Artemisinin population pharmacokinetics in children and adults with uncomplicated falciparum malaria

Sidhu,; Ashton,; Huong,; Hai, Hai; Karlsson,; Sy, Charlle; Jønsson,; Cong,

doi:10.1046/j.1365-2125.1998.00686.x

Cited by 5 publications

(13 citation statements)

References 2 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The increase is in accordance with earlier findings based on concentrations in plasma in both malaria patients and healthy volunteers (1,(3)(4)(5). The extent of the increase in artemisinin CL s /F values has been reported to be six-to sevenfold after standard treatment (1,4,22). In our study, the average increase in CL s /F from day 1 to 5 in the patients in the standarddose group was 5-fold, whereas the average increase in the escalating-dose group was 2.5-fold.…”

Section: Discussionmentioning

confidence: 45%

See 1 more Smart Citation

Artemisinin Pharmacokinetics and Efficacy in Uncomplicated-Malaria Patients Treated with Two Different Dosage Regimens

Gordi

Huong

Hai

et al. 2002

Antimicrob Agents Chemother

View full text Add to dashboard Cite

The immediate efficacies of two oral dosage regimens of artemisinin were investigated in 77 male and female adult Vietnamese falciparum malaria patients randomly assigned to treatment with either 500 mg of artemisinin daily for 5 days (group A; n ‫؍‬ 40) or artemisinin at a dose of 100 mg per day for 2 days, with the dose increased to 250 mg per day for 2 consecutive days and with a final dose of 500 mg on the fifth day (group B; n ‫؍‬ 37). Parasitemia was monitored every 4 h. The average parasite clearance time was longer in group B than in group A (means ؎ standard deviations, 50 ؎ 23 and 34 ؎ 14 h, respectively; P < 0.01). Artemisinin concentrations in saliva samples obtained on days 1 and 5 were quantified by high-performance liquid chromatography. The average oral clearance, based on saliva drug concentrations in group B patients, was twofold higher than that in group A patients on day 1 (P < 0.01), with no differences in drug half-lives (P ‫؍‬ 0.40), indicating a saturable first-pass metabolism. Female patients had higher oral clearance values on day 1. Artemisinin's pharmacokinetic parameters were similar on day 5 in both groups, although a significant increase in oral clearance from day 1 to day 5 was evident. Thus, artemisinin exhibited both dose-and time-dependent pharmacokinetics. The escalating dose studied did not result in higher artemisinin concentrations toward the end of the treatment period.Artemisinin and its semisynthetic family of derivatives are the most potent antimalarials available for treatment of falciparum malaria infections (15,25,26). Artemisinin has a short elimination half-life, a rapid onset of action, no major side effects, and markedly induces of its own metabolic elimination, resulting in five-to sevenfold decreases in its concentrations over 5 to 7 days of administration in both malaria patients and healthy subjects (1, 3-5). A major drawback with artemisinin and its derivatives is the high recrudescence rates within 2 to 3 weeks after monotherapy (14,17). It has proved difficult in field studies to determine whether the relapsed malaria episodes are due to new infections or the persistence of the previous one. However, true recrudescence has been described in patients kept in vector-free environments for longer periods of time (12,13,16). There is also evidence of true recrudescence, as determined by a PCR technique with patients treated with a combination of artemether and benflumetol (10) as well as artesunate alone (18). It has been suggested that the occurrence of recrudescence may partly be due to the decreasing artemisinin concentrations toward the end of treatment (4). Thus, the time-dependent kinetics of the drug can be of importance in dosing suggestions.Reports concerning dose-response studies with the artemisinin endoperoxides are lacking. Rectal administration of artemisinin was shown to have efficacy comparable to that of oral treatment in terms of the parasite clearance time (PCT) and the fever subsidence time (FST) in patients with uncomplicated falciparum mal...

show abstract

Section: Discussionmentioning

confidence: 45%

“…In a population kinetic study, lower CL/F values and volumes of distribution for artemisinin were found in female children (22). However, due to the small number of male and female children involved, sex was not concluded to influence the pediatric artemisinin kinetics.…”

Section: Discussionmentioning

confidence: 99%

Artemisinin Pharmacokinetics and Efficacy in Uncomplicated-Malaria Patients Treated with Two Different Dosage Regimens

Gordi

Huong

Hai

et al. 2002

Antimicrob Agents Chemother

View full text Add to dashboard Cite

show abstract

“…And the results of various clinical trials suggest that artemisinin derivatives are relatively safe drugs. 33,34) Our results clearly show for the first time that artemisinin and its derivatives are very potent compounds that can be used in combination with anticancer drugs to overcome MDR phenomena. …”

Section: Co-treatment Using Pirarubicin and Qinghaosu Or Doxorubicin mentioning

confidence: 90%

Modulation of Multidrug Resistance by Artemisinin, Artesunate and Dihydroartemisinin in K562/adr and GLC4/adr Resistant Cell Lines.

Reungpatthanaphong

Mankhetkorn

2002

Biological & Pharmaceutical Bulletin

View full text Add to dashboard Cite

Multidrug resistance (MDR) is a principle cause of failure in human drug treatment. MDR phenomena are intensively studied in anti-cancer, anti-bacterial, anti-paludism, and human immunodeficiency virus-1. [1][2][3][4][5] The MDR phenotype is characterized by a low free intracellular cytotoxic drug concentration in comparison with their corresponding drugsensitive cells. This is frequently associated with protein membrane transporters, such as P-glycoprotein and MRP1-protein, which ATP-dependently extrude cytotoxic agents out of cells, thus reducing their efficacy. To overcome MDR phenomena, the direct interaction between inhibitors and proteins has been researched by many groups. A variety of small molecules, such as verapamil, dihydropyridines, forskolin and cyclosporin were found to bind to P-glycoprotein and inhibit its ability to pump out antitumor drugs. 6-9) All compounds cited are difficult to use in vivo due to their toxicity. As a consequence, the clinical utility of non-toxic derivatives of these and other molecules as chemosensitizing agents has been extensively studied. 10,11) It was reported that in MDR plasmodium falciparum strains, the pfmdr-1 gene and pgh-1 were characterized, which has about 54% homology to mdr-1 gene of MDR cancer cells. [12][13][14][15] However, its function is still not clear. Recently, it was reported that qinghaosu is an effective compound against MDR plasmodium falciparum strains, 16,17) but studies regarding its effect on protein transporters have not been performed, neither in erythrocytes infected by MDR plasmodium falciparum strains nor in cancer MDR cells. Qinghaosu drugs such as artemisinin and artesunate are now in widespread use, particularly in Southast Asia, and are used as a prophylaxis in China. 18,19) In this study we have demonstrated that artemisinin, artesunate and dihydroartemisinin poorly inhibited P-glycoprotein and did not inhibit MRP1 protein function in multidrug resistant K562/adr cells, overexpression P-glycoprotein, or in GLC4/adr cells overexpression of MRP1-protein, respectively. However, they increased in cytotoxic effect induced by pirarubicin or doxorubicin only in MDR cell lines. We also demonstrated that these qinghaosu modulate mitochondrial function, leading to a decrease in intracellular ATP content in all cell lines tested. MATERIALS AND METHODS Cell Culture and Cytotoxicity AssayThe erythromyelogenous leukemic, K562, and its P-glycoprotein-overexpressing K562/adr, 20,21) and the human small cell lung cancer, GLC4 and its MRP1-overexpressing GLC4/adr, [22][23][24] were kindly provided by Professor Arlette Garnier-Suillerot, Laboratoire de Chimie Physique, Biomoleculaire et Cellulaire, UFR Sante Medecine Biologie Humaine, Universite de Paris Nord, France. These cells were routinely cultured in RPMI 1640 medium supplemented with 10% fetal calf serum (Gibco Biocult, Ltd.). The resistant K562/adr and GLC4/adr cells were cultured with 100 nM doxorubicin two weeks before the experiments. For the assays, a culture was initiated at 5ϫ10 5 cells ...

show abstract

“…25,26 Despite the relative lack of resistance to artemisinin derivatives noted to date, the cure rates using these drugs may be affected by the observed inter-individual variability in drug pharmacokinetics. 27 While there are several reasons for this variability, absorption from an intramuscular injection site may be unpredictable, especially in children who are comatose with little muscle activity. Two of the artemotil deaths in our study had parasitemia at the time of death, one at 38 hours and the other at 140 hours after the start of therapy.…”

Section: Discussionmentioning

confidence: 99%

A randomized controlled trial of artemotil (beta-arteether) in Zambian children with cerebral malaria.

Thuma¹,

Bhat²,

Mabeza³

et al. 2000

The American Journal of Tropical Medicine and Hygiene

View full text Add to dashboard Cite

Abstract. The efficacy and safety of intramuscular artemotil (ARTECEF ) was compared to intravenous quinine in African children with cerebral malaria. This prospective block randomized open-label study was conducted at two centers in Zambia. Subjects were children aged 0 to 10 years of age with cerebral malaria and a Blantyre Coma Score of 2 or less. Ninety two children were studied; 48 received artemotil and 44 quinine. No significant differences in survival, coma resolution time, neurologic sequelae, parasite clearance time, and fever resolution time were seen between the two regimens. Rates for negative malaria smears one month after therapy were similar in both groups. Artemotil was a well-tolerated drug in the 48 patients in this study. It appears to be at least therapeutically equivalent to quinine for the treatment of pediatric cerebral malaria. It has the advantage of being able to be given intramuscularly once daily for only five days.

show abstract

Artemisinin population pharmacokinetics in children and adults with uncomplicated falciparum malaria

Cited by 5 publications

References 2 publications

Artemisinin Pharmacokinetics and Efficacy in Uncomplicated-Malaria Patients Treated with Two Different Dosage Regimens

Artemisinin Pharmacokinetics and Efficacy in Uncomplicated-Malaria Patients Treated with Two Different Dosage Regimens

Modulation of Multidrug Resistance by Artemisinin, Artesunate and Dihydroartemisinin in K562/adr and GLC4/adr Resistant Cell Lines.

A randomized controlled trial of artemotil (beta-arteether) in Zambian children with cerebral malaria.

Contact Info

Product

Resources

About