the Garogh larIAM TARIB WAS FAMOUS HOW
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Both Lariam and Halfan were discovered at the Experimental Therapeutics Division of the Walter Reed Army Institute of Research (WRAIR) in Washington DC.3 In the earliest published reports, these two drugs had not yet been named, and they were still referred to by their respective Walter Reed experimental numbers: WR 142 490 and WR 171 669.1,4 Lariam and Halfan were the two main progeny of the WRAIR malaria drug discovery programme, which ran from 1963 until 1976.
Over a 15-year period, vast resources were voted by the US federal government to fund WRAIR's antimalaria drug research, which at the time was the largest drug discovery programme ever mounted. The political driving force behind the programme was the severe clinical setback experienced by the US military during the Vietnam War, when at one stage 1% of US combat troops were succumbing to malaria each day.6 Because of the size and urgency of the research task, WRAIR collaborated with numerous governmental, academic and commercial organizations, including 175 external contractors.7
From the early 1960s onwards, WRAIR screened over 250 000 potential antimalaria compounds.8 Lariam was number 142 490 in this long series, and Halfan was number 171 669. Because the US military was and remains forbidden by Congress from operating in the commercial sector, WRAIR engaged the holding companies F. Hoffmann-La Roche and Smith Kline Beecham to market these two promising novel agents.
The precise details of the three-way business agreement between WRAIR, the US federal government and the two multinational drug companies which marketed Lariam and Halfan have not been made public. It appears, however, that all of WRAIR's phase I and phase II clinical trial data on Lariam and Halfan were delivered as a free good to F. Hoffmann-La Roche and to Smith Kline Beecham. Drug approval was swiftly granted by the Food and Drug Administration (FDA): Lariam was approved in 1989 and Halfan in 1992.
From the perspective of the two drug companies chosen to act as the marketing arm of WRAIR, the primary commercial potential of Lariam and Halfan lay in their ability to prevent malaria in tourists and business travellers to the tropics. Prior to their obtaining FDA approval, however, no randomized Phase III tolerability study was carried out on either drug in a normal study population of healthy civilian volunteers.9 Likewise, there was no serious attempt prior to licensing to explore the potential drug-drug interactions of either Lariam and Halfan; some of the fatal drug reactions which followed may have been a direct consequence of the resulting gap in the prescribers' knowledge base.
Within months of their being licensed, major safety concerns around Lariam and Halfan began to emerge. These two compounds should have been welcomed by the public as being safe, effective and lifesaving pharmaceutical weapons in a world where international travel was increasing exponentially and where chloroquine-resistant malaria seemed to be spreading just as rapidly.10 Instead, consumers viewed the two new drugs with disquiet, and later with concern and alarm.
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THE SITUATION TODAY
Though still prescribed in most countries, both for preventing and treating malaria, Lariam is now known to cause neurotoxicity.11 This unexpected property came to prominence in the mid-1990s, when national pharmacovigilance centres, initially in Europe, began to receive recurring reports of neuropsychiatric adverse effects caused by this new antimalaria agent. In the Netherlands during 1998 and 1999, mefloquine was respectively the most and the second most cited drug in spontaneous reports of drug-related illness made to the Lareb Pharmacovigilance Foundation.12 Around the same time, it was reported that 60% of all the mefloquine occurrences notified to the WHO's Uppsala Monitoring Centre cited neuropsychiatric disturbance secondary to the drug.12
Belatedly, three randomized controlled trials were carried out in healthy volunteer populations, and were reported between 2001-2003.13-15 The studies confirmed mefloquine's potential for causing psychological illness, and all three study reports described an excess of neuropsychiatric adverse effects in the mefloquine arm.13-15 Around the same time an analysis of the cause of illness in 4524 travellers returning from sub-Saharan Africa to the northern hemisphere found that, excluding diarrhoea and fever as causes, mefloquine was the fifteenth most common cause of post-travel illness.16 A case control study of 564 Dutch travellers between 1997 to 2000 found a threefold increase in the incidence of psychiatric events with mefloquine use (OR 3.5, 95% CI 1.4-8.7), and a very high risk of psychiatric events in women users of the drug (OR 47.1, 95% CI 3.8-578.6).17 A survey of the recent literature shows that mefloquine has been causally associated with 19 deaths in users, including three suicides