14 November 2002 16:00 EST

by Edward Susman

[caption and credit]

Denver - Phase III studies of the anti-malarial compound tafenoquine, tested on Australian soldiers assigned to United Nations peacekeeping troops in East Timor, demonstrate the drug is at least as effective as the controversial drug mefloquine, researchers say. Next on the agenda: Figuring out exactly how the drugs work.

The half-life of tafenoquine - about 14 days - makes it an attractive candidate for prophylaxis against Plasmodium vivax, said Peter Nasveld, a physician from the Australian Defence Force in Canberra. Nasveld was among the contingent of troops patrolling East Timor, and presented his report at the annual meeting of the American Society of Tropical Medicine and Hygiene here.

The researchers assigned 462 soldiers to receive tafenoquine, and 153 to receive mefloquine (also called Larium) in a double-blind study. During the six-month tour of duty in East Timor, where P. vivax is endemic, no soldier in either group developed symptomatic malaria, the researchers found.

P. vivax affects about 100 million people worldwide, particularly in southern Asia and the Americas. Although infection can prove fatal, its course of illness is less severe than malaria caused by P. falciparum.

On their return to Australia, soldiers in the mefloquine cohort received primaquine, an 8-aminoquinoline compound, twice a day for 15 days. The tafenoquine patients were given placebo.

Five cases of malaria developed about four to five months later among the troops - four of the tafenoquine group, and one in the mefloquine/primaquine group - less than 1% in each group. All the malaria cases were attributed to P. vivax.

"We were pretty happy with the results," said Nasveld, adding side-effects were similar in both groups of patients. Tafenoquine is being jointly developed by the US Army and GlaxoSmithKline.

In the meantime, other researchers are actively investigating how the drugs block P. vivax infection, a puzzle that has remained unsolved for more than 20 years.

"No one knows how 8-aminoquinolines manage to control P. vivax," said Bruce Russell, a postdoctoral fellow at the US Armed Forces Research Institute of Medical Sciences, based in Bangkok, Thailand.

"We believe that once the drugs becomes concentrated in the liver cells, it prevents P. vivax from infecting patients," Russell said. Before going to work on the US Army project, Russell was stationed in East Timor with Australian forces, and was given experimental doses of tafenoquine in early testing of the drug.

Russell described methods of detecting and quantifying the exo-erythrocytic stage of infection by the P. vivax parasite, and observing the effects of both tafenoquine and primaquine by infecting the human hepatocyte cell line (HC-04) with Plasmodium sporozites.

"This work may give us the unique capability to sort out how these drugs work," Russell said.

Once the genetic sequencing of P. vivax is completed, an imminent event, Russell anticipates performing genetic microarray screens of the infected hepatocytes before and after they are challenged with tafenoquine or another drug in its class.

The differences in genetic patterns on the arrays could provide clues to the pathways being used by the drugs, Russell suggested.

Picture caption:
Left: map of East Timor. Right: blood smear with developing P. vivax, CDC/Dr. Mae Melvin.

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See also:
Focus on Plasmodium vivax
[Meeting report]
Barbara Sina
Trends in Parasitology, 2002, 18:7:287-289

Malaria prophylaxis/radical cure: recent experiences of the Australian Defence Force
M.D. Edstein, D.S. Walsh, C. Eamsila, et al.
Med Trop (Mars), 2001 61:56-8

Development of new drugs for chemoprophylaxis of malaria
W.K. Milhous
Med Trop (Mars), 2001 61:48-50

Malaria chemoprophylaxis with tafenoquine: a randomised study
B. Lell, J.F. Faucher, M.A. Missinou, et al.
Lancet, 2000 Jun 355:2041-5

Focus on Plasmodium vivax
[Meeting report]
Barbara Sina
Trends in Parasitology, 2002, 18:7:287-289

Antimalarial Chemotherapy: Mechanisms of Action, Resistance and New Directions in Drug Discovery
[Book Review]
Simon Croft
Drug Discovery Today, 2001, 6:22:1151

Swallowing the bitter pill of drug resistance
[Book]
David
C. Warhurst
Trends in Pharmacological Sciences, 2001, 22:8:437-438

Chemotherapy for Falciparum Malaria: The Armoury, the Problems and the Prospects
[Review]
P.A. Winstanley
Parasitology Today, 2000, 16:4:146-153
 

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