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| 2. |
- Blessborn, Daniel, et al.
(författare)
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Assay for screening self medication of common antimalarial drugs using the dried blood spot technique
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Annan publikation (populärvet., debatt m.m.)abstract
- The aim of the developed assay is to determine drug use and self medication in areas where achange in treatment policy has taken place. The assay will be a complement to interviewing patients and will increase reliability of the survey. Several of the drugs included in this screening assay have long half-lifes e.g. chloroquine, sulfadoxine, mefloquine, andlumefantrine and are detectable at least 7 days after administration. The sample collection is very simple, using 100 μl capillary whole blood applied onto Whatman 31 ET Chr filter paper.The drugs are extracted from the dried blood spot with two different extraction methods (due to the big differences in physico-chemical properties). Solid phase extraction is used as sample clean-up and separation is performed with gradient-LC with MS ion-trap detection. Detection limits (S/N > 5:1) at 50 ng/ml or better were achieved for all drugs except lumefantrine (200 ng/ml)
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| 3. |
- Blessborn, Daniel, et al.
(författare)
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Determination of Lumefantrine after Capillary Sampling onto Sampling Paper
- 2007
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Ingår i: The Royal Society of Tropical Medicine and Hygiene. - London.
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Konferensbidrag (refereegranskat)abstract
- The antimalarial lumefantrine was first synthesised and registered in China and is now commercially available as a coformulated product together with artemether (Coartem®/Riamet®). This combination is well tolerated and has proven highly efficacious for treatment of uncomplicated falciparum malaria. Lumefantrine is highly lipophilic with an extensive protein binding (99.9%). The day 7 plasma lumefantrine level has been shown to be an important determinant of treatment efficacy. To date no method has been published for the determination of lumefantrine after capillary sampling onto filter paper for field use. The aim of this work was to develop a method with adequate sensitivity for quantification of lumefantrine in capillary blood sampled onto filter paper. The method has been validated according to the current FDA guideline for bioanalytical method validation. Method: Whatman 31 ET Chr filter paper was pre-treated with an organic acid before sampling capillary blood to enable a high recovery of lumefantrine. Lumefantrine was extracted from the filter paper, then further purified using solid phase extraction and finally quantified with HPLC. Results: The between day variation is below 10 % over the range 0.4 to 25 µmol/l. The lower limit of quantification is 0.25 µmol/l in 100 µl capillary blood. No decrease in Lumefantrine concentration in dried blood spot is seen after 3 months at 37o C. The field sampling for lumefantrine assay with pre-treated Whatman 31 ET Chr has been tested in Tanzania with good results. Discussion: The field sampling for lumefantrine concentration assay with pre-treated Whatman 31 ET Chr has been evaluated and proven to be a valid method for field studies. The day 7 level after treatment can lumefantrine be accurately estimated in capillary blood to follow up compliance and efficacy. Validation data will be presented.
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| 4. |
- Blessborn, Daniel, et al.
(författare)
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Determination of pyronaridine in whole blood by automated solid-phase extraction and high-performance liquid chromatography
- 2003
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Ingår i: Therapeutic Drug Monitoring. - : Ovid Technologies (Wolters Kluwer Health). - 0163-4356 .- 1536-3694. ; 25:3, s. 264-270
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Tidskriftsartikel (refereegranskat)abstract
- A new extraction procedure for the analysis of pyronaridine in whole blood is presented. A weak cation exchanger with a carboxylic acid (CBA) sorbent was found to be a suitable solid phase sorbent for the extraction of pyronaridine. High-performance liquid chromatography with UV detection at 278 nm and an electrochemical detector at +0.75 V is used. The electrochemical detector gives higher selectivity than the UV detector. The separation was performed using a C18 reversed phase column with mobile phase of acetonitrile-phosphate buffer (0.01 mol/L, pH 2.5)- sodium perchlorate (1.0 mol/L; 22:77:1, v/v/v). The within-day RSDs were below 5% at all concentration levels between 75 nmol/L and 1500 nmol/L, and the between-day RSDs were below 14% at all concentration levels. The limit of quantification was about 50 nmol/L in 1000 microL whole blood with an RSD of 20% or less on a day-to-day basis. The stability of pyronaridine is increased if the pH is less than 3 in water solutions. In whole blood, the concentration decreases by about 10% for each freeze-thaw cycle performed. At room temperature (about 22 degrees C), pyronaridine concentration in whole blood decreases by about 10% within 12 to 24 hours.
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| 5. |
- Blessborn, Daniel, et al.
(författare)
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Development and validation of an automated solid-phase extraction and liquid chromatographic method for determination of lumefantrine in capillary blood on sampling paper
- 2007
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Ingår i: Journal of Pharmaceutical and Biomedical Analysis. - : Elsevier BV. - 0731-7085 .- 1873-264X. ; 45:2, s. 282-287
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Tidskriftsartikel (refereegranskat)abstract
- A bioanalytical method for the determination of lumefantrine in 100 μl blood applied onto sampling paper, by solid-phase extraction and liquid chromatography, has been developed and validated. Whatman 31 ET Chr sampling paper was pre-treated with 0.75 M tartaric acid before sampling capillary blood to enable a high recovery of lumefantrine. Lumefantrine was extracted from the sampling paper, then further purified using solid-phase extraction and finally quantified with HPLC. The between-day variation was below 10% over the range 0.4-25 μM. The lower limit of quantification was 0.25 μM in 100 μl capillary blood. No decrease in lumefantrine concentration in dried blood spot is seen after 4 months storage at 22 °C. The method was also evaluated in field samples from patients in Tanzania after treatment with lumefantrine/artemether. Lumefantrine could be estimated accurately enough to assess bioavailability and treatment compliance on day 7 (i.e. 4 days after the last dose) after a standard regimen with the lumefantrine/artemether combination.
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| 6. |
- Friberg Hietala, Sofia, 1973, et al.
(författare)
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Population pharmacokinetics and pharmacodynamics of artemether and lumefantrine during combination treatment in children with uncomplicated falciparum malaria in Tanzania
- 2010
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Ingår i: Antimicrobial agents and chemotherapy. - 1098-6596. ; 54:11, s. 4780-4788
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Tidskriftsartikel (refereegranskat)abstract
- The combination of artemether and lumefantrine is currently the first line treatment of uncomplicated falciparum malaria in mainland Tanzania. While the exposure to lumefantrine has been associated with the probability of adequate clinical and parasitological cure, increasing exposure to artemether and the active metabolite dihydroartemisinin has been shown to decrease the parasite clearance time. The aim of this analysis was to describe the pharmacokinetics and pharmacodynamics of artemether, dihydroartemisinin and lumefantrine in African children with uncomplicated malaria. In addition to drug concentrations and parasitemias from 50 Tanzanian children with falciparum malaria, peripheral parasite densities from 11 asymptomatic children were included in the model of the parasite dynamics. The population pharmacokinetics and pharmacodynamics of artemether dihydroartemisinin and lumefantrine were modeled in NONMEM. The distribution of artemether was described by a two-compartment model with a rapid absorption and elimination through metabolism to dihydroartemisinin. Dihydroartemisinin concentrations were adequately illustrated by a one compartment model. The pharmacokinetics of artemether was time dependent with typical oral clearance increasing from 2.6 L/h/kg on day one to 10 L/h/kg on day three. The pharmacokinetics of lumefantrine was sufficiently described by a one-compartment model with an absorption lag time. The typical value of CL/F was estimated to 77 mL/h/kg. The proposed semi-mechanistic model of parasite dynamics, while a rough approximation of the complex interplay between malaria parasite and the human host, adequately described the early effect of ARM and DHA concentrations on the parasite density in malaria patients. However the poor precision in some parameters illustrates the need for further data to support and refine this model. The patient study is registered at www.Clinical.Trials.gov, (NCT00336375).
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| 9. |
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| 11. |
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| 12. |
- Lindegårdh, Niklas, et al.
(författare)
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Development and validation of a bioanalytical method using automated solid-phase extraction and LC-UV for the simultaneous determination of lumefantrine and its desbutyl metabolite in plasma
- 2005
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Ingår i: Journal of Pharmaceutical and Biomedical Analysis. - : Elsevier BV. - 0731-7085 .- 1873-264X. ; 37:5, s. 1081-1088
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Tidskriftsartikel (refereegranskat)abstract
- A bioanalytical method for the determination of lumefantrine (LF) and its metabolite desbutyl-lumefantrine (DLF) in plasma by solid-phase extraction (SPE) and liquid chromatography has been developed. Plasma proteins were precipitated with acetonitrile: acetic acid (99:1, v/v) containing a DLF analogue internal standard before being loaded onto a octylsilica (3 M Empore) SPE column. Two different DLF analogues were evaluated as internal standards. The compounds were analysed by liquid chromatography UV detection on a SB-CN (250 mm x 4.6 mm) column with a mobile phase containing acetonitrile-sodium phosphate buffer pH (2.0; 0.1 M) (55:45, v/v) and sodium perchlorate 0.05 M. Different SPE columns were evaluated during method development to optimise reproducibility and recovery for LF, DLF and the two different DLF analogues. The within-day precisions for LF were 6.6 and 2.1% at 0.042 and 8.02 μ g/mL, respectively, and for DLF 4.5 and 1.5% at 0.039 and 0.777 μ g/mL, respectively. The between-day precisions for LF were 12.0 and 2.9% at 0.042 and 8.02 μ g/mL, respectively, while for DLF 0.7 and 1.2% at 0.039 and 0.777 μ g/mL, respectively. The limit of quantification was 0.024 and 0.021 μ g/mL for LF and DLF, respectively. Different amounts of lipids in plasma did not affect the absolute recovery of LF or DLF.
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| 13. |
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| 14. |
- Lindegårdh, Niklas
(författare)
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Development of Field-adapted Analytical Methods for the Determination of New Antimalarial Drugs in Biological Fluids
- 2003
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis deals with the development of analytical methods for the determination of new antimalarial drugs in biological fluids. The goal was to develop methods that facilitate clinical studies performed in the field, such as capillary blood sampling onto sampling paper.Methods for the determination of atovaquone (ATQ) in plasma, whole blood and capillary blood applied onto sampling paper were developed and validated. Automated solid-phase extraction (SPE) and liquid chromatography (LC) with UV absorbance detection was used to quantify ATQ. Venous blood contained higher levels of ATQ than capillary blood after a single dose of Malarone (ATQ + proguanil).Ion-pairing LC was used to separate amodiaquine (AQ), chloroquine (CQ) and their metabolites on a CN-column. A method for quantification of AQ, CQ and their metabolites in capillary blood applied onto sampling paper was developed and validated. Perchloric acid and acetonitrile were used to facilitate the extraction of the analytes from the sampling paper. The liquid extract was further cleaned by SPE.Methods for the determination of piperaquine (PQ) in plasma and whole blood using SPE and LC were developed and validated. Addition of trichloroacetic acid (TCA) to the samples prior to injection into the LC-system significantly enhanced the efficiency for the PQ peak. Serum and whole blood contained higher levels (about 300 nM) of PQ than plasma (about 200 nM) after a single oral dose of 340 mg PQ. This indicates that PQ may be taken up in the leucocytes and thrombocytes.
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| 15. |
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| 16. |
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| 17. |
- Lindegårdh, Niklas, et al.
(författare)
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Simultaneous quantitation of the highly lipophilic atovaquone and hydrophilic strong basic proguanil and its metabolites using a new mixed-mode SPE approach and steep-gradient LC
- 2005
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Ingår i: Journal of Chromatographic Science. - : Oxford University Press (OUP). - 0021-9665 .- 1945-239X. ; 43:5, s. 259-266
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Tidskriftsartikel (refereegranskat)abstract
- A bioanalytical method is described for the simultaneous quantitative analysis of the highly lipophilic atovaquone and the strong basic proguanil with metabolites in plasma. The drugs are extracted from protein precipitated plasma samples on a novel mixed-mode solid-phase extraction (SPE) column containing carboxypropyl and octyl silica as functional groups. The analytes are further separated and quantitated using a steep-gradient liquid chromatographic method on a Zorbax SB-CN column with UV detection at 245 nm. Two different internal standards (IS) are used in the method to compensate for both types of analytes. A structurally similar IS to atovaquone is added with acetonitrile to precipitate proteins from plasma. A structurally similar IS to proguanil and its metabolites is added with phosphate buffer before samples are loaded onto the SPE columns. A single elution step is sufficient to elute all analytes. The method is validated according to published guidelines and shows excellent performance. The within-day precisions, expressed as relative standard deviation, are lower than 5% for all analytes at three tested concentrations within the calibration range. The between-day precisions are lower than 13% for all analytes at the same tested concentrations. The limit of quantitation is 25 nM for the basic substances and 50 nM for atovaquone. Several considerations regarding development and optimization of a method for determination of analytes with such a difference in physiochemical properties are discussed.
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| 18. |
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| 19. |
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| 20. |
- Malm, Mikaela, et al.
(författare)
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Automated solid-phase extraction method for the determination of piperaquine in capillary blood applied onto sampling paper by liquid chromatography
- 2004
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Ingår i: Journal of Chromatography B. ; :809, s. 43-49
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Tidskriftsartikel (refereegranskat)abstract
- A bioanalytical method for the determination of piperaquine in 100 uL blood applied onto sampling paper, by solid-phase extraction and liquid chromatography, has been developed and validated. Blood spots were cut into small pieces prior to addition of 0.3 M perchloric acid, acetonitrile and phosphate buffer containing an internal standard. The liquid phase was loaded onto a mixed phase cation-exchange (MPC) solid-phase extraction column. Piperaquine and the internal standard were analysed by liquid chromatography and separated on a Chromolith Performance (100 mm x 4.6 mm) column with acetonitrile: phosphate buffer pH 2.5, I = 0.1 (8:92, v/v) at the flow of 3.5 mL/min. The UV detection was performed at 345 nm. the intra-assay precision was 12.0% at 0.150 uM, 7.3% at 1.25 uM and 7.3% at 2.25 uM. The inter-assay precison was 1.8% at 0.150 uM, 5.2% at 1.25 uM and 2.8% at 2.25 uM. The lower limit of quantification (LLOQ) was determined to 0.050 uM where the precison was 14.7%.
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| 21. |
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| 22. |
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| 23. |
- Tärning, Joel, 1977, et al.
(författare)
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Characterization of Human Urinary Metabolites of the Antimalarial Piperaquine
- 2006
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Ingår i: Drug Metabolism And Disposition. - : American Society for Pharmacology & Experimental Therapeutics (ASPET). - 0090-9556 .- 1521-009X. ; 34, s. 2011-9
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Tidskriftsartikel (refereegranskat)abstract
- Five metabolites of the antimalarial piperaquine (PQ) (1,3-bis-[4-(7chloroquinolyl-4)-piperazinyl-1]-propane) have been identified and their molecular structures characterized. After a p.o. dose of dihydroartemisinin-piperaquine, urine collected over 16 h from two healthy subjects was analyzed using liquid chromatography (LC)/UV, LC/tandem mass spectrometry (MS/MS), Fourier transform ion cyclotron resonance (FTICR)/MS, and H NMR. Five different peaks were recognized as possible metabolites [M1, 320 m/z; M2, M3, and M4, 551 m/z (PQ + 16 m/z); and M5, 567 m/z (PQ + 32 m/z)] using LC/MS/MS with gradient elution. The proposed carboxylic M1 has a theoretical monoisotopic molecular mass of 320.1166 m/z, which is in accordance with the FTICR/MS (320.1168 m/z) findings. The LC/MS/MS results also showed a 551 m/z metabolite (M2) with a distinct difference both in polarity and fragmentation pattern compared with PQ, 7-hydroxypiperaquine, and the other 551 m/z metabolites. We suggest that this is caused by N-oxidation of PQ. The results showed two metabolites (M3 and M4) with a molecular ion at 551 m/z and similar fragmentation pattern as both PQ and 7-hydroxypiperaquine; therefore, they are likely to be hydroxylated PQ metabolites. The molecular structures of M1 and M2 were also confirmed using H NMR. Urinary excretion rate in one subject suggested a terminal elimination half-life of about 53 days for M1. Assuming formation rate-limiting kinetics, this would support recent findings that the terminal elimination half-life of PQ has been underestimated previously.
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