the poison. ln medicine, it'S used in such small amounts that most experts deem it safe. "lt's fascinating,' says Dong, the Harvard researcher. "These are the most toxic sub stances known tO man, and they are also the most useful toxins used in medicine right now. BOtox works by temporarily immobiliz- ing muscle activity. lt does this by block- ing nerve-muscle communication, WhiCh makes the injected muscles unable tO con- tract. Paralyzing muscle activity is hOW BOtOX can steady a straying gaze, eliminate an eye- lid spasm or stop signaling from nerves that stimulate sweat in a person S armpit. BOtOX has alSO been shown tO prevent chronic migraines, but there, it'S unclear exactly why B0t0X works. (For doctors, reaching a firm understanding 0f how BOtOX prevents migraines will be tricky, since they don't know for certain what causes the severe headaches in the first place. ) "There were multiple clinical trials for migraines, and most 0f them failed," says Dr. Mitchell Brin, senior vice president of drug development at Allergan and chief scientific Offcer for BOtOX. "lt tOOk a long time tO figure out where tO inject and hOW much. ” T0day people wh0 receive B0t0X for migraine prevention get 31 inJ ections lll different spots on their head and neck. The effects Of Botox can last about three tO six months depending on the condition. The use Of BOtox for migraines was, like many other new applications for the drug, a kind 0f happy accident. A Beverly Hills plastic surgeon observed that people wh0 got BOtOX for wrinkles were reporting fewer headaches, paving the way for studies about migraines. Similarly, doctors in Europe were intrigued when they noticed that their pa- tients whO got BOtOX for facial spasms were sweating less than usual. "lt's pure serendipity, ' says Brin. THOUGH P OP 0 T 地 N ASSOCIATE phar- maceutical discovery with giant industrial laboratories and expansive, rigorous clinical trials, the mission creep for Botox—as with many other drugs that have received govern- ment approval for one specific use—has been driven by off-label use. ln the case ofBotox, doctors whO experl- ment off-label say they do so because they're looking for better treatment options for their patients. "ln my 30 years ofmedical practice, BOtOX is one Ofthe most impactful treatments I had ever seen; ” says Dr. Linda Brubaker, 38 TIME January 16 , 2017 WHAT BOTOX 儁 USED ド OR Best known fO 「 reducing facial wrinkles, Botox is approved by the FDA fo 「 the conditions below. The drug now brings in significantly more revenue for itS noncosmetic uses. FDA-APPROVED Rigorous cllnical trials were required before Botox was determined tO be safe and effective fo 「 these uses: 第 Strabismus (crossed eyes) ・ BIepharospasm (eyelid spasms) ■ CervicaI dystonia (severe neck spasms) ■ Severe underarm sweati ng 第 Upper-Iimb spasticity 第 Chronic-migraine prevention ■ Overactive bladder ■ Lower-Iimb spasticity ・ Some facial wrinkles dean and chiefdiversity offcer ofthe LOY01a University Chicago Stritch Sch0010f Medi- cine, wh0 independently studied B0t0X for overactive bladder before the FDA approved it for that condition in 2013. Many ofthe women she saw in her prac- tice didn't want t0 take drugs for the disor- der over the long term. Brubaker found that about 70 % ofwomen she treated with B0tox reported an average ofthree leaks a day, com- pared with the average of five leaks a day at the start Ofthe study. "lt's a very rewarding option for them,: ” she says. lt's true that BOtOX's ever expanding uses have been largely physician-driven. But drugmakers are also often aware ofoff-label uses long before those uses are offcially rec- ognized by the FDA; that's how B otox ended up being approved for wrinkles, after all. Some industry insiders say it's not un- usual, ifstill legally murky, for drug-company representatives and doctors tO share infor- mation with one another about the different ways an approved drug maybe used. lfa doc- tor notices that, say, a treatment for crossed eyes alSO "takes the lines out," he may men- tion it tO the representative from whom he buys the drugs. That rep may share that with another Ofhis clients, and so on. U. S. pharmaceutical companies are p rohibited from marketing a drug for un- approved purposes until they've submitted proofto the FDA ofits efflcacy and gotten the agency's green light. If they skip that step, they're breaking the law, and the penalties can be steep. ln 2010 , Allergan pleaded guilty and agreed to pay $ 600 million to resolve alle- gations that it unlawfully promoted Botox for conditions ー including headache s , p ain, sp asticity and juvenile cerebral palsy—that at the time were not approved by the FDA. ln one Ofthe complaints, prosecutors said that Allergan "illegally, vigo rously and without any thought to the possible negative health effects tO which it subjected patients, pro- moted off-label uses of Botox. ” The U. S. Department 0fJustice also argued that AI- lergan exploited on-label uses for cervical dystonia—a disorder characterized by ex- treme neck-muscle contractions—to grow off-label pain and headache sales. ” Prosecu- tors also argued that Allergan paid doctors tO give presentations and trainings tO other physicians about BOtOX uses that at the time were off-label. As part ofthe settlement, Allergan agreed tO plead guilty tO one criminal misdemeanor

TIME And 793 other problems. Drooling. Sweaty palms. Back pain. ErectiIe dysfunction. Migraines. He ar t trouble. D epression. 題 ow BO 亡 0 Became を e Drug Treating を ery を取 g ・ By Alexandra 部竈 er 血 00907 49102095 ろ 0177 160981441 市立図 雑誌 20953 - 1 ハ 6 JAPAN.. …定価 980 体体の 0 0 0

The trea t まれ F 0 R G E 1 W R ー N K [ E 5. B 0 T OX ー S N 0 W B E ー N G U S E 0 す 0 1 R E AT MIGRAINES, DEPRESSION, TWITCHING EYES, OVERACTIVE BLADDERS, SWEATY PALMS AND MORE. SOME CALL A MARVEL OF MEDICINE; OTHERS CAUTION THE RISKS ARE S れ、 U N K N OW N. ー N S ー 0 E 1 H E E X P し 0 0 ー N G B リ S ー N E 5 S A N 0 STRANGE SCIENCE OF B010X BY ALEXANDRA S ー第第 E 一Ⅳ PHOTO-ILLUSTRATION BY TIME

XIM Time Off What tO watch, read, ロ Botox Gets a Face-Lift see and dO The company that makes Botox 4 幻 HBO's The owns 800 patents for the drug—and u れ g 0 〃 e banishingwrinkles isjust one of 4 引 Movies: them. See how doctors are using HiddenFigures and Botox to treat all kinds of medical AMonster Calls conditions, from migraines and depression tO sweatypalms and 4 引 Rachel Cusk's Transit, plus new overactive bladder January books ByAIexandra SifferIin 34 47 ー Susanna Russian Spy Story Schrobsdorffon the mother-daughter What a report onthe Kremlin's bond meddling inthe U. S. presidential election means for the Putin-Trump 48 巨 0 Que stions relationship for conservative broadcaster Glenn ByMassimo Calabresi18 Beck PhiIippine Drug War TIME shows the toll ofPresident R0drigo Duterte's bloody campaign against illegal drugs and those ONTHE COVER. who use themphotographs 妙 lllustration 妙れ MetzforTIME JamesNachtwey 24 TIME ASla is pu sh TIME ASla ( Hor Kong) Limited. TIME publishes eght double issues. Each counts as two of 52 issues in an annual subscription. TIME may a 0 publish occasional extra issues. ◎ 2017 Time Asia (Hong Kong) l-imited. AllriÜ1ts reserved. ReprOductlOn in whOle in 代 w 曲 0 糶 en is prohibited. TlMEand the Border Design are protectedthrough trademark registration inthe し S. and magazinecirculates. Bureau Of CirculatiOns. ー′ 5 : げ物 e g.X)S ねーⅳ ces a に usthatyourmagazine is undeliverable, 、肥 have nofurtherobligation unless 、給78ei肥 acMrected addresswithin twoyears. CUSTOMERSERVICEANDSUBSCRIPTIONS F 24 / 7 ′ⅵ , 加 le 新 n れーー , ー、物忙れ / / “物ー浦一一物 .9 / 、・・ You may 引 email OJStomer ces center at 市ーー . ー 0 「旧 852 ) 312 & 5688 , orwrite Time Asia (Hong Kong.) 37 / 0 対 0 「 d 979 Kings RO , Quarry Bay, HO Kong 旧」 apan,these aree れ 4 ⅵ′れれ 0 1 研 012066 & 236 旧 Dial) 0r2-51-27FAt 0 , MinatO-ku. TO 0 1056227. A t 回一 : For information and rates• Hong KongTelephone: ( 852 ) 312 & 5169. Orvisit: 物ー .9 / ー航 . た旧 fO 「 ma も on is available at 物ー . ” / ーー一区 TO requestcustom reprints,visitü1E ′ . mm. M 胸セ、 make a 代 ion Ofou 「 mailing listavailable tO reputable firms. lfyou 、い u 旧 prefer 物物 0 目ⅳ your name, please contact ou 「 customer services center. TIME Asia is in Hong Kong and printed in and HO Kong. MCI (P) NO. 07 〃 08 / 2015. Malaysia KKDN no. PPS 676 / 03 / 201 022933 ). 0 The View 2 ー Conversation 引 For the kecord ldeas, OP 加 ion, innovations TheBrief 1 引 The dish on News 庁 0 t わ e し S. and food fraud, and around the world how mislabeled 引 The future of products make it tO Obamacare supermarket shelve s 引 French law 15 lls any one year protects workers more important who don'treply to than another? omce emails after hours 1 引 lnside the European Union's 8 ー Remembering new headquarters in Carrie Fisher (Star Brussels Wars), Debbie Reynolds (Singin' ユ引 AdmiralJames ⅲ the ⅲれ ) and Stavridis 0 Ⅱ why pop star George the U. S. should Michael bolster ties with lsrael 10 llstanbul mourns after a nightclub 1 引 Amne sty terrorist attack on lnternational's New Year's Eve AnnaNeistat on Russia's human- 12 llan Bremmer's rights abuses risk report for 2017 The Feature s A victim 可 0 summary executton な found the . Ⅳ avotas area onNO 既 30 Photograph 妙 James Nachtwey forTIME ノ 9d1 い「 1( 、おダ 1

it's been proved tO work for that condition. Now, thanks in large p art to off-label use, Botox—the wrinkle smoother that ex- ploded as a cultural phenomenon and med- ical triumph—is increasingly being drafted for problems that go farbeyond the cosmetic. The depression suffered by Rosenthal's pa- tient is Just one example on a list that in- cludes everything from excessive sweating and neck spasms to leaky bladders, pre- mature ejaculation, migraines, cold hands and even the dangerous cardiac condition Of atrial fibrillation after heart surgery, among others. The range 0f conditions for which dOCtors are now using BOtOX iS dizzying, re- flecting the drug's unique characteristic s as much as the drug industry 's unique strate - gies for creating a blockbuster. Botox iS a neurotoxin derived from the bacterium Clostridium botulinum. lngested in contaminated fOOd, it can interfere with key muscles in the body, causing paralysis and even death. But when injected in tiny doses intO targeted areas, it can block signals be- tween nerves and muscles, causing the mus- cles tO relax. That's how it smooths wrinkles: when you immobilize the muscles that sur- round fine lines, those lines are less likely to move—making them less noticeable. lt's also why it's FDA-approved to treat an overactive bladder: Botox can prevent involuntary mus- cle contractions that can cause people to feel like they have to pee even when they don't. ln 2015 , B0tox, produced by pharmaceu- tical maker Allergan, generated global reve- nue of $ 2.45 billion—more than halfofwhich came from therapeutic rather than cosmetic uses. That noncosmetic revenue iS likely t0 balloon in the years ahead as doctors try out URING A RECENT THERAPY session, one Of Dr. Norman Rosenthal's regulars said he was consider- ing suicide. lt wasn't the first time the pa- tient had entertained the thought, and even thoughhe was 0 Ⅱ antidepressants and always kept up with his appointments, Rosenthal, a licensed psychiatrist with a private practice ⅲ North Bethesda, Md. , wanted to 0ffer his patient something else. "I think you should get B0tox; ” Rosenthal told him. "You should schedule an appoint- ment on your way home. lt was peculiar advice coming from a shrink, but not without precedent. ln 2014 , Rosenthal, a clinical professor ofpsychiatry at Georgetown University Sch001 0f Medi- cine, and Dr. EriC Finzi, an assistant pro- fessor 0f psychiatry at George Washington SchooI of Medicine , published a study show- ing that when people with maJ0r depression got B0tOX, they reported fewer symptoms six weeks later than people who had been given placebo injections. "l'm always on the 100k- out for things that are unusual and interest- ing for depression, ' says Rosenthal, wh0 is widely considered an expert on the condi- tion. "l've found B0tox t0 be helpful, but it's still not malnstream. lt's also not approved by the U. S. F00d and Drug Administration (FDA) for depres- sion, not that that stops doctors from pre- scribing it that way. Such off-label use 0f Botox, like that of any FDA-approved drug, is legal in the U. S. That's because once a drug has been approved by the FDA for a condi- tion, licensed physicians are legally allowed tO prescribe it for any medical issue they think it could benefit, regardless ofwhether ' 夏 meet w physicians 0 are 題取 g ま e toxin everywhere--— for diseases YO WO ー never 取 OW abo MIN DONG, Harvard Medical School BO を ox ド 0 BOtOX was invented as a drug tO treat crossed eyes. TOday it's used on a wide range of disorders—some approved, some not. Here's what tO know: WHAT ー 5 B010X ? Botox comes from a bacterium called Clostridium botulinum that can cause severe fOOd poisoning if eaten. When the drug is injected, it delivers a tiny dose Of toxin that blocks communication between nerves and muscles. 0 0 E S ー N 5 U R A N 0 E 0 0 E R 打 ? Not forwrinkles. Some companies will cover it for FDA-approved medicaluses if Other therapies have not worked. Out Of pocket, it can cost $ 350 to $ 500 per injection. MOSt treatments require multiple shOts. ー 5 IT SAFE? The FDA requires Botox to bear a black-box warning— an alertthat the drug may come with major risks—but most experts agree it's safe when used correctly for approved conditions. Still, serious Side effects have been reported. 引に感 200 リⅲ / ⅵ畆 36 TIME January 16 , 2017

misbranding charge and pay $ 375 million. The company acknowledged that its mar- keting of B0tox led to off-label uses of the drug. Allergan also agreed to pay $ 225 mil- lion t0 resolve civil charges alleging that the marketing 0f B0tox had caused doctors to 61e false reimbursement claims, though Aller- gan denied wrongdoing. The company said in a statement that the settlement was in the best interest Of its stockholders because it avoided litigation costs and permits us tO focus our time and resources on... develop- ing new tre atments. As with any drug, Allergan is legally re- quired tO make known Botox's most severe potential side effects, and ⅲ 2009 the FDA required B0tox t0 bear ablack-boxwarning— the strongest type ofwarning label given t0 any drug—cautioning that there was evl- dence the drug had been linked to serious side effects.With Botox, this includes effects spreading from the injection site tO Other parts ofthe body, causing muscle weakness, double vision and drooping eyelids. ln physicians' offces—where patients typically don't see the box the vials are packed in and therefore may be unaware 0f the black-box warning—the onus is on doc- tors tO outline the potential risks with any patient choosing tO try BOtOX for any condi- tion, FDA-approved or not. Ray Chester, an attorney in Austin whO has represented several plaintiffs in lawsuits against Alle rgan, says that j ust about all the case s he has handled involved off-label use of the drug. ln 2014 a New York couple argued that Botox, which they chose t0 try off-label tO treat their son's cerebral-palsy symptoms, caused life-threatening complications. The family was awarded $ 6.75 million by a jury ・ Allergan, which initially planned t0 appeal' ended up privately settling the case with the family, and the terms ofthe settlement have been kept confidential. Though the off-label use 0f drugs makes many experts—including some at the FDA— uncomfortable, the practice is de rigueur in medicine. lt's hOW doctors learned that Lyr- ica, which is approved tO treat nerve pain, can treat anxiety, and how they learned that finasteride, a drug that treats enlarged pros- tates, can reduce male baldness. "A separate balancing ofrisks andbenefits is necessary for each intended use Ofa drug' even once it iS approved, tO ben- efits ofusing the product tO treat a particular disease or condition outweigh the says FDA press 0ffcer sarah peddicord. OFF-LABEL Once a drug has been approved fO 「 one condition, doctors can use itfor any disorder theythink it can help. Here are just a few uses doctors have embraced: ■ S 部可 y CO hands ■ Lockjaw ■ Back pain ■ Cleft-Iip scars ■ PainfuI sex ■ Depression ■ Premature ejaculation 第 Parkinson's- d isease symptoms ・ AnaI fissures ■ DrooIing ■ Teeth grinding balancing of ホ a 取 benents for each te 取臧 e 臧 use Of a drug, even once approved.' SARAH PEDDICOR D, FDA That's why for any off-label uses that Allergan wants tO market tO doctors and the public—depression, cold hands, atrial fibril- lation in heart-surgery patients—the com pany must conduct its own clinical trials tO show its efflcacy and safety. Allergan does not disclose its research and-development budget for Botox specifi cally, but the company's annual R&D bud- get is about $ 1.5 billion. "This drug is not done in terms Of its different applications, says Allergan's Brin. "lt still has many dif- ferent, exciting, meaningful opportunities for patients. ” THE STUDIES USING BOTOX for depression, like 0ther research into B0tox's off-label po- tential, were SO encouraging that they caught the attention of Allergan. ln Rosentha1 and Finzi's research, 74 people with major de- pressive disorder were randomly assigned tO receive BOtOX injections or a placebo. Six weeks later, 52 % ofthe people who received B0tox experienced a drop ⅲ reported symp- toms, compared with 15 % ofthe people given a placebo. "Over 50 % ofpeople responding is a high number,: ” says Finzi. "These are people whO have already tried Other treatments and they are significantly depre s s ed. ” Now Allergan hopes to replicate the findings on a larger scale, and the company iS currently running its own Phase 2 clini- cal trial. If its results are in line with Rosen- thal and Finzi's, it would be huge, pavmg the way for B0tox t0 0btain 0ffcial approval for the drug as a depression treatment. That wouldn't change anything for doctors , of course—they can already prescribe it 0 価 - label, and some do, with great results—but it would allow Allergan t0 begin marketing B0tox for depression, a change that could dramatically increase its adoption and S ales. still, Botox's use for depression raises a question that confounds some research- ers. ln some cases, hOW BOtOX works iS ev- ident: the toxin can block the signals be- tween nerves and muscles, which is why it can help calm an overactive bladder, say, or a twitching eye, or the facial muscles that make wrinkles more apparent. ln Other cases, however (With migraines as as with depression), scientists are flummoxed. They may have noticed that the drug works for a given condition, but they aren't al- ways sure why—in sciencespeak, they don't know what the mechanism is. With depression, Rosenthal and Finzi think it may relate tO what's known as 39