RESUMO
OBJECTIVE: This study investigated whether time-dependent artemisinin pharmacokinetics correlated to CYP3A4 or CYP2C19 activity in vivo. METHODS: Artemisinin (two oral doses per day of 250 mg) was given to nine healthy Vietnamese subjects for 7 days (day 1 to day 7). Single 20 mg doses of omeprazole were given orally on day -7, day 1, and day 7. Single doses of artemisinin and omeprazole were given in combination on day 14 after a 6-day washout period. The pharmacokinetics of artemisinin, omeprazole, hydroxyomeprazole, and omeprazole sulfone were evaluated on days -7, 1, 7, and 14. On the same days urine was collected for the determination of 6beta-hydroxycortisol and cortisol excretion. RESULTS: Areas under plasma concentration-time curves (AUC) for artemisinin and omeprazole decreased on day 7 to 20% (95% confidence intervals, 13%, 28%) and 35% (25%, 46%), respectively, compared with values on day 1. AUC ratios for hydroxyomeprazole/omeprazole increased 2.2-fold (1.7, 2.7) on day 7 compared with values on day 1. All values were normalized at day 14. There were no significant changes in the omeprazole sulfone/omeprazole ratio or in the 6beta-hydroxycortisol/cortisol ratio between the study days. In one subject found to have poor CYP2C19 metabolization, the elimination of omeprazole increased after artemisinin exposure, with no change in the hydroxyomeprazole/omeprazole AUC ratio. CONCLUSION: Artemisinin did not alter CYP3A4 activity, whereas an increase in CYP2C19 activity was observed. The increased elimination of omeprazole in both poor and extensive CYP2C19 metabolizers suggests artemisinin induces both CYP2C19 and another enzyme.
Assuntos
Antimaláricos/farmacologia , Artemisininas , Hidrocarboneto de Aril Hidroxilases , Sistema Enzimático do Citocromo P-450/metabolismo , Inibidores Enzimáticos/farmacocinética , Oxigenases de Função Mista/metabolismo , Omeprazol/farmacocinética , Sesquiterpenos/farmacologia , 2-Piridinilmetilsulfinilbenzimidazóis , Adulto , Antimaláricos/sangue , Antimaláricos/urina , Área Sob a Curva , Citocromo P-450 CYP2C19 , Citocromo P-450 CYP3A , Inibidores Enzimáticos/sangue , Inibidores Enzimáticos/urina , Humanos , Masculino , Pessoa de Meia-Idade , Omeprazol/análogos & derivados , Omeprazol/sangue , Omeprazol/urina , Valores de Referência , Sesquiterpenos/sangue , Sesquiterpenos/urina , Fatores de TempoRESUMO
Eight healthy male, Vietnamese subjects were administered 1 x 250, 2 x 250, and 4 x 250 mg artemisinin capsules in a cross-over design with randomized sequence with a 7-day washout period between administrations. The inter-individual variability in artemisinin pharmacokinetics was large with parameter coefficient of variation (CV) typically between 50-70%. The parameter with the smallest variability was the elimination half-life (CV approximately equal to 30-40%). Analysis of variance indicated also a large intra-subject variability. (CV, or = 24%) for the dose-normalized area under the plasma concentration-time curve (AUC/dose). The pharmacokinetic results suggested artemisinin to be subject to high pre-systemic extraction. Artemisinin half-life could not predict the extent of in vivo exposure to the drug, there being no correlation between half-life and oral clearance. Artemisinin oral plasma clearance was about 400 L h-1 exhibiting a slight decrease with dose, although the effect was weak. Thus results from studies using different artemisinin doses may, within the studied dose range, be compared without the complication of disproportionate changes in drug exposure with varying dose levels. Half-lives appeared to increase with dose. An observed period effect in the analysis of variance was tentatively associated with time-dependency in artemisinin pharmacokinetics. There was a high correlation between artemisinin plasma concentrations determined at various time-points after drug administration and the AUCs after the 500 and 1000 mg doses, but less so after the 250 mg dose. This may show a tentative approach to assess the systemic exposure of the patients to artemisinin from the determination of artemisinin plasma concentrations in one or two plasma samples only. Artemisinin was well tolerated with no apparent dose or time dependent effects on blood pressure, heart rate or body temperature.
Assuntos
Antimaláricos/farmacocinética , Artemisininas , Sesquiterpenos/farmacocinética , Administração Oral , Adulto , Análise de Variância , Antimaláricos/sangue , Área Sob a Curva , Pressão Sanguínea/efeitos dos fármacos , Estudos Cross-Over , Relação Dose-Resposta a Droga , Humanos , Individualidade , Masculino , Sesquiterpenos/sangueRESUMO
OBJECTIVE: To compare parasite clearance times after oral and rectal administration of artemisinin in adults with uncomplicated malaria and to relate pharmacodynamics with artemisinin kinetics and to disclose any pharmacokinetic changes during treatment. METHODS: Thirty male Vietnamese patients with falciparum malaria were randomized to treatment with 500 mg artemisinin daily by either the oral or rectal route of administration. Parasite densities in capillary blood were determined by microscopy every 4 to 6 hours. Artemisinin plasma concentrations on the first and last day of treatment were determined by HPLC and unbound fractions in plasma were determined by ultrafiltration. RESULTS: Mean parasite clearance times and 95% confidence intervals (95% CI) were 25 (95% CI, 16 to 33) and 29 (95% CI, 23 to 35) hours during oral and rectal treatment, respectively. The bioavailability after rectal relative to oral artemisinin was 30%. Artemisinin areas under the plasma concentration-time curve (AUC) on the fifth (last) day of oral or rectal treatment were 30% (95% CI, 4% to 56%) and 40% (95% CI, -6% to 91%), respectively, of those after the first dose. The fraction unbound in plasma was 15% (95% CI, 12% to 19%), increasing marginally during treatment. No relationship was found between main clinical end points and drug exposure, although indices for the rapidity of response onset were lower after oral treatment and correlated to unbound AUC values (rS = -0.7; p < 0.001). CONCLUSIONS: The similarity in parasite clearance times despite lower drug levels during rectal treatment suggests that initial oral doses may be unnecessarily high. The singular time dependency of artemisinin pharmacokinetics, attributed to autoinduction of drug elimination, has possible implications for combination chemotherapy. Decreasing artemisinin concentrations during treatment may partly explain recrudescences and increase the risk for resistance development.
Assuntos
Antimaláricos/administração & dosagem , Antimaláricos/farmacocinética , Artemisininas , Malária/sangue , Malária/tratamento farmacológico , Sesquiterpenos/administração & dosagem , Sesquiterpenos/farmacocinética , Administração Oral , Administração Retal , Adulto , Área Sob a Curva , Humanos , Malária/etnologia , Masculino , Pessoa de Meia-Idade , Fatores de Tempo , VietnãRESUMO
Pyrimethamine and cycloguanil resistance of Plasmodium falciparum has been linked to mutations in the dihydrofolate reductase (dhfr) portion of the dhfr-ts gene. In this paper, the DNA sequence of the dhfr-ts gene of 50 isolates from Vietnam and 2 clones (T9/94 and T9/96) isolated from a malaria patient from Thailand have been analyzed. A comparison between these isolates and clones showed differential mutation patterns. Forty-eight isolates were found to consist of mutations associated with Pyr. A novel leucine mutation at position 140 was found in the isolate VP8 and in clone T9/94. The isolate VP8 and the clone T9/94 were found to also have the characteristic changes at positions 16 (Val) and 108 (Thr) that have been found in cycloguanil-resistant isolates. The isolate VP35 was shown to be resistant to both antifolates, while the clone T9/96 was found to be sensitive to both antifolates and to have a sequence identical to that of wild-type dhfr-ts. The two clones from a single patient showed the coexistence of resistant and sensitive clones in the absence of treatment by antifolates. Since cycloguanil resistance seems to be rare in Vietnam, cycloguanil alone or in combination with other antimalarial agents might be an alternative for treatment and prophylaxis, even in areas with high resistance to pyrimethamine.
Assuntos
Plasmodium falciparum/genética , Mutação Puntual , Tetra-Hidrofolato Desidrogenase/genética , Timidilato Sintase/genética , Animais , Antimaláricos/farmacologia , Sequência de Bases , DNA de Protozoário/análise , Resistência a Medicamentos/genética , Antagonistas do Ácido Fólico/farmacologia , Humanos , Malária Falciparum/parasitologia , Dados de Sequência Molecular , Plasmodium falciparum/efeitos dos fármacos , Plasmodium falciparum/enzimologia , Proguanil , Pirimetamina/farmacologia , Tailândia , Triazinas/farmacologia , VietnãRESUMO
The reversing action of verapamil on the effect of chloroquine was found in in vivo experiments by using a model P. berghei resistant to chloroquine, an LNK65 isolate having a naturally lower resistance to the agent, and its polyresistant strain with the acquired resistance to chloroquine and fansidar, as well as by employing the chlorine-resistant P. falciparum isolates from the south of the Socialist Republic of Vietnam. The magnitude of this effect was related to the dose of verapamil, the frequency of administration of a combination of the agents in vivo, while that was associated to the concentration of verapamil and the level of isolate resistance to chloroquine in vitro which was the most pronounced. Taking into account the dose-dependent effect of verapamil, it can be suggested that increasing its concentration in combination with chloroquine can provide a more marked reversing action with lower chloroquine concentrations. The parameters accepted by the authors in evaluating the combined effect enable the effect of the verapamil/chloroquine concentration to be regarded as potentiation.
Assuntos
Antimaláricos/antagonistas & inibidores , Bloqueadores dos Canais de Cálcio/farmacologia , Cloroquina/antagonistas & inibidores , Plasmodium berghei/efeitos dos fármacos , Plasmodium falciparum/efeitos dos fármacos , Verapamil/farmacologia , Animais , Antimaláricos/uso terapêutico , Bloqueadores dos Canais de Cálcio/uso terapêutico , Cloroquina/uso terapêutico , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Interações Medicamentosas , Resistência a Medicamentos , Quimioterapia Combinada , Humanos , Malária/tratamento farmacológico , Malária/parasitologia , Malária Falciparum/parasitologia , Camundongos , Plasmodium berghei/isolamento & purificação , Plasmodium falciparum/isolamento & purificação , Verapamil/uso terapêuticoRESUMO
In this study, 638 patients with either Plasmodium falciparum or P. vivax malaria were treated with artemisinin (qinghaosu) that was isolated and formulated into tablets and capsules in Vietnam. In all cases, artemisinin treatment resulted in a rapid clearance of parasitemia and fever. Recrudescence rates were highest in those groups receiving treatment for five or less days (50%), but were between 10% and 23% for those groups receiving the drug for 5-10 days. A low recrudescent rate (9.5%) was also found when patients were treated with a combination of artemisinin for three days and tetracycline for five days. Thus, artemisinin represents a useful and economically feasible component of the malaria control program in Vietnam.