pegaptanib

ペガプタニブ

WordNet

1. the writing point of a pen (同)pen nib

PrepTutorEJDIC

1. ペン先 / (一般的に)とがった部分,先端(tip) / (鳥の)くちばし

Wikipedia preview

出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2015/06/09 22:26:40」(JST)

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[Wiki en表示]

Pegaptanib sodium

Systematic (IUPAC) name
RNA, ((2'-deoxy-2'-fluoro)C-Gm-Gm-A-A-(2'-deoxy-2'-fluoro)U-(2'-deoxy-2'-fluoro)C-Am-Gm-(2'-deoxy-2'-fluoro)U-Gm-Am-Am-(2'-deoxy-2'-fluoro)U-Gm-(2'-deoxy-2'-fluoro)C-(2'-deoxy-2'-fluoro)U-(2'-deoxy-2'fluoro)U-Am-(2'-deoxy-2'-fluoro)U-Am-(2'-deoxy-2'-fluoro)C-Am-(2'-deoxy-2'-fluoro)U-(2'deoxy-2'-fluoro)C-(2'-deoxy-2'-fluoro)C-Gm-(3'→3')-dT), 5'-ester with α,α'-[4,12-dioxo-6[[[5-(phosphoonoxy)pentyl]amino]carbonyl]-3,13-dioxa-5,11-diaza-1,15-pentadecanediyl]bis[ω-methoxypoly(oxy-1,2-ethanediyl)], sodium salt
Clinical data
Trade names	Macugen
AHFS/Drugs.com	monograph
MedlinePlus	a607057
Pregnancy category	US: B (No risk in non-human studies)
Legal status	US: ℞-only
Routes of administration	Intravitreal injection
Pharmacokinetic data
Half-life	10 days
Identifiers
CAS Registry Number	222716-86-1 Y
ATC code	S01LA03
DrugBank	DB04895 Y
UNII	2H1PA8H1EN Y
Chemical data
Formula	C294H342F13N107Na28O188P28[C2H4O]2n (n≈900)
Molecular mass	~50 kDa
Y (what is this?)  (verify)

Pegaptanib sodium injection (brand name Macugen) is an anti-angiogenic medicine for the treatment of neovascular (wet) age-related macular degeneration (AMD). It was discovered by NeXstar Pharmaceuticals and licensed in 2000 to EyeTech Pharmaceuticals, now OSI Pharmaceuticals, for late stage development and marketing in the United States. Outside the US pegaptanib is marketed by Pfizer. Approval was granted by the U.S. Food and Drug Administration (FDA) in December 2004.

Mechanism of action

Pegaptanib is a pegylated anti-vascular endothelial growth factor (VEGF) aptamer, a single strand of nucleic acid that binds with specificity to a particular target. Pegaptanib specifically binds to the 165 isoform of VEGF, a protein that plays a critical role in angiogenesis (the formation of new blood vessels) and increased permeability (leakage from blood vessels), two of the primary pathological processes responsible for the vision loss associated with neovascular AMD.

Pegaptanib works as an antagonist to VEGF, which when injected into the eye blocks the actions of VEGF. This then reduces the growth of the blood vessels located within the eye and works to control the leakage and swelling.

Means of administration

Pegaptanib is administered in a 0.3 mg dose once every six weeks by intravitreal injection. An intravitreal injection is one that is administered directly into the eye, more specifically, into the vitreous humour, or the jelly-like fluid within the eye. Pegaptanib has to be administered to the designated patient by an ophthalmologist in a sterile environment. Pegaptanib is marketed as a pre-filled syringe; however the syringe contains more than the recommended dose. Therefore, the eye care professionals must adjust the dose to the recommended amount before injections.

Preclinical trials

Pegaptanib underwent several preclinical studies in order to determine its safety and efficacy before moving into clinical trials.

Animal toxicology studies

Toxicology studies were conducted in rhesus monkeys, guinea pigs, rats, mice, and rabbits. After the administration of the aptamer into rhesus monkeys, no toxic effects where exhibited. It was also noted that there was no change in intraocular pressure and no immune response was taken against the API. Aside from the intravitreal administration of the pegaptanib, it was also found that subcutaneous and intravenous routes of administration were also effective at maintaining the desired blood plasma concentration. In rats, pegaptanib was successful at blocking VEGF-mediated vascular leakage almost entirely. The sustained release of the drug was tested in rabbits. It was found that using poly(lactic-co-glycolic) acid (PLGA) microspheres, which encapsulated the drug, the minimum dosing frequency was 6 weeks to maintain the desired pharmacological effect. This dosing interval is what carried over into the clinical trials and is still maintained today.

Clinical studies

Phase I

Phase I studies began in 1998 under Eyetech Pharmaceuticals. This study was conducted in 15 patients with wet AMD. Doses ranging from 0.25 to 30 mg per eye were injected into the eye, and patients were monitored for a period of three months. The results showed that 80% of the patients had stabilization or improvement, and 26.7% were showing improvement with no signs of toxicity.

Phase II

After the success of the Phase I study, Eyetech completed a Phase II study focusing on multiple injections. In this study, 21 patients with subfoveal choroidal neovascularization (CNV) secondary to AMD were given multiple intravitreal injections. Due to the presence of subfoveal CNV some patients were given a secondary treatment, photodynamic therapy (PDT) for this condition. Results showed that in 87.5% of patients who received only pegaptanib, vision stabilized or improved. In patients who received PDT alone only 50.5% saw a slight improvement. However, when the two therapies were administered together, the level of improvement reached 60% or better.

Phase III

After the success of the Phase I and Phase II trials, the FDA granted fast track designation for the Phase III clinical trials. In these trials, pegaptanib was studied in two identical controlled, double-blind randomized clinical studies that lasted for approximately two years each. For this study approximately 1200 patients with neovascular ("wet") age-related macular degeneration were randomly put into groups to receive either a placebo treatment or the designated 0.3 mg, 1 mg, or 3 mg of pegaptanib administered intravitreal injections every 6 weeks. Of the 1200 patients enrolled in the study approximately 892 received the varying doses of pegaptanib and approximately 298 received the placebo injection. At the end of the first year, patients continuing the study were re-randomized for the second year.

The primary efficacy endpoint for the study was denoted by the proportion of the patients who lost less than 15 letters of visual acuity from their assessed baseline over the 54 week assessment.

Results of the first year showcased promising results for pegaptanib. In groups treated with the 0.3 mg dose at the primary efficacy endpoint, experienced a statistically significant result.

• Study 1: 73% pegaptanib vs. 60% placebo
• Study 2: 67% pegaptanib vs. 53% placebo

Also, on average, pegaptanib 0.3 mg treated patients as well as the placebo patients continued to experience vision loss. However, the rate of vision decline was significantly lower than that of patients with the placebo treatment.

Moreover, it was also determined that the second year of treatment was less effective than the first year. Results of the primary efficacy endpoint are:

• Study 1: 57% pegaptanib vs. 56% placebo
• Study 2: 61% pegaptanib vs. 34% placebo

Regulatory information

Pegaptanib (pegaptanib sodium injection) has been approved in:

• United States (2004)
• Europe (2005)
• Canada (2006)
• Brazil (2005)
• Australia (Filled in 2006)

Side effects

Common side effects of pegaptanib include:

• Anterior chamber inflammation
• Raised intraocular pressure
• Punctate keratitis (small marks on the surface of the eye)
• Vitreous floaters (small particles or spots in the vision)
• Retinal damage (extremely adverse)
• Endophthalmitis (an infection inside the eye)
• Vitreous haemorrhage (bleeding inside of the eye)

Commercialization

The average cost of pegaptanib was approximately $5,300 per 5 syringes in the US. In 2004, when pegaptanib was approved it was a novel drug in its target and treatment for the treatment of AMD. However, the last large market sales occurred in 2010. Shortly after in 2011, sales began to decline due to the development of a more effective treatment, ranibizumab (a monoclonal antibody, Novartis) being developed and sold.

References

UpToDate Contents

全文を閲覧するには購読必要です。 To read the full text you will need to subscribe.

• 1. 加齢黄斑変性：治療および予防 age related macular degeneration treatment and prevention
• 2. 糖尿病性網膜症：予防および治療 diabetic retinopathy prevention and treatment
• 3. 内皮：プライマー the endothelium a primer
• 4. 網膜静脈閉塞：治療 retinal vein occlusion treatment

English Journal

• INCIDENCE OF PRESUMED ENDOPHTHALMITIS AFTER INTRAVITREAL INJECTION PERFORMED IN THE OPERATING ROOM: A Retrospective Multicenter Study.

• Casparis H, Wolfensberger TJ, Becker M, Eich G, Graf N, Ambresin A, Mantel I, Michels S.Source*Jules Gonin Eye Hospital, Lausanne, Switzerland; Departments of †Ophthalmology, and ‡Infectiology, Triemli Hospital Zurich, Zurich, Switzerland; and §Graf Biostatistics, Winterthur, Switzerland.
• Retina (Philadelphia, Pa.).Retina.2013 Aug 13. [Epub ahead of print]
• PURPOSE:: To evaluate the incidence of presumed endophthalmitis (EO) after intravitreal injection (IVI) of anti-vascular endothelial growth factor agents performed in the operating room.METHODS:: Retrospective study at 2 Swiss eye hospitals between 2004 and 2012. Hospital records were used to identi
• PMID 23945639

• Effect of VEGF and anti-VEGF compounds on retinal pigment epithelium permeability: an in vitro study.

• Campa C.SourceSt Paul's Eye Unit, Royal Liverpool University Hospital, Liverpool - United Kingdom.
• European journal of ophthalmology.Eur J Ophthalmol.2013 Aug 1;23(5):690-6. doi: 10.5301/ejo.5000248. Epub 2013 Mar 28.
• Objective: To evaluate the effect of 2 vascular endothelial growth factor (VEGF) isoforms (121 and 165) and 2 anti-VEGF compounds (ranibizumab and pegaptanib sodium) on the permeability of human retinal pigment epithelium (RPE) cells in vitro.
Methods: The RPE permeability was assessed on ARPE19 c
• PMID 23539459

• Minimizing the endophthalmitis rate following intravitreal injections using 0.25 % povidone-iodine irrigation and surgical mask.

• Shimada H, Hattori T, Mori R, Nakashizuka H, Fujita K, Yuzawa M.SourceDepartment of Ophthalmology, School of Medicine, Surugadai Hospital of Nihon University, 1-8-13 Surugadai, Kanda, Chiyodaku, Tokyo, 101-8309, Japan, sshimada@olive.ocn.ne.jp.
• Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv für klinische und experimentelle Ophthalmologie.Graefes Arch Clin Exp Ophthalmol.2013 Aug;251(8):1885-90. doi: 10.1007/s00417-013-2274-y. Epub 2013 Feb 7.
• BACKGROUND: To examine the efficacy of complying with an infection control manual for intravitreal injection of anti-vascular endothelial growth factor (VEGF) preparations in reducing the rate of endophthalmitis.METHODS: We retrospectively reviewed intravitreal anti-VEGF injections conducted by vitr
• PMID 23389553

Japanese Journal

• マクジェンの使用方法 (特集 Up to date 加齢黄斑変性)

• 白神 千恵子
• Oculista = オクリスタ (18), 38-43, 2014-09
• NAID 40020235855

• 臨床研究 糖尿病黄斑浮腫患者を対象としたペガプタニブナトリウムの国内第Ⅲ相臨床試験

• 石橋 達朗,湯澤 美都子,吉村 長久 [他]
• 日本眼科学会雑誌 118(9), 773-782, 2014-09
• NAID 40020205826

• ペガプタニブとベバシズマブの特性と使い方 (特集 抗VEGF薬をどう使う?)

• 本田 美樹
• 臨床眼科 67(12), 1840-1848, 2013-11
• NAID 40019831521

Related Links

• ペガプタニブナトリウム【pegaptanib sodium】の意味 ...- goo辞書

ペガプタニブナトリウム【pegaptanib sodium】とは。意味や解説、類語。加齢黄斑変性症の治療に用いられる分子標的薬。商品名マクジェン。硝子体に注入し、脈絡膜で新生血管の発生・発育を促進する血管内皮増殖因子（VEGF）の働きを ...

• Pegaptanib, a targeted anti-VEGF aptamer for ocular vascular ...

A higher-affinity aptamer becomes pegaptanib. As a strategy for generating anti-VEGF aptamers with still higher affinities, Ruckman et al. 14 used 2'-F-pyrimidine-substituted RNA libraries during the SELEX process ...

Related Pictures

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★リンクテーブル★

リンク元	「加齢黄斑変性」「nib」「ペガプタニブ」

「加齢黄斑変性」

　　[★]

英

age-related macular degeneration, age related macular degeneration, ARMD, AMD

同

老人性黄斑変性 老人性黄斑変性症 senile macular degeneration、老人性円板状黄斑変性 senile disciform macular degeneration、加齢黄斑変性、加齢黄斑変性症、加齢黄斑症、加齢性黄斑症、加齢性黄斑変性症

関

黄斑、黄斑変性症。黄斑疾患

[show details]

加齢黄斑変性 : 約 49,500 件
加齢黄斑変性症 : 約 20,000 件
加齢黄斑症 : 約 36,600 件
加齢性黄斑症 : 74 件
加齢性黄斑変性症 : 約 25,700 件

加齢黄斑症 : 約 194,000 件
加齢性黄斑症 : 95 件
加齢黄斑変性症 : 約 197,000 件
加齢性黄斑変性症 : 約 225,000 件

概念

• 加齢に伴って生じる黄斑変性
• 主として網膜色素上皮細胞、ブルッフ膜、脈絡膜毛細血管板の加齢変化に関係した黄斑変性の総称

疫学

• 60歳以上の片眼に発生し、70歳までに両眼性となり失明(SOP.147)。
• 欧米で頻度が高く失明の原因の第一位(3)。日本でも増加傾向(3)。
• 放置すれば約90%の症例で視力が0.1以下となる (3)
• (日本)有病率：0.87%。(欧米の半分) (3)
• (日本)5年間の発症率：0.8%(欧米と同程度) (3)

病型

• 1. 萎縮型(dry type)　　　：血管新生なし。網膜色素上皮細胞や脈絡膜毛細血管板の萎縮のみ。
• 2. 滲出型(exudative type)：血管新生あり　→　これは脈絡膜に由来する　←　こちらの方が治療の対象となる(3)。

2. = 老人性円板状黄斑変性症

病因

• 加齢。脈絡膜新生血管が発生する機序は不明

• 1. 加齢に伴う網膜色素上皮やブルッフ膜の脆弱化、黄斑部の炎症、酸化ストレス　？
• 2. VEGFの発現亢進

病態

2. 滲出型

• 黄斑部の加齢変性に基づいて脈絡膜新生血管, choroidal neovascularization, CNVが発生し、色素上皮状あるいは色素上皮下に伸びて出血・滲出を生じる。

[show details]

• 新生血管から出血や滲出(網膜。もちろん黄斑にも)　→　瘢痕化　→　視力の著明な低下や中心暗点

• 新生血管から出血・滲出の繰り返視し　→　網膜下血腫、硬性白斑、漿液性網膜剥離、網膜色素上皮剥離　→　線維性瘢痕 (3)

[show details]

病理

• 前駆病変：黄斑部に軟性ドルーゼン、網膜色素上皮異常
• 網膜下に血管新生(血管線維性増殖組織。つまり脈絡膜新生血管網)

脈絡膜新生血管分類

• 脈絡膜神経血管と網膜色素上皮との位置関係で分類
• 1型：網膜色素上皮下
• 2型：網膜色素上皮の上に達したもの

症状

• 変視症、視力低下、中心暗点

検査

フルオレセイン蛍光眼底造影

• 神経血管からの蛍光漏出を見る(3)。

インドシアニングリーン蛍光眼底造影

• 本方法は一般的に色素上皮下の新生血管を検出する際に用いられる(3)。

• 特殊病型のポリープ状脈絡膜血管症と網膜血管腫状増殖の確定診断に有用(3)。

光干渉断層計

• 新生血管の有無、網膜剥離、上皮剥離の有無を観察 (3)

治療

萎縮型加齢黄斑変性

参考4

有効な治療が確立していない。

• 生活指導：

• 禁煙：喫煙は病態の増悪因子

• 薬物療法：

• ビタミンA,C,E、およびZnのサプリメント (中等度から重症の患者には病態の進行リスクを下げる作用が見られた)

• 手術療法：(ドルーゼンを有する高リスク群を対象とした)レーザー治療。有効性については相反する研究結果が出ておりやらない方がよい。

滲出型加齢黄斑変性

• 1. レーザー光凝固療法　

• 脈絡膜新生血管が中心窩から離れている場合に利用できる。新生血管全体にレーザー光凝固を行いこれを破壊する。(3)

→　黄斑部は組織を損傷するので照射できない

• 2. (欧米)光感受性物質 + レーザー　→　光線力学療法

• 日本における光線力学的療法の治療成績は、欧米のそれより良好(3)
• 脈絡膜には光感受性物質であるベルテポルフィンが集積しやすい(3)。この物質を静注後、病変に弱いレーザー光を照射することで新生血管を閉塞する(3)。網膜に障害を来すことなく中心窩のCNVを破壊できる(3)。2004年より認可

• 3. 抗血管新生薬

• 脈絡膜新生血管の発生にVEGFが重要な役割を果たしている(3)。抗血管新生薬によりCNVを押さえようとする治療が臨床応用されてきている。例えば抗VEGF薬がある
• 抗VEGF薬：VEGFは血管新生を促進するサイトカインで、増殖糖尿病網膜症や加齢黄斑変性の眼内新生血管の発生にも関与(3)。bevacizumabの硝子体内治療が前述の眼内血管新生性疾患の治療に応用されつつある(3)。日本では保険未収載(2010年現在)。加齢黄斑変性を対象としたpegaptanibやranibizumabがある(3)。

予後

• 萎縮型加齢黄斑変性の患者は5年間で7%が滲出性加齢黄斑変性に移行する (参考4)

参考

• 1. 加齢黄斑変性症に対する光線力学的療法のガイドライン

http://www.nichigan.or.jp/member/guideline/karei.pdf

• 2. 加齢黄斑変性に対するPDT

http://www2.wind.ne.jp/tanakaganka/pdt.htm

• (3) 現代の眼科学 第10版第1刷 金原出版株式会社 ISBN 9784307351355
• 4. [charged] Age-related macular degeneration: Treatment and prevention - uptodate [1]
• 5. 難病情報センター | 加齢黄斑変性 - 難病情報センター

http://www.nanbyou.or.jp/entry/228

臨床関連

• 黄斑下の脈絡膜新生血管は、網膜色素線条症、強度近視、眼ヒストプラスマ症、外相殿脈絡膜破裂などに続発(SOP.149)

国試

• 105D036、103I079

「nib」

　　[★]

• 受容体のリガンド結合部を標的とした小分子化合物。

nib

• アキシチニブ axitinib
• ボスチニブ bosutinib
• ブリバニブ brivanib
• カネルチニブ canertinib
• セジラニブ cediranib
• ダサチニブ dasatinib　チロシンキナーゼ阻害薬　イマチニブ抵抗性の慢性骨髄性白血病、再発又は難治性のフィラデルフィア染色体陽性急性リンパ性白血病
• エルロチニブ erlotinib
• ゲフィチニブ gefitinib
• イマチニブ imatinib　チロシンキナーゼ阻害薬　CML、CKIT(CD117)陽性消化管間質腫瘍、
• ラパチニブ lapatinib
• レスタウルチニブ lestaurtinib
• リニファニブ linifanib
• ロナファーニブ lonafarnib
• ネラチニブ neratinib
• ニブリン nibrin
• ニロチニブ nilotinib　チロシンキナーゼ阻害薬　イマチニブ抵抗性の慢性期又は移行期の慢性骨髄性白血病
• パゾパニブ pazopanib
• ペガプタニブ pegaptanib
• ラニビズマブ ranibizumab
• セマキシニブ semaxinib
• ソラフェニブ sorafenib
• スニチニブ sunitinib　VEGFRやPDGFRチロシンキナーゼ阻害薬　イマチニブ抵抗性の消化管間質腫瘍、根治切除不能又は転移性の腎細胞癌
• ティピファニブ tipifarnib
• バンデタニブ vandetanib
• バタラニブ vatalanib

　 　

「ペガプタニブ」

　　[★]

英

pegaptanib

化

ペガプタニブナトリウム pegaptanib sodium

商

マクジェン

関

眼科用剤