Halofantrine Chloroquine

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. 

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. 

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. 

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 ... 

Adverse effects. Halofantrine may cause gastrointestinal symptoms pruritis occurs but to a lesser extent than with chloroquine which may be reason for it to be preferred. It prolongs the cardiac QT interval and may predispose to hazardous arrhythmia. The drug should therefore not be taken ... 

Chlorphenamine enhances the efficacy of chloroquine in acute uncomplicated falciparum malaria, but the disposition of chloroquine in these circumstances is unpredictable. Chloroquine (25 mg/kg) was given orally over 3 days in combination with chlorphenamine to Nigerian children with parasitemia (45). The peak whole blood chloroquine concentration was increased and the time to peak concentration shortened. In small trials there seemed to be an increase in QT interval with this combination, but less than with halofantrine (46). However, in other studies, the addition of chlorphenamine to chloroquine did not amplify the cardiac effects of chloroquine (46). 

There is an increased risk of dysrhythmias, including torsade de pointes, when halofantrine is combined with qui-nine/quinidine or chloroquine and any other drug that prolongs the QT interval (52). 

Sowunmi A, Fehintola FA, Ogundahunsi OA, Ofi AB, Happi TC, Oduola AM. Comparative cardiac effects of halofantrine and chloroquine plus chlorpheniramine in children with acute uncomphcated falciparum malaria. Trans R Soc Trop Med Hyg 1999 93(l) 78-83. 

Simooya OO, Sijumbil G, Lennard MS, Tucker GT. Halofantrine and chloroquine inhibit CYP2D6 activity in healthy Zambians. Br J Chn Pharmacol 1998 45(3) 315-17. 

Adverse effects with the dosages originally recommended have in general been mild, no more than nausea, diarrhea, headache, and pruritus (SEDA-13, 820) (2-4). Pruritus occurred markedly less often with halofantrine than with chloroquine (SEDA-16, 306). A comparison between high-dose chloroquine (35 mg/kg total in three daily doses) and halofantrine in the standard dose (total 25 mg/kg given at 6-hour intervals) in patients 4—14 years old showed a fairly similar frequency of adverse effects. Itching was a common adverse effect of chloroquine (4). 

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). 

Wildling E, Jenne L, Graninger W, Bienzle U, Kremsner PG. High dose chloroquine versus micronized halofantrine in chloroquine-resistant Plasmodium falciparum malaria. J Antimicrob Chemother 1994 33(4) 871-5. 

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). 

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. 

Clinically important, potentially hazardous interactions with amiodarone, astemizole, bepridil, carbamazepine, chloroquine, cisapride, clarithromycin, dihydroergotamine, disopyramide, ergotamine, grapefruit juice, halofantrine, haloperidol, itraconazole, ketoconazole, methadone, moxifloxacin, phenobarbital, phenytoin, pimozide, procainamide, quinidine, rifampicin, ritonavir, sotalol, St John s wort, telithromycin, terfenadine, voriconazole... 

Halofantrine is a potent blood schizontocidal agent with high activity against chloroquine-resistant and chloroquine-sensitive P, falciparum. The drug has been used at a dose of Ig/adult given daily for 3 days no phototoxicity or gastrointestinal problems were observed [138,139],... 

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. 

Drugs for clinical cure Drugs for radical cure Drugs for prophylaxis Quinine, halofantrine Primaquine Chloroquine, proguanil... 

An interesting entry (1992) is the phenanthrene compound halofantrine (Halofan). Earlier clinical trials exhibited 85% or better effectiveness, including some chloroquine-resistant P. falciparum strains. Since the drug does not eliminate exoerythrocytic parasites, the likelihood of relapse in the treatment of P. vivax is significant. 

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). 

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. 

An isolated report describes life-threatening hypoglycaemia in a 3-year-old boy, with uncomplicated malaria, 90 minutes after he took sulfadox-ine-pyrimethaniine (Fansidar). Mefloquine has been reported to reduce plasma glucose levels in healthy subjects. Artemisinin derivatives such as artemether may be associated with fewer episodes of hypoglycaemia than quinine in children with severe malaria. Chloroquine, amo-diaquine and halofantrine do not apparently stimulate the release of insulin. ... 

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