JP2021119192A - Pharmaceutical composition - Google Patents
Pharmaceutical composition Download PDFInfo
- Publication number
- JP2021119192A JP2021119192A JP2021079224A JP2021079224A JP2021119192A JP 2021119192 A JP2021119192 A JP 2021119192A JP 2021079224 A JP2021079224 A JP 2021079224A JP 2021079224 A JP2021079224 A JP 2021079224A JP 2021119192 A JP2021119192 A JP 2021119192A
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- JP
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- Prior art keywords
- diltiazem
- cis
- pharmaceutical composition
- current
- syndrome
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Images
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Abstract
Description
本発明は、不整脈及びQT延長症候群の治療並びに予防に有用な医薬組成物に関する。 The present invention relates to pharmaceutical compositions useful for the treatment and prevention of arrhythmias and long QT syndrome.
QT延長症候群は、心電図上のQT延長やT波の異常を示し、TdP (torsade de pointes)と
呼ばれる特殊な心室頻拍(ventricular tachycardia)や心室細動(ventricular fibrillati
on)などの重症心室性不整脈を生じることで、めまい、失神などの脳虚血症状や心臓突然
死を来す症候群である。QT延長症候群は、先天性と二次性に分けられ、先天性にはロマノ
・ワード症候群(Romano-Ward syndrome)やジャーベル−ランゲ・ニールセン症候群(Jerve
ll and Lange-Nielsen syndrome)などがある。また、二次性QT延長症候群は、薬剤などが
原因で二次的にQT延長が起こる症候群である。
Long QT syndrome shows abnormalities in QT prolongation and T waves on the electrocardiogram, and is a special type of ventricular tachycardia called TdP (torsade de pointes) or ventricular fibrillati.
It is a syndrome that causes cerebral ischemic symptoms such as dizziness and syncope and sudden cardiac death by causing severe ventricular arrhythmia such as on). Long QT syndrome is divided into congenital and secondary, with congenital Romano-Ward syndrome and Jervell-Lange-Neilsen syndrome.
ll and Lange-Nielsen syndrome). In addition, secondary QT prolongation syndrome is a syndrome in which QT prolongation occurs secondarily due to drugs or the like.
先天性QT延長症候群に含まれるティモシー(Timothy)症候群(QT延長症候群8型、LQT8)は
、L型Ca2+チャネルのαサブユニットをコードするCACNA1C遺伝子の変異を原因とする予後
不良の疾患であり、QT時間の延長、重症不整脈を来すのみならず、合指症、免疫不全、自
閉症などの全身性の機能異常を来すことを特徴とする。
Timothy syndrome (QT
ティモシー症候群については多くの研究がなされており、ティモシー症候群の治療に有
効な医薬として、ベラパミル(verapamil)、メキシレチン(mexiletine)、ラノラジン(rano
lazine)などが報告されているが、症例数が少なく、また効果が弱い。その他には、ティ
モシー症候群の患者由来のiPS細胞(human induced pluripotent stem cell (hiPSC))から
作製された心筋細胞(CM)を用いた実験などで、ロスコビチン(roscovitine)が、QT時間の
延長の原因となるL型カルシウムチャネル不活性化の遅延を改善することが報告されてい
る(非特許文献1−4)。しかしながら、ロスコビチンは抗がん剤として開発された薬物で
あり、ティモシー症候群に使用することはできない。
Much research has been done on Timothy Syndrome, and effective drugs for the treatment of Timothy Syndrome include verapamil, mexiletine, and rano.
lazine) etc. have been reported, but the number of cases is small and the effect is weak. In addition, in experiments using cardiomyocytes (CM) prepared from iPS cells (human induced pluripotent stem cells (hiPSC)) derived from patients with Timothy syndrome, roscovitine is the cause of prolonged QT interval. It has been reported to improve the delay of L-type calcium channel inactivation (Non-Patent Documents 1-4). However, Roscobitin is a drug developed as an anticancer drug and cannot be used for Timothy syndrome.
QT延長症候群の中には、CACNA1C遺伝子の変異を原因とするものの心臓以外の表現型を
有さず、QT延長、不整脈のみを症状とするティモシー亜型とも呼べる新たな疾患群が存在
することも判明してきている。
Among QT prolongation syndrome, there may be a new group of diseases that are caused by mutations in the CACNA1C gene but have no phenotype other than the heart and can be called Timothy subtypes that have only QT prolongation and arrhythmia as symptoms. It is becoming clear.
心不全は、近年、高齢化により爆発的に増加しているが、その予後は、心室細動を含む
重症の心室性不整脈の発症により大きく影響される。また、軽度のQT延長が観察されるが
、そのベースには、筋小胞体からのCa遊離に関わるリアノジン受容体チャネルの機能的な
障害があると考えられている。すなわち、リアノジン受容体チャネルを介して細胞内に放
出されるカルシウム量のピークが低下するため、これによるL型カルシウムチャネルの不
活性化が遅延し、結果的に活動電位プラトー相後半でカルシウムチャネルを介して細胞内
に流入するカルシウムイオンが増加して活動電位の延長(心電図上はQT時間の延長)とカル
シウム過負荷が生じると考えられる。
Heart failure has increased explosively in recent years due to aging, but its prognosis is greatly affected by the development of severe ventricular arrhythmia including ventricular fibrillation. In addition, mild QT prolongation is observed, which is thought to be based on the functional impairment of the ryanodine receptor channel involved in Ca release from the sarcoplasmic reticulum. That is, the peak amount of calcium released into cells via the ryanodine receptor channel is reduced, which delays the inactivation of L-type calcium channels, resulting in calcium channels in the latter half of the action potential plateau phase. It is considered that the amount of calcium ions flowing into the cells via the cells increases, resulting in prolongation of action potential (prolongation of QT time on the electrocardiogram) and calcium overload.
ジルチアゼム塩酸塩(Diltiazem hydrochloride, d-cis-Diltiazem hydrochloride)は、
ベンゾチアゼピン誘導体のカルシウムチャネル・ブロッカーである。電位依存性L型カル
シウムチャネルを濃度依存性にブロックすることにより、血管拡張作用を発揮して、高血
圧症や狭心症に適応を有する。一方、心臓の刺激伝導系におけるカルシウムチャネルも抑
制し、抗不整脈薬としても使用される。ジルチアゼムには、光学異性体としてD型とL型が
あるが、現在、臨床使用されているのはD型である。
Diltiazem hydrochloride (d-cis-Diltiazem hydrochloride) is
It is a calcium channel blocker of benzothiazepine derivatives. By blocking voltage-gated L-type calcium channels in a concentration-dependent manner, it exerts a vasodilatory effect and is indicated for hypertension and angina. On the other hand, it also suppresses calcium channels in the conduction system of the heart and is also used as an antiarrhythmic drug. Diltiazem has D-type and L-type as optical isomers, but currently, D-type is clinically used.
本発明は、不整脈及びQT延長症候群の治療並びに予防に有用な医薬組成物を提供するこ
とを目的とする。
An object of the present invention is to provide a pharmaceutical composition useful for the treatment and prevention of arrhythmia and long QT syndrome.
本発明者らは、上記目的を達成すべく鋭意研究を重ねた結果、d-cis-ジルチアゼムの光
学変異体であるl-cis-ジルチアゼムが、CALCN1C遺伝子変異を有するQT延長症候群の患者
由来のiPS細胞から分化誘導された心筋細胞において、電位依存性L型カルシウムチャネル
抑制は起こさずに、遅延した不活性化過程を有意に促進(改善)させることができるという
知見を得た(図1参照)。反対に、d-cis-ジルチアゼムは、電流ブロックを起こし、遅延し
た不活性化過程には全く影響を与えなかった。
As a result of intensive studies to achieve the above objectives, the present inventors have found that l-cis-diltiazem, which is an optical variant of d-cis-diltiazem, is an iPS derived from a patient with QT prolongation syndrome having a CALC N1C gene mutation. It was found that in cardiomyocytes induced to differentiate from cells, the delayed inactivation process can be significantly promoted (improved) without causing voltage-gated L-type calcium channel suppression (see FIG. 1). .. In contrast, d-cis-diltiazem caused current blocking and had no effect on the delayed inactivation process.
本発明は、これら知見に基づき、更に検討を重ねて完成されたものであり、次の医薬組
成物を提供するものである。
The present invention has been completed by further studying based on these findings, and provides the following pharmaceutical composition.
項1.l-cis-ジルチアゼム又はその塩を含む医薬組成物。
項2.不整脈の治療及び/又は予防用である、項1に記載の医薬組成物。
項3.心室性不整脈の治療及び/又は予防用である、項1に記載の医薬組成物。
項4.QT延長性の心室性不整脈の治療及び/又は予防用である、項1に記載の医薬組成物
。
項5.QT延長症候群の治療及び/又は予防用である、項1に記載の医薬組成物。
Item 1. l-cis-A pharmaceutical composition comprising diltiazem or a salt thereof.
Item 3.
Item 4.
本発明の医薬組成物は、L型カルシウムチャネルの遅延した不活性化過程を有意に促進
させることができる上、ピーク電流を抑制しないという優れた特性を有しており、結果と
してQT延長を改善することが可能である。そのため、本発明の医薬組成物は、QT延長症候
群や、QT延長を原因とする不整脈に対する治療及び予防効果が期待される。Ca電流のピー
クを抑制しないことから、いわゆる陰性変力作用がなく、心不全にも使用が可能である。
The pharmaceutical composition of the present invention has an excellent property that it can significantly promote the delayed inactivation process of L-type calcium channels and does not suppress the peak current, resulting in improved QT prolongation. It is possible to do. Therefore, the pharmaceutical composition of the present invention is expected to have therapeutic and preventive effects on long QT syndrome and arrhythmia caused by QT prolongation. Since it does not suppress the peak of Ca current, it has no so-called negative inotropic effect and can be used for heart failure.
従来、Ca過負荷をベースとするQT延長症候群には、決定的に有効な薬剤が無かったため
、本発明の医薬組成物は、画期的な治療薬となり得る。さらに、本発明の医薬組成物は、
心不全など心筋細胞内Ca過負荷を来した病態での重症不整脈の発症を抑制し、その予後を
改善できる可能性もある。そのため、本発明の医薬組成物は、より汎用性の高い薬剤とな
ることが期待される。
Conventionally, there has been no definitively effective drug for Ca overload-based long QT syndrome, so that the pharmaceutical composition of the present invention can be a breakthrough therapeutic drug. Furthermore, the pharmaceutical composition of the present invention
It may be possible to suppress the onset of severe arrhythmia in pathological conditions that cause cardiomyocyte Ca overload such as heart failure and improve its prognosis. Therefore, the pharmaceutical composition of the present invention is expected to be a more versatile drug.
以下、本発明について詳細に説明する。 Hereinafter, the present invention will be described in detail.
なお、本明細書において「含む(comprise)」とは、「本質的にからなる(essentially c
onsist of)」という意味と、「のみからなる(consist of)」という意味をも包含する。
In addition, in this specification, "comprise" means "essentially c".
It also includes the meaning of "onsist of" and the meaning of "consist of".
本発明の医薬組成物は、l-cis-ジルチアゼム又はその塩を含むことを特徴とする。 The pharmaceutical composition of the present invention is characterized by containing l-cis-diltiazem or a salt thereof.
l-cis-ジルチアゼム(l-cis-Diltiazem)は、化学名:(2R, 3R)−(−)−シス−
3−アセトキシ−5−[2−(ジメチルアミノ)エチル]−2,3−ジヒドロ−2−(4
−メトキシフェニル)−1,5−ベンゾチアゼピン−4(5H)−オンであり、以下の式
で示される構造を有している。
l-cis-Diltiazem has the chemical name: (2R, 3R)-(-)-cis-
3-acetoxy-5- [2- (dimethylamino) ethyl] -2,3-dihydro-2- (4)
-Methoxyphenyl) -1,5-benzothiazepine-4 (5H) -one, and has a structure represented by the following formula.
l-cis-ジルチアゼムは、フリーの状態又は塩の状態で使用することができる。塩として
は、例えば、ナトリウム、カリウム、カルシウム、マグネシウム、アルミニウム等の無機
塩基との塩;メチルアミン、エチルアミン、エタノールアミン等の有機塩基との塩;リジ
ン、アルギニン、オルニチン等の塩基性アミノ酸との塩及びアンモニウム塩が挙げられる
。当該塩は、酸付加塩であってもよく、かかる塩としては、例えば、塩酸、臭化水素酸、
ヨウ化水素酸、硫酸、硝酸、リン酸等の鉱酸;ギ酸、酢酸、プロピオン酸、シュウ酸、マ
ロン酸、コハク酸、フマル酸、マレイン酸、乳酸、リンゴ酸、酒石酸、クエン酸、メタン
スルホン酸、エタンスルホン酸等の有機酸;アスパラギン酸、グルタミン酸等の酸性アミ
ノ酸等との酸付加塩が挙げられる。また、l-cis-ジルチアゼムにはその水和物、溶媒和物
や結晶多形なども含まれる。
l-cis-Diltiazem can be used free or in salt form. Examples of the salt include salts with inorganic bases such as sodium, potassium, calcium, magnesium and aluminum; salts with organic bases such as methylamine, ethylamine and ethanolamine; and basic amino acids such as lysine, arginine and ornithine. Examples include salts and ammonium salts. The salt may be an acid addition salt, and examples thereof include hydrochloric acid, hydrobromic acid, and the like.
Mineral acids such as hydroiodic acid, sulfuric acid, nitrate, phosphoric acid; formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfone. Organic acids such as acids and ethanesulfonic acids; acid addition salts with acidic amino acids such as aspartic acid and glutamate can be mentioned. In addition, l-cis-diltiazem also contains its hydrates, solvates and polymorphs of crystals.
本発明の医薬組成物におけるl-cis-ジルチアゼムの含量は、医薬組成物全量中0.001〜1
00質量%、好ましくは0.01〜99.9質量%、より好ましくは0.1〜99質量%の範囲から適宜選択
することができる。
The content of l-cis-diltiazem in the pharmaceutical composition of the present invention is 0.001 to 1 in the total amount of the pharmaceutical composition.
It can be appropriately selected from the range of 00% by mass, preferably 0.01 to 99.9% by mass, and more preferably 0.1 to 99% by mass.
本発明の医薬組成物には、l-cis-ジルチアゼム以外にも、必要に応じて、賦形剤、結合
剤、崩壊剤、滑沢剤、着色剤、懸濁化剤、増粘剤、抗酸化剤、吸収促進剤、pH調節剤、保
存剤、防腐剤、安定化剤、界面活性剤、甘味剤、矯味剤、香料等の薬学的に許容される成
分を適宜配合することができる。
In addition to l-cis-zyrthiazem, the pharmaceutical compositions of the present invention include excipients, binders, disintegrants, lubricants, colorants, suspending agents, thickeners, and antioxidants, as required. Pharmaceutically acceptable ingredients such as oxidizing agents, absorption promoters, pH regulators, preservatives, preservatives, stabilizers, surfactants, sweeteners, flavoring agents, and fragrances can be appropriately blended.
賦形剤としては、例えば、乳糖、白糖、精製白糖、D−マンニトール、D−ソルビトー
ル、トウモロコシデンプン、バレイショデンプン、デキストリン、結晶セルロース、カル
ボキシメチルセルロースナトリウム、軽質無水ケイ酸、タルク、カオリン等が挙げられる
。
Examples of excipients include lactose, sucrose, refined sucrose, D-mannitol, D-sorbitol, corn starch, potato starch, dextrin, crystalline cellulose, sodium carboxymethyl cellulose, light anhydrous silicic acid, talc, kaolin and the like. ..
結合剤としては、例えば、α化デンプン、ゼラチン、アラビアゴム、メチルセルロース
、エチルセルロース、カルボキシメチルセルロース、カルボキシメチルセルロースナトリ
ウム、結晶セルロース、白糖、精製白糖、プルラン、ヒドロキシプロピルセルロース、ヒ
ドロキシプロピルメチルセルロース、ポリビニルピロリドン等が挙げられる。
Examples of the binder include pregelatinized starch, gelatin, gum arabic, methyl cellulose, ethyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, crystalline cellulose, sucrose, purified sucrose, purulan, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone and the like. Be done.
崩壊剤としては、例えば、乳糖、白糖、トウモロコシデンプン、バレイショデンプン、
カルボキシメチルセルロース、カルボキシメチルセルロースカルシウム、クロスカルメロ
ースナトリウム、カルボキシメチルスターチナトリウム、低置換度ヒドロキシプロピルセ
ルロース、アルギン酸、クロスポビドン等が挙げられる。
Examples of the disintegrant include lactose, sucrose, corn starch, potato starch, and the like.
Examples thereof include carboxymethyl cellulose, carboxymethyl cellulose calcium, croscarmellose sodium, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, alginic acid, crospovidone and the like.
滑沢剤としては、例えば、ステアリン酸、ステアリン酸マグネシウム、ステアリン酸カ
ルシウム、タルク、ポリエチレングリコール等が挙げられる。
Examples of the lubricant include stearic acid, magnesium stearate, calcium stearate, talc, polyethylene glycol and the like.
着色剤としては、例えば、三二酸化鉄、黄色三二酸化鉄、褐色酸化鉄、黒酸化鉄、酸化
チタン等が挙げられる。
Examples of the colorant include iron sesquioxide, yellow iron sesquioxide, brown iron oxide, black iron oxide, titanium oxide and the like.
懸濁化剤としては、例えば、ポリソルベート、ポリエチレングリコール、グリセリン等
が挙げられる。
Examples of the suspending agent include polysorbate, polyethylene glycol, glycerin and the like.
医薬組成物の製剤形態としては、例えば、タブレット(素錠、糖衣錠、発泡錠、フィル
ムコート錠、チュアブル錠、トローチ剤などを含む)、カプセル剤、丸剤、粉末剤(散剤)
、顆粒剤、細粒剤、液剤、懸濁液、乳濁液、ペースト、シロップ、注射剤(使用時に、蒸
留水又はアミノ酸輸液や電解質輸液等の輸液に配合して液剤として調製する場合を含む)
などの形態が挙げられる。これらの製剤は、常法に従って製造することができる。
Examples of the pharmaceutical composition form include tablets (including uncoated tablets, sugar-coated tablets, effervescent tablets, film-coated tablets, chewable tablets, troches, etc.), capsules, pills, and powders (powder).
, Granules, fine granules, liquids, suspensions, emulsions, pastes, syrups, injections (including the case of preparing as a liquid by blending with distilled water or infusions such as amino acid infusions and electrolyte infusions at the time of use. )
Such forms can be mentioned. These formulations can be produced according to a conventional method.
本発明の医薬組成物の投与方法は特に限定されず、例えば、動脈内投与、静脈内投与、
口腔内投与、直腸投与、経腸投与、経皮投与、経口投与などにより行うことができる。
The method of administering the pharmaceutical composition of the present invention is not particularly limited, and for example, intraarterial administration, intravenous administration, etc.
It can be administered by oral administration, rectal administration, enteral administration, transdermal administration, oral administration and the like.
本発明の医薬組成物は、ヒトを含む哺乳動物に対して投与される。 The pharmaceutical composition of the present invention is administered to mammals including humans.
本発明の医薬組成物の投与量は、患者の体重、年齢、性別、症状などの種々の条件に応
じて適宜決定することができる。
The dose of the pharmaceutical composition of the present invention can be appropriately determined according to various conditions such as body weight, age, sex, and symptoms of the patient.
本発明の医薬組成物は、不整脈の予防及び/又は治療に有用である。本発明における「
不整脈」とは、好ましくは心室性不整脈、より好ましくはQT延長性の心室性不整脈である
。また、好ましい「不整脈」としては、カルシウムハンドリング異常による心室性不整脈
も挙げられる。さらに、本発明の医薬組成物は、QT延長症候群の治療及び/又は予防にも
有用である。
The pharmaceutical composition of the present invention is useful for the prevention and / or treatment of arrhythmia. In the present invention, "
The "arrhythmia" is preferably a ventricular arrhythmia, more preferably a QT-prolonging ventricular arrhythmia. Further, as a preferable "arrhythmia", ventricular arrhythmia due to abnormal calcium handling can also be mentioned. Furthermore, the pharmaceutical composition of the present invention is also useful for the treatment and / or prevention of long QT syndrome.
本発明の医薬組成物は、L型カルシウムチャネルの遅延した不活性化過程を有意に促進
させることができる上、ピーク電流を抑制しないという優れた特性を有しており、結果と
してQT延長を改善することができる。そのため、本発明の医薬組成物は、QT延長症候群や
、QT延長により引き起こされる不整脈(特に、心室性不整脈)に対する治療及び予防効果が
期待される。
The pharmaceutical composition of the present invention has an excellent property that it can significantly promote the delayed inactivation process of L-type calcium channels and does not suppress the peak current, resulting in improved QT prolongation. can do. Therefore, the pharmaceutical composition of the present invention is expected to have a therapeutic and preventive effect on QT prolongation syndrome and arrhythmia caused by QT prolongation (particularly, ventricular arrhythmia).
その上、本発明の医薬組成物は、Ca電流のピークを抑制しないことから、いわゆる陰性
変力作用(心筋の収縮力を減少させる作用)がなく、心不全にも使用が可能である。
Moreover, since the pharmaceutical composition of the present invention does not suppress the peak of Ca current, it does not have a so-called negative inotropic action (action of reducing the contractile force of myocardium) and can be used for heart failure.
従来、Ca過負荷をベースとするQT延長症候群には、決定的に有効な薬剤が無かったため
、本発明の医薬組成物は、画期的な治療薬となり得る。さらに、本発明の医薬組成物は、
心不全など心筋細胞内Ca過負荷を来した病態での重症不整脈の発症を抑制し、その予後を
改善できる可能性もある。そのため、本発明の医薬組成物は、汎用性の高い薬剤となるこ
とが期待される。
Conventionally, there has been no definitively effective drug for Ca overload-based long QT syndrome, so that the pharmaceutical composition of the present invention can be a breakthrough therapeutic drug. Furthermore, the pharmaceutical composition of the present invention
It may be possible to suppress the onset of severe arrhythmia in pathological conditions that cause cardiomyocyte Ca overload such as heart failure and improve its prognosis. Therefore, the pharmaceutical composition of the present invention is expected to be a highly versatile drug.
現在、実臨床で使用されているのは光学異性体であるd-cis-ジルチアゼムであるが、以
下の実施例で示すように、d-cis-ジルチアゼムは電流ブロックを起こし、遅延した不活性
化過程には全く影響を与えなかった。このように、l-cis-ジルチアゼムは光学異性体であ
るd-cis-ジルチアゼムとは全く異なる効果を示す。
Currently, the optical isomer d-cis-diltiazem is used in clinical practice, but as shown in the examples below, d-cis-diltiazem causes current blocking and delayed inactivation. It had no effect on the process. Thus, l-cis-diltiazem exhibits a completely different effect from the optical isomer d-cis-diltiazem.
以下、本発明を更に詳しく説明するため実施例を挙げる。しかし、本発明はこれら実施
例等になんら限定されるものではない。
Hereinafter, examples will be given to explain the present invention in more detail. However, the present invention is not limited to these examples and the like.
<hiPSCの調製方法及び心筋細胞分化誘導>
LQT8でCACNA1C-A582D変異を有する患者の末梢血から、iPS細胞を分離調製した。方法の
詳細は、下記文献(1)に準拠した。また、健常者由来のiPS細胞も、以前の論文(2)
のように調製した。心筋細胞への分化誘導は、embryoid bodies (EBs) formation法を用
いた(3)。分化誘導後、培養20日目にコラゲナーゼとトリプシンを用いて、培養皿より
単離し培養に移行した。詳細は(3)を参照。
(1)Okita K, Yamakawa T, Matsumura Y et al. An efficient nonviral method to
generate integration-free human-induced pluripotent stem cells from cord blood a
nd peripheral blood cells. Stem Cells 2013;31:458-66.
(2)Kiyonaka S, Wakamori M, Miki T et al. RIM1 confers sustained activity and
neurotransmitter vesicle anchoring to presynaptic Ca2+channels. Nat Neurosci 200
7;10:691-701.
(3)Yang L, Soonpaa MH, Adler ED et al. Human cardiovascular progenitor cells
develop from a KDR+embryonic-stem-cell-derived population. Nature 2008;453:524-8
.
<Preparation method of hiPSC and induction of cardiomyocyte differentiation>
IPS cells were isolated and prepared from the peripheral blood of patients with the CACNA1C-A582D mutation in LQT8. The details of the method were based on the following document (1). In addition, iPS cells derived from healthy subjects were also described in the previous paper (2).
It was prepared as follows. The embryoid bodies (EBs) formation method was used to induce differentiation into cardiomyocytes (3). After induction of differentiation, on the 20th day of culturing, collagenase and trypsin were used to isolate from the culture dish and transfer to culturing. See (3) for details.
(1) Okita K, Yamakawa T, Matsumura Y et al. An efficient nonviral method to
generate integration-free human-induced pluripotent stem cells from cord blood a
nd peripheral blood cells. Stem Cells 2013; 31: 458-66.
(2) Kiyonaka S, Wakamori M, Miki T et al. RIM1 confers sustained activity and
neurotransmitter vesicle anchoring to presynaptic Ca 2+ channels.
7; 10: 691-701.
(3) Yang L, Soonpaa MH, Adler ED et al. Human cardiovascular progenitor cells
develop from a KDR + embryonic-stem-cell-derived population. Nature 2008; 453: 524-8
..
<遺伝子検索による確認>
LQT8患者及び健常者のiPS細胞由来の心筋細胞から、GenElute Mammalian Genomic DNA
Miniprep kit (Sigma-Aldrich, St 119 Louis, MO, USA)を用いて、ゲノムを分離した。
これに、古典的なPCR-サンガー法により遺伝子検査行い、CACNA1C-A582D変異が前者で発
現していることを確認した。分析は、3130 Genetic Analyzer及びBig Dye Terminator v3
.1 (Thermo Fisher Scientific, Waltham, MA, USA)を用いて行った。
<Confirmation by gene search>
GenElute Mammalian Genomic DNA from cardiomyocytes derived from iPS cells of LQT8 patients and healthy subjects
The genome was isolated using a Miniprep kit (Sigma-Aldrich, St 119 Louis, MO, USA).
Genetic testing was performed on this by the classical PCR-Sanger method, and it was confirmed that the CACNA1C-A582D mutation was expressed in the former. Analysis is 3130 Genetic Analyzer and Big Dye Terminator v3
.1 (Thermo Fisher Scientific, Waltham, MA, USA) was used.
<電気生理学的記録法>
iPS細胞から心筋細胞に分化誘導後、コラゲナーゼ及びトリプシンを用いて単離し、ゼ
ラチンでコートしたカバーガラス上に、短期間培養し電気生理学実験に供した。測定は全
細胞型パッチクランプを用い、記録はAxon 700B Multiclamp及びDigidata 1440 digitize
r hardware (Axon instruments, CA, USA)を用いて行った。また、データ解析には、pCla
mp 10.4のソフト(Moleculr Devices, CA, US)を使用した。心筋活動電位の記録は、心筋
分化後6-8週間後の細胞を用い、電流固定モードで記録した。l-cis-ジルチアゼムはAbcam
(Cambridge, UK)から購入し、d-cis-ジルチアゼムはSigma-Aldrich (St Louis, MO, USA
)から購入した。10μMのl-cis-ジルチアゼム又はd-cis-ジルチアゼムを含む溶液をデータ
取得の5分前に適用した。方法論の詳細は文献(4)に従った。
(4)最新パッチクランプ実験技術法.吉岡書店,京都,2011
<Electrophysiological recording method>
After inducing differentiation from iPS cells into cardiomyocytes, they were isolated using collagenase and trypsin, cultured on a gelatin-coated cover glass for a short period of time, and subjected to electrophysiological experiments. Measurements were performed using a whole cell patch clamp and recorded using the Axon 700B Multiclamp and Digidata 1440 digitize.
This was done using r hardware (Axon instruments, CA, USA). Also, for data analysis, pCla
I used mp 10.4 software (Moleculr Devices, CA, US). Cardiac action potentials were recorded in current-fixed mode using cells 6-8 weeks after myocardial differentiation. l-cis-Diltiazem is Abcam
Purchased from (Cambridge, UK), d-cis-Diltiazem is Sigma-Aldrich (St Louis, MO, USA)
) Purchased from. A solution containing 10 μM l-cis-diltiazem or d-cis-diltiazem was applied 5 minutes prior to data acquisition. Details of the methodology are in accordance with Ref. (4).
(4) Latest patch clamp experimental technique. Yoshioka Bookstore, Kyoto, 2011
<統計分析>
全てのデータは平均±標準誤差で示している。2つの正規分布したデータの群の間の比
較はスチューデントのt検定を用いて行い、イントラセルの比較は対応のあるt検定を使用
して行った。p<0.05の場合に統計学的に有意であるとした。
<Statistical analysis>
All data are shown as mean ± standard error. Comparisons between two normally distributed groups of data were performed using Student's t-test, and intracell comparisons were performed using paired t-tests. It was considered statistically significant when p <0.05.
図1に、以下の試験例における実験の概略を示す。ティモシー症候群(LQT8)患者から得
られた細胞より、iPS細胞を作製し、心筋細胞に分化させて、電気生理学的な方法でその
機能を評価するとともにCaチャネル電流の不活性化に影響する薬剤を探索した。得られた
実験結果を図2−7に示している。
FIG. 1 shows an outline of an experiment in the following test example. From cells obtained from patients with Timothy syndrome (LQT8), iPS cells are prepared, differentiated into cardiomyocytes, their functions are evaluated by electrophysiological methods, and drugs that affect the inactivation of Ca channel current are used. I searched. The experimental results obtained are shown in FIG. 2-7.
試験例1:LQT8-hiPSC-CMの電気生理学的性質
図2に、典型的な健常者(control)由来の細胞及びLQT8患者由来の細胞(LQT8-hiPSC-CM)
における全細胞型パッチクランプ法によるCaチャネルを通るバリウム電流記録の典型例を
示す。バリウムイオンをキャリアーとして使用することにより、いわゆるCa依存性Ca電流
の不活性化の関与を除外することができ、電位依存性Ca電流の不活性化を観察することが
できる。図2Bには、0 mVに脱分極したときの2つの電流トレースを重ね合わせて示して
おり、これらの情報から、LQT8-hiPSC-CMは、健常者由来の細胞と比べてピークのバリウ
ム電流を減少すること無く、その不活性化が遅延していることが分かる。
Test Example 1: Electrophysiological properties of LQT8-hiPSC-CM In Fig. 2, cells derived from typical healthy subjects (control) and cells derived from LQT8 patients (LQT8-hiPSC-CM)
A typical example of barium current recording through a Ca channel by the whole cell patch clamp method in the above is shown. By using barium ions as carriers, the involvement of so-called Ca-dependent Ca current inactivation can be excluded, and voltage-gated Ca current inactivation can be observed. FIG. 2B shows two current traces superimposed when depolarized to 0 mV. Based on this information, LQT8-hiPSC-CM has a peak barium current compared to cells derived from healthy subjects. It can be seen that the inactivation is delayed without diminishing.
試験例2:l-cis-ジルチアゼムのLQT8-hiPSC-CMに対する効果
l-cis-ジルチアゼムの作用を検討した結果を図3−5に示す。
Test Example 2: Effect of l-cis-diltiazem on LQT8-hiPSC-CM
The results of examining the action of l-cis-diltiazem are shown in Fig. 3-5.
図3は、カルシウムを電流のキャリアーとして使用した膜電位固定実験の結果である。
図3Bから、l-cis-ジルチアゼムがCaチャネル電流の不活性化を改善したのが明らかであ
る。図3Dから、l-cis-ジルチアゼム投与後、有意にr300値が低下しているのが分かる。
図3Eから、ピーク電流値はl-cis-ジルチアゼム投与前後で減少の傾向はあるものの、ru
ndownを考慮すると有意な減少ではなかった。また、図3Fから、l-cis-ジルチアゼムは
、定常状態の活性化及び不活性化ゲートの膜電位依存性にも影響しないことが分かる。
FIG. 3 shows the results of a membrane potential fixation experiment using calcium as a carrier of electric current.
From FIG. 3B, it is clear that l-cis-diltiazem improved the inactivation of Ca channel currents. From FIG. 3D, it can be seen that the r300 value decreased significantly after the administration of l-cis-diltiazem.
From FIG. 3E, the peak current value tends to decrease before and after administration of l-cis-diltiazem, but ru
Considering ndown, it was not a significant decrease. It can also be seen from FIG. 3F that l-cis-diltiazem does not affect the membrane potential dependence of the steady-state activation and inactivation gates.
図4は、バリウムを電流のキャリアーとして使用した電圧固定実験の結果である。図4
Bから、上記と同様にl-cis-ジルチアゼムがL型カルシウムチャネルの不活性化を改善す
る傾向が見られた。図4Dから、l-cis-ジルチアゼム投与後、有意にr300値が低下してい
るのが分かる。図4Eから、0 mVより脱分極側でl-cis-ジルチアゼム投与後には、L型カ
ルシウムチャネルの不活性化が完全に起こることが分かる。
FIG. 4 shows the results of a voltage fixing experiment using barium as a current carrier. Figure 4
From B, l-cis-diltiazem tended to improve the inactivation of L-type calcium channels as described above. From FIG. 4D, it can be seen that the r300 value decreased significantly after the administration of l-cis-diltiazem. From FIG. 4E, it can be seen that inactivation of L-type calcium channels completely occurs after administration of l-cis-diltiazem on the depolarizing side of 0 mV.
図3及び4の結果から、カルシウムチャネルタンパク質を通る電流のキャリアーとして
カルシウムであっても、また、バリウムであっても同様に、電流不活性化をl-cis-ジルチ
アゼムは、有意に促進したことが分かる。そして、結果的に図5A及びBに示されるよう
に、その持続時間は有意に短縮した。また、図5Cから、その他の活動電位のパラメータ
には有意な変化は無かった。
From the results shown in FIGS. 3 and 4, l-cis-diltiazem significantly promoted current inactivation regardless of whether calcium was the carrier of the current passing through the calcium channel protein or barium. I understand. And, as a result, as shown in FIGS. 5A and 5B, the duration was significantly shortened. Moreover, from FIG. 5C, there was no significant change in other action potential parameters.
上記の結果から、l-cis-ジルチアゼムは、QT延長症候群におけるQT時間(活動電位持続
時間に対応する)を短縮することを意味しており、病気の治療に役立つことをより直裁的
に示すものである。
From the above results, l-cis-diltiazem means shortening the QT interval (corresponding to the duration of action potential) in long QT syndrome, and more directly shows that it is useful for the treatment of diseases. It is a thing.
試験例3:d-cis-ジルチアゼムのLQT8-hiPSC-CMに対する効果
d-cis-ジルチアゼムの作用を検討した結果を図6−7に示す。
Test Example 3: Effect of d-cis-diltiazem on LQT8-hiPSC-CM
The results of examining the action of d-cis-diltiazem are shown in FIG. 6-7.
図6は、カルシウムを電流のキャリアーとして使用した膜電位固定実験の結果である。
図6Bから、d-cis-ジルチアゼムはCa電流の不活性化に全く影響しないことが分かる。図
6Cから、d-cis-ジルチアゼムはr300値に全く影響しないことが分かる。図6Dから、d-
cis-ジルチアゼムが約3分の1のレベルにCaチャネル電流を抑制したことが分かる。
FIG. 6 shows the results of a membrane potential fixation experiment using calcium as a carrier of electric current.
From FIG. 6B, it can be seen that d-cis-diltiazem has no effect on the inactivation of Ca current. From FIG. 6C, it can be seen that d-cis-diltiazem has no effect on the r300 value. From FIG. 6D, d-
It can be seen that cis-diltiazem suppressed Ca channel current to about one-third the level.
図7は、バリウムを電流のキャリアーとして使用した電圧固定実験の結果である。図7
Bから、上記と同様にd-cis-ジルチアゼムがL型カルシウムチャネルの不活性化に全く影
響しないことが分かる。図7Dから、d-cis-ジルチアゼム投与前後でr300値が変化しなか
ったことが分かる。
FIG. 7 shows the results of a voltage fixing experiment using barium as a current carrier. Figure 7
From B, it can be seen that d-cis-diltiazem has no effect on the inactivation of L-type calcium channels as described above. From FIG. 7D, it can be seen that the r300 value did not change before and after administration of d-cis-diltiazem.
臨床的に使用されているd-cis-ジルチアゼムは、l-cis-ジルチアゼムの光学異性体であ
るが、図6及び7に見られるように、カルシウム又はバリウムを電流キャリアーとして記
録したどちらの場合も、そのピーク電流を有意に減少するが(すなわち、従来知られてい
るとおりのCaチャネル阻害薬としては働くが)、脱分極に伴う電流不活性化には何らの影
響を与えなかった。したがって、薬効からみて、2つの光学異性体は、全く異なる作用を
心筋L型カルシウムチャネルに対して有することが判明した。
Clinically used d-cis-diltiazem is an optical isomer of l-cis-diltiazem, but in both cases calcium or barium was recorded as a current carrier, as seen in FIGS. 6 and 7. Although it significantly reduced its peak current (ie, acting as a previously known Ca channel inhibitor), it had no effect on current inactivation associated with depolarization. Therefore, from the viewpoint of drug efficacy, it was found that the two optical isomers have completely different actions on myocardial L-type calcium channels.
Claims (5)
。 The pharmaceutical composition according to claim 1, which is for the treatment and / or prevention of QT-prolonging ventricular arrhythmia.
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JP2002526411A (en) * | 1998-10-02 | 2002-08-20 | インセルム(アンスティチュ・ナショナル・ドゥ・ラ・サンテ・エ・ドゥ・ラ・ルシェルシュ・メディカル) | Use of diltiazem to treat retinal pathology |
JP2008528489A (en) * | 2005-01-20 | 2008-07-31 | ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ | QT interval adjustment method |
JP2009516691A (en) * | 2005-11-21 | 2009-04-23 | タツプ・フアーマシユーテイカル・プロダクツ・インコーポレイテツド | QT interval prolongation and associated disease treatment |
JP6954582B2 (en) * | 2016-12-22 | 2021-10-27 | 国立大学法人滋賀医科大学 | Pharmaceutical composition |
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JP2002526411A (en) * | 1998-10-02 | 2002-08-20 | インセルム(アンスティチュ・ナショナル・ドゥ・ラ・サンテ・エ・ドゥ・ラ・ルシェルシュ・メディカル) | Use of diltiazem to treat retinal pathology |
JP2008528489A (en) * | 2005-01-20 | 2008-07-31 | ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ | QT interval adjustment method |
JP2009516691A (en) * | 2005-11-21 | 2009-04-23 | タツプ・フアーマシユーテイカル・プロダクツ・インコーポレイテツド | QT interval prolongation and associated disease treatment |
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JAPANESE CIRCULATION JOURNAL, vol. 54, JPN6020039083, 1990, pages 117 - 125, ISSN: 0004977874 * |
THE JAPANESE JOURNAL OF PHARMACOLOGY, vol. 80, JPN6020039082, 1999, pages 319 - 325, ISSN: 0004977873 * |
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