Quinine Halofantrine

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. 

Halofantrine Quinine (greater risk with higher doses and intravenous use)... 

Chloroquine, halofantrine, quinine Chlorpromazine, haloperidol, flufenazine, lithium, mesoridazine, pimozide, prochlorperazine, roperidol, sultopride, sertindole, risjreridone, thioridazine, trifluoperazine... 

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). 

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). 

Quinine should not be combined with halofantrine, since both drugs impair atrioventricular conduction and since quinine can enhance the cardiotoxic effects of halofantrine by inhibiting its metabolism (47). 

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. 

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... 

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. 

Pyrimethamine/sulfadoxine and tetracycline have been shown to increase halofantrine levels, and may therefore increase its toxicity. Diltiazem, erythromycin, ketoconazole, mefloquine, quinine, and quinidine might also increase the toxicity of halofantrine because they have been shown to inhibit its metabolism in vitro. The manufacturer has therefore recommended caution with the concurrent use of potent CYP3A4 inhibitors. Fatty food markedly increases halofantrine levels, consequently it is recommended that halofantrine is taken on an empty stomach. Grapefruit juice has a similar effect Note that halofantrine is no longer widely marketed. 

A study in animals found that ketoconazole roughly doubled the AUC of halofantrine and inhibited its metabolism to the equipotent metabolite, desbutylhalofantrine. In in vitro studies, ketoconazole markedly inhibited the metabolism of halofantrine by CYP3A4. It has been suggested that the rise in halofantrine levels could reasonably be expected to increase toxicity. Other CYP3A4 inhibitors, diltiazem and erythromycin, also inhibited the metabolism of halofantrine in vitro, and might therefore do so clinically. The manufacturer recommended caution with the concurrent use of potent CYP3A4 inhibitors. Further study is needed of these potential pharmacokinetic interactions. Mefloquine, quinine and quinidine may also inhibit the metabolism of halofantrine by CYP3A4, see (b) below. 

In addition to possible additive QT-prolonging effects, quinidine and quinine have been shown in vitro to inhibit the metabolism of halofantrine by CYP3A4, and so may increase halofantrine levels, which could reasonably be expected to increase XoxxcxXy Animal studies found that although mefloquine alone did not significantly alter the QTc interval, it enhanced the effects of halofantrine by increasing blood levels. Similarly, a study in patients with malaria found that the risk of clinically relevant QT prolongation was increased twofold when halofantrine was used after mefloquine failure (7 of 10 patients) when compared with use as primary... 

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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