Halofantrine

The best example of the class of phenanthrene-methanols is halofantrine (66, Halfan [36167-63-2]) a dmg that is effective against chloroquine-resistant malaria and is now being evaluated in Africa. It produces temporary gastrointestinal disturbances. 

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]... 

A, A -dibutyl-2-bromoacetamide (C, H2oBrNO 40124-27-4) see Halofantrine di-tcrr-butyl dicarbonate see under bis( 1,1 -dimethylethyl) dicarbonate... 

Use of a hERG blocker in a patient also taking CYP3A4 inhibitors (e.g. antibacterial macrolides, azole antifungals, HIV protease inhibitors) or CYP2D6 inhibitors (quinidine, halofantrine, fluoxetine, paroxetine, thioridazine, terbinafine) the hERG blocker, if mostly metabolized by these CYP isoforms, may accumulate because... 

Khoo SM, Shackleford DM, Porter CJ, Edwards GA and Charman WN (2003) Intestinal Lymphatic Transport of Halofantrine Occurs After Oral Administration of a Unit-Dose Lipid-Based Formulation to Fasted Dogs. Pharm Res 20 pp 1460-1465. 

Humberstone AJ, Porter CJ and Charman WN (1996) A Physicochemical Basis for the Effect of Food on the Absolute Oral Bioavailability of Halofantrine. J Pharm Sci 85 pp 525-529. 

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. 

Erythromycin (especially intravenous use), halofantrine, some quinolones Amisulpride, haloperidol, sertindole, thioridazine, pimozide Cisapride... 

NSAID and warfarin ACE inhibitors and K-sparing dinretic Verapamil and beta-adrenergic antagonists Nenromnscnlar (NM) blockers and aminoglycosides Alcohol and benzodiazpines Thioridazine and halofantrine Clozapine and co-trimoxazole Increased risk of bleeding Increased risk of hyperkalaemia Bradycardia and asystole Increased NM blockade Increased sedation Increased risk of QT interval prolongation Increased risk of bone marrow suppression... 

Halofantrine, a 9-phenanthrenemethanol derivative, is a blood schizonticide and is active against Plasmodium vivax and chloroquine sensitive as well as chloroquine resistant strains of Plasmodium falciparum. As no parenteral preparation is available it cannot be used for severely ill patients. Oral absorption is slow and incomplete and is increased by a fatty meal. 

The major metabolite is as active as the parent drug but has a longer half-life. The elimination half-life of halofantrine is 1-2 days and of its metabolite 3-5 days. 

Halofantrine is usually well tolerated. Gastrointestinal complaints as well as pruritus and skin rashes may occur. It can prolong the QTc interval which can result in ventricular dysrythmias. Lume-fantrine has many similarities to halofantrine but seems not to prolong QTc. It is thus far only used in a fixed dose combination with artemether (see Section VI.a.2.5). 

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. 

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). 

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). ... 

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