Disease relevance of AIDS008015

• Halofantrine to prevent falciparum malaria on return from malarious areas [1].
• Halofantrine and pruritus [2].
• Blackwater fever after halofantrine [3].
• Because halofantrine was associated with electrocardiographic prolongation of the QT interval and ventricular arrhythmias, in vitro cardiac electrophysiologic studies (isolated perfused cardiac model and isolated ventricular myocytes) were conducted to test the hypothesis that halofantrine or its metabolite is responsible for cardiotoxicity [4].
• For most drugs, such an increase results in a desired increase in drug effect, but in others it may result in serious toxicity (halofantrine) [5].

Psychiatry related information on AIDS008015

• A dose of 9.6 ng/chick halofantrine induced amnesia at the beginning of a protein synthesis-dependent long-term memory stage, the last of three stages of memory postulated to underly memory formation in the chick following passive avoidance learning [6].

High impact information on AIDS008015

• Efficacy of low-dose halofantrine for second treatment of uncomplicated falciparum malaria [7].
• We compared the following antimalarial drugs in relation to subsequent Plasmodium falciparum gametocyte carriage: mefloquine, halofantrine, quinine, and the artemisinin derivatives [8].
• In-vitro chemosensitivity tests showed that most infections were due to chloroquine-resistant parasites, and that parasite maturation was inhibited by considerably lower concentrations of halofantrine than of chloroquine [9].
• Concomitant with the increase in mefloquine resistance was a corresponding increase in the level of resistance to halofantrine and quinine, suggesting a true multidrug-resistance phenotype [10].
• BACKGROUND: Halofantrine, an antimalarial drug that prolongs the QT interval, is metabolized into N-debutyl-halofantrine by cytochrome P450 (CYP) 3A4 [11].

Chemical compound and disease context of AIDS008015

• In a prospective electrocardiographic study of Karen patients with acute uncomplicated falciparum malaria, mefloquine (25 mg/kg) had no cardiac effects (n = 53), but halofantrine (72 mg/kg) induced consistent dose-related lengthening of the PR and QT intervals in all 61 patients treated [12].
• These results suggest that nanocapsule formulations could provide a more favorable halofantrine profile in the plasma and reduce the intravenous dose necessary and therefore the toxicity, thus suggesting the use of halofantrine by a parenteral route in severe malaria [13].
• Dose-finding and noncomparative clinical trials have confirmed the efficacy of halofantrine in the treatment of falciparum malaria in areas of chloroquine- and sulfonamide/pyrimethamine-resistant malaria and vivax malaria [14].
• None of the men receiving halofantrine developed falciparum malaria during the subsequent 28 days, whereas three men receiving chloroquine did develop this disease (P < .02) [15].
• Torsade de pointes occurred in 6 out of 8 clofilium-treated rabbits and 4 out of 6 of those which received halofantrine, but was not seen in any of the seven terfenadine-treated rabbits [16].

Biological context of AIDS008015

• Plasma pharmacokinetics of halofantrine and N-debutyl-halofantrine and QTc interval duration were studied during the following 168 hours [11].
• Halofantrine peak plasma concentrations and bioavailability on the first day of treatment were significantly lower in patients with malaria than in healthy volunteers [17].
• RESULTS: Compared with water, grapefruit juice increased halofantrine area under the plasma concentration versus time curve (AUC) and peak plasma concentration by 2.8-fold +/- 1.5-fold (P <.0001) and 3.2-fold +/- 1.3-fold (P <.0001), respectively [11].
• Using a ventricular action potential voltage clamp protocol, halofantrine and N-desbutylhalofantrine block of HERG current was greatest during phases 2 and 3 of the action potential waveform [18].
• The change in heart rate became significant after administration of 10 mg kg(-1) halofantrine (-23+/-9 beats min[-1]) whereas the increase in QTc was significant with only 1 mg kg(-1) halofantrine (22+/-10 ms) [19].

Anatomical context of AIDS008015

• Halofantrine produced a stereoselective block of the delayed rectifier potassium channel in isolated feline myocytes [4].
• Grapefruit juice increases the bioavailability of several orally administered CYP3A4 substrates by inhibiting CYP3A4 at the enterocyte level and could therefore increase the risk of halofantrine-induced QT interval prolongation [11].
• We here report on the effect of various 4-aminoquinolines, as well as pyronaridine, halofantrine and some bis-quinolines, on glutathione-mediated destruction of FP in aqueous solution, when FP was bound non-specifically to a protein, and when it was dissolved in human erythrocyte ghost membranes [20].
• 5. The results of these experiments suggest that any direct effects that halofantrine may have had on the effective refractory period of cardiac muscle cannot be separated from those of the vehicle [19].
• 4 In guinea-pig left papillary muscles the effective refractory period was increased significantly 60 min after addition of halofantrine; from 161+/-4 to 173+/-6 ms with 10 microM, 156+/-8 to 174+/-6 ms with 30 microM and 165+/-6 to 179+/-5 ms with 100 microM halofantrine [19].

Associations of AIDS008015 with other chemical compounds

• The comparison of IC50s between assays with autologous and nonimmune sera showed that monodesethylamodiaquine, halofantrine, pyrimethamine, and cycloguanil had similar IC50s [21].
• A rapid, accurate, and sensitive high-performance liquid chromatographic (HPLC) method, with ultraviolet detection, for simultaneous measurement of halofantrine (HAL) and desbutylhalofantrine (BHAL) in human serum is described [22].
• In vitro activities of chloroquine, quinine, cycloguanil, atovaquone, mefloquine, halofantrine, and artesunate were evaluated [23].
• We investigated the influence of lumefantrine and its major metabolite desbutyl-lumefantrine, as well as halofantrine, chloroquine, and mefloquine, on wild type hERG K+ channels in stably transfected human embryonic kidney cells (HEK293) using the whole cell patch-clamp technique [24].
• The in vitro activity of pyronaridine was evaluated against 62 isolates of Plasmodium falciparum from Libreville, Gabon using an isotopic, drug susceptibility microtest and was compared with amodiaquine, chloroquine, quinine, and halofantrine activities [25].

Gene context of AIDS008015

• 6. In conclusion, we have demonstrated that halofantrine is a potent inhibitor of CYP2D6 in vitro and can also be metabolised by the enzyme [26].
• An investigation of the interaction between halofantrine, CYP2D6 and CYP3A4: studies with human liver microsomes and heterologous enzyme expression systems [26].
• Inhibition by mefloquine of KvLQT1/minK in the human heart may in part explain the synergistic prolongation of QT interval observed when this drug is coadministered with the HERG antagonist halofantrine [27].
• Effect of the antimalarial drug halofantrine in the long QT syndrome due to a mutation of the cardiac sodium channel gene SCN5A [28].
• In contrast, halofantrine, in concentrations attainable with therapeutic dosages, significantly enhanced IFN-gamma-induced RNI production [29].

Analytical, diagnostic and therapeutic context of AIDS008015

• The likelihood of significant QTc prolongation (by more than 25% or a QTc of 0.55 s1/2 or more) was greater after halofantrine as retreatment following mefloquine failure than as primary treatment (7/10 vs 18/51; relative risk 2.0 [95% Cl 1.1-3.4], p = 0.04) [12].
• We studied the effect of grapefruit juice on halofantrine bioavailability and on QT interval prolongation associated with its oral administration [11].
• METHODS: Twelve healthy male and female volunteers received 500 mg of halofantrine with 250 mL of water, orange juice, or grapefruit juice (250 mL once a day of regular strength for 3 days and once at 12 hours before halofantrine administration), in a random order, during a crossover study [11].
• In an attempt to further elucidate the mechanism of QT interval prolongation, the effects of racemic halofantrine, its stereoisomers, and N-desbutylhalofantrine on repolarizing currents in isolated ventricular myocytes were studied with use of patch-clamp techniques [4].
• There have been increasing reports of halofantrine treatment failure, particularly in the eastern part of Thailand. The majority of treatment failures have been associated with incomplete drug absorption [30].

References