NEW YORK (Reuters Health) – Adding either of the potent gametocytocidal drugs primaquine and methylene blue to certain antimalarial combinations can safely block human-to-mosquito transmission and may be used for P. falciparum malaria control and elimination, researchers say.
Primaquine has been used for decades to treat P. vivax malaria; methylene blue, a laboratory dye in use for nearly a century, has been shown to act as an antimalarial agent when injected into the bloodstream, according to Michelle Roh of the University of California, San Francisco, and colleagues.
For their phase 2 randomized controlled trial, the team recruited males ages 5 to 50 years with asymptomatic P. falciparum malaria who were G6PD-normal and had gametocytes detected by blood smear. Females were excluded to mitigate the risk of hemolysis through incorrect classification (as normal) of G6PD-deficient female heterozygotes.
The primary efficacy endpoint, assessed in patients infected before and after treatment, was the median within-person percentage change in mosquito infectivity two and seven days after treatment, as assessed by membrane feeding.
As reported online February 5 in The Lancet Infectious Diseases, 80 participants were randomly assigned to one of four regimens (20 patients each): sulfadoxine-pyrimethamine and amodiaquine; sulfadoxine-pyrimethamine and amodiaquine plus a single dose of primaquine; dihydroartemisinin-piperaquine; or dihydroartemisinin-piperaquine plus three doses of methylene blue.
At baseline, 54 participants had infected at least one mosquito: 19 in the sulfadoxine-pyrimethamine and amodiaquine plus primaquine group; 12 each in the sulfadoxine-pyrimethamine/amodiaquine-alone and the dihydroartemisinin-piperaquine groups; and 11 in the dihydroartemisinin-piperaquine plus methylene blue group.
Median within-person reduction in mosquito infectivity on day two was 100% with the two regimens that contained primaquine or methylene blue – higher than a 10.2% reduction with sulfadoxine-pyrimethamine plus amodiaquine-alone and a 6.0% reduction with just dihydroartemisinin-piperaquine.
After exclusion of blue urine, adverse events were similar among the groups.
“The key take-home is that we are now able to know, with a high level of certainty, that primaquine and methylene blue can be used to effectively block transmission of malaria parasites to mosquitoes,” Roh told Reuters Health.
“Adding a transmission-blocking drug to our current regimens would be a low-cost intervention to ensure that the spread of malaria, including drug-resistant forms, is contained,” she said by email.
“Taking methylene blue can turn your urine blue, which may affect one’s adherence to the drug,” she noted. “This side effect was not seen as harmful, and given the limited number of drugs we have to fight malaria, methylene blue is a promising candidate that we can add to the malaria toolbox.”
Dr. Ric Price of the University of Oxford, UK, coauthor of a related editorial, told Reuters Health by email, “If malaria-endemic countries are going to succeed in eliminating malaria, more-aggressive interventions are needed to target the large numbers of apparently healthy individuals who harbor transmissible malaria parasites.”
“The only currently available drug that targets the sexual stages of P. falciparum is primaquine,” he noted. “This study highlights a potential role of methylene blue – another ‘old’ antimalarial – which was given once a day for three days.”
“Advantages of methylene blue are that, like primaquine, it is cheap and may have a role in increasing the rate at which asexual parasites are cleared from the blood,” he said. “Disadvantages include the need for a three-day regimen, rather than a single dose of primaquine, and discoloration of the urine.”
“Reliance on a single therapeutic intervention to reduce mosquito infectivity is risky,” Dr. Price cautioned. “Hence the inclusion of another drug to reduce transmission is welcome, but further clinical trials are needed to optimize the dose.”
SOURCES: http://bit.ly/2F15AMQ and http://bit.ly/2EmeqHN
Lancet Infect Dis 2018.
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