tetracycline and halofantrine

To investigate the effect of tetracycline co-administration on the pharmacokinetics of halofantrine in healthy subjects.. Eight healthy males were each given 500 mg single oral doses of halofantrine alone, or with tetracycline (500 mg 12 hourly for 7 days), in a crossover fashion. Blood samples collected at predetermined intervals were analyzed for halofantrine and its major metabolite, desbutylhalofantrine (HFM), using a validated HPLC method.. Co-administration of tetracycline and halofantrine resulted in a significant increase (P < 0.05) in the maximum plasma concentration (C(max)), total area under the concentration-time curve (AUC), and terminal elimination half-life (t(1/2,z)), compared with halofantrine alone. (C(max) 0.43 +/- 0.14 vs 1.06 +/- 0.44 microg ml(-1) (95% CI on the difference 0.30, 0.95); AUC 32.0 +/- 13.6 vs 63.7 +/- 20.1 microg ml(-1) h (95% CI 14.2, 49.1); t(1/2,z:) 90.8 +/- 17.9 vs 157.4 +/- 57.4 h (95% CI 21.7, 111.5)). Similarly, tetracycline caused a significant increase (P < 0.05) in the AUC and C(max) of HFM.. Tetracycline co-administration significantly increases the plasma concentrations of halofantrine and its major metabolite.

Topics: Adolescent; Adult; Anti-Bacterial Agents; Antimalarials; Area Under Curve; Cross-Over Studies; Half-Life; Humans; Male; Phenanthrenes; Tetracycline

New treatments for malaria are urgently needed in areas such as Thailand where highly drug-resistant strains of Plasmodium falciparum are prevalent. Mefloquine is rapidly losing efficacy and conventional doses of halofantrine are infective. We therefore used pharmacokinetic stimulation to design an extended-dose halofantrine regimen and tested it in 26 soldiers stationed along the Thai-Cambodian border. Halofantrine was given after meals as three doses of 500 mg each at 4-hr intervals on the first day, followed by 500 mg a day for six days (total dose 4.5 g). Twenty-six soldiers treated with quinine-tetracycline for seven days (Q7T7) served as controls. There were no significant differences in efficacy between halofantrine and Q7T7 (P > 0.1) as assessed by cure rate (92% versus 85%), mean parasite clearance time (82 hr versus 81 hr), or mean fever clearance time (93 hr versus 99 hr). Halofantrine was better tolerated than Q7T7. The side effects score was lower (2 versus 11; P < 0.001), there were less days on which side effects occurred (2.0 days versus 5.5 days; P < 0.001), and fewer patients had adverse effects on every treatment day (4% versus 42%; P < 0.01). High-dose halofantrine is as effective and better tolerated than quinine-tetracycline for multidrug-resistant falciparum malaria.

Topics: Adult; Animals; Chi-Square Distribution; Diarrhea; Dizziness; Drug Resistance; Drug Therapy, Combination; Humans; Malaria, Falciparum; Male; Mefloquine; Phenanthrenes; Plasmodium falciparum; Quinine; Tetracycline; Thailand; Vomiting

A 43 year old man with falciparum malaria acquired in East Africa was treated with quinine intravenously at a loading dose of 500 mg and subsequently 500 mg tid. Within 42 hours after initiation of treatment the parasitaemia increased from 2% to 16%. A RIII-resistance against quinine was suspected and therapy was switched to oral administration of halofantrine (500 mg at 6 hourly intervals) which led to complete recovery. Blood samples were cultured for malaria parasites 42 hours after start of therapy with quinine but before initiation of therapy with halofantrine. In vitro resistance testing was performed with samples directly derived from the patient and after 24 and 48 hours of culturing. In repeated tests an in vitro resistance to quinine could be confirmed (IC50: 25.6 x 10(-6) mol/l, IC99: > 51.2 x 10(-6) mol/l) while the strain was fully susceptible to chloroquine (IC50: < 0.4 x 10(-6) mol/l, IC99: 1.6 x 10(-6) mol/l), mefloquine (IC50: < 0.4 x 10(-6) mol/l, IC99: 3.2 x 10(-6) mol/l), tetracycline (IC50: 0.16 x 10(-6) mol/l, IC99: 0.32 x 10(-6) mol/l) and halofantrine (IC50: 0.02 x 10(-6) mol/l, IC99: 0.04 x 10(-6) mol/l). Increased susceptibility to quinine after addition of verapamil was noted. The presence of a specific mutation, on the pfmdr1-gene on chromosome 5, previously associated with chloroquine drug resistance, could be confirmed by polymerase chain reaction. To our knowledge a R III-in vivo and in vitro resistance of Plasmodium falciparum to quinine has not been described yet in East Africa.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Africa, Eastern; Animals; Antimalarials; Chloroquine; Drug Resistance; Humans; Malaria, Falciparum; Male; Mefloquine; Phenanthrenes; Plasmodium falciparum; Quinine; Tetracycline