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  • 1. Jansson, R.
    et al.
    Malm, Mikaela
    Högskolan Dalarna, Akademin Industri och samhälle, Kemiteknik.
    Roth, C.
    Ashton, M.
    Enantioselective and dose dependent intestinal absorption of eflornithine in rats2007Inngår i: Tropical medicine & international health, ISSN 1360-2276, E-ISSN 1365-3156, Vol. 12, nr s1, s. 245-246Artikkel i tidsskrift (Annet vitenskapelig)
  • 2. Jansson, R.
    et al.
    Malm, Mikaela
    Högskolan Dalarna, Akademin Industri och samhälle, Kemiteknik.
    Roth, C.
    Ashton, M.
    Enantioselective and nonlinear intestinal absorption of eflornithine in the rat2008Inngår i: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 52, nr 8, s. 2842-2848Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    This study aimed to investigate if the absorption of the human African trypanosomiasis agent eflornithine was stereospecific and dose dependent after oral administration. Male Sprague-Dawley rats were administered single doses of racemic eflornithine hydrochloride as an oral solution (750, 1,500, 2,000, or 3,000 mg/kg of body weight) or intravenously (375 or 1,000 mg/kg of body weight). Sparse blood samples were obtained for determination of eflornithine enantiomers by liquid chromatography with evaporative light-scattering detection (lower limit of quantification [LLOQ], 83 mu M for 300 mu l plasma). The full plasma concentration-time profile of racemic eflornithine following frequent sampling was determined for another group of rats, using a high-performance liquid chromatography-UV method (LLOQ, 5 mu M for 50 mu l plasma). Pharmacokinetic data were analyzed in NONMEM for the combined racemic and enantiomeric concentrations. Upon intravenous administration, the plasma concentration-time. profile of eflornithine was biphasic, with marginal differences in enantiomer kinetics (mean clearances of 14.5 and 12.6 ml/min/kg for L- and D-eflornithine, respectively). The complex absorption kinetics were modeled with a number of transit compartments to account for delayed absorption, transferring the drug into an absorption compartment from which the rate of influx was saturable. The mean bioavailabilities for L- and D-eflornithine were 41% and 62%, respectively, in the dose range of 750 to 2,000 mg/kg of body weight, with suggested increases to 47% and 83%, respectively, after a dose of 3,000 mg/kg of body weight. Eflornithine exhibited enantioselective absorption, with the more potent L-isomer being less favored, a finding which may help to explain why clinical attempts to develop an oral treatment have hitherto failed. The mechanistic explanation for the stereoselective absorption remains unclear.

  • 3.
    Lindkvist, Jenny
    et al.
    Högskolan Dalarna, Akademin Industri och samhälle, Kemiteknik.
    Malm, Mikaela
    Högskolan Dalarna, Akademin Industri och samhälle, Kemiteknik.
    Bergqvist, Yngve
    Högskolan Dalarna, Akademin Industri och samhälle, Kemiteknik.
    Determination of sulfonamides from capillary blood on sampling paper with solid-phase extraction, liquid chromatography and UV detection. [Poster]2006Inngår i: Analysdagarna, Göteborg, 2006Konferansepaper (Annet vitenskapelig)
  • 4.
    Lindkvist, Jenny
    et al.
    Högskolan Dalarna, Akademin Industri och samhälle, Kemiteknik.
    Malm, Mikaela
    Högskolan Dalarna, Akademin Industri och samhälle, Kemiteknik.
    Bergqvist, Yngve
    Högskolan Dalarna, Akademin Utbildning, hälsa och samhälle, Medicinsk vetenskap.
    Straightforward and rapid determination of sulfadoxine and sulfamethoxazole in capillary blood on sampling paper with liquid chromatography and UV detection2009Inngår i: Transactions of the Royal Society of Tropical Medicine and Hygiene, ISSN 0035-9203, E-ISSN 1878-3503, Vol. 103, nr 4, s. 371-376Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    A method for the determination of sulfadoxine and sulfamethoxazole in capillary blood on sampling paper has been developed and validated. The method is straightforward with minimal sample preparation, and is suitable for rural settings. Separation of sulfadoxine, sulfamethoxazole and internal standard was performed using a Purospher STAR RP-18 endcapped LC column (150 x 4.6 mm) with a mobile phase consisting of acetonitrile: sodium acetate buffer pH 5.2, 1=0.1 (1:2, v/v). For sulfadoxine, the within-day precision was 5.3% at 15 mu mol/l and 3.7% at 600 mu mol/l, while for sulfamethoxazole it was 5.7% at 15 mu mol/l and 3.8% at 600 mu mol/l. The tower limit of quantification was determined to 5 mu mol/l and precision was 5.5% and 5.0% for sulfadoxine and sulfamethoxazole, respectively.

  • 5.
    Malm, Mikaela
    Högskolan Dalarna, Akademin Industri och samhälle, Kemiteknik.
    Determination of eflornithine enantiomers in plasma, by solid-phase extraction and liquid chromatography with evaporative light-scattering detection – Selection of regression model.2006Inngår i: Analysdagarna, Göteborg, 2006Konferansepaper (Annet vitenskapelig)
  • 6.
    Malm, Mikaela
    Högskolan Dalarna, Akademin Industri och samhälle, Kemiteknik.
    Development of analytical methods for determination of drugs, used against tropical diseases, in biological fluids2006Licentiatavhandling, monografi (Annet vitenskapelig)
    Abstract [en]

    The overall aim of this thesis was to develop analytical methods for determination of drugs, used against tropical diseases, in biological fluids. For the treatment of malaria, piperaquine (PQ) is used in combination with another antimalarial. Human African trypanosomiasis is treated with eflornithine (DFMO), a chiral drug administered as a racemic mixture. A method for determination of PQ in capillary blood applied and dried onto sampling paper has been developed and validated. This method uses perchloric acid and acetonitrile to extract PQ from the biological matrix and sampling paper. The liquid phase is then loaded onto a strong cation-exchange solid-phase extraction column. PQ and the IS are separated on a Chromolith Performance column at high flow rate, allowing fast chromatography, and detected with UV absorbance detection. Capillary blood sampling onto sampling paper facilitates clinical studies performed in the field, eliminates need of venipuncture, simplify storage as well as transportation and makes handling samples safer for laboratory personnel. A method for determination of underivatized DFMO enantiomers in plasma has been developed and validated. Proteins are percipitated with trichloro acetic acid and the liquid phase is loaded onto a strong cation-exhange solid-phase extraction column. D-DFMO and L-DFMO and the IS are separated on a Chirobiotic TAG column with a chiral stationary phase. Detection is performed using evaporative light-scattering detection. This method allows study of behavior of individual enantiomers in humans. There is an indication that D-DFMO and L-DFMO differ and this needs to be investigated further. Therefore, a chiral method of determination is of value. This method has also been evaluated for determination of DFMO enantiomers in cerebrospinal-fluid.

  • 7.
    Malm, Mikaela
    et al.
    Högskolan Dalarna, Akademin Industri och samhälle, Kemiteknik.
    Bergqvist, Yngve
    Högskolan Dalarna, Akademin Industri och samhälle, Kemiteknik.
    Determination of eflornithine enantiomers in plasma and cerebrospinal fluid, by solid-phase extraction and liquid chromatography with evaporative light-scattering detection2005Inngår i: International Congress for Tropical medicine and Malaria, Marseille, 2005Konferansepaper (Fagfellevurdert)
  • 8.
    Malm, Mikaela
    et al.
    Högskolan Dalarna, Akademin Industri och samhälle, Kemiteknik.
    Bergqvist, Yngve
    Högskolan Dalarna, Akademin Industri och samhälle, Kemiteknik.
    Determination of eflornithine enantiomers in plasma, by solid-phase extraction and liquid chromatography with evaporative light-scattering detection2007Inngår i: Journal of Chromatography B: Biomedical Sciences and Applications, ISSN 1387-2273, E-ISSN 1878-5603, Vol. 846, nr 1-2, s. 98-104Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    A bioanalytical method for determination of eflomithine (DEMO) in 1000 p,L human plasma has been developed and validated. DFMO and the internal standard (IS) were analysed by liquid chromatography with evaporative light-scattering detection (ELSD). Separation was performed on a Chirobiotic TAG (250 mm x 4.6 mm) column with ethanol (99.5%):0.01 mol/L acetic acid-triethylamine buffer at the rate of 25:75% (v/v) with flow rate of 1.0 mL/min. For D-DFMO in plasma the inter-assay precision was 6.5% at 75 p,mol/L, 6.6% at 375 mu mol/L and 5.8% at 750 mu mol/L. For L-DFMO in plasma the inter-assay precision was 10.4% at 75 mu mol/L, 6.5% at 375 mu mol/L and 5.0% at 750 lumol/L. The lower limit of quantification (LLOQ) was determined to 25 mu mol/L where the precision was 4.3% and 5.7%, respectively.

  • 9.
    Malm, Mikaela
    et al.
    Högskolan Dalarna, Akademin Industri och samhälle, Kemiteknik.
    Bergqvist, Yngve
    Högskolan Dalarna, Akademin Industri och samhälle, Kemiteknik.
    Development of bioanalytical methods to support field based studies of drugs against tropical diseases in developing countries.2006Inngår i: Analysdagarna, Göteborg, 2006Konferansepaper (Annet vitenskapelig)
  • 10.
    Malm, Mikaela
    et al.
    Högskolan Dalarna, Akademin Industri och samhälle, Kemiteknik.
    Lindegårdh, Niklas
    Högskolan Dalarna, Akademin Industri och samhälle, Kemiteknik.
    Bergqvist, Yngve
    Högskolan Dalarna, Akademin Industri och samhälle, Kemiteknik.
    Automated solid-phase extraction method for the determination of piperaquine in capillary blood applied on sampling paper by liquid chromatography2004Inngår i: PBA, Florens, Italien, 2004Konferansepaper (Annet vitenskapelig)
  • 11.
    Malm, Mikaela
    et al.
    Högskolan Dalarna, Akademin Industri och samhälle, Kemiteknik.
    Lindegårdh, Niklas
    Högskolan Dalarna, Akademin Industri och samhälle, Kemiteknik.
    Bergqvist, Yngve
    Högskolan Dalarna, Akademin Industri och samhälle, Kemiteknik.
    Automated Solid-Phase Extraction method for the Determination of Piperaquine in Capillary/Venous Blood applied on Sampling Paper by Rapid Liquid Chromatography2004Inngår i: Journal of Chromatography A, ISSN 0021-9673, E-ISSN 1873-3778, nr B 809, s. 43 - 49Artikkel i tidsskrift (Fagfellevurdert)
  • 12.
    Malm, Mikaela
    et al.
    Högskolan Dalarna, Akademin Industri och samhälle, Kemiteknik.
    Lindkvist, Jenny
    Bergqvist, Yngve
    Högskolan Dalarna, Akademin Industri och samhälle, Kemiteknik.
    Importance of pre-analytical factors contributing to measurement uncertainty, when determining sulfadoxine and sulfamethoxazole from capillary blood dried on sampling paper.2008Inngår i: Journal of Chromatographic Science, ISSN 0021-9665, E-ISSN 1945-239X, Vol. 46, nr 9, s. 837-843Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    A bioanalytical method is developed and validated for determination of sulfadoxine (SD) and sulfamethoxazole (SM) in 100 µL capillary blood dried on sampling paper (Whatman 31ET Chr). SD and SM are extracted with 2000 µL perchloric acid and the liquid phase is loaded onto ENV+ solid-phase extraction columns. SD, SM, and the internal standard are separated on a Purospher STAR RP-18 liquid chromatography column (150 × 4.6 mm) with a mobile phase consisting of acetonitrile–sodium acetate buffer pH 5.2, I = 0.1 (33:67, v/v). Analytes are detected with UV at 256 nm. Lower limit of quantitation is 5 µmol/L, where precisions are 4.2% and 3.9% for SD and SM, respectively. Three brands of sampling papers have been compared with respect to absorption properties, extraction recoveries, and variations. Punching out dried blood spots (DBS) instead of cutting spots into strips prior to extraction has been evaluated by examining precision and accuracy of SD and SM determinations. Importance of uniformity of types of sampling paper, sampling volume and biological matrix, benefit of punching out discs from DBS, and impact on absorption properties of different brands of sampling papers are discussed. Avoiding pre-analytical errors whenever possible results in concentrations determined being more accurate and precise.

  • 13.
    Malm, Mikaela
    et al.
    Högskolan Dalarna, Akademin Industri och samhälle, Kemiteknik.
    Römsing, Susanne
    Högskolan Dalarna, Akademin Industri och samhälle, Kemiteknik.
    Obua, Celestino
    Bergqvist, Yngve
    Högskolan Dalarna, Akademin Industri och samhälle, Kemiteknik.
    Determination of lamivudine, zidovudine and nevirapine, in capillary blood sampled on filter paper, by liquid chromatography2009Inngår i: Journal of Chromatographic Science, ISSN 0021-9665, E-ISSN 1945-239X, Vol. 47, nr 10, s. 855-862Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    A bioanalytical method for determination of lamivudine (3TC), zidovudine (AZT), and nevirapine (NVP) in 100 μL capillary blood applied onto sampling paper has been developed and validated. The antiretroviral drugs (ARV) were analyzed by reversed phase gradient liquid chromatography with UV detection. Separation was performed on a Zorbax SB C8 (250 × 4.6 mm) column with a twostep gradient: (i) methanol.0.05 mol/L acetic acid-sodium acetate buffer (pH 3.95, 15:85 v/v) and (ii) methanol.0.05 mol/L acetic acid-sodium acetate buffer (pH 3.95, 50:50 v/v) with a flow rate of 1.0 mL/min. UV detection was performed at 260 nm. Total assay precisions were 6.3, 4.7, and 4.9% for 3TC at 0.34, 0.69, and 3.9 μg/mL, and 5.1, 5.5, and 3.2% for AZT at 0.40, 0.80, and 4.5 μg/mL. For NVP, total assay precisions were 5.2, 8.3, and 3.5% at 2.6, 4.5, and 8.8 μg/mL. Lower limit of quantifications (LLOQ) were 0.11 and 0.13 μg/mL for 3TC and AZT where the precisions were 2.0% for both the analytes. For NVP, LLOQ was 1.3 μg/mL where precision was 2.6%. Concentrations were determined for 10 h for two subjects receiving standard twice daily antiretroviral therapy containing 3TC, AZT, and NVP. Maximum 3TC concentrations were 2.5 and 2.8 μg/mL for subject 1 and 2, respectively. For AZT, maximum concentrations were 1.8 and 1.1 μg/mL while being 15 and 9.6 μg/mL for NVP. Pre-dose trough concentration of NVP was 11 μg/mL for subject 1 and 9.6 μg/mL for subject 2.

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