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Worse than the disease?
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As investigators debate its role in a series of military killings, anti-malaria drug mefloquine carries a long, strange history, DAVID AKIN reports
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By DAVID AKIN

Saturday, September 14, 2002 – Page F7

It was Master Sergeant William Wright's job in Afghanistan to teach villagers how to find underground water and dig wells.

He had arrived in March, part of the U.S. Army's 96th Civil Affairs Battalion. By May, his tour of duty had ended and he had persuaded his superiors to let him leave a day early so he could surprise his wife, Jennifer, and their three children at their home on the Fort Bragg army base near Lafayetteville, N.C.

But when he arrived home, he was surprised to find his wife sleeping with another man.

Sgt. Wright, who had never been known to act violently, promptly packed up his things and moved out of the house and into army barracks. But he returned home, police say, on June 29, and Jennifer Wright was never seen alive again.

A few weeks later, Sgt. Wright confessed to the strangulation of his former high-school sweetheart. Jennifer Wright, as it turned out, was the second of four Fort Bragg wives to be killed by their husbands in the span of a few weeks.

The killings had a few links. All the couples, say friends and families, had experienced marital troubles. Three of the four accused husbands had served in Afghanistan.

But there was another common denominator: Three of the four men, including Sgt. Wright, had taken mefloquine, a commonly prescribed anti-malarial medication marketed under the trade name Lariam by Swiss drug giant F. Hoffman-Roche Ltd.

Roche concedes that Lariam can cause severe neuropsychiatric disorders, including manic behaviour, acute psychosis with delusions, and aggressive mood swings, in a very small number of cases, about one in 10,000. Investigators have not yet concluded whether Lariam played any role in the Fort Bragg killings, but they are considering it.

The Canadian Somalia Commission of Inquiry also looked at Lariam when it investigated the 1993 beating death of a Somali teenager at the hands of Canadian troops. Many soldiers were given mefloquine while on duty in Somalia.

The commission, which was shut down prematurely by the federal government, was unable to sort out the difficult and complex science of mefloquine and the brain's chemistry. Ultimately, it decided that it could not say if mefloquine played in the events that led to the death of Shidane Arone.

But the commission certainly heard from soldiers and army medical staff that mefloquine provoked numerous psychological side effects among the troops in Somalia. "Ten patients experienced nightmares. . . . One patient heard voices and talked to himself. All were switched to [another anti-malarial agent] with no subsequent problems," its 1997 report said.

One Canadian army major said that the men in his unit used to joke that "if you get somebody angry, he's just going to walk into the old church tower and waste 20 people" and then say, "Oh, sorry, bad mefloquine trip."

Canadians in Somalia got their weekly dose of mefloquine on Wednesdays. The U.S. soldiers took their Lariam pill on Tuesdays, prompting some members of the U.S. forces to dub that day of the week "Psycho Tuesdays."

Canada's Department of National Defence has been prescribing mefloquine for its ground soldiers and navy personnel since 1992, a year before the drug was approved by Health Canada for civilian use. By all accounts, the Canadian mission in Afghanistan was unmarred by any incidents like those of the Somalia scandal -- but the troops did take mefloquine, and some reported strong nightmares and other psychological oddities.

Armies and mefloquine have grown up together -- like most anti-malarial drugs, it is the product of army medical research. Private-sector drug companies rarely initiate malaria research for the simple reason that there is little money to be made in wiping out a disease that affects the world's poorest people. But armies have an incentive to keep their soldiers healthy in the jungle.

"The motivation to pursue research on a malaria vaccine was not so much altruistic as it was imperial," Robert Desowitz wrote in his 1991 book The Malaria Capers. The malaria parasite was first discovered by a surgeon in the French army, and it was a surgeon in the British army who deduced that mosquitoes carried the disease. As the first great colonial powers of the modern world, the French and the British deployed significant resources to combat malaria.

But as their global presence faded, the United States filled the vacuum.

With malaria killing more U.S. soldiers than North Vietnamese bullets, finding a drug that could protect them become a top priority for the U.S. Army's medical researchers by the end of the 1960s.

In 1971, scientists at the Walter Reed Army Institute of Research in Baltimore discovered that quinoline-methanol, a chemical cousin to quinine known as mefloquine, was an excellent chemoprophylactic (a chemical condom) to shield those who took it from malaria.

The World Health Organization, Roche and the Walter Reed researchers agreed to jointly develop the drug and, by 1985, Roche was ready to manufacture it, receiving regulatory approval first in Europe and then later in North America.

It was seen as an important weapon to combat one of the world's leading health problems. Malaria infects more than 500 million people a year and, of those, nearly three million die, according to the World Health Organization.

But anecdotes of bizarre Lariam-influenced behaviour surfaced within a few years of the drug's commercial use.

In 1998, a schoolmaster in England stole 36,000 of school-trip money and then blamed the side effects of Lariam for his aberrant behaviour. Vanessa Brunt, who her family said was a healthy and happy 22-year-old student at Cambridge University, committed suicide in 1999 after receiving doses of Lariam. And this year, a former Democratic Congressman in Philadelphia was charged with defrauding friends and supporters of $10-million (U.S.). He told the judge in the case that he couldn't tell right from wrong because of the side effects of Lariam.

Even as early as 1993, H. A. H. Mashaal, the World Health Organization's senior malariologist from 1957 to 1982, put out the call for a broad review of mefloquine's use and related adverse effects.

But all of this doom and gloom about mefloquine is, according to some researchers, nothing more than the media's uninformed overreaction.

Last year, a group of Canada's top malaria and infectious-disease researchers wrote in the Canadian Medical Association Journal that "real and perceived intolerances to mefloquine have received substantial and occasionally irresponsible coverage in the Canadian media. As a result, many Canadian travellers refuse to take mefloquine, even when it is clearly the most appropriate choice."

They say mefloquine can be a literal lifesaver in certain parts of the world. Roche, too, is standing by its product, although it mailed out warnings this year to U.S. health-care practitioners in which it spelled out some of the potential neuropsychiatric reactions.

As for Master Sergeant William Wright, he remains in jail in North Carolina and faces a trial in the killing of his wife. Prosecutors are sure to point to a jealous husband who strangled his wife in a fit of rage. His lawyer, though, may dust off a pile of scientific studies and point the finger at one of the world's most popular anti-malarial drugs.

Anti-malaria arsenal

Experts say it is vitally important that anyone who travels to a region where there is a risk of malaria talk to their doctor well before travelling, usually six to eight weeks. There is no one drug that is suitable for all, nor is there there a malaria vaccine, though researchers at Oxford University began testing a potential one this summer in Gambia. This list contains the drugs' generic names, followed in brackets by trade names.

Chloroquine (Aralen). For more than 40 years, this has been the most widely used anti-malarial drug. As a result, though, malaria parasites in African and some parts of Asia are now resistant to it.
Mefloquine (Lariam). Now recommended as the first defence by Health Canada, the World Health Organization and the U.S. Centers for Disease Control. Has been a source of controversy due to its rare neuropsychiatric side effects (see main story). Highly effective in sub-Saharan Africa. Less so in some parts of southeast Asia.
Doxycyline (Vibramycin or Doryx). Generally now the choice for a patient who is unable to take chloroquine or mefloquine. Not suitable for pregnant or breast-feeding women, or for young children.
Atovaquone plus proguanil (Malarone). Only recently licensed in Canada, it is as effective as mefloquine and has significantly fewer side effects, but is a significantly more expensive drug.
Primaquine. Somewhat less effective than first-line drugs. Also requires a special blood test before it can be prescribed.

Not recommended
These drugs are no longer sanctioned in Canada, but travellers may see them sold in other countries.
Proguanil (Paludrine). Not recommended for malaria protection by Health Canada.
Pyrimethamine plus sulfadoxine (Fansidar). No longer available in Canada because it can cause severe skin reactions.

Sources: Health Canada; Dr. Jay Keystone, Toronto General Hospital's centre for travel and tropical medicine; The Globe and Mail