Mefloquine Artesunate

ACTs are currently recommended artemether-lume-fantrine, artesunate + amodiaquine, artesunate + mefloquine, artesunate + sulfadoxine-pyrimethamine [1, 5]. In areas with amodiaquine and sulfadoxine-pyrimethamine resistance exceeding 20%, i.e., SE Asia, artesunate + mefloquine or artemether-lumefantrine should be used [1,5]. 

Three currently-used artemisinin based combination therapies (ACT) artesunate-mefloquine, artemether-lumefantrine and dihydroartemisinin-piperaquine, have been proven highly simple, safe and effective in the treatment of multidrug resistant P. falciparum malaria. 

Artesunate-mefloquine Standard therapy in parts of Southeast Asia... 

Mefloquine is effective in treating most falciparum malaria. The drug is not appropriate for treating individuals with severe or complicated malaria, since quinine, quinidine, and artemisinins are more rapidly active, and since drug resistance is less likely with those agents. The combination of artesunate plus mefloquine showed excellent antimalarial efficacy in regions of Southeast Asia with some resistance to mefloquine, and this regimen is now one of the combination therapies recommended by the WHO for the treatment of uncomplicated falciparum malaria (Table 52-4). Artesunate-mefloquine is the first-line therapy for uncomplicated malaria in a number of countries in Asia and South America. 

Lumefantrine was inferior to artesunate + mefloquine in an open, randomized comparison in 617 patients in Thailand with uncomplicated multidrug-resistant malaria tropica, but produced two to four times fewer adverse effects, such as nausea, vomiting, dizziness, sleep disorders, or other neurological symptoms (4). 

In the last few years, variations on the basic stracmre have been launched in combination with other antimalarials (usually variations on the chloroquine structure) such as dihydroartemismin and piperaquine phosphate (Artekin), artemether and lumefantrine (Coartem), artesunate/mefloquine (Artequin) and artesunate, sulfamethoxypyrazine, and pyrimethamine (Co-Arinate). Currently, there is another fixed dose combination with an artemisinin derivative in clinical trials, pyronaridine/artesunate (Pyramax in Phase III). However, the tri-oxo scaffold system in artemisinins has led to the synthesis of not only artemisinin variations but to totally synthetic molecules with the trioxane moiety included, such as arterolane tosylate (81). This compound is in Phase II trials as a single agent under Ranbaxy and is in Phase I trials in combination with piperaquine phosphate, also under Ranbaxy. 

In an open, randomized comparison of mefloquine (25 mg/kg), artesunate (three doses of 4 mg/kg), artesunate + mefloquine (three doses of artesunate 100 mg+mefloquine 250 mg), and praziquantel (40 mg/kg) in 83 children with Schistosoma haematobium infection, the cure rates at day 26 were 21%, 25%, 61% and 88% respectively [14 ]. Both artesunate + mefloquine and praziquantel achieved egg reduction rates of over 95%. Abdominal pain was the most frequent adverse reaction, with a higher incidence among children treated with mefloquine (89%), mefloquineartesunate (83%), and artesunate (60%) than in those treated with praziquantel (40%). 

Sowunmi A, Gbotosho GO, Happi C, Okuboyejo T, Folarin O, Balogun S, Michael O. Therapeutic efficacy and effects of artesunate-mefloquine and mefloquine alone on malaria-associated anemia in children with uncomplicated Plasmodium falciparum malaria in Southwest Nigeria. Am J Trop Med Hyg 2009 8(6) 979-86. 

Keiser J, N Guessan NA, Adoubryn KD, Silue KD, Vounatsu P, Hatz C, Utzinger J, N Goran EK. Efficacy and safety of mefloquine, artesunate, mefloquine-artesunate and praziquantel against Schistosoma haematobium randomized, exploratory open-label trial. Clin Infect Dis 2010 50 1205-13. 

Antiprotozoal Drugs. Figure 5 Artemisinin combination therapy (ACT) Adding a 3-days artesunate course to mefloquine cleats the parasitaemia much more rapidly (A — A). The remaining parasites are exposed to higher mefloquine levels in ACT (B) compared to mefloquine monotherapy (B (with permission White, 1997 Antimicrob Agents Chemother 41 1413-1422). 

Artesunate x 3 days + mefloquine has been used in several Asian countries for MDR falciparum malaria. Artesunate 4 mg/kg/day x 3 day and mefloquine 25 mg/kg single splitting into 2 dose 6-8 hours apart (15 mg/kg then 10 mg/kg). 

Severe or complicated infections with P falciparum3 Artesunate, 2.4 mg/kg IV, every 12 hours for 1 day, then daily for two additional days follow with 7 day oral course of doxycycline or clindamycin or full treatment course of mefloquine or Malarone Artemether, 3.2 mg/kg IM, then 1.6 mg/kg/d IM follow with oral therapy as for artesunate... 

Bukirwa H, Orton L. Artesunate plus mefloquine versus mefloquine for treating uncomplicated malaria. Cochrane Database Syst Rev. 2005 CD004531. 

Quinine, mefloquine, chloroquine, artesunate, artemether and primaquine (gametocytocides) act on sexual forms and prevent transmission of the infection because the patient becomes noninfective and the parasite fails to develop in the mosquito (site 4). 

Artesunate is a water-soluble hemisuccinate derivative, available in parenteral and oral formulations. The parenteral drug is dispensed as powdered artesunic acid. Neutral aqueous solutions are unstable. Artesunate is effective by the intravenous, intramuscular, and oral routes in a dose of 10 mg/kg given for 5-7 days. The combination with mefloquine is very effective even against highly multi-resistant strains of Plasmodium falciparum, the combination must be given for at least 3 days. 

The artemisinin derivatives are limited by an unacceptable incidence of recrudescence with monotherapy, and they therefore need to be used in combination. A summary of prospective trials that looked specifically for adverse effects showed that artemisinins alone are very well tolerated (10). The same study showed no evidence of adverse interactions of artesunate with mefloquine, with an incidence of adverse effects similar to that expected from malaria and mefloquine (25 mg/kg) together. Reducing doses of mefloquine increases recrudescence rates to unacceptable levels (11). Combinations of artemisinins with quinine, co-trimoxazole, and doxycycUne are well tolerated. 

In a second Thai study, 652 adults and children were treated with artesunate plus mefloquine (15). A single dose of artesunate 4 mg/kg plus mefloquine 25 mg/kg gave a rapid response but did not improve cure rate. Artesunate given for 3 days in a total dose of 10 mg/kg plus mefloquine was 98% effective. The incidence of vomiting was significantly reduced by giving the mefloquine on day 2 of the treatment. There were no adverse effects attributed to artesunate. 

Table 1 Adverse effects of artesunate with or without mefloquine in acute uncomplicated malaria tropica...

Artemisinin derivatives (artesunate and artemether) for the treatment of multidrug-resistant Plasmodium falciparum malaria have been evaluated in 83 Karen pregnant women in Thailand 55 women were treated for recrudescent infection after quinine or mefloquine, 12 for uncomplicated hyperparasitemic episodes, and 16 had not declared their pregnancy when treated (32). 

Looareesuwan S, Viravan C, Vanijanonta S, WUairatana P, Suntharasamai P, Charoenlarp P, Arnold K, Kyle D, Canfield C, Webster K. Randomised trial of artesunate and mefloquine alone and in sequence for acute uncomplicated falciparum malaria. Lancet 1992 339(8797) 821. ... 

The combination of mefloquine with artesunate improves tolerance to mefloquine and the therapeutic response is faster (SEDA-21, 296). 

McGready R, Brockman A, Cho T, Cho D, van Vugt M, Luxemburger C, Chongsuphaj aisiddhi T, White NJ, Nosten F. Randomized comparison of mefloquine-artesunate versus quinine in the treatment of multidrug-resistant falciparum malaria in pregnancy. Trans R Soc Trop Med Hyg 2000 94(6) 689-93. 

Artemether pretreatment appears to modestly reduce mefloquine levels, whereas artemisinin and dihydroartemisinin do not affect the pharmacokinetics of mefloquine. If mefloquine is given shortly after artesunate its levels are lowered, but giving mefloquine two days in to artesunate treatment appears to raise mefloquine levels. The combined use of mefloquine with artemisinin derivatives might improve antimalarial activity. See also Co-artemeth-er + Mefloquine , p.224... 

The combined use of artesunate and mefloquine is one of the recommended treatment options in the WHO guidelines for the treatment of uncomplicated falciparum malaria, and for uncomplicated vivax malaria in selected areas. They say that mefloquine is usually given on day 2 of combined treatment. 

---