JP2007261962A - Endothelin receptor antagonist useful for pulmonary hypertension. - Google Patents
Endothelin receptor antagonist useful for pulmonary hypertension. Download PDFInfo
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Abstract
【課題】肺高血圧症に有用なエンドセリン受容体拮抗薬を提供する。
【解決手段】抗菌活性を有するスルホンアミド系医薬であるスルフィソキサゾール［Ｓｕｌｆｉｓｏｘａｚｏｌｅ、４−アミノ−Ｎ−（３，４−ジメチル−５−イソキサゾリル）ベンゼンスルホンアミド］からなる肺高血圧症に有用なエンドセリン受容体拮抗薬である。
【選択図】なしDisclosed is an endothelin receptor antagonist useful for pulmonary hypertension.
Useful for pulmonary hypertension comprising sulfisoxazole, 4-amino-N- (3,4-dimethyl-5-isoxazolyl) benzenesulfonamide, which is a sulfonamide drug having antibacterial activity. Is an endothelin receptor antagonist.
[Selection figure] None
Description
本発明は、肺高血圧症に有用なエンドセリン受容体拮抗薬に関するものであり、サルファ剤（Sulfisoxazole）の中でも臨床応用を感染症にとどまらず特定の循環器疾患即ち肺高血圧症に対して高い治療効果があるスルフォンアミド誘導体を発見し、その効能を証明し、同薬剤の処方（使用）用途を拡大させたものである。 The present invention relates to an endothelin receptor antagonist useful for pulmonary hypertension, and among sulfa drugs (Sulfisoxazole), the clinical application is not limited to infectious diseases, and has a high therapeutic effect on specific cardiovascular diseases, that is, pulmonary hypertension. They discovered a certain sulfonamide derivative, proved its efficacy, and expanded its prescription (use) application.
肺高血圧症は、循環するエンドセリン（ET)-1レベルの増加を含む疾病経過に関与する可能性がある内皮細胞機能不全を伴う。
肺高血圧症は難治性特定疾患であり治療を行なわない場合は2年生存率は50%を下回る。しかし有効な治療法は見つかっておらず、特にコンプライアンスの高い経口治療薬は現在日本で認可されていない。
Pulmonary hypertension is associated with endothelial cell dysfunction that may be involved in the disease course, including increased levels of circulating endothelin (ET) -1.
Pulmonary hypertension is a refractory specific disease, and if not treated, the 2-year survival rate is less than 50%. However, no effective treatment has been found, and a highly compliant oral treatment is not currently approved in Japan.
肺高血圧症については、今日までの学会などにおける報告により次のことが明らかになっている。
ETは、強力な血管作動性で、内皮細胞によって合成され分泌されるペプチドである（非特許文献１）。ETは、変換酵素の作用を通してbig ETから形成される(2)。ETは、心血管機能不全の重要な媒介である特定の酵素の処理によって生産される調節性ペプチドでもある（非特許文献２）。局所肺ET-1発現の増加によって軽度・中等度肺高血圧症（非特許文献３〜非特許文献４）が生じた症例で、循環するET-1（非特許文献５）血中濃度は増加する。これはこのペプチドが病原性プロセスに貢献する可能性があることを示唆する。
ETレセプター拮抗剤は、急性及び慢性低酸素症肺高血圧症を予防することができ、肺脈管の構造上のリモデリングを抑制させることができる（非特許文献６）。
モノクロタリン（MCT）は、肺高血圧、右室肥大と続発する慢性右心不全に至る肺血管性損害を生じさせる（非特許文献７）。
ETA-レセプター拮抗剤を用いてのET活性の抑制は、MCTによって誘発されたラット肺高血圧症モデルで、肺高血圧症と右室肥大を改善する（非特許文献８）。肺高血圧症では著しく増加した循環性心房性ナトリウム利尿ペプチド（ANP）が病態にかかわるという報告がされた。そして、それはANP分泌が重篤な肺高血圧症の血行力学的機能障害に反応して作動することを示唆する（非特許文献９）。
而してsulfisoxazole（SFX）は、グラム陽性及びグラム陰性バクテリアに対して広範囲にわたる抗菌活性を持つスルフォンアミド群の薬であること。加えて、SFXには迅速な吸収と排出によって特徴づけられる優れた薬理学的特性があることを明らかにした（非特許文献１０）。
なお、特許文献１にて紹介のエンドセリン受容体拮抗薬においては、スルフォンアミドが異なり本発明の対象とする肺高血圧症への適用は、効能が不明であり特定できない。
Regarding pulmonary hypertension, the following has been clarified by reports in academic societies and the like to date.
ET is a peptide that is potent vasoactive and is synthesized and secreted by endothelial cells (Non-patent Document 1). ET is formed from big ET through the action of converting enzymes (2) . ET is also a regulatory peptide produced by the treatment of specific enzymes that are important mediators of cardiovascular dysfunction (Non-Patent Document 2). In patients with mild / moderate pulmonary hypertension (Non-patent
The ET receptor antagonist can prevent acute and chronic hypoxic pulmonary hypertension, and can suppress structural remodeling of the pulmonary vasculature (Non-patent Document 6).
Monocrotaline (MCT) causes pulmonary vascular damage leading to pulmonary hypertension, right ventricular hypertrophy and chronic right heart failure (Non-patent Document 7).
Inhibition of ET activity using an ET A -receptor antagonist improves pulmonary hypertension and right ventricular hypertrophy in a rat pulmonary hypertension model induced by MCT (Non-patent Document 8). In pulmonary hypertension, a marked increase in circulating atrial natriuretic peptide (ANP) was reported to be involved in the pathology. And it suggests that ANP secretion operates in response to hemodynamic dysfunction in severe pulmonary hypertension (Non-patent Document 9).
Thus, sulfisoxazole (SFX) is a sulphonamide group drug with a wide range of antibacterial activity against gram-positive and gram-negative bacteria. In addition, SFX has been shown to have excellent pharmacological properties characterized by rapid absorption and excretion (Non-Patent Document 10).
The endothelin receptor antagonist introduced in
そこで我々発明者は、非特許文献１１によって、心室筋細胞における心臓自律機能、肺動脈血圧、生存率とANP顆粒の増減に関してMCT処理された肺高血圧症ラットを用いて、ETA拮抗作用を有するSFXの薬効を示し、更なる研究を経てスルフォンアミド誘導体を特定した本発明を開発したのである。 Therefore we inventors, the non-patent document 11, cardiac autonomic function in ventricular myocytes, using a pulmonary arterial blood pressure, MCT treated pulmonary hypertension rats with respect to changes in viability and ANP granules, SFX with ET A antagonism The present invention has been developed in which a sulfonamide derivative has been identified through further research.
式、 formula,
サルファ剤であるSulfisoxazoleはエンドセリン（ET）拮抗作用を有することが発表された（Biochem Biophy Res Com, 1994）。本発明による前記特定式のスルフォンアミド誘導体を経口投与させることで、肺高血圧症を示すラットでは、1.生存率が有意に改善した。2.自律神経機能の低下が抑制された。3.肺血圧の上昇が抑制された。4.ナトリウム利尿ペプチドの賛成が低く抑えられた。以上の動物実験のデータよりSulfisoxazoleの肺高血圧症に対する臨床応用への道が開かれた。
Sulfisoxazoleは諸外国では尿路及び消化管感染症の治療薬として広く用いられており、日本でも以前は経口薬として認可されていた。よって経口投与における臨床上の安全性は既に確立している。本エンドセリン受容体拮抗薬の新しい薬効の発見は臨床治療の内、第1相及び第2相試験を省略あるいは簡便化することが可能となる。
現在、米国で肺高血圧症の治療目的で経口投与されている薬剤ボセンタンは1錠に$55.00の費用が必要であり、同国のsulfisoxazole（1錠, 500mg, $0.26）より216倍も高価である。
現在日本で認可申請が出されている経口薬剤（ボセンタン；125mg錠：1ヶ月使用量60錠は3500米国ドル[38万円]に相当）の1/50程度であり、本発明のスルフォンアミド誘導体からなる肺高血圧症に有用なエンドセリン受容体拮抗薬の臨床適応が認められれば、その処方適応が拡大され安値でかつ有効な薬剤の普及に結びつき、医療経費の大幅な軽減につながり患者負担も軽減されるものである。
Sulfisoxazole, a sulfa drug, was announced to have endothelin (ET) antagonism (Biochem Biophy Res Com, 1994). Oral administration of the sulfonamide derivative of the specific formula according to the present invention significantly improved the survival rate in rats showing pulmonary hypertension. 2. Decreased autonomic nervous function was suppressed. 3. Increase in pulmonary blood pressure was suppressed. 4. Support for natriuretic peptides was low. The data from the above animal experiments have opened the way for clinical application of sulfisoxazole for pulmonary hypertension.
Sulfisoxazole is widely used as a treatment for urinary tract and gastrointestinal infections in other countries, and was previously approved as an oral drug in Japan. Therefore, clinical safety in oral administration has already been established. Discovery of a new drug effect of this endothelin receptor antagonist can omit or simplify
Currently, the drug bosentan administered orally for the treatment of pulmonary hypertension in the US costs $ 55.00 per tablet, and is 216 times more expensive than the country's sulfisoxazole (1 tablet, 500 mg, $ 0.26).
The sulfonamide derivative of the present invention is about 1/50 of the oral drug (Bosentan; 125 mg tablet: 60 tablets per month is equivalent to 3500 US dollars [380,000 yen]) currently submitted for approval in Japan. If a clinical indication of an endothelin receptor antagonist useful for pulmonary hypertension is recognized, its prescription indication will be expanded, leading to the spread of low-cost and effective drugs, leading to a significant reduction in medical costs and a reduction in patient burden It is what is done.
本発明のエンドセリン受容体拮抗薬におけるスルフォンアミド誘導体とは、前記の式に記載の通りである。
而してこのスルフォンアミド誘導体における各物質中で新規な特定物質は何か、及び特定物質と密接に関係する他の物質とは何か、並びにこれらの特定・関係意義（理由等）及びその他、本発明を実施するための最良の具体的条件などの形態は、次の実施例により詳細に紹介する。
The sulfonamide derivative in the endothelin receptor antagonist of the present invention is as described in the above formula.
Thus, what is a new specific substance in each substance in this sulfonamide derivative, what is another substance closely related to the specific substance, and the significance of these identification / relationship (reasons) and others, The best specific conditions for carrying out the present invention will be described in detail in the following examples.
本実施例は、本発明者等が肺高血圧症及び右室肥大と続発する右心不全の経口治療効果があるエンドセリン受容体拮抗薬（ETA）sulfisoxazole（SFX）の治療有効性を調べる研究によって本発明の前記式の特定スルフォンアミド誘導体SFX2とその効能を見出した経過と共に説明するものである。 This example is based on a study in which the present inventors investigated the therapeutic efficacy of endothelin receptor antagonist (ET A ) sulfisoxazole (SFX), which has an oral therapeutic effect on right heart failure secondary to pulmonary hypertension and right ventricular hypertrophy. The specific sulfonamide derivative SFX2 of the above-described formula of the invention and the effects thereof will be described together with the course of finding them.
１．研究の概要
＜背景＞
肺高血圧症は、最終的に右心不全を引き起こす難治性疾患である。エンドセリン受容体拮抗薬（ETA）の血管拡張作用は、肺高血圧症患者の治療に結びつく可能性が示唆されている。
＜方法＞
投与ケースは、肺高血圧症ラットにモノクロタリン（MCT）を１回投与するケース。及びこの後に本発明におけるスルフォンアミド誘導体（以下sulfisoxazole（SFX2）又は単にSFX2という）を投与するケースである。治療効果は、右室筋細胞と血漿におけるANP顆粒量（濃度）、自律神経活性、肺動脈圧の増減及び生存率を指標として評価した。
＜結果＞
sulfisoxazole（SFX2）のみでは動脈血圧を変えなかったが、モノクロタリン（MCT）で前処理したものは、これによって生じた肺動脈血圧の上昇を抑制した。SFX2は、右心不全によって生じる自律神経制御の低下を維持し、肺高血圧症ラットの生存を有意に改善した。
＜結語＞
抗菌薬（長い間臨床医学において使用されているsulfisoxazole(SFX2)）の新薬効能としてのエンドセリン拮抗作用が、ラットの実験モデルを通して肺高血圧症の治療のために効果があることが確認された。
＜承認＞
本研究は、米国国立衛生研究所によって発行されるLaboratory Animalsの注意と用法のためのガイド（NIH刊行No.85-23、1996年改訂）に従って遂行され大分大学医学部動物実験施設運営委員会の承認を得た。
1. Outline of Research <Background>
Pulmonary hypertension is an intractable disease that ultimately causes right heart failure. It has been suggested that the vasodilatory effect of endothelin receptor antagonist (ET A ) may lead to the treatment of patients with pulmonary hypertension.
<Method>
In the administration case, monocrotaline (MCT) is administered once to pulmonary hypertensive rats. In this case, the sulfonamide derivative (hereinafter referred to as sulfisoxazole (SFX2) or simply SFX2) in the present invention is administered. The therapeutic effect was evaluated by using ANP granule amount (concentration), autonomic nerve activity, increase / decrease in pulmonary artery pressure and survival rate in right ventricular myocytes and plasma as indices.
<Result>
Although sulfisoxazole (SFX2) alone did not change arterial blood pressure, pretreatment with monocrotaline (MCT) suppressed the increase in pulmonary arterial blood pressure caused by this. SFX2 maintained the reduced autonomic control caused by right heart failure and significantly improved the survival of pulmonary hypertensive rats.
<Conclusion>
Endothelin antagonism as a new drug effect of antibacterial drug (sulfisoxazole (SFX2) used in clinical medicine for a long time) has been confirmed to be effective for the treatment of pulmonary hypertension through an experimental model of rats.
<Approval>
This study was carried out in accordance with the Guide for Care and Use of Laboratory Animals published by the National Institutes of Health (NIH publication No. 85-23, revised in 1996) and approved by the Oita University School of Medicine Animal Experiment Facility Steering Committee Got.
２．研究の具体的な内容
＜ラットと飼育場所＞
肺高血圧症Wistarラット（10週齢、340-370g、雄）18匹のうち、MCT処理したラットにSFX2を経口投与したラット（SFX2ラット）と、MCT処理しただけのラット（MCTラット）に分けて各群で実験した。全てのラットは、セアック吉富製薬会社（東京、日本）から購入した。ラットは一定温度（22±2 ℃）に維持され明暗サイクル設定（LD 12:12 LD; 午前8時に照明点灯）のある耐光性の部屋（TB181又はTB182；ナショナル、大阪、日本）で、個々のケージにて飼育した。
＜動物モデルと研究計画＞
モノクロタリン（MCT）（Sigma Chemical社、セントルイス、MO、米国）は1MのNaOHによってpH7.40に調節し、滅菌蒸留水で希釈され10 mg/mlの濃度で保存した。1MのHClで希釈し、最終濃度80 mg/kgとしてラット皮下に注射した。飼料はSFX2グループとSFX2の投与のないMCTグループに分け、１日に１匹に付き20 gの標準飼料（CE-2、クレア、東京、日本）を与えた。SFX2グループのラットは、MCT注射後７日間から体重1 kg当たり1 gのsulfisoxazole（SFX2）を経口投与した。SFX2が肺高血圧症、右室肥大と慢性心不全で長期生存を改善するかどうか評価するために、我々発明者等はMCTとSFX2グループで生存率を比較した。ラットは毎日体重を量り、そして、SFX2摂取量を調整するために飼料の摂取量を測定した。
＜肺動脈血液血圧の測定＞
肺動脈圧測定のためにラットに麻酔（50 mg/kgのpentobarbital注入）をかけ、そして、肺動脈に圧力トランスデューサ（モデルTB-612T、日本、東京、日本）を挿入するために人工呼吸装置（モデルNo.141、New England Medical Instruments社、MA、米国）の下で開胸した。肺動脈圧は、コンピュータ化されたデータ収集システム（MacLab/8e、ADInstrumentsAD Instruments、コロラド・スプリングス、CO、米国）にて連続的にモニターされた。
＜ECG記録と心拍変動性＞
遠隔ECG無線送信機（TA11CTA-F40、Data Sciencesインターナショナル、セントポール、MN、米国）は、ラットの背面皮下に埋め込んだ。心嚢の双極導出ワイヤ電極は背面で皮膚下に配置した。ECG記録は、残留した麻酔薬と手術の影響を回避するために7日の回復期の後に行った。個々のラットのケージは、抑制されない状態で動物のECG無線信号を見つけるために、レシーバ（RLA1020、Data Sciencesインターナショナル）の上部に配置された。一日に数回、自動的に30分間5kHzの精度でECGを記録し、デジタルデータ・レコーダー（DR-M3、ティアック、東京、日本）で光磁気（MO）ディスクに保存した。DXP 115とPASHERVAR（キッセイ・コムテック、松本、日本）でプログラムされたsoftwareでデータを解析し、ECG信号のRR間隔の連続数列（すなわち、タコグラム）を得た。RR-間隔データは、高速フーリエ変換（FFT）によってパワースペクトル曲線を生成するのに用いられた。高速フーリエ変換アルゴリズムは、パワースペクトル密度(12)のスムーズな推定値を与える。我々の以前の実験(13)より低周波範囲（LF: 0.04-0.73 Hz）及び高周波範囲（HF: 0.73-2.0 Hz）が決められた。
＜電子顕微鏡検査＞
10週齢の雄のWistarラットにMCT処理をした対照群とSFX2投与ラットが用いられた。心筋細胞の微細構造解析が行われた。心房性ナトリウム利尿ペプチド（ANP）顆粒の検出のため、右室筋細胞を含んでいる小さい組織塊は2時間2.5 %のグルタルアルデヒドと2 %のパラホルムアルデヒド/0.1 Mのカコジル酸塩バッファ（pH 7.4）に固定された。更に2時間に渡り組織塊は四酸化オスミウムによってpostfixされ、エポキシ樹脂に埋め込まれた。薄切片は、酢酸ウラニルとクエン酸鉛塩で染色されJEOL電子顕微鏡で観察した。（モデルJEM-100CX、日本電子光学研究所、東京、日本）。
＜血漿心房性ナトリウム利尿ペプチド（ANP）濃度＞
血漿ANPサンプルは、冷却した注射器で動血から採取した。血漿採取のためのポリプロピレン管は、エチレンジアミン四酢酸（EDTA）とアプロチニンを含んでいる。血漿ANP濃度は、Radin等(14)の方法によりRIAキット法（Peninsula Laboratories, San Carlos, CA）を用いて決定した。
＜薬と薬品＞
MCT及びSFX2（4-amino-N（3,4-dimethyl-5-isooxazolyl）benzenesulfonamide）と他の全ての化学製品はSigma Chemical社（セントルイス, MO, USA)から購入した。
＜統計分析＞
統計比較は、生存率解析をnon-paired Student's ｔ検定によってなされた。生存率は、SFX2投与をうけたMCTラットとSFX2投与をうけてないMCTラットでKaplan-Meier曲線とLog-rank検定によって分析した。数値は、平均±SEとして表した。p値<0.05を統計学的に有意であるとみなした。
2. Details of the research <Rat and breeding place>
Out of 18 pulmonary hypertensive Wistar rats (10 weeks old, 340-370g, male), divided into MCT-treated rats orally administered SFX2 (SFX2 rats) and only MCT-treated rats (MCT rats) Each group was experimented. All rats were purchased from Seak Yoshitomi Pharmaceutical Company (Tokyo, Japan). Rats are kept in a constant temperature (22 ± 2 ° C) and are kept in a light-resistant room (TB181 or TB182; National, Osaka, Japan) with a light / dark cycle setting (LD 12:12 LD; lit at 8 am). Raised in cages.
<Animal model and research plan>
Monocrotaline (MCT) (Sigma Chemical Co., St. Louis, MO, USA) was adjusted to pH 7.40 with 1M NaOH, diluted with sterile distilled water and stored at a concentration of 10 mg / ml. It was diluted with 1M HCl and injected subcutaneously into rats to a final concentration of 80 mg / kg. The feed was divided into the SFX2 group and the MCT group without SFX2 administration, and 20 g of standard feed (CE-2, CLEA, Tokyo, Japan) was given per animal per day. Rats of the SFX2 group were orally administered 1 g of sulfisoxazole (SFX2) per kg of body weight from 7 days after MCT injection. To assess whether SFX2 improves long-term survival in pulmonary hypertension, right ventricular hypertrophy and chronic heart failure, we compared survival rates in the MCT and SFX2 groups. Rats were weighed daily and feed intake was measured to adjust SFX2 intake.
<Measurement of pulmonary blood pressure>
Rats were anesthetized (50 mg / kg pentobarbital infusion) for pulmonary artery pressure measurement and ventilator (Model No. to insert pressure transducer (Model TB-612T, Japan, Tokyo, Japan) into pulmonary artery) .141, New England Medical Instruments, MA, USA). Pulmonary artery pressure was continuously monitored with a computerized data acquisition system (MacLab / 8e, ADInstrumentsAD Instruments, Colorado Springs, CO, USA).
<ECG recording and heart rate variability>
A remote ECG radio transmitter (TA11CTA-F40, Data Sciences International, St. Paul, MN, USA) was implanted subcutaneously in the back of the rat. A pericardial bipolar lead wire electrode was placed under the skin on the back. ECG recordings were made after a 7-day recovery period to avoid residual anesthetic and surgical effects. Individual rat cages were placed on top of the receiver (RLA1020, Data Sciences International) to find the animal's ECG radio signal in an unsuppressed state. Several times a day, the ECG was automatically recorded with an accuracy of 5 kHz for 30 minutes and stored on a magneto-optical (MO) disk with a digital data recorder (DR-M3, TEAC, Tokyo, Japan). Data were analyzed with software programmed with DXP 115 and PASHERVAR (Kissey Comtech, Matsumoto, Japan) to obtain a continuous sequence of ECG signal RR intervals (ie, a tachogram). The RR-interval data was used to generate a power spectrum curve by fast Fourier transform (FFT). The fast Fourier transform algorithm gives a smooth estimate of the power spectral density (12) . Low frequency range (LF: 0.04-0.73 Hz) and high frequency range (HF: 0.73-2.0 Hz) were determined from our previous experiment (13) .
<Electron microscopy>
A 10-week-old male Wistar rat treated with MCT treatment and a SFX2-treated rat were used. Microstructure analysis of cardiomyocytes was performed. For the detection of atrial natriuretic peptide (ANP) granules, a small tissue mass containing right ventricular myocytes was collected for 2.5 hours with 2.5% glutaraldehyde and 2% paraformaldehyde / 0.1 M cacodylate buffer (pH 7.4). ). Over a further 2 hours, the tissue mass was postfixed with osmium tetroxide and embedded in epoxy resin. Thin sections were stained with uranyl acetate and lead citrate and observed with a JEOL electron microscope. (Model JEM-100CX, JEOL, Tokyo, Japan).
<Plasma atrial natriuretic peptide (ANP) concentration>
Plasma ANP samples were collected from the blood with a chilled syringe. Polypropylene tubes for plasma collection contain ethylenediaminetetraacetic acid (EDTA) and aprotinin. Plasma ANP concentration was determined using the RIA kit method (Peninsula Laboratories, San Carlos, Calif.) According to the method of Radin et al. (14) .
<Drugs and drugs>
MCT and SFX2 (4-amino-N (3,4-dimethyl-5-isooxazolyl) benzenesulfonamide) and all other chemical products were purchased from Sigma Chemical Co. (St. Louis, MO, USA).
<Statistical analysis>
Statistical comparisons were made by viability analysis by non-paired Student's t test. Survival was analyzed by Kaplan-Meier curve and Log-rank test in MCT rats receiving SFX2 and in MCT rats not receiving SFX2. Numerical values were expressed as mean ± SE. A p value <0.05 was considered statistically significant.
３．研究の結果
＜生存率の検定＞
肺高血圧症とその結果としての右心不全の進行によって、MCT処理されたラットの全ては10週以内に死亡する。図１は2つのグループ間の生存率の明らかな違い示している。MCT処理をうけているラットは、投与4週で死に始め、10週以内に全て死んだ。対照的にSFX2を投与されたラットは18匹のうち7匹が10週の観察期間の間に死亡しただけであった（生存率、61.1 %）。統計分析では、SFX2投与されたグループの生存率が有意に高いことが明らかになった（p値 = 0.0004）。
＜肺動脈圧（PABP）＞
MCT処理されたラットの5週目の肺動脈圧は、高度に上昇した（図2B）。肺動脈収縮期血圧（対照ラット：31.8±1.4 mmHg，MCT処理ラット：52.2±2.9 mmHg）と肺動脈拡張期血圧（対照ラット：27.0±1.4 mmHg、MCT処理ラット：38.0±1.6 mmHg）はMCT処理を受けることによって著明な上昇を示した。しかしながら、図2C示されるように、肺動脈収縮期圧（31.0±1.2 mmHg）と拡張期血圧（27.5±0.8 mmHg）はSFX2の経口投与により低く保たれた。MCT処理を受けている5匹のラットの肺動脈圧は42.8±0.3 mmHgであり、図2Dで示すようにそれは5匹の対照動物（28.4±0.1 mmHg）と5匹のSFX2投与をうけているラット（27.9±0.2 mmHg）より有意に高い（p < 0.001）。一方、SFX2は全身血圧を変えなかった[対照: 98.6±1.3 / 69.6±2.9 mmHg、SFX2: 95.0±1.4 / 64.3±1.0 mmHg]。
＜対照ラットと右心不全ラットのECG分析＞
図3A、3Bに示すように、対照ラット、MCT処理ラット及びSFX2投与ラットの典型的心電図記録を示す。肺高血圧症ラットのECGにおいて（図3B）、RR間隔は短くなり、Ｐ波振幅は拡大し、Ｒ波振幅は減少し、QT間隔は延長した。QRS時間は対照ラットと比較すると長くなった（図3A）。一方では、SFX2を投与されたラット（図3C）のECGパラメータは、対照ラットのそれらとほとんど一致した（図3A）。RR間隔のTrendgramsは対照ラット（図3D）と比較すると、肺高血圧症ラット（図3E）で変動が減少することが示された。心拍における心拍毎の変動性はSFX2投与によって維持された（図3F）。心拍変動のパワースペクトル解析は心血管系における自律神経活性の評価にて定量的で非観血的な方法であることが示されている(15)。SFX2投与によって、低周波領域値と高周波領域値は共に維持された（図3I）。一方で、両周波数帯パワー値は、SFX2投与を受けない肺高血圧症ラットで消失し、これはMCT処理されたラットの心臓自律神経機能の破綻を示すものである（図3H）。
＜心拍の連続記録と心拍変動のスペクトル・パラメータ（TP、HF、L/H比率）＞
MCT処理をうけているラットはその注射後の4週間後に心拍数の増加が認められた。この増加は本研究の観察期間を通じて維持された（図4A）。図4Bに示される棒グラフデータから、MCT処理をうけているラットは、5週またはそれ以降に心拍数の有意な増加を示した（MCTラット：316.9±5.1 bpm、SFX2投与をうけているラット：280.2±3.3 bpm、p < 0.01））。MCTのラットの全パワー値と高周波数パワー値は、MCT処理後4週以降に、著明に低下した（図4C、D、E、F)。図4Gで示すように、MCTラットとSFX2ラットのL/H比率はほぼ同一だった。両群のL/H比率を表わす棒グラフ・データは7、8週でわずかであるが、L/H比率の減少を示した（図4H）。
＜心房ナトリウム利尿ペプチド（ANP）顆粒とその血漿中濃度＞
右心房と右心室筋細胞の組織学的検査は、電子顕微鏡によって行った（図5）。MCTラットのゴルジ領域の心房性ナトリウム利尿ペプチド（ANP）顆粒の数が右心房筋細胞（データ非表示）と右室筋細胞で対照動物と比較すると著明に増加したことを示す（図5Aと5B）。しかしながらSFX2投与ラットの心筋細胞中のANP顆粒の数はほとんど対照と同一であった（図5A）。MCT処理された5週目のラットの血漿ANP濃度は対照ラットと比較すると増加を示した。一方、SFX2投与をうけているラットではANP濃度が対照ラットとほぼ同一でありSFX2はANPの上昇を抑制した（図5D）。
3. Results of the study <survival test>
Due to pulmonary hypertension and the resulting progression of right heart failure, all MCT-treated rats die within 10 weeks. FIG. 1 shows the obvious difference in survival between the two groups. Rats receiving MCT treatment began to die 4 weeks after administration and all died within 10 weeks. In contrast, only 7 of 18 rats that received SFX2 died during the 10-week observation period (survival rate, 61.1%). Statistical analysis revealed a significantly higher survival rate for the group receiving SFX2 (p-value = 0.0004).
<Pulmonary artery pressure (PABP)>
The pulmonary artery pressure at
<ECG analysis of control and right heart failure rats>
As shown in FIGS. 3A and 3B, typical electrocardiogram recordings of control rats, MCT-treated rats and SFX2-treated rats are shown. In ECG of pulmonary hypertensive rats (FIG. 3B), the RR interval was shortened, the P wave amplitude was increased, the R wave amplitude was decreased, and the QT interval was extended. QRS time was longer compared to control rats (Figure 3A). On the other hand, ECG parameters of rats administered SFX2 (FIG. 3C) were almost identical to those of control rats (FIG. 3A). Trendgrams of RR intervals were shown to decrease in pulmonary hypertensive rats (Figure 3E) compared to control rats (Figure 3D). Heart rate variability in heart rate was maintained by SFX2 administration (Figure 3F). Power spectrum analysis of heart rate variability has been shown to be a quantitative and noninvasive method for assessing autonomic activity in the cardiovascular system (15) . By SFX2 administration, both the low frequency region value and the high frequency region value were maintained (FIG. 3I). On the other hand, both frequency band power values disappeared in pulmonary hypertensive rats not receiving SFX2 administration, indicating a breakdown of cardiac autonomic function in MCT-treated rats (FIG. 3H).
<Continuous recording of heart rate and spectral parameters of heart rate variability (TP, HF, L / H ratio)>
Rats receiving MCT treatment showed an increase in
<Atrial natriuretic peptide (ANP) granules and their plasma concentrations>
Histological examination of the right atrium and right ventricular myocytes was performed with an electron microscope (Figure 5). The number of atrial natriuretic peptide (ANP) granules in the Golgi region of MCT rats is markedly increased compared to control animals in right atrial myocytes (data not shown) and right ventricular myocytes (Figure 5A and 5B). However, the number of ANP granules in cardiomyocytes of SFX2-treated rats was almost identical to the control (FIG. 5A). Plasma ANP concentration in MCT-treated rats at 5 weeks showed an increase compared to control rats. On the other hand, the ANP concentration in rats receiving SFX2 was almost the same as that in control rats, and SFX2 suppressed the increase in ANP (FIG. 5D).
４．考察
経口活性のあるスルフォンアミド誘導体SFX2はラットにおいてMCTによって誘発される実験的な肺高血圧症において心臓自律神経機能低下を予防し、肺動脈圧の上昇を抑制し、長期生存率を改善し、心房性ナトリウム利尿ペプチド（ANP）の過剰発現を減らすことで肺高血圧症治療薬としての作用を有することが証明された。
＜エンドセリン拮抗剤は、肺高血圧症を救う＞
肺高血圧症は進行性であり、最終的に右心不全で死に至る。軽度及び中等度肺高血圧症（3、4）を有する症例では、血中ETレベルが増加する。肺高血圧症のような異常肺血管血流患者において、肺動脈壁は内皮細胞でET生産を活性化する可能性がある。ETAレセプター（肺血管と気管支平滑筋及び心筋に存在）は、これらの組織(6)で血管収縮性であり気管支収縮性かつ陽性変カ効果を有する。ET1は、現在知られている最も強力な血管収縮薬であって血管平滑筋細胞収縮(1)を含む生物学的な様々な効果を引き起す。過去の報告でLU 135252（ETA拮抗薬）はMCT処理によって誘発された肺高血圧を軽減し右室肥大を抑制し、内皮代謝機能(16)を改善するとの研究がある。他のETA受容体拮抗剤であるBQ-123は肺高血圧症や右室肥大(17)を抑制した。さらにbosentanは低酸素症(18)によって誘発される肺動脈血圧（PABP）を低下させた。また以前の報告ではETA/ETB拮抗剤bosentanが肺血行力学や運動能力、更に肺高血圧症の患者の臨床転帰（19、20）を改善すると報告した。以上の報告にもとづいて、我々は経口活性を有するETA拮抗薬（SFX2）に肺高血圧症の治療効果があるか否かを調べた。SFX2は、本研究で劇的に肺高血圧症を改善した（図1,2）。これらの結果は過剰な内在性ETが肺高血圧症と心血管リモデリングの発現に関与することを示唆する。非ペプチド系ET拮抗剤の比較においてSFX2が肺高血圧症または右室収縮期圧を減らすことを指標とする他の経口拮抗薬と同等あるいはより強い作用を有することが判明した(20,21)。
＜ET拮抗薬は心不全治療薬として働く＞
心筋症ハムスターを用いた研究ではETA拮抗薬が左心及び右心機能を改善し死亡率を改善したとの報告が行われた(22)。Fauchier等は心拍変動解析の結果、右心不全患者は両心不全患者と同様に自律神経機能が低下すると報告した(23)。現在のコンセンサスでは心拍変動のパワースペクトル解析における高周波領域パワーが副交感神経を、低周波／高周波パワー比（L/H）が交感神経緊張を表すことが知られている(12,15,24,25)。我々は以前の報告で右心不全ラットが自律神経障害を生じることを示した。本研究ではSFX2の投与が自律神経の低下を予防し、心不全の進行に対して改善作用を有することを示した。特に心不全に伴う自律神経機能の低下に特徴的である高周波領域パワー値の維持にSFX2は有効に働いた。
＜心機能低下の指標としてのANP＞
ANPの生理的機能としては正酸素あるいは低酸素状態における肺動脈圧の維持、更に心肥大や肺血管モデリングの調節機構として役割を果たす。右心室負荷によって血漿のANP及びBNP濃度が上昇することが知られている(26)。このANPあるいはBNP血漿濃度と肺動脈血圧は明らかに相関する(27)。SFX2はANP血漿濃度を減らしたが、これは肺動脈血圧を下げることによる間接作用と、ANP受容体を経由する直接作用で心不全を改善すると考えられる。我々の知る限りでは右心不全を呈する心筋細胞中にANP顆粒を見出したものは本研究が最初であり、更にETAによるその軽減作用も初めての報告である。
＜SFX2の新しい治療薬としての意味＞
SFX2（スルフォンアミド誘導体）は本邦（日本）では点眼薬として低コスト抗菌薬として長く使用されて来た。また諸外国では尿路感染症や中耳炎の治療薬として小児に使われている。Chan等は以前、SFX2は選択的な非ペプチドETA受容体拮抗剤(11)である結果を受容体結合検査に基づいて報告した。この結果に基づいて我々はSFX2にはその抗細菌作用の他に肺高血圧治療のための薬理学的に有益な効果があるということを初めて証明した。ヒトではSFX2は１日2〜4gの経口量において2〜4時間で広範囲に血漿蛋白に密接に結びついて110〜２５０μg/mlの血漿濃度に到達する。そして、SFX2の単回投与量のおよそ95 %が24時間で腎臓によって排出される(10)。我々はSFX2の日々の経口投与が非感受性循環器疾患である肺高血圧症の治療に有益であると結論する。
＜結果＞
我々の研究によると、モノクロタリン（MCT）により肺高血圧症や慢性心不全になったラットにsulfisoxazole(SFX2)の経口投与が肺動脈血圧の諸症状を抑制して、心臓自律神経機能の低下を維持し、更に心筋細胞中や血漿中濃度におけるANPの増加を低下させて生存率を有意に改善することを証明した。すなわちSFX2の投与によって肺動脈圧の上昇が抑制され心臓自律神経機能の低下が抑制された。更にSFX2は心筋細胞のゴルジ領域のANP顆粒の増加の抑制を示し、引き続き生じる慢性心不全の生存率の有意な改善を証明した。
4). Discussion The orally active sulfonamide derivative SFX2 prevents cardiac autonomic dysfunction in experimental pulmonary hypertension induced by MCT in rats, suppresses increased pulmonary artery pressure, improves long-term survival, and atrial It has been proved that it has an action as a therapeutic agent for pulmonary hypertension by reducing the overexpression of natriuretic peptide (ANP).
<Endothelin antagonists save pulmonary hypertension>
Pulmonary hypertension is progressive and eventually leads to death with right heart failure. In cases with mild and moderate pulmonary hypertension (3, 4) , blood ET levels increase. In patients with abnormal pulmonary vascular blood flow, such as pulmonary hypertension, the pulmonary artery wall may activate ET production with endothelial cells. The ET A receptor (present in pulmonary blood vessels and bronchial smooth muscle and myocardium) is vasoconstrictive, bronchoconstrictive and has a positive effect on these tissues (6) . ET1 is the most potent vasoconstrictor currently known and causes a variety of biological effects including vascular smooth muscle cell contraction (1) . In previous reports LU 135252 (ET A antagonist) inhibits right ventricular hypertrophy reduce pulmonary hypertension induced by MCT treatment, there is research to improve endothelial metabolic function (16). BQ-123 is another ET A receptor antagonist inhibited pulmonary hypertension and right ventricular hypertrophy (17). Furthermore, bosentan reduced pulmonary arterial blood pressure (PABP) induced by hypoxia (18) . Previous reports have also reported that the ET A / ET B antagonist bosentan improves pulmonary hemodynamics and exercise capacity, as well as clinical outcomes in patients with pulmonary hypertension (19, 20) . Based on the above report, we investigated whether the ET A antagonist (SFX2) having oral activity have therapeutic effects of pulmonary hypertension. SFX2 dramatically improved pulmonary hypertension in this study (Figures 1 and 2). These results suggest that excessive endogenous ET is involved in the development of pulmonary hypertension and cardiovascular remodeling. In comparison with non-peptide ET antagonists, SFX2 was found to have the same or stronger effect than other oral antagonists whose index is to reduce pulmonary hypertension or right ventricular systolic pressure (20, 21) .
<ET antagonists work as heart failure treatments>
A study using cardiomyopathy hamsters reported that ETA antagonists improved left and right heart function and improved mortality (22) . As a result of heart rate variability analysis, Fauchier et al. Reported that patients with right heart failure declined in autonomic function as well as those with both heart failure (23) . In the current consensus, it is known that the high frequency region power in the power spectrum analysis of heart rate variability represents the parasympathetic nerve, and the low frequency / high frequency power ratio (L / H) represents the sympathetic tone (12,15,24,25). ) We have shown in previous reports that rats with right heart failure develop autonomic neuropathy. In this study, it was shown that the administration of SFX2 prevents the decrease of autonomic nerve and has an improvement effect on the progression of heart failure. In particular, SFX2 worked effectively in maintaining the power value in the high frequency region, which is characteristic of the decline in autonomic nervous function associated with heart failure.
<ANP as an indicator of decreased cardiac function>
As a physiological function of ANP, it plays a role in maintaining pulmonary artery pressure in normoxia or hypoxia, and also in regulating cardiac hypertrophy and pulmonary vascular modeling. It is known that plasma ANP and BNP concentrations are increased by right ventricular load (26) . This ANP or BNP plasma concentration is clearly correlated with pulmonary arterial blood pressure (27) . SFX2 reduced ANP plasma concentration, which is thought to improve heart failure through indirect action by lowering pulmonary arterial blood pressure and direct action via ANP receptors. In our knowledge we are that found ANP granules cardiomyocytes exhibiting right heart failure is beginning this study, it is also the first report mitigation action by further ET A.
<The meaning of SFX2 as a new therapeutic agent>
SFX2 (sulfonamide derivative) has long been used as a low-cost antibacterial agent in Japan (Japan). In other countries, it is used by children as a treatment for urinary tract infections and otitis media. Chan, etc. Previously, SFX2 reported results based a selective nonpeptide ET A receptor antagonist (11) to the receptor binding test. Based on this result, we have demonstrated for the first time that SFX2 has a pharmacologically beneficial effect for the treatment of pulmonary hypertension in addition to its antibacterial activity. In humans, SFX2 is closely associated with plasma proteins extensively in 2-4 hours at an oral dose of 2-4 g daily, reaching a plasma concentration of 110-250 μg / ml. And approximately 95% of a single dose of SFX2 is excreted by the kidney in 24 hours (10) . We conclude that daily oral administration of SFX2 is beneficial for the treatment of pulmonary hypertension, an insensitive cardiovascular disease.
<Result>
According to our study, oral administration of sulfisoxazole (SFX2) to rats with monocrotaline (MCT) caused pulmonary hypertension and chronic heart failure suppressed various symptoms of pulmonary arterial blood pressure and maintained the decline in cardiac autonomic function. Furthermore, it was proved that the survival rate was significantly improved by reducing the increase in ANP in cardiomyocytes and plasma concentrations. That is, the administration of SFX2 suppressed the increase in pulmonary artery pressure and the decrease in cardiac autonomic function. Furthermore, SFX2 showed a suppression of the increase in ANP granules in the Golgi region of cardiomyocytes, demonstrating a significant improvement in the survival rate of subsequent chronic heart failure.
上述文中の上付き（ ）内番号は、次の文献番号を示す。
Bellavere F, Balzani I, Masi GD, et al. Power spectral analysis of heart-rate variations improves assessment of diabetic cardiac autonomic neuropathy. Diabetes 1992; 41: 633-40.
Sanyal SN, Ono K. Derangement of autonomic nerve control in rat with right ventricular failure. Pathophysiology 2002; 8: 197-203.
Radin MJ, Jenkins JE, McCune SA, Jurin RR, Hamlin RL. Effects of enalapril and clonidine on glomerular structure, function, and atrial natriuretic peptide receptors in SHHF/Mcc-cp rats. J Cardiovasc Pharmacol 1992; 19: 464-72.
Akselrod S, Gordon D, Ubel FA, Shannon DC, Barger AC, Cohen RJ. Power spectrum analysis of heart rate fluctuation: A quantitative probe of beat-to-beat cardiovascular control. Science 1981; 213: 220-2.
Prie S, Leung TK, Cernacek P, Ryan JW, Dupuis J. The orally active ETA receptor antagonist (+)-(S)-2-(4, 6-dimethoxy-pyrimidin-2-yloxy)-3-methoxy-3, 3-diphenyl-propionic acid (LU 135252) prevents the development of pulmonary hypertension and endothelial metabolic dysfunction in monocrotaline-treated rats. J Pharmacol Exp Ther 1997; 282: 1312-18.
Miyauchi T, Yorikane R, Sakai S, et al. Contribution of endogenous endothelin-1 to the progression of cardiopulmonary alterations in rats with monocrotaline-induced pulmonary hypertension. Circ Res 1993; 73: 887-97.
Dicarlo VS, Chen SJ, Meng QC, et al. ETA-receptor antagonist prevents and reverses chronic hypoxia-induced pulmonary hypertension in rat. Am J Physiol 1995; 269: L690-7.
Galie N, Hinderliter AL, Torbicki A, et al. Effects of the oral endothelin-receptor antagonist bosentan on echocardiographic and Doppler measures in patients with pulmonary arterial hypertension. J Am Coll Cardiol 2003; 41: 138086.
Channick RN, Sitbon O, Barst RJ, Manes A, Rubin LJ. Endothelin receptor antagonists in pulmonary arterial hypertension. J Am Coll Cardiol 2004; 43: 62S-67S.
Hironori Y, Akira F, Masanao S, et al. The orally active nonpeptide selective endothelin ETA receptor antagonist YM598 prevents and reverses the development of pulmonary hypertension in monocrotaline-treated rats. Eur J Pharmacol 2004; 496: 129-39.
Yamauchi-Kohno R, Miyauchi T, Hoshino T, et al. Role of endothelin in deterioration of heart failure due to cardiomyopathy in hamsters: Increase in endothelin-1 production in the heart and beneficial effect of endothelin-A receptor antagonist on survival and cardiac function. Circulation 1999; 99: 2171-76.
Fauchier L, Babuty D, Melin A, Bonnet P, Cosnay P, Fauchier JP. Heart rate variability in severe right or left heart failure: the role of pulmonary hypertension and resistances. Eur J Heart Fail 2004; 6: 181-5.
Pagani M, Malfatto G, Pierini S, et al. Spectral analysis of heart rate variability in the assessment of autonomic diabetic neuropathy. J Auton Nerv Syst 1988; 23: 143-53.
Torre-Amione G, Young JB, Colucci WS, et al. Hemodynamic and clinical effects of tezosentan, an intravenous dual endothelin receptor antagonist, in patients hospitalized for acute decompensated heart failure. J Am Coll Cardiol 2003; 42: 140-7.
Klinger JR, Warburton RR, Pietras LA, Smithies O, Swift R, Hill NS. Genetic disruption of atrial natriuretic peptide causes pulmonary hypertension in normoxic and hypoxic mice. Am J Physiol 1999; 276: L86874.
Nagaya N, Nishikimi T, Okano Y, et al. Plasma brain natriuretic peptide levels increase in proportion to the extent of right ventricular dysfunction in pulmonary hypertension. J Am Coll Cardiol 1998; 31: 202-8.
Berman S, Byrns PJ, Bondy J, Smith PJ, Lezotte D. Otitis media-related antibiotic prescribing patterns, outcomes, and expenditures in a pediatric medicaid population. Pediatrics 1997; 100: 585-92.
The number in the superscript () in the above sentence indicates the next document number.
Bellavere F, Balzani I, Masi GD, et al. Power spectral analysis of heart-rate variations improves assessment of diabetic cardiac autonomic neuropathy. Diabetes 1992; 41: 633-40.
Sanyal SN, Ono K. Derangement of autonomic nerve control in rat with right ventricular failure.Pathophysiology 2002; 8: 197-203.
Radin MJ, Jenkins JE, McCune SA, Jurin RR, Hamlin RL.Effects of enalapril and clonidine on glomerular structure, function, and atrial natriuretic peptide receptors in SHHF / Mcc-cp rats.J Cardiovasc Pharmacol 1992; 19: 464-72.
Akselrod S, Gordon D, Ubel FA, Shannon DC, Barger AC, Cohen RJ. Power spectrum analysis of heart rate fluctuation: A quantitative probe of beat-to-beat cardiovascular control. Science 1981; 213: 220-2.
Prie S, Leung TK, Cernacek P, Ryan JW, Dupuis J. The orally active ET A receptor antagonist (+)-(S) -2- (4, 6-dimethoxy-pyrimidin-2-yloxy) -3-methoxy- 3, 3-diphenyl-propionic acid (LU 135252) prevents the development of pulmonary hypertension and endothelial metabolic dysfunction in monocrotaline-treated rats.J Pharmacol Exp Ther 1997; 282: 1312-18.
Miyauchi T, Yorikane R, Sakai S, et al. Contribution of principal endothelin-1 to the progression of cardiopulmonary alterations in rats with monocrotaline-induced pulmonary hypertension. Circ Res 1993; 73: 887-97.
Dicarlo VS, Chen SJ, Meng QC, et al. ET A -receptor antagonist prevents and reverses chronic hypoxia-induced pulmonary hypertension in rat.Am J Physiol 1995; 269: L690-7.
Galie N, Hinderliter AL, Torbicki A, et al. Effects of the oral endothelin-receptor antagonist bosentan on echocardiographic and Doppler measures in patients with pulmonary arterial hypertension.J Am Coll Cardiol 2003; 41: 138086.
Channick RN, Sitbon O, Barst RJ, Manes A, Rubin LJ. Endothelin receptor antagonists in pulmonary arterial hypertension. J Am Coll Cardiol 2004; 43: 62S-67S.
Hironori Y, Akira F, Masanao S, et al. The orally active nonpeptide selective endothelin ET A receptor antagonist YM598 prevents and reverses the development of pulmonary hypertension in monocrotaline-treated rats. Eur J Pharmacol 2004; 496: 129-39.
Yamauchi-Kohno R, Miyauchi T, Hoshino T, et al. Role of endothelin in deterioration of heart failure due to cardiomyopathy in hamsters: Increase in endothelin-1 production in the heart and beneficial effect of endothelin-A receptor antagonist on survival and cardiac function. Circulation 1999; 99: 2171-76.
Fauchier L, Babuty D, Melin A, Bonnet P, Cosnay P, Fauchier JP.Heart rate variability in severe right or left heart failure: the role of pulmonary hypertension and resistances.Eur J Heart Fail 2004; 6: 181-5.
Pagani M, Malfatto G, Pierini S, et al. Spectral analysis of heart rate variability in the assessment of autonomic diabetic neuropathy. J Auton Nerv Syst 1988; 23: 143-53.
Torre-Amione G, Young JB, Colucci WS, et al. Hemodynamic and clinical effects of tezosentan, an intravenous dual endothelin receptor antagonist, in patients hospitalized for acute decompensated heart failure.J Am Coll Cardiol 2003; 42: 140-7.
Klinger JR, Warburton RR, Pietras LA, Smithies O, Swift R, Hill NS. Genetic disruption of atrial natriuretic peptide causes pulmonary hypertension in normoxic and hypoxic mice.Am J Physiol 1999; 276: L86874.
Nagaya N, Nishikimi T, Okano Y, et al. Plasma brain natriuretic peptide levels increase in proportion to the extent of right ventricular dysfunction in pulmonary hypertension.J Am Coll Cardiol 1998; 31: 202-8.
Berman S, Byrns PJ, Bondy J, Smith PJ, Lezotte D. Otitis media-related antibiotic prescribing patterns, outcomes, and expenditures in a pediatric medicaid population.Pediatrics 1997; 100: 585-92.
本発明のエンドセリン受容体拮抗薬は、厚生労働省薬事食品衛生審議会より肺高血圧症治療薬として承認を受けることが可能であり、この用途特殊の認証後は、臨床試験の第2相及び第4相試験を開始し、更には最終的に肺高血圧症に対する処方適応を獲得するが容易である。そしてこの後は、前記優れた効果を呈することからこの種医療産業に有効に活用され大きく貢献することができると確信するものである。 The endothelin receptor antagonist of the present invention can be approved as a pulmonary hypertension treatment by the Ministry of Health, Labor and Welfare's Pharmaceutical Affairs Food Sanitation Council. It is easy to start a phase study and finally to obtain a prescription indication for pulmonary hypertension. And after this, since it exhibits the above-mentioned excellent effect, it is convinced that it can be effectively utilized and greatly contributed to this kind of medical industry.
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