治療 Alzheimer’s disease 的藥沒有突破

Bapineuzumab 這藥是愛爾蘭的 Elan 藥廠發展的、美國 Wyeth 藥廠投資買了所有權（Wyeth 藥廠後來被 Pfizer 併吞），後來 Johnson & Johnson 也怕吃不到甜頭，也投資於 Alan 藥廠。

Bapineuzumab binds to beta-amyloid, leading to its removal.  這十幾年期間做了好幾個studies/trials. 有時候看來好像有效, 藥廠股價就上漲。如2008年的六月； Wyeth 藥廠股票上升4.83%. (我相信這藥是當年 Pfizer 買 Wyeth 的原因之一；另一個藥是 Prevnar 13; I hope you guy have received Prevnar 13 vaccine).

但是對同一個 study/trial 再仔細分析同一 data, 一個月後 （2008 年七月底）又宣布無效且有很不好的副作用； 當天Wyeth 股價降12%; Alan 降42%。

一個藥有沒有效是一個大學問；在網路上流傳的妙方的問題大都出在這點。這也是兩派無法溝通的主因。因為網路上流傳的文章說有效（我看起來是「有笑」， I mean 「好笑」）。

Katy 的一個高中同學的兒子以前來苉大念了五，六年拿到生物統計的博士；現在在FDA 工作；去年九月我們有去看他；他説像他這樣的人才，FDA有近300 人；當時我們也有去看一個以前在苉城的好友，他們的女婿是FDA 的 statistics 部門的 director; 他是數學博士。Katy 一個朋友的丈夫以前在田那西大學當統計學教授；後來也去New Jersey Roche 藥廠工作。Katy 同學的兒子說，FDA 若增加 統計的人員，藥廠就相對的增加。以毒攻毒。

我沒有辦法告訴你藥有沒有效是怎麼決定的，因為我自己也不知道。但是我知道藥廠及 FDA 是怎麼知道的。

這期間 Eli Lilly 也發展他們自己的藥叫solanezumab (跟 Pfizer 的 bapineuzumab 很類似；其命運也大同小異 （可說是同病相憐）只是一切慢半拍而已. 2012 年Pfizer 心灰意懶開始想放棄時， Eli Lilly 還存一線希望繼續努力，2015 年七月還在說有 break through (突破），直到2016 年的11 月才正式宣布整個 project 泡湯 (went down the drain) 壽終正寢。

Scientific American （July 14, 2014) 有一篇文章叫 “Why Alzheimer’s drugs keep failing”; 因為他們的 editors 沒有在讀網路流傳的文章，不知道有那麼多的妙方。

為什麼會這樣呢？理論（theory) 多如牛毛；但最合乎常理的是：有Alzheimer’s disease 的人在臨床上開始有症狀的幾年甚或幾十年前就已經開始有那些 build up of beta amyloid plaque. 神経細胞可能早已受損害；所以現在把那些 beta amyloid plaque 除去也無濟於事了。 A doctor said “we are 25 years too late.”

幾乎所有專家都同意；腦部開始出現 beta amyloid 很多年後 （甚或幾十年後）才會開始有失智的症狀出現。因為已經証明有些人做那種特殊的 CT-PET scan 時發現有 beta amyloid build up, 但臨床上一切正常。

也是這個原因目前正常的人不應該做那種特殊的 CT-PET scan, 要不然萬一（其或然率是大大超過一萬分之一的）照出了  beta-amyloid plaque 的話, 不病死也會煩惱死了；especially we have nothing to offer, except red wine, 不過要全部靠紅酒可能要先醉死了。

If you still have energy and endurance to read (and you should as some said reading is better than red wine to prevent Alzheimer's disease), this is the link to the post I wrote nearly 4 years ago.)

http://doctorjytsai.blogspot.com/2014/02/what-disappointment-alzheimers.html

Resveratrol: the elusive 'Fountain of Youth' pill ?

(This article was originally posted in my old blog at vox.com on 2/11/2007; I may write a follow up post soon.)

A friend forwarded me an article about ‘Youth Pill’ asking my opinion.  The molecule of interest is Resveratrol, which is found on grape fruit skin and red wine.  It has been reported that reducing calories intake leads to a longer life, at least for yeasts and rats, and Resveratrol mimics this benefit without actually reducing calories intake.  David Sinclair (of Harvard Medical School) reported that yeasts fed with Resveratrol prolong the life by 60%.

Resveratrol is touted as anti-cancer, anti-viral, anti-aging, and life-prolonging.  My philosophy is that every thing has its purpose (sometimes I wonder even the appendix originally has its function, which has been ‘retired’ by the evolutionary process)  Seldom do we come across one thing for all purposes; it is almost too good to be true; when a thing is so perfect, caution should be exercised.

A scientific research at this early stage rarely attracts public attention, but Resveratrol is an exception and the reason is two-fold and related: It is touted as the 'Fountain of Youth' pill and the money may be generated from it.

But, a few points leads me to take David Sinclair seriously:
1.  He is not being sanctioned by Harvard Medical School.
2.  His experiment was reported in the prestigious Nature.
3.  Simple and small though it may be, yeast is ‘one of us’—eukaryotic, not prokaryotic.

In other words, we share a great many similar genes.  In fact, yeast is one of the most decorated organisms sharing many Nobel Prize glories over the years.  Roger Kornberg spent more than 20 years working on the yeast elucidating the mechanism of its transcription, and it happens that we also do it the same way.  He was honored with a Nobel Prize in Chemistry in 2006.  His Nobel Lecture is “The Molecular Basis of Eukaryotic Transcription.” 

During Beyond Gene Symposia organized by Nobel organization at Stockholm in December 2001 (James Watson had an opening remark, Francis Crick was not there), Roger Kornberg gave a talk “Eukaryotic Gene Transcription at Atomic Resolution.”—In my view, this talk played a crucial role in the selection of the Prize last year; how can one not be impressed by the elucidation of the elusive mechanism of eukaryotic transcription, detailed up to the atomic level.?

His father, Arthur Kornberg discovered the first DNA polymerase and got a Nobel Prize in 1959 in finding out how we synthesize DNA/RNA.  His brother, Harold, discovered DNA polymerase II and III.  This is ‘all in the family’ business. Arthur’s wife, Sylvy, was also a biochemist. The day after Arthur was awarded the Nobel Prize, she was quoted in a newspaper as saying “I was robbed”.  Roger’s wife is also a biochemist.  In his Nobel Banquet speech, he said, “It is an honor I share with many collaborators. My wife Yahli has been my closest collaborator. She has borne a double burden.  She is the wife of a scientist, and herself a scientist without a wife. . . .”

Harvard molecular biologists Mark Ptashne and Tom Moniatis formed a biotech company in 1980, and the ‘Fair Harvard’ faculty (story was told by the bitter James Watson) voted it down, Harvard was forced to withdraw, giving up its 20% stake in the company. Watson lamented, “Sixteen years later, the cost of that call would become apparent when the firm was sold to the pharmaceutical giant Wyeth for $1.25 billion.  And to this day, Harvard’s Department of Molecular and Cellular Biology lacks a designated endowment to support research above the cost of salaries.”  This lesson may play a role in Harvard’s reluctance to ‘sanction’ scientist like David Sinclair, even with the reported association of his with this industry.

Sinclair said, “I am not a doctor so I can’t speculate on how much we’re to drink, but I’ve increased my consumption since we made the discovery.” As a doctor, my response is that it’ll be OK as long as you do not drink more than your doctor does. 

So until the jury is out or until the ‘Fountain of Youth’ pill is discovered if you want to toast your good health, use red wine. And let's hope “a glass of red wine a day keeps the doctor away.”  Meanwhile if you want to live longer; eat less, exercise more, and pay attention to those all too often neglected preventive medicines.  Wishing you a prosperous and LONG life!

再談酒仙李白 （Poet Li Po, the god of wine revisited)

Will Durant 寫李白跟杜甫時，很多跟俊雄兄所說的 overlap (this is a compliment to Will Durant, not to Charles, Durant 不懂中文沒辨法了解中國古典詩之美，but he knows enough to know what he should talk about). 記得 Mei-Yu and Charles 曾討論過李白的「將進酒」which may be the next post.

Durant wrote Li Po “consoled himself with wine, and became one of the Six Idlers of the Bamboo Grove,” who took life without haste, and let their songs and poems earn their uncertain bread. Hearing the wine of Niauchung highly commended, Li set out at once for that city, three hundred miles away.”

(我的中文翻譯）

李白借酒消愁），變成了竹林六賢之一 [不過有人說是竹林七賢，那一個對?] 消遙過日），靠賣詩詞為生，有時三餐不繼。有一次他聽到南昌 (?)的酒很有名，他馬上趕去300 浬外的南昌。

In his wondering he [Li Po] met Tu Fu, who was to be his rival for China’s poetic crown; they exchanged lyrics, went hand in hand like brothers, and slept under the same coverlet until fame divided them.  Everybody loved them, for they were as harmless as saints, and spoke with the same pride and friendliness to paupers and kings.  Finally they entered Chang-An; and the jolly minister Ho loved Li’s poetry so well that he sold gold ornaments to buy him drinks.  Tu Fu describes him:

(我的中文翻譯）

李白雲遊四方時碰到了杜甫；他們兩人是爭中國桂冠詩人的對手。他們交換詩句，手牽手，睡同一棉被稱兄道弟。後來功成名就，同行相忌而分手。眾人都很喜歡這兩位詩仙，対皇帝或乞丐都同等待遇，一樣的友善或自豪。他們終於來到了長安。何大臣非常喜歡李白的詩，賣了金飾請李白喝酒。下面是杜甫描述李白：

As for Li Po, give him a jugful,

He will write one hundred poems.

He dozes in a wine-shop

On a city-street of Chang-An;

And though his Sovereign calls,

He will not board the Imperial barge.

“Please, your majesty,” says he,

“I am a god of wine.”

李白斗酒詩百篇，

長安市上酒家眠，

天子呼來不上船，

自稱臣是酒中仙。

（剛剛收到 Charles 送來的 email, 正好可以解釋上面杜甫的詩)

Charles just sent the following email, in which he expresses his sincere sympathy to those who cannot indulge wines. He also lamented that Lin Yutang's failure to be a Nobel laureate in literature is due to the fact that Lin never got benefits of wine, which might further enhance his creativity and put him in a more sublime mood. 道美與我都已經收到了 Charles 的 「sympathy card」。有個朋友說他有次喝太多酒，他太太打他㡬個嘴巴也不醒，還要上急診室，下次應學李白的様，叫人給你潑一桶冷水。

Lin was nominated to Nobel prize twice, but Nobel laureates tend to be novelists or poets and that is not his strength, even though his Moment in Peking did ear high claim.

(Charles 送來的 email)

昨天晚上重讀了林語堂的一篇文章「飲酒」。他説他是不飲酒的，原因是他喝一點酒就會昏昏沉沉、東倒西歪。可是他說他不能跳過這一個題目，因為他知道酒對中國的文化貢獻很大，有助於人類的創造力。他了解一個人喝酒後那一種半醉半醒的境界，掦掦得意的表情，使他非常羡慕，可見他對自己的不能喝酒，感觉到遗憾萬千。

我讀了那篇文章後，我很同情林語堂，同時也同情我不能喝酒或不能多喝酒的朋友，更對那些不喝酒的朋友惋惜，因為他們沒享受過喝了酒後，那種飃飃欲仙，像處於人間天堂的感覺。杜甫寫李白的一首詩：「李白斗酒詩百篇，長安市上酒家眠，天子呼來不上船，自稱臣是酒中仙」。李白在長安市酒舫喝了一斗酒，就寫出了一百首詩，醉了就在那𥚃睡了一埸長覺，皇帝派人来要李白進宮做官，但李白拒不上船，他認為我是酒中仙人，我怎能夠受到委屈，替皇帝做事？這正是林語堂說的，喝醉了酒後，會揚掦得意，天不怕地也不怕，你皇帝是老幾？

Beauty of Chinese poems: 唐玄宗, 楊貴妃, 李白, 酒仙

I have read Will Durant’s The Story of Civilization for nearly forty years; in fact, I have collected ten of its eleven volumes.  Its first volume is “Our Oriental Heritage” from which I learnt some of Chinese history, literature and culture.

(Unfortunately one needs to have some command of Chinese to appreciate this post).

華清宮, 荔枝, Empress Leeche  (email sent by Charles on 7/4/2016)

唐玄宗深深寵愛楊貴妃，是大家都知道的歷史故事，公元747年，玄宗在長安之東驪山之下，把舊時的「溫泉宮」大幅修建改名為「華清宮」，裡面有好幾座貴妃常常賜浴「待𠒇扶起嬌無力」（白居易長恨歌）的「華清池」，豪華奢侈、富麗堂皇，驪山下溫泉洶湧，冬天溫暖，是唐玄宗與楊貴妃長期避寒之地。史上詩人騷客，描述唐玄宗、楊貴妃、在華清宮醉生夢死、恣情享樂的詩詞文章，不勝枚舉，譬如、李白的「清平調」：「雲雨巫山枉斷腸」，白居易的「長恨歌」：「在天願作比翼鳥，在地願為連理枝，天長地久有時盡，此恨綿綿無限期」，我想每一個人都是熟悉的。

晚唐詩人杜牧（803-852） 有一次從東部往西行，過潼關要去長安，経過華清宮時，遠望驪山上華麗行宮、庭台樓閣，深有所感，寫下了這首有名的詩，「過華清宮」：

「長安回望繡成推，山頂千門次第開，一騎紅塵妃子笑，無人知是荔枝來。」

語譯：詩人杜牧騎馬或坐馬車去長安的途上，経過華清宮時，他回頭看到華清宮周圍，一片片的花蕞就像一推推刺繡般的美麗，他想像到以前每年夏天，幾位騎士，從長安直奔華清宮，紅塵滿道，驪山頂上堂皇行宮的門，一片片的開了，楊貴妃看到騎士們來了非常高興，大大的笑了，沒有人知道他們是專送荔枝來的。

楊貴妃袓藉巴蜀（四川），産荔枝，貴妃特喜荔枝，進宮後，每年夏天荔枝成熟時，有專差從巴蜀置騎數千里，送新鮮的荔枝到華清宮，譲差官累死，許多驛馬倒斃在路上，真是勞民傷財.

……………………………………………………………………………………………………

(The above is the email sent by Charles on the July 4^th of 2016, re-reading it inspires me to write this post.)

上面是 Charles 于2016 年的 July 4th 傳來的。 當時 Charles 從 Florida 千里專送荔枝來時， 我們也像貴妃一樣,「一騎紅塵妃子笑」的。

Will Durant 提到李白的另一首詩不知你們這些詩人有沒有提到 （我的FileMaker 裡找不到, except Charles 有稍為提到 「雲雨巫山枉斷腸」）。有次唐玄宗在 the Pavilion of Aloes (阿房宮？）辦個牡丹國宴 （royal Feast of the Peonies； 叫人去請李白來作詩讚美楊貴妃。李白到時醉茫茫的不能作詩 （too drunk for poetry); 宮廷侍侯人員往他臉上潑了一桶冷水，他才開始呤詩 （Durant wrote “and soon the poet burst into song”, 根據美玉教授以前的敎材, 這清平調是詞，是用來唱的。I think Will Durant got it right here.）

The glory of trailing clouds is in her garments,

And the radiance of a flower on her face.

O heavenly apparition, found only far above

On the top of the Mountain of Many Jewels,

Or in the fairy Palace of Crystal when the moon is up!

Yes I see her here in the earth’s garden —

The spring wind softly sweeps the balustrade,

And the dew-drops glisten thickly . . .

Vanquished are endless longings of love

Borne into the heart on the winds of spring.

我猜 Will Durant 是在說李白的清平調詞三首，不是非常忠實的翻譯， 但意思是在說貴妃比花嬌，但是有人讀出來李白暗藏諷刺，貴妃就不高興，譲玄宗也起懷疑、給李白一些錢把他打發掉了。（And yet the Lady Yang was persuaded that the poet had subtly satirized her; and from that moment she bred suspicion of him in the heart of the King.  He presented Li Po with a purse, and let him go.

《清平調詞三首》

雲想衣裳花相容，春風拂檻露華濃。

若非群玉山頭見，會向瑤台月下逢。

一枝穠豔露凝香，雲雨巫山枉斷腸。

借問漢宮誰得似，可憐飛燕倚新妝。

名花傾國兩相歡，長得君王帶笑看。

解釋春風無限恨，沉香亭北倚闌乾。

李白從此又再跑江湖了，只能再借酒澆愁 （Once again the poet took to the open road, and consoled himself with wine.) 他加入了 「飲中八仙」，這些八仙喝酒的故事傳遍長安 （He joined those “Eight Immortals of the Wine Cup” whose drinking were the talk of Chang-An.)

Did Churchill have depression (“the Black Dog”)?

Today (January 24) in 1965 Winston Churchill died. About a dozen years earlier Jock (John) Colville (Churchill's secretary) brought a minor matter of state to Churchill who was shaving; Churchill said to Colville, “Today is the twenty-fourth of January. It is the day my father died. It is the day that I shall die too.”

On January 9, 1965 Churchill went to bed without eating supper and never got out of bed again, by the twelfth, Dr. Moran diagnosed his last stroke, at which time Churchill was already unconscious; doctor thought the worst will come any moment soon; but Churchill lingered until January 24.

Churchill gave his six-volume WWII memoir to Anthony Montague Browne (another secretary) as Christmas gift in 1964. Montague Browne asked Churchill to sign his full name, by the sixth volume he could only scrawl “W”.

A few days ago a friend sent me an email, in which Churchill is described the greatest depression victim in British history, according the Lord Moran's (Churchill's personal physician from 1940-1965) diary.

This statement was disputed by two of Churchill's personal secretaries and many of the books I read about him, including William Manchester's The Last Lion.

Lord Moran (Dr. Charles MacMoran Wilson) is Churchill's personal physician and friend of 25 years. Nobody suspected him making up sensational stories to sell books. He claimed he had Churchill's permission to publish the book, which was not published until after Churchill's death. Churchill's son (Randolph) said sometimes the doctor may not see Churchill for 3 months at a stretch.

I checked out this book which had a title of “Churchill Taken from the diary of Lord Moran” from Carnegie Library several times over the years. The second edition apparently has a new title of “Churchill: The Struggle for Survival 1940-1965”. I didn't get an impression that depression was an issue at all. If Churchill ever felt depressed, it was probably few and far between. One of Churchill's daughters, Diana, did commit suicide in 1963.

When Lord Moran's diary was out, there was a book review on May 16, 1966 NY Times with a title of “The most fabulous invalid”.

If you read what Churchill did during the war (1939-1945) you would agree that he had no time to get depressed. After his retirement Churchill kept a very active life that both John Colville and Anthony Montague Browne expressed difficulty catching up, going to Sicily, Morocco, the French Riviera numerous times, also the Italian Riviera, Paris, Rome and New York. They once had to politely decline JFK's invitation to stay at White House for a few days. Churchill boarded Onassis' yacht Christina eight times, at times entertained by Maria Callus and Greta Garbo. It once encountered a fury storm on the way to the United States, during which Churchill insisted on sitting atop a piano in the lounge, supported by four strong Greek seamen, so he could watch the fury storm on the sea; he was 86 years old then.

His 8^th (and the last) sail on Christina was in late 1963; Jacqueline Kennedy (the the First Lady) was the guest on Christina right after Churchill got off the yacht. The rest is history.

Churchill also finished his six-volume “Memoirs of the Second World War” and four-volume of “A History of English-speaking People” during his retirement.

Churchill's family said that Lord Moran was not around to see how Churchill lived his active life. My own theory is that doctor tends to observe the “illness” (the depression or dubbed as “the Black Dog” in Churchill's case) of any given individual and may miss out the obvious (his active life).

An interesting side story is that current Archbishop of Canterbury, Justin Welby, announced in 2016 that after the DNA test, it confirmed that his biological father is Sir Anthony Montague Browne, Churchill's secretary. His mother also worked for Churchill during the war time.

Archbishop Welby said, “I know that I find who I am in Jesus Christ, not in genetics, and my identity in him never changes.” 

Archbishop of Canterbury to the 86 million Anglicans in the world is what Pope is to the 1.2 billion Catholics in the world.  On a light moment Churchill once offered FDR the prestige of being the Archbishop of Canterbury should he lose the election.  I forgot what position FDR offered Churchill; Chairman of the Federal Reserve? (I recall it was a non-elected position.)