The curious case of clioquinol
An indigestion drug blamed for a debilitating illness that affected thousands of people in the 1950s has been resurrected as a potential treatment for Alzheimer's disease. But not everyone is cheering for the drug, clioquinol, to make a comeback.
Walking with the help of his cane, polio survivor Herbert Schaumburg searched the halls of the conference building in Geneva, Switzerland. It was 1980, and Schaumburg was there to speak about a discontinued drug embroiled in a health scare scandal. Schaumburg ducked into a room, hoping to find the place for his scientific presentation, and was surprised to see a host of other disabled people. Some were in wheelchairs, others were blind and others relied on canes, just like him. "They greeted me warmly," says Schaumburg. "They thought I was one of them."
But Schaumburg wasn't one of them, because he didn't suffer from the same nervous system pain and paralysis that had brought them there. He had accidentally walked into a meeting of people who had come to share their experiences as victims of a debilitating condition with one another. In contrast, Schaumburg had come as a scientific expert to speak about the presumed cause of their illness, which had claimed a reported 10,000 victims. He had come to talk about a drug called clioquinol.
Across the ocean and two decades later, an Australian doctoral student named Ashley Bush came across clioquinol while exploring an unorthodox theory about Alzheimer's disease. The theory centers on the belief that the illness is triggered by a buildup of metals in the brain. And one drug that could stop that buildup, Bush discovered, was clioquinol, the same compound that had been implicated in the disease outbreak. "I've had a hell of a time with [this drug]," he says. "But I'm confident that we'll come out on top."
One of the earliest mass-marketed drugs, clioquinol has had a long and complicated history, with its reputation once seemingly beyond rescue. However, the blacklisted compound seems to be on its way to redemption -- Bush and other researchers who study neurodegenerative diseases are making a case for clioquinol's potential as a therapy. Lab tests have suggested that the compound inhibits an enzyme implicated in aging called clk-1. And new studies offer evidence that it may even fight cancer. With these findings and other new research, clioquinol perhaps has a chance of overcoming its haunted past.
A haunted history
Clioquinol acts as a mild metal chelator, binding metals like iron, copper and zinc in the body. Originally produced as a topical antiseptic, it was later marketed by the Swiss company Ciba-Geigy (now Novartis) in the 1930s as an effective amebicide for treating indigestion and diarrhea. A cheap over-the-counter drug with little to no apparent side effects at the time, it was used occasionally by Americans and Europeans when traveling abroad.
In Japan, however, people took clioquinol much more often. "They consumed it with heroic abandon," Schaumburg says. "Their doctrine was to be clean inside as well as out. The Japanese ate it the way you ate oatmeal every morning." An estimated 30,000 kilograms per year of clioquinol were consumed in Japan in the early 1950s.
In 1956, however, people in Japan began complaining of numbness, pain and intestinal distress. The symptoms only got worse, with many victims ending up paralyzed and blind, and the disease continued to spread. Baffled doctors named it subacute myelo-optic neuropathy, or SMON.
The Japanese government launched an extensive clinical and scientific investigation to find the source of SMON. Outbreaks had occurred in clusters, indicating a virus, but researchers couldn't come to any definite conclusions. Meanwhile, more people poured through doctors' offices with the illness. "When people got sick with diarrhea, the doctor would just give them more [clioquinol]," says Schaumburg. "They gave enormous amounts of the stuff."
The first real clue to the outbreak was tied to the illness's most bizarre symptom: patients' tongues would turn blackish green. In 1970, researchers tested the green deposit and found it to be an iron deposit of clioquinol. They quickly tested the drug on dogs and discovered clioquinol had the same deleterious neurologic effects on the animals.
Scientists at Ciba-Geigy were unable to reproduce the results, spurring them to call in Schaumburg, a neurologist at the Albert Einstein College of Medicine in New York, along with other experts to serve on a panel that reviewed 220 clinical cases for five days. Not every case was legitimate, and the scientists suspected that many of the 10,000 reported cases in Japan were unrelated. However, they agreed the disease was real and caused by clioquinol.
Whereas the Ciba-Geigy scientists had given the drug to dogs on an empty stomach, the Japanese scientists had given clioquinol to dogs after feeding them. It took a full belly of food for the drug to behave as it did in humans. Schaumburg subsequently cooperated in a series of toxicology studies with Ciba-Geigy scientists, and the team eventually reproduced a SMON-like illness in the brains of dogs.
Weighing the "boatload of horrible publicity," and fearful of more instances of the disease, Schaumburg says, Ciba-Geigy executives made a formal apology. "In view of the fact that medical products manufactured and sold by us have been responsible for the tragedy, we extend our apologies, frankly and without reservation, to the plaintiffs and their families," they said in a statement. In March 1985, Ciba-Geigy finally took the drug off the market worldwide, ending clioquinol's era as an over-the-counter pill.
The comeback
While pursuing his doctoral degree at the University of Melbourne in Australia in the 1990s, Ashley Bush unwittingly resurrected clioquinol as he developed his theory about Alzheimer's disease and amyloid plaques (the globs of protein found in the brains of individuals with Alzheimer's).
Scientists have hotly debated whether the amyloid plaques are the cause or the effect of the disease. Bush believes these amyloid plaques are precipitated by trace metals, such as zinc and copper accumulating in the brain, leading to Alzheimer's.
He has used evidence from clioquinol experiments to support his theory. In one study, Bush used a strain of mice that develop amyloid plaques in the brain. The mice that received clioquinol had half as many plaques after nine weeks of treatment when compared with their control counterparts. Although clioquinol is conventionally recognized as a metal chelator-binding metals and blocking their reactions -- Bush is convinced that it also functions as an ionophore, a compound that moves ions across cell membranes. Specifically, he believes that the drug moves metals from outside the cell, where they cause neuron damage, back inside it, where they are safely metabolized.
Despite positive results in his research, Bush's theory has frequently been dismissed by the mainstream research community. "It's amazing how fast people's eyes glaze over when you talk about metals in a biological conference. We're taught to ignore them," he says. "They call them trace metals, but at the concentrations they're in the brain, I don't know why the hell we call them trace."
Ignoring naysayers, Bush forged ahead and began clinical trials with the company Prana Biotechnology, which he co-founded in 1997 in his native city of Melbourne. In 2000, they launched a randomized, double-blind, phase 2 clinical trial involving 32 participants with Alzheimer's disease. The report showed that people with Alzheimer's on placebos deteriorated to a severely affected status, whereas the cognitive abilities of the clioquinol-treated group stayed steady over 36 weeks. The team saw no adverse effects due to clioquinol, thanks to low and controlled doses, and Prana prepared to ramp up production and run more trials with the drug.
Other experts remain concerned, however, about the therapeutic use of clioquinol. "There was no question the cause of SMON was clioquinol, [and] it's a very miserable neurological condition," says Masaaki Konagaya, a physician at the Suzuka hospital in Suzuka, Japan and a member of the country's SMON Research Commission. "As for potential treatment of Alzheimer's disease, the neurotoxicity of [clioquinol] should be noticed."
Schaumburg is also cautious when it comes to using the drug to combat Alzheimer's. "You have to be careful -- you're talking about giving it to those people for life. If you give a lot of medicine at a low level, eventually you'll get the same effect as if you gave a large dose at one time," he says. "This drug is potentially too toxic for these poor old people, -- for that reason, I wouldn't give it to my grandma."
However, Bush claims that of nearly 2,500 people diagnosed with SMON in Japan, 25% had never taken clioquinol.
"It was overdiagnosed," Schaumburg concedes. "A lot of people actually had MS [multiple sclerosis] -- Japanese doctors diagnosed anybody who was spastic. There were very few genuine cases."
Bush is skeptical that clioquinol caused any cases of SMON at all. "We learned the hard way that when you manufacture clioquinol, you create a toxic byproduct," he says, noting how Prana had been planning to ramp up production of the pill a few years ago when their batch became contaminated. Bush speculates that this same contaminant might have gotten into Ciba-Geigy's clioquinol two decades ago, possibly causing the SMON outbreak. "Maybe people [in Japan] had ingested the toxic byproduct," says Bush.
For Prana, it was too costly to attempt to purify the clioquinol; they decided to move on to a clioquinol derivative, PBT2, which seems to avoid the problems associated with clioquinol and offers even better results, according to Bush. "It benefits cognition in animals extremely quickly. They performed better than a normal mouse," he says. "It's the most potent preclinical agent out there."
Bush has since tested the clioquinol derivative in a preliminary clinical trial with 74 subjects, which showed a time- and dose-dependent improvement in performance on two frontal lobe tests compared to subjects on placebo 6. Bush says Prana plans to run two more phase 3 trials and claims that the drug could be on the market in as soon as three or four years.
Despite these results, however, Bush still feels like an underdog. "It's been a long time since I've been invited to an Alzheimer's conference, let me tell you," says Bush. "They're trying to ignore us, but we're publishing too much." Indeed, their positive results have gained them some respect. "I think it's perfectly viable strategy. It's wacky in an upbeat way, because the results look promising," says Sam Gandy, an Alzheimer's researcher at the Mount Sinai School of Medicine in New York. "Last year, before they had those results, it was just wacky."
Old drug, new hope
Researchers studying other neurodegenerative diseases also have hope for clioquinol. Steven Massa, a neurologist at the University of California-San Francisco reported that in a mouse model of Huntington's disease, the mice given clioquinol improved in outward symptoms and showed a decrease in the brain protein aggregates symptomatic of the disease. Julie Anderson, a neurobiologist at the Buck Institute for Age Research in Novato, California gave clioquinol to mice with a Parkinson's-like disease, showing that the drug offered some protection against the disease in mice.
Siegfried Hekimi, a biologist at McGill University who specializes in the mechanisms of aging, has a theory on why clioquinol seemingly protects the brain against Huntington's, Parkinson's and Alzheimer's. He has an inkling that the drug might work "because it does something that ultimately results in the slowing down of aging."
Specifically, Hekimi believes clioquinol binds an iron atom in the mitochondrial enzyme clk-1, thereby inhibiting it. Previous studies have shown that when the clk-1 enzyme is inhibited in mice and worms, the animals' aging process is slowed down. Hekimi gave clioquinol to Caenorhabditis elegans worms, which showed a marked decrease in growth -- remaining in the larval stage when untreated worms had already grown into adults; biochemical analysis also proved that the worms? clk-1 enzyme was inhibited.
Clioquinol is even being tested as a tool to fight cancer. Research out of the lab of Wei-Qun Ding at the University of Oklahoma showed that eight different human cancer cell lines were killed when treated with clioquinol.