治療結核病將有作用不一樣的新藥 bedaquiline

FDA Panel Endorses Novel Tuberculosis Drug

Miriam E. Tucker

Nov 29, 2012

SILVER SPRING, Maryland — A federal advisory panel voted unanimously yesterday 18 to 0 for efficacy but split 11 to 7 on safety in support of accelerated approval of a novel drug to combat multidrug-resistant tuberculosis (MDR-TB).

The US Food and Drug Administration's (FDA's) Anti-Infective Drugs Advisory Committee agreed with Janssen Therapeutics, a division of Janssen Products, LP, that the manufacturer's drug bedaquiline could be approved on the basis of phase 2 data using the surrogate study endpoint of sputum culture conversion rather than clinical cure because of the unmet treatment need.

Bedaquiline works via a novel mechanism of action: inhibition of a mycobacterial enzyme that is essential to the bacteria's action. The proposed drug indication is a part of combination therapy for the treatment of pulmonary TB caused by MDR Mycobacterium tuberculosis in adults, to be administered under directly observed therapy.

If approved by the FDA, bedaquiline would be the first new TB drug since the introduction of rifampin in 1970.

Although the TB rate has dropped significantly in the United States during the last few decades, the proportion of cases caused by MDR strains has increased worldwide. Most US cases of MDR-TB happen in foreign-born individuals, said Kenneth G. Castro, MD, director of the Division of Tuberculosis Elimination at the Centers for Disease Control and Prevention, Atlanta, Georgia.

Current multidrug regimens are long and difficult, and only 54% of patients with MDR-TB worldwide are successfully treated, said Andreas Diacon, MD, PhD, from Janssen.

According to Dr. Castro, "US recovery from the devastating impact of MDR-TB must be sustained. The global situation constitutes a health threat. Achieving TB elimination in the US and marked improvements globally will require new tools and novel approaches."

Phase 2 Data

Janssen's new drug application for bedaquiline was based on efficacy and safety data from 2 phase 2 trials, with 1 of the trials consisting of 2 distinct stages. As a condition of submission under accelerated approval, the company is obligated to conduct a confirmatory phase 3 trial.

The 2 studies involved a total of 441 patients with MDR-TB, defined as TB resistant to at least rifampin and isoniazid. In the first trial, 47 newly diagnosed South African patients in stage 1 and 161 newly diagnosed patients from 7 countries in stage 2 were randomly assigned in a 1:1 ratio to receive bedaquiline or placebo for 8 weeks and 24 weeks, respectively, along with a background regimen of other anti-TB drugs. They were followed up for 104 and 120 weeks, respectively.

The other study was an open-label multicenter evaluation of 233 non–newly diagnosed patients, with a 2-year follow-up.

In all 3 evaluations, the primary endpoint was time to sputum culture conversion, defined as 2 consecutive negative cultures with negative intermediate cultures.

Results showed that bedaquiline resulted in 33% faster culture conversion within 24 weeks, with a P value of less than .001. At 24 weeks, 78.8% had converted with bedaquiline vs 57.6% with placebo ( P = .008). In the open-label trial, 79.5% of patients had culture conversion at week 24, according to Brian Danneman, MD, from Janssen.

Reviewers from the FDA generally agreed with the company's efficacy analysis.

Safety Concerns

Significant safety concerns reported by both Janssen and the FDA included signals for increased risks for QT interval prolongation, hepatotoxicity, and a greater number of deaths in the bedaquiline group compared with in the placebo group.

In stage 2 of the randomized trial, more patients in the bedaquiline group had corrected QT values of 450 to 480 ms (26.6% vs 8.6%), and more patients receiving bedaquiline developed a more than 60-ms increase from a reference values group (9.1% vs 2.5%).

Hepatobiliary disorders and elevated transaminases occurred in 7 patients receiving bedaquiline vs 1 patient receiving placebo in that study (8.9% vs 1.2%).

Also in the second stage of the randomized study, 10 (12.7%) deaths occurred with bedaquiline vs 2 (2.5%) deaths in the placebo group. In the open-label study, there were 16 (6.9%) deaths, with 12 occurring during the trial. Half of the deaths were related to TB itself, and the others did not appear to be related to the drug, but the difference was statistically significant.

Proposed labeling would include recommendations for EKG monitoring and precautions regarding use of the drug in patients with prolonged QTc intervals and those receiving other drugs that also prolong the interval, as well as monitoring for other safety concerns.

Committee Support

In voting unanimously for efficacy, all of the committee members expressed support for the need of a new drug to treat MDR-TB, although several said that the confirmatory phase 3 trial would need to use hard clinical endpoints rather than sputum conversion.

"This is a great drug, it appears, based on the data presented to date...but we need additional data," said committee chair Thomas A. Moore, MD, clinical professor in the Department of Medicine, University of Kansas School of Medicine in Wichita.

However, the safety signals worried some panel members. "I'm concerned about the mortality. Ten out of 79 is quite a high number," said Fred Gordin, MD, chief of infectious diseases at the Veterans Affairs Medical Center, Washington, DC.

Dr. Gordin, who voted no on the safety question, noted that the long half-life of the drug — about 5 months — is also worrisome because the potential for long-term organ damage is not known.

"I personally would still favor approval, with the caveat that we need much more safety data.... There's clearly a role for this drug, but in many patients who have other options, I think it has to be very clear to providers that there are long-term safety issues," Dr. Gordin said.

Janssen's phase 3 trial is planned for 2013. It is designed as a double-blind study comparing 9 months of treatment with bedaquiline with treatment with placebo, both with a background regimen.

Participants in FDA advisory committee meetings are vetted for conflicts of interest and waivers may be granted if necessary. No waivers were granted for this meeting.

Medscape Medical News © 2012 WebMD, LLC

"微生物學史" 介紹

"微生物學史" 介紹

分類：未分類資料夾

2012/10/12 21:01

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筆者編著的《微生物學史—開天闢地的醫學拓荒者》經過漫長的編修過程，即將在今年十月底由合記圖書出版社出版發行 [抱歉!將再度延後到十一月底才能出書，唉!!]。以下兩篇文章：序文和後記，是出版前宣傳的一部分！在網路資訊爆炸的時代，出書、宣傳不容易，但如果書的內容完整豐富，能夠提供讀者有趣的資訊，又有詳細的索引可供快速查詢，相信這樣的「好書」還是有「網路搜尋」遠遠比不上的好處。

[將可以上網訂購: www.hochi.com.tw， 編號 216238-005C，19 x 26 cm 如 Time magazine 大小，360頁。 訂價六百元，目前可打九折]

*******

人生要活的快樂，也必須充實智慧。

要快樂，需要樂觀；

要智慧，最好先了解歷史。

微生物感染自古就是對健康最大的威脅，致使人類傷亡最主要的原因。人的知識如何從迷信，發展到認識細胞、細菌、病毒、疫苗、滅菌、抗生素、診斷、到醫療？ 這一本 「微生物學史」，為讀者彙集了超過兩百五十名從古希臘時代開始，對醫學發展有貢獻的人物傳記。有別於以往的醫學史，它附加了很多歷史故事，呈現微生物學的演變經過。以下是這本書的「序文」及「後記」。

序文

在醫學史上十大發現中，有三項和微生物感染直接有關： 微生物的發現、種牛痘的發展、盤尼西林(penicillin)的認識及大量生產。由此可看出，傳染病、感染症是人類史上最重要的疾病，也是到近代 (modern era)為止「醫學史」的骨幹。

 

近來仔細從網路搜尋引擎查閱這些大發現的關鍵人物傳記，發覺如果將歷史上對這門學問有貢獻的人物生活史收編，將會比看教科書上以「事」為主體所描寫的發展史，更有趣；而且將傳記中的「人」、「事」、「地」都予以查詢簡介，可以窺見歐洲歷史文化發展的一端，以後對歐洲的訊息可能會有更深層的感受。再者，最近十多年來快速研發的「網路搜尋」、「數位相片」，使我們可以坐在家裡，就查得出大多數所需的資料、圖片。因此決定從網路資料撰寫「微生物學史--開天闢地的醫學拓荒者」，和大家分享。

 

這本拓荒者傳記集的讀者群，將是以中文為主要語言者，並具有基本英文常識，對醫學、衛生、生理、健康及歷史有興趣的人士。筆者徵詢身邊親友、學生，平時就喜歡閱讀的人，覺得這本書收錄很多有趣的歷史故事，即使未必全瞭解、吸收，仍可學到不少醫學和非醫學的常識。

 

英文是科學、醫學的共通語言。用英文能查詢到更完整的資料，讀者也能再做各方的查證。因此本書人名、地名、醫學專有名詞等還是用英文書寫(除非已經成為日常用語的名詞，例如巴黎、羅馬、倫敦、紐約、雅典、納粹、拿破崙、維也納，等等)。作者也希望學生讀者習慣使用英文，因此很多句子，都附有英文。

 

其次，這裡所謂的微生物學將包含廣泛的對抗微生物感染的學問，如免疫學、感染控制、檢查微生物所需技術、抗微生物藥劑等等。除了用主要有貢獻人物的傳記來傳達歷史的演變，還有不少微生物學、免疫學名詞的簡單介紹、當時對科學發展有主要影響的人物，更納入很多題外話：當時和傳記主角有些關聯的人、事、地的介紹、還有筆者的小意見(括弧內以「按:」表示)。目的是一方面要瞭解當時的歷史背景，一方面是要使內容免得落於枯燥而使讀者失去興趣。這本書不像一般的傳統教科書，但是希望讀者仍能從其中吸取細菌學、免疫學、病毒學等的基本概念演變過程。

 

這本傳記集的寫法是：對微生物學感染症學有重大影響的歷史人物，先分類為七個章節 (一、確立致病原因的過程；二、其他細菌的發現；三、免疫學及疫苗的發展；四、感染控制及抗菌技術；五、微生物相關技術的發展；六、抗微生物藥劑的發展；七、病毒學的發展)，各章內的人物大約依照其生年排列，把從網路搜尋所得第一、二頁中，內容比較詳細的數篇傳記做為主要參考資料(例如：Wikipedia、Biography、Nobel Lectures等)，予以摘譯、編排、整理而成。有時會採用更多其他記載趣事的文章做為參考。基本上是一種搜尋、翻譯、編輯(search, translation and redaction) 的作業。書中介紹的學者總共超過兩百五十名，醫學名詞或是歷史故事也有六十餘件。

 

越是有名的人物，傳記越多，就得花更多時間瞭解、比較。可是廣泛的題目只能深入到某一地步，有些重要學者也只能短短地介紹。各種版本的傳記，都有其極限，最重要的原則是要有足夠有用有趣的資訊，更不能和原來的歷史、文意有偏差。什麼是有趣的資訊？對人物的生長背景，以及對「發現」、「研究」過程的描寫，不僅「有趣」，還可能刺激或鼓勵讀者的進取心、好奇心，應該都是有趣有用的資訊。讓讀者吸取古人的做事精神、增強求知慾、穩固自信心，或讓讀者對醫學微生物學產生興趣，是這本書的最高目的。有很多「人」、「事」、「物」的簡介不一定和微生物、傳染病、感染症相關，而且還可能比主要傳記人物的介紹更詳細，或同樣地有趣。(例如，討論阿拉伯學者Avicenna，也順便簡單介紹阿拉伯名字的寫法；Koch去過的VelikiBrijun Island觀光地的歷史；哥倫布的西航；第五章技術的發展，就提到玻璃及影像醫學；美國軍醫Walter Reed駐軍西部就提到Geronimo、Panama Canal；其他還有英國內戰、Spanish-American War、愛滋病出現的經過等等)。

內文提到的某些疾病，例如狂犬病、結核病、痲瘋、愛滋病等，會予以相當詳細的介紹，以便醫學生不必再查閱其他書本就可以學習。(這些資料採自筆者「傳染病防治手冊」第二版，再加入新的知識)。

做為參考資料的英文傳記都應該是具有相當正確的內容 (日本學者的資料是由日文Wikipedia及其他日文網路文章取得)。Wikipedia都會簡介其參考文獻，但有時還是會有錯誤的報導，因此盡可能參考多篇文章比較；本書的內容可信度和這些網路上查到的文章應該相同(2005年科學雜誌Nature報導，Wikipedia內容的錯誤率幾乎是大英百科全書Encyclopedia Britanica的水準：

http://en.wikipedia.org/wiki/Reliability_of_Wikipedia）

過去寫學術論文，資料出處是一定要註明期刊的年份、卷號、頁碼。不過這本書內的人、事、地，等等，雖然花了很多時間深入搜尋，可是有些可能是大多數歐洲人的常識，每項都寫下出處網址，無意義。反過來說，最可靠的傳記寫法，是要作者成為專業的醫學歷史家，精通拉丁文、法文、德文、義大利文，到歐洲各國圖書館查閱相關最原始資料，這對我當然是不可能的事。我相信網路上Wikipedia, Biography, Nobel Lectures的內容不是來自野史，因此判斷不必要一一詳細簡介文獻出處。不過難以找到的資料、對學者的批評，還是會指出其來源。

 

 

英文索引比中文索引詳細 (因為人名地名都還是使用英文，只在各章的大綱，加以 「英文姓」 的中文譯音)，是這本書很重要的一部份，因此也詳細地製作。學者出生地名、進修大學名稱也都盡量納入索引中。如此，以後到歐洲某一地方學術訪遊，可以從這本書的索引，查出該地曾經有過甚麼名學者工作過。讀者如果能夠善用索引，可以查得到很多本書內容。人名要用中、英文的「姓」查詢；大學則可以查英文或中文，例如：「Giessen大學」、「倫敦大學」等等。

 

這本「微生物學史」的寫法和過去的歷史書不一樣：一、它利用史上多位有成就的學者傳記來呈現歷史的演變，如此，對「發現」的過程及其背景會有更深切的認識；二、它將微生物學和其他學問的學者，以及將醫學知識和非學術的歷史故事混合介紹，以便使內容比較柔和生動、也讓讀者對當時的時空背景有進一步的瞭解；偶爾又有筆者的意見，以便拉近讀者和作者間的距離；三、它的資料完全依靠新發展的網路科學；又利用同樣地有革命性進步的數位技術，用個人的相片增強對 「人」的印象。

 

作者期待醫學或非醫學背景的各類讀者會將這本 「微生物學史」，拿來輕鬆地玩賞，同時吸收醫學的歷史及知識。也希望讀者將它作為參考書，多多利用目錄及索引的查詢，各取所需。

 

讀者們如有任何意見，敬請不吝賜教。(可留言在筆者部落格中，對筆者這本歷史傳記集的呈現法及內容給予意見、評論)。

 

はじめに　

医学史上最も重要な十大発見の内、微生物感染と直接関連して居るのが三つ、すなわち微生物の発見、種痘の発見、ペニシリンの発見及び大量生産などがあり、因みに感染症が人類に対して最大の脅威であり、近代史（modern era）に至るまでの医学歴史の主幹で有ることは明らかであります。近頃、インターネット捜索で微生物学、感染症などに貢献の有る人物の伝記ォ読んでいる内に、もしこれらの伝記ぉォ年代順にまとめれば、従来「病気」、「ばい菌」、「物事」等ォテーマとして書く医学史に比べると、よりいっそう詳しく医学パイオニアたちの人物像、歴史の背景，医学発展の経過、さらにヨーロッパ文化の進展ォ違った角度で理解出来るのではないかと思いつきました。それで、ネット捜索で得られる資料で、この「微生物学史--致命的伝染病から人類オ救った医学の先駆者たち」オ書く事にいたしました。

当初は、この本ォ医学歴史に興味のある読者群ォ対象にして書きましたが、原稿ォ読んで頂いた親友達と問い合わしたところ、内容に興味深い史実や常識などがいろいろ紹介されているので、読書家であれば、結構楽しんで頂けるとの結論でした。

次に、この本で所謂「微生物学」は広義的に免疫学、感染制御、微生物の検査及び感染症の診断に使われる技術、抗生物質などォ含みます。これらの学問の発展に著しい貢献の有る学者たちの伝記ォ通じて、医学史ォ了解して頂くと同時に、医学名詞の解釈、その時代の社会、文化に重要な影響ォもたらした人物の紹介，出来事、及び筆者の随筆等ォ加えました。勿論この本ォより一層面白く読んで頂くのが筆者の望むところであります。二十世紀のほぼ中ほどまでの主な学者ォ紹介しました。なれど、それ以後については、微生物学に貢献のある人物ォ嚢括するのは、学問の分野が細かくなったと共に、学者の伝記が不完全なので、非常に難しく成りました。これ等の仕事は後ほどどなたかに託するしかなりません。　　　　　　　　

この本の書き方は、まず全体ォ七章に分け、毎章のテーマに関与する主な学者ォ時代順に整え,各人物にの伝記ォ英語、或るいは日本語のgoogleで捜索し、主な資料（例えば　Wikipedia, Nobel Lectures, Biography等）の中から、よく知られていない、興味深い事実ォ選び、翻訳し、取りまとめたので、基本的にはsearch, translation, redaction等の作業であります。およそ２５０名以上に渡る学者、及び六十数件の医学名詞や歴史の出来事ォ紹介いたしました。

人物は有名なほど伝記も沢山書かれるものであり、それで書く前に、随分時間ォかけてその人物について了解しなけらばなりません。しかし、一人一人の資料に費やせる時間や本のスペースにはやはり限度があり、この伝記集に取り寄せた学者達も,非常に有名な方でも、ただ簡単に紹介されることも致し方ないのであります。異なった書き方の史書にはそれぞれの目的と限界があります。一番大切な原則は、歴史と人物の伝記元来の意味ォ忠実に紹介し、読者の方々に興味深い正確な事実ォ理解していただくことです。

学者の生い立ち、研究のケッキになる逸話、発見の経過、及び発見の影響などに重点ォ置きました。読者の皆様がこの本ォ読んで、微生物学や時代の出来事ともっと親しんで頂けるのがこの本の目的であることは申すまでもありません。

この本に採用された伝記物語の元来の資料には、詳しく参考文献が書かれており、その正確度には疑う余地はほとんど無いものであります。２００５年の科学雑誌Natureに報告された調査によりますと、Wikipediaの内容正確度は、Encyclopedia
Britanicaとほぼ同じとの事でした（http://en.wikipedia.org/wiki/Reliability_of_Wikipedia）。しかし稀には間違いがあるのも免れないと思います．それ故、できるだけ多数の信憑性の有る文章ォ参考にいたしました。

科学論文では資料の出所、雑誌の名前,巻数、ページ等ォ細かく注釈しなければ成りません。けれども、この本では、沢山の時間ォ掛けて「出来事」、「物事」などォ捜索しましたが、それらの出所は書き留めませんでした。なぜならほとんど全部がgoogleの第一、第二ページに有り、そのうち、多数はヨーロッパ歴史の常識だと思われるので、いちいち注釈するのは意味なしと見て控えました。然し、学者に対する批判や、探しにくい資料の出所は記して置きました。

この本の最後にある索引は詳しく英語と日本語に分けて製作いたしました。この索引ォよく使われると、本の中にある出来事、物事等ォ簡単に捜しだすことができると思います。

この「微生物学史」はその実、伝記集であり、その他、当時つながりのある歴史の出来事ォ註釈として加えたのであります。読者の皆様に心安く、楽しく読んでいただけるよう、心から望みます。

許清曉 醫師謹識

Clement C. S. Hsu, MD, FACP, FIDSA

2011 / 05

 

 

 

後記

這本「微生物學史—開天闢地的醫學拓荒者」能夠完成，筆者得先感謝多位親友的鼎力相助。劉長安先生及其夫人吳淑芬女士、馬玉麟醫師以及舍弟許清陽等幾位的校讀修改及鼓勵；榮金煥先生、姪女劉徐翠琳、和吳宜臻律師很寶貴的援助；馬夫人陳美玲老師以她精通的電腦技術、出版電腦教科書的經驗，無數次不厭其煩地修改、編排、檢查圖檔來源、畫圖、註解；譯著十餘本教材的周振英醫師的強力推薦；最後又經過合記出版社編輯們的精心修繕及編排等等，筆者心中的感激難以言表。而內人玉麗不斷的鼓勵及支持則是筆者能維持高度熱忱，在一年內完成這本書的原動力。不過，雖然筆者盡力蒐尋，企圖將大部分歷史上偉大微生物學拓荒者傳記納入書中，相信還有很多重要學者被遺漏，是令筆者遺憾的事。

 

歷史很有趣，可以讓我們從中學習；歷史很重要，不會使我們重犯同樣的錯誤。幾乎所有科學拓荒者共通的特質就是，在研究過程中，他們熟悉作業細節、有敏銳的觀察力、有強烈的好奇心、能夠發覺小小不尋常現象，認出其重要性，又能設法堅持追究到底。我們不能再犯的錯誤，就是以非理性、非科學的方法判斷世界上各種事物。

 

回顧過去偉大學者生平，他們多數在其他研究工作上都有很可觀的成績。除了「智力」的遺傳之外，觀察力、創意、有信心、不怕被批評異常、敢於堅持己見等特質，可能也是每位天生的、或是小時就養成的「性格」。實際上，不僅要有這種「性格」，「際遇」更是使這種人成功的重要因素。「際遇」有某些部分是要靠自己的努力、以及好的EQ(emotional quotient)，不過有時確實是力不從心，天不時與。「智力」、「性格」及「際遇」我們多半難以掌控或改變，其餘的，我們還可以盡人事。

 

兩千年來的醫學，一旦開始以理性、科學的方法研究，就如同幾何級數般地快速發展，不知止境。筆者相信推動這種「創意」、「創新」的基本原動力，來自人類「生存競爭」過程中最原始的本能行為：每一個人的潛在意識中都要呈現「我在這世界上存在過」，更要呈現「我的存在」比他人的更顯著。人與人互相競爭是社會進步的最主要原動力，而有「我」與「他」(「自我」與「非自我」)的區別，更是地球上生物最神秘、尚不可解的現象。

 

地球上有數十億人口。每個人在一生過程中，隨著其能力及機運，在人世間的「能見度」有高有低，或大或小，或亮或暗。不過，我們不必羨慕別人，也不必誇大自己或過度謙虛自卑。有人觀察天體星球宇宙，有人研究細菌分子原子，有人調查歷史地理人文，有人關心社區老少人心，各有自己努力的小園地。有人能夠發揮最大的能量，我們應該出聲給予最大的讚賞、鼓勵、與祝福；有人影響力侷限在鄰近的人群環境，我們也不忽視它帶給這些人的愉悅及將來的可能發展。每一個人的活動都是推動人類福祉的一個小螺絲。

人生努力的結果就像是有半杯水，我們可以因為水沒有滿杯而耿耿於懷，也可以因為擁有半杯水而知足惜福。我們生在此世，就是要過一個快樂的、有用的、有意義的人生。什麼是有意義的人生?有一位美國倫理學家Michael Josephson寫了一首很熱門的詩：”Live a life that matters”，可以共享。原文相當長，所以擷取中文翻譯「有意義的人生」後半段於下，作為結束：

『人生中什麼事情是重要的？人的價值要如何衡量？

重要的不是購買什麼，而是建造什麼；

不是得到什麼，而是付出什麼。

重要的不是自己的成功，而是做了哪些對人有益的事。

重要的不是自己學到什麼，而是教導了別人什麼。

重要的是對每件事全力以赴、心懷悲憫、充滿勇氣、或奉獻犧牲，

讓他人因此更富裕、更有能力、或受到鼓舞。

重要的不是能力，而是優良的品格。

重要的不是認識多少人，而是離開後能讓多少人懷念。

重要的不是在浮世傳揚聲名，而是在愛您的人心中留下回憶。

重要的是讓世人記得多久，是什麼樣的作為使人感懷。

快樂的生活並非來自偶然，也非命中注定，而是自己一連串的選擇。

選擇有意義的人生吧！』

(全文完)

 

基因療法不久的未來將盛行

Genes as Medicine: Molecular Therapy Comes of Age

Ricki Lewis, PhD

Nov 13, 2012

SAN FRANCISCO — Gene therapy is edging closer to mainstream medicine.

The first trial of gene therapy, for adenosine deaminase (ADA) deficiency, was conducted in the United States in 1990. On November 2, 2012, the European Commission approved the first gene therapy (for the treatment of lipoprotein lipase deficiency).

In gene therapy, researchers use stem cells or viruses to deliver functional copies of genes to patients whose own copies of the gene are mutated and causing disease. Viral vectors include adeno-associated virus, gamma retrovirus, and lentivirus ("gutted" HIV). In nondividing cells, the virally delivered genes remain extrachromosomal; in dividing cells, they integrate into the host genome and replicate.

Here at the American Society of Human Genetics 62nd Annual Meeting, researchers presented the results of clinical trials in which gene therapy is being used to treat patients with hemophilia B, Leber's congenital amaurosis type 2, and primary immune deficiencies.

Hemophilia B

Katherine High, MD, professor of pediatrics at the Perelman School of Medicine in Philadelphia, Pennsylvania, explained that hemophilia B (factor IX deficiency) affects 1 in 5000 men. In affected patients, less than 1% have severe disease, 1% to 5% have moderate disease, and 5% have mild disease.

Hemophilia B is an ideal candidate for gene therapy because minor improvement has a clinical impact. "Even a modest increase in clotting factor, in the 1% to 5% range, greatly ameliorates symptoms and prevents life-threatening bleeds," Dr. High said.

Existing treatment with recombinant clotting factor requires repeated treatments and is so expensive that only 20% of the world's patients use it. Gene therapy could change that by providing a 1-time treatment. "The goal is to get away from the peaks and troughs of factor IX and to institute a steady level that would prevent bleeds, so that more people can have a normal quality of life," Dr. High said.

Gene therapy uses a subtype of adeno-associated virus, which targets hepatocytes, to intravenously deliver the factor IX gene. Several patients now produce enough factor IX to greatly reduce the need for clotting factor. "This transforms hemophilia B into a mild disease," Dr. High noted.

Leber's Congenital Amaurosis

The immune-privileged nature of the retina makes it an excellent target for gene therapy, according to Jean Bennett, PhD, MD, professor of ophthalmology at Children's Hospital of Philadelphia (CHOP). He explained that, so far, more than 230 patients with Leber's congenital amaurosis type 2 (LCA2) have received gene therapy in clinical trials.

In LCA2, lack of the functional RPE65 enzyme prevents the isomerization of 11- cis-retinal that enables rhodopsin in photoreceptors to signal the visual cortex. "Patients can see very bright lights and large objects, but their vision decreases as the photoreceptors degenerate," Dr. Bennett said.

In gene therapy for LCA2, an ophthalmologic surgeon subretinally injects the therapeutic gene near the region with the most damage. Researchers conducting a phase 1/2 trial at CHOP originally treated the worst eye of the patient; the second eye has since been treated in most patients.

Indicators of successful outcome include activity in the visual cortex on functional magnetic resonance imaging (MRI), standard ophthalmological tests, and patient observations.

After the procedure, functional MRI shows, strikingly, that "neurons in the visual cortex are still responsive after decades of severe impairment," Dr. Bennett said. Efficacy has persisted beyond 5 years. A phase 3 trial will begin in December, Dr. Bennett told Medscape Medical News.

Primary Immune Deficiencies

More than 200 mutant genes cause primary immune deficiencies. For the 90% of patients without a compatible bone marrow donor, gene therapy could be an option. By targeting autologous hematopoietic stem cells, researchers could, theoretically, treat any such disease.

Clinical trials of gene therapy are underway for severe combined immune deficiency (SCID)-X1, SCID-ADA, chronic granulomatous disease, and Wiskott–Aldrich syndrome. In all of the diseases, the altered cells appear to have a selective advantage over the pathogenic ones.

A group at the SanRaffaele Scientific Institute Telethon in Milan, Italy, has cured SCID-ADA and Wiskott–Aldrich syndrome with gene therapy, scientific director Maria-Grazia Roncarolo, MD, reported.

Like hemophilia B, a minor correction (10%) for SCID-ADA can have a significant clinical effect, but enzyme replacement is extremely expensive. After gene therapy for SCID-ADA, patients respond to vaccines and rarely contract infections, Dr. Roncarolo said.

Gene therapy for SCID-X1 has also been successful. The program had a rocky start when 5 boys developed leukemia because the gene vector was inserted into an oncogene. The researchers corrected the problem, and they have since treated 18 patients. "All are alive, with median follow-up 6 years, and 15 patients are completely out of any treatment," she said. Other groups have treated 22 other patients, all successfully. GlaxoSmithKline will sponsor a phase 3 trial.

Dr. Roncarolo reported promising results for 3 patients treated for Wiskott–Aldrich syndrome, which have yet to be published. "All 3 patients had severe recurrent infection and eczema and 2 had gastrointestinal bleeding. There was robust gene transfer, no autoantibodies, and improved immune function and platelet counts," she said.

Genes as Medicine

With the successes stacking up, all of the researchers anticipate that many other conditions will respond to gene therapy. "We are getting close to using genes as medicine," organizer Beverly Davidson, PhD, from the University of Iowa in Iowa City, concluded.

Dr. High reports being a consultant for Genzyme Corporation and Amsterdam Molecular Therapeutics. Dr. Bennett reports being a coauthor on a patent for retarding blindness but waived financial interest in 2002. The other researchers have disclosed no relevant financial relationships.

American Society of Human Genetics (ASHG) 62nd Annual Meeting: Session 23. Presented November 8, 2012.

 

Targeted Therapies on the Horizon for Squamous Lung Cancers

Maurie Markman, MD

Nov 20, 2012

Comprehensive Genomic Characterization of Squamous Cell Lung Cancers

Cancer Genome Atlas Research Network; Hammerman PS, Hayes DN, Wilkerson MD, et al

Nature. 2012;489:519-525

Summary

In an effort to develop a firmer understanding of the genomic landscape that characterizes the development and progression of squamous cell lung cancer, investigators conducted a detailed qualitative and quantitative assessment of 178 such tumors, assessing both the types of abnormalities observed and the total number and percentage of cases with particular findings. As anticipated, the large majority of these cancers came from individuals with a history of tobacco exposure (96%). The histologic diagnosis of the tumor type was confirmed by a panel of expert lung pathologists.

The analysis revealed that individual squamous cell lung cancers demonstrate a rather large number of mutations in their exons (mean, 360 per tumor) and copy number of various genetic segments (mean, 323 per tumor), as well as a substantial number of genetic rearrangements (mean, 165 per tumor). However, despite the complexity observed, the investigators found recurrent mutations in 11 specific genes, suggesting that these abnormalities may serve as valid targets and possible "driver mutations" for clinical interventions. Particularly noteworthy were abnormalities of genes known to be involved in squamous cell differentiation (44% of samples) and in the response to oxidative stress. Abnormalities that had previously been shown to be relevant targets in adenocarcinoma (eg, activating mutations in EGFR) were very rare (< 1%).

Overall, 96% of tumors were demonstrated to have a defect that, based on evidence from others settings, could possibly be "druggable," or capable of being affected by a systemically delivered antineoplastic agent.

Viewpoint

Rather spectacular advances in our understanding of unique molecular profiles in subgroups of patients with adenocarcinoma of the lung have led to management strategies targeted to these findings (eg, activating mutations of EGFR and ALK rearrangement). In fact, evidence supports obtaining such information in designing optimal initial treatment of advanced/metastatic adenocarcinoma of the lung. ^[1]

These specific mutations, however, are rarely, if ever, observed in squamous cell lung cancer, as confirmed in the current report. Furthermore, prior to the current report, there was very little evidence to even suggest that the development of molecularly targeted approaches was a viable therapeutic strategy in this tumor type. This landmark paper provides the first solid evidence that potentially "druggable" targets are observed in the large majority of squamous cell lung tumors and several relatively frequent groups of molecular abnormalities are seen in this setting. Future research in this arena will need to focus on targeting these mutations with existing antineoplastic agents, or on developing new classes of drugs that can interfere with potential "driver" mutations in these cancers.

Abstract

References

1. Keedy VL, Temin S, Somerfield MR, et al. American Society of Clinical Oncology provisional clinical opinion: epidermal growth factor receptor (EGFR) Mutation testing for patients with advanced non-small-cell lung cancer considering first-line EGFR tyrosine kinase inhibitor therapy. J Clin Oncol. 2011;29:2121-2127. Abstract

   
   

Medscape Genomic Medicine © 2012 WebMD, LLC

Group A 鏈球菌引起的咽喉炎，每天一次或兩次的抗生素，療效相同

Occurrence of Group A β-Hemolytic
Streptococcal Pharyngitis in the Four Months After Treatment of an Index
Episode With Amoxicillin Once-daily or Twice-daily or With Cephalexin

Carlos E.
Armengol, MD, J. Owen Hendley, MD

Nov 21, 2012

Pediatr Infect Dis J. 2012;31(11):1124-1127. © 2012
Lippincott Williams & Wilkins

Abstract and Introduction

Abstract

Background:
Prospective studies using bacterial eradication as the endpoint have
demonstrated that once-daily amoxicillin is as effective as twice-daily
amoxicillin for treatment of Group A [beta]-hemolytic streptococcal (GABHS)
pharyngitis.



Objective: The aim of this study was to determine, in a retrospective
study, whether treatment of symptomatic GABHS pharyngitis with once-daily
amoxicillin was as effective in preventing clinical recurrences as twice-daily
amoxicillin or cephalexin in pediatric office practice, using patient-initiated
return visits for streptococcal pharyngitis as a pragmatic, clinical endpoint.



Methods: The charts of consecutive patients 2 years of age and older
with laboratory-proven GABHS pharyngitis for a period of 2 years were reviewed
to identify index cases of streptococcal pharyngitis and subsequent episodes.
Age, weight, antibiotic treatment and time from index to subsequent episodes of
GABHS pharyngitis were recorded.



Results: In 1402 index episodes, patients received amoxicillin
once-daily (231), amoxicillin twice-daily (846) or cephalexin (325). The risk
of symptomatic streptococcal pharyngitis in the 4 months after treatment of the
index episode was not statistically different among the 3 treatment groups:
amoxicillin once-daily (15.1%), amoxicillin twice-daily (19.6%) and cephalexin
(19.1%). There was a trend toward reduction in the risk of recurrences in the 6
weeks after completion of antibiotics in the cephalexin (9%) group compared
with the combined amoxicillin (13%) groups.



Conclusions: Amoxicillin once-daily or twice-daily was equally effective
in terms of frequency of recurrence of symptomatic GABHS pharyngitis.

Introduction

Group A [beta]-hemolytic streptococcal (GABHS) pharyngitis
is treated to prevent rheumatic fever and to ameliorate symptoms. A 10-day
course of amoxicillin is commonly prescribed in pediatric practice, usually as
a twice-daily or thrice-daily dosing regimen. Once-daily dosing of amoxicillin
has been endorsed by the American Academy of Pediatrics ^[1] and the
American Heart Association ^[2] because studies ^[3–7] have demonstrated the efficacy of once-daily dosing for
bacteriologic eradication in patients with GABHS pharyngitis. Four ^[3–6] of 5 studies
demonstrated eradication in more than 80% of patients at the first visit after
completion of therapy (); 2 ^[3,5] of the 5 provided data on clinical cure at a scheduled
follow-up visit after treatment.

Table 1. Summary of Randomized Controlled Trials of Once-daily
Amoxicillin

Study	Ages	Amoxicillin Once-daily Dose (10-day course)	Number in Amoxicillin Group	Comparison Group	Number in Comparison Group	Return Visit Intervals After Enrollment (days)	Percent Eradicated at 1st Visit After Treatment	Acquisition of New Serotype at 1st Visit After Treatment	Clinical Cure (%)
Shvartzman et al 3	3 y and up	50 mg/kg (750 mg max)	75	Penicillin vs. TID or QID	82	1–2, 14–21	100	n/a	No difference
Feder et al 4	3–18 y	750 mg	84	Penicillin vs. TID	77	1, 14–16, 24–31	89	n/a*	Not reported
Clegg et al 5	3–18 y	1000 mg (750 mg <40 kg)	326	Amoxicillin vs. BID	326	14–21 and 28–35	80	15 of 120	90.8
Lennon et al 6	5–12 y	1500 mg (750 mg < 30 kg)	177	Penicillin vs. BID	176	3–6, 12–16 and 26–36	87.3	5 of 44	Not reported
Pichichero et al 7	6 m to 12 y	775 mg (475 mg < 5 y) †	290	Penicillin vs. QID	289	3–5, 14–18, 38–45	65.3	n/a ‡	86

*Data on serotype acquisitions were presented in total for
all follow-up periods.



^†7-day course.



^‡Serotyping was not done at the first visit after treatment
completion.



BID indicates twice-daily; TID, thrice-daily; QID, 4 times daily.

Table 1. Summary of Randomized Controlled Trials of Once-daily
Amoxicillin

Study	Ages	Amoxicillin Once-daily Dose (10-day course)	Number in Amoxicillin Group	Comparison Group	Number in Comparison Group	Return Visit Intervals After Enrollment (days)	Percent Eradicated at 1st Visit After Treatment	Acquisition of New Serotype at 1st Visit After Treatment	Clinical Cure (%)
Shvartzman et al 3	3 y and up	50 mg/kg (750 mg max)	75	Penicillin vs. TID or QID	82	1–2, 14–21	100	n/a	No difference
Feder et al 4	3–18 y	750 mg	84	Penicillin vs. TID	77	1, 14–16, 24–31	89	n/a*	Not reported
Clegg et al 5	3–18 y	1000 mg (750 mg <40 kg)	326	Amoxicillin vs. BID	326	14–21 and 28–35	80	15 of 120	90.8
Lennon et al 6	5–12 y	1500 mg (750 mg < 30 kg)	177	Penicillin vs. BID	176	3–6, 12–16 and 26–36	87.3	5 of 44	Not reported
Pichichero et al 7	6 m to 12 y	775 mg (475 mg < 5 y) †	290	Penicillin vs. QID	289	3–5, 14–18, 38–45	65.3	n/a ‡	86

*Data on serotype acquisitions were presented in total for
all follow-up periods.



^†7-day course.



^‡Serotyping was not done at the first visit after treatment
completion.



BID indicates twice-daily; TID, thrice-daily; QID, 4 times daily.

Bacteriologic eradication of GABHS is not a pragmatic
endpoint from the perspective of the physician in office practice and the
child's parent. Follow-up throat cultures on each patient with GABHS
pharyngitis at a scheduled posttreatment office visit is not realistic.
Instead, effectiveness of treatment of "strep throat" is determined
by the frequency of recurrence of symptomatic pharyngitis necessitating a
return visit for diagnosis and treatment. Whether subsequent streptococcal
pharyngitis is from failure to eradicate the serotype causing the first episode
or from acquisition of a new serotype is of little practical interest to
parents. The frequency with which streptococcal pharyngitis is diagnosed in the
weeks after completion of once-daily therapy for an initial episode has not
been examined in clinical practice.

The current study was conducted in a private pediatric
office setting where antibiotic choice and dosing were at the discretion of the
treating pediatrician. The frequency of streptococcal pharyngitis in patients
treated for an index episode with once-daily amoxicillin, twice-daily
amoxicillin or cephalexin was compared during the 4-month period after
diagnosis of the index episode. The pragmatic endpoint of recurrence of
symptomatic streptococcal pharyngitis was the same for the 3 antibiotic
regimens.

Methods

Setting

A retrospective chart review was conducted using the patient
records at a private, general pediatric practice serving Charlottesville, VA,
and a 5-county area. The central office of this practice is open for scheduled
appointments 365 days per year until 10 P.M. each evening; 2 satellite offices
in this practice are closed in the evenings and on weekends. Satellite patients
are seen at the central office for urgent visits when the satellites are closed
or overbooked. The central and satellite offices use identical testing methods.
This study was approved by the University of Virginia Health Sciences Center
Institutional Review Board.

Collection of Specimens

Clinical scoring of patients was not done. Physicians in the
practice discourage testing asymptomatic patients, and patients are not seen
only for streptococcal testing. Instead, each patient is seen at a scheduled
office visit and evaluated by a physician before any testing. If the examining
physician judges the patient to have symptoms and signs consistent with
streptococcal pharyngitis, the physician personally collects the pharyngeal
specimen using 2 swabs, both of which are processed by a medical technologist
in the office's moderate complexity laboratory. A streptococcal rapid antigen
detection (RAD) test is done on 1 swab; when the RAD test is negative, the
second swab is inoculated on a sheep blood agar plate, which is incubated for
48 hours. ^[8] In our community, back-up throat cultures are done
routinely.

Identification of an Index Episode

Index episodes of GABHS pharyngitis in patients 2 years of
age and older were identified during August through May in 2 different year
spans: 2003 to 2004 and 2007 to 2008. Only the records of the central office
laboratory were reviewed to identify index patients; each patient's first
occurrence of a positive RAD test or back-up throat culture was designated the
index episode of streptococcal pharyngitis for that patient. Each patient's
chart was reviewed to record any subsequent streptococcal pharyngitis episodes
that were diagnosed at either the central or satellite offices in the ensuing 4
months. If a patient had episodes of streptococcal pharyngitis during both
study years, the patient was considered to have had 2 index episodes.

Definitions

Streptococcal pharyngitis was diagnosed in a child with
symptoms (eg, sore throat, fever, absence of cold symptoms) and a positive RAD
test or back-up throat culture. Episodes of symptomatic streptococcal
pharyngitis in the 4 months after treatment of the index episode were recorded.
Streptococcal strains were not serotyped.