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Development of Analytical Methods for the Determination of Antimalarials

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Development of Analytical Methods for the Determination of Antimalarials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ist of Papers This thesis is based on the following papers, which are referred to in the text by their Roman numerals. I Blessborn, D., Lindegårdh, N., Ericsson, Ö., Hellgren, U., Bergqvist, Y. (2003) Determination of Pyronaridine in Whole Blood by Auto- mated Solid Phase Extraction and High-Performance Liquid Chro- matography. Therapeutic Drug Monitoring, 25(3):264–270. II Lindegårdh, N., Blessborn, D., Bergqvist, Y. (2005) 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. Journal of Chroma- tographic Science, 43(5):259–266. III Blessborn, D., Neamin, G., Bergqvist, Y., Lindegårdh, N., (2006) A new approach to evaluate stability of amodiaquine and its metabolite in blood and plasma. Journal of Pharmaceutical and Biomedical Analysis, 41(1):207–212. IV Lindegårdh, N., Annerberg, A., Blessborn, D., Bergqvist, Y., Day, N., White. N.J. (2005) Development and validation of a bioanalyti- cal method using automated solid-phase extraction and LC-UV for the simultaneous determination of lumefantrine and its desbutyl me- tabolite in plasma. Journal of Pharmaceutical and Biomedical Analysis, 37(5):1081–1088. V Blessborn, D., Römsing, S., Annerberg, A., Sundquist, D., Björk- man, A., Lindegårdh, N., Bergqvist, Y. (2007) Development and validation of an automated solid-phase extraction and liquid chroma- tographic method for determination of lumefantrine in capillary blood on sampling paper. Journal of Pharmaceutical and Biomedi- cal Analysis, 45(2):282–287. VI Blessborn, D., Römsing, S., Bergqvist, Y., Lindegårdh, N. Assay for screening self medication of common antimalarial drugs using the dried blood spot technique. Manuscript. Reprints were made with kind permission from Wolters Kluwer Health, Pre- ston Publications, Inc., and Elsevier. Author’s contribution Paper I: Participated in the planning and carried out all experiments and wrote most of the paper. Paper II: Participated in the planning and performed most of the experi- ments and wrote the experimental section of the paper. Paper III: Took part of the planning and performed most of the experiments and participated in writing the paper. Paper IV: This paper was written by N. Lindegårdh and A. Annerberg. They also did most of the planning and performed most of the experiments. I took part in the initial development i.e. characterisation of the pysico- chemical properties of Lumefantrine and development of the LC method. Paper V: Planned and performed most of the experiments together with S. Römsing and wrote most of the paper. Paper VI: Participated in the planning and performed most of the experi- ments and wrote most of the manuscript. Contents 1 Introduction..................................................................................................9 2 Malaria.......................................................................................................11 2.1 Mosquitoes .........................................................................................11 2.2 Malaria ...............................................................................................12 2.3 Protection ...........................................................................................14 2.4 Antimalarial drugs in this thesis.........................................................15 2.4.1 Pyronaridine................................................................................15 2.4.2 Atovaquone-Proguanil (Malarone™) .........................................17 2.4.3 Amodiaquine...............................................................................19 2.4.4 Lumefantrine ..............................................................................20 2.4.5 Drugs in the Screening Method ..................................................23 2.4.5.1 Chloroquine.........................................................................23 2.4.5.2 Quinine................................................................................23 2.4.5.3 Sulfadoxine/Pyrimethamine................................................24 2.4.5.4 Mefloquine..........................................................................25 3 Method development .................................................................................27 3.1 Compound properties .........................................................................27 3.2 Liquid chromatography ......................................................................28 3.2.1 The LC-system............................................................................29 3.2.2 Detection.....................................................................................29 3.3 Solid phase extraction ........................................................................31 3.3.1 Sample pre-treatment prior SPE .................................................31 3.3.2 Conditioning ...............................................................................31 3.3.3 Sample loading ...........................................................................32 3.3.4 Washing ......................................................................................32 3.3.5 Elution ........................................................................................32 3.4 The sampling paper technique............................................................33 4 Method validation ......................................................................................35 4.1 Validation parameters ........................................................................35 4.1.1 Precision, Accuracy and Recovery .............................................35 4.1.2 Selectivity ...................................................................................37 4.1.3 Linearity and range and limit of quantification ..........................37 4.1.4 Stability.......................................................................................37 5 Conclusions and future aspects..................................................................39 6 Acknowledgements....................................................................................41 7 Summary in Swedish .................................................................................42 8 References..................................................................................................45 Abbreviations 4-CPB 4-chlorophenylbiguanide ATQ Atovaquone AQ Amodiaquine AQm Monodesethylamodiaquine AUC Area under the concentration-time curve Cmax Maximum concentration CBA Carboxylic acid CG Cycloguanil CV Coefficient of variation DBS Dried blood spots ESI Electrospray ionisation FDA US food and drug administration ICH International conference of harmonisation LC Liquid chromatography LLIN Long lasting impregnated nets LLOQ Lower limit of quantification m/z Mass to charge ratio MS Mass spectrometry PG Proguanil PND Pyronaridine RSD Relative standard deviation SPE Solid phase extraction t1/2 Elimination half life tmax Time to reach maximum concentration TDR Special programme for research & training in tropical diseases WHO World health organization 1 Introduction Malaria is present mainly in tropical areas of Africa, Asia and Latin Amer- ica. It is probably the most important parasitic infection in people and more than 250 million people fall ill every year. More than 90% of malaria cases and the great majority of malaria deaths occur in tropical Africa. The most severe cases of malaria are caused by the Plasmodium falciparum parasite and the parasite is transferred when a female mosquito of the Anopheles family is feeding blood. There are several ways to protect oneself from mosquito bites. Protective clothing, spraying household with insecticide repellents and using bednets are some protective measurements that are easily performed. Once an infec- tion has occurred, then antimalarial drug treatment is used. Drug resistance is widespread, so it is important that the drug used is effective against the local parasite population. Therefore, it’s important for travellers to know in what area the infection was contracted to decide what drug is appropriate for treatment. For the local population it’s important to know if a newly devel- oped parasite resistance is emerging. One of the tools to confirm drug resistance or other problems resulting in treatment failure is to determine drug concentration levels in the blood i.e. to verify if an appropriate drug level is reached. For this, liquid chromatogra- phy is often used. Accurate quantification of drug levels is
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