JP6802598B1 - 抗がん剤の効果増強剤 - Google Patents
抗がん剤の効果増強剤 Download PDFInfo
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- JP6802598B1 JP6802598B1 JP2020542334A JP2020542334A JP6802598B1 JP 6802598 B1 JP6802598 B1 JP 6802598B1 JP 2020542334 A JP2020542334 A JP 2020542334A JP 2020542334 A JP2020542334 A JP 2020542334A JP 6802598 B1 JP6802598 B1 JP 6802598B1
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Abstract
Description
[1] 抗がん剤の効果増強に使用するための、クエン酸塩類を含む医薬組成物。
[2] クエン酸塩類が、クエン酸のナトリウム塩、カリウム塩、カルシウム塩、マグネシウム塩、及びそれらの溶媒和物からなる群から選択される一又は二以上を含む、[1]の医薬組成物。
[3] 経口投与用である、[1]又は[2]の医薬組成物。
[4] クエン酸カリウム及びクエン酸ナトリウム水和物の組み合わせを含む、[1]〜[3]のいずれかの医薬組成物。
[5] クエン酸塩類を用いた抗がん剤の効果増強の可能性を判定する方法であって、
クエン酸塩類が投与されたがん患者の血液又は尿中の炭酸水素イオン濃度を測定し、該炭酸水素イオン濃度が増大している場合に、該患者に対し該クエン酸塩類が有効であると判定すること、ならびに/或いは、
該患者の尿pHを測定し、該尿pHがアルカリ化している場合に、該患者に対し該クエン酸塩類が有効であると判定すること、
を含む方法。
[6] クエン酸塩類を用いた抗がん剤の効果増強が有効であるがん患者を選別する方法であって、
クエン酸塩類が投与されたがん患者の血液又は尿中の炭酸水素イオン濃度を測定し、該炭酸水素イオン濃度が増大している場合に、該患者に対し該クエン酸塩類が有効であると判定すること、ならびに/或いは、
該患者の尿pHを測定し、該尿pHがアルカリ化している場合に、該患者に対し該クエン酸塩類が有効であると判定すること、
を含む方法。
[7] 尿のpH試験部材を備える使い捨てオムツ。
[8]さらに、前記有効であると判定された患者に対しクエン酸塩類及び抗がん剤を投与して、がんの治療を行うことを含む、[5]又は[6]の方法。
[9] クエン酸塩類が、クエン酸のナトリウム塩、カリウム塩、カルシウム塩、マグネシウム塩、及びそれらの溶媒和物からなる群から選択される一又は二以上を含む、[5]、[6]又は[8]のいずれかの方法。
[10] 投与が経口投与である、[5]、[6]、[8]又は[9]のいずれかの方法。
[11] クエン酸塩類が、クエン酸カリウム及びクエン酸ナトリウム水和物の組み合わせである、[5]、[6]、[8]〜[10]のいずれかの方法。
[12] がんの治療のため方法であって、がん患者にクエン酸塩類及び抗がん剤を投与することを含む方法。
[13] クエン酸塩類が、クエン酸のナトリウム塩、カリウム塩、カルシウム塩、マグネシウム塩、及びそれらの溶媒和物からなる群から選択される一又は二以上を含む、[12]の方法。
[14] クエン酸塩類を経口投与する、[12]又は[13]の方法。
[15] クエン酸塩類が、クエン酸カリウム及びクエン酸ナトリウム水和物の組み合わせである、[12]〜[15]のいずれかの方法。
[16] 抗がん剤の効果増強する方法において使用するための医薬の製造におけるクエン酸塩類の使用。
[17] クエン酸塩類が、クエン酸のナトリウム塩、カリウム塩、カルシウム塩、マグネシウム塩、及びそれらの溶媒和物からなる群から選択される一又は二以上を含む、[16]の使用。
[18] クエン酸塩類が、クエン酸カリウム及びクエン酸ナトリウム水和物の組み合わせである、[16]又は[17]の使用。
[19] 抗がん剤の効果増強する方法において使用するためのクエン酸塩類。
[20] クエン酸のナトリウム塩、カリウム塩、カルシウム塩、マグネシウム塩、及びそれらの溶媒和物からなる群から選択される一又は二以上の化合物である、[19]のクエン酸塩類。
[21] クエン酸カリウム及びクエン酸ナトリウム水和物の組み合わせである、[19]又は[20]のクエン酸塩類。
[22] 抗がん剤とクエン酸塩類とを含む配合剤。
[23] クエン酸塩類が、クエン酸のナトリウム塩、カリウム塩、カルシウム塩、マグネシウム塩、及びそれらの溶媒和物からなる群から選択される一又は二以上を含む、[22]の配合剤。
[24] クエン酸塩類が、クエン酸カリウム及びクエン酸ナトリウム水和物の組み合わせである、[22]又は[23]の配合剤。
[25] 抗がん剤とクエン酸塩類とを含む組み合わせ医薬。
[26] クエン酸塩類が、クエン酸のナトリウム塩、カリウム塩、カルシウム塩、マグネシウム塩、及びそれらの溶媒和物からなる群から選択される一又は二以上を含む、[25]の組み合わせ医薬。
[27] クエン酸塩類が、クエン酸カリウム及びクエン酸ナトリウム水和物の組み合わせである、[25]又は[26]の組み合わせ医薬。
酸性尿の男性(70歳)に以下の用法用量でクエン酸塩類を服用させた後、尿のpH値の変動を経時的に測定した。
(1)クエン酸カリウム・クエン酸ナトリウム水和物500mg錠(ウラリット(日本ケミファ株式会社))の6錠(3g)を食後に1回/日で服用
(2)クエン酸カリウム・クエン酸ナトリウム水和物の主な活性代謝物の炭酸水素イオンのナトリウム塩(500mg重曹錠「マイライン」(マイライン製薬))6錠(3g)を食後に1回/日で服用
クエン酸塩類を服用した後の尿のpHの測定結果を図1に示す。クエン酸カリウム・クエン酸ナトリウム水和物の500mg錠(ウラリット配合錠(日本ケミファ株式会社))の6錠(3g)を食後に1回/日で経口摂取することにより、尿のpHがアルカリ化され、維持された。
がん細胞の移植用のマウスに50mgのクエン酸カリウム・クエン酸ナトリウム水和物の散剤(ウラリット−U配合散(日本ケミファ株式会社))を経口投与した時の血液のクエン酸カリウム・クエン酸ナトリウム水和物の活性代謝物(炭酸水素イオン)の濃度を経時的に測定し、その結果を図2(A)に示した。
又、同マウスの投与後の尿のクエン酸カリウム・クエン酸ナトリウム水和物の活性代謝物(炭酸水素イオン)の濃度、及び尿のpHを経時的に測定し、その結果を図2(B)、及び図2(C)にそれぞれ示した。
尚、血中と尿中の炭酸水素イオン濃度は、東洋紡のダイヤカラー(炭酸水素イオン濃度測定用キット)で測定した。尿のpHは東洋濾紙製のpH試験紙で測定した。
担がんマウス(B16マウスメラノーマ細胞を皮下移植したモデル)に、(1)マウスの抗PD−1抗体(Bio X Cell、BE0146)(5mg/kg)の投与、(2)クエン酸カリウム・クエン酸ナトリウム水和物の配合散剤(ウラリット−U配合散(日本ケミファ株式会社))(10mg/日もしくは30mg/日/マウス(経口))の投与、あるいは(3)マウスの抗PD−1抗体(5mg/kg)及びクエン酸カリウム・クエン酸ナトリウム水和物の配合散剤(ウラリット−U配合散(日本ケミファ株式会社))(10mg/日もしくは30mg/日/マウス(経口))の併用投与を行い、腫瘍体積及びマウスの体重を経時的に測定した。クエン酸カリウム・クエン酸ナトリウム水和物は毎日投与し、抗PD−1抗体は、細胞移植した日の翌日(1日目)に、5mg/kg/日の用量にて腹腔内投与を一度だけ行った。
肝転移を伴った膵臓がんの患者(女性、83歳)は、膵臓がんの標準療法のゲムシタビン(商品名ジェムザール(イーライリリー))とnab−タキセル(商品名アブラキサン(大鵬薬品工業))の併用療法を受けたが、副作用のため、治療途中で断念した。2018年4月撮影のPET像(陽電子放射断層撮影))とCT像(コンピュータ断層撮影)に示された通り、肝臓に腫瘍が認められる厳しい状態であった(図4(A),(B))。
2001年7月に左乳房の部分切除後、2011年8月に乳がんが再発し、がん性胸膜炎を誘発した乳がん患者(54歳の女性)に2016年6月より、タモキシフェンのクエン酸塩(商品名タスオミン(バイエル薬品))の連日投与(20mg/日)とクエン酸カリウム・クエン酸ナトリウム水和物のクエン酸塩代謝物の炭酸水素イオンのナトリウム塩の連日投与(15g/日)を行った。
術後再発し、多発肺転移とがん性腹膜炎を伴うStageIVのS状結腸がんの患者(40歳の女性)に対して、2017年12月より、大腸がんの標準化学療法(FOLFOX+Bev)とクエン酸カリウム・クエン酸ナトリウム水和物の活性代謝物である炭酸水素イオンのナトリウム塩を毎日投与(10g/日))した。この治療期間、当該患者における尿のpHの変動と腫瘍マーカー(CEA及びCA19−9)レベルの推移を図6に示す。尿のpHはアルカリ化し、腫瘍マーカーのCEA及びCA19−9のレベルはいずれも低下した。また、肺部のCT画像からも多発肺転移がんが収まっていることが確認できた。この患者は高用量のビタミンCの点滴療法も糖尿病薬のメトホルミンの経口投与も全く受けていない。
肺門の縦郭リンパ節転移及び多発骨転移を伴うStage IVBの非小細胞肺腺がん患者(87歳の男性)に対して、2018年10月25日より2019年4月18日まで、クエン酸カリウム・クエン酸ナトリウム水和物の代謝物である炭酸水素イオンのナトリウム塩(10g/日)を連日で投与すると共に、100mgのUFT(大鵬薬品工業)の1カプセルを隔週で、凡そ1ヶ月間経口投与した(常量の5分の1以下の投与量)。図7に、クエン酸カリウム・クエン酸ナトリウム水和物の代謝物の炭酸水素イオンのナトリウム塩を半年間服用した前後の(A)PET画像、及び(B)肺部のCT画像をそれぞれ示す。この結果より、肺門の縦郭リンパ節転移や多発骨転移が完全消失したことが確認された。この非小細胞肺腺がんの患者は通常のがん化学療法も高用量のビタミンC点滴療法も糖尿病薬であるメトホルミンの経口投与も全く受けていない。
StageIVBの卵巣がん患者(57歳の女性)は、卵巣がんの標準化学療法(パクリタキセルとカルボプラチンとの併用)を2017年1月より3回に渡って受けると共に、クエン酸カリウム・クエン酸ナトリウム水和物の代謝産物の炭酸水素イオンのナトリウム塩を15g/日の用量にて連日投与を受けた。その結果、卵巣がんが縮小し始め、血中腫瘍マーカーのCA125が低下した。1年程効果が持続したが、2018年7月から卵巣がんが次第に大きくなり始め(図8は、2018年7月に撮影した(A)PET画像と(B)CT画像を示す)、CA125の値も199に増大した。そこで、クエン酸カリウム・クエン酸ナトリウム水和物の代謝産物投与の継続下、2018年8月30日より、エンドキサン50mg錠/日(常量の数分の1の量)を隔週で服用を開始した。その結果、CA125の値が次第に下がり始め、半年後の2019年2月に53に低下し、尿のpHは、8.5であった(図8(C))。この患者は高用量のビタミンC点滴療法も糖尿病薬のメトホルミンの経口投与も受けていない。
担がんマウス(PANC−1ヒト膵臓がん細胞株をマウスに皮下移植したモデル)に、ビヒクル(対照)を2週間毎日経口投与、テガフール・ギメラシル・オテラシルカリウム配合剤(ティーエスワン(大鵬薬品工業)(以下「S−1」と記載する)(18mg/kg/日)を2週間毎日経口投与、クエン酸カリウム・クエン酸ナトリウム水和物の配合散剤(ウラリット−U配合散(日本ケミファ株式会社)、以下「ウラリット」と記載する)(500mg/kg/日))を2週間毎日経口投与、S−1(18mg/kg/日)及びウラリット(500mg/kg/日)を、2週間毎日経口投与を行い、腫瘍体積とマウスの体重を経時的に測定した。
図9の(A)から、S−1(18mg/kg/日)単独投与群、ウラリット(500mg/kg/日))単独投与群と較べて、S−1(18mg/kg/日)とウラリット(500mg/kg/日)との併用群に於いて、有為な腫瘍増殖抑制効果が認められた。すなわち、担がんマウス(PANC−1ヒト膵臓がん細胞株をマウスに皮下移植したモデル)に於いて、ウラリット(500mg/kg/日))(アルカリ剤)によるS−1(18mg/kg/日)(抗がん剤)の抗腫瘍効果の増強が認められた。
大人用の紙おむつ(花王製のリリーフパンツタイプ)の吸水材部位にpH試験紙(東洋濾紙製のBTB(pH6.2−7.8))を取り込んで、尿のpH値を測定することが可能な紙おむつを作製した。作製した紙おむつを酸性尿の人(70歳の男性)に装着し、クエン酸カリウム・クエン酸ナトリウム水和物500mg錠(日本ケミファ製)の服用(4〜6錠)の前後で、排尿後の当該紙おむつの吸水材部位のpH試験紙の色の変化を観察した。服用前の吸水材部位は酸性(pH6.2)を示す黄色を呈したが、服用後(数時間後)の紙おむつの吸水材部位はアルカリ化した水色(7.4)を呈した。当該紙おむつを用いて、酸性尿の患者に対するクエン酸カリウム・クエン酸ナトリウム水和物錠の服用による中和効果を確認することができた。
Claims (4)
- 抗がん剤の効果増強に使用するための、クエン酸カリウム及びクエン酸ナトリウム水和物の組み合わせを含む医薬組成物であって、抗がん剤の効果増強のための有効成分としてビタミンCを含まない医薬組成物。
- 経口投与用である、請求項1に記載の医薬組成物。
- 抗がん剤ががん免疫療法剤である、請求項1又は2に記載の医薬組成物。
- がん免疫療法剤が抗PD−1抗体である、請求項3に記載の医薬組成物。
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