Halofantrine antimalarial

Halofantrine Antimalarial Cremophore EL, Ethanol, Maisine 35, Captex 355 Improvement in BA [97]... 

Antimalarial therapy employs the same agents and is based on the same principles. The blood-schizonticidal halofantrine is reserved for therapy only. The pyrimethamine-sulfadoxine combination may be used for initial selftreatment. 

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. 

Halofantrine was an important antimalarial drug. It is now infrequently used because of worldwide strain resistance phenomena. Tafenoquine is a new 8-amino-quinoline currently in clinical trials (Phase III) (Figure 8.26). ... 

Halofantrine (Hf) is a new phenanthrenemethanol antimalarial that shares many physicochemical similarities with cyclosporine and has been the subject of a number of investigations in our laboratory. Hf is orally active, well tolerated, and is finding increasing use in the treatment of malaria associated with multidrug resitant strains of Plasmodium falciparum. However, Hf is extremely lipophilic (log P 8) and poorly water soluble (<10 p,g/mL), and the bioavailability of Hf after oral administration of Hf.HCl tablets is low and variable. 

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]. 

Gastrointestinal adverse effects are more common with halofantrine than with other antimalarial drugs (11). 

Toivonen L, Viitasalo M, Siikamaki H, Raatikka M, Pohjola-Sintonen S. Provocation of ventricular tachycardia by antimalarial drug halofantrine in congenital long QT syndrome. Clin Cardiol 1994 17(7) 403-4. 

Halofantrine, a highly lipophilic antimalarial drug with poor and erratic absorption, is metabolized to its equi-potent metabolite desbutylhalofantrine and this is inhibited by oral ketoconazole (41). 

Baune B, Furlan V, Taburet AM, Farinotti R. Effect of selected antimalarial drugs and inhibitors of cytochrome P-450 3A4 on halofantrine metabolism by human liver microsomes. Drug Metab Dispos 1999 27(5) 565-8. 

Huee antimalarial drags have polycyclic ring systems (Fig. 9-10) in common. The flrst is the common tetracycline anti biotic, doxycycline. The second is one of the newer drags luticated for malaria, halofantrine. The third is the discontinued agent used in the South Pacific, aminoacridine. 

Halofantrine. Structurally, halofantrine (Halfan) differs from all other antimalarial drugs. It is a good example of drag de.sign that incorporates bioisosteric principle , as evidenced by the trifluoroethyl moiety. Halofantrine is schiz-... 

Halofantrine is another antimalarial dmg that is being used more now that resistance to chloroquine and quinine has developed. Its mode of action is not known. 

Halofantrine is metabolized into N-desbutyl halofantrine (13) in humans, and it also has antimalarial activity. 

Halofantrine, a synthetic phenanthrene-methanol, is a recently introduced antimalarial drug which is a blood schizonticide. The drug is effective against chloroquine-resistant P. falciparum but has been associated with cardiotoxicity, so it must be used with caution (76). 

Lumefantrine is a derivative of halofantrine that has been reported to exhibit antimalarial activity when combined with artemether in the treatment of multidrug-resistant Plasmodium falciparium. No evidence of cardiotoxicity has been reported with this combination, which may offer promise for successful treatment of resistant organisms. 

Bryson HM, Goa KL. Halofantrine a review of its antimalarial activity, pharmacokinetic properties, and therapeutio potential. Drugs 1992 43 236-258. 

The adverse effects of some antimalarials can be stereoselective. This could be due to pharmacokinetic and/or pharmacodynamic differences between the enantiomers. For halofantrine, evidence has arisen that the (-I-)... 

Figure 3 The enantiomers of halofantrine have similar antimalarial activities but may differ in their cardiotoxic effects. The figure illustrates the ability of varying concentrations of halofantrine enantiomers to inhibit the delayed rectifier potassium channel in feline ventricular myocytes. The (+) enantiomer appears to be more potent. (Figure plotted from data presented in Table II of Ref 16). 

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]. 

Cenni, B. Meyer, J. Brandt, R. Betschart, B. The antimalarial drug halofantrine is bound mainly to low and high density lipoproteins in human serum. Br. J. Clin. Pharmacol. 1995, 39, 519-526. 

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