Randomised trial of artesunate and mefloquine alone and in sequence for acute uncomplicated falciparum malaria

Looareesuwan, Sornchai; Viravan, C; Vanijanonta, S; Wilairatana, Polrat; Suntharasamai, Pravan; Charoenlarp, P; Arnold, Keith; Kyle, Dennis E.; Webster, Kenneth; Canfield, Craig J.

doi:10.1016/0140-6736(92)90276-9

Cited by 145 publications

(57 citation statements)

References 13 publications

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“…16 Rapid reduction in fever and the number of parasites were observed in P. vivax-infected patients treated with artesunate, similar to that in P. falciparum-infected patients in our previous study. 17 Table 2 shows that group IV patients had the most rapid PCT compared with other 3 groups. In group IV, primaquine was sequentially given at 72 hr, in which the mean Ϯ SD PCT was 41.1 Ϯ 14.3 hr (range ϭ 6-67 hr).…”

Section: Discussionmentioning

confidence: 95%

Efficacy of primaquine regimens for primaquine-resistant Plasmodium vivax malaria in Thailand.

Wilairatana

Silachamroon²,

Krudsood³

et al. 1999

The American Journal of Tropical Medicine and Hygiene

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Abstract. To define the current efficacy of Fansidar (F. Hoffmann-La Roche Ltd., Basel Switzerland) (pyrimethamine and sulfadoxine), primaquine in a high dose, and artesunate for treating acute Plasmodium vivax malaria, we conducted a comparative clinical trial of these 3 drugs in an open-label study. Patients (15-65 years old) were assigned to 1 of 4 treatments regimens in a serial order. Ninety percent of the patients were infected at Thailand-Myanmar border. Patients in group I (n ϭ 23) received Fansidar (3 tablets, 75 mg of pyrimethamine and 1,500 mg of sulfadoxine, a single dose on the first day), group II (n ϭ 23) received Fansidar (3 tablets, 75 mg of pyrimethamine and 1,500 mg of sulfadoxine, a single dose on the first day) and then received primaquine (30 mg a day for 14 days), group III (n ϭ 23) received primaquine (30 mg a day for 14 days), and group IV (n ϭ 23) received artesunate (200 mg once a day for 3 days) and then primaquine (30 mg a day for 14 days). Cure rates on day 28 of follow-up were 40%, 100%, 100%, and 100% in groups I, II, II, and IV, respectively. There were 4 and 5 patients in group I showing post-treatment reappearance of parasitemia at Յ 16 days and between 17 and 28 days, respectively. Patients in the other 3 groups showed negative parasitemias within 7 days after treatment. Artesunate plus primaquine (group IV) cleared parasitemia faster than the other 3 regimens. There is a high proportion of ineffectiveness of Fansidar for treatment of P. vivax malaria and it should be no longer used for treatment of P. vivax malaria acquired at the Thailand-Myanmar border. A high dose of primaquine is safe and effective in the treatment of P. vivax malaria during the 28-day follow-up period.Plasmodium vivax causes a clinically benign illness but relapse is frequent. It is a common cause of malaria in Asia and South America. In a recent study among a population residing on the western border of Thailand, P. vivax was found in 2,573 (54%) of 4,728 persons over a period of 2 years.

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Section: Discussionmentioning

confidence: 95%

Efficacy of primaquine regimens for primaquine-resistant Plasmodium vivax malaria in Thailand.

Wilairatana

Silachamroon²,

Krudsood³

et al. 1999

The American Journal of Tropical Medicine and Hygiene

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“…The drug is generally well tolerated, but may be occasionally associated with neuropsychiatric adverse effects. 9,10 A series of controlled studies showed high efficacy rates and good tolerability for the artesunate/mefloquine combination, [11][12][13][14][15][16][17][18][19][20] and consequently, it has become a standard regimen for the treatment of uncomplicated malaria in southeast Asia. However, treatment strategies differ in terms of treatment duration (from one day 13 to five or more days 18 ), and in terms of dosing.…”

Section: Introductionmentioning

confidence: 99%

Artesunate and mefloquine given simultaneously for three days via a prepacked blister is equally effective and tolerated as a standard sequential treatment of uncomplicated acute Plasmodium falciparum malaria: randomized, double-blind study in Thailand.

Krudsood¹,

Looareesuwan²,

Silachamroon³

et al. 2002

The American Journal of Tropical Medicine and Hygiene

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Abstract. The combination of artesunate and mefloquine is currently one of the most effective treatments against multidrug-resistant Plasmodium falciparum malaria. To improve patient compliance to such a combination, the two agents have been combined in a prepacked single blister. Patients were instructed to simultaneously co-administer the drugs once a day for three days. In the present randomized, double-blind, parallel group, comparative, single center study in Thailand, this concept was investigated in 204 adults and children with acute, uncomplicated P. falciparum malaria. Patients were randomized into two treatment groups and received once a day over a three-day period the following: Group A received artesunate, 4-5 mg/kg/day, and mefloquine, total dose ‫ס‬ 25 mg/kg, ∼8.5 mg/kg/day, simultaneously. Group B received artesunate, 4-5 mg/kg/day, and mefloquine, total dose ‫ס‬ 25 mg/kg, sequentially (i.e., no mefloquine dose on the first day, 15 mg/kg on the second day, and 10 mg/kg on the third day). Both treatment groups showed no relevant differences in baseline demographic and clinical characteristics. Intent-to-treat analysis revealed a cure rate at day 28 (primary endpoint) of 100% in group A and 99% in group B (difference not significant). The secondary endpoints of mean time to fever clearance (group A ‫ס‬ 34 hours, group B ‫ס‬ 31 hours) and mean time to parasite clearance (group A ‫ס‬ 44 hours group B ‫ס‬ 48 hours) were similar between groups (both differences not significant). Tolerability was good in both treatment groups, with no difference in the overall incidence of adverse events. There was a low incidence of nausea/vomiting (4.9% in both groups) and central nervous system side effects (4.9% in group A versus 8.8% in group B). These were comparable between groups and generally of a mild nature. The three-day combination of artesunate and mefloquine (Artequin, Mepha, Ltd., Aesch, Switzerland) with the introduction of mefloquine on day 1 offers a practical dosing regimen that is highly effective and well tolerated in patients of different ages with uncomplicated P. falciparum malaria. It is likely that the prepacked blister approach translates clinically into a better patient compliance, thereby contributing to limit the development of drug resistance.

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“…However, because of the high recrudescence rate when used as monotherapy, many current therapeutic regimens used in Southeast Asia include a combination of one of the artemisinin derivatives and mefloquine. [6][7][8][9] The combination therapy with other drugs (lumefantrine, tetracycline, pyrimethamine, desferrioxamine) is under evaluation. [10][11][12][13] Although pharmacokinetic data are incomplete, it has been established that all currently available artemisinin derivatives are metabolized rapidly to dihydroartemisinin, the biologically active main human metabolite.…”

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confidence: 99%

In vitro activity of dihydroartemisinin against clinical isolates of Plasmodium falciparum in Yaounde, Cameroon.

Ringwald¹,

Bickii²,

Basco³

1999

The American Journal of Tropical Medicine and Hygiene

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Abstract. The in vitro activities of dihydroartemisinin (the biologically active metabolite of artemisinin derivatives), chloroquine, monodesethylamodiaquine (the biologically active metabolite of amodiaquine), quinine, mefloquine, halofantrine, and pyrimethamine were assessed in 65 African isolates of Plasmodium falciparum from Yaoundé, Cameroon using an isotopic microtest. The 50% inhibitory concentration (IC 50 ) values for dihydroartemisinin were within a narrow range from 0.25 to 4.56 nM, with a geometric mean of 1.11 nM (95% confidence interval ϭ 0.96-1.28 nM). Dihydroartemisinin was equally active (P Ͼ 0.05) against the chloroquine-sensitive isolates (geometric mean IC 50 ϭ 1.25 nM, 95% confidence interval ϭ 0.99-1.57 nM) and the chloroquine-resistant isolates (geometric mean IC 50 ϭ 0.979 nM, 95% confidence interval ϭ 0.816-1.18 nM). A significant positive correlation was observed between the responses to dihydroartemisinin and mefloquine (r ϭ 0.662) or halofantrine (r ϭ 0.284), suggesting in vitro crossresistance. There was no correlation between the responses to dihydroartemisinin and other antimalarial drugs.Artemisinin (qinghaosu) has been used for centuries in traditional Chinese medicine for antimalarial treatment. 1 In 1972, Chinese scientists isolated the active principle from the plant Artemisia annua. 2 Artemisinin is a sesquiterpene lactone characterized by the presence of an endoperoxide that is associated with a potent antimalarial activity. Because artemisinin is chemically unstable and poorly soluble in water or oil, the carbonyl group at C-10 of the parent compound was reduced to obtain dihydroartemisinin. Several derivatives have been developed by adding an ether, ester, or other substituents to the hydroxyl group of dihydroartemisinin. These semi-synthetic derivatives include the water-soluble derivatives, sodium artesunate and artelinic acid, and the oilsoluble derivatives, artemether and arteether. With the exception of arteether and artelinic acid, these compounds are used to treat malarial infections in endemic countries, mainly in Southeast Asia and, to a lesser extent, in Africa and South America.Artemisinin derivatives are available in different formulations for oral, parenteral, and rectal administration. Clinical studies have shown that artemisinin derivatives are highly potent, rapidly acting, and well-tolerated blood schizontocides, resulting in shorter parasite clearance times than other antimalarial drugs. 3,4 Artemisinin derivatives are highly effective against Plasmodium falciparum isolates that are resistant to other drugs. These derivatives are indicated for the emergency treatment of severe and complicated falciparum malaria by parenteral administration and for the oral treatment of uncomplicated multidrug-resistant malaria. 5 So far, resistance to artemisinin derivatives has not been reported in clinical studies. However, because of the high recrudescence rate when used as monotherapy, many current therapeutic regimens used in Southeast Asia include a combination of o...

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Randomised trial of artesunate and mefloquine alone and in sequence for acute uncomplicated falciparum malaria

Cited by 145 publications

References 13 publications

Efficacy of primaquine regimens for primaquine-resistant Plasmodium vivax malaria in Thailand.

Efficacy of primaquine regimens for primaquine-resistant Plasmodium vivax malaria in Thailand.

Artesunate and mefloquine given simultaneously for three days via a prepacked blister is equally effective and tolerated as a standard sequential treatment of uncomplicated acute Plasmodium falciparum malaria: randomized, double-blind study in Thailand.

In vitro activity of dihydroartemisinin against clinical isolates of Plasmodium falciparum in Yaounde, Cameroon.

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