade name), for example
Glutathione: For example, Tachion Note (trade name)
Malotilate: For example, Kandec Tablet (trade name)
Methylmethionine sulfonium chloride: For example, Cavedin U Kowa (trade name)
Polyenphosphatidylcholine: For example, Blobin capsule (trade name)
Protoporphyrin salt (disodium salt): for example, prolumon tablet (trade name)
Branched-chain amino acid preparation: For example, Leveract (trade name)
Liver hydrolyzate: Prohepal tablet (trade name)
Interferon preparations (including pegylated interferon preparations): For example, Sumiferon (trade name)
Nucleic acid-related compound preparations: for example ribavirin (trade name)
These liver function improving agents may be used in the dosage regime described in the package insert.
In the above liver function improving agent, glycyrrhizinate, ursodeoxycholic acid, branched chain amino acid preparation, glucuronolactone, glutathione, and methylmethionine sulfonium chloride are preferable, and glycyrrhizinate and ursodeoxycholic acid are particularly preferable. .
以下、実施例に基づいて、本発明をより詳細に説明するが、本発明はこれらの例に限定されるものではない。
実施例１
ラエンネックとグリチルリチン酸モノアンモニウムとの併用による、生体外でのヒト肝癌細胞の増殖抑制効果を検討した。
［材料と実験方法］
試薬；胎盤抽出物としてはラエンネックを用いた。ＭＴＴアッセイはナカライより購入した。
細胞；ＨｅｐＧ２（肝癌細胞株、分化型、理化学研究所より入手）、ＨＬＥ（肝癌細胞株、未分化型、ＪＣＲＢ（Ｊａｐａｎｅｓｅ Ｃｏｌｌｅｃｔｉｏｎ ｏｆ Ｒｅｓｅａｒｃｈ Ｂｉｏｒｅｓｏｕｒｃｅｓ）より入手）は１０％血清含有ＤＭＥＭ培地、Ｈｕｈ−７（肝癌細胞株、高分化型、東北大加齢研究所より入手）は１０％血清含有ＲＰＭＩ培地でそれぞれ培養した。
細胞増殖抑制試験；ＨｅｐＧ２（１．５×１０３ｃｅｌｌｓ／９０μｌ／ｗｅｌｌ）、Ｈｕｈ−７（４．５×１０３ｃｅｌｌｓ／９０μｌ／ｗｅｌｌ）及びＨＬＥ（１．０×１０３ｃｅｌｌｓ／９０μｌ／ｗｅｌｌ）を９６穴プレートに播種して２４時間培養後、ラエンネック単独又はラエンネック及びグリチルリチン酸モノアンモニウムを添加した。４８時間後、ＭＴＴアッセイにより細胞増殖または抑制を判定した。
［結果と考察］
ラエンネック単独はＨｅｐＧ２、ＨＬＥ及びＨｕｈ−７細胞に対して、５％添加以降において濃度依存的な増殖抑制作用を示した（図１；ａ，ｂ，ｃ参照）。
また、ラエンネックとグリチルリチン酸モノアンモニウムの併用により有意な増殖抑制作用が示された（図２；ａ，ｂ，ｃ参照）。これらの結果より、ラエンネック、特にラエンネックとグリチルリチン酸モノアンモニウムの併用は臨床上有用である可能性が推測された。
実施例２
Ｂ型ウイルス、Ｃ型ウイルス、非Ｂ型非Ｃ型ウイルス、その他の原因によって罹患した肝炎患者のＱＯＬが、ラエンネック投与によって向上することを、本実施例で示す。
ウイルス性肝炎の場合、ウイルスの消失、ＧＰＴ値の低下が目標である。そのためには、副作用を少なくし、標準的治療方法（例えば、ペグインターフェロンとリバビリンとの併用療法）をいかに持続させうるかがポイントになる。
持続療法の一環として、標準的治療方法に先行してラエンネックをＣ１型、Ｃ２型肝炎患者に投与した場合、消失したウイルスが陽性に転じる例が少なく、またペグインターフェロンによる副作用中止例が減少する可能性を吉田がすでに示唆している（吉田健太郎、日本胎盤臨床研究会研究要覧 第１号（平成２０年）、３２−３３頁、４７頁、４９−５０頁）。しかし、吉田は、ラエンネックによる患者のＱＯＬ向上については定量的なデータは公表していない。
そこで、肝機能改善剤（ウルソデオキシコール酸とグリチルリチン酸モノアンモニウムとの併用）にラエンネックを追加し、ＧＯＴ、ＧＰＴ値の推移とＱＯＬ向上との関係を検討した。その結果、以下の知見が得られた。
ｉ）肝機能改善剤投与のレジメン
肝機能改善剤投与など治療の対象にした肝炎患者総数（７５９例）は表１のとおりであるが、患者の自覚所見、他覚所見（血液データ、血液生化学データ等変動）から肝機能改善剤投与のレジメンは、原則、以下のとおりとした。
第一段階：ウルソデオキシコール酸（６００ｍｇ／日）を経口投与
第二段階：ウルソデオキシコール酸に、さらにグリチルリチン酸モノアンモニウム（４０ｍｌ~６０ｍｌ週３回）を静脈内投与
第三段階：ウルソデオキシコール酸に併用するグリチルリチン酸モノアンモニウムを増量（６０ｍｌ~１００ｍｌ週３回）
第四段階：ウルソデオキシコール酸、グリチルリチン酸モノアンモニウムに、さらにビタミンＣ（６００ｍｇ経口）、ビタミンＥ（３００ｍｇ経口）、ラエンネック（筋肉内に週２回、１~３アンプル）併用
ｉｉ）臨床効果
ｉｉ−１）ＧＯＴ・ＧＰＴ値の推移
肝炎患者総数（７５９例）のうち、第三段階までにＧＰＴ値が低下しない患者は１２４例であった。そこで、これら患者にラエンネックを平成１９年３月から平成２１年８月の２３カ月に亘って併用すると、１１３例（男性：５２例、女性：６１例）にＧＰＴ値の低下を認めた（図３参照）。
ｉｉ−２）自覚症状を改善（ＱＯＬの向上）
ラエンネックを併用した１２４例のうちの５８例（表２）から自覚症状の変化（ＱＯＬの向上）に関するアンケートを回収することができた。
アンケートの結果は表３のとおりであるが、非代償性肝硬変のような不定愁訴が多い症状を明らかに改善することが分かり、ＧＰＴ値等の低下とＱＯＬの向上に関連性があることを明らかにすることができた。
自覚症状を改善することから、８９％の患者はラエンネックの併用を引き続き希望していることも分かった。
ｉｉ−３）インターフェロンとの併用
ラエンネックにＱＯＬ向上効果があることから、副作用が多発するインターフェロン療法との併用の有用性が示唆された。そこで、副作用のため、ペグインターフェロンα療法を中止したＣ型肝炎患者に、ペグインターフェロンαとラエンネック（１回３アンプル、筋肉内投与）との併用を試みた。その結果、併用開始後から、ＧＯＴ・ＧＰＴ値が低下し、ＨＣＶも消失した（図４参照）。
ｉｉ−４）副作用
ラエンネックを併用した患者１２４例のいずれにも重篤な副作用はなく、全身浮腫が１例、眠気が２例、全身掻痒感が５例見られた程度であった。
［結論］
ラエンネックを、肝機能改善剤（ウルソデオキシコール酸、グリチルリチン酸モノアンモニウム等）と併用すると、長期治療が可能になり、結果として、血液学的所見のみならず、ＱＯＬを著しく向上、肝機能を改善することが分かった。
また、Ｃ型肝炎患者に対するインターフェロン療法にラエンネックを併用すると、インターフェロン療法による副作用が軽減し、肝機能を改善する知見も得た。
実施例３
Ｃ型肝炎（ジェノタイプ２ａ）、代償性肝硬変、びまん性肝細胞末期癌に罹患した５０歳代の男性で、広島県のある病院で余命１カ月と宣告され、平成１９年４月９日に来院した。全身倦怠感、食欲不振等の自覚症状があり、顔面は茶色化していた。
平成１９年４月２０日：患者さんの同意を得て、ラエンネック（１回１アンプルの隔日筋肉内）とグリチルリチン酸モノアンモニウム（隔日に３アンプル静脈内）の併用投与を開始。ＵＦＴ（テガフール・ウラシル、毎日２錠経口投与）も処方した。その結果を経時的に示す。
・平成１９年１０月５日以降：ＧＯＴ、ＧＰＴ、γ−ＧＴＰ、ＡＦＴ、ＰＩＶＫＡ−ＩＩの各値が正常化。
・平成２０年６月２１日：びまん性肝細胞癌が著明に縮小し（ＣＴ検査）、それまで認めていた右側腹部の圧痛が消失したので、ラエンネックの投与を中止。
・平成２０年１０月１日：ＰＩＶＫＡ−ＩＩ値が上昇したので、ラエンネックの投与を再開。ラエンネックの投与量は週１回１アンプル。
・平成２１年１２月２８日以降：ラエンネックを週１回１アンプル、グリチルリチン酸モノアンモニウムを週１回３アンプル投与。ＵＦＴも毎日２錠処方。
・平成２２年２月２日現在：平成２１年１２月２８日時点に比べ、ＡＦＴ値は若干上昇、ＰＩＶＫＡ−ＩＩ値は変化せず。
・平成１９年４月２０日のラエンネックの併用投与開始後、特記すべき副作用は発生していない。この間の肝機能検査、血液検査データは表４にまとめた。
患者のＱＯＬの改善度は、ラエンネックの併用投与開始約３カ月後、約６カ月後、約１２カ月後にＳＦ−３６（ＭＯＳ ３６ Ｉｔｅｍ−Ｆｏｒｍ Ｈｅａｌｔｈ Ｓｕｒｖｅｙ，登録商標）を用いて測定した結果、健康状態は時間とともに明らかに改善されていることが分かった（表５参照）。患者はすでに職場復帰しており、平成１９年４月以降、３６か月経過した平成２２年４月現在も健康状態は良好である。
［結論］
実施例１で示した実験データ（図２；ａ，ｂ，ｃ）、即ち、ラエンネックをグリチルリチン酸モノアンモニウムと併用すると、抗肝癌作用が増強されることが臨床でも実証された。
なお、臨床の場では、グリチルリチン酸モノアンモニウムを長期間静脈内に投与するとＱＯＬが低下し、投与を断念せざるを得ないことを経験する。したがって、ＱＯＬ改善・維持のためには、ラエンネックとの併用が必要と結論付けられた。これは、実施例２で示されたラエンネックによる慢性肝疾患患者のＱＯＬ向上の知見と符合する。
実施例４
症例は５０歳代男性で、２５歳時に交通事故で輸血歴あり。特に著患なく仕事をしていた。平成２０年９月、全身倦怠感、腹部膨満、腹部不快を主訴に来院した。来院時腹部超音波検査で多量の腹水を認め、採血でＨＣＶ陽性および肝機能低下を認めた。肝硬変重症度分類（Ｃｈｉｌｄ−ｐｕｇｈ）スコアは１０点であった。他の医療機関に入院して肝庇護療法を行ったが、腹水は軽度減少したのみにとどまった。
退院後、当院で平成２０年１０月からラエンネックを１回１アンプル、６回／週の割合で静脈内に慎重に点滴投与した。
その後腹部ＣＴ検査でＳ６に肝細胞癌が発見された。投与２ヵ月後の平成２０年１２月には腹水の減少が見られ、平成２１年３月には腹水はほぼ消失した。腹部ＣＴでも肝臓容量の増加をみとめ肝機能も軽快し、肝硬変重症度分類（Ｃｈｉｌｄ−ｐｕｇｈ）スコアは、来院当初の１０点から、６点に好転した。
そこで、肝細胞癌に対し血管造影にて血管塞栓術を施行した。治療後軽度腹水は出現したものの、その後消失し、退院後、ラエンネック投与を再開し現在１９ヶ月を経過しているが、肝細胞癌の再発および肝機能の悪化、腹水の出現はなく経過は良好である。
来院時（平成２０年９月）と腹水がほぼ消失した時点（平成２１年４月）での血液検査等のデータを表６に、平成２０年１０月から平成２１年１０月までの腹部ダイナミックＣＴの画像の変化を図５及び図６に示す。
なお、特記すべき副作用は発生しなかった。
［結論］
ラエンネックは、静脈内に慎重に長期間点滴投与すれば、単独投与でも肝細胞癌の再発を抑制し、肝機能を著明に改善させる可能性があることを見出した。これらの知見は、実施例１で示した図１；ａ，ｂ，ｃの結果を立証したものになっている。
実施例５
ラエンネックとウルソデオキシコール酸との併用による、生体外でのヒト肝癌細胞の増殖抑制効果を検討した。材料と実験方法は、実施例１の材料と実験方法と同様である。なお、試験は独立して６回実施した。
［併用効果の有無の判定］
併用効果の有無の判定は以下のように行った。
「ラエンネック単独」と「ラエンネックとウルソデオキシコール酸との併用」について有意差検定を行い、ｐ＜０．０５を示した群をプールした（プール１）。
続いて、「ウルソデオキシコール酸単独」と「ラエンネックとウルソデオキシコール酸との併用」について、有意差検定を行い、ｐ＜０．０５を示した群をプールした（プール２）。
プール１とプール２の両者間でｐ＜０．０５を示した群を「併用効果あり」と判定した。
［結果と考察］
試験結果を図７に示す。図７に示されるように、ウルソデオキシコール酸に１０％、２０％ラエンネックを併用すると、ＨｅｐＧ２、ＨＬＥ及びＨｕｈ−７の何れの癌細胞に対しても、明らかな増殖抑制効果を示すことが判明し（図７の（ａ）、（ｂ）及び（ｃ）参照）、両薬物の併用は臨床上有用であると推測された。
実施例６
ラエンネックとグルクロノラクトンとの併用による、生体外でのヒト肝癌細胞の増殖抑制効果を検討した。材料と実験方法及び併用効果の有無の判定は、実施例５と同様である。
試験結果を図８に示す。図８に示されるように、グルクロノラクトンに１０％ラエンネックを併用すると、ＨｅｐＧ２及びＨｕｈ−７の癌細胞に対しては有意性のある増殖抑制効果を示さなかったが、ＨＬＥに対しては顕著な抑制効果を示した（図８の（ｂ）の●参照）。
実施例７
ラエンネックとグルタチオンとの併用による、生体外でのヒト肝癌細胞の増殖抑制効果を検討した。材料と実験方法及び併用効果の有無の判定は、実施例５と同様である。
試験結果を図９に示す。図９に示されるように、グルタチオンに１０％ラエンネックを併用すると、ＨｅｐＧ２及びＨｕｈ−７の癌細胞に対しては有意性のある増殖抑制効果を示さなかったが、ＨＬＥに対しては顕著な抑制効果を示した（図９の（ｂ）の●参照）。
実施例８
ラエンネックと分岐アミノ酸との併用による、生体外でのヒト肝癌細胞の増殖抑制効果を検討した。材料と実験方法及び併用効果の有無の判定は、実施例５と同様である。なお、ここで分岐アミノ酸としては、ロイシン：イソロイシン：バリン＝２：１：１．２（モル比）の組成からなるアミノ酸製剤を使用した。
試験結果を図１０に示す。図１０に示されるように、分岐アミノ酸に１０％ラエンネックを併用すると、ＨｅｐＧ２及びＨｕｈ−７の癌細胞に対しては有意性のある増殖抑制効果を示さなかったが、ＨＬＥに対しては顕著な抑制効果を示した（図１０の（ｂ）の●参照）。
実施例９
ラエンネックとメチルメチオニンスルホニウムクロリドとの併用による、生体外でのヒト肝癌細胞の増殖抑制効果を検討した。材料と実験方法及び併用効果の有無の判定は、実施例５と同様である。
試験結果を図１１に示す。図１１に示されるように、メチルメチオニンスルホニウムクロリドに１０％ラエンネックを併用すると、ＨｅｐＧ２及びＨｕｈ−７の癌細胞に対しては有意性のある増殖抑制効果を示さなかったが、ＨＬＥに対しては顕著な抑制効果を示した（図１１の（ｂ）の●参照）。 EXAMPLES Hereinafter, although this invention is demonstrated in detail based on an Example, this invention is not limited to these examples.
Example 1
We investigated the growth inhibition effect of human hepatocarcinoma cells in vitro by the combined use of Raenneck and monoammonium glycyrrhizinate.
[Materials and experimental methods]
Reagent : Laeneck was used as the placenta extract. MTT assay was purchased from Nacalai.
Cells; HepG2 (liver cancer cell lines, differentiated, obtained from RIKEN), HLE (liver cancer cell lines, undifferentiated, obtained from JCRB (Japanese Collection of Research Bioresources) ) 10% serum-containing DMEM medium, Huh-7 (Hepatoma cell line, well-differentiated type, obtained from Tohoku University Research Institute for Aging) were each cultured in RPMI medium containing 10% serum.
Cell growth inhibition test : HepG2 (1.5 × 10 3 cells / 90 μl / well), Huh-7 (4.5 × 10 3 cells / 90 μl / well) and HLE (1.0 × 10 3 cells / 90 μl / well) ) Was seeded in a 96-well plate and cultured for 24 hours, and then Raenec alone or Raennec and monoammonium glycyrrhizinate were added. After 48 hours, cell proliferation or suppression was determined by MTT assay.
[Results and discussion]
Raeneck alone showed a concentration-dependent growth inhibitory effect on HepG2, HLE and Huh-7 cells after addition of 5% (see FIG. 1; a, b, c).
Further, the combined use of Raeneck and monoammonium glycyrrhizinate showed a significant growth inhibitory effect (see FIG. 2; a, b, c). From these results, it was speculated that Raenec, particularly the combination of Raennec and monoammonium glycyrrhizinate may be clinically useful.
Example 2
This example shows that QOL of hepatitis patients affected by B virus, C virus, non-B non-C virus, and other causes is improved by administration of Raeneck.
In the case of viral hepatitis, the goal is to eliminate the virus and lower the GPT value. To that end, it is important to reduce side effects and maintain a standard treatment method (for example, peginterferon and ribavirin combination therapy).
As part of continuous therapy, when Laeneck is administered to patients with C1 and C2 hepatitis prior to standard treatment, fewer cases of lost virus become positive, and fewer cases of side effects with pegylated interferon may be discontinued. Yoshida has already suggested sex (Kentaro Yoshida, Japan Placental Clinical Study Group Research Manual No. 1 (2008), 32-33, 47, 49-50). However, Yoshida does not publish quantitative data on the patient's QOL improvement due to Raeneck.
Therefore, a Raeneck was added to a liver function improving agent (combination of ursodeoxycholic acid and monoammonium glycyrrhizinate), and the relationship between changes in GOT and GPT values and QOL improvement was examined. As a result, the following knowledge was obtained.
i) Regimens for administration of liver function improving agents The total number of hepatitis patients (759 cases) treated for liver function improving agent administration, etc. is as shown in Table 1, but the patient's subjective findings and other objective findings (blood data, blood life Based on changes in chemical data, etc., the regimen for administration of liver function improving agents was as follows in principle.
First stage: Ursodeoxycholic acid (600 mg / day) orally administered Second stage: Ursodeoxycholic acid and monoammonium glycyrrhizinate (40 ml to 60 ml three times a week) intravenously Third stage: Ursodeoxycholic Increase the amount of monoammonium glycyrrhizinate used in combination with acid (60 ml to 100ml 3 times a week)
Fourth stage: Combined use of ursodeoxycholic acid, monoammonium glycyrrhizinate, vitamin C (600 mg oral), vitamin E (300 mg oral), and raennek (intramuscularly twice a week, 1 to 3 ampoules) ii) Clinical effects ii -1) Transition of GOT / GPT value Out of the total number of hepatitis patients (759 cases), 124 patients whose GPT value did not decrease by the third stage. Therefore, when Laennec was used in combination for 23 months from March 2007 to August 2009 in these patients, a decrease in GPT value was observed in 113 cases (male: 52 cases, female: 61 cases) (Fig. 3).
ii-2) Improve subjective symptoms (improve QOL)
Questionnaires regarding changes in subjective symptoms (improved QOL) could be collected from 58 cases (Table 2) out of 124 cases combined with Laennec.
The results of the questionnaire are as shown in Table 3, but it is clear that symptoms with many indefinite complaints such as decompensated cirrhosis are clearly improved, and it is clear that there is a relationship between a decrease in GPT values and an improvement in QOL I was able to.
From improving the subjective symptoms, it was also found that 89% of patients continued to desire the combination of Raeneck.
ii-3) Concomitant use with interferon Since the Laeneck has a QOL improving effect, the usefulness of the combined use with interferon therapy with frequent side effects was suggested. Therefore, due to side effects, a combination of peginterferon α and Laennec (3 ampules once, intramuscular administration) was tried for hepatitis C patients who discontinued peginterferon α therapy. As a result, the GOT / GPT value decreased and HCV disappeared after the combined use was started (see FIG. 4).
ii-4) Side effects There were no serious side effects in any of the 124 patients combined with Laennec, and there were only 1 case of systemic edema, 2 cases of sleepiness, and 5 cases of generalized pruritus.
[Conclusion]
When combined with liver function improvers (ursodeoxycholic acid, monoammonium glycyrrhizinate, etc.), Raenneck enables long-term treatment. As a result, not only hematological findings but also QOL is significantly improved and liver function is improved. I found out that
In addition, when Laennec was used in combination with interferon therapy for hepatitis C patients, the side effects of interferon therapy were alleviated and the findings of improving liver function were also obtained.
Example 3
A man in his 50s who suffered from hepatitis C (genotype 2a), compensatory cirrhosis, and diffuse hepatocellular carcinoma. He was sentenced to one month of life in a hospital in Hiroshima Prefecture on April 9, 2007. I visited the hospital. He had subjective symptoms such as general malaise and loss of appetite, and his face was browned.
April 20, 2007: With the consent of the patient, Laennek (one ampoule once every other day in the muscles) and monoammonium glycyrrhizinate (every other day, 3 ampoules intravenously) were started. UFT (Tegafur uracil, 2 tablets daily) was also prescribed. The results are shown over time.
・ After October 5, 2007: GOT, GPT, γ-GTP, AFT, and PIVKA-II values are normalized.
・ June 21, 2008: The administration of Raeneck was discontinued because diffuse hepatocellular carcinoma markedly decreased (CT examination) and the tenderness of the right abdomen that had been recognized disappeared.
・ October 1, 2008: As PIVKA-II level increased, administration of Laennec was resumed. Raenex dose is 1 amp per week.
・ After December 28, 2009: Raphnecks were administered once per week for 1 ampoule and glycyrrhizinate monoammonium was administered once per week for 3 ampoules. UFT is also prescribed 2 tablets daily.
・ As of February 2, 2010: Compared to December 28, 2009, the AFT value increased slightly and the PIVKA-II value remained unchanged.
・ After starting the combination administration of Raennekku on April 20, 2007, no side effects to be noted have occurred. The liver function test and blood test data during this period are summarized in Table 4.
The patient's improvement in QOL was measured using SF-36 (MOS 36 Item-Form Health Survey (registered trademark)) about 3 months, about 6 months, and about 12 months after the start of combination administration of Raennex. The condition was found to improve significantly with time (see Table 5). The patient has already returned to work, and his health is still good as of April 2010, 36 months after April 2007.
[Conclusion]
The experimental data shown in Example 1 (FIG. 2; a, b, c), that is, it was also demonstrated clinically that anti-hepatocarcinogenic activity is enhanced when Laennec is used in combination with monoammonium glycyrrhizinate.
In clinical settings, when monoammonium glycyrrhizinate is administered intravenously for a long period of time, the QOL decreases and the administration is abandoned. Therefore, it was concluded that a combination with Laennecks was necessary for improving and maintaining QOL. This agrees with the knowledge of QOL improvement of patients with chronic liver disease due to Laenneq shown in Example 2.
Example 4
The case was a man in his 50s who had a blood transfusion due to a traffic accident when he was 25 years old. I was working without any particular problems. In September 2008, she visited the hospital complaining of general malaise, abdominal distension, and abdominal discomfort. Abdominal ultrasonography revealed a large amount of ascites at the visit, and blood collection revealed HCV positivity and decreased liver function. The cirrhosis severity classification (Child-pugh) score was 10 points. He was admitted to another medical institution and performed liver palliative therapy, but the ascites decreased only slightly.
After leaving the hospital, from October 2008, Raeneck was carefully administered intravenously at a rate of 1 ampoule once and 6 times / week.
Later, hepatocellular carcinoma was found in S6 by abdominal CT examination. Ascites decreased in December 2008 two months after administration, and ascites almost disappeared in March 2009. Abdominal CT also showed an increase in liver capacity and improved liver function. The cirrhosis severity classification (Child-pugh) score improved from 10 at the beginning of the visit to 6 points.
Therefore, vascular embolization was performed by angiography for hepatocellular carcinoma. Although mild ascites appeared after treatment, it disappeared afterwards, and after discharge, Laennec administration was resumed, and now 19 months have passed. However, there was no recurrence of hepatocellular carcinoma, worsening of liver function, and appearance of ascites. It is.
Table 6 shows data such as blood tests at the time of visit (September 2008) and when ascites almost disappeared (April 2009), and abdominal dynamics from October 2008 to October 2009 Changes in CT images are shown in FIGS.
There were no significant side effects.
[Conclusion]
Raenneck found that if intravenous infusion was carefully administered for a long period of time, recurrence of hepatocellular carcinoma could be suppressed even by single administration, and liver function could be significantly improved. These findings prove the results of FIG. 1; a, b, and c shown in Example 1.
Example 5
We investigated the growth-inhibitory effect of human hepatocarcinoma cells in vitro by the combined use of Raennec and ursodeoxycholic acid. The materials and experimental methods are the same as the materials and experimental methods of Example 1. The test was conducted 6 times independently.
[Determination of presence or absence of combined effect]
The presence or absence of the combined effect was determined as follows.
Significant difference tests were performed for “Laeneck alone” and “Combination of Raenneck and Ursodeoxycholic acid”, and the group showing p <0.05 was pooled (Pool 1).
Subsequently, a significant difference test was performed on “ursodeoxycholic acid alone” and “combination of Raeneck and ursodeoxycholic acid”, and the group showing p <0.05 was pooled (pool 2).
The group showing p <0.05 between bothpool 1 and pool 2 was determined as “combination effect”.
[Results and discussion]
The test results are shown in FIG. As shown in FIG. 7, when 10% and 20% raennecks were used in combination with ursodeoxycholic acid, it was found to show a clear growth inhibitory effect on any cancer cells of HepG2, HLE and Huh-7. (See FIGS. 7 (a), (b) and (c)), and the combined use of both drugs was presumed to be clinically useful.
Example 6
We investigated the growth inhibitory effect of human hepatocarcinoma cells in vitro by the combined use of Raennec and glucuronolactone. The determination of the presence of the material, the experimental method, and the combined effect is the same as in Example 5.
The test results are shown in FIG. As shown in FIG. 8, when glucuronolactone was used in combination with 10% Laennec, HepG2 and Huh-7 did not show a significant growth inhibitory effect on cancer cells, but were prominent for HLE. (See the ● in FIG. 8B).
Example 7
We investigated the growth inhibitory effect of human hepatocarcinoma cells in vitro by the combined use of Laennec and glutathione. The determination of the presence of the material, the experimental method, and the combined effect is the same as in Example 5.
The test results are shown in FIG. As shown in FIG. 9, when glutathione was used in combination with 10% Laennec, HepG2 and Huh-7 did not show a significant growth-inhibiting effect on cancer cells, but markedly suppressed against HLE. The effect was shown (see ● in FIG. 9B).
Example 8
We investigated the growth inhibitory effect of human hepatoma cells in vitro by the combined use of Laennec and branched amino acids. The determination of the presence of the material, the experimental method, and the combined effect is the same as in Example 5. Here, as the branched amino acid, an amino acid preparation having a composition of leucine: isoleucine: valine = 2: 1: 1.2 (molar ratio) was used.
The test results are shown in FIG. As shown in FIG. 10, when 10% Laennec was used in combination with a branched amino acid, HepG2 and Huh-7 did not show a significant growth inhibitory effect on cancer cells, but were prominent for HLE. An inhibitory effect was shown (see ● in FIG. 10B).
Example 9
We investigated the growth-inhibitory effect of human hepatoma cells in vitro by the combined use of Raennec and methylmethioninesulfonium chloride. The determination of the presence of the material, the experimental method, and the combined effect is the same as in Example 5.
The test results are shown in FIG. As shown in FIG. 11, when 10% Laeneck was used in combination with methylmethioninesulfonium chloride, HepG2 and Huh-7 did not show a significant growth inhibitory effect on cancer cells. A remarkable inhibitory effect was shown (see ● in FIG. 11B).
実施例１
ラエンネックとグリチルリチン酸モノアンモニウムとの併用による、生体外でのヒト肝癌細胞の増殖抑制効果を検討した。
［材料と実験方法］
試薬；胎盤抽出物としてはラエンネックを用いた。ＭＴＴアッセイはナカライより購入した。
細胞；ＨｅｐＧ２（肝癌細胞株、分化型、理化学研究所より入手）、ＨＬＥ（肝癌細胞株、未分化型、ＪＣＲＢ（Ｊａｐａｎｅｓｅ Ｃｏｌｌｅｃｔｉｏｎ ｏｆ Ｒｅｓｅａｒｃｈ Ｂｉｏｒｅｓｏｕｒｃｅｓ）より入手）は１０％血清含有ＤＭＥＭ培地、Ｈｕｈ−７（肝癌細胞株、高分化型、東北大加齢研究所より入手）は１０％血清含有ＲＰＭＩ培地でそれぞれ培養した。
細胞増殖抑制試験；ＨｅｐＧ２（１．５×１０３ｃｅｌｌｓ／９０μｌ／ｗｅｌｌ）、Ｈｕｈ−７（４．５×１０３ｃｅｌｌｓ／９０μｌ／ｗｅｌｌ）及びＨＬＥ（１．０×１０３ｃｅｌｌｓ／９０μｌ／ｗｅｌｌ）を９６穴プレートに播種して２４時間培養後、ラエンネック単独又はラエンネック及びグリチルリチン酸モノアンモニウムを添加した。４８時間後、ＭＴＴアッセイにより細胞増殖または抑制を判定した。
［結果と考察］
ラエンネック単独はＨｅｐＧ２、ＨＬＥ及びＨｕｈ−７細胞に対して、５％添加以降において濃度依存的な増殖抑制作用を示した（図１；ａ，ｂ，ｃ参照）。
また、ラエンネックとグリチルリチン酸モノアンモニウムの併用により有意な増殖抑制作用が示された（図２；ａ，ｂ，ｃ参照）。これらの結果より、ラエンネック、特にラエンネックとグリチルリチン酸モノアンモニウムの併用は臨床上有用である可能性が推測された。
実施例２
Ｂ型ウイルス、Ｃ型ウイルス、非Ｂ型非Ｃ型ウイルス、その他の原因によって罹患した肝炎患者のＱＯＬが、ラエンネック投与によって向上することを、本実施例で示す。
ウイルス性肝炎の場合、ウイルスの消失、ＧＰＴ値の低下が目標である。そのためには、副作用を少なくし、標準的治療方法（例えば、ペグインターフェロンとリバビリンとの併用療法）をいかに持続させうるかがポイントになる。
持続療法の一環として、標準的治療方法に先行してラエンネックをＣ１型、Ｃ２型肝炎患者に投与した場合、消失したウイルスが陽性に転じる例が少なく、またペグインターフェロンによる副作用中止例が減少する可能性を吉田がすでに示唆している（吉田健太郎、日本胎盤臨床研究会研究要覧 第１号（平成２０年）、３２−３３頁、４７頁、４９−５０頁）。しかし、吉田は、ラエンネックによる患者のＱＯＬ向上については定量的なデータは公表していない。
そこで、肝機能改善剤（ウルソデオキシコール酸とグリチルリチン酸モノアンモニウムとの併用）にラエンネックを追加し、ＧＯＴ、ＧＰＴ値の推移とＱＯＬ向上との関係を検討した。その結果、以下の知見が得られた。
ｉ）肝機能改善剤投与のレジメン
肝機能改善剤投与など治療の対象にした肝炎患者総数（７５９例）は表１のとおりであるが、患者の自覚所見、他覚所見（血液データ、血液生化学データ等変動）から肝機能改善剤投与のレジメンは、原則、以下のとおりとした。
第一段階：ウルソデオキシコール酸（６００ｍｇ／日）を経口投与
第二段階：ウルソデオキシコール酸に、さらにグリチルリチン酸モノアンモニウム（４０ｍｌ~６０ｍｌ週３回）を静脈内投与
第三段階：ウルソデオキシコール酸に併用するグリチルリチン酸モノアンモニウムを増量（６０ｍｌ~１００ｍｌ週３回）
第四段階：ウルソデオキシコール酸、グリチルリチン酸モノアンモニウムに、さらにビタミンＣ（６００ｍｇ経口）、ビタミンＥ（３００ｍｇ経口）、ラエンネック（筋肉内に週２回、１~３アンプル）併用
ｉｉ）臨床効果
ｉｉ−１）ＧＯＴ・ＧＰＴ値の推移
肝炎患者総数（７５９例）のうち、第三段階までにＧＰＴ値が低下しない患者は１２４例であった。そこで、これら患者にラエンネックを平成１９年３月から平成２１年８月の２３カ月に亘って併用すると、１１３例（男性：５２例、女性：６１例）にＧＰＴ値の低下を認めた（図３参照）。
ｉｉ−２）自覚症状を改善（ＱＯＬの向上）
ラエンネックを併用した１２４例のうちの５８例（表２）から自覚症状の変化（ＱＯＬの向上）に関するアンケートを回収することができた。
アンケートの結果は表３のとおりであるが、非代償性肝硬変のような不定愁訴が多い症状を明らかに改善することが分かり、ＧＰＴ値等の低下とＱＯＬの向上に関連性があることを明らかにすることができた。
自覚症状を改善することから、８９％の患者はラエンネックの併用を引き続き希望していることも分かった。
ラエンネックにＱＯＬ向上効果があることから、副作用が多発するインターフェロン療法との併用の有用性が示唆された。そこで、副作用のため、ペグインターフェロンα療法を中止したＣ型肝炎患者に、ペグインターフェロンαとラエンネック（１回３アンプル、筋肉内投与）との併用を試みた。その結果、併用開始後から、ＧＯＴ・ＧＰＴ値が低下し、ＨＣＶも消失した（図４参照）。
ｉｉ−４）副作用
ラエンネックを併用した患者１２４例のいずれにも重篤な副作用はなく、全身浮腫が１例、眠気が２例、全身掻痒感が５例見られた程度であった。
［結論］
ラエンネックを、肝機能改善剤（ウルソデオキシコール酸、グリチルリチン酸モノアンモニウム等）と併用すると、長期治療が可能になり、結果として、血液学的所見のみならず、ＱＯＬを著しく向上、肝機能を改善することが分かった。
また、Ｃ型肝炎患者に対するインターフェロン療法にラエンネックを併用すると、インターフェロン療法による副作用が軽減し、肝機能を改善する知見も得た。
実施例３
Ｃ型肝炎（ジェノタイプ２ａ）、代償性肝硬変、びまん性肝細胞末期癌に罹患した５０歳代の男性で、広島県のある病院で余命１カ月と宣告され、平成１９年４月９日に来院した。全身倦怠感、食欲不振等の自覚症状があり、顔面は茶色化していた。
平成１９年４月２０日：患者さんの同意を得て、ラエンネック（１回１アンプルの隔日筋肉内）とグリチルリチン酸モノアンモニウム（隔日に３アンプル静脈内）の併用投与を開始。ＵＦＴ（テガフール・ウラシル、毎日２錠経口投与）も処方した。その結果を経時的に示す。
・平成１９年１０月５日以降：ＧＯＴ、ＧＰＴ、γ−ＧＴＰ、ＡＦＴ、ＰＩＶＫＡ−ＩＩの各値が正常化。
・平成２０年６月２１日：びまん性肝細胞癌が著明に縮小し（ＣＴ検査）、それまで認めていた右側腹部の圧痛が消失したので、ラエンネックの投与を中止。
・平成２０年１０月１日：ＰＩＶＫＡ−ＩＩ値が上昇したので、ラエンネックの投与を再開。ラエンネックの投与量は週１回１アンプル。
・平成２１年１２月２８日以降：ラエンネックを週１回１アンプル、グリチルリチン酸モノアンモニウムを週１回３アンプル投与。ＵＦＴも毎日２錠処方。
・平成２２年２月２日現在：平成２１年１２月２８日時点に比べ、ＡＦＴ値は若干上昇、ＰＩＶＫＡ−ＩＩ値は変化せず。
・平成１９年４月２０日のラエンネックの併用投与開始後、特記すべき副作用は発生していない。この間の肝機能検査、血液検査データは表４にまとめた。
患者のＱＯＬの改善度は、ラエンネックの併用投与開始約３カ月後、約６カ月後、約１２カ月後にＳＦ−３６（ＭＯＳ ３６ Ｉｔｅｍ−Ｆｏｒｍ Ｈｅａｌｔｈ Ｓｕｒｖｅｙ，登録商標）を用いて測定した結果、健康状態は時間とともに明らかに改善されていることが分かった（表５参照）。患者はすでに職場復帰しており、平成１９年４月以降、３６か月経過した平成２２年４月現在も健康状態は良好である。
実施例１で示した実験データ（図２；ａ，ｂ，ｃ）、即ち、ラエンネックをグリチルリチン酸モノアンモニウムと併用すると、抗肝癌作用が増強されることが臨床でも実証された。
なお、臨床の場では、グリチルリチン酸モノアンモニウムを長期間静脈内に投与するとＱＯＬが低下し、投与を断念せざるを得ないことを経験する。したがって、ＱＯＬ改善・維持のためには、ラエンネックとの併用が必要と結論付けられた。これは、実施例２で示されたラエンネックによる慢性肝疾患患者のＱＯＬ向上の知見と符合する。
実施例４
症例は５０歳代男性で、２５歳時に交通事故で輸血歴あり。特に著患なく仕事をしていた。平成２０年９月、全身倦怠感、腹部膨満、腹部不快を主訴に来院した。来院時腹部超音波検査で多量の腹水を認め、採血でＨＣＶ陽性および肝機能低下を認めた。肝硬変重症度分類（Ｃｈｉｌｄ−ｐｕｇｈ）スコアは１０点であった。他の医療機関に入院して肝庇護療法を行ったが、腹水は軽度減少したのみにとどまった。
退院後、当院で平成２０年１０月からラエンネックを１回１アンプル、６回／週の割合で静脈内に慎重に点滴投与した。
その後腹部ＣＴ検査でＳ６に肝細胞癌が発見された。投与２ヵ月後の平成２０年１２月には腹水の減少が見られ、平成２１年３月には腹水はほぼ消失した。腹部ＣＴでも肝臓容量の増加をみとめ肝機能も軽快し、肝硬変重症度分類（Ｃｈｉｌｄ−ｐｕｇｈ）スコアは、来院当初の１０点から、６点に好転した。
そこで、肝細胞癌に対し血管造影にて血管塞栓術を施行した。治療後軽度腹水は出現したものの、その後消失し、退院後、ラエンネック投与を再開し現在１９ヶ月を経過しているが、肝細胞癌の再発および肝機能の悪化、腹水の出現はなく経過は良好である。
来院時（平成２０年９月）と腹水がほぼ消失した時点（平成２１年４月）での血液検査等のデータを表６に、平成２０年１０月から平成２１年１０月までの腹部ダイナミックＣＴの画像の変化を図５及び図６に示す。
なお、特記すべき副作用は発生しなかった。
［結論］
ラエンネックは、静脈内に慎重に長期間点滴投与すれば、単独投与でも肝細胞癌の再発を抑制し、肝機能を著明に改善させる可能性があることを見出した。これらの知見は、実施例１で示した図１；ａ，ｂ，ｃの結果を立証したものになっている。
ラエンネックとウルソデオキシコール酸との併用による、生体外でのヒト肝癌細胞の増殖抑制効果を検討した。材料と実験方法は、実施例１の材料と実験方法と同様である。なお、試験は独立して６回実施した。
［併用効果の有無の判定］
併用効果の有無の判定は以下のように行った。
「ラエンネック単独」と「ラエンネックとウルソデオキシコール酸との併用」について有意差検定を行い、ｐ＜０．０５を示した群をプールした（プール１）。
続いて、「ウルソデオキシコール酸単独」と「ラエンネックとウルソデオキシコール酸との併用」について、有意差検定を行い、ｐ＜０．０５を示した群をプールした（プール２）。
プール１とプール２の両者間でｐ＜０．０５を示した群を「併用効果あり」と判定した。
［結果と考察］
試験結果を図７に示す。図７に示されるように、ウルソデオキシコール酸に１０％、２０％ラエンネックを併用すると、ＨｅｐＧ２、ＨＬＥ及びＨｕｈ−７の何れの癌細胞に対しても、明らかな増殖抑制効果を示すことが判明し（図７の（ａ）、（ｂ）及び（ｃ）参照）、両薬物の併用は臨床上有用であると推測された。
実施例６
ラエンネックとグルクロノラクトンとの併用による、生体外でのヒト肝癌細胞の増殖抑制効果を検討した。材料と実験方法及び併用効果の有無の判定は、実施例５と同様である。
試験結果を図８に示す。図８に示されるように、グルクロノラクトンに１０％ラエンネックを併用すると、ＨｅｐＧ２及びＨｕｈ−７の癌細胞に対しては有意性のある増殖抑制効果を示さなかったが、ＨＬＥに対しては顕著な抑制効果を示した（図８の（ｂ）の●参照）。
実施例７
ラエンネックとグルタチオンとの併用による、生体外でのヒト肝癌細胞の増殖抑制効果を検討した。材料と実験方法及び併用効果の有無の判定は、実施例５と同様である。
試験結果を図９に示す。図９に示されるように、グルタチオンに１０％ラエンネックを併用すると、ＨｅｐＧ２及びＨｕｈ−７の癌細胞に対しては有意性のある増殖抑制効果を示さなかったが、ＨＬＥに対しては顕著な抑制効果を示した（図９の（ｂ）の●参照）。
実施例８
ラエンネックと分岐アミノ酸との併用による、生体外でのヒト肝癌細胞の増殖抑制効果を検討した。材料と実験方法及び併用効果の有無の判定は、実施例５と同様である。なお、ここで分岐アミノ酸としては、ロイシン：イソロイシン：バリン＝２：１：１．２（モル比）の組成からなるアミノ酸製剤を使用した。
試験結果を図１０に示す。図１０に示されるように、分岐アミノ酸に１０％ラエンネックを併用すると、ＨｅｐＧ２及びＨｕｈ−７の癌細胞に対しては有意性のある増殖抑制効果を示さなかったが、ＨＬＥに対しては顕著な抑制効果を示した（図１０の（ｂ）の●参照）。
実施例９
ラエンネックとメチルメチオニンスルホニウムクロリドとの併用による、生体外でのヒト肝癌細胞の増殖抑制効果を検討した。材料と実験方法及び併用効果の有無の判定は、実施例５と同様である。
試験結果を図１１に示す。図１１に示されるように、メチルメチオニンスルホニウムクロリドに１０％ラエンネックを併用すると、ＨｅｐＧ２及びＨｕｈ−７の癌細胞に対しては有意性のある増殖抑制効果を示さなかったが、ＨＬＥに対しては顕著な抑制効果を示した（図１１の（ｂ）の●参照）。 EXAMPLES Hereinafter, although this invention is demonstrated in detail based on an Example, this invention is not limited to these examples.
Example 1
We investigated the growth inhibition effect of human hepatocarcinoma cells in vitro by the combined use of Raenneck and monoammonium glycyrrhizinate.
[Materials and experimental methods]
Reagent : Laeneck was used as the placenta extract. MTT assay was purchased from Nacalai.
Cells; HepG2 (liver cancer cell lines, differentiated, obtained from RIKEN), HLE (liver cancer cell lines, undifferentiated, obtained from JCRB (Japanese Collection of Research Bioresources) ) 10% serum-containing DMEM medium, Huh-7 (Hepatoma cell line, well-differentiated type, obtained from Tohoku University Research Institute for Aging) were each cultured in RPMI medium containing 10% serum.
Cell growth inhibition test : HepG2 (1.5 × 10 3 cells / 90 μl / well), Huh-7 (4.5 × 10 3 cells / 90 μl / well) and HLE (1.0 × 10 3 cells / 90 μl / well) ) Was seeded in a 96-well plate and cultured for 24 hours, and then Raenec alone or Raennec and monoammonium glycyrrhizinate were added. After 48 hours, cell proliferation or suppression was determined by MTT assay.
[Results and discussion]
Raeneck alone showed a concentration-dependent growth inhibitory effect on HepG2, HLE and Huh-7 cells after addition of 5% (see FIG. 1; a, b, c).
Further, the combined use of Raeneck and monoammonium glycyrrhizinate showed a significant growth inhibitory effect (see FIG. 2; a, b, c). From these results, it was speculated that Raenec, particularly the combination of Raennec and monoammonium glycyrrhizinate may be clinically useful.
Example 2
This example shows that QOL of hepatitis patients affected by B virus, C virus, non-B non-C virus, and other causes is improved by administration of Raeneck.
In the case of viral hepatitis, the goal is to eliminate the virus and lower the GPT value. To that end, it is important to reduce side effects and maintain a standard treatment method (for example, peginterferon and ribavirin combination therapy).
As part of continuous therapy, when Laeneck is administered to patients with C1 and C2 hepatitis prior to standard treatment, fewer cases of lost virus become positive, and fewer cases of side effects with pegylated interferon may be discontinued. Yoshida has already suggested sex (Kentaro Yoshida, Japan Placental Clinical Study Group Research Manual No. 1 (2008), 32-33, 47, 49-50). However, Yoshida does not publish quantitative data on the patient's QOL improvement due to Raeneck.
Therefore, a Raeneck was added to a liver function improving agent (combination of ursodeoxycholic acid and monoammonium glycyrrhizinate), and the relationship between changes in GOT and GPT values and QOL improvement was examined. As a result, the following knowledge was obtained.
i) Regimens for administration of liver function improving agents The total number of hepatitis patients (759 cases) treated for liver function improving agent administration, etc. is as shown in Table 1, but the patient's subjective findings and other objective findings (blood data, blood life Based on changes in chemical data, etc., the regimen for administration of liver function improving agents was as follows in principle.
First stage: Ursodeoxycholic acid (600 mg / day) orally administered Second stage: Ursodeoxycholic acid and monoammonium glycyrrhizinate (40 ml to 60 ml three times a week) intravenously Third stage: Ursodeoxycholic Increase the amount of monoammonium glycyrrhizinate used in combination with acid (60 ml to 100
Fourth stage: Combined use of ursodeoxycholic acid, monoammonium glycyrrhizinate, vitamin C (600 mg oral), vitamin E (300 mg oral), and raennek (intramuscularly twice a week, 1 to 3 ampoules) ii) Clinical effects ii -1) Transition of GOT / GPT value Out of the total number of hepatitis patients (759 cases), 124 patients whose GPT value did not decrease by the third stage. Therefore, when Laennec was used in combination for 23 months from March 2007 to August 2009 in these patients, a decrease in GPT value was observed in 113 cases (male: 52 cases, female: 61 cases) (Fig. 3).
ii-2) Improve subjective symptoms (improve QOL)
Questionnaires regarding changes in subjective symptoms (improved QOL) could be collected from 58 cases (Table 2) out of 124 cases combined with Laennec.
The results of the questionnaire are as shown in Table 3, but it is clear that symptoms with many indefinite complaints such as decompensated cirrhosis are clearly improved, and it is clear that there is a relationship between a decrease in GPT values and an improvement in QOL I was able to.
From improving the subjective symptoms, it was also found that 89% of patients continued to desire the combination of Raeneck.
ii-4) Side effects There were no serious side effects in any of the 124 patients combined with Laennec, and there were only 1 case of systemic edema, 2 cases of sleepiness, and 5 cases of generalized pruritus.
[Conclusion]
When combined with liver function improvers (ursodeoxycholic acid, monoammonium glycyrrhizinate, etc.), Raenneck enables long-term treatment. As a result, not only hematological findings but also QOL is significantly improved and liver function is improved. I found out that
In addition, when Laennec was used in combination with interferon therapy for hepatitis C patients, the side effects of interferon therapy were alleviated and the findings of improving liver function were also obtained.
Example 3
A man in his 50s who suffered from hepatitis C (genotype 2a), compensatory cirrhosis, and diffuse hepatocellular carcinoma. He was sentenced to one month of life in a hospital in Hiroshima Prefecture on April 9, 2007. I visited the hospital. He had subjective symptoms such as general malaise and loss of appetite, and his face was browned.
April 20, 2007: With the consent of the patient, Laennek (one ampoule once every other day in the muscles) and monoammonium glycyrrhizinate (every other day, 3 ampoules intravenously) were started. UFT (Tegafur uracil, 2 tablets daily) was also prescribed. The results are shown over time.
・ After October 5, 2007: GOT, GPT, γ-GTP, AFT, and PIVKA-II values are normalized.
・ June 21, 2008: The administration of Raeneck was discontinued because diffuse hepatocellular carcinoma markedly decreased (CT examination) and the tenderness of the right abdomen that had been recognized disappeared.
・ October 1, 2008: As PIVKA-II level increased, administration of Laennec was resumed. Raenex dose is 1 amp per week.
・ After December 28, 2009: Raphnecks were administered once per week for 1 ampoule and glycyrrhizinate monoammonium was administered once per week for 3 ampoules. UFT is also prescribed 2 tablets daily.
・ As of February 2, 2010: Compared to December 28, 2009, the AFT value increased slightly and the PIVKA-II value remained unchanged.
・ After starting the combination administration of Raennekku on April 20, 2007, no side effects to be noted have occurred. The liver function test and blood test data during this period are summarized in Table 4.
The patient's improvement in QOL was measured using SF-36 (MOS 36 Item-Form Health Survey (registered trademark)) about 3 months, about 6 months, and about 12 months after the start of combination administration of Raennex. The condition was found to improve significantly with time (see Table 5). The patient has already returned to work, and his health is still good as of April 2010, 36 months after April 2007.
The experimental data shown in Example 1 (FIG. 2; a, b, c), that is, it was also demonstrated clinically that anti-hepatocarcinogenic activity is enhanced when Laennec is used in combination with monoammonium glycyrrhizinate.
In clinical settings, when monoammonium glycyrrhizinate is administered intravenously for a long period of time, the QOL decreases and the administration is abandoned. Therefore, it was concluded that a combination with Laennecks was necessary for improving and maintaining QOL. This agrees with the knowledge of QOL improvement of patients with chronic liver disease due to Laenneq shown in Example 2.
Example 4
The case was a man in his 50s who had a blood transfusion due to a traffic accident when he was 25 years old. I was working without any particular problems. In September 2008, she visited the hospital complaining of general malaise, abdominal distension, and abdominal discomfort. Abdominal ultrasonography revealed a large amount of ascites at the visit, and blood collection revealed HCV positivity and decreased liver function. The cirrhosis severity classification (Child-pugh) score was 10 points. He was admitted to another medical institution and performed liver palliative therapy, but the ascites decreased only slightly.
After leaving the hospital, from October 2008, Raeneck was carefully administered intravenously at a rate of 1 ampoule once and 6 times / week.
Later, hepatocellular carcinoma was found in S6 by abdominal CT examination. Ascites decreased in December 2008 two months after administration, and ascites almost disappeared in March 2009. Abdominal CT also showed an increase in liver capacity and improved liver function. The cirrhosis severity classification (Child-pugh) score improved from 10 at the beginning of the visit to 6 points.
Therefore, vascular embolization was performed by angiography for hepatocellular carcinoma. Although mild ascites appeared after treatment, it disappeared afterwards, and after discharge, Laennec administration was resumed, and now 19 months have passed. However, there was no recurrence of hepatocellular carcinoma, worsening of liver function, and appearance of ascites. It is.
Table 6 shows data such as blood tests at the time of visit (September 2008) and when ascites almost disappeared (April 2009), and abdominal dynamics from October 2008 to October 2009 Changes in CT images are shown in FIGS.
There were no significant side effects.
[Conclusion]
Raenneck found that if intravenous infusion was carefully administered for a long period of time, recurrence of hepatocellular carcinoma could be suppressed even by single administration, and liver function could be significantly improved. These findings prove the results of FIG. 1; a, b, and c shown in Example 1.
We investigated the growth-inhibitory effect of human hepatocarcinoma cells in vitro by the combined use of Raennec and ursodeoxycholic acid. The materials and experimental methods are the same as the materials and experimental methods of Example 1. The test was conducted 6 times independently.
[Determination of presence or absence of combined effect]
The presence or absence of the combined effect was determined as follows.
Significant difference tests were performed for “Laeneck alone” and “Combination of Raenneck and Ursodeoxycholic acid”, and the group showing p <0.05 was pooled (Pool 1).
Subsequently, a significant difference test was performed on “ursodeoxycholic acid alone” and “combination of Raeneck and ursodeoxycholic acid”, and the group showing p <0.05 was pooled (pool 2).
The group showing p <0.05 between both
[Results and discussion]
The test results are shown in FIG. As shown in FIG. 7, when 10% and 20% raennecks were used in combination with ursodeoxycholic acid, it was found to show a clear growth inhibitory effect on any cancer cells of HepG2, HLE and Huh-7. (See FIGS. 7 (a), (b) and (c)), and the combined use of both drugs was presumed to be clinically useful.
Example 6
We investigated the growth inhibitory effect of human hepatocarcinoma cells in vitro by the combined use of Raennec and glucuronolactone. The determination of the presence of the material, the experimental method, and the combined effect is the same as in Example 5.
The test results are shown in FIG. As shown in FIG. 8, when glucuronolactone was used in combination with 10% Laennec, HepG2 and Huh-7 did not show a significant growth inhibitory effect on cancer cells, but were prominent for HLE. (See the ● in FIG. 8B).
Example 7
We investigated the growth inhibitory effect of human hepatocarcinoma cells in vitro by the combined use of Laennec and glutathione. The determination of the presence of the material, the experimental method, and the combined effect is the same as in Example 5.
The test results are shown in FIG. As shown in FIG. 9, when glutathione was used in combination with 10% Laennec, HepG2 and Huh-7 did not show a significant growth-inhibiting effect on cancer cells, but markedly suppressed against HLE. The effect was shown (see ● in FIG. 9B).
Example 8
We investigated the growth inhibitory effect of human hepatoma cells in vitro by the combined use of Laennec and branched amino acids. The determination of the presence of the material, the experimental method, and the combined effect is the same as in Example 5. Here, as the branched amino acid, an amino acid preparation having a composition of leucine: isoleucine: valine = 2: 1: 1.2 (molar ratio) was used.
The test results are shown in FIG. As shown in FIG. 10, when 10% Laennec was used in combination with a branched amino acid, HepG2 and Huh-7 did not show a significant growth inhibitory effect on cancer cells, but were prominent for HLE. An inhibitory effect was shown (see ● in FIG. 10B).
Example 9
We investigated the growth-inhibitory effect of human hepatoma cells in vitro by the combined use of Raennec and methylmethioninesulfonium chloride. The determination of the presence of the material, the experimental method, and the combined effect is the same as in Example 5.
The test results are shown in FIG. As shown in FIG. 11, when 10% Laeneck was used in combination with methylmethioninesulfonium chloride, HepG2 and Huh-7 did not show a significant growth inhibitory effect on cancer cells. A remarkable inhibitory effect was shown (see ● in FIG. 11B).
本発明のＱＯＬ改善剤によれば、肝癌細胞を縮小させ、患者の自覚症状を改善し、ＱＯＬを向上させることができるので、末期の肝細胞癌も含めて肝細胞癌の治療において有用である。特に、本発明のＱＯＬ改善剤は、肝機能改善剤と併用すると、それらの相乗効果により肝細胞癌の増殖を顕著に抑制し得るので、肝細胞癌の治療に有用である。
According to the QOL improving agent of the present invention, hepatoma cells can be reduced, patient's subjective symptoms can be improved, and QOL can be improved, so that it is useful in the treatment of hepatocellular carcinoma including end-stage hepatocellular carcinoma. . In particular, the QOL improving agent of the present invention, when used in combination with a liver function improving agent, can significantly suppress the growth of hepatocellular carcinoma due to their synergistic effect, and thus is useful for the treatment of hepatocellular carcinoma.
Claims (9)
- ヒト胎盤抽出物を含有することを特徴とする、肝細胞癌患者のＱＯＬ（Ｑｕａｌｉｔｙ ｏｆ ｌｉｆｅ）改善剤。 A QOL (Quality of Life) improving agent for patients with hepatocellular carcinoma, characterized by containing human placenta extract.
- 肝細胞癌患者が、肝機能改善剤を投与されている請求項１記載のＱＯＬ改善剤。 The QOL improving agent according to claim 1, wherein the hepatocellular carcinoma patient is administered a liver function improving agent.
- 肝機能改善剤が、グリチルリチン酸塩、アデノシン三リン酸塩、フラビンアデニンジヌクレオチド、ウルソデオキシコール酸、ジクロロ酢酸ジイソプロピルアミン、グルクロノラクトン、グルタチオン、マロチラート、メチルメチオニンスルホニウムクロリド、ポリエンフォスファチジルコリン、プロトポルフィリン塩、分岐鎖アミノ酸製剤、肝水解物、インターフェロン製剤及び核酸関連化合物製剤から選ばれた少なくとも１種である請求項２記載のＱＯＬ改善剤。 Liver function improving agents are glycyrrhizinate, adenosine triphosphate, flavin adenine dinucleotide, ursodeoxycholic acid, diisopropylamine dichloroacetate, glucuronolactone, glutathione, malotilate, methylmethionine sulfonium chloride, polyenphosphatidylcholine, The QOL improving agent according to claim 2, which is at least one selected from a protoporphyrin salt, a branched-chain amino acid preparation, a liver hydrolyzate, an interferon preparation, and a nucleic acid-related compound preparation.
- ヒト胎盤抽出物がラエンネック（商品名、登録商標）である請求項１~３記載のＱＯＬ改善剤。 The QOL improving agent according to claims 1 to 3, wherein the human placenta extract is Raennec (trade name, registered trademark).
- ヒト胎盤抽出物の有効量を、肝細胞癌患者に投与する工程を含む、ＱＯＬの改善方法。 A method for improving QOL, comprising a step of administering an effective amount of human placenta extract to a patient with hepatocellular carcinoma.
- 肝細胞癌患者が、肝機能改善剤を投与されている請求項５記載のＱＯＬの改善方法。 The method for improving QOL according to claim 5, wherein the hepatocellular carcinoma patient is administered a liver function improving agent.
- 肝機能改善剤が、グリチルリチン酸塩、アデノシン三リン酸塩、フラビンアデニンジヌクレオチド、ウルソデオキシコール酸、ジクロロ酢酸ジイソプロピルアミン、グルクロノラクトン、グルタチオン、マロチラート、メチルメチオニンスルホニウムクロリド、ポリエンフォスファチジルコリン、プロトポルフィリン塩、分岐鎖アミノ酸製剤、肝水解物、インターフェロン製剤及び核酸関連化合物製剤から選ばれた少なくとも１種である請求項６記載のＱＯＬの改善方法。 Liver function improving agents are glycyrrhizinate, adenosine triphosphate, flavin adenine dinucleotide, ursodeoxycholic acid, diisopropylamine dichloroacetate, glucuronolactone, glutathione, malotilate, methylmethionine sulfonium chloride, polyenphosphatidylcholine, The method for improving QOL according to claim 6, wherein the method is at least one selected from a protoporphyrin salt, a branched-chain amino acid preparation, a liver hydrolyzate, an interferon preparation, and a nucleic acid-related compound preparation.
- ヒト胎盤抽出物がラエンネック（商品名、登録商標）である請求項５~７記載のＱＯＬの改善方法。 The method for improving QOL according to any one of claims 5 to 7, wherein the human placenta extract is Raennek (trade name, registered trademark).
- 肝細胞癌患者のＱＯＬを改善するための剤を調製するためのヒト胎盤抽出物の使用。 Use of human placenta extract to prepare an agent for improving QOL in patients with hepatocellular carcinoma.
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| JP2015526469A (en) * | 2012-08-20 | 2015-09-10 | ボリス, マルコシアンMarkosian, Boris | Placental vaccination therapy for cancer |
| WO2022191309A1 (en) * | 2021-03-12 | 2022-09-15 | ドクタープロラボジャパン株式会社 | Method for using placenta extract |
| EP4512395A1 (en) * | 2023-08-21 | 2025-02-26 | Bio Even | Composition comprising flavin adenine dinucleotide (fad), l-gsh, atp and myristic acid, alone or with a drug |
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| JP2015526469A (en) * | 2012-08-20 | 2015-09-10 | ボリス, マルコシアンMarkosian, Boris | Placental vaccination therapy for cancer |
| WO2022191309A1 (en) * | 2021-03-12 | 2022-09-15 | ドクタープロラボジャパン株式会社 | Method for using placenta extract |
| EP4512395A1 (en) * | 2023-08-21 | 2025-02-26 | Bio Even | Composition comprising flavin adenine dinucleotide (fad), l-gsh, atp and myristic acid, alone or with a drug |
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