用藥風險，男性女性大不相同The Drug-Dose Gender Gap By RONI CARYN RABIN

健康

用藥風險，男性女性大不相同

RONI CARYN RABIN 報道 2013年02月25日

Ellen Weinstein

大部分安眠藥的目的是讓你安睡八小時。近來，美國食品與藥品管理局（Food and Drug Administration，簡稱FDA）的研究者對一種用於治療半夜醒來的短效安眠藥進行評估，則是希望了解患者在次日早上醒來時，體內還殘餘着多少藥物。
結果在血液檢測中研究者發現了性別造成的差異：男性在代謝這種名為酒石酸唑吡坦(Intermezzo)的藥物時，速度比女性更快。最終FDA在批准該葯時，規定男性使用劑量為3.5毫克，女性為1.75毫克。

酒石酸唑吡坦中的有效成分為唑吡坦，它被用於其他多種助眠藥物中，其中包括了安必恩(Ambien)。但直至本月，FDA才規定將安必恩的女性服用劑量減半。
安眠藥絕對不是唯一有可能給女性帶來意想不到的、甚或是危險副作用的藥物。此前有幾項研究表明，女性在使用從阿司匹林(aspirin)到麻醉劑的多種藥物時，所出現的反應都不同於男性。研究者現在剛剛開始理解到該問題的廣度。有不少人相信正因為如此，女性在服藥後會發生過高比例的副反應，而且這些副作用往往非常嚴重。
“這不僅跟安必恩有關——它只揭示了冰山一角，”美國國家衛生研究所(National Institutes of Health)女性健康研究辦公室主任簡寧·克萊頓博士(Janine Clayton)這樣表示。“很多葯的效果都存在着性別差異，其中一些已經為人們熟知，但也有些還未被充分認識到。”
在1993年以前，育齡女性通常都不得參與各類新葯人體試驗。而在這一年，當FDA取消了禁令後，該機構的研究人員注意到，由於沒有女性參加有關阿司匹林對心臟病和腦卒中治療的里程碑式的研究，科學界對“阿司匹林對治療患該類疾病的女性是否真的有效存有疑慮。”
由於大量藥物的測試人群大多或全部為男性，科學家要等到藥物上市後，才有可能了解其對女性的副作用。美國政府問責局(Government Accountability Office)的一項調查發現，從1997年到2000年間被強制下架的10種藥物中，有八種對女性會構成更大的健康風險。
舉例來說，抗組胺葯特非那定(Seldane)和胃腸道葯西沙必利(Propulsid)在引發可能致命的心律不齊問題時，女性發病的機率都要比男性更高。克萊頓博士介紹說，目前仍在銷售的大量藥物所引發的心律不齊，在女性身上都表現得更為頻繁，其中包括抗生素、抗精神病葯、治療瘧疾藥物和降膽固醇藥物。女性服用的葯也往往比男性多。
藥效的性別差異表現在兩方面。一些葯，比如治療高血壓的維拉帕米(Verapamil)和抗生素紅霉素，看來對女性的療效更明顯。而在另一方面，據女性健康研究協會(Society for Women's Health Research)表示，相比男性，女性更容易在麻醉術中途蘇醒，也更有可能遭受麻醉劑導致的副作用。
研究還發現，酒精、香煙和可卡因對女性產生的作用與男性不同。
這不僅是因為女性的身材通常矮小一點。女性的體脂率較高，而且荷爾蒙波動大，每月出現月經周期，因此代謝藥物也會有所不同。韋斯利·林塞(Wesley Lindsey)是奧本大學(Auburn University)藥學院的助理教授，與人合著了一篇關於藥效性別差異的論文，他說：“一些藥物是更加偏於水溶性，往往會在血液中駐留；而另一些葯更可能在脂肪組織中駐留。”
“如果藥物是脂溶性的，”——也就是說被脂肪細胞吸收——“它就會由這些組織器官吸收，停留在體內的時間更長，”林塞博士進一步說，“身體無法快速將它代謝，你會發現這種葯的藥力更持久。”
在肝臟代謝、腎功能和某些特定的消化酶方面也存在着性別差異。口服避孕藥、更年期和絕經期激素療法使得女性用藥的問題顯得更為複雜。喬治城大學(Georgetown)健康、老化與疾病之性別差異研究中心的主管凱瑟琳·桑德伯格(Kathryn Sandberg)舉例說，比如一些研究認為在雌激素水平較低時，女性可能需要服用更高劑量的血管緊張素受體阻滯劑以降低血壓，因為這時她們體內的蛋白質含量升高，會導致血管收縮。
很多研究者認為，應當在新葯研發之初——甚至是在開展人體藥物試驗開始前，就收集藥效性別差異的數據。
桑德伯格博士說：“通往新葯的路徑始於最基礎的科學——你先要研究動物的疾病模式，就此發現藥物靶點。但現在有九成的科研人員仍然只研究雄性動物的疾病模式。”
在這方面已經出現了改進。在接受採訪時，FDA藥品評估和研究中心的羅伯特·坦普爾(Robert Temple)博士說，該機構於1993年制訂了新指南，要求在藥品研發的最早期階段就要開始注意研究藥效性別差異，同時也要分性別來解讀臨床實驗數據。
他說，有一種治療腸易激綜合症的葯叫阿洛司瓊（alosetron，商品名“羅腸欣”），對該葯的早期研究時顯示它對男性效果不顯著。因此在臨床試驗時只招募了女性志願者，在審批通過時也註明只能供女性患者服用。（由於存在嚴重副作用，現在該葯被限制銷售。）
也有些科學家認為，藥物代謝試驗只有10到15個志願者參加，規模太小，不足以發現藥效性別差異。根據近期的一項分析，就算現在參加臨床試驗的女性比以往多了，但在治療心臟病和腎臟病、甚至是癌症的臨床試驗中，參與的女性仍然較少。
林塞博士說：“現在有個大問題，那就是我們並不能確切地知道，性別會帶來多大的差異。我們對此實在知之甚少。”

讀者如對“The Consumer”欄目有評論或疑問，可發電郵至consumer@nytimes.com。
本文最初出版於2013年1月29日。
翻譯：Noey

The Drug-Dose Gender Gap

By RONI CARYN RABIN February 25, 2013 

 

Most sleeping pills are designed to knock you out for eight hours. When the Food and Drug Administration was evaluating a new short-acting pill for people to take when they wake up in the middle of the night, agency scientists wanted to know how much of the drug would still be in users' systems come morning.
Blood tests uncovered a gender gap: Men metabolized the drug, Intermezzo, faster than women. Ultimately the F.D.A. approved a 3.5 milligram pill for men, and a 1.75 milligram pill for women.

The active ingredient in Intermezzo, zolpidem, is used in many other sleeping aids, including Ambien. But it wasn't until earlier this month that the F.D.A. reduced doses of Ambien for women by half.

Sleeping pills are hardly the only medications that may have unexpected, even dangerous, effects in women. Studies have shown that women respond differently than men to many drugs, from aspirin to anesthesia. Researchers are only beginning to understand the scope of the issue, but many believe that as a result, women experience a disproportionate share of adverse, often more severe, side effects.

"This is not just about Ambien - that's just the tip of the iceberg," said Dr. Janine Clayton, director for the Office of Research on Women's Health at the National Institutes of Health. "There are a lot of sex differences for a lot of drugs, some of which are well known and some that are not well recognized."
Until 1993, women of childbearing age were routinely excluded from trials of new drugs. When the F.D.A. lifted the ban that year, agency researchers noted that because landmark studies on aspirin in heart disease and stroke had not included women, the scientific community was left "with doubts about whether aspirin was, in fact, effective in women for these indications."
Because so many drugs were tested mostly or exclusively in men, scientists may know little of their effects on women until they reach the market. A Government Accountability Office study found that 8 of 10 drugs removed from the market from 1997 through 2000 posed greater health risks to women.
For example, Seldane, an antihistamine, and the gastrointestinal drug Propulsid both triggered a potentially fatal heart arrhythmia more often in women than in men. Many drugs still on the market cause this arrhythmia more often in women, including antibiotics, antipsychotics, anti-malarial drugs and cholesterol-lowering drugs, Dr. Clayton said. Women also tend to use more medications than men.
The sex differences cut both ways. Some drugs, like the high blood pressure drug Verapamil and the antibiotic erythromycin, appear to be more effective in women. On the other hand, women tend to wake up from anesthesia faster than men and are more likely to experience side effects from anesthetic drugs, according to the Society for Women's Health Research.
Women also react differently to alcohol, tobacco and cocaine, studies have found.
It's not just because women tend to be smaller than men. Women metabolize drugs differently because they have a higher percentage of body fat and experience hormonal fluctuations and the monthly menstrual cycle. "Some drugs are more water-based and like to hang out in the blood, and some like to hang out in the fat tissue," said Wesley Lindsey, assistant professor of pharmacy practice at Auburn University, who is a co-author of a paper on sex-based differences in drug activity.
"If the drug is lipophilic" - attracted to fat cells - "it will move into those tissues and hang around for longer," Dr. Lindsey added. "The body won't clear it as quickly, and you'll see effects longer."
There are also sex differences in liver metabolism, kidney function and certain gastric enzymes. Oral contraceptives, menopause and post-menopausal hormone treatment further complicate the picture. Some studies suggest, for example, that when estrogen levels are low, women may need higher doses of drugs called angiotensin receptor blockers to lower blood pressure, because they have higher levels of proteins that cause the blood vessels to constrict, said Kathryn Sandberg, director of the Center for the Study of Sex Differences in Health, Aging and Disease at Georgetown.
Many researchers say data on these sex differences must be gathered at the very beginning of a drug's development - even before trials on human subjects begin.
"The path to a new drug starts with the basic science - you study an animal model of the disease, and that's where you discover a drug target," Dr. Sandberg said. "But 90 percent of researchers are still studying male animal models of the disease."
There have been improvements. In an interview, Dr. Robert Temple, with the Center for Drug Evaluation and Research at the F.D.A., said the agency's new guidelines in 1993 called for studies of sex differences at the earliest stages of drug development, as well as for analysis of clinical trial data by sex.
He said early research on an irritable bowel syndrome drug, alosetron (Lotronex), suggested it would not be effective in men. As a result, only women were included in clinical trials, and it was approved only for women. (Its use is restricted now because of serious side effects.)
But some scientists say drug metabolism studies with only 10 or 15 subjects are too small to pick up sex differences. Even though more women participate in clinical trials than in the past, they are still underrepresented in trials for heart and kidney disease, according to one recent analysis, and even in cancer trials.
"The big problem is we're not quite sure how much difference this makes," Dr. Lindsey said. "We just don't have a good handle on it."

Readers may submit comments or questions for The Consumer by e-mail to consumer@nytimes.com.