Mefloquine Halofantrine

Knowledge of local resistance patterns is important to determine the treatment regimen. There is increasing chloroquine and pyrimethamine-sulfado-xine (Fansidar) resistance in Africa and in some areas at the border of Thailand there is resistance for almost all antimalarial drugs including halofantrine, mefloquine and quinine. In these areas only the artemisinin derivatives (artemether, arteether, arte-sunate, dihydroartemisinin) are effective. 

The recently introduced antimalanal halofantrine (6) is an orally active blood schizonucide reported to be more than 95% effective in the treatment of malaria [S] Mefloquine hydrochloride (7) contmues to be useful m the prophylaxis and treatment of malaria [9]... 

For uncomplicated falciparum malaria there are several options (with the major drawback in brackets) halofantrine (arrhytmia), mefloquine (neurotoxicity), quinine (vomiting, tinnitus), artemether (recrudescence), atovaquone-proguanil (possible fast development of resistance). 

Sporadic resistance to mefloquine has been reported from many areas. At present, resistance appears to be uncommon except in regions of Southeast Asia with high rates of multidrug resistance (especially border areas of Thailand). Mefloquine resistance appears to be associated with resistance to quinine and halofantrine but not with resistance to chloroquine. 

Peytavin et al. [17] have reported on the chiral resolution of mefloquine, halofantrine, enpiroline, quinine, quinidine, chloroquine, and primaquine by subcritical fluid chromatography on a (S) naphthylurea column (250 X 4.6 mm ID). The mobile phase consisted of carbon dioxide, methanol, and triethylamine at a 3-ml/min flow rate. Except for primaquine and... 

In parallel, extensive studies on P. falciparum field isolates in Gabon [140-142], Senegal [143], Cambodia [118, 119, 144], and the Thailand Burmese border [145] corroborated the efficacy of FQ on the parasite whatever its resistance level to chloroquine or to other commonly used antimalarials mefloquine, quinine, halofantrine, and artemisinin derivatives [146, 147]. The cross reactivity observed in some studies with CQ was limited and it was demonstrated that it was caused by differences in initial parasitemia among isolates at the start of the assays [141]. Independance of susceptibility of P. falciparum with phenotypic variation of pfcrt gene, responsible for CQ resistance, could be suspected from these results, but this was demonstrated at the molecular level on Cambodia isolates [148] and extended further on other genes currently involved in resistance to aminoquinoline antimalarials [89, 90]. 

Chloroquine, quinine, mefloquine, halofantrine, proguanil, pyrimethamine, and tetracyclines blood schizontocides) kill these asexual forms. Drugs which act on this stage in the cycle of the parasite may be used for ... 

The loading dose shovild not be given if the patient has received quinine, quinidine or mefloquine in the previous 24 h see also warnings about halofantrine (below). 

Early laboratory studies suggested cross-resistance of halofantrine with mefloquine. In rats, parasites that are resistant to mefloquine, quinine, chloroquine, and amodiaquine are also markedly resistant to halofantrine (13). 

Lumefantrine is a synthetic aminoalcohol fluorene derivative, related to halofantrine and mefloquine (1). It was highly effective in uncomplicated chloroquine-resistant malaria tropica in an open, non-comparative trial in 102 patients in China when given in four oral doses over 48 hours (2). No significant adverse effects have been reported. It has also been marketed in a combination of artemether (20 mg) plus lumefantrine (120 mg). 

Instances of mefloquine resistance were reported in Tanzania in 1983, in Thailand in 1989, and in Africa (Malawi) in 1991. Resistance to combinations of mefloquine with sulfadoxine and pyrimethamine was reported in 1985 (SEDA-13, 808) (40 4). The possibility of crossresistance between mefloquine and halofantrine was raised in 1990 (SEDA-13, 808) (45). Currently there are extensive areas, including Thailand, Cambodia, Laos, Papua New Guinea, and Myanmar, where P. falciparum... 

Early laboratory studies suggested cross-resistance between mefloquine and halofantrine, but in a later rodent model cross-resistance was not absolute (SEDA-12, 700). 

Gay F, Bustos DG, Diquet B, Rojas Rivero L, Litaudon M, Pichet C, Danis M, Gentilini M. Cross-resistance between mefloquine and halofantrine. Lancet 1990 336(8725) 1262. 

Drugs used to treat an acute attack. Blood schizonticides are used to suppress an acute attack, and the various drugs used include oral chloroquine, mefloquine or quinine plus pyrimethamine or doxycycline or halofantrine. 

Among potential malarial treatments attributable to the program are 1) mefloquine, 2) halofantrine, 3) artemisinin, and 4) a compound currently known as WR238605. Mefloguine was developed jointly by Walter Reed, WHO, and Hoffman-LaRoche, Inc., and was recently approved for U.S. marketing by the U.S. Food and Drug Administration (FDA). Halofantrine is a potential prophylactic jointly developed by Walter Reed and SmithKline Beecham that may be effective... 

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. 

Pyrimethamine-sulfadoxine or, plus Tetracycline or, plus Clindamycin Mefloquine Halofantrine... 

Quinine resistance in P. falciparum more closely resembles resistance to mefloquine and halofantrine than to chloroquine. A number of different transporter genes may confer resistance to quinine. 

Five compounds may be considered within this class of drugs quinine, chloroquine and hydroxychloroquine, mefloquine, and halofantrine (Figs. 39.11 and 39.12). These compounds not only share a structural similarity but also are thought to have similar mechanisms of action, are effective on the same stage of the parasite, and may share similar mechanisms of resistance. 

Stereoselectivity has been reported in the pharmacokinetic properties of some of the chiral antimalarial drugs (chloroquine, hydroxychloroquine, halofantrine, and mefloquine Tables 1 and 3). Each of these drugs possesses low hepatic extraction ratios, large Vd and ranging from one day to months. Plasma protein binding has been reported to range from about 50% (chloroquine and hydroxychloroquine. Table 3) to over 99% (halofantrine [19]). Chloroquine and its hydroxylated congener. 

Some chiral metabolites of antimalarial drugs possess significant levels of antimalarial activity in comparison to parent drug. For example, the main circulating metabolite of halofantrine, ( )-desbutylhalofantrine, possesses an in vitro level of antimalarial activity similar to that of parent drug [42]. The enantiomers of this metabolite also share similar antimalarial activities in vitro. Stereoselectivity in pharmacokinetic properties of these chiral metabolites could influence an assessment of antimalarial activities. On the other hand, neither of the enantiomers of the major 4-carboxylic acid metabolite of mefloquine possesses antimalarial activity [43]. 

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. 

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