Mefloquine Plasmodium falciparum

The Plasmodium falciparum malaria PD model successfully described the antimalarial effect of artemisinin, mefloquine, and a combination of the two drugs... 

Following the development of synthetic antimalarial agents, such as chloroquine and mefloquine, the use of Cinchona alkaloid quinine declined. However, with the emergence of chloroquine-resistant and multiple-drug-resistant strains of malarial parasites, its use has become firmly reestablished. Quinine is the drug of choice for severe chloroquine-resistant malaria due to Plasmodium falciparum. In the U.S., the related alkaloid quinidine is recommended because of its wide availability and use as an antiarrhythmic agent. In many clinics in the tropics, quinine is the only effective treatment for severe malaria unfortunately, decreasing sensitivity of P. falciparum to quinine has already been reported from Southeast Asia. 

Brockelman CR, Monkolkeha S, Tanariya P (1981) Decrease in susceptibility of Plasmodium falciparum to mefloquine in continuous culture. Bull World Health Organ 59(2) 249-252... 

Lambros C, Notsch JD (1984) Plasmodium falciparum mefloquine resistance produced in vitro. Bull World Health Organ 62(3) 433-438... 

There was a high frequency of amphetamine abuse and withdrawal among patients from the Thai-Myanmar border area admitted to hospital with Plasmodium falciparum malaria (90). This co-morbidity can cause diagnostic confusion, alter malaria pathophysiology, and lead to drug interactions. Considering the potential neuropsychiatric adverse effects of mefloquine, an important component of current antimalarial treatment in Southeast Asia, it should be avoided in patients who abuse amphetamines. 

There are two reasons for the great interest being shown in artemisinin and its derivatives. First, there is little cross resistance with Plasmodium falciparum between the members of this series and the quinoline-based antimalarials like chloroquine (203). On the contrary, significant potentiation of effect is observed in combination with chloroquine analogs such as mefloquine (204). Second, the high lipid solubility of, for example, arte-mether ensures rapid penetration into the CNS, so these sesquiterpene lactones are first-... 

Mefloquine (t) 21 d) is similar in several respects to quinine although it does not intercalate with plasmodial DNA. It is used for malaria chemoprophylaxis, to treat uncomplicated Plasmodium falciparum (both chloroquine-sensitive and chloroquine resistant) and chloroquine-resistant Plasmodium vivax malaria. Mefloquine is rapidly absorbed from the gastrointestinal tract and its action is terminated by metabolism. When used for prophylaxis, 250 mg (base)/week should be taken, commencing 1-3 weeks before entering and continued for 4 weeks after leaving a malarious area. It should not be given to patients with hepatic or renal impairment. 

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. 

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, Wilairatana P, Chokejindachai W, Chalermrut K, Wernsdorfer W, Gemperli B, Gathmann I, Royce C. A randomized, double-blind, comparative trial of a new oral combination of artemether and benflumetol (CGP 56697) with mefloquine in the treatment of acute Plasmodium falciparum malaria in Thailand Am J Trop Med Hyg 1999 60(2) 238 3. 

Mefloquine, a fluorinated derivative of 4-quinoline methanol, is a product of the US Army s antimalarial research program. It is active against chloroquine-resistant Plasmodium falciparum, and has an excellent schizonti-cidal effect in the blood in experimentally induced Plasmodium vivax infections in volunteers. It is not gametocidal. P. vivax infections can persist after successful treatment of the falciparum infection with other drugs the fact that mefloquine is effective against both organisms is thus of practical importance (SEDA-13, 808). 

MacArthur J, Stennies GM, Macheso A, Kolczak MS, Green MD, Ali D, Barat LM, Kazembe PN, Ruebush TK 2nd. Efficacy of mefloquine and sulfadoxine-pyrimethamine for the treatment of uncomplicated Plasmodium falciparum infection in Machinga District, Malawi, 1998. Am J Trop Med Hyg 2001 65(6) 679-84. 

Smithuis FM, van Woensel JB, Nordlander E, Vantha WS, ter Kuile FO. Comparison of two mefloquine regimens for treatment of Plasmodium falciparum malaria on the northeastern Thai-Cambodian border. Antimicrob Agents Chemother 1993 37(9) 1977-81. 

Hoffman SL, Rustama D, Dimpudus AJ, Punjabi NH, Campbell JR, Oetomo HS, Marwoto HA, Harun S, Sukri N, Heizmann P, Laughlin LW. Rll and Rill type resistance of Plasmodium falciparum to combination of mefloquine and sulfadoxine/pyrimethamine in Indonesia. Lancet 1985 2 1039 0. 

Sidhu, A. B., Uhlemann, A. C., Valderramos, S. G., Valderramos, J. C., Krishna, S., and Fidock, D. A. (2006). Decreasing PfMDRl copy number in Plasmodium falciparum malaria heightens susceptibility to mefloquine, lumefantrine, halofantrine, quinine, and artemisinin. ]. Infect. Dis. 194,528-535. 

Mefloquine is an antimalarial preparation that acts as a blood schizonticide. It is indicated in the treatment of mild to moderate malaria caused by mefloquine-susceptible strains of Plasmodium falciparum or P. vivax and prevention of malaria caused by P. falciparum or P. vivax. Patients with acute P. vivax need subsequent treatment with 9-ami-noquinolone to prevent relapse. 

E. F. (1985) Cloning and characterization of mefloquine-resistant Plasmodium falciparum from Thailand. Am. J. Prop. Med. Hyg. 34 1022 1027. 

Wilson, C. M., Volkman, S. K., Thaithong, S. et al. (1993) Amplification of pfmdrl associated with mefloquine and halofantine resistance in Plasmodium falciparum from Thailand. Mol. Biochem. Parasitol. 57 151-160. 

Up to the middle of this century quinine (1) was used for the treatment of malaria, and with the widespread development of chloroquine-resistant strains of Plasmodium falciparum it has become important again. Quinine has been used for the treatment of malaria for more than 350 years and has its origin in Peru in the early 17th century. Quinine was the lead structure in the discovery of new synthetic derivatives like mefloquine that have higher antimalarial activity. This section will focus on other new quinoline alkaloids. The mechanism of antiplasmodial action and resistance of quinolines is well described elsewhere [116]. 

Flalofantrine is considered to be an alternative drug for treatment of both chloroquine-sensitive and chloroquine-resistant Plasmodium falciparum malaria, but its efficacy in mefloquine-resistant malaria may be questionable. The drug is metabolized via N-dealkylation to desbutylhalofantrine by CYP3A4 (Fig. 39.14). The metabolite appears to be several-fold more active than the administered drug. 

Mefloquine 274 is a useful alternative treatment agent for Plasmodium vivax malaria and Plasmodium falciparum malaria in areas, where chloroquine is still recommended as the first-hne therapeutic agent.Mefloquine is a chiral molecule with two asymmetric carbon centers, and it exists as a mixture of diastereomers. The drug is currently manufactured and sold as a racemate of the (+1—) R,S enantiomers by Hoffman-LaRoche. The (+) enantiomer is more effective in treating malaria, and the (—) enantiomer specifically binds to adenosine receptors in the central nervous system, which may explain some of its psychotropic effects.It is not known whether mefloquine can be transformed into its stereoisomer in vivo. 

Basco, L.K. Gillotin, C. Gimenez, F. Farinotti, R. Le Bras, J. In vitro activity of the enantiomers of mefloquine, halofantrine and enpiroline against Plasmodium falciparum. Br. J. Clin. Pharmacol. 1992, 33, 517-520. 

Rifampicin 600 mg daily was given to 7 healthy subjects for 7 days with a single 500-mg dose of mefloquine on day 7. The maximum plasma level of mefloquine decreased by 19% and the AUC decreased by 68%. Ri-fampiein, a potent enzyme-inducer, inereases the metabolism of mefloquine by the cytochrome P450 isoenzyme CYP3A4 in the liver and gut wall. The clinical relevance of this reduetion in mefloquine levels uncertain, but the authors suggest that simultaneous use of rifampicin and mefloquine should be avoided to prevent treatment failure and the risk of Plasmodium falciparum resistance to mefloquine. Until more is known, this would seem a sensible precaution. 

Quinine (10.33) has been the mainstay in treating chloroquine-resistant cases of malaria. It intercalates into DNA very little and acts on the parasites in some quite different, but as yet unknown, way from chloroquine (Estensen, Krey and Hahn, 1969). Quinine is a wasteful drug because a high proportion of each dose is oxidized, in the 2-position, by the patient s liver and the product is inactive. This defect was overcome by the insertion of non-oxidizable substituents into that position. A particularly successful drug of this kind is mefloquine (10.34) which, in a single dose of 0.5 g, can produce clinical cure in patients whose life is threatened by chloroquine-resistant strains of Plasmodium falciparum. This drug does not react in any way with DNA (Davidson et al., 1977). 

Adovelande J, Boulard Y, Berry J-P, Galle P, Slodzian G, Schrevel J. Detection and cartography of the fluorinated antimalarial drug mefloquine in normal and Plasmodium falciparum infected red blood cells by scanning ion microscopy and mass spectrometry. Biol Cell 1994 81 185-192. 

In 342 children with Plasmodium falciparum malaria who were randomly assigned to artesunatemefloquine or mefloquine alone all the children recovered clinically with similar fever clearance times [13. Parasite clearance was significantly faster in those who took the combination. Gameto-cyte carriage rates and drug-attributable reductions in hematocrit were significantly lower with the combination. Most of the adverse events were attributable to malaria. 

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. 

Praziquantel (40 mg/kg), mefloquine (25 mg/kg), artesunate (3 doses of 4 mg/kg), and mefioquine + artesunate (3 doses of artesunate 100 mg - - mefloquine 250mg) have been compared in a randomized open trial in 83 schoolchildren with Schistosoma haematobium infections [22 ]. The effects on Schistosoma mansoni, malaria parasitemia, soil-transmitted helminths, and intestinal protozoa were also determined. Cure rates were 88%, 21 %, 25 %, and 61 % respectively. Both mefloquine-I-artesunate and praziquantel resulted in greater than 95% egg reduction rates. There were significantly lower egg reduction rates with artesunate (85%) and mefloquine (74%). In children co-infected with S. mansoni, praziquantel and mefloquine+artesunate, but not mefloquine and artesunate alone, resulted in high cure rates and egg reduction rates. Mefloquine, artesunate, and mefloquine-I-artesunate completely cured infections due to Plasmodium falciparum. There were no effects against soil-transmitted helminths and intestinal protozoa. There were four cases of mild headache (two with mefloquine and two with praziquantel) and two cases of moderate coughing (one with artesunate and one with mefloquine) both symptoms were also reported before treatment. There were 48 mild and 70 moderate adverse events recorded at 24,48, and 72 hours after... 

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