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On Feb. 4, 2004, on a cold, snowy day in Gero, Gifu Prefecture, Haruhiko Nokiba’s 17-year-old son fell sick. The fevered teen visited a local doctor, tested negative for a flu virus but was prescribed an antiviral drug called Symmetrel. He took a capsule that evening and another the following morning, but he still felt unwell and feverish, so on Feb. 5 he saw a doctor again. This time he tested positive for type A influenza. He was given another, more recently approved antiviral called Tamiflu.

The son, whose name Nokiba would not reveal, came back home, had udon noodles for lunch and, just around noon, took his first capsule of Tamiflu. Nokiba, who is a salesman for a local hotel, had a meeting that afternoon, so at around 2 p.m. he checked his son’s room, saw him sound asleep and left home.

Then something bizarre happened. At around 3:45 p.m., police later learned, the teen bolted out the backdoor of the family’s detached house, barefoot and in pajamas. He left a line of footsteps in the thick snow as he trotted down a hill, crossed a railway track, climbed over a crash barrier and leaped onto a busy road, where the driver of an oncoming 10-ton truck saw him and slammed on the brakes. But he was not fast enough. The teen was run over and died on the spot.

Police concluded that it was a “traffic accident,” while locals rumored that it was a suicide. But Nokiba felt strongly that his son would have never killed himself. “He had no major problems in school at the time,” Nokiba told The Japan Times recently. “He played basketball at the school and his team had just had a game a week before, in which he was a starting player. He was gentle and had many friends. I know my son.”

Nokiba requested an investigation into the death by a semigovernmental agency that collects information on drugs. A year and a half later, he received a notice from the agency, which said that the teen’s “suicide” was linked to the first drug he took. Nokiba found it suspicious because there was no mention whatsoever of Tamiflu, the drug his son took shortly before running out of the house.

Today, Nokiba says he is convinced that it was Tamiflu that made his son act so weirdly. His conviction is growing, as a series of other mysterious deaths have emerged in recent years, including cases of youths having taken the drug who have jumped to their deaths from high-rise apartment buildings.

Popular in Japan

Tamiflu, or oseltamivir phosphate, manufactured by Swiss-based Roche Group and marketed in Japan by its subsidiary Chugai Pharmaceutical Co., is enormously popular in Japan, where a total of 35 million people have taken it for flu treatment since its approval in 2001 — accounting for more than 70 percent of its global consumption, according to the Health, Labor and Welfare Ministry.

But the blockbuster drug is under a cloud of doubt. Between 2000 and October 2006, 54 people, including 16 children, died after taking Tamiflu, health ministry statistics show.

The ministry, in May 2004, did make it mandatory for Chugai Pharmaceutical to mention “neuropsychiatric symptoms” in its leaflets, such as disturbances in consciousness, abnormal behavior, delirium, hallucination, delusion and convulsion as side effects. But the ministry for years did little more, despite tougher action demanded by Nokiba and others who have been concerned with the drug’s safety, on grounds that “no causal relationships” have been found between Tamiflu and abnormal behavior. It has argued that influenza itself might also be linked.

Doubts grow

The government has based its safety arguments on a report compiled at the ministry’s request last year by a researchers’ group headed by Yokohama City University Professor Shumpei Yokota. Dr. Yokota, who is a pediatrician, and seven other experts, surveyed some 2,800 doctors who treated children with a flu. They concluded last fall that the rates of abnormal behavior exhibited between those who took Tamiflu and those who didn’t were not statistically different.

Then came revelations last week that Dr. Yokota had been paid a total of 10 million yen by Chugai Pharmaceutical — the seller of Tamiflu — between 2001 and 2006, casting doubt on the credibility of the research. Yokota told a news conference that the “research grants” from Chugai did not influence the report’s outcome.

Officials of Yokohama City University said that the money — part of 48.6 million yen he received from about 10 drug makers during the 6-year period — was properly accounted for by the university. “It was not the kind of money the professor could use freely as an individual,” Shinji Imai, an administrator at the university, said. But he said that Yokota’s office has been allowed to use the grants for a wide range of purposes, such as to buy office supplies and equipment, finance travel expenses for academic trips and salaries for assistants.

Even before news broke of the payments, observers of Yokota’s work said the report was riddled with flaws. Dr. Rokuro Hama, chairman of the Osaka-based NPOJIP, a pharmaco-vigilance group, said the survey failed to take into account the fact that, with Tamiflu, most abnormal behaviors have taken place within six hours of the first or second dose. The survey compared the rates of abnormal behavior between Tamiflu users and nonusers over a seven-day period, concluding that their rate difference — 10.6 percent among nonusers and 11.9 percent among users — was too small to prove Tamiflu guilty.

Hama argued that if you compared the frequency of abnormal behavior in the daytime of the first day the patients got sick, it is almost four times higher among Tamiflu users than nonusers. He also pointed to a U.S. Food and Drug Administration memorandum in September 2006 that looked into cases mostly from Japan and said that FDA researchers “cannot rule out the possible contribution of oseltamivir to the adverse consequence over and above the adverse symptoms which may result from the natural history of influenza-illness.”

Ministry hits back

Responding to a barrage of criticism, Yasushi Jotatsu, a health ministry official in charge of drug safety, said Hama’s comparison cannot explain a large amount of abnormal behavior seen in other time slots. He said the FDA document was just a “discussion paper,” noting that many of the views expressed in the memorandum didn’t make it to the agency’s final conclusion in November 2006, which required Roche to revise its product label to mention “an increased risk of self-injury and confusion after taking Tamiflu.” Japan adopted the same warning level in May 2004, he said.

Jotatsu admitted, however, that the report was not comprehensive enough to evaluate the actions of children right before and after taking Tamiflu, saying the ministry is asking Yokota to conduct another, more detailed survey this year, covering at least 10,000 people.

Even so, the ministry finally issued a warning to doctors on Feb. 28 this year, after two more teenagers — a 14-year-old girl in Gamagori, Aichi Prefecture, and another 14-year-old boy in Sendai, Miyagi Prefecture — jumped to their deaths from condominium buildings in which they lived after taking Tamiflu earlier that month. While still negative on the drug’s link to the deaths, the ministry urged doctors to tell families of flu patients to keep their eye on minors, at least during the first two days, “regardless of whether or not the patients are prescribed Tamiflu.”

Is Tamiflu safe enough to be given to your child? Maybe not for a regular flu virus, said Dr. Kazuhiko Kabe, a pediatrician and chief of the newborn infants department at Aiiku Hospital in Tokyo. While many experts consider Tamiflu, at the moment, the No. 1 choice for a possible pandemic triggered by bird flu, he is not sure if it is safe or effective enough for such an outbreak.

Overuse

But he said people in Japan have used Tamiflu way too frequently, whereas in the U.S., for example, people would not normally visit a doctor every time they have flu-like symptoms or get tested for influenza. “Japanese people blindly believe that, if you come down with flu, you must take Tamiflu,” Kabe said. “That’s just abnormal.”

An excessive fear of flu might be explained by the exceptionally high prevalence in Japan of influenza-assoc- iated encephalopathy — inflammation of the brain caused by viral infection — among children, which can cause deaths and severe brain damage, Kabe said. Such complications have been found to occur at a much higher rate among Japanese and Taiwanese than people from other nations (the mechanism of the illness is yet to be fully understood). But Kabe said that most people can get over flu if they take good rest and endure three days of high fever. “Not all flu patients develop encephalopathy.”

Kabe has not prescribed Tamiflu this season for most patients, considering the rising number of sudden deaths. But informing parents about the pitfalls of using Tamiflu has been a challenge because faith in the drug remains strong among the public, despite the news reports of abnormal behavior, he said.

“My gut feeling tells me that Tamiflu was probably linked, albeit maybe not directly, in those reported cases. (But) there is a lot of demand for it from patients, and I bet some people have gone elsewhere to have the drug prescribed.”

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