The DOI matches its Crossref record; 27 of the 27 references it cites were found in a registry or an index.
Molecular and Pharmacological Determinants of the Therapeutic Response to Artemether-Lumefantrine in Multidrug-Resistant Plasmodium falciparum Malaria
Open accessAbstract
BACKGROUND: Our study examined the relative contributions of host, pharmacokinetic, and parasitological factors in determining the therapeutic response to artemether-lumefantrine (AL). METHODS: On the northwest border of Thailand, patients with uncomplicated Plasmodium falciparum malaria were enrolled in prospective studies of AL treatment (4- or 6-dose regimens) and followed up for 42 days. Plasma lumefantrine concentrations were measured by high performance liquid chromatography; malaria parasite pfmdr1 copy number was quantified using a real-time polymerase chain reaction assay (PCR), and in vitro drug susceptibility was tested. RESULTS: All treatments resulted in a rapid clinical response and were well tolerated. PCR-corrected failure rates at day 42 were 13% (95% confidence interval [CI], 9.6%-17%) for the 4-dose regimen and 3.2% (95% CI, 1.8%-4.6%) for the 6-dose regimen. Increased pfmdr1 copy number was associated with a 2-fold (95% CI, 1.8-2.4-fold) increase in lumefantrine inhibitory concentration(50) (P=.001) and an adjusted hazard ratio for risk of treatment failure following completion of a 4-dose regimen, but not a 6-dose regimen, of 4.0 (95% CI, 1.4-11; P=.008). Patients who had lumefantrine levels below 175 ng/mL on day 7 were more likely to experience recrudescence by day 42 (adjusted hazard ratio, 17; 95% CI, 5.5-53), allowing prediction of treatment failure with 75% sensitivity and 84% specificity. The 6-dose regimen ensured that therapeutic levels were achieved in 91% of treated patients. CONCLUSIONS: The lumefantrine plasma concentration profile is the main determinant of efficacy of artemether-lumefantrine. Amplification in pfmdr1 determines lumefantrine susceptibility and, therefore, treatment responses when plasma lumefantrine levels are subtherapeutic.
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Mefloquine resistance in Plasmodium falciparum and increased pfmdr1 gene copy number
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Self-citationClinical Pharmacokinetics and Pharmacodynamics of Artemether-Lumefantrine
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Malaria: progress, perils, and prospects for eradication
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The role of early detection and treatment in malaria elimination
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Metadata
- Authors
- Price, R. N., Uhlemann, A.-C., van Vugt, M., Brockman, A., Hutagalung, R., Nair, S., Nash, D., Singhasivanon, P., Anderson, T. J. C., Krishna, S., White, N. J., & Nosten, F.
- Venue
- Clinical Infectious Diseases
- Publisher
- Oxford University Press (OUP)
- Published
- 2006-06-01
- Volume
- 42
- Issue
- 11
- Pages
- 1570-1577
- ISSN
- 1058-4838 (ISSN-L)
- 1537-6591
- OpenAlex
- W2112261944
- Cited by
- 317
- References
- 27
- FWCI
- 19.89
- Type
- journal article
- Language
- en
- Open access
- bronze
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